Showing papers by "University of Kansas published in 2012"

Guidelines for the use and interpretation of assays for monitoring autophagy

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

When can categorical variables be treated as continuous? A comparison of robust continuous and categorical SEM estimation methods under suboptimal conditions.

Abstract: A simulation study compared the performance of robust normal theory maximum likelihood (ML) and robust categorical least squares (cat-LS) methodology for estimating confirmatory factor analysis models with ordinal variables. Data were generated from 2 models with 2-7 categories, 4 sample sizes, 2 latent distributions, and 5 patterns of category thresholds. Results revealed that factor loadings and robust standard errors were generally most accurately estimated using cat-LS, especially with fewer than 5 categories; however, factor correlations and model fit were assessed equally well with ML. Cat-LS was found to be more sensitive to sample size and to violations of the assumption of normality of the underlying continuous variables. Normal theory ML was found to be more sensitive to asymmetric category thresholds and was especially biased when estimating large factor loadings. Accordingly, we recommend cat-LS for data sets containing variables with fewer than 5 categories and ML when there are 5 or more categories, sample size is small, and category thresholds are approximately symmetric. With 6-7 categories, results were similar across methods for many conditions; in these cases, either method is acceptable.

Tolvaptan in patients with autosomal dominant polycystic kidney disease

Abstract: In this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V 2 -receptor antagonist, at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline. RESULTS Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P = 0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of followup, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P = 0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, −2.61 [mg per milliliter] −1 per year vs. −3.81 [mg per milliliter] −1 per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group). CONCLUSIONS Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948.)

A reconciled estimate of ice-sheet mass balance

Abstract: We combined an ensemble of satellite altimetry, interferometry, and gravimetry data sets using common geographical regions, time intervals, and models of surface mass balance and glacial isostatic adjustment to estimate the mass balance of Earth’s polar ice sheets. We find that there is good agreement between different satellite methods—especially in Greenland and West Antarctica—and that combining satellite data sets leads to greater certainty. Between 1992 and 2011, the ice sheets of Greenland, East Antarctica, West Antarctica, and the Antarctic Peninsula changed in mass by –142 ± 49, +14 ± 43, –65 ± 26, and –20 ± 14 gigatonnes year−1, respectively. Since 1992, the polar ice sheets have contributed, on average, 0.59 ± 0.20 millimeter year−1 to the rate of global sea-level rise.

Toxicity of nanomaterials

Abstract: Nanoscience has matured significantly during the last decade as it has transitioned from bench top science to applied technology. Presently, nanomaterials are used in a wide variety of commercial products such as electronic components, sports equipment, sun creams and biomedical applications. There are few studies of the long-term consequences of nanoparticles on human health, but governmental agencies, including the United States National Institute for Occupational Safety and Health and Japan's Ministry of Health, have recently raised the question of whether seemingly innocuous materials such as carbon-based nanotubes should be treated with the same caution afforded known carcinogens such as asbestos. Since nanomaterials are increasing a part of everyday consumer products, manufacturing processes, and medical products, it is imperative that both workers and end-users be protected from inhalation of potentially toxic NPs. It also suggests that NPs may need to be sequestered into products so that the NPs are not released into the atmosphere during the product's life or during recycling. Further, non-inhalation routes of NP absorption, including dermal and medical injectables, must be studied in order to understand possible toxic effects. Fewer studies to date have addressed whether the body can eventually eliminate nanomaterials to prevent particle build-up in tissues or organs. This critical review discusses the biophysicochemical properties of various nanomaterials with emphasis on currently available toxicology data and methodologies for evaluating nanoparticle toxicity (286 references).

Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: The lupus nephritis assessment with rituximab study†

Abstract: Objective To evaluate the efficacy and safety of rituximab in a randomized, double-blind, placebo-controlled phase III trial in patients with lupus nephritis treated concomitantly with mycophenolate mofetil (MMF) and corticosteroids. Methods Patients (n = 144) with class III or class IV lupus nephritis were randomized 1:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182. The primary end point was renal response status at week 52. Results Rituximab depleted peripheral CD19+ B cells in 71 of 72 patients. The overall (complete and partial) renal response rates were 45.8% among the 72 patients receiving placebo and 56.9% among the 72 patients receiving rituximab (P = 0.18); partial responses accounted for most of the difference. The primary end point (superior response rate with rituximab) was not achieved. Eight placebo-treated patients and no rituximab-treated patients required cyclophosphamide rescue therapy through week 52. Statistically significant improvements in serum complement C3, C4, and anti–double-stranded DNA (anti-dsDNA) levels were observed among patients treated with rituximab. In both treatment groups, a reduction in anti-dsDNA levels greater than the median reduction was associated with reduced proteinuria. The rates of serious adverse events, including infections, were similar in both groups. Neutropenia, leukopenia, and hypotension occurred more frequently in the rituximab group. Conclusion Although rituximab therapy led to more responders and greater reductions in anti-dsDNA and C3/C4 levels, it did not improve clinical outcomes after 1 year of treatment. The combination of rituximab with MMF and corticosteroids did not result in any new or unexpected safety signals.

Averting biodiversity collapse in tropical forest protected areas

Abstract: The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon(1-3). With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses(4-9). As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world's major tropical regions. Our analysis reveals great variation in reserve 'health': about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.

Uses and misuses of bioclimatic envelope modeling

Abstract: Bioclimatic envelope models use associations between aspects of climate and species' occurrences to estimate the conditions that are suitable to maintain viable populations. Once bioclimatic envelopes are characterized, they can be applied to a variety of questions in ecology, evolution, and conservation. However, some have questioned the usefulness of these models, because they may be based on implausible assumptions or may be contradicted by empirical evidence. We review these areas of contention, and suggest that criticism has often been misplaced, resulting from confusion between what the models actually deliver and what users wish that they would express. Although improvements in data and methods will have some effect, the usefulness of these models is contingent on their appropriate use, and they will improve mainly via better awareness of their conceptual basis, strengths, and limitations.

Early versus delayed decompression for traumatic cervical spinal cord injury: results of the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS).

Abstract: Background There is convincing preclinical evidence that early decompression in the setting of spinal cord injury (SCI) improves neurologic outcomes. However, the effect of early surgical decompression in patients with acute SCI remains uncertain. Our objective was to evaluate the relative effectiveness of early (<24 hours after injury) versus late (≥24 hours after injury) decompressive surgery after traumatic cervical SCI.

Combined results of searches for the standard model Higgs boson in pp collisions at √s = 7 TeV

Abstract: Combined results are reported from searches for the standard model Higgs boson in proton-proton collisions at sqrt(s)=7 TeV in five Higgs boson decay modes: gamma pair, b-quark pair, tau lepton pair, W pair, and Z pair. The explored Higgs boson mass range is 110-600 GeV. The analysed data correspond to an integrated luminosity of 4.6-4.8 inverse femtobarns. The expected excluded mass range in the absence of the standard model Higgs boson is 118-543 GeV at 95% CL. The observed results exclude the standard model Higgs boson in the mass range 127-600 GeV at 95% CL, and in the mass range 129-525 GeV at 99% CL. An excess of events above the expected standard model background is observed at the low end of the explored mass range making the observed limits weaker than expected in the absence of a signal. The largest excess, with a local significance of 3.1 sigma, is observed for a Higgs boson mass hypothesis of 124 GeV. The global significance of observing an excess with a local significance greater than 3.1 sigma anywhere in the search range 110-600 (110-145) GeV is estimated to be 1.5 sigma (2.1 sigma). More data are required to ascertain the origin of this excess.

Mitophagy: mechanisms, pathophysiological roles, and analysis

Abstract: 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.

