High throughput protein expression screening in the nervous system – needs and limitations

The cellular complexity of the brain (some estimate that there are up to 10³ different cell types) is exceeded by the synaptic complexity, with each of the ∼10¹¹ neurons in the brain having around 10³–10⁴ synapses. Proteomic studies of the synapse have revealed that the postsynaptic density is the most complex multiprotein structure yet identified, with ∼10³ different proteins. Such studies, however, use brain tissue with many different regions and therefore different cell types, and there is clear potential for heterogeneity of protein content at different synapses within and between brain regions. Although large-scale mRNA-based assays are in progress to map this sort of complexity at the cellular level, and indeed all brain-expressed genes, analysis of protein distribution (at synapses and other structures) is still in the very early stages. We review existing large-scale protein expression studies and the specific technical obstacles that need to be overcome before applying the scaling used in nucleic acid based approaches.     

Activity spaces in studies of the environment and physical activity: A review and synthesis of implications for causality

Activity spaces are increasingly used to understand how people interact with their environment and engage in activity but their use may raise challenges regarding causal inference. We conducted a systematic review of findings and the methodological, analytical and conceptual issues relevant to causal inference. Studies were included if they comprised a spatial summary of locations visited, assessed any part of the causal pathway between the environment, physical activity and health, and used quantitative or qualitative methods. We searched seven electronic databases in January 2018 and screened 11910 articles for eligibility. Forty-seven studies were included for review. Studies answered research questions about features of or environmental features within activity spaces using a range of spatial and temporal summary techniques. The conceptual challenge of using activity spaces to strengthen causal inference was rarely considered, although some studies discussed circularity, temporality, and plausibility. Future studies should use longitudinal and experimental designs and consider the potential and actual use of spaces for physical activity, and their relationship with total levels of activity.     

Partial heat acclimation of athletes with spinal cord lesion

Heat acclimation (HA) can improve thermoregulatory stability in able-bodied athletes in part by an enhanced sweat response. Athletes with spinal cord lesion are unable to sweat below the lesion and it is unknown if they can HA. Five paralympic shooting athletes with spinal cord lesion completed seven consecutive days HA in hot conditions (33.4 ± 0.6 °C, 64.8 ± 3.7 %rh). Each HA session consisted of 20 min arm crank exercise at 50 % $ \dot{V}{\text{O}}_{{ 2 {\text{peak}}}} $ followed by 40 min rest, or simulated shooting. Aural temperature (T _aur) was recorded throughout. Body mass was assessed before and after each session and a sweat collection swab was fixed to T12 of the spine. Fingertip whole blood was sampled at rest on days 1 and 7 for estimation of the change in plasma volume. Resting T _aur declined from 36.3 ± 0.2 °C on day 1 to 36.0 ± 0.2 °C by day 6 (P < 0.05). During the HA sessions mean, T _aur declined from 37.2 ± 0.2 °C on day 1, to 36.7 ± 0.3 °C on day 7 (P < 0.05). Plasma volume increased from day 1 by 1.5 ± 0.6 % on day 7 (P < 0.05). No sweat secretion was detected or changes in body mass observed from any participant. Repeated hyperthermia combined with limited evaporative heat loss was sufficient to increase plasma volume, probably by alterations in fluid regulatory hormones. In conclusion, we found that although no sweat response was observed, athletes with spinal cord lesion could partially HA.     

Community consultation in emergency neurotrauma research: results from a pre-protocol survey

Background

Uncertainty remains as to the role of decompressive craniectomy (DC) for primary evacuation of an acute subdural haematoma (ASDH). In 2011, a collaborative group of neurosurgeons, neuro-intensive care physicians and trial methodologists was formed in the UK with the aim of answering the following question: “What is the clinical- and cost-effectiveness of DC, in comparison to simple craniotomy for adult patients undergoing primary evacuation of an ASDH?” The proposed RESCUE-ASDH trial (Randomised Evaluation of Surgery with Craniectomy for patients Undergoing Evacuation of Acute Subdural Haematoma) is a multi-centre, pragmatic, parallel group randomised trial of DC versus simple craniotomy for adult head-injured patients with an ASDH. Clinical trials in the emergency setting face the problem that potential participants may be incapacitated and their next of kin initially unavailable. As a result, consent and enrolment of participants can often be difficult.

Method

In the current study, we aimed to assess public opinion regarding participation in the RESCUE-ASDH trial and acceptability of surrogate consent by conducting a pre-protocol community consultation survey.

