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Case Western Reserve University is a private research university in Cleveland, Ohio. The university was created in 1967 by the federation of Case Institute of Technology and Western Reserve University . TIME magazine described the merger as the creation of "Cleveland's Big-Leaguer" university.In U.S. News & World Report's 2013 rankings, Case Western Reserve's undergraduate program ranked 37th among national universities. The University is associated with 16 Nobel laureates. Other notable alumni include Paul Buchheit, creator and lead developer of Gmail; Craig Newmark, founder of craigslist.org; and Peter Tippett, who developed the anti-virus software Vaccine, which Symantec purchased and turned into the popular Norton AntiVirus. Case Western Reserve is particularly well known for its medical school, business school, dental school, law school, Frances Payne Bolton School of Nursing , Department of Biomedical Engineering and its biomedical teaching and research capabilities. Case Western is a member of the Association of American Universities.The university is approximately five miles east of downtown Cleveland in University Circle. It is contained within a 550-acre area containing numerous educational, medical, and cultural institutions. Case Western Reserve has a number of programs taught in conjunction with nearby institutions, including the Cleveland Clinic, the University Hospitals of Cleveland, the Louis Stokes Cleveland Department of Veteran's Affairs Medical Center, Cleveland Institute of Music, the Cleveland Hearing & Speech Center, the Cleveland Museum of Art, the Cleveland Museum of Natural History, and the Cleveland Play House.Case Western Reserve was the site of the famous Michelson-Morley interferometer experiment, conducted in 1887 by Albert A. Michelson of Case School of Applied Science and Edward W. Morley of Western Reserve University. This experiment proved the non-existence of the luminiferous ether and was later cited as convincing evidence in support of special relativity as proposed by Albert Einstein in 1905. Michelson became the first American to win a Nobel Prize in science. The commemorative Michelson-Morley Memorial Fountain is located on campus, near where the actual experiment was performed. Wikipedia.

Clemens N.A.,Case Western Reserve University
Journal of Psychiatric Practice | Year: 2012

As electronic health record systems become widely adopted and proposals are advanced to integrate mental health with general health systems, there is mounting pressure to include mental health information on the same basis as general health information without any requirement for active, individual patient consent to do so. A prime example is the current effort to change the Mental Health Information Act of the District of Columbia, which has, up till now, stood as a model for protection of the privacy of patients with mental illness, the requirement of informed consent for disclosure of health information, and delimitation of minimum necessary disclosure. Mental health information is exceptionally sensitive and potentially damaging if privacy is breached, which makes patients reluctant to seek treatment if they cannot be assured of confidentiality. In addition, there have been spectacular breaches of the security of large electronic health record databases. A subtle but more likely threat is the possibility that mental health information in networks could be fully accessible to all of the patient's providers in a network, not just those for whom it would be necessary to the patient's care. In the 1996 Supreme Court decision in Jaffee v. Redmond, the high court recognized that confidentiality is essential for patients to engage in effective psychotherapy, and HIPAA maintains that special status in the protection of psychotherapy notes as well as explicitly stating that it defers to state laws that are more protective of confidentiality than is HIPAA itself. Highly sensitive information also exists in mental health records aside from psychotherapy notes. Any change in the laws that govern informed consent for disclosure of mental health information must take these factors into account. Specifically, the author opposes any change that would assume tacit consent to release mental health information through an electronic health information exchange in the absence of a patient-initiated request to "opt out"; the requirement that the patient give active, informed and noncoerced consent to disclose information-"opt in"-must be preserved. © Lippincott Williams & Wilkins.

Francone T.D.,University of Rochester | Champagne B.,Case Western Reserve University
Surgical Clinics of North America | Year: 2013

Total proctocolectomy with ileal pouch anal anastomosis (IPAA) preserves fecal continence as an alternative to permanent end ileostomy in select patients with ulcerative colitis and familial adenomatous polyposis. The procedure is technically demanding, and surgical complications may arise. This article outlines both the early and late complications that can occur after IPAA, as well as the workup and management of these potentially morbid conditions. © 2013 Elsevier Inc.

Knothe Tate M.L.,Case Western Reserve University
Journal of Biomechanics | Year: 2011

The goal of this retrospective article is to place the body of my lab's multiscale mechanobiology work in context of top-down and bottom-up engineering of bone. We have used biosystems engineering, computational modeling and novel experimental approaches to understand bone physiology, in health and disease, and across time (in utero, postnatal growth, maturity, aging and death, as well as evolution) and length scales (a single bone like a femur, m; a sample of bone tissue, mm-cm; a cell and its local environment, γm; down to the length scale of the cell's own skeleton, the cytoskeleton, nm). First we introduce the concept of flow in bone and the three calibers of porosity through which fluid flows. Then we describe, in the context of organ-tissue, tissue-cell and cell-molecule length scales, both multiscale computational models and experimental methods to predict flow in bone and to understand the flow of fluid as a means to deliver chemical and mechanical cues in bone. Addressing a number of studies in the context of multiple length and time scales, the importance of appropriate boundary conditions, site specific material parameters, permeability measures and even micro-nanoanatomically correct geometries are discussed in context of model predictions and their value for understanding multiscale mechanobiology of bone. Insights from these multiscale computational modeling and experimental methods are providing us with a means to predict, engineer and manufacture bone tissue in the laboratory and in the human body. © 2010 Elsevier Ltd.

Cooperman D.,Case Western Reserve University
Journal of Pediatric Orthopaedics | Year: 2013

The term "acetabular dysplasia" suggests a smaller than normal acetabulum or one that is abnormally vertical. Acetabular dysplasia has been linked to the development of hip osteoarthritis over the last 90 years in 3 ways. First, it has been linked through the concept that biomechanical forces can cause osteoarthritis. A smaller than normal acetabulum will result in a smaller than normal contact surface between the femoral head and the acetabulum. This will generate increased pressure per unit of area, which will precipitate articular cartilage failure when the pressure reaches a critical point. Osteoarthritis will ensue in response to this cartilage failure. A more vertical than normal acetabulum will be associated with increased shear. When that shear reaches a critical level, articular cartilage will fail, leading that to osteoarthritis. This critical level, for a small or a steep acetabulum, may differ between individuals, based on their biology and their life styles. Second, it has been linked by multiple empirical studies. One of these is Wiberg's 1939 thesis entitled "Studies on Dysplastic Acetabula and Congenital Subluxation of the Hip Joint with Special reference to the Complication of Osteoarthritis." It is among the most quoted and most powerful works in the Orthopaedic literature connecting a disease entity with an antecedent. Third, the linkage is reenforced by an absence of glaring exceptions to the hypothesis that acetabular dysplasia causes osteoarthritis. Orthopaedic surgeons just do not report on dysplastic hips in the arthritis-free elderly. The inability of the Orthopaedic community to identify even 1 elderly, arthritis-free individual with significant hip dysplasia should not carry weight in establishing the concept that acetabular dysplasia causes osteoarthritis. However, the longer this case report goes unpublished, the more certain orthopaedic surgeons will be that the 2 are linked.Level of Evidence: Level V.

Adenuga P.,Case Western Reserve University
Plastic and reconstructive surgery | Year: 2014

This study focuses on the impact of preoperative narcotic medication use on outcomes of surgical treatment of migraine headaches. A retrospective comparative review was conducted with patients undergoing migraine surgery. Data gathered included demographic information, baseline migraine headache characteristics, migraine surgery sites, postoperative migraine headache characteristics 1 year or more following surgery, and preoperative migraine medication use. Patients were grouped based on preoperative narcotic medication use. The narcotic users were subdivided into low and high narcotic user groups. Preoperative migraine characteristics were comparable between groups and the outcomes of migraine surgery were compared between the groups. Outcomes in 90 narcotic users were compared with those for 112 patients not using narcotic medications preoperatively. Narcotic users showed statistically significantly less reduction in frequency, severity, and duration of migraine headaches after surgery. Narcotic users had clinical improvement in 66.7 percent of patients and elimination in 18.9 percent versus 86.6 and 36.6 percent, respectively, in the nonnarcotic group. The group that consumed narcotics had significantly lower rates of improvement in all migraine indices. Previous studies have discouraged the routine use of narcotic medications in the management of migraine medications. The authors' study demonstrates that narcotic medication use before migraine headache surgery may predispose patients to worse outcomes postoperatively. Because pain cannot be objectively documented, the question remains of whether this failure to improve the pain was indeed a suboptimal response to surgery or the need for narcotic substances. Risk, II.

Ismail-Beigi F.,Case Western Reserve University
New England Journal of Medicine | Year: 2012

A 39-year-old man with a 2-year history of type 2 diabetes mellitus presents for care. He has no microvascular or macrovascular complications. His family history is positive for type 2 diabetes and cardiovascular disease in his mother and older brother. On examination, his weight is 99.8 kg (220 lb), with a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 37, and his blood pressure is 125/85 mm Hg. His glycated hemoglobin level is 8.9%, serum creatinine level 1.0 mg per deciliter (88.4 μmol per liter), low-density lipoprotein (LDL) cholesterol 88 mg per deciliter (2.3 mmol per liter), high-density lipoprotein (HDL) cholesterol 45 mg per deciliter (1.2 mmol per liter), and triglyceride level 130 mg per deciliter (1.5 mmol per liter); he does not have microalbuminuria. His medications include metformin (500 mg twice daily), glipizide (5 mg twice daily), simvastatin (20 mg daily), and lisinopril (10 mg daily). What would you recommend to improve his glycemic control? Copyright © 2012 Massachusetts Medical Society.

Devireddy L.R.,Case Western Reserve University | Hart D.O.,Howard Hughes Medical Institute | Goetz D.H.,University of California at San Francisco | Green M.R.,Howard Hughes Medical Institute
Cell | Year: 2010

Intracellular iron homeostasis is critical for survival and proliferation. Lipocalin 24p3 is an iron-trafficking protein that binds iron through association with a bacterial siderophore, such as enterobactin, or a postulated mammalian siderophore. Here, we show that the iron-binding moiety of the 24p3-associated mammalian siderophore is 2,5-dihydroxybenzoic acid (2,5-DHBA), which is similar to 2,3-DHBA, the iron-binding component of enterobactin. We find that the murine enzyme responsible for 2,5-DHBA synthesis, BDH2, is the homolog of bacterial EntA, which catalyzes 2,3-DHBA production during enterobactin biosynthesis. RNA interference-mediated knockdown of BDH2 results in siderophore depletion. Mammalian cells lacking the siderophore accumulate abnormally high amounts of cytoplasmic iron, resulting in elevated levels of reactive oxygen species, whereas the mitochondria are iron deficient. Siderophore-depleted mammalian cells and zebrafish embryos fail to synthesize heme, an iron-dependent mitochondrial process. Our results reveal features of intracellular iron homeostasis that are conserved from bacteria through humans. © 2010 Elsevier Inc.

Hsu J.,Case Western Reserve University
Journal of the American Heart Association | Year: 2013

Genetics plays a large role in atherosclerosis susceptibility in humans and mice. We attempted to confirm previously determined mouse atherosclerosis-associated loci and use bioinformatics and transcriptomics to create a catalog of candidate atherosclerosis modifier genes at these loci. A strain intercross was performed between AKR and DBA/2 mice on the apoE(-/-) background generating 166 F2 progeny. Using the phenotype log10 of the aortic root lesion area, we identified 3 suggestive atherosclerosis quantitative trait loci (Ath QTLs). When combined with our prior strain intercross, we confirmed 3 significant Ath QTLs on chromosomes 2, 15, and 17, with combined logarithm of odds scores of 5.9, 5.3, and 5.6, respectively, which each met the genome-wide 5% false discovery rate threshold. We identified all of the protein coding differences between these 2 mouse strains within the Ath QTL intervals. Microarray gene expression profiling was performed on macrophages and endothelial cells from this intercross to identify expression QTLs (eQTLs), the loci that are associated with variation in the expression levels of specific transcripts. Cross tissue eQTLs and macrophage eQTLs that replicated from a prior strain intercross were identified. These bioinformatic and eQTL analyses produced a comprehensive list of candidate genes that may be responsible for the Ath QTLs. Replication studies for clinical traits as well as gene expression traits are worthwhile in identifying true versus false genetic associations. We have replicated 3 loci on mouse chromosomes 2, 15, and 17 that are associated with atherosclerosis. We have also identified protein coding differences and multiple replicated eQTLs, which may be useful in the identification of atherosclerosis modifier genes.

Gao X.P.A.,Case Western Reserve University | Zheng G.,Fudan University | Lieber C.M.,Harvard University
Nano Letters | Year: 2010

Nanowire field-effect transistors (NW-FETs) are emerging as powerful sensors for detection of chemical/biological species with various attractive features including high sensitivity and direct electrical readout. Yet to date there have been limited systematic studies addressing how the fundamental factors of devices affect their sensitivity. Here we demonstrate that the sensitivity of NWFET sensors can be exponentially enhanced in the subthreshold regime where the gating effect of molecules bound on a surface is the most effective due to the reduced screening of carriers in NWs. This principle is exemplified in both pH and protein sensing experiments where the operational mode of NW-FET biosensors was tuned by electrolyte gating. The lowest charge detectable by NW-FET sensors working under different operational modes is also estimated. Our work shows that optimization of NW-FET structure and operating conditions can provide significant enhancement and fundamental understanding for the sensitivity limits of NW-FET sensors. © 2010 American Chemical Society.

Famaey B.,French National Center for Scientific Research | Famaey B.,University of Bonn | McGaugh S.S.,University of Maryland College Park | McGaugh S.S.,Case Western Reserve University
Living Reviews in Relativity | Year: 2012

A wealth of astronomical data indicate the presence of mass discrepancies in the Universe. The motions observed in a variety of classes of extragalactic systems exceed what can be explained by the mass visible in stars and gas. Either (i) there is a vast amount of unseen mass in some novel form - dark matter - or (ii) the data indicate a breakdown of our understanding of dynamics on the relevant scales, or (iii) both. Here, we first review a few outstanding challenges for the dark matter interpretation of mass discrepancies in galaxies, purely based on observations and independently of any alternative theoretical framework. We then show that many of these puzzling observations are predicted by one single relation - Milgrom's law - involving an acceleration constant α0 (or a characteristic surface density ∑† = α0/G) on the order of the square-root of the cosmological constant in natural units. This relation can at present most easily be interpreted as the effect of a single universal force law resulting from a modification of Newtonian dynamics (MOND) on galactic scales. We exhaustively review the current observational successes and problems of this alternative paradigm at all astrophysical scales, and summarize the various theoretical attempts (TeVeS, GEA, BIMOND, and others) made to effectively embed this modification of Newtonian dynamics within a relativistic theory of gravity.

Minnes S.,Case Western Reserve University
Addiction science & clinical practice | Year: 2011

Abuse of drugs by pregnant women both in the United States and worldwide has raised many questions regarding the effects of prenatal drug exposure on the developing fetus and subsequent child outcomes. Studies using the neurobehavioral teratology model have been undertaken to determine specific prenatal drug effects on cognitive and behavioral development. Here we summarize the findings of studies that have investigated the developmental effects of prenatal exposure to tobacco, marijuana, stimulants, and opiates. These studies consider the timing and amount of prenatal exposure; other drug exposures; maternal characteristics; and other health, nutritional, and environmental factors. We review treatment options for pregnant, substance-dependent women and therapeutic interventions for exposed children.

Mak K.F.,Columbia University | Lee C.,Sungkyunkwan University | Hone J.,Columbia University | Shan J.,Case Western Reserve University | Heinz T.F.,Columbia University
Physical Review Letters | Year: 2010

The electronic properties of ultrathin crystals of molybdenum disulfide consisting of N=1,2,...,6 S-Mo-S monolayers have been investigated by optical spectroscopy. Through characterization by absorption, photoluminescence, and photoconductivity spectroscopy, we trace the effect of quantum confinement on the material's electronic structure. With decreasing thickness, the indirect band gap, which lies below the direct gap in the bulk material, shifts upwards in energy by more than 0.6 eV. This leads to a crossover to a direct-gap material in the limit of the single monolayer. Unlike the bulk material, the MoS2 monolayer emits light strongly. The freestanding monolayer exhibits an increase in luminescence quantum efficiency by more than a factor of 104 compared with the bulk material. © 2010 The American Physical Society.

Lui C.H.,Columbia University | Mak K.F.,Columbia University | Shan J.,Case Western Reserve University | Heinz T.F.,Columbia University
Physical Review Letters | Year: 2010

Since graphene has no band gap, photoluminescence is not expected from relaxed charge carriers. We have, however, observed significant light emission from graphene under excitation by ultrashort (30-fs) laser pulses. Light emission was found to occur across the visible spectral range (1.7-3.5A eV), with emitted photon energies exceeding that of the excitation laser (1.5A eV). The emission exhibits a nonlinear dependence on the laser fluence. In two-pulse correlation measurements, a dominant relaxation time of tens of femtoseconds is observed. A two-temperature model describing the electrons and their interaction with strongly coupled optical phonons can account for the experimental observations. © 2010 The American Physical Society.

Furlan A.J.,Case Western Reserve University
Current Cardiology Reports | Year: 2012

There have been only 3 positive Phase III randomized clinical trials in acute ischemic stroke, all reperfusion therapies (NINDS; PROACT II; ECASS III). The only approved acute stroke therapy is <3-hour IV tPA. Although numerous compounds have shown benefit in animal models of brain infarction, there has never been a positive Phase III randomized clinical trial of a neuroprotectant in acute ischemic stroke. There are many challenges to acute stroke clinical trials but chief among these are the very short therapeutic window ("time is brain") and the issue of stroke heterogeneity. Stroke is a syndrome and only a very small percentage of all stroke patients present to hospitals in time to consider reperfusion therapy. Many drugs have been rushed to trial prematurely based on inadequate preclinical testing. Many trials have been seriously underpowered due to overly optimistic treatment expectations and the risk of brain hemorrhage has precluded aggressive multimodal treatment strategies. Rather than simply relying on a clock, new imaging methods are being developed to identify patients with "tissue at risk" and "salvageable brain" regardless of time of stroke onset. The 7 STAIR conferences have been convened to address these and other challenges to acute ischemic stroke trial design and completion. © Springer Science+Business Media, LLC 2012.

Xu R.,Case Western Reserve University | Wang Q.,ThinTek LLC
Journal of the American Medical Informatics Association | Year: 2014

Objective A comprehensive and machineunderstandable cancer drug-side effect (drug-SE) relationship knowledge base is important for in silico cancer drug target discovery, drug repurposing, and toxicity predication, and for personalized risk-benefit decisions by cancer patients. While US Food and Drug Administration (FDA) drug labels capture well-known cancer drug SE information, much cancer drug SE knowledge remains buried the published biomedical literature. We present a relationship extraction approach to extract cancer drug-SE pairs from the literature. Data and methods We used 21 354 075 MEDLINE records as the text corpus. We extracted drug-SE cooccurrence pairs using a cancer drug lexicon and a clean SE lexicon that we created. We then developed two filtering approaches to remove drug-disease treatment pairs and subsequently a ranking scheme to further prioritize filtered pairs. Finally, we analyzed relationships among SEs, gene targets, and indications. Results We extracted 56 602 cancer drug-SE pairs. The filtering algorithms improved the precision of extracted pairs from 0.252 at baseline to 0.426, representing a 69% improvement in precision with no decrease in recall. The ranking algorithm further prioritized filtered pairs and achieved a precision of 0.778 for top-ranked pairs. We showed that cancer drugs that share SEs tend to have overlapping gene targets and overlapping indications. Conclusions The relationship extraction approach is effective in extracting many cancer drug-SE pairs from the literature. This unique knowledge base, when combined with existing cancer drug SE knowledge, can facilitate drug target discovery, drug repurposing, and toxicity prediction.

Luck R.E.,Case Western Reserve University | Lambert D.L.,University of Texas at Austin
Astronomical Journal | Year: 2011

This paper reports on the spectroscopic investigation of 238 Cepheids in the northern sky. Of these stars, about 150 are new to the study of the galactic abundance gradient. These new Cepheids bring the total number of Cepheids involved in abundance distribution studies to over 400. In this work, we also consider systematics between various studies and also those which result from the choice of models. We find that systematic variations exist at the 0.06dex level both between studies and model atmospheres. In order to control the systematic effects our final gradients depend only on abundances derived herein. A simple linear fit to the Cepheid data from 398 stars yields a gradient d[Fe/H]/dRG= -0.062 0.002dexkpc-1 which is in good agreement with previously determined values. We have also re-examined the region of the "metallicity island" of Luck et al. With the doubling of the sample in that region and our internally consistent abundances, we find that there is scant evidence for a distinct island. We also find in our sample the first reported Cepheid (V1033 Cyg) with a pronounced Li feature. The Li abundance is consistent with the star being on its redward pass toward the first giant branch. © 2011 The American Astronomical Society. All rights reserved.

Genotyping methods are essential to understand the transmission dynamics of Acinetobacter baumannii. We examined the representative genotypes of A. baumannii at different time periods in select locations in Ohio, using two rapid automated typing methods: PCR coupled with electrospray ionization mass spectrometry (PCR/ESI-MS), a form of multi-locus sequence typing (MLST), and repetitive-sequence-based-PCR (rep-PCR). Our analysis included 122 isolates from 4 referral hospital systems, in 2 urban areas of Ohio. These isolates were associated with outbreaks at 3 different time periods (1996, 2000 and 2005-2007). Type assignments of PCR/ESI-MS and rep-PCR were compared to each other and to worldwide (WW) clone types. The discriminatory power of each method was determined using the Simpson's index of diversity (DI). We observed that PCR/ESI-MS sequence type (ST) 14, corresponding to WW clone 3, predominated in 1996, whereas ST 12 and 14 co-existed in the intermediate period (2000) and ST 10 and 12, belonging to WW clone 2, predominated more recently in 2007. The shift from WW clone 3 to WW clone 2 was accompanied by an increase in carbapenem resistance. The DI was approximately 0.74 for PCR/ESI-MS, 0.88 for rep-PCR and 0.90 for the combination of both typing methods. We conclude that combining rapid automated typing methods such as PCR/ESI-MS and rep-PCR serves to optimally characterize the regional molecular epidemiology of A. baumannii. Our data also sheds light on the changing sequence types in an 11 year period in Northeast Ohio.

Khan M.A.,Case Western Reserve University
Current Rheumatology Reports | Year: 2013

HLA-B27 has a high degree of genetic polymorphism, with 105 known subtypes, named HLA-B*27:01 to HLA-B*27:106, encoded by 132 alleles. The most common subtypes associated with ankylosing spondylitis are HLA-B*27:05 (Caucasians), HLA-B*27:04 (Chinese), and HLA-B*27:02 (Mediterranean populations). For Chinese populations, HLA-B*27:04 is associated with a greater ankylosing spondylitis risk than HLA-B*27:05. Two subtypes, HLA-B27*06 and HLA-B27*09, seem to have no disease association. These differential disease associations of HLA-B27 subtypes, and the recent discovery that ERAP1 is associated with ankylosing spondylitis for patients with HLA-B27, have increased attempts to determine the function of HLA-B27 in disease pathogenesis by studying hemodynamic features of its protein structure, alterations of its peptidome, aberrant peptide handling, and associated molecular events. However, after 40 years we still do not fully know how HLA-B27 predisposes to ankylosing spondylitis and related spondyloarthritis. © 2013 Springer Science+Business Media New York.

Tang J.,Case Western Reserve University
Investigative ophthalmology & visual science | Year: 2013

Treatment with light in the far-red to near-infrared region of the spectrum (photobiomodulation [PBM]) has beneficial effects in tissue injury. We investigated the therapeutic efficacy of 670-nm PBM in rodent and cultured cell models of diabetic retinopathy. Studies were conducted in streptozotocin-induced diabetic rats and in cultured retinal cells. Diabetes-induced retinal abnormalities were assessed functionally, biochemically, and histologically in vivo and in vitro. We observed beneficial effects of PBM on the neural and vascular elements of retina. Daily 670-nm PBM treatment (6 J/cm(2)) resulted in significant inhibition in the diabetes-induced death of retinal ganglion cells, as well as a 50% improvement of the ERG amplitude (photopic b wave responses) (both P < 0.01). To explore the mechanism for these beneficial effects, we examined physiologic and molecular changes related to cell survival, oxidative stress, and inflammation. PBM did not alter cytochrome oxidase activity in the retina or in cultured retinal cells. PBM inhibited diabetes-induced superoxide production and preserved MnSOD expression in vivo. Diabetes significantly increased both leukostasis and expression of ICAM-1, and PBM essentially prevented both of these abnormalities. In cultured retinal cells, 30-mM glucose exposure increased superoxide production, inflammatory biomarker expression, and cell death. PBM inhibited all of these abnormalities. PBM ameliorated lesions of diabetic retinopathy in vivo and reduced oxidative stress and cell death in vitro. PBM has been documented to have minimal risk. PBM is noninvasive, inexpensive, and easy to administer. We conclude that PBM is a simple adjunct therapy to attenuate the development of diabetic retinopathy.

Szczotka-Flynn L.,Case Western Reserve University
Eye & contact lens | Year: 2013

Contact lens-associated corneal infiltrative events (CIEs) are presumed sterile events that have complicated contact lens wear for more than 30 years. There is consistent evidence that silicone hydrogel soft contact lenses increase CIE risk by twofold compared with low Dk hydrogel materials. The incidence of CIEs during silicone hydrogel extended wear ranges from 2% to 6% for symptomatic events and from 6% to 25% when asymptomatic events are included. For daily wear, with silicone hydrogels, the incidence of CIEs ranges from 2% to 3% for symptomatic events and from 7% to 20% when asymptomatic events are included. Despite the increased rate of CIEs with silicone hydrogels, the benefits of these lenses largely outweigh this risk for many patients. Most risk factors for CIEs observed with silicone hydrogels are consistent with CIE risk factors reported earlier with hydrogel lenses, such as bacterial bioburden on lens surfaces, and young age among others. Limiting the transfer of bacterial bioburden from the skin to lenses, lens cases and eventually to the eye is an obvious step forward for the prevention of CIEs across all lens types.

Jennings A.A.,Case Western Reserve University
Journal of Environmental Management | Year: 2013

Guidance values are used worldwide to regulate exposure to surface soil contamination. This analysis examines values applied to element contamination. In the United States, element guidance values have been promulgated by at least 6 federal agencies, 46 states and several regional, city, county, territorial, and autonomous Native American jurisdictions. Guidance values have also been promulgated in at least 71 other United Nations member states. A total of 5949 guidance values for 57 elements have been identified. These values are characterized, and detailed analyses are provided for the eight most frequently regulated elements (Pb, Cd, As, Ni, Cr, Hg, Cu, and Zn). More than 300 guidance values available for each of these are tabulated. These values span from 3.6 orders of magnitude for lead to 6.9 orders of magnitude for arsenic and are distributed in patterns that resemble those of lognormal random variables. However, nonrandom value clusters are also identified in each distribution. On average, the values used in the U.S. are higher than those used elsewhere around the world for noncarcinogenic contaminants, but are lower for carcinogenic contaminants. Approximately 31.4% of all values fall within uncertainty bounds computed from the U.S. Environmental Protection Agency cancer or noncancer risk model, but only 12.9% of carcinogenic arsenic and 7.5% of carcinogenic chromium (Cr-VI) guidance values fall within cancer risk model uncertainty bounds. © 2013 Elsevier Ltd.

Rajiah P.,Case Western Reserve University
International Journal of Vascular Medicine | Year: 2013

Computed tomography (CT) and magnetic resonance imaging (MRI) are the most commonly used imaging examinations to evaluate thoracic aortic diseases because of their high spatial and temporal resolutions, large fields of view, and multiplanar imaging reconstruction capabilities. CT and MRI play an important role not only in the diagnosis of thoracic aortic disease but also in the preoperative assessment and followup after treatment. In this review, the CT and MRI appearances of various acquired thoracic aortic conditions are described and illustrated. © 2013 Prabhakar Rajiah.

Hynes S.R.,Yale University | Lavik E.B.,Case Western Reserve University
Graefe's Archive for Clinical and Experimental Ophthalmology | Year: 2010

Background: Several mechanisms of retina degeneration result in the deterioration of the outer retina and can lead to blindness. Currently, with the exception of anti-angiogenic treatments for wet age-related macular degeneration, there are no treatments that can restore lost vision. There is evidence that photoreceptors and embryonic retinal tissue, transplanted to the subretinal space, can form new synapses with surviving host neurons. However, these transplants have yet to result in a clinical treatment for retinal degeneration. Methods: This article reviews the current literature on the transplantation of scaffolds with retinal and retinal pigmented epithelial (RPE) cells to the subretinal space. We discuss the types of cells and materials that have been investigated for transplantation to the subretinal space, summarize the current findings, and present opportunities for future research and the next generation of scaffolds for retinal repair. Results: Challenges to cell transplantation include limited survival upon implantation and the formation of abnormal cell architectures in vivo. Scaffolds have been shown to enhance cell survival and direct cell differentiation and organization in a number of models of retinal degeneration. Conclusions: The transplantation of cells within a scaffold represents a possible treatment to repair retinal degeneration and restore vision in effected patients. Materials have been developed for the delivery of retinal and RPE cells separately however, the development of a combined tissue-engineered scaffold targeting both cell populations represents a promising direction for retinal repair. © 2010 Springer-Verlag.

Prakash Y.S.,Rochester College | Martin R.J.,Case Western Reserve University
Pharmacology and Therapeutics | Year: 2014

In addition to their well-known roles in the nervous system, there is increasing recognition that neurotrophins such as brain derived neurotrophic factor (BDNF) as well as their receptors are expressed in peripheral tissues including the lung, and can thus potentially contribute to both normal physiology and pathophysiology of several diseases. The relevance of this family of growth factors lies in emerging clinical data indicating altered neurotrophin levels and function in a range of diseases including neonatal and adult asthma, sinusitis, influenza, and lung cancer. The current review focuses on 1) the importance of BDNF expression and signaling mechanisms in early airway and lung development, critical to both normal neonatal lung function and also its disruption in prematurity and insults such as inflammation and infection; 2) how BDNF, potentially derived from airway nerves modulate neurogenic control of airway tone, a key aspect of airway reflexes as well as dysfunctional responses to allergic inflammation; 3) the emerging idea that local BDNF production by resident airway cells such as epithelium and airway smooth muscle can contribute to normal airway structure and function, and to airway hyperreactivity and remodeling in diseases such as asthma. Furthermore, given its pleiotropic effects in the airway, BDNF may be a novel and appealing therapeutic target. © 2014 Elsevier Inc.

Malone K.,Case Western Reserve University
Hand Clinics | Year: 2013

The skeletal anatomy of the hand is composed of phalanges, metacarpal bones, and carpal bones. Its function is a product of the complex interactions between the power provided by the intrinsic and extrinsic musculature, the stability provided by the ligaments, and the structure provided by the bones, which serve as insertion and attachment sites for the muscles and ligaments. This article provides a detailed description of the skeletal anatomy of the human hand. © 2013 Elsevier Inc.

Stambler B.S.,Case Western Reserve University
International Archives of Medicine | Year: 2013

Traditionally, warfarin has been used to prevent stroke in patients with atrial fibrillation (AF), but data from large, multinational, prospective, randomized studies suggest that novel oral anticoagulants (NOACs) may be suitable alternatives. These include the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. These data showed that dabigatran 150 mg twice daily was more effective at preventing stroke than warfarin, with similar rates of major bleeding, while rivaroxaban 20 mg once daily was noninferior to warfarin, with no difference in major bleeding rates. In addition, apixaban 5 mg twice daily was shown to be superior to warfarin for preventing stroke, with lower bleeding rates. Currently, edoxaban is still in clinical trials. NOACs offer more predictable anticoagulant effects than warfarin and do not require regular monitoring; however, different NOACs are associated with varied drug interactions and limitations related to use in certain patient populations. Overall, the clinical data suggest that these novel agents will offer new options for stroke prevention in patients with AF. © 2013 Stambler; licensee BioMed Central Ltd.

MacFarlane P.M.,Case Western Reserve University
Respiratory physiology & neurobiology | Year: 2013

The premature transition from fetal to neonatal life is accompanied by an immature respiratory neural control system. Most preterm infants exhibit recurrent apnea, resulting in repetitive oscillations in O(2) saturation (intermittent hypoxia, IH). Numerous factors are likely to play a role in the etiology of apnea including inputs from the carotid chemoreceptors. Despite major advances in our understanding of carotid chemoreceptor function in the early neonatal period, however, their contribution to the initiation of an apneic event and its eventual termination are still largely speculative. Recent findings have provided a detailed account of the postnatal changes in the incidence of hypoxemic events associated with apnea, and there is anecdotal evidence for a positive correlation with carotid chemoreceptor maturation. Furthermore, studies on non-human animal models have shown that chronic IH sensitizes the carotid chemoreceptors, which has been proposed to perpetuate the occurrence of apnea. An alternative hypothesis is that sensitization of the carotid chemoreceptors could represent an important protective mechanism to defend against severe hypoxemia. The purpose of this review, therefore, is to discuss how the carotid chemoreceptors may contribute to the initiation and termination of an apneic event in the neonate and the use of xanthine therapy in the prevention of apnea. Published by Elsevier B.V.

King C.H.,Case Western Reserve University
Acta Tropica | Year: 2010

Simultaneous and sequential transmission of multiple parasites, and their resultant overlapping chronic infections, are facts of life in many underdeveloped rural areas. These represent significant but often poorly measured health and economic burdens for affected populations. For example, the chronic inflammatory process associated with long-term schistosomiasis contributes to anaemia and undernutrition, which, in turn, can lead to growth stunting, poor school performance, poor work productivity, and continued poverty. To date, most national and international programs aimed at parasite control have not considered the varied economic and ecological factors underlying multi-parasite transmission, but some are beginning to provide a coordinated approach to control. In addition, interest is emerging in new studies for the re-evaluation and recalibration of the health burden of helminthic parasite infection. Their results should highlight the strong potential of integrated parasite control in efforts for poverty reduction. © 2009 Elsevier B.V. All rights reserved.

