Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain.

© 2015 The Authors.Objective: Although Glucagon-like peptide 1 is a key regulator of energy metabolism and food intake, the precise location of GLP-1 receptors and the physiological relevance of certain populations is debatable. This study investigated the novel GLP-1R-Cre mouse as a functional tool to address this question. Methods: Mice expressing Cre-recombinase under the Glp1r promoter were crossed with either a ROSA26 eYFP or tdRFP reporter strain to identify GLP-1R expressing cells. Patch-clamp recordings were performed on tdRFP-positive neurons in acute coronal brain slices from adult mice and selective targeting of GLP-1R cells in vivo was achieved using viral gene delivery. Results: Large numbers of eYFP or tdRFP immunoreactive cells were found in the circumventricular organs, amygdala, hypothalamic nuclei and the ventrolateral medulla. Smaller numbers were observed in the nucleus of the solitary tract and the thalamic paraventricular nucleus. However, tdRFP positive neurons were also found in areas without preproglucagon-neuronal projections like hippocampus and cortex. GLP-1R cells were not immunoreactive for GFAP or parvalbumin although some were catecholaminergic. GLP-1R expression was confirmed in whole-cell recordings from BNST, hippocampus and PVN, where 100 nM GLP-1 elicited a reversible inward current or depolarisation. Additionally, a unilateral stereotaxic injection of a cre-dependent AAV into the PVN demonstrated that tdRFP-positive cells express cre-recombinase facilitating virally-mediated eYFP expression. Conclusions: This study is a comprehensive description and phenotypic analysis of GLP-1R expression in the mouse CNS. We demonstrate the power of combining the GLP-1R-CRE mouse with a virus to generate a selective molecular handle enabling future in vivo investigation as to their physiological importance

GLP-1 action in the mouse bed nucleus of the stria terminalis

Glucagon-like peptide-1 (GLP-1) injected into the brain reduces food intake. Similarly, activation of preproglucagon (PPG) cells in the hindbrain which synthesize GLP-1, reduces food intake. However, it is far from clear whether this happens because of satiety, nausea, reduced reward, or even stress. Here we explore the role of the bed nucleus of the stria terminalis (BNST), an area involved in feeding control as well as stress responses, in GLP-1 responses. Using cre-expressing mice we visualized projections of NTS PPG neurons and GLP-1R-expressing BNST cells with AAV-driven Channelrhodopsin-YFP expression. The BNST displayed many varicose YFP+ PPG axons in the ventral and less in the dorsal regions. Mice which express RFP in GLP-1R neurons had RFP+ cells throughout the BNST with the highest density in the dorsal part, suggesting that PPG neuron-derived GLP-1 acts in the BNST. Indeed, injection of GLP-1 into the BNST reduced chow intake during the dark phase, whereas injection of the GLP-1 receptor antagonist Ex9 increased feeding. BNST-specific GLP-1-induced food suppression was less effective in mice on high fat (HF, 60%) diet, and Ex9 had no effect. Restraint stress-induced hypophagia was attenuated by BNST Ex9 treatment, further supporting a role for endogenous brain GLP-1. Finally, whole-cell patch clamp recordings of RFP+ BNST neurons demonstrated that GLP-1 elicited either a depolarizing or hyperpolarizing reversible response that was of opposite polarity to that under dopamine. Our data support a physiological role for BNST GLP-1R in feeding, and suggest complex cellular responses to GLP-1 in this nucleus

Brain activation during face perception: evidence of a developmental change.

Behavioral studies suggest that children under age 10 process faces using a piecemeal strategy based on individual distinctive facial features, whereas older children use a configural strategy based on the spatial relations among the face's features. The purpose of this study was to determine whether activation of the fusiform gyrus, which is involved in face processing in adults, is greater during face processing in older children (12-14 years) than in younger children (8-10 years). Functional MRI scans were obtained while children viewed faces and houses. A developmental change was observed: Older children, but not younger children, showed significantly more activation in bilateral fusiform gyri for faces than for houses. Activation in the fusiform gyrus correlated significantly with age and with a behavioral measure of configural face processing. Regions believed to be involved in processing basic facial features were activated in both younger and older children. Some evidence was also observed for greater activation for houses versus faces for the older children than for the younger children, suggesting that processing of these two stimulus types becomes more differentiated as children age. The current results provide biological insight into changes in visual processing of faces that occur with normal development

