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

Educational outreach in an integrated clinical management tool for nurse-led non-communicable chronic disease management in primary care in South Africa: pragmatic cluster randomised controlled trial

Background: In many low-income countries, care for patients with non-communicable diseases (NCDs) and mental health conditions is provided by nurses. The benefits of nurse substitution and supplementation in NCD care in high income settings are well recognised, but evidence from low- and middle-income countries is limited. Primary Care 101 (PC101) is a programme designed to support and expand nurses’ role in NCD care, comprising a clinical management tool with enhanced prescribing provisions for nurses, and educational outreach. We evaluated the effectiveness of the programme on primary care nurses’ capacity to manage NCDs (ISRCTN20283604). Methods and findings: In a cluster randomised controlled trial design, 38 public sector primary care clinics in the Western Cape province, South Africa, were randomised. Nurses in the intervention clinics were trained to use the PC101 management tool during educational outreach sessions delivered by health department trainers and authorised to prescribe an expanded range of drugs for several NCDs. Control clinics continued use of the Practical Approach to Lung Health and HIV /AIDS in South Africa (PALSA PLUS) management tool and usual training. Patients attending these clinics with one or more of hypertension (3227), diabetes (1842), chronic respiratory disease (1157) or screened positive for depression (2466), totalling 4393 patients, were enrolled between March 2011 and October 2011. Primary outcomes were treatment intensification for hypertension, diabetes, and chronic respiratory disease cohorts, defined as the proportion of patients in whom treatment was escalated during follow-up over 14 months, and case detection in the depression cohort. Primary outcome data were analysed for 2110 (97%) intervention and 2170 (97%) control group patients. Treatment intensification rates in intervention clinics were not superior to those in the control group clinics [hypertension: 44% in the intervention group versus 40% in the controls, risk ratio (RR) 1.08 (95% CI: 0.94 to 1.24; p=0.252); diabetes: 57% v 50%, RR 1.10 (0.97 to 1.24;p=0.126); chronic respiratory disease: 14% v 12%, RR 1.08 (0.75 to 1.55; p=0.674); and case detection of depression: 18% v 24%, RR 0.76 (0.53 to 1.10; p=0.142)]. No adverse effects of the nurses’ expanded scope of practice were observed. Limitations of the study include dependence on self-reported diagnoses for inclusion in the patient cohorts, limited data on uptake of PC101 by users, reliance on process outcomes, and insufficient resources to measure important health outcomes, such as HbA1c, at follow-up. Conclusions: Educational outreach to primary care nurses through use of a management tool involving an expanded role in managing NCDs, is feasible and safe but was not associated with treatment intensification or case detection for index diseases. This notwithstanding, the intervention, with adjustments to improve its effectiveness, has been adopted for implementation in primary care clinics throughout South Africa

The health workforce crisis in Bangladesh: shortage, inappropriate skill-mix and inequitable distribution

<p>Abstract</p> <p>Background</p> <p>Bangladesh is identified as one of the countries with severe health worker shortages. However, there is a lack of comprehensive data on human resources for health (HRH) in the formal and informal sectors in Bangladesh. This data is essential for developing an HRH policy and plan to meet the changing health needs of the population. This paper attempts to fill in this knowledge gap by using data from a nationally representative sample survey conducted in 2007.</p> <p>Methods</p> <p>The study population in this survey comprised all types of currently active health care providers (HCPs) in the formal and informal sectors. The survey used 60 unions/wards from both rural and urban areas (with a comparable average population of approximately 25 000) which were proportionally allocated based on a 'Probability Proportion to Size' sampling technique for the six divisions and distribution areas. A simple free listing was done to make an inventory of the practicing HCPs in each of the sampled areas and cross-checking with community was done for confirmation and to avoid duplication. This exercise yielded the required list of different HCPs by union/ward.</p> <p>Results</p> <p>HCP density was measured per 10 000 population. There were approximately five physicians and two nurses per 10 000, the ratio of nurse to physician being only 0.4. Substantial variation among different divisions was found, with gross imbalance in distribution favouring the urban areas. There were around 12 unqualified village doctors and 11 salespeople at drug retail outlets per 10 000, the latter being uniformly spread across the country. Also, there were twice as many community health workers (CHWs) from the non-governmental sector than the government sector and an overwhelming number of traditional birth attendants. The village doctors (predominantly males) and the CHWs (predominantly females) were mainly concentrated in the rural areas, while the paraprofessionals were concentrated in the urban areas. Other data revealed the number of faith/traditional healers, homeopaths (qualified and non-qualified) and basic care providers.</p> <p>Conclusions</p> <p>Bangladesh is suffering from a severe HRH crisis--in terms of a shortage of qualified providers, an inappropriate skills-mix and inequity in distribution--which requires immediate attention from policy makers.</p

