Birmingham, AL, United States
Birmingham, AL, United States

The University of Alabama at Birmingham is a public university in Birmingham in the U.S. state of Alabama. Developed from an academic extension center established in 1936, the institution became an autonomous institution in 1969 and is today one of three institutions in the University of Alabama System. In the fall of 2013, 18,568 students from more than 110 countries were enrolled at UAB pursuing studies in 140 programs of study in 12 academic divisions leading to bachelor's, master's, doctoral, and professional degrees in the social and behavioral science, the liberal arts, business, education, engineering, and health-related fields such as medicine, dentistry, optometry, nursing, and public health.The UAB Health System, one of the largest academic medical centers in the United States, is affiliated with the university. UAB Hospital sponsors residency programs in medical specialties, including internal medicine, neurology, surgery, radiology, and anesthesiology. UAB Hospital is the only ACS verified Level I trauma center in Alabama, as rated by the American College of Surgeons Trauma Program.UAB is the state's largest employer, with more than 18,000 faculty and staff and over 53,000 jobs at the university and in the health system. An estimated 10 percent of the jobs in the Birmingham-Hoover Metropolitan Area and 1 in 33 jobs in the state of Alabama are directly or indirectly related to UAB. The university's overall annual economic impact was estimated to be $4.6 billion in 2010. Wikipedia.

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Minocherhomji S.,Copenhagen University | Tollefsbol T.O.,University of Alabama at Birmingham | Singh K.K.,Comprehensive Cancer Center
Epigenetics | Year: 2012

Most pathogenic mitochondrial DNA (mtDNA) mutations induce defects in mitochondrial oxidative phosphorylation (OXPHOS). However, phenotypic effects of these mutations show a large degree of variation depending on the tissue affected. These differences are difficult to reconcile with OXPHOS as the sole pathogenic factor suggesting that additional mechanisms contribute to the lack of genotype and clinical phenotype correlationship. An increasing number of studies have identified a possible effect on the epigenetic landscape of the nuclear genome as a consequence of mitochondrial dysfunction. In particular, these studies demonstrate reversible or irreversible changes in genomic DNA methylation profiles of the nuclear genome. Here we review how mitochondria damage checkpoint (mitocheckpoint) induces epigenetic changes in the nucleus. Persistent pathogenic mutations in mtDNA may also lead to epigenetic changes causing genomic instability in the nuclear genome. We propose that "mitocheckpoint" mediated epigenetic and genetic changes may play key roles in phenotypic variation related to mitochondrial diseases or host of human diseases in which mitochondrial defect plays aprimary role. © 2012 Landes Bioscience.

Jacobs B.A.,University of Texas at Dallas | Copes H.,University of Alabama at Birmingham
British Journal of Criminology | Year: 2015

Prior research suggests that serious predatory offenders are sufficiently committed to illicit conduct that they must neutralize good behaviour, rather than bad behaviour. Drawing from a sample of offenders who commit carjacking, we question that assumption. Specifically, our data reveal the manner in which such offenders neutralize bad conduct without meaningfully drifting. The notion of 'neutralization without drift' represents a theoretical refinement of neutralization theory and an extension of core conceptualization in the interpretation of criminal commitment. Through this concept, we attempt to make sense of how persistent predatory offenders who commit carjacking are able to embrace aggression, explain that it's not 'really them', neutralize bad rather than good conduct, yet retain their status as committed criminals. © 2014 The Author.

Varadarajulu S.,University of Alabama at Birmingham | Bang J.Y.,University of Alabama at Birmingham | Sutton B.S.,University of Alabama at Birmingham | Trevino J.M.,University of Alabama at Birmingham | Wilcox C.M.,University of Alabama at Birmingham
Gastroenterology | Year: 2013

Background & Aims Although surgery is the standard technique for drainage of pancreatic pseudocysts, use of endoscopic methods is increasing. We performed a single-center, open-label, randomized trial to compare endoscopic and surgical cystogastrostomy for pancreatic pseudocyst drainage. Methods Patients with pancreatic pseudocysts underwent endoscopic (n = 20) or surgical cystogastrostomy (n = 20). The primary end point was pseudocyst recurrence after a 24-month follow-up period. Secondary end points were treatment success or failure, complications, re-interventions, length of hospital stay, physical and mental health scores, and total costs. Results At the end of the follow-up period, none of the patients who received endoscopic therapy had a pseudocyst recurrence, compared with 1 patient treated surgically. There were no differences in treatment successes, complications, or re-interventions between the groups. However, the length of hospital stay was shorter for patients who underwent endoscopic cystogastrostomy (median, 2 days, vs 6 days in the surgery group; P <.001). Although there were no differences in physical component scores and mental health component scores (MCS) between groups at baseline on the Medical Outcomes Study 36-Item Short-Form General Survey questionnaire, longitudinal analysis showed significantly better physical component scores (P =.019) and mental health component scores (P =.025) for the endoscopy treatment group. The total mean cost was lower for patients managed by endoscopy than surgery ($7011 vs $15,052; P =.003). Conclusions In a randomized trial comparing endoscopic and surgical cystogastrostomy for pancreatic pseudocyst drainage, none of the patients in the endoscopy group had pseudocyst recurrence during the follow-up period, therefore there is no evidence that surgical cystogastrostomy is superior. However, endoscopic treatment was associated with shorter hospital stays, better physical and mental health of patients, and lower cost. Trial Registration: NCT00826501. © 2013 by the AGA Institute.

Sontheimer H.,University of Alabama at Birmingham | Bridges R.J.,University of Montana
Expert Opinion on Investigational Drugs | Year: 2012

Recent research has identified an important role for a cystineglutamate antiporter (system Xc) in the biology of malignant brain tumors. This transporter is effectively inhibited by sulfasalazine, a drug widely used to treat a number of chronic inflammatory conditions such as Crohn's disease. Preclinical data show that sulfasalazine is an effective inhibitor of tumor growth and tumor-associated seizures. These studies suggest that the cystineglutamate antiporter is a valuable drug target for which tumor-specific drugs can be generated. In the meantime, sulfasalazine may be considered as adjuvant treatment for malignant gliomas. © 2012 Informa UK, Ltd.

Feng X.,University of Alabama at Birmingham | McDonald J.M.,University of Alabama at Birmingham | McDonald J.M.,Veterans Administration Medical Center
Annual Review of Pathology: Mechanisms of Disease | Year: 2011

The skeleton provides mechanical support for stature and locomotion, protects vital organs, and controls mineral homeostasis. A healthy skeleton must be maintained by constant bone modeling to carry out these crucial functions throughout life. Bone remodeling involves the removal of old or damaged bone by osteoclasts (bone resorption) and the subsequent replacement of new bone formed by osteoblasts (bone formation). Normal bone remodeling requires a tight coupling of bone resorption to bone formation to guarantee no alteration in bone mass or quality after each remodeling cycle. However, this important physiological process can be derailed by a variety of factors, including menopause-associated hormonal changes, age-related factors, changes in physical activity, drugs, and secondary diseases, which lead to the development of various bone disorders in both women and men. We review the major diseases of bone remodeling, emphasizing our current understanding of the underlying pathophysiological mechanisms. Copyright © 2011 by Annual Reviews. All rights reserved.

Young M.E.,University of Alabama at Birmingham
Critical Reviews in Biochemistry and Molecular Biology | Year: 2013

Circadian rhythms are an integral part of life. These rhythms are apparent in virtually all biological processes studies to date, ranging from the individual cell (e.g. DNA synthesis) to the whole organism (e.g. behaviors such as physical activity). Oscillations in metabolism have been characterized extensively in various organisms, including mammals. These metabolic rhythms often parallel behaviors such as sleep/wake and fasting/feeding cycles that occur on a daily basis. What has become increasingly clear over the past several decades is that many metabolic oscillations are driven by cell-autonomous circadian clocks, which orchestrate metabolic processes in a temporally appropriate manner. During the process of identifying the mechanisms by which clocks influence metabolism, molecular-based studies have revealed that metabolism should be considered an integral circadian clock component. The implications of such an interrelationship include the establishment of a vicious cycle during cardiometabolic disease states, wherein metabolism-induced perturbations in the circadian clock exacerbate metabolic dysfunction. The purpose of this review is therefore to highlight recent insights gained regarding links between cell-autonomous circadian clocks and metabolism and the implications of clock dysfunction in the pathogenesis of cardiometabolic diseases. © 2013 Informa Healthcare USA, Inc.

Varadarajulu S.,University of Alabama at Birmingham | Hawes R.H.,University of Central Florida
Clinical Gastroenterology and Hepatology | Year: 2012

Over the past 2 decades, endoscopic ultrasound-guided fine-needle aspiration has evolved to become an indispensable tool for tissue acquisition in patients with gastrointestinal tumors. The technique is useful for biopsy of mucosal and submucosal lesions in which prior endoscopic biopsies have been nondiagnostic; to sample peri-intestinal structures such as lymph nodes; and to sample masses in the pancreas, liver, adrenal glands, gallbladder, and bile duct. Also, with the advent of neoadjuvant therapies for diseases such as pancreatic cancer, most patients require a tissue diagnosis before initiating treatment. This review provides a perspective on technical issues that are key for best practices in endoscopic ultrasound-guided fine-needle aspiration. © 2012 AGA Institute.

Parpura V.,University of Alabama at Birmingham | Zorec R.,University of Ljubljana | Zorec R.,Technology Park Ljubljana
Brain Research Reviews | Year: 2010

Gliotransmitters are chemicals released from glial cells fulfilling a following set of criteria: (i) they are synthesized by and/or stored in glia; (ii) their regulated release is triggered by physiological and/or pathological stimuli; (iii) they activate rapid (milliseconds to seconds) responses in neighboring cells; and (iv) they play a role in (patho)physiological processes. Astrocytes can release a variety of gliotransmitters into the extracellular space using several different mechanisms. In this review, we focus on exocytotic mechanism(s) underlying the release of three classes of gliotransmitters: (i) amino acids, such as, glutamate and d-serine; (ii) nucleotides, like adenosine 5'-triphosphate; and (iii) peptides, such as, atrial natriuretic peptide and brain-derived neurotrophic factor. It is becoming clear that astrocytes are endowed with elements that qualify them as cells communicating with neurons and other cells within the central nervous system by employing regulated exocytosis. © 2009 Elsevier B.V.

McDougal D.H.,Pennington Biomedical Research | Gamlin P.D.,University of Alabama at Birmingham
Vision Research | Year: 2010

Historically, it was assumed that the light-evoked neural signals driving the human pupillary light reflex (PLR) originated exclusively from rod and cone photoreceptors. However, a novel melanopsin-containing photoreceptive cell class has recently been discovered in the mammalian retina. These intrinsically-photosensitive retinal ganglion cells (ipRGCs) project to the pretectum, the retinorecipient area of the brain responsible for the PLR. This study was therefore designed to examine the relative contribution of rod, cone and the melanopsin photoresponses of ipRGCs to the human PLR. We establish that the melanopsin photoresponse of ipRGCs contributes significantly to the maintenance of half maximal pupilloconstriction in response to light stimuli of 30 s or longer, even at low photopic irradiances. Furthermore, we show that the melanopsin photoresponse contributes significantly to three-quarter maximal pupilloconstriction in response to light stimuli as short as 2 s. We also demonstrate that cone photoresponses driving pupilloconstriction adapt considerably and contribute little after 30 s, but rod photoresponses adapt less and contribute significantly to the maintenance of pupilloconstriction in response to steady-state light stimuli at irradiance levels which are below the threshold of the melanopsin photoresponse. © 2009 Elsevier Ltd. All rights reserved.

de los Campos G.,University of Alabama at Birmingham | Hickey J.M.,University of New England of Australia | Pong-Wong R.,Roslin Institute | Daetwyler H.D.,Australian Department of Primary Industries and Fisheries | Calus M.P.L.,Animal Breeding and Genomics Center
Genetics | Year: 2013

Genomic-enabled prediction is becoming increasingly important in animal and plant breeding and is also receiving attention in human genetics. Deriving accurate predictions of complex traits requires implementing whole-genome regression (WGR) models where phenotypes are regressed on thousands of markers concurrently. Methods exist that allow implementing these large-p with small-n regressions, and genome-enabled selection (GS) is being implemented in several plant and animal breeding programs. The list of available methods is long, and the relationships between them have not been fully addressed. In this article we provide an overview of available methods for implementing parametric WGR models, discuss selected topics that emerge in applications, and present a general discussion of lessons learned from simulation and empirical data analysis in the last decade. © 2013 by the Genetics Society of America.

Copes H.,University of Alabama at Birmingham | Hochstetler A.,Iowa State University | Forsyth C.J.,University of Louisiana at Lafayette
Criminology | Year: 2013

Considerable theoretical and empirical inquiry has focused on the role codes for violence play in generating crime. A large part of this work has examined the attitudes and codes condoning retaliation and violence as well as the prevalence of these among minorities residing in impoverished neighborhoods. Much about the nature of codes remains unknown, however, and this may in part reflect a narrow interest in beliefs about provocation and uses of violence among the inner-city poor. In this study, we elaborate on a code of violence as part of a system of order and honor as articulated by a network of White, working-class males in a southern U.S. city who participate in bar fights. The findings suggest that the code these men use prohibits predatory violence, puts exclusive limitations on situations that warrant violence, and constrains the level of violence in a fight. We detail the contours of this code (e.g., purpose of fighting, the rules of honorable fighting, and justifications for violating these rules) and discuss the code as both a cause and a consequence of behavior. © 2013 American Society of Criminology.

Jardine A.G.,University of Glasgow | Gaston R.S.,University of Alabama at Birmingham | Fellstrom B.C.,Uppsala University | Holdaas H.,University of Oslo
The Lancet | Year: 2011

Although advances in immunosuppression, tissue typing, surgery, and medical management have made transplantation a routine and preferred treatment for patients with irreversible renal failure, successful transplant recipients have a greatly increased risk of premature mortality because of cardiovascular disease and malignancy compared with the general population. Conventional cardiovascular risk factors such as hyperlipidaemia, hypertension, and diabetes are common in transplant recipients, partly because of the effects of immunosuppressive drugs, and are associated with adverse outcomes. However, the natural history of cardiovascular disease in such recipients differs from that in the general population, and only statin therapy has been studied in a large-scale interventional trial. Thus, the management of this disease and the balance between management of conventional risk factors and modification of immunosuppression is complex. © 2011 Elsevier Ltd.

Wake forest University and University of Alabama at Birmingham | Date: 2013-09-17

This disclosure relates to methods of using nitrite to detoxify stroma-free hemoglobin based blood substitutes. In particular, methods are described for using a blood substitute comprised of about equimolar amounts of nitrite and hemoglobin (e.g., nitrite-metHb) to treat, prevent, or ameliorate diseases of the blood in a subject, or as a blood replacement in a subject.

News Article | September 21, 2016

The promise of stem cells to treat cardiovascular disease may soon be a step closer to clinical application as scientists from three institutions seek to perfect and test three-dimensional “heart patches” in a large animal model — the last big hurdle before trials in human patients. In theory, the heart patches, engineered tissue composed of the several different types of cells that make up heart muscle, would be implanted to replace diseased or damaged tissue and would perform all the functions of healthy, beating heart muscle. Using stem cells to treat cardiovascular disease is a grail of regenerative medicine, explains Timothy J. Kamp, a University of Wisconsin-Madison cardiologist and co-director of the UW-Madison Stem Cell and Regenerative Medicine Center. Treating diseased hearts by implanting healthy, lab-grown cells to replace damaged tissue has been an aspiration of stem cell biologists since all-purpose human stem cells were first derived and cultured at UW-Madison in 1998. Working with teams from the University of Alabama at Birmingham and Duke University in a newly funded $8.6 million consortium, Kamp and his colleagues will seek to devise and seed with the appropriate mix of cells three-dimensional patches that will be used in a pig model, a close approximation in an animal to the human heart. The seven-year study is being funded by the National Institutes of Health. “The excitement here is we’re moving closer to patient applications,” says Kamp, a professor in the UW School of Medicine and Public Health (SMPH). “We’re at a stage when we need to see how these cells do in a large animal heart attack model. We’ll be making patches of heart muscle that can be applied to these injured areas.” Other types of cells have been tried for cardiac repair with limited success, Kamp notes, but the advent of embryonic and induced stem cell technologies brings a new precision to the problem: the ability to make in the lab all of the specific cell types that make up heart muscle and that could be more personalized to individual patients. To achieve that and to begin to lay out a game plan for how the technology can ultimately be applied to human patients, there are a number of big hurdles Kamp and his collaborators will need to overcome. The first challenge is to create in the lab the primary cell types that compose heart tissue: cardiomyocytes, the cells responsible for muscle contraction; fibroblasts, the cells that provide structural framework to tissue; and endothelial cells, the cells that line blood vessels. Kamp’s group previously has devised techniques for spinning fibroblasts in mice into progenitor master heart cells, cells capable of differentiating into all the different types of cells that make up heart muscle. Applied to human cells, the technology could provide a foundation for mass producing heart cells for clinical use in the laboratory. Another key obstacle, Kamp notes, is making cells that, when transplanted, do not prompt an immune response by a new host. “The body’s immune response is a big part of this,” he says. To test immune reaction to implanted cells, Kamp and his colleague, William Burlingham, from the SMPH’s Department of Surgery, will first transplant lab-made cells into mice engineered to have a human immune system. Ideally, cells can be made to at least partially match the human immune response, which might open the door to creating cells that do not need to be individually matched to a patient. Such technologies already exist for many solid organ transplants. In addition to creating the right mix of cells that aren’t rejected by a host, Kamp and his colleagues must forge cells that beat in rhythm with the new host: “Another barrier we are particularly concerned about is triggering arrhythmias,” says Kamp. “Will putting these cells in create a life-threatening ventricular arrhythmia? That is one of the risks that we need to overcome.” Finally, the UAB-Duke-Wisconsin group must devise a heart patch in a way that it can effectively integrate into the heart of a patient. The technology is not at all like “plugging in a USB drive,” says Kamp. Building the heart patch technology and testing it in a large animal model, Kamp says, will go a long way toward harnessing the potential of stem cells to treat heart disease, which in many respects is still unproven. “The proposed studies in animal models are essential to develop this novel therapy,” Kamp says, “but the gold standard, of course, is a human patient.”

News Article | February 15, 2017

Pierian Biosciences, the premier developer of life science technologies providing treatment directing data to aid physicians in selecting the most appropriate therapy for their patients with cancer, has named Mark S. Gelder, MD, as chief medical officer. “We rely on Mark to ensure the delivery of quality diagnostic assays: the immune-proximity assay, CEER®, recently renamed PathwayINTELTM, and our drug response profiling assay, MiCK®, recently renamed ChemoINTELTM,” says Robert Henry, president and chief executive officer of Pierian Biosciences. “We’ll also be looking for Mark to help us maintain our industry presence and guide the development of collaborative agreements with partners such as academic centers, pharmaceutical companies and oncologists.” In addition, Gelder provides medical, clinical and scientific oversight as well as helping to define the company’s strategic direction. Dr. Gelder brings more than 25 years of oncology clinical trial and drug development experience to Pieiran. He is board certified in Internal Medicine, Obstetrics and Gynecology and Gynecologic Oncology. As an experienced researcher and clinician, he has significant regulatory experience working closely with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and in various leadership roles at pharmaceutical companies including Pfizer, Wyeth, Bayer, GE Healthcare, Heron Therapeutics and Inovio Pharmaceuticals. A graduate of the University of Virginia School of Medicine, Gelder received his residency training in internal medicine at University of Virginia and an additional residency in obstetrics and gynecology at the University of Alabama at Birmingham. While at UAB, Gelder also completed a fellowship in gynecologic oncology. He is currently a fellow of the American College of Obstetrics and Gynecology. Pierian’s PathwayINTEL is a functional proteomic profiling assay which provides quantitative information on the expression and activation status of proteins of interest to identify the true oncogenic “driver” and allow selection of the most appropriate targeted and/or biologic therapy for cancer patients. ChemoINTEL, the company’s functional drug response profiling assay, provides actionable information to guide selection on the effectiveness of cytotoxic agents to enhance clinical treatment decision-making. About Pierian Biosciences Based in Franklin, Tenn., Pierian Biosciences is a privately held life sciences and clinical pathology laboratory company offering treatment-directing diagnostic data to support more effective and lower cost cancer treatment. The company’s technology includes the ChemoINTEL and the PathwayINTEL Assay platforms. The company has laboratories in Franklin, Tenn. and San Diego, CA. For more information visit

News Article | December 15, 2016

This rapidly fatal brain cancer has seen only two improvements in therapy in 30 years BIRMINGHAM, Ala. - In a paper published today in Cancer Research, researchers: 1) identify a biomarker enzyme associated with aggressive glioma brain tumors, 2) reveal the regulatory mechanism for that enzyme, and 3) demonstrate potent efficacy, using a mouse model of glioma, for a small molecule inhibitor they have developed. The inhibitor, GA11, retains a core structure that resembles natural inhibitors of the biomarker enzyme; but the inhibitor has been modified to help it pass through the blood-brain barrier. "In principle, both these features make GA11 an attractive drug candidate to target glioma stem-like cells in glioblastoma multiforme tumors," said Ichiro Nakano, M.D., Ph.D., and colleagues in the paper. Nakano, a professor of neurosurgery and academic neurosurgeon at the University of Alabama at Birmingham, and Vito Coviello and Concettina La Motta, University of Pisa, Italy, are doing further preclinical evaluation of the GA11 and its analogs. Glioblastoma multiforme, or GBM, is a formidable cancer foe. Only two therapeutic improvements have appeared in the past 30 years, increasing the average survival of patients from five months to 15 or 16 months, Nakano says. A GBM tumor is a mix of different cells that respond differently to therapies. Small numbers of glioma stem-like cells, or GSCs, drive the tumorigenicity of GBM and thus are prime targets for possible treatments. One GSC subtype called the mesenchymal GSC is more malignant and the most therapy-resistant, so Nakano and fellow researchers reasoned that identifying the regulatory molecules active in mesenchymal GSCs might lead to novel and effective therapeutics. Nakano and colleagues found that one form of the enzyme aldehyde dehydrogenase -- ALDH1A3 -- is a specific marker for mesenchymal GSCs, and his group is the first to show that, among the heterogeneous mix of cells in a GBM tumor, cells with high levels of ALDH1A3 expression were more tumorigenic in vivo than are cells that are low in ALDH1A3. The researchers also found that the FOXD1 transcription factor regulates the production of ALDH1A3 in mesenchymal GSCs. In clinical samples of high-grade gliomas from patients, the expression levels of both FOXD1 and ALDH1A3 were inversely correlated with disease progression -- gliomas with high levels were more rapidly fatal than were gliomas with low levels. Astonishingly, the same mechanism that drives the mesenchymal GSC tumorigenicity in humans acts in an evolutionarily distant organism, the fruit fly. Knocking down the expression of either the fruit fly version of the FOXD1 gene or the fruit fly version of ALDH1A3 blocks the formation of brain tumors in a brain cancer model of the fruit fly species Drosophila melanogaster, the researchers found. Thus, this signaling has been highly conserved in evolution. The FOXD1 transcription factor is normally active during development from a fertilized egg and embryo to a fetus, and it is silent after birth. The role of FOXD1 in GBM, Nakano and colleagues say, suggests that the mesenchymal GSCs have hijacked the molecular mechanism of normal embryonic development to promote tumor growth. In preclinical testing, GA11 was validated several ways. The researchers showed that it inhibited ALDH in yeast, reduced ALDH1 activity in cell-culture spheres of mesenchymal GSCs, inhibited proliferation of glioma spheres in cell culture, and inhibited xenograft growth of GBM in mouse brains. "In conclusion," Nakano and fellow researchers wrote, "the FOXD1-ALDH1A3 axis is critical for tumor initiation in mesenchymal GSCs, therefore providing possible new molecular targets for the treatment of GBM and other ALDH1-activated cancers." Nakano says his study of the role of GSCs in GBM is just one approach to treat glioma tumors. Other labs are pursuing immunotherapy, the use of check-point inhibitors, vaccination and efforts to increase sensitivity to radiotherapy. It will take combined therapies to treat glioblastoma, Nakano says. "We don't believe that one therapy will be effective." Nakano expects to launch a new clinical trial for glioblastoma in 2017, in conjunction with Burt Nabors, M.D., professor of neurology at UAB. Nakano says UAB will be the only site in the Deep South for this unique trial aimed at a molecular target in glioma stem cells, a target that is different from the ones described in the Cancer Research paper. The referral contact to Nakano's service will be Lydia P. Harrell. The Nakano lab is also working on brain metastases, tumors that spread into the brain from other parts of the body. Similar to high-grade gliomas, which originate in the brain, these metastatic brain tumors are lethal, and there are very few therapeutic options. Nakano believes the core stem cell genes and signaling pathways are shared between gliomas and brain metastases. "If so," he said, "the molecular targets identified for gliomas are most likely essential in brain metastases. Studies are underway, and similar to the glioma therapy development, I am working to develop clinical trials for brain metastasis, together with medical oncologists Mansoor Saleh, M.D., Andres Forero, M.D., and others at UAB." Besides Nakano, Coviello and La Motta, authors of the Cancer Research paper, "FOXD1-ALDH1A3 signaling is a determinant for the self-renewal and tumorigenicity of mesenchymal glioma stem cells," are Peng Cheng, Jia Wang, Zhuo Zhang, Sung-Hak Kim, Marat S. Pavlyukov and Mutsuko Minata, UAB Department of Neurosurgery and Comprehensive Cancer Center; Indrayani Waghmare and Madhuri Kango-Singh, Department of Biology, University of Dayton, Ohio; Stefania Sartini, Department of Pharmacy, University of Pisa, Italy; Ahmed Mohyeldin, Department of Neurological Surgery and the James Comprehensive Cancer Center, The Ohio State University; Claudia L.L. Valentim, Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic; Rishi Raj Chhipa and Biplab Dasgupta, Department of Oncology, Cincinnati Children's Hospital Medical Center; and Krishna P.L. Bhat, Department of Translational Molecular Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston.

BIRMINGHAM, Ala.--(BUSINESS WIRE)--Proton International and the University of Alabama at Birmingham (UAB) announced today they are securing necessary approvals to begin construction this year of a proton therapy center that will provide cancer patients with an effective treatment option that is an alternative to traditional radiation therapy. Proton therapy is a highly precise treatment for treating cancer and some non-cancerous tumors without many of the side effects that often accompany traditional radiation therapy. This will be the 4th of 7 centers Proton International has been involved with as one of the world’s leading developers of facilities offering this advanced therapy. The UAB center, which will be the first in the State, has been approved by an Administrative Law Judge appointed by the Alabama State Health Planning and Development Agency. The two-year construction process is expected to begin this year with an opening planned for 2019. Proton International will build and own the center with UAB physicians providing clinical services and providing the leadership for education and research within the facility. “This is a significant step forward in cancer treatment for residents of Alabama and surrounding areas,” said Will Ferniany, PhD, and CEO of the UAB Health System. “Proton therapy is an extremely advanced cancer-fighting technology. Coupled with the skill, experience and resources of the UAB Comprehensive Cancer Center, the UAB Proton Therapy Center will be a life-changing resource for thousands of cancer patients throughout our region.” The Comprehensive Cancer Center is the only National Cancer Institute Designated Cancer Center in Alabama. “UAB is joining a stellar group of 25 of the nation’s top hospitals and cancer treatment centers providing proton therapy to patients,” said Chris Chandler, CEO, who founded Proton International after developing, opening and overseeing the operation of some of the first proton centers in the U.S. and Europe. “This center will have advanced proton therapy technology – a fully featured system with dynamic peak pencil beam scanning, developed by Varian Medical Systems an important technology leader.” “Recent advances in imaging have made proton therapy much more viable,” said John Fiveash, M.D., professor in the UAB Department of Radiation Oncology. “It uses sophisticated imaging to create a 3D image of the tumor. It then delivers a focused beam of radiation, custom-sized and shaped, so that it paints the tumor site while leaving surrounding tissue generally untouched, reducing collateral damage.” It is conservatively estimated that some 250,000 cancer patients in the U.S. alone could benefit from proton therapy, which is mainly being used to treat solid cancer tumors, including tumors of the brain and central nervous system, spine, head and neck, lung, prostate, liver, gastrointestinal tract and colon, and some breast tumors. While it primarily treats single-site tumors, it can in some cases be used for treating cancer that has spread (metastasized) to surrounding tissue because of its focused dose capabilities. Protons are widely used to treat children, who are particularly sensitive to the effects of radiation therapy. Because of its precision in targeting tumors, proton therapy greatly reduces damage to nearby healthy tissue, which is the cause of most short- and long-term side-effects, including cancer recurrence later in life. The three-story UAB Proton Center will be built on the Campus of UAB. Planning and pre-treatment will continue to be done at UAB’s Hazelrig-Salter Radiation Oncology Center and medical staff will be exclusively from UAB. The center will enroll its patients in national proton therapy registries and will participate in clinical research studies to advance the application of proton therapy and determine best practices. In partnering with Proton International UAB has a team of proven providers. Proton International is currently participating in the development of 7 centers two of which are under construction; another set to break ground in March, and a memorandum of understanding approved for 4 others. PI’s turnkey development model significantly lowers project risk and provides access to long-term funding. For this project UAB and PI have selected Varian Medical Systems, an innovator in proton therapy systems Varian has been a longtime partner with UAB in the delivery of radiation therapy, and this new proton system will integrate UAB’s existing network of Varian products, including TrueBeam linear accelerators, Eclipse treatment planning, and ARIA information system. UAB Medicine comprises the School of Medicine and the $3 billion UAB Health System that includes all of the University of Alabama at Birmingham’s patient-care activities and 2,300 licensed beds in six hospitals, one of which is UAB Hospital — the third-largest public hospital in the United States, winner of the Women's Choice award, and one of U.S. News and World Report's Best Hospitals. UAB is the state of Alabama’s largest single employer and an internationally renowned research university and academic health center; its professional schools and specialty patient-care programs are consistently ranked among the nation’s top 50. UAB is the largest academic medical center in Alabama and one of the top four largest academic medical centers in the United States. UAB’s Center for Clinical and Translational Science is advancing innovative discoveries for better health as a two-time recipient of the prestigious Center for Translational Science Award. Find more information at and Proton International (PI) has an experienced team dedicated to bringing proton therapy to patients. The company works with hospitals and physician groups to develop one- and two-room proton therapy facilities, as well as larger facilities, on a turnkey basis. The PI team has developed and operated large centers and as well as the smaller alternatives. PI has centers under construction with Beaumont Hospital, Royal Oak, Mich., and the University Medical Center in Groningen, The Netherlands; as well as an upcoming project with Delray Medical Center, Delray Beach, Fla. PI’s business model ensures that projects are completed on time, on budget, and within the scope and needs of the Institution. Services include business planning, organizational structure, financing, building design and construction, installation and commissioning, equipment, staff training and more.

News Article | November 19, 2016

Leading higher education information and resource site has released its list of the Best Online Accelerated Nursing Degrees & Programs in the nation for 2016-2017. Using a variety of cost and educational outcome data to compare accredited programs side by side, the list rates the University of Saint Mary, University of Wyoming, The Sage Colleges, University of Indianapolis and Samford University as the top-scoring schools for accelerated nursing students. "As the demand for qualified nurses grows, more colleges are implementing fast-track education options for nursing students,” said Dan Schuessler, CEO and Founder of "These programs are rigorous, but the schools on our list stand out for providing the best quality education and support to help students comprehend quickly and ultimately start their careers in nursing sooner.” required schools to meet several basic requirements to be considered for the Best Online Accelerated Nursing Degrees & Programs list. Each college must be accredited by the Collegiate Nursing Education (CCNE) or Accreditation Commission for Education in Nursing (ACEN) and be a public or private not-for-profit institution to be included. They must also offer students job placement and academic counseling services to qualify. Individual school scores are then determined by weighing a variety of qualitative and quantitative data points, such as nursing certification pass rates, tuition costs and more. The Top 50 list of schools, as well as specific details on data and methodology used to determine ranking and scoring can be found at the link below: An alphabetical list of schools on the Best Online Accelerated Nursing Programs list for 2016-2017: Adelphi University Albany State University Ball State University Barry University Baylor University Clemson University Creighton University DeSales University Drexel University Duquesne University East Carolina University Georgia Southwestern State University Indiana Wesleyan University Jacksonville University Lewis University Loyola University Chicago Lynchburg College New Mexico State University - Main Campus New York University Northern Arizona University Ohio University - Main Campus Olivet Nazarene University Quinnipiac University Robert Morris University Rutgers University - Newark Saint Xavier University Samford University Seton Hall University Shenandoah University Simmons College Southern Nazarene University Texas Christian University The College of Saint Scholastica The Sage Colleges University of Alabama at Birmingham University of Arizona University of Delaware University of Hawaii at Manoa University of Indianapolis University of Memphis University of Miami University of North Florida University of Northern Colorado University of Saint Joseph University of Saint Mary University of Wyoming Utica College Valparaiso University West Virginia University Wilkes University began in 2011 to provide quality data and information about pursuing an affordable higher education. Our free community resource materials and tools span topics such as financial aid and college savings, opportunities for veterans and people with disabilities, and online learning resources. We feature higher education institutions that have developed online learning environments that include highly trained faculty, new technology and resources, and online support services to help students achieve educational and career success. We have been featured by nearly 1,100 postsecondary institutions and nearly 120 government organizations.

News Article | February 16, 2017

Bottom Line: Adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) who were not treated at specialized cancer centers had significantly worse five-year survival compared with children with these cancers who were treated at specialized cancer centers, whereas AYAs treated at specialized cancer centers had outcomes comparable to children treated at specialized cancer centers. Journal in Which the Study was Published: Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research. Author: Julie Wolfson, MD, MSHS, assistant professor in the Division of Pediatric Hematology-Oncology and member of the Institute for Cancer Outcomes and Survivorship at the University of Alabama at Birmingham. Background: AYAs, meaning those ages 15 to 39, with ALL and AML have significantly worse survival outcomes compared with children ages 14 and under, according to Wolfson. "A much smaller percentage of AYAs with cancer are treated at specialized cancer centers than children with cancer," she added. "We wanted to understand whether this difference in the site of cancer care is associated with the difference in survival outcomes." How the Study Was Conducted and Results: Wolfson and colleagues used data from the Los Angeles County Cancer Surveillance Program to identify patients diagnosed with ALL or AML from ages 1 to 39. Patients were considered to have been treated at a specialized cancer center if at any age they were cared for at any of the National Cancer Institute-designated Comprehensive Cancer Centers in Los Angeles County or if at the age of 21 or younger they were cared for at any of the Children's Oncology Group sites not designated a Comprehensive Cancer Center. Included in the analysis were 978 patients diagnosed with ALL as a child (ages 1 to 14), 402 patients diagnosed with ALL as an AYA (ages 15 to 39), 131 patients diagnosed with AML as a child, and 359 patients diagnosed with AML as an AYA. Among these groups, 70 percent, 30 percent, 74 percent, and 22 percent were treated at a specialized cancer center, respectively. Five-year relative survival rates declined with age for both ALL and AML. Wolfson explained that the researchers excluded data from children with ALL ages 1 to 9 in subsequent analysis because these patients have significantly improved survival compared with other groups, likely as a result of different disease biology. They found that AYAs diagnosed at ages 15 to 21 and 22 to 29 who were treated at specialized cancer centers had comparable overall and leukemia-specific survival to children diagnosed with ALL from ages 10 to 14 and treated at a specialized cancer center. Using the same referent population, AYAs in these age groups who were not treated at specialized cancer centers had an approximately two-fold increased risk of death. AYAs diagnosed at ages 30 to 39 had an approximately three-fold increased risk of death irrespective of where they received care. For AML, AYAs diagnosed at ages 15 to 21 who were treated at specialized cancer centers had comparable overall and leukemia-specific survival to children diagnosed from ages 1 to 14 and treated at a specialized cancer center. AYAs diagnosed at ages 15 to 21 who were not treated at a specialized cancer center had a 1.7-fold increased risk for death. AYAs diagnosed at ages 22 to 39 had an approximately three-fold increased risk of death irrespective of where they received care. Among AYAs ages 21 to 39, those who were uninsured or publicly insured had a more than 70 percent lower likelihood of being treated at a specialized cancer center compared with those who had private health insurance. Author Comment: "We found that AYAs diagnosed with ALL from age 15 to 29 or diagnosed with AML from age 15 to 21 who were treated at specialized cancer centers had better outcomes than their peers who were not treated at specialized cancer centers when each group was compared with children treated at specialized cancer centers," said Wolfson. "These data suggest that treatment at a specialized cancer center can mitigate the poor outcomes in younger AYAs compared with children. We were also able to identify some barriers to being treated at specialized cancer centers for AYAs, which we hope can be used to address the gap in provision of high-quality cancer care to a vulnerable population." "The fact that the older AYAs did not appear to benefit from treatment at a specialized cancer center suggests to us that the biology of the disease in these patients differs from that in younger individuals," continuedd Wolfson. "The most important thing we can do to help these patients is to enroll them on clinical trials so that we can better understand the biology of the disease and its response to therapy." Limitations: According to Wolfson, the main limitation of the study is that the data were obtained from a cancer registry, which does not provide detailed information about each patient's treatment regimen or the features of their disease. Funding & Disclosures: The study was supported by grants from the National Institutes of Health and the St. Baldrick's Foundation. Wolfson declares no conflicts of interest. About the American Association for Cancer Research Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 37,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and patient advocates residing in 108 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 30 conferences and educational workshops, the largest of which is the AACR Annual Meeting with nearly 19,500 attendees. In addition, the AACR publishes eight prestigious, peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual investigator grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and other policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit http://www. . To interview Julie Wolfson, contact Julia Gunther at or 215-446-6896.

News Article | December 8, 2016

A list of the nation’s Best Online Accounting Degree programs for 2016-2017 has been released by leading higher education information and resource provider The list ranks two- and four-year schools respectively, highlighting 100 colleges that offer the best overall combination of value and quality for online accounting students. Top scoring schools include Davenport University, University of Alabama at Birmingham, Northern State University, Dickinson State University and Cleary University (four-year) and Holmes Community College, Hutchinson Community College, Lone Star College, Western Nebraska Community College and Southwest Virginia Community College (two-year). "The American Institute of Certified Public Accountants showed a record number of accounting graduates were hired by public accounting firms in 2012,” said Dan Schuessler, CEO and Founder of “With that in mind, we were compelled to highlight and rank the schools making an effort to maximize affordability and provide flexible, high-quality learning options for accounting students.” To be eligible for placement on the rankings, a school must meet several minimum requirements. Colleges must be accredited, public or private not-for-profit institutions to qualify. Affordability standards are also set to include only schools who offer in-state tuition below $5,000 per year at two-year schools or $25,000 per year at four-year schools. More than a dozen additional statistics are compared to determine final scores and rankings for each qualifying school, such as aid offerings, graduation rates and more. For complete details on the data and methodology used to determine school scores, as well as the full ranking for the nation’s Best Online Accounting Degree programs visit: Auburn University Aurora University Baker College Belhaven University Bellevue University Brenau University Brescia University Cleary University Colorado Christian University Columbia College Concordia University - Saint Paul Dakota State University Dallas Baptist University Davenport University Dickinson State University East Carolina University Florida Atlantic University Franklin University Hawaii Pacific University Huntington University Indiana State University Indiana Wesleyan University Keiser University - Fort Lauderdale Kent State University at Kent Keystone College Lakeland College Liberty University Madonna University Missouri State University - Springfield Morehead State University National University Northern Arizona University Northern State University Northwestern Oklahoma State University Northwood University - Michigan Old Dominion University Saint Leo University Thomas Edison State College Tiffin University University of Alabama at Birmingham University of Charleston University of Houston - Downtown University of Houston - Victoria University of Louisiana at Monroe University of Maryland - University College University of Massachusetts - Amherst University of Michigan - Flint University of Minnesota - Crookston University of the Southwest Western Governors University began in 2011 to provide quality data and information about pursuing an affordable higher education. Our free community resource materials and tools span topics such as financial aid and college savings, opportunities for veterans and people with disabilities, and online learning resources. We feature higher education institutions that have developed online learning environments that include highly trained faculty, new technology and resources, and online support services to help students achieve educational and career success. We have been featured by nearly 1,100 postsecondary institutions and nearly 120 government organizations.

News Article | February 28, 2017

BIRMINGHAM, Ala. - Chronic inflammation after a heart attack can promote heart failure and death. University of Alabama at Birmingham researchers have now shown that activated T-cells -- part of the immune system's inflammatory response -- are both necessary and sufficient to produce such heart failure. "These studies," Shyam Bansal, Ph.D., Sumanth Prabhu, M.D., and colleagues write in the journal Circulation: Heart Failure, "provide important proof-of-concept for T-cells as disease mediators in heart failure." Two key experiments demonstrated this necessary and sufficient role for the activated T-cells, which presumably attack heart muscle tissue in an auto-immune fashion. The first key experiment involved removing a specific subset of activated T-cells from mouse models. Treating the mice with antibodies against CD4+ T-cells four weeks after experimental heart attacks -- to deplete that subset of T-cells -- prevented the progressive abnormal enlargement of the left ventricle that leads to heart failure, as compared with untreated mice. The second key experiment showed the effect of transferring activated T-cells from heart-attack mice to healthy mice. When spleen CD4+ T-cells were transferred from heart-attack donor mice to naïve recipient mice, they induced long-term left ventricle dysfunction, fibrosis and enlargement, hallmarks of heart failure. These findings could translate to the clinic, the researchers say. "Our data suggests that targeting specific immune cell subsets at defined stages of disease may represent a better approach to therapeutic immunomodulation to improve heart failure." Nearly one-quarter of people suffering heart attacks in the United States develop heart failure. Overall, patients with heart failure have a 50 percent chance of survival in five years. The current research evolved out of an impactful 2013 paper that was named one of the five most outstanding papers in Circulation Research for the year. In Remodeling of the Mononuclear Phagocyte Network Underlies Chronic Inflammation and Disease Progression in Heart Failure: Critical Importance of the Cardiosplenic Axis, Prabhu and colleagues showed that immune cells that are stored in the spleen were intricately involved in the heart failure that follows a heart attack, or infarction, in a mouse-model system. The splenic immune cells that invaded the heart tissue included pro-inflammatory macrophages and dendritic cells. Since a primary function of the dendritic cells is to present an antigen to T-cells, to activate the T-cells and begin the immune response, the researchers suspected that T-cell activation in the heart tissue, and perhaps heart-tissue injury caused by T-cells, might be central to the pathological heart enlargement that is called remodeling. Normally, the inflammatory response to tissue damage after infarction -- death of muscle tissue in a heart attack -- has two stages. First there is a beneficial, early acute inflammation response that removes dead cells and begins repairs to the injured area. Then, in healthy healing, the acute inflammation resolves, and a healing process follows. One problem in heart failure is a nonresolving, persistently overactive inflammation at the heart. T-lymphocyte cells are distinguished by surface markers. The group of T-cells that have CD4 contains many subsets that have specialized functions. These include pro-inflammatory T helper cells, or Th1, that produce interferon-γ and interleukin-2, or IL-2; anti-inflammatory Th2 cells that produce IL-4, IL-5 and IL-13; pro-inflammatory Th17 cells that secrete IL-17; and immunomodulatory regulatory T-cells, or Tregs, that globally suppress activation of immune responses. So the UAB researchers began to look for changes in subsets of T-cells over an eight-week period after heart attack. They found the CD4+ T-cells were globally expanded and activated during chronic ischemic heart failure, and that there was an expansion of memory T-cells in the spleen. In particular, they found significant expansion of CD3+CD8+ cytotoxic T-cells and CD3+CD4+ helper T-cells in circulating blood, as well as increased CD4+ subsets of Th1, Th2, Th17 and Treg cells, indicating a pro-inflammatory response. In the failing heart, they found increased CD8+ and CD4+ T-cells, and increased Th1, Th2, Th17 and Treg CD4+ subsets. They also found a marked reduction of the Th1/Th2 ratio, and an increased Th17/Treg ratio, as well as upregulation of the inflammatory Th2-type cytokines. In the spleen and mediastinal lymph nodes, they found significantly increased Th1, Th2, Th17 and Treg cells. The spleen showed increased expansion of antigen-experienced effector and memory CD4+ T-cells. Memory T-cells are the cells that become primed to mount a specific immune response when an antigen from a pathogen or injured tissue appears a second time. Memory cells are why vaccination is effective; however, in the case of heart failure, memory cells may be responsible for an ongoing capacity of T-cells to injure the heart. At UAB, Prabhu is the Mary Gertrude Waters Chair of Cardiovascular Medicine, and he directs the Division of Cardiovascular Disease and the Comprehensive Cardiovascular Center, UAB Department of Medicine. Besides Prabhu and Bansal, authors of the paper, "Activated T-lymphocytes are essential drivers of pathological remodeling in ischemic heart failure," are Mohamed Ameen Ismahil, Ph.D., Mehak Goel, Ph.D., Bindiya Patel, Tariq Hamid, Ph.D., and Gregg Rokosh, Ph.D., all of the UAB Division of Cardiovascular Disease. Bansal and Prabhu also are part of the Birmingham Veterans Affairs Medical Center medical service.

News Article | February 28, 2017
Site:, a leading career and education website focused on graduate programs in accounting and finance, has released its ranking of the Top Online Master’s in Accounting Programs. To be considered for the list, schools with an online master’s in accounting program were checked for not-for-profit status and accreditation from one of the six regional accreditation agencies in the US recognized by the US Department of Education. The online degrees from the schools on the list are also the same degrees granted to traditional, on-campus students. The rankings were based on factors measuring academic quality, student experience, and graduate success. The ranking uses a unique methodology that considers such factors as the average tuition cost per online credit hour; program accreditation by the AACSB, ACBSP, or IACBE; the average mid-career pay of alumni; and school rankings according to US News & World Report in the regional, national, and online categories. Rob Voce, founder of, said about the list: “Enrollment in online degree programs is increasing and schools are responding by offering more distance education programs at the graduate level - which can be particularly convenient for those who are already working full-time. Our ranking is designed to help these prospective students learn about and compare first-rate online master’s in accounting programs that offer long-term value.” Overall, 37 schools with online master’s in accounting programs satisfied the inclusion requirements and ranked on this list. Auburn University, in Auburn, Alabama, captured the top spot on the list, followed by the University of North Carolina at Chapel Hill in the second spot. As well as providing schools’ results on ranking factors, the Top Online Master’s in Accounting Programs list includes detailed information on schools’ admissions statistics and requirements as well as tuition comparisons. For the top-ranking schools the list also provides: The top schools on this year’s list are: 1. Auburn University Raymond J. Harbert College of Business (Auburn, AL) 2. University of North Carolina Kenan-Flagler Business School (Chapel Hill, NC) 3. University of Connecticut School of Business (Storrs, CT) 4. University of Massachusetts Amherst Isenberg School of Management (Amherst, MA) 5. Pennsylvania State University World Campus (State College, PA) 6. University of Southern California Marshall School of Business (Los Angeles, CA) 7. Emporia State University School of Business (Emporia, KS) 8. Rutgers, The State University of New Jersey Business School (New Brunswick, NJ) 9. Colorado State University College of Business (Fort Collins, CO) 10. University of Alabama at Birmingham Collat School of Business (Birmingham, AL) 11. University of Texas at Dallas Naveen Jindal School of Business (Richardson, TX) 12. St. John’s University Peter J. Tobin College of Business (Jamaica, NY) 13. Georgia Southern University College of Business Administration (Statesboro, GA) 14. Northeastern University D’Amore-McKim School of Business (Boston, MA) 15. DePaul University Kellstadt Graduate School of Business (Chicago, IL) 16. Golden Gate University Edward S. Ageno School of Business (San Francisco, CA) 17. Southern New Hampshire University College of Online and Continuing Education (Hooksett, NH) 18. California State University, Sacramento College of Business Administration (Sacramento, CA) 19. University of Scranton Kania School of Management (Scranton, PA) 20. Syracuse University Martin J. Whitman School of Management (Syracuse, NY) 21. University of Hartford Barney School of Business (West Hartford, CT) 22. University of Miami School of Business Administration (Coral Gables, FL) 23. George Mason University School of Business (Fairfax, VA) 24. University of South Dakota Beacom School of Business (Vermillion, SD) 25. Florida Atlantic University College of Business (Boca Raton, FL) 26. Stetson University M.E. Rinker Sr. Institute of Tax and Accountancy (DeLand, FL) 27. Rider University College of Business Administration (Lawrenceville, NJ) 28. New England College School of Graduate and Professional Studies (Henniker, NH) 29. Western Governors University (Salt Lake City, UT) 30. Indiana Wesleyan University DeVoe School of Business (Marion, IN) 31. Plymouth State University College of Business Administration (Plymouth, NH) 32. Bellevue University College of Business (Bellevue, NE) 33. Loyola University Chicago Quinlan School of Business (Chicago, IL) 34. Franklin University Ross College of Business (Columbus, OH) 35. Nova Southeastern University Huizenga College of Business (Fort Lauderdale, FL) 36. Saint Mary’s University Graduate School of Business and Technology (Winona, MN) 37. Baypath University School of Science & Management (Longmeadow, MA) *See the full rankings and program details here: About is a free online resource focused on providing accurate and up-to-date information on degrees, programs, and schools for prospective master’s in accounting students. The site also provides additional resources such as career outlooks, graduate student guides, scholarships, and more.’s goal is to be best in class.

News Article | November 10, 2016

Editors: An online press kit is available at As part of its mission to improve the quality, effectiveness, and efficiency of cancer care so that patients can live better lives, the National Comprehensive Cancer Network® (NCCN®) today announced the launch of Just Bag It: The NCCN Campaign for Safe Vincristine Handling. This campaign encourages health care providers to adopt a policy to always dilute and administer vincristine in a mini IV-drip bag to prevent a deadly medical error. Vincristine is a chemotherapy agent, widely used in patients with Leukemia or Lymphoma, which should be administered intravenously, or directly into the patient's vein. When it enters the blood, it is highly effective at blocking the growth of cancer by preventing cells from separating. However, vincristine is a neurotoxin that causes peripheral neuropathy when given intravenously and profound neurotoxicity if given into the spinal fluid, which flows around the spinal cord and brain. Many patients who receive vincristine have a treatment regimen that includes other chemotherapy drugs that are administered intrathecally, or injected into the spinal fluid with a syringe. If vincristine is mistakenly administered into the spinal fluid, it is uniformly fatal, causing ascending paralysis, neurological defects, and eventually death. In 2005, NCCN Chief Executive Officer Robert W. Carlson, MD, a medical oncologist, witnessed such a tragedy with a 21 year-old patient with Non-Hodgkin's Lymphoma named Christopher Wibeto. Wibeto was transferred to Carlson's care after receiving incorrectly administered vincristine at another hospital. Carlson watched the young man go from having a likely curable condition to deteriorating and dying within four days. Motivated by this tragic experience, Carlson spearheaded a national effort to address this deadly error when he arrived at NCCN, enlisting the help of its Best Practices Committee, which is dedicated to improving cancer treatment protocols. To ensure that vincristine is always administered properly, NCCN has issued guidelines advising health care providers to always dilute and administer vincristine in a mini IV-drip bag and never use a syringe to administer the medication. This precaution renders it impossible to accidentally administer the medication into the spinal fluid and greatly decreases the chances of improper dosage. All 27 NCCN Member Institutions have adopted policies in line with these guidelines, which are also recommended by the Institute for Safe Medication Practices, the Joint Commission, the World Health Organization, and the Oncology Nursing Society. "We are proud of this achievement and grateful for the support and participation of our Member Institutions in reaching this goal," Carlson said. "Our efforts will not stop here. We challenge all medical centers, hospitals, and oncology practices around the nation and the world to implement this medication safety policy so this error never occurs again." Surveys issued by the Institute for Safe Medication Practices (ISMP) show that over time, more hospitals have adopted a policy to always bag vincristine. According to ISMP data, the number of hospitals that have fully implemented the policy across their practice nearly doubled between February 2014 and February 2016. Earlier surveys indicated a similar increase between 2005 and 2012. Still, only about half of all respondents indicated that they have implemented the policy in all treatment settings, indicating that there is a long way to go. With 125 known cases of accidental death in the U.S. and abroad since the inception of vincristine use in the 1960s, this error is relatively rare. Still, it is unique in its level of mortality. Improvements in practice over the years, including manufacturer- and pharmacist-issued warning labels, have reduced the number of deaths, but the error continues to occur. Diluting vincristine into a mini IV-drip bag may entail a change in practice for some providers, but it is well worth the outcome of avoiding preventable deaths, according to Michael Cohen, RPh, MS, FASHP, President of ISMP. "One more life taken is one too many," Cohen said. "We are glad an organization of NCCN's influence has stepped up to bring this issue to national attention. Ending this devastating error should be a priority for all of us who care for and advocate on behalf of patients and their families." Some health care providers may associate the use of an IV bag with a heightened risk of extravasation, or the leaking of a chemotherapy drug into the tissue surrounding the intravenous administration site. But research shows that the risk of extravasation is extremely low. [1] "The Just Bag It campaign is the latest of NCCN's long-standing efforts to improve the safe use of drugs in cancer care," said F. Marc Stewart, MD, Medical Director of the Seattle Cancer Care Alliance and Member of the Fred Hutchinson Cancer Research Center, Professor of Medicine at University of Washington, and Co-Chair of the NCCN Best Practices Committee. "For more than 15 years, the Best Practices Committee has worked to ensure the highest standards of safety for patients." In 2008, the Best Practices Committee led the charge for NCCN to begin publishing Chemotherapy Order Templates (NCCN Templates®), which detail the most common regimens for many cancers and highlight safety parameters. These resources enable practitioners to standardize patient care, reduce medication errors, and anticipate and manage adverse events. There are more than 1,500 NCCN Templates® for 86 cancer types, and they are used by more than 10,000 subscribers. For more information about Just Bag It: The NCCN Campaign for Safe Vincristine Handling, or to report that a medical facility has adopted a vincristine policy, visit The National Comprehensive Cancer Network® (NCCN®), a not-for-profit alliance of 27 of the world's leading cancer centers devoted to patient care, research, and education, is dedicated to improving the quality, effectiveness, and efficiency of cancer care so that patients can live better lives. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The NCCN Member Institutions are: Fred & Pamela Buffett Cancer Center, Omaha, NE; Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; City of Hope Comprehensive Cancer Center, Los Angeles, CA; Dana-Farber/Brigham and Women's Cancer Center | Massachusetts General Hospital Cancer Center, Boston, MA; Duke Cancer Institute, Durham, NC; Fox Chase Cancer Center, Philadelphia, PA; Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, WA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Mayo Clinic Cancer Center, Phoenix/Scottsdale, AZ, Jacksonville, FL, and Rochester, MN; Memorial Sloan Kettering Cancer Center, New York, NY; Moffitt Cancer Center, Tampa, FL; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, Columbus, OH; Roswell Park Cancer Institute, Buffalo, NY; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center, Memphis, TN; Stanford Cancer Institute, Stanford, CA; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; UC San Diego Moores Cancer Center, La Jolla, CA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of Colorado Cancer Center, Aurora, CO; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; Vanderbilt-Ingram Cancer Center, Nashville, TN; and Yale Cancer Center/Smilow Cancer Hospital, New Haven, CT. [1] ISMP. Death and neurological devastation from intrathecal vinca alkaloids: Prepared in syringes = 120; Prepared in minibags = 0. ISMP Medication Safety Alert! 2013;18(18):3. The following files are available for download:

News Article | February 23, 2017

MAYWOOD, IL - Intensive treatment to lower systolic (top number) blood pressure to below 120 would prevent 107,500 deaths per year in the United States, according to a study by researchers at Loyola University Chicago and other centers. Two thirds of the lives saved would be men and two thirds would be aged 75 or older, according to the study, published in the journal Circulation. Senior author of the study is Richard S. Cooper, MD, chair of Loyola's Department of Public Health Sciences. First author is Adam P. Bress, PharmD, MS, of the University of Utah. Current guidelines recommend keeping systolic blood pressure below 140 mm Hg. When the treatment goal was lowered to a maximum of 120 mmHG, there was a major reduction in mortality, the study found. To determine whether intensive treatment to lower systolic blood pressure could alter mortality, researchers applied findings from a multicenter study called SPRINT to the U.S. adult population. (SPRINT stands for Systolic Blood Pressure Intervention Trial.) Loyola University Medical Center was among the centers that enrolled patients in the SPRINT trial, which included more than 9,350 adults ages 50 and older who had high blood pressure and were at high risk for cardiovascular disease. The SPRINT trial found there was a 27 percent reduction in mortality from all causes when systolic blood pressure was lowered to below 120 mm Hg, compared to the standard treatment of lowering blood pressure to below 140 mm Hg. While saving lives, an intensive blood pressure regimen also would cause serious side effects. The new study in Circulation estimated that approximately 56,100 more episodes of low blood pressure, 34,400 more episodes of fainting and 43,400 additional electrolyte disorders would occur annually with implementation of intensive systolic blood pressure lowering in U.S. adults who meet SPRINT criteria. Most of these effects do not have lasting consequences and are reversible by lowering blood pressure medications. High blood pressure, or hypertension, is a leading risk factor for heart disease, stroke, kidney failure, and other health problems. An estimated 1 in 3 people in the United States has high blood pressure. Blood pressure is measured in millimeters of mercury (mm Hg). Systolic blood pressure refers to the pressure in the arteries when the heart beats. The bottom number, diastolic, refers to the pressure between beats. In the SPRINT study, patients who were treated to achieve a standard target of less than 140 mm Hg received an average of two different blood pressure medications. The group intensively treated to achieve a target of less than 120 mm Hg received an average of three medications. (The study excluded certain patients, including diabetics and smokers.) Using data from the National Health & Nutrition Examination Survey, researchers determined that more than 18.1 million American adults met the criteria of patients enrolled in the SPRINT trial. Researchers estimated that, among these 18.1 million adults, fully implementing an intensive regimen to lower systolic blood pressure below 120 mm Hg would prevent 107,500 deaths per year. The study is titled, "Potential Deaths Averted and Serious Adverse Events Incurred from Adoption of the SPRINT Intensive Blood Pressure Regimen in the U.S.: Projections from NHANES." In addition to Dr. Cooper, other Loyola co-authors are Holly Kramer, MD, MPH, Rasha Khatib, PhD, Vinod K. Bansal, MD, Guichan Cao, MS, and Ramon Durazo-Arvizu, PhD. Other co-authors are from Henry Ford Hospital, Columbia University Medical Center and the University of Alabama at Birmingham. Findings from the study initially were presented at the American Heart Association's Council on Hypertension 2016 Scientific Sessions.

