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Bloomington, IN, United States

Indiana University is a multi-campus public university system in the state of Indiana, United States. Indiana University has a combined student body of more than 110,000 students, including approximately 43,000 students enrolled at the Indiana University Bloomington campus and approximately 31,000 students enrolled at the Indiana University – Purdue University Indianapolis campus. Wikipedia.

Bruza P.D.,Queensland University of Technology | Wang Z.,Ohio State University | Busemeyer J.R.,Indiana University
Trends in Cognitive Sciences | Year: 2015

What type of probability theory best describes the way humans make judgments under uncertainty and decisions under conflict? Although rational models of cognition have become prominent and have achieved much success, they adhere to the laws of classical probability theory despite the fact that human reasoning does not always conform to these laws. For this reason we have seen the recent emergence of models based on an alternative probabilistic framework drawn from quantum theory. These quantum models show promise in addressing cognitive phenomena that have proven recalcitrant to modeling by means of classical probability theory. This review compares and contrasts probabilistic models based on Bayesian or classical versus quantum principles, and highlights the advantages and disadvantages of each approach. © 2015 Elsevier Ltd.

Aguinis H.,Indiana University | Culpepper S.A.,University of Colorado at Denver | Pierce C.A.,University of Memphis
Journal of Applied Psychology | Year: 2010

We developed a new analytic proof and conducted Monte Carlo simulations to assess the effects of methodological and statistical artifacts on the relative accuracy of intercept- and slope-based test bias assessment. The main simulation design included 3,185,000 unique combinations of a wide range of values for true intercept- and slope-based test bias, total sample size, proportion of minority group sample size to total sample size, predictor (i.e., preemployment test scores) and criterion (i.e., job performance) reliability, predictor range restriction, correlation between predictor scores and the dummy-coded grouping variable (e.g., ethnicity), and mean difference between predictor scores across groups. Results based on 15 billion 925 million individual samples of scores and more than 8 trillion 662 million individual scores raise questions about the established conclusion that test bias in preemployment testing is nonexistent and, if it exists, it only occurs regarding intercept-based differences that favor minority group members. Because of the prominence of test fairness in the popular media, legislation, and litigation, our results point to the need to revive test bias research in preemployment testing. © 2010 American Psychological Association.

Seradjeh B.,Indiana University
Physical Review B - Condensed Matter and Materials Physics | Year: 2012

I study the effects of particle-hole imbalance on the exciton superfluid formed in a topological insulator thin film and obtain the mean-field phase diagram. At finite imbalance a spatially modulated condensate is formed, akin to the Fulde-Ferrell-Larkin-Ovchinnikov state in a superconductor, which preempts a first-order transition from the uniform condensate to the normal state at low temperatures. The imbalance can be tuned by changing the chemical potential at the two surfaces separately or, alternatively, by an asymmetric application of Zeeman fields at constant chemical potential. A vortex in the condensate carries a precisely fractional charge half of that of an electron. Possible experimental signatures for realistic parameters are discussed. © 2012 American Physical Society.

Seradjeh B.,Indiana University
Physical Review B - Condensed Matter and Materials Physics | Year: 2012

I study the edge states of the topological exciton condensate formed by a Coulomb interaction between two parallel surfaces of a strong topological insulator. When the condensate is contacted by superconductors with a π phase shift across the two surfaces, a pair of counterpropagating Majorana modes close the gap at the boundary. I propose a nanostructured system of topological insulators and superconductors that hosts unpaired Majorana fermions when and only when the exciton condensate forms. Therefore, measuring the Majorana signal in this structure provides a way of detecting the topological exciton condensate that is uniquely related to its topological nature. The relevant experimental signatures as well as implications for related systems are discussed. © 2012 American Physical Society.

Rescorla F.J.,Indiana University
Seminars in Pediatric Surgery | Year: 2012

Pediatric germ cell tumors represent a diverse group of tumors that present from in utero through adolescence at many nongonadal locations, from the neck to the sacrococcygeal region. Surgical resection remains the central element of management, and accurate surgical staging is essential to properly ascertain the correct risk-based treatment. The management for all benign tumors (mature and immature teratomas) and select completely resectable malignant tumors is surgery alone. Modern-day chemotherapy is extremely effective in infants and children with unresectable and metastatic disease and these children have a very high survival rate. The use of neoadjuvant chemotherapy allows vital organ preservation and there is no role for resection of vital structures at the time of initial presentation. © 2012 Elsevier Inc.

Hassan S.E.,Indiana University
Investigative Ophthalmology and Visual Science | Year: 2012

Purpose. The purpose of this study is to measure the accuracy and reliability of normally sighted, visually impaired, and blind pedestrians at making street crossing decisions using visual and/or auditory information. Methods. Using a 5-point rating scale, safety ratings for vehicular gaps of different durations were measured along a two-lane street of one-way traffic without a traffic signal. Safety ratings were collected from 12 normally sighted, 10 visually impaired, and 10 blind subjects for eight different gap times under three sensory conditions: (1) visual plus auditory information, (2) visual information only, and (3) auditory information only. Accuracy and reliability in street crossing decision-making were calculated for each subject under each sensory condition. Results. We found that normally sighted and visually impaired pedestrians were accurate and reliable in their street crossing decision-making ability when using either vision plus hearing or vision only (P > 0.05). Under the hearing only condition, all subjects were reliable (P > 0.05) but inaccurate with their street crossing decisions (P < 0.05). Compared to either the normally sighted (P 1/4 0.018) or visually impaired subjects (P 1/4 0.019), blind subjects were the least accurate with their street crossing decisions under the hearing only condition. Conclusions. Our data suggested that visually impaired pedestrians can make accurate and reliable street crossing decisions like those of normally sighted pedestrians. When using auditory information only, all subjects significantly overestimated the vehicular gap time. Our finding that blind pedestrians performed significantly worse than either the normally sighted or visually impaired subjects under the hearing only condition suggested that they may benefit from training to improve their detection ability and/or interpretation of vehicular gap times. © 2012 The Association for Research in Vision and Ophthalmology, Inc.

The proportionately low abundance of membrane proteins hampers their proteomic analysis, especially for a quantitative LC-MS/MS approach. To overcome this limitation, a method was developed that consists of one cell disruption step in a hypotonic reagent using liquid nitrogen, one isolation step using a low speed centrifugation, and three wash steps using high speed centrifugation. Pellets contained plasma, nuclear, and mitochondrial membranes, including their integral, peripheral, and anchored membrane proteins. The reproducibility of this method was verified by protein assay of four separate experiments with a CV of 7.7%, and by comparative LC-MS/MS label-free quantification of individual proteins between two experiments with 99% of the quantified proteins having a CV ≤30%. Western blot and LC-MS/MS results of markers for cytoplasm, nucleus, mitochondria, and their membranes indicated that the enriched membrane fraction was highly pure by the absence of, or presence of trace amounts of, nonmembrane marker proteins. The average yield of membrane proteins was 237 μg/10 million HT29-MTX cells. LC-MS/MS analysis of the membrane-enriched sample resulted in the identification of 2597 protein groups. In summary, the developed method is reproducible, produces a highly pure membrane fraction, and generates a high yield of membrane proteins. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Warden S.J.,Indiana University
Physician and Sportsmedicine | Year: 2010

Athletes often seek artificial means to gain advantage and prolong participation when competing. This often involves taking naturally occurring or chemically synthesized compounds. The World Anti-Doping Agency does not prohibit the use of nonsteroidal anti-inflammatory drugs (NSAIDs) because these agents are not performance enhancing, and their analgesic and anti-inflammatory effects are at best performance enabling. Consequently, athletes have relatively unrestricted access to NSAIDs, which are readily available as over-the-counter drugs. However, concern has been raised on athletes' prophylactic use of these agents. Data from many sporting fields have consistently demonstrated that many individuals self-administer NSAIDs prior to athletic participation to prevent pain and inflammation before it occurs. However, scientific evidence for this approach is currently lacking, and athletes should be aware of the potential risks in using NSAIDs as a prophylactic agent. These agents are not benign, and can produce significant side effects, including gastrointestinal and cardiovascular conditions, as well as musculoskeletal and renal side effects. The latter side effects appear paradoxical to the rationale for prophylactic use of NSAIDs. This article discusses current observations regarding athlete use of NSAIDs, and the possible benefits and potential risks of their use. © The Physician and Sportsmedicine.

Yoder M.C.,Indiana University
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2010

Endothelial cells provide the dynamic lining of blood vessels throughout the body and provide many tissue-specific functions, in addition to providing a nonthrombogenic surface for blood cells and conduit for oxygen and nutrient delivery. As might be expected, some endothelial cells are injured or become senescent and are sloughed into the bloodstream, and most circulating endothelial cells display evidence of undergoing apoptosis or necrosis. However, there are rare viable circulating endothelial cells that display properties consistent with those of a progenitor cell for the endothelial lineage. This article reviews historical and current literature to present some evidence that the endothelial lining of blood vessels may serve as a source for rare endothelial colony-forming cells that display clonal proliferative potential, self-renewal, and in vivo vessel forming ability. The article also discusses the current gaps in our knowledge to prove whether the colony-forming cells are in fact derived from vascular endothelium. © 2010 American Heart Association, Inc.

Lynch M.,Indiana University | Abegg A.,Washington University in St. Louis
Molecular Biology and Evolution | Year: 2010

A central problem in evolutionary theory concerns the mechanisms by which adaptations requiring multiple mutations emerge in natural populations. We develop a series of expressions that clarify the scaling of the time to establishment of complex adaptations with population size, mutation rate, magnitude of the selective disadvantage of intermediate-state alleles, and the complexity of the adaptation. In general, even in the face of deleterious intermediate steps, the time to establishment is minimized in populations with very large size. Under a broad range of conditions, the time to establishment also scales by no more than the square of the mutation rate, regardless of the number of sites contributing to the adaptive change, demonstrating that the emergence of complex adaptations is only weakly constrained by the independent acquisition of mutations at the underlying sites. Mutator alleles with deleterious side effects have only moderate effects on the rate of adaptation in large populations but can cause a quantum decrease in the time to establishment of some adaptive alleles in small populations, although probably not at a high enough rate to offset the increased deleterious mutation load. Transient hypermutability, whereby a subset of gamete-producing cells mutate at an elevated rate in a nonheritable manner, may also elevate the rate of adaptation, although the effect is modest and appears to result from a simple increase in the rate of transitions between intermediate states rather than from the saltational production of doublet mutations. Taken together, these results illustrate the plausibility of the relatively rapid emergence of specific complex adaptations by conventional population genetic mechanisms and provide insight into the relative incidences of various paths of allelic adaptation in organisms with different population genetic features. © The Author 2010. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved.

Matthews N.L.,Indiana University
Computers in Human Behavior | Year: 2015

An experiment tested if higher skilled players would experience diminished aggression related outcomes compared to lower skilled players due to flow state optimization. Specifically, the study observed if higher flow states made narrative-defined game goals more salient, thus reducing focus on the more peripheral violent content. After controlling for the amount, type, and context of violence, higher skilled players experienced lower levels of hostility and aggression related cognitions and greater levels of flow than lower skilled players. Additionally, skill altered players' perceptions as well, as higher skilled players experienced higher construal levels and perceived less violence than lower skilled players. © 2015 Elsevier Ltd.

Walvoord E.C.,Indiana University
Journal of Adolescent Health | Year: 2010

Whether the secular trend of a decreasing age of puberty has continued over the past 50 years remains controversial. Data that had been classically used to address this issue are reviewed and large epidemiologic studies, which had not previously been included, are now considered to challenge the conclusions of prior debates of this topic. The effect and timing of excessive weight gain are discussed in detail and recent observations about the opposing effects of obesity on the pubertal timing of girls versus boys are considered. The second half of the review examines both the causes and the long-term health consequences of early puberty, touching on the possible effect of stress and endocrine-disrupting chemicals along with the risks of reproductive cancers, metabolic syndrome, and psychosocial consequences during adolescence and beyond. © 2010 Society for Adolescent Health and Medicine. All rights reserved.

Vance G.H.,Indiana University
Archives of Pathology and Laboratory Medicine | Year: 2011

Context.-The US Food and Drug Administration (FDA) announced it will exercise authority over laboratorydeveloped tests (LDTs). Laboratory-developed tests have traditionally been developed and offered in laboratories as a service to patients and regulated under the Clinical Laboratory Improvement Amendments of 1988 (Clinical Laboratory Improvements Act). Laboratories now face potential dual regulatory oversight from both the Centers for Medicare and Medicaid Services (CMS) and the FDA. The College of American Pathologists (CAP) constructed a proposal to minimize redundancy of agency oversight and burden to laboratories. Modifications to the proposal continue while the laboratory community awaits release of the guidance documents that will stipulate FDA requirements. Objective.-To describe the historical context framing the entry of FDA into the oversight of LDTs and outline the CAP LDT Proposal in its current form. Data Sources.-PubMed review of published literature; United States Constitution; and online information resources from the National Institutes of Health, FDA, and US Government. Conclusion.-The College of American Pathologists is a leader in laboratory quality and has unique insights into the benefits and risks to patients presented by LDTs. Continued dialog with officials from the FDA and CMS will promote public and private collaborative efforts to assure innovation of diagnostic testing, public information, and patient safety for clinical diagnostic testing. Copyright © 2011 College of American Pathologists.

Wiley A.S.,Indiana University
American Journal of Human Biology | Year: 2010

Humans are unique among mammals in that many consume cow's milk or other dairy products well beyond the traditional age of weaning. Milk provides various nutrients and bioactive molecules to support growth and development, and the question arises as to whether this dietary behavior influences growth parameters. There is evidence that milk makes positive contributions to growth in height, but its associations with other aspects of body size, such as body mass index (BMI), are not well-established. National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2004 and multivariate regression analysis were used to test the hypothesis that milk (g) or total dairy product consumption (kJ) is associated with higher BMI percentile among US White, Black, and Mexican- American children of age 2-4 years (n 5 1,493) and 5-10 years (n 5 2,526). Younger children in the highest quartile of dairy intake had higher BMIs (β 5 7.5-8.0; P < 0.01) than those in the lowest two quartiles. Controlling for energy intake eliminated differences between QIV and QI. Among children of 5-10 years of age dairy intake had no relationship to BMI. Young children in the highest quartile of milk intake had higher BMIs than all lower quartiles (β 5 7.1-12.8; β 5 6.3-11.8 in energy-controlled models; P < 0.05). Among children of 5-10 years of age, those in QIV for milk intake had higher BMIs than those in QII (β 5 8.3; β 5 7.1 in energy-controlled model; P < 0.01). Controlling for total protein or calcium did not change the results. Milk had more consistent positive associations with BMI than did dairy products, and these were strongest among children of 2-4 years of age. Am. J. Hum. Biol. 22:517-525, 2010. © 2010 Wiley-Liss, Inc.

Kuppalli K.,University of California at San Diego | Livorsi D.,Indiana University | Talati N.J.,University of Pennsylvania | Osborn M.,Emory University
The Lancet Infectious Diseases | Year: 2012

We present a case of a patient with Lemierre's syndrome caused by Fusobacterium necrophorum who developed a right frontal lobe brain abscess. We summarise the epidemiology, microbiology, pathogenesis, clinical presentation, diagnosis, complications, therapy, and outcomes of Lemierre's syndrome. F necrophorum is most commonly associated with Lemierre's syndrome: a septic thrombophlebitis of the internal jugular vein. Patients usually present with an exudative tonsillitis, sore throat, dysphagia, and unilateral neck pain. Diagnosis of septic thrombophlebitis is best confirmed by obtaining a CT scan of the neck with contrast. Complications of the disease include bacteraemia with septic abscesses to the lungs, joints, liver, peritoneum, kidneys, and brain. Treatment should include a prolonged course of intravenous beta-lactam antibiotic plus metronidazole. © 2012 Elsevier Ltd.

Sexual health is an evolving paradigm that integrates a positive approach to sexuality with existing public health policy and practice for reducing the burdens of sexually transmitted infections, including those due to HIV. The sexual health paradigm rests in commitment to sexual rights, sexual knowledge, sexual choice, and sexual pleasure, as well as key elements of sexuality addressed by sexual desire, sexual arousal, and sexual function, and sexual behaviors. The sexual health paradigm offers new approaches to supporting general health and well being while reducing the burdens of sexual diseases and their consequences. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Boustani M.A.,Indiana University
Clinical interventions in aging | Year: 2010

Complexity science suggests that our current health care delivery system acts as a complex adaptive system (CAS). Such systems represent a dynamic and flexible network of individuals who can coevolve with their ever changing environment. The CAS performance fluctuates and its members' interactions continuously change over time in response to the stress generated by its surrounding environment. This paper will review the challenges of intervening and introducing a planned change into a complex adaptive health care delivery system. We explore the role of the "reflective adaptive process" in developing delivery interventions and suggest different evaluation methodologies to study the impact of such interventions on the performance of the entire system. We finally describe the implementation of a new program, the Aging Brain Care Medical Home as a case study of our proposed evaluation process.

Ahsan Z.S.,Indiana University | Yao J.,Stanford University
Arthroscopy - Journal of Arthroscopic and Related Surgery | Year: 2012

Purpose: The purpose of this systematic review was to address the incidence of complications associated with wrist arthroscopy. Given the paucity of information published on this topic, an all-inclusive review of published wrist arthroscopy complications was sought. Methods: Two independent reviewers performed a literature search using PubMed, Google Scholar, EBSCO, and Academic Megasearch using the terms "wrist arthroscopy complications," "complications of wrist arthroscopy," "wrist arthroscopy injury," and "wrist arthroscopy." Inclusion criteria were (1) Levels I to V evidence, (2) "complication" defined as an adverse outcome directly related to the operative procedure, and (3) explicit description of operative complications in the study. Results: Eleven multiple-patient studies addressing complications of wrist arthroscopy from 1994 to 2010 were identified, with 42 complications reported from 895 wrist arthroscopy procedures, a 4.7% complication rate. Four case reports were also found, identifying injury to the dorsal sensory branch of the ulnar nerve, injury to the posterior interosseous nerve, and extensor tendon sheath fistula formation. Conclusions: This systematic review suggests that the previously documented rate of wrist arthroscopy complications may be underestimating the true incidence. The report of various complications provides insight to surgeons for improving future surgical techniques. Level of Evidence: Level IV, systematic review of Levels I-V studies. © 2012 Arthroscopy Association of North America.

Sun Y.,University of Virginia | Day R.N.,Indiana University | Periasamy A.,University of Virginia
Nature Protocols | Year: 2011

Fluorescence lifetime imaging microscopy (FLIM) is now routinely used for dynamic measurements of signaling events inside living cells, including detection of protein-protein interactions. An understanding of the basic physics of fluorescence lifetime measurements is required to use this technique. In this protocol, we describe both the time-correlated single photon counting and the frequency-domain methods for FLIM data acquisition and analysis. We describe calibration of both FLIM systems, and demonstrate how they are used to measure the quenched donor fluorescence lifetime that results from FÃ ¶rster resonance energy transfer (FRET). We then show how the FLIM-FRET methods are used to detect the dimerization of the transcription factor CCAAT/enhancer binding protein-Î ± in live mouse pituitary cell nuclei. Notably, the factors required for accurate determination and reproducibility of lifetime measurements are described. With either method, the entire protocol including specimen preparation, imaging and data analysis takes ∼2 d. © 2011 Nature America, Inc. All rights reserved.

Ding Y.,Indiana University
Journal of Informetrics | Year: 2011

The evolution of the Web has promoted a growing interest in social network analysis, such as community detection. Among many different community detection approaches, there are two kinds that we want to address: one considers the graph structure of the network (topology-based community detection approach); the other one takes the textual information of the network nodes into consideration (topic-based community detection approach). This paper conducted systematic analysis of applying a topology-based community detection approach and a topic-based community detection approach to the coauthorship networks of the information retrieval area and found that: (1) communities detected by the topology-based community detection approach tend to contain different topics within each community; and (2) communities detected by the topic-based community detection approach tend to contain topologically-diverse sub-communities within each community. The future community detection approaches should not only emphasize the relationship between communities and topics, but also consider the dynamic changes of communities and topics. © 2011.

Hauser K.,Indiana University
International Journal of Robotics Research | Year: 2014

This paper formulates a new minimum constraint removal (MCR) motion planning problem in which the objective is to remove the fewest geometric constraints necessary to connect a start and goal state with a free path. It describes a probabilistic roadmap motion planner for MCR in continuous configuration spaces that operates by constructing increasingly refined roadmaps, and efficiently solves discrete MCR problems on these networks. A number of new theoretical results are given for discrete MCR, including a proof that it is NP-hard by reduction from SET-COVER. Two search algorithms are described that perform well in practice. The motion planner is proven to produce the optimal MCR with probability approaching 1 as more time is spent, and its convergence rate is improved with various efficient sampling strategies. It is demonstrated on three example applications: generating human-interpretable excuses for failure, motion planning under uncertainty, and rearranging movable obstacles. © The Author(s) 2013.

Morris J.L.,Indiana University
Clinical Therapeutics | Year: 2012

Background: Gaucher disease (GD) is the most common lysosomal storage disease, (frequency of 1:40,000 to 1:60,000). Ninety-Five percent of patients have type 1 (nonneuropathic type). Symptomatic patients with type 1 GD are treated with enzyme replacement therapy (ERT) to improve disease-induced effects on hemoglobin, platelets, and liver and spleen volume. Currently, several ERTs are available. Objective: The goal of this article was to review the pharmacology, efficacy, and safety data available for the use of a recently approved ERT, velaglucerase alfa, for the treatment of type 1 GD in symptomatic pediatric and adult patients. Methods: Serial searches of MEDLINE, EMBASE, and Cochrane databases for English-language, peer-reviewed, clinical data (using the search term velaglucerase alfa) were completed, with the final search in November 2011. All identified, peer-reviewed published human data were used for this review. Due to minimal peer-reviewed published data, those data reported via clinical trial registries or in the form of published abstracts were included. The manufacturer was contacted and given the opportunity to submit supplemental data for consideration of inclusion by the author. Results: Velaglucerase alfa is produced through gene activation technology and is identical to wild-type enzyme. As with other ERTs for type 1 GD, velaglucerase alfa targets accumulated glucocerebroside primarily within the lysosome of the macrophages in the affected organs and systems. When administered at doses of 60 U/kg intravenously, velaglucerase alfa follows linear pharmacokinetics and is rapidly eliminated, with a mean (SD) residence time or time for 63% of the dose to be cleared from systemic circulation of 14 (4) minutes. Four trials and early access program data reporting efficacy were identified for this review: 5 peer-reviewed publications, 3 clinical trial registry reports, and 1 abstract-only publication. Phase I/II data with an extension phase (n = 12) showed significant improvements (all, P < 0.004) in hemoglobin concentrations (21.7%), platelet counts (157.8%), and hepatic (-42.8%) and spleen (-79.3%) volumes at 48 months. Bone mineral density data reported out to 69 months for this extension population noted significant improvements in z score slope for both lumbar spine (0.14 z score unit per year; P < 0.01) and femoral head (0.08 z score unit per year; P < 0.01). Benchmarking of 7 patients with complete clinical datasets at 57 months identified achievement and maintenance of therapeutic goals set by the International Collaborative Gaucher Group for anemia, platelet counts, hepatosplenomegaly, and bone mineral density. Thirty-eight patients enrolled in an open-label, therapy-switch trial who received velaglucerase alfa at doses consistent with current doses of imiglucerase maintained hemoglobin (-0.101 g/dL [95% CI, -0.272 to 0.07]) and platelet counts (7.04% [95% CI, 0.54% to 13.53%]) at 53 weeks after therapy change. Phase III data evaluating 2 dosing regimens of velaglucerase alfa 60 and 45 U/kg intravenously every other week reported significant improvements in most measured clinical parameters at 12 months: hemoglobin concentrations (60 U/kg, 2.429 [0.324] g/dL [P < 0.0001]; 45 U/kg, 2.438 g/dL [95% CI, 1.488 to 3.389]), platelet counts (60 U/kg, 50.88 × 10 9/L [95% CI, 23.97 to 77.78]; 45 U/kg, 40.92 × 10 9/L [95% CI, 11.2 to 70.64]), spleen volumes (60 U/kg, -1.92% of body weight [95% CI, -3.04 to -0.79]; 45 U/kg, -1.87% of body weight [95% CI, -3.17 to -0.57]), and hepatic volumes (60 U/kg, -0.84% of body weight [95% CI, -1.58 to -0.11]). A subanalysis of the pediatric population showed clinical improvements at 12 months in both dosing groups: hemoglobin concentrations (60 U/kg, 1.74 g/dL [95% CI, 0.72 to 2.78]; 45 U/kg, 2.77 g/dL [95% CI, -0.99 to 6.53]), platelet counts (60 U/kg, 49.9 × 10 9/L [95% CI, -32.1 to 131.9]; 45 U/kg, 60.3 × 10 9/L [95% CI, -103.1 to 223.7]), spleen volumes (60 U/kg, -2.1 cm 3 [95% CI, -5.3 to 1.1]; 45 U/kg, -0.7 cm 3 [95% CI, -2.6 to 1.2]), and hepatic volumes (60 U/kg, -0.7 cm 3 [95% CI, -1.4 to 0.0]; 45 U/kg, -0.3 cm 3 [95% CI, -1.7 to 1.1]). Data comparing velaglucerase alfa with imiglucerase identified similar changes in hemoglobin concentrations at 1.624 g/dL and 1.488 g/dL, respectively, after 9 months of therapy. Safety was reported in 3 identified studies and in data reported from the early access program: 3 peer-reviewed publications, 3 studies reported in clinical trial registries, and 1 abstract publication. Patients experienced a minimal number of adverse effects, and most reactions were mild to moderate in severity; 1 patient developed an anaphylactoid reaction and was discontinued from the trial. Antibody formation has been described with velaglucerase alfa but when compared with that of imiglucerase, seroconversion is less frequent (1% and 23%, respectively). Dosing regimens, from 30 to 60 U/kg intravenously every other week, have been assessed. Currently, the manufacturer recommends 60 U/kg intravenously every other week; however, further studies and evaluation of current study dosing regimens are needed to determine if there is a lower effective dose. Conclusions: Although a minimal amount of data are available for this relatively new biological agent, velaglucerase alfa reportedly is effective in the achievement and maintenance of therapeutic goals in type 1 GD in both treatment-naive and patients previously treated with imiglucerase. This agent has been reasonably well tolerated in clinical trials and may be considered for use in symptomatic patients with type 1 GD. © 2012 Elsevier HS Journals, Inc.

Hoang L.L.,Indiana University
Applied Immunohistochemistry and Molecular Morphology | Year: 2015

Distinguishing between invasive urothelial carcinoma from other genitourinary lesions such as prostatic and renal carcinomas can be difficult, and may require highly sensitive immunohistochemical markers. GATA-binding protein 3 (GATA3) has been reported in a high percentage of urothelial and breast carcinomas. Mouse monoclonal uroplakin II (UPII) and p40 antibodies have recently been developed and demonstrated high specificity in urothelial carcinoma. This study evaluated the immunohistochemical staining sensitivities of UPII, GATA3, p40, and p63 in the detection of invasive urothelial carcinoma. UPII, GATA3, and p40 were further tested for specificity in lung, breast, colon, kidney, and prostate cancers. In all invasive urothelial carcinoma cases, UPII, GATA3, p40, and p63 exhibited sensitivities of 77.7%, 83.5%, 85.4%, and 80.6%, respectively. The combination of UPII, GATA3, and p40 antibodies stained 94.2% (97/103) of all invasive urothelial carcinoma cases, including 92.2% (71/77) of grade 2-3 urothelial carcinomas. In addition, GATA3 and UPII showed negative staining in lung squamous cell carcinomas and p40 showed negative staining in breast infiltrating ductal carcinomas. The combination of UPII, GATA3, and p40 showed negative staining in lung adenocarcinoma, colon adenocarcinoma, and renal carcinomas. In conclusion, UPII, GATA3, and p40, when used in combination, are highly sensitive in the differential diagnosis of invasive urothelial carcinoma. © 2015 Lippincott Williams & Wilkins, Inc.

Network pharmacology has emerged as a new topic of study in recent years. It aims to study the myriad relationships among proteins, drugs, and disease phenotypes. The concept of molecular connectivity maps has been proposed to establish comprehensive knowledge links between molecules of interest in a given biological context. Molecular connectivity maps between drugs and genes/proteins in specific disease contexts can be particularly valuable, since the functional approach with these maps helps researchers gain global perspectives on both the therapeutic profiles and toxicological profiles of candidate drugs. To assess drug pharmacological effect, we assume that "ideal" drugs for a patient can treat or prevent the disease by modulating gene expression profiles of this patient to the similar level with those in healthy people. Starting from this hypothesis, we build comprehensive disease-gene-drug connectivity relationships with drug-protein directionality (inhibit/activate) information based on a computational connectivity maps (C2Maps) platform. An interactive interface for directionality annotation of drug-protein pairs with literature evidences from PubMed has been added to the new version of C2Maps. We also upload the curated directionality information of drug-protein pairs specific for three complex diseases - breast cancer, colorectal cancer and Alzheimer disease. For relevant drug-protein pairs with directionality information, we use breast cancer as a case study to demonstrate the functionality of disease-specific searching. Based on the results obtained from searching, we perform pharmacological effect evaluation for two important breast cancer drugs on treating patients diagnosed with different breast cancer subtypes. The evaluation is performed on a well-studied breast cancer gene expression microarray dataset to portray how useful the updated C2Maps is in assessing drug efficacy and toxicity information. The C2Maps platform is an online bioinformatics resource that provides biologists with directional relationships between drugs and genes/proteins in specific disease contexts based on network mining, literature mining, and drug effect annotating. A new insight to assess overall drug efficacy and toxicity can be provided by using the C2Maps platform to identify disease relevant proteins and drugs. The case study on breast cancer correlates very well with the existing pharmacology of the two breast cancer drugs and highlights the significance of C2Maps database.

Fogel E.L.,Indiana University
Journal of Gastrointestinal Surgery | Year: 2011

Traditionally, patients with symptomatic sterile pancreatic necrosis or infected necrosis have been managed by open surgical debridement and removal of necrotic tissue. Within the last decade, however, reports of endoscopic pancreatic necrosectomy, an alternative minimally invasive approach, have demonstrated high success rates and low mortality rates. This report describes the indications, technique, and study outcome data of the procedure. While our experience with this technique has recently increased, better selection criteria are needed to identify patients who are most suitable for endoscopic therapy. © 2011 The Society for Surgery of the Alimentary Tract.

Using data on 838 middle adolescents, the current study compared the associations between three types of romantic involvement and alcohol, tobacco, and marijuana use. Off-time (i.e., serious romantic relationships) but not on-time (i.e., romantic socializing and dating) types of involvement were expected to be associated with increased odds of using each substance. Participating in romantic socializing was unrelated to substance use and dating was only positively associated with alcohol use. Participation in serious romantic relationships, however, was associated with an increased likelihood of having used each substance. Associations did not differ between males and females. Based on these results some but not all forms of romantic involvement may place middle adolescents at risk for substance use. Implications for parents and relationship education are discussed. © 2015 The Foundation for Professionals in Services for Adolescents.

Poplawski N.J.,Indiana University
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2010

We use the Papapetrou method of multipole expansion to show that a Dirac field in the Einstein-Cartan-Kibble-Sciama (ECKS) theory of gravity cannot form singular configurations concentrated on one- or two-dimensional surfaces in spacetime. Instead, such a field describes a nonsingular particle whose spatial dimension is at least on the order of its Cartan radius. In particular, torsion modifies Burinskii's model of the Dirac electron as a Kerr-Newman singular ring of the Compton size, by replacing the ring with a toroidal structure with the outer radius of the Compton size and the inner radius of the Cartan size. We conjecture that torsion produced by spin prevents the formation of singularities from matter composed of quarks and leptons. We expect that the Cartan radius of an electron, ∼ 10- 27   m, introduces an effective ultraviolet cutoff in quantum field theory for fermions in the ECKS spacetime. We also estimate a maximum density of matter to be on the order of the corresponding Cartan density, ∼ 1051   kg m- 3, which gives a lower limit for black-hole masses ∼ 1016   kg. This limit corresponds to energy ∼ 1043   GeV which is 39 orders of magnitude larger than the maximum beam energy currently available at the LHC. Thus, if torsion exists and the ECKS theory of gravity is correct, the LHC cannot produce micro black holes. © 2010 Elsevier B.V. All rights reserved.

Navari R.,Indiana University
Expert Opinion on Pharmacotherapy | Year: 2013

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in the quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient characteristics (female gender, younger age, low alcohol consumption, history of motion sickness) are the major risk factors for CINV. Palonosetron, a second-generation 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, has antiemetic activity at both central and gastrointestinal sites. In comparison to the first-generation 5-HT3 receptor antagonists, it has a higher potency, a significantly longer half-life, and a different molecular interaction with 5-HT3 receptors. Palonosetron has been approved for the prevention of acute CINV in patients receiving either moderately or highly emetogenic chemotherapy and for the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy. Compared to the first-generation 5-HT3 receptor antagonists, palonosetron in combination with dexamethasone has demonstrated better control of delayed CINV in patients receiving highly emetogenic chemotherapy and had a similar safety profile. Due to its efficacy in controlling both acute and delayed CINV, palonosetron may be very effective in the clinical settings of multiple-day chemotherapy and bone marrow transplantation. © 2013 Informa UK, Ltd.