Brain age predicts mortality

Age-associated disease and disability are placing a growing burden on society. However, ageing does not affect people uniformly. Hence, markers of the underlying biological ageing process are needed to help identify people at increased risk of age-associated physical and cognitive impairments and ultimately, death. Here, we present such a biomarker, ‘brain-predicted age’, derived using structural neuroimaging. Brain-predicted age was calculated using machine-learning analysis, trained on neuroimaging data from a large healthy reference sample (N = 2001), then tested in the Lothian Birth Cohort 1936 (N = 669), to determine relationships with age-associated functional measures and mortality. Having a brain-predicted age indicative of an older-appearing brain was associated with: weaker grip strength, poorer lung function, slower walking speed, lower fluid intelligence, higher allostatic load and increased mortality risk. Furthermore, while combining brain-predicted age with grey matter and cerebrospinal fluid volumes (themselves strong predictors) not did improve mortality risk prediction, the combination of brain-predicted age and DNA-methylation-predicted age did. This indicates that neuroimaging and epigenetics measures of ageing can provide complementary data regarding health outcomes. Our study introduces a clinically-relevant neuroimaging ageing biomarker and demonstrates that combining distinct measurements of biological ageing further helps to determine risk of age-related deterioration and death

High-Anxious Individuals Show Increased Chronic Stress Burden, Decreased Protective Immunity, and Increased Cancer Progression in a Mouse Model of Squamous Cell Carcinoma

In spite of widespread anecdotal and scientific evidence much remains to be understood about the long-suspected connection between psychological factors and susceptibility to cancer. The skin is the most common site of cancer, accounting for nearly half of all cancers in the US, with approximately 2–3 million cases of non-melanoma cancers occurring each year worldwide. We hypothesized that a high-anxious, stress-prone behavioral phenotype would result in a higher chronic stress burden, lower protective-immunity, and increased progression of the immuno-responsive skin cancer, squamous cell carcinoma. SKH1 mice were phenotyped as high- or low-anxious at baseline, and subsequently exposed to ultraviolet-B light (1 minimal erythemal dose (MED), 3 times/week, 10-weeks). The significant strengths of this cancer model are that it uses a normal, immunocompetent, outbred strain, without surgery/injection of exogenous tumor cells/cell lines, and produces lesions that resemble human tumors. Tumors were counted weekly (primary outcome), and tissues collected during early and late phases of tumor development. Chemokine/cytokine gene-expression was quantified by PCR, tumor-infiltrating helper (Th), cytolytic (CTL), and regulatory (Treg) T cells by immunohistochemistry, lymph node T and B cells by flow cytometry, adrenal and plasma corticosterone and tissue vascular-endothelial-growth-factor (VEGF) by ELISA. High-anxious mice showed a higher tumor burden during all phases of tumor development. They also showed: higher corticosterone levels (indicating greater chronic stress burden), increased CCL22 expression and Treg infiltration (increased tumor-recruited immuno-suppression), lower CTACK/CCL27, IL-12, and IFN-γ gene-expression and lower numbers of tumor infiltrating Th and CTLs (suppressed protective immunity), and higher VEGF concentrations (increased tumor angiogenesis/invasion/metastasis). These results suggest that the deleterious effects of high trait anxiety could be: exacerbated by life-stressors, accentuated by the stress of cancer diagnosis/treatment, and mediate increased tumor progression and/or metastasis. Therefore, it may be beneficial to investigate the use of chemotherapy-compatible anxiolytic treatments immediately following cancer diagnosis, and during cancer treatment/survivorship

Neurobiology of rodent self-grooming and its value for translational neuroscience

Self-grooming is a complex innate behaviour with an evolutionarily conserved sequencing pattern and is one of the most frequently performed behavioural activities in rodents. In this Review, we discuss the neurobiology of rodent self-grooming, and we highlight studies of rodent models of neuropsychiatric disorders-including models of autism spectrum disorder and obsessive compulsive disorder-that have assessed self-grooming phenotypes. We suggest that rodent self-grooming may be a useful measure of repetitive behaviour in such models, and therefore of value to translational psychiatry. Assessment of rodent self-grooming may also be useful for understanding the neural circuits that are involved in complex sequential patterns of action.National Institutes of Health (U.S.) (Grant NS025529)National Institutes of Health (U.S.) (Grant HD028341)National Institutes of Health (U.S.) (Grant MH060379