Determining the neurotransmitter concentration profile at active synapses

Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission

A mathematical model of the human metabolic system and metabolic flexibility

In healthy subjects some tissues in the human body display metabolic flexibility, by this we mean the ability for the tissue to switch its fuel source between predominantly carbohydrates in the post prandial state and predominantly fats in the fasted state. Many of the pathways involved with human metabolism are controlled by insulin, and insulin- resistant states such as obesity and type-2 diabetes are characterised by a loss or impairment of metabolic flexibility. In this paper we derive a system of 12 first-order coupled differential equations that describe the transport between and storage in different tissues of the human body. We find steady state solutions to these equations and use these results to nondimensionalise the model. We then solve the model numerically to simulate a healthy balanced meal and a high fat meal and we discuss and compare these results. Our numerical results show good agreement with experimental data where we have data available to us and the results show behaviour that agrees with intuition where we currently have no data with which to compare

Stomach cancer and occupational exposure to asbestos: a meta-analysis of occupational cohort studies

BACKGROUND: A recent Monographs Working Group of the International Agency for Research on Cancer concluded that there is limited evidence for a causal association between exposure to asbestos and stomach cancer. METHODS: We performed a meta-analysis to quantitatively evaluate this association. Random effects models were used to summarise the relative risks across studies. Sources of heterogeneity were explored through subgroup analyses and meta-regression. RESULTS: We identified 40 mortality cohort studies from 37 separate papers, and cancer incidence data were extracted for 15 separate cohorts from 14 papers. The overall meta-SMR for stomach cancer for total cohort was 1.15 (95% confidence interval 1.03–1.27), with heterogeneous results across studies. Statistically significant excesses were observed in North America and Australia but not in Europe, and for generic asbestos workers and insulators. Meta-SMRs were larger for cohorts reporting a SMR for lung cancer above 2 and cohort sizes below 1000. CONCLUSIONS: Our results support the conclusion by IARC that exposure to asbestos is associated with a moderate increased risk of stomach cancer

Metabolic Factors Limiting Performance in Marathon Runners

Each year in the past three decades has seen hundreds of thousands of runners register to run a major marathon. Of those who attempt to race over the marathon distance of 26 miles and 385 yards (42.195 kilometers), more than two-fifths experience severe and performance-limiting depletion of physiologic carbohydrate reserves (a phenomenon known as ‘hitting the wall’), and thousands drop out before reaching the finish lines (approximately 1–2% of those who start). Analyses of endurance physiology have often either used coarse approximations to suggest that human glycogen reserves are insufficient to fuel a marathon (making ‘hitting the wall’ seem inevitable), or implied that maximal glycogen loading is required in order to complete a marathon without ‘hitting the wall.’ The present computational study demonstrates that the energetic constraints on endurance runners are more subtle, and depend on several physiologic variables including the muscle mass distribution, liver and muscle glycogen densities, and running speed (exercise intensity as a fraction of aerobic capacity) of individual runners, in personalized but nevertheless quantifiable and predictable ways. The analytic approach presented here is used to estimate the distance at which runners will exhaust their glycogen stores as a function of running intensity. In so doing it also provides a basis for guidelines ensuring the safety and optimizing the performance of endurance runners, both by setting personally appropriate paces and by prescribing midrace fueling requirements for avoiding ‘the wall.’ The present analysis also sheds physiologically principled light on important standards in marathon running that until now have remained empirically defined: The qualifying times for the Boston Marathon

Can we prevent or treat multiple sclerosis by individualised vitamin D supply?