Rex D.K.,Indiana University
Gastroenterology Clinics of North America | Year: 2013

The primary goal of most colonoscopies, whether performed for screening, surveillance, or diagnostic examinations (those performed for symptoms or positive screening tests other than colonoscopy) is the detection of neoplasia and its subsequent removal by either endoscopic polypectomy or referral for surgical resection. Unfortunately, colonoscopy has proved to be a highly operator-dependent procedure with regard to detection. Variable detection results in some of the cancers that occur in the interval before the next colonoscopy. © 2013 Elsevier Inc.

MacDorman K.F.,Indiana University | Kageki N.,GetRobo.com
IEEE Robotics and Automation Magazine | Year: 2012

Recently, the concept of the uncanny valley has rapidly attracted interest in robotics and other scientific circles as well as in popular culture. According to Masahiro Mori, a robotics professor at the Tokyo Institute of Technology, who first researched on this subject, a person's response to a humanlike robot would abruptly shift from empathy to revulsion as it approached, but failed to attain, a lifelike appearance. This descent into eeriness is known as the uncanny valley. As healthy persons, we are represented at the second peak (moving). Then when we die, we are unable to move; the body goes cold, and the face becomes pale. Therefore, our death can be regarded as a movement from the second peak (moving) to the bottom of the uncanny valley (still). Researchers should begin to build an accurate map of the uncanny valley so that through robotics research they can begin to understand what makes them human.

Corrigan J.D.,Ohio State University | Hammond F.M.,Indiana University
Archives of Physical Medicine and Rehabilitation | Year: 2013

Growing evidence indicates that multiple types of brain injury, including traumatic brain injury, are dynamic conditions that continue to change years after onset. For a subset of individuals who incur these injuries, decline occurs over time and is likely due to progressive neurodegenerative processes, comorbid conditions, aging, behavioral choices, and/or psychosocial factors. Deterioration, whether directly or indirectly associated with the original brain injury, necessitates a clinical approach as a chronic health condition, including identification of risk and protective factors, protocols for early identification, evidence-based preventive and ameliorative treatment, and training in self-management. We propose that the acknowledgment of chronic brain injury will facilitate the research necessary to provide a disease management approach. © 2013 by the American Congress of Rehabilitation Medicine.

Lippert F.,Indiana University
Monographs in Oral Science | Year: 2013

Toothpaste is a paste or gel to be used with a toothbrush to maintain and improve oral health and aesthetics. Since their introduction several thousand years ago, toothpaste formulations have evolved considerably - from suspensions of crushed egg shells or ashes to complex formulations with often more than 20 ingredients. Among these can be compounds to combat dental caries, gum disease, malodor, calculus, erosion and dentin hypersensitivity. Furthermore, toothpastes contain abrasives to clean and whiten teeth, flavors for the purpose of breath freshening and dyes for better visual appeal. Effective toothpastes are those that are formulated for maximum bioavailability of their actives. This, however, can be challenging as compromises will have to be made when several different actives are formulated in one phase. Toothpaste development is by no means complete as many challenges and especially the poor oral substantivity of most active ingredients are yet to overcome. © 2013 S. Karger AG, Basel.

Kwo P.Y.,Indiana University
Clinics in Liver Disease | Year: 2013

The addition of boceprevir to peginterferon and ribavirin has improved sustained response rates markedly. Boceprevir is effective in treatment naïve, relapsers, partial responders, and null responders. Those with advanced fibrosis require 44 weeks of boceprevir therapy after a 4-week peg/ribavirin lead-in. The main side effect with boceprevir is anemia and ribavirin dose reduction is an effective strategy. This review examines the current treatment paradigm of boceprevir-based treatment of chronic hepatitis C, examining treatment paradigms, predictors of response, futility rules, as well as preliminary results from studies examining boceprevir efficacy in additional populations. Further follow-up in these cohorts will be required. © 2013 Elsevier Inc.

Lysaker P.H.,Roudebush Medical Center 116A | Lysaker P.H.,Indiana University | Dimaggio G.,Centro Of Terapia Metacognitiva Interpersonale
Schizophrenia Bulletin | Year: 2014

Models of schizophrenia, which focus exclusively on discrete symptoms and neurocognitive deficits, risk missing the possibility that a core feature of the disorder involves a reduced capacity to construct complex and integrated representations of self and others. This column details a new methodology that has been used to assess deficits in the metacognitive abilities that allow persons to form complex ideas about themselves and others and to use that knowledge to respond to psychosocial challenges in schizophrenia. Evidence is summarized supporting the reliability and validity of this method, as well as links this work has revealed between metacognition and psychosocial outcomes. It is suggested that this work points to the need to develop interventions which move beyond addressing symptoms and specific skills, and assist persons to recapture lost or atrophied metacognitive capacity and so form the kind of ideas about themselves and others needed, to move meaningfully toward recovery. © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.

Multidrug resistance has been increasing among Gram-negative bacteria and is strongly associated with the production of both chromosomal- and plasmid-encoded β-lactamases, whose number now exceeds 890. Many of the newer enzymes exhibit broad-spectrum hydrolytic activity against most classes of β-lactams. The most important plasmid-encoded β-lactamases include (a) AmpC cephalosporinases produced in high quantities, (b) the expanding families of extended-spectrum β-lactamases such as the CTX-M enzymes that can hydrolyze the advanced-spectrum cephalosporins and monobactams, and (c) carbapenemases from multiple molecular classes that are responsible for resistance to almost all β-lactams, including the carbapenems. Important plasmid-encoded carbapenemases include (a) the KPC β-lactamases originating in Klebsiella pneumoniae isolates and now appearing worldwide in pan-resistant Gram-negative pathogens and (b) metallo-β-lactamases that are produced in organisms with other deleterious β-lactamases, causing resistance to all β-lactams except aztreonam. β-Lactamase genes encoding these enzymes are often carried on plasmids that bear additional resistance determinants for other antibiotic classes. As a result, some infections caused by Gram-negative pathogens can now be treated with only a limited number, if any, antibiotics. Because multidrug resistance in Gram-negative bacteria is observed in both nosocomial and community isolates, eradication of these resistant strains is becoming more difficult. © 2010 BioMed Central Ltd.

Carley S.,Indiana University
Energy Policy | Year: 2011

This paper evaluates whether the U.S. electricity sector is directed away from carbon-intensive technological lock-in, and which factors are contributing, or have potential to contribute, to a possible reorientation of the industry. With the application of a historical analysis of the electricity sector from the late nineteenth century through current day, this analysis finds that, although the industry still relies primarily on carbon-intensive fossil fuel operations, several recent trends indicate that the industry is becoming less carbon intensive, smaller in generation system scale, and more sustainable in operations. Crucial drivers-firm level interactions with technological change, industry leadership and market structure, government intervention and policy momentum, and citizen involvement and behavior patterns-that have traditionally shaped the structure, scale, and environmental footprint of the industry, have also played a prominent role in recent transformations. These results indicate that triggering or extraordinary events may not be necessary to initiate an escape from carbon lock-in in the electricity sector. Complete escape is not yet definitive, however, and it remains to be seen whether the industry is able to transform entirely before any significant climate change disturbances occur. © 2010 Elsevier Ltd.

Cardiac allograft vasculopathy (CAV) is the principal cause of long-term graft failure following heart transplantation. Early identification of patients at risk of CAV is essential to target invasive follow-up procedures more effectively and to establish appropriate therapies. We evaluated the prognostic value of the first heart biopsy (median: 9 days post-transplant) versus all biopsies obtained within the first three months for the prediction of CAV and graft failure due to CAV. In a prospective cohort study, we developed multivariate regression models evaluating markers of atherothrombosis (fibrin, antithrombin and tissue plasminogen activator [tPA]) and endothelial activation (intercellular adhesion molecule-1) in serial biopsies obtained during the first three months post-transplantation from 172 patients (median follow-up = 6.3 years; min = 0.37 years, max = 16.3 years). Presence of fibrin was the dominant predictor in first-biopsy models (Odds Ratio [OR] for one- and 10-year graft failure due to CAV = 38.70, p = 0.002, 95% CI = 4.00-374.77; and 3.99, p = 0.005, 95% CI = 1.53-10.40) and loss of tPA was predominant in three-month models (OR for one- and 10-year graft failure due to CAV = 1.81, p = 0.025, 95% CI = 1.08-3.03; and 1.31, p = 0.001, 95% CI = 1.12-1.55). First-biopsy and three-month models had similar predictive and discriminative accuracy and were comparable in their capacities to correctly classify patient outcomes, with the exception of 10-year graft failure due to CAV in which the three-month model was more predictive. Both models had particularly high negative predictive values (e.g., First-biopsy vs. three-month models: 99% vs. 100% at 1-year and 96% vs. 95% at 10-years). Patients with absence of fibrin in the first biopsy and persistence of normal tPA in subsequent biopsies rarely develop CAV or graft failure during the next 10 years and potentially could be monitored less invasively. Presence of early risk markers in the transplanted heart may be secondary to ischemia/reperfusion injury, a potentially modifiable factor.

Butterworth J.F.,Indiana University
Regional Anesthesia and Pain Medicine | Year: 2010

Cardiovascular collapse, even death, may occur after intoxication with bupivacaine or related amide local anesthetic agents. The problem has been studied in myriad laboratories for more than 20 years. Nevertheless, there is consensus neither regarding which animal model best mimics this clinical catastrophe nor as to which ion channel, enzyme, or other local anesthetic binding site represents the point of initiation for the process. This review aimed to define the various credible mechanisms that have been proposed to explain cardiovascular collapse and death after administration of local anesthetics, particularly after bupivacaine and related agents. Copyright © 2010 by American Society of Regional Anesthesia and Pain Medicine.

Schmidt C.M.,Indiana University
Journal of Gastrointestinal Surgery | Year: 2011

Background: Necrotizing pancreatitis is the most severe end of the spectrum of acute pancreatitis. Interventional treatment (i.e., "who, when, and how") of necrotizing pancreatitis is an ongoing source of considerable controversy. Novel minimally invasive strategies are being increasingly employed to perform pancreatic necrosectomy. Methods: The Society for Surgery of the Alimentary Tract, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy recently convened a State-of-the-Art Conference to analyze the experience and evidence that these minimally invasive treatments are beneficial in select patients with necrotizing pancreatitis. Conclusions: This article serves as a general introduction to the State-of-the-Art Conference, Necrotizing Pancreatitis: Novel Minimally Invasive Strategies. © 2011 The Society for Surgery of the Alimentary Tract.

Goldberg R.B.,University of Miami | Mather K.,Indiana University
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2012

This review describes the effect of lifestyle change or metformin compared with standard care on incident type 2 diabetes and cardiometabolic risk factors in the Diabetes Prevention Program and its Outcome Study. The Diabetes Prevention Program was a randomized controlled clinical trial of intensive lifestyle and metformin treatments versus standard care in 3234 subjects at high risk for type 2 diabetes. At baseline, hypertension was present in 28% of subjects, and 53% had metabolic syndrome with considerable variation in risk factors by age, sex, and race. Over 2.8 years, type 2 diabetes incidence fell by 58% and 31% in the lifestyle and metformin groups, respectively, and metabolic syndrome prevalence fell by one-third with lifestyle change but was not reduced by metformin. In placebo-and metformin-treated subjects, the prevalence of hypertension and dyslipidemia increased during the Diabetes Prevention Program, whereas lifestyle intervention slowed these increases significantly. During long-term follow-up using modified interventions, type 2 diabetes incidence decreased to ∼5% per year in all groups. This was accompanied by significant improvement in cardiovascular disease risk factors over time in all treatment groups, in part associated with increasing use of lipid-lowering and antihypertensive medications. Thus a program of lifestyle change significantly reduced type 2 diabetes incidence and metabolic syndrome prevalence in subjects at high risk for type 2 diabetes. Metformin had more modest effects. © 2012 American Heart Association, Inc.

Marin-Franch I.,Indiana University | Foster D.H.,University of Manchester
IEEE Transactions on Pattern Analysis and Machine Intelligence | Year: 2013

The colors present in an image of a scene provide information about its constituent elements. But the amount of information depends on the imaging conditions and on how information is calculated. This work had two aims. The first was to derive explicitly estimators of the information available and the information retrieved from the color values at each point in images of a scene under different illuminations. The second was to apply these estimators to simulations of images obtained with five sets of sensors used in digital cameras and with the cone photoreceptors of the human eye. Estimates were obtained for 50 hyperspectral images of natural scenes under daylight illuminants with correlated color temperatures 4,000, 6,500, and 25,000 K. Depending on the sensor set, the mean estimated information available across images with the largest illumination difference varied from 15.5 to 18.0 bits and the mean estimated information retrieved after optimal linear processing varied from 13.2 to 15.5 bits (each about 85 percent of the corresponding information available). With the best sensor set, 390 percent more points could be identified per scene than with the worst. Capturing scene information from image colors depends crucially on the choice of camera sensors. © 1979-2012 IEEE.

Zhang N.,Indiana University
American journal of ophthalmology | Year: 2013

To examine surgical and refractive outcomes of phacoemulsification with intraocular lens (IOL) implant in eyes with prior trabeculectomy. Retrospective observational case-control study. The study compared eyes that underwent phacoemulsification with IOL implant at least 3 months post-trabeculectomy (n = 77) with eyes with either medically controlled glaucoma (n = 43) or no glaucoma (n = 50) at an academic institution. The main outcome measure was the difference between the expected and the actual postoperative refraction. Mean intraocular pressure (IOP) increased in trabeculectomy eyes from 8.7 ± 4.2 mm Hg to 10.7 ± 4.0 mm Hg (P < .0001), whereas it decreased in glaucoma control and normal control groups by 2.0 mm Hg (P = .003) and 2.1 mm Hg (P < .00001), respectively, with concurrent decrease in drops in the glaucoma control group (0.76 to 0.23, P < .0001). The difference from expected refractive outcome was -0.36 (more myopic) in trabeculectomy eyes compared with +0.23 (more hyperopic) in nonglaucoma controls and +0.40 in glaucoma controls (P < .0001). The correlation between change in IOP vs extent of refractive surprise was statistically significant (P = .01, r = -0.20). Final visual acuity was not affected by the difference in refractive error. The refractive surprise correlated to IOP change, with 2 mm Hg rise resulting in a -0.36 diopter shift between predicted and actual refraction. After cataract extraction, IOP decreased in controls and fewer drops were required, but IOP increased in the study group. Factors affecting refractive surprise in cataract surgery after trabeculectomy, especially IOP change and axial length, require further investigation. Copyright © 2013 Elsevier Inc. All rights reserved.

Rusyniak D.E.,Indiana University
Psychiatric Clinics of North America | Year: 2013

The drug with perhaps the greatest impact on the practice of Psychiatry is Methamphetamine. By increasing the extracellular concentrations of dopamine while slowly damaging the dopaminergic neurotransmission, Meth is a powerfully addictive drug whose chronic use preferentially causes psychiatric complications. Chronic Meth users have deficits in memory and executive functioning as well as higher rates of anxiety, depression, and most notably psychosis. It is because of addiction and chronic psychosis from Meth abuse that the Meth user is most likely to come to the attention of the practicing Psychiatrist/Psychologist. Understanding the chronic neurologic manifestations of Meth abuse will better arm practitioners with the diagnostic and therapeutic tools needed to make the Meth epidemic one of historical interest only. © 2013 Elsevier Inc.

Cole D.H.,Indiana University
Climate Law | Year: 2011

Global governance institutions for climate change, such as those established by the UNFCCC and the Kyoto Protocol, have so far failed to make a significant impact on greenhouse gas emissions. Following the lead of Elinor Ostrom, this paper offers an alternative theoretical framework for reconstructing global climate policy in accordance with the polycentric approach to governance pioneered in the early 1960s by Vincent Ostrom, Charles Tiebout, and Robert Warren. Instead of a thoroughly top-down global regime, in which lower levels of government simply carry out the mandates of international negotiators, a polycentric approach provides for greater experimentation, learning, and cross-influence among different levels and units of government, which are both independent and interdependent. After exploring several of the design flaws of the existing set of global institutions and organizations for greenhouse gas mitigation, the paper explores how those global institutions and organizations might be improved by learning from various innovative policies instituted by local, state, and regional governments. The paper argues that any successful governance system for stabilizing the global climate must function as part of a larger, polycentric set of nested institutions and organizations at various governmental levels. © 2012-IOS Press and the authors. All rights reserved.

Fan R.,Indiana University
American Journal of Surgical Pathology | Year: 2012

Neuroblastoma is the most common extracranial solid tumor to occur during infancy and early childhood. However, primary renal neuroblastoma is rare, and only scattered case reports exist in the English medical literature. We report 8 cases that accumulated at our institution over the past 15 years and summarize their clinicopathologic features. The composite picture of a patient with renal neuroblastoma is that of a boy of 17 months of age, who presented with a large renal mass, about 9 cm in size, accompanied by hypertension. The mass was typically hemorrhagic, either encapsulated or unencapsuated, and infiltrating. A renal neuroblastoma can be undifferentiated, poorly differentiated, or differentiating; it falls into either the favorable or the unfavorable histology category, and presentation at higher stages is the rule. The N-myc is usually unamplified, and the bone marrow is usually not involved at presentation. Unless the tumor is undifferentiated or very poorly differentiated, patients with renal neuroblastoma fare well, although not without new and improved modalities of treatment. Primary renal neuroblastoma is perhaps more common than people realize; a higher level of awareness and early recognition are important for its prognosis and management, as they are very different from Wilms tumor. Copyright © 2011 by Lippincott Williams &Wilkins.

Anthony T.G.,Rutgers University | Wek R.C.,Indiana University
Cell Metabolism | Year: 2012

During the progression of diabetes, crosstalk between ER stress and inflammation controls islet cell fate. In this issue, Lerner et al. (2012) and Oslowski et al. (2012) discover that thioredoxin-interacting protein (TXNIP) is a regulatory switch connecting the terminal unfolded protein response (UPR) and NLRP3 inflammasome to mediate β cell death. © 2012 Elsevier Inc.

Broxmeyer H.E.,Indiana University
Annals of the New York Academy of Sciences | Year: 2012

Cord blood (CB) transplantation has been used over the last 24 years to treat patients with malignant and nonmalignant disorders. CB has its advantages and disadvantages compared with other sources of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) for transplantation. More knowledge of the cytokines and intracellular signaling molecules regulating HSCs and HPCs could be used to modulate these regulators for clinical benefit. This review provides information about the general field of CB transplantation and about studies from the author's laboratory that focus on regulation of HSCs and HPCs by CD26/DPPIV, SDF-1/CXCL12, the Rheb2-mTOR pathway, SIRT1, DEK, cyclin-dependent kinase inhibitors, and cytokines/growth factors. Cryopreservation of CB HSCs and HPCs is also briefly discussed. © 2012 New York Academy of Sciences.

Background: A growing literature has documented that aphasia is frequently accompanied by deficits of short-term memory (STM) and working memory (WM), and that such memory impairments may negatively influence language abilities and aphasia treatment outcomes. Consequently, treating STM and WM impairments in individuals with aphasia should not only remediate these memory impairments but also positively affect their response to language therapy programmes.Aims: This paper critically reviews the aphasia literature pertaining to remediating, directly or indirectly, STM and WM deficits. Memory treatment protocols developed for other disordered as well as healthy populations are also discussed as possible therapy approaches to consider in future aphasia research.Main Contribution: Findings from a limited set of studies suggest that STM and WM impairments in individuals with aphasia do respond to treatment, and further that these treatments may also positively affect the language abilities of individuals with aphasia.Conclusions: Further research is warranted to establish the reliability and validity of these preliminary findings and to explore application of these treatments as well as those developed for nonaphasic populations to individuals representing a broader spectrum of aphasia types and severities. © 2012 Copyright 2012 Psychology Press, an imprint of the Taylor & Francis Group, an Informa business.

Morris D.L.,Indiana University
Molecular Endocrinology | Year: 2015

Chronic systemic inflammation is a hallmark feature of obesity and type 2 diabetes. Both resident and recruited islet macrophages contribute to the proinflammatory milieu of the diabetic islet. However, macrophages also appear to be critical for β -cell formation during development and support β-cell replication in experimental models of pancreas regeneration. In light of these findings, perhaps macrophages in the islet need to be viewed more as a fulcrum where deleterious inflammatory activation is balanced with beneficial tissue repair processes. Undoubtedly, defining the factors that contribute to the ontogeny, heterogeneity, and functionality of macrophages in normal, diseased, and regenerating islets will be necessary to determine whether that fulcrum can be moved to preserve functional β-cell mass in persons with diabetes. The intent of this review is to introduce the reader to emerging concepts of islet macrophage biology that may challenge the perception that macrophage accumulation in islets is merely a pathological feature of type 2 diabetes. © 2015 by the Endocrine Society.

Lynch M.,Indiana University
Genome Biology and Evolution | Year: 2011

Despite substantial attention from theoreticians, the evolutionary mechanisms that drive intra- and interspecific variation in the mutation rate remain unclear. It has often been argued that mutation rates associated with the major replicative polymerases have been driven down to their physiological limits, defined as the point at which further enhancement in replication fidelity incurs a cost in terms of reproductive output, but no evidence in support of this argument has emerged for cellular organisms. Here, it is suggested that the lower barrier to mutation rate evolution may ultimately be defined not by molecular limitations but by the power of random genetic drift. As the mutation rate is reduced to a very low level, a point will eventually be reached at which the small advantage of any further reduction is overwhelmed by the power of drift. This hypothesis is consistent with a number of observations, including the inverse relationship between the per-site mutation rate and genome size in microbes, the negative scaling between the per-site mutation rate and effective population size in eukaryotes, and the elevated error rates associated with less frequently deployed polymerases and repair pathways. © The Author(s) 2010.

Cheng L.,Indiana University
Current drug targets | Year: 2015

Prostate cancer is the most common and second most lethal cancer in men. The majority of prostate cancers are histologically similar to acinar adenocarcinomas and rely on androgen-dependent signaling for their development and progression. Androgen deprivation therapy is a mainstay of treatment regimens and we discuss the recent advancements in androgen-deprivation therapy. Recent advances in defining the genetic landscape of prostate cancer have shown that the depth of genetic heterogeneity surpasses what can be seen histologically and has the ability to redefine treatments. TMPRSS2-ETS family fusion proteins are unique to prostate cancer and we discuss their role in carcinogenesis, prognosis, and the development of TMPRSS2-ETS family gene fusion targeted therapy. Inactivation of the tumor suppressor PTEN leads to activation of the PI3K/Akt/mTOR pathway and we discuss the prognostic and treatment implications. Molecular genetic analysis has recently demonstrated that clinically aggressive high grade neuroendocrine prostate carcinomas contain a high prevalence of overexpression of Aurora A kinase and N-myc. We discuss the role of Aurora A kinase and N-myc in the development of the aggressive neuroendocrine phenotype and the development of targeted inhibitors of this specific genetic subtype. Lastly, we briefly discuss emerging genetic subtypes defined by either SPINK1 overexpression, CHD1 inactivation, or SPOP mutations. By reviewing the associations between the morphologic features and the molecular genetics of prostate cancer we hope to provide insight and guidance to the emerging options for targeted therapy.

Agarwal R.,Indiana University
Nephrology Dialysis Transplantation | Year: 2013

Background. Although the cardiac biomarker B-type natriuretic peptide (BNP) is strongly related to mortality in end-stage renal disease (ESRD), whether it is a predictor of weight change or blood pressure (BP) response upon probing dry weight among hypertensive hemodialysis patients remains unknown. The purpose of this study was to examine among people with hypertension on hemodialysis whether BNP is a biomarker of excess volume. Methods. Hypertensive hemodialysis patients (n = 150) were randomized to a control group (n = 50) or an ultrafiltration group (n = 100) and followed up for 30 dialysis treatments. After a baseline run-in of six treatments, those assigned to the ultrafiltration group had dry weight probed over 8 weeks. Forty-fourhour interdialytic ambulatory BP and predialysis BNP were measured at the end of run-in period, at 4 weeks and at 8 weeks. Results. The median BNP concentration was 93 pg/mL (interquartile range 31-257 pg/mL). The magnitude of decline in the BNP depended on the baseline concentration of BNP, but did not require probing dry weight or weight loss. No relationship existed between decline in postdialysis weight upon probing dry weight and baseline BNP. Furthermore, reduction in the BNP was not required for decline in postdialysis weight. Predialysis log BNP modestly predicted ambulatory systolic and pulse pressure independently of other risk factors. No relationship was found between decline in BP upon probing dry weight and baseline BNP. Upon probing dry weight, reduction in BNP was not required for decline in systolic ambulatory BP. Conclusion. Taken together, these data suggest that among hypertensive patients on hemodialysis BNP is not a volume marker. © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

O'Brien T.L.,Indiana University
Science Technology and Human Values | Year: 2012

Coauthored scholarship increased substantially across fields of science during the twentieth century, but it is unclear whether this growth reflects change in the behavior of individual scientists (i.e., career aging) or publishing differences between cohorts of researchers (i.e., cohort succession). I examine the publication records of an interdisciplinary sample of university scientists and find evidence of both career-aging and cohort-succession processes, although cohort differences are much more pronounced than individual changes. Specifically, scientists in this sample increased the percentage of their articles with coauthors by 0.63 percentage points annually. However, compared to those who received their PhDs between 1953 and 1962, scientists who entered the workforce between 1983 and 1991 coauthored approximately one third more of their early career articles (35.63 percentage points). Additionally, career-aging processes in coauthorship varied by PhD cohort, with earlier trained researchers increasing more rapidly. Overall, this article highlights cohort succession as a source of change in coauthorship, and underscores the importance of accounting for generational differences in studies of scientific careers. © The Author(s) 2012.

Deng S.,Dartmouth College | Viola L.,Dartmouth College | Ortiz G.,Indiana University
Physical Review Letters | Year: 2012

We present a time-reversal invariant s-wave superconductor supporting Majorana edge modes. The multiband character of the model together with spin-orbit coupling are key to realizing such a topological superconductor. We characterize the topological phase diagram by using a partial Chern number sum, and show that the latter is physically related to the parity of the fermion number of the time-reversal invariant modes. By taking the self-consistency constraint on the s-wave pairing gap into account, we also establish the possibility of a direct topological superconductor-to-topological insulator quantum phase transition. © 2012 American Physical Society.

Bhattacharjee S.,University of Notre Dame | Stahelin R.V.,University of Notre Dame | Stahelin R.V.,Indiana University | Speicher K.D.,Wistar Institute | And 2 more authors.
Cell | Year: 2012

Hundreds of effector proteins of the human malaria parasite Plasmodium falciparum constitute a "secretome" carrying a host-targeting (HT) signal, which predicts their export from the intracellular pathogen into the surrounding erythrocyte. Cleavage of the HT signal by a parasite endoplasmic reticulum (ER) protease, plasmepsin V, is the proposed export mechanism. Here, we show that the HT signal facilitates export by recognition of the lipid phosphatidylinositol-3-phosphate (PI(3)P) in the ER, prior to and independent of protease action. Secretome HT signals, including those of major virulence determinants, bind PI(3)P with nanomolar affinity and amino acid specificities displayed by HT-mediated export. PI(3)P-enriched regions are detected within the parasite's ER and colocalize with endogenous HT signal on ER precursors, which also display high-affinity binding to PI(3)P. A related pathogenic oomycete's HT signal export is dependent on PI(3)P binding, without cleavage by plasmepsin V. Thus, PI(3)P in the ER functions in mechanisms of secretion and pathogenesis. © 2012 Elsevier Inc.

Condom use remains central to sexually transmitted infections/HIV prevention among gay men and other men who have sex with men (MSM). To support the development of accurate and appropriate interventions, a better understanding is needed as to how the characteristics of a given sexual event differentially influence condom use during anal intercourse. Daily diary data were collected from (n = 3877) HIV-negative MSM who were members of several online Web sites facilitating social or sexual interactions with other men. Sexual event-specific factors related to condom use during anal intercourse were evaluated using logistic regression, with generalized estimating equation adjustment for multiple within-participant sexual events (STATA, 10.0; all P < 0.05). Participants contributed 25,149 behavioral diaries. Of these, men reported 730 (2.9%) acts of anal intercourse as insertive partner and 662 (2.6%) as receptive partner. Condoms were used during 25.5% (n = 184) of insertive events, and 18.8% (n = 125) of receptive events. For both insertive and receptive anal roles, condom use was more likely with casual partners (OR = 4.24-6.59). Positive ratings of sexual pleasure were associated with condom use among men who were the insertive partner during anal intercourse, whereas condom nonuse was significantly related to higher ratings of pleasure among men who were the receptive partner. Event-level relational and sexual-situational factors predict condom use differently, depending on whether men are the insertive or receptive partner in anal intercourse. Understanding these differences will help clinicians and health educators engage MSM in dialogue to increase condom use in situations where it is warranted.

Schwarz R.E.,Indiana University
Journal of Gastrointestinal Surgery | Year: 2015

Despite a continually decreasing incidence trend, gastric cancer remains a high-risk malignancy. Symptoms are often unspecific, and upper gastrointestinal endoscopy is the key modality for diagnosing early and intermediate-stage disease. Surgeons play a critical role in guiding and managing multiple aspects of gastric cancer diagnosis and care. Potentially curable gastric adenocarcinoma has to be free of distant metastasis and should be staged through endoscopic ultrasound and computed tomography. Early (T1N0) gastric cancer can be considered for endosopic mucosal resection or submucosal dissection. All other M0 stage groups should be evaluated for preoperative chemotherapy or chemoradiation followed by resection through a multidisciplinary approach. Laparoscopic staging, complete (R0) resection, and extended lymphadenectomy (D2 dissection) are critical operative components that optimize curability during gastrectomy. The morbidity potential after gastrectomy remains high; splenectomy and distal pancreatectomy should be avoided if possible to minimize postoperative complications. Laparoscopic gastric cancer resections are increasingly pursued and have not shown disadvantages to open gastrectomy as long as oncologic principles are followed. For the palliation of specific symptoms in patients with incurable gastric cancer, operative interventions should be applied selectively if less invasive modalities are insufficient and only if a meaningful benefit can be expected from a resection or bypass procedure. Prophylactic total gastrectomy should be considered for individuals at risk for hereditary diffuse-type gastric cancer through germline E-cadherin gene mutations. Surgeons engaging in gastric cancer care are expected to provide specialty expertise in order to plan and deliver appropriate care, minimize postoperative morbidity, and optimize resulting survival. © 2015, The Society for Surgery of the Alimentary Tract.

Wright P.J.,Indiana University
Archives of Sexual Behavior | Year: 2015

National panel data gathered in 2008 (T1) and 2010 (T2) from 420 Black and White US adults aged 18–89 years (M = 45.37, SD = 15.85) were employed to assess prospective associations between pornography consumption and premarital sex attitudes. Premarital sex attitudes were indexed via a composite measure of perceptions of the appropriateness of adults and teenagers having premarital sex. Wright’s (2011) sexual script acquisition, activation, application model (3AM) of media sexual socialization was used as the guiding theoretical framework. The 3AM maintains that sexual media may be used by consumers to inform their sexual scripts but that attitude change from exposure to sexual media is less likely when media scripts are incongruent with consumers’ preexisting scripts. Consistent with these postulates, the association between pornography consumption at T1 and more positive attitudes toward premarital sex at T2 was strongest for younger adults, who are less oppositional to premarital sex than older adults. Contrary to the position that associations between pornography consumption and premarital sex attitudes are due to individuals who already have positive attitudes toward premarital sex selecting content congruent with their attitudes, premarital sex attitudes at T1 did not predict pornography consumption at T2. © 2014, Springer Science+Business Media New York.

The accessory plasmid pAtC58 of the common laboratory strain of Agrobacterium tumefaciens confers numerous catabolic functions and has been proposed to play a role in virulence. Genomic sequencing of evolved laboratory strains of A. tumefaciens revealed the presence of multiple deletion events in the At plasmid, with reductions in plasmid size ranging from 25% to 30% (115-194 kb). Flanking both ends of the sites of these deletions is a short-nucleotide repeat sequence that is in a single copy in the deleted plasmids, characteristic of a phage- or transposon-mediated deletion event. This repeat sequence is widespread throughout the C58 genome, but concentrated on the At plasmid, suggesting its frequency to be nonrandom. In this study, we assess the prevalence of the larger of these deletions in multiple C58 derivatives and characterize its functional significance. We find that in addition to elevating virulence gene expression, this deletion is associated with a significantly reduced carriage cost to the cell. These observations are a clear demonstration of the dynamic nature of the bacterial genome and suggest a mechanism for genetic plasticity of these costly but otherwise stable plasmids. Additionally, this phenomenon could be the basis for some of the dramatic recombination events so ubiquitous within and among megaplasmids.