Risk of infections in renal cell carcinoma (RCC) and non-RCC patients treated with mammalian target of rapamycin inhibitors

Background: Mammalian target of rapamycin (mTOR) inhibitors are used in a variety of malignancies. Infections have been reported with these drugs. We performed an up-to-date meta-analysis to further characterise the risk of infections in cancer patients treated with these agents. Methods: Pubmed and oncology conferences' proceedings were searched for studies from January 1966 to June 2012. Studies were limited to phase II and III randomised controlled trials (RCTs) of everolimus or temsirolimus reporting on cancer patients with adequate safety profiles. Summary incidences, relative risks (RRs), and 95% confidence intervals (CIs) were calculated. Results: A total of 3180 patients were included. The incidence of all-grade and high-grade infections due to mTOR inhibitors was 33.1% (95% CI, 24.5–43.0%) and 5.6% (95% CI, 3.8–8.3%), respectively. Compared with controls, the RR of all-grade and high-grade infections due to mTOR inhibitors was 2.00 (95% CI, 1.76–2.28, P<0.001) and 2.60 (95% CI, 1.54–4.41, P<0.001), respectively. Subgroup analysis found no difference in incidences or risks between everolimus and temsirolimus or between different tumour types (renal cell carcinoma (RCC) vs non-RCC). Infections included respiratory tract (61.7%), genitourinary (29.4%), skin/soft tissue (4.2%), and others (4.9%). Conclusion: Treatment with mTOR inhibitors is associated with a significant increase in risk of infections. Close monitoring for any signs of infections is warranted

Trends and socioeconomic inequalities in cancer survival in England and Wales up to 2001.

We examined national trends and socioeconomic inequalities in cancer survival in England and Wales during the 1990s, using population-based data on 2.2 million patients who were diagnosed with one of the 20 most common cancers between 1986 and 1999 and followed up to 2001. Patients were assigned to one of five deprivation categories (from 'affluent' to 'deprived') using characteristics of their electoral ward of residence at diagnosis. We estimated relative survival up to 5 years after diagnosis, adjusting separately in each deprivation category for background mortality by age, sex and calendar period. We estimated trends in survival and in the difference in survival between deprivation categories ('deprivation gap') over the periods 1986-90, 1991-95 and 1996-99. We used period analysis to examine likely survival rates in the near future. Survival improved for most cancers in both sexes during the 1990s, and appears likely to continue improving for most cancers in the near future. The deprivation gap in survival between rich and poor was wider for patients diagnosed in the late 1990s than in the late 1980s. Increases in cancer survival in England and Wales during the 1990s are shown to be significantly associated with a widening deprivation gap in survival

Who Meets Whom: Access and Lobbying During the Coalition Years

In 2010, the incoming Coalition government announced that it would publish details of meetings between ministers and outside interests. We have collated and coded these data and, in this article, describe patterns of access between 2010 and 2015. In some respects, access is notably fragmented. No single organisation attends more than 2.5% of the 6292 meetings held by ministers. On the contrary, business, collectively, attends fully 45% of all meetings: more than twice the share of any other category of organisation. We also find evidence of distinctive policy communities characterised by high levels of access between particular interests and ministers within specific departments

Lymphatic Filariasis Control in Tanzania: Effect of Six Rounds of Mass Drug Administration with Ivermectin and Albendazole on Infection and Transmission.

