Showing papers by "University of Arkansas for Medical Sciences published in 2013"
Brown University1, National Institutes of Health2, Johns Hopkins University3, Pennington Biomedical Research Center4, University of Tennessee Health Science Center5, University of Minnesota6, Wake Forest University7, Baylor College of Medicine8, Centers for Disease Control and Prevention9, University of Texas Health Science Center at San Antonio10, University of Colorado Denver11, Harvard University12, University of Pittsburgh13, University of Washington14, University of Alabama at Birmingham15, University of Pennsylvania16, Mount Sinai St. Luke's and Mount Sinai Roosevelt17, University of Arkansas for Medical Sciences18
TL;DR: An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes.
Abstract: In 16 study centers in the United States, we randomly assigned 5145 overweight or obese patients with type 2 diabetes to participate in an intensive lifestyle interven tion that promoted weight loss through decreased caloric intake and increased physical activity (intervention group) or to receive diabetes support and education (control group). The primary outcome was a composite of death from cardiovascu lar causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina during a maximum follow-up of 13.5 years. Results The trial was stopped early on the basis of a futility analysis when the median fol low-up was 9.6 years. Weight loss was greater in the intervention group than in the control group throughout the study (8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end). The intensive lifestyle intervention also produced greater reductions in gly cated hemoglobin and greater initial improvements in fitness and all cardiovascular risk factors, except for low-density-lipoprotein cholesterol levels. The primary outcome occurred in 403 patients in the intervention group and in 418 in the control group (1.83 and 1.92 events per 100 person-years, respectively; hazard ratio in the intervention group, 0.95; 95% confidence interval, 0.83 to 1.09; P = 0.51). Conclusions An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes. (Funded by the National Institutes of Health and others; Look AHEAD ClinicalTrials.gov number, NCT00017953.)
2,048 citations
Columbia University1, Cambridge University Hospitals NHS Foundation Trust2, University of Wisconsin-Madison3, McGill University4, University of Sheffield5, University of Kentucky6, French Institute of Health and Medical Research7, University of Washington8, Creighton University9, University of Arkansas for Medical Sciences10
TL;DR: The key revisions include omission of terminology used before 1987, recommendations regarding the parameters and technical information that should be included in all histomorphometry articles, recommendations on how to handle dynamic parameters of bone formation in settings of low bone turnover, and updating of references.
Abstract: Before publication of the original version of this report in 1987, practitioners of bone histomorphometry communicated with each other in a variety of arcane languages, which in general were unintelligible to those outside the field. The need for standardization of nomenclature had been recognized for many years,(1) during which there had been much talk but no action. To satisfy this need, B Lawrence Riggs (ASBMR President, 1985 to 1986) asked A Michael Parfitt to convene an ASBMR committee to develop a new and unified system of terminology, suitable for adoption by the Journal of Bone and Mineral Research (JBMR) as part of its Instructions to Authors. The resulting recommendations were published in 1987(2) and were quickly adopted not only by JBMR but also by all respected journals in the bone field. The recommendations improved markedly the ability of histomorphometrists to communicate with each other and with nonhistomorphometrists, leading to a broader understanding and appreciation of histomorphometric data.
In 2012, 25 years after the development of the standardized nomenclature system, Thomas L Clemens (Editor in Chief of JBMR) felt that it was time to revise and update the recommendations. The original committee was reconvened by David W Dempster, who appointed one new member, Juliet E Compston. The original document was circulated to the committee members and was extensively revised according to their current recommendations. The key revisions include omission of terminology used before 1987, recommendations regarding the parameters and technical information that should be included in all histomorphometry articles, recommendations on how to handle dynamic parameters of bone formation in settings of low bone turnover, and updating of references.
2,035 citations
TL;DR: Recent advances in understanding how glucose metabolism sustains basic brain physiology are reviewed to form a comprehensive picture of the cooperation required between different systems and cell types, and the specific breakdowns in this cooperation that lead to disease.