Hyun I.,Case Western Reserve University
Journal of Clinical Investigation | Year: 2010

Discussion of the bioethics of human stem cell research has transitioned from controversies over the source of human embryonic stem cells to concerns about the ethical use of stem cells in basic and clinical research. Key areas in this evolving ethical discourse include the derivation and use of other human embryonic stem cell-like stem cells that have the capacity to differentiate into all types of human tissue and the use of all types of stem cells in clinical research. Each of these issues is discussed as I summarize the past, present, and future bioethical issues in stem cell research.

Cui Y.,Case Western Reserve University
Thoracic and Cardiovascular Surgeon | Year: 2010

This review updates the knowledge in the research field of cardiac lymphatic vessels by collecting both scientific evidence and hypotheses, including cardiac lymphatic vessel anatomy and lymph flow, the mechanism of cardiac lymphatic pumping, pathological findings and mechanisms of cardiac injury caused by lymph flow impairment, cardiac functional improvement by increasing lymph flow in the heart in patients with myocardial infarction, and the mechanisms of lymphangiogenesis. © Georg Thieme Verlag KG.

Hu W.,Whitehead Institute For Biomedical Research | Coller J.,Case Western Reserve University
Cell Research | Year: 2012

While many mechanisms have been proposed for microRNAs (miRNAs) function, most ultimately cause message degradation. A view has emerged that miRNAs silence gene expression by promoting the association of mRNA decay factors. Recent research results, however, suggest that in both zebrafish and fruit fly, translational inhibition is the initiating event of miRNA-mediated gene silencing. © 2012 IBCB, SIBS, CAS All rights reserved.

Park P.S.-H.,Case Western Reserve University
Current Medicinal Chemistry | Year: 2012

G protein-coupled receptors (GPCRs) play critical roles in cellular signal transduction and are important targets for therapeutics. Although these receptors have been intensely studied for quite some time, our understanding about their mechanism of action is still incomplete. GPCR activity has traditionally been viewed within the context of two-state models where the receptor is in equilibrium between a single inactive state and a single active state. This framework is too simple and restrictive to accommodate more recent observations made on these receptors, which instead point to a situation where the receptor can adopt several different active conformational substates with distinct functional effects. Structural and functional evidence for this emerging view is presented in this review. Implications of this emerging view in rationalizing diseased states and in drug discovery are also discussed. © 2012 Bentham Science Publishers.

Sellers S.,Q Vigilance LLC | Utian W.H.,Case Western Reserve University
Drugs | Year: 2012

Since the development of federal standards for drug approval, the practice of medicine has historically involved the compounding of medications based on a physicians determination that a US FDA-approved product either did not exist, or could not be used for medical reasons. Today, prescriptions for non-FDA-approved compounded drugs may be driven by fanciful and largely unregulated pharmacy advertisements to physicians and patients andor payer reimbursement policies, thus placing prescribers in the backseat for clinical decision making. This article outlines essential differences between FDA-approved drugs and compounded drugs and reasserts the primary medical role of physicians for determining what medical circumstances may necessitate treatment with non-FDA-approved products. In addition, liability concerns when prescribing non-FDA-approved drugs are discussed. While representing a US perspective, underlying principles apply globally in the setting of magistral and extemporaneous formulations produced outside national regulatory frameworks. Adis. © 2012 Springer International Publishing AG. All rights reserved.

Newman M.G.,Pennsylvania State University | Llera S.J.,Towson University | Erickson T.M.,Seattle Pacific University | Przeworski A.,Case Western Reserve University | Castonguay L.G.,Pennsylvania State University
Annual Review of Clinical Psychology | Year: 2013

Generalized anxiety disorder (GAD) is associated with substantial personal and societal cost yet is the least successfully treated of the anxiety disorders. In this review, research on clinical features, boundary issues, and naturalistic course, as well as risk factors and maintaining mechanisms (cognitive, biological, neural, interpersonal, and developmental), are presented. A synthesis of these data points to a central role of emotional hyperreactivity, sensitivity to contrasting emotions, and dysfunctional attempts to cope with strong emotional shifts via worry. Consistent with the Contrast Avoidance model, evidence shows that worry evokes and sustains negative affect, thereby precluding sharp increases in negative emotion. We also review current treatment paradigms and suggest how the Contrast Avoidance model may help to target key fears and avoidance tendencies that serve to maintain pathology in GAD. Copyright © 2013 by Annual Reviews.

Franco K.,Case Western Reserve University
Cleveland Clinic Journal of Medicine | Year: 2012

The prevalence of Asperger syndrome, a mild form of autism, appears to be rapidly increasing. This developmental disorder affects children and adults and can present challenges to providing medical care. In this update on Asperger syndrome, we offer guidance on how to interact with adult patients with the disorder. We also address proposed diagnostic changes scheduled to take effect in 2013.

Pawlowski M.S.,Case Western Reserve University | Kroupa P.,University of Bonn
Astrophysical Journal | Year: 2014

The satellite galaxies of the Milky Way (MW) align with and preferentially orbit in a vast polar structure (VPOS), which also contains globular clusters (GCs) and stellar and gaseous streams. Similar alignments have been discovered around several other host galaxies. We test whether recently discovered objects in the MW halo, the satellite galaxy/GC transition object named PSO J174.0675-10.8774 or Crater and three stellar streams, are part of the VPOS. Crater is situated close to the VPOS. Incorporating the new object in the VPOS-plane fit slightly improves the alignment of the plane with other features such as the Magellanic stream and the average orbital plane of the satellites co-orbiting in the VPOS. We predict Crater's proper motion by assuming that it, too, orbits in the VPOS. One of the three streams aligns well with the VPOS. Surprisingly, it appears to lie in the exact same orbital plane as the Palomar 5 stream and shares its distance, suggesting a direct connection between the two. The stream also crosses close to the Fornax dwarf galaxy and is oriented approximately along the galaxy's direction of motion. The two other streams cannot align closely with the VPOS because they were discovered in the direction of M31/M33, which is outside of the satellite structure. The VPOS thus attains two new members. This further emphasizes that the highly anisotropic and correlated distribution of satellite objects requires an explanation beyond the suggestion that the MW satellite system is an extreme statistical outlier of a ΛCDM sub-halo system. © 2014. The American Astronomical Society. All rights reserved..

Avery R.K.,Case Western Reserve University
Current Opinion in Infectious Diseases | Year: 2012

Purpose of Review: Influenza is a major cause of morbidity and sometimes mortality in immunocompromised patients, including solid-organ transplant (SOT) recipients. Current guidelines call for influenza immunization of SOT recipients from 3 months posttransplant onward; the stated reason for delaying immunization in the early posttransplant period is an efficacy rather than a safety issue. Despite concerns about possible rejection raised in small case series and studies of alloimmune responses in immunized patients, virtually all larger clinical studies have shown no increased risk of rejection or allograft dysfunction after influenza vaccination. Recent Findings: Further evidence, mostly supporting the safety of influenza vaccine, has been published during the past 2 years. For example, one study using a large database of 51 730 adult Medicare primary renal transplant recipients showed that influenza vaccination was actually associated with a lower risk of graft loss and death. It appears that actual influenza infection itself, rather than the vaccine, carries a risk of allograft dysfunction. Summary: At this time, influenza vaccine after SOT is considered clinically safe, and current evidence supports the guidelines' recommendations to immunize. The issue of optimal timing for efficacy still remains to be resolved. In addition, educational tools for increasing the acceptance of influenza vaccine in healthcare workers and family members are described. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Calabrese L.H.,Case Western Reserve University | Molloy E.,Park University | Berger J.,University of Pennsylvania
Nature Reviews Rheumatology | Year: 2015

Progressive multifocal leukoencephalopathy (PML) is a rare, opportunistic infection of the central nervous system, caused by reactivation of the ubiquitous JC virus. PML is a devastating disease that is frequently fatal, and although survival rates have improved, patients who survive PML often experience considerable neurological deficits. PML was associated with a variety of immunosuppressive therapies in the past decade, but attribution of causality is difficult owing to the presence of confounding factors and to an inadequate understanding of the underlying pathogenesis of this disease. This uncertainty has hindered efforts for shared decision-making between physicians and their patients and, in some cases, discouraged the use of potentially beneficial therapies. We propose a categorization of immunosuppressive agents according to their risk of PML to support a better-informed decision-making process when evaluating the risks and benefits of these therapies. © 2015 Macmillan Publishers Limited. All rights reserved.

Zidar D.A.,Case Western Reserve University
Endocrine, Metabolic and Immune Disorders - Drug Targets | Year: 2011

Chemokine receptors are a group of homologous seven transmembrane receptors (7TMR) that direct cell migration. Their ligands comprise a family of proteins that share structural, biochemical, and physiological features to govern leukocyte trafficking. Multiple endogenous chemokines with overlapping function have evolved for the majority of chemokine receptors. This duplicity of ligands has traditionally been seen to confer physiologic redundancy, especially as it pertains to chemotaxis mediated through G-protein activation. Yet, several recent reports also suggest that chemokine receptors are capable of differential signaling in a ligand-specific manner. This review will explore emerging concepts related to ligand bias at chemokine receptors. Recent studies show that although the endogenous ligands of CCR7 have apparent equipotency for G-protein signaling, they differentially activate the G-protein coupled receptor kinase (GRK)/β-arrestin system to selectively control receptor desensitization. In contrast, similar studies using endogenous ligands for CCR5, a human immunodeficiency virus (HIV) co-receptor, suggest this receptor is not subject to ligand bias by its principle chemokines. Nonetheless, this receptor does appear to be capable of biased agonism by synthetic chemokine analogues. These observations provide compelling evidence that ligand bias exists both as a naturally relevant and therapeutically important phenomenon. This review will highlight the evidence for differential signaling by CCR7 and CCR5, speculate on the physiologic relevance, and discuss the rationale behind the development of biased agonists for the treatment of HIV infection. © 2011 Bentham Science Publishers Ltd.

Maurice M.J.,Case Western Reserve University
Journal of endourology / Endourological Society | Year: 2013

Upper tract urothelial carcinoma has a high recurrence rate after endoscopic treatment. Immediate postoperative topical chemotherapy may reduce recurrences, as in bladder cancer. A reliable delivery method to the upper tract does not exist. We propose a new infusion pump technology for the delivery of topical chemotherapeutic agents to the upper tract. With the patient under general anesthesia, contrast is infused into the upper collecting system using a standard infusion pump. An optimal infusion rate is determined based on fluoroscopic filling of the upper collecting system and transduced intrapelvic pressures. Using this rate, the infusion is repeated postoperatively with the chemotherapeutic agent. We report one case of successful execution to demonstrate proof of concept. We are the first to describe retrograde upper tract chemotherapeutic irrigation with an intravenous pump. This technique may facilitate and standardize the delivery of intracavitary chemotherapy. Further investigation to determine whether it translates into improved safety and/or efficacy is warranted.

Buchner D.A.,Case Western Reserve University | Nadeau J.H.,Pacific Northwest Diabetes Research Institute
Genome Research | Year: 2015

Quantitative trait loci (QTLs) are being used to study genetic networks, protein functions, and systems properties that underlie phenotypic variation and disease risk in humans, model organisms, agricultural species, and natural populations. The challenges are many, beginning with the seemingly simple tasks of mapping QTLs and identifying their underlying genetic determinants. Various specialized resources have been developed to study complex traits in many model organisms. In the mouse, remarkably different pictures of genetic architectures are emerging. Chromosome Substitution Strains (CSSs) reveal many QTLs, large phenotypic effects, pervasive epistasis, and readily identified genetic variants. In contrast, other resources as well as genome-wide association studies (GWAS) in humans and other species reveal genetic architectures dominated with a relatively modest number of QTLs that have small individual and combined phenotypic effects. These contrasting architectures are the result of intrinsic differences in the study designs underlying different resources. The CSSs examine contextdependent phenotypic effects independently among individual genotypes, whereas with GWAS and other mouse resources, the average effect of each QTL is assessed among many individuals with heterogeneous genetic backgrounds. We argue that variation of genetic architectures among individuals is as important as population averages. Each of these important resources has particular merits and specific applications for these individual and population perspectives. Collectively, these resources together with high-throughput genotyping, sequencing and genetic engineering technologies, and information repositories highlight the power of the mouse for genetic, functional, and systems studies of complex traits and disease models. © 2015 Buchner and Nadeau.

Segraves R.T.,Case Western Reserve University
Journal of Sexual Medicine | Year: 2010

Introduction.: All of the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., text revision (DSM-IV-TR) criteria for sexual disorders have been criticized on multiple grounds, including that the criteria lack precision, that the requirement of marked distress is inappropriate, and that the specification of etiological subtypes should be deleted. Aim.: The goal of this article is to review evidence relevant to diagnostic criteria for male orgasmic disorder published since 1990. Methods.: Medline searches from 1990 forward were conducted using the terms male orgasmic disorder, anorgasmia, delayed ejaculation, retarded ejaculation, ejaculatory delay, and ejaculatory disorder. Early drafts of proposed alterations in diagnostic criteria were submitted to advisors. Main Outcome Measure.: Evidence reviewed was judged by current usage of terminology, evidence allowing precise definition of the syndrome, and evidence concerning separation of the syndrome from distress. Results.: The literature search indicated minimal use of the term male orgasmic disorder and minimal knowledge concerning psychogenic ejaculatory problems. Conclusions.: It is recommended that the term male orgasmic disorder be replaced with the term delayed ejaculation. Duration and severity criteria are recommended. Since many ejaculatory problems are idiopathic, it is recommended that the etiological subtypes due to psychological or due to combined factors be eliminated. © 2010 International Society for Sexual Medicine.

Allogeneic hematopoietic stem cell transplantation (SCT) is the only curative therapy for many malignant and nonmalignant conditions. Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication that limits successful outcomes. Preclinical models suggest that IPS represents an immune mediated attack on the lung involving elements of both the adaptive and the innate immune system. However, the etiology of IPS in humans is less well understood. To explore the disease pathway and uncover potential biomarkers of disease, we performed two separate label-free, proteomics experiments defining the plasma protein profiles of allogeneic SCT patients with IPS. Samples obtained from SCT recipients without complications served as controls. The initial discovery study, intended to explore the disease pathway in humans, identified a set of 81 IPS-associated proteins. These data revealed similarities between the known IPS pathways in mice and the condition in humans, in particular in the acute phase response. In addition, pattern recognition pathways were judged to be significant as a function of development of IPS, and from this pathway we chose the lipopolysaccaharide-binding protein (LBP) protein as a candidate molecular diagnostic for IPS, and verified its increase as a function of disease using an ELISA assay. In a separately designed study, we identified protein-based classifiers that could predict, at day 0 of SCT, patients who: 1) progress to IPS and 2) respond to cytokine neutralization therapy. Using cross-validation strategies, we built highly predictive classifier models of both disease progression and therapeutic response. In sum, data generated in this report confirm previous clinical and experimental findings, provide new insights into the pathophysiology of IPS, identify potential molecular classifiers of the condition, and uncover a set of markers potentially of interest for patient stratification as a basis for individualized therapy.

Stein C.M.,Case Western Reserve University
PLoS Pathogens | Year: 2011

Several candidate gene studies have provided evidence for a role of host genetics in susceptibility to tuberculosis (TB). However, the results of these studies have been very inconsistent, even within a study population. Here, we review the design of these studies from a genetic epidemiological perspective, illustrating important differences in phenotype definition in both cases and controls, consideration of latent M. tuberculosis infection versus active TB disease, population genetic factors such as population substructure and linkage disequilibrium, polymorphism selection, and potential global differences in M. tuberculosis strain. These considerable differences between studies should be accounted for when examining the current literature. Recommendations are made for future studies to further clarify the host genetics of TB. © 2011 Catherine M. Stein.

Khan M.A.,Case Western Reserve University
Current rheumatology reports | Year: 2013

HLA-B27 has a high degree of genetic polymorphism, with 105 known subtypes, named HLA-B*27:01 to HLA-B*27:106, encoded by 132 alleles. The most common subtypes associated with ankylosing spondylitis are HLA-B*27:05 (Caucasians), HLA-B*27:04 (Chinese), and HLA-B*27:02 (Mediterranean populations). For Chinese populations, HLA-B*27:04 is associated with a greater ankylosing spondylitis risk than HLA-B*27:05. Two subtypes, HLA-B27*06 and HLA-B27*09, seem to have no disease association. These differential disease associations of HLA-B27 subtypes, and the recent discovery that ERAP1 is associated with ankylosing spondylitis for patients with HLA-B27, have increased attempts to determine the function of HLA-B27 in disease pathogenesis by studying hemodynamic features of its protein structure, alterations of its peptidome, aberrant peptide handling, and associated molecular events. However, after 40 years we still do not fully know how HLA-B27 predisposes to ankylosing spondylitis and related spondyloarthritis.

Lederman M.M.,Case Western Reserve University
Thrombosis and Haemostasis | Year: 2010

In July 1982, the occurrence of three cases of acquired immunodeficiency syndrome (AIDS) in men with haemophilia was an immediate signal to Oscar Ratnoff that AIDS was transmissible through blood products. Work that he led provided important and clear indication that the AIDS agent was transmissible through pooled plasma products and had rapidly infected many men who had haemophilia. Before the blood supply was protected, the risk for infection in haemophilia was related directly to the intensity of therapy with pooled anti-haemophilic factor concentrates. Studies performed among the small proportion of haemophiliacs who remained uninfected despite heavy exposure to these plasma products revealed that the rare protective genotype - homozygosity for the 32 base pair deletion in the CCR5 gene was heavily concentrated in this population. Among those who did not have this protective genotype, a state of diminished immune activation distinguished these high risk uninfected haemophiliacs from haemophiliacs who later acquired human immunodeficiency virus (HIV) infection and from healthy uninfected controls. Immune activation state may not only predict risk for HIV acquisition but also appears to be an important predictor and likely determinant of HIV disease progression. The potential drivers of immune activation in chronic HIV infection include HIV itself, other co-infecting pathogens, homeostatic responses to cytopenia as well as the recently recognised phenomenon of translocation of microbial products across a damaged gut mucosal surface. This latter process is particularly compelling as clinical studies have shown a good relationship between indices of microbial translocation and markers of both immune activation and T cell homeostasis in chronic HIV infection. More recently, we have also found evidence that these microbial products also may drive a heightened tendency to thrombus formation in HIV infection via induction of monocyte tissue factor expression. Thus systemic exposure to microbial elements that are translocated through a gut mucosa damaged in the first few weeks of HIV infection may contribute to the pathogenesis of both immune deficiency and the heightened risk for vascular events that have been noted in persons with HIV infection. © Schattauer 2010.

Onders R.P.,Case Western Reserve University
Handbook of Clinical Neurology | Year: 2012

Tetraplegia can lead to chronic respiratory failure. The need for tracheostomy mechanical ventilation significantly increases the cost of care, decreases the quality of life of the patient, and decreases life expectancy in spinal cord injury (SCI) because of pneumonias. Phrenic nerve stimulation was initially developed in the 1960s and diaphragm pacing was developed in the 1990s; both have the ability to remove a patient from positive pressure ventilation and allow them to breathe with their own diaphragm, decreasing posterior lung lobe atelectasis and pneumonia risk. This chapter summarizes the current surgical techniques, ventilator weaning options, and long-term results of functional electrical stimulation in restoring respiratory function. © 2012 Elsevier B.V.

King C.H.,Case Western Reserve University
Advances in Parasitology | Year: 2010

Over the past five decades, accurate and comparable assessment of disease burden due to different 'worm' infections has proven problematic. Estimates of the health impact of helminths have varied significantly, depending on the assessor's perspective and the approaches taken to quantifying disease effects on patient performance status. Past surveys have frequently suffered from misclassification bias due to the lack of a diagnostic 'gold' standard. At the same time, there has been a tendency to define disease based solely on late-onset, 'pathognomonic' outcomes that can be uniquely attributed to each pathogen. However, we are now gaining a much better understanding of the role of helminths in anaemia causation, impaired growth and development, and poor school or work performance. With a new appreciation of the link between long-term, parasite-mediated inflammation and the patient's lifetime risk of disability, we recognise that the bulk of worm-associated diseases is found in the latter, 'non-specific' categories, with relevance to individual performance status and detriment to regional levels of human capital. Appropriately, the emerging use of comprehensive disability metrics such as the quality-adjusted life year (QALY)-as opposed to the widely used disability-adjusted life year (DALY) metrics-will better capture the impact of helminthic infections on the long-term health of Asian and other developing world populations. This improved, more valid assessment is expected to provide evidence favouring preventive over curative intervention for control of these highly prevalent diseases. © 2010 Elsevier Ltd.

Rosenblatt C.,Case Western Reserve University
ChemPhysChem | Year: 2014

The instrumentation associated with near-field scanning optical microscopy (NSOM) can be exploited to provide three-dimensional structure and dynamic information about liquid crystals at scales not possible with diffraction-limited tools. This Minireview focuses on our use of NSOM techniques to probe spatial variations of the nematic director and the nematic orientational order parameter on length scales as small as a few nanometers. Coming closer: Near-field scanning optical microscopy (NSOM) is exploited to provide three-dimensional structure and dynamic information about liquid crystals at scales as small as a few nanometers. (Image courtesy of Prof. Antonio De Luca.) © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Sreekanth K.V.,Case Western Reserve University
Nature Materials | Year: 2016

Optical sensor technology offers significant opportunities in the field of medical research and clinical diagnostics, particularly for the detection of small numbers of molecules in highly diluted solutions. Several methods have been developed for this purpose, including label-free plasmonic biosensors based on metamaterials. However, the detection of lower-molecular-weight (<500 Da) biomolecules in highly diluted solutions is still a challenging issue owing to their lower polarizability. In this context, we have developed a miniaturized plasmonic biosensor platform based on a hyperbolic metamaterial that can support highly confined bulk plasmon guided modes over a broad wavelength range from visible to near infrared. By exciting these modes using a grating-coupling technique, we achieved different extreme sensitivity modes with a maximum of 30,000 nm per refractive index unit (RIU) and a record figure of merit (FOM) of 590. We report the ability of the metamaterial platform to detect ultralow-molecular-weight (244 Da) biomolecules at picomolar concentrations using a standard affinity model streptavidin–biotin. © 2016 Nature Publishing Group

McGaugh S.S.,Case Western Reserve University | Schombert J.M.,University of Oregon
Astronomical Journal | Year: 2014

We combine Spitzer 3.6 μm observations of a sample of disk galaxies spanning over 10 mag in luminosity with optical luminosities and colors to test population synthesis prescriptions for computing stellar mass. Many commonly employed models fail to provide self-consistent results: the stellar mass estimated from the luminosity in one band can differ grossly from that of another band for the same galaxy. Independent models agree closely in the optical (V band), but diverge at longer wavelengths. This effect is particularly pronounced in recent models with substantial contributions from TP-AGB stars. We provide revised color-mass-to-light ratio relations that yield self-consistent stellar masses when applied to real galaxies. The B - V color is a good indicator of the mass-to-light ratio. Some additional information is provided by V - I, but neither it nor J - Ks are particularly useful for constraining the mass-to-light ratio on their own. In the near-infrared, the mass-to-light ratio depends weakly on color, with typical values of 0.6 M⊙/L⊙ in the Ks band and 0.47 M⊙/L⊙ at 3.6 μm. © 2014. The American Astronomical Society. All rights reserved.

Hoover D.G.,University of Delaware | Rodriguez-Palacios A.,Case Western Reserve University
Infectious Disease Clinics of North America | Year: 2013

Clostridium difficile is a human intestinal pathogen most frequently involved in diarrheal illnesses following the administration of antibiotics. There is growing concern that some C difficile infections (CDI) may be acquired from ingestion of C difficile spores in contaminated foods. The number of CDI cases is increasing with a heightening in the severity of disease symptoms and an increasing number of community-associated infections not connected to health care-associated risk. This article provides an overview of information related to assessing the risk of foodborne transmission of CDI, highlighting studies on C difficile relevant to food safety in health care settings. © 2013 Elsevier Inc.

Von Lintig J.,Case Western Reserve University
Annual Review of Nutrition | Year: 2010

Carotenoids affect a rich variety of physiological functions in nature and are beneficial for human health, serving as antioxidants in lipophilic environments and blue light filters in the macula of human retina. These dietary compounds also serve as precursors of a unique set of apo-carotenoid cleavage products, including retinoids. Although knowledge about retinoid biology has tremendously increased, the metabolism of retinoids' parent precursors remains poorly understood. Recently, molecular players in carotenoid metabolism have been identified and biochemically characterized. Moreover, mutations in their corresponding genes impair carotenoid metabolism and induce various pathologies in animal models. Polymorphisms in these genes alter carotenoid and retinoid homeostasis in humans as well. This review summarizes our current knowledge about the molecular/biochemical basis of carotenoid metabolism and particularly the physiological role of carotenoids in retinoid-dependent physiological processes. Copyright © 2010 by Annual Reviews. All rights reserved.

McDonald D.,Case Western Reserve University
Viruses | Year: 2010

Dendritic cells initiate and sustain immune responses by migrating to sites of pathogenic insult, transporting antigens to lymphoid tissues and signaling immune specific activation of T cells through the formation of the immunological synapse. Dendritic cells can also transfer intact, infectious HIV-1 to CD4 T cells through an analogous structure, the infectious synapse. This replication independent mode of HIV-1 transmission, known as trans-infection, greatly increases T cell infection in vitro and is thought to contribute to viral dissemination in vivo. This review outlines the recent data defining the mechanisms of trans-infection and provides a context for the potential contribution of trans-infection in HIV-1 disease. © 2010 by the authors.

Hyun I.,Case Western Reserve University
Journal of Law, Medicine and Ethics | Year: 2010

This paper discusses exceptional circumstances under which patients outside of clinical trials are likely to receive innovative stem cell-based interventions. These circumstances involve: (1) stem cell interventions not initially amenable to a clinical trials approach; (2) expanded access to investigational stem cell products (" compassionate use" ); and (3) off-label uses of FDA approved stem cell products. This paper proposes a new approach to regulating these exceptional cases. © 2010 American Society of Law, Medicine & Ethics, Inc.

Lyytinen K.,Case Western Reserve University | Damsgaard J.,Copenhagen Business School
European Journal of Information Systems | Year: 2011

In this article we propose a new complementary approach to investigate Inter-Organizational Information Systems (IOIS) adoption called configuration analysis. We motivate the need for a new approach by the common observation that the structure and the strategy of an IOIS are interdependent and that the IOIS adoptions consequently cluster orderly. For example, an IOIS setup with a powerful customer as a hub and many suppliers as spokes frequently surfaces across diffusion studies. Yet, this fact has not been integrated into existing analyses, and its implications have not been fully developed. We propose that IOIS scholars need to look beyond the single adopting organization in IOIS adoption studies and in contrast consider adoption units what we call an adoption configuration. Each such configuration can be further characterized along the following dimensions: (1) vision, (2) key functionality, (3) mode of interaction, (4) structure and (5) mode of appropriation. In addition, these dimensions do not co-vary independently. For example, a particular organizing vision assumes a specific inter-organizational structure. A typology of IOIS configurations for adoption analysis is laid out consisting of dyadic, hub and spoke, industry and community configurations. Specific forms or adoption analysis are suggested for each type of configuration. Overall, configuration analysis redirects IOIS adoption studies both at the theoretical and the methodological level, and a corresponding research agenda is sketched. © 2011 Operational Research Society Ltd. All rights reserved.

Lee Y.,Case Western Reserve University
Seminars in cutaneous medicine and surgery | Year: 2011

Photodynamic therapy (PDT) involves the activation of a photosensitizing drug, which preferentially localizes to diseased skin, by irradiation with light to cause selective cytotoxic damage. Since its discovery in the early 20th century and the development of topical photosensitizers 2 decades ago, PDT is increasingly being used in dermatology for a wide range of neoplastic, inflammatory, and infectious cutaneous conditions. Topical 5-aminolevulinic acid and methyl aminolevulinic acid, the most commonly used agents in PDT, have received Food and Drug Administration approval for the treatment of actinic keratoses, and many second-generation photosensitizers are under investigation. Compared with conventional therapies, PDT has the advantage of being noninvasive and capable of field treatment. It is also associated with quicker recovery periods and excellent cosmetic results. Because of these benefits, PDT is being evaluated as a potential treatment option for many dermatologic conditions and has been shown to be effective for certain nonmelanoma skin cancers. Although research is still limited, PDT might also have a therapeutic benefit for cutaneous T-cell lymphoma, acne, psoriasis, leishmaniasis, and warts, among others. This article is a review of the clinical applications of PDT in dermatology and summarizes the current evidence in literature describing its efficacy, safety, and cosmetic outcome. Published by Elsevier Inc.

Tsao J.,Novartis | Jiang Y.,Case Western Reserve University
Magnetic Resonance in Medicine | Year: 2013

We describe a generalized version of hierarchical IDEAL that can flexibly handle arbitrary chemical species at arbitrary echo times. The proposed work is fast and robust, and it has three key features: (1) multiresolution approach, which allows the method to handle images with disjoint regions, makes it less susceptible to local optima, and reduces the ambiguity of the separation; (2) direct phase estimation, which bypasses the phase wrapping issue, and (3) efficient algebraic formulation, which enables fast calculation and insensitivity to spatially varying phase across the image, from sources such as partial echo acquisition, receiver coils, motion, and flow. Representative results at 1.5 T and 3 T are presented from human ankle, wrist, and a water/oil/silicone phantom. © 2012 Wiley Periodicals, Inc.

Wesson D.W.,Case Western Reserve University
Current Biology | Year: 2013

Sniffing is a specialized respiratory behavior that is essential for the acquisition of odors [1-4]. Perhaps not independent of this, sniffing is commonly displayed during motivated [5-7] and social behaviors [8, 9]. No measures of sniffing among interacting animals are available, however, calling into question the utility of this behavior in the social context. From radiotelemetry recordings of nasal respiration, I found that investigation by one rat toward the facial region of a conspecific often elicits a decrease in sniffing frequency in the conspecific. This reciprocal display of sniffing was found to be dependent upon the rat's social status in two separate paradigms, with subordinates reliably decreasing their sniffing frequency upon being investigated in the face by dominant rats. Failure of subordinates to decrease their sniffing frequency shortened the latency for agonistic behavior by dominant rats, reflecting that decreases in sniffing serve as appeasement signals during social interactions. Rats rendered unable to smell persisted in displaying reciprocal sniffing behavior, demonstrating the independence of this behavior from olfaction. Oxytocin treatment in rats with established social hierarchies abolished agonistic behaviors and reciprocal sniffing displays. Together, these findings demonstrate that rodents utilize sniffing behaviors communicatively, not only to collect [6, 10-14] but also to convey information. © 2013 Elsevier Ltd.

Schmaier A.H.,Case Western Reserve University
Science translational medicine | Year: 2014

A newly created antibody to the active site of Factor XIIa protects against clotting of extracorporeal bypass circuitry without bleeding risk in vivo, obviating the need for heparin (Larsson et al., this issue).

Colley D.G.,University of Georgia | Secor W.E.,Centers for Disease Control and Prevention | King C.H.,Case Western Reserve University
The Lancet | Year: 2014

Human schistosomiasis-or bilharzia-is a parasitic disease caused by trematode fl ukes of the genus Schistosoma. By conservative estimates, at least 230 million people worldwide are infected with Schistosoma spp. Adult schistosome worms colonise human blood vessels for years, successfully evading the immune system while excreting hundreds to thousands of eggs daily, which must either leave the body in excreta or become trapped in nearby tissues. Trapped eggs induce a distinct immune-mediated granulomatous response that causes local and systemic pathological eff ects ranging from anaemia, growth stunting, impaired cognition, and decreased physical fi tness, to organ-specifi c eff ects such as severe hepatosplenism, periportal fi brosis with portal hypertension, and urogenital infl ammation and scarring. At present, preventive public health measures in endemic regions consist of treatment once every 1 or 2 years with the isoquinolinone drug, praziquantel, to suppress morbidity. In some locations, elimination of transmission is now the goal; however, more sensitive diagnostics are needed in both the fi eld and clinics, and integrated environmental and health-care management will be needed to ensure elimination. © Chataway et al. Open Access article distributed under the terms of CC BY.

Bonfield T.L.,Case Western Reserve University
Discovery medicine | Year: 2010

Adult human mesenchymal stem cells (hMSCs) are the focus of a number of clinical applications. The advantage of hMSCs is that they are immuno-modulatory and versatile due to their secreted bioactive molecules that are anti-inflammatory and regenerative. These cells have the potential to orchestrate reparative processes in diseased or injured tissues. Much of the diversity and uniqueness of hMSCs is defined by their response to the milieu of injured tissue. hMSCs are sensitive to their site-specific microenvironment, and it is anticipated that they will deliver the bioactive agents in a site-specific manner quite different from the way pharmaceutical drugs work. This review highlights current concepts of such functions with a focus on the clinical utility of hMSCs in the treatment of lung diseases.

Valadkhan S.,Case Western Reserve University
RNA Biology | Year: 2010

The spliceosome, the ribonucleoprotein assembly that removes the intervening sequences from pre-mRNAs through splicing, is one of the most complex cellular machines. In humans it is composed of ∼150 proteins and five RNAs (snRNAs). One of the snRNAs, U6, contains sequences analogous to all the RNA elements that form the active site of the group II introns, ribozymes that perform a splicing reaction mechanistically identical to spliceosomal splicing. Interestingly, U6 is the only snRNA that is indispensable for splicing and in vitro, in complex with another snRNA, it can catalyze a primordial splicing reaction in the absence of all other spliceosomal factors. On the other hand, discovery of an RNase H-like domain in a spliceosomal protein that is closely associated with splice sites suggests that proteins may be involved in formation of the active site. Thus, whether the spliceosome is an RNA or RNA-protein catalyst remains uncertain. © 2010 Landes Bioscience.