News Article | December 5, 2016

PORTLAND, OR - New research shows that quickly identifying patients with high-risk acute myeloid leukemia (AML), and speeding the process to find them a stem cell donor and performing the transplant earlier, can significantly improve their chances of surviving for at least two years after diagnosis without a relapse. The research was conducted by SWOG, the cancer clinical trials group that is part of the National Cancer Institute's (NCI) National Clinical Trials Network, the oldest and largest cancer research network in the nation. Results will be presented Monday, Dec. 5 at the 58th American Society of Hematology Annual Meeting by Dr. John Pagel, chief of the Hematologic Malignancies program at the Swedish Cancer Institute in Seattle, WA and co-principal investigator for the SWOG research study, called S1203. Pagel's presentation is one of 18 made by SWOG investigators at the 2016 ASH annual meeting, held in San Diego, CA. "We are very excited to share these results," Pagel said. "This study showed we can get significantly more high-risk AML patients to a stem cell transplant before their cancer recurs by simply working hard to identify an appropriate donor and proceeding to transplantation as soon as possible. When we do, more high-risk patients live longer and are likely cured. This process may establish a new standard of care." AML is a fast-growing type of cancer, common in the elderly, in which the bone marrow makes too many white blood cells. According to NCI statistics, there will be an estimated 19,950 new cases of AML in 2016, with an estimated 10,430 deaths, in the United States. Only 27 percent of AML patients survive five years after their diagnosis, NCI data shows. Some are at even greater risk. High-risk AML marked by certain genetic mutations is more resistant to chemotherapy, and even if it responds to chemotherapy, can more quickly cause relapse and death. These high-risk patients are the population that Pagel and his team wanted to help when they designed and launched S1203. Previous research had shown that high-risk AML patients can live longer if they use a donor's stem cells to get an allogeneic hematopoietic cell transplant, or allogeneic HCT, after chemotherapy and before a relapse. But only about 40 percent of these high-risk patients do so. An allogeneic HCT is a complicated process of transplanting a type of stem cell from healthy donors, or in select cases, from cord blood, to patients with certain cancers of the bone marrow and blood. Could Pagel and his team more quickly identify high-risk AML patients, and more quickly get them a transplant? If they did, how much of a difference would it make to their survival? These are the questions the SWOG team set out to answer. To more rapidly identify high-risk patients, the SWOG team created a protocol that involved running a DNA test on patients immediately upon their AML diagnosis. The test checks for genetic mutations that signal high-risk - and likely extremely difficult to cure - variants of the disease, with results returning in about a week. Working with the National Marrow Donor Program (NMDP), they also created a process to rapidly identify stem cell donors for these high-risk patients. All patients in the trial got a cheek swab upon diagnosis, and DNA on the swab was used to find a donor in the worldwide registry, or investigators worked with relatives, such as siblings, to find a match even while the patient was undergoing chemotherapy. This coordinated, proactive approach is different. Often, doctors and patients wait until after chemotherapy, when the cancer returns, to begin to seek an allogeneic HCT. Pagel and his team enrolled 738 eligible patients to the trial, and 159 of them - or about 22 percent - were identified as high-risk. Out of 159 high-risk patients, 107 had the stem cell transplant. The results were clear. Pagel and his team increased the transplant rate for high-risk patients from the 40 percent standard to a whopping 64 percent. And two-year survival for high-risk patients also increased significantly. Typically, only about 22 percent of high-risk patients survive two years after their cancer diagnosis. Pagel and his team saw that two-year survival rate increase to 45 percent for high-risk patients who got the transplant. "The big message here is 'Don't delay identifying a donor,'" Pagel said. "Find these high-risk patients fast - and get them a transplant fast - and you can save lives. This only requires a simple, coordinated approach to testing and transplant searches. It's not complicated, but it makes an impact." The co-principal investigator of the S1203 study team is Dr. Guillermo Garcia-Manero of University of Texas MD Anderson Cancer Center. The study team also includes: Megan Othus, Ph.D., of Fred Hutchinson Cancer Research Center; Dr. Min Fang of the University of Washington and the Seattle Cancer Care Alliance; Dr. Jerald Radich of the University of Washington and the Seattle Cancer Care Alliance; Dr. David A. Rizzieri of Duke University and the Duke Cancer Institute; Dr. Guido Marcucci of City of Hope; Dr. Stephen A. Strickland, Jr. of Vanderbilt University and Vanderbilt-Ingram Cancer Center; Dr. Mark. R. Litzow of Mayo Clinic; Dr. M. Lynn Savoie of University of Calgary and Arnie Charbonneau Cancer Institute; Dr. Stephen R. Spellman of the Center for International Blood & Marrow Transplant Research; Dr. Dennis L. Confer of the National Marrow Donor Program; Dr. Jeffrey W. Chell of the National Marrow Donor Program; Dr. Maria Brown of Rush University Medical Center; Dr. Bruno Medeiros of Stanford University Medical Center; Dr. Mikkael Sekeres of Cleveland Clinic; Dr. Tara Lin of the University of Kansas Cancer Center; Dr. Geoffrey Uy of Washington University School of Medicine in St. Louis; Dr. Bayard L. Powell of Wake Forest Baptist Health; Dr. Jonathan Kolitz of Norwell Health; Dr. Richard A. Larson of the University of Chicago; Dr. Richard M. Stone of Dana-Farber Cancer Institute; Dr. David Claxton of Penn State Cancer Institute; Dr. James Essell of Oncology Health Care; Dr. Selina Luger from Penn Medicine; Dr. Sanjay Mohan from Vanderbilt University and Vanderbilt-Ingram Cancer Center; Anna Moseley, M.S. of Fred Hutchinson Cancer Research Center; Dr. Harry Erba of University of Alabama at Birmingham School of Medicine; and Frederick R. Appelbaum of Fred Hutchinson Cancer Research Center. S1203 was supported by the National Cancer Institute through grants CA180888; CA180819; CA18020; CA180821; CA180863; CA077202; and CCSRI 021039. SWOG is part of the National Cancer Institute's National Clinical Trials Network, the nation's oldest and largest cancer research network, and is a major part of the cancer research infrastructure in the U.S. and the world. SWOG has over 12,000 members in 46 states and six foreign countries who design and conduct cancer clinical trials to improve the lives of people with cancer. Founded in 1956, SWOG's 1,300 trials have led to the approval of 14 cancer drugs, changed more than 100 standards of cancer care, and saved more than 2 million years of human life. Learn more at

News Article | April 20, 2016

Three archaeological sites that may have been used by Vikings around 1,000 years ago were excavated recently in Canada. If confirmed, the discoveries would add to the single known Viking settlement in the New World, located at L'Anse aux Meadows on the northern tip of Newfoundland. Excavated in the 1960s, that Viking outpost was used for a short period of time around 1,000 years agoas well. Sagas from the time of the Vikings tell tales of their journeys into the New World, mentioning places named "Helluland" (widely believed to be modern-day Baffin Island), "Markland" (widely believed to be Labrador) and "Vinland," which is a more mysterious location that some archaeologists have argued could be Newfoundland. [See Photos of the Newfound Viking Sites] Even so, pinpointing actual Viking remains or other clues of Viking settlements has been difficult, making the three sites — two in Newfoundland and the other in the Arctic — intriguing to archaeologists. Sarah Parcak, a professor at the University of Alabama at Birmingham, and her colleagues spotted the so-called Point Rosee site in southern Newfoundland while scanning satellite imagery, and announced their discovery a few weeks ago. The team found what may be a hearth used to roast bog iron, as well as a structure, of some type, made with turf. Radiocarbon dating suggests that the site was used sometime between the ninth and 13th centuries. These finds, the researchers say, suggest that Vikings may have used the site, though more dating information and excavation are needed to confirm that idea, they said. Additionally, even if it is a Viking site, it's uncertain how long the Vikings lived there. "I think that all of us would be in agreement in urging you to relay the preliminary nature of the findings — the unconfirmed cultural and period affiliations," said team co-director Gregory Mumford, who is also a professor at the University of Alabama at Birmingham. Another possible Viking site turned up after archaeologists investigated a series of peculiar holes in a small town called Sop's Arm near White Bay, about 120 miles (200 kilometers) south of L'Anse aux Meadows. Archaeologists say that these "pitfalls," which have been known to exist near the town, would have been used to trap large animals, such as caribou. [Fierce Fighters: 7 Secrets of Viking Seamen] In 1961, Helge Ingstad, the archaeologist who would excavate L'Anse aux Meadows, was guided to the pitfalls by a local man named Watson Budden. Ingstad thought it was likely that the Vikings had constructed the holes, but he didn't excavate them. In 2010, archaeologists surveyed and excavated the pitfalls. They found that the pitfalls form a 269-foot-long (82 meters) system that lies in an almost straight line, the team wrote in an article published in the journal Acta Archaeologica in 2012. Each of the pits is about 23 to 33 feet (7 to 10 m) long and about 5 to 7.5 feet (1.5 to 2.3 m) deep. Perhaps the Vikings drove animals toward the pits, where they would have fallen in and been killed, said Kevin Mcaleese, a curator of archaeology and ethnology at the Provincial Museum of Newfoundland and Labrador. The team did find stones inside the pitfalls that could have injured animals that had fallen inside. However, the archaeologists didn't find any artifacts and were unable to obtain clear radiocarbon dates for the pits. "No Newfoundland and Labrador aboriginal group or archaeological culture is known in historic times or in ancient times to have regularly trapped animals with pitfalls," Mcaleese said. "I am developing a research plan for the site and area, but have not yet secured funds." Kent Budden, nephew of Watson Budden, collected a number of what he suspects are Norse artifacts from the Sop's Arm area, including an iron ax and other iron artifacts, as well as a stone that has what could be a serpent carved into it. Kent Budden died in 2008, and his brother Owen Budden showed photographs of the artifacts to Live Science. (Before he died, Kent Budden also gave a presentation of the collection, which can now be seen on YouTube.) Mcaleese said he is not very familiar with the collection. "What I have seen does not appear to be Norse, and my colleagues think similarly," he said. The Vikings also may have settled, at least for a bit, in Nanook on Baffin Island. Researchers recently discovered the remains of a building that may have been constructed by the Vikings and artifacts that may have been used in metalworking. Among the artifacts was a stone crucible that may "represent the earliest evidence of high-temperature nonferrous metalworking in the New World north of Mesoamerica," wrote a team of archaeologists in a paper published in 2014 in the journal Geoarchaeology. A structure that may have been used by the Vikings was in the process of being excavated in 2012, when lead archaeologist Patricia Sutherland was abruptly fired from the Canadian Museum of Civilization (now called the Canadian Museum of History) and the excavations were terminated.  Many Canadian archaeologists condemned Sutherland's abrupt termination and the decision to end the project. They noted that the Canadian government, which owned the museum and funded her project, proceeded to pour millions of dollars into locating and excavating a ship destroyed in 1847 during the ill-fated Franklin expedition. This expedition, led by Sir John Franklin, aimed to find a sea route through the Canadian Arctic between the Atlantic and Pacific Oceans. The expedition ended with the death of Franklin and his crew. This funding decision led to accusations that the federal government favored research into British remains over those of the Vikings. In 2015, a new federal government was elected, but it remains unknown whether it will fund new research at the Nanook site. One of the mysteries that researchers have been trying to solve is the location of a place that the Viking sagas call "Vinland" (wine land). Historical texts describe a place where grapes and timber could be found. [In Photos: Viking Voyage Discovered] Famed Viking explorer Leif Ericson is said to have led an expedition to Vinland. The sagas say that Ericson was so impressed by what he found that he told his crew that, "from now on, we have two jobs on our hands: On one day, we shall gather grapes, and on the next, we shall cut grapevines and chop down the trees to make a cargo for my ship." The stories, as translated by Einar Haugen in the 1942 book "Voyages to Vinland: The First American Saga," go on to say that "Leif gave this country a name to suit its resources: He called it Vinland." Grapes don't grow as far north as Newfoundland, leaving some researchers to speculate that Vinland is located farther south, possibly around New Brunswick, Nova Scotia or Maine. Others think that Newfoundland is Vinland and that the "grapes" could refer to wild berries, which are found in abundance in Newfoundland. So far, no potential Viking sites have been discovered south of Newfoundland, although a coin, minted in Norway between A.D. 1065 and 1080, was discovered in Maine in 1957 by an amateur archaeologist at a Native American site. How the coin arrived at that site is a mystery. The 7 Most Mysterious Archaeological Finds on Earth Copyright 2016 LiveScience, a Purch company. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

News Article | November 20, 2016

An analysis of collegiate graduate and post-graduate programs by has determined the best places to earn a Master’s and Doctorate Degree Online in the nation for 2016-2017. As a leader in online higher education resources, the site measured cost and quality data to determine the top online programs for each degree level, identifying Western New Mexico University, Fort Hays State University, University of Central Arkansas, Arkansas State University and Wilmington University as the top scoring schools for earning an online master’s degree and the University of Colorado Denver, University of Mississippi, Indiana State University, University of Arkansas and Texas A&M University as the top scoring schools for earning an online doctorate degree. "As of 2013, over 23 percent of master’s and doctoral level students were completing their degrees entirely online,” said Dan Schuessler, CEO and Founder of "Our list pinpoints the schools around the nation who are providing students affordable, quality options when it comes to earning a post-baccalaureate degree, with the bonus of greater learning flexibility provided by online curriculum.” Schools must meet specific criteria to qualify for the Best Online Master’s Degree Programs & Best Online Doctorate Degree Programs lists. All institutions must be accredited, public or private not-for-profit entities and must offer in-state tuition and fees under $25,000 per year. Eligible institutions are further evaluated and scored based on a variety of data points, such as financial aid offerings, graduation rates and online program variety, to determine overall cost and quality rankings by school. Full rankings, as well as specific details on data and methodology used to determine school scores can be found at the following pages: All colleges highlighted for excellence in Online Master’s Programs for 2016-2017 are listed below: Adams State University Arkansas State University - Main Campus Ball State University Brenau University Chadron State College Columbus State University Concordia University-Saint Paul Delta State University East Carolina University Embry-Riddle Aeronautical University - Worldwide Emporia State University Fort Hays State University Graceland University - Lamoni Indiana State University Indiana Wesleyan University Liberty University Missouri State University - Springfield New Mexico State University - Main Campus North Carolina Central University North Carolina State University at Raleigh Northern Arizona University Northwestern State University of Louisiana Oklahoma State University - Main Campus Purdue University - Main Campus Saint Leo University Southeastern Oklahoma State University Southern Arkansas University Main Campus The University of Texas at Brownsville (University of Texas Rio Grande Valley) The University of Texas at Tyler Troy University University of Alabama at Birmingham University of Arkansas University of Arkansas at Little Rock University of Central Arkansas University of Central Missouri University of Colorado Denver University of Idaho University of Louisiana at Monroe University of Memphis University of Nebraska at Kearney University of North Carolina at Greensboro University of North Dakota University of Southern Mississippi University of West Alabama Wayland Baptist University Webster University Western Carolina University Western Kentucky University Western New Mexico University Wilmington University All colleges highlighted for excellence in Online Doctorate Programs for 2016-2017 are listed below: Allen College Amridge University Clemson University Colorado State University - Fort Collins Hampton University Harding University Indiana State University Kansas State University Keiser University - Fort Lauderdale Liberty University Mississippi State University Northern Arizona University Oregon State University Pennsylvania State University - Main Campus Rutgers University - New Brunswick Southern Illinois University - Edwardsville Stony Brook University Temple University Texas A & M University - College Station Texas A & M University - Commerce Texas Tech University The University of Alabama The University of Montana The University of Tennessee - Knoxville The University of Texas at Tyler The University of Texas Medical Branch Union Institute & University University at Buffalo University of Alabama in Huntsville University of Alaska Fairbanks University of Arizona University of Arkansas University of California - Berkeley University of Colorado Denver University of Delaware University of Florida University of Louisiana at Monroe University of Massachusetts - Amherst University of Michigan - Flint University of Minnesota - Twin Cities University of Mississippi University of Nebraska - Lincoln University of North Carolina at Chapel Hill University of North Carolina at Greensboro University of North Dakota University of Northern Colorado University of South Carolina - Columbia University of the Cumberlands Virginia Commonwealth University Wilmington University began in 2011 to provide quality data and information about pursuing an affordable higher education. Our free community resource materials and tools span topics such as financial aid and college savings, opportunities for veterans and people with disabilities, and online learning resources. We feature higher education institutions that have developed online learning environments that include highly trained faculty, new technology and resources, and online support services to help students achieve educational and career success. We have been featured by nearly 1,100 postsecondary institutions and nearly 120 government organizations.

News Article | November 15, 2016

Providing access to NCCN Templates® through Cerner's PowerChart Oncology™ will help practitioners make informed treatment decisions based on up-to-date, standard protocols FORT WASHINGTON, PA--(Marketwired - November 15, 2016) - The National Comprehensive Cancer Network® (NCCN®) is collaborating with Cerner to integrate the NCCN Chemotherapy Order Templates (NCCN Templates®) into PowerChart Oncology™, the oncology-specific solution within Cerner's electronic health record (EHR), as electronic chemotherapy protocols for use by health care providers. NCCN Templates® will be available for PowerChart Oncology users in 2017. "We are collaborating with Cerner to provide practitioners with access to evidence-based treatment protocols at the point of care to help provide patients with the most up-to-date regimens possible for their specific diagnoses," said Dr. Robert W. Carlson, CEO, NCCN. As part of the integration, Cerner's EHR will link to, providing end-user access to NCCN Templates and the corresponding NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), helping practitioners make treatment decisions based on up-to-date, evidence-based standard protocols. "At Cerner, we constantly work to provide solutions that support the oncology care team as they make the best treatment decisions possible. Our collaboration with NCCN will further this mission by providing clinicians with direct access to the evidence-based NCCN Chemotherapy Order Templates in their PowerChart Oncology workflow," said Susan Stiles, Oncology solution executive at Cerner. "We have always recommended that clients use NCCN Guidelines® and NCCN Templates and now they will be integrated into PowerChart Oncology. This will help providers follow the most up-to-date treatment plans and be more available to focus on what is most important, their patients." The information contained in the NCCN Templates is based on the NCCN Guidelines. NCCN Templates include chemotherapy and immunotherapy regimens with literature support, supportive care agents, monitoring parameters and safety instructions. A goal of the NCCN Templates is to enhance patient safety by empowering health care providers to standardize patient care, reduce medical errors, and anticipate and manage adverse events. NCCN continues to expand the library of chemotherapy order templates to work toward improved safe and effective use of drugs and biologics in cancer care. For more information about NCCN Templates, visit Cerner's health information technologies connect people, information and systems at more than 25,000 provider facilities worldwide. Recognized for innovation, Cerner solutions assist clinicians in making care decisions and enable organizations to manage the health of populations. The company also offers an integrated clinical and financial system to help health care organizations manage revenue, as well as a wide range of services to support clients' clinical, financial and operational needs. Cerner's mission is to contribute to the systemic improvement of health care delivery and the health of communities. Nasdaq: CERN. For more information about Cerner, visit, read our blog at, connect with us on Twitter at and on Facebook at Our website, blog, Twitter account and Facebook page contain a significant amount of information about Cerner, including financial and other information for investors. The National Comprehensive Cancer Network® (NCCN®), a not-for-profit alliance of 27 of the world's leading cancer centers devoted to patient care, research, and education, is dedicated to improving the quality, effectiveness, and efficiency of cancer care so that patients can live better lives. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The NCCN Member Institutions are: Fred & Pamela Buffett Cancer Center, Omaha, NE; Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; City of Hope Comprehensive Cancer Center, Los Angeles, CA; Dana-Farber/Brigham and Women's Cancer Center | Massachusetts General Hospital Cancer Center, Boston, MA; Duke Cancer Institute, Durham, NC; Fox Chase Cancer Center, Philadelphia, PA; Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, WA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Mayo Clinic Cancer Center, Phoenix/Scottsdale, AZ, Jacksonville, FL, and Rochester, MN; Memorial Sloan Kettering Cancer Center, New York, NY; Moffitt Cancer Center, Tampa, FL; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, Columbus, OH; Roswell Park Cancer Institute, Buffalo, NY; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center, Memphis, TN; Stanford Cancer Institute, Stanford, CA; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; UC San Diego Moores Cancer Center, La Jolla, CA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of Colorado Cancer Center, Aurora, CO; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; Vanderbilt-Ingram Cancer Center, Nashville, TN; and Yale Cancer Center/Smilow Cancer Hospital, New Haven, CT. The following files are available for download:

MORRISVILLE, N.C., March 01, 2017 (GLOBE NEWSWIRE) -- Novan, Inc. (“the Company” or “Novan”) (NASDAQ:NOVN) today announced that preclinical data demonstrating the anti-viral effects of the Company’s nitric oxide-releasing drug candidates will be presented at the 31st International Papillomavirus Conference in Cape Town, South Africa. Thomas Broker, Ph.D., and Louise Chow, Ph.D., both of the University of Alabama at Birmingham, or UAB, are scheduled to present “Antiviral Efficacy of Nitric Oxide-Releasing Drug Candidates in Suppressing Productive Infection by HPV-18 in the Organotypic Epithelial Raft Culture Model System” on Thursday, Mar. 2. Drs. Broker and Chow are professors in the Department of Biochemistry and Molecular Genetics at UAB’s School of Medicine. The Broker-Chow research program has been focused on human papillomavirus, or HPV, for more than 33 years. “We are very excited by the continuing success of the investigational nitric oxide-releasing agents against HPV infections,” said Dr. Broker. “The data we are presenting showed significant inhibition of the high-risk HPV-18 genotype and reduction of the E6 viral protein in the raft culture model. We are quite pleased that the testing results from our laboratory have had a very constructive impact in elucidating some of the probable mechanisms of action and the affected cellular and viral pathways.” Published studies have demonstrated that the E6 protein impedes the body’s ability to recognize HPV-infected cells and disrupts the cells’ ability to repair DNA damage and prevent abnormal cellular replication. As a result, E6 is believed to be a primary driver of HPV-related cancers and other abnormal growths. “The findings generated in Broker-Chow’s human tissue model support the novel mechanism of action of Novan’s topical SB206 anti-viral development program,” said Nathan Stasko, Ph.D., President and Chief Executive Officer of Novan. “HPV affects millions of Americans, and we believe nitric oxide-releasing drug candidates have incredible potential not only for the topical treatment of genital, common and plantar warts caused by HPV, but also against cancers associated with high-risk HPV subtypes.” Top-line results from Novan’s Phase 2 clinical trial with SB206 for the treatment of genital warts caused by HPV were announced in November 2016. HPV refers to a large family of double-stranded DNA viruses that induce abnormal growths on the skin or mucosal surfaces. HPV affects nearly 80 million Americans, and an estimated 14 million new cases of the virus are reported each year, according to the Centers for Disease Control and Prevention, or CDC. There are over 100 subtypes of the virus, characterized as low-risk or high-risk based on their cancer-causing potential. The virus is typically transmitted via direct skin-to-skin contact through disruptions in the normal skin barrier. All warts are caused by HPV, including genital and perianal warts, common warts and plantar warts. Genital warts are among the world's most common sexually transmitted diseases. Genital warts are usually flesh-colored growths that can be raised, flat or cauliflower-shaped and are typically found on the surface of the external genitalia or in and around the anus. In males, they can appear on the surface of the penis and scrotum, and in females inside the vagina or on the cervix. Genital warts carry a substantial psychosocial burden due to the shame and embarrassment related to having a sexually transmitted disease as well as the inconvenience and discomfort of current treatment modalities. Current treatment options for genital warts consist of ablative procedures that cut, burn or freeze the warts but do not address the underlying viral infection, and there are no currently approved oral or topical prescription products indicated for the treatment of genital warts with a direct anti-viral mechanism of action. Novan, Inc. is a late-stage pharmaceutical company focused on redefining the standard of care in dermatology through the development and commercialization of innovative therapies using the Company’s nitric oxide-releasing platform. Nitric oxide plays a vital role in the natural immune system response against microbial pathogens and is a critical regulator of inflammation. Our ability to harness nitric oxide and its multiple mechanisms of action has enabled us to create a platform with the potential to generate differentiated, first-in-class product candidates. We are rapidly advancing programs in five dermatological conditions with significant unmet medical need. We believe that our ability to conveniently deploy nitric oxide on demand in topical formulations allows us the potential to significantly improve patient outcomes in a variety of skin diseases and positions us to be a commercially successful leader in the dermatology market. For more information, visit the Company’s website at This press release contains forward-looking statements including, but not limited to, statements related to pharmaceutical development of nitric oxide-releasing product candidates, expected performance of our product candidates, publication and presentation of our trial results in the medical community and future prospects of our business and our product candidates. Forward-looking statements are subject to a number of risks and uncertainties that could cause actual results to differ materially from our expectations, including, but not limited to, uncertainties and risks in the clinical development process, including, among others, length, expense, ability to enroll patients, reliance on third parties, and that results of earlier research and preclinical or clinical trials may not be predictive of results, conclusions or interpretations of later research or trials; the lengthy and unpredictable nature of the U.S. Food and Drug Administration’s drug approval process; whether we will be able to obtain additional funding when needed; and other risks and uncertainties described in our prospectus dated Sept. 20, 2016, filed with the Securities and Exchange Commission, or SEC, in our quarterly report filed with the SEC on Form 10-Q for the three months ended Sept. 30, 2016, and in any subsequent filings with the SEC. These forward-looking statements speak only as of the date of this press release, and Novan disclaims any intent or obligation to update these forward-looking statements to reflect events or circumstances after the date of such statements, except as may be required by law.

News Article | November 28, 2016

Leading higher education information and resource provider is highlighting schools with top online health sciences degree programs in a new ranking for 2016-2017. Two lists compare four-year and two-year schools offering health science degree programs nationwide, determining which offer the best combination of cost and quality for students. Of the lists of top 100 colleges, the highest finishers among four-year schools include the University of Mississippi, Washburn University, Siena Heights University, Weber State University and Davenport University, while top two-year schools include East Mississippi Community College, Holmes Community College, Hutchinson Community College, Metropolitan Community College and Barton County Community College. "Employment in healthcare occupations is projected to grow 19 percent, or much faster than the national average, from 2014 to 2024,” said Dan Schuessler, CEO and Founder of “Students pursuing health science degrees can now find affordable, high quality learning options online through these schools, who are ultimately being highlighted here for their efforts to help students excel.” has several minimum eligibility requirements each school on their rankings must meet. Colleges must be accredited, public or private not-for-profit institutions and must offer in-state tuition rates as follows: under $5,000 per year for two-year schools; under $25,000 per year for four-year schools. Those meeting eligibility requirements are then scored and ranked based on more than a dozen school-specific statistics, including financial aid offerings and graduation rates. Each school recognized on the top online health sciences degree programs list is included below. For more information on each school’s score and the data and methodology used to rank each can be found at: The Best Two-Year Schools for Online Health Sciences Students in 2016-2017: Allen County Community College Barton County Community College Beaufort County Community College Bluegrass Community and Technical College Central Texas College Colby Community College Collin College Columbus State Community College Cowley County Community College Crowder College Dakota College at Bottineau East Mississippi Community College Forsyth Technical Community College Gateway Community and Technical College GateWay Community College Great Falls College Montana State University Hazard Community and Technical College Holmes Community College Hutchinson Community College Indian Hills Community College Kansas City Kansas Community College Kilgore College Lakeshore Technical College Lanier Technical College Lenoir Community College Madisonville Community College Maysville Community and Technical College Metropolitan Community College National Park College North Central Missouri College North Dakota State College of Science Northwest Mississippi Community College Oklahoma City Community College Pamlico Community College Panola College Pitt Community College San Juan College Seward County Community College and Area Technical School Sinclair College Southwest Mississippi Community College Southwestern Community College Spokane Community College Spokane Falls Community College State Fair Community College Three Rivers Community College Truckee Meadows Community College Tyler Junior College Western Nebraska Community College Western Wyoming Community College Williston State College The Best Four-Year Schools for Online Health Sciences Students in 2016-2017: Allen College Augusta University Baker College Brigham Young University - Idaho Clarkson College Concordia University - Saint Paul Dakota State University Davenport University East Carolina University Ferris State University Goodwin College Granite State College Indiana University - Purdue University Indianapolis Keiser University - Fort Lauderdale Kent State University at Kent Midway College Midwestern State University Mississippi University for Women Montana State University - Billings Nebraska Methodist College of Nursing & Allied Health North Carolina A & T State University Northern Arizona University Oregon Institute of Technology Peirce College Presentation College Rutgers University - New Brunswick Siena Heights University St. Petersburg College SUNY Polytechnic Institute The University of Texas Health Science Center at San Antonio Thomas University Tiffin University University of Alabama at Birmingham University of Arkansas at Little Rock University of Cincinnati - Main Campus University of Florida University of Louisiana at Monroe University of Mississippi University of Missouri - Columbia University of Northern Colorado University of Oklahoma - Health Sciences Center University of Southern Indiana University of Toledo Viterbo University Washburn University Weber State University Western Carolina University Western Kentucky University Winston-Salem State University Youngstown State University began in 2011 to provide quality data and information about pursuing an affordable higher education. Our free community resource materials and tools span topics such as financial aid and college savings, opportunities for veterans and people with disabilities, and online learning resources. We feature higher education institutions that have developed online learning environments that include highly trained faculty, new technology and resources, and online support services to help students achieve educational and career success. We have been featured by nearly 1,100 postsecondary institutions and nearly 120 government organizations.

News Article | November 10, 2016

This week the U.S. elected businessman and reality TV star Donald Trump as its 45th president. As Scientific American has reported in the run-up to the election, Trump's views on science, health and medicine appear unformed at best, ignorant and destructive at worst. To get an idea of what top minds in science, health and research are thinking, we reached out to Scientific American's Board of Advisers to get their quick-fire reactions to the election outcome. The excerpts, some of them edited for length, appear below. The two largest nations in the English-speaking world have just suffered catastrophes at the hands of voters—in both cases the uneducated, anti-intellectual portion of voters. Science in both countries will be hit extremely hard: In the one case, by the xenophobically inspired severing of painstakingly built-up relationships with European partners; in the other case by the election of an unqualified, narcissistic, misogynistic sick joke as president. In neither case is the disaster going to be short-lived: in America because of the nonretirement rule of the Supreme Court; in Britain because Brexit is irreversible. There are top scientists in America and Britain—talented, creative people, desperate to escape the redneck bigotry of their home countries. Dear New Zealand, you are a deeply civilized small nation, with a low population in a pair of beautiful, spacious islands. You care about climate change, the future of the planet and other scientifically important issues. Why not write to all the Nobel Prize winners in Britain and America, write to the Fields medalists, Kyoto and Crafoord Prize and International Cosmos Prize winners, the Fellows of the Royal Society, the elite scientists in the National Academy of Sciences, the Fellows of the British Academy and similar bodies in America. Offer them citizenship. The contribution that creative intellectuals can make to the prosperity and cultural life of a nation is out of all proportion to their numbers. You could make New Zealand the Athens of the modern world. Yes, dear New Zealand, I know it’s an unrealistic, surreal pipe dream. But on the day after U.S. election day, in the year of Brexit, the distinction between the surreal and the awfulness of the real seems to merge in a bad trip from which a pipe dream is the only refuge. President-elect Trump's upset election caught many by surprise. We have not heard very much from him or his colleagues on his views on science and basic research, so I can only say that I hope that he recognizes the long-term value of basic research investment and will support the agencies of the U.S. government that support and pursue it, including the National Science Foundation. Like many, I was caught off guard by these election results. It is the will of the U.S. people, and given the polarity of the power, we can anticipate a number of significant and long-lasting changes. I do think that given the reality of today’s world and the checks and balances built into America, that exactly how these changes will play out is to be determined. I anticipate that many will be surprised by what can be done, and what cannot be done within government. I personally was born into poverty, and everything I have accomplished I did on my own. The best way to maximize professional success and rewards is to work hard; to maximize society is to be charitable; to maximize equality is to be ethical; to maximize peace is to be peaceful. I see myself taking more personal responsibility for the welfare of others close to me, and continue to be the best possible scientist, for what we are and what we will be is largely governed by the scientific discoveries that we apply to move humanity forward. —Harold “Skip” Garner, Executive director and professor, Primary Care Research Network and the Center for Bioinformatics and Genetics, Edward Via College of Osteopathic Medicine A smaller than projected voter turnout (approximately seven million Democrats and two million Republicans less than the 2012 election) was likely the cause of the outcome. Unexpected outcomes are part of scientific life and we are experts at learning from them. —Michael Gazzaniga, director, Sage Center for the Study of the Mind, University of California, Santa Barbara Fundamental research, dealing with climate change and the environment, nuclear weapons treaties, international relations, women’s rights, health and welfare, and more generally, public policy based on empirical reality, all have been dealt a blow. The president-elect has expressed disinterest or disdain for the results of scientific analyses relevant for public policy, and the vice president–elect has been an open enemy of science. It remains to be seen how this will play out, but a Republican congress seems unlikely to put many checks on this. First, I think that the forecasting capability of the media and others involved in studying elections and the interaction of the social sciences is flawed. That's clear. Regardless, this is a strong country, a strong democracy with great intellectual capacity and good will, with a deep sense of human rights and social justice shared among the people. I think at the end of the day the American people, as a whole, will provide a good balance of judgment. I think the issue of American international competitiveness in science, technology and arts research will continue to be a centerpiece of policy considerations going forward. Importantly, a number of Supreme Court justices will likely be appointed during the next administration, and with one party governing all aspects of the government—the legislative, judicial and executive—the influence on the judicial system and future development of a progressive social policy is of concern. America's prominence and international influence is largely based on the prestige and trust the U.S. enjoys, in part a result of the last century’s contributions to advancing science, medicine, technology and the pursuit of social justice. Our position as trusted members of the global community must be maintained and improved if we are to positively impact global development for the benefit of our own citizens as well as those of the world. —Robert E. Palazzo, dean, University of Alabama at Birmingham College of Arts and Sciences At this moment, November 9, 2016, I am sick in heart and spirit, bereft of even a shred of optimism. All the ideals of the enlightenment on which our country was founded, all the principles of reason and open-mindedness that undergird the practice of science that we so fervently cherish, and to which we can rightfully attribute our progress in improving the welfare of humankind, have been effectively and thoroughly repudiated. The significance of the result of the election—that those opposing these beliefs will now either control or greatly influence every branch of the U.S. government—cannot be overemphasized. In such a moment it’s natural to search the past for lessons. All successful civilizations throughout history have ultimately perished. Further, the evolution of our country's democracy is following an ancient script: the seeds of Trump's philosophical victory can be found in the very multicultural, multi-viewpoint, open-armed inclusiveness of the democratic ideal America has pursued since its beginnings. In his article in New York Magazine, Andrew Sullivan finds in Plato's Republic, written 2,400 years ago, the view that a “rainbow-flag polity” is the most inherently unstable, and that “tyranny is probably established out of no other regime than democracy.” It does indeed make you wonder if last night wasn’t inevitable. My deepest worry is that this transition really could signal the end of the American Republic and the light it tried for 240 years, at least on paper, to shine on all the world. What it means for the practice of science in this country, the rights of women and minorities, the future of our planet’s health, the survival of all the creatures with whom we share the Earth and for our relationships with other nations, I have no stomach to predict. But it does very much seem right now that the winning faction of the U.S. populace has decided that the Earth really is flat, and that will be the guiding principle for governance from this moment on. What is there to say? It's especially scary that there won't be separation of powers. It's also shocking (if the numbers are accurate) the percentage of women (and men) who voted for Trump. And of course science, climate, you name it ... you have to wonder. The one “plus” from this result is that reducing poverty may move higher on the agenda of the right as well as the left. But it should scare us Europeans into developing stronger and better coordinated pan-European policies to offer countervailing power to the U.S. —Martin Rees, Astronomer Royal and emeritus professor of cosmology and astrophysics, Institute of Astronomy, University of Cambridge This administration may be the least science- and science education–friendly one in generations. One possible nominee for the education department, Ben Carson, is a young-Earth creationist. Vice President[–elect] Pence has supported antievolution legislation in Indiana and has even pronounced evolution as unscientific on the floor of the House of Representatives. At the National Center for Science Education, we found that creationists are emboldened to act locally and at the state level when the “bully pulpit” of the presidency favors them—even if the federal government has little or no role in determining local curricula. Nominees for Energy [the Department of Energy], EPA [U.S. Environmental Protection Agency], NIH [National Institutes of Health], NSF (National Science Foundation] and other agencies are likely to be equally problematic and, of course, many members of the administration have declared their rejection of climate change. Should they and their appointees act upon that belief, agreements made with China and other nations by the current administration are at risk—which means that the future of the planet is at risk. Science and science education did not come out ahead in this election. Science was sidelined during the presidential campaign and we will have to wait to see the science policy of the new administration with an open mind. —Terry Sejnowski, professor and laboratory head of Computational Neurobiology Laboratory, Salk Institute for Biological Studies When it appeared Trump would win, the Dow plunged 800 points in after-hours trading, and pundits predicted [Wednesday] would be the worst economic collapse since 9/11 and the 2008 meltdown. As I write this, the Dow is up 265 points, the NASDAQ up 43 points. Predictions are hard to make, especially about the future, particularly in elections and economics. With that caveat I predict: Markets will be fine and economic growth will continue steady and may even improve one half to 1 percent in 2017. No wall will be built on the Mexican border (and Canadians will not build a wall blocking us!). We will not change our nuclear policies, we will not adopt “no first use” policy (as Obama did not either), and we will go another four years without using nuclear weapons. North Korea ... oh who the hell knows what that wingnut will do, but very likely nothing will change and eventually the country will go out of business with their failing economy, and North and South Korea will reunite just like East and West Germany did. Putin will hesitate to challenge NATO or take further territory in eastern Europe. ISIS will be completely eradicated before the end of 2017, but global terrorism will not be, as no president or government can reduce it to zero, but it will continue to fail as a means of bringing about political change. Tensions in the Middle East will continue as they have since I was in college and voted for the first time in 1972. Some things never change. Stay calm everyone. We have a strong republic that will continue growing stronger. We have lots of checks and balances in place to prevent any extreme actions taken by anyone, and as Pres. Obama has been reiterating this past year to those pessimists who think things are bad and getting worse, this is and will continue to be the best time there has ever been to be alive. Advancement of science transcends partisan boundaries and is fundamental for human health, and is a bedrock for U.S. technological advances and the economy. Hopefully, this will continue under any new administration. Although there is a rise in nationalism around the world, I think it is important that the international openness of science, its collaborations and its benefits be maintained for the benefit of all. The main questions are whether Trump/Pence will 1) support science research as a core to the economic engine and American competitiveness and 2) use science outcomes to inform policymaking. The rhetoric on the campaign trail implies “no” on both counts, but the desire to make good on campaign promises to promote our economic interests implies that they should. —Michael E. Webber, co-director, Clean Energy Incubator, and associate professor, Department of Mechanical Engineering, University of Texas at Austin It took the U.S. two decades to go from climate obstructionist to climate leader, and one ugly season to throw it away. Now we will see if we are truly a nation of laws and due process, or as weak as we tend to characterize some dictatorships. I am embarrassed for my generation and am having trouble facing a younger generation that have very basic questions about our selfishness. If there is a “silver lining” it is that we are a nation of strong institutions and now we shall see, are our ideals up to the task? My state of California—hardly popular to the Trump voters—offers a hopeful perspective. The problem today is that the U.S. has truly “hit its stride” on climate, and, while also far from perfect, was progressing. Now, advocates of sustainability and intra- and inter-national equity and partnership must re-tool, but without any buffer or luxury of time. Above all, this new strategy and route to integrate and partner must evolve fast, and must find common ground with an electorate infused with the sad anger and pessimism that led to the Trump victory. What California—and Morocco, Kenya, Denmark, Bangladesh, The Vatican, Germany, Nicaragua, and others—offer are imperfect but very real examples that show that our energy and material system can actually evolve much faster than previously thought. It takes steadily evolving technology. But more important is the development of a coherent plan. What we have just done is to steal from our children's future—and personally from my two dear daughters. This article has been updated to include comment from Daniel Kammen. ​

News Article | December 13, 2016

LA JOLLA, CA - December 13, 2016 - Diet composition around the time of pregnancy may influence whether offspring become obese, according to a new study using animal models at The Scripps Research Institute (TSRI). "Your diet itself matters, not just whether you are gaining excess weight or developing gestational diabetes," said TSRI Associate Professor Eric Zorrilla, who led the study in collaboration with Tim R. Nagy of the University of Alabama at Birmingham and Barry E. Levin of the Veterans Affairs (VA) Medical Center of East Orange, New Jersey, and Rutgers University. In fact, the researchers found that giving females a typical American, or Western, diet appeared to set the next generation up for lifelong obesity issues. This work was published recently in the American Journal of Physiology and featured in APSselect, a collection of the best research papers from all journals published by the American Physiological Society. It's Not Just about Weight The researchers made this discovery by studying two lines of rats, one selectively bred to be obesity-resistant to a high-fat diet and one bred to be unusually vulnerable. Rats from each group were fed either a diet with the same overall fat, saturated fat, carbohydrate and protein levels as a typical Western diet, or a lower-fat, higher-grain control diet. The scientists found that female rats given a Western diet in the weeks leading up to pregnancy, during pregnancy and during nursing had offspring more prone to obesity at birth, during early adolescence and--many months later--through adulthood. This occurred even if the mothers themselves did not overeat and maintained a healthy weight, body fat and insulin status. Zorrilla said the results were surprising because, whereas previous studies had shown that overweight mothers were more likely to have overweight offspring, the new findings suggest that diet alone can make a difference independent of weight gain. The Western diet seemed to set in motion a metabolic "program" that lasted throughout the rat's life. Although these rats slimmed down during puberty and early adulthood, they still showed a lower basal metabolic rate (less energy expended at while rest) and higher food intake during that time, which led to a return of obesity in mid-adulthood. "What we found interesting was that you sometimes see the same thing in humans, when a kid goes through a growth spurt," said study first author Jen Frihauf, who recently completed her PhD through the University of California, San Diego, while working in the Zorrilla lab at TSRI. The researchers also spotted an interesting difference in the effects of the Western diet between the obesity-vulnerable and obesity-resistant lines: in females, the diet impaired the reproduction of the obesity vulnerable lines. Significantly fewer of females were able to reproduce, and those that did reproduce had fewer offspring. "This wasn't the focus of the study, but it supports the idea that a Western diet promotes infertility in mothers vulnerable to diet-induced obesity," said Zorrilla. The researchers also identified elevated levels of several molecules, such as insulin and hormones called leptin and adiponectin, starting at birth in both the Western diet and genetically vulnerable offspring. This hormone profile may serve as an early biomarker for detecting obesity risk. The Takeaway for Moms: Better Nutrition Research is ongoing into which aspects of a Western diet trigger these effects--and the molecular changes in the offspring responsible for them. Zorrilla said the findings should raise awareness of the importance of a healthy pre- and post-natal diet. For example, doctors may want to discuss nutrition with all women who are pregnant or are planning to become pregnant, not just those already overweight. "Doctors often use weight gain as a hallmark of a healthy pregnancy," said Frihauf. "But we realized there was something going on in utero that wasn't detectable in the mother's weight." Frihauf added that few pregnant women, even in the United States, eat a high-fat, high-sugar diet all day, every day. "We're not trying to tell pregnant women not to occasionally splurge on a piece of cake," she said. Studies have also shown that paternal diet, through "epigenetic" mechanisms that control how genes are expressed, can affect obesity risk in offspring, added Zorrilla, so nutritional information may be valuable for potential fathers as well. In addition to Zorrilla, Nagy, Levin and Frihauf, the study, "Maternal Western Diet Increases Adiposity Even in Male Offspring of Obesity-Resistant Rat Dams: Early Endocrine Risk Markers," was authored by Éva M. Fekete, previous of TSRI and now at The University of Wisconsin-Madison. This study was supported by the National Institutes of Health (grants R01DK-070118, R01DK-30066, R01DK-076896, F31DA026708-01A2, R21DK-077616, P30DK-056336 and P30DK-079626) and the Research Service of the VA. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .

As reported in JNCCN, a recent study from McGill University shows that while opioid use increases during treatment in older patients with breast cancer, most do not continue use into survivorship; however, use of anxiolytics and antidepressants remains high in survivors FORT WASHINGTON, PA--(Marketwired - November 21, 2016) - A new McGill University study published in the November issue of JNCCN - Journal of the National Comprehensive Cancer Network found that most patients with breast cancer aged 65 and older use psychotropic and opioid medications during active treatment and often in the first year of survivorship, despite this population's vulnerability to adverse events. According to the authors, this study highlights the need for a multidimensional approach to distress and anxiety that includes comprehensive psychological intervention. The study, "Psychotropic and Opioid Medication Use in Older Patients with Breast Cancer across the Care Trajectory: A Population-Based Cohort Study," is available free-of-charge until February 28, 2017 on According to principle investigator, Ari Meguerditchian, MD, MSc, FRCS, Assistant Professor in the Departments of Surgery and Oncology, and member of the Clinical and Health Informatics Research Group at McGill University, "Women over 65 represent the fastest growing segment of breast cancer survivors. The fact that so many of them need mediations for anxiety, depression, and distress even after active cancer care highlights the fact that we know so little about the specific needs of these patients." The researchers followed more than 19,500 women, 65 years or older, diagnosed with incident, non-metastatic breast cancer in Quebec, Canada, and analyzed the use of anxiolytics, antidepressants, antipsychotics, and opioids from precancer baseline through active care and into first-year survivorship. The most prescribed drugs within the population were anxiolytics and antidepressants. Although the percentage of patients on opioids and antipsychotics was lower than the other drugs, with 16.2 percent of patients using antipsychotics and 25 percent using opioids, the authors noted a marked increase in use of opioids and antipsychotics-4.5- and 7-fold, respectively-from baseline to active care. More than 50 percent of women studied used anxiolytics during care-an increase from 36 percent at baseline-and the vast majority of those women (44.4 percent) continued use of the medication into first-year survivorship. Moreover, use of antidepressants among the cohort was 22.4 percent, with 22.3 percent continuing use into survivorship. Dr. Meguerditchian further noted, "Chronic use of these drugs is related to an increased risk of adverse events among these women, notably medication-related falls and injuries. Many studies suggest that this segment of the population is over-medicated." Conversely, the authors saw a notable drop-off in use of antipsychotics and opioids in first-year survivorship. This is likely due, at least in part, to the fact that antipsychotics and opioids are used to treat physical side effects of treatment, such as extreme nausea and pain, which decrease dramatically after treatment. Anxiolytics and antidepressants, on the other hand, are generally prescribed to combat the psychological aspects of diagnosis and treatment such as distress and anxiety, which have an extended effect on the patient. "Our findings raise important questions about the lasting psychological impact of cancer, such as uncertainty of recurrence, family hardships, etc. Are we supporting our older patients as they move to survivorship? How can we best address their needs?" said Dr. Meguerditchian. According to Crystal Denlinger, MD, FACP, Chief, GI Medical Oncology, and Associate Professor in the Department of Hematology/Oncology at Fox Chase Cancer Center, "This study represents an important overview of high-risk medication use in a vulnerable population, namely older breast cancer survivors. The fact that women increase their use of psychotropic and opioid medications during treatment is not surprising due to the current treatment of nonmetastatic breast cancer (ie, surgery and cytotoxic chemotherapy), but the trend toward continued use into survivorship warrants further evaluation as to cause. Given the current campaign to curb opioid abuse in the general population, understanding the reasons for use of these medications and development of better interventions to address underlying causes is critical to ensuring the best outcomes for this, and potentially other, patient populations." About JNCCN - Journal of the National Comprehensive Cancer Network More than 23,000 oncologists and other cancer care professionals across the United States read JNCCN-Journal of the National Comprehensive Cancer Network. This peer-reviewed, indexed medical journal provides the latest information about best clinical practices, health services research, and translational medicine. JNCCN features updates on the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), review articles elaborating on guidelines recommendations, health services research, and case reports highlighting molecular insights in patient care. JNCCN is published by Harborside Press. Visit To inquire if you are eligible for a FREE subscription to JNCCN, visit About the National Comprehensive Cancer Network The National Comprehensive Cancer Network® (NCCN®), a not-for-profit alliance of 27 of the world's leading cancer centers devoted to patient care, research, and education, is dedicated to improving the quality, effectiveness, and efficiency of cancer care so that patients can live better lives. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The NCCN Member Institutions are: Fred & Pamela Buffett Cancer Center, Omaha, NE; Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; City of Hope Comprehensive Cancer Center, Los Angeles, CA; Dana-Farber/Brigham and Women's Cancer Center | Massachusetts General Hospital Cancer Center, Boston, MA; Duke Cancer Institute, Durham, NC; Fox Chase Cancer Center, Philadelphia, PA; Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, WA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Mayo Clinic Cancer Center, Phoenix/Scottsdale, AZ, Jacksonville, FL, and Rochester, MN; Memorial Sloan Kettering Cancer Center, New York, NY; Moffitt Cancer Center, Tampa, FL; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, Columbus, OH; Roswell Park Cancer Institute, Buffalo, NY; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center, Memphis, TN; Stanford Cancer Institute, Stanford, CA; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; UC San Diego Moores Cancer Center, La Jolla, CA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of Colorado Cancer Center, Aurora, CO; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; Vanderbilt-Ingram Cancer Center, Nashville, TN; and Yale Cancer Center/Smilow Cancer Hospital, New Haven, CT. 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As published in JNCCN, a recent project out of Canada shows that programs identifying stress and distress in patients with cancer increase health care professionals' confidence and awareness of patient-centeredness; outcomes are influenced by site-based navigators and practice size FORT WASHINGTON, PA--(Marketwired - November 01, 2016) - As many as 60 percent of patients with cancer report distress following a cancer diagnosis, and this stress can have significant impacts on patients' well-being, resulting in psychosocial problems, physical side effects, and dissatisfaction with their health care. To examine the impact of distress on patients and health care professionals (HCPs), Linda Watson, PhD, RN, CancerControl Alberta, Alberta Health Services, led the implementation of screening for distress (SFD) as a new standard of care across 17 provincial cancer care sites. More than 250 HCPs across cancer care facilities in Alberta, Canada, participated in educational sessions and adopted this standard of practice. Dr. Watson and Dr. Rie Tamagawa, a senior researcher in provincial practices, found that HCPs who participated in this educational program and utilized SFD routinely reported improved confidence in detecting patient distress and increased awareness of the importance of a patient-centered approach to care. The study, "The Effects of a Provincial-Wide Implementation of Screening for Distress on Health Care Professionals' Confidence and Understanding of Patient-Centered Care in Oncology", is published in the October issue of JNCCN - Journal of the National Comprehensive Cancer Network. Complimentary access to the article is available until December 15, 2016 at "Distress can be caused by a variety of issues, concerns, or symptoms, but how distress is experienced and what underlies a person's distress is unique to each person and changes over time. The SFD helps clinicians identify distressed patients and their issues, concerns, or symptoms driving their distress. This project has demonstrated that through clinical review and targeted response to the patient priority issue, improved clinical outcomes and patient experiences can be achieved," said Dr. Watson. For Dr. Watson's quality improvement project, the SFD intervention was implemented as a standard of care at all cancer care facilities in Alberta over a 10-month period. HCPs at all sites completed educational sessions prior to implementation of this new practice. HCPs also completed surveys before and after implementation. Results of the project illustrated a significant increase in participants' confidence in identifying, assessing, and managing distress, as well as their awareness of person-centered care principles following the implementation. HCPs at smaller community cancer centers reported greater person-centered awareness as compared to HCPs at larger tertiary sites throughout the study. HCPs at those smaller sites identified more benefits from the SFD intervention relative to HCPs at the larger sites. This variance, Dr. Tamagawa reports, is likely because smaller, more remote cancer centers have patient navigation as part of their model of care and physicians are treating multiple tumor types. These are likely to contribute to personable patient-provider relationships. The benefits of the SFD was more salient for HCPs taking care of multiple tumor types, suggesting that such intervention is well adopted by physicians who practice as generalist model of care. On the other hand, physicians from larger centers tend to be single-tumor specialists at hospitals that do not employ patient navigation programs -- these participants reported lower awareness in person-centeredness in general, and the SFD intervention potentially posed an additional workload. Prior to adequate SFD training and with less time for patient relationship-building, physicians often lack confidence in their ability to identify and treat patient distress in a timely manner. The study highlighted that SFD intervention can help build this confidence and awareness of person-centered care delivery regardless of the types of care facilities. In Alberta, Dr. Watson shared, "We have found that utilizing a SFD tool that spans the physical, emotional, social, spiritual, practical, and informational domains has been helpful as it reflects the whole patient experience. It has been our experience that using a tool that helps the patient to specify their particular area of concern facilitates meaningful interventions." "Patient distress has received little attention from clinicians, but can have a large impact on patient quality of life. As such, screening for distress will become increasingly important in clinical practices, so information on its implementation is useful for practitioners," said Jimmie C. Holland, MD, Wayne R. Chapman Chair in Psychiatric Oncology, Memorial Sloan Kettering Cancer Center, and Chair of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Panel for Distress Management. Complimentary access to the article is available until December 15, 2016 at About JNCCN - Journal of the National Comprehensive Cancer Network More than 24,000 oncologists and other cancer care professionals across the United States read JNCCN-Journal of the National Comprehensive Cancer Network. This peer-reviewed, indexed medical journal provides the latest information about best clinical practices, health services research, and translational medicine. JNCCN features updates on the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), review articles elaborating on guidelines recommendations, health services research, and case reports highlighting molecular insights in patient care. JNCCN is published by Harborside Press. Visit To inquire if you are eligible for a FREE subscription to JNCCN, visit About the National Comprehensive Cancer Network The National Comprehensive Cancer Network® (NCCN®), a not-for-profit alliance of 27 of the world's leading cancer centers devoted to patient care, research, and education, is dedicated to improving the quality, effectiveness, and efficiency of cancer care so that patients can live better lives. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The NCCN Member Institutions are: Fred & Pamela Buffett Cancer Center, Omaha, NE; Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; City of Hope Comprehensive Cancer Center, Los Angeles, CA; Dana-Farber/Brigham and Women's Cancer Center | Massachusetts General Hospital Cancer Center, Boston, MA; Duke Cancer Institute, Durham, NC; Fox Chase Cancer Center, Philadelphia, PA; Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, WA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Mayo Clinic Cancer Center, Phoenix/Scottsdale, AZ, Jacksonville, FL, and Rochester, MN; Memorial Sloan Kettering Cancer Center, New York, NY; Moffitt Cancer Center, Tampa, FL; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, Columbus, OH; Roswell Park Cancer Institute, Buffalo, NY; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center, Memphis, TN; Stanford Cancer Institute, Stanford, CA; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; UC San Diego Moores Cancer Center, La Jolla, CA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of Colorado Cancer Center, Aurora, CO; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; Vanderbilt-Ingram Cancer Center, Nashville, TN; and Yale Cancer Center/Smilow Cancer Hospital, New Haven, CT. The following files are available for download:

