mTORC1-S6K Activation by Endotoxin Contributes to Cytokine Up-Regulation and Early Lethality in Animals

Background: mTORC1 (mammalian target of rapamycin complex 1) activation has been demonstrated in response to endotoxin challenge, but the mechanism and significance are unclear. We investigated the effect of mTORC1 suppression in an animal model of endotoxemia and in a cellular model of endotoxin signaling. Methodology/Principal Findings: Mice were treated with the mTORC1 inhibitor rapamycin or vehicle prior to lethal endotoxin challenge. Mortality and cytokine levels were assessed. Cultured macrophage-like cells were challenged with endotoxin with or without inhibitors of various pathways known to be upstream of mTORC1. Activated pathways, including downstream S6K pathway, were assessed by immunoblots. We found that mTORC1-S6K suppression by rapamycin delayed mortality of mice challenged with lethal endotoxin, and was associated with dampened circulating levels of VEGF, IL-1b, IFN-c and IL-5. Furthermore, in vitro cellular studies demonstrated that LPS (lipopolysaccharide) activation of mTORC1-S6K still occurs in the presence of PI3K-Akt inhibition alone, but can be suppressed by concurrent inhibition of PI3K-Akt and MEK-ERK pathways. Conclusions/Significance: We conclude that cellular activation of mTORC1-S6K contributes to cytokine up-regulation an

Hormonal response to lipid and carbohydrate meals during the acute postprandial period

<p>Abstract</p> <p>Background</p> <p>Optimizing the hormonal environment during the postprandial period in favor of increased anabolism is of interest to many active individuals. Data are conflicting regarding the acute hormonal response to high fat and high carbohydrate feedings. Moreover, to our knowledge, no studies have compared the acute hormonal response to ingestion of lipid and carbohydrate meals of different size.</p> <p>Methods</p> <p>We compared the hormonal response to lipid and carbohydrate meals of different caloric content during the acute postprandial period. Nine healthy men (22 ± 2 years) consumed in a random order, cross-over design one of four meals/beverages during the morning hours in a rested and fasted state: dextrose at 75 g (300 kcals), dextrose at 150 g (600 kcals), lipid at 33 g (300 kcals), lipid at 66 g (600 kcals). Blood samples were collected Pre meal, and at 0.5 hr, 1 hr, 2 hr, and 3 hr post meal. Samples were assayed for testosterone, cortisol, and insulin using ELISA techniques. Area under the curve (AUC) was calculated for each variable, and a 4 × 5 ANOVA was used to further analyze data.</p> <p>Results</p> <p>A meal × time effect (p = 0.0003) was noted for insulin, with values highest for the dextrose meals at the 0.5 hr and 1 hr times, and relatively unaffected by the lipid meals. No interaction (p = 0.98) or meal (p = 0.39) effect was noted for testosterone, nor was an interaction (p = 0.99) or meal (p = 0.65) effect noted for cortisol. However, a time effect was noted for both testosterone (p = 0.04) and cortisol (p < 0.0001), with values decreasing during the postprandial period. An AUC effect was noted for insulin (p = 0.001), with values higher for the dextrose meals compared to the lipid meals (p < 0.05). No AUC effect was noted for testosterone (p = 0.85) or cortisol (p = 0.84).</p> <p>Conclusions</p> <p>These data indicate that 1) little difference is noted in serum testosterone or cortisol during the acute postprandial period when healthy men consume lipid and dextrose meals of different size; 2) Both testosterone and cortisol experience a drop during the acute postprandial period, which is similar to what is expected based on the normal diurnal variation--feeding with lipid or dextrose meals does not appear to alter this pattern; 3) dextrose meals of either 75 g or 150 g result in a significant increase in serum insulin, in particular at 0.5 hr and 1 hr post-ingestion; 4) lipid meals have little impact on serum insulin.</p

Risk adjustment for inter-hospital comparison of primary cesarean section rates: need, validity and parsimony