Alter G.,Massachusetts Institute of Technology | Sekaly R.P.,Case Western Reserve University
Vaccine | Year: 2015

Since the development of the first vaccine over 200 years ago, vaccines have saved millions of lives and have become the most cost-effective modern medical intervention. However, over 70 years ago, Freund recognized that the effectiveness of the vaccine-induced immune responses could be vastly improved via the co-delivery of inflammation-induced agents, giving birth to the adjuvant field. Since the first description of adjuvants, revolutionary discoveries, including the discovery of dendritic cells and pattern recognition receptors, that drive remarkably different biological profiles, have opened the landscape of opportunities for the development of novel adjuvants able to trigger a remarkably diverse inflammatory profiles, thereby qualitatively and quantitatively skewing adaptive immunity in a tailored manner against target pathogens. However, mounting data point to a critical role for pre-existing inflammation as a predictor of vaccine responsiveness. Thus, in this review we will discuss novel opportunities by which pre-existing inflammation may be modulated, skewed, or tuned via next-generation vaccine approaches to enhanced vaccine-induced immunity in the elderly, immunocompromised, or subjects with chronic diseases. © 2015 .

Catalano P.M.,Case Western Reserve University
Reproduction | Year: 2010

There has been a significant increase over the past few decades in the number of reproductive age women who are either overweight or obese. Overweight and obese women are at increased risk for having decreased insulin sensitivity as compared with lean or average weight women. The combination of obesity and decreased insulin sensitivity increases the long-term risk of these individuals developing the metabolic syndrome and associated problems of diabetes, hypertension, hyperlipidemia, and cardiovascular disorders. Because of the metabolic alterations during normal pregnancy, particularly the 60% decrease in insulin sensitivity, overweight and obese women are at increased risk of metabolic dysregulation in pregnancy, i.e. gestational diabetes, preeclampsia, and fetal overgrowth. Hence, pregnancy can be considered as a metabolic stress test for the future risk of the metabolic syndrome. In this review, we will review the underlying pathophysiology related to these disorders. Most importantly, an understanding of these risks provides an opportunity for prevention. For example, a planned pregnancy offers an opportunity to address weight control prior to conception. At the very least, by avoiding excessive weight gain during pregnancy, this may prevent excessive weight retention post partum. Finally, based on the concept of in utero programming, these lifestyle measures may not only have short- and long-term benefits for the woman but also for her offspring as well. © 2010 Society for Reproduction and Fertility.

Brown T.T.,Johns Hopkins University | McComsey G.A.,Case Western Reserve University
Antiviral Therapy | Year: 2010

Background: We aimed to determine whether antiretroviral therapy (ART) initiation with efavirenz (EFV) is associated with decreases in 25-hydroxyvitamin D (25[OH]D) compared with non-EFV regimens. Methods: 25(OH)D was measured from stored plasma samples in 87 ART-naive HIV-positive patients prior to ART initiation with EFV-containing (n=51) or non-EFV-containing (89% with protease inhibitors; n=36) regimens from a single clinic in Cleveland (OH, USA). A repeat measurement was made 6-12 months after ART initiation. The change in 25(OH)D after ART initiation and the prevalence of patients with hypovitaminosis D (≤37.5 nmol/l [15 ng/ml]) after ART initiation was compared in those who initiated ART with and without EFV using multivariable linear and modified Poisson regression, respectively. Results: Prior to ART initiation, the median (interquartile range [IQR]) 25(OH)D concentration was 52.7 nmol/l (IQR 32.2-72.1), with 33% prevalence of hypovitaminosis D. After 6-12 months of ART, 25(OH)D decreased by a mean ±se of -12.7 ±3.7 nmol/l in the EFV group relative to the non-EFV group (P=0.001) after adjustment for baseline 25(OH)D concentration, race and season (non-summer versus summer) at the visit 6-12 months after ART initiation. Similarly, after multivariable adjustment, the risk of hypovitaminosis D after ART initiation was significantly higher in the EFV group compared with the non-EFV group (prevalence ratio 1.8 [95% confidence interval 1.2-2.8]; P=0.007). Conclusions: ART initiation with EFV is associated with significant decreases in 25(OH)D and an increased risk of hypovitaminosis D compared with non-EFV regimens. ©2010 International Medical Press.

Ernst O.P.,Kings College | Lodowski D.T.,Case Western Reserve University | Elstner M.,Karlsruhe Institute of Technology | Hegemann P.,Humboldt University of Berlin | And 2 more authors.
Chemical Reviews | Year: 2014

Animal rhodopsins are employed in visual and nonvisual phototransduction, in the maintenance of the circadian clock and as photoisomerases. Animal rhodopsins are specialized G-protein-coupled receptors (GPCRs). Structures of animal and microbial rhodopsins differ largely and are drawn in opposite orientations with respect to the membrane. Light absorption initiates functions of both microbial and animal rhodopsins and the wavelength dependence of the absorption efficiency determines the colors of the proteins. The initial photochemical reaction in microbial and animal rhodopsins is known to be one of the fastest and most efficient chemical events in biology. Judging from the large number of new rhodopsin variants unearthed by genomic and metagenomic sequencing, new interesting functions of retinal proteins will continue to be discovered. This applies to both microbial and animal rhodopsins, and will lead to new breakthroughs in understanding microbial, invertebrate, and vertebrate physiology and evolution.

Gorodeski G.I.,Case Western Reserve University
Autonomic Neuroscience: Basic and Clinical | Year: 2015

Purinergic effects in vivo are local, specific, transient, and affect target cells in a paracrine or autocrine manner. Purinergic signalling is involved in the regulation of numerous functions in the male and female reproductive tract organs. Analysis of functional expression of purinoceptors suggests that P2Y2 receptors are involved in the regulation of luminal fluid secretion in vivo; P2X1 and P2X2 in the regulation of smooth muscle cell contraction of blood vessels and tubular organs; P2X2 in the regulation of sperm cell maturation; P2X3 in activation of sensory nerve fibers involved in reflex activities and pain; P2X4 in the regulation of tight junctional resistance and epithelial transport in female reproductive tract epithelia, and in the regulation of luminal acidification in the epididymis, vas deferens and probably the vagina and ectocervix; P2Y1 and P2Y2 in the regulation of cell proliferation; P2X5 and P2X7A in the regulation of epithelial cell terminal differentiation and apoptosis; and A1 receptors in the regulation of sperm cell capacitation. Translational studies suggested that cellular levels of the P2X7A receptor could be used as a biomarker for the early detection of breast, ectocervix, endocervix, endometrial and bladder cancers. Data also suggested that the P2X7A mechanism could be used as a pharmaceutical target for the prevention and treatment of epithelial neoplasia through the induction of apoptosis. © 2015 Elsevier B.V.

Qu L.,Beijing Institute of Technology | Vaia R.A.,Air Force Research Lab | Dai L.,Case Western Reserve University
ACS Nano | Year: 2011

A simple multiple contact transfer technique has been developed for controllable fabrication of multilevel, multicomponent microarchitectures of vertically aligned carbon nanotubes (VA-CNTs). Three dimensional (3-D) multicomponent micropatterns of aligned single-walled carbon nanotubes (SWNTs) and multiwalled carbon nanotubes (MWNTs) have been fabricated, which can be used to develop a newly designed touch sensor with reversible electrical responses for potential applications in electronic devices, as demonstrated in this study. The demonstrated dependence of light diffraction on structural transfiguration of the resultant CNT micropattern also indicates their potential for optical devices. Further introduction of various components with specific properties (e.g., ZnO nanorods) into the CNT micropatterns enabled us to tailor such surface characteristics as wettability and light response. Owing to the highly generic nature of the multiple contact transfer strategy, the methodology developed here could provide a general approach for interposing a large variety of multicomponent elements (e.g., nanotubes, nanorods/wires, photonic crystals, etc.) onto a single chip for multifunctional device applications. © 2011 American Chemical Society.

Saleem Y.,Case Western Reserve University
Circulation. Cardiovascular imaging | Year: 2015

BACKGROUND: To examine the association between the American Heart Association's 7 metrics of ideal cardiovascular health (ICH) and the presence of subclinical coronary atherosclerosis as assessed by coronary artery calcification (CAC) using electron-beam computed tomography.METHODS AND RESULTS: This study is a cross-sectional analysis of data obtained on 3121 male and female patients evaluated at the Cooper Clinic in Dallas, Texas, between 1997 and 2007. We included men aged ≥45 and women aged ≥55 without known cardiovascular disease and for whom information on all ICH metrics and a CAC score were available. Patients were grouped into 3 categories according to their number of ICH metrics: favorable (4-7 ICH metrics), intermediate (3 metrics), and unfavorable (0-2 metrics). Patients with favorable ICH profiles had a lower prevalence and severity of subclinical atherosclerosis than those with unfavorable or intermediate ICH profiles as estimated by CAC. This inverse association of CAC with ICH metrics was evident whether the presence of coronary calcium was defined as CAC score>0, CAC score>100, or CAC score>400. Patients with favorable ICH profiles had odds of coronary calcium (CAC>0) less than half of those for patients with unfavorable profiles (odds ratio 0.41; 95% confidence interval, 0.34-0.50) and patients with intermediate ICH profiles had odds of detectable CAC 32% lower (odds ratio 0.68; 95% confidence interval, 0.57-0.82).CONCLUSIONS: A statistically significant association was found between a favorable level of ICH metrics and less or absent subclinical atherosclerosis as measured by CAC underscoring the importance of primordial prevention. © 2014 American Heart Association, Inc.

Gupta A.S.,Case Western Reserve University
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2011

Nanomedicine approaches have revolutionized the treatment of cancer and vascular diseases, where the limitations of rapid nonspecific clearance, poor biodistribution and harmful side effects associated with direct systemic drug administration can be overcome by packaging the agents within sterically stabilized, long-circulating nanovehicles that can be further surface-modified with ligands to actively target cellular/molecular components of the disease. With significant advancements in genetics, proteomics, cellular and molecular biology and biomaterials engineering, the nanomedicine strategies have become progressively refined regarding the modulation of surface and bulk chemistry of the nanovehicles, control of drug release kinetics, manipulation of nanoconstruct geometry and integration of multiple functionalities on single nanoplatforms. The current review aims to capture the various nanomedicine approaches directed specifically toward vascular diseases during the past two decades. Analysis of the promises and limitations of these approaches will help identify and optimize vascular nanomedicine systems to enhance their efficacy and clinical translation in the future. From the Clinical Editor: Nanomedicine-based approaches have had a major impact on the treatment and diagnosis of malignancies and vascular diseases. This review discusses various nanomedicine approaches directed specifically toward vascular diseases during the past two decades, highlighting their advantages, limitations and offering new perspectives on future applications. © 2011 Elsevier Inc.

McManus J.M.,Case Western Reserve University
Journal of visualized experiments : JoVE | Year: 2012

Multifunctionality, the ability of one peripheral structure to generate multiple, distinct behaviors(1), allows animals to rapidly adapt their behaviors to changing environments. The marine mollusk Aplysia californica provides a tractable system for the study of multifunctionality. During feeding, Aplysia generates several distinct types of behaviors using the same feeding apparatus, the buccal mass. The ganglia that control these behaviors contain a number of large, identified neurons that are accessible to electrophysiological study. The activity of these neurons has been described in motor programs that can be divided into two types, ingestive and egestive programs, based on the timing of neural activity that closes the food grasper relative to the neural activity that protracts or retracts the grasper(2). However, in isolated ganglia, the muscle movements that would produce these behaviors are absent, making it harder to be certain whether the motor programs observed are correlates of real behaviors. In vivo, nerve and muscle recordings have been obtained corresponding to feeding programs(2,3,4), but it is very difficult to directly record from individual neurons(5). Additionally, in vivo, ingestive programs can be further divided into bites and swallows(1,2), a distinction that is difficult to make in most previously described in vitro preparations. The suspended buccal mass preparation (Figure 1) bridges the gap between isolated ganglia and intact animals. In this preparation, ingestive behaviors - including both biting and swallowing - and egestive behaviors (rejection) can be elicited, at the same time as individual neurons can be recorded from and stimulated using extracellular electrodes(6). The feeding movements associated with these different behaviors can be recorded, quantified, and related directly to the motor programs. The motor programs in the suspended buccal mass preparation appear to be more similar to those observed in vivo than are motor programs elicited in isolated ganglia. Thus, the motor programs in this preparation can be more directly related to in vivo behavior; at the same time, individual neurons are more accessible to recording and stimulation than in intact animals. Additionally, as an intermediate step between isolated ganglia and intact animals, findings from the suspended buccal mass can aid in interpretation of data obtained in both more reduced and more intact settings. The suspended buccal mass preparation is a useful tool for characterizing the neural control of multifunctionality in Aplysia.

Gaines A.D.,Case Western Reserve University
Culture, Medicine and Psychiatry | Year: 2011

While much of Medical Anthropology was and is what we can call "Normal" (following Kuhn) Medical Anthropology, I coined the term Millennial Medical Anthropology for that branch of the discipline that, in the 1990s, was departing from the Normal research paradigms and was deserving of a distinct sobriquet. This paper considers the Strong Program in Medical Anthropology's Millennial Medical Anthropology and its key subdivisions, the Cultural Studies of Science and Cultural Bioethics. Specifically it considers Medical Anthropology's movement from the past into an ethical future wherein Normal Biomedicine, Bioethics and Global Health are problematized. This provides the basis for the construction of a truly anthropological global health (i. e., Global, Global Health or Global Health 2.0). © 2010 Springer Science+Business Media, LLC.

Ludington-Hoe S.M.,Case Western Reserve University
Current Women's Health Reviews | Year: 2011

A comprehensive review of the evidence documenting preterm infant physiologic responses to Kangaroo Care (KC - intermittent skin-to-skin contact) and Kangaroo Mother Care (KMC - 24/7 skin-to-skin contact) has been conducted. Kangaroo Care's effects on preterm infant heart rate, bradycardia, respiratory rate, apnea, oxygen saturation, cerebral oxygenation, supplemental oxygen needs, oxygen consumption, desaturation episodes, temperature, rewarming, blood glucose, serum bilirubin, cholecystokinin, gastrin, somatostatin, weight gain or change, sleep and crying, brain maturation and complexity, infection, stress, and pain are reviewed, as are KC's effects with congenital heart defect infants. Documented effects of KC on prevention and amelioration of maternal depression, swifter delivery of the placenta and involution, and decreased likelihood of postpartal anemia are presented. Guidelines based on dosage (duration and frequency) of KC are provided, as is a summary of actual and potential benefits of KC, including use at end-of-life. Kangaroo Care's role in moving to the new paradigms of non-separation of the infant and mother during hospitalization and parents as primary providers of neonatal care concludes the manuscript. © 2011 Bentham Science Publishers Ltd.

Redline R.W.,Case Western Reserve University
Seminars in Perinatology | Year: 2015

The clinical utility of placental pathology is both overestimated and underestimated, and the overall quality of placental pathology reporting, even at major medical centers, is highly variable. Clear benefits of examining placentas include the immediate diagnosis of treatable conditions in both the mother and the infant, clarification of the underlying etiology of adverse pregnancy outcomes, estimation of recurrence risk, and guidance for the management of future pregnancies. In order to realize these benefits and get the most out of their pathology departments, it is critical for clinicians to understand the range and implications of placental lesions. This article will review the nomenclature, diagnostic criteria and pitfalls, and clinical significance of seven common placental disease processes and a handful of other lesions. © 2014 Elsevier Inc.

Lawrence B.M.,Case Western Reserve University
Experimental Brain Research | Year: 2010

Previously, we have shown that the reaction times (RTs) of exogenously generated saccadic eye movements decrease with an increase in the number of response alternatives (Lawrence et al. in J Vis 8(26):1-7, 2008; Lawrence and Gardella in Exp Brain Res 195(3):413-418, 2009). Because this pattern of RTs is in the direction opposite that predicted by Hick (Q J Exp Psychol 4:11-26, 1952), we termed the effect an "anti- Hick's" effect. In the present study, we examined whether this effect characterizes saccades in general, or only those saccades that are exogenously generated. An anti-Hick's effect was found for exogenous, but not for endogenous, saccades. These results demonstrate a clear dissociation between exogenously and endogenously generated saccades and place an important constraint on the anti-Hick's effect. © 2010 Springer-Verlag.

Anderson J.M.,Case Western Reserve University
Journal of Materials Science: Materials in Medicine | Year: 2015

Exploiting the inflammatory response on biomaterials research and development requires an in-depth understanding of the cellular and molecular mechanisms involved in the events comprising the tissue response continuum. Examples of how the biomaterial surface chemistry may modulate the foreign body reaction to biomaterials. The utilization of different surface chemistries on biomaterials may provide biological design criteria for the appropriate use and function of biomaterials when used in medical devices and prostheses. © 2015, Springer Science+Business Media New York.

Silver D.J.,Fred Hutchinson Cancer Research Center | Silver J.,Case Western Reserve University
Current Opinion in Neurobiology | Year: 2014

Chondroitin sulfate proteoglycans (CSPGs) are a diverse family of extracellular matrix (ECM) molecules that make significant contributions to the patterning and routing of migrating neural cells and extending axons. Three distinct modes of migration mediation result from the relative abundance and positioning of expressed CSPGs, the profile of CSPG receptors expressed by the motile cell types, and the overall way in which the CSPGs integrate into and stabilize the neural ECM. Here we discuss recent findings that help to clarify the molecular mechanisms that underlie these distinct migration-regulating properties as they pertain to neural development, CNS injury, and gliomagenesis. © 2014 Elsevier Ltd.

Hatzoglou M.,Case Western Reserve University
Journal of Biological Chemistry | Year: 2010

Regulation of cell volume is of great importance because persistent swelling or shrinkage leads to cell death. Tissues experience hypertonicity in both physiological (kidney medullar cells) and pathological states (hypernatremia). Hypertonicity induces an adaptive gene expression program that leads to cell volume recovery or apoptosis under persistent stress. We show that the commitment to apoptosis is controlled by phosphorylation of the translation initiation factor eIF2α, the master regulator of the stress response. Studies with cultured mouse fibroblasts and cortical neurons show that mutants deficient in eIF2α phosphorylation are protected from hypertonicity- induced apoptosis. A novel link is revealed between eIF2α phosphorylation and the subcellular distribution of the RNA-binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1). Stress-induced phosphorylation of eIF2α promotes apoptosis by inducing the cytoplasmic accumulation of hnRNP A1, which attenuates internal ribosome entry site-mediated translation of anti-apoptotic mRNAs, including BclxL that was studied here. Hypertonic stress induced the eIF2α phosphorylation-independent formation of cytoplasmic stress granules (SGs, structures that harbor translationally arrested mRNAs) and the eIF2α phosphorylation-dependent accumulation of hnRNP A1 in SGs. The importance of hnRNP A1 was demonstrated by induction of apoptosis in eIF2α phosphorylation-deficient cells that express exogenous cytoplasmic hnRNP A1. We propose that eIF2α phosphorylation during hypertonic stress promotes apoptosis by sequestration of specific mRNAs in SGs in a process mediated by the cytoplasmic accumulation of hnRNP A1. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Furlan A.J.,Case Western Reserve University | Jauss M.,University Hospital Jena
Stroke | Year: 2013

Despite 3 recent randomized clinical trials, the management of patients with cryptogenic stroke and patent foramen ovale remains unsettled. The primary results of Evaluation of the STARFlex Septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale (CLOSURE), Percutaneous Closure of Patent Foramen Ovale in Cryptogenic Stroke (PC), and Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) were the same; the intent to treat analysis for the primary end point in all 3 trials failed to demonstrate superiority of device closure compared with medical therapy. CLOSURE put the brakes on indiscriminate device closure of patent foramen ovales in patients with cryptogenic stroke or transient ischemic attack. RESPECT suggested, but did not prove, that highly selected patients without vascular risk factors, with a cortical infarct on baseline magnetic resonance imaging and a substantial patent foramen ovale shunt may benefit from the Amplatzer device during a multiple-year period. In the absence of definitive clinical trial results, the precise definition of which patient subgroups should be considered for patent foramen ovale device closure should be agreed to by the stakeholder societies and the Food and Drug Administration. © 2013 American Heart Association, Inc.

Richter J.D.,University of Massachusetts Medical School | Coller J.,Case Western Reserve University
Cell | Year: 2015

Among the three phases of mRNA translation - initiation, elongation, and termination - initiation has traditionally been considered to be rate limiting and thus the focus of regulation. Emerging evidence, however, demonstrates that control of ribosome translocation (polypeptide elongation) can also be regulatory and indeed exerts a profound influence on development, neurologic disease, and cell stress. The correspondence of mRNA codon usage and the relative abundance of their cognate tRNAs is equally important for mediating the rate of polypeptide elongation. Here, we discuss recent results showing that ribosome pausing is a widely used mechanism for controlling translation and, as a result, biological transitions in health and disease. © 2015 Elsevier Inc.

Ulbricht R.,FOM Institute for Atomic and Molecular Physics | Hendry E.,University of Exeter | Shan J.,Case Western Reserve University | Heinz T.F.,Columbia University | Bonn M.,FOM Institute for Atomic and Molecular Physics
Reviews of Modern Physics | Year: 2011

Time-resolved, pulsed terahertz spectroscopy has developed into a powerful tool to study charge carrier dynamics in semiconductors and semiconductor structures over the past decades. Covering the energy range from a few to about 100 meV, terahertz radiation is sensitive to the response of charge quasiparticles, e.g., free carriers, polarons, and excitons. The distinct spectral signatures of these different quasiparticles in the THz range allow their discrimination and characterization using pulsed THz radiation. This frequency region is also well suited for the study of phonon resonances and intraband transitions in low-dimensional systems. Moreover, using a pump-probe scheme, it is possible to monitor the nonequilibrium time evolution of carriers and low-energy excitations with sub-ps time resolution. Being an all-optical technique, terahertz time-domain spectroscopy is contact-free and noninvasive and hence suited to probe the conductivity of, particularly, nanostructured materials that are difficult or impossible to access with other methods. The latest developments in the application of terahertz time-domain spectroscopy to bulk and nanostructured semiconductors are reviewed. © 2011 American Physical Society.

Kanavy H.E.,Case Western Reserve University
Seminars in cutaneous medicine and surgery | Year: 2011

Melanoma is a particularly aggressive type of skin cancer, and its incidence has been increasing steadily since the 1970s. This article will review the extensive epidemiologic data demonstrating that ultraviolet radiation (UVR) exposure, from the sun or artificial tanning beds, is the most important environmental risk factor for melanoma; the multiple detrimental effects of UVR on human skin, including DNA damage through the formation of dimeric photoproducts, gene mutations, oxidative stress, inflammation, and immunosuppression, all of which contribute to melanomagenesis; and the evidence that protection from UVR exposure, whether by melanin or by sunscreen, reduces the risk of developing melanoma. Copyright © 2011 Elsevier Inc. All rights reserved.

Zhu L.,Case Western Reserve University
Journal of Physical Chemistry Letters | Year: 2014

Polymer dielectrics having high dielectric constant, high temperature capability, and low loss are attractive for a broad range of applications such as film capacitors, gate dielectrics, artificial muscles, and electrocaloric cooling. Unfortunately, it is generally observed that higher polarization or dielectric constant tends to cause significantly enhanced dielectric loss. It is therefore highly desired that the fundamental physics of all types of polarization and loss mechanisms be thoroughly understood for dielectric polymers. In this Perspective, we intend to explore advantages and disadvantages for different types of polarization. Among a number of approaches, dipolar polarization is promising for high dielectric constant and low loss polymer dielectrics, if the dipolar relaxation peak can be pushed to above the gigahertz range. In particular, dipolar glass, paraelectric, and relaxor ferroelectric polymers are discussed for the dipolar polarization approach. (Figure Presented). © 2014 American Chemical Society.

Gosain A.K.,Case Western Reserve University
Plastic and Reconstructive Surgery | Year: 2010

Background: Nasal tip hemangiomas cause significant parental distress and can negatively affect the psychological development of a child. Treatment is controversial, with numerous modalities available for reconstruction. The authors outline their combined medical and surgical approach to treating nasal tip hemangiomas and describe their preferred surgical technique. Methods: A retrospective review was performed of all nasal tip hemangiomas presenting to the Multidisciplinary Vascular Anomalies Clinics at the Children's Hospital of Wisconsin and Children's Hospital of Michigan from 1999 to 2007. Parameters for review included onset age, symptoms, medical therapies (laser with or without steroid) used, age and status of lesion at time of surgery, outcomes, and complications. Results: Twenty-five patients met inclusion criteria, with a mean onset age of 1.43 months. Most received steroids and pulsed dye laser therapy (mean no. of laser treatments, 3.5) during the proliferative and plateau phases of the tumor's natural history. Surgical resection after involution has been performed using an open rhinoplasty technique on 15 patients thus far. Eleven of them had surgical correction in the postinvolutional phase, and at parental request, four had early surgical correction during the proliferative-plateau phases. In the early treatment cohort, one child developed a hematoma postoperatively; the same patient required a revision rhinoplasty for alar rim asymmetry. Acceptable aesthetic results were obtained in both groups. Conclusions: A combined medical and surgical approach offers the best method to treat the Cyrano nose. The authors' treatment algorithm uses early medical management to accelerate involution of the lesion, providing optimal conditions for excision. Early surgical treatment also allows satisfactory results but may require secondary correction. An open rhinoplasty approach with skin resection is the authors' preferred technique. Copyright © 2010 by the American Society of Plastic Surgeons.

Kemp D.E.,Case Western Reserve University
Journal of Affective Disorders | Year: 2014

Background The most commonly used pharmacologic therapies for bipolar depression are mood stabilizers, atypical antipsychotics, and antidepressants. This paper reviews common side effects associated with these medications and provides recommendations for managing adverse medication effects in clinical practice.Methods Narrative review based on literature searches of Medline and evidence-based treatment guidelines for agents that have been approved by the US Food and Drug Administration and/or are commonly used to treat bipolar depression.Results Side effects of bipolar depression pharmacotherapies are common and vary by medication, with weight gain, metabolic dysregulation, sedation/somnolence, and akathisia among those observed most frequently. These adverse events (weight gain and sedation/somnolence, in particular) negatively affect treatment adherence in patients with bipolar disorder. Furthermore, endocrine and metabolic comorbidities, weight gain, and obesity may reduce the likelihood of positive clinical responses to pharmacologic therapies. Clinicians may consider switching patients to bipolar depression medication(s) with a lower propensity for sedation or adverse metabolic effects. Lifestyle modification (e.g., dietary changes, exercise) is an important component in the treatment of weight gain/obesity, dyslipidemia, hypertension, and hyperglycemia; in addition, a wide range of medications are available as therapeutic options for patients in whom non-pharmacologic management strategies are insufficient. The use of adjunctive medication may also reduce treatment-related sedation and somnolence.Limitations The selection of relevant studies from the literature search relied primarily on the author's expertise in the area of bipolar depression and knowledge of the issues addressed.Conclusion Successful treatment of bipolar depression extends beyond managing mood symptoms to also monitoring adverse medication events and managing associated medical disorders. © 2014 Elsevier B.V. All rights reserved.

Salomon R.G.,Case Western Reserve University
Circulation Research | Year: 2012

Free radical-induced oxidation of membrane phospholipids generates complex mixtures of oxidized phospholipids (oxPLs). The combinatorial operation of a few dozen reaction types on a few dozen phospholipid structures results in the production of a dauntingly vast diversity of oxPL molecular species. Structural identification of the individual oxPL in these mixtures is a redoubtable challenge that is absolutely essential to allow determination of the biological activities of individual species. With an emphasis on cardiovascular consequences, this Review focuses on biological activities of oxPLs whose molecular structures are known and highlights 2 diametrically opposite approaches that were used to determine those structures, that is, (1) the classic approach from bioactivity of a complex mixture to isolation and structural characterization of the active molecule followed by confirmation of the structure by unambiguous chemical synthesis and (2) hypothesis of products that are likely to be generated by lipid oxidation, followed by synthesis, and then detection in vivo guided by the availability of authentic standards, and last, characterization of biological activities. Especially important for the application of the second paradigm is the capability of LC-MS/MS and derivatizations to selectively detect and quantify specific oxPL in complex mixtures, without the need for their isolation or complete separation. This technology can provide strong evidence for identity by comparisons with pure, well-characterized samples available by chemical syntheses. Those pure samples are critical for determining the biological activities attributable to specific molecular species of oxPLs in the complex mixtures generated in vivo as a consequence of oxidative stress. © 2012 American Heart Association, Inc.

Chim H.,Case Western Reserve University
Plastic and reconstructive surgery | Year: 2010

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Define the difference between vascular tumors and malformations. 2. Distinguish between the natural history of hemangiomas and that of vascular malformations. 3. Identify the different types of hemangiomas and vascular malformations and understand evaluation, treatment, and complications. 4. Understand the role of lymphaticovenular anastomoses in the treatment of extremity lymphedema. BACKGROUND: The International Society for the Study of Vascular Anomalies classification, which is the most widely accepted classification system in use, divides vascular anomalies into vascular tumors (inclusive of hemangiomas) and malformations. This serves as a guideline for diagnosis, evaluation, and treatment of these lesions. METHODS: Although hemangiomas tend to have a predictable clinical course over the first year of life, going through proliferating, involuting, and involuted stages, vascular malformations demonstrate growth commensurate with age, often becoming more prominent in puberty. In addition, they never regress, and persist throughout life. RESULTS: Different modalities of treatment may be appropriate for vascular tumors and different subsets of vascular malformations. Details are provided in this review. Lymphaticovenular anastomoses provide an excellent addition to our methods of treatment of extremity lymphedema, and are made possible through development of supermicrosurgical techniques. CONCLUSIONS: Vascular anomalies have a high prevalence in the general population. Thus, it is vital that the plastic surgeon has a good understanding of classification, evaluation, and treatment options. Lymphedema is another common condition that is encountered. Understanding of lymphaticovenular anastomoses and their applications aids treatment planning for select patients.

King C.H.,Case Western Reserve University
Acta Tropica | Year: 2015

Health metrics based on health-adjusted life years have become standard units for comparing the disease burden and treatment benefits of individual health conditions. The Disability-Adjusted Life Year (DALY) and the Quality-Adjusted Life Year (QALY) are the most frequently used in cost-effect analyses in national and global health policy discussions for allocation of health care resources. While sometimes useful, both the DALY and QALY metrics have limitations in their ability to capture the full health impact of helminth infections and other 'neglected tropical diseases' (NTDs). Gaps in current knowledge of disease burden are identified, and interim approaches to disease burden assessment are discussed. © 2013 Elsevier B.V.

Abbas A.I.,Case Western Reserve University
Nucleic acids research | Year: 2010

RNA editing is a post-transcriptional modification of pre-mRNA that results in increased diversity in transcriptomes and proteomes. It occurs in a wide variety of eukaryotic organisms and in some viruses. One of the most common forms of pre-mRNA editing is A-to-I editing, in which adenosine is deaminated to inosine, which is read as guanosine during translation. This phenomenon has been observed in numerous transcripts, including the mammalian 5-HT(2C) receptor, which can be edited at five distinct sites. Methods used to date to quantify 5-HT(2C) receptor editing are labor-intensive, expensive and provide limited information regarding the relative abundance of 5-HT(2C) receptor editing variants. Here, we present a novel, ultra high-throughput method to quantify 5-HT(2C) receptor editing, compare it to a more conventional method, and use it to assess the effect of a range of genetic and pharmacologic manipulations on 5-HT(2C) editing. We conclude that this new method is powerful and economical, and we provide evidence that alterations in 5-HT(2C) editing appear to be a result of regional changes in brain activity, rather than a mechanism to normalize 5-HT(2C) signaling.

Wang Q.,Pennsylvania State University | Zhu L.,Case Western Reserve University
Journal of Polymer Science, Part B: Polymer Physics | Year: 2011

This review highlights the frontier scientific research in the development of polymer nanocomposites for electrical energy storage applications. Considerable progress has been made over the past several years in the enhancement of the energy densities of the polymer nanocomposites via tuning the chemical structures of ceramic fillers and polymer matrix and engineering the polymer-ceramic interfaces. This article summarizes a range of current approaches to dielectric polymer nanocomposites, including the ferroelectric polymer matrix, increase of the dielectric permittivity using high-permittivity ceramic fillers and conductive dopants, preparation of uniform composite films based on surface-functionalized fillers, and utilization of the interfacial coupling effect. Primary attentions have been paid to the dielectric properties at different electric fields and their correlation with film morphology, chemical structure, and filler concentration. This article concludes with a discussion of scientific issues that remain to be addressed as well as recommendations for future research. © 2011 Wiley Periodicals, Inc.

Berg J.,Case Western Reserve University
American Journal of Bioethics | Year: 2012

The computer revolution has had an enormous effect on all aspects of the practice of medicine, yet little thought has been given to the role of social media in identifying treatment choices for incompetent patients. We are currently living in the "Internet age" and many people have integrated social media into all aspects of their lives. As use becomes more prevalent, and as users age, social media are more likely to be viewed as a source of information regarding medical care preferences. This article explores the ethical and legal issues raised by the use of social media in surrogate decision making. © 2012 Copyright Taylor and Francis Group, LLC.