1,021 citations
University of Oklahoma1, American Association of Colleges of Pharmacy2, University of Arkansas for Medical Sciences3, Western New England University4, Oregon State University5, University of Florida6, University of Missouri–Kansas City7, Wingate University8, Creighton University9, St. Louis College of Pharmacy10, Indian Health Service11, Ohio State University12, Thomas Jefferson University13, University of California, San Francisco14, West Virginia University15
TL;DR: The CAPE 2013 Educational Outcomes were released at the AACP July 2013 Annual meeting and have been revised to include 4 broad domains, 15 subdomains, and example learning objectives.
Abstract: An initiative of the Center for the Advancement of Pharmacy Education (formerly the Center for the Advancement of Pharmaceutical Education) (CAPE), the CAPE Educational Outcomes are intended to be the target toward which the evolving pharmacy curriculum should be aimed. Their development was guided by an advisory panel composed of educators and practitioners nominated for participation by practitioner organizations. CAPE 2013 represents the fourth iteration of the Educational Outcomes, preceded by CAPE 1992, CAPE 1998 and CAPE 2004 respectively. The CAPE 2013 Educational Outcomes were released at the AACP July 2013 Annual meeting and have been revised to include 4 broad domains, 15 subdomains, and example learning objectives.
783 citations
TL;DR: Mental health problems were significantly associated with sex, race/ethnicity, religiosity, relationship status, living on campus, and financial situation, and the prevalence of conditions varied substantially across the campuses.
Abstract: We estimated the prevalence and correlates of mental health problems among college students in the United States. In 2007 and 2009, we administered online surveys with brief mental health screens to random samples of students at 26 campuses nationwide. We used sample probability weights to adjust for survey nonresponse. A total of 14,175 students completed the survey, corresponding to a 44% participation rate. The prevalence of positive screens was 17.3% for depression, 4.1% for panic disorder, 7.0% for generalized anxiety, 6.3% for suicidal ideation, and 15.3% for nonsuicidal self-injury. Mental health problems were significantly associated with sex, race/ethnicity, religiosity, relationship status, living on campus, and financial situation. The prevalence of conditions varied substantially across the campuses, although campus-level variation was still a small proportion of overall variation in student mental health. The findings offer a starting point for identifying individual and contextual factors that may be useful to target in intervention strategies.
506 citations
TL;DR: There was a significant association between operator and hospital volume and adverse outcomes and a need for future research into identifying the safety measures in AF ablations and instituting appropriate interventions to improve overall AF ablation outcomes.
Abstract: Background—Atrial fibrillation ablation has made tremendous progress with respect to innovation, efficacy, and safety. However, limited data exist regarding the burden and trends in adverse outcomes arising from this procedure. The aim of our study was to examine the frequency of adverse events attributable to atrial fibrillation (AF) ablation and the influence of operator and hospital volume on outcomes. Methods and Results—With the use of the Nationwide Inpatient Sample, we identified AF patients treated with catheter ablation. We investigated common complications including cardiac perforation and tamponade, pneumothorax, stroke, transient ischemic attack, vascular access complications (hemorrhage/hematoma, vascular complications requiring surgical repair, and accidental arterial puncture), and in-hospital death described with AF ablation, and we defined these complications by using validated International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. An estimated 93...
448 citations
TL;DR: Mouse models with cell-specific deletion of the estrogen receptor (ER) α, the androgen receptor (AR) or the receptor activator of nuclear factor κB ligand (RANKL), as well as cascade-selective estrogenic compounds have provided novel insights into the function and signalling of ERα and AR.
Abstract: Mouse models with cell-specific deletion of the estrogen receptor (ER) α, the androgen receptor (AR) or the receptor activator of nuclear factor κB ligand (RANKL), as well as cascade-selective estrogenic compounds have provided novel insights into the function and signalling of ERα and AR. The studies reveal that the effects of estrogens on trabecular versus cortical bone mass are mediated by direct effects on osteoclasts and osteoblasts, respectively. The protection of cortical bone mass by estrogens is mediated via ERα, using a non-nucleus-initiated mechanism. By contrast, the AR of mature osteoblasts is indispensable for the maintenance of trabecular bone mass in male mammals, but not required for the anabolic effects of androgens on cortical bone. Most unexpectedly, and independently of estrogens, ERα in osteoblast progenitors stimulates Wnt signalling and periosteal bone accrual in response to mechanical strain. RANKL expression in B lymphocytes, but not T lymphocytes, contributes to the loss of trabecular bone caused by estrogen deficiency. In this Review, we summarize this evidence and discuss its implications for understanding the regulation of trabecular and cortical bone mass; the integration of hormonal and mechanical signals; the relative importance of estrogens versus androgens in the male skeleton; and, finally, the pathogenesis and treatment of osteoporosis.