Caputo J.,Indiana University
Journal of health and social behavior | Year: 2013

Despite the proliferation of studies documenting the relationship between physical limitation and depressive symptoms in the United States, we currently do not know (1) whether physical impairment is associated with other dimensions of emotional well-being and (2) if these associations differ for men and women as well as married and nonmarried adults. We use panel data from two national samples to examine gender and marital status variations in the impact of physical limitation on four indicators of mental health. We find that physical limitation is associated with increases in depressive symptoms and negative feelings as well as decreases in positive emotions. Although the patterns are complex, we also find gender and marital status differences in these associations. Our results provide additional support for Aneshensel's (1992; Aneshensel, Rutter, and Lachenbruch 1991) argument about the highly contingent nature of stress reactivity and contribute to theory about both gender and marital status differences in the impact of stress on mental health.

Parker G.F.,Indiana University
Psychiatric Services | Year: 2010

Objectives: In 2005, in response to the shooting death of a police officer by a paranoid man, Indiana passed a law authorizing police to seize firearms without a warrant if they believe the person owning the firearm is dangerous because the person has a mental illness and is noncompliant with psychiatric medication or if the person has a propensity for violent or unstable conduct. This study sought to determine the use of this law in Indianapolis. Methods: All Indianapolis firearm seizure cases that had a final hearing in 2006 and 2007 were identified; demographic information, seizure circumstances, and hearing outcome were recorded. Results: A total of 55 cases were heard in 2006, and 78 were heard in 2007. The defendants were predominantly white (83%) and male (81%). Risk of suicide was the leading reason for confiscation (56% in 2006 and 71% in 2007), followed by substance abuse (29% and 27%, respectively), risk of violence (22% and 13%, respectively), and domestic disturbance (24% and 8%, respectively). Psychosis was a factor in only 11% and 9% of cases, respectively. A large majority of cases resulted in immediate detention (69% and 78%, respectively). In 2006, 95% of cases resulted in involuntary or voluntary surrender of the seized weapons to the court, but in 2007, only 22% of cases resulted in involuntary or voluntary surrender. However, in 2007 68% of cases resulted in court-ordered retention because of failure to appear (26%) or inability to be served (42%). Conclusions: Firearm seizure by police was rarely a result of psychosis; instead, risk of suicide was the leading reason. The application of the law by both police and the court changed over the first two years of its use.

Thoits P.A.,Indiana University
Journal of Health and Social Behavior | Year: 2011

Over the past 30 years investigators have called repeatedly for research on the mechanisms through which social relationships and social support improve physical and psychological well-being, both directly and as stress buffers. I describe seven possible mechanisms: social influence/social comparison, social control, role-based purpose and meaning (mattering), self-esteem, sense of control, belonging and companionship, and perceived support availability. Stress-buffering processes also involve these mechanisms. I argue that there are two broad types of support, emotional sustenance and active coping assistance, and two broad categories of supporters, significant others and experientially similar others, who specialize in supplying different types of support to distressed individuals. Emotionally sustaining behaviors and instrumental aid from significant others and empathy, active coping assistance, and role modeling from similar others should be most efficacious in alleviating the physical and emotional impacts of stressors. © American Sociological Association 2011.

This paper presents an analysis of the correlation between the number of globular clusters (N GCM) in giant galaxies and the mass of the galaxies' central supermassive black hole (M SMBH). I construct a sample of 20 elliptical, spiral, and S0 galaxies with known SMBH masses and with accurately measured GC system properties derived from wide-field imaging studies. The coefficients of the best-fitting N GC-M SMBH relation for the early-type galaxies are consistent with those from previous work but in some cases have smaller relative errors. I examine the correlation between N GC and M SMBH for various subsamples and find that elliptical galaxies show the strongest correlation, while S0 and pseudobulge galaxies exhibit increased scatter. I also compare the quality of the fit of the numbers of metal-poor GCs versus SMBH mass and the corresponding fit for metal-rich GCs. I supplement the 20 galaxy sample with 10 additional galaxies with reliable N GC determinations but without measured M SMBH. I use this larger sample to investigate correlations between N GC and host galaxy properties like total galaxy luminosity and stellar mass, and bulge luminosity and mass. I find that the tightest correlation is between N GC and total galaxy stellar mass. This lends support to the notion that N GC and M SMBH are not directly linked but are correlated because both quantities depend on the host galaxy potential. Finally, I use the N GC-M SMBH relation derived from the 20 galaxy sample to calculate predicted M SMBH values for the 10 galaxies with accurate N GC measurements but without measured SMBH masses. © 2012. The American Astronomical Society. All rights reserved.

Ding W.-X.,University of Kansas Medical Center | Yin X.-M.,Indiana University
Biological Chemistry | Year: 2012

Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. The removal of damaged mitochondria through autophagy, a process called mitophagy, is thus critical for maintaining proper cellular functions. Indeed, mitophagy has been recently proposed to play critical roles in terminal differentiation of red blood cells, paternal mitochondrial degradation, neurodegenerative diseases, and ischemia or drug-induced tissue injury. Removal of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition. Recent progress in mitophagy studies reveals that mitochondrial priming is mediated either by the Pink1-Parkin signaling pathway or the mitophagic receptors Nix and Bnip3. In this review, we summarize our current knowledge on the mechanisms of mitophagy. We also discuss the pathophysiological roles of mitophagy and current assays used to monitor mitophagy. Copyright © by Walter de Gruyter • Berlin • Boston.

Olson K.R.,Indiana University
Antioxidants and Redox Signaling | Year: 2012

Significance: Hydrogen sulfide (H2S) is garnering increasing interest as a biologically relevant signaling molecule. The effects of H 2S have now been observed in virtually every organ system and numerous physiological processes. Recent Advances: These studies have not only opened a new field of "gasotransmitter" biology, they have also led to the development of synthetic H2S "donating" compounds with the potential to be parlayed into a variety of therapeutic applications. Critical Issues: Often lost in the exuberance of this new field is a critical examination or understanding of practical aspects of H2S chemistry and biology. This is especially notable in the areas of handling and measuring H2S, evaluating biosynthetic and metabolic pathways, and separating physiological from pharmacological responses. Future Directions: This brief review describes some of the pitfalls in H2S chemistry and biology that can lead or have already led to misleading or erroneous conclusions. The intent is to allow individuals entering or already in this burgeoning field to critically analyze the literature and to assist them in the design of future experiments. © 2012 Mary Ann Liebert, Inc.

Qu X.,Indiana University
Development (Cambridge, England) | Year: 2012

Glycosaminoglycans (GAGs) play a central role in embryonic development by regulating the movement and signaling of morphogens. We have previously demonstrated that GAGs are the co-receptors for Fgf10 signaling in the lacrimal gland epithelium, but their function in the Fgf10-producing periocular mesenchyme is still poorly understood. In this study, we have generated a mesenchymal ablation of UDP-glucose dehydrogenase (Ugdh), an essential biosynthetic enzyme for GAGs. Although Fgf10 RNA is expressed normally in the periocular mesenchyme, Ugdh mutation leads to excessive dispersion of Fgf10 protein, which fails to elicit an FGF signaling response or budding morphogenesis in the presumptive lacrimal gland epithelium. This is supported by genetic rescue experiments in which the Ugdh lacrimal gland defect is ameliorated by constitutive Ras activation in the epithelium but not in the mesenchyme. We further show that lacrimal gland development requires the mesenchymal expression of the heparan sulfate N-sulfation genes Ndst1 and Ndst2 but not the 6-O and 2-O-sulfation genes Hs6st1, Hs6st2 and Hs2st. Taken together, these results demonstrate that mesenchymal GAG controls lacrimal gland induction by restricting the diffusion of Fgf10.

Background: This study examines the relationships between circadian preference and caffeine use with academic performance and hours spent studying for recent high school graduates entering their first year of college. Method: Entering first-year college students enrolled at 90 baccalaureate-level institutions across the USA were invited to complete the Beginning College Survey of Student Engagement (BCSSE) and the Composite Scale of Morningness (CSM) as well as answer questions regarding caffeine consumption. Surveys were administered on each campus during the summer months of 2013. Only those that graduated from a US high school in the spring of 2013 were included in this study. The final sample for this study included 25,200 students that completed the BCSSE, CSM, and questions regarding caffeine consumption. Results: Evening types (E-types) were significantly less likely to report earning A/A−’s in high school and less likely to study 16 or more hours per week compared to intermediate or morning types (M-types) (p < 0.05). Overall, entering first-year students reported an average of 1.1 servings of caffeine per day, with 39 % reporting no caffeine consumption. M-types were more likely to consume no caffeine (54 %) compared to E-types that also indicated no daily caffeine (31 %) (p < 0.05). However, E-types were approximately 2.5 times more likely to consume three or more daily servings of caffeine (18 %) compared to M-types that consume the same amount (7 %) (p < 0.05). M-types that consumed no caffeine reported the highest grades with nearly 64 % reporting they earned mostly A’s or A-’s in high school. However, the apparent advantage that morning types had over evening types regarding high school grades was completely ameliorated once three or more servings of caffeine were consumed per day. Conclusions: This study provides additional information to educators and health professionals to create programs and provide resource to help adolescents better understand the impact of their sleep behaviors and use of caffeine on their academic performance. © 2014, Springer-Verlag Berlin Heidelberg.

Agarwal R.,Indiana University
Kidney International | Year: 2010

Vitamin D receptor agonists (VDRAs) inhibit the renin-angiotensin system (RAS) and reduce podocyte loss and fibrosis over and above RAS blockade. Several studies in humans show that VDRAs are antiproteinuric and have the potential to delay the progression of renal disease. Whether VDRAs will accomplish this goal among proteinuric patients with chronic kidney disease needs to be tested in randomized controlled trials. © 2010 International Society of Nephrology.

Toda Y.,Vanderbilt University | Pink M.,Indiana University | Johnston J.N.,Vanderbilt University
Journal of the American Chemical Society | Year: 2014

The first highly diastereo- and enantioselective additions of a halogen and phosphoramidic acid to unactivated alkenes have been developed, catalyzed by a chiral Brønsted acid. A unique feature of these additions is the opportunity for stereocontrol at two noncontiguous chiral centers, carbon and phosphorus, leading to cyclic P-chiral phosphoramidates. In addition to their inherent value, the phosphoramidates are precursors to enantioenriched epoxy allylamines. © 2014 American Chemical Society.

Nguyen T.T.,Indiana University
Investigative ophthalmology & visual science | Year: 2012

To confirm the expression of monocarboxylate transporters (MCT) 1, 2, and 4 in rabbit CE and to test the hypothesis that cellular buffering contributed by HCO 3 -, NBCe1, and carbonic anhydrase (CA) activity facilitates lactate-H + efflux thereby controlling corneal hydration in vivo. MCT1-4 expression of rabbit endothelium was examined by Western blotting and immunofluorescence staining. Lactate-induced acidification (LIA) was measured in perfused CE in the presence and absence of HCO 3 - and acetazolamide (ACTZ) using tissue treated with siRNA specific to MCT1, 2, and 4. Corneal thickness and lactate concentration were measured in New Zealand White rabbits treated with the topical CA inhibitor Azopt, and from eyes that were injected intracamerally with ouabain, disodium 4,4'-diisothiocyanatostilbene-2,2'-disulfonate (DIDS), and shRNA specific to the 1Na +:2HCO 3 - cotransporter NBCe1. MCT1 and MCT4 are localized to the lateral membrane, while MCT2 is apical. Cell pH measurements showed LIA in response to 40 mM lactate in bicarbonate free (BF) Ringer's that was inhibited by niflumic acid and by MCT siRNA knockdown, and significantly reduced in the presence of HCO 3 -. Lactate-dependent proton flux in vitro was not significantly greater in the presence of HCO 3 - or reduced by ACTZ. However, when active transport, NBCe1, or CA activity was disrupted in vivo, corneal edema ensued and was associated with significant corneal lactate accumulation. MCT1, 2, and 4 are expressed in rabbit CE on both the apical and basolateral surfaces and function to transport lactate-H +. Lactate-H + flux is facilitated by active transport, HCO 3 - transport and CA activity, disruption of which causes corneal edema in vivo and indicates that facilitation of lactate efflux is a component of the endothelial pump.

Kircik L.,Indiana University
Journal of Drugs in Dermatology | Year: 2010

Atopic dermatitis (AD) is a chronic inflammatory skin condition affecting a predominantly pediatric population and characterized by a cycle of flare and remission. Pruritus associated with AD results in substantial quality of life, societal, financial and emotional burdens for patients and their caregivers. Daily management of AD is usually based on application of an emollient and a topical corticosteroid, topical immunomodulator and/or oral antihistamine for the management of flares. A new nonsteroidal lamellar matrix cream has been introduced for use in a variety of dermatologic conditions including AD. Its ingredients mimic stratum corneum components which may help repair and restore skin barrier function and decrease transepidermal water loss. This article reviews the role of topical therapy in AD management, and evaluates the usefulness of the lamellar matrix cream in reducing time to flare, limiting the use of agents with greater side-effect profiles and lowering the overall cost of treatment. Copyright © 2010 Journal of Drugs in Dermatology.

Holtzworth-Munroe A.,Indiana University
Aggression and Violent Behavior | Year: 2011

Intimate partner violence (IPV) and parental separation are two related and serious potential problems faced by children; both are associated with increased risks for children. Proponents of mediation for separating parents believe that, relative to traditional adversarial court proceedings, mediation may lead to better outcomes for children by decreasing parental conflict. However, the question of whether mediation should be conducted with parents experiencing IPV is a contentious one, although few arguments on either side of the debate have been supported by empirical research. We examine some of the specific controversies regarding mediation in the context of IPV, including whether universal IPV screening should be required, whether mediation procedures should be modified to accommodate reports of IPV, and whether knowledge of IPV should lead to changes in mediation agreement content. We also consider directions for future research to address important, unanswered questions in this area. © 2011 Elsevier Ltd.

Fortenberry J.D.,Indiana University
Hormones and Behavior | Year: 2013

This article is part of a Special Issue "Puberty and Adolescence".Sexuality emerges as a major developmental element of puberty and the adolescent years that follow. However, connecting the sexuality that emerges with puberty and elements of adult sexuality is difficult because much adolescent sexuality research addresses the transition to partnered sexual behaviors (primarily coitus) and consequences such as unplanned pregnancy and sexually transmitted infections. This review proposes a framework of an expanded understanding of puberty and adolescent sexuality from the perspective of four hallmarks of adult sexuality: sexual desire; sexual arousal; sexual behaviors; and, sexual function. This approach thus addresses important gaps in understanding of the ontogeny of sex and the continuum of sexuality development from adolescence through the adult lifespan. © 2013 Elsevier Inc..

Stefanek M.E.,Indiana University | Stefanek M.E.,Indiana University Bloomington
Journal of the National Cancer Institute | Year: 2011

It has been more than 30 years since the first consensus development meeting was held to deal with guidelines of mammography screening. Although the National Cancer Institute has wisely focused on the science of screening and of screening benefits vs harm, many professional organizations, advocacy groups, and the media have maintained a focus on establishing who should be screened and promoting recommendations for which age groups should be screened. Guidelines have been developed not only for mammography but also for screening at virtually all major cancer sites, especially for prostate cancer, and most recently, with the preliminary results of the National Lung Screening Trial, for lung cancer. It seems clear that we have done an inadequate job of educating screening candidates about the harms and benefits of cancer screening, including the extent to which screening can reduce cancer mortality. We must also question whether our practice of summoning women to have mammograms, while providing men informed choice for prostate cancer screening, is consistent with a scientific analysis of the relative harms and benefits. We have spent a staggering amount of time and energy over the past several decades developing, discussing, and debating guidelines. Professional and advocacy groups have spent much time aggressively advocating the adoption of guidelines supported by their respective groups. It seems that it would be much more productive to devote such energy to educating screening candidates about the harms and benefits of screening and to engaging in shared decision making. © The Author 2011.

State governments have taken the lead on U.S. energy and climate policy. It is not yet clear, however, whether state energy policy portfolios can generate results in a similar magnitude or manner to their presumed carbon mitigation potential. This article seeks to address this lack of policy evidence and contribute empirical insights on the carbon mitigation effects of state energy portfolios within the U.S. electricity sector. Using a dynamic, long-term electricity dispatch model with U.S. power plant, utility, and transmission and distribution data between 2010 and 2030, this analysis builds a series of state-level policy portfolio scenarios and performs a comparative scenario analysis. Results reveal that state policy portfolios have modest to minimal carbon mitigation effects in the long run if surrounding states do not adopt similar portfolios as well. The difference in decarbonization potential between isolated state policies and larger, more coordinated policy efforts is due in large part to carbon leakage, which is the export of carbon intensive fossil fuel-based electricity across state lines. Results also confirm that a carbon price of $50/metric ton CO2e can generate substantial carbon savings. Although both policy options - an energy policy portfolio or a carbon price - are effective at reducing carbon emissions in the present analysis, neither is as effective alone as when the two strategies are combined. © 2011 Elsevier B.V.

Rex D.K.,Indiana University
American Journal of Gastroenterology | Year: 2012

There is limited and mixed evidence regarding whether the use of sedation affects detection during colonoscopy. There is no convincing evidence that the level of sedation (deep vs. moderate) affects detection. © 2012 by the American College of Gastroenterology.

McQuilton P.,University of Cambridge | St Pierre S.E.,Harvard University | Thurmond J.,Indiana University
Nucleic Acids Research | Year: 2012

FlyBase (http://flybase.org) is the leading database and web portal for genetic and genomic information on the fruit fly Drosophila melanogaster and related fly species. Whether you use the fruit fly as an experimental system or want to apply Drosophila biological knowledge to another field of study, FlyBase can help you successfully navigate the wealth of available Drosophila data. Here, we review the FlyBase web site with novice and less-experienced users of FlyBase in mind and point out recent developments stemming from the availability of genome-wide data from the modENCODE project. The first section of this paper explains the organization of the web site and describes the report pages available on FlyBase, focusing on the most popular, the Gene Report. The next section introduces some of the search tools available on FlyBase, in particular, our heavily used and recently redesigned search tool QuickSearch, found on the FlyBase homepage. The final section concerns genomic data, including recent modENCODE (http://www.modencode.org) data, available through our Genome Browser, GBrowse. © The Author(s) 2011.

Ballen K.K.,Massachusetts General Hospital | Gluckman E.,University Paris Diderot | Broxmeyer H.E.,Indiana University
Blood | Year: 2013

Umbilical cord blood is an alternative hematopoietic stem cell source for patients with hematologic diseases who can be cured by allogeneic hematopoietic cell transplantation. Initially, umbilical cord blood transplantation was limited to children, given the low cell dose infused. Both related and unrelated cord blood transplants have been performed with high rates of success for a variety of hematologic disorders and metabolic storage diseases in the pediatric setting. The results for adult umbilical cord blood transplantation have improved, with greater emphasis on cord blood units of sufficient cell dose and human leukocyte antigen match and with the use of double umbilical cord blood units and improved supportive care techniques. Cord blood expansion trials have recently shown improvement in time to engraftment. Umbilical cord blood is being compared with other graft sources in both retrospective and prospective trials. The growth of the field over the last 25 years and the plans for future exploration are discussed. Copyright © 2011 by The American Society of Hematology; all rights reserved.

Bogenschutz E.D.,Indiana University
Medicine and science in sports and exercise | Year: 2011

Throwing is a vigorous activity that generates large internal loads. There is limited evidence of the effect of these loads on bone adaptation. The aim of this study was to investigate the 1) magnitude of bone adaptation within the midshaft humerus of female fast-pitch softball players and 2) influence of throwing mechanics (windmill vs overhand throwing) on the magnitude of adaptation. Midshaft humeral bone mass, structure, and estimated strength were assessed via peripheral quantitative computed tomography in fast-pitch softball players (throwers; n = 15) and matched controls (controls; n = 15). The effect of throwing was examined by comparing dominant-to-nondominant differences in throwers to controls, whereas the influence of mechanics was determined by comparing dominant-to-nondominant differences in throwers who primarily play as pitcher (windmill thrower), catcher (overhand thrower), or fielder (overhand thrower). Throwers had greater dominant-to-nondominant difference in midshaft humeral bone mass, structure, and estimated strength relative to controls (all P < 0.05). The largest effect was for estimated torsional strength with throwers having a mean dominant-to-nondominant difference of 22.5% (range = 6.7%-43.9%) compared with 4.4% (range = -8.3% to 17.5%) in controls (P < 0.001). Throwing mechanics seemed to influence the magnitude of skeletal adaptation, with overhand throwers having more than double dominant-to-nondominant difference in midshaft humeral bone mass, structure, and estimated strength than windmill throwers (all P < 0.05). Throwing induces substantial skeletal adaptation at the midshaft humerus of the dominant upper extremity. Throwing mechanics seems to influence the magnitude of adaptation, as catchers and fielders (overhand throwers) had twice as much adaptation as pitchers (windmill throwers). The latter finding may have implications for skeletal injury risk at the midshaft humerus in throwing athletes.

Flory S.L.,Indiana University
Restoration Ecology | Year: 2010

Restoration of communities invaded by exotic plants requires effective eradication of the invader and reestablishment of the resident plant community. Despite the commonly cited need for techniques to accomplish such goals, studies that test strategies for removing invasive plants, monitor effects on resident communities, and incorporate replicate sites are generally lacking. Microstegium vimineum is an exotic annual grass that is rapidly invading forests in the eastern United States and threatening to reduce biodiversity and inhibit forest regeneration. I conducted a field experiment at eight sites over two growing seasons in southern Indiana to evaluate hand-weeding (HW), a postemergent grass-specific herbicide (POST), and the postemergent herbicide plus a preemergent herbicide (POST + PRE) for removing Microstegium. Compared to reference plots (REF), the three treatments each reduced Microstegium biomass at the end of the growing seasons to relatively low levels. However, after the second year of the experiment, POST and POST + PRE resulted in very little spring cover of Microstegium, but HW plots were significantly reinvaded. HW and POST, but not POST + PRE, increased resident plant community productivity and spring resident community cover compared to reference plots. The amount of light at the research sites did not alter the effectiveness of treatments, but the recovery of resident communities was positively correlated with light availability under HW and POST + PRE. These results indicate that natural systems invaded by Microstegium can be restored using the POST or HW treatments, which will effectively remove the invasion and allow the resident plant community to recover when used over multiple growing seasons. © 2008 Society for Ecological Restoration International.

One of the ways that conservation and capitalism intersect is in ethical consumption, the shaping of purchasing decisions by an evaluation of the moral attributes of objects on offer. It is increasingly important as a way that people think that they can affect the world around them, including protecting the natural environment. This paper describes commodity fetishism in ethical consumption, and the degree to which this fetishism makes it difficult for ethical consumers to be effective both in their evaluation of objects on offer and in influencing the world around them. It looks at three forms of fetishism in ethical consumption: fetishism of objects, fetishism of the purchase and consumption of objects, fetishism of nature. © 2010 The Author Journal compilation © 2010 Editorial Board of Antipode.

Imperiale T.F.,Indiana University | Imperiale T.F.,Center for Innovation | Ransohoff D.F.,University of North Carolina at Chapel Hill | Itzkowitz S.H.,Mount Sinai School of Medicine | And 5 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: An accurate, noninvasive test could improve the effectiveness of colorectal-cancer screening. METHODS: We compared a noninvasive, multitarget stool DNA test with a fecal immunochemical test (FIT) in persons at average risk for colorectal cancer. The DNA test includes quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, plus a hemoglobin immunoassay. Results were generated with the use of a logistic-regression algorithm, with values of 183 or more considered to be positive. FIT values of more than 100 ng of hemoglobin per milliliter of buffer were considered to be positive. Tests were processed independently of colonoscopic findings. RESULTS: Of the 9989 participants who could be evaluated, 65 (0.7%) had colorectal cancer and 757 (7.6%) had advanced precancerous lesions (advanced adenomas or sessile serrated polyps measuring ≥1 cm in the greatest dimension) on colonoscopy. The sensitivity for detecting colorectal cancer was 92.3% with DNA testing and 73.8% with FIT (P = 0.002). The sensitivity for detecting advanced precancerous lesions was 42.4% with DNA testing and 23.8% with FIT (P<0.001). The rate of detection of polyps with high-grade dysplasia was 69.2% with DNA testing and 46.2% with FIT (P = 0.004); the rates of detection of serrated sessile polyps measuring 1 cm or more were 42.4% and 5.1%, respectively (P<0.001). Specificities with DNA testing and FIT were 86.6% and 94.9%, respectively, among participants with nonadvanced or negative findings (P<0.001) and 89.8% and 96.4%, respectively, among those with negative results on colonoscopy (P<0.001). The numbers of persons who would need to be screened to detect one cancer were 154 with colonoscopy, 166 with DNA testing, and 208 with FIT. CONCLUSIONS: In asymptomatic persons at average risk for colorectal cancer, multitarget stool DNA testing detected significantly more cancers than did FIT but had more false positive results. Copyright © 2014 Massachusetts Medical Society.

Tenner S.,New York University | Baillie J.,Carteret MedicalGroup | Dewitt J.,Indiana University | Vege S.S.,Mayo Medical School
American Journal of Gastroenterology | Year: 2013

This guideline presents recommendations for the management of patients with acute pancreatitis (AP). During the past decade, there have been new understandings and developments in the diagnosis, etiology, and early and late management of the disease. As the diagnosis of AP is most often established by clinical symptoms and laboratory testing, contrast-enhanced computed tomography (CECT) and/or magnetic resonance imaging (MRI) of the pancreas should be reserved for patients in whom the diagnosis is unclear or who fail to improve clinically. Hemodynamic status should be assessed immediately upon presentation and resuscitative measures begun as needed. Patients with organ failure and/or the systemic inflammatory response syndrome (SIRS) should be admitted to an intensive care unit or intermediary care setting whenever possible. Aggressive hydration should be provided to all patients, unless cardiovascular and/or renal comorbidites preclude it. Early aggressive intravenous hydration is most beneficial within the first 12-24 h, and may have little benefit beyond. Patients with AP and concurrent acute cholangitis should undergo endoscopic retrograde cholangiopancreatography (ERCP) within 24 h of admission. Pancreatic duct stents and/or postprocedure rectal nonsteroidal anti-inflammatory drug (NSAID) suppositories should be utilized to lower the risk of severe post-ERCP pancreatitis in high-risk patients. Routine use of prophylactic antibiotics in patients with severe AP and/or sterile necrosis is not recommended. In patients with infected necrosis, antibiotics known to penetrate pancreatic necrosis may be useful in delaying intervention, thus decreasing morbidity and mortality. In mild AP, oral feedings can be started immediately if there is no nausea and vomiting. In severe AP, enteral nutrition is recommended to prevent infectious complications, whereas parenteral nutrition should be avoided. Asymptomatic pancreatic and/or extrapancreatic necrosis and/or pseudocysts do not warrant intervention regardless of size, location, and/or extension. In stable patients with infected necrosis, surgical, radiologic, and/or endoscopic drainage should be delayed, preferably for 4 weeks, to allow the development of a wall around the necrosis. © 2013 by the American College of Gastroenterology.

Dixon B.E.,Indiana University
AMIA ... Annual Symposium proceedings / AMIA Symposium. AMIA Symposium | Year: 2011

There is increasing interest in leveraging electronic health data across disparate sources for a variety of uses. A fallacy often held by data consumers is that clinical data quality is homogeneous across sources. We examined one attribute of data quality, completeness, in the context of electronic laboratory reporting of notifiable disease information. We evaluated 7.5 million laboratory reports from clinical information systems for their completeness with respect to data needed for public health reporting processes. We also examined the impact of health information exchange (HIE) enhancement methods that attempt to improve completeness. The laboratory data were heterogeneous in their completeness. Fields identifying the patient and test results were usually complete. Fields containing patient demographics, patient contact information, and provider contact information were suboptimal. Data processed by the HIE were often more complete, suggesting that HIEs can support improvements to existing public health reporting processes.

Fuqua J.S.,Indiana University
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Precocious puberty is a common problem affecting up to 29 per 100 000 girls per year. The earliest identified neuroendocrine change in early puberty thus far is increased kisspeptin secretion from the arcuate nucleus and the anteroventral paraventricular nucleus of the hypothalamus. The regulation of kisspeptin secretion is not well understood, but neurokinin B and dynorphin provide autocrine regulation. The etiologies of precocious puberty may be subdivided into GnRH-dependent and GnRH-independent causes. GnRH-dependent precocious puberty, often called central precocious puberty (CPP), is usually treated with GnRH analogs. Newer developments in the treatment of CPP include expanded data on the safety and efficacy of the subdermal histrelin implant, which is useful for long-term treatment, although removal may be difficult in some cases. Preliminary data suggest that the implant may be left in place for up to 2 years without loss of biochemical suppression. In the last 2 years, more data have been published concerning extended-release leuprolide acetate injections that indicate that the 11.25-mg dose may not provide full biochemical suppression but may clinically suppress signs of puberty, including the accelerated growth velocity and advanced skeletal maturation seen in CPP. Treatment options for familial male-limited precocious puberty and McCune-Albright syndrome are expanding as well, although data are preliminary. Long-term outcome studies of CPP indicate overall good menstrual and reproductive function, but the prevalence of polycystic ovary syndrome may be higher than in the general population. Remarkably few studies have evaluated the behavioral and psychological outcomes of precocious puberty, in contrast to early normal maturation. Additional outcome studies of endocrine, metabolic, and psychological effects of CPP are clearly needed. Copyright © 2013 by The Endocrine Society.

Marshalleck F.,Indiana University
Techniques in Vascular and Interventional Radiology | Year: 2010

The spectrum of pediatric vascular pathology differs from the adult population and it varies greatly to include congenital and acquired disorders. Although catheter-directed angiography remains the gold standard, most vascular conditions in the child can be adequately diagnosed with magnetic resonance angiography, computed tomographic angiography, or duplex/Doppler ultrasonography with only a few exceptions, such as intrarenal arterial stenosis, small vessel vasculitides, and visceral vascular malformations. The advancement of catheter and wire technology has made it increasingly possible for complex arterial interventions to be performed in children, including embolization, angioplasty with stent insertion, thrombolysis, and endovascular neurological procedures. More angiographic procedures are being performed with the aim of also being therapeutic. Special considerations in children include the use of appropriate equipment and adequate dosing of contrast and of the various medications used during angiography, particularly in patients less than 15 kg in weight. This article will focus on the management of renovascular hypertension, liver transplant hepatic arterial intervention, and the use of carbon dioxide gas as a contrast agent in the child. © 2010 Elsevier Inc.

Smith L.M.,Yale University | Reynolds H.L.,Indiana University
Ecology | Year: 2015

Net pairwise plant-soil feedbacks (PSF) may be an important factor structuring plant communities, yet the influence of abiotic context on PSF is not yet understood. Abiotic factors such as light availability can alter plant-soil interactions, potentially resulting in strong context dependence of PSF. Here, we present an experiment in which we measured whole-soil net pairwise feedbacks amongst six common forest understory species across a gradient of light availability. Light treatments were imposed throughout both phases (the conditioning phase and the response phase) of the feedback experiment. Across the plant community, PSF shifted from negative at high light availability to weakly positive under low light (P = 0.013). Differences in the biomass of plants during the conditioning phase did not fully explain lightimposed differences in feedbacks, indicating that reduced light availability qualitatively changes the nature of PSF rather than simply weakening feedbacks by reducing plant growth. Results indicate that abiotic context can fundamentally alter the role of PSF in structuring plant communities. © 2015 by the Ecological Society of America.

Schneider W.H.,Indiana University
Transfusion Medicine Reviews | Year: 2013

The adequacy and safety of blood transfusion in sub-Saharan Africa is the subject of much concern, yet there have been very few studies of its history. An overview of that record finds that transfusions were first reported in Africa (sub-Saharan and excluding South Africa) in the early 1920s, and organized transfusion practices were established before the Second World War. Blood transfusion grew rapidly after 1945, along with the construction of new hospitals and expanded health services in Africa. Significant differences existed between colonial powers in the organization of transfusion services, but these converged after independence as their use continued to grow and decentralized and hospital-based practices were adopted. It was only after the oil crisis in the mid-1970s that health spending declined and the collection, testing, and transfusion of blood began to level off. Thus, when the AIDS crisis hit transfusion services, they were already struggling to meet the needs of patients. At this time, foreign assistance as well as the World Health Organization and the League of Red Cross Societies helped respond to both the immediate problem of testing blood, and for some countries, support existed for the broader reorganization of transfusion. Overall, the history shows that transfusion was adopted widely and quickly, limited mainly by the availability of knowledgeable doctors and hospital facilities. There was less resistance than expected by Africans to receive transfusions, and the record shows a remarkable flexibility in obtaining blood. The dangers of disease transmission were recognized from an early date but were balanced against the potential lifesaving benefits of transfusion. © 2013 Elsevier Inc.

Roos K.L.,Indiana University
Handbook of clinical neurology | Year: 2014

Encephalitis is an infectious or inflammatory disorder of the brain that presents with fever, headache, and an altered level of consciousness. There may also be focal or multifocal neurologic deficits, and focal or generalized seizure activity. Of the infectious etiologies, herpesviruses are the most common and some of the few treatable viral causative agents of encephalitis. The etiology, clinical presentation, diagnosis, and treatment of viral encephalitis is discussed in this chapter. © 2014 Elsevier B.V. All rights reserved.