BACKGROUND: Cesarean section rates is often used as an indicator of quality of care in maternity hospitals. The assumption is that lower rates reflect in developed countries more appropriate clinical practice and general better performances. Hospitals are thus often ranked on the basis of caesarean section rates. The aim of this study is to assess whether the adjustment for clinical and sociodemographic variables of the mother and the fetus is necessary for inter-hospital comparisons of cesarean section (c-section) rates and to assess whether a risk adjustment model based on a limited number of variables could be identified and used. METHODS: Discharge abstracts of labouring women without prior cesarean were linked with abstracts of newborns discharged from 29 hospitals of the Emilia-Romagna Region (Italy) from 2003 to 2004. Adjusted ORs of cesarean by hospital were estimated by using two logistic regression models: 1) a full model including the potential confounders selected by a backward procedure; 2) a parsimonious model including only actual confounders identified by the "change-in-estimate" procedure. Hospital rankings, based on ORs were examined. RESULTS: 24 risk factors for c-section were included in the full model and 7 (marital status, maternal age, infant weight, fetopelvic disproportion, eclampsia or pre-eclampsia, placenta previa/abruptio placentae, malposition/malpresentation) in the parsimonious model. Hospital ranking using the adjusted ORs from both models was different from that obtained using the crude ORs. The correlation between the rankings of the two models was 0.92. The crude ORs were smaller than ORs adjusted by both models, with the parsimonious ones producing more precise estimates. CONCLUSION: Risk adjustment is necessary to compare hospital c-section rates, it shows differences in rankings and highlights inappropriateness of some hospitals. By adjusting for only actual confounders valid and more precise estimates could be obtained

Metabolic and endocrine profiles and reproductive parameters in dairy cows under grazing conditions: effect of polymorphisms in somatotropic axis genes

<p>Abstract</p> <p>Background</p> <p>The present study hypothesized that GH-AluI and IGF-I-SnabI polymorphisms do change the metabolic/endocrine profiles in Holstein cows during the transition period, which in turn are associated with productive and reproductive parameters.</p> <p>Methods</p> <p>Holstein cows (Farm 1, primiparous cows, n = 110, and Farm 2, multiparous cows, n = 76) under grazing conditions were selected and GH and IGF-I genotypes were determined. Blood samples for metabolic/endocrine determinations were taken during the transition period and early lactation in both farms. Data was analyzed by farm using a repeated measures analyses including GH and IGF-I genotypes, days and interactions as fixed effects, sire and cow as random effects and calving date as covariate.</p> <p>Results and Discussion</p> <p>Frequencies of GH and IGF-I alleles were L:0.84, V:0.16 and A:0.60, B:0.40, respectively. The GH genotype was not associated with productive or reproductive variables, but interaction with days affected FCM yield in multiparous (farm 2) cows (LL yielded more than LV cows) in early lactation. The GH genotype affected NEFA and IGF-I concentrations in farm 1 (LV had higher NEFA and lower IGF-I than LL cows) suggesting a better energy status of LL cows.</p> <p>There was no effect of IGF-I genotype on productive variables, but a trend was found for FCM in farm 2 (AB cows yielded more than AA cows). IGF-I genotype affected calving first service interval in farm 1, and the interaction with days tended to affect FCM yield (AB cows had a shorter interval and yielded more FCM than BB cows). IGF-I genotype affected BHB, NEFA, and insulin concentrations in farm 1: primiparous BB cows had lower NEFA and BHB and higher insulin concentrations. In farm 2, there was no effect of IGF-I genotype, but there was an interaction with days on IGF-I concentration, suggesting a greater uncoupling somatropic axis in AB and BB than AA cows, being in accordance with greater FCM yield in AB cows.</p> <p>Conclusion</p> <p>The GH and IGF-I genotypes had no substantial effect on productive parameters, although IGF-I genotype affected calving-first service interval in primiparous cows. Besides, these genotypes may modify the endocrine/metabolic profiles of the transition dairy cow under grazing conditions.</p