430 citations
TL;DR: Despite being untested, medication apps represent a possible strategy that pharmacists can recommend to nonadherent patients and incorporate into their practice.
Abstract: Objectives To provide an overview of medication adherence, discuss the potential for smartphone medication adherence applications (adherence apps) to improve medication nonadherence, evaluate features of adherence apps across operating systems (OSs), and identify future opportunities and barriers facing adherence apps. Practice description Medication nonadherence is a common, complex, and costly problem that contributes to poor treatment outcomes and consumes health care resources. Nonadherence is difficult to measure precisely, and interventions to mitigate it have been largely unsuccessful. Practice innovation Using smartphone adherence apps represents a novel approach to improving adherence. This readily available technology offers many features that can be designed to help patients and health care providers improve medication-taking behavior. Main outcome measures Currently available apps were identified from the three main smartphone OSs (Apple, Android, and Blackberry). In addition, desirable features for adherence apps were identified and ranked by perceived importance to user desirability using a three-point rating system: 1, modest; 2, moderate; or 3, high. The 10 highest-rated apps were installed and subjected to user testing to assess app attributes using a standard medication regimen. RESULTS 160 adherence apps were identified and ranked. These apps were most prevalent for the Android OS. Adherence apps with advanced functionality were more prevalent on the Apple iPhone OS. Among all apps, MyMedSchedule, MyMeds, and RxmindMe rated the highest because of their basic medication reminder features coupled with their enhanced levels of functionality. Conclusion Despite being untested, medication apps represent a possible strategy that pharmacists can recommend to nonadherent patients and incorporate into their practice.
420 citations
TL;DR: Patients with CNCP prescribed opioids had significantly higher rates of OUDs compared with those not prescribed opioids, and duration of opioid therapy was more important than daily dose in determining OUD risk.
Abstract: Objective
Increasing rates of opioid use disorders (abuse and dependence) among patients prescribed opioids are a significant public health concern. We investigated the association between exposure to prescription opioids and incident opioid use disorders (OUDs) among individuals with a new episode of a chronic non-cancer pain (CNCP) condition.
401 citations
TL;DR: The guidelines in this paper have been developed to assist the clinician in the consideration of factors and are updates the original publication from 2008.
399 citations
Harvard University1, Cincinnati Children's Hospital Medical Center2, Cleveland Clinic3, Riley Hospital for Children4, University of Arkansas for Medical Sciences5, Boston Children's Hospital6, Veterans Health Administration7, University of Michigan8, University of Pennsylvania9, University of Alabama at Birmingham10, University of Minnesota11, Mount Sinai Hospital12, Medical College of Wisconsin13, University of Southern California14, University of Pittsburgh15, Stanford University16, Children's Medical Center of Dallas17, University of Florida18, Washington University in St. Louis19, University of Toronto20
TL;DR: Smaller patient size, renal dysfunction, hepatic dysfunction, and biventricular assist device use were associated with mortality, whereas extracorporeal membrane oxygenation before implantation and congenital heart disease were not.
Abstract: Background—Recent data suggest that the Berlin Heart EXCOR Pediatric ventricular assist device is superior to extracorporeal membrane oxygenation for bridge to heart transplantation. Published data...
TL;DR: Baseline egg-specific IgE levels and initial reaction characteristics were important predictors of the likelihood of resolution, and a calculator to estimate resolution probabilities using these variables was established.