Starkman G.D.,Case Western Reserve University
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences | Year: 2011

The combination of general relativity (GR) and the Standard Model of particle physics disagrees with numerous observations on scales from our Solar System up. In the canonical concordance model of Lambda cold dark matter (LCDM) cosmology, many of these contradictions between theory and data are removed or alleviated by the introduction of three completely independent new components of stress energy-the inflaton, dark matter and dark energy. Each of these in its turn is meant to have dominated (or to currently dominate) the dynamics of the Universe. There is, until now, no non-gravitational evidence for any of these dark sectors, nor is there evidence (though there may be motivation) for the required extension of the Standard Model. An alternative is to imagine that it is GR that must be modified to account for some or all of these disagreements. Certain coincidences of scale even suggest that one might expect not to make independent modifications of the theory to replace each of the three dark sectors. Because they must address the most different types of data, attempts to replace dark matter with modified gravity are the most controversial. A phenomenological model (or family of models), modified Newtonian dynamics, has, over the last few years, seen several covariant realizations. We discuss a number of challenges that any model that seeks to replace dark matter with modified gravity must face: the loss of Birkhoff's theorem, and the calculational simplifications it implies; the failure to explain clusters, whether static or interacting, and the consequent need to introduce dark matter of some form, whether hot dark matter neutrinos or dark fields that arise in new sectors of the modified gravity theory; the intrusion of cosmological expansion into the modified force law, which arises precisely because of the coincidence in scale between the centripetal acceleration at which Newtonian gravity fails in galaxies and the cosmic acceleration. We conclude with the observation that, although modified gravity may indeed manage to replace dark matter, it is likely to do so by becoming or at least incorporating a dark matter theory itself. © 2011 The Royal Society.

Das A.K.,Case Western Reserve University | Kumar K.,University of Connecticut | Sung C.-J.,University of Connecticut
Combustion and Flame | Year: 2011

This work experimentally investigates the effect of the presence of water vapor on the laminar flame speeds of moist syngas/air mixtures using the counterflow twin-flame configuration. The experimental results presented here are for fuel lean syngas mixtures with molar percentage of hydrogen in the hydrogen and carbon monoxide mixture varying from 5% to 100%, for an unburned mixture temperature of 323K, and under atmospheric pressure. At a given equivalence ratio, the effect of varying amount of water vapor addition on the measured laminar flame speed is demonstrated. The experimental laminar flame speeds are also compared with computed values using chemical kinetic mechanisms reported in the literature. It is found that laminar flame speed varies non-monotonically with addition of water for the carbon monoxide rich mixtures. It first increases with increasing amount of water addition, reaches a maximum value, and then decreases. An integrated reaction path analysis is further conducted to understand the controlling mechanism responsible for the non-monotonic variation in laminar flame speed due to water addition. On the other hand, for higher values of H2/CO ratio the laminar flame speed monotonically decreases with increasing water addition. It is shown that the competition between the chemical and thermal effects of water addition leads to the observed response. Furthermore, reaction rate sensitivity analysis as well as binary diffusion coefficient sensitivity analysis are conducted to identify the possible sources of discrepancy between the experimental and predicted values. The sensitivity results indicate that the reaction rate constant of H2+OH=H2O+H is worth revisiting and refinement of binary diffusion coefficient data of N2-H2O, N2-H2, and H2-H2O pairs can be considered. © 2010 The Combustion Institute.

Since their introduction to clinical practice in the 1950s, sulfonylureas have been widely prescribed for use in patients with type 2 diabetes. Of all the other medications currently available for clinical use, only metformin has been used more frequently. However, several new drug classes have emerged that are reported to have equal glucose-lowering efficacy and greater safety when added to treatment of patients in whom metformin monotherapy is no longer sufficient. Moreover, current arguments also suggest that the alternative drugs may be superior to sulfonylureas with regard to the risk of cardiovascular complications. Thus, while there is universal agreement that metformin should remain the first-line pharmacologic therapy for those in whom lifestylemodification is insufficient to control hyperglycemia, there is no consensus as to which drug should be added to metformin. Therefore, given the current controversy, we provide a Point-Counterpoint on this issue. In the preceding point narrative, Dr. Abrahamson provides his argument suggesting that avoiding use of sulfonylureas as a class of medication as an add-on to metformin is not appropriate as there are many patients whose glycemic control would improve with use of these drugs with minimal risk of adverse events. In the counterpoint narrative below, Dr. Genuth suggests there is no longer a need for sulfonylureas to remain a first-line addition to metformin for those patients whose clinical characteristics are appropriate and whose health insurance and/or financial resources make an alternative drug affordable. © 2015 by the American Diabetes Association.

Mariotti D.,University of Ulster | Sankaran R.M.,Case Western Reserve University
Journal of Physics D: Applied Physics | Year: 2011

Low-pressure, low-temperature plasmas are widely used for materials applications in industries ranging from electronics to medicine. To avoid the high costs associated with vacuum equipment, there has always been a strong motivation to operate plasmas at higher pressures, up to atmospheric. However, high-pressure operation of plasmas often leads to instabilities and gas heating, conditions that are unsuitable for materials applications. The recent development of microscale plasmas (i.e. microplasmas) has helped realize the sustainment of stable, non-thermal plasmas at atmospheric pressure and enable low-cost materials applications. There has also been an unexpected benefit of atmospheric-pressure operation: the potential to fabricate nanoscale materials which is not possible by more conventional, low-pressure plasmas. For example, in a high-pressure environment, nanoparticles can be nucleated in the gas phase from vapour (or solid metal) precursors. Alternatively, non-thermal, atmospheric-pressure plasmas can be coupled with liquids such as water or ethanol to nucleate and modify solution-phase nanoparticles. In this perspective paper, we review some of these recent efforts and provide an outlook for the rapidly emerging field of atmospheric-pressure plasmas for nanofabrication. © 2011 IOP Publishing Ltd.

Davis M.P.,Case Western Reserve University
Expert Review of Neurotherapeutics | Year: 2011

The purpose of this article is to systematically review the use of fentanyl as an analgesic for breakthrough pain. This article found that the oral transmucosal fentanyl (OTFC) had a quicker onset to analgesia than oral immediate-release opioids. Intranasal fentanyl (INFS) had a quicker onset to analgesia than buccal tablets, which in turn had a quicker onset to analgesia than OTFC. Patient acceptance and global rating of efficacy were greater for INFS than for buccal fentanyl. OTFC and INFS have been used effectively to reduce acute pain in children who are opioid-naive. Abuse and addiction to OTFC, fentanyl buccal tablets and INFS was low, owing to patient selection. © 2011 Expert Reviews Ltd.

Shaikh A.G.,Case Western Reserve University
Journal of Neurophysiology | Year: 2012

The interaction between the magnetic field of a magnetic resonance imaging (MRI) machine and ion currents within the inner-ear endolymph results in a Lorentz force. This force produces a pressure that pushes on the cupula within the semicircular canals causing nystagmus and vertigo. Here I discuss several implications of this unique and noninvasive way to stimulate the vestibular system in experimental neurophysiology and clinical neurology. © 2012 the American Physiological Society.

McHenry C.R.,Case Western Reserve University | Phitayakorn R.,Harvard University
Oncologist | Year: 2011

Follicular neoplasms of the thyroid gland include benign follicular adenoma and follicular carcinoma. Currently, a follicular carcinoma cannot be distinguished from a follicular adenoma based on cytologic, sonographic, or clinical features alone. The pathogenesis of follicular carcinoma may be related to iodine deficiency and various oncogene and/or microRNA activation. Advances in molecular testing for genetic mutations may soon allow for preoperative differentiation of follicular carcinoma from follicular adenoma. Until then, a patient with a follicular neoplasm should undergo a diagnostic thyroid lobectomy and isthmusectomy, which is definitive treatment for a benign follicular adenoma or a minimally invasive follicular cancer. Additional therapy is necessary for invasive follicular carcinoma including completion thyroidectomy, postoperative radioactive iodine ablation, whole body scanning, and thyrotropin suppressive doses of thyroid hormone. Less than 10% of patients with follicular carcinoma will have lymph node metastases, and a compartment-oriented neck dissection is reserved for patients with macroscopic disease. Regular follow-up includes history and physical examination, cervical ultrasound and serum TSH, and thyroglobulin and antithyroglobulin antibody levels. Other imaging studies are reserved for patients with an elevated serum thyroglobulin level and a negative cervical ultrasound. Systemic metastases most commonly involve the lung and bone and less commonly the brain, liver, and skin. Microscopic metastases are treated with high doses of radioactive iodine. Isolated macroscopic metastases can be resected with an improvement in survival. The overall ten-year survival for patients with minimally invasive follicular carcinoma is 98% compared with 80% in patients with invasive follicular carcinoma. © AlphaMed Press.

Jackman J.E.,Ohio State University | Gott J.M.,Case Western Reserve University | Gray M.W.,Dalhousie University
RNA | Year: 2012

The tRNA His guanylyltransferase (Thg1) family of enzymes comprises members from all three domains of life (Eucarya, Bacteria, Archaea). Although the initial activity associated with Thg1 enzymes was a single 3′-to-5′ nucleotide addition reaction that specifies tRNA His identity in eukaryotes, the discovery of a generalized base pair-dependent 3′-to-5′ polymerase reaction greatly expanded the scope of Thg1 family-catalyzed reactions to include tRNA repair and editing activities in bacteria, archaea, and organelles. While the identification of the 3′-to-5′ polymerase activity associated with Thg1 enzymes is relatively recent, the roots of this discovery and its likely physiological relevance were described ∼30 yr ago. Here we review recent advances toward understanding diverse Thg1 family enzyme functions and mechanisms. We also discuss possible evolutionary origins of Thg1 family-catalyzed 3′-to-5′ addition activities and their implications for the currently observed phylogenetic distribution of Thg1-related enzymes in biology. Published by Cold Spring Harbor Laboratory Press. Copyright © 2012 RNA Society.

Niemeyer K.E.,Case Western Reserve University | Sung C.-J.,University of Connecticut
Combustion and Flame | Year: 2011

The importance of graph search algorithm choice to the directed relation graph with error propagation (DRGEP) method is studied by comparing basic and modified depth-first search, basic and R-value-based breadth-first search (RBFS), and Dijkstra's algorithm. By using each algorithm with DRGEP to produce skeletal mechanisms from a detailed mechanism for n-heptane with randomly-shuffled species order, it is demonstrated that only Dijkstra's algorithm and RBFS produce results independent of species order. In addition, each algorithm is used with DRGEP to generate skeletal mechanisms for n-heptane covering a comprehensive range of autoignition conditions for pressure, temperature, and equivalence ratio. Dijkstra's algorithm combined with a coefficient scaling approach is demonstrated to produce the most compact skeletal mechanism with a similar performance compared to larger skeletal mechanisms resulting from the other algorithms. The computational efficiency of each algorithm is also compared by applying the DRGEP method with each search algorithm on the large detailed mechanism for n-alkanes covering n-octane to n-hexadecane with 2115 species and 8157 reactions. Dijkstra's algorithm implemented with a binary heap priority queue is demonstrated as the most efficient method, with a CPU cost two orders of magnitude less than the other search algorithms. © 2010 The Combustion Institute.

Bedogni B.,Case Western Reserve University
Pigment Cell and Melanoma Research | Year: 2014

The Notch signaling pathway is an evolutionarily conserved, intercellular signaling cascade. Notch was first described in the early 1900s when a mutant Drosophila showed notches on the wing margins. Studies of the role of Notch signaling have ever since flourished, and the pleiotropic nature of the Notch gene is now evident. Indeed, the Notch signaling pathway plays key roles in cell fate decisions, tissue patterning, and morphogenesis during development. However, deregulation of this pathway can contribute to cell transformation and tumorigenesis. Several reports have now highlighted the role of Notch signaling in a variety of malignancies where Notch can either be an oncogene or a tumor suppressor depending on the cell context. Here, we summarize the major components of Notch signaling with an aim to emphasize the contribution of deregulated Notch signaling in melanomagenesis. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Robinson S.,Case Western Reserve University
Journal of Neurosurgery: Pediatrics | Year: 2012

Object. Preterm infants are at risk for perinatal complications, including germinal matrix-intraventricular hemorrhage (IVH) and subsequent posthemorrhagic hydrocephalus (PHH). This review summarizes the current understanding of the epidemiology, pathophysiology, management, and outcomes of IVH and PHH in preterm infants. Methods. The MEDLINE database was systematically searched using terms related to IVH, PHH, and relevant neurosurgical procedures to identify publications in the English medical literature. To complement information from the systematic search, pertinent articles were selected from the references of articles identified in the initial search. Results. This review summarizes the current knowledge regarding the epidemiology and pathophysiology of IVH and PHH, primarily using evidence-based studies. Advances in obstetrics and neonatology over the past few decades have contributed to a marked improvement in the survival of preterm infants, and neurological morbidity is also starting to decrease. The incidence of IVH is declining, and the incidence of PHH will likely follow. Currently, approximately 15% of preterm infants who suffer severe IVH will require permanent CSF diversion. The clinical presentation and surgical management of symptomatic PHH with temporary ventricular reservoirs (ventricular access devices) and ventriculosubgaleal shunts and permanent ventriculoperitoneal shunts are discussed. Preterm infants who develop PHH that requires surgical treatment remain at high risk for other related neurological problems, including cerebral palsy, epilepsy, and cognitive and behavioral delay. This review highlights numerous opportunities for further study to improve the care of these children. Conclusions. A better grasp of the pathophysiology of IVH is beginning to impact the incidence of IVH and PHH. Neonatologists conduct rigorous Class I and II studies to advance the outcomes of preterm infants. The need for well-designed multicenter trials is essential because of the declining incidence of IVH and PHH, variations in referral patterns, and neonatal ICU and neurosurgical management. Well-designed multicenter trials will eventually produce evidence to enable neurosurgeons to provide their smallest, most vulnerable patients with the best practices to minimize perioperative complications and permanent shunt dependence, and most importantly, optimize long-term neurodevelopmental outcomes.

Tian C.,Case Western Reserve University
PloS one | Year: 2012

Otitis media is a middle ear disease common in children under three years old. Otitis media can occur in normal individuals with no other symptoms or syndromes, but it is often seen in individuals clinically diagnosed with genetic diseases such as CHARGE syndrome, a complex genetic disease caused by mutation in the Chd7 gene and characterized by multiple birth defects. Although otitis media is common in human CHARGE syndrome patients, it has not been reported in mouse models of CHARGE syndrome. In this study, we report a mouse model with a spontaneous deletion mutation in the Chd7 gene and with chronic otitis media of early onset age accompanied by hearing loss. These mice also exhibit morphological alteration in the Eustachian tubes, dysregulation of epithelial proliferation, and decreased density of middle ear cilia. Gene expression profiling revealed up-regulation of Muc5ac, Muc5b and Tgf-β1 transcripts, the products of which are involved in mucin production and TGF pathway regulation. This is the first mouse model of CHARGE syndrome reported to show otitis media with effusion and it will be valuable for studying the etiology of otitis media and other symptoms in CHARGE syndrome.

Kingsberg S.A.,University Hospitals Case Medical Center | Rezaee R.L.,Case Western Reserve University
Menopause | Year: 2013

Objective: This review aims to describe low sexual desire (1) as a construct within theoretical models of female sexual response, (2) as a sexual disorder with evolving or competing nosology between the DSM-IV-TR and the DSM 5, and (3) as a clinical condition that healthcare providers need to manage, and the current status of treatment options. Methods: We conducted a literature review of the epidemiology, diagnosis, and treatment of low sexual desire/hypoactive sexual desire disorder (HSDD). Results: The prevalence rate of low sexual desire is high, reaching 43%, whereas that of HSDD comes close to 10%. The DSM 5 categories of female sexual disorders include female sexual interest/arousal disorder, which is a combination of the DSM-IV-TR disorders HSDD and female sexual arousal disorder. Treatment paradigms vary and are individualized based on the biopsychosocial components of desire that are compromised in a woman. The two primary approaches to treating HSDD are psychotherapy/sex therapy (individual or couples) and pharmacotherapy. To date, there are no Food and Drug Administration-approved pharmacologic treatments. However, four investigational drugs are in mid- to late-stage clinical trial development. Conclusions: Low sexual desire is the most prevalent sexual problem in women and should be assessed and treated by healthcare professionals. Currently, there are only modest evidence-based nonpharmacologic treatment options and no approved pharmacologic options. Despite these treatment limitations, healthcare providers can address many of the sexual health concerns of women. © 2013 by The North American Menopause Society.

Overholser J.C.,Case Western Reserve University
Journal of Contemporary Psychotherapy | Year: 2014

The present article confronts several areas of concern that could undermine the integrity of clinical psychology. A critical review is provided in the hopes of pushing for change, primarily in the way that academic clinical psychologists conduct their work. Six standards are proposed toward which all members of the clinical psychology faculty should aspire. First, it is important for clinical psychologists to integrate the science and practice of psychology. Second, the training and supervision of all applied skills in clinical psychology assumes that the instructor has remained active in the front-lines delivery of clinical services. Third, it is important to conduct research on clinical samples, striving to understand the mind of patients who are struggling with mental illness. Fourth, it is helpful to retain a modest and flexible view about the potential benefits derived from empirically supported treatments. Fifth, even when accepting a bio-psycho-social model, psychologists should maintain a dominant focus on psychological factors. Sixth, ethical issues pervade many aspects of a professor’s work, and it is important to avoid dual relationships that could impair objectivity and professionalism. If these six standards are widely adopted, clinical psychology can remain a strong and vibrant field. © 2014, Springer Science+Business Media New York.

Gill H.S.,Case Western Reserve University
Acta Crystallographica Section F: Structural Biology and Crystallization Communications | Year: 2010

The environment of individual tryptophans in known protein structures and the effectiveness of four commercial robotic UV microscopes to illuminate tryptophan-containing protein crystals by either tryptophan fluorescence (epi-illumination) or absorbance (transmission) are evaluated. In agreement with other studies, tryptophan residues are found on average to be largely buried in protein structures (with ∼84% of their surface area buried) and to be surrounded by partially polar microenvironments (with ∼43% of their surface area covered by polar residues), which suggests an inherent degree of fluorescence signal quenching. In bacterial genomes, up to one-third (∼18.5% on average) of open reading frames are deficient in tryptophan. In the laboratory, because of the attenuation of UV light by the media commonly used in sitting-drop and hanging-drop crystallization trials, it was often necessary to simplify the light path by manually removing or inverting the supporting media. Prolonged exposure (minutes) to UV light precipitates some protein samples. The absorbance spectra of many commercially available media in crystallization trials are presented. The advantages of using tryptophan absorbance over fluorescence for characterizing crystals are discussed. © 2010 International Union of Crystallography All rights reserved.

Malakooti B.,Case Western Reserve University
Journal of Intelligent Manufacturing | Year: 2012

Decision making is concerned with evaluating and/or ranking possible alternatives of action. In this paper, we develop a model for the process of decision making. Understanding the decision process can provide insights into how humans make decisions, understand their decision making approaches, and how they differ from each other. We believe that decision makers who are conscious of their decision process types can make more effective and balanced decisions. In this paper, we present a new decision process model based on the following four dimensions where each dimension is defined by two opposing types: Information Processing (Concrete and Abstract), Alternative Generation (Adaptive and Constructive), Alternative Evaluation (Moderate and Bold), and Decision Closure (Organized and Flexible). Furthermore, an approach for assessing each of the four decision process types by a mathematical function is presented. In a much boarder scope than decision making, these assessed functions can be used to evaluate and rank alternatives. The decision process model can also be used in conjunction with multiple criteria decision making and multiple objective optimization. The model can also be used to explain the reasons that the classical decision making models fail to describe real decision makers' behavior, and mistakenly label such behavior as irrational. The proposed decision process model can be used for developing new behavioral, rational, and intelligent decision making theories and approaches. Extensions of this work may include group decision making, organizational decision making, team formation, and risk behavior analysis. Experimental results of overfour hundred engineering students are reported. A web site has been developed for users (http://car.cwru.edu/decision/). © Springer Science+Business Media, LLC 2010.

Martin R.J.,Case Western Reserve University
Comprehensive Physiology | Year: 2012

Apnea of prematurity is a significant problem due to immaturity of the central neural control circuitry responsible for integrating afferent input and central rhythm. In this review, we provide an overview of the pathogenesis of apnea of prematurity--including our current understanding of the role that afferent input to the brain stem plays in synergy with the central pattern generation circuitry in the emergence of apnea of prematurity. We then discuss the interplay of apnea, bradycardia, desaturation, as well as the genesis of central, mixed, and obstructive apnea. Finally, we provide a summary of the physiological basis for current therapeutic approaches to treating apnea of prematurity, and conclude with an overview of proposed long-term consequences of the resultant intermittent hypoxic episodes. © 2012 American Physiological Society

Berger N.A.,Case Western Reserve University
Annals of the New York Academy of Sciences | Year: 2014

Overweight and obesity have reached pandemic levels on a worldwide basis and are associated with increased risk and worse prognosis for many but not all malignancies. Pathophysiologic processes that affect this association are reviewed, with a focus on the relationship between type 2 diabetes mellitus and cancer, lessons learned from the use of murine models to study the association, the impact of obesity on pancreatic cancer, the effects of dietary fats and cholesterol on cancer promotion, and the mechanisms by which the intestinal microbiome affects obesity and cancer. © 2014 New York Academy of Sciences.

Beall C.M.,Case Western Reserve University
American Journal of Human Biology | Year: 2013

Objectives: This report presents a perspective on the broad research trends in the biology of human populations at high-altitude and their contributions to the improved understanding of evolution and adaptation. A focus is on the research that has occurred over the past 50 years of anthropological fieldwork on the Andean, Tibetan, and, to a lesser extent, the East African plateaus. Methods: With an emphasis on fieldwork studies, this report presents and illustrates major concepts and research designs in published high-altitude studies. Results: Early use of a single population-multiple stress research design focused on Andean Quechua, sometimes in comparison with European or admixed Andean-European samples. That design identified physical and sociocultural environmental factors including cold and under nutrition as well as high-altitude hypobaric hypoxia. Researchers accumulated evidence supporting the hypothesis of four modes of adaptation to a complex Andean highland environment: cultural, acclimatization, developmental, and genetic. The discovery that Andean biological patterns were not replicated among Tibetan highlanders stimulated research on the extent and origins of the contrasts. It also shifted emphasis to a multiple population - single stress study design. The discovery of oxygen-homeostasis-associated genetic loci and traits in all multicellular animals has transformed high-altitude research. Paradoxically, genomic analyses identifying the pertinent biological pathways are likely to return interest to environmental factors other than hypoxia. Conclusions: Details of the proximate mechanisms, the biochemical, and physiological processes underlying the three modes of biological adaptation are accumulating. Better understanding of oxygen-homeostasis processes leads to questions about crossadaptation with other environmental factors. The particulars of the ultimate mechanisms, the evolutionary, and microevolutionary history underlying the population differences are also emerging. For example, similar hemoglobin phenotypes among Tibetan and Ethiopian Amhara highlanders associate with different genetic loci and the variants at those loci are present in most populations regardless of altitude. Continuing fieldwork is urgent because modernization and migration are changing the traditional ways of life and patterns of exposure to the environment among highlanders everywhere. Am. J. Hum. Biol. 25:141-147, 2013. © 2013 Wiley Periodicals, Inc.

Mak K.F.,Columbia University | Shan J.,Case Western Reserve University | Heinz T.F.,Columbia University
Physical Review Letters | Year: 2011

Significant excitonic effects were observed in graphene by measuring its optical conductivity in a broad spectral range including the two-dimensional π-band saddle-point singularities in the electronic structure. The strong electron-hole interactions manifest themselves in an asymmetric resonance peaked at 4.62 eV, which is redshifted by nearly 600 meV from the value predicted by ab initio GW calculations for the band-to-band transitions. The observed excitonic resonance is explained within a phenomenological model as a Fano interference of a strongly coupled excitonic state and a band continuum. Our experiment also showed a weak dependence of the excitonic resonance in few-layer graphene on layer thickness. This result reflects the effective cancellation of the increasingly screened repulsive electron-electron (e-e) and attractive electron-hole (e-h) interactions. © 2011 American Physical Society.

Weiss M.A.,Case Western Reserve University
FEBS Letters | Year: 2013

Dominant mutations in the human insulin gene can lead to pancreatic β-cell dysfunction and diabetes mellitus due to toxic folding of a mutant proinsulin. Analogous to a classical mouse model (the Akita mouse), this monogenic syndrome highlights the susceptibility of human β-cells to endoreticular stress due to protein misfolding and aberrant aggregation. The clinical mutations directly or indirectly perturb native disulfide pairing. Whereas the majority of mutations introduce or remove a cysteine (leading in either case to an unpaired residue), non-cysteine-related mutations identify key determinants of folding efficiency. Studies of such mutations suggest that the evolution of insulin has been constrained not only by its structure and function, but also by the susceptibility of its single-chain precursor to impaired foldability. © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Devendra G.P.,University of California at San Francisco | Rane A.A.,Case Western Reserve University | Krasuski R.A.,Cleveland Clinic
JACC: Cardiovascular Interventions | Year: 2012

Objectives: This study was designed to assess the prevalence of provoked exercise desaturation (PED) in patients with patent foramen ovale (PFO) referred for cardiovascular evaluation and to evaluate the impact of PFO closure. Background: Platypnea orthodeoxia syndrome is a rare, mechanistically obscure consequence of PFO that results in oxygen desaturation during postural changes. In our clinical experience, however, it is far less common than desaturation during exercise. Methods: This was a single-center prospective study of 50 patients with newly diagnosed PFO. Each patient underwent standardized assessment for arterial oxygen saturation with pulse oximetry during postural changes and stair climbing exercise. Provoked exercise desaturation was defined as a desaturation of at least 8% from baseline to <90%. All patients who underwent closure were reevaluated 3 months after the procedure. Those with baseline PED were similarly reassessed for desaturation at follow-up. Results: Mean age of the cohort was 46 ± 17 years, 74% were female, 30% had migraines, and 48% had experienced a cerebrovascular event. Seventeen patients (34%) demonstrated PED. Provoked exercise desaturation patients seemed demographically similar to non-PED patients. Ten PED patients underwent PFO closure (2 surgical, and 8 percutaneous). Drop in oxygen saturation was improved by an average of 10.1 ± 4.2% after closure (p < 0.001), and New York Heart Association functional class improved by a median of 1.5 classes (interquartile range: 0.75 to 2.00, p = 0.008). Conclusions: One-third of patients referred for assessment of PFO experience oxygen desaturation during stair exercise. Closure of PFO seems to ameliorate this phenomenon and improve functional status. © 2012 American College of Cardiology Foundation.

De Rham C.,University of Geneva | Gabadadze G.,New York University | Tolley A.J.,Case Western Reserve University
Physical Review Letters | Year: 2011

We construct four-dimensional covariant nonlinear theories of massive gravity which are ghost-free in the decoupling limit to all orders. These theories resum explicitly all the nonlinear terms of an effective field theory of massive gravity. We show that away from the decoupling limit the Hamiltonian constraint is maintained at least up to and including quartic order in nonlinearities, hence excluding the possibility of the Boulware-Deser ghost up to this order. We also show that the same remains true to all orders in a similar toy model. © 2011 American Physical Society.

Kelly A.K.W.,Case Western Reserve University
Current Sports Medicine Reports | Year: 2011

Physical activity can play a vital role in the treatment and prevention of many of the long-term effects of childhood cancer and cancer therapy. Specifically, physical activity may attenuate the long-term risk for adverse cardiovascular effects, low bone density, obesity, and poor quality-of-life measures. Physicians caring for long-term survivors of cancer should be prepared to evaluate the survivor's risk for long-term effects and provide accurate advice regarding the prescription of physical activity for the management and prevention of these problems. Knowing when physical activity prescription can help mitigate the late effects of childhood cancer and cancer therapy, and the barriers to physical activity for survivors, will help physicians provide quality care to childhood cancer survivors. Copyright © 2011 by the American College of Sports Medicine.

Xu K.,Case Western Reserve University
Advances in experimental medicine and biology | Year: 2011

We investigated the effect of a heat-shock protein co-inducer, arimoclomol (CytRx, LA, CA), on hypoxia-adaptive responses using a rat model of simulated altitude exposure (hypobaric hypoxia).Cognitive function was measured using a T-maze and an object recognition test.Motor function was measured using an inclined-screen test and an adhesion removal test. Immunohistochemical analyses were assessed in brain for heat-shock protein 70 (HSP 70), intercellular adhesion molecule 1 (ICAM- 1) and apoptosis (TUNEL staining). Results show that both cognitive and motor performances were improved in rats treated with arimoclomol during hypoxic exposure; the hypoxia-induced expression of HSP70 and ICAM-1, and TUNEL-positive cells were reduced in brain with the treatment.Our data suggest that the arimoclomol treatment reduces the hypoxia-induced stress in brain tissue, and also improves the behavioral performance in rats during hypoxic adaptation.

Hickman Jr. R.L.,Case Western Reserve University
AACN advanced critical care | Year: 2010

The uncertain trajectory of chronic critical illness exposes the patient's family to heightened levels of psychological distress. Symptoms of psychological distress affect more than half of family members exposed to the patient's chronic critical illness. Although symptoms often dissipate over time, a significant proportion of family members will remain at moderate to high risk for psychological distress well after the patient's death or discharge from the intensive care unit. Family members of chronically critically ill patients are often involved in the decision making for the patients. Irrational or uninformed decision making can occur when family members experience high levels of psychological distress. Attention to the psychological needs and provision of support to family members enhance the formulation of treatment decisions consistent with the patient's preferences and mitigate unnecessary resource use. In this article, the impact of chronic critical illness on family members' risk for depression, anxiety, and posttraumatic stress disorder is described and a review of evidence-based strategies to support the psychological needs of family members coping with a patient's chronic critical illness is provided.

Dalton J.E.,Health Outcomes Sciences | Dalton J.E.,Case Western Reserve University
Statistics in Medicine | Year: 2013

Calibration in binary prediction models, that is, the agreement between model predictions and observed outcomes, is an important aspect of assessing the models' utility for characterizing risk in future data. A popular technique for assessing model calibration first proposed by D. R. Cox in 1958 involves fitting a logistic model incorporating an intercept and a slope coefficient for the logit of the estimated probability of the outcome; good calibration is evident if these parameters do not appreciably differ from 0 and 1, respectively. However, in practice, the form of miscalibration may sometimes be more complicated. In this article, we expand the Cox calibration model to allow for more general parameterizations and derive a relative measure of miscalibration between two competing models from this more flexible model. We present an example implementation using data from the US Agency for Healthcare Research and Quality. © 2012 John Wiley & Sons, Ltd.

Thompson G.H.,Case Western Reserve University
Journal of Pediatric Orthopaedics | Year: 2011

Background: Femoral head containment in Legg-Calvé-Perthes disease (LCPD) can be either surgical or nonsurgical. The Salter or innominate osteotomy is a common method of surgical containment. This is a review of the technique and results of this osteotomy in LCPD. Methods: The operative technique is relatively simple but requires considerable experience to perform correctly. It can be used alone or in combination with a proximal femoral varus osteotomy. The indications for a Salter osteotomy are essentially the same as in any form of containment treatment in LCPD. This includes: age at clinical onset of 6 to 10 years (perhaps, 5 y in female), more than one-half capital femoral epiphyseal involvement (Catterall groups III or IV, Salter-Thompson group B, and lateral pillar groups B, B/C, and C), and a good range of hip motion before surgery. The osteotomy alone is usually indicated for younger children with recent clinical onset and no femoral head deformity or subluxation. The combined procedure is better suited for older children and those with subluxation or a deformed femoral head. Results: Currently, the results of treatment are best determined at skeletal maturity using the Stulberg et al classification. When used alone, approximately 90% to 95% of the involved hips will have achieved a Stulberg et al class I, II, or III result. When combined with a proximal femoral varus osteotomy, the results are somewhat less because of the older age at onset and/or the presence of a deformed hip. Conclusions: The Salter osteotomy in LCPD is an effective method of surgical treatment that can alter the natural history of the disease process. The main advantage of this osteotomy is its effect on femoral head remodeling during remaining growth. Copyright © 2011 by Lippincott Williams & Wilkins.

Caplan A.I.,Case Western Reserve University | West M.D.,Biotime, Inc.
Stem Cells Translational Medicine | Year: 2014

To stimulate a broad discussion between academics, practicing physicians, corporate managers, and members of the regulatory community, we describe a proposal for a new regulatory pathway for human cell- and tissue-based products. The new components of the pathway are intended to accelerate patient access to a wide array of novel therapeutics, strengthen R&D infrastructure, and expand patient numbers and timelines for efficacy testing through a transparent and publicly accessible website for real-time reporting of outcome data and 5- to 10-year, long-term follow-up. © AlphaMed Press 2014.

Kubit B.,University of California at Davis | Jack A.I.,Case Western Reserve University
Frontiers in Human Neuroscience | Year: 2013

The right temporo-parietal junction (rTPJ) has been associated with two apparently disparate functional roles: in attention and in social cognition. According to one account, the rTPJ initiates a "circuit-breaking" signal that interrupts ongoing attentional processes, effectively reorienting attention. It is argued this primary function of the rTPJ has been extended beyond attention, through a process of evolutionarily cooption, to play a role in social cognition. We propose an alternative account, according to which the capacity for social cognition depends on a network which is both distinct from and in tension with brain areas involved in focused attention and target detection: the default mode network. Theory characterizing the rTPJ based on the area's purported role in reorienting may be falsely guided by the co-occurrence of two distinct effects in contiguous regions: activation of the supramarginal gyrus (SMG), associated with its functional role in target detection; and the transient release, during spatial reorienting, of suppression of the angular gyrus (AG) associated with focused attention. Findings based on meta-analysis and resting functional connectivity are presented which support this alternative account. We find distinct regions, possessing anti-correlated patterns of resting connectivity, associated with social reasoning (AG) and target detection (SMG) at the rTPJ. The locus for reorienting was spatially intermediate between the AG and SMG and showed a pattern of connectivity with similarities to social reasoning and target detection seeds. These findings highlight a general methodological concern for brain imaging. Given evidence that certain tasks not only activate some areas but also suppress activity in other areas, it is suggested that researchers need to distinguish two distinct putative mechanisms, either of which may produce an increase in activity in a brain area: functional engagement in the task versus release of suppression. © 2013 Kubit and Jack.