News Article | December 15, 2016

Why does a mole rat live 30 years but a mouse only three? With $1.5 billion in the bank, Google’s anti-aging spinout Calico is rich enough to find out. At a laboratory outside San Francisco, money from the founders of Google maintains a large number of naked mole rats. The hairless rodents require exacting, expensive conditions to thrive: they live in coöperative colonies like ants, led by a queen rat. But what is truly extraordinary is that they can live about 30 years—10 times longer than a mouse. The rodents belong to Calico Labs, short for the California Life Company. In 2013, the cofounder of Google, Larry Page, announced that his company would form Calico and fund it lavishly to carry out a long-term project, trying to sort out the causes of aging and do something about them. The company’s mission: to build a Bell Labs of aging research. It hoped to extend the human life span by coming up with a breakthrough as important, and as useful to humanity, as the transistor has been. There are reasons to think aging can be slowed in fundamental ways. Among Calico’s first hires was Cynthia Kenyon, now its vice president of aging research, who 20 years ago showed that altering a single DNA letter in a laboratory roundworm made it live six weeks instead of three. There is something hair-raising about Kenyon’s videos of old, should-be-dead worms wriggling vigorously across a petri dish. So Google’s founders created an academic-­biotech hybrid they call an R&D company to follow up on such clues, providing nearly unlimited funding to a group of top researchers. Calico has hired stars like artificial-intelligence specialist Daphne Koller. With equal contributions from Google’s parent company, Alphabet, and the drug company AbbVie, it has $1.5 billion in the bank. But despite the hype around its launch—Time magazine asked, “Can Google Solve Death?”—Calico has remained a riddle, a super-­secretive company that three years in hasn’t published anything of note, rebuffs journalists, and asks visiting scientists to sign nondisclosure agreements. In fact, Calico has other researchers “a little miffed,” says Felipe Sierra, director of the division of aging biology at the National Institute on Aging. “We want to know what they are doing so we can focus on other things, or collaborate. They are a research company, so what are they researching?” MIT Technology Review has learned that Calico is, in effect, an elite university research group housed within a corporate bunker, doing mostly basic science. It has more than 100 employees and has assembled a Noah’s ark of yeast, worms, and more exotic creatures like the naked mole rats, which are kept at the Buck Institute for Research on Aging, about 30 miles from Calico’s South San Francisco headquarters. What’s different about a mole rat? That is the sort of costly, open-ended question Calico can afford to ask. And then there’s the seven-year study Calico is financing that will follow 1,000 mice from birth to death to search for biomarkers of aging. Right now, there’s no proven test for a person’s “biological” age; finding one would be scientifically useful and possibly lucrative. “They don’t open the kimono much,” says Brian ­Kennedy, a Buck Institute scientist who interacts with Calico. “I think they believe we need a broader grasp on the biology of aging. They recognize it can’t possibly be ­simple.” The Google founders aren’t the first billionaires to decide that aging is the “most fundamental unsolved problem in biology,” as Calico’s press releases put it. Larry Ellison, the cofounder of Oracle, gave away $335 million to scientists studying aging before redirecting his foundation’s grants toward eliminating polio in 2013. The investor Peter Thiel has also donated to the anti-aging cause, and there’s even a $500,000 Palo Alto Longevity Prize to anyone who can radically extend the life of a mammal. The difficulty is that scientists don’t know enough about why animals age. Calico’s Hal Barron, hired from Roche to lead its drug development efforts, told the National Academy of Medicine in 2015 that there would be no short-term payoff. “We believe you have to take a very long view,” he said, “and not rush into the clinic until you really know what you are doing.” A hundred and seventy five years ago most people died from infections, not from old age. Thanks to vaccines, better nutrition, and all-around improvements in public health and medicine, life expectancy at birth in wealthy nations has doubled from 40 to around 80 years, an average gain of 2.5 years per decade. But now that we live longer, we have traded up to a new set of killers that are harder to beat: cancer, heart disease, stroke, and dementia. For all these diseases, aging is the single biggest risk factor. An 80-year-old is 40 times as likely to die from cancer as someone middle-aged. The risk for Alzheimer’s rises by 600 times. But what if it were possible to postpone all these deaths by treating aging itself? “I think we have failed in our effort to attack chronic disease when we attack them one by one,” Sierra says. “And the reason is that they have one major risk factor, which is the biology of aging.” Overarching theory David Botstein is Calico’s chief scientific officer. He is 74, with a grizzled shadow of beard reaching up from his collar. In November, I found him at a lecture hall at MIT, where he offered a rare window onto experiments under way at Calico. Botstein, a well-known Princeton geneticist whom Calico recruited out of near retirement, was in town to celebrate the birthday of a successful former student, now a sexagenarian. “The pleasure is coming to see old friends,” he says. “The not-so-­pleasure is if these guys are 60, what am I?” In his lecture, Botstein described several technologies—four, in fact—that Calico has for isolating old yeast cells from the daughter cells that bud off them. (One project has the institutional-sounding name Mother Enrichment Program.) These old cells are tracked and subjected to a comprehensive analysis of which genes are turned up or turned down, a technique that is Botstein’s specialty. Botstein told me Calico is exactly what Google intended: a Bell Labs working on fundamental questions, with the best people, the best technology, and the most money. “Instead of ideas chasing the money, they have given us a very handsome sum of money and want us to do something about the fact that we know so little about aging,” says Botstein. “It’s a hard problem; it’s an unmet need; it is exactly what Larry Page thinks it is. It’s something to which no one is really in a position to pay enough attention, until maybe us.” Botstein says no one is going to live forever—that would be perpetuum mobile, or perpetual motion, which defies the laws of thermodynamics. But he says ­Kenyon’s experiments on worms are a “perfectly good” example of the life span’s malleability. So is the fact that rats fed near-starvation diets can live as much as 45 percent longer. The studies Botstein described in yeast cells concerned a fundamental trade-off that cells make. In good times, with lots of food, they grow fast. Under stresses like heat, starvation, or aging, they hunker down to survive, grow slowly, and often live longer than normal. “Shields down or shields up,” as ­Botstein puts it. Such trade-offs are handled through biochemical pathways that respond to nutrients; one is called TOR, and another involves insulin. These pathways have already been well explored by other scientists, but Calico is revisiting them using the newest technology. “A lot of our effort is in trying to verify or falsify some of the theories,” Botstein says, adding that he thinks much of the science on aging so far is best consumed “with a dose of sodium chloride.” Some molecules touted as youth elixirs that can act through such pathways—like resveratrol, a compound in red wine—never lived up to their early hype. According to Botstein, aging research is still seeking a truly big insight. Imagine, he says, doctors fighting infections without knowing what a virus is. Or think back to cancer research in the 1960s. There were plenty of theories then. But it was the discovery of oncogenes—specific genes able to turn cells cancerous—that provided scientists with their first real understanding of what causes tumors. “What we are looking for, I think above everything else, is to be able to contribute to a transformation like that,” he says. “We’d like to find ways for people to have a longer and healthier life. But by how much, and how—well, I don’t know.” Botstein says a “best case” scenario is that Calico will have something profound to offer the world in 10 years. That time line explains why the company declines media interviews. “There will be nothing to say for a very long time, except for some incremental scientific things. That is the problem.” To get there, Calico is ratcheting up its expertise and skills. Botstein says it has demonstrated it could decode a human genome from scratch, without peeking at the official genome map. That’s a difficult task requiring significant investment in computing and know-how. But Calico got the right answer, so it’s confident of accurately mapping the genome of the naked mole rat—a job he says is half done. And a precise understanding of how the mole rat’s genes are organized may hold clues to its long life. “A lot of what we do is technology development,” says Botstein. “It’s not interesting, and it’s not supposed to be interesting. It’s how you put one foot in front of the other so you don’t trip on yourself.” Big disappointment To some, Calico’s heavy bet on basic biology is a wrong turn. The company is “my biggest disappointment right now,” says Aubrey de Grey, an influential proponent of attempts to intervene in the aging process and chief science officer of the SENS Research Foundation, a charity an hour’s drive from Calico that promotes rejuvenation technology. It is being driven, he complains, “by the assumption that we still do not understand aging well enough to have a chance to develop therapies.” Indeed, some competitors are far more aggressive in pursuing interventions than Calico is. “They are very committed to these fundamental mechanisms, and bless them for doing that. But we are committed to putting drugs into the clinic and we might do it first,” says Nathaniel David, president and cofounder of Unity Biotechnology. This year, Jeff Bezos joined investors who put $127 million behind Unity, a startup in San Francisco that’s developing drugs to zap older, “senescent” cells that have stopped dividing. These cells are suspected of releasing cocktails of unhelpful old-age signals, and by killing them, Unity’s drugs could act to rejuvenate tissues. The company plans to start with a modestly ambitious test in arthritic knees. De Grey’s SENS Foundation, for its part, has funded Oisin Biotechnologies, a startup aiming to rid bodies of senescent cells using gene therapy. Other scientists say it is time to begin large human studies of “geroprotectors”—drugs that could decelerate aging altogether. One such effort is being spearheaded by gerontologists at Albert ­Einstein College of Medicine, in New York. The medication they hope to test, metformin, is used to treat diabetes. It cropped up as an anti-aging prospect after scientists reviewing medical records found that people taking it not only were much less likely to die than other diabetics but died at a 15 percent lower rate than all other patients. Metformin lowers blood sugar levels, one clue it may have something in common with a low-calorie diet. But getting a study off the ground hasn’t been easy. To convince the U.S. Food and Drug Administration to approve the trial, doctors decided to measure metformin’s effectiveness in preventing three separate diseases: heart attack, dementia, and cancer. “They do not recognize aging as a disease, so what we have done is choose diseases of aging with minimal overlap in their causes,” says Steven Austad, a biologist at the University of Alabama at Birmingham and scientific director of the American Federation for Aging Research, which has endorsed the metformin study. “If it simultaneously delays them, that would indicate a slowed rate of aging.” The trial is designed to involve 6,000 people and would last six years. It would be the first large study of a geroprotector in volunteers, according to S. Jay ­Olshansky, a public health researcher at the University of Illinois at Chicago. He therefore rates the trial as significant no matter whether it flops or, as he hopes, sets off “the most groundbreaking events in public health in this century.” The only problem is who will pay for the trial, expected to cost $65 million. The chance the NIH will pay for the entire study is “remote,” says Austad, and since metformin is an old drug not covered by patents, drug companies aren’t interested either. Instead, Olshansky and Austad are going with what’s become a favorite play in research on aging: they plan to hit up billionaires for the money. Funding a groundbreaking advance, Olshansky promises potential investors, could be their “ticket to immortality.” Playing the long game The science of aging is easy to disregard, given its long historical connection to alchemy, quacks, and vitamin pushers. Even now, many scientists do their utmost to avoid the phrase “anti-aging research”—sounding as it does like a promise made on a tin of skin cream. “There are a lot of charlatans in aging research. I should be careful in what I say, but it attracts pretty quirky people,” says Gary Churchill, a mouse geneticist at the Jackson Laboratory, in Bar Harbor, Maine. It can’t help, either, that the people who bankroll this science keep saying they hope to live forever. Bill Maris, the former head of Google Ventures who hatched the idea for Calico, has said he thinks it is possible people could live “for 500 years.” That’s pretty unlikely. In that sense, Calico’s creation of a strictly controlled research fortress staffed by recognized leaders makes sense as an inoculum against hokum, maybe even from the people paying the bills. “They are playing the long game,” Churchill says. “It’s a good strategy. It could leave them positioned a decade from now to have something.” Churchill’s work with Calico gives some idea of how long it could take. In April 2016, the company agreed to pay for a large experiment at Jackson Labs to search for a “biomarker” of aging—a molecule, which they hope to find in the blood, whose quantity or properties change with “biological” age, not just with the hands on the clock. Such a diagnostic could be extraordinarily useful, and profitable. But searching for such a marker is not cheap. At Jackson Labs, Churchill’s team plans to follow 1,000 mice, drawing blood and placing them inside special cages where food and water intake can be precisely measured and the rodents’ droppings and urine collected. Half the mice will be on a calorie-restricted diet to extend their lives—necessary to confirm whether a biomarker really tags them as biologically younger. The experiment will generate millions of readings—for levels of growth hormones and glucose, among other things. Churchill wouldn’t say how much Calico is paying, but simply feeding that many mice could cost $3 million. “We’ve mapped it out, planned it. It’s immense, and we’d never be able to do this with the NIH,” he says. “The willingness to invest in the long term is the most appealing thing about Calico.” Churchill says the ideal biomarker of aging would actually estimate how much longer you have left to live, barring any unforeseen events. And the readout would change if you took a drug or adopted a diet that somehow rescheduled your appointment with the Grim Reaper. With a test like that, companies could see whether their drugs actually influenced aging without waiting many, many years for the answer. Finding such a blood marker would be the kind of breakthrough that aging research so desperately needs—and that Calico was created to discover.

News Article | October 27, 2016

Newly published data from the Long-Term Oxygen Treatment Trial (LOTT) show that oxygen use is not beneficial for most people with chronic obstructive pulmonary disease (COPD) and moderately low levels of blood oxygen. It neither boosted their survival nor reduced hospital admissions for study participants. Previous research showed that long-term oxygen treatment improves survival in those with COPD and severely low levels of blood oxygen. However, a long-standing question remained whether a different group of COPD patients--those with moderately low levels of blood oxygen--also benefit. The study was funded by the National Heart, Lung, and Blood Institute (NHLBI)--a part of the National Institutes of Health--and the Centers for Medicare & Medicaid Services. The study, the largest of its kind to evaluate the effectiveness of home oxygen in this group of patients, is published in the current online issue of the New England Journal of Medicine. The 738 patients enrolled in this study had COPD and moderately low levels of blood oxygen (in contrast to severely low blood oxygen levels) at rest or during exercise. In the current study, patients with moderately low levels of blood oxygen are defined as those with a blood oxygen saturation (SpO2) between 89 and 93 percent at rest (moderate resting hypoxemia), or a SpO2 below 90 percent during the 6-minute walk test. Patients with severely low blood oxygen levels are defined as those with a SpO2 equal to or less than 88 percent at rest. This latter group was excluded from the LOTT study because prior studies showed that they benefit from long-term oxygen treatment. Blood oxygen saturation or SpO2 refers to the percentage of oxygen-saturated hemoglobin relative to total hemoglobin in the blood and is measured through a pulse oximeter. A pulse oximeter is a special probe that indirectly measures oxygen levels in the blood, often by attachment to the finger. "These results provide insight into a long-standing question about oxygen use in patients with COPD and moderately low levels of blood oxygen. For the most part, this treatment did not improve or prolong life in study participants," said James P. Kiley, Ph.D., director of NHLBI's Division of Lung Diseases. "The findings also underscore the need for new treatments for COPD." Researchers say patients with any form of COPD should check with their doctors before making changes in their treatment plans. "We want to make it clear that LOTT was not designed to assess individual responses to oxygen treatment and that individual responses can vary. Each COPD patient should discuss their own personal situation with their healthcare provider," said William C. Bailey, M.D., Professor Emeritus at the University of Alabama at Birmingham School of Medicine, and study Chair. COPD, the third leading cause of death in the United States, is a progressive lung disease triggered primarily by cigarette smoking, although up to 20 percent of patients with COPD never smoked. Symptoms include shortness of breath, chronic coughing, and wheezing. The disease also causes low oxygen levels in the blood. About 15 million people have been diagnosed with COPD in the United States and another 10 million may be undiagnosed. For decades, oxygen has been one of the main treatment tools for patients with COPD and low oxygen levels. It involves the use of metal tank cylinders containing oxygen or concentrators that extract oxygen from air; both systems deliver the gas through a nasal tube or mask. The LOTT study is a randomized clinical trial to determine whether oxygen use could help COPD patients with moderately low levels of blood oxygen. The seven-year study, which included patients from 42 medical centers throughout the United States, began in 2009 and was completed in 2015. In the study, half of the patients received long-term oxygen and the other half did not. The researchers found no significant differences between the two groups based on how long patients survived, and the amount of time leading to their first hospitalization. They also found no differences in other important benchmarks, such as the rates at which the patients were hospitalized or experienced worsening of COPD symptoms. Nor did researchers find statistically significant differences between the groups in quality of life, levels of depression or anxiety, lung function, or ability to walk for short periods. Although no cure for COPD exists, there are a number of treatment options, including the use of bronchodilators and steroids, as well as pulmonary rehabilitation, surgery, and lung transplantation. Researchers worldwide are also studying new medications and exploring other approaches such as gene therapy. They continue to emphasize the importance of not smoking tobacco in preventing or slowing the progression of COPD. What Are the Signs and Symptoms of COPD? http://www. Medicare coverage for home use of oxygen: https:/ About the National Heart, Lung, and Blood Institute (NHLBI): Part of the National Institutes of Health, the National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis,and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at http://www. . About the National Institutes of Health (NIH): NIH, the nation's medical research agency,includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www. .

News Article | November 10, 2016

Immunotherapy has revolutionized treatment options in oncology, neurology, and many infectious diseases and now there is fresh hope that the same method could be used to treat or functionally cure HIV, according to two related studies from Perelman School of Medicine at the University of Pennsylvania, the University of Alabama at Birmingham (UAB), and the National Institutes of Health (NIH). Published online today in the New England Journal of Medicine, the research offers new insights into how immunotherapy could be used to develop a functional cure for HIV and eliminate the need for people living with the virus to take a daily regimen of medications. The study, which examined chronically HIV-infected participants, found that injections of one broadly neutralizing HIV antibody (bNAb), known as VRC01, were safe, generated high levels of the antibody, and modestly delayed the time of HIV viral rebound compared to historical controls. However, suppression did not surpass 8 weeks in the majority of participants. By demonstrating that HIV-specific antibodies could be successfully administered as long-acting agents to suppress or even kill HIV-infected cells, this method is a first step toward the ultimate goal of durable suppression of HIV in the absence of ART. "I would compare these findings to early days of HIV treatment research in the late 1980s," said Pablo Tebas, MD, a senior author of the study and director of the AIDS Clinical Trials Unit at Penn. "In this study, we looked at one antibody, but we think it may take combinations of more potent antibodies to successfully control the virus." In the early years of HIV drug development, the first antiretroviral medicines were used as single agents to treat people living with HIV. The virus quickly developed resistance and rebounded in the blood. As additional antiretroviral drugs were introduced to target various aspects of HIV, combination drugs led to more effective and prolonged viral suppression. Currently, most people living with HIV take a once-daily combination of antiretroviral therapy (ART), which prolongs life expectancy and improves overall health, but cannot completely eradicate the virus. Adherence to a daily HIV medication continues to be a challenge for many people living with HIV, especially in resource-limited settings. However, the vast majority of people living with HIV experience rapid rebound if ART is stopped or interrupted, making those people sicker and more likely to spread the virus to others. Through bNAb immunotherapy, people living with HIV could potentially receive an injection of antibodies or another immunological intervention that would suppress the virus. The injection would remove HIV from a person's blood and enable control of the virus without a daily ART regimen. "For the near future, it is unlikely that we will be able to fully eradicate HIV once a person has been infected. But a functional cure is a reasonable intermediate goal," Tebas said. A functional HIV cure means that while the virus would still exist in a person's body in extremely small amounts, virus replication would be durably suppressed, disease progression drastically slowed, and symptoms of infection stopped - all without the need for daily medications. "The goal of immunotherapy is to eliminate the need to take a pill every single day while simultaneously chipping away at the latent reservoir of virus-infected cells. However, we are still years away from that goal. And even if a person is able to be functionally cured of HIV, long-term follow-up will be essential to ensure that the virus doesn't return to high levels," Tebas said. The bNAb tested in this trial did not provide long-lasting virus control in participants. Investigators tested historical blood samples from trial participants that were stored at both Penn and UAB's Centers for AIDS Research (CFAR) in order to determine if there was pre-existing resistance to bNAb immunotherapy and reveal its limitations as a potential cure. They found that the trial participants with the shortest times of HIV suppression harbored viruses that were resistant to the bNAb. "We found that many trial participants had HIV that was resistant to the bNAb immunotherapy long before they entered the trial. This pre-existing resistance to HIV-targeting bNAbs was a barrier to effective immunotherapy here, and will continue to present challenges to HIV bNAb therapies moving forward," said Katharine Bar, MD, first author of the study and director of Viral and Molecular Core of the Penn Center for AIDS Research (CFAR). Bar notes that this study was a collaborative effort between several institutions. "The close collaboration between the Penn and UAB CFARs with the AIDS Clinical Trials Group (ACTG) enabled us to characterize the pre-existing resistance and identify it as a key barrier to developing bNAb immunotherapy as an HIV cure. Continued collaboration between CFARs and the ACTG will be instrumental as we continue to move this research forward." Future trials that are now in development will test whether combinations of more potent bNAbs can provide durable virus suppression and potentially reduce the size of the persistent reservoir. The research team for the Penn/UAB study also included James A. Hoxie and Mark Bardsley of Penn's Perelman School of Medicine; Nancy Tustin of the Children's Hospital of Philadelphia; and Edgar T. Overton of the University of Alabama at Birmingham. Findings from both studies, which were funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH (U01AI068636), appear in the Nov. 24 print issue of the New England Journal of Medicine.

News Article | November 10, 2016

Immunotherapy has revolutionized treatment options in oncology, neurology, and many infectious diseases and now there is fresh hope that the same method could be used to treat or even functionally cure HIV, according to two related studies from Perelman School of Medicine at the University of Pennsylvania, the University of Alabama at Birmingham (UAB), and the National Institutes of Health (NIH). Published online in the New England Journal of Medicine, the research offers new insights into how immunotherapy could be used to develop a functional cure for HIV and eliminate the need for people living with the virus to take a daily regimen of medications. The study, which examined chronically HIV-infected participants, found that injections of one broadly neutralizing HIV antibody (bNAb), known as VRC01, were safe, generated high levels of the antibody, and modestly delayed the time of HIV viral rebound compared to historical controls. However, suppression did not surpass 8 weeks in the majority of participants. By demonstrating that HIV-specific antibodies could be successfully administered as long-acting agents to suppress or even kill HIV-infected cells, this method is a first step toward the ultimate goal of durable suppression of HIV in the absence of ART. "I would compare these findings to early days of HIV treatment research in the late 1980s," said Pablo Tebas, MD, a senior author of the study and director of the AIDS Clinical Trials Unit at Penn. "In this study, we looked at one antibody, but we think it may take combinations of more potent antibodies to successfully control the virus." In the early years of HIV drug development, the first antiretroviral medicines were used as single agents to treat people living with HIV. The virus quickly developed resistance and rebounded in the blood. As additional antiretroviral drugs were introduced to target various aspects of HIV, combination drugs led to more effective and prolonged viral suppression. Currently, most people living with HIV take a once-daily combination of antiretroviral therapy (ART), which prolongs life expectancy and improves overall health, but cannot completely eradicate the virus. Adherence to a daily HIV medication continues to be a challenge for many people living with HIV, especially in resource-limited settings. However, the vast majority of people living with HIV experience rapid rebound if ART is stopped or interrupted, making those people sicker and more likely to spread the virus to others. Through bNAb immunotherapy, people living with HIV could potentially receive an injection of antibodies or another immunological intervention that would suppress the virus. The injection would remove HIV from a person's blood and enable control of the virus without a daily ART regimen. "For the near future, it is unlikely that we will be able to fully eradicate HIV once a person has been infected. But a functional cure is a reasonable intermediate goal," Tebas said. A functional HIV cure means that while the virus would still exist in a person's body in extremely small amounts, virus replication would be durably suppressed, disease progression drastically slowed, and symptoms of infection stopped -- all without the need for daily medications. "The goal of immunotherapy is to eliminate the need to take a pill every single day while simultaneously chipping away at the latent reservoir of virus-infected cells. However, we are still years away from that goal. And even if a person is able to be functionally cured of HIV, long-term follow-up will be essential to ensure that the virus doesn't return to high levels," Tebas said. The bNAb tested in this trial did not provide long-lasting virus control in participants. Investigators tested historical blood samples from trial participants that were stored at both Penn and UAB's Centers for AIDS Research (CFAR) in order to determine if there was pre-existing resistance to bNAb immunotherapy and reveal its limitations as a potential cure. They found that the trial participants with the shortest times of HIV suppression harbored viruses that were resistant to the bNAb. "We found that many trial participants had HIV that was resistant to the bNAb immunotherapy long before they entered the trial. This pre-existing resistance to HIV-targeting bNAbs was a barrier to effective immunotherapy here, and will continue to present challenges to HIV bNAb therapies moving forward," said Katharine Bar, MD, first author of the study and director of Viral and Molecular Core of the Penn Center for AIDS Research (CFAR). Bar notes that this study was a collaborative effort between several institutions. "The close collaboration between the Penn and UAB CFARs with the AIDS Clinical Trials Group (ACTG) enabled us to characterize the pre-existing resistance and identify it as a key barrier to developing bNAb immunotherapy as an HIV cure. Continued collaboration between CFARs and the ACTG will be instrumental as we continue to move this research forward." Future trials that are now in development will test whether combinations of more potent bNAbs can provide durable virus suppression and potentially reduce the size of the persistent reservoir.

News Article | November 10, 2016

The administration of VRC01, a potent and broadly neutralizing HIV-specific antibody, is safe, is well-tolerated, generated high plasma concentrations and modestly delayed the return of HIV viral rebound in HIV-1 infected individuals after they stopped receiving antiretroviral therapy, according to a study published in the New England Journal of Medicine by researchers at the University of Alabama at Birmingham, the National Institutes of Health and the University of Pennsylvania Penn Center for AIDS Research. "Monoclonal antibodies are revolutionizing our approach to many diseases in oncology and rheumatolgy," said Edgar T. Overton, M.D., co-director of the UAB Alabama Vaccine Research Clinic. "In this study, we tested whether a broadly neutralizing antibody against HIV could stop replicating virus. While a single antibody only modestly delayed viral rebound, we demonstrated that this strategy can be improved and potentially lead us to effective therapeutic HIV vaccine strategies. We are excited to pursue this approach in our ongoing efforts to end the HIV epidemic." Two clinical trials were conducted under the National Institutes of Health and the AIDS Clinical Trials Group in 24 HIV-1 infected individuals undergoing analytical treatment interruption, which measures changes in immunological response. The open-label trial in which both the researchers and participants were aware of the administered treatment showed that markers of of HIV virus replication were surpressed for at least four weeks after the VRC01 was administered and HIV treatment was stopped, but all participants failed to maintain durable viral suppression in the absence of antiretroviral therapy. Further studies looking at more potent antibodies and combinations of bNAbs like VRC01 will likely be required to achieve sustained remission of the virus in HIV-1 infected individuals after halting ART. "We are excited to be on the forefront of the global efforts to end AIDS," Overton said.

News Article | November 22, 2016

PITTSBURGH, Nov. 22, 2016 - People living with serious illness who receive palliative care have better quality of life and fewer symptoms than those who don't receive palliative care, according to a new study by researchers at the University of Pittsburgh School of Medicine. Published today in the Journal of the American Medical Association (JAMA), the study is the first meta-analysis of the effect of palliative care as it relates to patients' quality of life, symptom burden and survival. Palliative care is health care for people living with serious illness and focuses on providing patients with relief from their symptoms, pain and stress of a serious illness, whatever the diagnosis. Palliative care can either refer to a specific service that is provided by physicians and nurses who have received specialized training in this type of care, or an overall approach to care for patients with serious illness, which would include palliative care when provided by a specialist or by a non-palliative care specialist (like an oncologist or a primary care physician). This study took a broad approach and looked at the philosophy of palliative care. The researchers conducted a systematic review of 43 trials of palliative care interventions, including 12,731 adults with serious illness and 2,479 of their family caregivers. Researchers also performed a meta-analysis to investigate the overall association between palliative care and three outcomes often linked with palliative care--patients' quality of life, symptom burden and survival. A meta-analysis is the statistical process of combining the results of multiple trials, which gives researchers an overall effect for interventions. "Taken all together, this is a very compelling message," said Dio Kavalieratos, Ph.D., assistant professor of medicine in the Section of Palliative Care and Medical Ethics in Pitt's Division of General Internal Medicine and lead author of the study. "People's quality of life and symptoms improved; their satisfaction with their health care improved--all during what is likely one of the most difficult periods of their lives." Researchers also determined that palliative care was associated with improvements in advance care planning, patient and caregiver satisfaction with care, and lower health care utilization. There was mixed evidence of improvement with site of death, patient mood, health care expenditures, and caregiver quality of life, mood or burden. "Historically, palliative care has overwhelmingly focused on individuals with cancer, but anyone with a serious illness, be it cancer, heart failure, multiple sclerosis or cystic fibrosis, deserves high-quality, individualized care that focuses on reducing their suffering and improving their quality of life," Kavalieratos said. "We need to find ways of integrating palliative care concepts in patients' usual care experiences so it isn't a luxury, but a standard part of health care for those living with serious illness." Over the past five years, much attention has been paid to the idea that palliative care improves patients' survival, Kavalieratos added. Although some individual studies had shown that, the association didn't play out when multiple studies were pooled together in the meta-analysis. "As a field, we need to develop new methods of studying how palliative care impacts people with serious illness and their caregivers," Kavalieratos added. "These methods should not burden patients and caregivers who participate in this research, but also need to be rigorous enough to capture what's going on at this critical point in people's lives." The researchers received funding support from several agencies, including the Agency for Healthcare Research and Quality (K12HS022989); National Heart, Lung, and Blood Institute (K01HL13346); National Institutes of Health (KL2TR000146); and National Institute of Nursing Research (K99NR015903). Those involved in the study included 10 staff members from Pitt, as well as others from the University of North Carolina at Chapel Hill, University of Alabama at Birmingham, University of Toronto and Virginia Tech. About the University of Pittsburgh School of Medicine As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support. Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region's economy. For more information about the School of Medicine, see http://www. .

News Article | February 21, 2017

PHILADELPHIA -- It is commonly known that testosterone levels decrease as men age, but until last year, little was known about the effects of testosterone treatment in older men with low testosterone. Today, in a group of papers published in the Journal of the American Medical Association (JAMA) and JAMA Internal Medicine, researchers found that testosterone treatment improved bone density and anemia for men over 65 with unequivocally low testosterone. However, testosterone treatment did not improve cognitive function, and it increased the amount of plaque buildup in participants' coronary arteries. A team of researchers from the Perelman School of Medicine at the University of Pennsylvania, and twelve other medical centers in the United States, in partnership with the National Institute on Aging, conducted The Testosterone Trials (TTrials), a coordinated group of seven trials, which studied the effects of testosterone treatment for one year as compared to placebo for men 65 and older with low testosterone. The first paper, which reported that testosterone treatment improved sexual function and mood, was published in February 2016. Today's publications of the Bone, Anemia, Cognition and Cardiovascular Trials conclude the primary results of the study. Researchers found that testosterone treatment improved bone density and estimated bone strength, as determined by quantitative computed tomography (CT). The treatment also increased hemoglobin concentrations, corrected the anemia of men who had no other identifiable cause of anemia and corrected the anemia of men who had an identifiable cause, such as iron deficiency. While these conclusions proved testosterone to be beneficial to the participants, testosterone treatment did not improve memory or any other measure of cognitive function. "The paper reporting the results of the first three trials published last year was the first to show there were advantages to giving testosterone treatment to older men with low testosterone levels, and the bone and anemia trial results further support a benefit," said the principal investigator Peter J. Snyder, MD, a professor of Medicine in the Division of Endocrinology, Diabetes and Metabolism. "However, the increase of plaque buildup in the coronary artery shows that this treatment may also have some risk" In the cardiovascular trial, researchers assessed coronary artery plaque buildup by CT angiography. That assessment showed more plaque buildup in men treated with testosterone than in men treated with placebo. Nonetheless, in all 788 men in the TTrials, the number of major adverse cardiovascular events was similar in the men treated with testosterone as in the men treated with placebo. However, Snyder added, "treating 788 men for one year is far too few to draw conclusions about the clinical significance of the increase in coronary artery plaque volume and the cardiovascular risk of testosterone treatment." The TTrials are now the largest trials to examine the efficacy of testosterone treatment in men 65 and older whose testosterone levels are low due seemingly to age alone. TTrials researchers screened 51,085 men to find 790 who qualified with a sufficiently low testosterone level and who met other criteria. The men enrolled were randomized into two groups: one to take a daily testosterone gel and the other a daily placebo gel, for one year. Efficacy was then evaluated at months three, six, nine and 12. "Final decisions about testosterone treatment for older men will depend on balancing the results from these seven TTrials with the results from a much larger and longer term trial designed to assess cardiovascular and prostate risk in the future," said Snyder. The TTrials were conducted at 12 additional medical centers across the country including Albert Einstein College of Medicine, Baylor College of Medicine, Brigham and Women's Hospital, Harbor-UCLA Medical Center, University of Alabama at Birmingham, Northwestern University Feinberg School of Medicine, Puget Sound Health Care System, University of California at San Diego School of Medicine, University of Florida School of Medicine, University of Minnesota School of Medicine, University of Pittsburgh School of Public Health, and Yale School of Medicine. The Testosterone Trials were supported by a grant from the National Institute on Aging (NIA), National Institutes of Health (U01 AG030644). The TTrials were also supplemented by funds from the National Heart, Lung and Blood Institute, National Institute of Neurological Diseases and Stroke, and National Institute of Child Health and Human Development. AbbVie (formerly Solvay and Abbott Laboratories) also provided funding, AndroGel, and placebo gel. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.

News Article | December 21, 2016

Mountain Measurement, Inc. has established the NCLEX® Program Reports Panel of Nursing Experts. This group of nursing education leaders will provide their expertise to the makers of the NCLEX® Program Reports and the nursing education community at large. Portland, OR, December 21, 2016 --( “We are excited to collaborate with some of the finest leaders in nursing program evaluation.” - Brian Bontempo, PhD, Principal Consultant, Mountain Measurement. “We anticipate that this collaboration will improve the quality of training provided to NCLEX® Program Reports subscribers, which will help nursing program administrators and faculty across the US and Canada to improve their program’s curriculum and instruction.” The short-term goals of the NCLEX® Program Reports Panel of Experts include developing new NCLEX® Program Reports Professional Development Seminars and publishing journal articles about how to use the NCLEX® Program Reports. Long-term goals include modifying the content, format and style of the information provided in the NCLEX® Program Reports. “These goals speak to the heart of program evaluation standards, fundamental concepts of evaluation quality, and the critical importance and meaningful use of what is learned from program evaluation.” - Karen J. Saewert, PhD, RN, CPHQ, CNE, ANEF, Member, Panel of Experts. Panel members include: Roseann Colosimo, PhD, MSN, RN from the University of Nevada Las Vegas. Education: Saint John’s College (BS), Catholic University of America (MS), and The Ohio State University (PhD) Cathy Dearman, PhD, RN from the University of West Florida. Education: Mississippi University for Women (BS), University of Alabama at Birmingham (MS), University of Mississippi (PhD) Judith M. Pelletier, MSN, RN, CNE from the Upper Cape Cod Regional Technical School. Education: University of Lowell (BSN) and Salem State University (MSN) Karen J. Saewert, PhD, RN, CPHQ, CNE, ANEF from Arizona State University. Education: Arizona State University (BSN and MS) and University of Arizona (PhD) About the NCLEX® Program Reports The NCLEX® Program Reports are downloadable PDF files that describe the performance of a nursing program’s graduates on the NCLEX® Examination. Subscribing nursing education programs use the Reports to track program growth, reform curriculum or modify instructional methodology. The Reports are produced by Mountain Measurement, Inc. on behalf of Pearson VUE and the National Council of State Boards of Nursing. About Mountain Measurement, Inc. Mountain Measurement is a leader in psychometrics, analytics, data visualization and reporting. Mountain Measurement primarily serves the K–12 and licensure and certification sectors of the testing industry. Media contact: Brian Bontempo, Ph.D. Mountain Measurement, Inc. +1 503 284-1288 Portland, OR, December 21, 2016 --( )-- Mountain Measurement, Inc. has established the NCLEX® Program Reports Panel of Nursing Experts. This group of nursing education leaders will provide their expertise to the makers of the NCLEX® Program Reports and the nursing education community at large.“We are excited to collaborate with some of the finest leaders in nursing program evaluation.” - Brian Bontempo, PhD, Principal Consultant, Mountain Measurement. “We anticipate that this collaboration will improve the quality of training provided to NCLEX® Program Reports subscribers, which will help nursing program administrators and faculty across the US and Canada to improve their program’s curriculum and instruction.”The short-term goals of the NCLEX® Program Reports Panel of Experts include developing new NCLEX® Program Reports Professional Development Seminars and publishing journal articles about how to use the NCLEX® Program Reports. Long-term goals include modifying the content, format and style of the information provided in the NCLEX® Program Reports. “These goals speak to the heart of program evaluation standards, fundamental concepts of evaluation quality, and the critical importance and meaningful use of what is learned from program evaluation.” - Karen J. Saewert, PhD, RN, CPHQ, CNE, ANEF, Member, Panel of Experts.Panel members include:Roseann Colosimo, PhD, MSN, RN from the University of Nevada Las Vegas. Education: Saint John’s College (BS), Catholic University of America (MS), and The Ohio State University (PhD)Cathy Dearman, PhD, RN from the University of West Florida. Education: Mississippi University for Women (BS), University of Alabama at Birmingham (MS), University of Mississippi (PhD)Judith M. Pelletier, MSN, RN, CNE from the Upper Cape Cod Regional Technical School. Education: University of Lowell (BSN) and Salem State University (MSN)Karen J. Saewert, PhD, RN, CPHQ, CNE, ANEF from Arizona State University. Education: Arizona State University (BSN and MS) and University of Arizona (PhD)About the NCLEX® Program ReportsThe NCLEX® Program Reports are downloadable PDF files that describe the performance of a nursing program’s graduates on the NCLEX® Examination. Subscribing nursing education programs use the Reports to track program growth, reform curriculum or modify instructional methodology. The Reports are produced by Mountain Measurement, Inc. on behalf of Pearson VUE and the National Council of State Boards of Nursing.About Mountain Measurement, Inc.Mountain Measurement is a leader in psychometrics, analytics, data visualization and reporting. Mountain Measurement primarily serves the K–12 and licensure and certification sectors of the testing industry.Media contact:Brian Bontempo, Ph.D. Mountain Measurement, Inc. +1 503 284-1288 Click here to view the list of recent Press Releases from Mountain Measurement

Sanders P.W.,University of Alabama at Birmingham | Sanders P.W.,Medical Center
Journal of the American Society of Nephrology | Year: 2012

The tubular nephron is responsible for reabsorption and catabolism of filtered low molecular weight proteins that include Ig free light chains. In the setting of a plasma cell dyscrasia, significant amounts of free light chains, now monoclonal proteins, present to the tubular nephron for disposal. The result may be clinical renal dysfunction in the form of AKI, progressive CKD, and end-stage kidney disease. Here, I review the mechanisms involved in these processes that result in tubular injury, including proximal tubulopathy and cast nephropathy. Copyright © 2012 by the American Society of Nephrology.

Duffield J.S.,University of Washington | Lupher M.,Promedior | Thannickal V.J.,University of Alabama at Birmingham | Wynn T.A.,National Institute of Allergy and Infectious Diseases
Annual Review of Pathology: Mechanisms of Disease | Year: 2013

Myofibroblasts accumulate in the spaces between organ structures and produce extracellular matrix (ECM) proteins, including collagen I. They are the primary "effector" cells in tissue remodeling and fibrosis. Previously, leukocyte progenitors termed fibrocytes and myofibroblasts generated from epithelial cells through epithelial-to-mesenchymal transition (EMT) were considered the primary sources of ECM-producing myofibroblasts in injured tissues. However, genetic fate mapping experiments suggest that mesenchyme-derived cells, known as resident fibroblasts, and pericytes are the primary precursors of scar-forming myofibroblasts, whereas epithelial cells, endothelial cells, and myeloid leukocytes contribute to fibrogenesis predominantly by producing key fibrogenic cytokines and by promoting cell-to-cell communication. Numerous cytokines derived from T cells, macrophages, and other myeloid cell populations are important drivers of myofibroblast differentiation. Monocyte-derived cell populations are key regulators of the fibrotic process: They act as a brake on the processes driving fibrogenesis, and they dismantle and degrade established fibrosis. We discuss the origins, modes of activation, and fate of myofibroblasts in various important fibrotic diseases and describe how manipulation of macrophage activation could help ameliorate fibrosis. © 2013 by Annual Reviews. All rights reserved.

Kharkar S.,University of Alabama at Birmingham | Knowlton R.,University of California at San Francisco
Epilepsy and Behavior | Year: 2015

Magnetoencephalography (MEG) is an important tool in the presurgical evaluation of patients with medically refractory epilepsy. The appropriate utilization and interpretation of MEG studies can increase the proportion of patients who may be able to further pursue surgical evaluation, refine surgical planning, and potentially increase the probability of seizure freedom after surgery. The aim of this paper is to provide the reader with a comprehensive but accessible guide to MEG, with particular emphasis on acquiring a working knowledge of MEG analysis, identifying patient groups that are most likely to benefit, and clarifying the limitations of this technology. © 2014 Elsevier Inc.

Adams P.C.,University of Western Ontario | Barton J.C.,Southern Iron Disorders Center | Barton J.C.,University of Alabama at Birmingham
Blood | Year: 2010

Hemochromatosis is a common genetic disorder in which iron may progressively accumulate in the liver, heart, and other organs. The primary goal of therapy is iron depletion to normalize body iron stores and to prevent or decrease organ dysfunction. The primary therapy to normalize iron stores is phlebotomy. In this opinion article, we discuss the indications for and monitoring of phlebotomy therapy to achieve iron depletion, maintenance therapy, dietary and pharmacologic maneuvers that could reduce iron absorption, and the role of voluntary blood donation. © 2010 by The American Society of Hematology.

Gadde K.M.,Duke University | Allison D.B.,University of Alabama at Birmingham | Ryan D.H.,Pennington Biomedical Research Center | Peterson C.A.,VIVUS | And 3 more authors.
The Lancet | Year: 2011

Obesity is associated with a reduction in life expectancy and an increase in mortality from cardiovascular diseases, cancer, and other causes. We therefore assessed the efficacy and safety of two doses of phentermine plus topiramate controlled-release combination as an adjunct to diet and lifestyle modification for weight loss and metabolic risk reduction in individuals who were overweight and obese, with two or more risk factors. In this 56-week phase 3 trial, we randomly assigned overweight or obese adults (aged 18-70 years), with a body-mass index of 27-45 kg/m2 and two or more comorbidities (hypertension, dyslipidaemia, diabetes or prediabetes, or abdominal obesity) to placebo, once-daily phentermine 7·5 mg plus topiramate 46·0 mg, or once-daily phentermine 15·0 mg plus topiramate 92·0 mg in a 2:1:2 ratio in 93 centres in the USA. Drugs were administered orally. Patients were randomly assigned by use of a computer-generated algorithm that was implemented through an interactive voice response system, and were stratified by sex and diabetic status. Investigators, patients, and study sponsors were masked to treatment. Primary endpoints were the percentage change in bodyweight and the proportion of patients achieving at least 5 weight loss. Analysis was by intention to treat. This study is registered with Clinical, number NCT00553787. Of 2487 patients, 994 were assigned to placebo, 498 to phentermine 7·5 mg plus topiramate 46·0 mg, and 995 to phentermine 15·0 mg plus topiramate 92·0 mg; 979, 488, and 981 patients, respectively, were analysed. At 56 weeks, change in bodyweight was -1·4 kg (least-squares mean -1·2, 95 CI -1·8 to -0·7), -8·1 kg (-7·8, -8·5 to -7·1; p<0·0001), and -10·2 kg (-9·8, -10·4 to -9·3; p<0·0001) in the patients assigned to placebo, phentermine 7·5 mg plus topiramate 46·0 mg, and phentermine 15·0 mg plus topiramate 92·0 mg, respectively. 204 (21) patients achieved at least 5 weight loss with placebo, 303 (62; odds ratio 6·3, 95 CI 4·9 to 8·0; p<0·0001) with phentermine 7·5 mg plus topiramate 46·0 mg, and 687 (70; 9·0, 7·3 to 11·1; p<0·0001) with phentermine 15·0 mg plus topiramate 92·0 mg; for ≥10 weight loss, the corresponding numbers were 72 (7), 182 (37; 7·6, 5·6 to 10·2; p<0·0001), and 467 (48; 11·7, 8·9 to 15·4; p<0·0001). The most common adverse events were dry mouth (24 [2], 67 [13], and 207 [21] in the groups assigned to placebo, phentermine 7·5 mg plus topiramate 46·0 mg, and phentermine 15·0 mg plus topiramate 92·0 mg, respectively), paraesthesia (20 [2], 68 [14], and 204 [21], respectively), constipation (59 [6], 75 [15], and 173 [17], respectively), insomnia (47 [5], 29 [6], and 102 [10], respectively), dizziness (31 [3], 36 [7], 99 [10], respectively), and dysgeusia (11 [1], 37 [7], and 103 [10], respectively). 38 (4) patients assigned to placebo, 19 (4) to phentermine 7·5 mg plus topiramate 46·0 mg, and 73 (7) to phentermine 15·0 mg plus topiramate 92·0 mg had depression-related adverse events; and 28 (3), 24 (5), and 77 (8), respectively, had anxiety-related adverse events. The combination of phentermine and topiramate, with office-based lifestyle interventions, might be a valuable treatment for obesity that can be provided by family doctors. Vivus. © 2011 Elsevier Ltd.

Papp J.R.,National Center for HIV AIDS | Schachter J.,University of California at San Francisco | Gaydos C.A.,Johns Hopkins University | Van Der Pol B.,University of Alabama at Birmingham
MMWR Recommendations and Reports | Year: 2014

This report updates CDC's 2002 recommendations regarding screening tests to detect Chlamydia trachomatis and Neisseria gonorrhoeae infections (CDC. Screening tests to detect Chlamydia trachomatis and Neisseria gonorrhoeae infections-2002. MMWR 2002;51[No. RR-15]) and provides new recommendations regarding optimal specimen types, the use of tests to detect rectal and oropharyngeal C. trachomatis and N. gonorrhoeae infections, and circumstances when supplemental testing is indicated.The recommendations in this report are intended for use by clinical laboratory directors, laboratory staff, clinicians, and disease control personnel who must choose among the multiple available tests, establish standard operating procedures for collecting and processing specimens, interpret test results for laboratory reporting, and counsel and treat patients. The performance of nucleic acid amplification tests (NAATs) with respect to overall sensitivity, specificity, and ease of specimen transport is better than that of any of the other tests available for the diagnosis of chlamydial and gonococcal infections. Laboratories should use NAATs to detect chlamydia and gonorrhea except in cases of child sexual assault involving boys and rectal and oropharyngeal infections in prepubescent girls and when evaluating a potential gonorrhea treatment failure, in which case culture and susceptibility testing might be required. NAATs that have been cleared by the Food and Drug Administration (FDA) for the detection of C. trachomatis and N. gonorrhoeae infections are recommended as screening or diagnostic tests because they have been evaluated in patients with and without symptoms. Maintaining the capability to culture for both N. gonorrhoeae and C. trachomatis in laboratories throughout the country is important because data are insufficient to recommend nonculture tests in cases of sexual assault in prepubescent boys and extragenital anatomic site exposure in prepubescent girls. N. gonorrhoeae culture is required to evaluate suspected cases of gonorrhea treatment failure and to monitor developing resistance to current treatment regimens. Chlamydia culture also should be maintained in some laboratories to monitor future changes in antibiotic susceptibility and to support surveillance and research activities such as detection of lymphogranuloma venereum or rare infections caused by variant or mutated C. trachomatis.

Lee J.,University of Alabama at Birmingham | Giordano S.,University of Alabama at Birmingham | Zhang J.,University of Alabama at Birmingham | Zhang J.,Birmingham Medical Center
Biochemical Journal | Year: 2012

Reactive oxygen and nitrogen species change cellular responses through diverse mechanisms that are now being defined. At low levels, they are signalling molecules, and at high levels, they damage organelles, particularly the mitochondria. Oxidative damage and the associated mitochondrial dysfunction may result in energy depletion, accumulation of cytotoxic mediators and cell death. Understanding the interface between stress adaptation and cell death then is important for understanding redox biology and disease pathogenesis. Recent studies have found that one major sensor of redox signalling at this switch in cellular responses is autophagy. Autophagic activities are mediated by a complex molecular machinery including more than 30 Atg (AuTophaGy-related) proteins and 50 lysosomal hydrolases. Autophagosomes form membrane structures, sequester damaged, oxidized or dysfunctional intracellular components and organelles, and direct them to the lysosomes for degradation. This autophagic process is the sole known mechanism for mitochondrial turnover. It has been speculated that dysfunction of autophagy may result in abnormal mitochondrial function and oxidative or nitrative stress. Emerging investigations have provided new understanding of how autophagy of mitochondria (also known as mitophagy) is controlled, and the impact of autophagic dysfunction on cellular oxidative stress. The present review highlights recent studies on redox signalling in the regulation of autophagy, in the context of the basic mechanisms of mitophagy. Furthermore, we discuss the impact of autophagy on mitochondrial function and accumulation of reactive species. This is particularly relevant to degenerative diseases in which oxidative stress occurs over time, and dysfunction in both the mitochondrial and autophagic pathways play a role. © 2011 The Author(s).

Bhatt S.P.,Birmingham Medical Center | Dransfield M.T.,University of Alabama at Birmingham
Translational Research | Year: 2013

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the lung associated with progressive airflow limitation and punctuated by episodes of acute exacerbation. There is growing recognition that the inflammatory state associated with COPD is not confined to the lungs but also involves the systemic circulation and can impact nonpulmonary organs. Epidemiologic and mechanistic studies indicate that COPD is associated with a high frequency of coronary artery disease, congestive heart failure and cardiac arrhythmias, independent of shared risk factors. Possible pathways include complex interrelationships between chronic low-grade systemic inflammation and oxidative stress as well as shared risk factors such as age, cigarette smoking, and environmental pollutants. In this review, we provide an overview of the epidemiologic data linking COPD with cardiovascular disease, comment on the interrelationships among COPD, inflammation, and cardiovascular disease, and highlight diagnostic and therapeutic challenges. © 2013 Mosby, Inc. All rights reserved.

Dodson M.,University of Alabama at Birmingham | Darley-Usmar V.,University of Alabama at Birmingham | Zhang J.,University of Alabama at Birmingham | Zhang J.,Birmingham Medical Center
Free Radical Biology and Medicine | Year: 2013

It has been established that the key metabolic pathways of glycolysis and oxidative phosphorylation are intimately related to redox biology through control of cell signaling. Under physiological conditions glucose metabolism is linked to control of the NADH/NAD redox couple, as well as providing the major reductant, NADPH, for thiol-dependent antioxidant defenses. Retrograde signaling from the mitochondrion to the nucleus or cytosol controls cell growth and differentiation. Under pathological conditions mitochondria are targets for reactive oxygen and nitrogen species and are critical in controlling apoptotic cell death. At the interface of these metabolic pathways, the autophagy-lysosomal pathway functions to maintain mitochondrial quality and generally serves an important cytoprotective function. In this review we will discuss the autophagic response to reactive oxygen and nitrogen species that are generated from perturbations of cellular glucose metabolism and bioenergetic function. © 2013 Elsevier Inc. All rights reserved.

Younes A.,University of Texas M. D. Anderson Cancer Center | Bartlett N.L.,Washington University in St. Louis | Leonard J.P.,Cornell University | Kennedy D.A.,Seattle Genetics | And 3 more authors.
New England Journal of Medicine | Year: 2010

BACKGROUND: Hodgkin's lymphoma and anaplastic large-cell lymphoma are the two most common tumors expressing CD30. Previous attempts to target the CD30 antigen with monoclonal-based therapies have shown minimal activity. To enhance the antitumor activity of CD30-directed therapy, the antitubulin agent monomethyl auristatin E (MMAE) was attached to a CD30-specific monoclonal antibody by an enzyme-cleavable linker, producing the antibody-drug conjugate brentuximab vedotin (SGN-35). METHODS: In this phase 1, open-label, multicenter dose-escalation study, we administered brentuximab vedotin (at a dose of 0.1 to 3.6 mg per kilogram of body weight) every 3 weeks to 45 patients with relapsed or refractory CD30-positive hematologic cancers, primarily Hodgkin's lymphoma and anaplastic large-cell lymphoma. Patients had received a median of three previous chemotherapy regimens (range, one to seven), and 73% had undergone autologous stem-cell transplantation. RESULTS: The maximum tolerated dose was 1.8 mg per kilogram, administered every 3 weeks. Objective responses, including 11 complete remissions, were observed in 17 patients. Of 12 patients who received the 1.8-mg-per-kilogram dose, 6 (50%) had an objective response. The median duration of response was at least 9.7 months. Tumor regression was observed in 36 of 42 patients who could be evaluated (86%). The most common adverse events were fatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheral neuropathy. CONCLUSIONS: Brentuximab vedotin induced durable objective responses and resulted in tumor regression for most patients with relapsed or refractory CD30-positive lymphomas in this phase 1 study. Treatment was associated primarily with grade 1 or 2 (mild-to-moderate) toxic effects. (Funded by Seattle Genetics; number, NCT00430846.) Copyright © 2010 Massachusetts Medical Societ.

Basu R.,University of Alabama at Birmingham | O'Quinn D.B.,University of Alabama at Birmingham | Silberger D.J.,University of Alabama at Birmingham | Schoeb T.R.,University of Alabama at Birmingham | And 4 more authors.
Immunity | Year: 2012

Interleukin-22 (IL-22) is central to host protection against bacterial infections at barrier sites. Both innate lymphoid cells (ILCs) and T cells produce IL-22. However, the specific contributions of CD4+ T cells and their developmental origins are unclear. We found that the enteric pathogen Citrobacter rodentium induced sequential waves of IL-22-producing ILCs and CD4+ T cells that were each critical to host defense during a primary infection. Whereas IL-22 production by ILCs was strictly IL-23 dependent, development of IL-22-producing CD4+ T cells occurred via an IL-6-dependent mechanism that was augmented by, but not dependent on, IL-23 and was dependent on both transcription factors T-bet and AhR. Transfer of CD4+ T cells differentiated with IL-6 in the absence of TGF-β (" Th22" cells) conferred complete protection of infected IL-22-deficient mice whereas transferred Th17 cells did not. These findings establish Th22 cells as an important component of mucosal antimicrobial host defense. © 2012 Elsevier Inc.

Nandakumar V.,University of Alabama at Birmingham | Vaid M.,University of Alabama at Birmingham | Katiyar S.K.,University of Alabama at Birmingham | Katiyar S.K.,Birmingham Medical Center
Carcinogenesis | Year: 2011

The anti-skin carcinogenic effects of green tea catechins have been studied extensively in vitro and in vivo models but the precise epigenetic molecular mechanisms are still unclear. Accumulating data suggest that dietary phytochemicals may alter cancer risk by modifications of epigenetic processes in the cells. The present study was designed to investigate whether tea catechins, particularly (-)-epigallocatechin-3-gallate (EGCG), would modify epigenetic events to regulate DNA methylation-silenced tumor suppressor genes in skin cancer cells. DNA methylation, histone modifications and tumor suppressor gene expressions were studied in detail using human epidermoid carcinoma A431 cells as an in vitro model after EGCG treatment using cytostaining, western blotting, dot blot analysis, real-time polymerase chain reaction and enzymatic activity assays. Our study shows that EGCG treatment decreased global DNA methylation levels in A431 cells in a dose-dependent manner. EGCG decreased the levels of 5-methylcytosine, DNA methyltransferase (DNMT) activity, messenger RNA (mRNA) and protein levels of DNMT1, DNMT3a and DNMT3b. EGCG decreased histone deacetylase activity and increased levels of acetylated lysine 9 and 14 on histone H3 (H3-Lys 9 and 14) and acetylated lysine 5, 12 and 16 on histone H4 but decreased levels of methylated H3-Lys 9. Additionally, EGCG treatment resulted in re-expression of the mRNA and proteins of silenced tumor suppressor genes, p16INK4a and Cip1/p21. Together, our study provides new insight into the epigenetic mechanism of action of EGCG that may contribute to the chemoprevention of skin cancer and may have important implications for epigenetic therapy. © The Author 2011. Published by Oxford University Press. All rights reserved.

