Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice.

BackgroundSpinal Toll-like receptors (TLRs) and signaling intermediaries have been implicated in persistent pain states. We examined the roles of two major TLR signaling pathways and selected TLRs in a mononeuropathic allodynia.MethodsL5 spinal nerve ligation (SNL) was performed in wild type (WT, C57BL/6) male and female mice and in male Tlr2-/-Tlr3-/-, Tlr4-/-, Tlr5-/-, Myd88-/-, Triflps2, Myd88/Triflps2, Tnf-/-, and Ifnar1-/- mice. We also examined L5 ligation in Tlr4-/- female mice. We examined tactile allodynia using von Frey hairs. Iba-1 (microglia) and GFAP (astrocytes) were assessed in spinal cords by immunostaining. Tactile thresholds were analyzed by 1- and 2-way ANOVA and the Bonferroni post hoc test was used.ResultsIn WT male and female mice, SNL lesions resulted in a persistent and robust ipsilateral, tactile allodynia. In males with TLR2, 3, 4, or 5 deficiencies, tactile allodynia was significantly, but incompletely, reversed (approximately 50%) as compared to WT. This effect was not seen in female Tlr4-/- mice. Increases in ipsilateral lumbar Iba-1 and GFAP were seen in mutant and WT mice. Mice deficient in MyD88, or MyD88 and TRIF, showed an approximately 50% reduction in withdrawal thresholds and reduced ipsilateral Iba-1. In contrast, TRIF and interferon receptor null mice developed a profound ipsilateral and contralateral tactile allodynia. In lumbar sections of the spinal cords, we observed a greater increase in Iba-1 immunoreactivity in the TRIF-signaling deficient mice as compared to WT, but no significant increase in GFAP. Removing MyD88 abrogated the contralateral allodynia in the TRIF signaling-deficient mice. Conversely, IFNβ, released downstream to TRIF signaling, administered intrathecally, temporarily reversed the tactile allodynia.ConclusionsThese observations suggest a critical role for the MyD88 pathway in initiating neuropathic pain, but a distinct role for the TRIF pathway and interferon in regulating neuropathic pain phenotypes in male mice

Insulin resistance in type 1 diabetes: what is ‘double diabetes’ and what are the risks?

In this review, we explore the concept of ‘double diabetes’, a combination of type 1 diabetes with features of insulin resistance and type 2 diabetes. After considering whether double diabetes is a useful concept, we discuss potential mechanisms of increased insulin resistance in type 1 diabetes before examining the extent to which double diabetes might increase the risk of cardiovascular disease (CVD). We then go on to consider the proposal that weight gain from intensive insulin regimens may be associated with increased CV risk factors in some patients with type 1 diabetes, and explore the complex relationships between weight gain, insulin resistance, glycaemic control and CV outcome. Important comparisons and contrasts between type 1 diabetes and type 2 diabetes are highlighted in terms of hepatic fat, fat partitioning and lipid profile, and how these may differ between type 1 diabetic patients with and without double diabetes. In so doing, we hope this work will stimulate much-needed research in this area and an improvement in clinical practice

A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features.

Childhood onset clinical syndromes involving intellectual disability and dysmorphic features, such as polydactyly, suggest common developmental pathways link seemingly unrelated phenotypes. We identified a consanguineous family of Saudi origin with varying complex features including intellectual disability, speech delay, facial dysmorphism and polydactyly. Combining, microarray based comparative genomic hybridisation (CGH) to identify regions of homozygosity, with exome sequencing, led to the identification of homozygous mutations in five candidate genes (RSPH6A, ANKK1, AMOTL1, ALKBH8, TRAPPC6A), all of which appear to be pathogenic as predicted by Proven, SIFT and PolyPhen2 and segregate perfectly with the disease phenotype. We therefore looked for differences in expression levels of each protein in HEK293 cells, expressing either the wild-type or mutant full-length cDNA construct. Unexpectedly, wild-type TRAPPC6A appeared to be unstable, but addition of the proteasome inhibitor MG132 stabilised its expression. Mutations have previously been reported in several members of the TRAPP complex of proteins, including TRAPPC2, TRAPPC9 and TRAPPC11, resulting in disorders involving skeletal abnormalities, intellectual disability, speech impairment and developmental delay. TRAPPC6A joins a growing list of proteins belonging to the TRAPP complex, implicated in clinical syndromes with neurodevelopmental abnormalities

A Metasystem of Framework Model Organisms to Study Emergence of New Host-Microbe Adaptations

An unintended consequence of global industrialization and associated societal rearrangements is new interactions of microbes and potential hosts (especially mammals and plants), providing an opportunity for the rapid emergence of host-microbe adaptation and eventual establishment of new microbe-related diseases. We describe a new model system comprising the model plant Arabidopsis thaliana and several microbes, each representing different modes of interaction, to study such “maladaptations”. The model microbes include human and agricultural pathogens and microbes that are commonly considered innocuous. The system has a large knowledge base corresponding to each component organism and is amenable to high-throughput automation assisted perturbation screens for identifying components that modulate host-pathogen interactions. This would aid in the study of emergence and progression of host-microbe maladaptations in a controlled environment

Bias and heteroscedastic memory error in self-reported health behavior: an investigation using covariance structure analysis

BACKGROUND: Frequent use of self-reports for investigating recent and past behavior in medical research requires statistical techniques capable of analyzing complex sources of bias associated with this methodology. In particular, although decreasing accuracy of recalling more distant past events is commonplace, the bias due to differential in memory errors resulting from it has rarely been modeled statistically. METHODS: Covariance structure analysis was used to estimate the recall error of self-reported number of sexual partners for past periods of varying duration and its implication for the bias. RESULTS: Results indicated increasing levels of inaccuracy for reports about more distant past. Considerable positive bias was found for a small fraction of respondents who reported ten or more partners in the last year, last two years and last five years. This is consistent with the effect of heteroscedastic random error where the majority of partners had been acquired in the more distant past and therefore were recalled less accurately than the partners acquired more recently to the time of interviewing. CONCLUSIONS: Memory errors of this type depend on the salience of the events recalled and are likely to be present in many areas of health research based on self-reported behavior

Precise detection of rearrangement breakpoints in mammalian chromosomes

<p>Abstract</p> <p>Background</p> <p>Genomes undergo large structural changes that alter their organisation. The chromosomal regions affected by these rearrangements are called breakpoints, while those which have not been rearranged are called synteny blocks. We developed a method to precisely delimit rearrangement breakpoints on a genome by comparison with the genome of a related species. Contrary to current methods which search for synteny blocks and simply return what remains in the genome as breakpoints, we propose to go further and to investigate the breakpoints themselves in order to refine them.</p> <p>Results</p> <p>Given some reliable and non overlapping synteny blocks, the core of the method consists in refining the regions that are not contained in them. By aligning each breakpoint sequence against its specific orthologous sequences in the other species, we can look for weak similarities inside the breakpoint, thus extending the synteny blocks and narrowing the breakpoints. The identification of the narrowed breakpoints relies on a segmentation algorithm and is statistically assessed. Since this method requires as input synteny blocks with some properties which, though they appear natural, are not verified by current methods for detecting such blocks, we further give a formal definition and provide an algorithm to compute them.</p> <p>The whole method is applied to delimit breakpoints on the human genome when compared to the mouse and dog genomes. Among the 355 human-mouse and 240 human-dog breakpoints, 168 and 146 respectively span less than 50 Kb. We compared the resulting breakpoints with some publicly available ones and show that we achieve a better resolution. Furthermore, we suggest that breakpoints are rarely reduced to a point, and instead consist in often large regions that can be distinguished from the sequences around in terms of segmental duplications, similarity with related species, and transposable elements.</p> <p>Conclusion</p> <p>Our method leads to smaller breakpoints than already published ones and allows for a better description of their internal structure. In the majority of cases, our refined regions of breakpoint exhibit specific biological properties (no similarity, presence of segmental duplications and of transposable elements). We hope that this new result may provide some insight into the mechanism and evolutionary properties of chromosomal rearrangements.</p

Cardiometabolic risk factors and quality of life in severely obese children and adolescents in the Netherlands

BACKGROUND: The prevalence of severe obesity in children and adolescents is increasing. However, little is known about cardiometabolic risk factors and quality of life of children with severe obesity.Therefore, the aim of this study was to assess the demographic characteristics and the prevalence of cardiometabolic risk factors and quality of life in severely obese children and adolescents undergoing intensive inpatient treatment for obesity. METHODS: Data were collected between August 2009 and April 2011 on 16 children (8-13y) and 64 adolescents (13-19y) with severe obesity (SDS-BMI >= 3.0 or SDS-BMI >= 2.3 and comorbidity) participating in an RCT evaluating two intensive inpatient treatment programs for obesity. Demographic, anthropometric, clinical characteristics and two components of the EuroQol for the assessment of quality of life are described. RESULTS: Eighty percent of participants in this study had at least one cardiometabolic risk factor in addition to severe obesity. Low HDL-cholesterol and hypertension were most prevalent (65.0% respectively 31.2%). The highest significant correlations were found between SDS-BMI and SDS-waist circumference, fasting plasma insulin and HOMA-IR (correlation coefficients respectively 0.80, 0.49, and 0.48). With regard to quality of life, the mean utility score of the participants was 0.79 on a scale of 0.0 to 1.0 on the EuroQol questionnaire and their mean individual valuation was 69.1 on a scale of 0 to100. CONCLUSION: Cardiometabolic risk factors are already highly prevalent in this group of severely obese children and adolescents. The score of 69.1 found for quality of life in this study suggests that participants experience important limitations in their quality of life. However, quality of life is not associated with the prevalence of cardiometabolic risk factors. TRIAL REGISTRATION: Netherlands Trial Register (NTR1678, registered 20-Feb-2009)

Ancient DNA Suggests Dwarf and ‘Giant’ Emu Are Conspecific

) is unclear. King Island Emu were mainly distinguished by their much smaller size and a reported darker colour compared to modern Emu. oxidase subunit I (COI) region (1,544 bp), as well as a region of the melanocortin 1 receptor gene (57 bp) were sequenced using a multiplex PCR approach. The results show that haplotypes for King Island Emu fall within the diversity of modern Emu.These data show the close relationship of these emu when compared to other congeneric bird species and indicate that the King Island and modern Emu share a recent common ancestor. King Island emu possibly underwent insular dwarfism as a result of phenotypic plasticity. The close relationship between the King Island and the modern Emu suggests it is most appropriate that the former should be considered a subspecies of the latter. Although both taxa show a close genetic relationship they differ drastically in size. This study also suggests that rates of morphological and neutral molecular evolution are decoupled