Corey K.E.,Massachusetts General Hospital | Chalasani N.,Indiana University
Clinical Gastroenterology and Hepatology | Year: 2014

Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of liver disease in the United States and is associated with an increased risk of cardiovascular disease (CVD) and cardiovascular (CV) mortality, independent of traditional cardiovascular risk factors. CVD is one of the most common causes of death among individuals with NAFLD and management of NAFLD must extend beyond liver disease to include CVD risk modification. Clinicians should assess CVD risk with the Framingham Risk Score and screen for CVD risk factors including dyslipidemia, diabetes mellitus, hypertension, tobacco use, and the metabolic syndrome. CVD risk factors, particularly dyslipidemia, require aggressive medical management to reduce the high risk of CVD events and death in individuals with NAFLD. © 2014 AGA Institute.

Lee J.Y.,Indiana University
Pediatric endocrinology reviews : PER | Year: 2013

In the past decade, research in genetic disorders of hypophosphatemia has significantly expanded our understanding of phosphate metabolism. X-linked hypophosphatemia (XLH) is the most common inherited form of rickets due to renal phosphate wasting. Recent understanding of the mechanisms of disease and role of fibroblast growth factor 23 (FGF-23) in XLH and other hypophosphatemic disorders have opened new potential therapeutic avenues. We will discuss the current standard of treatment for XLH as well as promising future directions under study.

Hollenhorst P.C.,Indiana University | McIntosh L.P.,University of British Columbia | Graves B.J.,University of Utah | Graves B.J.,Howard Hughes Medical Institute
Annual Review of Biochemistry | Year: 2011

ETS proteins are a group of evolutionarily related, DNA-binding transcriptional factors. These proteins direct gene expression in diverse normal and disease states by binding to specific promoters and enhancers and facilitating assembly of other components of the transcriptional machinery. The highly conserved DNA-binding ETS domain defines the family and is responsible for specific recognition of a common sequence motif, 5′-GGA(A/T)-3′. Attaining specificity for biological regulation in such a family is thus a conundrum. We present the current knowledge of routes to functional diversity and DNA binding specificity, including divergent properties of the conserved ETS and PNT domains, the involvement of flanking structured and unstructured regions appended to these dynamic domains, posttranslational modifications, and protein partnerships with other DNA-binding proteins and coregulators. The review emphasizes recent advances from biochemical and biophysical approaches, as well as insights from genomic studies that detect ETS-factor occupancy in living cells. © 2011 by Annual Reviews. All rights reserved.

Haas D.M.,Indiana University
The Cochrane database of systematic reviews | Year: 2013

Progesterone, a female sex hormone, is known to induce secretory changes in the lining of the uterus essential for successful implantation of a fertilized egg. It has been suggested that a causative factor in many cases of miscarriage may be inadequate secretion of progesterone. Therefore, progestogens have been used, beginning in the first trimester of pregnancy, in an attempt to prevent spontaneous miscarriage. To determine the efficacy and safety of progestogens as a preventative therapy against miscarriage. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 August 2013), reference lists from relevant articles, attempting to contact authors where necessary, and contacted experts in the field for unpublished works. Randomized or quasi-randomized controlled trials comparing progestogens with placebo or no treatment given in an effort to prevent miscarriage. Two review authors assessed trial quality and extracted data. Fourteen trials (2158 women) are included. The meta-analysis of all women, regardless of gravidity and number of previous miscarriages, showed no statistically significant difference in the risk of miscarriage between progestogen and placebo or no treatment groups (Peto odds ratio (Peto OR) 0.99; 95% confidence interval (CI) 0.78 to 1.24) and no statistically significant difference in the incidence of adverse effect in either mother or baby.A subgroup analysis of placebo controlled trials did not find a difference in the rate of miscarriage with the use of progestogen (10 trials, 1028 women; Peto OR 1.15; 95% CI 0.88 to 1.50).In a subgroup analysis of four trials involving women who had recurrent miscarriages (three or more consecutive miscarriages; four trials, 225 women), progestogen treatment showed a statistically significant decrease in miscarriage rate compared to placebo or no treatment (Peto OR 0.39; 95% CI 0.21 to 0.72). However, these four trials were of poorer methodological quality. No statistically significant differences were found between the route of administration of progestogen (oral, intramuscular, vaginal) versus placebo or no treatment. No significant differences in the rates of preterm birth, neonatal death, or fetal genital anomalies/virilization were found between progestogen therapy versus placebo/control. There is no evidence to support the routine use of progestogen to prevent miscarriage in early to mid-pregnancy. However, there seems to be evidence of benefit in women with a history of recurrent miscarriage. Treatment for these women may be warranted given the reduced rates of miscarriage in the treatment group and the finding of no statistically significant difference between treatment and control groups in rates of adverse effects suffered by either mother or baby in the available evidence. Larger trials are currently underway to inform treatment for this group of women.

Tucker S.,University of Washington | Vitins A.,University of Washington | Pikaard C.S.,University of Washington | Pikaard C.S.,Indiana University
Current Opinion in Cell Biology | Year: 2010

Nucleolar dominance is an epigenetic phenomenon that occurs in genetic hybrids and describes the expression of 45S rRNA genes inherited from one progenitor due to the silencing of the other progenitor's rRNA genes. Nucleolar dominance is a manifestation of rRNA gene dosage control, which also occurs in non-hybrids, regulating the number of active rRNA genes according to the cellular demand for ribosomes and protein synthesis. Ribosomal RNA gene silencing involves changes in DNA methylation and histone modifications, but the molecular basis for choosing which genes to silence remains unclear. Recent studies indicate a role for short interfering RNAs (siRNAs) or structured regulatory RNAs in rRNA gene silencing in plants or mammals, respectively, suggesting that RNA may impart specificity to the choice mechanism. © 2010 Elsevier Ltd.

Liangpunsakul S.,Indiana University
World Journal of Gastroenterology | Year: 2010

AIM: To examine the association between macronutrient dietary patterns and alcohol consumption using the Third National Health and Nutritional Examination Survey III. METHODS: A total of 9877 subjects (5144 males) constituted the study cohort. Dietary interviews were conducted with all examinees by a trained dietary interviewer in a mobile examination center (MEC). Subjects reported all foods and beverages consumed except plain drinking water for the previous 24-h time period. Physical examination and history of alcohol consumption were obtained. Pearson correlation coefficients were used to evaluate the association of the levels of alcohol consumption and the percentage of energy derived from macronutrients. Univariate and multivariate regression analyses were performed accounting for the study sampling weight to further explore the relationships between alcohol consumption and calories derived from each macronutrient. RESULTS: Subjects who drank were younger than nondrinker controls in both genders (P < 0.01). Alcohol intake was inversely associated with body mass index and body weight in women. Of all macronutrients, carbohydrate intake was the first to decrease with increasing alcohol consumption. In the multivariate analyses, the level of alcohol consumption was found to be an independent predictor associated with lower intake of other macronutrients. CONCLUSION: Our results show that there is an alteration in the daily dietary pattern with increasing alcohol consumption and that energy derived from alcoholic beverages substitutes that from other macronutrients such as carbohydrate, protein, and fat © 2010 Baishideng.

Benson M.D.,Indiana University | Benson M.D.,Richard udebush Veterans Affair Medical Center
Muscle and Nerve | Year: 2013

Liver transplantation as a specific treatment of transthyretin amyloidosis was first performed in 1990. The rationale for this treatment was that removal of the source (liver) of the amyloid precursor protein (mutated transthyretin) would stop progression of the disease. Indeed, after orthotopic liver transplantation (OLT), mutant transthyretin (TTR) is rapidly cleared from circulation. In the last 20 years, >2000 familial amyloidotic polyneuropathy (FAP) patients have received liver transplants. For these patients, prospective monitoring has shown prolongation of life compared with FAP patients who have not undergone liver transplantation. The most favorable results have been for FAP patients with the Val30Met TTR mutation. Less favorable results have been seen for patients with other TTR mutations where progression of amyloid tissue deposition has been documented as the result of amyloid fibril formation from normal (wild-type) TTR. Although it is obvious that OLT has benefited many FAP patients, there remains a need for further therapies. © 2012 Wiley Periodicals, Inc.

Mack K.M.L.,Indiana University
Oikos | Year: 2012

The evolution and maintenance of mutually beneficial interactions has been one of the oldest problems for evolutionary theory. For cooperation to be stable, mechanisms such as spatial population structure must exist that prevent non-cooperative individuals from invading cooperative groups. Selection for certain traits like increased dispersal can erode that structure. Here, I used a spatially explicit individual based dual lattice computer simulation to investigate how the evolution of dispersal interacts with the evolution of mutualism and how this interaction affects the stability of mutualism in the face of non-mutualists. I ran simulations manipulating the self-structuring phenotype, dispersal distance, over a range of environmental conditions, as well as letting both dispersal and mutualism evolve independently, with and without a cost of dispersal. I found that environmental productivity is negatively correlated with the stability of mutualism, and that the stability of mutualism relied on the ability of mutualists to evolve shorter dispersal distances than non-mutualists. The inclusion of a dispersal cost essentially fixed the upper limit of dispersal, and therefore limits the ability of non-mutualists to evolve higher average dispersal than mutualists, but as costs are relaxed, the differences are recovered. These results show how selection on seemingly unrelated traits can align suites of traits into holistic life history strategies. © 2011 The Authors. Oikos © 2012 Nordic Society Oikos.

This paper revisits the relationship between nurse staffing and quality of care in nursing homes using an instrumental variables approach. Most prior studies rely on cross-sectional evidence, which renders causal inference problematic and policy recommendations inappropriate. We exploit legislation changes regarding minimum staffing requirements in eight states between 2000 and 2001 as exogenous shocks to nurse staffing levels. We find that registered nurse staffing has a large and significant impact on quality of care, and that there is no evidence of a significant association between nurse aide staffing and quality of care. A comparison of the IV estimation to the OLS estimation of the first-difference model suggests that ignoring endogeneity would lead to an underestimation of how nurse staffing affects quality of care in nursing homes. © 2014 Elsevier B.V.

Rex D.K.,Indiana University
American Journal of Gastroenterology | Year: 2014

Water exchange (water infusion with water removal primarily during insertion) and water immersion (water infusion with water removal during withdrawal) reduce patient discomfort during colonoscope insertion compared with air insufflation, and represent a major achievement in colonoscopy. Hsieh et al. found that water exchange, relative to water immersion, resulted in more painless insertions to the cecum and improved adenoma detection in the right colon. However, water exchange is also associated with better bowel cleansing and longer insertion and procedure times. These factors are not specific to water exchange, but could account for all or part of the better results with water exchange. Additional controlled investigation is needed to define the benefits of water exchange compared with water immersion. © 2014 by the American College of Gastroenterology.

Yassen G.H.,Indiana University
Journal of oral science | Year: 2011

The aim of this paper was to review in vitro and in situ studies that directly compared the use of bovine teeth as a substitute for human teeth in dental experiments. A PubMed search was conducted for papers published from 1953 to December 30, 2010 using the following keywords: "human bovine enamel" or "human bovine dentin" or "human bovine teeth". The abstracts of the studies resulting from the keyword search were read, and all papers that compared human and bovine teeth were fully read. Only original articles written in English and directly comparing human and bovine substrates were included in the review. The search was supplemented by manual searches of the reference lists from each identified paper. Out of 76 studies initially selected, 68 fulfilled the selection criteria for inclusion. The studies covered seven categories: dental morphology, chemical composition, physical properties, dental caries, dental erosion/abrasion, bonding/adhesive strength, and marginal microleakage. Inconsistent data exist regarding whether bovine teeth can be considered an appropriate substitute for human teeth in dental research. Morphological, chemical compostion and physical property differences between the two substrates must be considered when interpreting results obtained from any experiment using bovine tooth substrate.

Maluccio M.,Indiana University | Covey A.,Sloan Kettering Cancer Center
CA Cancer Journal for Clinicians | Year: 2012

Hepatocellular carcinoma (HCC) is one of the few cancers in which a continued increase in incidence has been observed over several years. As such, there has been a focus on safe and accurate diagnosis and the development of treatment algorithms that take into consideration the unique complexities of this patient population. In the past decade, there have been improvements in nonsurgical treatment platforms and better standardization with respect to the diagnosis and patient eligibility for liver transplant. How to navigate patients through the challenges of treatment is difficult and depends on several factors: 1) patient-related variables such as comorbid conditions that influence treatment eligibility; 2) liver-related variables such as Child-Pugh score; and 3) tumor-related variables such as size, number, pattern of spread within the liver, and vascular involvement. The objectives of this review are to put into perspective the current treatment options for patients with HCC, the unique advantages and disadvantages of each treatment approach, and the evidence that supports the introduction of sorafenib into the multidisciplinary management of HCC. CA Cancer J Clin 2012;. © 2012 American Cancer Society. Copyright © 2012 American Cancer Society, Inc.

The addition of telaprevir or boceprevir to pegylated interferon (PEG-INF) and ribavirin (RBV) has improved sustained viral response (SVR) rates in genotype-1-infected individuals. The recent publication of Phase III trials has made it possible to examine pretreatment and on-treatment predictors of response in genotype 1 naïve patients. Both telaprevir- and boceprevir-based therapy improve SVR rates in most treatment groups including individuals who are difficult-to-treat such as those with a high viral load, Black patients and those with advanced fibrosis. Although data sets were not complete, patients with IL28B CT and TT genotype appear to significantly improve when these agents are combined with PEG-INF and RBV. The presence of the IL-28B CC genotype appears to be predictive for a short duration of therapy. On-treatment viral response is also predictive of the SVR: approximately half of the patients are successfully treated with short duration and response-guided therapy. © 2012 John Wiley & Sons A/S.

Page M.G.,Basilea Pharmaceutica International Ltd. | Bush K.,Indiana University
Current Opinion in Pharmacology | Year: 2014

Multidrug-resistant Gram-negative bacteria continue to pose a threat, with many infections caused by these pathogens being virtually untreatable. A number of new antibacterial agents are in late stage clinical development to treat these infections. Drugs in known classes such as new quinolones, aminoglycosides, tetracyclines, and β-lactams have been designed to evade many of the known resistance mechanisms, whereas newer drug classes include novel β-lactamase inhibitors in combination with new or approved β-lactams, and a peptidomimetic that have entered full clinical development. The establishment of public-private partnerships and an increase in pharmaceutical interest in antibacterial R&D are encouraging signs for the future. © 2014 Published by Elsevier Ltd.

Flockhart D.A.,Indiana University
Journal of Clinical Psychiatry | Year: 2012

Monoamine oxidase inhibitors (MAOIs) are effective treatments for depression that has atypical features or that has failed to respond to other antidepressants. However, MAOIs are underused because clinicians are concerned about dietary and drug interactions with this class of medication. Hypertensive crisis and serotonin syndrome can occur in rare cases due to interactions between MAOIs and foods containing tyramine as well as interactions with serotonergic and sympathomimetic agents. A better understanding of the foods and drugs that can cause adverse reactions, as well as knowledge of newer MAOIs with mechanisms of action and delivery methods that reduce these risks, may help clinicians to consider the use of these medications, when appropriate, in their patients with depression. © Copyright 2012 Physicians Postgraduate Press Inc.

DeWitt J.,Indiana University
Gastrointestinal Endoscopy Clinics of North America | Year: 2012

Pancreatic cystic neoplasms represent a wide spectrum of invariably benign to precancerous and malignant tumors. Endoscopic ultrasound-guided pancreatic cyst ablation with ethanol and/or paclitaxel offers a nonoperative treatment for patients refusing or not eligible for surgery. Histopathology after resection in these patients has shown variable degrees of cyst epithelial ablation ranging from 0% to 100%. Future research investigating the safety of this procedure, modifications of reported ablation techniques, choice and number of the lavage agents used, and criteria to optimize selection of the appropriate pancreatic cysts for treatment is needed. © 2012 Elsevier Inc.

Evan A.P.,Indiana University
Pediatric Nephrology | Year: 2010

All stones share similar presenting symptoms, and urine supersaturation with respect to the mineral phase of the stone is essential for stone formation. However, recent studies using papillary biopsies of stone formers have provided a view of the histology of renal crystal deposition which suggests that the early sequence of events leading to stone formation differs greatly, depending on the type of stone and on the urine chemistry leading to supersaturation. Three general pathways for kidney stone formation are seen: (1) stones fixed to the surface of a renal papilla at sites of interstitial apatite plaque (termed Randall's plaque), as seen in idiopathic calcium oxalate stone formers; (2) stones attached to plugs protruding from the openings of ducts of Bellini, as seen in hyperoxaluria and distal tubular acidosis; and (3) stones forming in free solution in the renal collection system, as in cystinuria. The presence of hydroxyapatite crystals in either the interstitial or tubule compartment (and sometimes both) of the renal medulla in stone formers is the rule and has implications for the initial steps of stone formation and the potential for renal injury. © 2009 IPNA.

Close S.L.,Indiana University
Fundamental and Clinical Pharmacology | Year: 2012

Pharmacogenetics have been touted as the future of personalized medicine where genetic biomarkers will guide therapeutic approach. The currently approved thienopyridines, prasugrel and clopidogrel, are prodrugs requiring conversion to active metabolite through the cytochrome P450 system. Genetic variation has been associated with the pharmacokinetic, pharmacodynamic, and clinical response to clopidogrel, but not to prasugrel. This review aims to summarize the recent pharmacogenetic findings associated with the response to thienopyridine treatment. Additionally, considerations for the incorporation of genetic biomarkers into clinical practice will be discussed in the context of thienopyridines. © 2011 The Author Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique.

Sinha A.D.,Indiana University
Blood Purification | Year: 2011

Despite advancements in dialysis therapy, the subjective clinical examination still remains the standard of care in managing volume removal in chronic dialysis. While there is no definitive trial establishing that dry weight management guided by an assistive technology is superior to the clinical method, there is ample evidence that there is a need for these technologies to be developed. Mortality, cardiovascular morbidity, and sequelae of volume overload remain far too common under the current paradigm. Recent studies indicate that the mortality associated with volume overload is independent of hypertension, suggesting that if mortality is to be improved, then a measure of volume independent of blood pressure must be developed. Even when considered as an integrated whole, the clinical method is inaccurate at setting dry weight when compared to the use of assistive technologies. A recent secondary analysis of a randomized trial showed that relative plasma volume (RPV) slope is responsive to change in volume status and may be useful in guiding therapy for hypertension. The only large randomized trial to investigate the ability of an assistive technology to manage volume removal in hemodialysis patients is the Crit-Line Intradialytic Monitoring Benefit Study, which found harm associated with RPV monitoring. However, the design of this trial did not require the RPV group to actually receive this intervention. Assistive technologies offer an opportunity to improve on the subjective clinical exam for the setting of dry weight, but well designed and adequately powered clinical trials are needed. Copyright © 2011 S. Karger AG, Basel.

Chirgwin J.M.,Indiana University
Anti-Cancer Agents in Medicinal Chemistry | Year: 2012

Advanced cancers of the prostate and breast commonly progress by metastasizing to the skeleton, where they are incurable but cause serious morbidity and contribute to mortality. Growth of tumor in bone takes several years, opening a large window for pharmaceutical prevention of metastatic progression. Bone provides a unique microenvironment for tumor growth, including niches occupied by hematopoietic and mesenchymal stem cells. Recent data suggest that circulating tumor cells usurp these niches and compete with the normal stem cell occupants. Agents that encourage normal hematopoiesis or bone formation could inhibit colonization of bone by tumor stem cells and prevent or delay metastatic progression. It may be possible to develop high-throughput assays to test compounds for their ability to suppress tumor stem cell occupation of skeletal niches, thus decreasing metastatic progression in at-risk patients. © 2012 Bentham Science Publishers.

Pavlis G.L.,Indiana University
Computers and Geosciences | Year: 2011

This paper describes an implementation of a three-component, three-dimensional plane wave migration method to image P-to-S converted waves that arrive following the direct P waves of teleseismic earthquakes. The programs described assume that the input data have been deconvolved to produce a set of vector impulse response functions with the initial P pulse centered at time 0. This method was implemented as three different application programs called pwstack, pwmig, and gridstacker. pwstack produces local-scale plane wave decompositions using the pseudostation concept. The output of pwstack is an estimate of the plane wave response over a grid of slowness vectors interpolated onto a regular grid in space. The Gaussian smoother that is used for the pseudostation method has the additional benefit of serving as a type of spatial antialiasing filter. The program called pwmig takes the output of pwstack and inverts the plane wave data for radial and transverse scattering potential using an inverse generalized Radon transform. Data can be back-projected using a conventional longitudinal, radial, transverse coordinate system or a novel depth-variable method that computes a transformation matrix linking each vector sample to an equivalent dipping-layer coordinate system at the corresponding scattering point. Because pwmig is a prestack method, a final program, gridstacker, is needed to stack data from multiple events that characterize real data. gridstacker is a general solution for stacking data with different grid geometries and variable data quality. Weighting functions can be defined externally by a user-supplied recipe or one can use a set of robust estimation methods coded in gridstacker. The programs are validated with simulation data produced by recently developed elastic finite-difference code and a model that simulates the edge of a subduction zone. Finally, I show an example of an application of these programs to image the western United States with the USArray. © 2011 Elsevier Ltd.

Microstructures associated with cataclasites and mylonites in the Red River shear zone in the Diancang Shan block, Yunnan Province, China show evidence for both reaction hardening and softening at lower greenschist facies metamorphic conditions. The earliest fault-rocks derived from Triassic porphyritic orthogneiss protoliths are cataclasites. Brittle fractures and crushed grains are cemented by newly precipitated quartz. These cataclasites are subsequently overprinted by mylonitic fabrics. Truncations and embayments of relic feldspars and biotites show that these protolith minerals have been dissolved and incompletely replaced by muscovite, chlorite, and quartz. Both K-feldspar and plagioclase porphyroclasts are truncated by muscovite alone, suggesting locally metasomatic reactions of the form: 3K-feldspar+2H+=muscovite+6SiO2(aq)+2K+. Such reactions produce muscovite folia and fish, and quartz bands and ribbons. Muscovite and quartz are much weaker than the reactant feldspars and these reactions result in reaction softening. Moreover, the muscovite tends to align in contiguous bands that constitute textural softening. These mineral and textural modifications occurred at constant temperature and drove the transition from brittle to viscous deformation and the shift in deformation mechanism from cataclasis to dissolution-precipitation and reaction creep. These mylonitic rocks so produced are cut by K-feldspar veins that interrupt the mylonitic fabric. The veins add K-feldspar to the assemblage and these structures constitute both reaction and textural hardening. Finally these veins are boudinaged by continued viscous deformation in the mylonitic matrix, thus defining a late ductile strain event. Together these overprinting textures and microstructures demonstrate several oscillations between brittle and viscous deformation, all at lower greenschist facies conditions where only frictional behavior is predicted by experiments. The overlap of the depths of greenschist facies conditions with the base of the crustal seismic zone suggests that the implied oscillations in strain rate may have been related to the earthquake cycle. © 2012 Elsevier B.V.

Conway S.J.,Indiana University
Cellular and molecular life sciences : CMLS | Year: 2014

Periostin, also termed osteoblast-specific factor 2, is a matricellular protein with known functions in osteology, tissue repair, oncology, cardiovascular and respiratory systems, and in various inflammatory settings. However, most of the research to date has been conducted in divergent and circumscribed areas meaning that the overall understanding of this intriguing molecule remains fragmented. Here, we integrate the available evidence on periostin expression, its normal role in development, and whether it plays a similar function during pathologic repair, regeneration, and disease in order to bring together the different research fields in which periostin investigations are ongoing. In spite of the seemingly disparate roles of periostin in health and disease, tissue remodeling as a response to insult/injury is emerging as a common functional denominator of this matricellular molecule. Periostin is transiently upregulated during cell fate changes, either physiologic or pathologic. Combining observations from various conditions, a common pattern of events can be suggested, including periostin localization during development, insult and injury, epithelial-mesenchymal transition, extracellular matrix restructuring, and remodeling. We propose mesenchymal remodeling as an overarching role for the matricellular protein periostin, across physiology and disease. Periostin may be seen as an important structural mediator, balancing appropriate versus inappropriate tissue adaption in response to insult/injury.

Rebec G.V.,Indiana University
Antioxidants and Redox Signaling | Year: 2013

Significance: Dysregulation of cortical and striatal neuronal processing plays a critical role in Huntington's disease (HD), a dominantly inherited condition that includes a progressive deterioration of cognitive and motor control. Growing evidence indicates that ascorbate (AA), an antioxidant vitamin, is released into striatal extracellular fluid when glutamate is cleared after its release from cortical afferents. Both AA release and glutamate uptake are impaired in the striatum of transgenic mouse models of HD owing to a downregulation of glutamate transporter 1 (GLT1), the protein primarily found on astrocytes and responsible for removing most extracellular glutamate. Improved understanding of an AA-glutamate interaction could lead to new therapeutic strategies for HD. Recent Advances: Increased expression of GLT1 following treatment with ceftriaxone, a beta-lactam antibiotic, increases striatal glutamate uptake and AA release and also improves the HD behavioral phenotype. In fact, treatment with AA alone restores striatal extracellular AA to wild-type levels in HD mice and not only improves behavior but also improves the firing pattern of neurons in HD striatum. Critical Issues: Although evidence is growing for an AA-glutamate interaction, several key issues require clarification: the site of action of AA on striatal neurons; the precise role of GLT1 in striatal AA release; and the mechanism by which HD interferes with this role. Future Directions: Further assessment of how the HD mutation alters corticostriatal signaling is an important next step. A critical focus is the role of astrocytes, which express GLT1 and may be the primary source of extracellular AA. Antioxid. Redox Signal. 19, 2115-2128. © Copyright 2013, Mary Ann Liebert, Inc. 2013.

Evans J.P.,University of North Carolina at Chapel Hill | Meslin E.M.,Indiana University | Marteau T.M.,Kings College London | Caulfield T.,University of Alberta
Science | Year: 2011

Unrealistic expectations and uncritical translation of genetic discoveries may undermine other promising approaches to preventing disease and improving health.

Objective: "Open" transcortical and transcallosal approaches allow gross total colloid cyst resection but require a wider surgical corridor through normal brain tissue compared with endoscopic techniques. Although the use of tubular retractor systems has been previously reported, the minimum required diameter size for the retractor tube has been approximately 16 to 22 mm. Our objective was to explore the use of smaller retractor tubes for total resection of colloid cysts. Methods: A minitubular retractor with a 12-mm diameter was used to access and resect colloid cysts using microsurgical techniques while preserving stereoscopic vision as an alternative to open and endoscopic surgical routes. Results: This technique was adopted in five patients with larger than 10-mm colloid cysts to allow for gross total resection of the cysts in every case without any complication. Conclusions: Smaller retractor tubes may be used for resection of colloid cysts while minimizing brain retraction injury and potentially improving outcomes. © 2013 Elsevier Inc.

Cook S.P.,Indiana University
Synlett | Year: 2014

Artemisinin represents one of the most important discoveries in the fight against malaria over the last 50 years. As the first endoperoxide-containing natural product, artemisinin has attracted chemists and biologists alike with its potent activity and rapid onset against malaria-causing Plasmodium species. Since its disclosure in 1979, artemisinin has been the subject of several elegant syntheses. Herein, the evolution of synthetic strategy is discussed in the context of artemisinin. © Georg Thieme Verlag Stuttgart · New York.

Mather K.J.,Indiana University
Reviews in Endocrine and Metabolic Disorders | Year: 2013

Insulin resistance affects the vascular endothelium, and contributes to systemic insulin resistance by directly impairing the actions of insulin to redistribute blood flow as part of its normal actions driving muscle glucose uptake. Impaired vascular function is a component of the insulin resistance syndrome, and is a feature of type 2 diabetes. On this basis, the vascular endothelium has emerged as a therapeutic target where the intent is to improve systemic metabolic state by improving vascular function. We review the available literature presenting studies in humans, evaluating the effects of metabolically targeted and vascular targeted therapies on insulin action and systemic metabolism. Therapies that improve systemic insulin resistance exert strong concurrent effects to improve vascular function and vascular insulin action. RAS-acting agents and statins have widely recognized beneficial effects on vascular function but have not uniformly produced the hoped-for metabolic benefits. These observations support the notion that systemic metabolic benefits can arise from therapies targeted at the endothelium, but improving vascular insulin action does not result from all treatments that improve endothelium-dependent vasodilation. A better understanding of the mechanisms of insulin's actions in the vascular wall will advance our understanding of the specificity of these responses, and allow us to better target the vasculature for metabolic benefits. © 2013 Springer Science+Business Media New York.

Arrieta A.,Indiana University
Health Policy | Year: 2011

Objectives: To test the hypothesis that the health reform enacted in Peru in 1997 increased the rate of cesarean sections in the private sector due to non-clinical factors. Methods: Different rounds of the Demographic and Health Survey are used to estimate determinants of c-section rates in private and public facilities before and after the healthcare reform. Estimations are based on a pooled linear regression controlling by obstetric and socioeconomic characteristics. Results: C-section rates in the private sector grew from 28 to 53% after the health reform. Compared to the Ministry of Health (MOH), giving birth in a private hospital in the post-reform period adds 19% to the probability of c-section. Conclusions: The health reform implemented in the private sector increased physician incentives to over-utilize c-sections. The reform consolidated and raised the market power of private health insurers, but at the same time did not provide mechanisms to enlarge, regulate and disclose information of private providers. All these factors created the conditions for fee-for-service paid providers to perform more c-sections. Comparable trends in c-section rates have been observed in Latin American countries who implemented similar reforms in their private sector, suggesting a need to rethink the role of private health providers in developing countries. © 2010 Elsevier Ireland Ltd.

Rajashekhar G.,Indiana University
Journal of cellular physiology | Year: 2011

Chronic inflammation is tightly linked to diseases associated with endothelial dysfunction including aberrant angiogenesis. To better understand the endothelial role in pro-inflammatory angiogenesis, we analyzed signaling pathways in continuously activated endothelial cells, which were either chronically exposed to soluble TNF or the reactive oxygen species (ROS) generating H2O2, or express active transmembrane TNF. Testing in an in vitro capillary sprout formation assay, continuous endothelial activation increased angiogenesis dependent on activation of p38 MAP kinase, NADPH oxidase, and matrix metalloproteinases (MMP). p38 MAP kinase- and MMP-9-dependent angiogenesis in our assay system may be part of a positive feed forward autocrine loop because continuously activated endothelial cells displayed up-regulated ROS production and subsequent endothelial TNF expression. The pro-angiogenic role of the p38 MAP kinase in continuously activated endothelial cells was in stark contrast to the anti-angiogenic activity of the p38 MAP kinase in unstimulated control endothelial cells. In vivo, using an experimental prostate tumor, pharmacological inhibition of p38 MAP kinase demonstrated a significant reduction in tumor growth and in vessel density, suggesting a pro-angiogenic role of the p38 MAP kinase in pathological angiogenesis in vivo. In conclusion, our results suggest that continuous activation of endothelial cells can cause a switch of the p38 MAP kinase from anti-angiogenic to pro-angiogenic activities in conditions which link oxidative stress and autocrine TNF production. Copyright © 2010 Wiley-Liss, Inc.

Crystal J.D.,Indiana University
Behavioural Processes | Year: 2013

A growing body of research suggests that rats represent and remember specific earlier events from the past. An important criterion for validating a rodent model of episodic memory is to establish that the content of the representation is about a specific event in the past rather than vague information about remoteness. Recent evidence suggests that rats may also represent events that are anticipated to occur in the future. An important capacity afforded by a representation of the future is the ability to plan for the occurrence of a future event. However, relatively little is known about the content of represented future events and the cognitive mechanisms that may support planning. This article reviews evidence that rats remember specific earlier events from the past, represent events that are anticipated to occur in the future, and develops criteria for validating a rodent model of future planning. These criteria include representing a specific time in the future, the ability to temporarily disengage from a plan and reactivate the plan at an appropriate time in the future, and flexibility to deploy a plan in novel conditions. © 2012 Elsevier B.V.

Guise T.A.,Indiana University
Cell | Year: 2013

In order to establish themselves in distal sites, metastatic cancer cells need to acquire organ-specific traits. Zhang et al. provide evidence in breast cancer that a tumor cell's acquisition of properties for successful bone metastasis is influenced by signals from the stroma of the primary tumor. © 2013 Elsevier Inc.

Liu X.,Indiana University
Journal of the American Society for Information Science and Technology | Year: 2013

The goal of this study was to propose novel cyberlearning resource-based scientific referential metadata for an assortment of publications and scientific topics, in order to enhance the learning experiences of students and scholars in a cyberinfrastructure-enabled learning environment. By using information retrieval and meta-search approaches, different types of referential metadata, such as related Wikipedia pages, data sets, source code, video lectures, presentation slides, and (online) tutorials for scientific publications and scientific topics will be automatically retrieved, associated, and ranked. In order to test our method of automatic cyberlearning referential metadata generation, we designed a user experiment to validate the quality of the metadata for each scientific keyword and publication and resource-ranking algorithm. Evaluation results show that the cyberlearning referential metadata retrieved via meta-search and statistical relevance ranking can help students better understand the essence of scientific keywords and publications. © 2013 ASIS&T.