Zigmond R.E.,Case Western Reserve University
Frontiers in Molecular Neuroscience | Year: 2012

Adult peripheral neurons, in contrast to adult central neurons, are capable of regeneration after axonal damage. Much attention has focused on the changes that accompany this regeneration in two places, the distal nerve segment (where phagocytosis of axonal debris, changes in the surface properties of Schwann cells, and induction of growth factors and cytokines occur) and the neuronal cell body (where dramatic changes in cell morphology and gene expression occur). The changes in the axotomized cell body are often referred to as the "cell body response." The focus of the current review is a family of cytokines, the glycoprotein 130 (gp130) cytokines, which produce their actions through a common gp130 signaling receptor and which function as injury signals for axotomized peripheral neurons, triggering changes in gene expression and in neurite outgrowth. These cytokines play important roles in the responses of sympathetic, sensory, and motor neurons to injury. The best studied of these cytokines in this context are leukemia inhibitory factor (LIF) and interleukin (IL)-6, but experiments with conditional gp130 knockout animals suggest that other members of this family, not yet determined, are also involved. The primary gp130 signaling pathway shown to be involved is the activation of Janus kinase (JAK) and the transcription factors Signal Transducers and Activators of Transcription (STAT), though other downstream pathways such as mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) may also play a role. gp130 signaling may involve paracrine, retrograde, and autocrine actions of these cytokines. Recent studies suggest that manipulation of this cytokine system can also stimulate regeneration by injured central neurons. © 2012 Zigmond.

Interactions among genomic loci (also known as epistasis) have been suggested as one of the potential sources of missing heritability in single locus analysis of genome-wide association studies (GWAS). The computational burden of searching for interactions is compounded by the extremely low threshold for identifying significant p-values due to multiple hypothesis testing corrections. Utilizing prior biological knowledge to restrict the set of candidate SNP pairs to be tested can alleviate this problem, but systematic studies that investigate the relative merits of integrating different biological frameworks and GWAS data have not been conducted. We developed four biologically based frameworks to identify pairwise interactions among candidate SNP pairs as follows: (1) for each human protein-coding gene, a set of SNPs associated with that gene was constructed providing a gene-based interaction model, (2) for each known biological pathway, a set of SNPs associated with the genes in the pathway was constructed providing a pathway-based interaction model, (3) a set of SNPs associated with genes in a disease-related subnetwork provides a network-based interaction model, and (4) a framework is based on the function of SNPs. The last approach uses expression SNPs (eSNPs or eQTLs), which are SNPs or loci that have defined effects on the abundance of transcripts of other genes. We constructed pairs of eSNPs and SNPs located in the target genes whose expression is regulated by eSNPs. For all four frameworks the SNP sets were exhaustively tested for pairwise interactions within the sets using a traditional logistic regression model after excluding genes that were previously identified to associate with the trait. Using previously published GWAS data for type 2 diabetes (T2D) and the biologically based pair-wise interaction modeling, we identify twelve genes not seen in the previous single locus analysis. We present four approaches to detect interactions associated with complex diseases. The results show our approaches outperform the traditional single locus approaches in detecting genes that previously did not reach significance; the results also provide novel drug targets and biomarkers relevant to the underlying mechanisms of disease.

Akolkar R.,Case Western Reserve University
Journal of Power Sources | Year: 2013

Dendritic growth of lithium during galvanostatic electrodeposition is modeled. The time-dependent concentration distribution near the lithium surface is computed by numerically solving the transport equation inside the diffusion boundary layer. The dendrite propagation rate, i.e., the dendrite tip current density, is calculated by analyzing the various overpotentials that develop at the dendrite tip and at the flat electrode surface. The surface overpotential at the dendrite tip due to its radius of curvature is also incorporated in the model; however, for typical dendrite tip radii, it is shown that this surface overpotential is very small. The dendrite tip propagation rate predicted by the model agrees reasonably well with experimental data from the literature. For dendritic growth under pure activation control, a simplified analytical expression for the tip current density is derived. The analytical expression shows that dendritic growth is suppressed in systems that exhibit a lower charge transfer coefficient. © 2013 Elsevier B.V. All rights reserved.

Susswein A.J.,Bar - Ilan University | Chiel H.J.,Case Western Reserve University
Progress in Neurobiology | Year: 2012

Nitric oxide (NO) regulates Aplysia feeding by novel mechanisms, suggesting new roles for NO in controlling the behavior of higher animals. In Aplysia, (1) NO helps maintain arousal when produced by neurons responding to attempts to swallow food; (2) NO biases the motor system to reject and reposition food that resists swallowing; (3) if mechanically resistant food is not successfully swallowed, NO mediates the formation and expression of memories of food inedibility; (4) NO production at rest inhibits feeding, countering the effects of food stimuli exciting feeding. At a cellular level, NO-dependent channels contribute to the resting potential of neurons controlling food finding and food consumption. Increases in l-arginine after animals eat act as a post-feeding inhibitory signal, presumably by modulating NO production at rest. NO also signals non-feeding behaviors that are associated with feeding inhibition. Thus, depending on context, NO may enhance or inhibit feeding behavior. The different functions of NO may reflect the evolution of NO signaling from a response to tissue damage that was then elaborated and used for additional functions. These results suggest that in higher animals (1) elicited and background transmitter release may have similar effects; (2) NO may be produced by neurons without firing, influencing adjacent neurons; (3) background NO production may contribute to a neuron's resting potential; (4) circulating factors affecting background NO production may regulate spatially separated neurons; (5) l-arginine can be used to regulate neural activity; (6) l-arginine may be an effective post-ingestion metabolic signal to regulate feeding. © 2012 Elsevier Ltd.

Background: Independent data sources can be used to augment post-marketing drug safety signal detection. The vast amount of publicly available biomedical literature contains rich side effect information for drugs at all clinical stages. In this study, we present a large-scale signal boosting approach that combines over 4 million records in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and over 21 million biomedical articles.Results: The datasets are comprised of 4,285,097 records from FAERS and 21,354,075 MEDLINE articles. We first extracted all drug-side effect (SE) pairs from FAERS. Our study implemented a total of seven signal ranking algorithms. We then compared these different ranking algorithms before and after they were boosted with signals from MEDLINE sentences or abstracts. Finally, we manually curated all drug-cardiovascular (CV) pairs that appeared in both data sources and investigated whether our approach can detect many true signals that have not been included in FDA drug labels. We extracted a total of 2,787,797 drug-SE pairs from FAERS with a low initial precision of 0.025. The ranking algorithm combined signals from both FAERS and MEDLINE, significantly improving the precision from 0.025 to 0.371 for top-ranked pairs, representing a 13.8 fold elevation in precision. We showed by manual curation that drug-SE pairs that appeared in both data sources were highly enriched with true signals, many of which have not yet been included in FDA drug labels.Conclusions: We have developed an efficient and effective drug safety signal ranking and strengthening approach We demonstrate that large-scale combining information from FAERS and biomedical literature can significantly contribute to drug safety surveillance. © 2014 Xu and Wang; licensee BioMed Central Ltd.

Valadkhan S.,Case Western Reserve University
Progress in Molecular Biology and Translational Science | Year: 2013

The spliceosomes, large ribonucleoprotein (RNP) assemblies that remove the intervening sequences from pre-mRNAs, contain a large number of proteins and five small nuclear RNAs (snRNAs). One snRNA, U6, contains highly conserved sequences that are thought to be the functional counterparts of the RNA elements that form the active site of self-splicing group II intron ribozymes. An in vitro-assembled, protein-free complex of U6 with U2, the base-pairing partner in the spliceosomal catalytic core, can catalyze a two-step splicing reaction in the absence of all other spliceosomal factors, suggesting that the two snRNAs may form all or a large share of the spliceosomal active site. On the other hand, several spliceosomal proteins are thought to help in the formation of functionally required RNA-RNA interactions in the catalytic core. Whether they also contribute functional groups to the spliceosomal active site, and thus whether the spliceosomes are RNA or RNP enzymes remain uncertain. © 2013 Elsevier Inc.

Matisoff G.,Case Western Reserve University
Journal of Environmental Radioactivity | Year: 2014

Although 137Cs has been used extensively to study soil erosion and particle transport in the terrestrial environment, there has been much less work using excess or unsupported 210Pb (210Pbxs) to study the same processes. Furthermore, since 137Cs activities in soils are decreasing because of radioactive decay, some locations have an added complication due to the addition of Chernobyl-derived 137Cs, and the activities of 137Cs in the southern hemisphere are low, there is a need to develop techniques that use 210Pbxs to provide estimates of rates of soil erosion and particle transport. This paper reviews the current status of 210Pbxs methods to quantify soil erosion rates, to identify and partition suspended sediment source areas, and to determine the transport rates of particles in the terrestrial landscape. Soil erosion rates determined using 210Pbxs are based on the unsupported 210Pb (210Pbxs) inventory in the soil, the depth distribution of 210Pbxs, and a mass balance calibration ('conversion model') that relates the soil inventory to the erosion rate using a 'reference site' at which neither soil erosion nor soil deposition has occurred. In this paper several different models are presented to illustrate the effects of different model assumptions such as the timing, depth and rates of the surface soil mixing on the calculated erosion rates. The suitability of model assumptions, including estimates of the depositional flux of 210Pbxs to the soil surface and the post-depositional mobility of 210Pb are also discussed. 210Pb can be used as one tracer to permit sediment source area identification. This sediment 'fingerprinting' has been extended far beyond using 210Pb as a single radioisotope to include numerous radioactive and stable tracers and has been applied to identifying the source areas of suspended sediment based on underlying rock type, land use (roads, stream banks, channel beds, cultivated or uncultivated lands, pasture lands, forested lands, construction sites, undisturbed lands) or style of erosion (sheet wash, rills, bank). The transport time of particles in the terrestrial system can be estimated using 7Be/210Pbxs radionuclide ratios and from mass balance models of 210Pbxs and/or 7Be in streams. Watershed residence times can be calculated from the radionuclide inventory and the erosional loss rate. © 2014 Elsevier Ltd.

McGaugh S.S.,Case Western Reserve University
Canadian Journal of Physics | Year: 2014

The concordance model of cosmology, ΛCDM, provides a satisfactory description of the evolution of the universe and the growth of large-scale structure. Despite considerable effort, this model does not at present provide a satisfactory description of small-scale structure and the dynamics of bound objects like individual galaxies. In contrast, MOND provides a unique and predictively successful description of galaxy dynamics, but is mute on the subject of cosmology. Here I briefly review these contradictory world views, emphasizing the wealth of distinct interlocking lines of evidence that went into the development of ΛCDM while highlighting the practical impossibility that it can provide a satisfactory explanation of the observed MOND phenomenology in galaxy dynamics. I also briefly review the baryon budget in groups and clusters of galaxies where neither paradigm provides an entirely satisfactory description of the data. Relatively little effort has been devoted to the formation of structure in MOND; I review some of what has been done. While it is impossible to predict the power spectrum of the microwave background temperature fluctuations in the absence of a complete relativistic theory, the amplitude ratio of the first to second peaks was correctly predicted a priori. However, the simple model that makes this predictions does not explain the observed amplitude of the third and subsequent peaks (3e, 4e, ...). MOND anticipates that structure forms more quickly than in ΛCDM. This motivated the prediction that reionization would happen earlier in MOND than originally expected in ΛCDM, as subsequently observed. This also provides a natural explanation for massive, early clusters of galaxies and large, empty voids. However, it is far from obvious that the mass spectrum of galaxy clusters or the power spectrum of galaxies can be explained in MOND, two things that ΛCDM does well. Critical outstanding issues are the development of an acceptable relativistic parent theory for MOND, and the reality of the non-baryonic dark matter of ΛCDM. Do suitable dark matter particles exist, or are they a modern æther? © 2015 Published by NRC Research Press.

Yu D.,Nanyang Technological University | Goh K.,Nanyang Technological University | Wang H.,Nanyang Technological University | Wei L.,Nanyang Technological University | And 4 more authors.
Nature Nanotechnology | Year: 2014

Micro-supercapacitors are promising energy storage devices that can complement or even replace batteries in miniaturized portable electronics and microelectromechanical systems. Their main limitation, however, is the low volumetric energy density when compared with batteries. Here, we describe a hierarchically structured carbon microfibre made of an interconnected network of aligned single-walled carbon nanotubes with interposed nitrogen-doped reduced graphene oxide sheets. The nanomaterials form mesoporous structures of large specific surface area (396 m 2 g-1) and high electrical conductivity (102 S cm-1). We develop a scalable method to continuously produce the fibres using a silica capillary column functioning as a hydrothermal microreactor. The resultant fibres show a specific volumetric capacity as high as 305 F cm-3 in sulphuric acid (measured at 73.5 mA cm-3 in a three-electrode cell) or 300 F cm-3 in polyvinyl alcohol (PVA)/H 3 PO 4 electrolyte (measured at 26.7 mA cm-3 in a two-electrode cell). A full micro-supercapacitor with PVA/H 3 PO 4 gel electrolyte, free from binder, current collector and separator, has a volumetric energy density of ∼6.3 mWh cm-3 (a value comparable to that of 4 V-500 μAh thin-film lithium batteries) while maintaining a power density more than two orders of magnitude higher than that of batteries, as well as a long cycle life. To demonstrate that our fibre-based, all-solid-state micro-supercapacitors can be easily integrated into miniaturized flexible devices, we use them to power an ultraviolet photodetector and a light-emitting diode. © 2014 Macmillan Publishers Limited.

Kingsberg S.A.,Case Western Reserve University | Krychman M.L.,Southern California Center for Sexual Health and Survivorship Medicine
Journal of Sexual Medicine | Year: 2013

Introduction. Vaginal atrophy results from a decrease in circulating estrogen and is experienced by approximately 50% of postmenopausal women. Its symptoms affect multiple dimensions of genitopelvic health, sexuality, and overall quality of life. Nonhormonal over-the-counter treatments may provide temporary symptom relief, but the condition is progressive, and hormonal treatment may be warranted. Aim.: The study aims to review the literature and discuss the impact of atrophic vaginitis and various treatment options, including the resistance and barriers to the use of local estrogen therapy for atrophic vaginitis. This article also aims to provide a greater awareness of the condition and the difficulties in communicating effectively with patients, and to provide strategies to help healthcare professionals acquire effective communication skills to initiate a candid dialogue with patients who may be suffering in silence and may benefit from therapy. Methods.: This review was based on peer-reviewed publications on the topic of atrophic vaginitis and local estrogen therapy identified from key word searches of PubMed, in addition to landmark studies/surveys and treatment guidelines/recommendations on menopause available in the literature and on the Internet. Main Outcome Measures.: The main outcomes are the impact of atrophic vaginitis and the various treatment options, including the resistance and barriers to the use of local estrogen therapy. Results.: Minimally absorbed local vaginal estrogen therapy enables administration of estrogen doses much lower than systemic doses used for vasomotor symptoms. Local therapy is also the first-line pharmacologic treatment recommended by the North American Menopause and International Menopause Societies. Despite treatment options, the sensitive nature of the condition and embarrassment may prohibit or limit many women from openly discussing symptoms with healthcare professionals. Many are hesitant to initiate hormonal treatment because of safety concerns. Conclusions.: Healthcare professionals should initiate and encourage frank and candid conversation about vaginal atrophy at annual visits and provide follow-up and treatment as needed. © 2013 International Society for Sexual Medicine.

McGaugh S.S.,Case Western Reserve University | Schombert J.M.,University of Oregon
Astrophysical Journal | Year: 2015

We estimate the stellar masses of disk galaxies with two independent methods: a photometrically self-consistent color?mass-to-light ratio relation (CMLR) from population synthesis models, and the baryonic Tully?Fisher relation (BTFR) calibrated by gas-rich galaxies. These two methods give consistent results. The CMLR correctly converts distinct Tully?Fisher relations in different bands into the same BTFR. The BTFR is consistent with Mb ∝ Vf 4 over nearly six decades in mass, with no hint of a change in slope over that range. The intrinsic scatter in the BTFR is negligible, implying that the IMF of disk galaxies is effectively universal. The gas-rich BTFR suggests an absolute calibration of the stellar mass scale that yields nearly constant mass-to-light ratios in the near-infrared (NIR): 0.57 M⊙/ L⊙ in Ks and 0.45 M⊙/ L⊙ at 3.6 μm. There is only modest intrinsic scatter (∼0.12 dex) about these typical values. There is no discernible variation with color or other properties: the NIR luminosity is a good tracer of stellar mass. © 2015. The American Astronomical Society. All rights reserved.

Dai L.,Case Western Reserve University | Chang D.W.,Ulsan National Institute of Science and Technology | Baek J.-B.,Ulsan National Institute of Science and Technology | Lu W.,Energ2 Inc.
Small | Year: 2012

It is estimated that the world will need to double its energy supply by 2050. Nanotechnology has opened up new frontiers in materials science and engineering to meet this challenge by creating new materials, particularly carbon nanomaterials, for efficient energy conversion and storage. Comparing to conventional energy materials, carbon nanomaterials possess unique size-/surface-dependent (e.g., morphological, electrical, optical, and mechanical) properties useful for enhancing the energy-conversion and storage performances. During the past 25 years or so, therefore, considerable efforts have been made to utilize the unique properties of carbon nanomaterials, including fullerenes, carbon nanotubes, and graphene, as energy materials, and tremendous progress has been achieved in developing high-performance energy conversion (e.g., solar cells and fuel cells) and storage (e.g., supercapacitors and batteries) devices. This article reviews progress in the research and development of carbon nanomaterials during the past twenty years or so for advanced energy conversion and storage, along with some discussions on challenges and perspectives in this exciting field. Progress in the research and development of carbon nanomaterials during the past twenty years or so is reviewed with reference to their use in advanced energy conversion and storage applications. Some discussion of the challenges and perspectives in this exciting field is also presented. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Gilmore E.C.,Case Western Reserve University | Walsh C.A.,Howard Hughes Medical Institute
Wiley Interdisciplinary Reviews: Developmental Biology | Year: 2013

The study of human developmental microcephaly is providing important insights into brain development. It has become clear that developmental microcephalies are associated with abnormalities in cellular production, and that the pathophysiology of microcephaly provides remarkable insights into how the brain generates the proper number of neurons that determine brain size. Most of the genetic causes of 'primary' developmental microcephaly (i.e., not associated with other syndromic features) are associated with centrosomal abnormalities. In addition to other functions, centrosomal proteins control the mitotic spindle, which is essential for normal cell proliferation during mitosis. However, the brain is often uniquely affected when microcephaly genes are mutated implying special centrosomal-related functions in neuronal production. Although models explaining how this could occur have some compelling data, they are not without controversy. Interestingly, some of the microcephaly genes show evidence that they were targets of evolutionary selection in primates and human ancestors, suggesting potential evolutionary roles in controlling neuronal number and brain volume across species. Mutations in DNA repair pathway genes also lead to microcephaly. Double-stranded DNA breaks appear to be a prominent type of damage that needs to be repaired during brain development, yet why defects in DNA repair affect the brain preferentially and if DNA repair relates to centrosome function, are not clearly understood. © 2012 Wiley Periodicals, Inc.

Mansur D.B.,Case Western Reserve University
Expert Review of Anticancer Therapy | Year: 2014

Proton beams offer specific dosimetric advantages for radiation therapy. Their depth-dose relationship is characterized by the Bragg peak beyond which no dose is deposited. The elimination of exit dose for passively scattered proton beams results in greatly reduced low and intermediate doses to distant uninvolved normal tissues, but little or no difference in conformality of higher prescription doses immediately surrounding the targeted tissue. This approach is highly desirable in certain clinical scenarios such as the treatment of pediatric patients with curable malignancies for whom protons will theoretically reduce the risk of treatment related late effects. However, typical proton facilities are too large to be well integrated into most existing urban cancer centers where space is at a premium. The use of a new compact proton facility can more feasibly be incorporated into existing medical center space. In addition, they are associated with much lower cost than the typical mega-facility. The smaller capacity of this type of proton facility is quite reasonable as long as this limited and relatively expensive technology is reserved for those patients who stand to benefit the most. © 2014 Informa UK, Ltd.

Shojaei H.,Case Western Reserve University
Modern Pathology | Year: 2016

Yolk sac tumors occur at both gonadal and extra-gonadal sites. A recent case of ovarian endometrioid-pattern yolk sac tumor with strong diffuse expression of TTF-1 illustrated the potential for misdiagnosis due to divergent expression of endodermal lineage markers. The aim of this study was to investigate the expression of four divergent endodermal lineage markers, TTF-1, CDX2, Hep Par 1, and Napsin A, in gonadal and extra-gonadal yolk sac tumors of differing age, sex, and location (excluding foci of overt hepatoid differentiation). We identified 26 cases (5 ovarian, 15 testicular, and 6 extra-gonadal) containing yolk sac tumor as identified by typical histology and confirmed by positive immunohistochemical staining for alpha-fetoprotein and glypican-3. Mixed or ambiguous foci were confirmed by immunohistochemistry (SALL4 positive and Oct-4 negative). The relative proportion of three histologic patterns: reticular/cystic, solid/myxoid, and glandular was estimated. Percent positivity for the four divergent endodermal lineage markers was compared within yolk sac tumor areas according to site, age group, and histologic pattern. High-level (>25%) staining for one or more divergent endodermal lineage markers was seen in eleven cases: Hep Par 1 in seven cases, all post-pubertal, TTF-1 in four cases, two ovarian and two extra-gonadal, and CDX2 in three cases, with no age or site predilection. No case highly expressed all three divergent endodermal lineage markers, but four co-expressed high levels of two markers: two ovarian yolk sac tumors with TTF-1 and Hep Par 1, one testicular yolk sac tumor with CDX2 and Hep Par 1, and one extra-gonadal yolk sac tumors with TTF-1 and CDX2. While no absolute correlation of high-level divergent endodermal lineage marker expression with histologic subtype was observed, TTF-1 and CDX2 expression was predominantly seen in reticular/cystic and glandular areas while Hep Par 1 was most frequent in myxoid/solid and glandular areas.Modern Pathology advance online publication, 22 July 2016; doi:10.1038/modpathol.2016.131. © 2016 United States & Canadian Academy of Pathology

Wang Y.,Case Western Reserve University
Oncogene | Year: 2015

RNF126 is an E3 ubiquitin ligase. The deletion of RNF126 gene was observed in a wide range of human cancers and is correlated with improved disease-free and overall survival. These data highlight the clinical relevance of RNF126 in tumorigenesis and cancer therapy. However, the specific functions of RNF126 remain largely unknown. Homologous recombination (HR)-mediated DNA double-strand break repair is important for tumor suppression and cancer therapy resistance. Here, we demonstrate that RNF126 facilitates HR by promoting the expression of BRCA1, in a manner independent of its E3 ligase activity but depending on E2F1, a well-known transcription factor of BRCA1 promoter. In support of this result, RNF126 promotes transactivation of BRCA1 promoter by directly binding to E2F1. Most importantly, an RNF126 mutant lacking 11 amino acids that is responsible for the interaction with E2F1 has a dominant-negative effect on BRCA1 expression and HR by suppressing E2F1-mediated transactivation of BRCA1 promoter and blocking the enrichment of E2F1 on BRCA1 promoter. Lastly, RNF126 depletion leads to the increased sensitivity to ionizing radiation and poly (ADP-ribose) polymerase inhibition. Collectively, our results suggest a novel role of RNF126 in promoting HR-mediated repair through positive regulation on BRCA1 expression by direct interaction with E2F1. This study not only offers novel insights into our current understanding of the biological functions of RNF126 but also provides a potential therapeutic target for cancer treatment.Oncogene advance online publication, 3 August 2015; doi:10.1038/onc.2015.198. © 2015 Macmillan Publishers Limited

Weinberg D.S.,Case Western Reserve University
Journal of Pediatric Orthopaedics | Year: 2015

BACKGROUND:: When individuals with asymmetric lower extremities present for evaluation of limb-length inequality, correction can occur at the tibia, femur, or in both bones; however, there are limited data available to justify either technique. The aim of this study is to examine the normal ratio of tibia length/femur length (T/F), and to explore the relationship between T/F ratio and osteoarthritis of the spine, hips, and knees. METHODS:: Bone lengths of 1152 cadaveric femora and tibiae from the Hamann-Todd osteological collection were measured. Degenerative joint disease was graded in the hip, knee, and spine. Correlations between the ratio of T/F and osteoarthritis were evaluated with multiple regression analysis. RESULTS:: The average ratio of T/F was 0.80±0.03. There was a strong correlation between age and arthritis at all sites, with standardized β ranging from 0.44 to 0.57 (P<0.0005 for all). There was a significant correlation between increasing T/F and hip arthritis (standardized β=0.08, P=0.006), and knee arthritis (standardized β=0.08, P=0.008). DISCUSSION:: Increasing tibia length relative to femur length was found to be a significant predictor of ipsilateral hip and knee arthritis. Therefore, we recommend that when performing limb lengthening, surgical planning should lean toward recreating the normal ratio of 0.80. In circumstances where one bone is to be overlengthened relative to the other, bias should be toward overlengthening the femur. This same principle can be applied to limb-reduction surgery, where in certain circumstances, one may choose to preferentially shorten the tibia. CLINICAL RELEVANCE:: This is the first study to report long-term consequences of lower extremity segment disproportion. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Silver J.,Case Western Reserve University | Schwab M.E.,ETH Zurich | Popovich P.G.,Ohio State University
Cold Spring Harbor Perspectives in Biology | Year: 2015

Animal studies are now showing the exciting potential to achieve significant functional recovery following central nervous system (CNS) injury by manipulating both the inefficient intracellular growth machinery in neurons, as well as the extracellular barriers, which further limit their regenerative potential. In this review, we have focused on the three major glial cell types: oligodendrocytes, astrocytes, and microglia/macrophages, in addition to some of their precursors, which form major extrinsic barriers to regrowth in the injured CNS. Although axotomized neurons in the CNS have, at best, a limited capacity to regenerate or sprout, there is accumulating evidence that even in the adult and, especially after boosting their growth motor, neurons possess the capacity for considerable circuit reorganization and even lengthy regeneration when these glial obstacles to neuronal regrowth are modified, eliminated, or overcome. © 2015 Cold Spring Harbor Laboratory Press. All rights reserved.

Shaikh A.G.,Case Western Reserve University
Journal of Stroke and Cerebrovascular Diseases | Year: 2014

Objective: The motion perception and the vestibulo-ocular reflex (VOR) each serve distinct functions. The VOR keeps the gaze steady on the target of interest, whereas vestibular perception serves a number of tasks, including awareness of self-motion and orientation in space. VOR and motion perception might abide the same neurophysiological principles, but their distinct anatomical correlates were proposed. In patients with cerebellar stroke in distribution of medial division of posterior inferior cerebellar artery, we asked whether specific location of the focal lesion in vestibulocerebellum could cause impaired perception of motion but normal eye movements. Methods/Results: Thirteen patients were studied, 5 consistently perceived spinning of surrounding environment (vertigo), but the eye movements were normal. This group was called "disease model." Remaining 8 patients were also symptomatic for vertigo, but they had spontaneous nystagmus. The latter group was called "disease control." Magnetic resonance imaging in both groups consistently revealed focal cerebellar infarct affecting posterior cerebellar vermis (lobule IX). In the "disease model" group, only part of lobule IX was affected. In the disease control group, however, complete lobule IX was involved. Conclusions: This study discovered a novel presentation of cerebellar stroke where only motion perception was affected, but there was an absence of objective neurologic signs. © 2014 by National Stroke Association.

Blinman T.,Childrens Hospital of Philadelphia | Ponsky T.,Case Western Reserve University
Pediatrics | Year: 2012

This article discusses the potential benefits and challenges of minimally invasive surgery for infants and small children, and discusses why pediatric minimally invasive surgery is not yet the surgical default or standard of care. Minimally invasive methods offer advantages such as smaller incisions, decreased risk of infection, greater surgical precision, decreased cost of care, reduced length of stay, and better clinical information. But none of these benefits comes without cost, and these costs, both monetary and risk-based, rise disproportionately with the declining size of the patient. In this review, we describe recent progress in minimally invasive surgery for infants and children. The evidence for the large benefits to the patient will be presented, as well as the considerable, sometimes surprising, mechanical and physiological challenges surgeons must manage. Copyright © 2012 by the American Academy of Pediatrics.

Cui L.,Case Western Reserve University
AMIA ... Annual Symposium proceedings / AMIA Symposium. AMIA Symposium | Year: 2012

Sudden Unexpected Death in Epilepsy (SUDEP) is a poorly understood phenomenon. Patient cohorts to power statistical studies in SUDEP need to be drawn from multiple centers due to the low rate of reported SUDEP incidences. But the current practice of manual chart review of Epilepsy Monitoring Units (EMU) patient discharge summaries is time-consuming, tedious, and not scalable for large studies. To address this challenge in the multi-center NIH-funded Prevention and Risk Identification of SUDEP Mortality (PRISM) Project, we have developed the Epilepsy Data Extraction and Annotation (EpiDEA) system for effective processing of discharge summaries. EpiDEA uses a novel Epilepsy and Seizure Ontology (EpSO), which has been developed based on the International League Against Epilepsy (ILAE) classification system, as the core knowledge resource. By extending the cTAKES natural language processing tool developed at the Mayo Clinic, EpiDEA implements specialized functions to address the unique challenges of processing epilepsy and seizure-related clinical free text in discharge summaries. The EpiDEA system was evaluated on a corpus of 104 discharge summaries from the University Hospitals Case Medical Center EMU and achieved an overall precision of 93.59% and recall of 84.01% with an F-measure of 88.53%. The results were compared against a gold standard created by two epileptologists. We demonstrate the use of EpiDEA for cohort identification through use of an intuitive visual query interface that can be directly used by clinical researchers.

Kelly R.B.,Case Western Reserve University
American Family Physician | Year: 2010

Dietary factors that influence lipid levels include modification of nutritional components, consumption of specific foods, use of food additives and supplements, and major dietary approaches. The most beneficial changes result from reducing intake of saturated and trans fats; increasing intake of polyunsaturated and monounsaturated fats; fortifying foods with plant stanols or sterols; isocalorically adding tree nuts to the diet; consuming one or two alcoholic drinks per day; and adopting a Portfolio, Mediterranean, low-carbohydrate, or low-fat diet. Smaller but still beneficial effects result from reducing intake of dietary cholesterol, increasing intake of soluble fiber and soy protein, and eating fatty marine fish or taking marine-derived omega-3 fatty acid supplements. Red yeast rice supplements have effects similar to those of statin medications and are better tolerated in some patients. Regular aerobic exercise has beneficial effects on lipid levels, particularly if performed for at least 120 minutes per week. Brief physician counseling will have relatively small effects on unselected patients, so efforts should be concentrated on patients who are motivated and ready to make lifestyle changes. © 2010 American Academy of Family Physicians.

Boron W.F.,Case Western Reserve University
Biochimica et Biophysica Acta - Proteins and Proteomics | Year: 2010

The soluble enzyme carbonic anhydrase II (CAII) plays an important role in CO2 influx and efflux by red blood cells (RBCs), a process initiated by changes in the extracellular [CO2] (CO2-initiated CO2 transport). Evidence suggests that CAII may be part of a macromolecular complex at the inner surface of the RBC membrane. Some have suggested CAII specifically binds to a motif on the cytoplasmic C terminus (Ct) of the Cl-HCO3 exchanger AE1 and some other members of the SLC4 family of HCO3 - transporters, a transport metabolon. Moreover, others have suggested that this bound CAII enhances the transport of HCO3 --related species-HCO3 -, CO3 {double bond, long}, or CO3 {double bond, long} ion pairs-when the process is initiated by altering the activity of the transporter (HCO3 --initiated HCO3 - transport). In this review, I assess the theoretical roles of CAs in the transport of CO2 and HCO3 --related species, concluding that although the effect of bound CAII on CO2-initiated CO2 transport is expected to be substantial, the effect of bound CAs on HCO3 --initiated HCO3 - transport is expected to be modest at best. I also assess the experimental evidence for CAII binding to AE1 and other transporters, and the effects of this binding on HCO3 --initiated HCO3 - transport. The early conclusion that CAII binds to the Ct of AE1 appears to be the result of unpredictable effects of GST in the GST fusion proteins used in the studies. The early conclusion that bound CAII speeds HCO3 --initiated HCO3 - transport appears to be the result of CAII accelerating the pH changes used as a read-out of transport. Thus, it appears that CAII does not bind directly to AE1 or other SLC4 proteins, and that bound CAII does not substantially accelerate HCO3 --initiated HCO3 - transport. © 2009.

Komar A.A.,Cleveland State University | Hatzoglou M.,Case Western Reserve University
Cell Cycle | Year: 2011

Translation of cellular mRNAs via initiation at internal ribosome entry sites (IRESs) has received increased attention during recent years due to its emerging significance for many physiological and pathological stress conditions in eukaryotic cells. Expression of genes bearing IRES elements in their mRNAs is controlled by multiple molecular mechanisms, with IRES-mediated translation favored under conditions when cap-dependent translation is compromised. In this review, we discuss recent advances in the field and future directions that may bring us closer to understanding the complex mechanisms that guide cellular IRES-mediated expression. We present examples in which the competitive action of IRES-transacting factors (ITAFs) plays a pivotal role in IRES-mediated translation and thereby controls cell-fate decisions leading to either pro-survival stress adaptation or cell death. © 2011 Landes Bioscience.

