Origin of ultradian pulsatility in the hypothalamic–pituitary–adrenal axis

The hypothalamic–pituitary–adrenal (HPA) axis is a neuroendocrine system that regulates the circulating levels of vital glucocorticoid hormones. The activity of the HPA axis is characterized not only by a classic circadian rhythm, but also by an ultradian pattern of discrete pulsatile release of glucocorticoids. A number of psychiatric and metabolic diseases are associated with changes in glucocorticoid pulsatility, and it is now clear that glucocorticoid responsive genes respond to these rapid fluctuations in a biologically meaningful way. Theoretical modelling has enabled us to identify and explore potential mechanisms underlying the ultradian activity in this axis, which to date have not been identified successfully. We demonstrate that the combination of delay with feed-forward and feedback loops in the pituitary–adrenal system is sufficient to give rise to ultradian pulsatility in the absence of an ultradian source from a supra-pituitary site. Moreover, our model enables us to predict the different patterns of glucocorticoid release mediated by changes in hypophysial-portal corticotrophin-releasing hormone levels, with results that parallel our experimental in vivo data

Double Averaging Analysis Applied to a Large Eddy Simulation of Coupled Turbulent Overlying and Porewater Flow

Freestream turbulence in rivers is a key contributor to the flux of dissolved nutrients, carbon, and other ecologically important solutes into porewater. To advance understanding of turbulent hyporheic exchange and porewater transport, we investigate flow over and through a rough bed of spheres using large eddy simulation (LES). We apply double averaging (combined space and time averaging) to the LES results to determine the mean velocity distribution, momentum balance, and drag forces. Our simulations show large-scale freestream structures interacting strongly with vortices generated at the surfaces of individual spheres to control turbulent momentum fluxes into the bed. The transition between turbulent flow and Darcy flow occurs over the first row of spheres, where turbulence decays rapidly and turbulent kinetic energy, Reynolds stress, and drag forces peak. Below this region, turbulence is only present in the high-velocity flow in open pore throats. Experimental observations suggest that minimum mean porewater velocity occurs in the first open pore space below the transition region, but our results show that the minimum occurs between the first and second pore spaces. The simulation mean porewater velocities are approximately half those captured in measurements because the model resolves the entire flow continuum while measurements can access high-velocity fluid in open pores. The high-resolution dual time-space averaging of the LES resolves both turbulent and mean flow features that are important to interfacial solute and particle fluxes, providing a means to include turbulent hyporheic exchange in upscaled river models, which has not been achieved to date

Olive phenology as a sensitive indicator of future climatic warming in the Mediterranean

Experimental and modelling work suggests a strong dependence of olive flowering date on spring temperatures. Since airborne pollen concentrations reflect the flowering phenology of olive populations within a radius of 50 km, they may be a sensitive regional indicator of climatic warming. We assessed this potential sensitivity with phenology models fitted to flowering dates inferred from maximum airborne pollen data. Of four models tested, a thermal time model gave the best fit for Montpellier, France, and was the most effective at the regional scale, providing reasonable predictions for 10 sites in the western Mediterranean. This model was forced with replicated future temperature simulations for the western Mediterranean from a coupled ocean-atmosphere general circulation model (GCM). The GCM temperatures rose by 4·5 °C between 1990 and 2099 with a 1% per year increase in greenhouse gases, and modelled flowering date advanced at a rate of 6·2 d per °C. The results indicated that this long-term regional trend in phenology might be statistically significant as early as 2030, but with marked spatial variation in magnitude, with the calculated flowering date between the 1990s and 2030s advancing by 3–23 d. Future monitoring of airborne olive pollen may therefore provide an early biological indicator of climatic warming in the Mediterranean

Intensified shigellosis epidemic associated with sexual transmission in men who have sex with men - Shigella fexneri and s. Sonnei in England, 2004 to end of February 2015

Surveillance data suggest an intensification of the shigellosis epidemic associated with sexual transmission in men who have sex with men (MSM) in England with separate introductions into the population. In 2014, sexual transmission between MSM might have accounted for 97%, 89%, and 43% of non-travel associated Shigella flexneri 3a and S. flexneri 2a, and S. sonnei diagnoses. Clinicians should sensitively ascertain sexual history for men with enteric infections to facilitate prompt diagnosis and appropriate management

Cytokine Expression by Inflammatory Cells Obtained from the Spinal Cords of Lewis Rats with Experimental Autoimmune Encephalomyelitis Induced by Inoculation with Myelin Basic Protein and Adjuvants