Conventional assessments of outcomes in deaf children with cochlear implants (CIs) have focused primarily on endpoint or product measures of speech and language. Little attention has been devoted to understanding the basic underlying core neurocognitive factors involved in the development and processing of speech and language. In this study, we examined the development of factors related to the quality of phonological information in immediate verbal memory, including immediate memory capacity and verbal rehearsal speed, in a sample of deaf children after >10 yrs of CI use and assessed the correlations between these two process measures and a set of speech and language outcomes. Of an initial sample of 180 prelingually deaf children with CIs assessed at ages 8 to 9 yrs after 3 to 7 yrs of CI use, 112 returned for testing again in adolescence after 10 more years of CI experience. In addition to completing a battery of conventional speech and language outcome measures, subjects were administered the Wechsler Intelligence Scale for Children-III Digit Span subtest to measure immediate verbal memory capacity. Sentence durations obtained from the McGarr speech intelligibility test were used as a measure of verbal rehearsal speed. Relative to norms for normal-hearing children, Digit Span scores were well below average for children with CIs at both elementary and high school ages. Improvement was observed over the 8-yr period in the mean longest digit span forward score but not in the mean longest digit span backward score. Longest digit span forward scores at ages 8 to 9 yrs were significantly correlated with all speech and language outcomes in adolescence, but backward digit spans correlated significantly only with measures of higher-order language functioning over that time period. While verbal rehearsal speed increased for almost all subjects between elementary grades and high school, it was still slower than the rehearsal speed obtained from a control group of normal-hearing adolescents. Verbal rehearsal speed at ages 8 to 9 yrs was also found to be strongly correlated with speech and language outcomes and Digit Span scores in adolescence. Despite improvement after 8 additional years of CI use, measures of immediate verbal memory capacity and verbal rehearsal speed, which reflect core fundamental information processing skills associated with representational efficiency and information processing capacity, continue to be delayed in children with CIs relative to NH peers. Furthermore, immediate verbal memory capacity and verbal rehearsal speed at 8 to 9 yrs of age were both found to predict speech and language outcomes in adolescence, demonstrating the important contribution of these processing measures for speech-language development in children with CIs. Understanding the relations between these core underlying processes and speech-language outcomes in children with CIs may help researchers to develop new approaches to intervention and treatment of deaf children who perform poorly with their CIs. Moreover, this knowledge could be used for early identification of deaf children who may be at high risk for poor speech and language outcomes after cochlear implantation as well as for the development of novel targeted interventions that focus selectively on these core elementary information processing variables.

Wolf M.,Northwestern University | White K.E.,Indiana University
Current Opinion in Nephrology and Hypertension | Year: 2014

High levels of fibroblast growth factor 23 (FGF23) cause the rare disorders of hypophosphatemic rickets and are a risk factor for cardiovascular disease and death in patients with chronic kidney disease (CKD). Despite major advances in understanding FGF23 biology, fundamental aspects of FGF23 regulation in health and in CKD remain mostly unknown. RECENT FINDINGS: Autosomal dominant hypophosphatemic rickets (ADHR) is caused by gain-of-function mutations in FGF23 that prevent its proteolytic cleavage, but affected individuals experience a waxing and waning course of phosphate wasting. This led to the discovery that iron deficiency is an environmental trigger that stimulates FGF23 expression and hypophosphatemia in ADHR. Unlike osteocytes in ADHR, normal osteocytes couple increased FGF23 production with commensurately increased FGF23 cleavage to ensure that normal phosphate homeostasis is maintained in the event of iron deficiency. Simultaneous measurement of FGF23 by intact and C-Terminal assays supported these breakthroughs by providing minimally invasive insight into FGF23 production and cleavage in bone. These findings also suggest a novel mechanism of FGF23 elevation in patients with CKD, who are often iron deficient and demonstrate increased FGF23 production and decreased FGF23 cleavage, consistent with an acquired state that mimics the molecular pathophysiology of ADHR. SUMMARY: Iron deficiency stimulates FGF23 production, but normal osteocytes couple increased FGF23 production with increased cleavage to maintain normal circulating levels of biologically active hormone. These findings uncover a second level of FGF23 regulation within osteocytes, failure of which culminates in elevated levels of biologically active FGF23 in ADHR and perhaps CKD. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Rizzo M.T.,Indiana University
Clinica Chimica Acta | Year: 2011

Compelling experimental and clinical evidence supports the notion that cyclooxygenase-2, the inducible isoform of cyclooxygenase, plays a crucial role in oncogenesis. Clinical and epidemiological data indicate that aberrant regulation of cyclooxygenase-2 in certain solid tumors and hematological malignancies is associated with adverse clinical outcome. Moreover, findings extrapolated from experimental studies in cultured tumor cells and animal tumor models indicate that cyclooxygenase-2 critically influences all stages of tumor development from tumor initiation to tumor progression. Cyclooxygenase-2 elicits cell-autonomous effects on tumor cells resulting in stimulation of growth, increased cell survival, enhanced tumor cell invasiveness, stimulation of neovascularization, and tumor evasion from the host immune system. Additionally, the oncogenic effects of cyclooxygenase-2 stem from its unique ability to impact tumor cell surroundings and create a proinflammatory environment conducive for tumor development, growth and progression. The initial enthusiasm generated by the availability of cyclooxygenase-2 selective inhibitors for cancer prevention and therapy has been lessened by the severe cardiovascular adverse side effects associated with their long-term use, as well as by the mixed results of recent clinical trials evaluating the efficacy of cyclooxygenase-2 inhibitors in adjuvant chemotherapy. Therefore, our ability to efficiently target the oncogenic effects of cyclooxygenase-2 for therapeutic and preventive purposes strictly depends on a better understanding of the spatial and temporal aspects of its activation in tumor cells along with a clearer elucidation of the signaling networks whereby cyclooxygenase-2 affects tumor cells and their interactions with the tumor microenvironment. This knowledge has the potential of leading to the identification of novel cyclooxygenase-2-dependent molecular and signaling networks that can be exploited to improve cancer prevention and therapy. © 2010 Elsevier B.V.

Filsecker M.,University of Duisburg - Essen | Hickey D.T.,Indiana University
Computers and Education | Year: 2014

This study investigated the effects of external rewards on fifth graders' motivation, engagement and learning while playing an educational game. We were interested in exploring whether the feedback-rich environment of the game could mitigate the predicted negative effects of external rewards. Data of students' engagement and learning were collected and analyzed at multiple levels. A quasi-experimental design was used to examine the effect of external rewards in one group (n = 50) compared to a control group without such rewards (n = 56). According to the results, the external rewards did not undermine students' motivation (e.g., at proximal and distal levels), however they did not foster disciplinary engagement. On the other hand, students in the reward condition showed significantly larger gains in conceptual understanding (proximal) and non-significantly larger gains in achievement (distal). These results suggest that the predicted negative consequences of external rewards may be addressed in this new generation of learning environments. Future research and contributions of the study are provided. © 2014 Elsevier Ltd. All rights reserved.

Molitoris B.A.,Indiana University
Journal of Clinical Investigation | Year: 2014

Acute kidney injury (AKI) remains a major clinical event with rising incidence, severity, and cost; it now has a morbidity and mortality exceeding acute myocardial infarction. There is also a documented conversion to and acceleration of chronic kidney disease to end-stage renal disease. The multifactorial nature of AKI etiologies and pathophysiology and the lack of diagnostic techniques have hindered translation of preclinical success. An evolving understanding of epithelial, endothelial, and inflammatory cell interactions and individualization of care will result in the eventual development of effective therapeutic strategies. This review focuses on epithelial and endothelial injury mediators, interactions, and targets for therapy.

Gupta S.K.,Indiana University | Vitanza J.M.,Meritage Pharma | Collins M.H.,University of Cincinnati
Clinical Gastroenterology and Hepatology | Year: 2015

Background & Aims: No treatment has been approved by the U.S. Food and Drug Administration for eosinophilic esophagitis (EoE). We investigated the efficacy and safety of a new formulation of oral budesonide suspension (OBS), a corticosteroid, in a prospective, placebo-controlled, dose-ranging study. Methods: Subjects 2-18 years old with symptoms of EoE and peak eosinophil counts ≥20/high-power field at ≥2 levels of the esophagus were randomly assigned to groups given placebo or low-dose, medium-dose, or high-dose OBS for 12 weeks. Doses and volumes were adjusted on the basis of patients' age to cover the entire esophagus. The primary efficacy end point was compound response to therapy (peak eosinophil counts ≤6/high-power field at all levels of the esophagus and ≥50% reduction in EoE symptom score). Multiple safety parameters were evaluated. Results: Data from 71 subjects who completed all efficacy assessments were included in the primary efficacy analysis. At the end of 12 weeks, there were significantly greater percentages of responders in groups given medium-dose OBS (52.6%, P = .0092) and high-dose OBS (47.1%, P= .0174) than in the group given placebo (5.6%); there was no significant difference in percentages of responders between the low-dose OBS (11.8%) and placebo groups (P= .5282). The significant compound responses noted in the medium-dose and high-dose OBS groups were accounted for by the significant histologic responses; in contrast, all 4 groups (including the placebo group) had large symptom responses, and there was no significant difference in the percentage of subjects with a symptom response in either OBS group compared with the placebo group (P ≥ .1235). There were no unexpected safety concerns or signals. Conclusions: Peak eosinophil counts were significantly reduced throughout the esophagus in pediatric patients with EoE who were given medium-dose and high-dose OBS. There was a large symptom response to placebo that was similar to symptom responses in the OBS groups; symptom response did not distinguish OBS from placebo. ClinicalTrials.gov number, NCT00762073. © 2015 AGA Institute.

Navari R.M.,Indiana University | Navari R.M.,Harper Cancer Research Institute
Drugs | Year: 2013

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. The use of a combination of a serotonin 5-HT 3 receptor antagonist, dexamethasone and a neurokinin 1 (NK 1) receptor antagonist has significantly improved the control of acute and delayed emesis in single-day chemotherapy. Palonosetron, a second-generation 5-HT3 receptor antagonist with a different half-life, a different binding capacity and a different mechanism of action than the first-generation 5-HT3 receptor antagonists appears to be the most effective agent in its class. Aprepitant, the first and only agent clinically available in the NK1 receptor antagonist drug class has been used effectively as an additive agent to the 5-HT3 receptor antagonists and dexamethasone to control CINV. Rolapitant and netupitant are other NK1 receptor antagonists that are currently in phase III clinical trials. Despite the control of emesis, nausea has not been well controlled by current agents. Olanzapine, a US-FDA approved antipsychotic, has emerged in recent trials as an effective preventative agent for CINV, as well as a very effective agent for the treatment of breakthrough emesis and nausea. Clinical trials using gabapentin, cannabinoids and ginger have not been definitive regarding their efficacy in the prevention of CINV. Additional studies are necessary for the control of nausea and for the control of CINV in the clinical settings of multiple-day chemotherapy and bone marrow transplantation. © 2013 Springer International Publishing Switzerland.

Broxmeyer H.E.,Indiana University
Journal of Experimental Medicine | Year: 2013

Erythropoietin (EPO), a humoral regulator of erythropoiesis and replacement therapy for selected red blood cell disorders in EPO-deficient patients, has been implicated in a wide range of activities on diverse cell, tissue, and organ types. EPO signals via two receptors, one comprising EPO receptor (EPOR) homodimers and the other a heterodimer of EPOR and CD131-the common β chain component of the GM-CSF, interleukin (IL)-3, and IL-5 receptors. Ligation of EPORs triggers various signaling pathways, including the JAK2- STAT5 and MAPK-NF-κB pathways, depending both on the receptor and the target cell type. A new study in this issue reveals a novel EPO-triggered pathway involving a Spi2A serpin-lysosome-cathepsin cascade that is initiated through the homodimeric EPOR complex and is required for the survival of erythroid progenitors. A full understanding of EPO's effects on various cell types and their potential clinical relevance requires more work on the signaling events initiated through both EPORs, the effects of other cytokines and growth factors that modulate EPO's actions, and a comparison of the effects of full-length versus truncated forms of EPO. © 2013 Broxmeyer.

Fidler D.P.,Indiana University
IEEE Security and Privacy | Year: 2011

As software, we now understand Stuxnet. As a political event, we're still debating its significance. Although consensus doesn't exist, reactions to Stuxnet suggest that the worm's political repercussions may surpass its technical achievementsimpact that might affect conditions influencing online privacy. © 2006 IEEE.

Hall A.M.,University of Zurich | Molitoris B.A.,Indiana University
Physiology | Year: 2014

Acute kidney injury (AKI) is a major global health problem; much research has been conducted on AKI, and numerous agents have shown benefit in animal studies, but none have translated into treatments. There is, therefore, a pressing unmet need to increase knowledge of the pathophysiology of AKI. Multiphoton microscopy (MPM) provides a tool to non-invasively visualize dynamic events in real time and at high resolution in rodent kidneys, and in this article we review its application to study novel mechanisms and treatments in different forms of AKI. © 2014 Int. Union Physiol. Sci./Am. Physiol. Soc.

Bush K.,Indiana University
Journal of Global Antimicrobial Resistance | Year: 2013

Carbapenemases, b-lactamases that inactivate carbapenems and most β-lactam antibiotics, are most widely known for their ability to confer resistance to β-lactams. They include serine carbapenemases, such as the widespread KPC family of enzymes, and the metallo-β-lactamases that contain the IMP, NDM and VIM enzyme families acquired by Gram-negative bacteria on transferable elements. These enzymes are almost always produced by organisms that encode at least one other β-lactamase, with as many as eight different β-lactamase genes detected in a single isolate. This consortium of β-lactamases includes a full spectrum of molecular and biochemical characteristics, providing the producing organism with a range of catalytic activities. In addition to the variety of β-lactamases found in carbapenemaseproducing Gram-negative pathogens are multiple other resistance factors, especially aminoglycosidemodifying enzymes and 16S rRNA methylases that confer resistance to aminoglycosides. Other acquired genes encode fluoroquinolone, trimethoprim, sulfonamide, rifampicin and chloramphenicol resistance determinants on mobile elements that travel together with β-lactamase genes. Thus, the recent proliferation of transferable carbapenemases serves to magnify resistance to virtually all antibiotic classes. Judicial use of current antibiotics and a quest for novel antibacterial agents are necessary, as multidrug-resistant bacteria continue to multiply. © 2013 International Society for Chemotherapy of Infection and Cancer.

Grollman E.A.,Indiana University
Journal of Health and Social Behavior | Year: 2012

Research on perceived discrimination has overwhelmingly focused on one form of discrimination, especially race discrimination, in isolation from other forms. The present article uses data from the Black Youth Culture Survey, a nationally representative, racially and ethnically diverse sample of 1,052 adolescents and young adults to investigate the prevalence, distribution, and mental and physical health consequences of multiple forms of perceived discrimination. The findings suggest that disadvantaged groups, especially multiply disadvantaged youth, face greater exposure to multiple forms of discrimination than their more privileged counterparts. The experience of multiple forms of discrimination is associated with worse mental and physical health above the effect of only one form and contributes to the relationship between multiple disadvantaged statuses and health. These findings suggest that past research may misspecify the discrimination-health relationship and fails to account for the disproportionate exposure to discrimination faced by multiply disadvantaged individuals. © American Sociological Association 2012.

Weilbaecher K.N.,University of Washington | Guise T.A.,Indiana University | McCauley L.K.,University of Michigan
Nature Reviews Cancer | Year: 2011

When cancer metastasizes to bone, considerable pain and deregulated bone remodelling occurs, greatly diminishing the possibility of cure. Metastasizing tumour cells mobilize and sculpt the bone microenvironment to enhance tumour growth and to promote bone invasion. Understanding the crucial components of the bone microenvironment that influence tumour localization, along with the tumour-derived factors that modulate cellular and protein matrix components of bone to favour tumour expansion and invasion, is central to the pathophysiology of bone metastases. Basic findings of tumourĝ€"bone interactions have uncovered numerous therapeutic opportunities that focus on the bone microenvironment to prevent and treat bone metastases. © 2011 Macmillan Publishers Limited. All rights reserved.

Edmonds B.T.,Indiana University
Current Opinion in Obstetrics and Gynecology | Year: 2014

Purpose of review To discuss the role for shared decision-making in obstetrics/gynecology and to review evidence on the impact of decision aids on reproductive health decision-making. Recent findings Among the 155 studies included in a 2014 Cochrane review of decision aids, 31 (29%) addressed reproductive health decisions. Although the majority did not show evidence of an effect on treatment choice, there was a greater uptake of mammography in selected groups of women exposed to decision aids compared with usual care; and a statistically significant reduction in the uptake of hormone replacement therapy among detailed decision aid users compared with simple decision aid users. Studies also found an effect on patient-centered outcomes of care, such as medication adherence, quality-of-life measures, and anxiety scores. In maternity care, only decision analysis tools affected final treatment choice, and patient-directed aids yielded no difference in planned mode of birth after cesarean. Summary There is untapped potential for obstetricians/gynecologists to optimize decision support for reproductive health decisions. Given the limited evidence-base guiding practice, the preference-sensitive nature of reproductive health decisions, and the increase in policy efforts and financial incentives to optimize patients' satisfaction, it is increasingly important for obstetricians/gynecologists to appreciate the role of shared decision-making and decision support in providing patient-centered reproductive healthcare. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Johnson M.S.,Indiana University
Journal of vascular and interventional radiology : JVIR | Year: 2010

PURPOSE: To evaluate the safety and effectiveness of the retrievable Option inferior vena cava (IVC) filter in patients at risk for pulmonary embolism (PE). MATERIALS AND METHODS: This was a prospective, multicenter, single-arm clinical trial. Subjects (N = 100) underwent implantation of the IVC filter and were followed for 180 days; subjects whose filters were later removed were followed for 30 days thereafter. The primary objective was to determine whether the one-sided lower limit of the 95% CI for the observed clinical success rate was at least 80%. Clinical success was defined as technical success (deployment of the filter such that it was judged suitable for mechanical protection from PE) without subsequent PE, significant filter migration or embolization, symptomatic caval thrombosis, or other complications. RESULTS: Technical success was achieved in 100% of subjects. There were eight cases of recurrent PE, two cases of filter migration (23 mm), and three cases of symptomatic caval occlusion/thrombosis (one in a subject who also experienced filter migration). No filter embolization or fracture occurred. Clinical success was achieved in 88% of subjects; the one-sided lower limit of the 95% CI was 81%. Retrieval was successful at a mean of 67.1 days after implantation (range, 1-175 d) for 36 of 39 subjects (92.3%). All deaths (n = 17) and deep vein thromboses (n = 18) were judged to have resulted from preexisting or intercurrent illnesses or interventions and unrelated to the filter device; all deaths were judged to be unrelated to PE. CONCLUSIONS: Placement and retrieval of the Option IVC filter were performed safely and with high rates of clinical success. Copyright (c) 2010 SIR. Published by Elsevier Inc. All rights reserved.

Ulbright T.M.,Indiana University
International Journal of Gynecological Pathology | Year: 2014

Dr Robert E. Scully greatly advanced our understanding of germ cell neoplasia to the extent that it is difficult to narrow the discussion of his contributions to this topic so that it can be covered in a brief article. This article accordingly focuses on some of the recent developments concerning 2 of his major contributions in this area-the gonadoblastoma (GB) and variant morphologies of yolk sac tumor. GB was defined by Dr Scully in 1953 and its features elaborated in detail by him in 1970. This neoplasm occurred in young patients who often displayed phenotypic sex ambiguities and frequently presented with primary amenorrhea. It was bilateral in 40%, and consisted of circumscribed nests of small sex cord cells and germinoma-like cells admixed with round deposits of eosinophilic, hyaline, often calcified material. These nests were set in a spindle cell gonadal stroma with Leydig-like or lutein-like cells. Because of his work we now understand that this precursor to invasive germ cell tumors occurs in patients with a specific form of disorder of sex development, namely gonadal dysgenesis, and only in those who have a particular portion of the Y chromosome, the GB locus/TSPY gene, within the gonadal tissue. An essential element to the development of GB appears to be a defect in the genetic pathway that leads to the development of Sertoli cells. Improperly formed Sertoli cells predispose to "delayed maturation" of the gonocytes of the gonad and predispose them to undergo malignant transformation. "Undifferentiated gonadal tissue" has been proposed as the precursor to the development of GB and consists of an unorganized mixture of apparently non-neoplastic germ cells, germ cells with delayed maturation, and neoplastic germ cells with sex cord cells and gonadal stroma. Two variant morphologies of yolk sac tumor were also recognized by Dr Scully. In the hepatoid variant features similar to hepatocellular carcinoma occurred, although primitive glandular foci and lack of liver involvement permitted its distinction in most cases. More recently this variant has been found to occasionally produce bile in canalicular-like structures and to stain strongly for both SALL4 and glypican 3, 2 recently described markers of yolk sac tumor. Recognition of hepatoid yolk sac tumor was followed by the description of a potential mimic, primary ovarian hepatoid carcinoma, which, however, occurred in a significantly older patient population and was occasionally associated with surface epithelial neoplasia. The endometrioid-like variant of yolk sac tumor simulated primary endometrioid adenocarcinoma. It can be suspected on routine stains because of primitive appearing nuclei, frequent subnuclear vacuoles, and in some cases association with more usual yolk sac tumor. Its recognition is now facilitated by a panel of immunohistochemical stains that are often expressed differentially in these 2 neoplasms-endometrioid-like yolk sac tumor: positive for SALL4, glypican 3, and α-fetoprotein; endometrioid adenocarcinoma: positive for cytokeratin 7 and epithelial membrane antigen. Finally, Dr Scully contributed one of the first cases in the literature of yet another nuance in the complicated world of yolk sac neoplasia, namely the development of some tumors on the background of a surface epithelial neoplasm. This is analogous to the more common development of choriocarcinoma from carcinoma and, in the case of yolk sac tumor, diagnosis is aided clinically by the usual older age of the patient and nature of the associated neoplasia. © 2014 International Society of Gynecological Pathologists.

Chalasani N.,Indiana University | Chalasani N.,Clarian Digestive Diseases Center | Bjornsson E.,Reykjavik University
Gastroenterology | Year: 2010

Idiosyncratic drug-induced liver injury (DILI) is a rare disorder that is not related directly to dosage and little is known about individuals who are at increased risk. There are no suitable preclinical models for the study of idiosyncratic DILI and its pathogenesis is poorly understood. It is likely to arise from complex interactions among genetic, nongenetic host susceptibility, and environmental factors. Nongenetic risk factors include age, sex, and other diseases (eg, chronic liver disease or human immunodeficiency virus infection). Compound-specific risk factors include daily dose, metabolism characteristics, and propensity for drug interactions. Alcohol consumption has been proposed as a risk factor for DILI from medications, but there is insufficient evidence to support this. Many studies have explored genetic defects that might be involved in pathogenesis and focused on genes involved in drug metabolism and the immune response. Multicenter databases of patients with DILI (the United States Drug Induced Liver Injury Network, DILIGEN, and the Spanish DILI registry) are important tools for clinical and genetic research. A genome-wide association study of flucloxacillin hepatotoxicity has yielded groundbreaking results and many similar studies are underway. Nonetheless, DILI is challenging to investigate because of its rarity, the lack of experimental models, the number of medications that might cause it, and challenges to diagnosis. © 2010 AGA Institute.

Lane B.W.,Indiana University
Journal of Transport Geography | Year: 2010

The unprecedented increase in gasoline costs between August 2005 and July 2008 has become a major public issue in the US. Of the contentions and potential solutions surrounding higher gasoline costs, one receiving relatively little attention has been the role of public transit. This research examines that question by analyzing the relationship between gasoline prices and transit ridership from January 2002 to April 2008 in nine major US cities. Regression analysis is used to assess the degree to which variability in rail and bus transit ridership is attributable to gasoline costs and fluctuations in gasoline cost, controlling for service changes, seasonality, and inherent trending. The results indicate that a small but statistically significant amount of ridership fluctuation is due to changes in gasoline prices. The results are discussed in light of the policy and practical implications of higher gasoline prices for mass transit and the potential for long term changes in US travel behavior. © 2009 Elsevier Ltd. All rights reserved.

Prior research has indicated that self-reported violent media exposure is associated with poorer performance on some neuropsychological tests in adolescents. This study aimed to examine the relationship of executive functioning to violent television viewing in healthy young adult males and examine how brain structure is associated with media exposure measures. Sixty-five healthy adult males (ages 18-29) with minimal video game experience estimated their television viewing habits over the past year and, during the subsequent week, recorded television viewing time and characteristics in a daily media diary. Participants then completed a battery of neuropsychological laboratory tests quantifying executive functions and underwent a magnetic resonance imaging (MRI) scan. Aggregate measures of executive functioning were not associated with measures of overall television viewing (any content type) during the past week or year. However, the amount of television viewing of violent content only, as indicated by both past-year and daily diary measures, was associated with poorer scores on an aggregate score of inhibition, interference control and attention, with no relationship to a composite working memory score. In addition, violent television exposure, as measured with daily media diaries, was associated with reduced frontoparietal white matter volume. Future longitudinal work is necessary to resolve whether individuals with poor executive function and slower white matter growth are more drawn to violent programming, or if extensive media violence exposure modifies cognitive control mechanisms mediated primarily via prefrontal cortex. Impaired inhibitory mechanisms may be related to reported increases in aggression with higher media violence exposure. Copyright © 2014 Elsevier Inc. All rights reserved.

Olson K.R.,Indiana University
Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology | Year: 2012

Sulfur is a versatile molecule with oxidation states ranging from -2 to +6. From the beginning, sulfur has been inexorably entwined with the evolution of organisms. Reduced sulfur, prevalent in the prebiotic Earth and supplied from interstellar sources, was an integral component of early life as it could provide energy through oxidization, even in a weakly oxidizing environment, and it spontaneously reacted with iron to form iron-sulfur clusters that became the earliest biological catalysts and structural components of cells. The ability to cycle sulfur between reduced and oxidized states may have been key in the great endosymbiotic event that incorporated a sulfide-oxidizing α-protobacteria into a host sulfide-reducing Archea, resulting in the eukaryotic cell. As eukaryotes slowly adapted from a sulfidic and anoxic (euxinic) world to one that was highly oxidizing, numerous mechanisms developed to deal with increasing oxidants; namely, oxygen, and decreasing sulfide. Because there is rarely any reduced sulfur in the present-day environment, sulfur was historically ignored by biologists, except for an occasional report of sulfide toxicity. Twenty-five years ago, it became evident that the organisms in sulfide-rich environments could synthesize ATP from sulfide, 10 years later came the realization that animals might use sulfide as a signaling molecule, and only within the last 4 years did it become apparent that even mammals could derive energy from sulfide generated in the gastrointestinal tract. It has also become evident that, even in the present-day oxic environment, cells can exploit the redox chemistry of sulfide, most notably as a physiological transducer of oxygen availability. This review will examine how the legacy of sulfide metabolism has shaped natural selection and how some of these ancient biochemical pathways are still employed by modern-day eukaryotes. © 2012 Springer-Verlag.

Sunsay C.,Indiana University Northwest | Rebec G.V.,Indiana University
Behavioral Neuroscience | Year: 2014

The prediction-error model of dopamine (DA) signaling has largely been confirmed with various appetitive Pavlovian conditioning procedures and has been supported in tests of Pavlovian extinction. Studies have repeatedly shown, however, that extinction does not erase the original memory of conditioning as the prediction-error model presumes, putting the model at odds with contemporary views that treat extinction as an episode of learning rather than unlearning of conditioning. Here, we combined fast-scan cyclic voltammetry (FSCV) with appetitive Pavlovian conditioning to assess DA release directly during extinction and reinstatement. DA was monitored in the nucleus accumbens core, which plays a key role in reward processing. Following at least 4 daily sessions of 16 tone-food pairings, fast-scan cyclic voltammetry was performed while rats received additional tone-food pairings followed by tone alone presentations (i.e., extinction). Acquisition memory was reinstated with noncontingent presentations of reward and then tested with cue presentation. Tone-food pairings produced transient (1- to 3-s) DA release in response to tone. During extinction, the amplitude of the DA response decreased significantly. Following presentation of 2 noncontingent food pellets, subsequent tone presentation reinstated the DA signal. Our results support the prediction-error model for appetitive Pavlovian extinction but not for reinstatement. © 2014 American Psychological Association.

Pescosolido B.A.,Indiana University
Journal of Health and Social Behavior | Year: 2013

By the 1990s, sociology faced a frustrating paradox. Classic work on mental illness stigma and labeling theory reinforced that the "mark" of mental illness created prejudice and discrimination for individuals and family members. Yet that foundation, coupled with deinstitutionalization of mental health care, produced contradictory responses. Claims that stigma was dissipating were made, while others argued that intervention efforts were needed to reduce stigma. While signaling the critical role of theory-based research in establishing the pervasive effects of stigma, both claims directed resources away from social science research. Yet the contemporary scientific foundation underlying both claims was weak. A reply came in a resurgence of research directed toward mental illness stigma nationally and internationally, bringing together researchers from different disciplines for the first time. I report on the general population's attitudes, beliefs, and behavioral dispositions that targeted public stigma and implications for the next decade of research and intervention efforts. © American Sociological Association 2013.

Lai T.,Indiana University
Journal of Combinatorial Theory. Series A | Year: 2014

We solve and generalize an open problem posted by James Propp (Problem 16 in New Perspectives in Geometric Combinatorics, Cambridge University Press, 1999) on the number of tilings of quasi-hexagonal regions on the square lattice with every third diagonal drawn in. We also obtain a generalization of Douglas' theorem on the number of tilings of a family of regions of the square lattice with every second diagonal drawn in. © 2013 Elsevier Inc.

Rey-Dios R.,University of Mississippi Medical Center | Cohen-Gadol A.A.,Indiana University
Acta Neurochirurgica | Year: 2013

Background: Fluorescent technology has recently become a valuable tool in the surgical management of neoplastic and vascular lesions. The availability of microscope-integrated fluorescent modules has facilitated incorporation of this technology within the microsurgical workflow. The currently available microscope integrated modules use 5-aminolevulinic acid (5-ALA) and indocyanine green (ICG) as fluorophores. Methods: Fluorescein sodium is a fluorescent molecule that has been used specifically in ophthalmology for the treatment of retinal angiography. A new microscope-integrated fluorescent module has been recently developed for fluorescein. We employed this technology to maximize resection of tumors and perform intraoperative angiography to guide microsurgical management of aneurysms and arteriovenous malformations. Results: Fluorescein fluorescence allows the surgeon to appreciate fluorescent structures through the oculars while visualizing non-fluorescent tissues in near natural colors. Therefore, the operator can proceed with microsurgery under the fluorescent mode. We present three representative cases in which the use of fluorescein fluorescence was found useful in the surgeon's decision making during surgery. Conclusions: The applications of this new microscope-integrated fluorescent module are multiple, and include vascular and oncologic neurosurgery. Further clinical investigations with large patient cohorts are needed to fully establish the role of this new technology. © 2013 Springer-Verlag Wien.

Maglinte D.D.T.,Indiana University
Radiologic Clinics of North America | Year: 2013

Fluoro/radiographic contrast examination of the small bowel (SB) and its cross-sectional hybrid (computed tomographic enteroclysis) have evolved into important consultative tools in formulating a more confident management course in the treatment of SB disease. The low incidence of SB diseases and their nonspecific clinical presentation require the proven performance characteristics of enteral volume-challenged examination to shorten the lag time of diagnosis or exclude its presence. Reliable exclusion of a SB abnormality is an important diagnosis for radiologists to make in the work-up of the patient with persistent unexplained abdominal symptoms. © 2013 Elsevier Inc.

Hellman R.N.,Indiana University
Seminars in Nephrology | Year: 2011

Nephrogenic systemic fibrosis is a new disease whose incidence has peaked and receded over the past decade. It occurs in the presence of significant renal impairment, either acute or chronic (MDRD creatinine clearance of <30 mL/min/1.73 m 2), and is associated with the administration of gadolinium-based contrast (GBC). Since 2006, the incidence of this disease has decreased markedly in patients with renal impairment, mainly owing to protocols that have not administered GBC to patients with creatinine clearances of less than 30 mL/min/1.73 m 2, and in some cases with the use of less toxic and lower doses of GBC. The purpose of this article is to review the current status of GBC use for imaging in patients with kidney disease. © 2011 Elsevier Inc.

Rex D.K.,Indiana University
Gastrointestinal Endoscopy | Year: 2013

Colonoscopic splenic injury appears greatly underreported and may have an incidence rate that qualifies it as a significant public health issue given current clinical volumes of colonoscopy. The spectrum of clinical injury is likely much broader than reflected in reported cases. Better and earlier recognition of mild injury might prevent serious bleeding later through prescription of reduced physical activity. To date, investigation of splenic injury has been case reports. Systematic investigation of splenic injury is needed to determine accurate incidence rates and to identify technical rules for colonoscopy technique that will minimize this complication. Colonoscopic splenic injury warrants more attention. Copyright © 2013 by the American Society for Gastrointestinal Endoscopy.

Talarico Jr. E.F.,Indiana University
Clinical Anatomy | Year: 2013

This article describes a paradigm of teaching in the anatomy laboratory where students interact with the families of the deceased persons whom they are dissecting. This approach focuses learning anatomy and medicine on the patient via the implementation of five guiding principles: the First Patient; Knowledge; Reflection and Reflective Practice; Treating the Total Patient; and Professionalism. Physician training typically begins with cadaveric dissection (i.e., dissection of the first patient), and therefore the medical school gross anatomy course provides an ideal environment for multifaceted educational experiences where cadaveric dissection is used to teach structure and function as well as the skills and competencies critical to patient care. Here, these principles are described, and the impact on student doctors and outcomes discussed. The results suggest that mastery of basic science knowledge and competencies, including professionalism, compassion, and leadership skill is enhanced by this protocol. Clin. Anat. 2013. © 2012 Wiley Periodicals, Inc.