Kalayjian R.C.,Case Western Reserve University
Advances in Chronic Kidney Disease | Year: 2010

Antiretroviral therapy (ART) preserves kidney function in patients with human immunodeficiency virus (HIV)-associated nephropathy (HIVAN). Emerging data also document substantial renal benefits of ART in the general HIV-infected population, which is associated in part with suppression of HIV-1 viral replication. The extent to which the response to ART differs in persons with HIVAN compared with those with other HIV-associated kidney disorders is unknown. Beneficial effects of corticosteroids and angiotensin-converting enzyme inhibitors on kidney function also are suggested by retrospective cohort studies and uncontrolled trials of patients with HIVAN. Underexposure to ART or inadequate ART dosing in HIV-infected patients with CKD may curtail the optimal benefits that may be derived from this therapy. © 2010 National Kidney Foundation, Inc.

Qin H.,Case Western Reserve University
Genetic epidemiology | Year: 2012

When dense markers are available, one can interrogate almost every common variant across the genome via imputation and single nucleotide polymorphism (SNP) test, which has become a routine in current genome-wide association studies (GWASs). As a complement, admixture mapping exploits the long-range linkage disequilibrium (LD) generated by admixture between genetically distinct ancestral populations. It is then questionable whether admixture mapping analysis is still necessary in detecting the disease associated variants in admixed populations. We argue that admixture mapping is able to reduce the burden of massive comparisons in GWASs; it therefore can be a powerful tool to locate the disease variants with substantial allele frequency differences between ancestral populations. In this report we studied a two-stage approach, where candidate regions are defined by conducting admixture mapping at stage 1, and single SNP association tests are followed at stage 2 within the candidate regions defined at stage 1. We first established the genome-wide significance levels corresponding to the criteria to define the candidate regions at stage 1 by simulations. We next compared the power of the two-stage approach with direct association analysis. Our simulations suggest that the two-stage approach can be more powerful than the standard genome-wide association analysis when the allele frequency difference of a causal variant in ancestral populations, is larger than 0.4. Our conclusion is consistent with a theoretical prediction by Risch and Tang ([2006] Am J Hum Genet 79:S254). Surprisingly, our study also suggests that power can be improved when we use less strict criteria to define the candidate regions at stage 1. © 2012 Wiley Periodicals, Inc.

Malakooti B.,Case Western Reserve University
Journal of Intelligent Manufacturing | Year: 2011

In this paper, Systematic decision process (SDP) for solving Multiple CriteriaDecision Making problemswith application for manufacturing location selection is introduced. SDP is a comprehensive approach which is based on eliciting strength of preferences for assessing additive utility functions. SDP consists of three steps: I. assessing weights, II. assessing qualitative criteria, and III. ranking alternatives using the assessed additive utility function. Strengths of preferences can be expressed by using either qualitative or numerical ratings. If the decision maker is inconsistent in his/her responses, such inconsistencies are identified by the method. It is shown that the method has advantages in terms of simplicity and accuracy compared to existing methods such as Analytical Hierarchy Process. Furthermore, a quadratic optimization method for assessing weights of additive utility function by use of pair comparison of actual alternatives is developed. Computational experiments are provided. © Springer Science+Business Media, LLC 2009.

Zhu J.,Case Western Reserve University
Biomaterials | Year: 2010

In this review, we explore different approaches for introducing bioactivity into poly(ethylene glycol) (PEG) hydrogels. Hydrogels are excellent scaffolding materials for repairing and regenerating a variety of tissues because they can provide a highly swollen three-dimensional (3D) environment similar to soft tissues. Synthetic hydrogels like PEG-based hydrogels have advantages over natural hydrogels, such as the ability for photopolymerization, adjustable mechanical properties, and easy control of scaffold architecture and chemical compositions. However, PEG hydrogels alone cannot provide an ideal environment to support cell adhesion and tissue formation due to their bio-inert nature. The natural extracellular matrix (ECM) has been an attractive model for the design and fabrication of bioactive scaffolds for tissue engineering. ECM-mimetic modification of PEG hydrogels has emerged as an important strategy to modulate specific cellular responses. To tether ECM-derived bioactive molecules (BMs) to PEG hydrogels, various strategies have been developed for the incorporation of key ECM biofunctions, such as specific cell adhesion, proteolytic degradation, and signal molecule-binding. A number of cell types have been immobilized on bioactive PEG hydrogels to provide fundamental knowledge of cell/scaffold interactions. This review addresses the recent progress in material designs and fabrication approaches leading to the development of bioactive hydrogels as tissue engineering scaffolds. © 2010 Elsevier Ltd.

Sankaran R.M.,Case Western Reserve University
Journal of Physics D: Applied Physics | Year: 2011

The exceptional mechanical, chemical, thermal, electrical and optical properties of single-walled carbon nanotubes (SWCNTs) have tantalized the scientific community for over two decades. However, SWCNTs must be prepared with a high degree of uniformity, which represents a significant synthetic challenge, to make the envisioned technological applications a reality. Among the various approaches that have been developed to synthesize SWCNTs, plasma-based processes are attractive because of their important role in the electronics industry. In this perspective paper, the most recent and promising applications of plasma technology for chirality-controlled SWCNT synthesis are presented including preparation of well-defined catalysts, selective nucleation etching and reacting tubes after growth. Overall, these strategies have achieved improved uniformity over the structure and properties of SWCNTs and offer great potential for the integration of these novel materials in future electronic and optical devices. © 2011 IOP Publishing Ltd.

Lee P.-C.,U.S. National Institutes of Health | Rietsch A.,Case Western Reserve University
Trends in Microbiology | Year: 2015

Type III secretion systems (T3SSs) are complex nanomachines that export proteins from the bacterial cytoplasm across the cell envelope in a single step. They are at the core of the machinery used to assemble the bacterial flagellum, and the needle complex many Gram-negative pathogens use to inject effector proteins into host cells and cause disease. Several models have been put forward to explain how this export is energized, and the mechanism has been the subject of considerable debate. Here we present an overview of these models and discuss their relative merits. Recent evidence suggests that the proton motive force (pmf) is the primary energy source for type III secretion, although contribution from refolding of secreted proteins has not been ruled out. The mechanism by which the pmf is converted to protein export remains enigmatic. © 2015 Elsevier Ltd.

Kerr D.S.,Case Western Reserve University
Neurotherapeutics | Year: 2013

Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q10 (CoQ10; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ10), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ10), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have varied from open-label/uncontrolled, open-label/controlled, or double-blind/placebo-controlled/crossover. Primary outcomes have ranged from single, clinically-relevant scores to multiple measures. Eight of these trials have been well-controlled, completed trials. Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients. One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients. Despite the paucity of benefits found so far, well-controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicenter collaboration, and the selection of very few, clinically relevant, primary outcomes. © 2013 The American Society for Experimental NeuroTherapeutics, Inc.

Sahoo S.S.,Case Western Reserve University
AMIA ... Annual Symposium proceedings / AMIA Symposium. AMIA Symposium | Year: 2012

The widespread use of paper or document-based forms for capturing patient information in various clinical settings, for example in epilepsy centers, is a critical barrier for large-scale, multi-center research studies that require interoperable, consistent, and error-free data collection. This challenge can be addressed by a web-accessible and flexible patient data capture system that is supported by a common terminological system to facilitate data re-usability, sharing, and integration. We present OPIC, an Ontology-driven Patient Information Capture (OPIC) system that uses a domain-specific epilepsy and seizure ontology (EpSO) to (1) support structured entry of multi-modal epilepsy data, (2) proactively ensure quality of data through use of ontology terms in drop-down menus, and (3) identify and index clinically relevant ontology terms in free-text fields to improve accuracy of subsequent analytical queries (e.g. cohort identification). EpSO, modeled using the Web Ontology Language (OWL), conforms to the recommendations of the International League Against Epilepsy (ILAE) classification and terminological commission. OPIC has been developed using agile software engineering methodology for rapid development cycles in close collaboration with domain expert and end users. We report the result from the initial deployment of OPIC at the University Hospitals Case Medical Center (UH CMC) epilepsy monitoring unit (EMU) as part of the NIH-funded project on Sudden Unexpected Death in Epilepsy (SUDEP). Preliminary user evaluation shows that OPIC has achieved its design objectives to be an intuitive patient information capturing system that also reduces the potential for data entry errors and variability in use of epilepsy terms.

Holmes M.R.,Case Western Reserve University
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2013

Background Children who have been exposed to intimate partner violence (IPV) experience a wide variety of short-term social adjustment and emotional difficulties, including externalizing behavioral problems such as aggression. While children are affected by IPV at all ages, little is known about the long-term consequences of IPV exposure at younger ages. Because early experiences provide the foundation for later development, children exposed to IPV as an infant or toddler may experience worse negative outcomes over time than children never exposed. Methods Using the National Survey of Child and Adolescent Well-Being (NSCAW), latent growth curve modeling was conducted to examine whether early IPV exposure occurring between birth and age three (n = 107), compared with no exposure (n = 339), affects the development of aggressive behavior over 5 years. This modeling allowed for empirical exploration of developmental trajectories, and considered whether initial social development trajectories and change over time vary according to early IPV exposure. Results Children who were exposed to more frequent early IPV did not have significantly different aggressive behavior problems initially than children who were never exposed. However, over time, the more frequently children were exposed between birth and 3 years, the more aggressive behavior problems were exhibited by age eight. Conclusions Results indicate a long-term negative behavioral effect on children who have been exposed to IPV at an early age. An initial assessment directly following exposure to IPV may not be able to identify behavior problems in young children. Because the negative effects of early IPV exposure are delayed until the child is of school age, early intervention is necessary for reducing the risk of later aggressive behavior. © 2013 Association for Child and Adolescent Mental Health.

Klatt N.R.,National Institute of Allergy and Infectious Diseases | Funderburg N.T.,Case Western Reserve University | Brenchley J.M.,National Institute of Allergy and Infectious Diseases
Trends in Microbiology | Year: 2013

The advent of combination antiretroviral therapy (cART) has significantly improved the prognosis of human immunodeficiency virus (HIV)-infected individuals. However, individuals treated long-term with cART still manifest increased mortality compared to HIV-uninfected individuals. This increased mortality is closely associated with inflammation, which persists in cART-treated HIV-infected individuals despite levels of plasma viremia below detection limits. Chronic, pathological immune activation is a key factor in progression to acquired immunodeficiency syndrome (AIDS) in untreated HIV-infected individuals. One contributor to immune activation is microbial translocation, which occurs when microbial products traverse the tight epithelial barrier of the gastrointestinal tract. Here we review the mechanisms underlying microbial translocation and its role in contributing to immune activation and disease progression in HIV infection. © 2012 .

Kerkis I.,Butantan Institute | Caplan A.I.,Case Western Reserve University
Tissue Engineering - Part B: Reviews | Year: 2012

Dental pulp from deciduous (baby) teeth, which are discarded after exfoliation, represents an advantageous source of young stem cells. Herein, we discuss the methods of deciduous teeth stem cell (DTSC) isolation and cultivation. We show that based on these methods, at least three different stem cell populations can be identified: a population similar to bone marrow-derived mesenchymal stem cells, an epithelial stem-like cells, and/or a mixed population composed of both cell types. We analyzed the embryonic origin and stem cell niche of DTSCs with respect to the advantages they can provide for their future use in cell therapies and regenerative medicine. In vitro and in vivo differentiation of the DTSC populations, their developmental potential, immunological compatibility, tissue engineering, and transplantation use in studies in animal models are also the focus of the current report. We briefly describe the derivation of induced pluripotent stem (iPS) cells from DTSCs, which can be obtained more easily and efficiently in comparison with human fibroblasts. These iPS cells represent an interesting model for the investigation of pediatric diseases and disorders. The importance of DTSC banking is also discussed. © 2012, Mary Ann Liebert, Inc.

HIV-specific cellular immune responses are associated with control of viremia and delayed disease progression. An effective therapeutic vaccine could mimic these effects and reduce the need for continued antiretroviral therapy. DermaVir, a topically administered plasmid DNA-nanomedicine expressing HIV (CladeB) virus-like particles consisting of 15 antigens, induces predominantly central memory T-cell responses. Treated HIV-infected adults (HIV RNA <50 and CD4 >350) were randomized to placebo or escalating DermaVir doses (0.1 or 0.4 mg of plasmid DNA at weeks 1, 7, and 13 in the low- and intermediate-dose groups and 0.8 mg at weeks 0, 1, 6, 7, 12, and 13 in the high-dose group), n = 5-6 evaluable subjects per group. Immunogenicity was assessed by a 12-day cultured interferon-γ enzyme-linked immunosorbent spot assay at baseline and at weeks 9, 17, and 37 using 1 Tat/Rev and 3 overlapping Gag peptide pools (p17, p24, and p15). Groups were comparable at baseline. The study intervention was well tolerated, without dose-limiting toxicities. Most responses were highest at week 17 (4 weeks after last vaccination) when Gag p24 responses were significantly greater among intermediate-dose group compared with control subjects [median (IQR): 67,600 (5633-74,368) versus 1194 (9-1667)] net spot-forming units per million cells, P = 0.032. In the intermediate-dose group, there was also a marginal Gag p15 response increase from baseline to week 17 [2859 (1867-56,933), P = 0.06], and this change was significantly greater than in the placebo group [0 (-713 to 297), P = 0.016]. DermaVir administration was associated with a trend toward greater HIV-specific, predominantly central memory T-cell responses. The intermediate DermaVir dose tended to show the greatest immunogenicity, consistent with previous studies in different HIV-infected patient populations.

Snyder R.E.,Case Western Reserve University
Theoretical Population Biology | Year: 2010

Although perturbations from a stable equilibrium must ultimately vanish, they can grow initially, and the maximum initial growth rate is called reactivity. Reactivity thus identifies systems that may undergo transient population surges or drops in response to perturbations; however, we lack biological and mathematical intuition about what makes a system reactive. This paper presents upper and lower bounds on reactivity for an arbitrary linearized model, explores their strictness, and discusses their biological implications. I find that less stable systems (i.e. systems with long transients) have a smaller possible range of reactivities for which no perturbations grow. Systems with more species have a higher capacity to be reactive, assuming species interactions do not weaken too rapidly as the number of species increases. Finally, I find that in discrete time, reactivity is determined largely by mean interaction strength and neither discrete nor continuous time reactivity are sensitive to food web topology. © 2010 Elsevier Inc. All rights reserved.

De Georgia M.A.,Case Western Reserve University
Journal of Critical Care | Year: 2014

The concept of brain death was formulated in 1968 in the landmark report A Definition of Irreversible Coma. While brain death has been widely accepted as a determination of death throughout the world, many of the controversies that surround it have not been settled. Some may be rooted in a misconstruction about the history of brain death. The concept evolved as a result of the convergence of several parallel developments in the second half of the 20th century including advances in resuscitation and critical care, research into the underlying physiology of consciousness, and growing concerns about technology, medical futility, and the ethics of end of life care. Organ transplantation also developed in parallel, and though it clearly benefited from a new definition of death, it was not a principal driving force in its creation. Since 1968, the concept of brain death has been extensively analyzed, debated, and reworked. Still there remains much misunderstanding and confusion, especially in the general public. In this comprehensive review, I will trace the evolution of the definition of brain death as death from 1968 to the present, providing background, history and context. © 2014 Elsevier Inc.

Sheikh S.,Case Western Reserve University
International Journal of Advanced Manufacturing Technology | Year: 2013

This paper presents a multi-objective flexible flow shop scheduling problem with limited time lag between stages. n jobs are available to schedule in a predetermined due window. A mixed integer linear programming model with the objectives of maximizing the total profit gained from scheduled jobs and minimizing deviation from the due date is introduced. Due to non-deterministic polynomial-time-hard complexity, the problem is solved with an efficient genetic algorithm. A heuristic mechanism is devised in every generation of the genetic algorithm to assure the solution feasibility. This heuristic also decreases the total solution time by reducing the search space. Computational results show that the presented approach finds solutions of good quality in reasonable runtimes. © 2012 Springer-Verlag London Limited.

Akolkar R.,Case Western Reserve University
ECS Electrochemistry Letters | Year: 2013

Diffusion-controlled mass transport of cupric ions during copper electrodeposition of high aspect ratio through-silicon via (TSV) structures is analyzed using a steady-state diffusion-reaction model. The model yields a single dimensionless parameter, i.e., the Thiele modulus (?), which is used to characterize the cupric ion mass transport limitations prevailing in the system. The Thiele modulus allows comparative analysis of numerous TSV metallization studies reported in the literature, even though these studies utilize operating parameters vastly different from one another. It is shown that literature studies reporting mass transport induced void formation during TSV filling correspond to a Thiele modulus ? > 1 indicative of severe cupric ion depletion within the TSV. Conversely, studies reporting void-free TSV filling correspond to a Thiele modulus ? < 1 indicative of minimal cupric ion depletion. The Thiele modulus is used to develop general guidelines for selecting operating parameters, such as the current density, during metallization of various TSV sizes. © 2012 The Electrochemical Society.

Segraves R.T.,Case Western Reserve University | Balon R.,Wayne State University
Pharmacology Biochemistry and Behavior | Year: 2014

Most of the available antidepressant medications, including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, and dual noradrenergic/serotonergic reuptake inhibitors have been reported to be associated with sexual dysfunction in both sexes. This manuscript reviews evidence concerning the relative incidence of treatment emergent sexual dysfunction in men being treated with antidepressant drugs. Both double-blind controlled trials and large clinical series report a high incidence of sexual dysfunction, especially ejaculatory delay, with serotonergic drugs. The incidence of sexual dysfunction in men appears to be much lower with drugs whose primary mechanism of action involves adrenergic or dopaminergic systems. © 2013 Elsevier Inc.

Dolan E.A.,Case Western Reserve University
American Journal of Hospice and Palliative Medicine | Year: 2011

Malignant bowel obstruction is common in individuals with intra-abdominal and pelvic malignancies and results in considerable suffering. Treatments target both the resolution of obstruction and symptom management. Emerging procedures include stents placement in the bowel to return patency and newer surgical procedures that are evolving to be less invasive. The use of medical interventions like corticosteroids, alone or in concert with additional drugs, can be utilized to achieve resolution of obstruction. Throughout treatment, it is important to also aggressively treat obstructive symptoms like pain and nausea/vomiting. This can mostly be achieved with medications, but use of venting percutaneous endoscopic gastrostomy (PEG) can also relieve symptoms. Parenteral hydration and nutrition use remain controversial with this population. The factor most closely tied to prognosis is performance status. © SAGE Publications 2011.

Albert J.M.,Case Western Reserve University
Biometrics | Year: 2011

The goal of mediation analysis is to assess direct and indirect effects of a treatment or exposure on an outcome. More generally, we may be interested in the context of a causal model as characterized by a directed acyclic graph (DAG), where mediation via a specific path from exposure to outcome may involve an arbitrary number of links (or "stages"). Methods for estimating mediation (or pathway) effects are available for a continuous outcome and a continuous mediator related via a linear model, while for a categorical outcome or categorical mediator, methods are usually limited to two-stage mediation. We present a method applicable to multiple stages of mediation and mixed variable types using generalized linear models. We define pathway effects using a potential outcomes framework and present a general formula that provides the effect of exposure through any specified pathway. Some pathway effects are nonidentifiable and their estimation requires an assumption regarding the correlation between counterfactuals. We provide a sensitivity analysis to assess the impact of this assumption. Confidence intervals for pathway effect estimates are obtained via a bootstrap method. The method is applied to a cohort study of dental caries in very low birth weight adolescents. A simulation study demonstrates low bias of pathway effect estimators and close-to-nominal coverage rates of confidence intervals. We also find low sensitivity to the counterfactual correlation in most scenarios. © 2011, The International Biometric Society.

Dell'Osso L.F.,Case Western Reserve University
Annals of the New York Academy of Sciences | Year: 2011

We studied the mechanisms of oscillopsiasuppressionin subjects with infantile nystagmus syndrome, fusion maldevelopment nystagmus syndrome, and acquired nystagmus (AN). Hypothetical possibilities for perceptual stability were the following: (1) epochs of clear and stable vision during foveation periods of nystagmus waveforms; (2) cancellation by efference copy of motor output; (3) a combination of the effects of both foveation-period stability and efference-copy cancellation; or (4) elevated motion-detection threshold and vision suppression. Observations, studies, and models of oscillopsia suppression allowed comparison of these possibilities. Data from individual subjects supported some of the putative hypotheses. However, only one hypothesis remained viable that could explain howallsubjects maintained perceptual stability despite their different nystagmus types, waveforms, and variability. Robust suppression of oscillopsia was only possible using efference-copy feedback of the motor output containing these specific nystagmus signals to cancel that motion from the retinal error signals. In cases of AN, where oscillopsia couldnotbe suppressed, the deficit was postulated to interfere with or lie outside of this efference-copy feedback loop. © 2011 New York Academy of Sciences.

Baer T.,University of North Carolina at Chapel Hill | Dunbar R.C.,Case Western Reserve University
Journal of the American Society for Mass Spectrometry | Year: 2010

The ASMS conference on ion spectroscopy brought together at Asilomar on October 1620, 2009 a large group of mass spectrometrists working in the area of ion spectroscopy. In this introduction to the field, we provide a brief history, its current state, and where it is going. Ion spectroscopy of intermediate size molecules began with photoelectron spectroscopy in the 1960s, while electronic spectroscopy of ions using the photodissociation "action spectroscopic" mode became active in the next decade. These approaches remained for many years the main source of information about ionization energies, electronic states, and electronic transitions of ions. In recent years, high-resolution laser techniques coupled with pulsed field ionization and sample cooling in molecular beams have provided high precision ionization energies and vibrational frequencies of small to intermediate sized molecules, including a number of radicals. More recently, optical parametric oscillator (OPO) IR lasers and free electron lasers have been developed and employed to record the IR spectra of molecular ions in either molecular beams or ion traps. These results, in combination with theoretical ab initio molecular orbital (MO) methods, are providing unprecedented structural and energetic information about gas-phase ions. © 2010.

Palczewski K.,Case Western Reserve University
FASEB Journal | Year: 2011

THE FASEB JOURNAL is a pillar among biomedical publications, contributing greatly by disseminating the results of vision research during its lifetime. Progress over this period has been remarkable. George Wald (1) provided the first chemical understanding of the fundamental processes governing vision: the photoisomerization of 11-cis-retinal to all-transretinal and the enzymatic regeneration of this chromophore. Contributions of this extraordinary scientist (2, 3) set the stage for discoveries ranging from gross recording of various electrical responses to light to elucidation of signal transduction at a structural level, and from characterization of retinal diseases to successful treatments. © FASEB.

Both affinity and specificity for ligands directly influence the functions of biological macromolecules. Some investigators assume that there is a consistent relationship between the affinity of a receptor molecule for its cognate ligand(s) and the specificity of that same receptor (affinity for cognate versus non-cognate ligands). However, analysis of the range of physical factors that account for changes in affinity, in any particular direction and to any particular degree, of a receptor for a cognate ligand suggests strongly that such factors can have disparate effects on the affinities of the receptor for different non-cognate ligands. Therefore, there can be no simple relationship between affinity and specificity as defined by relative binding of the receptor to cognate and non-cognate ligands. © 2010 Elsevier Ltd. All rights reserved.

Miller R.H.,Case Western Reserve University
Discovery medicine | Year: 2010

Developing effective therapies for serious neurological insults remains a major challenge for biomedical research. Despite intense efforts, the ability to promote functional recovery after contusion injuries, ischemic insults, or the onset of neurodegenerative diseases in the brain and spinal cord remains very limited even while the need for such therapies is increasing with an aging population. Recent studies suggest that cellular therapies utilizing mesenchymal stem cells (MSCs) may provide a functional benefit in a wide range of neurological insults. MSCs derived from a variety of tissue sources have been therapeutically evaluated in animal models of stroke, spinal cord injury, and multiple sclerosis. In each situation, treatment with MSCs results in substantial functional benefit and these pre-clinical studies have led to the initiation of a number of clinical trials worldwide in neural repair.

Pawlowski M.S.,Case Western Reserve University
Monthly Notices of the Royal Astronomical Society | Year: 2016

It is sometimes argued that the uneven sky coverage of the Sloan Digital Sky Survey (SDSS) biases the distribution of satellite galaxies discovered by it to align with the polar plane defined by the 11 brighter, classical MilkyWay (MW) satellites. This might prevent the SDSS satellites from adding significance to the MW's vast polar structure (VPOS). We investigate whether this argument is valid by comparing the observed situation with model satellite distributions confined to the exact SDSS footprint area. We find that the SDSS satellites indeed add to the significance of the VPOS and that the survey footprint rather biases away from a close alignment between the plane fitted to the SDSS satellites and the plane fitted to the 11 classical satellites. Finding the observed satellite phase-space alignments of both the classical and SDSS satellites is an ~5σ event with respect to an isotropic distribution. This constitutes a robust discovery of the VPOS and makes it more significant than the Great Plane of Andromeda (GPoA). Motivated by the GPoA, which consists of only about half of M31's satellites, we also estimate which fraction of the MW satellites is consistent with being part of an isotropic distribution. Depending on the underlying satellite plane width, only 2 to 6 out of the 27 consideredMWsatellites are expected to be drawn from isotropy, and an isotropic component of ≳50 per cent of the MW satellite population is excluded at 95 per cent confidence. © 2015 The Authors.

Fasiello M.,Case Western Reserve University
Journal of Cosmology and Astroparticle Physics | Year: 2013

A generalized theory of multi-field Galileons has been recently put forward. This model stems from the ongoing effort to embed generic Galileon theories within brane constructions. Such an approach has proved very useful in connecting interesting and essential features of these theories with geometric properties of the branes embedding. We investigate the cosmological implications of a very restrictive multi-field Galileon theory whose leading interaction is solely quartic in the scalar field π and lends itself nicely to an interesting cosmology. The bispectrum is characterized by a naturally small amplitude (fNL∼1) and an equilateral shape-function. The trispectrum of curvature fluctuations has features which are quite distinctive with respect to their P(X,φ) counterpart. We also show that, despite an absent cubic Lagrangian in the full theory, non-Gaussianities in this model cannot produce the combination of a small bispectrum alongside with a large trispectrum. We further expand on this point to draw a lesson on what having a symmetry in the full background independent theory entails at the level of fluctuations and vice-versa.© 2013 IOP Publishing Ltd and Sissa Medialab srl.

Malemud C.J.,Case Western Reserve University
Drugs and Aging | Year: 2010

Several recent in vitro investigations and experimental studies performed in animal models of osteoarthritis (OA) sustained the previously held view that interleukin (IL)-1 or tumour necrosis factor-α (TNFα) disrupt the metabolism of synovial joint tissues. The evidence to date indicates that, in addition to IL-1 and TNFα, other pro-inflammatory cytokines, including IL-6, members of the IL-6 protein superfamily, IL-7, IL-17 and IL-18, can also promote articular cartilage extracellular matrix protein degradation or synergize with other cytokines to amplify and accelerate cartilage destruction. Most importantly, many of these cytokines have been implicated in causing synovial tissue activation and damage to subchondral bone as well as altering cartilage homeostasis in spontaneously occurring or surgically induced animal models of OA and in transgenic mice genetically primed to develop OA. In this regard, these pro-inflammatory cytokines may also play a significant role in the pathogenesis of human OA. However, attempts to modify the progression of human OA in well designed, controlled clinical trials with an IL-1 receptor antagonist protein (IRAP) have not been successful. Several anabolic cytokines (also termed growth factors), including transforming growth factor-β (TGF-β), insulin-like growth factor-1 (IGF-1), fibroblast growth factor-2 (FGF-2), platelet-derived growth factor (PDGF) and connective tissue growth factor (CTGF), have also been proposed as regulators of skeletal long bone growth and development as well as cartilage and bone homeostasis. TGF-β, IGF-1 and FGF-2, in particular, have been characterized as potential chondroprotective agents. Thus, enzymatic disruption and removal of these growth factors from cartilage extracellular matrix proteins, as in the case of TGF-β and FGF-2, or disruption of their function, as in the case of the enhanced binding of free IGF-1 with IGF binding proteins in OA joint synovial fluid, may compromise and ultimately be responsible for the inadequate repair of articular cartilage in OA. An improved understanding of the cellular and molecular mechanisms by which pro-inflammatory andor anabolic cytokines alter both the structure and function of synovial joints may eventually result in the commercial development of disease-modifying OA drugs (DMOADs). Since the prevalence of OA is high in the elderly population, future development of DMOADs must also take into account potential differences in the way DMOADs would be metabolized in the older individual compared with younger people. © 2010 Adis Data Information BV. All rights reserved.

Xiao T.S.,Case Western Reserve University
Immunological Reviews | Year: 2015

Inflammasomes are oligomeric signaling complexes that promote caspase activation and maturation of proinflammatory cytokines. Structural and biophysical studies have shed light on the mechanisms of nucleic acid recognition and signaling complex assembly involving the AIM2 (absent in myeloma 2) and IFI16 (γ-interferon-inducible protein 16) inflammasomes. However, our understanding of the mechanisms of the NLRP3 (nucleotide-binding oligomerization-like receptor family, pyrin domain-containing protein 3) activation, either by nucleic acids or by other reported stimuli, has remained elusive. Exciting recent progress on the filament formation by the ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) pyrin domain and the IFI16-double stranded DNA complex has established that the formation of higher order polymers is one of the general mechanisms for signaling platform assembly in innate immune system. The paradigm-changing discovery of the extracellular function of the NLRP3-ASC inflammasome has opened the door for therapeutic targeting the inflammasome filament formation for various clinical conditions. Future characterization of the canonical and non-canonical inflammasome complexes will undoubtedly reveal more surprises on their structure and function and enrich our understanding of the molecular mechanisms of ligand recognition, activation, and regulation. © 2015 John Wiley & Sons A/S.

Jennings A.A.,Case Western Reserve University
Journal of Environmental Management | Year: 2012

Regulatory guidance values are used worldwide to control residential exposure to surface soil contamination. A total of 1,991 values used in 44 United Nations member states plus 4 territories or administrative regions to control exposure to seven polycyclic aromatic hydrocarbons (PAH) generally considered to be carcinogenic or mutagenic (benz(a)anthracene, benzo(a)pyrene, benzo(b)fluoranthene, benzo(k)fluoranthene, dibenzo(a,h)anthracene, chrysene and indeno(1,2,3-c,d)pyrene) are examined. The distributions of these values vary over 6.3-7.2 orders of magnitude and resemble the distributions of lognormal random variables. The U.S. Environmental Protection Agency (USEPA) values fall near the low end of these distributions and exert a modest influence on the values from other U.S. jurisdictions. On average, 17 additional jurisdictions use USEPA values and 21% of all guidance values fall within uncertainty bounds approximated from the USEPA risk model. An average of 62% of U.S. guidance values fall below the median value, but this varies from 43% for chrysene to 70% for dibenz(a,h)anthracene and benzo(a)pyrene. Although the magnitudes of guidance values differ, the ratios of values often reflect the relationships implied by benzo(a)pyrene Toxicity Equivalency Factors (TEFs). This influence is strongest in RGVs from U.S. jurisdictions. © 2012 Elsevier Ltd.

The effect of nonthymidine nucleoside reverse-transcriptase inhibitors (NRTIs) on fat mitochondrial DNA (mtDNA) content and function is unclear. A5202 randomized antiretroviral therapy-naive human immunodeficiency virus-infected subjects to abacavir-lamivudine (ABC/3TC) versus tenofovir DF-emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir-ritonavir (ATV/r). A5224s, substudy of A5202, enrolled 269 subjects with fat measurements by dual-energy x-ray absorptiometry and computed tomography. A subset of subjects underwent fat biopsies at baseline and week 96 for mtDNA content (real-time polymerase chain reaction) and oxidative phosphorylation nicotinamide adenine dinucleotide (reduced) dehydrogenase (complex I) and cytochrome c oxidase (complex IV) activity levels (immunoassays). Intent-to-treat analyses were performed using analysis of variance and paired t tests. Fifty-six subjects (87% male; median age, 39 years) were included; their median body mass index, CD4 cell count, and fat mtDNA level were 26 kg/m(2), 227 cells/μL, and 1197 copies/cell, respectively. Fat mtDNA content decreased within the ABC/3TC and TDF/FTC groups (combining EFV and ATV/r arms; median change, -341 [interquartile range, -848 to 190; P = .03] and -400 [-661 to -221; P < .001] copies/cell, respectively), but these changes did not differ significantly between the 2 groups (P = .57). Complex I and IV activity decreased significantly in the TDF/FTC group (median change, -12.45 [interquartile range, -24.70 to 2.90; P = .003] and -8.25 [-13.90 to -1.30; P < .001], optical density × 10(3)/μg, respectively) but not the ABC/3TC group. Differences between the ABC/3TC and TDF/FTC groups were significant for complex I (P = .03). ABC/3TC and TDF/FTC significantly and similarly decreased fat mtDNA content, but only TDF/FTC decreased complex I and complex IV activity levels. NCT00118898.