Martinez F.J.,University of Michigan | Martinez F.J.,New York Medical College | De Andrade J.A.,University of Alabama at Birmingham | Anstrom K.J.,Duke Clinical Research Institute | And 2 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Acetylcysteine has been suggested as a beneficial treatment for idiopathic pulmonary fibrosis, although data from placebo-controlled studies are lacking. METHODS: In our initial double-blind, placebo-controlled trial, we randomly assigned patients who had idiopathic pulmonary fibrosis with mild-to-moderate impairment in pulmonary function to receive a three-drug regimen of prednisone, azathioprine, and acetylcysteine; acetylcysteine alone; or placebo. The study was interrupted owing to safety concerns associated with the three-drug regimen. The trial continued as a two-group study (acetylcysteine vs. placebo) without other changes; 133 and 131 patients were enrolled in the acetylcysteine and placebo groups, respectively. The primary outcome was the change in forced vital capacity (FVC) over a 60-week period. RESULTS: At 60 weeks, there was no significant difference in the change in FVC between the acetylcysteine group and the placebo group (-0.18 liters and -0.19 liters, respectively; P = 0.77). In addition, there were no significant differences between the acetylcysteine group and the placebo group in the rates of death (4.9% vs. 2.5%, P = 0.30 by the log-rank test) or acute exacerbation (2.3% in each group, P>0.99). CONCLUSIONS: As compared with placebo, acetylcysteine offered no significant benefit with respect to the preservation of FVC in patients with idiopathic pulmonary fibrosis with mild-to-moderate impairment in lung function. Copyright © 2014 Massachusetts Medical Society.

Singh S.,University of California at San Francisco | Bittner V.,University of Alabama at Birmingham
Current Atherosclerosis Reports | Year: 2015

Familial hypercholesterolemia is among the commonest inherited metabolic disorders and is characterized by severely elevated LDL cholesterol levels. Mutations in four genes have been noted in patients with familial hypercholesterolemia (FH): LDL receptor (most common), apolipoprotein B (Apo B), proprotein convertase subtilin/kexin 9 (PCSK9), and low-density lipoprotein receptor adaptor protein (LDLRAP). In most cases, inheritance is autosomal co-dominant with homozygotes having double the LDL cholesterol levels of heterozygotes. Autosomal recessive inheritance is rare. The prevalence of the heterozygous state has been estimated at 1 in 200 to 1 in 500 and of the homozygous state from 1 in 160,000 to 1 in 1,000, 000. Three formal diagnostic criteria have been proposed to diagnose FH in practice-MedPed, Simon Broome, and Dutch Lipid Clinic Network. The role of genetic testing and cascade screening among families is discussed in this review. © 2015, Springer Science+Business Media New York.

News Article | December 8, 2016

REDWOOD CITY, Calif.--(BUSINESS WIRE)--Dextera Surgical Inc. (Nasdaq:DXTR), manufacturer of the smallest-profile and most maneuverable articulating surgical stapling platform on the market for minimally invasive surgery, today announced the enrollment of the first U.S. patient in the MicroCutter Assisted Thoracic Surgery Hemostasis (MATCH) Registry, a prospective, open-label, multi-center registry enrolling up to 120 patients undergoing lung resections in which surgical stapling is required. The registry will evaluate the effectiveness of the MicroCutter 5/80 surgical stapler for hemostasis (stopping the flow of blood) and the procedure enabling aspects of the device in lobectomy or segmentectomy lung surgery procedures using a variety of minimally invasive techniques including video assisted thoracic surgery (VATS) and robotic assisted surgeries as well as in open surgery. Leading centers in the United States will be participating in the MATCH Registry, including the Mayo Clinic (Rochester, Minn.), where the first U.S. MATCH patient was enrolled. Additionally, ten patients have already been enrolled internationally at the James Cook University Hospital (Middlesbrough, UK). Other leading research institutions expected to participate in the MATCH Registry include University of Alabama at Birmingham, the University of Texas MD Anderson Cancer Center, and the Royal Infirmary in Edinburgh, Scotland, as well as several additional international sites. “The MATCH Registry will provide important clinical data regarding the hemostasis performance of the MicroCutter 5/80 while capturing video evidence of the ability of the device to navigate in tight spaces to enable less-invasive methods for treating patients undergoing lung surgery,” said David Rice, M.B., B.Ch., F.R.C.S.I., professor at the University of Texas MD Anderson Cancer Center, Houston. “We are proud to be working with these surgical pioneers at leading institutions to gather important clinical data on the MicroCutter 5/80 and its utility in thoracic surgery procedures,” said Julian Nikolchev, president and CEO, Dextera Surgical. The MicroCutter 5/80 Stapler is the world's first and only five-millimeter surgical stapler that articulates to 80 degrees in each direction. The MicroCutter 5/80 Stapler is manufactured and cleared for use in the United States for transection and resection in multiple open or minimally invasive urologic, thoracic and pediatric surgical procedures, as well as application for transection, resection and/or creation of anastomoses in the small and large intestine, and the transection of the appendix. The MicroCutter 30 White Reload has application in vascular tissue. Dextera Surgical (Nasdaq:DXTR) designs and manufactures proprietary stapling devices for minimally invasive surgical procedures. In the U.S., surgical staplers are routinely used in more than one million minimally invasive laparoscopic, video-assisted or robotic-assisted surgical procedures annually. Dextera Surgical also markets the only automated anastomosis devices for coronary artery bypass graft (CABG) surgery on the market today: the C-Port® Distal Anastomosis Systems and PAS-Port® Proximal Anastomosis System. These products, sold by Dextera Surgical under the Cardica brand name, have demonstrated long-term reliable clinical performance for more than a decade. The statements in this press release regarding expected actions of the MATCH Registry and the information it will provide are "forward-looking statements." There are a number of important factors that could cause actual results to differ materially from those indicated by these forward-looking statements, including those described in Dextera Surgical’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2016, under the caption “Risk Factors,” filed with the U.S. Securities and Exchange Commission on November 10, 2016. Dextera Surgical expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein. You are encouraged to read Dextera Surgical’s reports filed with the U.S. Securities and Exchange Commission, available at

Researchers at the University of Alabama at Birmingham came to that conclusion after being tasked with identifying the qualifying measure of endangerment for the species by the International Union for Conservation of Nature, or IUCN. Kemp's ridley turtles are currently classified as critically endangered on the IUCN's Red List of Threatened Species. The species was on the brink of extinction in the 1980s, but a Mexico-U.S. bi-national conservation program initiated in 1978 was able to reverse its decline. The decades of intense conservation efforts were evident by 2009, with the Kemp's ridley exhibiting an exponential recovery rate that was expected to continue for many years. However, an unanticipated downturn occurred in 2010 when the amount of nesting dropped significantly, and since that time, the species has not regained an upward trajectory to recovery. How many Kemp's ridley turtles should there be in the Gulf? Scientists and conservationists weren't sure; there was a lack of data between 1880, when the species was discovered, and the start of the conservation efforts in 1978. UAB's study, led by Thane Wibbels, Ph.D., a biology professor in the College of Arts and Sciences, and doctoral student Elizabeth Bevan, set out to answer that question through the evaluation of a historic film recorded in 1947 by Andres Herrera, a Mexican sportsman, on the Kemp's ridley's primary nesting beach in the western Gulf of Mexico near Rancho Nuevo, Mexico. The film captured a mass-nesting event known as an arribada, involving tens of thousands of nesting turtles on a single day in 1947. It would help provide a rare benchmark for evaluating the historic population size of a species prior to its becoming endangered, which is usually not available for endangered species. Uncovering the original riddle of the ridley Prior to the film, the location of the Kemp's ridley nesting grounds was a mystery. After hearing about a large mass nesting of sea turtles from locals, Herrera recognized the significance of such a unique biological phenomenon and became committed to documenting this unique event for society. During a two-year period, Herrera flew his own plane 33 times over the Gulf Coast north of Tampico, Mexico, conducting aerial surveys in search of the mass sea turtle nesting. In 1947, he finally uncovered the event, but his discovery would remain unknown to the scientific community for more than a dozen years. "At the time of the film's development, no one was able to connect the dots between the phenomenon of the mass nesting and that the nests belonged to the Kemp's ridley sea turtles," Wibbels said. "Herrera was a hobby enthusiast who wasn't aware of the pursuit in the scientific world to uncover this location. Meanwhile, Archie Carr, who was considered to be the world's leading sea turtles expert, had been searching for the nesting beaches for this species for decades." Carr searched for the Kemp's ridley nesting beaches in all of the usual nesting regions—Florida, the Caribbean and the northern Gulf of Mexico; but after 20 years, he had found nothing. "He had no logical explanation for the fact that this abundant turtle was seemingly not breeding or nesting," Bevan said. "Scientists began to wonder whether the Kemp's ridley could actually be a hybrid turtle." The dots were finally connected, and part of the mystery debunked, by Henry Hildebrand, Ph.D., from the University of Corpus Christi, who heard about the film and viewed it in 1961. Later that year, Hildebrand presented that film at the annual meeting of the American Society of Ichthyologists and Herpetologists, revealing the news to the scientific community for the first time. It was estimated by some who viewed the original black-and-white footage that there were more than 40,000 nesting Kemp's ridley sea turtles on the beach that day. Wibbels and Bevan's recent study reflects more conservative, but still remarkable, numbers. Wibbels and Bevan calculate that there were 26,000 sea turtles on a 1- to 2-mile stretch of beach on the day the film was taken. The results from UAB's study published this week indicate that approximately 120,000 to 180,000 nests were laid over the entire 1947 nesting season in contrast to approximately 14,000 nests in the most recent nesting season. This new information on the historic population size greatly increases the mystery surrounding the abrupt decline in the recovery of this endangered species since 2009. The number of nests laid in the 2015 nesting season represents a 34 percent decline in comparison to 2009, and this occurred during a time when exponential growth of the population back toward historic levels was expected. What this means for conservation Intense conservation efforts are continuing, and this critically endangered species is protected throughout its range. "Because the Kemp's ridley is so protected, scientists believe that potential factors limiting its recovery may be habitat-related," Bevan said. "Another hypothesis among the field is that environmental pollution, in particular the 2010 Deepwater Horizon oil spill, may have significantly impacted the population, and many years may be required before the species regains an exponential recovery rate." An alternative hypothesis is that the Gulf of Mexico ecosystem may have changed over the past seven decades since the Herrera film was recorded, and can no longer support the abundance of Kemp's ridleys documented in the 1947 film. For example, studies have shown that the abundance of blue crabs, a preferred food item for the Kemp's ridley, has significantly declined in the northern Gulf of Mexico in recent decades. "The Kemp's ridley could be significantly impacted by long-term changes and the overall health of the Gulf of Mexico ecosystem because of its near exclusivity to the area and presence as a higher-trophic-level predator," Bevan said. "That's why it's so important that we continue our research into the mystery of its stalled growth." "Solving the mystery will require continued monitoring of turtles on the nesting beach, a better understanding of the ecology of the Kemp's ridley in its foraging and developmental habitats, and an evaluation of potential changes in the Gulf of Mexico ecosystem since the 1947 Herrera film," Wibbels added. More information: Bevan, E., T. Wibbels, B. M. Z. Najera, L. Sarti, F. I. Martinez, J. M. Cuevas, B. J. Gallaway, L. J. Pena, and P. M. Burchfield. 2016. Estimating the historic size and current status of the Kemp's ridley sea turtle (Lepidochelys kempii) population. Ecosphere 7 (3):e01244. DOI: 10.1002/ecs2.1244

SAN ANTONIO--(BUSINESS WIRE)--Seattle Genetics, Inc. (NASDAQ: SGEN), a global biotechnology company, today presented data from an ongoing phase 1 clinical trial evaluating SGN-LIV1A for patients with metastatic breast cancer (MBC), with particular focus on triple-negative MBC (TN MBC), at the 39th San Antonio Breast Cancer Symposium (SABCS) taking place in San Antonio, Texas, December 6-10, 2016. SGN-LIV1A is an investigational antibody-drug conjugate (ADC) which consists of a LIV-1-targeted monoclonal antibody linked to the cell-killing agent monomethyl auristatin E (MMAE) by a protease-cleavable linker. LIV-1 is a protein expressed by most metastatic breast cancers. SGN-LIV1A is one of four clinical-stage empowered antibody therapies under development by Seattle Genetics for solid tumors. “Breast cancer is the most common cancer among women, with an estimated 1.67 million new cases per year worldwide. About 15 to 20 percent of breast cancers are triple negative, which means they lack expression of three breast cancer-associated proteins that serve as key therapeutic targets. Triple-negative breast cancers are more aggressive and generally have poor prognoses,” said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. “The data presented at SABCS on SGN-LIV1A demonstrate promising early antitumor activity with a 37 percent partial response rate in patients with triple negative metastatic breast cancer, for which there are no available targeted treatments. We are enrolling additional patients with triple negative metastatic breast cancer in our phase 1 study to optimize the dose and inform the next steps for development of SGN-LIV1A in this population with high unmet need.” Interim data from the ongoing phase 1 study of SGN-LIV1A in patients with MBC were previously presented at the 2015 SABCS. The following updated results from this trial describe safety data for all patients and antitumor activity data for patients with TN MBC. Interim Analysis of a Phase 1 Study of the Antibody-Drug Conjugate SGN-LIV1A in Patients with Metastatic Breast Cancer (Poster# P6-12-04, Poster Session 6 - Treatment: New Drugs and Treatment Strategies at 7:30 – 9:00 a.m. CT on Saturday, December 10, 2016) Data were reported from 53 patients with LIV-1-expressing MBC who were treated with SGN-LIV1A monotherapy administered every three weeks. Of these patients, 35 had TN MBC. The median age of all patients was 56 years. Patients had received a median of four prior systemic therapies for metastatic disease. Key findings presented by Dr. Andres Forero-Torres, University of Alabama at Birmingham included: More information about the SGN-LIV1A phase 1 clinical trial, including enrolling centers, is available by visiting SGN-LIV1A is a novel investigational ADC targeted to LIV-1 protein utilizing Seattle Genetics’ proprietary ADC technology. LIV-1 is expressed by most metastatic breast cancers. It has also been detected in a number of other cancers, including melanoma, prostate, ovarian, and cervical cancer. SGN-LIV1A consists of a LIV-1-targeted monoclonal antibody linked to a potent microtubule-disrupting agent, monomethyl auristatin E (MMAE) by a protease-cleavable linker, using the same technology as ADCETRIS (brentuximab vedotin). It is designed to bind to LIV-1 on cancer cells and release the cell-killing agent into target cells upon internalization. SGN-LIV1A may also cause antitumor activity through other mechanisms, including activation of an immune response. Breast cancer is a cancer which forms in breast tissue. Metastatic breast cancer occurs when the cancer has spread to other parts of the body. While most new diagnoses of breast cancer are made at an early stage, approximately one-third of these patients will eventually develop recurrent or metastatic disease. Breast cancers are commonly categorized by the expression (or lack thereof) of three key proteins, which serve are targets for therapeutics. These include the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Triple-negative breast cancer (TNBC) lacks all three proteins and HR+/HER2- breast cancer expresses one or both hormone receptors (HR) but not HER2. According to the World Health Organization, breast cancer is the second most common cancer in the world and the most frequent cancer among women with an estimated 1.67 million new cancer cases diagnosed in 2012. Furthermore, breast cancer ranks as the fifth cause of death from cancer overall. New treatment approaches are needed to improve outcomes for breast cancer patients, particularly for those with TNBC where there are currently no available targeted therapies. Seattle Genetics is an innovative biotechnology company that develops and commercializes novel antibody-based therapies for the treatment of cancer. The company’s industry-leading antibody-drug conjugate (ADC) technology harnesses the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. ADCETRIS® (brentuximab vedotin), the company’s lead product, in collaboration with Takeda Pharmaceutical Company Limited, is the first in a new class of ADCs commercially available globally in 65 countries for relapsed classical Hodgkin lymphoma (HL) and relapsed systemic anaplastic large cell lymphoma (sALCL). Seattle Genetics is also advancing vadastuximab talirine (SGN-CD33A; 33A), an ADC in a phase 3 trial for acute myeloid leukemia. Headquartered in Bothell, Washington, Seattle Genetics has a robust pipeline of innovative therapies for blood-related cancers and solid tumors designed to address significant unmet medical needs and improve treatment outcomes for patients. The company has collaborations for its proprietary ADC technology with a number of companies including AbbVie, Astellas, Bayer, Celldex, Genentech, GlaxoSmithKline and Pfizer. More information can be found at Certain of the statements made in this press release are forward looking, such as those, among others, relating to the therapeutic potential of SGN-LIV1A and its possible benefits and uses, and planned development activities including clinical trials to optimize dose. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the inability to show sufficient activity in this recently initiated clinical trial and the risk of adverse events as SGN-LIV1A advances in clinical trials and regulatory actions. More information about the risks and uncertainties faced by Seattle Genetics is contained under the caption “Risk Factors” included in the company’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2016 filed with the Securities and Exchange Commission. Seattle Genetics disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

News Article | March 2, 2017

BIRMINGHAM, AL, March 02, 2017-- Dr. Wayne Finley has been included in Marquis Who's Who. As in all Marquis Who's Who biographical volumes, individuals profiled are selected on the basis of current reference value. Factors such as position, noteworthy accomplishments, visibility, and prominence in a field are all taken into account during the selection process.A medical educator with more than six decades of experience, Dr. Finley is highly regarded for mentoring, inspiring, and motivating emerging physicians and graduate students so that they are set up for success at the start of their careers. Retired since 1996, he concluded his career with the University of Alabama School of Medicine, where he dedicated more than 36 years in a variety of roles, serving as Professor; Epidemiology and Public Health; and Chairman of Faculty Council. Certified by the American Board of Medical Genetics and Genomics, Dr. Finley served on the genetic counseling committee of the Children's Bureau of the U.S. Department HEW and on the National Research Resources Council of the National Institute of Health. He was a senior scientist for the Comprehensive Cancer Center and the Cystic Fibrosis Research Center at the University of Alabama at Birmingham (UAB). In recognition of his professional excellence, Dr. Finley was recognized by the Distinguished Faculty Lecturer Award, endowment of the Sara C. and Wayne H. Finley Chair in Medical Genetics, and renaming the Reynolds-Finley Historical Library and Annual Lecture by the UAB. He received community awards including the Lifetime Achievement Award from the Birmingham Business Journal. Named to the Alabama Healthcare Hall of Fame and presented the President's Medal by UAB, Dr. Finley was also honorably selected for inclusion into Who's Who in America, Who's Who in American Education, Who's Who in Medicine and Healthcare, Who's Who in Science and Engineering, and Who's Who in the South and Southwest.Before establishing his career in medicine, Dr. Finley served his country as a member of the U.S. Army Infantry in Germany in 1946 and later in the Army Chemical Corps and ultimately achieved the rank of Lieutenant Colonel in the Reserves. After his service, he attended Jacksonville State University, where he earned a Bachelor of Science in 1948, and the University of Alabama, where he achieved a Master of Arts in 1950, a Master of Science in 1955, a Ph.D. in 1958, and an MD in 1960. A fellow of the American College of Medical Genetics and Genomics, Dr. Finley remained at the top of his field through his memberships in American Medical Association, American Association for the Advancement of Science, New York Academy of Sciences, Society for Experimental Biology and Medicine, American Institute of Chemists, American Federation for Clinical Research, American College of Medical Genetics and Genomics, American Society of Human Genetics, the Southern Medical Association, Medical Association of the State of Alabama, and Jefferson County Medical Society. As he looks to the future, Dr. Finley intends to enjoy his retirement while taking on select consulting projects as they arise.About Marquis Who's Who :Since 1899, when A. N. Marquis printed the First Edition of Who's Who in America , Marquis Who's Who has chronicled the lives of the most accomplished individuals and innovators from every significant field of endeavor, including politics, business, medicine, law, education, art, religion and entertainment. Today, Who's Who in America remains an essential biographical source for thousands of researchers, journalists, librarians and executive search firms around the world. Marquis publications may be visited at the official Marquis Who's Who website at

TEMPE, Ariz., Dec. 19, 2016 (GLOBE NEWSWIRE) -- Capstone Therapeutics Corp. (OTCQB:CAPS) (“the Company”) and LipimetiX Development, Inc., the Company’s drug development joint venture (“JV”) announced today that the JV’s lead commercial drug candidate, AEM-28-14, showed substantial and statistically-significant LDL cholesterol (LDLc) reductions in a hypercholesterolemic primate study at Wake Forest University.  Following a single IV administration of escalating doses up to 5mg/kg, LDLc exhibited a mean reduction of 64% from baseline at 24 hours, 46% from baseline at 3 days and 16% from baseline at 7 days, despite the study animals remaining on a high fat/cholesterol diet through the full study. A PDF accompanying this announcement is available at Dennis I. Goldberg, PhD, President and CEO of LipimetiX Development, Inc. stated “AEM-28-14 has shown clinically-relevant levels of cholesterol reduction in multiple validated preclinical models and may be the most powerful lipid reduction agent yet discovered.  Primate models are often predictive of a molecule’s therapeutic performance in humans.  Accordingly, we see the LDLc reduction in this primate model as consistent with the benefits that we hope to deliver to Homozygous Familial Hypercholesterolemia (HoFH) patients…powerful cholesterol lowering combined with duration of effect.” The JV’s development goals are to conduct Phase 1a, 1b, and 2a human clinical trials with AEM-28-14 to show an acceptable safety profile and cholesterol reduction efficacy in HoFH, an orphan genetic disease characterized by extremely high LDLc due to inherited defects in the LDL receptor pathway from both parents.  The hypercholesterolemia associated with HoFH is difficult to treat since it is refractory to drugs and biologics, such as statins and PCSK9 inhibitors, that increase the expression and functionality of the LDL receptor in normal patients. Apolipoprotein E (Apo E) is in a class of protein that occurs throughout the body.  Apo E is essential for the normal metabolism of cholesterol and triglycerides.  After a meal, the postprandial (or post-meal) lipid load is packaged in lipoproteins and secreted into the blood stream.  Apo E targets cholesterol and triglyceride-rich lipoproteins to specific receptors in the liver, decreasing these levels in the blood.  Defective metabolism of cholesterol and triglyceride-rich lipoprotein remnants plays an important role in the development of diseases of the coronary, cerebral and peripheral arteries often leading to heart attack and stroke. The University of Alabama at Birmingham (“UAB”) scientists patented the first chimeric Apo E mimetic peptide in 1999, reducing the 299 amino acid native Apo E into a 28 amino acid, dual domain peptide that can be delivered therapeutically.  One domain inserts into a lipoprotein surface and the second domain binds to the Apo E receptors in the liver.  In 2010, our JV’s founding scientist, Dr. Dennis Goldberg, obtained worldwide right to patents for Apo E mimetic peptides from the UAB Research Foundation (“UABRF”).  The JV has an Exclusive License Agreement with the University of Alabama at Birmingham Research Foundation for AEM-28 and its analogs. The JV has continued research in to a new generation of chimeric Apo E peptides and has discovered AEM-28-14, resulting in a USPTO and PCT patent filing in 2015 supporting claims for a broad domain of Apo E mimetic peptides.  AEM-28-14 was found to be more potent (as tested in multiple animal models) than the parent molecule, AEM-28.  Currently the JV intends to concentrate its development efforts on AEM-28-14. Subject to continued favorable study results and funding availability, the JV may pursue regulatory approval of AEM-28-14 as treatment for Homozygous Familial Hypercholesterolemia and other orphan indications in dyslipidemia. Capstone Therapeutics is a biotechnology company committed to developing novel therapeutic peptides aimed at helping patients with under-served medical conditions.  The Company is focused on development and commercialization of Chimeric Apo E Mimetic Peptides through the LipimetiX Development, Inc. joint venture and currently owns 59.3% of the joint venture. Capstone’s corporate headquarters are in Tempe, Arizona.  For more information, please visit the Company's website:  For more information on LipimetiX Development, please visit the JV’s website: Statements in this press release or otherwise attributable to Capstone regarding our business that are not historical facts are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.  These forward-looking statements involve risks and uncertainties that could cause actual results to differ materially from predicted results.  These risks include the factors discussed in our Form 10-K for the fiscal year ended December 31, 2015, and other documents we file with the U.S. Securities and Exchange Commission. Editor’s Note:  This press release is also available under the Investors section of the Company’s website at

News Article | November 12, 2016

WASHINGTON -- Patients with rheumatoid arthritis whose rheumatologists and primary-care physicians coordinate their care have a higher likelihood of being screened for hyperlipidemia, a key risk factor for coronary heart disease, according to new research findings presented this week at the 2016 ACR/ARHP Annual Meeting in Washington. Rheumatoid arthritis (RA) is a chronic disease that causes pain, stiffness, swelling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3 million Americans have RA, and the disease typically affects women twice as often as men. Patients with RA have an increased prevalence for coronary heart disease (CHD). Some data suggests that RA patients are not being screened properly for hyperlipidemia, so researchers at the University of Alabama at Birmingham conducted a study to evaluate lipid testing patterns among RA patients. They looked at whether patients screened for hyperlipidemia received care from a primary-care physician (PCP), a rheumatologist or both. The study was conducted to identify the extent of the screening and management gaps for hyperlipidemia among the RA patient population, said Iris Navarro-Millan, MD, Assistant Professor of Medicine at UAB and a lead author of the study. "You could argue that screening for hyperlipidemia, a traditional risk factor, should be addressed by primary-care physicians, but there are a number of patients with RA who only see a rheumatologist," she said. "Patients see a specialist for a comorbidity (in this case RA), and do not establish care with a PCP, and this results in gaps in standard of care, such as screening and management for hyperlipidemia. We decided to focus on hyperlipidemia because CHD is the most common cause of death among patients with RA. Therapies for RA also affect lipid profiles in these patients, which adds complexity to the issue of cardiovascular risk reduction in patients with RA." The study linked commercial and public health plan claims data together from 2006 to 2010. Participants in the study were required to have at least 12 months of continuous medical and pharmacy coverage at baseline, have two or more physician diagnoses plus relevant DMARD and/or biologic prescriptions to categorize them as having RA, plus two years of follow-up. Excluded were patients with prevalent myocardial infarction (MI), stroke or CHD at baseline, or those who had a diagnosis of hyperlipidemia or were using hyperlipidemia medications at baseline. The researchers organized the patterns of care at baseline as visited a PCP only, visited a rheumatologist only or visited both types of physicians. They used logistic regression to determine the how likely patients were to be screened for hyperlipidemia during two years of follow-up based on their pattern of care.The study measured hyperlipidemia screening in 13,319 RA patients, including 83 percent women. Twenty-six percent were between the ages of 41-60 and 74 percent were older than 65. Eighteen percent of the RA patients did not see a PCP at the 12-month baseline. The results showed that 42 percent of patients seeing a PCP only were screened for hyperlipidemia, 40 percent of patients seeing only a rheumatologist were screened, and 47 percent of patients seeing both a PCP and rheumatologist were screened. After controlling for multiple potential confounders, the researchers found that RA patients who received combined care had a 32 percent increase in the likelihood of being screened for hyperlipidemia. Rheumatologists may not always consider hyperlipidemia screenings as part of RA patient care, the researchers concluded. Improved coordination of care between PCPs and rheumatologists could help RA patients get necessary cardiovascular screenings. The study's findings help raise awareness that the RA patient population is inadequately screened and managed for hyperlipidemia, said Dr. Navarro-Millan. "Our goal is to develop an intervention that can facilitate communication between specialties with the goal of decreasing health care fragmentation and reduce CHD risk in these patients," she said. "We anticipate that patient activation and knowledge will be a key element for the success of such intervention, since patients with RA are less likely to be aware of their increased risk for CHD." This research was supported by funding from the Rheumatology Research Foundation and the NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases. About the American College of Rheumatology Headquartered in Atlanta, Ga., the American College of Rheumatology is an international medical society representing over 9,400 rheumatologists and rheumatology health professionals with a mission to Advance Rheumatology! In doing so, the ACR offers education, research, advocacy and practice management support to help its members continue their innovative work and provide quality patient care. Rheumatologists are experts in the diagnosis, management and treatment of more than 100 different types of arthritis and rheumatic diseases. For more information, visit http://www. . The ACR/ARHP Annual Meeting is the premier meeting in rheumatology. With more than 450 sessions and thousands of abstracts, it offers a superior combination of basic science, clinical science, tech-med courses, career enhancement education and interactive discussions on improving patient care. For more information about the meeting, visit http://www. , or join the conversation on Twitter by following the official #ACR16 hashtag.

News Article | February 15, 2017

American Family Care (AFC), the nation’s leading provider of urgent care, occupational medicine, and accessible primary care, celebrates its role in the current health care revolution with a rededication ceremony for its recently renovated clinic in Hoover, Alabama. Local government officials and other dignitaries will help celebrate the occasion on Tuesday, January 31 at 1680 Montgomery Highway, Hoover, AL 35216. Originally opened in 1982, the Hoover clinic was the company’s first medical center – and is what many consider to be the epicenter of the urgent care industry. Since the opening of AFC’s Hoover clinic, the urgent care concept has grown dramatically. According to the most updated number from the Urgent Care Association of America (UCAOA), there are more than 7,000 centers in the U.S. providing full-service urgent care medicine – including x-rays, lab work and extended hours. “Our success is the direct result of the hard work and dedication of our employees and franchisees who work tirelessly to deliver kind, compassionate health care around the corner and around the nation,” said D. Bruce Irwin, M.D., founder and CEO of AFC. “We are both proud and humbled by our role in helping to create an industry that is providing patients with greater access to quality health care.” Born the son of a cobbler in Center Point, Alabama, Dr. Bruce Irwin earned an undergraduate degree from Birmingham-Southern College and graduated from the School of Medicine at University of Alabama at Birmingham. While working in the Emergency Room of Brookwood Medical Center, he discovered that some non-critical emergencies were clogging up the waiting rooms. Despite his lack of education and experience in business, Irwin sketched a business plan for a network of urgent care clinics on a notepad. More than three decades later, that vision has revolutionized how millions of people gain access to health care. When: Tuesday, January 31 from 6 p.m. to 7 p.m. About American Family Care: Founded by Dr. Bruce Irwin with a single location in 1982, American Family Care has pioneered the concept of non-emergency room urgent care. With its 2013 acquisition of the Doctors Express, AFC has become the nation’s leading provider of urgent care, accessible primary care, and occupational medicine, with more than 170 clinics and 500 in-network physicians caring for 2 million patients a year. Ranked by Inc. Magazine as one of the fastest growing companies in the U.S., AFC’s stated mission is to provide the best healthcare possible, in a kind and caring environment, while respecting the rights of all patients, in an economical manner, at times and locations convenient to the patient. For more information, visit

News Article | February 21, 2017

LOS ANGELES -- Research published today found testosterone treatment improved bone density and anemia for men over 65 with low testosterone. But the treatment didn't improve patients' cognitive function, and it increased the amount of plaque buildup in participants' coronary arteries, according to four studies published in the Journal of the American Medical Association (JAMA) and JAMA Internal Medicine. A team of researchers from LA BioMed and 12 other medical centers in the U.S., in partnership with the National Institute on Aging, conducted The Testosterone Trials (TTrials), a coordinated group of seven trials, which studied the effects of testosterone treatment for one year as compared to placebo for men 65 and older with low testosterone. Four of those studies were published today. "While we have long known that testosterone levels decrease as men age, very little was known about the effects of testosterone treatment in older men with low testosterone until last year," said Ronald S. Swerdloff, MD, an LA BioMed researcher and co-author of the four studies. "Our first published research last year found benefits to testosterone treatment, and this latest series of studies finds further benefits in terms of improving bone density and anemia. However, the cardiovascular study showed that the testosterone treatment group had increased plaque buildup in coronary arteries, suggesting a possible risk factor." In the cardiovascular trial, researchers assessed coronary artery plaque buildup by CT angiography. That assessment showed more plaque buildup in men treated with testosterone than in men treated with placebo. Nonetheless, in all 788 men in the TTrials, the number of major adverse cardiovascular events was similar in the men treated with testosterone as in the men treated with placebo. "We want to emphasize that this study was exploratory and emphasizes the need for a large-scale, well-controlled, long-term safety trial to determine if there is an increased risk of heart damage or death," Dr. Swerdloff said. "As with all medications the physician and patient need to balance the benefits and risks of treatment." Dr. Christina Wang, an LA BioMed researcher and co-author of the four studies, noted that the researchers also found that testosterone treatment improved bone density and estimated bone strength, as determined by CT. "After one year of treatment, older men with low testosterone significantly increased bone density and estimated bone strength compared to those on placebo," said Dr. Wang. "A larger and longer trial would be needed to determine if testosterone treatment reduces fracture risk." Testosterone treatment also increased hemoglobin concentrations, corrected the anemia of men who had no other identifiable cause of anemia and corrected the anemia of men who had an identifiable cause, such as iron deficiency. While these conclusions proved testosterone to be beneficial to the participants, testosterone treatment did not improve memory or any other measure of cognitive function. "As a result of these findings, physicians may wish to consider measuring testosterone in men age 65 and older who have unexplained anemia and symptoms suggestive of low testosterone levels," said Dr. Swerdloff. The TTrials are now the largest trials to examine the efficacy of testosterone treatment in men 65 and older whose testosterone levels are low due seemingly to age alone. TTrials researchers screened 51,085 men to find 790 who qualified with a sufficiently low testosterone level and who met other criteria. The men enrolled were randomized into two groups: one to take a daily testosterone gel and the other a daily placebo gel, for one year. Efficacy was then evaluated at months three, six, nine and 12. "Final decisions about testosterone treatment for older men will depend on balancing the results from these seven TTrials with the results from a much larger and longer term trial designed to assess cardiovascular and prostate risk in the future," said principal investigator Peter J. Snyder, MD, University of Pennsylvania Perelman School of Medicine professor of medicine in the Division of Endocrinology, Diabetes and Metabolism. In addition to LA BioMed and University of Pennsylvania, the TTrials were conducted at Albert Einstein College of Medicine, Baylor College of Medicine, Brigham and Women's Hospital, University of Alabama at Birmingham, Northwestern University Feinberg School of Medicine, Puget Sound Health Care System, University of California at San Diego School of Medicine, University of Florida School of Medicine, University of Minnesota School of Medicine, University of Pittsburgh School of Public Health and Yale School of Medicine. The Testosterone Trials were supported by a grant from the National Institute on Aging (NIA), National Institutes of Health (U01 AG030644). The TTrials were also supplemented by funds from the National Heart, Lung and Blood Institute, National Institute of Neurological Diseases and Stroke, and National Institute of Child Health and Human Development. AbbVie (formerly Solvay and Abbott Laboratories) also provided funding, AndroGel, and placebo gel. Founded in 1952, LA BioMed is one of the country's leading nonprofit independent biomedical research institutes. It has approximately 100 principal researchers conducting studies into improved treatments and therapies for cancer, inherited diseases, infectious diseases, illnesses caused by environmental factors and more. It also educates young scientists and provides community services, including prenatal counseling and childhood nutrition programs. LA BioMed is academically affiliated with the David Geffen School of Medicine at UCLA and located on the campus of Harbor-UCLA Medical Center. For more information, please visit http://www.

News Article | December 13, 2016

Promising results of a clinical trial of a new drug, used in combination with chemotherapy, to treat newly diagnosed acute myeloid leukemia (AML) patients, were presented Dec. 3 at the 58th American Society of Hematology Annual Meeting in San Diego. The drug, vadastuximab talirine, also called 33A, was proven safe in a Phase 1b study, and may help cancer patients achieve remission without multiple rounds of chemotherapy, and improve long-term outcomes. The trial involved 42 newly diagnosed AML patients who received 33A in addition to standard chemotherapy.  The overall cure rate of chemotherapy alone is typically between 40 and 50 percent for patients younger than 60 years old, but the study revealed higher remission rates for people receiving the combination treatment. After a single round of treatment, 78 percent of participants attained remission. According to the researchers, many patients were rid of signs of the disease 28 days after starting treatment. The drug is an antibody-drug conjugate that targets and kills the protein CD33, which is present on leukemic blasts in about 90 percent of AML patients, according to press release about the trial. Patients did not experience increased toxicity or mortality from 33A, and side effects were comparable to what patients would experience with chemotherapy alone. As for the most common side effects, about 55 percent of patients reported nausea, 33 percent reported diarrhea, and 31 experienced constipation. “I think we can safely give vadastuximab talirine in combination with chemotherapy,” said lead study author Harry Erba, M.D., Ph.D., of the University of Alabama at Birmingham. “The next question to study is whether it improves long-term disease-free survival. There’s much reason to be hopeful that such an investigation will have positive results.” Johnathan Drachman, M.D., the Chief Medical Officer and Executive Vice President of Research and Development at Seattle Genetics, in a statement said: “We are pleased with the growing body of data demonstrating that vadastuximab talirine, also known as 33 A, has a promising overall tolerability and activity profile in clinical trials for patients with AML.” He continued: “Our most advanced 33A clinical study, CASCADE, is a randomized phase 3 trial designed to test 33A in combination with hypomethylating agents, or HMAs, in approximately 500 older patients with newly diagnosed AML. Based on the encouraging data presented at ASH, we believe 33A has the potential for clinical development in multiple AML settings, with the goal of providing new treatment options for patients struggling with this aggressive and life-threatening disease.” Biotechnology company Seattle Genetics Inc., supported funding for this research.

News Article | February 16, 2017

Scientists at the Gladstone Institutes and the University of California, San Francisco (UCSF), together with collaborators in Europe, discovered that a common type of cell within the human reproductive and intestinal tracts assists HIV in infecting immune cells. Understanding how these cells aid HIV could lead to new methods that prevent HIV transmission. The human reproductive system and intestinal tract are lined with a protective layer of cells, called the mucosa. Breaches in these layers, which can be caused by physical trauma or some sexually transmitted diseases, allow HIV to bypass the protective surface to access immune cells that can be infected by HIV. In the new study, published in PLOS Pathogens, scientists used an experimental system that models the mucosa and surrounding tissues. Surprisingly, they discovered that fibroblasts, connective tissue cells that are one of the most abundant types of cells in the mucosa, greatly increase HIV infection of immune cells. One way they do this is by transporting the virus to the body's immune cells, without themselves becoming infected, through a process called trans-infection. "We were interested in understanding how cells commonly found in mucosal tissues affect the ability of HIV to infect immune cells," explained Nadia Roan, PhD, a visiting investigator at Gladstone and assistant professor at UCSF who is the senior author of the study. "We discovered that, remarkably, mucosal fibroblasts could potently increase how well HIV infected immune cells. Knowing how this occurs at the molecular level can help us find new ways to fight the virus." The researchers examined mucosal fibroblasts from the cervix, uterus, foreskin, male urethra, and intestines--all portals of HIV entry. They found that fibroblasts from all of these tissues increased HIV infection. They did this not only by trans-infection, but also by making the immune cells more prone to infection by HIV. In future research supported by the National Institutes of Health, the researchers will study exactly how mucosal fibroblasts make immune cells more "infectable", which could ultimately lead to new targets for preventing HIV. The scientists also tested a second abundant cell type found in mucosal tissues: epithelial cells. These cells line the mucosa, where they allow helpful substances to pass through to tissues in the body and also provide a barrier against harmful substances. What the scientists discovered was that in contrast to fibroblasts, epithelial cells secrete high levels of antiviral proteins that inhibit infection. "Our work suggests that breaches in the mucosa allow HIV to bypass an antiviral environment to access fibroblasts, which in turn boost levels of HIV infection in CD4 T cells," said Warner Greene, MD, PhD, director of the Gladstone Institute of Immunology and Virology who was a senior investigator on the study. "Knowing the specific cells that allow HIV to take advantage of breaches in our defenses will enable us to find better ways to limit HIV transmission rates." Other Gladstone researchers on the study include Jason A. Neidleman, Nargis Kohgadai, and Karen S. Jang. Researchers from the University of California, San Francisco, Ulm University Medical Center (Germany), Aarhus University (Denmark), University of Alabama at Birmingham, and San Francisco General Hospital also took part in the research. Funding was provided by National Institutes of Health, the Center for AIDS Research, UCSF, the Danish Research Council, the Lundbeck Foundation, and the Bill and Melinda Gates Foundation. To ensure our work does the greatest good, the Gladstone Institutes focuses on conditions with profound medical, economic, and social impact--unsolved diseases of the brain, the heart, and the immune system. Affiliated with the University of California, San Francisco, Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease.

News Article | December 1, 2016

The Center to Advance Palliative Care (CAPC) is pleased to announce the launch of three new Palliative Care Leadership Centers (PCLC) focused specifically on the development of home and office-based palliative care. Selected in 2015, the three are now open for enrollment. The launch is the latest effort by CAPC to develop the nation’s palliative care programs beyond the hospital into the community setting where people actually live. The point of community-based palliative care is to maintain a person’s life at home or place of residence by maximizing quality of life, optimizing function and providing care that supports goals and preferences. Studies show that people facing serious illness also prefer to be in their own environment. Palliative care is specialized medical care for people with serious illnesses. It focuses on relieving the symptoms and stress of a serious illness. The goal is to improve quality of life for both the patient and the family. Provided by a specially-trained team of doctors, nurses, social workers and other specialists, palliative care teams work together with a patient’s doctors to provide an extra layer of support. Palliative care is appropriate at any age and at any stage in a serious illness and can be provided along with curative treatment. In addition to the Palliative Care Leadership Centers, CAPC provides an online curriculum, virtual office hours with experts, webinars, videos, podcasts and an online forum targeted to integrating palliative care into community settings. CAPC also recently released Palliative Care in the Home: A Guide to Program Design – the first reference guide of its kind. The PCLC initiative provides intensive training and a full-year of mentoring to teams from hospitals, hospice, home health, medical group practices and other health care organizations. CAPC launched the PCLC initiative in 2003 to catalyze palliative care program development and growth. A demonstrably effective method for the diffusion of palliative care innovation, PCLC training reduces the opportunity costs for palliative care program startup and delivery. It also standardizes best practices for all areas of program development and growth, including business and financial planning, clinical and staffing models, measurement and staffing. The three new Palliative Care Leadership Centers focused on home and office-based palliative care are: Northwell Health, New Hyde Park, New York Presbyterian Healthcare Services, Albuquerque, New Mexico University of Virginia Health System (UVA), Charlottesville, Virginia They join six other long-standing PCLCs: Fairview Health System, Minneapolis, Minnesota Mount Carmel Health System, Columbus, Ohio Palliative Care Center of the Bluegrass, Lexington, Kentucky University of Alabama at Birmingham (UAB), Birmingham, Alabama University of California, San Francisco (UCSF), San Francisco, California VCU Massey Cancer Center, Richmond, Virginia All Palliative Care Leadership Centers were selected through a highly competitive process that focused on clinical excellence, outstanding leadership, reputation and experience. "To truly meet the needs of our society's most complex and vulnerable patients, palliative care must be delivered where people facing serious illness actually live. We must expand beyond the hospital setting to reach people living at home, in nursing homes, and receiving care in their clinician's offices," said CAPC Director, Diane E. Meier, MD. “Practical how-to knowledge, intensive coaching and mentoring from experienced leaders, and support for successful program-building through the PCLC initiative results in deep organizational capacity to serve this high-need population." Older adults with multiple chronic conditions make up 66 percent of Medicare fee-for-service beneficiaries and account for 93 percent of total Medicare expenditures. These people are at the highest risk for poor outcomes. Therefore, providers have strong incentives to make sure that patients and their families receive palliative care outside the clinical setting. About CAPC The Center to Advance Palliative Care (CAPC) is a national, member-based organization dedicated to increasing the availability of quality palliative care services for people facing serious illness. CAPC provides hospitals, hospices, payers and other health care organizations with the tools, training, technical assistance and metrics needed to support the successful implementation and integration of palliative care. To learn more about CAPC, visit

News Article | December 13, 2016

The Alliance for Clinical Research Excellence and Safety (ACRES), in partnership with the British Standards Institution (BSI), has announced advances in the third-phase of their global initiative to create standards for the accreditation of high-performing clinical research sites worldwide, thus promoting professionalism and excellence in clinical research while accelerating medicines development and enhancing clinical trials performance, safety and quality. The Global Standards for Excellence (GSE) Working Party, formally launched in mid-November, brings together a team of global content experts from multiple domains to work with the BSI professional standards-writers to fast-track the development and testing of standards and metrics for assuring site excellence. This announcement marks the continuing progress of the global accreditation effort launched by the ACRES enterprise-wide collaborative three years ago. Led by co-chairs Arti Bajpai, President, Compliance and Quality Integration (CQI) Consulting and Amir Kalali, Vice-President, Quintiles, the GSE Working Party encompasses ten cross-functional teams working across seven core domains and three specialty domains to create standards to provide the foundation for globally recognized accreditation of research sites. Standardization and accreditation has been shown to substantially improve connectivity, interoperability, productivity, sustainability and efficiency in the conduct of clinical trials, reducing time to start-up and study completion, thereby accelerating the clinical trials process and medicines development. Domain Team Leaders include: Anthony Rissling, CTMG, Inc.; Katie Porter, Hamilton Health Sciences; Mary Westrick, University of Wisconsin; Ivo Ivanov, AstraNova; Sara Monday, ACRES; Penny Jester, University of Alabama at Birmingham; Nadina Jose, Anidan Group Pte Ltd; Larry Kennedy, Quality Management Institute; Nonna Stepanov, Mountain State Health Alliance (MSHA) and Terry Stubbs, ActivMed Practices and Research, Inc. Steven Hirschfeld, NIH, will serve in a liaison role. Over the next 6-9 months, the teams—each with 3-6 members bringing extensive experience in every aspect of clinical research—will work with professional standards writers from BSI to complete a set of draft standards. These will be circulated worldwide for review and comment by the entire stakeholder community--particularly research sites--but also sponsors, regulators, ethics committees, CROs, IT providers, investigators and patients. After revision based upon the comments and feedback, this initial set of standards will be pilot tested prior to a staged initiation of a unique accreditation process currently being developed in parallel with the standards. The ACRES “Dynamic Accreditation”™ process, based upon proven high-performance models from other industries, will differ from traditional accreditation schemes by using information flowing in real-time during normal workflow to immediately identify potential challenges and opportunities for improvement, not unlike the air-traffic control feedback system utilized for global air transportation and safety. Greg Koski, ACRES co-founder and CEO, noted that “prominent industry leaders, such as Freda Lewis-Hall, CMO at Pfizer and Briggs Morrison, CEO of Syndax Pharmaceuticals and a member of ACRES Board of Directors, have previously underscored the importance of high-performing sites in improving clinical trial performance. The standards and processes now being developed will provide an effective mechanism and incentives for sites to improve without imposing new bureaucratic and financial burdens.” Sara Monday, ACRES VP of Site Development and Support and ACRES liaison between BSI and the teams, notes “In collaboration with BSI, our Domain teams include research professionals from around the world, each working toward one common goal: establishing standards of excellence in the clinical trials industry. This effort will bring much needed changes to our industry and will lead to the accreditation of research sites globally”. Rob Turpin, Healthcare Market Development Manager, and Bei Ma, VP, Global Healthcare Development, are leading the BSI contribution. Turpin noted that BSI’s partnership with ACRES "takes advantage of a unique opportunity afforded by its multi-stakeholder global alliance to accelerate the development of standards that will surely enhance the entire clinical research and drug development process. We commend ACRES for its leadership of this challenging yet immensely valuable process and are delighted to be part of it.” The Alliance for Clinical Research Excellence and Safety (ACRES) is a non-profit alliance working in the public interest. Bringing together stakeholders spanning the clinical research ecosystem to build an open, integrated global system based in principles of Accountable Research™, ACRES adapts lessons from industries successfully implementing principles of systems and safety engineering, such as transportation, communications and information technology. For more information, please contact Mary F. Tobin, PhD, Special Advisor to the President and CEO at mtobin(at)acresglobal(dot)net

News Article | February 21, 2017

New Haven, Conn.-- Older men with low testosterone levels showed improved bone density and strength, as well as reduced anemia, after one year of testosterone therapy, according to a new study conducted at Yale and other sites. The therapy had no impact on cognitive function, however, and may worsen plaque in coronary arteries, said the researchers. The results of the four trials were published online Feb. 21 in two journals, JAMA and JAMA Internal Medicine. The studies, known as the TTrials, are the largest trials to examine the efficacy of testosterone treatment in men 65 and older whose testosterone levels are low due to age. At 12 study sites across the country, 790 participants were given testosterone gel or a placebo applied daily to the skin. Over a year, investigators measured the effects of testosterone on four areas: anemia, bone density and strength, cardiovascular health, and cognitive function. The findings are the second set of results from the long-term TTrials, which demonstrated the benefit of testosterone therapy on sexual function in older men with low testosterone in a report published last year. "Looking globally at testosterone therapy, the strongest evidence is for sexual function," said Thomas Gill, M.D., the Humana Foundation Professor of Medicine and a lead author. The latest studies demonstrate that if a man with low serum testosterone is going to be prescribed testosterone for diminished sexual function, he may have some additional benefits on hemoglobin levels and bone density, Gill noted. While the outcome of the cardiovascular trial raises concern, he said, a larger and longer study would be needed to determine the clinical significance of the findings. The TTrials were conducted at 12 additional medical centers, including Albert Einstein College of Medicine, Baylor College of Medicine, Brigham and Women's Hospital, Harbor-UCLA Medical Center, University of Alabama at Birmingham, Northwestern University Feinberg School of Medicine, Puget Sound Health Care System, University of California at San Diego School of Medicine, University of Florida School of Medicine, University of Minnesota School of Medicine, University of Pennsylvania, and University of Pittsburgh School of Public Health. The studies were funded primarily by the National Institute on Aging, part of the National Institutes of Health (NIH). Additional funding came from the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, all part of NIH. Additional funding, and the study drug and placebo, were provided by AbbVie Pharmaceuticals.

News Article | December 20, 2016

Experimenting with human cells and mice, Johns Hopkins researchers have found that a genetic mutation that alters a protein called NOD1 may increase susceptibility to human cytomegalovirus (CMV) infection. CMV is a common pathogen that infects almost 60 percent of adults in the U.S., according to the Centers for Disease Control and Prevention (CDC), and can lead to devastating developmental defects in fetuses and severe disease in people with weakened immune systems. In a report on the new research, published Nov. 14 in the Proceedings of the National Academy of Sciences, the Johns Hopkins team says it now has what it believes is the first evidence that NOD1, a protein with a well-known role in inducing the innate immune response, has an integral role in the control of CMV and that certain variants of it may create higher risk of CMV infection. "Our results suggest that this protein explains why not every person is at the same risk for CMV, and that we might someday be able to develop tests to identify and manage those who are at an increased risk for CMV-related disease," says Ravit Boger, M.D., associate professor of pediatrics at the Johns Hopkins University School of Medicine. Building upon previous research, in which Boger's team identified NOD2 as a protein that controls CMV, its sister molecule, NOD1, was shown to also be important in the control of CMV infection in the new study. In studies with human fibroblasts that make up connective tissue, Boger's team tested whether NOD1 activity could affect CMV replication in cultures of cells grown in the lab. To do this, the researchers upregulated NOD1 by treating the cells with a bacterial fragment. They also genetically engineered cells to contain nonfunctional forms of NOD1. The results showed that cells in which NOD1 was activated had decreased levels of CMV replication compared to controls. In mouse experiments, the researchers treated the animals with two doses of iE-DAP, another bacterial NOD1 activator, and subsequently infected them with mouse CMV. Two weeks later, organs and intracardiac blood were collected from the mice and grown in dishes. The cells were monitored for areas of cell death, an indicator of viral activity. Compared to control mice not treated with the NOD1 activator, virus replication in iE-DAP-treated mice was significantly reduced. How changes in NOD1 protein determine its function against CMV remains to be determined. According to the research team, individuals with NOD1 mutations may be at higher risk of CMV infection because of changes in the protein's shape, which can cause changes in the protein's function. Therefore, the protein's ability to regulate CMV can vary based on these mutations. Boger cautions that NOD1 is not the only factor in determining risk of CMV infection and that this is simply one piece of a larger puzzle in determining risk. She says her team must now investigate the cell signaling pathways involving the NOD proteins to precisely pin down how NOD1 and NOD2 interact with CMV and the other systems within our cells. "We do not yet know how NOD1 accomplishes this function, or if NOD1 and NOD2 coordinate or work independently in the control of CMV," says Boger. CMV is transmitted from person to person through body fluids and can infect people of all ages, though nearly one in three people has the virus by age 5. Most people show no signs or symptoms of infection, while others develop such symptoms as a fever, sore throat and fatigue. One in 150 babies in the U.S. is born with a congenital CMV infection, and of those, one in five suffers from complications, according to the CDC, which can include including hearing loss, vision loss, cerebral palsy, cognitive impairments and microcephaly. CMV has not drawn the same attention in the medical and scientific community as the much less common Zika virus, despite causing similar neurological complications, says Boger. In addition, CMV causes colitis in individuals with Crohn's disease and patients with suppressed immune systems, making it a significant risk to transplant recipients. Other researchers involved in this study are Yi-Hsin Fan, Sujayita Roy, Rupkatha Mukhopadhyay and Arun Kapoor of the Johns Hopkins University School of Medicine; Priya Duggal and Genevieve L. Wojcik of the Johns Hopkins Bloomberg School of Public Health; and Robert F. Pass of the University of Alabama at Birmingham. This research was supported by the Johns Hopkins Institute of Clinical and Translational Research. Genotyping services were provided by The Johns Hopkins University under NO1-HV-48195 from the National Heart, Lung, and Blood Institute.

The International Nurses Association is pleased to welcome Cherie P. Huey, RN, BSN, Registered Nurse, to their prestigious organization with her upcoming publication in the Worldwide Leaders in Healthcare. Cherie P. Huey holds over 36 years of experience and an extensive expertise in all facet of nursing. She is currently serving patients at the UAB Hospital in Birmingham, Alabama, specializing as a charge nurse and transplant coordinator. Cherie P. Huey’s career in nursing began in 1980 when she graduated with her Associate of Science Degree in Nursing from Jefferson State Community College in Birmingham. An advocate for continuing education, Cherie went on to obtain her Bachelor of Science Degree in Nursing in 1985 from the University of Alabama at Birmingham. Furthermore, Cherie holds additional certification in Basic Life Support and Parish Nursing. During her long and successful nursing career, Cherie has become an expert transplant nurse, and a specialist in the management of clinical documentation. Cherie has always wanted to be a nurse and loves fulfilling her calling, and it’s this that she attributes her success to. When she is not assisting her patients, Cherie is a Heart Walk volunteer, and is active in her church. Learn more about Cherie P. Huey here: and be sure to read her upcoming publication in Worldwide Leaders in Healthcare.