Yoder M.C.,Indiana University
Current Opinion in Hematology | Year: 2015

Purpose of review Methods to isolate endothelial cells from murine and human pluripotent stem cells continue to evolve and increasingly diverse endothelial cell populations have been generated. This review provides an update of key articles published within the past year that report on some of those advances. Recent findings Cooperative interactions among microRNA (miRNA), transcription factors and some downstream interacting proteins have been reported to enhance endothelial specification from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Endothelial cell differentiation can also be modulated by various growth factor additions, Notch pathway activation or inhibition, and modulation of the microenvironment of the differentiating ESC and iPSC. Functionality of the derived endothelium has been demonstrated by a variety of in-vitro and in-vivo assays. Finally, two recent reports have identified endothelial progenitor populations with robust proliferative potential. Summary Progress in differentiating endothelial cells from ESC and iPSC has been made. The recent report of formation of endothelial colony forming cells from human ESC and iPSC provides a protocol that can generate clinically relevant numbers of cells for human cell therapy. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

In this paper, we will discuss the nuances of pediatric eosinophilic esophagitis based on symptoms, diagnostics and therapy. The diagnostics will include endoscopy, histology and anesthesia. Therapeutics will include the diet, drugs and 'distress'. Future directions in terms of clinical presentation and diagnostics will be discussed and important issues such as repeated exposure to anesthetic agents and effects of therapy on growth and psychological distress will be listed. © 2014 S. Karger AG, Basel.

Chambers R.A.,Indiana University
Drug and Alcohol Dependence | Year: 2013

Background: As knowledge deepens about how new neurons are born, differentiate, and wire into the adult mammalian brain, growing evidence depicts hippocampal neurogenesis as a special form of neuroplasticity that may be impaired across psychiatric disorders. This review provides an integrated-evidence based framework describing a neurogenic basis for addictions and addiction vulnerability in mental illness. Methods: Basic studies conducted over the last decade examining the effects of addictive drugs on adult neurogenesis and the impact of neurogenic activity on addictive behavior were compiled and integrated with relevant neurocomputational and human studies. Results: While suppression of hippocampal neurogenic proliferation appears to be a universal property of addictive drugs, the pathophysiology of addictions involves neuroadaptative processes within frontal-cortical-striatal motivation circuits that the neurogenic hippocampus regulates via direct projections. States of suppressed neurogenic activity may simultaneously underlie psychiatric and cognitive symptoms, but also confer or signify hippocampal dysfunction that heightens addiction vulnerability in mental illness as a basis for dual diagnosis disorders. Conclusions: Research on pharmacological, behavioral and experiential strategies that enhance adaptive regulation of hippocampal neurogenesis holds potential in advancing preventative and integrative treatment strategies for addictions and dual diagnosis disorders. © 2013 Elsevier Ireland Ltd.

Knowles M.R.,University of North Carolina at Chapel Hill | Daniels L.A.,University of North Carolina at Chapel Hill | Davis S.D.,Indiana University | Zariwala M.A.,University of North Carolina at Chapel Hill | Leigh M.W.,University of North Carolina at Chapel Hill
American Journal of Respiratory and Critical Care Medicine | Year: 2013

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia that leads to oto-sino-pulmonary diseases and organ laterality defects in approximately 50% of cases. The estimated incidence of PCD is approximately 1 per 15,000 births, but the prevalence of PCD is difficult to determine, primarily because of limitations in diagnostic methods that focus on testing ciliary ultrastructure and function. Diagnostic capabilities have recently benefitted from (1) documentation of low nasal nitric oxide production in PCD and (2) discovery of biallelic mutations in multiple PCD-causing genes. The use of these complementary diagnostic approaches shows that at least 30% of patients with PCD have normal ciliary ultrastructure. More accurate identification of patients with PCD has also allowed definition of a strong clinical phenotype, which includes neonatal respiratory distress in >80% of cases, daily nasal congestion and wet cough starting soon after birth, and early development of recurrent/chronic middle-ear and sinus disease. Recent studies, using advanced imaging and pulmonary physiologic assessments, clearly demonstrate early onset of lung disease in PCD, with abnormal air flow mechanics by age 6-8 years that is similar to cystic fibrosis, and age-dependent onset of bronchiectasis. The treatment ofPCDis not standardized, and there are no validated PCD-specific therapies. Most patients with PCD receive suboptimal management, which should include airway clearance, regular surveillance of pulmonary function and respiratory microbiology, and use of antibiotics targeted to pathogens. The PCD Foundation is developing a network of clinical centers, which should improve diagnosis and management of PCD. Copyright © 2013 by the American Thoracic Society.

Agarwal R.,Indiana University
Seminars in Dialysis | Year: 2012

This review discusses 10 current controversies regarding the dialysis patient with hypertension. The clinician is faced with a dilemma at the bedside on how to evaluate blood pressure and treat this condition in a patient on long-term hemodialysis. The evidence base to give firm recommendations is thin, but the epidemiological evidence tells us to do nothing. This appears to be an incorrect strategy, at least based on what we know today. Evaluating home BP in every dialysis patient, evaluating volume status on a regular basis, and treating hypertension predominantly with nonpharmacological strategies are worthwhile. © 2012 Wiley Periodicals, Inc.

Delph L.F.,Indiana University | Kelly J.K.,University of Kansas
New Phytologist | Year: 2014

Summary: Balancing selection refers to a variety of selective regimes that maintain advantageous genetic diversity within populations. We review the history of the ideas regarding the types of selection that maintain such polymorphism in flowering plants, notably heterozygote advantage, negative frequency-dependent selection, and spatial heterogeneity. One shared feature of these mechanisms is that whether an allele is beneficial or detrimental is conditional on its frequency in the population. We highlight examples of balancing selection on a variety of discrete traits. These include the well-referenced case of self-incompatibility and recent evidence from species with nuclear-cytoplasmic gynodioecy, both of which exhibit trans-specific polymorphism, a hallmark of balancing selection. We also discuss and give examples of how spatial heterogeneity in particular, which is often thought unlikely to allow protected polymorphism, can maintain genetic variation in plants (which are rooted in place) as a result of microhabitat selection. Lastly, we discuss limitations of the protected polymorphism concept for quantitative traits, where selection can inflate the genetic variance without maintaining specific alleles indefinitely. We conclude that while discrete-morph variation provides the most unambiguous cases of protected polymorphism, they represent only a fraction of the balancing selection at work in plants. © 2013 New Phytologist Trust.

Dalsing M.C.,Indiana University
Journal of Vascular Surgery | Year: 2011

The physician/surgeon's interactions with industry have come under scrutiny in recent years for several reasons. Although some think that the professional medical association or society may provide an avenue to allow such interactions with less risk, there are concerns and challenges for such organizations as it relates to ethical and professional norms of their members. This is one surgeon's review of some pertinent information regarding what the professional medical society provides to its members and what role industry plays in the society's ability to provide these benefits. There is an exploration of the risks involved and practical methods to control inherent conflicts of interest involved in this interaction. © 2011 Society for Vascular Surgery.

Rexroth D.F.,Indiana University
Journal of aging and health | Year: 2013

Examine the relationship of demographics and health conditions, alone and in combination, on objective measures of cognitive function in a large sample of community-dwelling older adults. Baseline data from 2,782 participants in the Advanced Cognitive Training in Independent and Vital Elderly (ACTIVE) study were used to examine relationships of demographics and health conditions with composite scores of memory, reasoning, and speed of processing. Younger age, increased education, and White race were independently associated with better performance in each cognitive domain after adjusting for gender and health conditions. Male gender, diabetes, and suspected clinical depression were associated with poorer cognitive functioning; suspected clinical depression was associated with lower reasoning and diabetes and history of stroke with slower speed of processing. Age, education, and race are consistently associated with cognitive performance in this sample of older community-dwelling adults. Diabetes, stroke, and suspected clinical depression had independent but weaker effects on cognition.

Meslin E.M.,Indiana University
Public Health Genomics | Year: 2010

With the domestic and international proliferation of biobanks and their associated connections to health information databases, scholarly attention has been turning from the ethical issues arising from the construction of biobanks to the ethical issues that emerge in their operation and management. Calls for greater transparency in governance structures, coupled with stern reminders of the value of maintaining public trust, are seen as critical components in the success of these resources. Two different approaches have been adopted for addressing these types of ethical issues: the first is a 'top-down' approach which focuses on developing policy, procedures, regulations and guidelines to aid decision-makers. The second is a 'bottom-up' approach, which begins with those who are most affected by the issues and attempts to inductively develop consensus recommendations and policy. While both approaches have merit, I argue that more work needs to be done on 'bottom-up' strategies if trust and transparency are to be more than mere slogans. Using 2 case examples from Indiana, the paper summarizes data from a set of surveys we recently conducted that address issues arising from biobanks that provide some insight into issues associated with trust and transparency. Copyright © 2010 S. Karger AG, Basel.

Groh W.J.,Indiana University
Heart Rhythm | Year: 2012

The muscular dystrophies are a group of inherited diseases affecting skeletal muscle that also affect cardiac muscle. Cardiac involvement occurs as a degenerative process with fibrosis and fatty replacement of the myocardium. Electrophysiologists are asked to participate in the care of muscular dystrophy patients because of the risk of atrial arrhythmias, conduction disease, bradycardia, ventricular arrhythmias, and sudden death. Duchenne, Becker, and limb-girdle types 2C-2F and 2I are muscular dystrophies in which the development of a dilated cardiomyopathy is common. Arrhythmias and conduction disease occur after the development of the dilated cardiomyopathy. Patients are considered for pacemakers or implantable cardioverter-defibrillators on the basis of guidelines used for nonischemic cardiomyopathies. Myotonic types 1 and 2, Emery-Dreifuss, limb-girdle type 1B, and facioscapulohumeral muscular dystrophies present with conduction disease and associated arrhythmias and variably with a dilated cardiomyopathy. In myotonic type 1, Emery-Dreifuss, and limb-girdle type 1B muscular dystrophies, conduction abnormalities are frequent and often require pacing. Recent studies support the use of prophylactic implantable cardioverter-defibrillators rather than pacemakers. In all the muscular dystrophies, respiratory muscle involvement can impact quality and quantity of life and needs to be factored in when considering a prophylactic device. © 2012 Heart Rhythm Society.

Ott M.A.,Indiana University
Journal of Adolescent Health | Year: 2010

A careful examination of young men's sexuality by health professionals in pediatrics, primary care, and reproductive health is foundational to adolescent male sexual health and healthy development. Through a review of existing published data, this article provides background and a developmental framework for sexual health services for adolescent boys. The article first defines and provides an overview of adolescent boys' sexual health, and then discusses developmentally focused research on the following topics: (1) early romantic relationships and the evolution of power and influence within these relationships; (2) developmental "readiness" for sex and curiosity; (3) boys' need for closeness and intimacy; (4) adopting codes of masculinity; (5) boys' communicating about sex; and (6) contextual influences from peers, families, and providers. This article concludes by examining the implications of these data for sexual health promotion efforts for adolescent males, including human papillomavirus vaccination. © 2010 Society for Adolescent Medicine.

Pishchalnikov Y.A.,Indiana University
Journal of endourology / Endourological Society | Year: 2013

Conduct a laboratory evaluation of a novel low-pressure, broad focal zone electrohydraulic lithotripter (TRT LG-380). Mapping of the acoustic field of the LG-380, along with a Dornier HM3, a Storz Modulith SLX, and a XiXin CS2012 (XX-ES) lithotripter was performed using a fiberoptic hydrophone. A pig model was used to assess renal response to 3000 shockwaves (SW) administered by a multistep power ramping protocol at 60 SW/min, and when animals were treated at the maximum power setting at 120 SW/min. Injury to the kidney was assessed by quantitation of lesion size and routine measures of renal function. SW amplitudes for the LG-380 ranged from (P(+)/P(-)) 7/-1.8 MPa at PL-1 to 21/-4 MPa at PL-11 while focal width measured ~20 mm, wider than the HM3 (8 mm), SLX (2.6 mm), or XX-ES (18 mm). For the LG-380, there was gradual narrowing of the focal width to ~10 mm after 5000 SWs, but this had negligible effect on breakage of model stones, because stones positioned at the periphery of the focal volume (10 mm off-axis) broke nearly as well as stones at the target point. Kidney injury measured less than 0.1% FRV (functional renal volume) for pigs treated using a gradual power ramping protocol at 60 SW/min and when SWs were delivered at maximum power at 120 SW/min. The LG-380 exhibits the acoustic characteristics of a low-pressure, wide focal zone lithotripter and has the broadest focal width of any lithotripter yet reported. Although there was a gradual narrowing of focal width as the electrode aged, the efficiency of stone breakage was not affected. Because injury to the kidney was minimal when treatment followed either the recommended slow SW-rate multistep ramping protocol or when all SWs were delivered at fast SW-rate using maximum power, this appears to be a relatively safe lithotripter.

Pridemore W.A.,Indiana University
British Journal of Criminology | Year: 2011

Dozens of cross-national studies of homicide have been published. Virtually all have reported an association between inequality and homicide, leading scholars to draw strong conclusions about this relationship. Unfortunately, each of these studies failed to control for poverty, even though poverty is the most consistent predictor of area homicide rates in the US empirical literature and a main confounder of the inequality-homicide association. The cross-national findings are also incongruent with US studies, which have yielded inconsistent results for the inequality-homicide association. In the present study, I replicated two prior studies in which a significant inequality-homicide association was found. After the original results were replicated, models that included a measure of poverty were estimated to see whether its inclusion had an impact on the inequality-homicide association. When effects for poverty and inequality were estimated in the same model, there was a positive and significant poverty-homicide association, while the inequality-homicide association disappeared in two of three models. These findings were consistent across different samples, data years, measures of inequality, dependent variables (overall and sex-specific homicide rates) and estimation procedures. The new results are congruent with what we know about poverty, inequality and homicide from the US empirical literature and suggest that the strong conclusions drawn about the inequality-homicide association may need to be reassessed, as the association may be a spurious result of model misspecification. © The Author 2011. Published by Oxford University Press on behalf of theCentre for Crime and Justice Studies (ISTD). All rights reserved.

Agarwal R.,Indiana University
Hypertension | Year: 2010

Among chronic hemodialysis patients, 217 hospitalizations per 1000 patient-years are attributed to congestive heart failure; some are attributable to unrecognized hypervolemia. Hypervolemia can be detected by relative plasma volume (RPV) monitoring. The purpose of this study was to examine among 308 patients on long-term hemodialysis the value of slope of RPV compared with either ultrafiltration (UF) volume or UF rate index in determining all-cause mortality. RPV slopes were calculated by least-squares regression. These slopes were related to all-cause mortality in unadjusted and adjusted Cox proportional hazards models. Over a median follow-up of 30 months (interquartile range: 14 to 54 months) 96 patients (31%) died, yielding a crude mortality rate of 113/1000 patient-years. We found the following: (1) RPV slope measurements were of prognostic significance (hazard ratio of flatter slopes [>1.39%/h]: 1.72; P=0.01); (2) the UF volume alone was not prognostically informative (hazard ratio of higher UF volume [>2.7 L of dialysis]: 0.78; P=0.23); (3) the UF rate index alone was also not prognostically informative (hazard ratio of higher UF rate index [>8.4 mL/kg per hour]: 0.89; P=0.6); and (4) the prognostic relationship of RPV slope to mortality was independent of conventional and unconventional cardiovascular risk factors including the UF volume, UF rate, or UF volume per kilogram of postweight. RPV monitoring yields information that is prognostically important and independent of several risk factors including UF volume, aggressiveness of UF, and interdialytic ambulatory blood pressure. Its use to assess excess volume-related morbidity among chronic hemodialysis patients should be tested in randomized, controlled trials. © 2010 American Heart Association, Inc.

Berg M.T.,Indiana University | Loeber R.,University of Pittsburgh
Journal of Quantitative Criminology | Year: 2011

The persistent link between offending and victimization is one of the most robust empirical findings in criminological research. Despite important efforts to isolate the sources of this phenomenon, it is not fully understood. Much attention has been paid to the role of individual-level factors; however, few studies have systematically integrated neighborhood conditions. Using prospective data from the Pittsburgh Youth Study the current research examines a set of hypotheses regarding the interplay of neighborhood structural conditions and the victim-offender overlap. A multilevel analytical technique is applied to the data which purges time-varying covariates of all time-stable unobserved heterogeneity. Results indicate that the relationship between offending and victimization is pronounced in disadvantaged neighborhoods, while offending is not significantly related to victimization risk in contexts marked by lower levels of disadvantage. The implications of the results for theory are discussed, along with recommendations for future research. © 2011 Springer Science+Business Media, LLC.

Cornetta K.,Indiana University | Brown C.G.,Indiana University Bloomington
Academic Medicine | Year: 2013

The current description of personalized medicine by the National Institutes of Health is "the science of individualized prevention and therapy." Although physicians are beginning to see the promise of genetic medicine coming to fruition, the rapid pace of sequencing technology, informatics, and computer science predict a revolution in the ability to care for patients in the near future. The enthusiasm expressed by researchers is well founded, but the expectations voiced by the public do not center on advancing technology. Rather, patients are asking for personalized care: a holistic approach that considers physical, mental, and spiritual well-being. This perspective considers psychological, religious, and ethical challenges that may arise as the precision of preventive medicine improves. Psychological studies already highlight the barriers to single gene testing and suggest significant barriers to the predictive testing envisioned by personalized medicine. Certain religious groups will likely mount opposition if they believe personalized medicine encourages embryo selection. If the technology prompts cost-containment discussions, those concerned about the sanctity of life may raise ethical objections. Consequently, the availability of new scientific developments does not guarantee advances in treatment because patients may prove unwilling to receive and act on personalized genetic information. This perspective highlights current efforts to incorporate personalized medicine and personalized care into the medical curriculum, genetic counseling, and other aspects of clinical practice. Because these efforts are generally independent, the authors offer recommendations for physicians and educators so that personalized medicine can be implemented in a manner that meets patient expectations for personalized care.

Srinivas S.P.,Indiana University
Experimental Eye Research | Year: 2012

The barrier integrity of the corneal endothelium, which is conferred by its tight and adherens junctions, is critical for the maintenance of deturgescence of the corneal stroma. Although characteristically leaky, the barrier integrity restricts fluid leakage into the stroma such that the rate of leak does not exceed the rate of the endothelial active fluid transport directed toward the aqueous humor. At a molecular level, the barrier integrity is influenced by the actin cytoskeleton and microtubules, which are coupled to tight and adherens junctions via a variety of linker proteins. Since the cytoskeleton is affected by Rho family small GTPases and p38 MAP kinase, among others, many pathophysiological stimuli induce plasticity to the cytoskeleton and thereby elicit dynamic regulation of the barrier integrity. This review presents an overview of the impact of several bioactive factors on the barrier integrity of the corneal endothelium through altered actin cytoskeleton and/or disassembly of microtubules. The main focus is on the effect of TNF-α (tumor necrosis factor-α) which is a pro-inflammatory molecule found in the intraocular milieu during allograft rejection and anterior uveitis. This cytokine elicits acute activation of p38 MAP kinase, induces disassembly of microtubules, disrupts the peri-junctional actomyosin ring, and concomitantly breaks down the barrier integrity. These effects of TNF-α could be inhibited by stabilizing the microtubules, co-treating with a selective p38 MAP kinase inhibitor, and elevating intracellular cAMP via A2B receptors or direct exposure to forskolin. Overall, the corneal edema following a potential breakdown of the endothelial barrier integrity can be rescued pharmacologically by inhibiting specific cell-signaling mechanisms. © 2011 Elsevier Ltd.

Agarwal R.,Indiana University
Hypertension | Year: 2010

Blood pressure measured before and after dialysis does not agree well with those recorded outside the dialysis unit. Whether recordings obtained outside the dialysis unit are of greater prognostic value than blood pressure obtained just before and after dialysis remains incompletely understood. Among 326 patients on long-term hemodialysis, blood pressure was self-measured at home for 1 week, over an interdialytic interval by ambulatory recording and before and after dialysis over 2 weeks. Over a mean follow-up of 32 (SD 20) months, 102 patients died (31%), yielding a crude mortality rate of 118/1000 patient years. Systolic but not diastolic blood pressure was found to be of prognostic importance. Adjusted and unadjusted multivariate analyses showed increasing quartiles of ambulatory and home systolic blood pressure to be associated with all-cause mortality (adjusted hazard ratios for increasing quartiles of ambulatory: 2.51, 3.43, 2.62; and for home blood pressure: 2.15, 1.7, 1.44). Mortality was lowest when home systolic blood pressure was between 120 to 130 mm Hg and ambulatory systolic blood pressure was between 110 to 120 mm Hg. Blood pressure recorded before and after dialysis was not statistically significant (P=0.17 for predialysis, and P=0.997 for postdialysis) in predicting mortality. Out-of-dialysis unit blood pressure measurement provided superior prognostic information compared to blood pressure within the dialysis unit (likelihood ratio test, P<0.05). Out-of-dialysis unit blood pressure among hemodialysis patients is prognostically more informative than that recorded just before and after dialysis. Therefore, the management of hypertension among these patients should focus on blood pressure recordings outside the dialysis unit. Copyright © 2010 American Heart Association. All rights reserved.

Olson K.R.,Indiana University
Respiratory Physiology and Neurobiology | Year: 2011

There is considerable controversy surrounding the initial step that transduces a fall in PO2 into a physiological signal, i.e., the "oxygen sensor" in chemoreceptors. Initial studies on systemic and respiratory vessels suggested that the metabolism of hydrogen sulfide (H 2S) could serve as the oxygen sensor. This model was subsequently extended to chemoreceptors in fish and tissues of other animals. In this model, constitutive production of biologically active H 2S is offset by H 2S oxidation; when oxygen availability falls, production of H 2S exceeds metabolism, and the resultant increase in intracellular H 2S initiates the appropriate physiological responses. This model is supported by observations that the effects of hypoxia and H 2S are similar, if not identical in many tissues: hypoxic responses are inhibited by inhibitors of H 2S biosynthesis and augmented by sulfur donating molecules, and the tipping point between H 2S production and oxidation occurs at physiologically relevant PO2s. Recent studies from other laboratories support this mechanism of O 2 sensing in the carotid body. This review summarizes information that supports the H 2S metabolic hypothesis in these tissues with emphasis on the carotid chemoreceptors. Evidence suggesting that H 2S is not involved in oxygen sensing in the carotid body is also critically evaluated. © 2011 Elsevier B.V.

Wright P.J.,Indiana University | Randall A.K.,University of Arizona
Computers in Human Behavior | Year: 2012

Sexually transmitted infections (STIs) continue to pose a threat to the public health in the United States. Many sexual behaviors increase an individual's risk of STI contraction. Chief among these are having unprotected sex, having sex with multiple partners, and either paying for sex or having sex for pay. The present study used General Social Survey (GSS) data from 2000, 2002, and 2004 to explore the association between exposure to internet pornography and these STI risk behaviors among adult US males. After controlling for demographic and individual difference covariates, internet pornography consumption was positively associated with having sex with multiple partners, engaging in paid sex, and having had extramarital sex. Internet pornography consumption was unrelated to having unprotected sex. Subsequent GSSs have not asked participants about exposure to internet pornography. As the GSS is the only ongoing, full-probability, national survey assessing social beliefs and behaviors, the present report provides unique insight into the risky sexual behavior patterns of adult male internet pornography consumers in the United States. © 2012 Elsevier Ltd. All rights reserved.

Plotkin L.I.,Indiana University
Current Osteoporosis Reports | Year: 2014

Studies from the 1950s and 1960s already recognize the fact that osteocytes, although long living cells, die, as evidenced by accumulation of osteocytic lacunae devoid of cells. More recently, it was demonstrated that these cells die by apoptosis. The rate of osteocyte apoptosis is regulated by the age of the bone, as well as by systemic hormones, local growth factors, cytokines, pharmacological agents, and mechanical forces. Apoptotic osteocytes, in turn, recruit osteoclasts to initiate targeted bone resorption. This results in the removal of "dead" bone and may improve the mechanical properties of the skeleton. However, the molecular regulators of osteocyte survival and targeted bone remodeling are not completely known. In this review, the current knowledge on the molecular mechanism that lead to osteocyte death or survival, and the signals that mediate targeted bone resorption is discussed. © 2014 Springer Science+Business Media.

Rehman Laghari K.U.,Orange S.A. | Connelly K.,Indiana University | Crespi N.,Orange S.A.
IEEE Communications Magazine | Year: 2012

In recent years, the quality of experience notion has become a major research theme within the telecommunications community. QoE is an assessment of the human experience when interacting with technology and business entities in a particular context. A communication ecosystem encompasses various domains such as technical aspects, business models, human behavior, and context. For each aspect of a communication ecosystem, various models have been developed. However, few models have been designed to integrate all aspects of a communication ecosystem to understand human behavioral needs in a detailed and structured way. While existing models have produced the basic sketch of QoE modeling, more concepts and interdomain mapping are to be incorporated in order to have a clear picture of QoE in communication ecosystems. The aim of the current work is to build on the existing research being conducted in disparate disciplines about human behavior in order to provide a high-level model that can be adapted to many specific contexts and to encourage future research which examines these crossdomain relationships. © 1979-2012 IEEE.

Treadwell P.A.,Indiana University
Clinics in Dermatology | Year: 2015

Systemic conditions may have pigmentary associations. Prompt recognition of these associations allows the practitioner to initiate the appropriate workup and therapy when indicated. This contribution highlights some of the clinical features of neurofibromatosis 1, LEOPARD syndrome, acanthosis nigricans, hypomelanosis of Ito, incontinentia pigmenti, CHILD syndrome, and piebaldism to assist the dermatologist in making the proper diagnosis. © 2015 Elsevier Inc.

Terry N.P.,Indiana University
Chest | Year: 2015

Mobile health (mHealth) combines the decentralization of health care with patient centeredness. Mature mHealth applications (apps) and services could provide actionable information, coaching, or alerts at a fraction of the cost of conventional health care. Diff erent categories of apps attract diverse safety and privacy regulation. It is too early to tell whether these apps can overcome questions about their use cases, business models, and regulation. © 2015 American College Of Chest Physicians.

Hoggatt J.,Massachusetts General Hospital | Pelus L.M.,Indiana University
Expert Opinion on Investigational Drugs | Year: 2014

Introduction: Granulocyte colony-stimulating factor (G-CSF; filgrastim) and its pegylated form (pegfilgrastim) are widely used to treat neutropenia associated with myelosuppressive chemotherapy and bone marrow transplantation, AIDS-associated or drug-induced neutropenia, and neutropenic diseases. G-CSF facilitates restoration of neutrophil counts, decreases incidence of infection/febrile neutropenia and reduces resource utilization. G-CSF is also widely used to mobilize peripheral blood stem cells for hematopoietic transplant. Areas covered: We review the therapeutic use, cost effectiveness and disease impact of G-CSF for neutropenia, development of G-CSF biosimilars and current next-generation discovery efforts. Expert opinion: G-CSF has impacted the treatment and survival of patients with congenital neutropenias. For chemotherapy-associated neutropenia, cost effectiveness and impact on survival are still unclear. G-CSFs are expensive and require systemic administration. Market entry of new biosimilars, some with enhanced half-life profiles, will probably reduce cost and increase cost effectiveness. There is no evidence that marketed or late development biosimilars display effectiveness superior to current G-CSFs. Second-generation compounds that mimic the activity of G-CSF at its receptor, induce endogenous ligand(s) or offer adjunct activity have been reported and represent attractive G-CSF alternatives, but are in preclinical stages. A significant therapeutic advance will require reduced depth and duration of neutropenia compared to current G-CSFs. © 2014 Informa UK, Ltd.

Feigenbaum H.,Indiana University
Journal of the American Society of Echocardiography | Year: 2010

M-mode echocardiography is considered to be obsolete by many. The technique rarely is included in American Society of Echocardiography standards documents, except for M-mode measurements, which have limited value. The superior temporal resolution of M-mode echocardiography is frequently overlooked. Doppler recordings reflect blood velocity, whereas M-mode motion of cardiac structures reflect volumetric blood flow. The 2 examinations are hemodynamically complementary. In the current digital era, recording multiple cardiac cycles of two-dimensional echocardiographic images is no longer necessary. However, there are times when intermittent or respiratory changes occur. The M-mode technique is an effective and efficient way to record the necessary multiple cardiac cycles. In certain situations, M-mode recordings of the valves and interventricular septum can be particularly helpful in making a more accurate and complete echocardiographic cardiac assessment, thus helping to make the examination more cost-effective. © 2010 American Society of Echocardiography.

Stahelin R.V.,Indiana University | Stahelin R.V.,University of Notre Dame
Expert Opinion on Therapeutic Targets | Year: 2014

Filoviruses are filamentous lipid-enveloped viruses and include Ebola (EBOV) and Marburg, which are morphologically identical but antigenically distinct. These viruses can be very deadly with outbreaks of EBOV having clinical fatality as high as 90%. In 2012 there were two separate Ebola outbreaks in the Democratic Republic of Congo and Uganda that resulted in 25 and 4 fatalities, respectively. The lack of preventive vaccines and FDA-approved therapeutics has struck fear that the EBOV could become a pandemic threat. The Ebola genome encodes only seven genes, which mediate the entry, replication, and egress of the virus from the host cell. The EBOV matrix protein is VP40, which is found localized under the lipid envelope of the virus where it bridges the viral lipid envelope and nucleocapsid. VP40 is effectively a peripheral protein that mediates the plasma membrane binding and budding of the virus prior to egress. A number of studies have demonstrated specific deletions or mutations of VP40 to abrogate viral egress but to date pharmacological inhibition of VP40 has not been demonstrated. This editorial highlights VP40, which is the most abundantly expressed protein of the virus and discusses VP40 as a potential therapeutic target. © 2014 Informa UK, Ltd.

Guise T.,Indiana University
Seminars in oncology | Year: 2010

Some of the most common cancer types, including breast cancer, prostate cancer, and lung cancer, show a predilection to metastasize to bone. The molecular basis of this preferential growth of cancer cells in the bone microenvironment has been an area of active investigation. Although the precise molecular mechanisms underlying this process remain to be elucidated, it is now increasingly being recognized that the unique characteristics of the bone niche provide homing signals to cancer cells, and create a microenvironment conducive for the cancer cells to colonize. Concomitantly, cancer cells release several regulatory factors that result in abnormal bone destruction and/or formation. This complex bidirectional interplay between tumor cells and bone microenvironment establishes a "vicious cycle" that leads to a selective growth advantage for the cancer cells. The molecular insights gained on the underpinnings of bone metastasis in recent years have also provided us with avenues to devise innovative approaches for therapeutic intervention. The goal of this review is to describe our current understanding of molecular pathophysiology of cancer metastases to bone, as well as its therapeutic implications. Copyright © 2010. Published by Elsevier Inc.

Kwo P.Y.,Indiana University
Current Gastroenterology Reports | Year: 2014

The burden of liver disease continues to increase in the United States, with the epidemics of hepatitis C, alcoholic liver disease, and the coming wave of nonalcoholic fatty liver disease patients all contributing to a high burden of individuals with end-stage liver disease. The complications of cirrhosis have been related to portal hypertension or synthetic dysfunction with variceal bleeding, ascites, hepatic encephalopathy, jaundice, hepatorenal syndrome, and the pulmonary complications of cirrhosis being described classically. Over the past decade, a body of evidence has now been assembled demonstrating that hyponatremia is also an important complication in patients with decompensated cirrhosis, with recent data demonstrating that hyponatremia is an important prognostic indicator in those with cirrhosis [1••]. Seminal research has demonstrated the pathophysiologic role of the hyperdynamic circulation and vasodilation in those with decompensated cirrhosis that leads to many of the complications, including hyponatremia [2•]. Moreover, a new class of drugs, the vaptans, have provided important insights into the pathophysiology and potential therapy of those with hyponatremia and possibly in those with hyponatremia and cirrhotic ascites [3]. However, there are safety concerns with some drugs in this class. In this article, the pathophysiology of hyponatremia, clinical relevance to patients with decompensated cirrhosis, and management options will be addressed. © Springer Science+Business Media 2014.

Objective: There is a debate if the [NO] required to influence vascular smooth muscle is below 50 nM or much higher. Electrodes with 30 μm and larger diameter report [NO] below 50 nM, whereas those with diameters of <10-12 μm report hundreds of nM. This study examined how size of electrodes influenced [NO] measurement due to NO consumption and unstirred layer issues. Methods: Electrodes were 2 mm disk, 30 μm × 2 mm carbon fiber, and single 7 μm diameter carbon fiber within open tip microelectrode, and exposed 7 μm carbon fiber of ~15 μm to 2 mm length. Results: All electrodes demonstrated linear calibrations with sufficient stirring. As stirring slowed, 30 μm and 2 mm electrodes reported much lower [NO] due to unstirred layers and high NO consumption. The three 7 μm microelectrodes had minor stirring issues. With limited stirring with NO present, 7 μm open tip microelectrodes advanced toward 30 μm and 2 mm electrodes experienced dramatically decreased current within 10-50 μm of the larger electrodes due to high NO consumption. None of the 7 μm microelectrodes interacted. Conclusions: The data indicate large electrodes underestimate [NO] due to excessive NO consumption under conditions where unstirred layers are unavoidable and true microelectrodes are required for valid measurements. © 2012 John Wiley & Sons Ltd.

