Is insulin a satiety signal? Insulin treatment antagonises starvation-induced increases in neuropeptide Y concentrations in the arcuate nucleus of the rat

Neuropeptide Y (NPY), the most powerful appetite stimulant known, is synthesised in hypothalamic arcuate nucleus (ARC). NPY levels rise in the ARC and in appetite-regulating hypothalamic nuclei in food-deprived rats, and may drive compensatory hyperphagia in starvation. Circulating insulin levels fall in starvation and insulin deficiency has been postulated to stimulate hypothalamic NPY; this supports the suggestion that insulin acts on the brain to inhibit feeding. We tested this hypothesis by determining whether the increase in NPY in the ARC of starved rats was suppressed by insulin treatment. Adult male Wistar rats were studied. Controls (n=8) were freely-fed and two other groups were food-deprived for 72 hours, both losing 20% of initial weight (p<O.OOI vs controls). One food·deprived group n=10) received insulin (5 U/kg/day) injected subcutaneously twice daily and both other groups recieved saline. Mean blood glucose values (measured in tail-prick samples) were 5.9± 0.1 mmoVI in controls, 4.6± 0.3 mmol/l in food-deprived (p<O.OOI. vs controls) and in insulin·treated 4.4± 0.3 mmol/I (p<O.OOI vs controls; NS vs food-deprived group). Final plasma insulin levels in insulin·treated rats were higher than in saline-treated food-deprived rats (46.6± 8.9 vs 28.9± 4.5 pmol/l; p<O.OOI) and comparable with controls (52.6± 16.2 pmol/l; p=NS). ARC NPY concentrations rose significantly above controls in food·deprived rats (14.18± 1.79 vs 8.4± 2.16 fmol/ug protein; p<O.OOI) and were intermediate in the insulin-treated food-deprived group (11.19± 1.36 fmol/ug protein: p<O.OI vs controls and p<O.OOI vs saline-treated, food deprived). Other hypothalamic regions showed no differences between groups. Insulin therefore antagonises fasting·induced increases in NPY concentrations in the ARC. This is consistent with the hypotheses that insulin deficiency stimulates hypothalamic NPY synthesis, and that peripheral insulin acts as a satiety factor by inhibiting hypothalamic NPY

A Nonparametric Method for the Derivation of α/β Ratios from the Effect of Fractionated Irradiations

Multifractionation isoeffect data are commonly analysed under the assumption that cell survival determines the observed tissue or tumour response, and that it follows a linear-quadratic dose dependence. The analysis is employed to derive the α/β ratios of the linear-quadratic dose dependence, and different methods have been developed for this purpose. A common method uses the so-called Fe plot. A more complex but also more rigorous method has been introduced by Lam et al. (1979). Their method, which is based on numerical optimization procedures, is generalized and somewhat simplified in the present study. Tumour-regrowth data are used to explain the nonparametric procedure which provides α/β ratios without the need to postulate analytical expressions for the relationship between cell survival and regrowth delay

Potential loss of nutrients from different rearing strategies for fattening pigs on pasture

Nutrient load and distribution on pasture were investigated with fattening pigs that: 1) spend a proportion of or their entire life on pasture, 2) were fed either restrictively or ad libitum, and 3) were weaned at different times of the year. The N and P retention in pigs decreased the longer they were kept on pasture. The contents of soil inorganic N and exchangeable K were significantly raised compared to the soil outside the enclosures but with no differences between treatments. Pig grazing did not affect extractable soil P. Regular moving of huts, feeding and water troughs was effective in ensuring that nutrients were more evenly distributed on the paddocks. Grass cover, as determined by spectral reflectance, was not related to the experimental treatments but only to time of year. During spring and summer, grass was present in parts of the paddocks, whereas during autumn and winter the pigs kept grass cover below 10%. Fattening pigs on pasture carries a high risk of nutrient loss and it is concluded that the most environmentally acceptable way of keeping fattening pigs on pasture involves a combination of reduced dietary N intake, reduced stocking rate and seasonal rather than all year production

Forgotten fatalities: British military, mining, and maritime accidents since 1900.