Darwin Core: an evolving community-developed biodiversity data standard.

Abstract: Biodiversity data derive from myriad sources stored in various formats on many distinct hardware and software platforms. An essential step towards understanding global patterns of biodiversity is to provide a standardized view of these heterogeneous data sources to improve interoperability. Fundamental to this advance are definitions of common terms. This paper describes the evolution and development of Darwin Core, a data standard for publishing and integrating biodiversity information. We focus on the categories of terms that define the standard, differences between simple and relational Darwin Core, how the standard has been implemented, and the community processes that are essential for maintenance and growth of the standard. We present case-study extensions of the Darwin Core into new research communities, including metagenomics and genetic resources. We close by showing how Darwin Core records are integrated to create new knowledge products documenting species distributions and changes due to environmental perturbations.

Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: Lessons learned from acetaminophen hepatotoxicity

Abstract: Hepatotoxicity is a serious problem during drug development and for the use of many established drugs. For example, acetaminophen overdose is currently the most frequent cause of acute liver failure in the United States and Great Britain. Evaluation of the mechanisms of drug-induced liver injury indicates that mitochondria are critical targets for drug toxicity, either directly or indirectly through the formation of reactive metabolites. The consequence of these modifications is generally a mitochondrial oxidant stress and peroxynitrite formation, which leads to structural alterations of proteins and mitochondrial DNA and, eventually, to the opening of mitochondrial membrane permeability transition (MPT) pores. MPT pore formation results in a collapse of mitochondrial membrane potential and cessation of adenosine triphosphate synthesis. In addition, the release of intermembrane proteins, such as apoptosis-inducing factor and endonuclease G, and their translocation to the nucleus, leads to nuclear DNA frag...

OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies

Abstract: The human organic anion and cation transporters are classified within two SLC superfamilies. Superfamily SLCO (formerly SLC21A) consists of organic anion transporting polypeptides (OATPs), while the organic anion transporters (OATs) and the organic cation transporters (OCTs) are classified in the SLC22A superfamily. Individual members of each superfamily are expressed in essentially every epithelium throughout the body, where they play a significant role in drug absorption, distribution and elimination. Substrates of OATPs are mainly large hydrophobic organic anions, while OATs transport smaller and more hydrophilic organic anions and OCTs transport organic cations. In addition to endogenous substrates, such as steroids, hormones and neurotransmitters, numerous drugs and other xenobiotics are transported by these proteins, including statins, antivirals, antibiotics and anticancer drugs. Expression of OATPs, OATs and OCTs can be regulated at the protein or transcriptional level and appears to vary within each family by both protein and tissue type. All three superfamilies consist of 12 transmembrane domain proteins that have intracellular termini. Although no crystal structures have yet been determined, combinations of homology modelling and mutation experiments have been used to explore the mechanism of substrate recognition and transport. Several polymorphisms identified in members of these superfamilies have been shown to affect pharmacokinetics of their drug substrates, confirming the importance of these drug transporters for efficient pharmacological therapy. This review, unlike other reviews that focus on a single transporter family, briefly summarizes the current knowledge of all the functionally characterized human organic anion and cation drug uptake transporters of the SLCO and the SLC22A superfamilies. LINKED ARTICLES BJP recently published a themed section on Transporters. To view the papers in this section visit http://dx.doi.org/10.1111/bph.2011.164.issue-7

The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation.

