Variation in mouse pelvic morphology maps to locations enriched in Sox9 Class II and Pitx1 regulatory features

Variation in pelvic morphology has a complex genetic basis and its patterning and specification is governed by conserved developmental pathways. Whether the mechanisms underlying the differentiation and specification of the pelvis also produce the morphological covariation on which natural selection may act, is still an open question in evolutionary developmental biology. We use high‐resolution quantitative trait locus (QTL) mapping in the F34 generation of an advanced intercross experiment (LG,SM‐G34) to characterize the genetic architecture of the mouse pelvis. We test the prediction that genomic features linked to developmental patterning and differentiation of the hind limb and pelvis and the regulation of chondrogenesis are overrepresented in QTL. We find 31 single QTL trait associations at the genome‐ or chromosome‐wise significance level coalescing to 27 pleiotropic loci. We recover further QTL at a more relaxed significance threshold replicating locations found in a previous experiment in an earlier generation of the same population. QTL were more likely than chance to harbor Pitx1 and Sox9 Class II chromatin immunoprecipitation‐seq features active during development of skeletal features. There was weak or no support for the enrichment of seven more categories of developmental features drawn from the literature. Our results suggest that genotypic variation is channeled through a subset of developmental processes involved in the generation of phenotypic variation in the pelvis. This finding indicates that the evolvability of complex traits may be subject to biases not evident from patterns of covariance among morphological features or developmental patterning when either is considered in isolation

The use of etoricoxib to treat an idiopathic stabbing headache: a case report

According to the International Headache Society, idiopathic stabbing headache (ISH), an indomethacin-responsive headache syndrome, is a paroxysmal disorder of short duration manifested as head pain occurring as a single stab or a series of stabs involving the area supplied in the distribution of the first division of the trigeminal nerve. Stabs last for approximately a few seconds, occurring and recurring from once to multiple times per day in an irregular frequency, with no underlying attributable disorder

A longitudinal examination of plasma neurofilament light and total tau for the clinical detection and monitoring of Alzheimer's disease

We examined baseline and longitudinal associations between plasma neurofilament light (NfL) and total tau (t-tau), and the clinical presentation of Alzheimer's disease (AD). A total of 579 participants (238, normal cognition [NC]; 185, mild cognitive impairment [MCI]; 156, AD dementia) had baseline blood draws; 82% had follow-up evaluations. Plasma samples were analyzed for NfL and t-tau using Simoa technology. Baseline plasma NfL was higher in AD dementia than MCI (standardized mean difference = 0.55, 95% CI: 0.37–0.73) and NC (standardized mean difference = 0.68, 95% CI: 0.49–0.88), corresponded to Clinical Dementia Rating scores (OR = 1.94, 95% CI: 1.35–2.79]), and correlated with all neuropsychological tests (r's = 0.13–0.42). Longitudinally, NfL did not predict diagnostic conversion but predicted decline on 3/10 neuropsychological tests. Baseline plasma t-tau was higher in AD dementia than NC with a small effect (standardized mean difference = 0.33, 95% CI: 0.10–0.57) but not MCI. t-tau did not statistically significant predict any longitudinal outcomes. Plasma NfL may be useful for the detection of AD dementia and monitoring of disease progression. In contrast, there was minimal evidence in support of plasma t-tau

Respiratory Evolution Facilitated the Origin of Pterosaur Flight and Aerial Gigantism

Pterosaurs, enigmatic extinct Mesozoic reptiles, were the first vertebrates to achieve true flapping flight. Various lines of evidence provide strong support for highly efficient wing design, control, and flight capabilities. However, little is known of the pulmonary system that powered flight in pterosaurs. We investigated the structure and function of the pterosaurian breathing apparatus through a broad scale comparative study of respiratory structure and function in living and extinct archosaurs, using computer-assisted tomographic (CT) scanning of pterosaur and bird skeletal remains, cineradiographic (X-ray film) studies of the skeletal breathing pump in extant birds and alligators, and study of skeletal structure in historic fossil specimens. In this report we present various lines of skeletal evidence that indicate that pterosaurs had a highly effective flow-through respiratory system, capable of sustaining powered flight, predating the appearance of an analogous breathing system in birds by approximately seventy million years. Convergent evolution of gigantism in several Cretaceous pterosaur lineages was made possible through body density reduction by expansion of the pulmonary air sac system throughout the trunk and the distal limb girdle skeleton, highlighting the importance of respiratory adaptations in pterosaur evolution, and the dramatic effect of the release of physical constraints on morphological diversification and evolutionary radiation

Reproductive responses to varying food supply in a population of Darwin's finches: Clutch size, growth rates and hatching synchrony

I show how food shortage affects reproduction in a population of Darwin's Medium Ground Finches, Geospiza fortis . Despite the common occurrence of starvation and absence of nest predation, hatching is typically nighly synchronous and adaptive brood reductionappears to be absent. Variation in both growth rates and clutch size in association with the varying conditions is documented. This variation is interpreted as being a direct response to environmental conditions rather than adaptive phenotypic plasticity. I conclude that selection pressures to raise one or two chicks during times of food shortage, or to delay growth rates, are weak or absent.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47759/1/442_2004_Article_BF00378307.pd

Care management for Type 2 diabetes in the United States: a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>This systematic review and meta-analysis aims at assessing the composition and performance of care management models evaluated in the last decade and their impact on patient important outcomes.</p> <p>Methods</p> <p>A comprehensive literature search of electronic bibliographic databases was performed to identify care management trials in type 2 diabetes. Random effects meta-analysis was used when feasible to pool outcome measures.</p> <p>Results</p> <p>Fifty-two studies were eligible. Most commonly reported were surrogate outcomes (such as HbA1c and LDL), followed by process measures (clinic visit or testing frequency). Less frequently reported were quality of life, patient satisfaction, self-care, and healthcare utilization. Most care management modalities were carved out from primary care. Meta-analysis demonstrated a statistically significant but trivial reduction of HbA1c (weighted difference in means -0.21%, 95% confidence interval -0.40 to -0.03, p < .03) and LDL-cholesterol (weighted difference in means -3.38 mg/dL, 95% confidence interval -6.27 to -0.49, p < .02).</p> <p>Conclusions</p> <p>Most care management programs for patients with type 2 diabetes are 'carved-out', accomplish limited effects on metabolic outcomes, and have unknown effects on patient important outcomes. Comparative effectiveness research of different models of care management is needed to inform the design of medical homes for patients with chronic conditions.</p

Effects of Anti-VEGF on Predicted Antibody Biodistribution: Roles of Vascular Volume, Interstitial Volume, and Blood Flow

BACKGROUND: The identification of clinically meaningful and predictive models of disposition kinetics for cancer therapeutics is an ongoing pursuit in drug development. In particular, the growing interest in preclinical evaluation of anti-angiogenic agents alone or in combination with other drugs requires a complete understanding of the associated physiological consequences. METHODOLOGY/PRINCIPAL FINDINGS: Technescan™ PYP™, a clinically utilized radiopharmaceutical, was used to measure tissue vascular volumes in beige nude mice that were naïve or administered a single intravenous bolus dose of a murine anti-vascular endothelial growth factor (anti-VEGF) antibody (10 mg/kg) 24 h prior to assay. Anti-VEGF had no significant effect (p>0.05) on the fractional vascular volumes of any tissues studied; these findings were further supported by single photon emission computed tomographic imaging. In addition, apart from a borderline significant increase (p = 0.048) in mean hepatic blood flow, no significant anti-VEGF-induced differences were observed (p>0.05) in two additional physiological parameters, interstitial fluid volume and the organ blood flow rate, measured using indium-111-pentetate and rubidium-86 chloride, respectively. Areas under the concentration-time curves generated by a physiologically-based pharmacokinetic model changed substantially (>25%) in several tissues when model parameters describing compartmental volumes and blood flow rates were switched from literature to our experimentally derived values. However, negligible changes in predicted tissue exposure were observed when comparing simulations based on parameters measured in naïve versus anti-VEGF-administered mice. CONCLUSIONS/SIGNIFICANCE: These observations may foster an enhanced understanding of anti-VEGF effects in murine tissues and, in particular, may be useful in modeling antibody uptake alone or in combination with anti-VEGF

RNAi-Mediated c-Rel Silencing Leads to Apoptosis of B Cell Tumor Cells and Suppresses Antigenic Immune Response In Vivo

c-Rel is a member of the Rel/NF-κB transcription factor family and is predominantly expressed in lymphoid and myeloid cells, playing a critical role in lymphocyte proliferation and survival. Persistent activation of the c-Rel signal transduction pathway is associated with allergies, inflammation, autoimmune diseases, and a variety of human malignancies. To explore the potential of targeting c-Rel as a therapeutic agent for these disorders, we designed a small interfering RNA (siRNA) to silence c-Rel expression in vitro and in vivo. C-Rel-siRNA expression via a retroviral vector in a B cell tumor cell line leads to growth arrest and apoptosis of the tumor cells. Silencing c-Rel in primary B cells in vitro compromises their proliferative and survival response to CD40 activation signals, similar to the impaired response of c-Rel knockout B cells. Most important, in vivo silencing of c-Rel results in significant impairment in T cell-mediated immune responses to antigenic stimulation. Our study thus validates the efficacy of c-Rel-siRNA, and suggests the development of siRNA-based therapy, as well as small molecular inhibitors for the treatment of B cell tumors as well as autoimmune diseases

Statistical Multiplicity in Systematic Reviews of Anaesthesia Interventions: A Quantification and Comparison between Cochrane and Non-Cochrane Reviews

BACKGROUND: Systematic reviews with meta-analyses often contain many statistical tests. This multiplicity may increase the risk of type I error. Few attempts have been made to address the problem of statistical multiplicity in systematic reviews. Before the implications are properly considered, the size of the issue deserves clarification. Because of the emphasis on bias evaluation and because of the editorial processes involved, Cochrane reviews may contain more multiplicity than their non-Cochrane counterparts. This study measured the quantity of statistical multiplicity present in a population of systematic reviews and aimed to assess whether this quantity is different in Cochrane and non-Cochrane reviews. METHODS/PRINCIPAL FINDINGS: We selected all the systematic reviews published by the Cochrane Anaesthesia Review Group containing a meta-analysis and matched them with comparable non-Cochrane reviews. We counted the number of statistical tests done in each systematic review. The median number of tests overall was 10 (interquartile range (IQR) 6 to 18). The median was 12 in Cochrane and 8 in non-Cochrane reviews (difference in medians 4 (95% confidence interval (CI) 2.0-19.0). The proportion that used an assessment of risk of bias as a reason for doing extra analyses was 42% in Cochrane and 28% in non-Cochrane reviews (difference in proportions 14% (95% CI -8 to 36). The issue of multiplicity was addressed in 6% of all the reviews. CONCLUSION/SIGNIFICANCE: Statistical multiplicity in systematic reviews requires attention. We found more multiplicity in Cochrane reviews than in non-Cochrane reviews. Many of the reasons for the increase in multiplicity may well represent improved methodological approaches and greater transparency, but multiplicity may also cause an increased risk of spurious conclusions. Few systematic reviews, whether Cochrane or non-Cochrane, address the issue of multiplicity