Castellani R.J.,University of Maryland, Baltimore | Smith M.A.,Case Western Reserve University
Journal of Pathology | Year: 2011

With each failure of anti-amyloid-β therapy in clinical trials, new trials are initiated with no hint of slowing down. This may be due, in part, to the fact that the amyloid cascade hypothesis has been so modified over time that it is now impossible to confirm or deny. The hypothesis now states, in effect, that invisible molecules target invisible structures. Still relevant, however, are multiple factors that surely cast some doubt but have either been rationalized or overlooked. Among these are the poor correlation between amyloid-β deposits and disease, the substantial differences between familial and sporadic disease, pathological assessment that indicates the secondary nature of lesions/proteins/cascades, the fact that soluble species are poorly reproducible laboratory phenomena, and the irrelevance of synaptic assessment to pathological interpretation. Although not yet dogma, the premature addition of mild cognitive impairment as the implied in vivo homologue to the soluble toxin-synapse interaction is also problematic. In either case, the amyloid cascade hypothesis continues to dominate the Alzheimer's disease literature and grant applications. The more the neuroscience community perseverates along these lines in the face of accumulating outcome data to the contrary, the more one is left to wonder whether the hypothesis is too big to fail. © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Fiore G.L.,University of Fribourg | Rowan S.J.,Case Western Reserve University | Weder C.,University of Fribourg
Chemical Society Reviews | Year: 2013

Polymers that can easily be repaired after being damaged are attractive as this characteristic can improve the reliability, functionality, and lifetime of many products. In the last decade, researchers have thus developed new approaches to create stimuli-responsive polymer systems, which have the ability to autonomously heal or can be repaired upon exposure to an external stimulus. This review summarizes the current knowledge of optically healable or photo-healable polymers. The use of light as a stimulus for healing offers several attractive features, including the ability to deliver the stimulus locally, which opens up the possibility of healing the material under load, as well as the ability to tailor the wavelength of light to selectively address a specific component of the material, e.g. only the damaged parts. So far, two main classes of optically healable polymers have been explored, which are structurally dynamic polymers and mechanically activated reactive systems. © 2013 The Royal Society of Chemistry.

Malemud C.J.,Case Western Reserve University
Current Opinion in Rheumatology | Year: 2015

Purpose of review Evidence accumulated since 2010 indicates that human osteoarthritis should now be reclassified as a systemic musculoskeletal disease rather than a focal disorder of synovial joints. Recent findings Inflammation was seen as the key component promoting synovitis as well as progression of cartilage and bone destruction in osteoarthritis. Thus, metabolic-triggered inflammation involving cytokines, adipokines, abnormal metabolites, acute phase reactants and even complement, all appear to play major roles in osteoarthritis pathophysiology. Immune-mediated inflammation involving T cells and B cells as well as macrophages is now considered a common finding in osteoarthritis synovial tissue. Many experimental and clinical analyses showed that the proinflammatory cytokines, which stimulate matrix metalloproteinase and a disintegrin and metalloproteinase with thrombospondin motif gene transcription in normal and osteoarthritis human chondrocyte cultures, are also present at significantly elevated levels in the synovial fluid of osteoarthritis patients compared with nonarthritic synovial fluids. Summary Human osteoarthritis is a systemic musculoskeletal disorder involving activation of innate and adaptive immune systems accompanied by inflammation exemplified by the elevated production of proinflammatory cytokines, which play a significant role in the progression of the disease. The future of novel therapies for osteoarthritis should consider developing drug development strategies designed to inhibit proinflammatory cytokine-induced signal transduction. These strategies have been successful in the development of drugs for the treatment of rheumatoid arthritis. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

William B.M.,Case Western Reserve University | Armitage J.O.,University of Nebraska Medical Center
Best Practice and Research: Clinical Haematology | Year: 2013

Peripheral T-cell and NK-cell lymphomas are uncommon disorders accounting for 10-15% of all non-Hodgkin lymphomas (NHL). The NHL classification project represents the first attempt to systematically study the distribution of NHL subtypes based on a collaborative international effort and it confirmed the wide geographic variation in the frequency of different subtypes of PTCL. Subsequently, the International T-cell Lymphoma Project (ITLP), the largest collaborative international effort to date, reported prevalence and outcomes of 1314 cases of PTCL from 22 institutions worldwide with central pathology review. The ITLP consortium launched a prospective study, the T-cell project, in September 2006 aimed at collecting an exhaustive clinical and biologic data set on 1000 patients with PTCL for better definition of prognostic factors that would influence outcomes of these patients. This review aims to describe the difference in frequency and outcomes for various subtypes of PTCL based on these studies. © 2013 Elsevier Ltd. All rights reserved.

Hyun I.,Case Western Reserve University
Cell Stem Cell | Year: 2013

Managing patients' therapeutic hope and spiritual distress - in addition to tighter regulation of commercial therapies and improved patient understanding - may offer a more comprehensive approach to reducing the overall incidence of stem cell tourism. Such patient support must occur early in the clinical relationship after appropriate assessment and discussion. © 2013 Elsevier Inc.

Horowitz A.,Cleveland Clinic | Horowitz A.,Case Western Reserve University | Seerapu H.R.,Cleveland Clinic
Cellular Signalling | Year: 2012

Recent findings have drawn attention to the role of membrane traffic in the signaling of vascular endothelial growth factor (VEGF). The significance of this development stems from the pivotal function of VEGF in vasculogenesis and angiogenesis. The outline of the regulation of VEGF receptor (VEGFR) signaling by membrane traffic is similar to that of the epidermal growth factor receptor (EGFR), a prototype of the intertwining between membrane traffic and signaling. There are, however, unique features in VEGFR signaling that are conferred in part by the involvement of the co-receptor neuropilin (Nrp). Nrp1 and VEGFR2 are integrated into membrane traffic through the adaptor protein synectin, which recruits myosin VI, a molecular motor that drives inward trafficking [17,. 21,. 64]. The recent detection of only mild vascular defects in a knockin mouse model that expresses Nrp1 lacking a cytoplasmic domain [. 104], questions the co-receptor's role in VEGF signaling and membrane traffic. The regulation of endocytosis by ephrin-B2 is another feature unique to VEGR2/3 [. 18,. 19], but it awaits a mechanistic explanation. Current models do not fully explain how membrane traffic bridges between VEGFR and the downstream effectors that produce its functional outcome, such as cell migration. VEGF-A appears to accomplish this task in part by recruiting endocytic vesicles carrying RhoA to internalized active VEGFR2 [58]. © 2012 Elsevier Inc.

Li Y.,Key Laboratory of Cluster Science | Zhao Y.,Key Laboratory of Cluster Science | Cheng H.,Key Laboratory of Cluster Science | Hu Y.,Key Laboratory of Cluster Science | And 3 more authors.
Journal of the American Chemical Society | Year: 2012

Graphene quantum dots (GQDs) represent a new class of quantum dots with unique properties. Doping GQDs with heteroatoms provides an attractive means of effectively tuning their intrinsic properties and exploiting new phenomena for advanced device applications. Herein we report a simple electrochemical approach to luminescent and electrocatalytically active nitrogen-doped GQDs (N-GQDs) with oxygen-rich functional groups. Unlike their N-free counterparts, the newly produced N-GQDs with a N/C atomic ratio of ca. 4.3% emit blue luminescence and possess an electrocatalytic activity comparable to that of a commercially available Pt/C catalyst for the oxygen reduction reaction (ORR) in an alkaline medium. In addition to their use as metal-free ORR catalysts in fuel cells, the superior luminescence characteristic of N-GQDs allows them to be used for biomedical imaging and other optoelectronic applications. © 2011 American Chemical Society.

Mieyal J.J.,Case Western Reserve University | Mieyal J.J.,Louis okes Veterans Affairs Medical Research Center | Chock P.B.,U.S. National Institutes of Health
Antioxidants and Redox Signaling | Year: 2012

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) have become recognized as second messengers for initiating and/or regulating vital cellular signaling pathways, and they are known also as deleterious mediators of cellular stress and cell death. ROS and RNS, and their cross products like peroxynitrite, react primarily with cysteine residues whose oxidative modification leads to functional alterations in the proteins. In this Forum, the collection of six review articles presents a perspective on the broad biological impact of cysteine modifications in health and disease from the molecular to the cellular and organismal levels, focusing in particular on reversible protein-S-glutathionylation and its central role in transducing redox signals as well as protecting proteins from irreversible cysteine oxidation. The Forum review articles consider the role of S-glutationylation in regulation of the peroxiredoxin enzymes, the special redox environment of the mitochondria, redox regulation pertinent to the function of the cardiovascular system, mechanisms of redox-activated apoptosis in the pulmonary system, and the role of glutathionylation in the initiation, propagation, and treatment of neurodegenerative diseases. Several common themes emerge from these reviews; notably, the probability of crosstalk between signaling/regulation mechanisms involving protein-S-nitrosylation and protein-S-glutathionylation, and the need for quantitative analysis of the relationship between specific cysteine modifications and corresponding functional changes in various cellular contexts. © 2012, Mary Ann Liebert, Inc.

Lin S.,Northwestern University | Wang B.,Case Western Reserve University | Getsios S.,Northwestern University
Seminars in Cell and Developmental Biology | Year: 2012

Eph receptor tyrosine kinases mediate cell-cell communication by interacting with ephrin ligands residing on adjacent cell surfaces. In doing so, these juxtamembrane signaling complexes provide important contextual information about the cellular microenvironment that helps orchestrate tissue morphogenesis and maintain homeostasis. Eph/ephrin signaling has been implicated in various aspects of mammalian skin physiology, with several members of this large family of receptor tyrosine kinases and their ligands present in the epidermis, hair follicles, sebaceous glands, and underlying dermis. This review focuses on the emerging role of Eph receptors and ephrins in epidermal keratinocytes where they can modulate proliferation, migration, differentiation, and death. The activation of Eph receptors by ephrins at sites of cell-cell contact also appears to play a key role in the maturation of intercellular junctional complexes as keratinocytes move out of the basal layer and differentiate in the suprabasal layers of this stratified, squamous epithelium. Furthermore, alterations in the epidermal Eph/ephrin axis have been associated with cutaneous malignancy, wound healing defects and inflammatory skin conditions. These collective observations suggest that the Eph/ephrin cell-cell communication pathway may be amenable to therapeutic intervention for the purpose of restoring epidermal tissue homeostasis and integrity in dermatological disorders. © 2011 Elsevier Ltd.

Kean T.,Case Western Reserve University | Thanou M.,Kings College London
Advanced Drug Delivery Reviews | Year: 2010

Chitosan is a natural polysaccharide that has attracted significant scientific interest during the last two decades. It is a potentially biologically compatible material that is chemically versatile (-NH2 groups and various Mw). These two basic properties have been used by drug delivery and tissue engineering scientists to create a plethora of formulations and scaffolds that show promise in healthcare. Despite the high number of published studies, chitosan is not approved by the FDA for any product in drug delivery, and as a consequence very few biotech companies are using this material. This review will aim to provide information on these biological properties that affect chitosan's safe use in drug delivery. The term "Chitosan" represents a large group of structurally different chemical entities that may show different biodistribution, biodegradation and toxicological profiles. Here we aim to review research in this area and critically discuss chitosan's potential to be used as a generally regarded as safe (GRAS) material. © 2009 Elsevier B.V. All rights reserved.

Stacey D.W.,Case Western Reserve University
Genes and Cancer | Year: 2010

Our understanding of cell cycle control has been based largely upon studies of synchronized cultures, often focused upon the early stages of the cell cycle following stimulation of quiescent cultures. These studies showed that cyclin D1 and p27 Kip1 (p27) each respond to the growth environment of the cell and together control entry into the cell cycle. In contrast, all cell cycle phases were considered in these studies of actively growing cultures, including events leading to withdrawal from the cell cycle. This approach relies upon the techniques of microinjection, quantitative image analysis, and time-lapse microscopy. The results provide critical new detail to our understanding of the roles of cyclin D1 and p27 in cell cycle regulation. Three critical observations resulting from this work will be described here to demonstrate that 1) cyclin D1 levels oscillate through the normal cell cycle, 2) checkpoint kinases are able to suppress cyclin D1 during S phase, and 3) the level of p27 is determined by a dynamic interaction between cyclin D1 and p27 so as to determine the rate of cell cycle progression. Based upon these observations, a model of cell cycle control is presented in which ras activity stimulates cyclin D1 during G2 phase, resulting in commitment of the cell to continued cell cycle progression. During G1 phase, ras activity suppresses the level of p27 protein, most of which is bound to cyclin D1, resulting in regulation of the rate of proliferation. This model predicted the involvement of checkpoint kinases in regulating cyclin D1 and the role of checkpoint kinases in the protection of neural cells against reactive oxygen. The substantiation of these 2 predictions serves as general validation of the model. © The Author(s) 2011.

Hanseth O.,University of Oslo | Lyytinen K.,Case Western Reserve University
Journal of Information Technology | Year: 2010

We propose a design theory that tackles dynamic complexity in the design for Information Infrastructures (IIs) defined as a shared, open, heterogeneous and evolving socio-technical system of Information Technology (IT) capabilities. Examples of IIs include the Internet, or industry-wide Electronic Data Interchange (EDI) networks. IIs are recursively composed of other infrastructures, platforms, applications and IT capabilities and controlled by emergent, distributed and episodic forms of control. II's evolutionary dynamics are nonlinear, path dependent and influenced by network effects and unbounded user and designer learning. The proposed theory tackles tensions between two design problems related to the II design: (1) the bootstrap problem: IIs need to meet directly early users needs in order to be initiated; and (2) the adaptability problem: local designs need to recognize II's unbounded scale and functional uncertainty. We draw upon Complex Adaptive Systems theory to derive II design rules that address the bootstrap problem by generating early growth through simplicity and usefulness, and the adaptability problem by promoting modular and generative designs. We illustrate these principles by analyzing the history of Internet exegesis. © 2010 JIT Palgrave Macmillan All rights reserved.

McGaugh S.,Case Western Reserve University | Milgrom M.,Weizmann Institute of Science
Astrophysical Journal | Year: 2013

We employ recently published measurements of the velocity dispersions in the newly discovered dwarf satellite galaxies of Andromeda to test our previously published predictions of this quantity. The data are in good agreement with our specific predictions for each dwarf made a priori with modified Newtonian dynamics (MOND), with reasonable stellar mass-to-light ratios, and no dark matter, while Newtonian dynamics point to quite large mass discrepancies in these systems. MOND distinguishes between regimes where the internal field of the dwarf, or the external field of the host, dominates. The data appear to recognize this distinction, which is a unique feature of MOND not explicable in ΛCDM. © 2013. The American Astronomical Society. All rights reserved.

Chambers D.A.,National Health Research Institute | Glasgow R.E.,University of Colorado at Denver | Stange K.C.,Case Western Reserve University
Implementation Science | Year: 2013

Background: Despite growth in implementation research, limited scientific attention has focused on understanding and improving sustainability of health interventions. Models of sustainability have been evolving to reflect challenges in the fit between intervention and context.Discussion: We examine the development of concepts of sustainability, and respond to two frequent assumptions -'voltage drop,' whereby interventions are expected to yield lower benefits as they move from efficacy to effectiveness to implementation and sustainability, and 'program drift,' whereby deviation from manualized protocols is assumed to decrease benefit. We posit that these assumptions limit opportunities to improve care, and instead argue for understanding the changing context of healthcare to continuously refine and improve interventions as they are sustained. Sustainability has evolved from being considered as the endgame of a translational research process to a suggested 'adaptation phase' that integrates and institutionalizes interventions within local organizational and cultural contexts. These recent approaches locate sustainability in the implementation phase of knowledge transfer, but still do not address intervention improvement as a central theme. We propose a Dynamic Sustainability Framework that involves: continued learning and problem solving, ongoing adaptation of interventions with a primary focus on fit between interventions and multi-level contexts, and expectations for ongoing improvement as opposed to diminishing outcomes over time.Summary: A Dynamic Sustainability Framework provides a foundation for research, policy and practice that supports development and testing of falsifiable hypotheses and continued learning to advance the implementation, transportability and impact of health services research. © 2013 Chambers et al.; licensee BioMed Central Ltd.

Nagaoka S.I.,Washington State University | Hodges C.A.,Case Western Reserve University | Albertini D.F.,University of Kansas Medical Center | Hunt P.A.,Washington State University
Current Biology | Year: 2011

Segregation of homologs at the first meiotic division (MI) is facilitated by crossovers and by a physical constraint imposed on sister kinetochores that facilitates monopolar attachment to the MI spindle. Recombination failure or premature separation of homologs results in univalent chromosomes at MI, and univalents constrained to form monopolar attachments should be inherently unstable and trigger the spindle assembly checkpoint (SAC) [1]. Although univalents trigger cell-cycle arrest in the male [2-5], this is not the case in mammalian oocytes [6, 7]. Because the spindle assembly portion of the SAC appears to function normally [8-10], two hypotheses have been proposed to explain the lack of response to univalents: (1) reduced stringency of the oocyte SAC to aberrant chromosome behavior [7], and (2) the ability of univalents to satisfy the SAC by forming bipolar attachments [6]. The present study of Mlh1 mutant mice demonstrates that metaphase alignment is not a prerequisite for anaphase onset and provides strong evidence that MI spindle stabilization and anaphase onset require stable bipolar attachment of a critical mass - but not all - of chromosomes. We postulate that subtle differences in SAC-mediated control make the human oocyte inherently error prone and contribute to the age-related increase in aneuploidy. © 2011 Elsevier Ltd.

Psychological and psychiatric anthropology have long questioned the universality of psychiatric diagnoses, bringing to light the fluidity of mental disorder, and recognizing that the experience and expression of psychopathology is influenced by complex and interacting genetic, environmental, and cultural factors. The majority of our discussions, however, have remained centered around the role of culture in shaping mental illness: drawing attention to subjective experiences of mental illness and culturally patterned modes of symptom presentation, and interrogating the cogency of universal diagnostic rubrics. Psychological and psychiatric anthropology have yet to robustly engage the broadly assumed universal validity of psychiatric medications and the ways in which they are prescribed and experienced. This article provides an introduction into the fields of pharmacogenomics and ethnopsychopharmacology, areas of inquiry seeking to understand the ways in which genetic variability occurring between, and within, large population groups influences individual ability to metabolize psychotropic medications. This piece further addresses the complex issue of psychopharmaceutical efficacy, stressing the ways in which, just as with psychopathology, medications and their outcomes are likewise influenced by the complex interactions of genes, environment, and culture. Lastly, ways in which anthropology can and should engage with the growing fields of pharmacogenomics and ethnopsychopharmacology are suggested. © 2012 Springer Science+Business Media, LLC.

Katz D.M.,Case Western Reserve University
Handbook of Experimental Pharmacology | Year: 2014

Rett syndrome (RTT) is a devastating neurodevelopmental disorder with autistic features caused by loss-of-function mutations in the gene encoding methyl-CpGbinding protein 2 (MECP2), a transcriptional regulatory protein. RTT has attracted widespread attention not only because of the urgent need for treatments, but also because it has become a window into basic mechanisms underlying epigenetic regulation of neuronal genes, including BDNF. In addition, work in mouse models of the disease has demonstrated the possibility of symptom reversal upon restoration of normal gene function. This latter finding has resulted in a paradigm shift in RTT research and, indeed, in the field of neurodevelopmental disorders as a whole, and spurred the search for potential therapies for RTT and related syndromes. In this context, the discovery that expression of BDNF is dysregulated in RTT and mouse models of the disease has taken on particular importance. This chapter reviews the still evolving story of how MeCP2 might regulate expression of BDNF, the functional consequences of BDNF deficits in Mecp2 mutant mice, and progress in developing BDNFtargeted therapies for the treatment of RTT. © Springer-Verlag Berlin Heidelberg 2014.

Bailit J.,Case Western Reserve University
Seminars in Perinatology | Year: 2012

The patient characteristics that influence cesarean rates are well known. However, there are many non clinical factors that also influence cesarean rates. Understanding these non clinical factors and how they can be changed to improve care is an important part of obstetrics. Provider staffing patterns, the types of providers and how information can be used to effectively change practice patterns are explored in this article. © 2012 Elsevier Inc.

Sprecher R.C.,Case Western Reserve University
Laryngoscope | Year: 2010

Objectives/Hypothesis: The goal is to review the efficacy and safety of bioabsorbable miniplates as an alternative to autologous grafts in single-stage laryngotracheal reconstruction for subglottic stenosis. Study Design: Case series. Methods: A standard approach to the laryngotracheal complex is performed. The cricoid cartilage and first two tracheal rings are incised vertically, including the tracheostoma if present. A poly-L-lactic-acid- polyglycolic-acid bioabsorbable miniplate was cut to an approximate 1- to 1.5-cm length and 3- to 4-mm width, and placed over the cricoid defect. This plate was sutured in place using 4-0 undyed nylon sutures, securing the plate at each end to the cricoid cartilage. Care was taken to place these sutures submucosally in the tracheal lumen. If there was concern for suprastomal collapse, additional plates were placed inferiorly. The patient was taken back to the intensive care unit with a penrose drain in place and left sedated and intubated for 1 week and then re-evaluated in the operating room. Results: The procedure has been performed on 10 patients. All patients had a well-healed and fully mucosalized anterior tracheal wall with no evidence of plate or suture exposure at the time of extubation. There were no postoperative complications directly attributable to the use of the absorbable plate. All patients were successfully decannulated at the time of discharge. Long-term follow-up ranges from 14 to 63 months. No patients have required revision laryngotracheal reconstruction or repeat tracheostomy. Conclusions: This study demonstrates that the use of bioabsorbable plates in select patients is a safe and effective alternative to the use of autologous cartilage grafts for single-stage laryngotracheal reconstruction for anterior subglottic stenosis. Donor site morbidity is eliminated, and operative time is decreased. © 2009 The American Laryngological, Rhinological and Otological Society, Inc.

McGaugh S.,Case Western Reserve University | Milgrom M.,Weizmann Institute of Science
Astrophysical Journal | Year: 2013

We compare the recently published velocity dispersions for 17 Andromeda dwarf spheroidals with estimates of the modified Newtonian dynamics predictions, based on the luminosities of these dwarfs, with reasonable stellar mass-to-light values and no dark matter. We find that the two are consistent within the uncertainties. We further predict the velocity dispersions of another 10 dwarfs for which only photometric data are currently available. © 2013. The American Astronomical Society. All rights reserved..

George D.R.,Penn Medicine | Whitehouse P.J.,Case Western Reserve University
Gerontologist | Year: 2011

In the therapeutic void created by over 20 failed Alzheimer's disease drugs during the past decade, a new marketplace of "brain fitness" technology products has emerged. Ranging from video games and computer software to mobile phone apps and hand-held devices, these commercial products promise to maintain and enhance the memory, concentration, visual and spatial skills, verbal recall, and executive functions of individual users. It is instructive to view these products as sociocultural objects deeply imbued with the values and ideologies of our age; consequently, this article offers a critique of the brain fitness technology marketplace while identifying limitations in the capacity of commercial products to realistically improve cognitive health. A broader conception of brain health is presented, going beyond the reductionism of the commercial brain fitness marketplace and asking how our most proximate relationships and local communities can play a role in supporting cognitive and psychosocial well-being. This vision is grounded in recent experiences at The Intergenerational School in Cleveland, OH, a multigenerational community-oriented learning environment that is implementing brain fitness technology in novel ways. © 2011 The Author.

Pagadala M.R.,Cleveland Clinic | McCullough A.J.,Case Western Reserve University
Clinics in Liver Disease | Year: 2012

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disease. Nonalcoholic steatohepatitis (NASH), the more severe form of NAFLD, has an increased risk for progression to cirrhosis. The available data suggest increased morbidity and mortality among those patients with advanced histologic severity such as NASH and fibrosis. Despite the lack of a universally accepted histologic definition of NAFLD and inconsistency among pathologists regarding histologic findings essential to the diagnosis of NASH, a few studies have identified specific histologic findings (particularly fibrosis regardless of stage) that are able to predict NAFLD-related mortality as being most important. © 2012 Elsevier Inc.

Harr M.W.,Case Western Reserve University
Cold Spring Harbor perspectives in biology | Year: 2010

Calcium is a versatile and dynamic 2nd messenger that is essential for the survival of all higher organisms. In cells that undergo activation or excitation, calcium is released from the endoplasmic/sarcoplasmic reticulum to activate calcium-dependent kinases and phosphatases, thereby regulating numerous cellular processes; for example, apoptosis and autophagy. In the case of apoptosis, endogenous ligands or pharmacological agents induce prolonged cytosolic calcium elevation, which in turn leads to cell death. In contrast, there is now evidence that calcium regulates autophagy by several mechanisms, and these may be important for maintaining cell survival. Here we summarize what is known about how calcium regulates these life and death decisions. We pay particular attention to pathways that have been described in lymphocytes and cardiomyocytes, as these systems provide optimal models for understanding calcium signaling in the context of normal cell physiology.

Eubanks J.D.,Case Western Reserve University
American Family Physician | Year: 2010

Cervical radiculopathy is a disease process marked by nerve compression from herniated disk material or arthritic bone spurs. This impingement typically produces neck and radiating arm pain or numbness, sensory deficits, or motor dysfunction in the neck and upper extremities. Magnetic resonance imaging or computed tomographic myelography can confirm neurologic compression. The overall prognosis of persons with cervical radiculopathy is favorable. Most patients improve over time with a focused, nonoperative treatment course. There is little high-quality evidence on the best nonoperative therapy for cervical radiculopathy. Cervical collars may be used for a short period of immobilization, and traction may temporarily decompress nerve impingement. Medications may help alleviate pain and neuropathic symptoms. Physical therapy and manipulation may improve neck discomfort, and selective nerve blocks target nerve root pain. Although the effectiveness of individual treatments is controversial, a multimodal approach may benefit patients with cervical radiculopathy and associated neck pain. Copyright © 2010 American Academy of Family Physicians.

Bailit J.L.,Case Western Reserve University
American Journal of Obstetrics and Gynecology | Year: 2010

Objective The purpose of this study was to determine the rates of late preterm inductions without a medical indication from birth certificate data and to compare them with rates that were obtained from medical charts. Study Design The Ohio Perinatal Quality Collaborative, which comprises 20 hospitals in Ohio that came together in 2008 for the purpose of decreasing nonmedically indicated scheduled deliveries, abstracted data on all scheduled births between 36 weeks and 38 weeks 6 days of gestation. We compared labor inductions with "elective" documented or no indication documented in charts to birth certificate data for inductions with no maternal or fetal complications recorded. Results Birth certificates overestimate rates of induction without medical indication compared with chart abstraction (11% vs 1%; P < .0001). The monthly difference between chart abstraction and birth certificates averages 10.1%. Conclusion Birth certificates overestimate nonmedically indicated inductions by 11-fold. Until birth certificate data improve, nonmedically indicated induction rates that are calculated from birth certificates should be interpreted with caution. © 2010 Mosby, Inc. All rights reserved.

This study sought to investigate the frequency, predictors, and detailed qualitative and quantitative assessment of optical coherence tomography (OCT)-detected stent edge dissections. Its impact on subsequent management and clinical outcomes were also investigated. OCT is a high-resolution imaging modality that can lead to more frequent recognition and accurate assessment of vascular injuries during percutaneous coronary intervention (PCI). From September 2010 to June 2011, all patients with OCT post-PCI were enrolled. Edge dissections were defined as disruptions of the arterial lumen surface in both the 5-mm distal and proximal stent edges. Qualitative and quantitative analyses of all edges were performed at 0.2-mm intervals. In total, 395 edges (249 lesions in 230 patients) were analyzed. The overall incidence of OCT-detected edge dissection was 37.8%, and most (84%) were not apparent on angiography. Independent predictors for OCT-detected dissections were presence of atherosclerotic plaque at stent edges, calcification angle, minimum fibrous cap thickness, thin-cap fibroatheromas, stent/lumen eccentricity, and vessel overstretching. Mean dissection length measured 2.04 ± 1.60 mm, 96.2% appeared as flaps, and 52.8% extended beyond the intima/atheroma layer. Additional stenting was performed in 22.6% of all dissections, which were longer, had bigger dimensions, and promoted deeper vascular injury. The 12-month major adverse cardiac event rate was similar between patients with (7.95%) and without (5.69%, p = 0.581) dissections. High rates of stent edge dissections were detected by OCT, usually related to the presence of atherosclerosis at stent edges and to PCI technique. Detailed OCT assessment of dissection severity was possible and affected the subsequent management of this complication. Non-flow-limiting, small, and superficial dissections left untreated proved benign. Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Nicholls S.J.,Case Western Reserve University | Nicholls S.J.,Cleveland Clinic
Cleveland Clinic Journal of Medicine | Year: 2012

The AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) found, in an interim analysis, no cardiovascular benefit from taking extended-release niacin (Niaspan). In fact, there was a trend toward a greater risk of ischemic stroke, which did not reach statistical significance. But questions remain about this complex trial, which included intensive statin therapy in the active-treatment group and the control group.

Park P.S.H.,Case Western Reserve University
Advances in Pharmacology | Year: 2014

Rhodopsin is the light receptor in rod photoreceptor cells of the retina that initiates scotopic vision. In the dark, rhodopsin is bound to the chromophore 11 cis retinal, which locks the receptor in an inactive state. The maintenance of an inactive rhodopsin in the dark is critical for rod photoreceptor cells to remain highly sensitive. Perturbations by mutation or the absence of 11 cis retinal can cause rhodopsin to become constitutively active, which leads to the desensitization of photoreceptor cells and, in some instances, retinal degeneration. Constitutive activity can arise in rhodopsin by various mechanisms and can cause a variety of inherited retinal diseases including Leber congenital amaurosis, congenital night blindness, and retinitis pigmentosa. In this review, the molecular and structural properties of different constitutively active forms of rhodopsin are overviewed, and the possibility that constitutive activity can arise from different active-state conformations is discussed. © 2014 Elsevier Inc.

Schmaier A.H.,Case Western Reserve University
Thrombosis Research | Year: 2014

The plasma contact activation (CAS) and kallikrein/kinin (KKS) systems consist of 4 proteins: factor XII, prekallikrein, high molecular weight kininogen, and the bradykinin B2 receptor. Murine genetic deletion of factor XII (F12-/-), prekallikrein (Klkb1-/-), high molecular weight kininogen (Kgn1-/-) and the bradykinin B2 receptor (Bdkrb2 -/-) yield animals protected from thrombosis. With possible exception of F12-/- and Kgn1-/- mice, the mechanism(s) for thrombosis protection is not reduced contact activation. Bdkrb2-/- mice are best characterized and they are protected from thrombosis through over expression of components of the renin angiotensin system (RAS) leading to elevated prostacyclin with vascular and platelet inhibition. Alternatively, prolylcarboxypeptidase, a PK activator and degrader of angiotensin II, when deficient in the mouse leads to a prothrombotic state. Its mechanism for increased thrombosis also is mediated in part by components of the RAS. These observations suggest that thrombosis in mice of the CAS and KKS are mediated in part through the RAS and independent of reduced contact activation. © 2014 Elsevier Ltd. All rights reserved.

Wang W.,Case Western Reserve University
Nature Medicine | Year: 2016

Genetic mutations in TAR DNA-binding protein 43 (TARDBP, also known as TDP-43) cause amyotrophic lateral sclerosis (ALS), and an increase in the presence of TDP-43 (encoded by TARDBP) in the cytoplasm is a prominent histopathological feature of degenerating neurons in various neurodegenerative diseases. However, the molecular mechanisms by which TDP-43 contributes to ALS pathophysiology remain elusive. Here we have found that TDP-43 accumulates in the mitochondria of neurons in subjects with ALS or frontotemporal dementia (FTD). Disease-associated mutations increase TDP-43 mitochondrial localization. In mitochondria, wild-type (WT) and mutant TDP-43 preferentially bind mitochondria-transcribed messenger RNAs (mRNAs) encoding respiratory complex I subunits ND3 and ND6, impair their expression and specifically cause complex I disassembly. The suppression of TDP-43 mitochondrial localization abolishes WT and mutant TDP-43-induced mitochondrial dysfunction and neuronal loss, and improves phenotypes of transgenic mutant TDP-43 mice. Thus, our studies link TDP-43 toxicity directly to mitochondrial bioenergetics and propose the targeting of TDP-43 mitochondrial localization as a promising therapeutic approach for neurodegeneration. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Ramachandra I.,Case Western Reserve University
PACE - Pacing and Clinical Electrophysiology | Year: 2010

Background: The number of implantable cardioverter defibrillator (ICD) replacements is increasing, which adds to patient risk and costs. Objectives: To understand the impact of increasing ICD longevity on need for replacements, costs, and some of the risks. Methods: Using the Veterans Affairs records, veterans with ICD implants between June 1992 and April 2007 and dead as of April 2009 were identified. Data were obtained by retrospective records review. The longevity of each ICD was the duration from implant to explant. For each ICD, the longevity needed to avoid one replacement was defined as longevity of that ICD plus the longevity of the subsequent ICD. Results: The study cohort had 164 patients with 301 ICD implants. Ninety-two patients had at least one ICD replacement. Two patients were excluded for missing data. Twenty-seven patients had an ICD explanted for reasons other than battery depletion. Sixty-three patients received 83 ICDs for battery depletion alone. Among 27 patients who had ICD replacements for other reasons, four patients may have avoided a device infection related to ICD replacement if the initial ICD had lasted 7 years. If all ICDs had lasted 5, 7, or 9 years, then 26%, 58%, and 84% of patients, respectively, would not have needed an ICD replacement. Also 17, 37, and 53 ICD replacements, respectively, would have been avoided, saving US$314,500- US$980,500 over 15 years at 2005 Medicare re-imbursement rates. Conclusions: Prolongation of battery life to 7 or 9 years is important to reduce patient risks and decrease costs. © 2009 Wiley Periodicals, Inc.

Two groups of cationic macrocycles with contrasting behaviors have been investigated. The boron group has singlet states well below triplet states. This is the standard behavior for most macrocycles without transition metals. The aluminum group has triplet states stabilized through metal-centered and macrocycle-centered separation of unpaired electrons. The cationic boron subphthalocyanine (1B) has a triplet state whose unpaired electrons are delocalized in the conjugated ring. This is not surprising because a conjugated macrocycle can act as an electron buffer for multiple electrons. On the other hand, coexistence of metal-centered and ligand-centered distributions of unpaired electrons leads to the stabilized triplet state of 1Al. Results from the spin density, natural bond orbital (NBO) charges, and electron localization function (ELF) indicate distinguishable electron distributions between 1B and 1Al. The metal-centered unpaired electron in the triplet state of 1Al leads to the longer Al-N bond length and smaller N-Al-N bond angle compared with these in its singlet state. Consistent with this, the TDDFT study suggests a significant energy relaxation after the first vertical singlet-to-triplet transition. The ligand-centered unpaired electron in the triplet state of 1Al leads to the odd number of π electrons in the macrocycle. NICS values of this macrocycle are distinguishable from these of an aromatic or an antiaromatic macrocycle. The two highest singly occupied orbitals in the triplet state of 1Al are almost degenerate, spatially separated, and have little overlap. This rationalizes its stabilized triplet state. The stabilization mechanism of an unpaired electron at the tetrahedral corner above the central aluminum can also be rationalized by considering the spatial requirement in the valence shell electron pair repulsion (VSEPR) model. The metal-centered and ligand-centered separation of unpaired electrons also leads to stabilized triplet states in some other cationic macrocycles. It is hoped that this theoretical study will stimulate more synthetic attempts to access the experimentally unknown 1Al and more interest in the experimentally known 1B. © 2012 Elsevier Ltd. All rights reserved.