News Article | February 15, 2017

Development of host-cell directed therapies that could restore cellular function during M. tuberculosis infection, such as a 'release and kill' strategy, could shorten drug treatment of TB patients BIRMINGHAM, Ala. - Mycobacterium tuberculosis has been called "the perfect pathogen." These bacteria hijack human macrophages, persist inside the cells to evade immune destruction, and then prevent the macrophage from undergoing programmed cell death. This provides a niche where they grow in a protected environment that is hard to reach with antibiotics. An end to that hijacking may now be possible, as University of Alabama at Birmingham researchers explain in the journal Scientific Reports. In a proof-of-concept experiment, they were able to specifically force M. tuberculosis-infected macrophages into programmed cell death called apoptosis, thereby releasing the sheltered M. tuberculosis bacteria from the macrophage. The released pathogenic bacteria could then be killed by a lower concentration of rifampicin, one of the front-line tuberculosis antibiotics that is ineffective against the sheltered intracellular bacteria. This strategy has been dubbed "release and kill," by Jim Sun, Ph.D., and colleagues, and if developed to clinical application, it could mean greatly shortened treatment periods for patients with tuberculosis, which now last at least six months. Their preclinical findings show, for the first time, that drug-induced selective apoptosis of M. tuberculosis-infected macrophages is achievable. Furthermore, drug-induced apoptosis could also improve the adaptive immune response against the pathogen and potentiate vaccines. More than 10 million people develop active tuberculosis disease each year, and 1.8 million die. This latest paper expands upon seminal results published by Sun and colleagues last year. They identified a macrophage enzyme called PPM1A as a central component of both the antiviral and antibacterial responses of macrophages. When M. tuberculosis infects macrophages, they found that it induced the upregulation of PPM1A, which in turn caused what Sun called "immune paralysis" of the macrophages. Specifically, the heightened PPM1A levels abrogated the ability of macrophages to send out an "alarm signal" (the efficient production of cytokines and chemokines) in response to pathogen-associated molecules like lipopolysaccharide, it blocked the rush to the "scene of the fire" (migration of macrophages in response to a chemotactic signal of infection from other cells), and it prevented the macrophage's ability to "put out the fire" (by impairing the macrophage's capacity to engulf, or phagocytose, bacteria, the first step in the normal defense against bacterial infections). In this latest Scientific Reports paper, the UAB researchers greatly expand their understanding of PPM1A's role beyond immune paralysis. They show how the abnormal upregulation of this macrophage enzyme provoked by M. tuberculosis acts as a checkpoint that ends the macrophage's ability to undergo both intrinsic and extrinsic apoptosis. Apoptosis is a normal, daily event. Between 50 billion and 70 billion cells in an adult undergo apoptotic death every day. Intrinsic apoptosis responds to a signal of cell aging or dysfunction from the inside, and extrinsic apoptosis responds to a 'death signal' from outside the cell. The normal apoptosis of a macrophage after it has engulfed an invading bacterium leads to priming of cell-mediated immunity, helps to kill the intracellular bacteria and limits harmful tissue inflammation. M. tuberculosis blocks these events, and when the bacteria are ready to exit the macrophage to disseminate, they induce necrosis, not apoptosis, of the cell, which evades stimulation of an immune reaction. PPM1A is the protein called Protein Phosphatase, Mg2+/Mn2+-dependent 1A. Besides showing that the heightened PPM1A production blocked intrinsic and extrinsic apoptosis, Sun and colleagues examined its mechanism of action. In a variety of elegant experiments using PPM1A overexpression or knockdown mutants, kinome analysis, and a selective inhibitor of PPM1A, the researchers showed that PPM1A controls a downstream effector of apoptosis, the c-Jun N-terminal kinase enzyme, or JNK. Elevated PPM1A levels in overexpression mutants or M. tuberculosis-infected macrophages inactivated JNK. This inactivation could be bypassed by sub-toxic treatment with the JNK agonist anisomysin to induce selective apoptotic killing of M. tuberculosis-infected human macrophages. Sun is a Research Fellow in the UAB Department of Medicine, Division of Infectious Diseases, mentored by Olaf Kutsch, Ph.D. Besides Sun and Kutsch, authors of the paper, "Mycobacterium tuberculosis exploits the PPM1A signaling pathway to block host macrophage apoptosis," are Kaitlyn Schaaf, Samuel R. Smith, Alexandra Duverger, Frederic Wagner, Frank Wolschendorf and Andrew O. Westfall, UAB Department of Medicine.

de los Campos G.,University of Alabama at Birmingham | Vazquez A.I.,University of Alabama at Birmingham | Fernando R.,Iowa State University | Klimentidis Y.C.,University of Arizona | Sorensen D.,University of Aarhus
PLoS Genetics | Year: 2013

Despite important advances from Genome Wide Association Studies (GWAS), for most complex human traits and diseases, a sizable proportion of genetic variance remains unexplained and prediction accuracy (PA) is usually low. Evidence suggests that PA can be improved using Whole-Genome Regression (WGR) models where phenotypes are regressed on hundreds of thousands of variants simultaneously. The Genomic Best Linear Unbiased Prediction (G-BLUP, a ridge-regression type method) is a commonly used WGR method and has shown good predictive performance when applied to plant and animal breeding populations. However, breeding and human populations differ greatly in a number of factors that can affect the predictive performance of G-BLUP. Using theory, simulations, and real data analysis, we study the performance of G-BLUP when applied to data from related and unrelated human subjects. Under perfect linkage disequilibrium (LD) between markers and QTL, the prediction R-squared (R2) of G-BLUP reaches trait-heritability, asymptotically. However, under imperfect LD between markers and QTL, prediction R2 based on G-BLUP has a much lower upper bound. We show that the minimum decrease in prediction accuracy caused by imperfect LD between markers and QTL is given by (1-b)2, where b is the regression of marker-derived genomic relationships on those realized at causal loci. For pairs of related individuals, due to within-family disequilibrium, the patterns of realized genomic similarity are similar across the genome; therefore b is close to one inducing small decrease in R2. However, with distantly related individuals b reaches very low values imposing a very low upper bound on prediction R2. Our simulations suggest that for the analysis of data from unrelated individuals, the asymptotic upper bound on R2 may be of the order of 20% of the trait heritability. We show how PA can be enhanced with use of variable selection or differential shrinkage of estimates of marker effects. © 2013 de los Campos et al.

Volpicelli-Daley L.A.,University of Alabama at Birmingham | Luk K.C.,University of Pennsylvania | Lee V.M.-Y.,University of Pennsylvania
Nature Protocols | Year: 2014

This protocol describes a primary neuronal model of formation of α-synuclein (α-syn) aggregates that recapitulate features of the Lewy bodies and Lewy neurites found in Parkinson's disease brains and other synucleinopathies. This model allows investigation of aggregate formation, their impact on neuron function, and development of therapeutics. Addition of preformed fibrils (PFFs) synthesized from recombinant α-syn to neurons seeds the recruitment of endogenous α-syn into aggregates characterized by detergent insolubility and hyperphosphorylation. Aggregate formation follows a lag phase of 2-3 d, followed by formation in axons by days 4-7, spread to somatodendritic compartments by days 7-10 and neuron death ∼14 d after PFF addition. Here we provide methods and highlight the crucial steps for PFF formation, PFF addition to cultured hippocampal neurons and confirmation of aggregate formation. Neurons derived from various brain regions from nontransgenic and genetically engineered mice and rats can be used, allowing interrogation of the effect of specific genes on aggregate formation. © 2014 Nature America, Inc. All rights reserved.

Michaelis L.C.,Medical College of Wisconsin | Erba H.P.,University of Alabama at Birmingham
Current Opinion in Hematology | Year: 2015

PURPOSE OF REVIEW: The treatment of acute myeloid leukemia (AML) in older persons remains a tremendous clinical challenge. AML in older patients is more often associated with biologically unfavorable features, and these patients are less likely to tolerate or accept intensive therapy. There have not been substantial improvements in outcome for this group of patients despite decades of research. In this review, we summarize the most substantial contributions in the past 2 years. RECENT FINDINGS: There have been three major research themes in the recently published literature for older patients with AML: methods to predict response to therapy, models to predict toxicity of therapy in older, less-fit patients, and investigation of novel agents for AML patients with either newly diagnosed or relapsed disease. An unexpected recent finding has been the observation that complete remission in this disease may not necessarily translate into an overall survival advantage, and conversely, survival benefit has been demonstrated without any improvement in complete remission. SUMMARY: Although anthracycline and cytarabine-based therapy remains the standard of care for older patients with AML, this option remains suboptimal for the vast majority of patients. We argue for a national research agenda that may help to accelerate progress for older people with AML. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Abraham W.T.,Ohio State University | Stevenson L.W.,Brigham and Women's Hospital | Bourge R.C.,University of Alabama at Birmingham | Lindenfeld J.A.,Vanderbilt University | And 2 more authors.
The Lancet | Year: 2016

Background In the CHAMPION trial, significant reductions in admissions to hospital for heart failure were seen after 6 months of pulmonary artery pressure guided management compared with usual care. We examine the extended efficacy of this strategy over 18 months of randomised follow-up and the clinical effect of open access to pressure information for an additional 13 months in patients formerly in the control group. Methods The CHAMPION trial was a prospective, parallel, single-blinded, multicentre study that enrolled participants with New York Heart Association (NYHA) Class III heart failure symptoms and a previous admission to hospital. Patients were randomly assigned (1:1) by centre in block sizes of four by a secure validated computerised randomisation system to either the treatment group, in which daily uploaded pulmonary artery pressures were used to guide medical therapy, or to the control group, in which daily uploaded pressures were not made available to investigators. Patients in the control group received all standard medical, device, and disease management strategies available. Patients then remained masked in their randomised study group until the last patient enrolled completed at least 6 months of study follow-up (randomised access period) for an average of 18 months. During the randomised access period, patients in the treatment group were managed with pulmonary artery pressure and patients in the control group had usual care only. At the conclusion of randomised access, investigators had access to pulmonary artery pressure for all patients (open access period) averaging 13 months of follow-up. The primary outcome was the rate of hospital admissions between the treatment group and control group in both the randomised access and open access periods. Analyses were by intention to treat. This trial is registered with, number NCT00531661. Findings Between Sept 6, 2007, and Oct 7, 2009, 550 patients were randomly assigned to either the treatment group (n=270) or to the control group (n=280). 347 patients (177 in the former treatment group and 170 in the former control group) completed the randomised access period in August, 2010, and transitioned to the open access period which ended April 30, 2012. Over the randomised access period, rates of admissions to hospital for heart failure were reduced in the treatment group by 33% (hazard ratio [HR] 0·67 [95% CI 0·55-0·80]; p<0·0001) compared with the control group. After pulmonary artery pressure information became available to guide therapy during open access (mean 13 months), rates of admissions to hospital for heart failure in the former control group were reduced by 48% (HR 0·52 [95% CI 0·40-0·69]; p<0·0001) compared with rates of admissions in the control group during randomised access. Eight (1%) device-related or system related complications and seven (1%) procedure-related adverse events were reported. Interpretation Management of NYHA Class III heart failure based on home transmission of pulmonary artery pressure with an implanted pressure sensor has significant long-term benefit in lowering hospital admission rates for heart failure. Funding St Jude Medical Inc. © 2016 Elsevier Ltd.

Kushi L.H.,Kaiser Permanente | Doyle C.,American Physical Society | McCullough M.,Nutritional Epidemiology | Rock C.L.,University of California at San Diego | And 6 more authors.
CA Cancer Journal for Clinicians | Year: 2012

The American Cancer Society (ACS) publishes Nutrition and Physical Activity Guidelines to serve as a foundation for its communication, policy, and community strategies and, ultimately, to affect dietary and physical activity patterns among Americans. These Guidelines, published approximately every 5 years, are developed by a national panel of experts in cancer research, prevention, epidemiology, public health, and policy, and they reflect the most current scientific evidence related to dietary and activity patterns and cancer risk. The ACS Guidelines focus on recommendations for individual choices regarding diet and physical activity patterns, but those choices occur within a community context that either facilitates or creates barriers to healthy behaviors. Therefore, this committee presents recommendations for community action to accompany the 4 recommendations for individual choices to reduce cancer risk. These recommendations for community action recognize that a supportive social and physical environment is indispensable if individuals at all levels of society are to have genuine opportunities to choose healthy behaviors. The ACS Guidelines are consistent with guidelines from the American Heart Association and the American Diabetes Association for the prevention of coronary heart disease and diabetes, as well as for general health promotion, as defined by the 2010 Dietary Guidelines for Americans and the 2008 Physical Activity Guidelines for Americans. Copyright © 2012 American Cancer Society, Inc.

Sharief S.,Rush University Medical Center | Jariwala S.,Montefiore Medical Center | Kumar J.,New York Medical College | Muntner P.,University of Alabama at Birmingham | Melamed M.L.,Yeshiva University
Journal of Allergy and Clinical Immunology | Year: 2011

Background: Previous research supports a possible link between low vitamin D levels and atopic disease. However, the association between low vitamin D levels and total and allergen-specific IgE levels has not been studied. Objective: We sought to test the association between serum 25-hydroxyvitamin D (25[OH]D) deficiency (<15 ng/mL) and insufficiency (15-29 ng/mL) and allergic sensitization measured by serum IgE levels in a US nationally representative sample of 3136 children and adolescents and 3454 adults in the National Health and Nutrition Examination Survey 2005-2006. Methods: The association of 25(OH)D deficiency with 17 different allergens was assessed after adjustment for potential confounders, including age; sex; race/ethnicity; obesity, low socioeconomic status; frequency of milk intake; daily hours spent watching television, playing videogames, or using a computer; serum cotinine levels; and vitamin D supplement use. Results: In children and adolescents allergic sensitization to 11 of 17 allergens was more common in those with 25(OH)D deficiency. Compared with sufficient vitamin D levels of greater than 30 ng/mL, after multivariate adjustment, 25(OH)D levels of less than 15 ng/mL were associated with peanut (odds ratio [OR], 2.39; 95% CI, 1.29-4.45), ragweed (OR, 1.83; 95% CI, 1.20-2.80), and oak (OR, 4.75; 95% CI, 1.53-4.94) allergies (P < .01 for all). Eight other allergens were associated with 25(OH)D deficiency, with P values of less than .05 but greater than .01. There were no consistent associations seen between 25(OH)D levels and allergic sensitization in adults. Conclusion: Vitamin D deficiency is associated with higher levels of IgE sensitization in children and adolescents. Further research is needed to confirm these findings. © 2011 American Academy of Allergy, Asthma & Immunology.

Sweetwyne M.T.,University of Pennsylvania | Murphy-Ullrich J.E.,University of Alabama at Birmingham
Matrix Biology | Year: 2012

Thrombospondin 1 (TSP1) plays major roles in both physiologic and pathologic tissue repair. TSP1 through its type 1 repeats is a known regulator of latent TGF-β activation and plays a role in wound healing and fibrosis. Binding of the TSP N-terminal domain to cell surface calreticulin in complex with LDL-receptor related protein 1 stimulates intermediate cell adhesion, cell migration, anoikis resistance, collagen expression and matrix deposition in an in vivo model of the foreign body response. There is also emerging evidence that TSP EGF-like repeats alter endothelial cell-cell interactions and stimulate epithelial migration through transactivation of EGF receptors. The mechanisms underlying these functions of TSP1 and the implications for physiologic and pathologic wound repair and fibrosis will be discussed. © 2012 International Society of Matrix Biology.

Bailis W.,University of Pennsylvania | Yashiro-Ohtani Y.,University of Pennsylvania | Fang T.,University of Pennsylvania | Hatton R.,University of Alabama at Birmingham | And 3 more authors.
Immunity | Year: 2013

Two models are proposed to explain Notch function during helper T (Th) cell differentiation. One argues that Notch instructs one Th cell fate over the other, whereas the other posits that Notch function is dictated by cytokines. Here we provide a detailed mechanistic study investigating the role of Notch in orchestrating Th cell differentiation. Notch neither instructed Th cell differentiation nor did cytokines direct Notch activity, but instead, Notch simultaneously regulated the Th1, Th2, and Th17 cell genetic programs independently of cytokine signals. In addition to regulating these programs in both polarized and nonpolarized Th cells, we identified Ifng as a direct Notch target. Notch bound the Ifng CNS-22 enhancer, where it synergized with Tbet at the promoter. Thus, Notch acts as an unbiased amplifier of Th cell differentiation. Our data provide a paradigm for Notch in hematopoiesis, with Notch simultaneously orchestrating multiple lineage programs, rather than restricting alternate outcomes. © 2013 Elsevier Inc.

Koster D.A.,Weizmann Institute of Science | Crut A.,University Claude Bernard Lyon 1 | Shuman S.,Sloan Kettering Institute | Bjornsti M.-A.,University of Alabama at Birmingham | Dekker N.H.,Technical University of Delft
Cell | Year: 2010

Entangling and twisting of cellular DNA (i.e., supercoiling) are problems inherent to the helical structure of double-stranded DNA. Supercoiling affects transcription, DNA replication, and chromosomal segregation. Consequently the cell must fine-tune supercoiling to optimize these key processes. Here, we summarize how supercoiling is generated and review experimental and theoretical insights into supercoil relaxation. We distinguish between the passive dissipation of supercoils by diffusion and the active removal of supercoils by topoisomerase enzymes. We also review single-molecule studies that elucidate the timescales and mechanisms of supercoil removal. © 2010 Elsevier Inc.

Patel R.P.,University of Alabama at Birmingham | Hogg N.,Medical College of Wisconsin | Kim-Shapiro D.B.,Wake forest University
Cardiovascular Research | Year: 2011

Nitrite was once thought to have little physiological relevance. However, nitrite is now being increasingly recognized as a therapeutic or possibly even physiological precursor of nitric oxide (NO) that is utilized when needed to increase blood flow. It is likely that different mechanisms for nitrite bioconversion occur in different tissues, but in the vascular system, there is evidence that erythrocyte haemoglobin (Hb) is responsible for the oxygen-dependent reduction of nitrite to modulate blood flow. Here, we review the complex chemical interactions of Hb and nitrite and discuss evidence supporting its role in vasodilation. We also discuss ongoing work focused on defining the precise mechanisms for export of NO activity from red blood cells and of other pathways that may mediate nitrite-dependent vasodilation. © 2010 The Author.

Athar M.,University of Alabama at Birmingham | Kopelovich L.,U.S. National Cancer Institute
Cancer Prevention Research | Year: 2011

Therapeutic and preventive effects of rapamycin include reduced risk of nonmelanoma skin cancer (NMSC). In this issue of the journal (beginning on page 1011), Checkley and colleagues report that rapamycin inhibits mTOR complex 1 in murine epidermis, thereby inhibiting tumor promotion mediated by tetradecanoyl phorbol-13 acetate in association with a strong anti-inflammatory effect. Rapamycin is an immunosuppressive drug for preventing graft rejection in organ transplant recipients and reduces the risk of NMSC and Kaposi's sarcoma in this population, albeit by mechanisms distinct from immunosuppression. Important future directions include identifying molecular predictors of rapamycin/rapalog sensitivity or resistance (potentially, for example, PI3K pathway alterations and KRAS mutations) and combined non-rapalog, mTOR-targeting approaches, all of which should increase efficacy and minimize toxicity. ©2011 AACR.

Spaide R.F.,Vitreous Retina Macula Consultants of New York | Spaide R.F.,Ear and Throat Hospital | Curcio C.A.,University of Alabama at Birmingham
Retina | Year: 2010

Purpose: To characterize the known appearance of cuticular drusen, subretinal drusenoid deposits (reticular pseudodrusen), and soft drusen as revealed by multimodal fundus imaging and to create an explanatory model that accounts for these observations. Methods: Reported color, fluorescein angiographic, autofluorescence, and spectral domain optical coherence tomography images of patients with cuticular drusen, soft drusen, and subretinal drusenoid deposits were reviewed, as were actual images from affected eyes. Representative histological sections were examined. The geometry, location, and imaging characteristics of these lesions were evaluated. A hypothesis based on the Beer-Lambert law of light absorption was generated to fit these observations. Results: Cuticular drusen appear as numerous, uniform, round, yellow-white punctate accumulations under the retinal pigment epithelium (RPE). Soft drusen are larger, yellow-white dome-shaped mounds of deposit under the RPE. Subretinal drusenoid deposits are polymorphous light-gray interconnected accumulations above the RPE. Based on the model, both cuticular and soft drusen appear yellow because of the removal of shorter wavelength light by a double pass through the RPE. Subretinal drusenoid deposits, which are located on the RPE, are not subjected to short-wavelength attenuation and therefore are more prominent when viewed with blue light. The location and morphology of extracellular material in relationship to the RPE, and associated changes to RPE morphology and pigmentation, appeared to be the primary determinants of druse appearance in different imaging modalities. Conclusion: Although cuticular drusen, subretinal drusenoid deposits, and soft drusen are composed of common components, they are distinguishable by multimodal imaging because of differences in location, morphology, and optical filtering effects by drusenoid material and the RPE. Copyright © by Ophthalmic Communications Society, Inc.

Kahan S.M.,University of Alabama at Birmingham | Wherry E.J.,University of Pennsylvania | Zajac A.J.,University of Alabama at Birmingham
Virology | Year: 2015

Although robust and highly effective anti-viral T cells contribute to the clearance of many acute infections, viral persistence is associated with the development of functionally inferior, exhausted, T cell responses. Exhaustion develops in a step-wise and progressive manner, ranges in severity, and can culminate in the deletion of the anti-viral T cells. This disarming of the response is consequential as it compromises viral control and potentially serves to dampen immune-mediated damage. Exhausted T cells are unable to elaborate typical anti-viral effector functions. They are characterized by the sustained upregulation of inhibitory receptors and display a gene expression profile that distinguishes them from prototypic effector and memory T cell populations. In this review we discuss the properties of exhausted T cells; the virological and immunological conditions that favor their development; the cellular and molecular signals that sustain the exhausted state; and strategies for preventing and reversing exhaustion to favor viral control. © 2014 Elsevier Inc.

Fritsche L.G.,University of Michigan | Fariss R.N.,Biological Imaging Core | Stambolian D.,University of Pennsylvania | Abecasis G.R.,University of Michigan | And 2 more authors.
Annual Review of Genomics and Human Genetics | Year: 2014

Genetic and genomic studies have enhanced our understanding of complex neurodegenerative diseases that exert a devastating impact on individuals and society. One such disease, age-related macular degeneration (AMD), is a major cause of progressive and debilitating visual impairment. Since the pioneering discovery in 2005 of complement factor H (CFH) as a major AMD susceptibility gene, extensive investigations have confirmed 19 additional genetic risk loci, and more are anticipated. In addition to common variants identified by now-conventional genome-wide association studies, targeted genomic sequencing and exome-chip analyses are uncovering rare variant alleles of high impact. Here, we provide a critical review of the ongoing genetic studies and of common and rare risk variants at a total of 20 susceptibility loci, which together explain 40-60% of the disease heritability but provide limited power for diagnostic testing of disease risk. Identification of these susceptibility loci has begun to untangle the complex biological pathways underlying AMD pathophysiology, pointing to new testable paradigms for treatment. Copyright © 2014 by Annual Reviews. All rights reserved.

Basu R.,University of Alabama at Birmingham | Whitley S.K.,University of Alabama at Birmingham | Bhaumik S.,University of Alabama at Birmingham | Zindl C.L.,University of Alabama at Birmingham | And 5 more authors.
Nature Immunology | Year: 2015

Interleukin 17 (IL-17)-producing helper T cells (TH 17 cells) and CD4 + inducible regulatory T cells (iTreg cells) emerge from an overlapping developmental program. In the intestines, the vitamin A metabolite retinoic acid (RA) is produced at steady state and acts as an important cofactor to induce iTreg cell development while potently inhibiting TH 17 cell development. Here we found that IL-1 was needed to fully override RA-mediated expression of the transcription factor Foxp3 and induce protective TH 17 cell responses. By repressing expression of the negative regulator SOCS3 dependent on the transcription factor NF-κB, IL-1 increased the amplitude and duration of phosphorylation of the transcription factor STAT3 induced by TH 17-polarizing cytokines, which led to an altered balance in the binding of STAT3 and STAT5 to shared consensus sequences in developing T cells. Thus, IL-1 signaling modulated STAT activation downstream of cytokine receptors differently to control the TH 17 cell-iTreg cell developmental fate. © 2015 Nature America, Inc.

New Rochelle, NY, November 16, 2016--A new study found significant changes in white matter pathways in the brains of individuals with autism spectrum disorder (ASD) using a novel technique called Automated Fiber Quantification (AFQ). Evidence of both increases and decreases in diffusion across white matter tracts and the relationship of these changes to patient age are reported in Brain Connectivity, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available free on the Brain Connectivity website until December 16, 2016. Lauren Libero, UC Davis M.I.N.D. Institute, Sacramento, CA, Wesley Burge, Hrishikesh Deshpande, and Rajesh Kana, University of Alabama at Birmingham, and Franco Pestilli, Indiana University, Bloomington, describe the AFQ technique in the article entitled "White Matter Diffusion of Major Fiber Tracts Implicated in Autism Spectrum Disorder." AFQ gives researchers access to diffusion information along an entire tract of white matter, instead of having to rely on average measures, which may improve their ability to identify clinical differences that are linked to microstructural changes in the brain. "Autism researchers have hypothesized that the disorder is caused by large-scale disruptions in brain connectivity," says Christopher Pawela, PhD, Co-Editor-in-Chief of Brain Connectivity and Assistant Professor, Medical College of Wisconsin. "Lauren Libero and colleagues support this hypothesis by demonstrating that subtle alterations of white matter tracts, which are the structural wiring system in the brain, are present in affected individuals. They performed this work using their newly developed magnetic resonance imaging methodology that provides increased sensitivity to white matter changes." Brain Connectivity is the essential peer-reviewed journal covering groundbreaking findings in the rapidly advancing field of connectivity research at the systems and network levels. Published 10 times per year in print and online, the Journal is under the leadership of Founding and Co-Editors-in-Chief Christopher Pawela, PhD, Assistant Professor, Medical College of Wisconsin, and Bharat Biswal, PhD, Chair of Biomedical Engineering, New Jersey Institute of Technology. It includes original peer-reviewed papers, review articles, point-counterpoint discussions on controversies in the field, and a product/technology review section. To ensure that scientific findings are rapidly disseminated, articles are published Instant Online within 72 hours of acceptance, with fully typeset, fast-track publication within 4 weeks. Tables of content and a sample issue may be viewed on the Brain Connectivity website. Mary Ann Liebert, Inc., publishers is a privately held, fully integrated media company known for establishing authoritative medical and biomedical peer-reviewed journals, including Journal of Neurotrauma and Therapeutic Hypothermia and Temperature Management. Its biotechnology trade magazine, GEN (Genetic Engineering & Biotechnology News), was the first in its field and is today the industry's most widely read publication worldwide. A complete list of the firm's 80 journals, newsmagazines, and books is available on the Mary Ann Liebert, Inc., publishers website.

News Article | November 19, 2016

Participating in yoga is relatively safe, according to a new study from researchers at the University of Alabama at Birmingham who conducted the first large-scale examination of yoga-related injuries. Their conclusions? Injuries are more common in older participants, and having a qualified instructor is important. Yoga is an increasingly popular practice in America. The Yoga in America Study, commissioned by the Yoga Journal and Yoga Alliance, says 36.7 million Americans participate in yoga. UAB researchers from the Center for Injury Sciences studied data from the National Electronic Injury Surveillance System compiled from 2001 and 2014 for the study published in the Orthopedic Journal of Sports Medicine. "Yoga injuries are relatively rare, and as you might expect, the incidence tends to rise with the age of the participant," said Thomas Swain, MPH, a research assistant at the Center for Injury Sciences and first author of the study. "We did find that the injury rate is increasing over time, which may be a reflection of the increase in popularity of yoga, leading to an increase in inexperienced participants who do not take the necessary precautions to avoid injury." Swain's team found the overall rate of yoga-related injuries climbed to 17 per 100,000 participants in 2014, up from 10 per 100,000 in 2001. The injury rate for older participants was higher. Those 65 and older experienced an injury rate of 58 per 100,000. Individuals ages 45-64 saw an injury rate of 18 per 100,000, while those between 18-44 years of age had an injury rate of 12 per 100,000. Overall, the team found 29,590 yoga-related injuries during the study period. Nearly half were injuries to the trunk, and sprains or strains accounted for 45 percent of all injuries. "The incidence of fracture was highest in the older population, some three times higher than in the younger population," Swain said. "For all injuries, the actual risk might be higher than our numbers show, as we surveyed results only from those who sought medical attention in an emergency department." As with any sport or physical activity, the authors say it is important to be sure you are physically capable of the undertaking. "Talk to your physician before taking up yoga, be cautious, and recognize your personal limitations, particularly if you are over 65," Swain said. "Yoga is harder and more demanding than some people believe," said Gerald McGwin, Ph.D., the director of the Center for Injury Sciences and a co-author of the study. McGwin took up yoga on the advice of a physician following a running injury. "You need a realistic view of your own abilities, and you need to understand that some poses might be too challenging and inappropriate. A qualified, certified yoga instructor can help you with that assessment and is essential to a safe experience." Stephen Fletcher, owner of the Yoga Circle, is a certified yoga instructor. He recommends looking for an instructor who is certified by the Yoga Alliance, the largest nonprofit association representing the yoga community. "You want an instructor who has had good training and has some experience in the field," Fletcher said. "To avoid injury, you want someone who has a good understanding of anatomy and understands how muscle groups interact and align." When starting out in yoga, Fletcher says to look for a slower-paced yoga class for an introductory experience. Smaller classes could be beneficial as well, as the instructor may have more time to work one-on-one with each participant. Swain and McGwin also suggest that national standards for yoga instructor certification should be created and that safety and injury prevention information should be aggressively taught to all yoga practitioners. "There are many benefits to yoga, and overall our findings show it is relatively safe," McGwin said. "But there is an injury risk, especially for older populations, and that risk should not be ignored." The Center for Injury Sciences is part of the Division of Acute Care Surgery, Department of Surgery, in the UAB School of Medicine. McGwin is also a professor of epidemiology in the UAB School of Public Health.

News Article | March 9, 2016

Whenever a paper about CRISPR–Cas9 hits the press, the staff at Addgene quickly find out. The non-profit company is where study authors often deposit molecular tools that they used in their work, and where other scientists immediately turn to get them. It is also where other scientists immediately turn to get their hands on these reagents. “We get calls within minutes of a hot paper publishing,” says Joanne Kamens, executive director of the company in Cambridge, Massachusetts. Addgene's phones have been ringing a lot since early 2013, when researchers first reported1, 2, 3 that they had used the CRISPR–Cas9 system to slice the genome in human cells at sites of their choosing. “It was all hands on deck,” Kamens says. Since then, molecular biologists have rushed to adopt the technique, which can be used to alter the genome of almost any organism with unprecedented ease and finesse. Addgene has sent 60,000 CRISPR-related molecular tools — about 17% of its total shipments — to researchers in 83 countries, and the company's CRISPR-related pages were viewed more than one million times in 2015. Much of the conversation about CRISPR–Cas9 has revolved around its potential for treating disease or editing the genes of human embryos, but researchers say that the real revolution right now is in the lab. What CRISPR offers, and biologists desire, is specificity: the ability to target and study particular DNA sequences in the vast expanse of a genome. And editing DNA is just one trick that it can be used for. Scientists are hacking the tools so that they can send proteins to precise DNA targets to toggle genes on or off, and even engineer entire biological circuits — with the long-term goal of understanding cellular systems and disease. “For the humble molecular biologist, it's really an extraordinarily powerful way to understand how the genome works,” says Daniel Bauer, a haematologist at the Boston Children's Hospital in Massachusetts. “It's really opened the number of questions you can address,” adds Peggy Farnham, a molecular biologist at the University of Southern California, Los Angeles. “It's just so fun.” Here, Nature examines five ways in which CRISPR–Cas9 is changing how biologists can tinker with cells. There are two chief ingredients in the CRISPR–Cas9 system: a Cas9 enzyme that snips through DNA like a pair of molecular scissors, and a small RNA molecule that directs the scissors to a specific sequence of DNA to make the cut. The cell's native DNA repair machinery generally mends the cut — but often makes mistakes. That alone is a boon to scientists who want to disrupt a gene to learn about what it does. The genetic code is merciless: a minor error introduced during repair can completely alter the sequence of the protein it encodes, or halt its production altogether. As a result, scientists can study what happens to cells or organisms when the protein or gene is hobbled. But there is also a different repair pathway that sometimes mends the cut according to a DNA template. If researchers provide the template, they can edit the genome with nearly any sequence they desire at nearly any site of their choosing. In 2012, as laboratories were racing to demonstrate how well these gene-editing tools could cut human DNA, one team decided to take a different approach. “The first thing we did: we broke the scissors,” says Jonathan Weissman, a systems biologist at the University of California, San Francisco (UCSF). Weissman learned about the approach from Stanley Qi, a synthetic biologist now at Stanford University in California, who mutated the Cas9 enzyme so that it still bound DNA at the site that matched its guide RNA, but no longer sliced it. Instead, the enzyme stalled there and blocked other proteins from transcribing that DNA into RNA. The hacked system allowed them to turn a gene off, but without altering the DNA sequence4. The team then took its 'dead' Cas9 and tried something new: the researchers tethered it to part of another protein, one that activates gene expression. With a few other tweaks, they had built a way to turn genes on and off at will5. Several labs have since published variations on this method; many more are racing to harness it for their research6 (see 'Hacking CRISPR'). One popular application is to rapidly generate hundreds of different cell lines, each containing a different guide RNA that targets a particular gene. Martin Kampmann, another systems biologist at UCSF, hopes to screen such cells to learn whether flipping certain genes on or off affects the survival of neurons exposed to toxic protein aggregates — a mechanism that is thought to underlie several neurodegenerative conditions, including Alzheimer's disease. Kampmann had been carrying out a similar screen with RNA interference (RNAi), a technique that also silences genes and can process lots of molecules at once, but which has its drawbacks. “RNAi is a shotgun with well-known off-target effects,” he says. “CRISPR is the scalpel that allows you to be more specific.” Weissman and his colleagues, including UCSF systems biologist Wendell Lim, further tweaked the method so that it relied on a longer guide RNA, with motifs that bound to different proteins. This allowed them to activate or inhibit genes at three different sites all in one experiment7. Lim thinks that the system can handle up to five operations at once. The limit, he says, may be in how many guide RNAs and proteins can be stuffed into a cell. “Ultimately, it's about payload.” That combinatorial power has drawn Ron Weiss, a synthetic biologist at the Massachusetts Institute of Technology (MIT) in Cambridge, into the CRISPR–Cas9 frenzy. Weiss and his colleagues have also created multiple gene tweaks in a single experiment8, making it faster and easier to build complicated biological circuits that could, for example, convert a cell's metabolic machinery into a biofuel factory. “The most important goal of synthetic biology is to be able to program complex behaviour via the creation of these sophisticated circuits,” he says. When geneticist Marianne Rots began her career, she wanted to unearth new medical cures. She studied gene therapy, which targets genes mutated in disease. But after a few years, she decided to change tack. “I reasoned that many more diseases are due to disturbed gene-expression profiles, not so much the single genetic mutations I had been focused on,” says Rots, at the University Medical Center Groningen in the Netherlands. The best way to control gene activity, she thought, was to adjust the epigenome, rather than the genome itself. The epigenome is the constellation of chemical compounds tacked onto DNA and the DNA-packaging proteins called histones. These can govern access to DNA, opening it up or closing it off to the proteins needed for gene expression. The marks change over time: they are added and removed as an organism develops and its environment shifts. In the past few years, millions of dollars have been poured into cataloguing these epigenetic marks in different human cells, and their patterns have been correlated with everything from brain activity to tumour growth. But without the ability to alter the marks at specific sites, researchers are unable to determine whether they cause biological changes. “The field has met a lot of resistance because we haven't had the kinds of tools that geneticists have had, where they can go in and directly test the function of a gene,” says Jeremy Day, a neuroscientist at the University of Alabama at Birmingham. CRISPR–Cas9 could turn things around. In April 2015, Charles Gersbach, a bioengineer at Duke University in Durham, North Carolina, and his colleagues published9 a system for adding acetyl groups — one type of epigenetic mark — to histones using the broken scissors to carry enzymes to specific spots in the genome. The team found that adding acetyl groups to proteins that associate with DNA was enough to send the expression of targeted genes soaring, confirming that the system worked and that, at this location, the epigenetic marks had an effect. When he published the work, Gersbach deposited his enzyme with Addgene so that other research groups could use it — and they quickly did. Gersbach predicts that a wave of upcoming papers will show a synergistic effect when multiple epigenetic markers are manipulated at once. The tools need to be refined. Dozens of enzymes can create or erase an epigenetic mark on DNA, and not all of them have been amenable to the broken-scissors approach. “It turned out to be harder than a lot of people were expecting,” says Gersbach. “You attach a lot of things to a dead Cas9 and they don't happen to work.” Sometimes it is difficult to work out whether an unexpected result arose because a method did not work well, or because the epigenetic mark simply doesn't matter in that particular cell or environment. Rots has explored the function of epigenetic marks on cancer-related genes using older editing tools called zinc-finger proteins, and is now adopting CRISPR–Cas9. The new tools have democratized the field, she says, and that has already had a broad impact. People used to say that the correlations were coincidental, Rots says — that if you rewrite the epigenetics it will have no effect on gene expression. “But now that it's not that difficult to test, a lot of people are joining the field.” Epigenetic marks on DNA are not the only genomic code that is yet to be broken. More than 98% of the human genome does not code for proteins. But researchers think that a fair chunk of this DNA is doing something important, and they are adopting CRISPR–Cas9 to work out what that is. Some of it codes for RNA molecules — such as microRNAs and long non-coding RNAs — that are thought to have functions apart from making proteins. Other sequences are 'enhancers' that amplify the expression of the genes under their command. Most of the DNA sequences linked to the risk of common diseases lie in regions of the genome that contain non-coding RNA and enhancers. But before CRISPR–Cas9, it was difficult for researchers to work out what those sequences do. “We didn't have a good way to functionally annotate the non-coding genome,” says Bauer. “Now our experiments are much more sophisticated.” Farnham and her colleagues are using CRISPR–Cas9 to delete enhancer regions that are found to be mutated in genomic studies of prostate and colon cancer. The results have sometimes surprised her. In one unpublished experiment, her team deleted an enhancer that was thought to be important, yet no gene within one million bases of it changed expression. “How we normally classify the strength of a regulatory element is not corresponding with what happens when you delete that element,” she says. More surprises may be in store as researchers harness CRISPR–Cas9 to probe large stretches of regulatory DNA. Groups led by geneticists David Gifford at MIT and Richard Sherwood at the Brigham and Women's Hospital in Boston used the technique to create mutations across a 40,000-letter sequence, and then examined whether each change had an effect on the activity of a nearby gene that made a fluorescent protein10. The result was a map of DNA sequences that enhanced gene expression, including several that had not been predicted on the basis of gene regulatory features such as chromatin modifications. Delving into this dark matter has its challenges, even with CRISPR–Cas9. The Cas9 enzyme will cut where the guide RNA tells it to, but only if a specific but common DNA sequence is present near the cut site. This poses little difficulty for researchers who want to silence a gene, because the key sequences almost always exist somewhere within it. But for those who want to make very specific changes to short, non-coding RNAs, the options can be limited. “We cannot take just any sequence,” says Reuven Agami, a researcher at the Netherlands Cancer Institute in Amsterdam. Researchers are scouring the bacterial kingdom for relatives of the Cas9 enzyme that recognize different sequences. Last year, the lab of Feng Zhang, a bioengineer at the Broad Institute of MIT and Harvard in Cambridge, characterized a family of enzymes called Cpf1 that work similarly to Cas9 and could expand sequence options11. But Agami notes that few alternative enzymes found so far work as well as the most popular Cas9. In the future, he hopes to have a whole collection of enzymes that can be targeted to any site in the genome. “We're not there yet,” he says. Gersbach's lab is using gene-editing tools as part of an effort to understand cell fate and how to manipulate it: the team hopes one day to grow tissues in a dish for drug screening and cell therapies. But CRISPR–Cas9's effects are permanent, and Gersbach's team needed to turn genes on and off transiently, and in very specific locations in the tissue. “Patterning a blood vessel demands a high degree of control,” he says. Gersbach and his colleagues took their broken, modified scissors — the Cas9 that could now activate genes — and added proteins that are activated by blue light. The resulting system triggers gene expression when cells are exposed to the light, and stops it when the light is flicked off12. A group led by chemical biologist Moritoshi Sato of the University of Tokyo rigged a similar system13, and also made an active Cas9 that edited the genome only after it was hit with blue light14. Others have achieved similar ends by combining CRISPR with a chemical switch. Lukas Dow, a cancer geneticist at Weill Cornell Medical College in New York City, wanted to mutate cancer-related genes in adult mice, to reproduce mutations that have been identified in human colorectal cancers. His team engineered a CRISPR–Cas9 system in which a dose of the compound doxycycline activates Cas9, allowing it to cut its targets15. The tools are another step towards gaining fine control over genome editing. Gersbach's team has not patterned its blood vessels just yet: for now, the researchers are working on making their light-inducible system more efficient. “It's a first-generation tool,” says Gersbach. Cancer researcher Wen Xue spent the first years of his postdoc career making a transgenic mouse that bore a mutation found in some human liver cancers. He slogged away, making the tools necessary for gene targeting, injecting them into embryonic stem cells and then trying to derive mice with the mutation. The cost: a year and US$20,000. “It was the rate-limiting step in studying disease genes,” he says. A few years later, just as he was about to embark on another transgenic-mouse experiment, his mentor suggested that he give CRISPR–Cas9 a try. This time, Xue just ordered the tools, injected them into single-celled mouse embryos and, a few weeks later — voilá. “We had the mouse in one month,” says Xue. “I wish I had had this technology sooner. My postdoc would have been a lot shorter.” Researchers who study everything from cancer to neurodegeneration are embracing CRISPR-Cas9 to create animal models of the diseases. It lets them engineer more animals, in more complex ways, and in a wider range of species. Xue, who now runs his own lab at the University of Massachusetts Medical School in Worcester, is systematically sifting through data from tumour genomes, using CRISPR–Cas9 to model the mutations in cells grown in culture and in animals. Researchers are hoping to mix and match the new CRISPR–Cas9 tools to precisely manipulate the genome and epigenome in animal models. “The real power is going to be the integration of those systems,” says Dow. This may allow scientists to capture and understand some of the complexity of common human diseases. Take tumours, which can bear dozens of mutations that potentially contribute to cancer development. “They're probably not all important in terms of modelling a tumour,” says Dow. “But it's very clear that you're going to need two or three or four mutations to really model aggressive disease and get closer to modelling human cancer.” Introducing all of those mutations into a mouse the old-fashioned way would have been costly and time-consuming, he adds. Bioengineer Patrick Hsu started his lab at the Salk Institute for Biological Studies in La Jolla, California, in 2015; he aims to use gene editing to model neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease in cell cultures and marmoset monkeys. That could recapitulate human behaviours and progression of disease more effectively than mouse models, but would have been unthinkably expensive and slow before CRISPR–Cas9. Even as he designs experiments to genetically engineer his first CRISPR–Cas9 marmosets, Hsu is aware that this approach may be only a stepping stone to the next. “Technologies come and go. You can't get married to one,” he says. “You need to always think about what biological problems need to be solved.”

News Article | October 23, 2015

In 1961, when more and more people were buying television sets to go with their radios, the BBC wanted to work out the best times to air its programmes. So its audience-research department decided to ask a sample of people across the United Kingdom to record what they were doing every half hour of the day, and to indicate whether the TV or radio was on. The result was a trove of 2,363 diaries filled with the everyday details of British lives. “8 a.m., Eating breakfast,” read one; “8.30 a.m., Taking children to school; 9 a.m., Cleaning away, washing up and listening to Housewives' Choice” — a popular radio record-request programme of the day. Today, these files are part of the biggest collection of time-use diaries in the world, kept by the Centre for Time Use Research at the University of Oxford, UK. The centre's holdings have been gathered from nearly 30 countries, span more than 50 years and cover some 850,000 person-days in total. They offer the most detailed portrait ever created of when people work, sleep, play and socialize — and of how those patterns have changed over time. “It certainly is unique,” says Ignace Glorieux, a sociologist at the Dutch-speaking Free University of Brussels. “It started quite modest, and now it's a huge archive.” The collection is helping to solve a slew of scientific and societal puzzles — not least, a paradox about modern life. There is a widespread perception in Western countries that life today is much busier than it once was, thanks to the unending demands of work, family, chores, smartphones and e-mails. But the diaries tell a different story: “We do not get indicators at all that people are more frantic,” says John Robinson, a sociologist who works with time-use diaries at the University of Maryland, College Park. In fact, when paid and unpaid work are totted up, the average number of hours worked every week has not changed much since the 1980s in most countries of the developed world. Epidemiologists, meanwhile, are mining the diaries to explain how lifestyle changes are contributing to a rise in many chronic diseases. The diaries “were the greatest asset I could possibly have”, says physiologist Edward Archer at the University of Alabama at Birmingham, who used the data in a 2013 study1 of obesity. Now, the Oxford centre is testing a major update to its 50-year-old methods. In addition to asking people to complete a handwritten diary, it last year began giving them an electronic fitness tracker and a small camera that snaps a stream of pictures of their day (see 'The gadget guinea pig'). “The idea is to be a bit more adventurous,” says Teresa Harms, a sociology research fellow who is leading the project. “Are new technologies better than what we've been doing all these years?” Ironically for a scientific institute dedicated to time use, the researchers at the Oxford centre are no better at time management than anyone else. If anything, they are worse. One day in July, students were playing a game of croquet on the lawn outside the centre's home: a stone building in the placid grounds of St Hugh's College. But inside, things were more fraught. One flustered postdoc had slept through her alarm and arrived at 10.33 a.m. — more than an hour late for her meeting. The centre's ebullient founder and co-director, sociologist Jonathan Gershuny, cheerily admitted that his own time management is “terrible” — shortly before locking himself out of his office without his keys, ensuring that he would arrive for his next appointment catastrophically late. None of this seems to have slowed down Gershuny, who can trace the origins of the centre to the 1970s, when he was starting his career at the University of Sussex in Brighton, UK. Gershuny wanted to predict what society and the economy would look like in future decades — but he realized that there was very little empirical evidence showing how people actually spend their time. Gershuny started to search for surveys in which people had been asked to record their daily activities. Among his first discoveries were the BBC diaries. Another thousand or so journals, recorded in the 1930s, turned up in a mouldering old tea chest at the university. As Gershuny's diary collection grew, it became obvious that the records had been gathered by many different investigators around the world for many different purposes. To align the data and make meaningful comparisons, he would have to put them into a standardized form. So in the 1980s — by then working at the University of Bath, UK — he developed the Multinational Time Use Study: a system in which every activity is given one of 41 codes (gardening, 9; sleeping, 16; relaxing, 36). In an early project that assessed diaries from the United States and the United Kingdom, Gershuny and Robinson showed in 1988 that women in both nations were spending less time on domestic work, whereas men were doing slightly more — a consequence of women's increasing entry into paid employment and of shifting societal norms2. By the early 2000s, many countries had started to collect standardized time-use data; the US Bureau of Labor Statistics started gathering them annually in 2003. These efforts were driven by a growing global interest in understanding the impacts of time use on economies and on well-being. But the diary bank still remained something of a side line for Gershuny until 2008, when he won funding to develop a centre at Oxford dedicated to time-use research. Then, in 2013, the centre was awarded two major grants: €2.5 million (US$2.8 million) from the European Research Council and £3.7 million (US$5.7 million) from the UK Economic and Social Research Council (ESRC), to exploit the diary bank and to launch a major collection of time-use diaries in the United Kingdom. “We were paid suddenly to do the things that I'd been agitating to do,” Gershuny says. And one of those things has been to find out why some people feel so busy all the time. In 1930, the economist John Maynard Keynes wrote an essay predicting life 100 years ahead. The United States and Europe would be so prosperous that people would work just 15 hours a week, he said, and the main concern for “our grandchildren” would be how to fill their copious leisure time. That's not quite how things are turning out — something that Gershuny started to think about in the early 2000s. He was feeling desperately busy — more so than in the past — and people around him were complaining that they were stressed out and working harder as well. Books on the matter were proliferating, with titles such as Fighting for Time3, Busier than Ever4 and Work Without End5. Survey data hinted at the problem too: in the United States, the proportion of people reporting6 that they 'always' felt rushed was 24% in 1965 but 34% in 2004. Yet when researchers used diary data to look into the matter, a different picture emerged. Analyses showed that people in many countries routinely overestimate the amount of time that they spend working — in the United States, by some 5–10% on average7 (see 'The truth about time'). But those who work longer hours tend to overestimate by the most: people who guess that they work 75-hour weeks, for example, can be over by more than 50%, and those of certain professions — teachers, lawyers, police officers — overestimate by more than 20%. (Scientists were not the worst exaggerators: they estimate working close to 42 hours per week on average, whereas diaries clock them at 39 hours)8. In a 2005 study9, Gershuny compared the BBC diaries from 1961 with UK diaries collected in 1983–84 and 2001, adding up the number of minutes per day spent on paid work, unpaid work (such as chores around the house) and other activities. He wanted to know whether people were actually working longer hours than they did 40 years ago. The answer was that it depends. Men had reduced the number of hours they spent on paid work, increased those in unpaid work and overall came out ahead, with just under 50 minutes more free time per day. Women were doing more paid work — again reflecting their movement into the workplace over the decades — and less unpaid work, producing little change overall. Studies in the United States and western European countries have shown similar patterns: little overall change in work time and, at least in some studies and groups, a slight growth in leisure time. All in all, there is little support for the idea that everyone is working harder than ever before. “When you look at national averages of time-use data, it doesn't really show up,” says Oriel Sullivan, a sociologist who now co-directs the centre with Gershuny. But certain groups have experienced a different trend. According to analyses by Gershuny, Sullivan and other time-use researchers, two demographic groups are, in fact, working harder. One consists of employed, single parents, who put in exceptionally long hours compared to the average; the other comprises well-educated professionals10, particularly those who also have small children. People in this latter group find themselves pushed to work hard and under societal pressure to spend quality time with their kids. “The combination of those pressures has meant that there is this group for which time pressure is particularly pertinent,” Sullivan says. These findings, the researchers say, could help to explain why there is a widespread perception that life is busier for everyone. Sullivan and Gershuny propose that the time-squeezed professional group includes many of the academics who study and discuss the phenomenon, as well as the journalists who write about it — in other words, the people in society with a loud voice. But Gershuny suggests that changing attitudes to work and leisure may also play a part. In nineteenth-century Europe, having ample leisure time signified a person of high social status: one philosopher described the literary types in Paris around 1840, who had such an abundance of time that it was fashionable to walk a turtle on a leash through the arcades. In the twenty-first century, the situation has reversed, so that being busy is a signal of a privileged social position — and therefore an impression that some people are keen to give. Gershuny calls being busy in the modern day a “badge of honour”, and Glorieux agrees. “The first thing we say when we meet people is 'I'm busy',” he says. “Suppose we say, 'I'm not busy; I have nothing to do; I was watching some TV.' It's not what people want to say.” People might also feel busier because of an increase in multitasking, especially with computers and smartphones. The US time-use diaries are poor at recording how long people engage with their devices, says Robinson — in part, he suspects, because they have become so prevalent that people don't even report when they are on them. The diary bank at Oxford has revealed other changes in how people use their time. In 2011, Oxford centre postdoc Evrim Altintaş drew on diaries collected in the United States between 1965 and 2013 to examine how much time parents spend on 'developmental childcare' — engaging with children through reading, talking and helping with homework11. Activities of this type are strongly associated with better educational scores, behaviour and other positive outcomes in later life. Altintaş found that parents overall were spending more time on developmental childcare in the 2000s than they were in the 1960s and 1970s, but she found a bigger increase among parents who both had university degrees than for those who had high-school diplomas or less. She estimated that a child born to a highly educated mother in the early 2000s would receive 27 minutes more developmental childcare per day than one born to less-educated parents — adding up to 657 extra hours of focused attention for that child during the first four years of life. “That puts the children who are born to less-educated parents at a real disadvantage,” Altintaş says. The diaries have also exposed trends that could affect the health of adults. In his study on obesity1, Archer analysed more than 50,000 diary days collected between 1965 and 2010 and divided women's time into paid work, household work, personal care and free time. Then he calculated what that meant for the amount of energy they were burning up. The results showed that women in 2010 were spending around 12 hours less per week on cooking, cleaning, laundry and other domestic work than women in 1965, and that had shifted towards more-sedentary pursuits such as using a computer. As a result, the team estimated that working women today are burning some 130 kilocalories per day less than those in the 1960s, and they proposed that this could be one explanation for the rise of obesity in the United States. (Archer stresses that he is not saying that women should do more housework; rather, the work reinforces public-health advice encouraging more physical activity of any kind.) At Oxford, Gershuny and Harms are attempting to carry out more-detailed analyses of energy use in collaboration with researchers at the US National Cancer Institute in Rockville, Maryland. Harms has been matching up entries in a selection of diaries to a list, widely used in research, of more than 800 activities alongside estimates of the energy burned doing each. (It includes entries as specific as playing darts, coalmining, whirlpool-sitting and casino gambling.) The study, which is still under way, has so far shown that a gym session or other structured work-out accounts for only a small fraction of the energy that a person typically burns each day. Activities such as paid work and childcare often burn more — because even if they are less physically intense, they take up longer periods of time. “The real metabolic activity is built up during the working day,” Harms says. Since Gershuny started his diary bank, time-use research has become a thriving industry: there are now several hundred researchers in the field. But time-use diaries have weaknesses, and the biggest is that they can be wrong: people quickly forget what they were doing and record their days inaccurately — or they can lie. The desire to improve accuracy is one of the motivations behind CAPTURE-24: Gershuny and Harms's project to collect a new generation of diaries using some of the latest gadgets around. So far, about 150 people have each spent 24 hours wearing a watch-like accelerometer strapped to their wrists and a small camera, which takes around three pictures per minute, hung around their necks. They also jot down what they are doing for every 10-minute slot of the day in a conventional paper diary. The aim is to see whether the devices can provide more-useful information for the researchers than a standard paper diary alone. The accelerometer should collect more-accurate data on body movement and energy use, one reason that the project has earned support from biomedical-research funders the British Heart Foundation and the Wellcome Trust, both in London, as well as the ESRC. The photos could keep a more faithful record of when and what people eat — food diaries are notoriously unreliable — or reveal important nuances in people's interactions with children. (It is harder to say that you were focusing on childcare when the camera pictures show that you were checking your phone.) In her preliminary analyses, Harms has found that gadget diaries and paper diaries show the same sequence of events, but that the gadgets reveal details that paper diaries missed. Most researchers in the field agree that the future lies in collecting data through phones and other devices. “Maybe this will bring a new boost to time-use research,” Glorieux says. He anticipates a situation in which reams of diary data — such as location, heart rate, calories burned and even ambient noise — are collected through phones and linked-up gadgets. The researchers at Oxford are keen to grow their diary collection in other ways. They recently added ones from China, South Korea and India, and they are trying to include more from Eastern European and developing countries. And Gershuny holds out hope that there are more tea chests of old diaries still waiting to be found. Then, scientists can begin to examine cultural differences in how people from different regions work, rest and play. So many questions, so much data, so little time. Clearly, doing all this is going to take a lot more than Keynes's 15 hours a week. But the scientists hope to get there, by taking it one day at a time.

News Article | February 20, 2017

The best colleges with online programs in the state of Alabama have been ranked by The Community for Accredited Online Schools, a leading resource provider for higher education information. Among the 19 four-year schools that made the list, Auburn University, University of Alabama, University of Alabama at Birmingham, Samford University and Judson College came in as the top five schools. Nine of the state’s two-year schools also ranked, with Wallace State Community College Hanceville, Gadsden State Community College, Bevill State Community College, Wallace Community College Selma and Lurleen B. Wallace Community College taking the top five spots. “Interest in online schools in Alabama is quickly growing,” said Doug Jones, CEO and founder of “The schools on our list offer high-quality online options for students who not only want greater flexibility, but also the reliability of attending an accredited higher education institution.” Schools on the Best Online Schools list must meet specific base requirements to be included: each must be institutionally accredited, public or private not-for-profit. Each college was also scored based on additional criteria such as the availability of post-graduation job resources, student/teacher ratio, graduation rate and financial aid opportunities. For more details on where each school falls in the rankings and the data and methodology used to determine the lists, visit: Alabama’s Best Online Four-Year Schools for 2017 include the following: Alabama A & M University Alabama State University Amridge University Athens State University Auburn University Auburn University at Montgomery Faulkner University Jacksonville State University Judson College Samford University Spring Hill College The University of Alabama Troy University United States Sports Academy University of Alabama at Birmingham University of Alabama in Huntsville University of North Alabama University of South Alabama University of West Alabama Alabama’s Best Online Two-Year Schools for 2017 include the following: Bevill State Community College Calhoun State Community College Gadsden State Community College Jefferson State Community College Lurleen B. Wallace Community College Northwest-Shoals Community College Snead State Community College Wallace Community College - Selma Wallace State Community College - Hanceville ### About Us: was founded in 2011 to provide students and parents with quality data and information about pursuing an affordable, quality education that has been certified by an accrediting agency. Our community resource materials and tools span topics such as college accreditation, financial aid, opportunities available to veterans, people with disabilities, as well as online learning resources. We feature higher education institutions that have developed online learning programs that include highly trained faculty, new technology and resources, and online support services to help students achieve educational success.