Abstract: Background There are few studies on the natural history of egg allergy, and most are single-site and nonlongitudinal and have not identified early predictors of outcomes. Objective We sought to describe the natural course of egg allergy and to identify early prognostic markers. Methods Children age 3 to 15 months were enrolled in a multicenter observational study with either (1) a convincing history of an immediate allergic reaction to egg, milk, or both with a positive skin prick test (SPT) response to the trigger food and/or (2) moderate-to-severe atopic dermatitis and a positive SPT response to egg or milk. Children enrolled with a clinical history of egg allergy were followed longitudinally, and resolution was established based on successful ingestion. Results The cohort with egg allergy consists of 213 children followed to a median age of 74 months. Egg allergy resolved in 105 (49.3%) children at a median age of 72 months. Factors that were most predictive of resolution included the following: initial reaction characteristics (isolated urticaria/angioedema vs other presentations), baseline egg-specific IgE level, egg SPT wheal size, atopic dermatitis severity, IgG 4 level, and IL-4 response (all P Conclusions In this cohort of infants with egg allergy, approximately one half had resolved over 74 months of follow-up. Baseline egg-specific IgE levels and initial reaction characteristics were important predictors of the likelihood of resolution.
TL;DR: New research and novel research methodologies are necessary to establish the protein needs and optimal patterns of protein intake for older persons.
Abstract: Background.
Protein is a macronutrient essential for growth, muscle function, immunity and overall tissue homeostasis. Suboptimal protein intake can significantly impact physical function and overall health in older adults.
University of Barcelona1, Mayo Clinic2, Cedars-Sinai Medical Center3, University of Arkansas for Medical Sciences4, Rutgers University5, University of Ostrava6, University of Hamburg7, Erasmus University Rotterdam8, Harvard University9, Tufts University10, University of Turin11, New York University12, University of Maryland, Baltimore13, University of Liège14, University of Bologna15, Lille University of Science and Technology16, National and Kapodistrian University of Athens17, University of Hong Kong18, Vrije Universiteit Brussel19, Hospital Italiano de Buenos Aires20, University of Gothenburg21, National Institutes of Health22, University of Nantes23, University of Pavia24, Complutense University of Madrid25
TL;DR: It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria.
Abstract: Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥ 20%) and absolute number (≥ 2 × 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL.
Mayo Clinic1, University of Southern California2, Johns Hopkins University3, Pfizer4, National Institutes of Health5, University of Minnesota6, University of Rochester7, University of Toronto8, University of California, Los Angeles9, King's College London10, University of New South Wales11, United States Department of Veterans Affairs12, University of Arkansas for Medical Sciences13, University of California, San Diego14, Emory University15, University of Washington16, University of California, San Francisco17, Northwestern University18, Sunnybrook Research Institute19, University of Pittsburgh20, Veterans Health Administration21, Center for Drug Evaluation and Research22, University of Iowa23
TL;DR: An overview of neuropsychiatric symptoms in Alzheimer's disease is presented, followed by syndrome‐specific synthetic reviews and recommendations prepared by NPS‐PIA workgroups on depression, apathy, sleep, agitation, and psychosis.
Abstract: Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer's first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer's Association convened a research roundtable on the topic of NPS in AD. A major outcome of the roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer's Research and Treatment (ISTAART). The NPS-PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome-specific synthetic reviews and recommendations prepared by NPS-PIA workgroups on depression, apathy, sleep, agitation, and psychosis.
TL;DR: Four molecular classes of HNSCC are confirmed consistent with signatures established for squamous carcinoma of the lung, including deregulation of the KEAP1/NFE2L2 oxidative stress pathway, differential utilization of the lineage markers SOX2 and TP63, and preference for the oncogenes PIK3CA and EGFR.
Abstract: Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal heterogeneous disease. Beyond the role of human papilloma virus (HPV), no validated molecular characterization of the disease has been established. Using an integrated genomic analysis and validation methodology we confirm four molecular classes of HNSCC (basal, mesenchymal, atypical, and classical) consistent with signatures established for squamous carcinoma of the lung, including deregulation of the KEAP1/NFE2L2 oxidative stress pathway, differential utilization of the lineage markers SOX2 and TP63, and preference for the oncogenes PIK3CA and EGFR. For potential clinical use the signatures are complimentary to classification by HPV infection status as well as the putative high risk marker CCND1 copy number gain. A molecular etiology for the subtypes is suggested by statistically significant chromosomal gains and losses and differential cell of origin expression patterns. Model systems representative of each of the four subtypes are also presented.