Apart from its principal role in bone metabolism and calcium homeostasis, vitamin D has been attributed additional effects including an immunomodulatory, anti-inflammatory, and possibly even neuroprotective capacity which implicates a possible role of vitamin D in autoimmune diseases like multiple sclerosis (MS). Indeed, several lines of evidence including epidemiologic, preclinical, and clinical data suggest that reduced vitamin D levels and/or dysregulation of vitamin D homeostasis is a risk factor for the development of multiple sclerosis on the one hand, and that vitamin D serum levels are inversely associated with disease activity and progression on the other hand. However, these data are not undisputable, and many questions regarding the preventive and therapeutic capacity of vitamin D in multiple sclerosis remain to be answered. In particular, available clinical data derived from interventional trials using vitamin D supplementation as a therapeutic approach in MS are inconclusive and partly contradictory. In this review, we summarise and critically evaluate the existing data on the possible link between vitamin D and multiple sclerosis in light of the crucial question whether optimization of vitamin D status may impact the risk and/or the course of multiple sclerosis

Missed Opportunities: Family History and Behavioral Risk Factors in Breast Cancer Risk Assessment Among a Multiethnic Group of Women

BACKGROUND: Clinician’s knowledge of a woman’s cancer family history (CFH) and counseling about health-related behaviors (HRB) is necessary for appropriate breast cancer care. OBJECTIVE: To evaluate whether clinicians solicit CFH and counsel women on HRB; to assess relationship of well visits and patient risk perception or worry with clinician’s behavior. DESIGN: Cross-sectional population-based telephone survey. PARTICIPANTS: Multiethnic sample; 1,700 women from San Francisco Mammography Registry with a screening mammogram in 2001–2002. MEASUREMENTS: Predictors: well visit in prior year, self-perception of 10-year breast cancer risk, worry scale. Outcomes: Patient report of clinician asking about CFH in prior year, or ever counseling about HRB in relation to breast cancer risk. Multivariate models included age, ethnicity, education, language of interview, insurance/mammography facility, well visit, ever having a breast biopsy/follow-up mammography, Gail-Model risk, Jewish heritage, and body mass index. RESULTS: 58% reported clinicians asked about CFH; 33% reported clinicians ever discussed HRB. In multivariate analysis, regardless of actual risk, perceived risk, or level of worry, having had a well visit in prior year was associated with increased odds (OR = 2.3; 95% CI 1.6, 3.3) that a clinician asked about CFH. Regardless of actual risk of breast cancer, a higher level of worry (OR = 1.9; 95% CI 1.4, 2.6) was associated with increased odds that a clinician ever discussed HRB. CONCLUSIONS: Clinicians are missing opportunities to elicit family cancer histories and counsel about health-related behaviors and breast cancer risk. Preventive health visits offer opportunities for clinicians to address family history, risk behaviors, and patients’ worries about breast cancer

Resistant starch and protein intake enhances fat oxidation and feelings of fullness in lean and overweight/obese women

BACKGROUND: Diets high in either resistant starch or protein have been shown to aid in weight management. We examined the effects of meals high in non-resistant or resistant starch with and without elevated protein intake on substrate utilization, energy expenditure, and satiety in lean and overweight/obese women. METHODS: Women of varying levels of adiposity consumed one of four pancake test meals in a single-blind, randomized crossover design: 1) waxy maize (control) starch (WMS); 2) waxy maize starch and whey protein (WMS+WP); 3) resistant starch (RS); or 4) RS and whey protein (RS+WP). RESULTS: Total post-prandial energy expenditure did not differ following any of the four test meals (WMS = 197.9 ± 8.9; WMS+WP = 188 ± 8.1; RS = 191.9 ± 8.9; RS+WP = 195.8 ± 8.7, kcals/180 min), although the combination of RS+WP, but not either intervention alone, significantly increased (P <0.01) fat oxidation (WMS = 89.5 ± 5.4; WMS+WP = 84.5 ± 7.2; RS = 97.4 ± 5.4; RS+WP = 107.8 ± 5.4, kcals/180 min). Measures of fullness increased (125 % vs. 45 %) and hunger decreased (55 % vs. 16 %) following WP supplemented versus non-whey conditions (WMS+WP, RS+WP vs. WMS, RS), whereas circulating hunger and satiety factors were not different among any of the test meals. However, peptide YY (PYY) was significantly elevated at 180 min following RS+WP meal. CONCLUSIONS: The combined consumption of dietary resistant starch and protein increases fat oxidation, PYY, and enhances feelings of satiety and fullness to levels that may be clinically relevant if maintained under chronic conditions. This trial was registered at clinicaltrials.gov as NCT02418429