Control of lymphatic filariasis (LF) in most countries of sub-Saharan Africa is based on annual mass drug administration (MDA) with a combination of ivermectin and albendazole, in order to interrupt transmission. We present findings from a detailed study on the effect of six rounds of MDA with this drug combination as implemented by the National Lymphatic Filariasis Elimination Programme (NLFEP) in a highly endemic rural area of north-eastern Tanzania.\ud The effect of treatment on transmission and human infection was monitored in a community- and a school-based study during an 8-year period (one pre-intervention and 7 post-intervention years) from 2003 to 2011. Before intervention, 24.5% of the community population had microfilariae (mf) in the blood, 53.3% had circulating filarial antigens (CFA) and 78.9% had specific antibodies to the recombinant filarial antigen Bm14. One year after the sixth MDA, these values had decreased considerably to 2.7%, 19.6% and 27.5%, respectively. During the same period, the CFA prevalence among new intakes of Standard 1 pupils in 10 primary schools decreased from 25.2% to 5.6%. In line with this, transmission by the three vectors (Anopheles gambiae, An. funestus and Culex quinquefasciatus) as determined by dissection declined sharply (overall vector infectivity rate by 99.3% and mean monthly transmission potential by 99.2% between pre-intervention and fifth post-intervention period). A major shift in vector species composition, from predominantly anopheline to almost exclusively culicine was observed over the years. This may be largely unrelated to the MDAs but may have important implications for the epidemiology of LF in the area. Six MDAs caused considerable decrease in all the measured indices for transmission and human infection. In spite of this, indices were still relatively high in the late period of the study, and it may take a long time to reach the recommended cut-off levels for interruption of transmission unless extra efforts are made. These should include increased engagement of the target population in the control activities, to ensure higher treatment coverage. It is expected that the recent initiative to distribute insecticide impregnated bed nets to every household in the area will also contribute towards reaching the goal of successful LF elimination

Field evidence for the upwind velocity shift at the crest of low dunes

Wind topographically forced by hills and sand dunes accelerates on the upwind (stoss) slopes and reduces on the downwind (lee) slopes. This secondary wind regime, however, possesses a subtle effect, reported here for the first time from field measurements of near-surface wind velocity over a low dune: the wind velocity close to the surface reaches its maximum upwind of the crest. Our field-measured data show that this upwind phase shift of velocity with respect to topography is found to be in quantitative agreement with the prediction of hydrodynamical linear analysis for turbulent flows with first order closures. This effect, together with sand transport spatial relaxation, is at the origin of the mechanisms of dune initiation, instability and growth.Comment: 13 pages, 6 figures. Version accepted for publication in Boundary-Layer Meteorolog

Appetite, gut hormone and energy intake responses to low volume sprint interval and traditional endurance exercise.

Sprint interval exercise improves several health markers but the appetite and energy balance response is unknown. This study compared the effects of sprint interval and endurance exercise on appetite, energy intake and gut hormone responses. Twelve healthy males [mean (SD): age 23 (3) years, body mass index 24.2 (2.9) kg m(-2), maximum oxygen uptake 46.3 (10.2) mL kg(-1) min(-1)] completed three 8 h trials [control (CON), endurance exercise (END), sprint interval exercise (SIE)] separated by 1 week. Trials commenced upon completion of a standardised breakfast. Sixty minutes of cycling at 68.1 (4.3) % of maximum oxygen uptake was performed from 1.75-2.75 h in END. Six 30-s Wingate tests were performed from 2.25-2.75 h in SIE. Appetite ratings, acylated ghrelin and peptide YY (PYY) concentrations were measured throughout each trial. Food intake was monitored from buffet meals at 3.5 and 7 h and an overnight food bag. Appetite (P 0.05). Therefore, relative energy intake (energy intake minus the net energy expenditure of exercise) was lower in END than that in CON (15.7 %; P = 0.006) and SIE (11.5 %; P = 0.082). An acute bout of endurance exercise resulted in lower appetite perceptions in the hours after exercise than sprint interval exercise and induced a greater 24 h energy deficit due to higher energy expenditure during exercise

Cosmic Hydrogen Was Significantly Neutral a Billion Years After the Big Bang

The ionization fraction of cosmic hydrogen, left over from the big bang, provides crucial fossil evidence for when the first stars and quasar black holes formed in the infant universe. Spectra of the two most distant quasars known show nearly complete absorption of photons with wavelengths shorter than the Ly-alpha transition of neutral hydrogen, indicating that hydrogen in the intergalactic medium (IGM) had not been completely ionized at a redshift z~6.3, about a billion years after the big bang. Here we show that the radii of influence of ionizing radiation from these quasars imply that the surrounding IGM had a neutral hydrogen fraction of tens of percent prior to the quasar activity, much higher than previous lower limits of ~0.1%. When combined with the recent inference of a large cumulative optical depth to electron scattering after cosmological recombination from the WMAP data, our result suggests the existence of a second peak in the mean ionization history, potentially due to an early formation episode of the first stars.Comment: 14 Pages, 2 Figures. Accepted for publication in Nature. Press embargo until publishe