Posterior capsule opacification (PCO) is a debilitating and relatively common complication of cataract surgery despite modern medical and surgical advances. The pathophysiology of this condition has largely been attributed to peptide mediators, such as transforming growth factor-beta (TGFβ), epidermal growth factor (EGF) and matrix metalloproteinases (MMPs), with the inhibition of these and other related molecules showing promising results. Studies have also shown that the levels of interleukin-6 are elevated in the eyes following cataract surgery and in various ocular inflammatory disorders that predispose to PCO development. This review proposes, utilizing ocular and extra-ocular disease models, several potential pathways through which IL-6 may modulate the activity of TGFβ, EGF, MMP-2/-9 and immune cells to promote PCO. Among the IL-6-mediated pathways discussed are the transactivation of EGF receptor, the up-regulation of TGFβ and MMP-2/-9, and the loss of ocular immune privilege through trans-signaling, down-regulation of T-regulatory cells (Tregs) and up-regulation of Th17 cells. After establishing both the potential role of ocular IL-6 in the development of PCO and the apparent upstream activity of IL-6 in relation to the known mediators of PCO, the author hypothesizes that intraoperative anti-IL-6 therapy may be of great benefit in reducing all parameters of PCO pathogenesis. This review also provides a strong basis for carrying out multiple experimental studies with IL-6 inhibitors to further elucidate the specific pathways by which IL-6 may promote PCO as well as to better determine what role inflammation may play in this disease process. © 2013 Elsevier Ltd.

Bligh-Glover W.Z.,Case Western Reserve University
American Journal of Forensic Medicine and Pathology | Year: 2012

A homicidal shooting with an air gun is reported. The history, mechanisms of action, and crime scene implications of air guns are discussed. The wounds produced by air guns are compared to those produced by powder firearms. Copyright © 2012 Lippincott Williams & Wilkins.

Tarini B.A.,University of Michigan | Goldenberg A.J.,Case Western Reserve University
Annual Review of Genomics and Human Genetics | Year: 2012

Continued technological advances have made the prospect of routine whole-genome sequencing (WGS) imminent. To date, much of the discussion about WGS has focused on its application and use in clinical medicine. Relatively little attention has been paid to the potential integration of WGS into newborn screening programs. Given the structure and scope of these programs, it is possible that the early applications of WGS will occur in state-run newborn screening programs. Assessment of the pressing ethical issues currently facing the newborn screening community will provide insight into the challenges that lie ahead in the genomics era. © 2012 by Annual Reviews. All rights reserved.

Lankhorst C.E.,University Hospitals Case Medical Center | Wish J.B.,Case Western Reserve University
Blood Reviews | Year: 2010

Chronic kidney disease (CKD) is a widespread health problem in the world and anemia is a common complication. Anemia conveys significant risk for cardiovascular disease, faster progression of renal failure and decreased quality of life. Patients with CKD can have anemia for many reasons, including but not invariably their renal insufficiency. These patients require a thorough evaluation to identify and correct causes of anemia other than erythropoietin deficiency. The mainstay of treatment of anemia secondary to CKD has become erythropoiesis-stimulating agents (ESAs). The use of ESAs does carry risks and these agents need to be used judiciously. Iron deficiency often co-exists in this population and must be evaluated and treated. Correction of iron deficiency can improve anemia and reduce ESA requirements. Partial, but not complete, correction of anemia is associated with improved outcomes in patients with CKD. © 2009 Elsevier Ltd. All rights reserved.

Lattif A.A.,Case Western Reserve University
Journal of Microbiology, Immunology and Infection | Year: 2011

Background: Candida albicans and Candida glabrata are the major causes of vulvovaginal candidiasis (VVC) in Indian women with diabetes mellitus. Little information is available regarding the genotyping of Candida species isolated from Indian diabetic women with VVC. Methods: In this study, a total of 57 Candida species, comprising Candida albicans and Candida glabrata, isolated from Indian women with VVC, were genotyped and tested for fluconazole susceptibility. Arbitrarily primed polymerase chain reaction (AP-PCR) was used to genotype C glabrata isolates, whereas Southern blot hybridization using a Candida albicans repetitive element-2 (CARE-2) probe was used to genotype C albicans. Results: Genotyping showed that all the C albicans isolates were genetically heterogenous. The pattern of DNA bands obtained after AP-PCR for C glabrata strains were predominantly conformed to genotype A. In vitro fluconazole-susceptibility testing of the isolates using the Clinical and Laboratory Standards Institute M27A2 protocol showed that more than 93% of the Candida isolates were susceptible. Conclusions: Ninety-five percent of the C albicans isolates analyzed were different and genetically unrelated. The analysis of the AP-PCR DNA banding pattern of C glabrata isolates showed that it resembled genotype " A" The Candida isolates were found to be susceptible to fluconazole, with minimum inhibitory concentrations ranging from 0.5μg/mL to 8μg/mL. This correlates with the use of fluconazole as a first-choice antifungal for treating VVC in India. © 2011.

Kaufman E.S.,Case Western Reserve University
Journal of Electrocardiology | Year: 2011

One of the most important and challenging aspects of caring for patients with congenital long QT syndrome (LQTS) is assessing an individual's risk of sudden cardiac death (SCD) because of torsades de pointes. Current risk assessment integrates clinical and genetic features known to be associated with SCD, but more accurate methods of risk assessment could lead to more appropriate use of therapies, potentially saving lives and avoiding overtreatment. Conventional indices of risk include sex, age, extent of QT prolongation, history of symptoms (syncope or aborted SCD), and genetic subtype. The biophysical properties of specific mutations (eg, those that affect transmembrane segments of the ion channel protein or those that cause a dominant negative effect on ion channel function vs haplotype insufficiency) also contribute to risk. A growing body of basic mechanistic and clinical evidence points to heterogeneity of repolarization as a potent determinant of risk in LQTS patients. Mechanistically, heterogeneities of repolarization provide substrate for reentry, which likely causes perpetuation of torsades de pointes. Clinical markers that reflect heterogeneity of repolarization include abnormal microvolt-level T wave alternans, increased Tpeak-end interval, and dispersion of mechanical contraction time. The optimal methodology for using these indices as risk predictors in LQTS remains under active investigation. Further studies are needed to determine how indices of heterogeneity such as microvolt-level T wave alternans, Tpeak-end interval, and dispersion of mechanical contraction can be incorporated into models of risk prediction in LQTS, both for initial risk stratification and for assessment of efficacy of therapies. Copyright © 2011 Published by Elsevier Inc. All rights reserved.

Yang Y.,Case Western Reserve University
Polyhedron | Year: 2012

A comparative study of subphthalocyanines and phthalocyanines was carried out using high-level quantum chemistry calculations. These calculations represent the highest computational level that has been employed in a systematic study of such oligopyrrolic macrocycles. The boron-phthalocyanine coordination mode is quite different from many other metal-phthalocyanine modes. A metal-ligand bond in a subphthalocyanine is shorter and stronger than that in a phthalocyanine. All metal-ligand bonds are polar bonds with both covalent and ionic natures. The thermodynamic data is consistent with the relative stability of subphthalocyanines and phthalocyanines that have been examined. Fukui functions suggest that the attack perpendicular to the carbon atoms adjacent to the meso nitrogen atoms is probably an initial step for the decomposition of a subphthalocyanine. © 2011 Elsevier Ltd. All rights reserved.

Pikuleva I.A.,Case Western Reserve University | Curcio C.A.,University of Alabama at Birmingham
Progress in Retinal and Eye Research | Year: 2014

Historically understudied, cholesterol in the retina is receiving more attention now because of genetic studies showing that several cholesterol-related genes are risk factors for age-related macular degeneration (AMD) and because of eye pathology studies showing high cholesterol content of drusen, aging Bruch's membrane, and newly found subretinal lesions. The challenge before us is determining how the cholesterol-AMD link is realized. Meeting this challenge will require an excellent understanding these genes' roles in retinal physiology and how chorioretinal cholesterol is maintained. In the first half of this review, we will succinctly summarize physico-chemical properties of cholesterol, its distribution in the human body, general principles of maintenance and metabolism, and differences in cholesterol handling in human and mouse that impact on experimental approaches. This information will provide a backdrop to the second part of the review focusing on unique aspects of chorioretinal cholesterol homeostasis, aging in Bruch's membrane, cholesterol in AMD lesions, a model for lesion biogenesis, a model for macular vulnerability based on vascular biology, and alignment of AMD-related genes and pathobiology using cholesterol and an atherosclerosis-like progression as unifying features. We conclude with recommendations for the most important research steps we can take towards delineating the cholesterol-AMD link. © 2014 Elsevier Ltd.

Calabrese L.H.,Case Western Reserve University | Rose-John S.,University of Kiel
Nature Reviews Rheumatology | Year: 2014

IL-6 has been linked to numerous diseases associated with inflammation, including rheumatoid arthritis, inflammatory bowel disease, vasculitis and several types of cancer. Moreover, IL-6 is important in the induction of hepatic acute-phase proteins for the trafficking of acute and chronic inflammatory cells, the differentiation of adaptive T-cell responses, and tissue regeneration and homeostatic regulation. Studies have investigated IL-6 biology using cell-bound IL-6 receptors expressed predominantly on hepatocytes and certain haematopoietic cells versus activation mediated by IL-6 and soluble IL-6 receptors via a second protein, gp130, which is expressed throughout the body. Advances in this research elucidating the differential effects of IL-6 activation provide important insights into the role of IL-6 in health and disease, as well as its potential as a therapeutic target. Knowledge of the basic biology of IL-6 and its signalling pathways can better inform both the research agenda for IL-6-based targeted therapies as well as the clinical use of strategies affecting IL-6-mediated inflammation. This Review covers novel, emerging aspects of the biology of IL-6, which might lead to more specific blockade of IL-6 signalling without compromising the protective function of this cytokine in the body's defence against infections. © 2014 Macmillan Publishers Limited. All rights reserved.

Boron W.F.,Case Western Reserve University
Experimental Physiology | Year: 2010

The traditional dogma has been that all gases diffuse through all membranes simply by dissolving in the lipid phase of the membrane. Although this mechanism may explain how most gases move through most membranes, it is now clear that some membranes have no demonstrable gas permeability, and that at least two families of membrane proteins, the aquaporins (AQPs) and the Rhesus (Rh) proteins, can each serve as pathways for the diffusion of both CO2 and NH3. The knockout of RhCG in the renal collecting duct leads to the predicted consequences in acid-base physiology, providing a clear-cut role for at least one gas channel in the normal physiology of mammals. In our laboratory, we have found that surface-pH (pHS) transients provide a sensitive approach for detecting CO2 and NH3 movement across the cell membranes of Xenopus oocytes. Using this approach, we have found that each tested AQP and Rh protein has its own characteristic CO2/NH3 permeability ratio, which provides the first demonstration of gas selectivity by a channel. Our preliminary AQP1 data suggest that all the NH3 and less than half of the CO2 move along with H2O through the four monomeric aquapores. The majority of CO2 takes an alternative route through AQP1, possibly the central pore at the four-fold axis of symmetry. Preliminary data with two Rh proteins, bacterial AmtB and human erythroid RhAG, suggest a similar story, with all the NH3 moving through the three monomeric NH3 pores and the CO2 taking a separate route, perhaps the central pore at the three-fold axis of symmetry. The movement of different gases via different pathways is likely to underlie the gas selectivity that these channels exhibit. © 2010 The Authors. Journal compilation © 2010 The Physiological Society.

Kim E.,Case Western Reserve University | Thomas C.R.,Oregon Health And Science University
Journal of Thoracic Oncology | Year: 2015

Introduction: Thymoma is a rare and unique tumor with a long natural history that makes it difficult to study. Consequently, there is a dearth of prospective diagnostic or therapeutic clinical trials. To our knowledge, there has not been an analysis of conditional survival of thymoma in the literature. The specific aim of this study was to study the 5-year conditional survivals of a large population of thymoma patients. Methods: Cases of thymoma were extracted from the Surveillance, Epidemiology, and End Results registry (1973-2011) and categorized into Masaoka-Koga stage groupings. The primary outcomes compared overall survival (OS), cause specific survival (CSS), and 5-year conditional OS and CSS, by stage. OS and CSS were calculated using the Kaplan-Meier method with the log-rank test for significance using SAS v9.3. Conditional survival was the probability of surviving an additional 5 years at any point in follow-up, and used analysis of variance to test significance. Results: A total of 2182 patients met inclusion criteria and were categorized as Masaoka-Koga stage groupings of I and IIA ("localized," 24%), IIB ("regional," 16%), III and IV ("distant," 50%), and unknown (10%). Median age was 56 (18-91), and 53% were male. Earlier stages had better OS (p < 0.0001) and CSS (p < 0.0001). Twenty-year OS for local, regional, and distant stages were 42%, 30%, and 18%, respectively. Conditional survivals remained largely unchanged throughout follow-up. Conclusions: Conditional survival provides more relevant survival estimates for patients during follow-up. Further studies should investigate the possibility that thymoma should be considered a chronic disease. © 2015 by the International Association for the Study of Lung Cancer.

Munson M.R.,Case Western Reserve University
Administration and policy in mental health | Year: 2010

This study explored the illness perceptions, attitudes towards mental health services and adherence behaviors among a group of adolescents in treatment for mood disorders in an urban city in the United States. Seventy adolescents completed a battery of questionnaires assessing demographics (e.g., gender, family income), perceptions of illness (e.g., consequences, treatment control) and overall attitudes towards mental health services. Adolescents and their parents also reported on the youth's adherence to both psychotropic medication and mental health appointments. Simultaneous logistic regression analyses revealed that attitudes and family income made a significant and unique contribution in explaining adolescents' adherence behaviors. Interventions that help adolescents become aware of their attitudes toward mental health services and provide information on dimensions of mood disorders, such as the chronic nature of depression and the effectiveness of treatment, may impact adherence behavior. Also, among a group of families with access to services, yearly family income remained a significant barrier to attending appointments all of the time. Policy implications are discussed.

Tolley A.J.,Case Western Reserve University
Lecture Notes in Physics | Year: 2015

Models of modified gravity in the infrared are especially appealing for their late-time cosmology. We review different models before focusing on the cosmology of massive gravity.We start by information derived from its decoupling limit where a self-acceleration solution can be found but suffers from strong coupling issues in the vector modes. This feature is carried through for most FRW self-accelerating solutions in the full theory. We emphasize the role played by inhomogeneous solutions which reduce to a self-accelerating FRW solution on distances comparable to our current Universe but are inhomogeneous at larger distances. We also give an overview of cosmological solutions in extensions of massive gravity such as bi-gravity and quasi-dilaton massive gravity. © Springer International Publishing Switzerland 2015.

Ismail-Beigi F.,Case Western Reserve University
Archives of Iranian Medicine | Year: 2012

Type 2 diabetes (T2DM) is an incompletely understood chronic, progressive multifactorial disease with insulin resistance and decreased (3-cell function playing dominant roles in its genesis. The worldwide incidence of the disease is rapidly increasing to pandemic proportions. The increase in incidence of T2DM is attributable to changes in lifestyle, diet and obesity, but other causes remain to be defined. The disease is a major cause of early mortality due to atherosclerosis and cardiovascular disease (CVD), and is the leading cause of blindness, leg amputations, and chronic renal disease. Hyperglycemia inT2DM becomes manifest once insulin secretion is no longer adequate for the metabolic demands of the individual. The approach to glycemic management of the disease is increasingly based on understanding the underlying pathophysiology. Efforts to maintain and preserve β-cell function during the earlier phases of the disease may have important implications in prevention of subsequent complications of T2DM. Finally, the approach to glycemic management of the disease should be individualized by considering the psycho-socio-economic condition of each patient, and glycemic targets should reflect presence of comor-bid conditions, age of the patient, the stage of their disease in terms of duration, presence of macro-and micro-vascular complications, and propensity for severe hypoglycemia.

Lacks D.J.,Case Western Reserve University
Angewandte Chemie - International Edition | Year: 2012

Capricious charges: The electrostatic charging that occurs when two surfaces come into contact is familiar to everyone, and has been known for millennia. Nonetheless, the scientific understanding of the phenomenon is poor, and it is not possible to reliably predict which surface will charge positively and which will charge negatively. Recent work shows why electrostatic charging may never be predictable. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Mercer B.M.,Case Western Reserve University
Seminars in Perinatology | Year: 2013

The optimal mode of delivery when periviable birth is anticipated has been the subject of considerable discussion. Potentially, cesarean delivery could avert intrapartum fetal trauma and asphyxia and allow timed delivery to assure readiness of neonatal intensive care resources. However, cesarean delivery in the early preterm period commonly necessitates a classical vertical uterine incision involving the fundus with its associated acute and long-term risks to the mother and future pregnancies. In this study we evaluated the currently available literature regarding routine cesarean delivery, cesarean delivery for fetal malpresentation, and cesarean delivery for fetal indication near the limit of viability. Randomized controlled trials of adequate size regarding this issue are lacking. Data from retrospective and observational studies do not support routine cesarean delivery for all early preterm infants. Cesarean delivery may offer survival advantage to the periviable growth-restricted infant regardless of fetal presentation and appears to offer survival benefit to the malpresenting fetus. © 2013 Elsevier Inc.

Anderson A.B.,Case Western Reserve University
Physical Chemistry Chemical Physics | Year: 2012

When standard reversible potentials for bulk solution reactions, U 0, are known, the reversible potentials when the reactant and product are adsorbed on an electrocatalyst surface, U rev surf, are given in terms of these potentials and the adsorption Gibbs energy bond strengths: U rev surf = U 0 + Δ adsG (Ox)/F - Δ adsG (R)/F When the Δ adsG (Ox) and Δ adsG (Red) values are known at potential U rev surf, this equation is exact. When the overpotential for a multi-electron transfer reaction is minimal, each electron transfer takes place at the standard reversible potential for the overall reaction. In the case of O 2 reduction to water via the intermediate step OOH(aq) → O(aq) + OH(aq), or via O 2(g) → 2O(aq), the respective endergonic O-O dissociation Gibbs energies are shown to be 2.52 eV and 4.76 eV. When the oxygen product and water reactant adsorb weakly, as on platinum, the adsorption Gibbs energies, Δ adsG, for O, OH, and OOH intermediates can be uniquely predicted using these data. All of the above depend exclusively on experimentally determined data. Reversible potentials have been calculated for oxygen reduction steps on the platinum electrocatalyst surface using Interface 1.0, a comprehensive computational code for the potential dependence of the electrochemical interface. Using these results as benchmarks, eqn (i) is found to be accurate to around 0.1 V when the Δ adsG are values calculated for the potentials of zero charge, instead of 1.229 V, which is a significant simplification. The variation in Δ adsG values between the calculated potentials of zero charge and 1.229 V are found to be 0.2 eV V -1 or less. Prior work, using internal adsorption energies calculated at the potential of zero charge in place of Gibbs energies in eqn (i) was found to be accurate to within about 0.2 V. On platinum Δ adsG of the reaction OOH(ads) → O(ads) + OH(ads) is calculated at the potential of zero charge for the reactant and product to be about 1.2 eV exergonic under Langmuir conditions, and this Gibbs energy loss reduces the 1.229 V four-electron reversible potential on the platinum surface to an effective reversible potential of about 0.93 V for this mechanism on platinum. The effective reversible potential is a consequence of efficiency loss, not kinetics. Based on these values, the onset potential for four-electron oxygen reduction will be less than or equal to the effective reversible potential and on pure Pt(111) it appears to be equal to it. © 2012 the Owner Societies.

Wilson R.D.,Case Western Reserve University
Journal of Stroke and Cerebrovascular Diseases | Year: 2012

An evidenced-based approach to detecting and treating dysphagia needs to be informed by the costs and risks associated with pneumonia. In this study, the cost of pneumonia during hospitalization after stroke and the effect of pneumonia on mortality were estimated. The effect of pneumonia on mortality and costs for different levels of risk were analyzed as well. The data come from the 2005 and 2006 Nationwide Inpatient Sample. Regression models, including the propensity for pneumonia, were used to estimate the in-hospital mortality-associated pneumonia, as well as the marginal cost of pneumonia on the hospitalization. A stratified analysis based on quintile of propensity for pneumonia was also undertaken. There were 183,976 hospitalizations for stroke in the sample. The adjusted relative risk of death associated with pneumonia was 2.0 (95% confidence interval [CI], 1.9-2.1). The average marginal cost of pneumonia on the hospitalization was $27,633 (95% CI, $27,078-$27,988). The quintile of hospitalizations with the highest propensity for pneumonia had the highest average marginal cost associated with pneumonia and the lowest adjusted relative risk of death. There was an inverse relationship between adjusted relative risk of death and propensity for pneumonia. The data indicate that pneumonia after stroke is associated with higher mortality and hospitalization costs. Patients with the lowest risk for pneumonia have the highest risk for death associated with pneumonia. Screening is important at all levels of risk. © 2012 by National Stroke Association.

Sass R.G.,Case Western Reserve University
American Journal of Bioethics | Year: 2013

Although excess blood collection has characterized U.S. national disasters, most dramatically in the case of September 11, periodic shortages of blood have recurred for decades. In response, I propose a new model of medical philanthropy, one that specifically uses charitable contributions to health care as blood donation incentives. I explain how the surge in blood donations following 9/11 was both transient and disaster-specific, failing to foster a greater continuing commitment to donate blood. This underscores the importance of considering blood donation incentives. I defend charitable incentives as an alternative to financial incentives, which I contend would further extend neoliberal market values into health care. I explain my model's potential appeal to private foundations or public-private partnerships as a means for expanding both the pool of blood donors and the prosocial benefit of each act of blood donation. Finally I link my analysis to the empirical literature on blood donation incentives. © 2013 Copyright Taylor and Francis Group, LLC.

Cook L.E.,Case Western Reserve University
The journal of knee surgery | Year: 2012

A recent development to better recreate joint kinematics has been a change from a multiradius (MR) design to a single radius (SR) design. We analyzed 559 primary total knee arthroplasty (TKA) procedures which used either a SR (n = 426 Triathlon; Stryker Orthopaedics, Mahwah, NJ) or MR of curvature knee system (n = 133 Duracon; Stryker Orthopaedics, Mahwah, NJ) (79.3% follow-up; 705 total TKA procedures identified). Patients were administered a modification of the Knee Society score (KSS) (3.9 years average follow-up). The SR design showed improvements over the MR design in pain (p = 0.021), stability (p = 0.002), flexion (p = 0.006), ability to completely straighten the knee (p = 0.025), stair climbing (p = 0.0001), walking (p = 0.0001), use of assistive devices (p = 0.0005), postoperative knee score (p = 0.0005), and postoperative function (p < 0.0001). Analysis of the change in KSS knee (p = 0.002) and function scores (p = 0.002) from preoperative visit to postoperative follow-up favored the SR design as well. These data support the use of SR implants and provide evidence of improved outcomes in terms of function, stability, and pain.

Adler J.H.,Case Western Reserve University
Harvard Environmental Law Review | Year: 2011

Stabilizing atmospheric concentrations of greenhouse gases at double their pre-industrial levels (or lower) will require emission reductions far in excess of what can be achieved at a politically acceptable cost with current or projected levels of technology. Substantial technological innovation is required if the nations of the world are to come anywhere close to proposed emission reduction targets. Neither traditional federal support for research and development of new technologies nor traditional command-and-control regulations are likely to spur sufficient innovation. Technology inducement prizes, on the other hand, have the potential to significantly accelerate the rate of technological innovation in the energy sector. This Article outlines the theory and history of the use of inducement prizes to encourage and direct inventive efforts and technological innovation and identifies several comparative advantages inducement prizes have over traditional grants and subsidies for encouraging the invention and development of climate-friendly technologies. While no policy measure guarantees technological innovation, greater reliance on inducement prizes would increase the likelihood of developing and deploying needed technologies in time to alter the world's climate future. Whatever their faults in other contexts, prizes are particularly well suited to the climate policy challenge.

Sharp R.R.,Cleveland Clinic | Sharp R.R.,Case Western Reserve University
Genetics in Medicine | Year: 2011

As we look to a time when whole-genome sequencing is integrated into patient care, it is possible to anticipate a number of ethical challenges that will need to be addressed. The most intractable of these concern informed consent and the responsible management of very large amounts of genetic information. Given the range of possible findings, it remains unclear to what extent it will be possible to obtain meaningful patient consent to genomic testing. Equally unclear is how clinicians will disseminate the enormous volume of genetic information produced by whole-genome sequencing. Toward developing practical strategies for managing these ethical challenges, we propose a research agenda that approaches multiplexed forms of clinical genetic testing as natural laboratories in which to develop best practices for managing the ethical complexities of genomic medicine. © 2011 Lippincott Williams & Wilkins.

Schnetz M.P.,Case Western Reserve University
PLoS genetics | Year: 2010

CHD7 is one of nine members of the chromodomain helicase DNA-binding domain family of ATP-dependent chromatin remodeling enzymes found in mammalian cells. De novo mutation of CHD7 is a major cause of CHARGE syndrome, a genetic condition characterized by multiple congenital anomalies. To gain insights to the function of CHD7, we used the technique of chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-Seq) to map CHD7 sites in mouse ES cells. We identified 10,483 sites on chromatin bound by CHD7 at high confidence. Most of the CHD7 sites show features of gene enhancer elements. Specifically, CHD7 sites are predominantly located distal to transcription start sites, contain high levels of H3K4 mono-methylation, found within open chromatin that is hypersensitive to DNase I digestion, and correlate with ES cell-specific gene expression. Moreover, CHD7 co-localizes with P300, a known enhancer-binding protein and strong predictor of enhancer activity. Correlations with 18 other factors mapped by ChIP-seq in mouse ES cells indicate that CHD7 also co-localizes with ES cell master regulators OCT4, SOX2, and NANOG. Correlations between CHD7 sites and global gene expression profiles obtained from Chd7(+/+), Chd7(+/-), and Chd7(-/-) ES cells indicate that CHD7 functions at enhancers as a transcriptional rheostat to modulate, or fine-tune the expression levels of ES-specific genes. CHD7 can modulate genes in either the positive or negative direction, although negative regulation appears to be the more direct effect of CHD7 binding. These data indicate that enhancer-binding proteins can limit gene expression and are not necessarily co-activators. Although ES cells are not likely to be affected in CHARGE syndrome, we propose that enhancer-mediated gene dysregulation contributes to disease pathogenesis and that the critical CHD7 target genes may be subject to positive or negative regulation.

Akolkar R.,Case Western Reserve University
Journal of Power Sources | Year: 2014

Increased propensity for dendritic lithium electrodeposition during sub-ambient temperature operation has been widely reported in lithium battery systems, yet is not fully understood. In the present paper, a mathematical model is developed to quantify the dendritic growth rate during lithium electrodeposition at sub-ambient temperature. This model builds on a diffusion-reaction framework presented recently by Akolkar [J. Power Sources 232 (2013) 23-28]. Using a steady-state diffusion model with a concentration- dependent diffusion coefficient, the lithium-ion concentration depletion in the stagnant Nernst diffusion boundary layer near the lithium surface is modeled. A surface electrochemical reaction model is then employed to correlate the lithium concentration depletion to the dendrite growth rate. Temperature effects on the lithium-ion transport and its electrochemical surface reaction are incorporated in the model via an Arrhenius-type temperature-dependence of the diffusion coefficient and the apparent charge transfer coefficient. It is shown that lowering the system temperature has the effect of increasing the lithium-ion diffusion resistance and decreasing the surface film thickness - conditions favorable for the formation of dendrites during lithium electrodeposition. © 2013 Elsevier B.V. All rights reserved.

Zhou L.,Case Western Reserve University
Seminars in Immunopathology | Year: 2012

Abstract O-fucosylglycans on Notch extracellular domain epidermal growth factor (EGF) repeats are critical in modulating Notch signaling by altering the sensitivity of Notch receptors to activation by Notch ligands. Mice lacking Notch O-fucosylglycans display granulo-monocytic myeloproliferation, hematopoietic stem cell dysfunction and aberrant stem cell niche occupancy. The inability of the stem cells/progenitors that lack Notch O-fucosylglycans to transcribe Notch signaling activation is attributed by a loss of effective Notch-ligand interaction. These findings, in conjunction with myeloproliferation identified in mouse models with defective Notch cleavage or ligand endocytosis, reveal emerging new roles of Notch in hematopoietic stem cell biology and myeloid homeostasis. © Springer-Verlag 2012.

Romani A.M.P.,Case Western Reserve University
Metal Ions in Life Sciences | Year: 2013

Magnesium, the second most abundant cation within the cell, plays an important role in numerous biological functions. Experimental evidence indicates that mammalian cells tightly regulate cellular magnesium ion content through speci fic mechanisms controlling Mg2+ entry and efflux across the cell membrane and the membrane of various cellular organelles as well as intracellular Mg2+ buffering under resting conditions and following hormonal and metabolic stimuli. This chapter will provide an assessment of the various mechanisms controlling cellular Mg2+ homeostasis and transport, and the implications changes in cellular Mg2+ content play under physiological and pathological conditions. © Springer Science+Business Media Dordrecht 2013.

Tsybovsky Y.,Case Western Reserve University
Advances in Experimental Medicine and Biology | Year: 2010

ATP-binding cassette transporters (ABC transporters) utilize the energy of ATP hydrolysis to translocate an unusually diverse set of substrates across cellular membranes. ABCA4, also known as ABCR, is a ~250 kDa single-chain ABC transporter localized to the disk margins of vertebrate photoreceptor outer segments. It is composed of two symmetrically organized halves, each comprising six membrane-spanning helices, a large glycosylated exocytoplasmic domain located inside the disk, and a cytoplasmic domain with an ATP-binding cassette. Hundreds of mutations in ABCA4 are known to cause impaired vision and blindness such as in Stargardt disease as well as related disorders. Biochemical and animal model studies in combination with patient analyses suggest that the natural substrate of ABCA4 is retinylidene-phosphatidylethanolamine (N-retinylidene-PE), a precursor of potentially toxic diretinal compounds. ABCA4 prevents accumulation of N-retinylidene-PE inside the disks by transporting it to the cytoplasmic side of the disk membrane where it can dissociate, allowing the released all-trans-retinal to enter the visual cycle. The pathogenesis of diseases caused by mutations in ABCA4 is complex, comprising a loss-of-function component as well as photoreceptor stress caused by protein mislocalization and misfolding. © Springer Science+Business Media, LLC 2010.

Leonard D.A.,Grand Valley State University | Bonomo R.A.,Case Western Reserve University | Powers R.A.,Grand Valley State University
Accounts of Chemical Research | Year: 2013

Despite 70 years of clinical use, β-lactam antibiotics still remain at the forefront of antimicrobial chemotherapy. The major challenge to these life-saving therapeutics is the presence of bacterial enzymes (i.e., β-lactamases) that can hydrolyze the β-lactam bond and inactivate the antibiotic. These enzymes can be grouped into four classes (A-D). Among the most genetically diverse are the class D β-lactamases. In this class are β-lactamases that can inactivate the entire spectrum of β-lactam antibiotics (penicillins, cephalosporins, and carbapenems).Class D β-lactamases are mostly found in Gram-negative bacteria such as Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, and Acinetobacter baumannii. The active-sites of class D β-lactamases contain an unusual N-carboxylated lysine post-translational modification. A strongly hydrophobic active-site helps create the conditions that allow the lysine to combine with CO2, and the resulting carbamate is stabilized by a number of hydrogen bonds. The carboxy-lysine plays a symmetric role in the reaction, serving as a general base to activate the serine nucleophile in the acylation reaction, and the deacylating water in the second step.There are more than 250 class D β-lactamases described, and the full set of variants shows remarkable diversity with regard to substrate binding and turnover. Narrow-spectrum variants are most effective against the earliest generation penicillins and cephalosporins such as ampicillin and cephalothin. Extended-spectrum variants (also known as extended-spectrum β-lactamases, ESBLs) pose a more dangerous clinical threat as they possess a small number of substitutions that allow them to bind and hydrolyze later generation cephalosporins that contain bulkier side-chain constituents (e.g., cefotaxime, ceftazidime, and cefepime). Mutations that permit this versatility seem to cluster in the area surrounding an active-site tryptophan resulting in a widened active-site to accommodate the oxyimino side-chains of these cephalosporins. More concerning are the class D β-lactamases that hydrolyze clinically important carbapenem β-lactam drugs (e.g., imipenem). Whereas carbapenems irreversibly acylate and inhibit narrow-spectrum β-lactamases, class D carbapenemases are able to recruit and activate a deacylating water. The rotational orientation of the C6 hydroxyethyl group found on all carbapenem antibiotics likely plays a role in whether the deacylating water is effective or not.Inhibition of class D β-lactamases is a current challenge. Commercially available inhibitors that are active against other classes of β-lactamases are ineffective against class D enzymes. On the horizon are several compounds, consisting of both β-lactam derivatives and non-β-lactams, that have the potential of providing novel leads to design new mechanism-based inactivators that are e