Olson K.R.,Indiana University
Respiratory Physiology and Neurobiology | Year: 2013

Hydrogen sulfide (H2S) metabolism has been proposed as the oxygen (O2) sensing mechanism coupling hypoxia to effector responses in a variety of tissues including vascular and chemoreceptor cells. Implicit in this sensing system is a mechanism for regulating intracellular H2S concentration, presumably through oxidation. However, verification of this mechanism, or any other pathway of H2S signaling has been hampered by the lack of suitable methods for measuring intracellular concentration and distribution profiles. Here, intracellular H2S concentration profiles are modeled using simple monoexponential diffusion equations and current knowledge of H2S biosynthetic and metabolic pathways. The models predict that; (1) while both mitochondrial oxidation and simple diffusion out of the cell can reduce H2S concentration, the former is considerably more effective as an effector of intracellular H2S and (2) exogenously applied H2S may have unanticipated effects on endogenous signaling processes. In addition, these models provide additional support for mitochondrial H2S oxidation as the key couple in H2S-mediated O2 sensing. © 2013 Elsevier B.V.

Rahurkar S.,University of Alabama at Birmingham | Vest J.R.,City College of New York | Menachemi N.,Indiana University
Health Affairs | Year: 2015

Health information exchange (HIE), which is the transfer of electronic information such as laboratory results, clinical summaries, and medication lists, is believed to boost efficiency, reduce health care costs, and improve outcomes for patients. Stimulated by federal financial incentives, about two-thirds of hospitals and almost half of physician practices are now engaged in some type of HIE with outside organizations. To determine how HIE has affected such health care measures as cost, service use, and quality, we identified twenty-seven scientific studies, extracted selected characteristics from each, and metaanalyzed these characteristics for trends. Overall, 57 percent of published analyses reported some benefit from HIE. However, articles employing study designs having strong internal validity, such as randomized controlled trials or quasi-experiments, were significantly less likely than others to associate HIE with benefits. Among six articles with strong internal validity, one study reported paradoxical negative effects, three studies found no effect, and two studies reported that HIE led to benefits. Furthermore, these two studies had narrower focuses than the others. Overall, little generalizable evidence currently exists regarding benefits attributable to HIE. © 2015 Project HOPE-The People-to-People Health Foundation, Inc.

Pleskac T.J.,Michigan State University | Busemeyer J.R.,Indiana University
Psychological Review | Year: 2010

The 3 most often-used performance measures in the cognitive and decision sciences are choice, response or decision time, and confidence. We develop a random walk/diffusion theory-2-stage dynamic signal detection (2DSD) theory-that accounts for all 3 measures using a common underlying process. The model uses a drift diffusion process to account for choice and decision time. To estimate confidence, we assume that evidence continues to accumulate after the choice. Judges then interrupt the process to categorize the accumulated evidence into a confidence rating. The model explains all known interrelationships between the 3 indices of performance. Furthermore, the model also accounts for the distributions of each variable in both a perceptual and general knowledge task. The dynamic nature of the model also reveals the moderating effects of time pressure on the accuracy of choice and confidence. Finally, the model specifies the optimal solution for giving the fastest choice and confidence rating for a given level of choice and confidence accuracy. Judges are found to act in a manner consistent with the optimal solution when making confidence judgments. © 2010 American Psychological Association.

Anferov V.,Indiana University
Physics in Medicine and Biology | Year: 2010

Proton beam losses in various components of a treatment nozzle generate secondary neutrons, which bring unwanted out of field dose during treatments. The purpose of this study was to develop an analytic method for estimating neutron dose to a distant organ at risk during proton therapy. Based on radiation shielding calculationmethods proposed by Sullivan, we developed an analytical model for converting the proton beam losses in the nozzle components and in the treatment volume into the secondary neutron dose at a point of interest. Using the MCNPx Monte Carlo code, we benchmarked the neutron dose rates generated by the proton beam stopped at various media. The Monte Carlo calculations confirmed the validity of the analytical model for simple beam stop geometry. The analytical model was then applied to neutron dose equivalent measurements performed on double scattering and uniform scanning nozzles at the Midwest Proton Radiotherapy Institute (MPRI). Good agreement was obtained between the model predictions and the data measured at MPRI. This work provides a method for estimating analytically the neutron dose equivalent to a distant organ at risk. This method can be used as a tool for optimizing dose delivery techniques in proton therapy. © 2010 Institute of Physics and Engineering in Medicine.

Shaw S.L.,Indiana University
Current Opinion in Plant Biology | Year: 2013

The interphase microtubule arrays in flowering plant cells assemble at the cell cortex into patterns that affect cellular morphogenesis. A decade of live cell imaging studies has provided significant information about the in vivo properties of the microtubule polymers. Efforts to extrapolate individual properties to larger roles in organizing or patterning the microtubule array have produced models focused on self-organization and local levels of biological control. Recent studies looking at cortical microtubule arrays as they transition from an existing pattern to a new pattern have re-emerged as a testbed for examining these models and the molecular hypotheses underpinning them. The evidence suggests that microtubule patterning is locally controlled on the scale of a cell face, using or circumventing self-organizating properties as necessary. © 2013 Elsevier Ltd.

Bosslet G.T.,Indiana University
American Journal of Respiratory and Critical Care Medicine | Year: 2015

Background: There is controversy about how to manage requests by patients or surrogates for treatments that clinicians believe should not be administered. Purpose: This multisociety statement provides recommendations to prevent and manage intractable disagreements about the use of such treatments in intensive care units. Methods: The recommendations were developed using an iterative consensus process, including expert committee development and peer review by designated committees of each of the participating professional societies (American Thoracic Society, American Association for Critical Care Nurses, American College of Chest Physicians, European Society for Intensive Care Medicine, and Society of Critical Care). Main Results: The committee recommends: (1) Institutions should implement strategies to prevent intractable treatment conflicts, including proactive communication and early involvement of expert consultants. (2) The term "potentially inappropriate" should be used, rather than futile, to describe treatments that have at least some chance of accomplishing the effect sought by the patient, but clinicians believe that competing ethical considerations justify not providing them. Clinicians should explain and advocate for the treatment plan they believe is appropriate. Conflicts regarding potentially inappropriate treatments that remain intractable despite intensive communication and negotiation should be managed by a fair process of conflict resolution; this process should include hospital review, attempts to find a willing provider at another institution, and opportunity for external review of decisions. When time pressures make it infeasible to complete all steps of the conflict-resolution process and clinicians have a high degree of certainty that the requested treatment is outside accepted practice, they should seek procedural oversight to the extent allowed by the clinical situation and need not provide the requested treatment. (3) Use of the term "futile" should be restricted to the rare situations in which surrogates request interventions that simply cannot accomplish their intended physiologic goal. Clinicians should not provide futile interventions. (4) The medical profession should lead public engagement efforts and advocate for policies and legislation about when life-prolonging technologies should not be used. Conclusions: The multisociety statement on responding to requests for potentially inappropriate treatments in intensive care units provides guidance for clinicians to prevent and manage disputes in patients with advanced critical illness. Copyright © 2015 by the American Thoracic Society.

The N-type voltage-gated calcium channel (Cav 2.2) has gained immense prominence in the treatment of chronic pain. While decreased channel function is ultimately anti-nociceptive, directly targeting the channel can lead to multiple adverse side effects. Targeting modulators of channel activity may facilitate improved analgesic properties associated with channel block and a broader therapeutic window. A novel interaction between Cav 2.2 and collapsin response mediator protein 2 (CRMP-2) positively regulates channel function by increasing surface trafficking. We recently identified a CRMP-2 peptide (TAT-CBD3), which effectively blocks this interaction, reduces or completely reverses pain behavior in a number of inflammatory and neuropathic models. Importantly, TAT-CBD3 did not produce many of the typical side effects often observed with Cav 2.2 inhibitors. Notably chronic pain mechanisms offer unique challenges as they often encompass a mix of both neuropathic and inflammatory elements, whereby inflammation likely causes damage to the neuron leading to neuropathic pain, and neuronal injury may produce inflammatory reactions. To this end, we sought to further disseminate the ability of TAT-CBD3 to alter behavioral outcomes in two additional rodent pain models. While we observed that TAT-CBD3 reversed mechanical hypersensitivity associated with a model of chronic inflammatory pain due to lysophosphotidylcholine-induced sciatic nerve focal demyelination (LPC), injury to the tibial nerve (TNI) failed to respond to drug treatment. Moreover, a single amino acid mutation within the CBD3 sequence demonstrated amplified Cav 2.2 binding and dramatically increased efficacy in an animal model of migraine. Taken together, TAT-CBD3 potentially represents a novel class of therapeutics targeting channel regulation as opposed to the channel itself.

Chapman R.F.,Indiana University
British Journal of Sports Medicine | Year: 2013

Performance in athletic activities that include a significant aerobic component at mild or moderate altitudes shows a large individual variation. Physiologically, a large portion of the negative effect of altitude on exercise performance can be traced to limitations of oxygen diffusion, either at the level of the alveoli or the muscle microvasculature. In the lung, the ability to maintain arterial oxyhaemoglobin saturation (SaO2) appears to be a primary factor, ultimately influencing oxygen delivery to the periphery. SaO2 in hypoxia can be defended by increasing ventilatory drive; however, during heavy exercise, many athletes demonstrate limitations to expiratory flow and are unable to increase ventilation in hypoxia. Additionally, increasing ventilatory work in hypoxia may actually be negative for performance, if dyspnoea increases or muscle blood flow is reduced secondary to an increased sympathetic outflow (eg, the muscle metaboreflex response). Taken together, some athletes are clearly more negatively affected during exercise in hypoxia than other athletes. With careful screening, it may be possible to develop a protocol for determining which athletes may be the most negatively affected during competition and/or training at altitude.

Kostrominova T.Y.,Indiana University
Free Radical Biology and Medicine | Year: 2010

In this study skeletal muscles from 1.5- and 10-month-old Cu/Zn superoxide dismutase (SOD1) homozygous knockout (JLSod1-/-) mice obtained from The Jackson Laboratory (C57Bl6/129SvEv background) were compared with muscles from age- and sex-matched heterozygous (JLSod1+/-) littermates. The results of this study were compared with previously published data on two different strains of Sod1-/- mice: one from Dr. Epstein's laboratory (ELSod1-/-; C57Bl6 background) and the other from Cephalon, Inc. (CSod1-/-; 129/CD-1 background). Grouping of succinate dehydrogenase-positive fibers characterized muscles of Sod1-/- mice from all three strains. The 10-month-old Sod1-/- C and JL mice displayed pronounced denervation of the gastrocnemius muscle, whereas the ELSod1-/- mice displayed a small degree of denervation at this age, but developed accelerated age-related denervation later on. Denervation markers were up-regulated in skeletal muscle of 10-month-old JLSod1-/- mice. This study is the first to show that metallothionein mRNA and protein expression was up-regulated in the skeletal muscle of 10-month-old JLSod1-/- mice and was mostly localized to the small atrophic muscle fibers. In conclusion, all three strains of Sod1-/- mice develop accelerated age-related muscle denervation, but the genetic background has significant influence on the progress of denervation. © 2010 Elsevier Inc.

OBJECTIVE: To review and evaluate cystic fibrosis transmembrane conductance regulator (CFTR) modulators for the treatment of cystic fibrosis (CF). DATA SOURCES: Literature was accessed through MEDLINE (1977-January 2012), the Cochrane Library, and International Pharmaceutical Abstracts (1977-March 2012). Search terms included ivacaftor, VX-770, VX-809, ataluren, PTC 124, CFTR modulator, and cystic fibrosis. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were evaluated for inclusion. Clinical trials and relevant review articles were evaluated for each CFTR modulator. DATA SYNTHESIS: CF is caused by a mutation in the gene that encodes for the CFTR protein; mutations can be separated into 5 different classes. Ivacaftor is a new CFTR potentiator that helps the CFTR channel open properly in patients with the CFTR mutation, G551D. Patients in one study had significant decreases in sweat chloride values and increases in pulmonary function tests. Ivacaftor was approved by the Food and Drug Administration (FDA) to be taken orally at a dose of 150 mg twice a day in G551D CF patients older than 6 years. Additional studies are investigating the use of ivacaftor in other gating mutations and in younger patients. VX-809 is a CFTR corrector that modulates the folding and trafficking of CFTR. VX-809 was originally studied alone in patients with F508del mutation but is now being used in combination with ivacaftor in Phase 2 studies. Ataluren allows the read through of premature stop codons, and studies in patients with CF with nonsense mutations show an increase in chloride transportation. Ataluren requires 3 times a day dosing and is currently in a Phase 3 placebo-controlled study. CONCLUSIONS: Three new agents, ivacaftor, VX-809, and ataluren, target the basic defects in CFTR production. Ivacaftor was recently FDA approved, while the other 2 agents are still in clinical trials. Patients with CF will benefit from personalized medicine based on their specific genotype.

Zhang P.,Indiana University
BMC systems biology | Year: 2012

Typical analysis of time-series gene expression data such as clustering or graphical models cannot distinguish between early and later drug responsive gene targets in cancer cells. However, these genes would represent good candidate biomarkers. We propose a new model - the dynamic time order network - to distinguish and connect early and later drug responsive gene targets. This network is constructed based on an integrated differential equation. Spline regression is applied for an accurate modeling of the time variation of gene expressions. Then a likelihood ratio test is implemented to infer the time order of any gene expression pair. One application of the model is the discovery of estrogen response biomarkers. For this purpose, we focused on genes whose responses are late when the breast cancer cells are treated with estradiol (E2). Our approach has been validated by successfully finding time order relations between genes of the cell cycle system. More notably, we found late response genes potentially interesting as biomarkers of E2 treatment.

Huang H.,Indiana University
BMC bioinformatics | Year: 2012

Over the past decade, pathway and gene-set enrichment analysis has evolved into the study of high-throughput functional genomics. Owing to poorly annotated and incomplete pathway data, researchers have begun to combine pathway and gene-set enrichment analysis as well as network module-based approaches to identify crucial relationships between different molecular mechanisms. To meet the new challenge of molecular phenotype discovery, in this work, we have developed an integrated online database, the Pathway And Gene Enrichment Database (PAGED), to enable comprehensive searches for disease-specific pathways, gene signatures, microRNA targets, and network modules by integrating gene-set-based prior knowledge as molecular patterns from multiple levels: the genome, transcriptome, post-transcriptome, and proteome. The online database we developed, PAGED http://bio.informatics.iupui.edu/PAGED is by far the most comprehensive public compilation of gene sets. In its current release, PAGED contains a total of 25,242 gene sets, 61,413 genes, 20 organisms, and 1,275,560 records from five major categories. Beyond its size, the advantage of PAGED lies in the explorations of relationships between gene sets as gene-set association networks (GSANs). Using colorectal cancer expression data analysis as a case study, we demonstrate how to query this database resource to discover crucial pathways, gene signatures, and gene network modules specific to colorectal cancer functional genomics. This integrated online database lays a foundation for developing tools beyond third-generation pathway analysis approaches on for discovering molecular phenotypes, especially for disease-associated pathway/gene-set enrichment analysis.

Wu X.,Indiana University
BMC bioinformatics | Year: 2012

Current network-based microarray analysis uses the information of interactions among concerned genes/gene products, but still considers each gene expression individually. We propose an organized knowledge-supervised approach - Integrative eXpression Profiling (IXP), to improve microarray classification accuracy, and help discover groups of genes that have been too weak to detect individually by traditional ways. To implement IXP, ant colony optimization reordering (ACOR) algorithm is used to group functionally related genes in an ordered way. Using Alzheimer's disease (AD) as an example, we demonstrate how to apply ACOR-based IXP approach into microarray classifications. Using a microarray dataset - GSE1297 with 31 samples as training set, the result for the blinded classification on another microarray dataset - GSE5281 with 151 samples, shows that our approach can improve accuracy from 74.83% to 82.78%. A recently-published 1372-probe signature for AD can only achieve 61.59% accuracy in the same condition. The ACOR-based IXP approach also has better performance than the IXP approach based on classic network ranking, graph clustering, and random-ordering methods in an overall classification performance comparison. The ACOR-based IXP approach can serve as a knowledge-supervised feature transformation approach to increase classification accuracy dramatically, by transforming each gene expression profile to an integrated expression files as features inputting into standard classifiers. The IXP approach integrates both gene expression information and organized knowledge - disease gene/protein network topology information, which is represented as both network node weights (local topological properties) and network node orders (global topological characteristics).

In resource-poor settings, mortality is at its highest during the first 3 months after combination antiretroviral treatment (cART) initiation. A clear predictor of mortality during this period is having a low CD4 count at the time of treatment initiation. The objective of this study was to evaluate the effect on survival and clinic retention of a nurse-based rapid assessment clinic for high-risk individuals initiating cART in a resource-constrained setting. The USAID-AMPATH Partnership has enrolled more than 140,000 patients at 25 clinics throughout western Kenya. High Risk Express Care (HREC) provides weekly or bi-weekly rapid contacts with nurses for individuals initiating cART with CD4 counts of ≤100 cells/mm3. All HIV-infected individuals aged 14 years or older initiating cART with CD4 counts of ≤100 cells/mm3 were eligible for enrolment into HREC and for analysis. Adjusted hazard ratios (AHRs) control for potential confounding using propensity score methods. Between March 2007 and March 2009, 4,958 patients initiated cART with CD4 counts of ≤100 cells/mm3. After adjusting for age, sex, CD4 count, use of cotrimoxazole, treatment for tuberculosis, travel time to clinic and type of clinic, individuals in HREC had reduced mortality (AHR: 0.59; 95% confidence interval: 0.45-0.77), and reduced loss to follow up (AHR: 0.62; 95% CI: 0.55-0.70) compared with individuals in routine care. Overall, patients in HREC were much more likely to be alive and in care after a median of nearly 11 months of follow up (AHR: 0.62; 95% CI: 0.57-0.67). Frequent monitoring by dedicated nurses in the early months of cART can significantly reduce mortality and loss to follow up among high-risk patients initiating treatment in resource-constrained settings.

Fichman P.,Indiana University
Journal of Information Science | Year: 2011

Question answering (Q&A) sites, where communities of volunteers answer questions, may provide faster, cheaper, and better services than traditional institutions. However, like other Web 2.0 platforms, user-created content raises concerns about information quality. At the same time, Q&A sites may provide answers of different quality because they have differen communities and technological platforms. This paper compares answer quality on four Q&A sites: Askville, WikiAnswers, Wikipedia Reference Desk, and Yahoo! Answers. Findings indicate that: (1) similar collaborative processes on these sites result in a wide range of outcomes, and significant differences in answer accuracy, completeness, and verifiability were evident; (2) answer multiplication does not always result in better information; it yields more complete and verifiable answers but does not result in higher accuracy levels; and (3) a Q&A site's popularity does not correlate with its answer quality, on all three measures. © Chartered Institute of Library and Information Professionals 2011.

Al-Tawfiq J.A.,Indiana University | Memish Z.A.,Alfaisal University
Trends in Microbiology | Year: 2014

The Middle East respiratory syndrome coronavirus (MERS-CoV) was first described in 2012 and, subsequently, many cases were reported with a lower case fatality rate than initial cases. Humans can become infected within their communities and transmission can then be amplified in the healthcare setting. Contact investigation among cases shows a variable amount of spread among family members and healthcare workers. So far, circulating virus strains remain similar under continuous monitoring, with no genetic changes. Here, we discuss the transmission pattern, phylogenetic evolution, and pathogenesis of MERS-CoV infection. © 2014 Elsevier Ltd. All rights reserved.

Bragulat V.,Indiana University
Obesity (Silver Spring, Md.) | Year: 2010

Food aromas can be powerful appetitive cues in the natural environment. Although several studies have examined the cerebral responses to food images, none have used naturalistic food aromas to study obesity. Ten individuals (five normal-weight and five obese) were recruited to undergo 24 h of food deprivation. Subjects were then imaged on a 3T Siemens Trio-Tim scanner (Siemens, Erlangen, Germany) while smelling four food-related odors (FRO; two sweet odors and two fat-related) and four "nonappetitive odors" (NApO; e.g., Douglas fir). Before the imaging session, subjects rated their desire to eat each type of food to determine their most preferred (P-FRO). Across all 10 subjects, P-FRO elicited a greater blood oxygenation level dependent (BOLD) response than the NApO in limbic and reward-related areas, including the bilateral insula and opercular (gustatory) cortex, the anterior and posterior cingulate, and ventral striatum. Obese subjects showed greater activation in the bilateral hippocampus/parahippocampal gyrus, but lean controls showed more activation in the posterior insula. Brain areas activated by food odors are similar to those elicited by cues of addictive substances, such as alcohol. Food odors are highly naturalistic stimuli, and may be effective probes of reward-related networks in the context of hunger and obesity.

Bush K.,Indiana University | Pucci M.J.,New Haven Pharmaceuticals
Biochemical Pharmacology | Year: 2011

Antibiotic resistance issues necessitate the continued discovery and development of new antibacterial agents. Efforts are ongoing in two approaches to find new compounds that are effective against antibiotic-resistant pathogens. These efforts involve modification of existing classes including fluoroquinolones, tetracyclines, aminoglycosides, and β-lactams and identification of inhibitors against previously unexploited antibacterial targets. Examples of both approaches are described here with emphasis on compounds in late pre-clinical or clinical stages of development. © 2011 Elsevier Inc. All rights reserved.

Wolverton S.E.,Indiana University | Harper J.C.,University of Alabama at Birmingham
American Journal of Clinical Dermatology | Year: 2013

Isotretinoin is a remarkably effective drug for severe, recalcitrant acne vulgaris. Soon after the drug's release in the early 1980s, a number of important adverse effects were reported subsequently leading to a variety of medical and medicolegal controversies. Three of these controversies will be highlighted concerning the putative role of isotretinoin in (1) depression and suicide, (2) inflammatory bowel disease, and (3) iPledge and pregnancy prevention programs. It appears that a very small subset of patients receiving isotretinoin for acne are at risk for depression, which is very manageable provided there is adequate patient awareness of the possibility, maximum communication between the patient and physician, and cessation of therapy if clinically important depression occurs (after which the depression rapidly resolves in a week or less). Multiple controlled studies actually suggest a very favorable effect of isotretinoin on depression and anxiety common in the population requiring isotretinoin. With regard to inflammatory bowel disease, in just one study, only ulcerative colitis association with isotretinoin reached statistical significance. The actual incidence of this association is strikingly low. Finally, it is clear that even the most recent pregnancy prevention program (iPledge) is no more successful than prior programs; there will likely always be a small number of female patients becoming pregnant while receiving isotretinoin for acne vulgaris. © 2013 Springer International Publishing Switzerland (outside the USA).

Moczek A.P.,Indiana University
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

Phenotypic plasticity in general and polyphenic development in particular are thought to play important roles in organismal diversification and evolutionary innovation. Focusing on the evolutionary developmental biology of insects, and specifically that of horned beetles, I explore the avenues by which phenotypic plasticity and polyphenic development have mediated the origins of novelty and diversity. Specifically, I argue that phenotypic plasticity generates novel targets for evolutionary processes to act on, as well as brings about trade-offs during development and evolution, thereby diversifying evolutionary trajectories available to natural populations. Lastly, I examine the notion that in those cases in which phenotypic plasticity is underlain by modularity in gene expression, it results in a fundamental trade-off between degree of plasticity and mutation accumulation. On one hand, this trade-off limits the extent of plasticity that can be accommodated by modularity of gene expression. On the other hand, it causes genes whose expression is specific to rare environments to accumulate greater variation within species, providing the opportunity for faster divergence and diversification between species, compared with genes expressed across environments. Phenotypic plasticity therefore contributes to organismal diversification on a variety of levels of biological organization, thereby facilitating the evolution of novel traits, new species and complex life cycles. © 2010 The Royal Society.

Carley S.,Indiana University
Review of Policy Research | Year: 2011

U.S. energy and climate policy has evolved from the bottom-up, led by state governments, and internationally recognized for the use of unconventional and innovative policy instruments. This study focuses on policy instruments adopted throughout the era of state energy policy innovation that aim to diversify, decentralize, and decarbonize the electricity sector. Specific attention is devoted to the renewable portfolio standard, net metering, interconnection standards, tax incentives, public benefit funds, and energy efficiency resource standards. This analysis synthesizes the findings from the energy policy literature and provides a summary of the current state of understanding about the effects of various state energy policy instruments, and concludes with a discussion of broader trends that have emerged from the use of policy instruments in the state energy policy innovation era. © 2011 by The Policy Studies Organization.

Wilkes D.S.,Indiana University
Seminars in Immunology | Year: 2012

Lung transplantation is considered a definitive treatment for many lung diseases. However, rejection and other pathologic entities are major causes of morbidity and mortality for lung transplant recipients. Primary graft dysfunction (PGD) and obliterative bronchiolitis (OB) are the leading causes of early and late mortality, respectively. While the immune basis of PGD has not been clearly defined, evidence is emerging about roles for autoantibodies in this process. Similarly, the pathogenesis of OB has been linked recently to autoimmunity. This review will highlight the current understanding of autoantibodies in PGD and OB post lung transplantation. © 2011 Elsevier Ltd.

Kaplan M.H.,Indiana University
Immunological Reviews | Year: 2013

CD4+ T-helper cells regulate immunity and inflammation through the acquisition of potential to secrete specific cytokines. The acquisition of cytokine-secreting potential, in a process termed T-helper cell differentiation, is a response to multiple environmental signals including the cytokine milieu. The most recently defined subset of T-helper cells are termed Th9 and are identified by the potent production of interleukin-9 (IL-9). Given the pleiotropic functions of IL-9, Th9 cells might be involved in pathogen immunity and immune-mediated disease. In this review, I focus on recent developments in understanding the signals that promote Th9 differentiation, the transcription factors that regulate IL-9 expression, and finally the potential roles for Th9 cells in immunity in vivo. © 2013 John Wiley & Sons A/S.

Hewitt S.M.,U.S. National Institutes of Health | Badve S.S.,Indiana University | True L.D.,University of Washington
Clinical Cancer Research | Year: 2012

Molecular assays have been routinely applied to improve diagnosis for the last 25 years. Assays that guide therapy have a similar history; however, their evolution has lacked the focus on analytic integrity that is required for the molecularly targeted therapies of today. New molecularly targeted agents require assays of greater precision/quantitation to predict the likelihood of response, i.e., to identify patients whose tumors will respond, while at the same time excluding and protecting those patients whose tumors will not respond or in whom treatment will cause unacceptable toxicity. The handling of tissue has followed a fit-for-purpose approach focused on appropriateness for diagnostic needs, which is less rigorous than the demands of new molecular assays that interrogate DNA, RNA, and proteins in a quantitative, multiplex manner. There is a new appreciation of the importance and fragility of tissue specimens as the source of analytes to direct therapy. By applying a total test paradigm and defining and measuring sources of variability in specimens, we can develop a set of specifications that can be incorporated into the clinical-care environment to ensure that a specimen is appropriate for analysis and will return a true result. ©2012 AACR.

Maier B.,Indiana University
Discovery medicine | Year: 2010

Diabetes, a disorder of glucose homeostasis, has risen to near epidemic proportions world-wide and may be the single most important risk factor for cardiovascular, kidney, and eye disease. Dysfunction and destruction of islet beta cells, caused in part by the systemic or local release of pro-inflammatory cytokines, underlies all forms of diabetes. A major effort in diabetes research in recent years has been to identify new factors or pathways that can be therapeutically targeted to reduce cytokine action on the beta cell. Recent studies have suggested that an ancient and poorly understood protein, eIF5A, may be critical to cytokine release and signaling. Interestingly, eIF5A is the only protein to contain the unique amino acid hypusine, which is a polyamine-derived modification of amino acid lysine residue. This modification is catalyzed by the sequential actions of the inhibitable enzymes deoxyhypusine synthase and deoxyhypusine hydroxylase. Because the hypusine modification is absolutely required for eIF5A action in cytokine signaling, we propose that this modification could serve as a new drug target for islet beta cell protection in the setting of diabetic inflammation.

Boulton M.E.,Indiana University
Experimental Eye Research | Year: 2014

The retinal pigment epithelium contains three major types of pigment granules; melanosomes, lipofuscin and melanolipofuscin. Melanosomes in the retinal pigment epithelium (RPE) are formed during embryogenesis and mature during early postnatal life while lipofuscin and melanolipofuscin granules accumulate as a function of age. The difficulty in studying the formation and consequences of melanosomes and lipofuscin granules in RPE cell culture is compounded by the fact that these pigment granules do not normally occur in established RPE cell lines and pigment granules are rapidly lost in adult human primary culture. This review will consider options available for overcoming these limitations and permitting the study of melanosomes and lipofuscin in cell culture and will briefly evaluate the advantages and disadvantages of the different protocols. © 2014 The Author.

Alley Jr. W.R.,Indiana University Bloomington | Mann B.F.,Indiana University Bloomington | Novotny M.V.,Indiana University Bloomington | Novotny M.V.,Indiana University
Chemical Reviews | Year: 2013

Extensive glycomic and glycoproteomic data that can be generated with modern techniques and instrumentation are likely to enrich the systems biology approach. Glycosylation provides additional structural diversity to the already specialized protein molecules. The diverse set of cells mediating both the innate and adaptive immunity engage glycoproteins with both N- and O-linked glycans. the greatest analytical challenge for glycoproteomic (and proteomic) investigations of biological mixtures remains the inherent complexity of the samples and the associated difficulties with detection, quantitative measurement, and structural characterization of low-abundant glycoproteins. In both proteomics and glycoproteomics, the now routine immunodepletion strategies are employed for removal of the most abundant proteins. Substantial advances in bioinformatics to facilitate computer-assisted data analysis and processing in the evaluations of the highly complex analytical data add to the unprecedented opportunities for future explorations of different glycomes and glycoproteomes.

Haas D.M.,Indiana University
Pharmacogenomics | Year: 2014

Pharmacogenetics as a tool to aid clinicians implement individualized pharmacotherapy is utilized in some areas of medicine. Pharmacogenetics in pregnancy is still a developing field. However, there are several areas of obstetric therapeutics where data are emerging that give glimpses into future therapeutic possibilities. These include opioid pain management, antihypertensive therapy, antidepressant medications, preterm labor tocolytics, antenatal corticosteroids and drugs for nausea and vomiting of pregnancy, to name a few. More data are needed to populate the therapeutic models and to truly determine if pharmacogenetics will aid in individualizing pharmacotherapy in pregnancy. The objective of this review is to summarize current data and highlight research needs. © 2014 Future Medicine Ltd.

Benson M.D.,Indiana University
Amyloid | Year: 2012

Current dogma for transthyretin (TTR) pathogenesis is that mutations in TTR alter its structure such that the tetramer becomes unstable and prone to release of monomer which then becomes the putative building block of the fibril. This hypothesis is supported by thermodynamic data showing decreased stability of mutant TTR tetrameric proteins and accelerated fibril formation under acidic conditions in vitro. There are, however, a number of questions that are not readily answered by this simplistic model of a very complex disease. Worrisome questions still to be answered include: 1. If the monomer is the precursor of the fibril, why do fibril deposits contain large amounts of wild-type TTR and not just variant 2. If destabilized tetramers can form fibrils in vitro, why do we consistently find partial proteolysis of fibril subunit proteins If enzymatic proteolysis is a required step in fibril formation, are the findings of in vitro fibril formation relevant to the true pathogenesis 3. With some TTR mutations (e.g. 122ΔVal), it would appear that very little TTR is present in the blood (probably due to degradation prior to hepatic secretion). Enough mutant TTR circulates to the heart and nerves to cause pathology but, if the mutant only serves to initiate fibril deposition, why are not the deposits mainly wild-type TTR4. Since mutated TTR is present from birth, why is TTR amyloidosis of such delayed onset What is the role of aging factors5. Do the variations in biochemical analyses of heart and nerve versus choroid and leptomeningeal fibrils tell us something about pathogenesis These are questions we need to address. Do not expect quick and easy answers. Hopefully, they will generate thought and discussion. © 2012 Informa UK, Ltd.

Foster J.,Indiana University Bloomington | Lehnert R.,Indiana University
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2015

The classical propagation of certain Lorentz-violating fermions is known to be governed by geodesics of a four-dimensional pseudo-Finsler b space parametrized by a prescribed background covector field. This work identifies systems in classical physics that are governed by the three-dimensional version of Finsler b space and constructs a geodesic for a sample non-constant choice for the background covector. The existence of these classical analogues demonstrates that Finsler b spaces possess applications in conventional physics, which may yield insight into the propagation of SME fermions on curved manifolds. © 2015 The Authors.