Abstract: Acetaminophen (APAP) overdose is the predominant cause of acute liver failure in the United States. Toxicity begins with a reactive metabolite that binds to proteins. In rodents, this leads to mitochondrial dysfunction and nuclear DNA fragmentation, resulting in necrotic cell death. While APAP metabolism is similar in humans, the later events resulting in toxicity have not been investigated in patients. In this study, levels of biomarkers of mitochondrial damage (glutamate dehydrogenase [GDH] and mitochondrial DNA [mtDNA]) and nuclear DNA fragments were measured in plasma from APAP-overdose patients. Overdose patients with no or minimal hepatic injury who had normal liver function tests (LTs) (referred to herein as the normal LT group) and healthy volunteers served as controls. Peak GDH activity and mtDNA concentration were increased in plasma from patients with abnormal LT. Peak nuclear DNA fragmentation in the abnormal LT cohort was also increased over that of controls. Parallel studies in mice revealed that these plasma biomarkers correlated well with tissue injury. Caspase-3 activity and cleaved caspase-3 were not detectable in plasma from overdose patients or mice, but were elevated after TNF-induced apoptosis, indicating that APAP overdose does not cause apoptosis. Thus, our results suggest that mitochondrial damage and nuclear DNA fragmentation are likely to be critical events in APAP hepatotoxicity in humans, resulting in necrotic cell death.

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

Abstract: The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta)<2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.

BEAGLE: An Application Programming Interface and High-Performance Computing Library for Statistical Phylogenetics

Abstract: Phylogenetic inference is fundamental to our understanding of most aspects of the origin and evolution of life, and in recent years, there has been a concentration of interest in statistical approaches such as Bayesian inference and maximum likelihood estimation. Yet, for large data sets and realistic or interesting models of evolution, these approaches remain computationally demanding. High-throughput sequencing can yield data for thousands of taxa, but scaling to such problems using serial computing often necessitates the use of nonstatistical or approximate approaches. The recent emergence of graphics processing units (GPUs) provides an opportunity to leverage their excellent floating-point computational performance to accelerate statistical phylogenetic inference. A specialized library for phylogenetic calculation would allow existing software packages to make more effective use of available computer hardware, including GPUs. Adoption of a common library would also make it easier for other emerging computing architectures, such as field programmable gate arrays, to be used in the future. We present BEAGLE, an application programming interface (API) and library for high-performance statistical phylogenetic inference. The API provides a uniform interface for performing phylogenetic likelihood calculations on a variety of compute hardware platforms. The library includes a set of efficient implementations and can currently exploit hardware including GPUs using NVIDIA CUDA, central processing units (CPUs) with Streaming SIMD Extensions and related processor supplementary instruction sets, and multicore CPUs via OpenMP. To demonstrate the advantages of a common API, we have incorporated the library into several popular phylogenetic software packages. The BEAGLE library is free open source software licensed under the Lesser GPL and available from http://beagle-lib.googlecode.com. An example client program is available as public domain software.

The evolutionary basis of risky adolescent behavior: Implications for science, policy, and practice

Abstract: This article proposes an evolutionary model of risky behavior in adolescence and contrasts it with the prevailing developmental psychopathology model. The evolutionary model contends that understanding the evolutionary functions of adolescence is critical to explaining why adolescents engage in risky behavior and that successful intervention depends on working with, instead of against, adolescent goals and motivations. The current article articulates 5 key evolutionary insights into risky adolescent behavior: (a) The adolescent transition is an inflection point in development of social status and reproductive trajectories; (b) interventions need to address the adaptive functions of risky and aggressive behaviors like bullying; (c) risky adolescent behavior adaptively calibrates over development to match both harsh and unpredictable environmental conditions; (d) understanding evolved sex differences is critical for understanding the psychology of risky behavior; and (e) mismatches between current and past environments can dysregulate adolescent behavior, as demonstrated by age-segregated social groupings. The evolutionary model has broad implications for designing interventions for high-risk youth and suggests new directions for research that have not been forthcoming from other perspectives.

Association Between BRCA1 and BRCA2 Mutations and Survival in Women with Invasive Epithelial Ovarian Cancer

Abstract: Results The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P.001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P.001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.640.84; P.001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P.001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity=.003). Conclusion Among patients with invasive EOC, having a germline mutation inBRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.

Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

Abstract: BACKGROUND: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.METHODS: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers.RESULTS: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10(-13) for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 × 10(-14)), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 × 10(-15)). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%).Conclusions/Impact: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis. Cancer Epidemiol Biomarkers Prev; 1-14. ©2011 AACR.

Prevalence of Obesity among Adults from Rural and Urban Areas of the United States: Findings from NHANES (2005-2008).

Abstract: Purpose: Rural residents have higher rates of chronic diseases compared to their urban counterparts, and obesity may be a major contributor to this disparity. This study is the first analysis of obesity prevalence in rural and urban adults using body mass index classification with measured height and weight. In addition, demographic, diet, and physical activity correlates of obesity across rural and urban residence are examined. Methods: Analysis of body mass index (BMI), diet, and physical activity from 7,325 urban and 1,490 rural adults in the 2005-2008 National Health and Nutrition Examination Survey (NHANES). Findings: The obesity prevalence was 39.6% (SE = 1.5) among rural adults compared to 33.4% (SE = 1.1) among urban adults (P= .006). Prevalence of obesity remained significantly higher among rural compared to urban adults controlling for demographic, diet, and physical activity variables (odds ratio = 1.18, P= .03). Race/ethnicity and percent kcal from fat were significant correlates of obesity among both rural and urban adults. Being married was associated with obesity only among rural residents, whereas older age, less education, and being inactive was associated with obesity only among urban residents. Conclusions: Obesity is markedly higher among adults from rural versus urban areas of the United States, with estimates that are much higher than the rates suggested by studies with self-reported data. Obesity deserves greater attention in rural America.

Cognitive Team Diversity and Individual Team Member Creativity: A Cross-Level Interaction

Abstract: We theorized and tested the conditions under which cognitive team diversity is positively related to individual team member creativity. Hierarchical linear modeling results using 316 employees on 6...

Study of high-p(T) charged particle suppression in PbPb compared to pp collisions at root s(NN)=2.76 TeV

Abstract: The transverse momentum spectra of charged particles have been measured in pp and PbPb collisions at sqrt(sNN) = 2.76 TeV by the CMS experiment at the LHC. In the transverse momentum range pt = 5-10 GeV/c, the charged particle yield in the most central PbPb collisions is suppressed by up to a factor of 5 compared to the pp yield scaled by the number of incoherent nucleon-nucleon collisions. At higher pt, this suppression is significantly reduced, approaching roughly a factor of 2 for particles with pt in the range pt=40-100 GeV/c.

Adult Bone Marrow Cell Therapy Improves Survival and Induces Long-Term Improvement in Cardiac Parameters A Systematic Review and Meta-Analysis

Abstract: Background—Despite rapid clinical translation and widespread enthusiasm, the therapeutic benefits of adult bone marrow cell (BMC) transplantation in patients with ischemic heart disease continue to remain controversial. A synthesis of the available data is critical to appreciate and underscore the true impact of this promising approach. Methods and Results—A total of 50 studies (enrolling 2625 patients) identified by database searches through January 2012 were included. Weighted mean differences for changes in left ventricular (LV) ejection fraction, infarct size, LV end-systolic volume, and LV end-diastolic volume were estimated with random-effects meta-analysis. Compared with control subjects, BMC-treated patients exhibited greater LV ejection fraction (3.96%; 95% confidence interval, 2.90–5.02; P<0.00001) and smaller infarct size (−4.03%, 95% confidence interval, −5.47 to −2.59; P<0.00001), LV end-systolic volume (−8.91 mL; 95% confidence interval, −11.57 to −6.25; P<0.00001), and LV end-diastolic volu...

Mutations in the colony stimulating factor 1 receptor ( CSF1R ) gene cause hereditary diffuse leukoencephalopathy with spheroids

Abstract: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS In one kindred, we confirmed the de novo occurrence of the mutation Follow-up sequencing identified an additional CSF1R mutation in an individual diagnosed with corticobasal syndrome In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis