Evidence of a metabolic memory to early-life dietary restriction in male C57BL/6 mice

<p>Background: Dietary restriction (DR) extends lifespan and induces beneficial metabolic effects in many animals. What is far less clear is whether animals retain a metabolic memory to previous DR exposure, that is, can early-life DR preserve beneficial metabolic effects later in life even after the resumption of ad libitum (AL) feeding. We examined a range of metabolic parameters (body mass, body composition (lean and fat mass), glucose tolerance, fed blood glucose, fasting plasma insulin and insulin-like growth factor 1 (IGF-1), insulin sensitivity) in male C57BL/6 mice dietary switched from DR to AL (DR-AL) at 11 months of age (mid life). The converse switch (AL-DR) was also undertaken at this time. We then compared metabolic parameters of the switched mice to one another and to age-matched mice maintained exclusively on an AL or DR diet from early life (3 months of age) at 1 month, 6 months or 10 months post switch.</p> <p>Results: Male mice dietary switched from AL-DR in mid life adopted the metabolic phenotype of mice exposed to DR from early life, so by the 10-month timepoint the AL-DR mice overlapped significantly with the DR mice in terms of their metabolic phenotype. Those animals switched from DR-AL in mid life showed clear evidence of a glycemic memory, with significantly improved glucose tolerance relative to mice maintained exclusively on AL feeding from early life. This difference in glucose tolerance was still apparent 10 months after the dietary switch, despite body mass, fasting insulin levels and insulin sensitivity all being similar to AL mice at this time.</p> <p>Conclusions: Male C57BL/6 mice retain a long-term glycemic memory of early-life DR, in that glucose tolerance is enhanced in mice switched from DR-AL in mid life, relative to AL mice, even 10 months following the dietary switch. These data therefore indicate that the phenotypic benefits of DR are not completely dissipated following a return to AL feeding. The challenge now is to understand the molecular mechanisms underlying these effects, the time course of these effects and whether similar interventions can confer comparable benefits in humans.</p&gt

Cumulate causes for the low contents of sulfide-loving elements in the continental crust

Despite the economic importance of chalcophile (sulfide-loving) and siderophile (metal-loving) elements (CSEs), it is unclear how they become enriched or depleted in the continental crust, compared with the oceanic crust. This is due in part to our limited understanding of the partitioning behaviour of the CSEs. Here I compile compositional data for mid-ocean ridge basalts and subduction-related volcanic rocks. I show that the mantle-derived melts that contribute to oceanic and continental crust formation rarely avoid sulfide saturation during cooling in the crust and, on average, subduction-zone magmas fractionate sulfide at the base of the continental crust prior to ascent. Differentiation of mantle-derived melts enriches lower crustal sulfide- and silicate-bearing cumulates in some CSEs compared with the upper crust. This storage predisposes the cumulate-hosted compatible CSEs (such as Cu and Au) to be recycled back into the mantle during subduction and delamination, resulting in their low contents in the bulk continental crust and potentially contributing to the scarcity of ore deposits in the upper continental crust. By contrast, differentiation causes the upper oceanic and continental crust to become enriched in incompatible CSEs (such as W) compared with the lower oceanic and continental crust. Consequently, incompatible CSEs are predisposed to become enriched in subduction-zone magmas that contribute to continental crust formation and are less susceptible to removal from the continental crust via delamination compared with the compatible CSEs

Stromal Cell-Derived Factor 1 Polymorphism in Retinal Vein Occlusion

BACKGROUND: Stromal cell-derived factor 1 (SDF1) has crucial role in the regulation of angiogenesis and ocular neovascularisation (NV). The purpose of this study was to evaluate the association between SDF1-3'G(801)A polymorphism and NV complications of retinal vein occlusion (RVO). METHODS: 130 patients with RVO (median age: 69.0, range 35-93 years; male/female- 58/72; 55 patients had central RVO, 75 patients had branch RVO) were enrolled in this study. In the RVO group, 40 (30.8%) patients were diagnosed with NV complications of RVO and 90 (69.2%) patients without NVs. The median follow up period was 40.3 months (range: 18-57 months). The SDF1-3'G(801)A polymorphism was detected by PCR-RFLP. Allelic prevalence was related to reference values obtained in the control group consisted of 125 randomly selected, age and gender matched, unrelated volunteers (median age: 68.0, range 36-95 years; male/female- 53/72). Statistical analysis of the allele and genotype differences between groups (RVO patients vs controls; RVO patients with NV vs RVO patients without NV) was determined by chi-squared test. P value of <0.05 was considered statistically significant. RESULTS: Hardy-Weinberg criteria was fulfilled in all groups. The SDF1-3'G(801)A allele and genotype frequencies of RVO patients were similar to controls (SDF1-3'A allele: 22.3% vs 20.8%; SDF1-3'(801)AA: 5.4% vs 4.8%, SDF1-3'(801)GG: 60.8% vs 63.2%). The frequency of SDF1-3'(801)AA and SDF1-3'(801)GA genotypes, as well as the SDF1-3'(801)A allele frequency were higher in RVO patients with NV versus in patients without NV complication (SDF1-3'(801)AA+AG genotypes: 57.5% vs 31.1%, p = 0.008; SDF1-3'(801)A allele: 35.0% vs 16.7%, p = 0.002) or versus controls (SDF1-3'(801)AA+AG genotypes 57.5% vs 36.8%, p = 0.021; SDF1-3'(801)A allele: 35.0% vs 20.8% p = 0.01). Carrying of SDF1-3'(801)A allele increased the risk of neovascularisation complications of RVO by 2.69 (OR, 95% CI = 1.47-4.93). CONCLUSION: These findings suggest that carrying SDF1-3'(801)A allele plays a role in the development of neovascular complications in retinal vein occlusion

One million dog vaccinations recorded on mHealth innovation used to direct teams in numerous rabies control campaigns

<div><p>Background</p><p>Canine transmitted rabies kills an estimated 59,000 people annually, despite proven methods for elimination through mass dog vaccination. Challenges in directing and monitoring numerous remote vaccination teams across large geographic areas remain a significant barrier to the up-scaling of focal vaccination programmes to sub-national and national level. Smartphone technology (mHealth) is increasingly being used to enhance the coordination and efficiency of public health initiatives in developing countries, however examples of successful scaling beyond pilot implementation are rare. This study describes a smartphone app and website platform, “Mission Rabies App”, used to co-ordinate rabies control activities at project sites in four continents to vaccinate over one million dogs.</p><p>Methods</p><p>Mission Rabies App made it possible to not only gather relevant campaign data from the field, but also to direct vaccination teams systematically in near real-time. The display of user-allocated boundaries on Google maps within data collection forms enabled a project manager to define each team’s region of work, assess their output and assign subsequent areas to progressively vaccinate across a geographic area. This ability to monitor work and react to a rapidly changing situation has the potential to improve efficiency and coverage achieved, compared to regular project management structures, as well as enhancing capacity for data review and analysis from remote areas. The ability to plot the location of every vaccine administered facilitated engagement with stakeholders through transparent reporting, and has the potential to motivate politicians to support such activities.</p><p>Results</p><p>Since the system launched in September 2014, over 1.5 million data entries have been made to record dog vaccinations, rabies education classes and field surveys in 16 countries. Use of the system has increased year-on-year with adoption for mass dog vaccination campaigns at the India state level in Goa and national level in Haiti.</p><p>Conclusions</p><p>Innovative approaches to rapidly scale mass dog vaccination programmes in a sustained and systematic fashion are urgently needed to achieve the WHO, OIE and FAO goal to eliminate canine-transmitted human deaths by 2030. The Mission Rabies App is an mHealth innovation which greatly reduces the logistical and managerial barriers to implementing large scale rabies control activities. Free access to the platform aims to support pilot campaigns to better structure and report on proof-of-concept initiatives, clearly presenting outcomes and opportunities for expansion. The functionalities of the Mission Rabies App may also be beneficial to other infectious disease interventions.</p></div

Altered multisensory temporal integration in obesity

Eating is a multisensory behavior. The act of placing food in the mouth provides us with a variety of sensory information, including gustatory, olfactory, somatosensory, visual, and auditory. Evidence suggests altered eating behavior in obesity. Nonetheless, multisensory integration in obesity has been scantily investigated so far. Starting from this gap in the literature, we seek to provide the first comprehensive investigation of multisensory integration in obesity. Twenty male obese participants and twenty male healthy-weight participants took part in the study aimed at describing the multisensory temporal binding window (TBW). The TBW is defined as the range of stimulus onset asynchrony in which multiple sensory inputs have a high probability of being integrated. To investigate possible multisensory temporal processing deficits in obesity, we investigated performance in two multisensory audiovisual temporal tasks, namely simultaneity judgment and temporal order judgment. Results showed a wider TBW in obese participants as compared to healthy-weight controls. This holds true for both the simultaneity judgment and the temporal order judgment tasks. An explanatory hypothesis would regard the effect of metabolic alterations and low-grade inflammatory state, clinically observed in obesity, on the temporal organization of brain ongoing activity, which one of the neural mechanisms enabling multisensory integration

Diagnostic delay for giant cell arteritis – a systematic review and meta-analysis

Background Giant cell arteritis (GCA), if untreated, can lead to blindness and stroke. The study’s objectives were to (1) determine a new evidence-based benchmark of the extent of diagnostic delay for GCA and (2) examine the role of GCA-specific characteristics on diagnostic delay. Methods Medical literature databases were searched from inception to November 2015. Articles were included if reporting a time-period of diagnostic delay between onset of GCA symptoms and diagnosis. Two reviewers assessed the quality of the final articles and extracted data from these. Random-effects meta-analysis was used to pool the mean time-period (95% confidence interval (CI)) between GCA symptom onset and diagnosis, and the delay observed for GCA-specific characteristics. Heterogeneity was assessed by I 2 and by 95% prediction interval (PI). Results Of 4128 articles initially identified, 16 provided data for meta-analysis. Mean diagnostic delay was 9.0 weeks (95% CI, 6.5 to 11.4) between symptom onset and GCA diagnosis (I 2 = 96.0%; P < 0.001; 95% PI, 0 to 19.2 weeks). Patients with a cranial presentation of GCA received a diagnosis after 7.7 (95% CI, 2.7 to 12.8) weeks (I 2 = 98.4%; P < 0.001; 95% PI, 0 to 27.6 weeks) and those with non-cranial GCA after 17.6 (95% CI, 9.7 to 25.5) weeks (I 2 = 96.6%; P < 0.001; 95% PI, 0 to 46.1 weeks). Conclusions The mean delay from symptom onset to GCA diagnosis was 9 weeks, or longer when cranial symptoms were absent. Our research provides an evidence-based benchmark for diagnostic delay of GCA and supports the need for improved public awareness and fast-track diagnostic pathways

Agenesia e lipoma de corpo caloso: relato de caso

The agenesis and lipoma of the corpus callosum is a very rare association. We report the case of a 18-years old woman with rare epileptic seizures since the age of 6 years, normal neurological examination, as well as normal electroencephalogram. The brain computed tomography scanning and the magnetic resonance showed the lipoma and the agenesis of the corpus callosum.A agenesia e lipoma do corpo caloso é uma associação muito rara. Relatamos o caso de uma paciente de 18 anos com raras crises epilépticas desde os 6 anos de idade, exame neurológico normal, assim como eletrencefalograma normal. A tomografia computadorizada de crânio e a ressonância magnética mostraram o lipoma e a agenesia de corpo caloso.Escola Paulista de MedicinaUNIFESP, EPMSciEL

Feature engineering and a proposed decision-support system for systematic reviewers of medical evidence

Objectives: Evidence-based medicine depends on the timely synthesis of research findings. An important source of synthesized evidence resides in systematic reviews. However, a bottleneck in review production involves dual screening of citations with titles and abstracts to find eligible studies. For this research, we tested the effect of various kinds of textual information (features) on performance of a machine learning classifier. Based on our findings, we propose an automated system to reduce screeing burden, as well as offer quality assurance. Methods: We built a database of citations from 5 systematic reviews that varied with respect to domain, topic, and sponsor. Consensus judgments regarding eligibility were inferred from published reports. We extracted 5 feature sets from citations: alphabetic, alphanumeric +, indexing, features mapped to concepts in systematic reviews, and topic models. To simulate a two-person team, we divided the data into random halves. We optimized the parameters of a Bayesian classifier, then trained and tested models on alternate data halves. Overall, we conducted 50 independent tests. Results: All tests of summary performance (mean F3) surpassed the corresponding baseline, P<0.0001. The ranks for mean F3, precision, and classification error were statistically different across feature sets averaged over reviews; P-values for Friedman's test were .045, .002, and .002, respectively. Differences in ranks for mean recall were not statistically significant. Alphanumeric+ features were associated with best performance; mean reduction in screening burden for this feature type ranged from 88% to 98% for the second pass through citations and from 38% to 48% overall. Conclusions: A computer-assisted, decision support system based on our methods could substantially reduce the burden of screening citations for systematic review teams and solo reviewers. Additionally, such a system could deliver quality assurance both by confirming concordant decisions and by naming studies associated with discordant decisions for further consideration. © 2014 Bekhuis et al

TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.

DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions.This work was supported by funding from the Medical Research Council and the European Research Council (ERC, 281847) (A.P.J.), the Lister Institute for Preventative Medicine (A.P.J. and G.S.S.), Medical Research Scotland (L.S.B.), German Federal Ministry of Education and Research (BMBF, 01GM1404) and E-RARE network EuroMicro (B.W), Wellcome Trust (M. Hurles), CMMC (P.N.), Cancer Research UK (C17183/A13030) (G.S.S. and M.R.H), Swiss National Science Foundation (P2ZHP3_158709) (O.M.), AIRC (12710) and ERC/EU FP7 (CIG_303806) (S.S.), Cancer Research UK (C6/A11224) and ERC/EU FP7 (HEALTH-F2- 2010-259893) (A.N.B. and S.P.J.).This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.345