News Article | November 6, 2016

The Best Online Colleges in Alabama have been identified for 2016-2017 by leading online higher education information provider After cross-analyzing more than a dozen school-specific statistics, more than 25 colleges in the state were recognized for providing affordable, quality online education programs. Alabama’s leaders include Judson College, Troy University, University of Alabama at Birmingham, University of North Alabama and the University of Alabama among four-year programs, and Gadsden State Community College, Wallace Community College’s Main, Selma Campus and Hanceville Campus and Snead State Community College among two-year programs. "In the fall semester of 2015 more than 8,500 students enrolled in Alabama public colleges and universities were distance learners,” said Dan Schuessler, CEO and Founder of "As a growing number of students seek online education options, we felt it was important to spotlight the schools in the state offering the best combination of value, flexibility and program options for online students.” Schools are required to meet several minimum qualifications in order to be eligible for the Best Online Colleges in Alabama list. All colleges must hold accreditation and be either a two- or four-year public or private not-for-profit institution. Baseline cost criteria was also set to measure affordability: each two-year school must offer annual in-state tuition under $5,000 and each four-year school must offer annual in-state tuition under $25,000 to qualify. Qualifying colleges are scored and ranked based on several statistics, including qualitative and quantitative data on financial aid, institutional graduation rates and more. All schools included on’s 2016-2017 Best Online Colleges in Alabama ranking are listed below. Further information on each school’s score and the methodology used to determine scores can be found at: The 2016-2017 Best Two-Year Online Colleges in Alabama, in alphabetical order: The 2016-2017 Best Four-Year Online Colleges in Alabama, in alphabetical order: Alabama A & M University Alabama State University Amridge University Athens State University Auburn University Auburn University at Montgomery Faulkner University Heritage Christian University Jacksonville State University Judson College The University of Alabama Troy University United States Sports Academy University of Alabama at Birmingham University of Alabama in Huntsville University of North Alabama University of West Alabama began in 2011 to provide quality data and information about pursuing an affordable higher education. Our free community resource materials and tools span topics such as financial aid and college savings, opportunities for veterans and people with disabilities, and online learning resources. We feature higher education institutions that have developed online learning environments that include highly trained faculty, new technology and resources, and online support services to help students achieve educational and career success. We have been featured by nearly 1,100 postsecondary institutions and nearly 120 government organizations.

News Article | October 6, 2016

There may be a limit to how long humans can live, according to a new study. The oldest known person was Jeanne Calment, a French woman who died in 1997 at age 122. Calment's longevity record is unlikely to be broken, the researchers said. "In contrast to previous suggestions that human longevity can be extended ever further, our data strongly suggest that the duration of life is limited," the researchers wrote in their study, published today (Oct. 5) in the journal Nature. However, the new findings don't mean that researchers know for sure that humans will never live longer than 122 years, said Steven Austad, a professor of biology and aging at the University of Alabama at Birmingham, who was not involved in the study. He said that scientists used to believe that the limit to the human life span was 110 years until somebody lived to be older than that, which shows that it is tough to predict what this limit can be for humans. [Extending Life: 7 Ways to Live Past 100] In the new study, the researchers looked at the Human Mortality Database, an international database with detailed mortality data that's maintained by researchers at the University of California, Berkeley and the Max Plank Institutes in Germany. The database contains information on how long people have lived in recent decades in many countries. The researchers found that, in at least 40 countries and territories, the number of people surviving to age 70 and older has increased since 1900. This suggests that people's life expectancy, or the estimate of how long a person may expect to live, has increased. However, if there is no limit to how long people can live, then the greatest increases in survival rates over time should have occurred among those people who are the oldest, the researchers hypothesized. But the data showed that the greatest increase in survival rates among people in the oldest age groups in most countries peaked around 1980, and has not changed since. This may suggest that, after all, there may be a natural limit to how long people can live, the researchers said. The scientists also looked to see how old the very oldest people were when they died. They focused on deaths between 1968 and 2006, in France, Japan, the United Kingdom and the United States, which are the four countries with the largest numbers of people who have lived longer than 110 years, according to the International Database on Longevity. The researchers also looked at the maximum reported age at death between 1972 and 2015 reported by another source, called the Gerontology Research Group. The researchers found that, though the maximum reported age at death did increase until the 1990s, it has actually plateaued, and even slightly decreased since the time Jeanne Calment died. But Austad said that the human life span could likely still be extended. Experiments on mice have shown that these animals live longer if their calorie intake is restricted or if their genes are manipulated, he said. If researchers found medications or lifestyle factors such as special diets that are better than the ones known today, that could allow humans to live longer, too, he said.

Baddley J.W.,University of Alabama at Birmingham
Medical Mycology | Year: 2011

Despite improvements in the antifungal armamentarium and diagnostic modalities, invasive aspergillosis (IA) remains an important cause of morbidity and mortality in immunocompromised patients. There is an emergence of non-traditional groups at risk for IA, including intensive care unit (ICU) patients, post-operative patients, those with chronic pulmonary diseases, patients with AIDS and patients on immunomodulating drugs (TNF-α inhibitors). Identification of clinical risk factors for IA may help in determining which patients require risk modification and other prevention measures. © 2011 ISHAM.

Owsley C.,University of Alabama at Birmingham
Vision Research | Year: 2013

Older adults commonly report difficulties in visual tasks of everyday living that involve visual clutter, secondary task demands, and time sensitive responses. These difficulties often cannot be attributed to visual sensory impairment. Techniques for measuring visual processing speed under divided attention conditions and among visual distractors have been developed and have established construct validity in that those older adults performing poorly in these tests are more likely to exhibit daily visual task performance problems. Research suggests that computer-based training exercises can increase visual processing speed in older adults and that these gains transfer to enhancement of health and functioning and a slowing in functional and health decline as people grow older. © 2012 Elsevier Ltd.

Thompson S.R.,University of Alabama at Birmingham
Trends in Microbiology | Year: 2012

In eukaryotes, mRNAs are primarily translated through a cap-dependent mechanism whereby initiation factors recruit the 40S ribosomal subunit to a cap structure at the 5' end of the mRNA. However, some viral and cellular messages initiate protein synthesis without a cap. They use a structured RNA element termed an internal ribosome entry site (IRES) to recruit the 40S ribosomal subunit. IRESs were discovered over 20 years ago, but only recently have studies using a model IRES from dicistroviruses expanded our understanding of how a 3D RNA structure can capture and manipulate the ribosome to initiate translation. © 2012 Elsevier Ltd.

Wright J.,University of Alabama at Birmingham | Kahn R.A.,Emory University | Sztul E.,University of Alabama at Birmingham
Cellular and Molecular Life Sciences | Year: 2014

Eukaryotic cells require selective sorting and transport of cargo between intracellular compartments. This is accomplished at least in part by vesicles that bud from a donor compartment, sequestering a subset of resident protein "cargos" destined for transport to an acceptor compartment. A key step in vesicle formation and targeting is the recruitment of specific proteins that form a coat on the outside of the vesicle in a process requiring the activation of regulatory GTPases of the ARF family. Like all such GTPases, ARFs cycle between inactive, GDP-bound, and membrane-associated active, GTP-bound, conformations. And like most regulatory GTPases the activating step is slow and thought to be rate limiting in cells, requiring the use of ARF guanine nucleotide exchange factor (GEFs). ARF GEFs are characterized by the presence of a conserved, catalytic Sec7 domain, though they also contain motifs or additional domains that confer specificity to localization and regulation of activity. These domains have been used to define and classify five different sub-families of ARF GEFs. One of these, the BIG/GBF1 family, includes three proteins that are each key regulators of the secretory pathway. GEF activity initiates the coating of nascent vesicles via the localized generation of activated ARFs and thus these GEFs are the upstream regulators that define the site and timing of vesicle production. Paradoxically, while we have detailed molecular knowledge of how GEFs activate ARFs, we know very little about how GEFs are recruited and/or activated at the right time and place to initiate transport. This review summarizes the current knowledge of GEF regulation and explores the still uncertain mechanisms that position GEFs at "budding ready" membrane sites to generate highly localized activated ARFs. © 2014 Springer.

Travis L.B.,University of Rochester | Wahnefried W.D.,University of Alabama at Birmingham | Allan J.M.,Northumbria University | Wood M.E.,University of Vermont | Ng A.K.,Dana-Farber Cancer Institute
Nature Reviews Clinical Oncology | Year: 2013

Second and higher-order malignancies now comprise about 18% of all incident cancers in the USA, superseding first primary cancers of the breast, lung, and prostate. The occurrence of second malignant neoplasms (SMN) is influenced by a myriad of factors, including the late effects of cancer therapy, shared aetiological factors with the primary cancer (such as tobacco use, excessive alcohol intake, and obesity), genetic predisposition, environmental determinants, host effects, and combinations of factors, including gene-environment interactions. The influence of these factors on SMN in survivors of adult-onset cancer is reviewed here. We also discuss how modifiable behavioural and lifestyle factors may contribute to SMN, and how these factors can be managed. Cancer survivorship provides an opportune time for oncologists and other health-care providers to counsel patients with regard to health promotion, not only to reduce SMN risk, but to minimize co-morbidities. In particular, the importance of smoking cessation, weight control, physical activity, and other factors consonant with adoption of a healthy lifestyle should be consistently emphasized to cancer survivors. Clinicians can also play a critical role by endorsing genetic counselling for selected patients and making referrals to dieticians, exercise trainers, and others to assist with lifestyle change interventions. © 2013 Macmillan Publishers Limited. All rights reserved.

Robert S.M.,University of Alabama at Birmingham | Sontheimer H.,University of Alabama at Birmingham
Cellular and Molecular Life Sciences | Year: 2014

Malignant gliomas are relentless tumors that offer a dismal clinical prognosis. They develop many biological advantages that allow them to grow and survive in the unique environment of the brain. The glutamate transporters system x c - and excitatory amino acid transporters (EAAT) are emerging as key players in the biology and malignancy of these tumors. Gliomas manipulate glutamate transporter expression and function to alter glutamate homeostasis in the brain, which supports their own growth, invasion, and survival. As a consequence, malignant cells are able to quickly destroy and invade surrounding normal brain. Recent findings are painting a larger picture of these transporters in glioma biology, and as such are providing opportunities for clinical intervention for patients. This review will detail the current understanding of glutamate transporters in the biology of malignant gliomas and highlight some of the unique aspects of these tumors that make them so devastating and difficult to treat. © 2013 Springer Basel.

Abrams M.,University of Alabama at Birmingham
Behavioral and Brain Sciences | Year: 2014

Smaldino suggests that patterns that give rise to group-level cultural traits can also increase individual-level cultural diversity. I distinguish social roles and related social network structures and discuss ways in which each might maintain diversity. I suggest that cognitive analogs of "cohesion," a property of networks that helps maintenance of diversity, might mediate the effects of social roles on diversity.

To determine the therapeutic efficacy and immunomodulatory effect of an anti-human death receptor 5 (DR5) antibody, TRA-8, in eliminating macrophage subsets in a mouse model of type II collagen-induced arthritis (CIA). A human/mouse-chimeric DR5-transgenic mouse, under the regulation of a mouse 3-kb promoter and a loxP-flanked STOP cassette, was generated and crossed with an ubiquitous Cre (Ubc.Cre) mouse and a lysozyme M-Cre (LysM.Cre)-transgenic mouse to achieve inducible or macrophage-specific expression. Chicken type II collagen was used to induce CIA in mice, which were then treated with an anti-human DR5 antibody, TRA-8. Clinical scores, histopathologic severity, macrophage apoptosis and depletion, and T cell subset development were evaluated. In human/mouse DR5-transgenic Ubc.Cre mice with CIA, transgenic DR5 was most highly expressed on CD11b+ macrophages, with lower expression on CD4+ T cells. In human/mouse DR5-transgenic LysM.Cre mice, transgenic DR5 was restrictively expressed on macrophages. Both in vivo near-infrared imaging of caspase activity and TUNEL staining demonstrated that TRA-8 rapidly induced apoptosis of macrophages in inflamed synovium. Depletion of pathogenic macrophages by TRA-8 led to significantly reduced clinical scores for arthritis; decreased macrophage infiltration, synovial hyperplasia, osteoclast formation, joint destruction, cathepsin activity, and inflammatory cytokine expression in joints; reduced numbers of Th17 cells; and an increased number of Treg cells in draining lymph nodes. The anti-human DR5 antibody TRA-8 was efficacious in reducing the severity of arthritis via targeted depletion of macrophages and immunomodulation. Our data provide preclinical evidence that TRA-8 is a potential novel biologic agent for rheumatoid arthritis therapy. Copyright © 2012 by the American College of Rheumatology.

Mazurenko O.,University of Alabama at Birmingham
Journal of healthcare management / American College of Healthcare Executives | Year: 2012

Previous research has found that physician career satisfaction is declining, but no study has examined the relationship between market factors and physician career satisfaction. Using a theoretical framework, we examined how various aspects of the market environment (e.g., munificence, dynamism, complexity) are related to overall career satisfaction. Nationally representative data from the 2008 Health Tracking Physician Survey were combined with environmental market variables from the 2008 Area Resource File. After controlling for physician and practice characteristics, at least one variable each representing munificence, dynamism, and complexity was associated with satisfaction. An increase in the market number of primary care physicians per capita was positively associated with physician career satisfaction (OR = 2.11, 95% CI: 1.13 to 3.9) whereas an increase in the number of specialists per capita was negatively associated with physician satisfaction (OR = 0.68, 95% CI: 0.48 to 0.97). Moreover, an increase in poverty rates was negatively associated with physician career satisfaction (OR = 0.95, 95% CI: 0.91 to 1.01). Lastly, physicians practicing in states with a malpractice crisis (OR = 0.81, 95% CI: 0.68 to 0.96) and/or those who perceived high competition in their markets (OR = 0.76, 95% CI: 0.61 to 0.95) had lower odds of being satisfied. A better understanding of an organization's environment could assist healthcare managers in shaping their policies and strategies to increase physician satisfaction.

Barreto A.D.,University of Houston | Alexandrov A.V.,University of Alabama at Birmingham
Stroke | Year: 2012

Background and Purpose-: Current ischemic stroke reperfusion therapy consists of intravenous thrombolysis given in eligible patients after review of a noncontrast CT scan and a time-based window of opportunity. Rapid clot lysis has a strong association with clinical improvement but remains incomplete in many patients. This review appraises novel adjunctive or alternative approaches to current reperfusion strategies being tested in all trial phases. SUMMARY OF REVIEW-: Alternative approaches to current reperfusion therapy can be separated into 4 main categories: (1) combinatory approaches with other drugs or devices; (2) novel systemic thrombolytic agents; (3) endovascular medical or mechanical reperfusion treatments; and (4) noninvasive or minimally invasive Methods to augment cerebral blood flow and alleviate intracranial blood flow steal. Conclusions-: Reperfusion treatments must be provided as fast as possible in patients most likely to benefit. Patients who fail to rapidly reperfuse may benefit from other strategies that maintain collateral flow or protect tissue at risk. © 2011 American Heart Association, Inc.

Bali V.,University of Alabama at Birmingham | Bebok Z.,University of Alabama at Birmingham
International Journal of Biochemistry and Cell Biology | Year: 2015

Scope Synonymous codon usage has been a focus of investigation since the discovery of the genetic code and its redundancy. The occurrences of synonymous codons vary between species and within genes of the same genome, known as codon usage bias. Today, bioinformatics and experimental data allow us to compose a global view of the mechanisms by which the redundancy of the genetic code contributes to the complexity of biological systems from affecting survival in prokaryotes, to fine tuning the structure and function of proteins in higher eukaryotes. Studies analyzing the consequences of synonymous codon changes in different organisms have revealed that they impact nucleic acid stability, protein levels, structure and function without altering amino acid sequence. As such, synonymous mutations inevitably contribute to the pathogenesis of complex human diseases. Yet, fundamental questions remain unresolved regarding the impact of silent mutations in human disorders. In the present review we describe developments in this area concentrating on mechanisms by which synonymous mutations may affect protein function and human health. Purpose This synopsis illustrates the significance of synonymous mutations in disease pathogenesis. We review the different steps of gene expression affected by silent mutations, and assess the benefits and possible harmful effects of codon optimization applied in the development of therapeutic biologics. Physiological and medical relevance Understanding mechanisms by which synonymous mutations contribute to complex diseases such as cancer, neurodegeneration and genetic disorders, including the limitations of codon-optimized biologics, provides insight concerning interpretation of silent variants and future molecular therapies. © 2015 Elsevier Ltd. All rights reserved.

Morris J.J.,University of Alabama at Birmingham | Morris J.J.,Michigan State University
Trends in Genetics | Year: 2015

Black Queen (BQ) functions are biological processes that yield neither purely private nor purely public products. This partitioning of benefits, also called 'leakiness', can produce negative frequency dependence of fitness in microbial communities, allowing coexistence between function-performing helpers and function-requiring beneficiaries. The ubiquity of leakiness favors a 'race to the bottom' as members of a community lose the ability to perform functions whose products are available from the environment. Rather than being social altruists, helpers are merely those populations that lost this race and got stuck in their role as function performers. Here I discuss many such BQ functions and the microbial communities that evolve around them. I also compile evidence from laboratory evolution experiments as well as phylogenetic reconstructions that show that organisms gain greater fitness increases from gene/function loss events than is commonly expected. Finally, I consider possible consequences of long-term BQ-stabilized coexistence, including sympatric speciation and the evolution of true mutualisms. © 2015 Elsevier Ltd.

Belov G.A.,University of Maryland University College | Sztul E.,University of Alabama at Birmingham
Journal of virology | Year: 2014

Viruses are obligatory intracellular parasites and utilize host elements to support key viral processes, including penetration of the plasma membrane, initiation of infection, replication, and suppression of the host's antiviral defenses. In this review, we focus on picornaviruses, a family of positive-strand RNA viruses, and discuss the mechanisms by which these viruses hijack the cellular machinery to form and operate membranous replication complexes. Studies aimed at revealing factors required for the establishment of viral replication structures identified several cellular-membrane-remodeling proteins and led to the development of models in which the virus used a preexisting cellular-membrane-shaping pathway "as is" for generating its replication organelles. However, as more data accumulate, this view is being increasingly questioned, and it is becoming clearer that viruses may utilize cellular factors in ways that are distinct from the normal functions of these proteins in uninfected cells. In addition, the proteincentric view is being supplemented by important new studies showing a previously unappreciated deep remodeling of lipid homeostasis, including extreme changes to phospholipid biosynthesis and cholesterol trafficking. The data on viral modifications of lipid biosynthetic pathways are still rudimentary, but it appears once again that the viruses may rewire existing pathways to generate novel functions. Despite remarkable progress, our understanding of how a handful of viral proteins can completely overrun the multilayered, complex mechanisms that control the membrane organization of a eukaryotic cell remains very limited. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Iyer R.R.,Teva Branded Pharmaceutical Products R and D Inc. | Pluciennik A.,Thomas Jefferson University | Napierala M.,University of Alabama at Birmingham | Napierala M.,Polish Academy of Sciences | Wells R.D.,Texas A&M University
Annual Review of Biochemistry | Year: 2015

DNA mismatch repair is a conserved antimutagenic pathway that maintains genomic stability through rectification of DNA replication errors and attenuation of chromosomal rearrangements. Paradoxically, mutagenic action of mismatch repair has been implicated as a cause of triplet repeat expansions that cause neurological diseases such as Huntington disease and myotonic dystrophy. This mutagenic process requires the mismatch recognition factor MutSβ and the MutLα (and/or possibly MutLγ) endonuclease, and is thought to be triggered by the transient formation of unusual DNA structures within the expanded triplet repeat element. This review summarizes the current knowledge of DNA mismatch repair involvement in triplet repeat expansion, which encompasses in vitro biochemical findings, cellular studies, and various in vivo transgenic animal model experiments. We present current mechanistic hypotheses regarding mismatch repair protein function in mediating triplet repeat expansions and discuss potential therapeutic approaches targeting the mismatch repair pathway. Copyright © 2015 by Annual Reviews. All rights reserved.

Martineau M.,University of Munster | Parpura V.,University of Alabama at Birmingham | Parpura V.,University of Rijeka | Mothet J.-P.,Aix - Marseille University
Frontiers in Synaptic Neuroscience | Year: 2014

Accumulating evidence during the last decade established that D-serine is a key signaling molecule utilized by neurons and astroglia in the mammalian central nervous system. D-serine is increasingly appreciated as the main physiological endogenous coagonist for synaptic NMDA receptors at central excitatory synapses; it is mandatory for long-term changes in synaptic strength, memory, learning, and social interactions. Alterations in the extracellular levels of D-serine leading to disrupted cell-cell signaling are a trademark of many chronic or acute neurological (i.e., Alzheimer disease, epilepsy, stroke) and psychiatric (i.e., schizophrenia) disorders, and are associated with addictive behavior (i.e., cocaine addiction). Indeed, fine tuning of the extracellular levels of D-serine, achieved by various molecular machineries and signaling pathways, is necessary for maintenance of accurate NMDA receptor functions. Here, we review the experimental data supporting the notion that astroglia and neurons use different pathways to regulate levels of extracellular D-serine. © 2014 Martineau, Parpura and Mothet.

Stegall M.D.,Mayo Medical School | Gaston R.S.,University of Alabama at Birmingham | Cosio F.G.,Mayo Medical School | Matas A.,University of Minnesota
Journal of the American Society of Nephrology | Year: 2015

A common lament is that long-term kidney transplant outcomes remain the same despite improvements in early graft survival. To be fair, progress has been made - in both our understanding of chronic injury and modestly, graft survival. However, we are still a long way from actually solving this important and difficult problem. In this review, we outline recent data supporting the existence of several causes of renal allograft loss, the incidences of which peak at different time points after transplantation. On the basis of this broadened concept of chronic renal allograft injury, we examine the challenges of clinical trial design in longterm studies, including the use of surrogate end points and biomarkers. Finally, we suggest a path forward that, ultimately, may improve long-term renal allograft survival. Copyright © 2015 by the American Society of Nephrology.

Ochoa-Putman C.,University of Alabama at Birmingham | Vaidya U.K.,University of Alabama at Birmingham
Composites Part A: Applied Science and Manufacturing | Year: 2011

Hybrid materials featuring thermoplastic polymer composites in conjunction with metals are being increasingly used as structural materials in military and commercial transport vehicles, and for protection of buildings and infrastructure. Hybrid materials offer improved options compared to its constituents; however the compatibility of the interface between a metal and polymer/composite strongly influences the structural response. This study focuses on the effect of surface treatment to improve adhesion between organic polymer(s) with steel reinforcement. The primary approaches to provide maximize interfacial adhesion are via surface modification to create greater surface area, and to impart free radical surfaces to create new surface bonds with the introduced chemical functionalities. Plasma activated chemical vapor deposition (PACVD) was used to impart silicon, carbon and hydrogen radicals to the metal surface. Thermoplastic polymers namely polypropylene (PP), polypropylene maleic anhydride (PP-MA), and thermoplastic polyurethane (TPU) were used to investigate the effect of polar groups (NH, CO and OH) on the surface energy and adhesion. In addition, a thermoset resin embedded with fullerene was also considered to evaluate the interfacial adhesion. The degree of modification of the polymers was determined by Fourier Transform Infrared Spectroscopy (FTIR), and Nuclear Magnetic Resonance (NMR) for the absorption of polar groups. Plasma coating was analyzed by energy dispersive spectrometry and scanning electron microscopy (EDS/SEM). The increment in surface energy was determined by contact angle measurements. This work establishes the basis that polar groups and free radicals improve adhesion between a thermoplastic polymer and a metal surface. © 2011 Elsevier Ltd. All rights reserved.

Winstead C.J.,University of Alabama at Birmingham
Immunology Letters | Year: 2014

The basic functions of the immune system are protection from pathogens and maintenance of tolerance to self. The maintenance of commensal microbiota at mucosal surfaces adds a layer of complexity to these basic functions. Recent reports suggest follicular helper T cells (Tfh), a CD4+ T cell subset specialized to provide help to B cells undergoing isotype switching and affinity maturation in germinal centers (GC), interact with the microbiota and are essential to maintenance of mucosal barriers. Complicating the issue is ongoing controversy in the field regarding origin of the Tfh subset and its distinction from other effector CD4 T cell phenotypes (Th1/Th17/Treg). This review focuses on the differentiation, phenotypic plasticity, and function of CD4 T cells, with an emphasis on commensal-specific GC responses in the gut. © 2014 Elsevier B.V..

Esposito M.,Free University of Colombia | Kawai R.,University of Alabama at Birmingham | Lindenberg K.,University of California at San Diego | Van Den Broeck C.,Hasselt University
Physical Review Letters | Year: 2010

We study the efficiency at maximum power, η*, of engines performing finite-time Carnot cycles between a hot and a cold reservoir at temperatures Th and Tc, respectively. For engines reaching Carnot efficiency ηC=1-Tc/Th in the reversible limit (long cycle time, zero dissipation), we find in the limit of low dissipation that η* is bounded from above by ηC/(2-ηC) and from below by ηC/2. These bounds are reached when the ratio of the dissipation during the cold and hot isothermal phases tend, respectively, to zero or infinity. For symmetric dissipation (ratio one) the Curzon-Ahlborn efficiency ηCA=1-√Tc/Th is recovered.

Yancey B.,University of Alabama at Birmingham | Vyazovkin S.,University of Alabama at Birmingham
Physical Chemistry Chemical Physics | Year: 2014

Research on nanoconfined chemical reactions has the potential of discovering novel means for controlling chemical reactivity which is a task of great fundamental and practical significance. This study is the first attempt to probe the effect of nanoconfinement on the kinetics and mechanism of reactions that occur entirely in the solid state. FTIR, NMR, pXRD, TGA and DSC were employed to analyze the thermally initiated trimerization of sodium dicyanamide in bulk and organically modified nanopores. Nanoconfinement did not cause apparent changes in the net reaction mechanism but decelerated the reaction kinetics dramatically. Kinetic analysis linked the deceleration to a dramatic decrease in the preexponential factor. This is an original effect which is especially noteworthy considering that for nanoconfined liquid state reactions the effect is opposite: significant acceleration due to an increase in the preexponential factor. We propose that the difference arises respectively from disordering of the solid reaction media compared to ordering of the liquid reaction media. © 2014 the Partner Organisations.

Thornell I.M.,University of Alabama at Birmingham | Bevensee M.O.,University of Alabama at Birmingham
Journal of Physiology | Year: 2015

Key points: We previously reported that the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) directly stimulates heterologously expressed electrogenic Na+/bicarbonate cotransporter NBCe1-A in an excised macropatch from the Xenopus oocyte, and indirectly stimulates NBCe1-B and -C in the intact oocyte primarily through inositol 1,4,5-trisphosphate/Ca2+. In the current study, we expand on a previous observation that PIP2 may also directly stimulate NBCe1 in the intact oocyte. In this study on oocytes, we co-expressed either NBCe1-B or -C and a voltage-sensitive phosphatase (VSP), which depletes PIP2 without changing inositol 1,4,5-trisphosphate, and monitored NBCe1-mediated currents with the two-electrode voltage-clamp technique or pHi changes using Vm/pH-sensitive microelectrodes. Activating VSP inhibited NBCe1-B and -C outward currents and NBCe1-mediated pHi increases, and changes in NBCe1 activity paralleled changes in surface PIP2. This study is a quantitative assessment of PIP2 itself as a regulator of NBCe1-B and -C in the intact cell, and represents the first use of VSP to characterize the PIP2 sensitivity of a transporter. These data combined with our previous work demonstrate that NBCe1-B and -C are regulated by two PIP2-mediated signalling pathways. Specifically, a decrease in PIP2 per se can inhibit NBCe1, whereas hydrolysis of PIP2 to inositol 1,4,5-trisphosphate/Ca2+ can stimulate the transporter. The electrogenic Na+/bicarbonate cotransporter (NBCe1) of the Slc4 gene family is a powerful regulator of intracellular pH (pHi) and extracellular pH (pHo), and contributes to solute reabsorption and secretion in many epithelia. Using Xenopus laevis oocytes expressing NBCe1 variants, we have previously reported that the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) directly stimulates NBCe1-A in an excised macropatch, and indirectly stimulates NBCe1-B and -C in the intact oocyte primarily through inositol 1,4,5-trisphosphate (InsP3)/Ca2+. In the current study, we used the two-electrode voltage-clamp technique alone or in combination with pH/voltage-sensitive microelectrodes or confocal fluorescence imaging of plasma membrane PIP2 to characterize the PIP2 sensitivity of NBCe1-B and -C in whole oocytes by co-expressing a voltage-sensitive phosphatase (VSP) that decreases PIP2 and bypasses the InsP3/Ca2+ pathway. An oocyte depolarization that activated VSP only transiently stimulated the NBCe1-B/C current, consistent with an initial rapid depolarization-induced NBCe1 activation, and then a subsequent slower VSP-mediated NBCe1 inhibition. Upon repolarization, the NBCe1 current decreased, and then slowly recovered with an exponential time course that paralleled PIP2 resynthesis as measured with a PIP2-sensitive fluorophore and confocal imaging. A subthreshold depolarization that minimally activated VSP caused a more sustained increase in NBCe1 current, and did not lead to an exponential current recovery following repolarization. Similar results were obtained with oocytes expressing a catalytically dead VSP mutant at all depolarized potentials. Depleting endoplasmic reticulum Ca2+ did not inhibit the NBCe1 current recovery following repolarization from VSP activation, demonstrating that changes in InsP3/Ca2+ were not responsible. This study demonstrates for the first time that depleting PIP2 per se inhibits NBCe1 activity. The data in conjunction with previous findings implicate a dual PIP2 regulatory pathway for NBCe1 involving both PIP2 itself and generated InsP3/Ca2+. © 2014 The Authors.

Background: The objective of this study was to investigate whether the levels of glucose or certain amino acids could regulate the expression of a cell cycle repressor protein p27(Kip1), thereby dictating the risk of cancer in either obesity or caloric/dietary restriction. Previously, we identified and reported four different upstream molecular signaling pathways of p27 expression in human breast cancer cells. We called these four pathways as pathway #1, #2, #3 and #4. We found that 4-hydroxytamoxifen - but not tamoxifen - up-regulated the expression of p27 using pathway #1 which consisted mainly of receptor tyrosine kinases and mTORC1. We now investigate, using 4-hydroxytamoxifen as a reference anti-cancer agents, whether (a) the moderate increase in the concentration of D-(+)-glucose could down-regulate and, conversely, (b) the deficiency of D-(+)-glucose or certain L-amino acids could up-regulate the expression of p27 in these cells using pathway #2 which consists mainly of AMPK and mTORC1.Results: Using human MDA-MB-231 breast cancer cells in vitro, these hypotheses were tested experimentally by performing p27-luciferase reporter transfection assays and western immunoblot analyses. The results obtained are consistent with these hypotheses. Furthermore, the results indicated that, although 4-hydroxytamoxifen used primarily pathway #1 to down-regulate the phosphorylation of 4E-BP1 and up-regulate the expression of p27, it also secondarily down-regulated the phosphorylation of S6K1. In contrast, the deficiency of D-(+)-glucose or L-leucine used primarily pathway #2 to down-regulate the phosphorylation of S6K1, but they also secondarily down-regulated the phosphorylation of 4E-BP1 and up-regulated the expression of p27. Finally, deficiency of D-(+)-glucose or L-leucine - but not 4-hydroxytamoxifen - up-regulated the expression of mitochondrial ATP5A and SIRT3.Conclusions: (a) 4-Hydroxitamoxifen used primarily pathway #1 to up-regulate the expression of p27. (b) Moderate increase in the concentration of D-(+)-glucose used primarily pathway #2 to down-regulate the expression of p27. © Deficiency of D-(+)-glucose or L-leucine also used primarily pathway #2 to up-regulate the expression of p27. (d) Deficiency of D-(+)-glucose or L-leucine - but not 4-hydroxytamoxifen - up-regulated the expression of mitochondrial ATP5A in the Complex V of respiratory oxidation-phosphorylation chain and mitochondrial SIRT3. The SIRT3 is one of the seven mammalian anti-aging as well as anti-metabolic sirtuins. © 2011 Eto; licensee BioMed Central Ltd.

Dranka B.P.,University of Alabama at Birmingham | Hill B.G.,University of Alabama at Birmingham | Darley-Usmar V.M.,University of Alabama at Birmingham
Free Radical Biology and Medicine | Year: 2010

The endothelium is not considered to be a major energy-requiring organ, but nevertheless endothelial cells have an extensive mitochondrial network. This suggests that mitochondrial function may be important in response to stress and signaling in these cells. In this study, we used extracellular flux analysis to measure mitochondrial function in adherent bovine aortic endothelial cells (BAEC). Under basal conditions, BAEC use only ∼ 35% of their maximal respiratory capacity. We calculate that this represents an intermediate respiratory state between States 3 and 4, which we define as Stateapparent equal to 3.64. Interestingly, the apparent respiratory control ratio (maximal mitochondrial oxygen consumption/non-ADP-linked respiration) in these cells is on the order of 23, which is substantially higher than that which is frequently obtained with isolated mitochondria. These results suggest that mitochondria in endothelial cells are highly coupled and possess a considerable bioenergetic reserve. Because endothelial cells are exposed to both reactive oxygen (ROS) and reactive nitrogen species in the course of vascular disease, we hypothesized that this reserve capacity is important in responding to oxidative stress. To test this, we exposed BAEC to NO or ROS alone or in combination. We found that exposure to nontoxic concentrations of NO or low levels of hydrogen peroxide generated from 2,3-dimethoxy-1,4-napthoquinone (DMNQ) had little impact on basal mitochondrial function but both treatments reversibly decreased mitochondrial reserve capacity. However, combined NO and DMNQ treatment resulted in an irreversible loss of reserve capacity and was associated with cell death. These data are consistent with a critical role for the mitochondrial reserve capacity in endothelial cells in responding to oxidative stress. © 2010 Elsevier Inc. All rights reserved.

Navarro-Millan I.,University of Alabama at Birmingham | Curtis J.R.,University of Alabama at Birmingham
Current Opinion in Rheumatology | Year: 2013

Purpose of Review: To highlight recent evidence from the clinical trials of anti-tumor necrosis factor (TNF) and non anti-TNF biologics for rheumatoid arthritis (RA) focused on comparative clinical efficacy including safety outcomes and medication discontinuation. Recent Findings: Patients with RA are sometimes able to attain low disease activity or remission since the introduction of biologic therapy for RA. Biologics like anti-TNF, anti-interleukin-6 (IL-6), anti-CD20 and those that modulate T-cell co-stimulation have consistently shown good efficacy in patients with RA. Preliminary data from comparative efficacy studies to evaluate the potential differences between anti-TNF and non anti-TNF biologics have shown little differences among these. There is ongoing work in comparative efficacy to answer this question further. Summary: Biologic therapy in RA has significantly changed the course of RA in the last decade. Recently published clinical trials have been focused on comparative efficacy, cardiovascular safety of biologics and potential anti-TNF therapy discontinuation in patients with RA. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Fields D.A.,The University of Oklahoma Health Sciences Center | Allison D.B.,University of Alabama at Birmingham
Obesity | Year: 2012

The objective of this study was to determine the accuracy, precision, bias, and reliability of percent fat (%fat) determined by air-displacement plethysmography (ADP) with the pediatric option against the four-compartment model in 31 children (4.1 1.2 years, 103.3 10.2 cm, 17.5 3.4 kg). %Fat was determined by (BOD POD Body Composition System; COSMED USA, Concord, CA) with the pediatric option. Total body water (TBW) was determined by isotope dilution (2H2 O; 0.2 g/kg) while bone mineral was determined by dual-energy X-ray absorptiometry (DXA) (Lunar iDXA v13.31; GE, Fairfield, CT and analyzed using enCore 2010 software). The four-compartment model by Lohman was used as the criterion measure of %fat. The regression for %fat by ADP vs. %fat by the four-compartment model did not deviate from the line of identity where: y = 0.849(x) 4.291. ADP explained 75.2% of the variance in %fat by the four-compartment model while the standard error of the estimate (SEE) was 2.09 %fat. The Bland-Altman analysis showed %fat by ADP did not exhibit any bias across the range of fatness (r = 0.04; P = 0.81). The reliability of ADP was assessed by the coefficient of variation (CV), within-subject SD, and Cronbach's α. The CV was 3.5%, within-subject SD was 0.9%, and Cronbach's α was 0.95. In conclusion, ADP with the pediatric option is accurate, precise, reliable, and without bias in estimating %fat in children 2-6 years old. © 2011 The Obesity Society.

Gower B.A.,University of Alabama at Birmingham | Casazza K.,University of Alabama at Birmingham
Journal of Clinical Densitometry | Year: 2013

Historically, obesity was thought to be advantageous for maintaining healthy bones due to the greater bone mineral density observed in overweight individuals. However, recent observations of increased fracture in some obese individuals have led to concern that common metabolic complications of obesity, such as type 2 diabetes, metabolic syndrome, impaired glucose tolerance, insulin resistance, hyperglycemia, and inflammation may be associated with poor bone health. In support of this hypothesis, greater visceral fat, a hallmark of insulin resistance and metabolic syndrome, is associated with lower bone mineral density. Research is needed to determine if and how visceral fat and/or poor metabolic health are causally associated with bone health. Clinicians should consider adding a marker metabolic health, such as waist circumference or fasting plasma glucose concentration, to other known risk factors for osteoporosis and fracture. © 2013 The International Society for Clinical Densitometry.

Vance D.E.,University of Alabama at Birmingham
Medical Science Monitor | Year: 2010

HIV cognitive impairments are a common occurrence. Although some of the etiologies of such cognitive impairments are understood, some of the causes are not always straightforward because adults with HIV represent a very heterogenous population. Unfortunately, many of the studies that investigate cognition in this population rely on convenience samples of HIV-positive adults who may lack cognitive stimulation due to poor education or unemployment, both of which can promote negative neuroplasticity. By the same token, other adults with HIV may be cognitively stimulated by their work, educational pursuits, and intellectual interests which may promote positive neuroplasticity which may be protective against cognitive impairments. Implications for how this impacts research as well as prevention and intervention of cognitive impairments are posited. © Med Sci Monit, 2010.

Calhoun D.A.,University of Alabama at Birmingham
Current Hypertension Reports | Year: 2010

Obstructive sleep apnea (OSA) and hypertension commonly coexist. Observational studies indicate that untreated OSA is associated with an increased risk of prevalent hypertension, whereas prospective studies of normotensive cohorts suggest that OSA may increase the risk of incident hypertension. Randomized evaluations of continuous positive airway pressure (CPAP) indicate an overall modest effect on blood pressure. However, these studies do indicate a wide variation in the blood pressure effects of CPAP, with some patients, on an individual basis, manifesting a large antihypertensive benefit. OSA is particularly common in patients with resistant hypertension. The reason for this high prevalence of OSA is not fully explained, but data from our laboratory suggest that it may be related to the high occurrence of hyperaldosteronism in patients with resistant hypertension. We hypothesize that aldosterone excess worsens OSA by promoting accumulation of fluid in the neck, which then contributes to increased upper airway resistance. © Springer Science+Business Media, LLC 2010.

Yuen H.K.,University of Alabama at Birmingham
Spinal Cord | Year: 2013

Study design:one group pre- and post-test design.Objectives:The primary aim was to examine both the short- and long-term effects of an oral home telecare program on improving gingival health among adults with tetraplegia.Methods:Eight adults with tetraplegia participated. The oral home telecare program consisted of individualized oral hygiene training in the use of assistive devices (powered toothbrush and adapted flosser and/or oral irrigator) using personal computer-based videoconferencing between each participant and an occupational therapist. Training was conducted on an average of five 15-30 min sessions across 3 months. During these training sessions, supervised practice of oral hygiene, and provision of immediate corrective feedback and positive reinforcement in the use of adaptive oral hygiene devices was emphasized. Gingival health assessment using the Löe-Silness gingival index (LSGI) was conducted at baseline, 6 and 12 months.Results:From baseline to 6 months, participants showed statistically significant differences (that is, improvement with less gingival inflammation) in their LSGI scores (z=2.18, P=.03). From baseline to 12 months, participants also showed a statistically significant difference (that is, improvement, z=2.03; P=0.04) in their LSGI scores.Conclusion:This study indicates that preventive oral home telecare with repeated oral hygiene training in the use of adaptive devices improved gingival health at 6 and 12 months among adults with tetraplegia. © 2013 International Spinal Cord Society All rights reserved.

Patel P.S.,University of Alabama at Birmingham | Kearney J.F.,University of Alabama at Birmingham
Journal of Immunology | Year: 2015

Currently, ∼20% of the global population suffers from an allergic disorder. Allergies and asthma occur at higher rates in developed and industrialized countries. It is clear that many human atopic diseases are initiated neonatally and herald more severe IgE-mediated disorders, including allergic asthma, which is driven by the priming of Th2 effector T cells. The hygiene hypothesis attempts to link the increased excessively sanitary conditions early in life to a default Th2 response and increasing allergic phenomena. Despite the substantial involvement of IgE Abs in such conditions, little attention has been paid to the effects of early microbial exposure on the B cell repertoire prior to the initiation of these diseases. In this study, we use Ab-binding assays to demonstrate that Streptococcus pneumoniae and house dust mite (HDM) bear similar phosphorylcholine (PC) epitopes. Neonatal C57BL/6 mice immunized with a PC-bearing pneumococcal vaccine expressed increased frequencies of PC-specific B cells in the lungs following sensitizing exposure to HDM as adults. Anti-PC IgM Abs in the lung decreased the interaction of HDM with pulmonary APCs and were affiliated with lowered allergy-associated cell infiltration into the lung, IgE production, development of airway hyperresponsiveness, and Th2 T cell priming. Thus, exposure of neonatal mice to PC-bearing pneumococci significantly reduced the development of HDM-induced allergic disease during adult life. Our findings demonstrate that B cells generated against conserved epitopes expressed by bacteria, encountered early in life, are also protective against the development of allergic disease during adult life. Copyright © 2015 by The American Association of Immunologists, Inc.

Funk A.J.,University of Alabama at Birmingham | McCullumsmith R.E.,University of Alabama at Birmingham | Haroutunian V.,Mount Sinai School of Medicine | Meador-Woodruff J.H.,University of Alabama at Birmingham
Neuropsychopharmacology | Year: 2012

Recent evidence suggests that schizophrenia may result from alterations of integration of signaling mediated by multiple neurotransmitter systems. Abnormalities of associated intracellular signaling pathways may contribute to the pathophysiology of schizophrenia. Proteins and phospho-proteins comprising mitogen activated protein kinase (MAPK) and 3′-5′-cyclic adenosine monophosphate (cAMP)-associated signaling pathways may be abnormally expressed in the anterior cingulate (ACC) and dorsolateral prefrontal cortex (DLPFC) in schizophrenia. Using western blot analysis we examined proteins of the MAPK- and cAMP-associated pathways in these two brain regions. Postmortem samples were used from a well-characterized collection of elderly patients with schizophrenia (ACC=36, DLPFC=35) and a comparison (ACC=33, DLPFC=31) group. Near-infrared intensity of IR-dye labeled secondary antisera bound to targeted proteins of the MAPK- and cAMP-associated signaling pathways was measured using LiCor Odyssey imaging system. We found decreased expression of Rap2, JNK1, JNK2, PSD-95, and decreased phosphorylation of JNK1/2 at T183/Y185 and PSD-95 at S295 in the ACC in schizophrenia. In the DLPFC, we found increased expression of Rack1, Fyn, Cdk5, and increased phosphorylation of PSD-95 at S295 and NR2B at Y1336. MAPK- and cAMP-associated molecules constitute ubiquitous intracellular signaling pathways that integrate extracellular stimuli, modify receptor expression and function, and regulate cell survival and neuroplasticity. These data suggest abnormal activity of the MAPK- and cAMP-associated pathways in frontal cortical areas in schizophrenia. These alterations may underlie the hypothesized hypoglutamatergic function in this illness. Together with previous findings, these data suggest that abnormalities of intracellular signaling pathways may contribute to the pathophysiology of schizophrenia. © 2012 American College of Neuropsychopharmacology. All rights reserved.

Warriner A.H.,University of Alabama at Birmingham | Saag K.G.,University of Alabama at Birmingham
Orthopedic Clinics of North America | Year: 2013

Osteoporosis, the presence of either low bone mineral density or a history of a fragility fracture, is known to be associated with an increased risk of future fracture. Fracture prevention is possible through use of both nonpharmacologic and prescription treatments. Despite recent controversy regarding the safety of calcium supplementation and the appropriate dosing of calcium and vitamin D, calcium and vitamin D remain an important part of bone health. However, prescription osteoporosis treatments should be considered for those at higher risk for fracture, and there are currently several treatment options available. © 2013 Elsevier Inc.

Johnson V.A.,University of Alabama at Birmingham
Topics in HIV medicine : a publication of the International AIDS Society, USA | Year: 2010

This December 2010 version of the International AIDS Society-USA (IAS-USA) drug resistance mutations list updates the figures last published in December 2009 (Johnson VA et al, Top HIV Med, 2009;17:138-145). This update includes 9 new mutations- E138G and E138K for etravirine (Haddad M et al, CROI, 2010; Abstract 574, and Vingerhoets J et al, Antivir Ther, 2010;15 [Suppl 2]:A125); E92Q for raltegravir (Geretti AM et al, Antivir Ther, 2010;15 [Suppl 2]:A62; Cooper et al, N Engl J Med, 2008;359:355-365; and Malet I et al, Antimicrob Agents Chemother, 2008;52:1351-1358); and M36L, M36V, H69R, L89I, L89M, and L89V for tipranavir/ritonavir. In addition, the tipranavir/ritonavir N83D mutation designation was changed to boldface to indicate its recognition as a major mutation rather than a minor mutation. The mutations I13V, K20M/R, E35G, and L90M were removed from the tipranavir/ritonavir bar, reflecting new understanding. For etravirine, L100I*, K101P*, and Y181C*/I*/V* are denoted with asterisks (instead of bolded) to reflect that these individual mutations each have the greatest impact (ie, highest weighting scores) on reduced phenotypic susceptibility and impaired clinical response when compared with other etravirine mutations (Haddad M et al, CROI, 2010; Abstract 574). In addition, user notes d, n, r, w, and z were revised.

Core G.B.,University of Alabama at Birmingham
Plastic and Reconstructive Surgery | Year: 2013

BACKGROUND: Effective lower eyelid blepharoplasty is possible in a virtually closed fashion without either an anterior subciliary skin incision or a transconjunctival incision, both of which put the patient at risk for lower lid retraction. METHODS: Over a 6-year period, the author performed lower lid rejuvenation with only a lateral incision in 89 consecutive cases in 86 women and three men ranging in age from 42 to 65 years. Patients with lower lid laxity, prior surgery, trauma, significant excess skin, or festoons were excluded. Grading the aged eyelid in stages 1 to 3, with 3 being advanced, this procedure is indicated for stage 1 and 2 patients, characterized by deep nasojugal grooves, herniated lower lid compartment fat, mild to moderate rhytides, and increased lower lid height. The technique uses a lateral incision with dissection under the orbicularis and anterior to the orbital septum with release of the orbitomalar ligament. Loupe magnification is used. The nasal orbicularis fibers are released and the fat compartments are released and sewn to the midface fat using 6-0 transcutaneous sutures. An orbicularis muscle lift is performed for support and a lateral retinacular suspension is performed if necessary. RESULTS: Follow-up ranged from 3 months to 6 years, and there have been no major complications. All patients have been satisfied with the results. CONCLUSIONS: Lateral incision-only lower lid blepharoplasty allows all necessary structures to be addressed for rejuvenation by recontouring in selected patients without anterior or posterior incisions into the central part of the lid. Copyright © 2013 by the American Society of Plastic Surgeons.

Wang H.E.,University of Alabama at Birmingham | Yealy D.M.,University of Pittsburgh
Annals of Emergency Medicine | Year: 2012

Study objective: As a recommended strategy for optimally managing critical illness, regionalization of care involves matching the needs of the target population with available hospital resources. The national supply and characteristics of hospitals providing specialized critical care services is currently unknown. We seek to characterize the current distribution of specialized care centers in the United States. Methods: Using public data linked with the American Hospital Association directory and US Census, we identified US general acute hospitals providing specialized care for ST-segment elevation myocardial infarction (STEMI) (<40 annual primary percutaneous coronary interventions reported in Medicare Hospital Compare), stroke (The Joint Commission certified stroke centers), trauma (American College of Surgeons or state-designated, adult or pediatric, level I or II), and pediatric critical care (presence of a pediatric ICU) services. We determined the characteristics and state-level distribution and density of specialized care centers (centers per state and centers per state population). Results: Among 4,931 acute care hospitals in the United States, 1,325 (26.9%) provided one of the 4 defined specialized care services, including 574 STEMI, 763 stroke, 508 trauma, and 457 pediatric critical care centers. Approximately half of the 1,325 hospitals provided 2 or more specialized services, and one fifth provided 3 or 4 specialized services. There was variation in the number of each type of specialized care center in each state: STEMI median 7 interquartile range (IQR 2 to 14), stroke 8 (IQR 3 to 17), trauma 6 (IQR 3 to 11), pediatric specialized care 6 (IQR 3 to 11). Similarly, there was variation in the number of each type of specialized care center per population: STEMI median 1 center per 585,135 persons (IQR 418,729 to 696,143), stroke 1 center per 412,188 persons (IQR 321,604 to 572,387), trauma 1 center per 610,589 persons (IQR 406,192 to 917,588), and pediatric critical care 1 center per 665,282 persons (IQR 441,525 to 942,254). The national distribution patterns differed for each type of specialized care center. Conclusion: The distribution of specialized care centers varies across the United States. These observations highlight unanswered questions about the regional organization of specialized care in the United States. © 2012 American College of Emergency Physicians.

Alexandrov A.V.,University of Alabama at Birmingham
Journal of Internal Medicine | Year: 2010

Alexandrov AV (University of Alabama Hospital, Birmingham, AL, USA). Current and future recanalization strategies for acute ischemic stroke (Review). J Intern Med 2010; 267: 209-219. In a quest for stroke treatment, reperfusion proved to be the first key to the puzzle. Systemic tissue plasminogen activator (tPA), the first and currently the only approved treatment, is also the fastest way to initiate thrombolyis for acute ischemic stroke. tPA works by induction of mostly partial recanalization since stroke patients often have large thrombus burden. Thus, early augmentation of fibrinolysis and multi-modal approach to improve recanalization are desirable. This review focuses on the following strategies available to clinicians now or being tested in clinical trials: (a) faster initiation of tPA infusion; (b) sonothrombolysis; (c) intra-arterial revascularization, bridging intravenous and intra-arterial thrombolysis, mechanical thrombectomy and aspiration; and (d) novel experimental approaches. Despite these technological advances, no single strategy was yet proven to be a 'silver bullet' solution to reverse acute ischemic stroke. Better outcomes are expected with faster treatment leading to early, at times just partial flow improvement rather than achieving complete recanalization with lengthy procedures. Arterial re-occlusion can occur with any of these approaches, and it remains a challenge since it leads to poor outcomes and no clinical trial data are available yet to determine safe strategies to prevent or reverse re-occlusion. © 2010 Blackwell Publishing Ltd.

Guyette N.,University of Alabama at Birmingham
Investigative ophthalmology & visual science | Year: 2013

Low tear volume limits the use of nonstimulated (NS) microcapillary tear collection in aqueous-deficient (AD) patients. Adding a small amount of "washout" fluid to the eye prior to tear collection is a potentially viable alternative method for abundant proteins, but is relatively untested for low-abundance biomarkers. This study determined the feasibility of the washout (WO) method as an NS alternative for low-abundance biomarkers. NS and WO biomarker profiles were compared between AD patients and non-AD controls to determine if the two methods identify the same intergroup differences. Matching NS and WO tears were collected from 48 patients by micropipette, the WO sample after instillation of 10 μL saline. Tear cytokine levels were measured by 27-Plex Bio-Rad assay. Bland-Altman analyses for each biomarker determined the agreement between tear sample types. Patients were grouped as AD or non-AD based on Schirmer score to determine if NS profile between-group differences were preserved in WO tears. Bland-Altman plots showed good biomarker level agreement between NS and WO tears for most cytokines. Five biomarkers, among those most often cited as differing in AD dry eye, differed significantly between non-AD and AD groups in both tear types. Additional biomarker differences were seen in NS tears only. The WO tear collection method is a viable alternative to NS tears for many low-abundance biomarkers and is able to replicate major NS tear differences between dry eye groups. More subtle intergroup differences are lost in WO samples because of reduced statistical power.

Weech-Maldonado R.,University of Alabama at Birmingham
Medical care | Year: 2012

Cultural competency has been espoused as an organizational strategy to reduce health disparities in care. To examine the relationship between hospital cultural competency and inpatient experiences with care. The first model predicted Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores from hospital random effects, plus fixed effects for hospital cultural competency, individual race/ethnicity/language, and case-mix variables. The second model tested if the association between a hospital's cultural competency and HCAHPS scores differed for minority and non-Hispanic white patients. The National CAHPS Benchmarking Database's (NCBD) HCAHPS Surveys and the Cultural Competency Assessment Tool of Hospitals Surveys for California hospitals were merged, resulting in 66 hospitals and 19,583 HCAHPS respondents in 2006. Dependent variables include 10 HCAHPS measures: 6 composites (communication with doctors, communication with nurses, staff responsiveness, pain control, communication about medications, and discharge information), 2 individual items (cleanliness and quietness of patient rooms), and 2 global items (overall hospital rating, and whether patient would recommend hospital). Hospitals with greater cultural competency have better HCAHPS scores for doctor communication, hospital rating, and hospital recommendation. Furthermore, HCAHPS scores for minorities were higher at hospitals with greater cultural competency on 4 other dimensions: nurse communication, staff responsiveness, quiet room, and pain control. Greater hospital cultural competency may improve overall patient experiences, but may particularly benefit minorities in their interactions with nurses and hospital staff. Such effort may not only serve longstanding goals of reducing racial/ethnic disparities in inpatient experience, but may also contribute to general quality improvement.

Pappas P.G.,University of Alabama at Birmingham
Mycoses | Year: 2012

Invasive candidiasis and mucosal candidiasis are among the most important health care associated infections; in its invasive form, candidiasis is associated with substantial morbidity and mortality. Among the currently available antifungal agents, the echinocandins are the among the most potent agents against Candida species. As a class, these agents are well tolerated and rapidly fungicidal. Among the echinocandins, micafungin has been studied most extensively. This paper reviews the results from the largest studies of micafungin among patients with invasive and esophageal candidiasis, and supports the use of echinocandins in this increasingly common disorder. © 2012 Blackwell Verlag GmbH.

Gordetsky J.B.,University of Alabama at Birmingham
American Journal of Surgical Pathology | Year: 2016

Recent studies have suggested that multiparametric magnetic resonance imaging (MRI)/ultrasound (US) fusion–guided prostate biopsy can detect more clinically significant prostate cancers, which could impact patient management. As many of the studies evaluating MRI/US fusion–guided prostate biopsy were conducted in specialized quaternary care centers, the question remains whether this technology is transferable to general practice. Our study assesses the diagnostic ability of MRI/US fusion–guided prostate biopsy compared with standard biopsy in the new era of prostate cancer Grade Grouping. We reviewed our prostate biopsy database evaluating men who underwent MRI/US fusion–guided prostate biopsy with concurrent standard 12-core extended-sextant biopsy. Patient demographics and pathologic findings were reviewed. All patient biopsies were performed by 1 of 2 urologic oncologists. Tumors were given a Grade Group for each biopsy based on the core with the highest grade in each case. A total of 191 patients underwent MRI/US fusion–guided biopsy with concurrent 12-core extended sextant biopsy, with a cancer detection rate of 56%. The average number of biopsy cores obtained via the targeted approach was significantly less than those obtained by standard biopsy, 4.8 cores versus 12 cores, respectively, P<0.001. There was no difference in cancer detection between targeted and standard biopsy, 41.4% and 49.2%, respectively, P=0.15. However, when comparing the 2 techniques, the degree of detection of ≥Grade Group 3 tumors significantly favored targeted biopsy over standard biopsy (P=0.009). MRI/US fusion–guided prostate biopsy is equivalent to the standard-of-care 12-core biopsy in terms of cancer detection and superior in detecting higher grade disease. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Yi J.S.,University of Alabama at Birmingham | Cox M.A.,University of Alabama at Birmingham | Zajac A.J.,University of Alabama at Birmingham
Immunology | Year: 2010

T-cell exhaustion is characterized by the stepwise and progressive loss of T-cell functions and can culminate in the physical deletion of the responding cells. Exhaustion is well-defined during chronic lymphocytic choriomeningitis virus infection and commonly develops under conditions of antigen-persistence, which occur following many chronic infections that are of significant public health concern including hepatitis B virus, hepatitis C virus and human immunodeficiency virus infections, as well as during tumour outgrowth. Exhaustion is not a uniformly disabled setting as a gradation of phenotypic and functional defects can manifest, and these cells are distinct from prototypic effector, memory and also anergic T cells. We are gaining insights into the extrinsic and intrinsic factors that determine the severity of exhaustion. These include the duration and magnitude of antigenic activation, availability of CD4 T-cell help, the levels of stimulatory and suppressive cytokines, as well as the expression of activatory and inhibitory receptors. More information is now becoming available regarding the molecular mechanisms that attenuate the responsiveness of exhausted T cells. As the parameters that dictate exhaustion are more thoroughly defined, this is fostering the development of methods that prevent and rejuvenate functionally inferior responses. In this article we discuss our current understanding of the properties of exhausted T cells and the mechanisms that promote and maintain this state. © 2010 The Authors.