TL;DR: Since routine PCV13 immunization in 2010, invasive pneumococcal infections decreased 42% overall and 53% for children <24 months of age in 2011 compared with the average number of cases for 2007 to 2009.
Abstract: Background:The 13-valent pneumococcal conjugate vaccine (PCV13) was introduced for routine administration to infants and children in 2010 in the United States. We have monitored clinical and microbiologic features of invasive pneumococcal infections among children before and after PCV13 use.Methods:
TL;DR: Evidence from reviewed research and the new research presented indicates that households with marginal food security should not be classified as food secure, as is the current practice, but should be reported in a separate discrete category.
Mayo Clinic1, University of Udine2, University of Alabama at Birmingham3, Radboud University Nijmegen4, Yeshiva University5, Johns Hopkins University6, University of Pittsburgh7, University of Oviedo8, Peter MacCallum Cancer Centre9, University of Michigan10, University of Arkansas for Medical Sciences11, Institute of Oncology Ljubljana12, Brown University13, Institut Gustave Roussy14
TL;DR: Fundamental issues relating to the basic definition of margin adequacy, uniform reporting standards for margins, optimal method of specimen dissection, and the role of intraoperative frozen section evaluation, require further clarification and standardization.
Abstract: Adequate resection margins are critical to the treatment decisions and prognosis of patients with head and neck squamous cell carcinoma (HNSCC). However, there are numerous controversies regarding reporting and interpretation of the status of resection margins. Fundamental issues relating to the basic definition of margin adequacy, uniform reporting standards for margins, optimal method of specimen dissection, and the role of intraoperative frozen section evaluation, all require further clarification and standardization. Future horizons for margin surveillance offer the possible use of novel methods such as "molecular margins" and contact microscopic endoscopy, However, the limitations of these approaches need to be understood. The goal of this review was to evaluate these issues to define a more rational, standardized approach for achieving resection margin adequacy for patients with HNSCC undergoing curative resection.
TL;DR: A meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals ofAfrican ancestry provides strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.
Abstract: Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations.
TL;DR: Patients with a chronic condition increasingly used more resources in a group of children's hospitals than patients without a chroniccondition, and the greatest growth was observed in hospitalized children with chronic conditions affecting 2 or more body systems.
Abstract: Objective To compare inpatient resource use trends for healthy children and children with chronic health conditions of varying degrees of medical complexity. Design Retrospective cohort analysis. Setting Twenty-eight US children's hospitals. Patients A total of 1 526 051 unique patients hospitalized from January 1, 2004, through December 31, 2009, who were assigned to 1 of 5 chronic condition groups using 3M's Clinical Risk Group software. Intervention None. Main Outcome Measures Trends in the number of patients, hospitalizations, hospital days, and charges analyzed with linear regression. Results Between 2004 and 2009, hospitals experienced a greater increase in the number of children hospitalized with vs without a chronic condition (19.2% vs 13.7% cumulative increase, P Conclusions Patients with a chronic condition increasingly used more resources in a group of children's hospitals than patients without a chronic condition. The greatest growth was observed in hospitalized children with chronic conditions affecting 2 or more body systems. Children's hospitals must ensure that their inpatient care systems and payment structures are equipped to meet the protean needs of this important population of children.
TL;DR: Histologic evidence in mice and humans alike indicates that inadequate osteoblast-mediated refilling of resorption cavities created during bone remodeling is responsible for skeletal fragility in mice.
Abstract: Mice are increasingly used for investigation of the pathophysiology of osteoporosis because their genome is easily manipulated, and their skeleton is similar to that of humans. Unlike the human skeleton, however, the murine skeleton continues to grow slowly after puberty and lacks osteonal remodeling of cortical bone. Yet, like humans, mice exhibit loss of cancellous bone, thinning of cortical bone, and increased cortical porosity with advancing age. Histologic evidence in mice and humans alike indicates that inadequate osteoblast-mediated refilling of resorption cavities created during bone remodeling is responsible. Mouse models of progeria also show bone loss and skeletal defects associated with senescence of early osteoblast progenitors. Additionally, mouse models of atherosclerosis, which often occurs in osteoporotic participants, also suffer bone loss, suggesting that common diseases of aging share pathophysiological pathways. Knowledge of the causes of skeletal fragility in mice should therefore be applicable to humans if inherent limitations are recognized.