Background Comparative long-term trends in fatal accident rates in the UK’s most hazardous occupations have not been reported. Aims To compare trends in fatal accident rates in six of the most hazardous occupations (the three armed forces, merchant shipping, sea fishing and coal mining) and the general British workforce during peacetime years since 1900. Methods Examinations of annual mortality reports, returns, inquiry files and statistics. The main outcome measure was the fatal accident rate per 100 000 population employed. Results These six occupations accounted for ~40% of all fatal accidents in the British workforce. Fatal accident rates were highest in merchant shipping to 1914 (400–600 per 100 000) and in the Royal Air Force and sea fishing by the early 1920s (around 300 per 100 000). Since the 1950s sea fishing has remained the most hazardous occupation (50–200). Widespread reductions in fatal accident rates for each occupation have been greatest in recent years in the three armed forces and merchant shipping. Compared with the general workforce, relative risks of fatalities have increased in recent decades in all these occupations except shipping. Conclusions All six occupations still have high fatal accident rates. The greatly increased fatalities in sea fishing generally and in the Royal Air Force during its early years reflect, for different reasons, cultures of extreme risk-taking in these two sectors. Reductions in fatality rates in the armed forces over the last 20 years are due largely to decreases in land transport accidents

Expression of AT1R, AT2R and AT4R and their roles in extravillous trophoblast invasion in the human

The placental renin-angiotensin system (RAS) is active from early pregnancy and may have a role in placentation. Angiotensin II (AngII) acts via binding to receptor types AT1R and AT2R. Recently smaller peptide members of the angiotensin family have been recognised as having biological relevance. Angiotensin (3-8) (AngIV) has a specific receptor (AT4R) and evokes hypertrophy, vasodilatation and vascular inflammatory response. The aim of this study was to characterise placental expression of AT1R, AT2R and AT4R, and to determine whether AngII and AngIV regulate extravillous trophoblast (EVT) invasion, apoptosis and proliferation. Placental samples were obtained from women undergoing elective surgical termination of pregnancy (TOP) at 8-10 weeks gestation (early TOP), 12-14 weeks gestation (mid TOP) or at delivery following normal pregnancy or with pre-eclampsia (PE). Immunohistochemistry and qRT-PCR were performed to determine placental mRNA and protein expression of AT1R, AT2R and AT4R was done at all gestational ages. EVT invasion following culture with AngII or AngIV was assessed in early placental tissue using Matrigel invasion assays. Invasion was assessed on day 6 of culture and placental explants were harvested for immunohistochemical analysis of apoptosis and proliferation. The results from qRT-PCR and immunohistochemistry showed placental AT1R expression which did not vary with gestation. The highest levels of expression of AT2R were found in early and mid TOP placentae compared to term pregnancy. Expression of AT4R was increased in term placentae, with a significant reduction in PE placentae. Moreover, culture with AngIV or AngII increased EVT invasion from placental explants, which showed increased trophoblast proliferation and reduced apoptosis. This study has characterised expression of AT4R and AT1R and AT2R in human placenta throughout normal pregnancy and in PE. Both AngIV and AngII may play an important role in normal pregnancy