Evans P.A.,University of Liverpool | Grisin A.,University of Liverpool | Lawler M.J.,Indiana University
Journal of the American Chemical Society | Year: 2012

The bismuth-mediated two-component hemiacetal/oxa-conjugate addition of δ-trialkylsilyloxy and δ-hydroxy α,β-unsaturated aldehydes and ketones with alkyl aldehydes provides the syn-1,3-dioxanes in a highly efficient and stereoselective manner. The key advantages of this protocol are its operational simplicity and its ability to directly access electron-withdrawing groups without recourse to oxidation state adjustments. © 2012 American Chemical Society.

Van Der Pol B.,Indiana University
Expert Review of Molecular Diagnostics | Year: 2013

Chlamydia trachomatis and Neisseria gonorrhoeae (CT/NG) are the most common sexually transmitted bacterial infections globally and account for the majority of the infections monitored by public health surveillance systems. Therefore, access to diagnostic tools that facilitate identification of these infections is critical to sexually transmitted infection control efforts. The cobas ® 4800 system is a fully automated system that incorporates nucleic acid extraction and real-time PCR. The cobas 4800 CT/NG assay is one component of the test menu available on this system. The cobas 4800 CT/NG assay has excellent sensitivity and specificity as a result of dual primer targets, it utilizes self-obtained sample types, and is only one assay in a larger menu of tests that are performed on a system that is easy to use and maintain. © 2013 2013 Expert Reviews Ltd.

We describe the use of an intraoperative CT scan obtained using the Medtronic O-arm (Littleton, Massachusetts) for image-guided cannulation of the foramen ovale not previously accessible with the use of fluoroscopy alone. Unlike previously described procedures, this technique does not require placement of an invasive head clamp and may be used with an awake patient. To describe the use of intraoperative neuronavigation for accessing skull base foramina and, specifically, cannulating of the foramen ovale during percutaneous rhizotomy procedures using an intraoperative image guidance CT scanner (Medtronic O-arm, Littleton, Massachusetts). A noninvasive Landmark Fess Strap attached to a spine reference frame was applied to the heads of 4 patients who harbored a difficult-to-access foramen ovale. An intraoperative HD3D skull base scan using a Medtronic O-arm was obtained, and Synergy Spine software was used to create 3D reconstructions of the skull base. Using image guidance, we navigated the needle to percutaneously access the foramen ovale by the use of a single tract for successful completion of balloon compression of the trigeminal nerve. All 4 patients (3 females and 1 male; ages 65-75) underwent the procedure with no complications. Based on our experience, neuronavigation with the use of intraoperative O-arm CT imaging is useful during these cases.

The method of fluorescence lifetime imaging microscopy (FLIM) is a quantitative approach that can be used to detect Förster resonance energy transfer (FRET). The use of FLIM to measure the FRET that results from the interactions between proteins labeled with fluorescent proteins (FPs) inside living cells provides a non-invasive method for mapping interactomes. Here, the use of the phasor plot method to analyze frequency domain (FD) FLIM measurements is described, and measurements obtained from cells producing the 'FRET standard' fusion proteins are used to validate the FLIM system for FRET measurements. The FLIM FRET approach is then used to measure both homologous and heterologous protein-protein interactions (PPI) involving the CCAAT/enhancer-binding protein alpha (C/EBPα). C/EBPα is a transcription factor that controls cell differentiation, and localizes to heterochromatin where it interacts with the heterochromatin protein 1 alpha (HP1α). The FLIM-FRET method is used to quantify the homologous interactions between the FP-labeled basic leucine zipper (BZip) domain of C/EBPα. Then the heterologous interactions between the C/EBPa BZip domain and HP1a are quantified using the FRET-FLIM method. The results demonstrate that the basic region and leucine zipper (BZip) domain of C/EBPα is sufficient for the interaction with HP1α in regions of heterochromatin. © 2013 Elsevier Inc.

Yoder M.C.,Indiana University
Cold Spring Harbor Perspectives in Medicine | Year: 2012

Human endothelial progenitor cells (EPCs) have been generally defined as circulating cells that express a variety of cell surface markers similar to those expressed by vascular endothelial cells, adhere to endothelium at sites of hypoxia/ischemia, and participate in new vessel formation. Although no specific marker for an EPC has been identified, a panel of markers has been consistently used as a surrogate marker for cells displaying the vascular regenerative properties of the putative EPC. However, it is now clear that a host of hematopoietic and vascular endothelial subsets display the same panel of antigens and can only be discriminated by an extensive gene expression analysis or use of a variety of functional assays that are not often applied. This article reviews our current understanding of the many cell subsets that constitute the term EPC and provides a concluding perspective as to the various roles played by these circulating or resident cells in vessel repair and regeneration in human subjects. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.

Unlike the general population, among hemodialysis patients body mass index (BMI) is related to blood pressure (BP) and mortality inversely. To explore the reasons for this risk-factor paradox, the cross-sectional association of obesity with the following factors was examined: the prevalence of hypertension, its control, and echocardiographic left ventricular mass index (LVMI). Longitudinal follow-up explored the relationship of BMI with all-cause mortality. Furthermore, it explored whether poorer survival in leaner individuals was related to either high BP or greater LVMI. Among 368 hemodialysis patients, both the prevalence of hypertension and its poor control were inversely related to BMI. BMI was also inversely associated with evidence of excess extracellular fluid volume, but adjustment for this variable did not completely remove the inverse relationship between BP and BMI. Over 1122 patient-years of cumulative follow-up (median: 2.7 years), 119 patients (32%) died. In the first 2 years of follow-up, the mortality hazard for the lowest BMI group was increased; thereafter, the survival curves were similar. Adjusting for several risk factors including BP and LVMI did not remove the inverse relationship of BMI with mortality. In conclusion, leaner patients on dialysis have a higher prevalence of hypertension, poorer control of hypertension, more LVMI, and greater evidence of extracellular fluid volume excess. However, volume explains the greater prevalence or poorer control of hypertension only partially. Leaner patients have an accelerated mortality rate in the first 2 years; this is not completely explained by BP, LVMI, or other cardiovascular or dialysis-specific risk factors. © 2011 American Heart Association, Inc.

This paper presents preliminary results from direct imaging of P to S conversion data from the Earthscope Transportable Array (TA). Input data are receiver function estimates from the Earthscope Automated Receiver Function Survey (EARS). The waveforms from EARS were first stacked to produce composite events from 60 different source regions defined by a radial grid with a center in the western United States (U.S.). The composite waveforms were imaged with a three-dimensional, prestack migration method using a plane wave decomposition and an inverse generalized Radon transform algorithm to yield estimates of radial and transverse component scattering potential from each composite event. Data deficiencies limited this processing to 50 of the composite events. The migrated results from these 50 events were stacked to produce a final threedimensional image volume examined in this paper through three-dimensional visualization techniques. The crust-mantle boundary, the 410 km, and 660 km discontinuities are imaged. An erratic negative conversion at the depth that has been suggested as the seismic lithosphere-asthenosphere boundary is observed in these results, but I avoid interpreting this feature as it may be biased by interference with first-order, free-surface multiples from the Moho. The most significant new feature imaged by this technique is a series of east-dipping conversions directly above the 410 km discontinuity. This feature is imaged in the region immediately above the transition zone across the entire western U.S., although it becomes partly obscured in Arizona by interference with what I interpret as sediment reverberations that contaminate some stations in southern California and the Rio Grande Rift. Overlaying these results with published tomography models suggests that this feature is linked to the Juan de Fuca-Farallon slab. I follow this hypothesis to build a three-dimensional model of the top of the Farallon slab that honors the new data and results from published tomography models. The model clarifies that these dipping features are consistent with a bending plate model of the slab. Using a simple kinematic model of the geometry of the slab window linked to the widening of the San Andreas system, I argue that the same dipping features seen under Nevada are consistent with those seen to the north, suggesting that there is a continuous, relatively smooth slab-related boundary layer under most of the western U.S. © 2011 Geological Society of America.

Janssen M.A.,Arizona State University | Holahan R.,Arizona State University | Lee A.,Arizona State University | Ostrom E.,Arizona State University | Ostrom E.,Indiana University
Science | Year: 2010

Governance of social-ecological systems is a major policy problem of the contemporary era. Field studies of fisheries, forests, and pastoral and water resources have identified many variables that influence the outcomes of governance efforts. We introduce an experimental environment that involves spatial and temporal resource dynamics in order to capture these two critical variables identified in field research. Previous behavioral experiments of commons dilemmas have found that people are willing to engage in costly punishment, frequently generating increases in gross benefits, contrary to game-theoretical predictions based on a static pay-off function. Results in our experimental environment find that costly punishment is again used but lacks a gross positive effect on resource harvesting unless combined with communication. These findings illustrate the importance of careful generalization from the laboratory to the world of policy. Copyright 2010 by the American Association for the Advancement of Science; all rights reserved.

Ding Y.,Indiana University
Journal of the American Society for Information Science and Technology | Year: 2011

Ranking authors is vital for identifying a researcher's impact and standing within a scientific field. There are many different ranking methods (e.g., citations, publications, h-index, PageRank, and weighted PageRank), but most of them are topic-independent. This paper proposes topic-dependent ranks based on the combination of a topic model and a weighted PageRank algorithm. The author-conference-topic (ACT) model was used to extract topic distribution of individual authors. Two ways for combining the ACT model with the PageRank algorithm are proposed: simple combination (I-PR) or using a topic distribution as a weighted vector for PageRank (PR-t). Information retrieval was chosen as the test field and representative authors for different topics at different time phases were identified. Principal component analysis (PCA) was applied to analyze the ranking difference between I-PR and PR-t. © 2011 ASIST.

Trescot A.M.,Pain and Headache Center | Faynboym S.,Indiana University
Pain Physician | Year: 2014

Background: Pain clinicians have always been challenged by the variability of response to pain treatment. Differences in the degree of pain stimulation and pain sensitivity, weight and age differences, prior opioid use and tolerance, as well as the differences in bioavailability of various opioid formulations have been cited as causes for the wide variability in analgesia seen with opioids. Genetics may explain the variability of responses and help to predict more effective (or less dangerous) medication choices and doses. Genetics may also help to predict the response to specific opioids and antidepressants.Objectives: In this review article, we discuss the genetic influence of nociception, analgesia, and hyoanalgesia. The CYP450 enzymes involved in the metabolism and activity of opioids and adjuvant analgesics are genetically controlled, as are the opioid receptors and a variety of brain chemistries.Methods: This article discusses the specific pain implications of genetic variations in CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A7, OPRM1, OPRK1, OPRD1, COMT, GABA, UGT, MC1R, GCH1, ABCB1, P-glycoprotein, 5HTR1A, 5HTR2A, MTHFR, CACNA2D2, and 5-HTTLPR.Results: Recent research findings suggest the relationship between genetic predisposition and clinical behavior, including the risk of opioid misuse and addiction. While urine drug testing may hint at genetic issues regarding opioid metabolism, cheek swab DNA testing has become economically viable, and we review the current and future genetic pain issues that may influence the decisions that pain clinicians make every day.Conclusion: Genetic testing may explain and predict many of the clinical responses seen with opioids and adjuvant medications, and may help the clinician identify those patients at genetic risk of opioid misuse and addiction. © 2014, American Society of Interventional Pain Physicians, All rights reserved.

Al-Tawfiq J.A.,Saudi Aramco | Al-Tawfiq J.A.,Indiana University | Memish Z.A.,Ministry of Health | Memish Z.A.,Alfaisal University
Trends in Microbiology | Year: 2014

The Middle East respiratory syndrome coronavirus (MERS-CoV) was first described in 2012 and, subsequently, many cases were reported with a lower case fatality rate than initial cases. Humans can become infected within their communities and transmission can then be amplified in the healthcare setting. Contact investigation among cases shows a variable amount of spread among family members and healthcare workers. So far, circulating virus strains remain similar under continuous monitoring, with no genetic changes. Here, we discuss the transmission pattern, phylogenetic evolution, and pathogenesis of MERS-CoV infection. © 2014 Elsevier Ltd.

Regev A.,Indiana University
Seminars in Liver Disease | Year: 2014

Despite intensive ongoing research, drug-induced live injury (DILI) remains a serious issue for care providers and patients, and has been a major cause of drug withdrawal and non-approval by regulatory authorities in the past 50 years. Consequently, DILI remains a major concern for the pharmaceutical industry and a leading cause for attrition during drug development. In most instances, severe DILI is an uncommon idiosyncratic reaction, which typically does not present during preclinical phases or early clinical phases of drug development. In the majority of cases, drugs that caused severe DILI in humans have not shown clear and consistent hepatotoxic signals in preclinical assessment including animal studies, cell cultures, or other methods. Despite intensive efforts to develop better biomarkers that would help in predicting DILI risk in earlier phases of drug development, such biomarkers are currently not supported by sufficient evidence and are not yet available for routine use by drug makers. Due to the lack of effective and accurate methods for prediction of idiosyncratic DILI during preclinical phases of drug development, different drug makers have adopted different approaches, which are often not supported by strong systematic evidence. Based on growing experience, it is becoming increasingly evident that milder forms of liver injury occurring during clinical development, when assessed correctly, may significantly enhance our ability to predict the drug's potential to cause more severe liver injury postmarketing. Strategies based on this concept have been adopted by many drug makers, and are being increasingly implemented during drug development. Meticulous causality assessment of individual hepatic cases and adherence to strict hepatic discontinuation rules are critical components of this approach and have to rely on thorough clinical evaluation and occasionally on assessment by liver experts experienced with DILI and drug development. Copyright © 2014 by Thieme Medical Publishers, Inc.

Niculescu III A.B.,Indiana University
Journal of Clinical Psychiatry | Year: 2014

Identifying genes for psychiatric disorders using traditional genetic approaches has thus far proven quite difficult. Reasons for this include the complexity of these disorders and the poor definition of the clinical phenotype. However, recent studies have demonstrated the power of an approach called convergent functional genomics (CFG). CFG is a methodology that integrates different types of data to increase the ability to identify genes involved in various psychiatric and nonpsychiatric disorders. The work exemplified in this article integrated human brain and blood gene expression data, relevant animal model brain and blood gene expression data, and human genetic data to identify candidate genes and blood biomarkers for schizophrenia. © Copyright 2014 Physicians Postgraduate Press, Inc.

Amacher D.E.,Sciadvisor Toxicology Consulting | Chalasani N.,Indiana University
Seminars in Liver Disease | Year: 2014

Several drugs have been associated with the potential for drug-induced hepatic steatosis (DIHS) and/or phospholipidosis (DIPL), a lysosomal storage disorder. Drug-induced hepatic steatosis is generally a chronic but reversible affliction and may involve drug accumulation in the liver. Fat accumulation may be either macrovesicular or microvesicular in nature. Commonly used medications associated with DIHS include amiodarone, valproate, tamoxifen, methotrexate, and some chemotherapeutic and antiretroviral agents. Two recently approved medications for the treatment of hereditary homozygous hypercholesterolemia have also been noted to cause hepatic steatosis. For some compounds such as methotrexate and tamoxifen, the underlying metabolic risk factors such as obesity and metabolic syndrome may exacerbate their potential to cause DIHS and its progression. In this article, the authors discuss the preclinical screening and mechanisms of DIHS and DIPL, and review specific examples of drugs commonly used in clinical practice that are known to cause DIHS. Copyright © 2014 by Thieme Medical Publishers, Inc.

Donchin A.,Indiana University
Bioethics | Year: 2010

Reproductive tourism is a manifestation of a larger, more inclusive trend toward globalization of capitalist cultural and material economies. This paper discusses the development of cross-border assisted reproduction within the globalized economy, transnational and local structural processes that influence the trade, social relations intersecting it, and implications for the healthcare systems affected. I focus on prevailing gender structures embedded in the cross-border trade and their intersection with other social and economic structures that reflect and impact globalization. I apply a social connection model of responsibility for unjust outcomes and consider strategies to counter structural injustices embedded in this industry. The concluding section discusses policy reforms and proposals for collaborative action to preclude further injustices and extend full human rights to all. © 2010 Blackwell Publishing Ltd.

The purpose of this article is to evaluate and compare the artifacts caused by metal implants in breast MR images acquired with dual-echo Dixon and two conventional fat-suppression techniques. Two types of biopsy markers were embedded into a uniform fat-water emulsion. T1-weighted gradient-echo images were acquired on a clinical 3-T MRI scanner with three different fat-suppression techniques-conventional or quick fat saturation, spectrally selective adiabatic inversion recovery (SPAIR), and dual-echo Dixon-and the 3D volumes of artifacts were measured. Among the subjects of a clinical breast MRI study using the same scanner, five patients were found to have one or more metal implants. The artifacts in Dixon and SPAIR fat-suppressed images were evaluated by three radiologists, and the results were compared with those of the phantom study. In the phantom study, the artifacts appeared as interleaved bright and dark rings on SPAIR and quick-fat-saturation images, whereas they appeared as dark regions with a thin bright rim on Dixon images. The artifacts imaged with the Dixon technique had the smallest total volume. However, the reviewers found larger artifact diameters on patient images using the Dixon sequence because only the central region was recognized as an artifact on the SPAIR images. Metal implants introduce artifacts of different types and sizes, according to the different fat-suppression techniques used. The dual-echo Dixon technique produces a larger central void, allowing the implant to be easily identified, but presents a smaller overall artifact volume by obscuring less area in the image, according to a quantitative phantom study.

Shiffrin R.M.,Indiana University
Topics in Cognitive Science | Year: 2010

This commentary gives a personal perspective on modeling and modeling developments in cognitive science, starting in the 1950s, but focusing on the author's personal views of modeling since training in the late 1960s, and particularly focusing on advances since the official founding of the Cognitive Science Society. The range and variety of modeling approaches in use today are remarkable, and for many, bewildering. Yet to come to anything approaching adequate insights into the infinitely complex fields of mind, brain, and intelligent systems, an extremely wide array of modeling approaches is vital and necessary. © 2010 Cognitive Science Society, Inc.

The purpose of this study was to examine component positioning, limb alignment, and the early functional range of motion of a pinless image-free computer-assisted navigation system, and compare it to conventional intramedullary component alignment methods. A total of 72 patients underwent cemented total knee arthroplasty. The pinless navigation group consisted of 40 knees in 39 patients, while the conventional group comprised 33 knees in 33 patients. Preoperative and postoperative radiographs were evaluated for coronal and sagittal alignment. Functional assessment was evaluated by early postoperative range of motion. There was no statistical significance when examining individual component alignment or early functional range of motion. When evaluating ability to achieve overall anatomic tibiofemoral alignment within a range of 4 to 7 degrees valgus, the conventional group was able to accomplish this 39% of the time, whereas the pinless navigation group succeeded in 65% of cases (p < 0.03). The tourniquet time was mean 59.5 minutes (range: 48 to 77 minutes) for the conventional group, compared with mean 71.9 minutes (range: 54 to 97 minutes) for the navigation group (p < 0.0001, 95% CI). The pinless navigation technique improved coronal anatomic alignment without complications that have been cited with use of femoral or tibial reference tracker pins or intramedullary alignment guides. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Left ventricular (LV) hypertrophy is an established cardiovascular risk factor, yet little is known about its trajectory in people with chronic kidney disease. The goal of this prospective research study was to describe the trajectory of LV mass index, its relationship with blood pressure (BP), and specifically to compare the relationship of BP measured in the clinic and 24-hour ambulatory BP monitoring with LV mass index. Among 274 veterans with chronic kidney disease followed for over ≤4 years, the rate of growth of log LV mass index was inversely related to baseline LV mass index; it was rapid in the first 2 years, and plateaued subsequently. Systolic BP also significantly increased, but linearly, 1.7 mm Hg/y by clinic measurements and 1.8 mm Hg/y by 24-hour ambulatory BP. Cross-sectional and longitudinal associations of both clinic BP and 24-hour ambulatory BP with LV mass index were similar; both BP recording methods were associated with LV mass index and its growth over time. Controlled hypertension, masked uncontrolled hypertension, and uncontrolled hypertension categories had increasing LV mass index when diagnosed by 24-hour ambulatory and awake BP (P<0.05 for linear trend) but not sleep BP. After accounting for clinic BP both at baseline and longitudinally, LV mass index among individuals was additionally predicted by the difference in sleep systolic BP and clinic systolic BP (P=0.032). In conclusion, among people with chronic kidney disease, the growth of LV mass index is rapid. Research-grade clinic BP is useful to assess LV mass index and its growth over time. © 2016 American Heart Association, Inc.

Chronic low-grade inflammation has emerged as a key contributor to the pathogenesis of Polycystic Ovary Syndrome (PCOS). A dietary trigger such as glucose is capable of inciting oxidative stress and an inflammatory response from mononuclear cells (MNC) of women with PCOS, and this phenomenon is independent of obesity. This is important because MNC-derived macrophages are the primary source of cytokine production in excess adipose tissue, and also promote adipocyte cytokine production in a paracrine fashion. The proinflammatory cytokine tumor necrosis factor-α (TNFα) is a known mediator of insulin resistance. Glucose-stimulated TNFα release from MNC along with molecular markers of inflammation are associated with insulin resistance in PCOS. Hyperandrogenism is capable of activating MNC in the fasting state, thereby increasing MNC sensitivity to glucose; and this may be a potential mechanism for promoting diet-induced inflammation in PCOS. Increased abdominal adiposity is prevalent across all weight classes in PCOS, and this inflamed adipose tissue contributes to the inflammatory load in the disorder. Nevertheless, glucose ingestion incites oxidative stress in normal weight women with PCOS even in the absence of increased abdominal adiposity. In PCOS, markers of oxidative stress and inflammation are highly correlated with circulating androgens. Chronic suppression of ovarian androgen production does not ameliorate inflammation in normal weight women with the disorder. Furthermore, in vitro studies have demonstrated the ability of pro-inflammatory stimuli to upregulate the ovarian theca cell steroidogenic enzyme responsible for androgen production. These findings support the contention that inflammation directly stimulates the polycystic ovary to produce androgens. © 2011 Elsevier Inc. All rights reserved.

Sharfuddin A.,Indiana University
Clinical Journal of the American Society of Nephrology | Year: 2014

Kidney transplantation can be associated with various complications that vary from vascular complications to urologic disorders to immunologic adverse effects. In evaluating the recipient with graft dysfunction, clinicians can choose among several imaging modalities, including ultrasonography, nuclear medicine studies, computed tomography, and magnetic resonance imaging. This review discusses the evaluation of the kidney transplant recipient using these imaging procedures, emphasizing the clinical diagnostic utility and role of each modality. A kidney biopsy is often required as a gold standard for diagnostic purposes. However, because of the inherent risks of a kidney biopsy, noninvasive imaging in diagnosing causes of graft dysfunction is a highly desired tool used and needed by the transplant community. Because the diagnostic accuracy varies depending on the time course and nature of the transplant-related complication, this review also addresses the advantages and limitations of each modality. The recent advances in kidney transplant imaging techniques and their clinical implications are also discussed. © 2014 by the American Society of Nephrology.

Myotonic muscular dystrophy (MMD) is caused by an abnormal function of RNA-binding proteins (RBP) resulting in DNA spliceopathy. A case of a patient, with MMD multiple basal and squamous cell carcinomas and dysplastic nevi, is described. The association between MMD and non-melanoma skin cancer has been reported before; however, this association was described before the genetic defect of myotonic dystrophy has been fully elucidated. The author proposes a genetic mechanism on how abnormal function of RBP can result or contribute to the development of human skin cancer and propose an explanation for this association between MMD and cutaneous carcinogenesis. © 2009 Springer-Verlag.

El-Achkar T.M.,Indiana University
Kidney International | Year: 2012

Ischemic preconditioning (IPC) is a powerful phenomenon whereby an episode of ischemic injury protects the kidney from subsequent injury. Xu et al. provide new insights into the protective effects of delayed IPC and its inhibition of apoptosis by implicating a modulatory role for the microRNA miR-21. This study adds another layer to our understanding of IPC, but also hints at the complexity of the system triggered by this process. © 2012 International Society of Nephrology.

Wysong P.R.,Indiana University
Pain Management Nursing | Year: 2014

This study explored the beliefs and self-reported practices of nurses related to pain assessment in nonverbal patients. A convenience sample of 74 nurses from one Midwestern community hospital responded to a researcher-developed questionnaire based on established pain standards and clinical practice recommendations. Areas of nonverbal pain assessment beliefs and practices with low scores were identified. One-way analysis of variance with Tukey post hoc tests showed a significant difference in belief scores based on unit worked. No significant differences in beliefs or practices were found based on age, years of experience, or degree. Paired t tests showed significant differences between general pain beliefs and nonverbal pain beliefs, between general pain beliefs and practices, and between nonverbal pain beliefs and practices. Additional testing using Pearson correlation coefficients demonstrated that only three out of seven questions relating to beliefs were significantly correlated with similar questions related to practices. Good reliability of the instrument was demonstrated by Cronbach alpha coefficient α = 0.82. Recommendations include further education for hospital nurses related to pain assessment standards in nonverbal patients, as well as utilization of techniques to integrate this knowledge into nurses' belief systems and practice environment. © 2014 American Society for Pain Management Nursing.

Moe S.M.,Indiana University
Seminars in Dialysis | Year: 2010

Calcium balance is an overall assessment of the net calcium taken in minus the net calcium taken out. It can only be assessed when patients are in steady state and requires complicated isotope methods that can simultaneously assess intestinal absorption and endogenous secretion, urinary and stool excretion, bone calcium uptake and removal, and dialysate calcium removal. By virtue of the need for steady state, formal balance studies cannot be accurately carried out in patients on dialysis. However, many of the components of calcium balance have been assessed. Importantly, because 99% of calcium is in bone, studies must accurately assess both the rapidly exchangeable calcium from the bone surface and the net bone calcium balance that results from the difference in bone formation minus resorption. While it is tempting to adjust the dialysate calcium concentration to correct the net positive calcium balance that is likely present in patients who receive calcium-based phosphate binders, the reality is that the highly variable, yet important, role of bone cannot be easily assessed at the bedside. Thus, it is best to prevent the calcium overload in the first place by avoiding high-dose calcium-based phosphate binders and optimizing bone remodeling. © 2010 Wiley Periodicals, Inc.

Bala H.,Indiana University
Journal of Operations Management | Year: 2013

Prior research on information technology (IT)-enabled supply chain management (SCM) has primarily focused on macro-level issues (e.g., IT capabilities related to SCM, and SCM design and optimization) and outcomes (e.g., firm performance). There has been limited research that focuses on micro-level outcomes related to employees who actually execute SCM processes in organizations. These employee-level outcomes are important because successful implementation of SCM systems and processes hinges on SCM employees' support and commitment. I develop and test a model positing that SCM employees' perceptions of changes in their work process characteristics, i.e., process complexity and process rigidity, following a new SCM system implementation will influence their job outcomes, i.e., job performance, job satisfaction, job anxiety, and job security, and their perceptions of process outcomes, i.e., process performance and relationship quality. The model incorporates a holistic appraisal of the extent of change - change radicalness - as a mechanism between work process characteristics and outcomes. The model is supported in three studies conducted in the context of three different SCM system implementations (N = 278, 282, and 304, respectively). In particular, I found that individuals perceived a significant change in their work process characteristics following an SCM system implementation, and changes in work process characteristics had a significant impact on job and process outcomes. These findings contribute to the information systems and operations management literatures and their intersections by offering insights on challenges related to IT-enabled SCM innovation implementation in organizations. © 2013 Elsevier B.V. All rights reserved.

Heo S.,Indiana University
European journal of cardiovascular nursing : journal of the Working Group on Cardiovascular Nursing of the European Society of Cardiology | Year: 2012

Social status may impact health-related quality of life (HRQOL), hospitalization, and mortality in patients with heart failure (HF). To determine if social status was associated with HRQOL and event-free survival. Higher social status (quality of perceived support, emotional support, marital status, and economic status) is related to better HRQOL and event-free survival after controlling covariates (New York Heart Association [NYHA] functional class, comorbidity status, and age). Patients (N = 147, 61 ± 11 years old, 70% male, 62% NYHA class III/IV) provided data on HRQOL (measured by the Minnesota Living with Heart Failure questionnaire) and social status. Event-free survival data were collected by medical record reviews and patient or family interviews. Hierarchical regression analysis and survival analysis were used to test the hypothesis. Better quality of perceived support, better economic status, better functional status, older age, and less comorbidity were related to better HRQOL (R2 = .365, p = <.001). Only economic status predicted event-free survival. Attention should be given to those who have lower social support to improve HRQOL and those who have lower economic status to improve event-free survival.

Bonanno J.A.,Indiana University
Experimental Eye Research | Year: 2012

The corneal endothelium is responsible for maintaining the hydration of the cornea. This is through a "Pump-Leak" mechanism where the active transport properties of the endothelium represent the "Pump" and the stromal swelling pressure represents the "Leak". For the "Pump", Na +, K + ATPase activity and the presence of HCO 3 -, Cl -, and carbonic anhydrase activity are required. Several basolateral (stromal side) anion transporters, apical (facing the aqueous humor) ion channels and water channels have been identified that could support a model for ion secretion as the basis for the endothelial pump, however evidence of sustained anion fluxes, osmotic gradients or the need for water channels is lacking. This has prompted consideration of other models, such as Electro-osmosis, and consideration of metabolite flux as components of the endothelial pump. Although the conditions under which the "Pump" is supported are known, a complete model of the endothelial "Pump" has yet to emerge. © 2011 Elsevier Ltd.

Ziegler M.A.,Indiana University
Microcirculation (New York, N.Y. : 1994) | Year: 2010

Peripheral arterial disease is a major health problem and there is a significant need to develop therapies to prevent its progression to claudication and critical limb ischemia. Promising results in rodent models of arterial occlusion have generally failed to predict clinical success and led to questions of their relevance. While sub-optimal models may have contributed to the lack of progress, we suggest that advancement has also been hindered by misconceptions of the human capacity for compensation and the specific vessels which are of primary importance. We present and summarize new and existing data from humans, Ossabaw miniature pigs, and rodents which provide compelling evidence that natural compensation to occlusion of a major artery (i) may completely restore perfusion, (ii) occurs in specific pre-existing small arteries, rather than the distal vasculature, via mechanisms involving flow-mediated dilation and remodeling (iii) is impaired by cardiovascular risk factors which suppress the flow-mediated mechanisms and (iv) can be restored by reversal of endothelial dysfunction. We propose that restoration of the capacity for flow-mediated dilation and remodeling in small arteries represents a largely unexplored potential therapeutic opportunity to enhance compensation for major arterial occlusion and prevent the progression to critical limb ischemia in the peripheral circulation.

Rogol A.D.,Indiana University
The American journal of managed care | Year: 2011

Growth hormone (GH) therapy has evolved rapidly since the introduction of recombinant human GH (rhGH). The increase in the availability and safety of GH therapy has also increased the number of US Food and Drug Administration (FDA) indications for use in both children and adults. FDA indications in children include GH deficiency (GHD), Turner syndrome, idiopathic short stature, small for gestational age with failure to attain normal growth percentiles, Prader-Willi syndrome (PWS), chronic renal insufficiency, Noonan syndrome, and short stature due to short stature homeobox gene haploinsufficiency. Children and adolescents with GHD have demonstrated the greatest response to GHD therapy. The primary objective of rhGH therapy in children is to increase height velocity; however, the therapy also has benefits related to improved body composition, especially in children with conditions like PWS. Treatment of adult GHD primarily targets improvements in body composition, quality of life, and surrogate markers for cardiovascular disease. The safety reports of rhGH in children are generally good, but there have been a small number of cases of raised intracranial pressure, scoliosis, and muscle and joint discomfort. In adults, many side effects can be managed with dose titration at the initiation of treatment and dose reduction if side effects occur.

Kramer K.J.,Indiana University
Anesthesia progress | Year: 2012

This study aimed to compare continuous intravenous infusion combinations of propofol-remifentanil and propofol-ketamine for deep sedation for surgical extraction of all 4 third molars. In a prospective, randomized, double-blinded controlled study, participants received 1 of 2 sedative combinations for deep sedation for the surgery. Both groups initially received midazolam 0.03 mg/kg for baseline sedation. The control group then received a combination of propofol-remifentanil in a ratio of 10 mg propofol to 5 μg of remifentanil per milliliter, and the experimental group received a combination of propofol-ketamine in a ratio of 10 mg of propofol to 2.5 mg of ketamine per milliliter; both were given at an initial propofol infusion rate of 100 μg/kg/min. Each group received an induction loading bolus of 500 μg/kg of the assigned propofol combination along with the appropriate continuous infusion combination . Measured outcomes included emergence and recovery times, various sedation parameters, hemodynamic and respiratory stability, patient and surgeon satisfaction, postoperative course, and associated drug costs. Thirty-seven participants were enrolled in the study. Both groups demonstrated similar sedation parameters and hemodynamic and respiratory stability; however, the ketamine group had prolonged emergence (13.6 ± 6.6 versus 7.1 ± 3.7 minutes, P = .0009) and recovery (42.9 ± 18.7 versus 24.7 ± 7.6 minutes, P = .0004) times. The prolonged recovery profile of continuously infused propofol-ketamine may limit its effectiveness as an alternative to propofol-remifentanil for deep sedation for third molar extraction and perhaps other short oral surgical procedures, especially in the ambulatory dental setting.

Uversky V.N.,University of South Florida | Uversky V.N.,Indiana University | Uversky V.N.,Russian Academy of Sciences
Chemical Reviews | Year: 2011