TL;DR: Contracting with an off-site telemedicine-based collaborative care team can yield better outcomes than implementing practice- based collaborative care with locally available staff, according to this multisite randomized pragmatic comparative effectiveness trial.
Abstract: Using telemedicine technologies, off-site mental health specialists collaborating with on-site primary care physicians yielded better depression outcomes than practice-based care with staff available on-site. In this study of mostly rural, unemployed, and uninsured patients with treatment-resistant depression and numerous comorbidities, those patients assigned to a telemedicine-based group had significantly and substantially greater treatment response rates, remission rates, reductions in depression severity, and increases in mental health status and quality of life than patients assigned to the practice-based care group.
TL;DR: It is reported that platelet immunoreceptor tyrosine activation motif (ITAM) signaling, but not GPCR signaling, is critical for the prevention of inflammation-induced hemorrhage, highlighting a potential clinical complication of novel antithrombotic agents directed toward the ITAM signaling pathway.
Abstract: Platelets play a critical role in maintaining vascular integrity during inflammation, but little is known about the underlying molecular mechanisms. Here we report that platelet immunoreceptor tyrosine activation motif (ITAM) signaling, but not GPCR signaling, is critical for the prevention of inflammation-induced hemorrhage. To generate mice with partial or complete defects in these signaling pathways, we developed a protocol for adoptive transfer of genetically and/or chemically inhibited platelets into thrombocytopenic (TP) mice. Unexpectedly, platelets with impaired GPCR signaling, a crucial component of platelet plug formation and hemostasis, were indistinguishable from WT platelets in their ability to prevent hemorrhage at sites of inflammation. In contrast, inhibition of GPVI or genetic deletion of Clec2, the only ITAM receptors expressed on mouse platelets, significantly reduced the ability of platelets to prevent inflammation-induced hemorrhage. Moreover, transfusion of platelets without ITAM receptor function or platelets lacking the adapter protein SLP-76 into TP mice had no significant effect on vascular integrity during inflammation. These results indicate that the control of vascular integrity is a major function of immune-type receptors in platelets, highlighting a potential clinical complication of novel antithrombotic agents directed toward the ITAM signaling pathway.
TL;DR: In healthy older adults, HMB supplementation preserves muscle mass during 10 days of bed rest, and differences in function parameters could not be observed due to the sample size of the study.
University of Texas MD Anderson Cancer Center1, University of North Carolina at Chapel Hill2, Fred Hutchinson Cancer Research Center3, NewYork–Presbyterian Hospital4, Emory University5, Fox Chase Cancer Center6, Icahn School of Medicine at Mount Sinai7, University of South Florida8, University of Arkansas for Medical Sciences9, Johnson & Johnson Pharmaceutical Research and Development10, Janssen Pharmaceutica11
TL;DR: No dose-related or cumulative toxicity was apparent across all disease indications and a dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease and the sustained CRP suppression.