Stroke recovery in rats after 24h-delayed intramuscular neurotrophin-3 infusion

Objective Neurotrophin‐3 (NT3) plays a key role in the development and function of locomotor circuits including descending serotonergic and corticospinal tract axons and afferents from muscle and skin. We have previously shown that gene therapy delivery of human NT3 into affected forelimb muscles improves sensorimotor recovery after stroke in adult and elderly rats. Here, to move toward the clinic, we tested the hypothesis that intramuscular infusion of NT3 protein could improve sensorimotor recovery after stroke. Methods Rats received unilateral ischemic stroke in sensorimotor cortex. To simulate a clinically feasible time to treatment, 24 hours later rats were randomized to receive NT3 or vehicle by infusion into affected triceps brachii for 4 weeks using implanted catheters and minipumps. Results Radiolabeled NT3 crossed from the bloodstream into the brain and spinal cord in rodents with or without strokes. NT3 increased the accuracy of forelimb placement during walking on a horizontal ladder and increased use of the affected arm for lateral support during rearing. NT3 also reversed sensory impairment of the affected wrist. Functional magnetic resonance imaging during stimulation of the affected wrist showed spontaneous recovery of peri‐infarct blood oxygenation level–dependent signal that NT3 did not further enhance. Rather, NT3 induced neuroplasticity of the spared corticospinal and serotonergic pathways. Interpretation Our results show that delayed, peripheral infusion of NT3 can improve sensorimotor function after ischemic stroke. Phase I and II clinical trials of NT3 (for constipation and neuropathy) have shown that peripheral high doses are safe and well tolerated, which paves the way for NT3 as a therapy for stroke

Placental expression of adenosine A2A receptor and hypoxia inducible factor-1 alpha in early pregnancy, term and pre-eclamptic pregnancies: interactions with placental renin-angiotensin system

Normal placentation occurs under low oxygen tensions yet hypoxia is also implicated in placental pathologies such as pre-eclampsia (PE). Hypoxia-inducible factors (HIFs), adenosine and tissue renin-angiotensin-system (RAS) are known to promote angiogenesis and vascularisation. We hypothesised that placental adenosine A2AR receptor and HIF-1α would change through pregnancy in association with the RAS. Placentae were obtained from women undergoing elective surgical termination of pregnancy (TOP) at ≤10 weeks’ (early TOP) and >10 weeks’ (mid TOP) gestations; at delivery from normotensive (NT) and PE pregnancy. Results were compared to our previously reported data on the angiotensin receptors: AT1R, AT2R and AT4R. Protein expression of both A2AR and HIF-1α was highest in early TOP and positively correlated through pregnancy (P<0.0001): expression was higher in PE than NT at delivery (P<0.0001 for both). The A2AR positively correlated with the AT4R in placentae in early pregnancy (r=0.53; P=0.035), but not in 3rd trimester samples. Our findings suggest a role for adenosine and RAS in promoting placentation and as a potential adaptation to poor placental perfusion in pre-eclampsia

Image analysis with deep learning to predict breast cancer grade, ER status, histologic subtype, and intrinsic subtype

RNA-based, multi-gene molecular assays are available and widely used for patients with ER-positive/HER2-negative breast cancers. However, RNA-based genomic tests can be costly and are not available in many countries. Methods for inferring molecular subtype from histologic images may identify patients most likely to benefit from further genomic testing. To identify patients who could benefit from molecular testing based on H&E stained histologic images, we developed an image analysis approach using deep learning. A training set of 571 breast tumors was used to create image-based classifiers for tumor grade, ER status, PAM50 intrinsic subtype, histologic subtype, and risk of recurrence score (ROR-PT). The resulting classifiers were applied to an independent test set (n = 288), and accuracy, sensitivity, and specificity of each was assessed on the test set. Histologic image analysis with deep learning distinguished low-intermediate vs. high tumor grade (82% accuracy), ER status (84% accuracy), Basal-like vs. non-Basal-like (77% accuracy), Ductal vs. Lobular (94% accuracy), and high vs. low-medium ROR-PT score (75% accuracy). Sampling considerations in the training set minimized bias in the test set. Incorrect classification of ER status was significantly more common for Luminal B tumors. These data provide proof of principle that molecular marker status, including a critical clinical biomarker (i.e., ER status), can be predicted with accuracy >75% based on H&E features. Image-based methods could be promising for identifying patients with a greater need for further genomic testing, or in place of classically scored variables typically accomplished using human-based scoring