The majority of Chlamydia trachomatis genital infections in humans are asymptomatic and without clinical evidence of complications at the time of diagnosis. The natural history of chlamydial infection in humans, including the duration of infection and factors influencing resolution of infection, is not yet completely understood. This is in part attributable to the inherent challenges and ethical considerations in studying untreated chlamydia in humans. An improved understanding of the natural history of chlamydia in humans has implications for chlamydia screening and treatment recommendations. In April 2008, the Centers for Disease Control and Prevention convened an advisory group for the Chlamydia Immunology and Control Expert Advisory Meeting, in which studies related to chlamydia natural history, pathogenesis, and immunobiology were reviewed and gaps in our knowledge that would have implications for prevention and control of C. trachomatis infection were identified. This article summarizes the key questions posed and the evidence reviewed on the duration of untreated, uncomplicated genital chlamydial infection in humans and the factors associated with chlamydia resolution. © 2010 by the Infectious Diseases Society of America. All rights reserved.

Mannon R.B.,University of Alabama at Birmingham
Kidney International | Year: 2010

Late failure of a kidney transplant continues to be a major problem after transplantation, in spite of more potent immunosuppressive strategies and the focus of clinical management shifting toward prolonging long-term graft survival. It is now recognized that graft failure occurs because of two major complications: death with a functioning graft and intrinsic allograft failure. Recent studies of late kidney graft loss have indicated a complexity of findings, including etiologies that are both immune and non-immune. These studies suggest that late graft failure is not an inevitable fact and that further investigation into the etiology of transplant graft failure may lead to a new understanding of the biology that will provide novel therapeutic strategies and biomarkers. In this review, we will focus on late allograft failure due to intrinsic injury to the transplant. The role of immune monitoring will be discussed in the context of monitoring for ongoing injury or for identifying late injury. A variety of methodologies have been used, including genomics, proteomics, and metabolomics, not only for monitoring allograft injury but also for identifying markers of graft failure that are more sensitive than serum creatinine. The available studies, as they relate to late or chronic graft injury, will also be reviewed. © 2010 International Society of Nephrology.

Walters B.C.,University of Alabama at Birmingham
PM and R | Year: 2010

The application of electrical current to injured tissue is known to promote healing. The use of this modality in healing the injured spinal cord to promote neurologic recovery has been introduced as a potential treatment for patients who previously had minimal hope of recovery. In in vitro and in vivo experiments, neural regeneration has been seen to occur, especially when an oscillating field is used. With this modality, an electrical current is applied in which the polarity changes direction on a periodic basis, preventing the "die-back" phenomenon of severed neural pathways. This mechanism of recovery has been demonstrated in several species in which sacrifice has been undertaken and spinal cords examined. In a study of humans, a small number of patients participated in a single phase Ia trial in which the safety of an implantable device was demonstrated, with indications of probable benefit, consistent with laboratory and animal studies. In addition, a number of additional patients were treated, and their results were examined along with the original cohort and were compared with historical control subjects. The device used in this mode of treatment has not been approved for use in the general spinal cord-injured population, pending further study. A larger multi-institutional trial needs to be done to further demonstrate efficacy and effectiveness, and outcomes will need to be agreed upon by spinal cord injury researchers, patients, and regulators before widespread use will be permitted. Unfortunately, some subtle changes experienced and valued by patients are not recognized as important or desirable by regulators or by all researchers. © 2010 by the American Academy of Physical Medicine and Rehabilitation.

Singh J.A.,University of Alabama at Birmingham
Journal of managed care pharmacy : JMCP | Year: 2012

In 2011, the Agency for Health Care Research and Quality (AHRQ) published a systematic review on the comparative effectiveness of disease-modifying anti-rheumatic drugs (DMARDs) used to treat adults with rheumatoid arthritis (RA). The publication was an update to a 2007 report. A total of 258 published articles were used in the AHRQ review to compare the effectiveness of corticosteroids, and oral and biologic DMARDs in the treatment of RA. Head-to-head studies and prospective cohort trials were used to compare one drug to another in determining efficacy and effectiveness. AHRQ compiled this report in an attempt to summarize and integrate the available data for clinicians to make evidence based practice decisions for their patients since there is limited consensus among the medical community regarding the comparative effectiveness of drugs used to treat RA. The report reveals there is still much research to be done concerning the side effects of these agents and their influence in different patient subgroups. To: (a) utilize review findings to make diagnostic and treatment management decisions in clinical practice, (b) inform clinicians on the findings from the updated AHRQ's 2011 comparative effectiveness review on drug therapy for RA in adults, and (c) identify shortcomings in the current research and future directions revealed by the report. Rheumatoid arthritis is a major public health burden. The 2011 updated AHRQ report includes several new medications approved by the FDA since 2007. The review includes 31 head-to-head randomized clinical trials (RCTs), 1 head-to-head nonrandomized controlled trial, 44 placebo controlled trials, 28 meta-analyses or systematic reviews, and 107 observational studies. Most of the studies used for the comparative analysis are of fair quality with an insufficient to moderate strength of evidence assigned to the findings (Table 1). A mixed treatment comparisons (MTC)meta-analysis from the AHRQ report found that the biologic etanercept has a higher probability of improvement in disease activity compared with other biologic DMARDs, but the MTC findings have a low strength of evidence and caution is recommended in the interpretation of this weak evidence. For patients with early RA, limited evidence precludes conclusions about the superiority of one combination therapy versus another. The data are also inconclusive for comparisons of therapeutic similarity among oral DMARDs including the limitation created by differences inmethotrexate (MTX) dosing across trials. Extensive clinical experience over the years support the preferred use of MTX in most patients versus other oral DMARDs as well as its use in multidrug regimens, whereas there is little data on the use of oral DMARDs in combination with biologic agents. The review does not support a specific biologic DMARD over another due to the lack of head-to-head trials comparing these agents using validated RA outcome measures. The data show that the majority of biologics have approximately the same efficacy except for anakinra, which was found to be less effective. The biologic and oral DMARDs are similar in overall tolerability, but several studies suggest that adverse events are more common with biologic DMARDs versus oral DMARDs. Based on limited evidence, the oral DMARDs do not appear to have an increased risk of severe adverse events including cardiovascular events and cancer. Although most studies also found no increased risk of cardiovascular events or cancer with the biologic DMARDs, cohort studies show an increased risk of heart failure with adalimumab, etanercept, and infliximab compared with oral DMARDs. The updated AHRQ review synthesizes the current literature on therapies used for the treatment of RA in adults. The investigators are also able to identify pertinent research gaps in the literature that can be addressed with future research.

Pappas P.G.,University of Alabama at Birmingham
American Journal of the Medical Sciences | Year: 2010

Opportunistic fungi are a constantly evolving group of pathogens that plague a growing group of vulnerable patients. These include hospitalized patients, especially those in the intensive care unit; stem cell and solid organ transplant recipients; patients treated with immunosuppressant medications; those with advanced human immunodeficiency virus or other acquired immunodeficiency conditions; and patients with organ failure syndromes. Rapid diagnosis of invasive fungal infection is essential to optimize outcomes. Several newer nonculture-based diagnostics, including the Aspergillus galactomannan enzyme-linked immunosorbent assay, the β-D-glucan assay and the multiplex polymerase chain reaction-based assays, may emerge as important tools facilitating early intervention with effective antifungal therapy. Newer azoles, including posaconazole, isavuconazole and ravuconazole, will potentially provide more effective therapeutic options in the future, diminishing the role for amphotericin B. © 2010 Lippincott Williams & Wilkins.

Zhi D.,University of Alabama at Birmingham | Chen R.,Baylor College of Medicine
PLoS ONE | Year: 2012

Recently, whole-genome sequencing, especially exome sequencing, has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases. However, it is unclear whether this approach can be generalized and effectively applied to other Mendelian diseases with high locus heterogeneity. Moreover, the current exome sequencing approach has limitations such as false positive and false negative rates of mutation detection due to sequencing errors and other artifacts, but the impact of these limitations on experimental design has not been systematically analyzed. To address these questions, we present a statistical modeling framework to calculate the power, the probability of identifying truly disease-causing genes, under various inheritance models and experimental conditions, providing guidance for both proper experimental design and data analysis. Based on our model, we found that the exome sequencing approach is well-powered for mutation detection in recessive, but not dominant, Mendelian diseases with high locus heterogeneity. A disease gene responsible for as low as 5% of the disease population can be readily identified by sequencing just 200 unrelated patients. Based on these results, for identifying rare Mendelian disease genes, we propose that a viable approach is to combine, sequence, and analyze patients with the same disease together, leveraging the statistical framework presented in this work. © 2012 Zhi, Chen.

Willig A.L.,University of Alabama at Birmingham | Overton E.T.,University of Alabama at Birmingham
Current HIV/AIDS Reports | Year: 2014

With the advances in antiretroviral therapy (ART), HIV infection has been transformed into a chronic medical condition that can be effectively managed like diabetes or hypertension. For HIV care providers, the focus of care for many patients has shifted from prevention of opportunistic infection and AIDS-related conditions to age-related cardiometabolic comorbidities, including cardiovascular disease, diabetes, obesity, and frailty. Numerous reports have highlighted that these diseases are occurring at an earlier age among HIV-infected persons. However, there is an ongoing debate regarding the role of HIV infection, ART, and other factors that may underlie the accelerated occurrence of these diseases. Herein, we review the epidemiology of the US HIV epidemic with regards to several metabolic comorbidities and address mechanisms that likely contribute to the current nature of HIV disease. © 2014 Springer Science+Business Media.

Xu G.,University of Alabama at Birmingham | Chen J.,University of Alabama at Birmingham | Jing G.,University of Alabama at Birmingham | Shalev A.,University of Alabama at Birmingham
Diabetes | Year: 2012

Although loss of functional β-cell mass is a hallmark of diabetes, no treatment approaches that halt this process are currently available. We recently identified thioredoxin-interacting protein (TXNIP) as an attractive target in this regard. Glucose and diabetes upregulate β-cell TXNIP expression, and TXNIP overexpression induces β-cell apoptosis. In contrast, genetic ablation of TXNIP promotes endogenous β-cell survival and prevents streptozotocin (STZ)- and obesity-induced diabetes. Finding an oral medication that could inhibit β-cell TXNIP expression would therefore represent a major breakthrough. We were surprised to discover that calcium channel blockers inhibited TXNIP expression in INS-1 cells and human islets and that orally administered verapamil reduced TXNIP expression and β-cell apoptosis, enhanced endogenous insulin levels, and rescued mice from STZ-induced diabetes. Verapamil also promoted β-cell survival and improved glucose homeostasis and insulin sensitivity in BTBR ob/ob mice. Our data further suggest that this verapamil-mediated TXNIP repression is conferred by reduction of intracellular calcium, inhibition of calcineurin signaling, and nuclear exclusion and decreased binding of carbohydrate response element-binding protein to the E-box repeat in the TXNIP promoter. Thus, for the first time, we have identified an oral medication that can inhibit proapoptotic β-cell TXNIP expression, enhance β-cell survival and function, and prevent and even improve overt diabetes. © 2012 by the American Diabetes Association.

Murdaugh D.L.,University of Alabama at Birmingham | Cox J.E.,University of Alabama at Birmingham | Cook E.W.,University of Alabama at Birmingham | Weller R.E.,University of Alabama at Birmingham
NeuroImage | Year: 2012

Behavioral studies have suggested that food cues have stronger motivating effects in obese than in normal-weight individuals, which may be a risk factor underlying obesity. Previous cross-sectional neuroimaging studies have suggested that this difference is mediated by increased reactivity to food cues in parts of the reward system in obese individuals. To date, however, only a few prospective neuroimaging studies have been conducted to examine whether individual differences in brain activation elicited by food cues can predict differences in weight change. We used functional magnetic resonance imaging (fMRI) to investigate activation in reward-system as well as other brain regions in response to viewing high-calorie food vs. control pictures in 25 obese individuals before and after a 12-week psychosocial weight-loss treatment and at 9-mo follow-up. In those obese individuals who were least successful in losing weight during the treatment, we found greater pre-treatment activation to high-calorie food vs. control pictures in brain regions implicated in reward-system processes, such as the nucleus accumbens, anterior cingulate, and insula. We found similar correlations with weight loss in brain regions implicated by other studies in vision and attention, such as superior occipital cortex, inferior and superior parietal lobule, and prefrontal cortex. Furthermore, less successful weight maintenance at 9-mo follow-up was predicted by greater post-treatment activation in such brain regions as insula, ventral tegmental area, putamen, and fusiform gyrus. In summary, we found that greater activation in brain regions mediating motivational and attentional salience of food cues in obese individuals at the start of a weight-loss program was predictive of less success in the program and that such activation following the program predicted poorer weight control over a 9-mo follow-up period. © 2011.

Zhang H.-G.,University of Louisville | Grizzle W.E.,University of Alabama at Birmingham
American Journal of Pathology | Year: 2014

Normal and diseased cells release bilayered membrane-bound nanovesicles into interstitial spaces and into bodily fluids. A subgroup of such microvesicles is called exosomes and is described in blood as 30 to 100 nm in diameter and as spherical to cup-shaped nanoparticles with specific surface molecular characteristics (eg, expression of the tetraspanins CD9, CD81, and CD63). Extracellular microvesicles provide local signals (eg, autocrine and paracrine) and distant endocrine signals to cells via the transfer of their contents, which include signal proteins, lipids, miRNAs, and functional mRNAs. Exosomes and related microvesicles also aid cells in exporting less-needed molecules and potentially harmful molecules, including drugs; in the case of neoplasia, the export of chemotherapeutic drugs may facilitate cellular chemoresistance. Cancers have adapted the exosome and related microvesicles as a pathway by which neoplastic cells communicate with each other (autocrine) and with nonneoplastic cells (paracrine and endocrine); via this pathway, cancer suppresses the immune system and establishes a fertile local and distant environment to support neoplastic growth, invasion, and metastases. Because exosomes mirror and bind to the cells from which they arise, they can be used for delivery of drugs, vaccines, and gene therapy, as biomarkers and targets. We review how exosomes and related extracellular microvesicles facilitate the progression and metastases of cancers and describe how these microvesicles may affect clinical care. © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Rostand S.G.,University of Alabama at Birmingham
Clinical Journal of the American Society of Nephrology | Year: 2010

Vitamin D deficiency has increasingly been recognized in the general population and especially in African Americans whose deep skin pigmentation makes vitamin D photosynthesis inefficient. Over the last decade there has been increasing interest in the role that vitamin D deficiency may play in BP modulation because many epidemiologic studies have shown an inverse association between serum vitamin D concentration and BP. There is a high prevalence of vitamin D deficiency in African Americans who also have an increased susceptibility to develop hypertension and its consequences. This paper will review the circumstances leading to vitamin D deficiency in the African American population and will also discuss how vitamin D deficiency can affect the renin-angiotensin system, free radical production, inflammatory processes, and carbohydrate tolerance that in turn influence vascular endothelial function and vascular structure producing increased vascular resistance. It will speculate that the presence of vitamin D deficiency throughout life from its earliest phases may adversely affect the microvasculature in African Americans, thereby playing a major role in the genesis and maintenance of hypertension. Copyright © 2010 by the American Society of Nephrology.

Bellis S.L.,University of Alabama at Birmingham
Biomaterials | Year: 2011

Despite many years of in vitro research confirming the effectiveness of RGD in promoting cell attachment to a wide variety of biomaterials, animal studies evaluating tissue responses to implanted RGD-functionalized substrates have yielded more variable results. The goals of this report are to present some of the reasons why cell culture studies may not always reliably predict in vivo responses, and more importantly, to highlight potential applications that may benefit from the use of RGD peptides. © 2011 Elsevier Ltd.

Uddin N.,University of Alabama at Birmingham
Proceedings of the IEEE | Year: 2012

The primary objective of this paper is to present and discuss geotechnical issues and challenges for the design and stability of massive energy storage caverns in hard rock formations. In general, the challenges which confront the construction of massive underground caverns are a combination of the geological, hydrological, geochemical, geothermal, and geotechnical. The identification and remediation of the geotechnical challenges will be qualitatively discussed here and this discussion will be anchored with a particular practical example. © 2006 IEEE.

Agarwal A.,University of Alabama at Birmingham
Transactions of the American Clinical and Climatological Association | Year: 2013

Tissue injury may result as a consequence of a physical, chemical, or biological insult. Such injury recruits an adaptive response to restore homeostasis and protect against further injury. One of the most prompt protective and adaptive responses by all tissues is the robust activation of the highly inducible, anti-inflammatory, anti-oxidant, and anti-apoptotic protein, heme oxygenase-1 (HO-1). HO-1, a microsomal enzyme, catalyzes the breakdown of pro-oxidant heme, which is released from heme proteins to equimolar quantities of iron, carbon monoxide, and biliverdin. Biliverdin is converted to bilirubin by biliverdin reductase. The beneficial effects of HO-1 expression are not merely due to heme degradation but are also attributed to the cytoprotective properties of the byproducts of the reaction. Manipulation of this enzymatic system in a myriad of disease models has provided substantial evidence to support its role as a cytoprotective enzyme and is therefore an emerging therapeutic molecule.

Benavente O.R.,University of British Columbia | Hart R.G.,Population Health Research Institute | McClure L.A.,University of Alabama at Birmingham | Szychowski J.M.,University of Alabama at Birmingham | Coffey C.S.,University of Iowa
New England Journal of Medicine | Year: 2012

BACKGROUND: Lacunar infarcts are a frequent type of stroke caused mainly by cerebral small-vessel disease. The effectiveness of antiplatelet therapy for secondary prevention has not been defined. METHODS: We conducted a double-blind, multicenter trial involving 3020 patients with recent symptomatic lacunar infarcts identified by magnetic resonance imaging. Patients were randomly assigned to receive 75 mg of clopidogrel or placebo daily; patients in both groups received 325 mg of aspirin daily. The primary outcome was any recurrent stroke, including ischemic stroke and intracranial hemorrhage. RESULTS: The participants had a mean age of 63 years, and 63% were men. After a mean follow-up of 3.4 years, the risk of recurrent stroke was not significantly reduced with aspirin and clopidogrel (dual antiplatelet therapy) (125 strokes; rate, 2.5% per year) as compared with aspirin alone (138 strokes, 2.7% per year) (hazard ratio, 0.92; 95% confidence interval [CI], 0.72 to 1.16), nor was the risk of recurrent ischemic stroke (hazard ratio, 0.82; 95% CI, 0.63 to 1.09) or disabling or fatal stroke (hazard ratio, 1.06; 95% CI, 0.69 to 1.64). The risk of major hemorrhage was almost doubled with dual antiplatelet therapy (105 hemorrhages, 2.1% per year) as compared with aspirin alone (56, 1.1% per year) (hazard ratio, 1.97; 95% CI, 1.41 to 2.71; P<0.001). Among classifiable recurrent ischemic strokes, 71% (133 of 187) were lacunar strokes. All-cause mortality was increased among patients assigned to receive dual antiplatelet therapy (77 deaths in the group receiving aspirin alone vs. 113 in the group receiving dual antiplatelet therapy) (hazard ratio, 1.52; 95% CI, 1.14 to 2.04; P = 0.004); this difference was not accounted for by fatal hemorrhages (9 in the group receiving dual antiplatelet therapy vs. 4 in the group receiving aspirin alone). CONCLUSIONS: Among patients with recent lacunar strokes, the addition of clopidogrel to aspirin did not significantly reduce the risk of recurrent stroke and did significantly increase the risk of bleeding and death. (Funded by the National Institute of Neurological Disorders and Stroke and others; SPS3 number, NCT00059306.) Copyright © 2012 Massachusetts Medical Society. All rights reserved.

Owsley C.,University of Alabama at Birmingham
Optometry and Vision Science | Year: 2012

Being a licensed driver in the United States and many other countries facilitates health and well-being. Based on the vision standards in most states, individuals with worse than 20/40 visual acuity who desire licensure are denied through the usual licensure application process. However, >40 states have bioptic telescope licensing programs where applicants can gain licensure contingent on meeting specific requirements. Despite the existence of the bioptic telescope and these licensing programs since the 1970s, there has been little rigorous scientific study of this topic. Here, I offer an organizing perspective for a research agenda on driving with bioptic telescopes, with the long-term practical goal being to provide an evidence basis for licensure policies and training programs. Copyright © 2012 American Academy of Optometry.

Khashab M.A.,Johns Hopkins Medical Institutions | Varadarajulu S.,University of Alabama at Birmingham
Current Opinion in Gastroenterology | Year: 2012

PURPOSE OF REVIEW: Endoscopic ultrasonography (EUS) has taken on more of a therapeutic role in recent years. This review will focus on the therapeutic applications of EUS. RECENT FINDINGS: Multiple studies on the therapeutic applications of EUS have been published. EUS facilitates endoscopic drainage of pancreatic fluid collections (PFCs) including walled-off pancreatic necrosis, management of refractory gastrointestinal bleeding from gastric varix or vasculature by fine-needle injection and decompression of obstructive pancreatic or biliary ductal systems following failed access by standard endoscopic or radiological techniques. SUMMARY: The indications and role of therapeutic EUS have expanded rapidly in recent years. The procedures can be technically challenging, requiring expertise in both endosonography and endoscopic retrograde cholangiopancreatography. Refinement in echoendoscope design and dedicated accessories are required to further expand the applications of therapeutic EUS. Copyright © Lippincott Williams & Wilkins.

Dutton G.R.,University of Alabama at Birmingham | Lewis C.E.,University of Alabama at Birmingham
Progress in Cardiovascular Diseases | Year: 2015

Given the array of adverse health consequences of obesity, including increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD), the Look AHEAD trial (N = 5145) was conducted to test the hypothesis that an intensive lifestyle intervention (ILI) for weight loss would achieve significantly greater reductions in CVD morbidity and mortality than a control condition of diabetes support and education (DSE) among participants with T2DM. A number of significant and long-term improvements were observed for ILI, including body weight, physical fitness and physical function, glucose control, quality-of-life (QoL), and healthcare costs. However, ILI did not significantly reduce CVD-related morbidity/mortality (i.e., CVD death, non-fatal MI, non-fatal stroke, hospitalized angina) after nearly 10 years of follow-up. There was a suggestion of heterogeneity of response based on the history of prior CVD at baseline (p = 0.06). Despite the overall lack of CVD risk reduction, ILI remains important for care of patients with T2DM, particularly when accompanied by medication management. In particular, ILI may be an appealing option for patients wanting to minimize medication intensification. Also, ILI carries with it other potential benefits important to patients (e.g., improvements in physical functioning and QoL). Based on data from other trials, intensive medication management, such as tight glycemic control, is not without potential risks, which should be weighed in making treatment decisions. Future research is needed to determine if results observed in this trial would be replicated among younger patients, those without established T2DM, and/or those with no pre-existing CVD. © 2015 Elsevier Inc.

Graven L.J.,Florida State University | Grant J.,University of Alabama at Birmingham
Journal of Cardiovascular Nursing | Year: 2013

Background: Approximately 50% of individuals living with heart failure (HF) experience depressive symptoms. Social support has been found to have a positive influence on depressive symptoms in individuals with HF. Objective: The purposes of this review were to (1) examine recent literature regarding the impact of social support on depressive symptoms in individuals with HF, (2) synthesize findings across those studies, (3) assess potential areas of future research regarding social support, and (4) identify implications for nursing practice. Methods: An integrative review of current empirical literature was conducted through a search of the CINAHL and PsycARTICLES computerized databases for the period of January 2000 to December 2010. The key words used for the search were heart failure, social support, coping, depressive symptoms, and depression. Results: Fifteen studies matched inclusion criteria. Eleven of these studies found social support to prevent or reduce depressive symptoms. Emotional and tangible support as coping resources or strategies, the perceived availability of or satisfaction with support, and assistance with problem solving positively influenced depressive symptoms. Perceived emotional and tangible support and the presence and availability of social networks lessened depression in patients with HF. Findings from 4 studies on the impact of social support were not statistically significant. Different definitions of social support and a variety of measurement instruments used made it difficult to generalize study findings. Conclusions: Social support seems to positively impact and influence the psychological well-being of those with HF. Additional research is needed to identify specific characteristics of support that is effective in influencing depressive symptoms in this population. Furthermore, more research is needed regarding how factors such as ethnicity influence depressive symptoms and depression. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Yamada T.,University of Alabama at Birmingham
Circulation Journal | Year: 2013

Transthoracic epicardial catheter ablation is a useful supplemental or even preferred strategy to eliminate cardiac arrhythmias in the electrophysiology laboratory. The indication for this technique has extended to a diverse range of cardiac arrhythmias, including scar-related ventricular tachycardia (VT), idiopathic VTs, accessory pathways, atrial tachycardias, inappropriate sinus tachycardia, and atrial fibrillation, as the epicardial substrates of these tachyarrhythmias have become increasingly recognized. When endocardial ablation and epicardial ablation through the cardiac veins are unsuccessful, transthoracic epicardial ablation should be the next option. Intrapericardial access is usually obtained through a subxiphoidal pericardial puncture. This approach might not be possible in patients with pericardial adhesions caused by prior cardiac surgery or pericarditis. In such cases, a hybrid procedure involving surgical access with a subxiphoid pericardial window and limited anterior or lateral thoracotomy might be a feasible and safe method of performing epicardial catheter ablation in the electrophysiology laboratory. Potential complications associated with this technique include bleeding and collateral damage to the coronary artery and phrenic nerve. Although the risk of these complications is low, electrophysiologists who attempt epicardial catheter ablation should know the complications associated with this technique, how to minimize their occurrence, and how to rapidly recognize and treat the complications that they encounter. This review discusses the indications, techniques, and complications of transthoracic epicardial catheter ablation.

Muzny C.A.,University of Alabama at Birmingham | Schwebke J.R.,University of Alabama at Birmingham
Current Infectious Disease Reports | Year: 2013

Bacterial vaginosis (BV) is the most common cause of vaginal infection, yet its pathogenesis remains controversial. Although it has never been proven to be a sexually transmitted diseases the epidemiological evidence favoring this is quite robust. Although BV is characterized by its polymicrobial nature, it is highly likely that the inciting organism is Gardnerella vaginalis. © 2013 Springer Science+Business Media New York.

Marson D.C.,University of Alabama at Birmingham
American Journal of Geriatric Psychiatry | Year: 2013

In contrast to issues such as treatment and research consent capacity, financial capacity has received relatively little clinical and ethical attention in the dementia literature. Yet issues of financial capacity emerge frequently in patients with Alzheimer disease, Parkinson disease, and related dementias, and commonly present ethical and clinical challenges for clinicians treating these patients. These issues include whether a patient with possible dementia has sufficient capacity to manage independently their financial affairs, needs referral for financial capacity assessment, and/or is being financially exploited or abused by others. The accurate identification, assessment and successful handling of such financial capacity issues can have a substantial impact on the financial and psychological well-being of patients and their family members. This commentary presents an overview of financial capacity and associated clinical and ethical issues in dementia and describes a set of possible clinician roles regarding these issues as they arise in clinical practice. The commentary concludes with a section describing educational resources available to clinicians and bioethicists seeking additional guidance in handling financial capacity issues. The ultimate goal of the article is to focus clinical and ethical attention on a neglected capacity that is of fundamental importance for patients, families, and healthcare and legal professionals. © 2013 American Association for Geriatric Psychiatry.

Sivley M.D.,University of Alabama at Birmingham
Optometry and Vision Science | Year: 2013

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by accumulation of Gb-3 (globotriaosylceramide) in cellular lysosomes of tissues throughout the body. With advancing age, lysosomal Gb-3 accumulates in blood vessel walls, nerve cells, smooth muscle, and vital organs. Premature death commonly results from renal failure, heart attack, and stroke when the diagnosis is delayed or overlooked. One of the earliest and most distinctive physical features of FD is a whorl-like keratopathy. This finding is easily identifiable during a routine eye examination with a slit lamp, making eye care practitioners uniquely postured to identify patients and families with this incurable genetic disorder. Much of the pain, suffering, and adverse impact of FD can be avoided if an alert eye care expert sees the patient at an early age, identifies the condition, and makes the appropriate referral. The importance of obtaining a thorough medical history, ancestral health history, and review of systems to correlate ocular and systemic manifestations is emphasized. This report reviews the multisystem involvement of FD and describes the clinical characteristics and expected chronological appearance of ophthalmic and systemic manifestations. The discoveries of late-onset variants, increased prevalence, and modified inheritance pattern of FD are discussed. The profound therapeutic effects of recombinant enzyme replacement therapy (ERT) on multiple organ systems are detailed and demonstrated in a Fabry proband. Improved quality and quantity of life after initiation of ERT underscore the importance of early recognition and correlation of FD symptoms and clinical signs. Treatment strategies and the effectiveness of new adjunctive chaperone therapy are addressed. Copyright © 2013 American Academy of Optometry.

Chalela J.A.,Medical University of South Carolina | Lopez J.I.,University of Alabama at Birmingham
Nutrition in Clinical Practice | Year: 2013

Hunger strikes are not infrequent occurrences in military and civilian prisons. Although practicing clinicians are familiar with the management of patients who have limited oral intake, managing hunger strikers is unfamiliar to most. The psychological, physiological, and social events that surround hunger strikes are very complex and need to be understood by those caring for hunger strike patients. To provide adequate medical care to hunger strike patients, clinicians most understand the physiological events that ensue after prolonged starvation. Careful vigilance for development of refeeding syndrome is of key importance. A multidisciplinary approach to hunger strikes is of utmost importance, and involvement of a multidisciplinary clinical team as well as prison officials is essential. © 2012 American Society for Parenteral and Enteral Nutrition.

Elewski B.E.,University of Alabama at Birmingham
Expert Review of Dermatology | Year: 2013

Onychomycosis is a common nail infection for which treatment options are limited, and no new treatment have been introduced for over 10 years. While patients might prefer a topical therapy, efficacy with ciclopirox and amorolfine lacquers has been disappointing especially in moderate to severe disease. Efinaconazole 10% solution is a new triazole antifungal, specifically developed for the topical treatment of onychomycosis. Its physicochemical properties, antifungal activity and formulation are all important aspects of the development program and are reviewed here. Efinaconazole 10% solution may provide the first viable alternative to oral therapy for onychomycosis. Mycologic cure rates are comparable to those seen with oral itraconazole, and greater than reported with ciclopirox lacquer. © 2013 Informa UK Ltd.

Cui X.,University of Alabama at Birmingham
Applied Immunohistochemistry and Molecular Morphology | Year: 2015

The commonly used Nottingham Grading System in breast cancer takes into consideration the presence of tubular formation, nuclear pleomorphism, and the mitotic index (MI), among which the latter has been shown to be the most powerful prognostic factor. In practice, histologic grading is highly subjective, with only moderate interobserver reproducibility. Phosphorylation of histone H3 has been demonstrated to be a specific event in the mitotic phase, and is negligible during interphase. In this study, we evaluated the efficacy of Phosphohistone H3 (PHH3) in the breast cancer grading of 97 consecutive biopsy specimens. PHH3 antibodies clearly revealed discrete, strong nuclear immunoreactivity in mitotically active cells even under low magnification. The PHH3 MI showed a significant correlation with that derived by hematoxylin and eosin (H&E) staining as well as the Ki-67 proliferation index. Further, the pairwise κ-value of the MI was significantly increased, and the pairwise agreement was also markedly improved by PHH3 immunostaining, although a significant proportion of breast cancer cases were upgraded by use of the PHH3 MI. Our data showed that PHH3 provided a more sensitive and accurate MI with less interobserver variability when compared with conventional H&E staining, thus emphasizing its potentially increased value in practice. Reconsideration of breast cancer grading with integration of PHH3 should be considered if it continues to demonstrate superiorly to traditional H&E staining. © 2015 Lippincott Williams & Wilkins, Inc.

Finan P.H.,Johns Hopkins University | Goodin B.R.,University of Alabama at Birmingham | Smith M.T.,Johns Hopkins University
Journal of Pain | Year: 2013

Ample evidence suggests that sleep and pain are related. However, many questions remain about the direction of causality in their association, as well as mechanisms that may account for their association. The prevailing view has generally been that they are reciprocally related. The present review critically examines the recent prospective and experimental literature (2005-present) in an attempt to update the field on emergent themes pertaining to the directionality and mechanisms of the association of sleep and pain. A key trend emerging from population-based longitudinal studies is that sleep impairments reliably predict new incidents and exacerbations of chronic pain. Microlongitudinal studies employing deep subjective and objective assessments of pain and sleep support the notion that sleep impairments are a stronger, more reliable predictor of pain than pain is of sleep impairments. Recent experimental studies suggest that sleep disturbance may impair key processes that contribute to the development and maintenance of chronic pain, including endogenous pain inhibition and joint pain. Several biopsychosocial targets for future mechanistic research on sleep and pain are discussed, including dopamine and opioid systems, positive and negative affect, and sociodemographic factors. Perspective This critical review examines the recent prospective and experimental research (2005-present) on the association of sleep and pain in an attempt to identify trends suggestive of directionality and potential mechanisms. An update on this literature is needed to guide future clinical efforts to develop and augment treatments for chronic sleep disturbance and chronic pain. © 2013 by the American Pain Society.

Pappas P.G.,University of Alabama at Birmingham
Current Opinion in Infectious Diseases | Year: 2013

PURPOSE OF REVIEW: The recent outbreak of fungal meningitis related to contaminated methylprednisolone acetate injections represents an important cause of morbidity and continues to be a significant public health problem in the United States. RECENT FINDINGS: As of August 2013, there have been 749 cases and 63 deaths in 20 states associated with epidemic fungal meningitis, most of these because of Exserohilum rostratum. Clinical experience in managing these cases has grown dramatically in the last several months; most patients require at least 6 months of antifungal therapy for complicated disease. Most patients are treated with voriconazole, with or without liposomal amphotericin B, for central nervous system and paraspinal complications of the disease. For disease involving the sacroiliac and peripheral joints, voriconazole alone has been preferred. MRI spine imaging has identified several cases of asymptomatic disease, suggesting an aggressive diagnostic approach to exposed asymptomatic patients. Mortality remains low (<10%), but morbidity relating to persistent symptoms and treatment-associated toxicity is high. SUMMARY: The ongoing fungal meningitis epidemic demonstrates an important achievement for the public health community. Important questions remain relating to the diagnosis, management, and long-term outcomes of these patients. Important research questions pertaining to specific risks influencing disease manifestations remain unanswered. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Allon M.,University of Alabama at Birmingham
Clinical Journal of the American Society of Nephrology | Year: 2015

Arteriovenous grafts (AVGs) are prone to frequent thrombosis that is superimposed on underlying hemodynamically significant stenosis, most commonly at the graft-vein anastomosis. There has been great interest in detecting AVG stenosis in a timely fashion and performing preemptive angioplasty, in the belief that this will prevent AVG thrombosis. Three surveillance methods (static dialysis venous pressure, flow monitoring, and duplex ultrasound) can detect AVG stenosis. Whereas observational studies have reported that surveillance with preemptive angioplasty substantially reduces AVG thrombosis, randomized clinical trials have failed to confirm such a benefit. There is a high frequency of early AVG restenosis after angioplasty caused by aggressive neointimal hyperplasia resulting from vascular injury. Stent grafts prevent AVG restenosis better than balloon angioplasty, but they do not prevent AVG thrombosis. Several pharmacologic interventions to prevent AVG failure have been evaluated in randomized clinical trials. Anticoagulation or aspirin plus clopidogrel do not prevent AVG thrombosis, but increase hemorrhagic events. Treatment of hyperhomocysteinemia does not prevent AVG thrombosis. Dipyridamole plus aspirin modestly decreases AVG stenosis or thrombosis. Fish oil substantially decreases the frequency of AVG stenosis and thrombosis. In patients who have exhausted all options for vascular access in the upper extremities, thigh AVGs are a superior option to tunneled internal jugular vein central vein catheters (CVCs). An immediate-use AVG is a reasonable option in patients with recurrent CVC dysfunction or infection. Tunneled femoral CVCs have much worse survival than internal jugular CVCs. © 2015 by the American Society of Nephrology.

Visscher K.M.,University of Alabama at Birmingham | Weissman D.H.,University of Michigan
BMC Medicine | Year: 2011

During the past two decades, the advent of functional magnetic resonance imaging (fMRI) has fundamentally changed our understanding of brain-behavior relationships. However, the data from any one study add only incrementally to the big picture. This fact raises important questions about the dominant practice of performing studies in isolation. To what extent are the findings from any single study reproducible? Are researchers who lack the resources to conduct a fMRI study being needlessly excluded? Is pre-existing fMRI data being used effectively to train new students in the field? Here, we will argue that greater sharing and synthesis of raw fMRI data among researchers would make the answers to all of these questions more favorable to scientific discovery than they are today and that such sharing is an important next step for advancing the field of cognitive neuroscience. © 2011 Visscher and Weissman; licensee BioMed Central Ltd.

Richman J.S.,University of Alabama at Birmingham
Methods in Enzymology | Year: 2011

The analysis of large and complex databases poses many challenges. Such databases arise in health-services, electronic medical records, insurance, and other commercial data sources where both the number of observations and variables can be enormous. The problems are particularly acute in genomics and proteomics where the number of variables is typically much higher than the number of observations. Extant methods seek to balance the demands of making efficient use of the data with the need to maintain the flexibility required to detect complex relationships and interactions. To overcome some limitations of current methods, a novel analytical tool, Multivariate Neighborhood Sample Entropy (MN-SampEn) is introduced. It is a generalization of Sample Entropy to multivariate data that inherits many of Sample Entropy's desirable properties. In principle, it selects significant covariates without reference to an underlying model and provides predictions similar to those of k-Nearest-Neighbor methods, with fewer covariates required. However, adaptation to multivariate data requires that several additional optimization issues be addressed. Several optimization strategies are discussed and tested on a set of MALDI mass spectra. With some optimization strategies, MN-SampEn identified a reduced set of covariates and exhibited lower predictive error rates than k-Nearest Neighbors. © 2011 Elsevier Inc.

Sharp P.M.,University of Edinburgh | Hahn B.H.,University of Alabama at Birmingham
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

The major cause of acquired immune deficiency syndrome (AIDS) is human immunodeficiency virus type 1 (HIV-1). We have been using evolutionary comparisons to trace (i) the origin(s) of HIV-1 and (ii) the origin(s) of AIDS. The closest relatives of HIV-1 are simian immunodeficiency viruses (SIVs) infecting wild-living chimpanzees (Pan troglodytes troglodytes) and gorillas (Gorilla gorilla gorilla) in west central Africa. Phylogenetic analyses have revealed the origins of HIV-1: chimpanzees were the original hosts of this clade of viruses; four lineages of HIV-1 have arisen by independent cross-species transmissions to humans and one or two of those transmissions may have been via gorillas. However, SIVs are primarily monkey viruses: more than 40 species of African monkeys are infected with their own, species-specific, SIV and in at least some host species, the infection seems non-pathogenic. Chimpanzees acquired from monkeys two distinct forms of SIVs that recombined to produce a virus with a unique genome structure. We have found that SIV infection causes CD4+ T-cell depletion and increases mortality in wild chimpanzees, and so the origin of AIDS is more ancient than the origin of HIV-1. Tracing the genetic changes that occurred as monkey viruses adapted to infect first chimpanzees and then humans may provide insights into the causes of the pathogenicity of these viruses. This journal is © 2010 The Royal Society.

Korf B.R.,University of Alabama at Birmingham
Discovery Medicine | Year: 2013

Although some have wondered whether the sequencing of the human genome has led to major advances in medicine, in fact there are multiple examples where genomics has been integrated into medical practice. In the area of prevention, genomic approaches are now used for non-invasive prenatal testing of fetal DNA in the maternal circulation, for expanded preconceptional screening for carrier status, for autosomal recessive disorders, and for assessment of risk of common disease. In the area of diagnosis, major advances have been made in cytogenomics and in use of whole exome or whole genome sequencing. In therapeutics, pharmacogenetic testing is now feasible, tumor genome sequencing is being used to guide cancer therapy, and genomic discoveries are enabling development of new targeted therapies. Ultimately it is possible that genome sequencing may be done for all individuals on a routine basis, though there remain significant technical, ethical, and medical systems challenges to be overcome. It is likely that integration of genomics into medical practice will occur gradually over a long period of time, but the process is now well underway. © Discovery Medicine.

Chapleau C.A.,University of Alabama at Birmingham | Pozzo-Miller L.,University of Alabama at Birmingham
Neural Plasticity | Year: 2012

Activation of TrkB receptors by brain-derived neurotrophic factor (BDNF) followed by MAPK/ERK signaling increases dendritic spine density and the proportion of mature spines in hippocampal CA1 pyramidal neurons. Considering the opposing actions of p75NTR and Trk receptors in several BDNF actions on CNS neurons, we tested whether these receptors also have divergent actions on dendritic spine density and morphology. A function-blocking anti- p75NTR antibody (REX) did not affect spine density by itself but it prevented BDNF's effect on spine density. Intriguingly, REX by itself increased the proportion of immature spines and prevented BDNF's effect on spine morphology. In contrast, the Trk receptor inhibitor k-252a increased spine density by itself, and prevented BDNF from further increasing spine density. However, most of the spines in k-252a-treated slices were of the immature type. These effects of k-252a on spine density and morphology required neuronal activity because they were prevented by TTX. These divergent BDNF actions on spine density and morphology are reminiscent of opposing functional signaling by p75NTR and Trk receptors and reveal an unexpected level of complexity in the consequences of BDNF signaling on dendritic morphology. © 2012 Christopher A. Chapleau and Lucas Pozzo-Miller.

Cervical cancer is the leading cause of cancer death among women in Ghana. Despite the availability of cervical cancer screening in healthcare facilities throughout the country, less than 4 % of Ghanaian women seek preventive cervical cancer screenings regularly. There is a lack of culturally relevant cervical cancer education material available in Ghana. The aims of this study were to assess the social cultural factors that influence cervical cancer screening behaviors and the health communication preferences of Ghanaian women. A focus group guide based on the constructs of the PEN-3 model was used to conduct six focus groups that were stratified by educational attainment. Thirty-four women participated in the study. The qualitative data revealed that most participants were not aware of cervical cancer or cervical cancer screening. However, many of the participants were willing to seek screening if they knew more about it. The most common sources of health information were television, radio, friends, and family. And the participants preferred inspirational cervical-cancer-screening messages that would be delivered by a doctor and a cancer survivor. © 2014 Springer Science+Business Media New York.

Phipps M.C.,University of Alabama at Birmingham | Xu Y.,University of Alabama at Birmingham | Bellis S.L.,University of Alabama at Birmingham
PLoS ONE | Year: 2012

The recruitment of mesenchymal stem cells (MSCs) is a vital step in the bone healing process, and hence the functionalization of osteogenic biomaterials with chemotactic factors constitutes an important effort in the tissue engineering field. Previously we determined that bone-mimetic electrospun scaffolds composed of polycaprolactone, collagen I and nanohydroxyapatite (PCL/col/HA) supported greater MSC adhesion, proliferation and activation of integrin-related signaling cascades than scaffolds composed of PCL or collagen I alone. In the current study we investigated the capacity of bone-mimetic scaffolds to serve as carriers for delivery of an MSC chemotactic factor. In initial studies, we compared MSC chemotaxis toward a variety of molecules including PDGF-AB, PDGF-BB, BMP2, and a mixture of the chemokines SDF-1α, CXCL16, MIP-1α, MIP-1β, and RANTES. Transwell migration assays indicated that, of these factors, PDGF-BB was the most effective in stimulating MSC migration. We next evaluated the capacity of PCL/col/HA scaffolds, compared with PCL scaffolds, to adsorb and release PDGF-BB. We found that significantly more PDGF- BB was adsorbed to, and subsequently released from, PCL/col/HA scaffolds, with sustained release extending over an 8-week interval. The PDGF-BB released was chemotactically active in transwell migration assays, indicating that bioactivity was not diminished by adsorption to the biomaterial. Complementing these studies, we developed a new type of migration assay in which the PDGF-BB-coated bone-mimetic substrates were placed 1.5 cm away from the cell migration front. These experiments confirmed the ability of PDGF-BB-coated PCL/col/HA scaffolds to induce significant MSC chemotaxis under more stringent conditions than standard types of migration assays. Our collective results substantiate the efficacy of PDGF-BB in stimulating MSC recruitment, and further show that the incorporation of native bone molecules, collagen I and nanoHA, into electrospun scaffolds not only enhances MSC adhesion and proliferation, but also increases the amount of PDGF-BB that can be delivered from scaffolds. © 2012 Phipps et al.

Dhossche D.M.,University of Mississippi Medical Center | Ross C.A.,The Colin A Ross Institute For Psychological Trauma | Stoppelbein L.,University of Alabama at Birmingham
Acta Psychiatrica Scandinavica | Year: 2012

Objective: Catatonia is considered a unique syndrome of motor signs, at times life-threatening when aggravated by autonomic dysfunction and fever, but eminently treatable with specific medical treatments, if recognized early. Catatonia commonly occurs in children and adolescents with a wide range of associated disorders. The role of deprivation, abuse, or trauma in the development of pediatric catatonia is examined. Method: Reports considering deprivation, abuse, or trauma as precipitants of catatonia in pediatric cases are culled from the classic writings on catatonia and from a selective review of modern contributions. Results: Kahlbaum gave trauma a central role in catatonia in many young adult cases. Kanner described children with psychogenic catalepsy. Anaclitic depression, a condition found by Spitz in deprived institutionalized children, strongly resembles stuporous catatonia. Leonhard considered lack of communication with the mother or substitute mother as an important risk factor for childhood catatonia. Children including those with autism who experience emotional and physical trauma sometimes develop catatonia. The clinical descriptions of children with classic catatonic syndromes and those of contemporary refugee children with a syndrome labeled Pervasive Refusal Syndrome are similar. Conclusion: The literature supports the view that deprivation, abuse, and trauma can precipitate catatonia in children and adolescents. © 2011 John Wiley & Sons A/S.

McKeown J.L.,University of Alabama at Birmingham
Anesthesiology Clinics | Year: 2015

Adequate treatment of pain is of utmost importance in making uncomplicated the perioperative course for geriatric surgical patients. Effective analgesia reduces morbidity, improves patient and family satisfaction, and is a natural expectation of high-quality care. Pain treatment in older adults is more complicated than in younger counterparts, and great consideration must be given to age-related changes in physiology and pharmacokinetics. Pain treatment must be individualized based on each patient's profile. Side effects must be minimized and organ toxicity avoided. When complications occur they may be more severe, and treatment must be prompt. Alternative plans for analgesia must be readily enacted. © 2015 Elsevier Inc..

Momaya A.,University of Alabama at Birmingham | Fawal M.,University of Alabama at Birmingham | Estes R.,University of Alabama at Birmingham
Sports Medicine | Year: 2015

Performance-enhancing substances (PESs) have unfortunately become ubiquitous in numerous sports, often tarnishing the spirit of competition. Reported rates of PES use among athletes are variable and range from 5 to 31 %. More importantly, some of these substances pose a serious threat to the health and well-being of athletes. Common PESs include anabolic–androgenic steroids, human growth hormone, creatine, erythropoietin and blood doping, amphetamines and stimulants, and beta-hydroxy-beta-methylbutyrate. With recent advances in technology, gene doping is also becoming more conceivable. Sports medicine physicians are often unfamiliar with these substances and thus do not routinely broach the topic of PESs with their patients. However, to effect positive change in the sports community, physicians must educate themselves about the physiology, performance benefits, adverse effects, and testing methods. In turn, physicians can then educate athletes at all levels and prevent the use of potentially dangerous PESs. © 2015, Springer International Publishing Switzerland.

New J.S.,University of Alabama at Birmingham | King R.G.,University of Alabama at Birmingham | Kearney J.F.,University of Alabama at Birmingham
Immunological Reviews | Year: 2016

Natural immunoglobulin derived from innate-like B lymphocytes plays important roles in the suppression of inflammatory responses and represents a promising therapeutic target in a growing number of allergic and autoimmune diseases. These antibodies are commonly autoreactive and incorporate evolutionarily conserved specificities, including certain glycan-specific antibodies. Despite this conservation, exposure to bacterial polysaccharides during innate-like B lymphocyte development, through either natural exposure or immunization, induces significant changes in clonal representation within the glycan-reactive B cell pool. Glycan-reactive natural antibodies (NAbs) have been reported to play protective and pathogenic roles in autoimmune and inflammatory diseases. An understanding of the composition and functions of a healthy glycan-reactive NAb repertoire is therefore paramount. A more thorough understanding of NAb repertoire development holds promise for the design of both biological diagnostics and therapies. In this article, we review the development and functions of NAbs and examine three glycan specificities, represented in the innate-like B cell pool, to illustrate the complex roles environmental antigens play in NAb repertoire development. We also discuss the implications of increased clonal plasticity of the innate-like B cell repertoire during neonatal and perinatal periods, and the prospect of targeting B cell development with interventional therapies and correct defects in this important arm of the adaptive immune system. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Haas B.R.,University of Alabama at Birmingham | Sontheimer H.,University of Alabama at Birmingham
Cancer Research | Year: 2010

Malignant gliomas metastasize throughout the brain by infiltrative cell migration into peritumoral areas. Invading cells undergo profound changes in cell shape and volume as they navigate extracellular spaces along blood vessels and white matter tracts. Volume changes are aided by the concerted release of osmotically active ions, most notably K + and Cl -. Their efflux through ion channels along with obligated water causes rapid cell shrinkage. Suitable ionic gradients must be established and maintained through the activity of ion transport systems. Here, we show that the Sodium-Potassium-Chloride Cotransporter Isoform-1 (NKCC1) provides the major pathway for Cl - accumulation in glioma cells. NKCC1 localizes to the leading edge of invading processes, and pharmacologic inhibition using the loop diuretic bumetanide inhibits in vitro Transwell migration by 25% to 50%. Short hairpin RNA knockdowns of NKCC1 yielded a similar inhibition and a loss of bumetanide-sensitive cell volume regulation. A loss of NKCC1 function did not affect cell motility in two-dimensional assays lacking spatial constraints but manifested only when cells had to undergo volume changes during migration. Intracranial implantation of human gliomas into severe combined immunodeficient mice showed a marked reduction in cell invasion when NKCC1 function was disrupted genetically or by twice daily injection of the Food and Drug Administration-approved NKCC1 inhibitor Bumex. These data support the consideration of Bumex as adjuvant therapy for patients with high-grade gliomas. ©2010 AACR.

Kaiser K.A.,University of Alabama at Birmingham | Shikany J.M.,University of Alabama at Birmingham | Keating K.D.,University of Alabama at Birmingham | Allison D.B.,University of Alabama at Birmingham
Obesity Reviews | Year: 2013

We provide arguments to the debate question and update a previous meta-analysis with recently published studies on effects of sugar-sweetened beverages (SSBs) on body weight/composition indices (BWIs). We abstracted data from randomized controlled trials examining effects of consumption of SSBs on BWIs. Six new studies met these criteria: (i) human trials, (ii) ≥3 weeks duration, (iii) random assignment to conditions differing only in consumption of SSBs and (iv) including a BWI outcome. Updated meta-analysis of a total of seven studies that added SSBs to persons' diets showed dose-dependent increases in weight. Updated meta-analysis of eight studies attempting to reduce SSB consumption showed an equivocal effect on BWIs in all randomized subjects. When limited to subjects overweight at baseline, meta-analysis showed a significant effect of roughly 0.25 standard deviations (more weight loss/less weight gain) relative to controls. Evidence to date is equivocal in showing that decreasing SSB consumption will reduce the prevalence of obesity. Although new evidence suggests that an effect may yet be demonstrable in some populations, the integrated effect size estimate remains very small and of equivocal statistical significance. Problems in this research area and suggestions for future research are highlighted. © 2013 International Association for the Study of Obesity.

Although there is general agreement that most forms of common disease develop as a consequence of a combination of factors, including genetic, environmental and behavioural contributors, the actual mechanistic basis of how these factors initiate or promote diabetes, cancer, neurodegenerative and cardiovascular diseases in some individuals but not in others with seemingly identical risk factor profiles, is not clearly understood. In this respect, consideration of the potential role for mitochondrial genetics, damage and function in influencing common disease susceptibility seems merited, given that the prehistoric challenges were the original factors that moulded cellular function, and these were based upon the mitochondrial-nuclear relationships that were established during evolutionary history. These interactions were probably refined during prehistoric environmental selection events that, at present, are largely absent. Contemporary risk factors such as diet, sedentary lifestyle and increased longevity, which influence our susceptibility to a variety of chronic diseases were not part of the dynamics that defined the processes of mitochondrial-nuclear interaction, and thus cell function. Consequently, the prehistoric challenges that contributed to cell functionality and evolution should be considered when interpreting and designing experimental data and strategies. Although several molecular epidemiological studies have generally supported this notion, studies that probe beyond these associations are required. Such investigation will mark the initial steps for mechanistically addressing the provocative concept that contemporary human disease susceptibility is the result of prehistoric selection events for mitochondrial-nuclear function, which increased the probability for survival and reproductive success during evolution. © 2013 Biochemical Society.

Muzny C.A.,University of Alabama at Birmingham
Sexually transmitted diseases | Year: 2012

The random amplified polymorphic DNA technique was used to delineate the genetic relatedness of Trichomonas vaginalis isolates among 3 pairs of mutually infected women who have sex with women in sexual partnerships. One of the 3 pairs of women shared a T. vaginalis isolate with the same random amplified polymorphic DNA banding patterns. Shared use of washcloths to cleanse the vaginal area after receptive oral sex was the most likely method of T. vaginalis transmission among this pair of women.

Fowler K.B.,University of Alabama at Birmingham
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America | Year: 2013

The association between congenital cytomegalovirus (CMV) infection and sensorineural hearing loss (SNHL) was first described almost 50 years ago. Studies over the intervening decades have further described the relationship between congenital CMV infection and SNHL in children. However, congenital CMV infection remains a leading cause of SNHL in children in the United States and the world today. As more CMV infections are identified, it is important to recognize that infants who are born to seroimmune mothers are not completely protected from SNHL, although their hearing loss is often milder than that seen in CMV-infected infants following primary maternal infections. Late-onset and progressive hearing losses occur following congenital CMV infection, and CMV-infected infants should be evaluated regularly to provide for early detection of hearing loss and appropriate intervention. Fluctuating hearing loss that is not explained by concurrent middle ear infections is another characteristic of CMV-related hearing loss in children. Challenges still remain in predicting which children with congenital CMV infection will develop hearing loss and, among those who do develop loss, whether or not the loss will continue to deteriorate.

Aaron K.J.,University of Alabama at Birmingham | Sanders P.W.,University of Alabama at Birmingham
Mayo Clinic Proceedings | Year: 2013

The objective of this review was to provide a synthesis of the evidence on the effect of dietary salt and potassium intake on population blood pressure, cardiovascular disease, and mortality. Dietary guidelines and recommendations are outlined, current controversies regarding the evidence are discussed, and recommendations are made on the basis of the evidence. Designed search strategies were used to search various databases for available studies. Randomized trials of the effect of dietary salt intake reduction or increased potassium intake on blood pressure, target organ damage, cardiovascular disease, and mortality were included. Fifty-two publications from January 1, 1990, to January 31, 2013, were identified for inclusion. Consideration was given to variations in the search terms used and the spelling of terms so that studies were not overlooked, and search terms took the following general form: (dietary salt or dietary sodium or [synonyms]) and (dietary potassium or [synonyms]) and (blood pressure or hypertension or vascular disease or heart disease or chronic kidney disease or stroke or mortality or [synonyms]). Evidence from these studies demonstrates that high salt intake not only increases blood pressure but also plays a role in endothelial dysfunction, cardiovascular structure and function, albuminuria and kidney disease progression, and cardiovascular morbidity and mortality in the general population. Conversely, dietary potassium intake attenuates these effects, showing a linkage to reduction in stroke rates and cardiovascular disease risk. Various subpopulations, such as overweight and obese individuals and aging adults, exhibit greater sensitivity to the effects of reduced salt intake and may gain the most benefits. A diet that includes modest salt restriction while increasing potassium intake serves as a strategy to prevent or control hypertension and decrease cardiovascular morbidity and mortality. Thus, the body of evidence supports population-wide sodium intake reduction and recommended increases in dietary potassium intake as outlined by current guidelines as an essential public health effort to prevent kidney disease, stroke, and cardiovascular disease. © 2013 Mayo Foundation for Medical Education and Research.