Abstract: Purpose: To evaluate the safety and pharmacokinetics of siltuximab, an anti–interleukin-6 chimeric monoclonal antibody (mAb) in patients with B-cell non-Hodgkin lymphoma (NHL), multiple myeloma, or Castleman disease. Experimental Design: In an open-label, dose-finding, 7 cohort, phase I study, patients with NHL, multiple myeloma, or symptomatic Castleman disease received siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks. Response was assessed in all disease types. Clinical benefit response (CBR; composite of hemoglobin, fatigue, anorexia, fever/night sweats, weight, largest lymph node size) was also evaluated in Castleman disease. Results: Sixty-seven patients received a median of 16 siltuximab doses for a median of 8.5 (maximum 60.5) months; 29 were treated 1 year or longer. There was no dose-limiting toxicity, antibodies to siltuximab, or apparent dose–toxicity relationship. The most frequently reported possible drug-related adverse events were thrombocytopenia (25%), hypertriglyceridemia (19%), neutropenia (19%), leukopenia (18%), hypercholesterolemia (15%), and anemia (10%). None of these events led to dose delay/discontinuation except for neutropenia and thrombocytopenia ( n = 1 each). No treatment-related deaths occurred. C-reactive protein (CRP) suppression was most pronounced at 12 mg/kg every 3 weeks. Mean terminal-phase half-life of siltuximab ranged 17.73 to 20.64 days. Thirty-two of 37 (86%) patients with Castleman disease improved in 1 or more CBR component; 12 of 36 evaluable Castleman disease patients had radiologic response [complete response (CR), n = 1; partial response (PR), n = 11], including 8 of 19 treated with 12 mg/kg; 2 of 14 (14%) evaluable NHL patients had PR; 2 of 13 (15%) patients with multiple myeloma had CR. Conclusion: No dose-related or cumulative toxicity was apparent across all disease indications. A dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease and the sustained CRP suppression. Randomized studies are ongoing in Castleman disease and multiple myeloma. Clin Cancer Res; 19(13); 3659–70. ©2013 AACR .
TL;DR: Judicious use of renal biopsy has uncovered NDRD alone or superimposed on DN in the majority of such biopsies, and ATN is emerging as an important category of NDRd, which has not been reported previously.
Abstract: Summary Background and objectives Renal biopsies performed in diabetic patients are increasing in number and complexity. This study sought to determine the usefulness of renal biopsy in patients with diabetes and the predictability of diagnosing diabetic nephropathy (DN) versus nondiabetic renal disease (NDRD) from clinical and laboratory data. Design, setting, participants, & measurements To assess modern trends, a retrospective study was performed of clinical-pathologic findings in all patients with diabetes who had a biopsy in 2011. Among 2642 native kidney biopsies, 620 (23.5%) were from patients with diabetes. Results The cohort included 371 men (60.7%) aged a median (interquartile range) 62 years (52–69) with 10-year (5–15) duration of diabetes mellitus (DM). Median serum creatinine was 2.5 mg/dl (1.6–4.4), and 52% of patients had stage 4–5 CKD. On biopsy, 37% of patients had DN alone, 36% had NDRD alone, and 27% had DN plus NDRD. In NDRD alone, FSGS (22%), hypertensive nephrosclerosis (18%), acute tubular necrosis (ATN) (17%), IgA nephropathy (11%), membranous GN (8%), and pauci-immune GN (7%) comprised 80% of diagnoses, compared with ATN (43%), hypertensive nephrosclerosis (19%), FSGS (13%), and IgA nephropathy (7%) for DN plus NDRD. In multivariate analyses, longer duration of DM was associated with a greater likelihood of DN and a lower likelihood of NDRD: each added year of DM reduced the odds of NDRD by 5% (odds ratio, 0.95; 95% confidence interval, 0.91 to 0.98; P =0.004). DM duration ≥12 years was the best predictor (58% sensitivity, 73% specificity) of DN alone. Conclusions Approximately one-quarter of all renal biopsies are performed in patients with DM. Judicious use of renal biopsy has uncovered NDRD alone or superimposed on DN in the majority of such biopsies. ATN is emerging as an important category of NDRD, which has not been reported previously.
TL;DR: It is suggested that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment, and additional studies of folate receptor autoimmunity and leucovsky calcium treatment in children with ASDs are warranted.
Abstract: Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood–brain barrier Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (753%) of FRAs was found In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case Children with FRAs were treated with oral leucovorin calcium (2 mg kg−1 per day; maximum 50 mg per day) Treatment response was measured and compared with a wait-list control group Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior Approximately one-third of treated children demonstrated moderate to much improvement The incidence of adverse effects was low This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted
TL;DR: It is demonstrated that osteocytes are the major source of the cytokine RANKL involved in osteoclast formation in cancellous bone and thus bone resorption.
TL;DR: Simvastatin attenuates increases in cardiorespiratory fitness and skeletal muscle mitochondrial content when combined with exercise training in overweight or obese patients at risk of the metabolic syndrome.