Hypernovae and Other Black-Hole-Forming Supernovae

During the last few years, a number of exceptional core-collapse supernovae (SNe) have been discovered. Their kinetic energy of the explosions are larger by more than an order of magnitude than the typical values for this type of SNe, so that these SNe have been called `Hypernovae'. We first describe how the basic properties of hypernovae can be derived from observations and modeling. These hypernovae seem to come from rather massive stars, thus forming black holes. On the other hand, there are some examples of massive SNe with only a small kinetic energy. We suggest that stars with non-rotating black holes are likely to collapse "quietly" ejecting a small amount of heavy elements (Faint supernovae). In contrast, stars with rotating black holes are likely to give rise to very energetic supernovae (Hypernovae). We present distinct nucleosynthesis features of these two types of "black-hole-forming" supernovae. Hypernova nucleosynthesis is characterized by larger abundance ratios (Zn,Co,V,Ti)/Fe and smaller (Mn,Cr)/Fe. Nucleosynthesis in Faint supernovae is characterized by a large amount of fall-back. We show that the abundance pattern of the most Fe deficient star, HE0107-5240, and other extremely metal-poor carbon-rich stars are in good accord with those of black-hole-forming supernovae, but not pair-instability supernovae. This suggests that black-hole-forming supernovae made important contributions to the early Galactic (and cosmic) chemical evolution.Comment: 49 pages, to be published in "Stellar Collapse" (Astrophysics and Space Science; Kluwer) ed. C. L. Fryer (2003

Eight common genetic variants associated with serum dheas levels suggest a key role in ageing mechanisms

Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands-yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10-36), SULT2A1 (rs2637125; p = 2.61×10-19), ARPC1A (rs740160; p = 1.56×10-16), TRIM4 (rs17277546; p = 4.50×10-11), BMF (rs7181230; p = 5.44×10-11), HHEX (rs2497306; p = 4.64×10-9), BCL2L11 (rs6738028; p = 1.72×10-8), and CYP2C9 (rs2185570; p = 2.29×10-8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS

Burden of illness of Pompe disease in patients only receiving supportive care

Background: Pompe disease is an orphan disease for which enzyme replacement therapy (ERT) recently became available. This study aims to estimate all relevant aspects of burden of illness-societal costs, use of home care and informal care, productivity losses, and losses in health-related quality of life (HRQoL)-for adult Pompe patients only receiving supportive care. Methods: We collected data on all relevant aspects of burden of illness via a questionnaire. We applied a societal perspective in calculating costs. The EQ-5D was used to estimate HRQoL. Results: Eighty adult patients (87% of the total Dutch adult Pompe population) completed a questionnaire. Disease severity ranged from mild to severe. Total annual costs were estimated at €22,475 (range €0-169,539) per adult Pompe patient. Patients on average received 8 h of home care and 19 h of informal care per week. Eighty-five percent of the patients received informal care from one or more caregivers; 40% had stopped working due to their disease; another 20% had reduced their working hours. HRQoL for Pompe patients who only received supportive care was estimated at 0.72, 17% lower than the Dutch population at large. Conclusions: Adult Pompe disease is associated with a considerable burden of illness at both the societal and patient levels. The disease leads to substantial costs and dependency on medical devices, home care, and informal care, and has a high impact on the patient's social network. In addition, patients are limited in their ability to work and have significantly reduced HRQoL

Do Dispersing Monkeys Follow Kin? Evidence from Gray-cheeked Mangabeys (Lophocebus albigena)

Among social vertebrates, immigrants may incur a substantial fitness cost when they attempt to join a new group. Dispersers could reduce that cost, or increase their probability of mating via coalition formation, by immigrating into groups containing first- or second-degree relatives. We here examine whether dispersing males tend to move into groups containing fathers or brothers in gray-cheeked mangabeys (Lophocebus albigena) in Kibale National Park, Uganda. We sampled blood from 21 subadult and adult male mangabeys in 7 social groups and genotyped them at 17 microsatellite loci. Twelve genotyped males dispersed to groups containing other genotyped adult males during the study; in only 1 case did the group contain a probable male relative. Contrary to the prediction that dispersing males would follow kin, relatively few adult male dyads were likely first- or second-degree relatives; opportunities for kin-biased dispersal by mangabeys appear to be rare. During 4 yr of observation, adult brothers shared a group only once, and for only 6 wk. Mean relatedness among adult males sharing a group was lower than that among males in different groups. Randomization tests indicate that closely related males share groups no more often than expected by chance, although these tests had limited power. We suggest that the demographic conditions that allow kin-biased dispersal to evolve do not occur in mangabeys, may be unusual among primates, and are worth further attention

Comparison of the benefits of cochlear implantation versus contra-lateral routing of signal hearing aids in adult patients with single-sided deafness: study protocol for a prospective within-subject longitudinal trial