Inflammatory cells were obtained from the spinal cords of rats with acute experimental autoimmune encephalomyelitis EAE induced by inoculation with myelin basic protein MBP and adjuvants. Reverse transcriptase-polymerase chain reaction RT-PCR was used to investigate the expression of mRNA for interleukin-2 IL-2 , IL-4, IL-10 and interferon-gamma (IFN-gamma) by cells from groups of rats studied 10-21 days after inoculation. On all days of study, the inflammatory cells, which were predominantly lymphocytes, expressed mRNA for IL-2, IL-4, IL-10 and IFN-gamma. In the mRNA from normal rat spinal cord tissue, there was little expression of cytokine mRNA. Cells from a short-term MBP-reactive T cell line expressed all the cytokines. Densitometry was used to measure the products of PCR, to assess the expression of each cytokine relative to that of beta-actin. IL-2 mRNA was expressed throughout the course of disease and reached a peak on day 18, during late clinical recovery. IFN-gamma was expressed throughout the course of the disease and was also high during late recovery. IL-4 mRNA was present in the spinal cord throughout the course of the disease, with a slight rise during late recovery. Relative expression of IL-10 rose to a peak on days 17-19, during late recovery from clinical disease. This study indicates that IL-2, IL-4, IL-10 and IFN-gamma are expressed by inflammatory cells in the spinal cord in EAE, with the relative expression of all cytokines being high during late clinical recovery

Lack of effect of high-protein vs. high-carbohydrate meal intake on stress-related mood and eating behavior

<p>Abstract</p> <p>Background</p> <p>Consumption of meals with different macronutrients, especially high in carbohydrates, may influence stress-related eating behavior. We aimed to investigate whether consumption of high-protein vs. high-carbohydrate meals influences stress-related mood, food reward, i.e. 'liking' and 'wanting', and post-meal energy intake.</p> <p>Methods</p> <p>Participants (n = 38, 19m/19f, age = 25 ± 9 y, BMI = 25.0 ± 3.3 kg/m²) came to the university four times, fasted, once for a stress session receiving a high-protein meal, once for a rest session receiving a high-protein meal, once for a stress session receiving a high-carbohydrate meal and once for a rest session receiving a high-carbohydrate meal (randomized cross-over design). The high-protein and high-carbohydrate test meals (energy percentage protein/carbohydrate/fat 65/5/30 vs. 6/64/30) matched for energy density (4 kJ/g) and daily energy requirements (30%). Stress was induced using an ego-threatening test. Pre- and post-meal 'liking' and 'wanting' (for bread, filling, drinks, dessert, snacks, stationery (non-food alternative as control)) was measured by means of a computer test. Following the post-meal 'wanting' measurement, participants received and consumed their wanted food items (post-meal energy intake). Appetite profile (visual analogue scales), mood state (Profile Of Mood State and State Trait Anxiety Inventory questionnaires), and post-meal energy intake were measured.</p> <p>Results</p> <p>Participants showed increased feelings of depression and anxiety during stress (P < 0.01). Consumption of the test meal decreased hunger, increased satiety, decreased 'liking' of bread and filling, and increased 'liking' of placebo and drinks (P < 0.0001). Food 'wanting' decreased pre- to post-meal (P < 0.0001). The high-protein vs. high-carbohydrate test meal induced lower subsequent 'wanting' and energy intake (1.7 ± 0.3 MJ vs. 2.5 ± 0.4 MJ) only in individuals characterized by disinhibited eating behavior (factor 2 Three Factor Eating Questionnaire, n = 16), during rest (P ≤ 0.01). This reduction in 'wanting' and energy intake following the high-protein meal disappeared during stress.</p> <p>Conclusions</p> <p>Consumption of a high-protein vs. high-carbohydrate meal appears to have limited impact on stress-related eating behavior. Only participants with high disinhibition showed decreased subsequent 'wanting' and energy intake during rest; this effect disappeared under stress. Acute stress overruled effects of consumption of high-protein foods.</p> <p>Trial registration</p> <p>The study was registered in the Dutch Trial Register (<a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2040">NTR1904</a>). The protocol described here in this study deviates from the trial protocol approved by the Medical Ethical Committee of the Maastricht University as it comprises only a part of the approved trial protocol.</p