Results

One hundred and seventy-one subjects completed the survey. Eighty-four percent of participants responded positively when asked if they would participate in the proposed trial. Ninety-six percent and 91 % answered positively when asked if they found surrogate consent by their next of kin and an independent doctor acceptable, respectively. None of the characteristics of the study population were found to affect the decision to participate or the acceptability of surrogate consent by the next of kin. Being religious showed a trend towards higher acceptability of surrogate consent by a doctor. Conversely, an education to degree level and above showed a trend towards reduced acceptability of surrogate consent by a doctor.

Conclusions

Our community consultation survey shows that the proposed trial is acceptable to the public. In addition, the results suggest high levels of acceptability of surrogate consent by next of kin or independent doctor amongst our community.     

Preconception Healthcare Delivery at a Population Level: Construction of Public Health Models of Preconception Care

A key challenge of preconception healthcare is identifying how it can best be delivered at a population level. To review current strategies of preconception healthcare, explore methods of preconception healthcare delivery, and develop public health models which reflect different preconception healthcare pathways. Preconception care strategies, programmes and evaluations were identified through a review of Medline and Embase databases. Search terms included: preconception, pre-pregnancy, intervention, primary care, healthcare, model, delivery, program, prevention, trial, effectiveness, congenital disorders OR abnormalities, evaluation, assessment, impact. Inclusion criteria for review articles were: (1) English, (2) human subjects, (3) women of childbearing age, (4) 1980–current data, (5) all countries, (6) both high risk and universal approaches, (7) guidelines or recommendations, (8) opinion articles, (9) experimental studies. Exclusion criteria were: (1) non-human subjects, (2) non-English, (3) outside of the specified timeframe, (4) articles on male healthcare. The results of the literature review were synthesised into public health models of care: (1) primary care; (2) hospital-based and inter-conception care; (3) specific preconception care clinics; and, (4) community outreach. Fifteen evaluations of preconception care were identified. Community programmes demonstrated a significant impact on substance use, folic acid supplementation, diabetes optimization, and hyperphenylalaninemia. An ideal preconception visits entail risk screening, education, and intervention if indicated. Subsequently, four public health models were developed synthesizing preconception-care delivery at a population level. Heterogeneity of risk factors, health systems and strategies of care reflect the lack of consensus about the best way to deliver preconception care. The proposed models aim to reflect differing aspects of preconception healthcare delivery.     

Group 2 Innate Lymphoid Cells Are Critical for the Initiation of Adaptive T Helper 2 Cell-Mediated Allergic Lung Inflammation

1. Download : Download high-res image (260KB)
2. Download : Download full-size image

     

Protection against colitis by CD100-dependent modulation of intraepithelial γδ T lymphocyte function

Intraepithelial γδ T lymphocytes (γδ IEL) have important roles in repair of tissue damage at epithelial sites, such as skin and intestine. Molecules that orchestrate these γδ T-cell functions are not well defined. Recently, interaction of the semaphorin CD100 on skin γδ T cells with plexin B2 on keratinocytes was shown to be important for effective γδ T-cell function in the epidermis, which raised the possibility that CD100 may exert similar functions in the intestinal tract. In this study, we find that CD100 is expressed on all IEL, and plexin B2 is present on all epithelial cells of the mouse colon. Using the dextran sulfate sodium (DSS) mouse model of colitis, disease severity is significantly exacerbated in CD100-deficient (CD100^−/−) mice, with increased colon ulceration and mucosal infiltration with inflammatory cells. The severe colitis in CD100^−/− mice is attributable to the failure of the colon epithelium to mount a proliferative response to damage. Unlike wild-type γδ IEL, γδ IEL from CD100^−/− mice fail to produce keratinocyte growth factor-1 (KGF-1) in response to DSS treatment. Administration of recombinant KGF-1 to CD100^−/− animals ameliorates disease and reverses colitis susceptibility. These results demonstrate that CD100-mediated signals are critical for effective activation of γδ IEL to produce growth factors, including KGF-1, that are required for healing of the colon epithelium during colitis.     

Delusions and prediction error: clarifying the roles of behavioural and brain responses

Griffiths and colleagues provided a clear and thoughtful review of the prediction error model of delusion formation [Cognitive Neuropsychiatry, 2014 April 4 (Epub ahead of print)]. As well as reviewing the central ideas and concluding that the existing evidence base is broadly supportive of the model, they provide a detailed critique of some of the experiments that we have performed to study it. Though they conclude that the shortcomings that they identify in these experiments do not fundamentally challenge the prediction error model, we nevertheless respond to these criticisms. We begin by providing a more detailed outline of the model itself as there are certain important aspects of it that were not covered in their review. We then respond to their specific criticisms of the empirical evidence. We defend the neuroimaging contrasts that we used to explore this model of psychosis arguing that, while any single contrast entails some ambiguity, our assumptions have been justified by our extensive background work before and since.