Background Individuals with a unilateral severe-to-profound hearing loss, or single-sided deafness, report difficulty with listening in many everyday situations despite having access to well-preserved acoustic hearing in one ear. The standard of care for single-sided deafness available on the UK National Health Service is a contra-lateral routing of signals hearing aid which transfers sounds from the impaired ear to the non-impaired ear. This hearing aid has been found to improve speech understanding in noise when the signal-to-noise ratio is more favourable at the impaired ear than the non-impaired ear. However, the indiscriminate routing of signals to a single ear can have detrimental effects when interfering sounds are located on the side of the impaired ear. Recent published evidence has suggested that cochlear implantation in individuals with a single-sided deafness can restore access to the binaural cues which underpin the ability to localise sounds and segregate speech from other interfering sounds. Methods/Design The current trial was designed to assess the efficacy of cochlear implantation compared to a contra-lateral routing of signals hearing aid in restoring binaural hearing in adults with acquired single-sided deafness. Patients are assessed at baseline and after receiving a contra-lateral routing of signals hearing aid. A cochlear implant is then provided to those patients who do not receive sufficient benefit from the hearing aid. This within-subject longitudinal design reflects the expected care pathway should cochlear implantation be provided for single-sided deafness on the UK National Health Service. The primary endpoints are measures of binaural hearing at baseline, after provision of a contra-lateral routing of signals hearing aid, and after cochlear implantation. Binaural hearing is assessed in terms of the accuracy with which sounds are localised and speech is perceived in background noise. The trial is also designed to measure the impact of the interventions on hearing- and health-related quality of life. Discussion This multi-centre trial was designed to provide evidence for the efficacy of cochlear implantation compared to the contra-lateral routing of signals. A purpose-built sound presentation system and established measurement techniques will provide reliable and precise measures of binaural hearing. Trial registration Current Controlled Trials http://www.controlled-trials.com/ISRCTN33301739 (05/JUL/2013

Circum-Mediterranean cultural heritage and medicial plant uses in traditional animal healthcare: a field survey in eight selected areas within the RUBIA project

During the years 2003¿2005, a comparative ethnobotanical field survey was conducted on remedies used in traditional animal healthcare in eight Mediterranean areas. The study sites were selected within the EU-funded RUBIA project, and were as follows: the upper Kelmend Province of Albania; the Capannori area in Eastern Tuscany and the Bagnocavallo area of Romagna, Italy; Cercle de Ouezanne, Morocco; Sierra de Aracena y Picos de Aroche Natural Park in the province of Huelva, Spain; the St. Catherine area of the Sinai Peninsula, Egypt; Eastern and Western Crete, Greece; the Paphos and Larnaca areas of Cyprus; and the Mitidja area of Algeria. One hundred and thirty-six veterinary preparations and 110 plant taxa were recorded in the survey, with Asteraceae and Lamiaceae being the most quoted botanical families. For certain plant species the survey uncovered veterinary phytotherapeutical indications that were very uncommon, and to our knowledge never recorded before. These include Anabasis articulata (Chenopodiaceae), Cardopatium corymbosum (Asteraceae), Lilium martagon (Liliaceae), Dorycnium rectum (Fabaceae), Oenanthe pimpinelloides (Apiaceae), Origanum floribundum (Lamiaceae), Tuberaria lignosa (Cistaceae), and Dittrichia graveolens (Asteraceae). These phytotherapeutical indications are briefly discussed in this report, taking into account modern phytopharmacology and phytochemistry. The percentage of overall botanical veterinary taxa recorded in all the study areas was extremely low (8%), however when all taxa belonging to the same botanical genus are considered, this portion increases to 17%. Nevertheless, very few plant uses were found to be part of a presumed "Mediterranean" cultural heritage in veterinary practices, which raises critical questions about the concept of Mediterraneanism in ethnobotany and suggests that further discussion is required. Nearly the half of the recorded veterinary plant uses for mammals uncovered in this survey have also been recorded in the same areas in human folk medicine, suggesting a strong link between human and veterinary medical practices, and perhaps also suggesting the adaptive origins of a few medical practices. Since most of the recorded data concern remedies for treating cattle, sheep, goats, and camels, it would be interesting to test a few of the recorded phytotherapeuticals in the future, to see if they are indeed able to improve animal healthcare in breeding environments, or to raise the quality of dairy and meat products in the absence of classical, industrial, veterinary pharmaceuticals