Ghrelin Indirectly Activates Hypophysiotropic CRF Neurons in Rodents

Ghrelin is a stomach-derived hormone that regulates food intake and neuroendocrine function by acting on its receptor, GHSR (Growth Hormone Secretagogue Receptor). Recent evidence indicates that a key function of ghrelin is to signal stress to the brain. It has been suggested that one of the potential stress-related ghrelin targets is the CRF (Corticotropin-Releasing Factor)-producing neurons of the hypothalamic paraventricular nucleus, which secrete the CRF neuropeptide into the median eminence and activate the hypothalamic-pituitary-adrenal axis. However, the neural circuits that mediate the ghrelin-induced activation of this neuroendocrine axis are mostly uncharacterized. In the current study, we characterized in vivo the mechanism by which ghrelin activates the hypophysiotropic CRF neurons in mice. We found that peripheral or intra-cerebro-ventricular administration of ghrelin strongly activates c-fos – a marker of cellular activation – in CRF-producing neurons. Also, ghrelin activates CRF gene expression in the paraventricular nucleus of the hypothalamus and the hypothalamic-pituitary-adrenal axis at peripheral level. Ghrelin administration directly into the paraventricular nucleus of the hypothalamus also induces c-fos within the CRF-producing neurons and the hypothalamic-pituitary-adrenal axis, without any significant effect on the food intake. Interestingly, dual-label immunohistochemical analysis and ghrelin binding studies failed to show GHSR expression in CRF neurons. Thus, we conclude that ghrelin activates hypophysiotropic CRF neurons, albeit indirectly

Whole genome sequencing reveals high clonal diversity of Escherichia coli isolated from patients in a tertiary care hospital in Moshi, Tanzania

Abstract Background Limited information regarding the clonality of circulating E. coli strains in tertiary care hospitals in low and middle-income countries is available. The purpose of this study was to determine the serotypes, antimicrobial resistance and virulence genes. Further, we carried out a phylogenetic tree reconstruction to determine relatedness of E. coli isolated from patients in a tertiary care hospital in Tanzania. Methods E. coli isolates from inpatients admitted at Kilimanjaro Christian Medical Centre between August 2013 and August 2015 were fully genome-sequenced at KCMC hospital. Sequence analysis was done for identification of resistance genes, Multi-Locus Sequence Typing, serotyping, and virulence genes. Phylogeny reconstruction using CSI Phylogeny was done to ascertain E. coli relatedness. Stata 13 (College Station, Texas 77,845 USA) was used to determine Cohen’s kappa coefficient of agreement between the phenotypically tested and whole genome sequence predicted antimicrobial resistance. Results Out of 38 E. coli isolates, 21 different sequence types (ST) were observed. Eight (21.1%) isolates belonged to ST131; of which 7 (87.5.%) were serotype O25:H4. Ten (18.4%) isolates belonged to ST10 clonal complex; of these, four (40.0%) were ST617 with serotype O89:H10. Twenty-eight (73.7%) isolates carried genes encoding beta-lactam resistance enzymes. On average, agreement across all drugs tested was 83.9%. Trimethoprim/sulphamethoxazole (co-trimoxazole) showed moderate agreement: 45.8%, kappa =15% and p = 0.08. Amoxicillin-clavulanate showed strongest agreement: 87.5%, kappa = 74% and p = 0.0001. Twenty-two (57.9%) isolates carried virulence factors for host cells adherence and 25 (65.7%) for factors that promote E. coli immune evasion by increasing survival in serum. The phylogeny analysis showed that ST131 clustering close together whereas ST10 clonal complex had a very clear segregation of the ST617 and a mix of the rest STs. Conclusion There is a high diversity of E. coli isolated from patients admitted to a tertiary care hospital in Tanzania. This underscores the necessity to routinely screen all bacterial isolates of clinical importance in tertiary health care facilities. WGS use for laboratory-based surveillance can be an effective early warning system for emerging pathogens and resistance mechanisms in LMICs

Iron Status Predicts Treatment Failure and Mortality in Tuberculosis Patients: A Prospective Cohort Study from Dar es Salaam, Tanzania

Experimental data suggest a role for iron in the course of tuberculosis (TB) infection, but there is limited evidence on the potential effects of iron deficiency or iron overload on the progression of TB disease in humans. The aim of the present analysis was to examine the association of iron status with the risk of TB progression and death.\ud We analyzed plasma samples and data collected as part a randomized micronutrient supplementation trial (not including iron) among HIV-infected and HIV-uninfected TB patients in Dar es Salaam, Tanzania. We prospectively related baseline plasma ferritin concentrations from 705 subjects (362 HIV-infected and 343 HIV-uninfected) to the risk of treatment failure at one month after initiation, TB recurrence and death using binomial and Cox regression analyses. Overall, low (plasma ferritin<30 µg/L) and high (plasma ferritin>150 µg/L for women and>200 µg/L for men) iron status were seen in 9% and 48% of patients, respectively. Compared with normal levels, low plasma ferritin predicted an independent increased risk of treatment failure overall (adjusted RR = 1.95, 95% CI: 1.07 to 3.52) and of TB recurrence among HIV-infected patients (adjusted RR = 4.21, 95% CI: 1.22 to 14.55). High plasma ferritin, independent of C-reactive protein concentrations, was associated with an increased risk of overall mortality (adjusted RR = 3.02, 95% CI: 1.95 to 4.67). Both iron deficiency and overload exist in TB patients and may contribute to disease progression and poor clinical outcomes. Strategies to maintain normal iron status in TB patients could be helpful to reduce TB morbidity and mortality