There is no standard of care for older patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive therapy, and prognosis with currently recommended low-intensity therapies (decitabine, azacitidine, and low-dose cytarabine [LDAC]) remains poor. One promising strategy is to combine low-intensity treatments with novel agents. Gemtuzumab ozogamicin, tipifarnib, and barasertib have been investigated in phase 2/3 or 3 trials combined with LDAC, and phase 3 trials are currently investigating sapacitabine plus decitabine, and volasertib plus LDAC in AML. This review discusses current treatment recommendations and the development of combination therapies for older patients unfit for intensive therapy. © 2014 The Authors.

Roth T.L.,University of Alabama at Birmingham | Sweatt J.D.,University of Alabama at Birmingham
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2011

Experiences during early development profoundly affect development of the central nervous system (CNS) to impart either risk for or resilience to later psychopathology. Work in the developmental neuroscience field is providing compelling data that epigenetic marking of the genome may underlie aspects of this process. Experiments in rodents continue to show that experiences during sensitive periods of development influence DNA methylation patterns of several genes. These experience-induced DNA methylation patterns represent stable epigenetic modifications that alter gene transcription throughout the lifespan and promote specific behavioral outcomes. We discuss the relevance of these findings to humans, and also briefly discuss these findings in the broader contexts of cognition and psychiatric disorder. We conclude by discussing the implications of these observations for future research. © 2010 The Authors. Journal of Child Psychology and Psychiatry © 2010 Association for Child and Adolescent Mental Health. Published by Blackwell Publishing.

Levitan E.B.,University of Alabama at Birmingham
American Journal of Epidemiology | Year: 2011

The limitations of examining mediating factors by adjusting for them in standard regression models have been well-documented in the literature. Although alternative analytic models have been suggested, they are rarely used. In the accompanying article, Mumford et al. (Am J Epidemiol. 2010;173(2):145-156) use marginal structural linear mixed models to determine the association between dietary fiber intake and cholesterol through pathways that do not involve estradiol. Their findings suggest that overall high fiber intake decreases levels of total and low density lipoprotein (LDL) cholesterol and that there are multiple pathways through which fiber can act. The estradiol-mediated pathway seems to lead to increases in total and LDL cholesterol which are more than counterbalanced by pathways leading to decreases in total and LDL cholesterol. In addition to answering a scientifically interesting question, this work provides a concrete example of the use of marginal structural models for examination of direct effects and may serve as a guide to future researchers. © 2010 The Author.

Montgomery E.B.,University of Alabama at Birmingham
Movement Disorders | Year: 2012

Though microelectrode recordings likely increase the risks and costs of DBS, incremental improvement in accuracy may translate into improved outcomes that justify these risks and costs. Clinically based, controlled studies to resolve these issues are problematic. Until such studies are reported, physicians must rely on indirect evidence. The spatial variability of physiologically defined optimal targets, as determined by microelectrode recording (MER), necessary for targeting the STN was calculated. Study of the effectiveness of a MER algorithm was based on the number of penetrations required. The radius of the volume with a 99% chance of including the physiologically defined optimal target, based on 108 cases, was 4.5 mm. This is larger than the estimated radius of the DBS effect, which is variously estimated to be 2 to 3.9 mm. The 99% confidence radius in the plane orthogonal to the lead was 3.2 mm. In 70% of cases, the imaging-based trajectories corresponded to the physiologically defined optimal target. For the remaining 30% of cases, 70% required only a single additional MER tract. The radii of the 99% confidence volume and area may be larger than the effective radius of stimulation. Surveying within those volumes or areas is therefore necessary to assure that at least 99% of cases will cover the physiologically defined target. The MER algorithm was robust in detecting the physiologically defined optimal target. However, there are significant caveats in interpretation of the data. © 2012 Movement Disorder Society.

Landier W.,University of Alabama at Birmingham
Cancer | Year: 2016

Ototoxicity is a well-established toxicity associated with a subgroup of antineoplastic therapies that includes platinum chemotherapy, radiation or surgery involving the ear and auditory nerve, and supportive care agents such as aminoglycoside antibiotics and loop diuretics. The reported prevalence of ototoxicity in patients who have received potentially ototoxic therapy ranges from 4% to 90% depending on factors such as age of the patient population, agent(s) used, cumulative dose, and administration techniques. The impact of ototoxicity on subsequent health-related and psychosocial outcomes in these patients can be substantial, and the burden of morbidity related to ototoxic agents is particularly high in very young children. Considerable interindividual variability in the prevalence and severity of ototoxicity has been observed among patients receiving similar treatment, suggesting genetic susceptibility as a risk factor. The development and testing of otoprotective agents is ongoing; however, to the author's knowledge, no US Food and Drug Administration-approved otoprotectants are currently available. Prospective monitoring for ototoxicity allows for comparison of auditory outcomes across clinical trials, as well as for early detection, potential alterations in therapy, and auditory intervention and rehabilitation to ameliorate the adverse consequences of hearing loss. © 2016 American Cancer Society.

Parker-Autry C.Y.,University of Alabama at Birmingham
International urogynecology journal | Year: 2012

Vitamin D is a micronutrient vital in calcium homeostasis and musculoskeletal function. Vitamin D insufficiency is a common variant of vitamin D deficiency that shows clinical signs of rickets and osteomalacia. The clinical significance of vitamin D insufficiency is being explored in several medical conditions. However, the most robust work suggests a role in musculoskeletal disease. The pelvic floor is a unique part of the body and the function of which is dependent on interrelationships between muscle, nerve, connective tissue, and bone. Pelvic floor disorders result when these relationships are disrupted. This paper reviews current knowledge regarding vitamin D nutritional status, the importance of vitamin D in muscle function, and how insufficient or deficient vitamin D levels may play a role in the function of the female pelvic floor.

Rosenthal E.L.,University of Alabama at Birmingham | Warram J.M.,University of Alabama at Birmingham | Bland K.I.,University of Alabama at Birmingham | Zinn K.R.,University of Alabama at Birmingham
Annals of Surgery | Year: 2015

Objective: To review the current trends in optical imaging to guide oncologic surgery. Background: Surgical resection remains the cornerstone of therapy for patients with early stage solid malignancies and more than half of all patients with cancer undergo surgery each year. The technical ability of the surgeon to obtain clear surgical margins at the initial resection remains crucial to improve overall survival and long-term morbidity. Current resection techniques are largely based on subjective and subtle changes associated with tissue distortion by invasive cancer. As a result, positive surgical margins occur in a significant portion of tumor resections, which is directly correlated with a poor outcome. Methods: Acomprehensive reviewof studies evaluating optical imaging techniques is performed. Results: A variety of cancer imaging techniques have been adapted or developed for intraoperative surgical guidance that have been shown to improve functional and oncologic outcomes in randomized clinical trials. There are also a large number of novel, cancer-specific contrast agents that are in early stage clinical trials and preclinical development that demonstrate significant promise to improve real-time detection of subclinical cancer in the operative setting. Conclusions: There has been an explosion of intraoperative imaging techniques that will become more widespread in the next decade. Copyright © 2014 by Lippincott Williams & Wilkins.

Rautiainen S.,Karolinska Institutet | Levitan E.B.,University of Alabama at Birmingham | Mittleman M.A.,Beth Israel Deaconess Medical Center | Wolk A.,Karolinska Institutet
European Journal of Heart Failure | Year: 2015

Aims: Although numerous studies have investigated fruit and vegetable consumption in association with cardiovascular diseases (CVD) such as coronary heart disease and stroke, a limited number of studies have investigated the association with heart failure. The aim of this study was to assess the association between fruit and vegetable intake and the incidence of heart failure among women. Methods and results: In September 1997, a total of 34 319 women (aged 49-83 years) from the Swedish Mammography Cohort, free of cancer and CVD at baseline, completed a food-frequency questionnaire. Women were followed for incident heart failure (diagnosis as primary or secondary cause) through December 2011 using administrative health registries. Over 12.9 years of follow-up (442 348 person-years), we identified 3051 incident cases of heart failure. Total fruit and vegetable consumption was inversely associated with the rate of heart failure {the multivariable-adjusted rate ratio (RR) in the highest quintile compared with the lowest was 0.80 [95% confidence interval (CI) 0.70-0.90]}. Fruit (mutually adjusted for vegetables) were not significantly associated with rate of heart failure (RR 0.94; 95% CI 0.83-1.07), whereas vegetables showed an inverse association (RR 0.83; 95% CI 0.73-0.95). When investigating the shape of association, we found evidence of a non-linear association (P = 0.01), and the lowest rates of heart failure were observed among women consuming ≤5 servings/day of fruit and vegetables, without further decrease with increasing intake. Conclusions: In this population-based prospective cohort study of women, higher total consumption of fruit and vegetables was inversely associated with the incidence of heart failure. © 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology.

Taub E.,University of Alabama at Birmingham
Developmental Psychobiology | Year: 2012

There are striking similarities between the visual defect of amblyopia and the motor deficit of the extremities produced by such types of damage to the central nervous system (CNS) as stroke and traumatic brain injury, both after and before maturity. Part of the motor deficit of the extremities following CNS injury can be attributed to a learning phenomenon termed "learned nonuse" or if present from birth, "developmental disregard." The same mechanism is hypothesized to be involved in the development of amblyopia. Treatments that are efficacious in the remediation of these defects, Constraint-Induced Movement therapy and amblyopia training, also share a number of strong similarities. In addition, plastic brain changes are produced by CI therapy and are hypothesized to occur during amblyopia training. © 2010 Wiley Periodicals, Inc.

Bolus N.E.,University of Alabama at Birmingham
Journal of Nuclear Medicine Technology | Year: 2013

The purpose of this paper is to briefly explain report 160 of the National Council on Radiation Protection and Measurement and the significance of the report to medical imaging as a whole and nuclear medicine specifically. The implications of the findings of report 160 have had repercussions and will continue to affect all of ionizing radiation medical imaging. The nuclear medicine community should have an understanding of why and how report 160 is important. After reading this article, the nuclear medicine technologist will be familiar with the main focus of report 160, the significant change that has occurred since the 1980s in the ionizing radiation exposure of people in the United States, the primary background source of ionizing radiation in the United States, the primary medical exposure to ionizing radiation in the United States, trends in nuclear medicine procedures and patient exposure, and a comparison of population doses between 2006 and the early 1980s as outlined in report 160. © 2013 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Hughey L.C.,University of Alabama at Birmingham
Dermatologic Therapy | Year: 2011

Approaching the hospitalized patient with skin disease can be daunting. This article focuses on a practical approach to the patient with targetoid lesions. The discussion focuses on differentiating erythema multiforme from Stevens-Johnson syndrome and toxic epidermal necrolysis. In addition, the article offers a concise review of the broader differential diagnosis of targetoid lesions including ecthyma gangrenosum, fixed drug eruption, erythemamultiforme-like drug reaction, vasculitis, acute hemorrhagic edema of infancy, erythema chronicum migrans, connective tissue diseases, and blistering diseases. © 2011 Wiley Periodicals, Inc.

Austin E.L.,University of Alabama at Birmingham
Women and Health | Year: 2013

Concerns regarding sexual orientation disclosure to health care providers have been suggested as a barrier to care which may account for documented differences in the health care utilization of lesbians relative to heterosexual women. This study explored the correlates of sexual orientation disclosure to health care providers among 934 lesbian women living in urban and non-urban areas of the South. Psychosocial resources, such as self-esteem, social support, and mastery, along with several lesbian-specific experiences (proportion of lesbian, gay, bisexual, or transgender friends, access to the lesbian, gay, bisexual, or transgender community, degree of being "out"), were all independently associated with greater likelihood of having disclosed to a health care provider. Internalized homophobia and lesbian-related stigma decreased the likelihood of disclosure. Lesbians living in non-urban areas were significantly less likely to have disclosed than women in urban areas, suggesting that disclosure may present a special concern for populations in non-urban areas. © 2013 Copyright Taylor and Francis Group, LLC.

Tita A.T.N.,University of Alabama at Birmingham
Obstetrics and Gynecology | Year: 2010

Objective: To compare outcomes among neonates delivered after documentation of fetal lung maturity before 39 weeks and those delivered at 39 or 40 weeks. Methods: This was a retrospective cohort study of women with singleton pregnancy delivered at 36 0/7 to 38 6/7 weeks after positive fetal lung maturity testing (based on amniotic fluid lecithin to sphingomyelin ratio) or at 39 0/7 to 40 6/7 weeks (without maturity testing) at our center from 1999 to 2008. Women with fetuses with major congenital anomalies, cord prolapse, nonreassuring antepartum testing, placental abruption, or oligohydramnios were excluded. A primary composite neonatal outcome included death, adverse respiratory outcomes, hypoglycemia, treated hyperbilirubinemia, generalized seizures, necrotizing enterocolitis, hypoxic ischemic encephalopathy, periventricular leukomalacia, and suspected or proven sepsis. Results: There were 459 neonates delivered at 36 to 38 weeks and 13,339 delivered at 39 to 40 weeks; mean birth weight was 3,107±548 g and 3,362±439 g, respectively. The risk of the composite adverse neonatal outcome was 6.1% for the 36- to 38-week group compared with 2.5% for the 39- to 40-week group (relative risk 2.4; confidence interval [CI] 1.7-3.5). After multivariable adjustment, early delivery remained significantly associated with an increased risk of the composite outcome (adjusted odds ratio [OR]1.7; CI 1.1-2.6) as well as several individual outcomes, including respiratory distress syndrome (adjusted OR 7.6; CI 2.2-26.6), treated hyperbilirubinemia (adjusted OR 11.2; CI 3.6-34), and hypoglycemia (adjusted OR 5.8; CI 2.4-14.3). Conclusion: Neonates delivered at 36 to 38 weeks after confirmed fetal lung maturity are at higher risk of adverse outcomes than those delivered at 39 to 40 weeks. © 2010 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins.

Saag M.S.,University of Alabama at Birmingham
Topics in Antiviral Medicine | Year: 2012

Numerous investigational antiretroviral agents are in clinical development. Among them are festinavir (BMS986001), a thymidine analogue similar to stavudine with reduced potential for toxicity; GS-7340, a prodrug of tenofovir that achieves greater intracellular concentrations; MK-1439, a nonnucleoside analogue reverse transcriptase inhibitor (NNRTI) that retains activity against common NNRTI-associated resistance mutations; and albuvirtide, a longacting parenteral fusion inhibitor. Investigational integrase strand transfer inhibitors (InSTIs) include elvitegravir, recently approved by the US Food and Drug Administration (FDA) as part of a once-daily, singletablet formulation with cobicistat/tenofovir/emtricitabine; dolutegravir, which maintains some activity against raltegravir- and elvitegravir-resistant mutants; and S/GSK1265744, which also maintains some activity against resistance mutations in the integrase gene and is being developed as a long-lasting parenteral agent. Novel 2-(quinolin-3-yl)acetic acid derivatives (LEDGINs), agents that were originally thought to inhibit the interaction of integrase with its cofactor lens epithelium-derived growth factor p75 (LEDGF/ p75), are active against InSTI-resistant mutants and to have additive activity when combined with InSTIs. © 2012, IAS-USA.

Bowling C.B.,Birmingham Atlanta Geriatric Research | Muntner P.,University of Alabama at Birmingham
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2012

The National Kidney Foundation (NKF), Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification expanded the focus of chronic kidney disease (CKD) management from end-stage renal disease (ESRD) to the entire spectrum of kidney disease including early kidney damage through the stages of kidney disease to kidney failure. A consequence of these guidelines is that a large number of older adults are being identified as having CKD, many of whom will not progress to ESRD. Concerns have been raised that reduced estimated glomerular filtration rate (eGFR) among older adults may not represent "disease" and using age-specific cut-points for staging CKD has been proposed. This implies that among older adults, CKD, as currently defined, may be benign. Several recent studies have shown that among people greater than or equal to 80 years old, CKD is associated with an increased risk for concurrent complications of CKD (eg, anemia, acidosis) and adverse outcomes including mortality and cardiovascular disease (CVD). Further, among older adults, CKD is associated with problems not traditionally thought to be associated with kidney disease. These nondisease-specific outcomes include functional decline, cognitive impairment, and frailty. Future research studies are necessary to determine the impact of concurrent complications of CKD and nondisease-specific problems on mortality and functional decline, the longitudinal trajectories of CKD progression, and patient preferences among the oldest old with CKD. © The Author 2012. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.

Bell D.S.H.,University of Alabama at Birmingham
Southern Medical Journal | Year: 2010

Correction of hyperlipidemia with statins is often limited by the side-effect of statin-induced myalgias. Vitamin D deficiency is also associated with myalgias that resolve with correction of the vitamin D deficiency. Myalgias associated with statin therapy may also resolve with correction of vitamin D deficiency. This case report presents a case where cardioprotective lipid levels were achieved with a powerful statin only after correction of vitamin D deficiency. Copyright © 2010 by The Southern Medical Association.

Wang H.E.,University of Alabama at Birmingham
Prehospital emergency care : official journal of the National Association of EMS Physicians and the National Association of State EMS Directors | Year: 2013

Despite its long history and current prominence in U.S. communities, only limited data describe the national characteristics of emergency medical services (EMS) care in the United States. We sought to characterize out-of-hospital EMS care in the United States. We conducted an analysis of the 2010 National Emergency Medical Services Information System (NEMSIS) research data set, encompassing EMS emergency response data from 29 states. From these data, we estimated the national number and incidence of EMS responses. We also characterized EMS responses and the patients receiving care. There were 7,563,843 submitted EMS responses, corresponding to an estimated national incidence of 17.4 million EMS emergency responses per year (56 per 1,000 person-years). The EMS response incidence varied by U.S. Census region (South 137.4 per 1,000 population per year, Northeast 85.2, West 39.7, and Midwest 33.3). The use of lights and sirens varied across Census regions (Northeast 90.3%, South 76.7%, West 68.8%, and Midwest 67.5%). The percentage of responses resulting in patient contact varied across Census regions (range 78.4% to 95.7%). The EMS time intervals were similar between Census regions; response median 5 minutes (interquartile range [IQR] 3-9), scene 14 minutes (10-20), and transport 11 minutes (7-19). Underserved populations (the elderly, minorities, rural residents, and the uninsured) were large users of EMS resources. These data highlight the breadth and diversity of EMS demand and care in the United States.

Ogunrinu T.A.,University of Alabama at Birmingham | Sontheimer H.,University of Alabama at Birmingham
Journal of Biological Chemistry | Year: 2010

Glutathione (GSH) is an essential antioxidant responsible for the maintenance of intracellular redox homeostasis. As tumors outgrow their blood supply and become hypoxic, their redox homeostasis is challenged by the production of nitric oxide and reactive oxygen species (ROS). In gliomas, the sustained import of L-cystine via the L-cystine/L-glutamate exchanger, system x c -, is rate-limiting for the synthesis of GSH. We show that hypoxia causes a significant increase in NO and ROS but without affecting glioma cell growth. This is explained by a concomitant increase in the utilization of GSH, which is accompanied by an increase in the cell-surface expression of xCT, the catalytic subunit of system x c -, and L-cystine uptake. Growth was inhibited when GSH synthesis was blocked by buthionine sulfoximine (BSO), an inhibitor of the enzyme required for GSH synthesis, or when cells were deprived of L-cystine. These findings suggest that glioma cells show an increased requirement for GSH to maintain growth under hypoxic conditions. Therefore, approaches that limit GSH synthesis such as blocking system x c - may be considered as an adjuvant to radiation or chemotherapy. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Calfa G.,University of Alabama at Birmingham | Hablitz J.J.,University of Alabama at Birmingham | Pozzo-Miller L.,University of Alabama at Birmingham
Journal of Neurophysiology | Year: 2011

Dysfunctions of neuronal and network excitability have emerged as common features in disorders associated with intellectual disabilities, autism, and seizure activity, all common clinical manifestations of Rett syndrome (RTT), a neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Here, we evaluated the consequences of Mecp2 mutation on hippocampal network excitability, as well as synapse structure and function using a combination of imaging and electrophysiological approaches in acute slices. Imaging the amplitude and spatiotemporal spread of neuronal depolarizations with voltage-sensitive dyes (VSD) revealed that the CA1 and CA3 regions of hippocampal slices from symptomatic male Mecp2 mutant mice are highly hyperexcitable. However, only the density of docked synaptic vesicles and the rate of release from the readily releasable pool are impaired in Mecp2 mutant mice, while synapse density and morphology are unaffected. The differences in network excitability were not observed in surgically isolated CA1 minislices, and blockade of GABAergic inhibition enhanced VSD signals to the same extent in Mecp2 mutant and wild-type mice, suggesting that network excitability originates in area CA3. Indeed, extracellular multiunit recordings revealed a higher level of spontaneous firing of CA3 pyramidal neurons in slices from symptomatic Mecp2 mutant mice. The neuromodulator adenosine reduced the amplitude and spatiotemporal spread of VSD signals evoked in CA1 of Mecp2 mutant slices to wild-type levels, suggesting its potential use as an anticonvulsant in RTT individuals. The present results suggest that hyperactive CA3 pyramidal neurons contribute to hippocampal dysfunction and possibly to limbic seizures observed in Mecp2 mutant mice and RTT individuals. © 2011 the American Physiological Society.

Cuddapah V.A.,University of Alabama at Birmingham | Sontheimer H.,University of Alabama at Birmingham
Journal of Biological Chemistry | Year: 2010

Glioblastoma multiforme is the most common and lethal primary brain cancer in adults. Tumor cells diffusely infiltrate the brain making focal surgical and radiation treatment challenging. The invasion of glioma cells into normal brain is facilitated by the activity of ion channels aiding dynamic regulation of cell volume. Recent studies have specifically implicated ClC-3, a voltage-gated chloride channel, in this process. However, the interaction between ClC-3 activity and cell movement is poorly understood. Here, we demonstrate that ClC-3 is highly expressed on the plasma membrane of human glioma cells where its activity is regulated through phosphorylation via Ca2+/calmodulin- dependent protein kinase II (CaMKII). Intracellular infusion of autoactivated CaMKII via patch pipette enhanced chloride currents 3-fold, and this regulation was inhibited by autocamtide-2 related inhibitory peptide, a CaMKII-specific inhibitor. CaMKII modulation of chloride currents was also lost upon stable small hairpin RNA knockdown of ClC-3 channels indicating a specific interaction of ClC-3 and CaMKII. In ClC-3-expressing cells, inhibition of CaMKII reduced glioma invasion to the same extent as direct inhibition of ClC-3. The importance of the molecular interaction of ClC-3 and CaMKII is further supported by our finding that CaMKII co-localizes and co-immunoprecipitates with ClC-3. ClC-3 and CaMKII also co-immunoprecipitate in tissue biopsies from patients diagnosed with grade IV glioblastoma. These tumor samples show 10-fold higher ClC-3 protein expression than nonmalignant brain. These data suggest that CaMKII is a molecular link translating intracellular calcium changes, which are intrinsically associated with glioma migration, to changes in ClC-3 conductance required for cell movement. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Ovalle F.,University of Alabama at Birmingham
Diabetes Research and Clinical Practice | Year: 2010

A number of patients with diabetes require very high (>2Ukg-1day-1), or extremely high (>3Ukg-1day-1), insulin doses for the management of their hyperglycemia. Unfortunately, many of the physicians who treat these patients limit themselves to prescribing ever higher doses of insulin, without questioning why. Furthermore, when the insulin requirements get to be extreme, demanding an explanation, clinicians are frequently lost in a sea of literature where there is not a single paper dealing with this problem systematically.A systematic approach to the evaluation of these patients is necessary to facilitate an appropriate diagnosis, select the most reasonable therapy, and hopefully improve the long-term outcome of these patients. This manuscript intends to provide the clinician with a review of the literature pertinent for the differential diagnosis, work-up, and management of these patients.We will review the definitions of insulin sensitivity during normality, the various degrees or categories of insulin resistance, and the expected insulin requirements during each of these states. Subsequently, we propose a simple alphabetic mnemonic approach to help remember the differential diagnosis, and a clinical algorithm to help guide the work-up of these patients. Lastly, we briefly discuss general management considerations in these conditions. © 2010 Elsevier Ireland Ltd.

Meeran S.M.,University of Alabama at Birmingham | Ahmed A.,University of Alabama at Birmingham | Tollefsbol T.O.,University of Alabama at Birmingham
Clinical Epigenetics | Year: 2010

The emergent interest in cancer epigenetics stems from the fact that epigenetic modifications are implicated in virtually every step of tumorigenesis. More interestingly, epigenetic changes are reversible heritable changes that are not due to the alteration in DNA sequence but have potential to alter gene expression. Dietary agents consist of many bioactive ingredients which actively regulate various molecular targets involved in tumorigenesis. We present evidence that numerous bioactive dietary components can interfere with various epigenetic targets in cancer prevention and therapy. These agents include curcumin (turmeric), genistein (soybean), tea polyphenols (green tea), resveratrol (grapes), and sulforaphane (cruciferous vegetables). These bioactive components alter the DNA methylation and histone modifications required for gene activation or silencing in cancer prevention and therapy. Bioactive components mediate epigenetic modifications associated with the induction of tumor suppressor genes such as p21 WAF1/CIP1 and inhibition of tumor promoting genes such as the human telomerase reverse transcriptase during tumorigenesis processes. Here, we present considerable evidence that bioactive components and their epigenetic targets are associated with cancer prevention and therapy which should facilitate novel drug discovery and development. In addition, remarkable advances in our understanding of basic epigenetic mechanisms as well as the rapid progress that is being made in developing powerful new technologies, such as those for sensitive and quantitative detection of epigenetic and epigenomic changes in cancer biology, hold great promise for novel epigenetic approaches to cancer prevention and therapy. © Springer-Verlag 2010.

Schneider L.,University of Alabama at Birmingham | Zhang J.,University of Alabama at Birmingham
Molecular Neurodegeneration | Year: 2010

The pathological changes occurring in Parkinson's and several other neurodegenerative diseases are complex and poorly understood, but all clearly involve protein aggregation. Also frequently appearing in neurodegeneration is mitochondrial dysfunction which may precede, coincide or follow protein aggregation. These observations led to the concept that protein aggregation and mitochondrial dysfunction either arise from the same etiological factors or are interactive. Understanding the mechanisms and regulation of processes that lead to protein aggregation or mitochondrial dysfunction may therefore contribute to the design of better therapeutics. Clearance of protein aggregates and dysfunctional organelles is dependent on macroautophagy which is the process through which aged or damaged proteins and organelles are first degraded by the lysosome and then recycled. The macroautophagy-lysosomal pathway is essential for maintaining protein and energy homeostasis. Not surprisingly, failure of the lysosomal system has been implicated in diseases that have features of protein aggregation and mitochondrial dysfunction. This review summarizes 3 major topics: 1) the current understanding of Parkinson's disease pathogenesis in terms of accumulation of damaged proteins and reduction of cellular bioenergetics; 2) evolving insights into lysosomal function and biogenesis and the accumulating evidence that lysosomal dysfunction may cause or exacerbate Parkinsonian pathology and finally 3) the possibility that enhancing lysosomal function may provide a disease modifying therapy. © 2010 Schneider and Zhang; licensee BioMed Central Ltd.

Harish A.,University of Alabama at Birmingham | Allon M.,University of Alabama at Birmingham
Clinical Journal of the American Society of Nephrology | Year: 2011

Background and objectives There are a limited number of publications on the features of arteriovenous graft infection in hemodialysis patients. The authors compared the clinical presentation, complications, and outcomes of infections of thigh and upper extremity grafts. Design, setting, participants, and measurements The authors queried a prospective access database at a large university medical center and identified 132 patients with graft infections (40 in the thigh and 92 in the upper extremity) requiring surgical excision. The authors collected information regarding the microbiology, complications, and clinical outcomes. Results The two graft groups were similar in age, gender, race, and frequency of diabetes. The median age of infected grafts was 162 days for thigh grafts versus 168 days for upper extremity grafts (P = 0.35). Thigh graft infections were more likely than upper extremity graft infections to be caused by a Gram-negative rod (31% versus 4%; P = 0.003), and more likely to result in a metastatic infection (15% versus 3%; P = 0.02). The duration of hospitalization associated with graft infection was similar (10.8 ± 5.4 versus 8.7 ± 6.3 days; P = 0.09). Finally, median catheter dependence was longer after thigh graft than upper arm graft infections (319 versus 237 days; P = 0.04). Conclusions As compared with upper extremity graft infections, thigh graft infections requiring excision are more likely to be caused by Gram-negative bacteria and to result in serious metastatic complications. These differences may require different empiric antibiotics and a higher index of suspicion for infection in hemodialysis patients with thigh grafts. © 2011 by the American Society of Nephrology.

Askenazi D.,University of Alabama at Birmingham
Pediatric Nephrology | Year: 2012

Acute kidney injury (AKI) is a common event in several neonatal populations, and those neonates with AKI have poor outcomes. Serum creatinine (SCr)-based definitions of AKI are not ideal and are additionally limited in neonates whose SCr reflects the maternal creatinine level at birth and normally drops over the first weeks of life dependent on gestational age. Recent studies show that urine and serum biomarkers may provide a better basis than SCr on which to diagnose AKI. In this month's issue of Pediatric Nephrology, Sarafidis et al. show that urine neutrophil gelatinase-associated lipocalin (uNGAL), serum NGAL (sNGAL), and urine cystatin c (uCysC) are highest in those neonates with asphyxia who have elevated SCr. Furthermore, those with asphyxia without a concomitant rise in SCr levels have elevated levels of biomarkers compared to controls, suggesting a dose response. Once the SCr level returns to normal, the levels of novel AKI biomarkers continue to be elevated. While these findings strengthen the argument for the clinical use of these AKI biomarkers, further work is needed before they can be implemented in clinical practice. Large-scale observational multi-center studies are needed to test these biomarkers against hard clinical endpoints. In addition, randomized intervention trials which use biomarkers to define AKI need to be performed. © IPNA 2011.

Dokland T.,University of Alabama at Birmingham
Virus Research | Year: 2010

Porcine reproductive and respiratory syndrome virus (PRRSV) is an enveloped, positive-sense single-stranded RNA virus belonging to the Arteriviridae family. Arteriviruses and coronaviruses are grouped together in the order Nidovirales, based on similarities in genome organization and expression strategy. Over the past decade, crystal structures of several viral proteins, electron microscopic studies of the virion, as well as biochemical and in vivo studies on protein-protein interactions have led to a greatly increased understanding of PRRSV structural biology. At this point, crystal structures are available for the viral proteases NSP1α, NSP1β and NSP4 and the nucleocapsid protein, N. The NSP1α and NSP1β structures have revealed additional non-protease domains that may be involved in modulation of host functions. The N protein forms a dimer with a novel fold so far only seen in PRRSV and other nidoviruses. Cryo-electron tomographic studies have shown the three-dimensional organization of the PRRSV virion and suggest that the viral nucleocapsid has an asymmetric, linear arrangement, rather than the isometric core previously described. Together, these studies have revealed a closer structural relationship between arteri- and coronaviruses than previously anticipated. © 2010 Elsevier B.V.

Mueller T.M.,University of Alabama at Birmingham | Haroutunian V.,Mount Sinai School of Medicine | Meador-Woodruff J.H.,University of Alabama at Birmingham
Neuropsychopharmacology | Year: 2014

The molecular mechanisms of schizophrenia have been under investigation for decades; however, the exact causes of this debilitating neuropsychiatric disorder are still unknown. Previous studies have identified multiple affected neurotransmitter systems, brain regions, and cell types, each making a unique contribution to symptom presentation and pathophysiology. Numerous studies have identified gene and protein expression changes in schizophrenia, but the role of post-translational modifications, specifically N-glycosylation, has only recently become a target of investigation. N-glycosylation of molecules associated with glutamatergic neurotransmission is disrupted in schizophrenia, but it was unknown if these alterations are exclusive to the glutamatergic system or due to a more generalized deficit.In normal human cortex, we found evidence for N-glycosylation of the α1, β1, and β2 γ-aminobutyric type A receptor (GABAA R) subunits using deglycosylation protein shift assays. This was confirmed with lectin affinity assays that revealed glycan attachment on the α1, α4, and β1-3 GABAA R subunits. Examining GABAA R subunit N-glycosylation in matched pairs of schizophrenia (N=14) and comparison (N=14) of superior temporal gyrus revealed a smaller molecular mass of immature N-glycans on the α1 subunit, more immature N-glycosylation of the 49-kDa β1 subunit isoform, and altered total N-glycosylation of the β2 GABAA R subunit in schizophrenia. Measures of altered N-glycosylation of the β1 and β2 subunits were confounded by an increased apparent molecular mass of all β1 and β2 subunit isoforms in schizophrenia. Although N-glycosylation of α1, β1, and β2 were all changed in schizophrenia, the concentrations of GABAA R subunits themselves were unchanged. These findings suggest that disruptions of N-glycosylation in schizophrenia are not exclusive to glutamate and may indicate a potential disruption of a central cell signaling process in this disorder. © 2014 American College of Neuropsychopharmacology.

Hameed O.,University of Alabama at Birmingham
American Journal of Surgical Pathology | Year: 2010

Invasive urothelial carcinoma is characterized by a number of histologic variants that can sometimes lead to diagnostic difficulty. In addition to those described by the World Health Organization, 2 additional variants have recently been described, invasive urothelial carcinoma with chordoid features and urothelial carcinoma with abundant myxoid stroma, both being characterized by the presence of a prominent myxoid stroma. This report describes a peculiar type of cystitis that closely mimicked myxoid urothelial carcinoma. A transurethral resection specimen from a 73-year-old woman with an earlier diagnosis of invasive urothelial carcinoma focally displayed rounded, epithelioid cells arranged in a corded manner and separated by myxoid stroma; this was originally misinterpreted as recurrent invasive carcinoma. A review of the case with immunohistochemical studies showed the component cells to be polyclonal B-lymphocytes, based upon which the diagnosis of malignancy was reversed. This peculiar form of cystitis, herein termed myxoid cystitis with "chordoid" lymphocytes, has not been described earlier and should be considered among the mimics of invasive urothelial carcinoma, especially those with a myxoid stroma. © 2010 by Lippincott Williams & Wilkins.

Collawn S.S.,University of Alabama at Birmingham
Annals of Plastic Surgery | Year: 2010

Skin tightening occurs with the use of fractional lasers, radiofrequency, and Smartlipo. The fractional lasers Fraxel (1550 nm; Solta Medical, Inc., Hayward, CA) and Affirm (1440 nm, 1320 nm) (Cynosure, Westford, MA) when used in combination tighten skin and lessen solar keratoses, and improve acne scars. With radiofrequency, further tightening occurs. Smartlipo (Cynosure, Westford, MA) (1064 nm or the newer MPX with combined 1064 nm and 1320 nm) results in skin tightening and has been very helpful in improving skin tightness and smoothness on the neck either singularly or in combination with the above procedures; and with the addition of the Affirm fractional CO2 laser (Cynosure, Westford, MA), further skin improvement and tightening occurs. Copyright © 2010 by Lippincott Williams & Wilkins.

Andukuri A.,University of Alabama at Birmingham
Tissue engineering. Part C, Methods | Year: 2013

Endothelial progenitor cell (EPC)-capturing techniques have led to revolutionary strategies that can improve the performance of cardiovascular implant devices and engineered tissues by enhancing re-endothelialization and angiogenesis. However, these strategies are limited by controversies regarding the phenotypic identities of EPCs as well as their inability to target and prevent the other afflictions associated with current therapies, namely, thrombosis and neointimal hyperplasia. Therefore, the goal of this study was to study the efficacy of a bioinspired multifunctional nanomatrix in recruiting and promoting the differentiation of EPCs toward an endothelial lineage. The bioinspired nanomatrix combines multiple components, including self-assembled peptide amphiphiles (PAs) that include cell adhesive ligands, nitric oxide (NO)-producing donors, and enzyme-mediated degradable sequences to achieve an endothelium-mimicking character. In this study, human peripheral blood mononuclear cells (PBMNCs) were isolated and cultured on the bioinspired multifunctional nanomatrix. Initial cell adhesion, lectin staining, acetylated low-density lipoprotein uptake, and expression of endothelial markers, including CD31, CD34, von Willebrand Factor, and VEGFR2, were analyzed. The results from this study indicate that the NO releasing bioinspired multifunctional nanomatrix promotes initial adhesion of EPCs when compared to control surfaces. The expression of endothelial markers is also increased on the bioinspired multifunctional nanomatrix, suggesting that it directs the differentiation of EPCs toward an endothelial phenotype. The bioinspired nanomatrix therefore provides a novel biomaterial-based platform for capturing as well as directing EPC behavior. Therefore, this study has the potential to positively impact the patency of cardiovascular devices such as stents and vascular grafts as well as enhanced angiogenesis for ischemic or engineered tissues.

Hwang T.-C.,University of Missouri | Kirk K.L.,University of Alabama at Birmingham
Cold Spring Harbor Perspectives in Medicine | Year: 2013

Cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-gated anion channel with two remarkable distinctions. First, it is the only ATP-binding cassette (ABC) transporter that is known to be an ion channel-almost all others function as transport ATPases. Second, CFTR is the only ligand-gated channel that consumes its ligand (ATP) during the gating cycle-a consequence of its enzymatic activity as an ABC transporter. We discuss these special properties of CFTR in the context of its evolutionary history as an ABC transporter. Other topics include the mechanisms by which CFTR gating is regulated by phosphorylation of its unique regulatory domain and our current view of the CFTR permeation pathway (or pore). Understanding these basic operating principles of the CFTR channel is central to defining the mechanisms of action of prospective cystic fibrosis drugs and to the development of new, rational treatment strategies. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.

Darley-Usmar V.M.,University of Alabama at Birmingham | Ball L.E.,Medical University of South Carolina | Chatham J.C.,University of Alabama at Birmingham
Journal of Molecular and Cellular Cardiology | Year: 2012

The post-translational modification of serine and threonine residues of nuclear and cytoplasmic proteins by the O-linked attachment of the monosaccharide β-N-acetyl-glucosamine (O-GlcNAc) is emerging as an important mechanism for the regulation of numerous biological processes critical for normal cell function. Active synthesis of O-GlcNAc is essential for cell viability and acute activation of pathways resulting in increased protein O-GlcNAc levels improves the tolerance of cells to a wide range of stress stimuli. Conversely sustained increases in O-GlcNAc levels have been implicated in numerous chronic disease states, especially as a pathogenic contributor to diabetic complications. There has been increasing interest in the role of O-GlcNAc in the heart and vascular system and acute activation of O-GlcNAc levels have been shown to reduce ischemia/reperfusion injury, attenuate vascular injury responses as well mediate some of the detrimental effects of diabetes and hypertension on cardiac and vascular function. Here we provide an overview of our current understanding of pathways regulating protein O-GlcNAcylation, summarize the different methodologies for identifying and characterizing O-GlcNAcylated proteins and subsequently focus on two emerging areas: 1) the role of O-GlcNAc as a potential regulator of cardiac metabolism and 2) the cross talk between O-GlcNAc and reactive oxygen species. This article is part of a Special Section entitled "Post-translational Modification.". © 2011 Elsevier Ltd.

Riley B.H.,University of Alabama at Birmingham
Journal of Child and Adolescent Psychiatric Nursing | Year: 2010

TOPIC: A greater number of gay males, lesbians, and bisexual females or males (GLB) are "coming out" during adolescence. Discussion includes nursing implications.PURPOSE: The purpose of this paper is to review the process of GLB disclosure, highlight the trend toward earlier outing, and discuss its implications for nursing practice. SOURCES: Sources include scholarly published literature, professional organization documents, and GLB advocacy publications. CONCLUSIONS: Nurses need to update their knowledge of coming-out issues, as well as nondisclosing sexual behavior, to assess youth and family needs and direct care appropriately. © 2010 Wiley Periodicals, Inc.

Zhou D.,University of Alabama at Birmingham
Nature genetics | Year: 2010

We show that knockdown of KLF1 in human and mouse adult erythroid progenitors markedly reduces BCL11A levels and increases human gamma-globin/beta-globin expression ratios. These results suggest that KLF1 controls globin gene switching by directly activating beta-globin and indirectly repressing gamma-globin gene expression. Controlled knockdown of KLF1 in adult erythroid progenitors may provide a method to activate fetal hemoglobin expression in individuals with beta-thalassemia or sickle cell disease.

Bell D.S.H.,University of Alabama at Birmingham
Southern Medical Journal | Year: 2010

Chronic metformin use results in vitamin B12 deficiency in 30% of patients. Exhaustion of vitamin B12 stores usually occurs after twelve to fifteen years of absolute vitamin B12 deficiency. Metformin has been available in the United States for approximately fifteen years. Vitamin B12 deficiency, which may present without anemia and as a peripheral neuropathy, is often misdiagnosed as diabetic neuropathy, although the clinical findings are usually different. Failure to diagnose the cause of the neuropathy will result in progression of central and/or peripheral neuronal damage which can be arrested but not reversed with vitamin B12 replacement. To my knowledge, this is the first report of metformin-induced vitamin B12 deficiency causing neuropathy. Copyright © 2010 by The Southern Medical Association.

Costa-Ferreira A.,University of Alabama at Birmingham
Plastic and Reconstructive Surgery | Year: 2014

BACKGROUND:: Abdominoplasty using a more superficial plane of dissection has several advantages. Previous studies described a trilaminar structure (superficial and deep fat compartments separated by Scarpa fascia) in the lower abdominal wall. Controversy still exists on compartment dominance and changes with increasing adiposity. This study aims to gain a clearer understanding on these issues.METHODS:: The study was performed on the surgical specimens of 41 female patients submitted to a full abdominoplasty. A morphometric study was done on 82 sides to evaluate the thickness of the fat layers at predetermined locations (point A over external obliqus, point B over rectus abdominis muscle). A histological study was done in 31 samples to analyze the structure of the fat compartments and Scarpa fascia.RESULTS:: A trilaminar structure was always present and Scarpa fascia did not become vestigial with increasing adiposity. The total thickness at point B was significantly higher than point A and this difference was mainly due to the superficial compartment. The deep fat compartment was always thinner than the superficial corresponding to 25% of the total thickness in point A and 23% in point B. It was less susceptible to increase in thickness in cases of obesity. The histologic study demonstrated constant morphology, Scarpa average thickness of 0.29 mm(A) and 0.28 mm(B).CONCLUSION:: This study demonstrates a trilaminar structure with superficial compartment dominance and Scarpa fascia presence irrespective of the adiposity in the lower abdominal wall. The deep fat compartment has a minor contribution to the lower abdominal wall thickness.CLINICAL QUESTION/ LEVEL OF EVIDENCE:: Not applicable (Basic Science Study) ©2014American Society of Plastic Surgeons

Hilton D.J.,University of Alabama at Birmingham
Optics Express | Year: 2012

We develop a new characteristic matrix-based method to analyze cyclotron resonance experiments in high mobility two-dimensional electron gas samples where direct interference between primary and satellite reflections has previously limited the frequency resolution. This model is used to simulate experimental data taken using terahertz time-domain spectroscopy that show multiple pulses from the substrate with a separation of 15 ps that directly interfere in the time-domain. We determine a cyclotron dephasing lifetime of 15.1±0.5 ps at 1.5 K and 5.0±0.5 ps at 75 K. © 2012 Optical Society of America.

Bertocchio J.-P.,French Institute of Health and Medical Research | Warnock D.G.,University of Alabama at Birmingham | Jaisser F.,French Institute of Health and Medical Research
Kidney International | Year: 2011

Slowing the progression of chronic kidney diseases (CKDs) requires new and effective treatment approaches. Aldosterone classically acts on the distal nephron: it facilitates sodium reabsorption, potassium secretion, and participates in blood pressure control. Recently, new targets of aldosterone have been described including the heart and the vasculature, and other kidney cells such as mesangial cells, podocytes, and renal fibroblasts. The pathophysiological implications of increased mineralocorticoid receptor (MR) expression and activation (either dependent on aldosterone or direct ligand-independent activation) and its blockade have been illustrated with ex vivo in cell cultures and in vivo in experimental animal models of CKD, including diabetic and hypertensive nephropathies, and glomerulopathies. The beneficial effects of the MR antagonists are independent of the hypertensive effect of aldosterone, indicating that blocking the activation of the MR may have unique clinical importance. Several studies have reported efficacy and safety studies with spironolactone or eplerenone in patients with kidney diseases. In this review, we discuss the recent results reported in experimental and clinical research in this field, and emphasize the direct activation of the MR that can occur in pathological states associated with CKD, even in the absence of increased circulating levels of aldosterone. © 2011 International Society of Nephrology.

Tolwani A.,University of Alabama at Birmingham | Wille K.M.,University of Alabama at Birmingham
Blood Purification | Year: 2012

Because of the potential side effects of heparin, methods of regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT) have been gaining wider acceptance with the development of simplified and safer protocols. Advantages of RCA include the avoidance of systemic anticoagulation and heparin-induced thrombocytopenia. The disadvantage is that citrate can add complexity and labor intensity to CRRT. Frequent monitoring of electrolytes, ionized calcium, and acid-base status is required, due to the potential for hypernatremia, metabolic alkalosis, and systemic ionized hypocalcemia. If properly monitored, complications associated with RCA are uncommon. A variety of methods of delivering RCA are described in the literature. Overall, studies of RCA, as compared to unfractionated heparin, report better filter survival times and less bleeding. In this section, we summarize the characteristics of citrate as an anticoagulant and provide an update of citrate use in CRRT. Copyright © 2012 S. Karger AG, Basel.

Williams M.S.,University of Alabama at Birmingham
Ghana medical journal | Year: 2012

The age-standardized mortality rate for cervical cancer in Ghana, West Africa is more than three times the global cervical cancer mortality rate (27.6/100,000 vs. 7.8/100,000 respectively). The Pap test and visual inspection with acetic acid are available at public and private hospitals in Ghana. Approximately, 2.7% of Ghanaian women obtain cervical cancer screenings regularly. Men in middle-income countries play a key role in cervical cancer prevention. Increasing spousal support for cervical cancer screening may increase screening rates in Ghana. Five focus groups were conducted with Ghanaian men (N = 29) to assess their cervical cancer and cervical cancer screening knowledge and beliefs. The qualitative data was analyzed via indexed coding. Targets for education interventions were identified including inaccurate knowledge about cervical cancer and stigmatizing beliefs about cervical cancer risk factors. Cultural taboos regarding women's health care behaviours were also identified. Several participants indicated that they would be willing to provide spousal support for cervical cancer screening if they knew more about the disease and the screening methods. Men play a significant role in the health behaviours of some Ghanaian women. Cervical cancer education interventions targeting Ghanaian men are needed to correct misconceptions and increase spousal support for cervical cancer screening.

Chugh S.S.,University of Alabama at Birmingham | Clement L.C.,University of Alabama at Birmingham | Mac C.,University of Alabama at Birmingham
American Journal of Kidney Diseases | Year: 2012

The pathogenesis of minimal change disease (MCD), considered to be the simplest form of nephrotic syndrome, has been one of the major unsolved mysteries in kidney disease. In this review, recent landmark studies that have led to the unraveling of MCD are discussed. A recent study now explains the molecular basis of major clinical and morphologic changes in MCD. Overproduction of angiopoietin-like 4 (ANGPTL4) in podocytes in MCD causes binding of ANGPTL4 to the glomerular basement membrane, development of nephrotic-range selective proteinuria, diffuse effacement of foot processes, and loss of glomerular basement membrane charge, but is not associated with changes shown by light microscopy in the glomerular and tubulointerstitial compartments. At least some of this ability of ANGPTL4 to induce proteinuria is linked to a deficiency of sialic acid residues because oral supplementation with sialic acid precursor N-acetyl-d-mannosamine improves sialylation of podocyte-secreted ANGPTL4 and significantly decreases proteinuria. Animal models of MCD, recent advances in potential biomarkers, and studies of upstream factors that may initiate glomerular changes also are discussed. In summary, recent progress in understanding MCD is likely to influence the diagnosis and treatment of MCD in the near future. © 2012 National Kidney Foundation, Inc.

Swanson M.W.,University of Alabama at Birmingham
Optometry and Vision Science | Year: 2012

Purpose. Large population studies carried out in the United States, while addressing refractive error prevalence, have published little addressing the modes of refractive correction. As such, there are little data in the biomedical literature concerning the characteristics of the contact lens wearing population in the United States. The purpose of this project was to develop estimates of the demographic characteristics of a cross section of contact lens wearers in the United States based on those who wore contact lenses on the day of their National Health and Nutrition Examination Survey (NHANES) examination. Methods. The NHANES is a nationally representative sample of the U.S. population. As part of NHANES, the type of refractive correction used is collected during a mobile medical clinic examination along with demographic variables. Data files from the 2005-2006 and 2007-2008 NHANES were obtained from the National Center for Health Statistics. Demographic characteristics of the U.S. population using contacts during the medical clinic examination were derived. Associations between demographic variables and contact lens use were explored in age-stratified univariate and multivariate analyses taking into account the complex sampling frame. Results. In univariate analysis, age (p < 0.001) and the availability of health insurance (p = 0.007) have negative associations with contact lens use, while female gender (p < 0.001), higher socioeconomic status (p < 0.001), and higher educational attainment (p < 0.001) are associated with increased contact lens use. In multivariate analysis, age (p < 0.001), socioeconomic status (p < 0.001), the interaction of age with gender (p < 0.001), and the interaction of socioeconomic status with education (p = 0.002) are associated with contact lens use. Conclusions. Four demographic variables, age, socioeconomic status, age-gender interaction, and socioeconomic status-education interaction, defined those likely to be using contact lens on any given day in the United States. Together, these four variables identify almost 9 of 10 contact lens users. © 2012 American Academy of Optometry.

Soletsky B.,Baylor College of Medicine | Feig D.I.,University of Alabama at Birmingham
Hypertension | Year: 2012

Epidemiologic studies, animal models, and preliminary clinical trials in children implicate uric acid in the development of essential hypertension. Controversy remains as to whether the observations indicate a general mechanism or a surrogate phenomenon. We sought to determine whether uric acid is a causative mediator of increased blood pressure (BP) and impaired vascular compliance. We report a randomized, double-blinded, placebo-controlled trial comparing 2 mechanisms of urate reduction with placebo in prehypertensive, obese, adolescents, aged 11 to 17 years. Subjects were randomized to the xanthine oxidase inhibitor, allopurinol, uricosuric, probenecid, or placebo. Subjects treated with urate-lowering therapy experienced a highly significant reduction in BP. In clinic systolic BP fell 10.2 mm Hg and diastolic BP fell 9.0 mm Hg in treated patients compared with a rise of 1.7 mm Hg and 1.6 mm Hg systolic and diastolic BP, respectively in patients on placebo. Urate-lowering therapy also resulted in significant reduction in systemic vascular resistance. These data indicate that, at least in adolescents with prehypertension, uric acid causes increased BP that can be mitigated by urate lowering therapy. © 2012 American Heart Association, Inc.

Sowell B.,University of Alabama at Birmingham | Fast V.G.,University of Alabama at Birmingham
Heart Rhythm | Year: 2012

Strong electrical shocks can cause focal arrhythmias, the mechanism of which is not well known. Strong shocks have been shown to produce diastolic Ca i 2+ increase, which may initiate focal arrhythmias via spontaneous Ca i 2+ rise (SCR), activation of inward Na +/Ca 2+ exchange current (I NCX), and rise in membrane potential (V m). It can be hypothesized that this mechanism is responsible for generation of shock-induced arrhythmias. The purpose of this study was to examine the roles of SCRs and I NCX in shock-induced arrhythmias. The occurrence of SCRs during shock-induced arrhythmias was assessed in neonatal rat myocyte cultures. Simultaneous V m-Ca i 2+ optical mapping at arrhythmia source demonstrated that V m upstrokes always preceded Ca i 2+ transients, and V m-Ca i 2+ delays were not different between arrhythmic and paced beats (5.5 ± 0.9 and 5.7 ± 0.4 ms, respectively, P =.5). Shocks caused gradual rise of diastolic Ca i 2+ consistent with membrane electroporation but no significant Ca i 2+ rises immediately before V m upstrokes. Application of the Ca i 2+ chelator BAPTA-AM (10 μmol/L) decreased the duration of shock-induced arrhythmias whereas application of the I NCX inhibitor KB-R7943 (2 μmol/L) increased it, indicating that, despite the absence of SCRs, changes in Ca i 2+ affected arrhythmias. It is hypothesized that this effect is mediated by Ca i 2+ inhibition of outward I K1 current and destabilization of resting V m. The possible role of I K1 was supported by application of the I K1 inhibitor BaCl 2 (0.2 mmol/L), which increased the arrhythmia duration. Shock-induced arrhythmias in neonatal rat myocyte monolayers are not caused by SCRs and inward I NCX. However, these arrhythmias depend on Ca i 2+ changes, possibly via Ca i 2+-dependent modulation of outward I K1 current.

Bryant A.S.,University of Alabama at Birmingham | Cerfolio R.J.,University of Alabama at Birmingham
Journal of Thoracic and Cardiovascular Surgery | Year: 2014

Objective The objective of the present study was to determine the long-term fate and factors of compensatory hyperhidrosis (CH) in patients who have undergone video-assisted thoracoscopic sympathotomy for focal hyperhidrosis. Methods The same quality-of-life survey was administered 6 months postoperatively and then annually to all patients who underwent video-assisted thoracoscopic sympathotomy for hyperhidrosis. A second rib (R2)/R3 sympathotomy was most commonly performed until September 2007 and then R4/R5 sympathotomy was used. Results From January 1999 until December 2012, 193 patients underwent video-assisted thoracoscopic sympathotomy for hyperhidrosis, of whom, 173 had provided ≥1 year of postoperative survey information. No operative mortalities occurred. Of the 173 patients, 133 (77%) reported "clinically bothersome" CH. This rate had decreased to an average of 35% at 5 and 12 years postoperatively. Univariate analysis showed the CH incidence was significantly greater for the patients who had undergone R2/R3 versus R4/R5 sympathotomy (P <.001), had had multiple sites of sweating at presentation (P <.001), had used oral medication to control hyperhidrosis preoperatively (P =.022), or were female (P =.002). On multivariate analysis, only R2/R3 versus R4/R5 sympathotomy (P <.021) and multiple sites of sweating at presentation (P <.037) remained statistically significant. Twelve patients (6.2%) regretted having the operation for CH. Conclusions Patients who undergo sympathotomy for hyperhidrosis will commonly report "clinically bothersome" compensatory hyperhidrosis. CH will more likely if R2/R3 sympathetic interruption has been performed instead of R4/R5 and in patients who present with multiple areas of sweating. The severity of clinically bothersome CH decreased during the first 3 years postoperatively.

Gao Y.,University of Alabama at Birmingham | Tollefsbol T.O.,University of Alabama at Birmingham
Current Medicinal Chemistry | Year: 2015

Epigenetics, the study of heritable changes in gene expression without modifying the nucleotide sequence, is among the most important topics in medicinal chemistry and cancer prevention and therapy. Among those changes, DNA methylation and histone modification have been shown to be associated with various types of cancers in a number of ways, many of which are regulated by dietary components that are mostly found in plants. Although mechanisms of nutrient components affecting histone acetylation/deacetylation in cancer are widely studied, how those natural compounds affect cancer through other histone modifications, such as methylation, phosphorylation and ubiquitylation, is rarely reviewed. Thus, this review article discusses impacts on histone acetylation as well as other histone modifications by nutrient components, such as genistein, resveratrol, curcumin, epigallocatechin-3-gallate (EGCG), 3,3'-diindolylmethane (DIM), diallyl disulfide, garcinol, procyanidin B3, quercetin, sulforaphane and other isothiocyanates that have been recently reported in vivo as well as in various types of cancer cell lines. © 2015 Bentham Science Publishers.