Missense mutations in the central domains of cardiac myosin binding protein-C and their potential contribution to hypertrophic cardiomyopathy.

Myosin binding protein-C (MyBP-C) is a multidomain protein that regulates muscle contraction. Mutations in MYBPC3, the gene encoding for the cardiac variant (henceforth called cMyBP-C), are amongst the most frequent causes of hypertrophic cardiomyopathy. Most mutations lead to a truncated version of cMyBP-C, which is most likely unstable. However, missense mutations have also been reported, which tend to cluster in the central domains of the cMyBP-C molecule. This suggests that these central domains are more than just a passive spacer between the better characterized N- and C-terminal domains. Here, we investigated the potential impact of four different missense mutations, E542Q, G596R, N755K, and R820Q, which are spread over the domains C3 to C6, on the function of MyBP-C on both the isolated protein level and in cardiomyocytes in vitro. Effect on domain stability, interaction with thin filaments, binding to myosin, and subcellular localization behavior were assessed. Our studies show that these missense mutations result in slightly different phenotypes at the molecular level, which are mutation specific. The expected functional readout of each mutation provides a valid explanation for why cMyBP-C fails to work as a brake in the regulation of muscle contraction, which eventually results in a hypertrophic cardiomyopathy phenotype. We conclude that missense mutations in cMyBP-C must be evaluated in context of their domain localization, their effect on interaction with thin filaments and myosin, and their effect on protein stability to explain how they lead to disease.

Tools for faculty assessment of interdisciplinary competencies of healthcare students: an integrative review.

Increasingly, interprofessional teamwork is required for the effective delivery of public health services in primary healthcare settings. Interprofessional competencies should therefore be incorporated within all health and social service education programs. Educational innovation in the development of student-led clinics (SLC) provides a unique opportunity to assess and develop such competencies. However, a suitable assessment tool is needed to appropriately assess student progression and the successful acquisition of competencies. This study adopts an integrative review methodology to locate and review existing tools utilized by teaching faculty in the assessment of interprofessional competencies in pre-licensure healthcare students. A limited number of suitable assessment tools have been reported in the literature, as highlighted by the small number of studies included. Findings identify use of existing scales such as the Interprofessional Socialization and Valuing Scale (ISVS) and the McMaster Ottawa Scale with Team Observed Structured Clinical Encounter (TOSCE) tools plus a range of other approaches, including qualitative interviews and escape rooms. Further research and consensus are needed for the development of teaching and assessment tools appropriate for healthcare students. This is particularly important in the context of interprofessional, community-partnered public health and primary healthcare SLC learning but will be of relevance to health students in a broad range of clinical learning contexts.

Student-Led Clinics in Aotearoa New Zealand: A Scoping Review with Stakeholder Consultation.

BACKGROUND: Student-led clinics have gained increasing attention as a mechanism for students across various health professions to gain authentic interprofessional clinical placement experience during their educational programme. PURPOSE: This scoping review is designed to identify and describe experiences relating to student-led clinics in Aotearoa New Zealand. METHODS: The review involved five key steps: 1) identifying the research question; 2) identifying relevant studies; 3) study selection; 4) charting the data; and 5) collating, summarising and reporting the results. DISCUSSION: Student-led health clinics present invaluable educational opportunities for authentic collaborative practice and capacity to improve population health and well-being, especially in marginalised and disadvantaged communities. Clinic establishment and operation require consideration of a complex set of factors. CONCLUSION: Community consultation (including with Indigenous populations) should precede establishment of clinics. There is scope for more reporting and objective evaluation to ensure best practice is being determined, developed, and achieved.

The Role of the Clinical Exercise Physiologist in Reducing the Burden of Chronic Disease in New Zealand.

Clinical exercise physiologists (CEPs) specialize in managing long-term, non-communicable health conditions using scientific rehabilitative exercise prescription, which alleviates the burden of these conditions on health care systems. This is evident, particularly in Australia (AUS), where they are registered as health care workers. CEPs have been shown to reduce the physical burden of long-term conditions on populations and the economic load that these place on national health departments. This article aims to evidence the effectiveness of CEPs in Noncommunicable Disease (NCD) rehabilitation, the cost-effectiveness of supervised exercise prescription for various NCDs by CEPs in AUS, and related cost-effectiveness New Zealand (NZ) burden of disease. This article highlights the important role NZ. CEPs can play in reducing chronic disease cost if given the same opportunities as Australian CEPs within NZ's health care system.

EBV+ HHV-8+ Multicentric Castleman Disease With Plasmablastic Aggregates in an HIV+ Man: An Evolving Clinicopathologic Entity.

We report a case of EBV+ and HHV-8+ multicentric Castleman disease with plasmablastic aggregates in an HIV-positive individual. A 41-year-old man presented in early 2015 with fevers, sweats, weight loss, intractable itching, and on subsequent testing was found to be HIV positive. Investigations showed cervical lymphadenopathy and splenomegaly. He was treated for HIV and his symptoms resolved. His symptoms recurred in January 2016, and a provisional diagnosis of multicentric Castleman disease was entertained. The HHV-8 (human herpesvirus-8) and EBV (Epstein-Barr virus) viral load was elevated. A left supraclavicular lymph node core biopsy was performed, which showed features of multicentric Castleman disease with plasmablastic aggregates that are EBV (EBER) and HHV-8 positive. He responded well to rituximab treatment and remains well with no symptoms at recent follow-up.

Oral Nicotine Alters Uterine Histo-Morphology but Does Not Disrupt the Estrous Cycle in Female Rats.

INTRODUCTION: The primary goal of nicotine replacement therapy (NRT) is to reduce smoking related harms by introducing low nicotine products. In spite of being a potential mode of NRT, there is lack of information on the risks and safety of long term oral nicotine usage on the female reproductive system. METHODS: We evaluated the effects of 30 µg/mL oral nicotine consumption on the estrous cycle, circulating estradiol levels, and uterine and ovarian morphology after 2 or 7 weeks of intake by female Sprague-Dawley rats. RESULTS: Estrous phase frequencies were similar between nicotine treated and control groups throughout the study, no changes were detected in nicotine-treated animals before and during the nicotine exposure period, and circulating estradiol levels were comparable between animals in both groups after 2 weeks of nicotine consumption. Histological examination of uteri from the nicotine group revealed a significant decrease in the height of uterine surface epithelium and an increase in the height of glandular epithelium compared to control animals; yet, the ovaries did not show attrition or changes in follicular appearance due to nicotine. CONCLUSIONS: These preclinical studies suggest that nicotine intake results in structural changes in uterine tissues without disrupting estrous cyclicity or estradiol hormone levels. Though oral nicotine may not be totally risk-free, continuing research on this mode of nicotine administration is worthwhile to determine optimal dosing and duration of consumption for its potential use as an NRT.

Subcellular localization of rat CYP2E1 impacts metabolic efficiency toward common substrates.

Cytochrome P450 2E1 (CYP2E1) detoxifies or bioactivates many low molecular-weight compounds. Most knowledge about CYP2E1 activity relies on studies of the enzyme localized to endoplasmic reticulum (erCYP2E1); however, CYP2E1 undergoes transport to mitochondria (mtCYP2E1) and becomes metabolically active. We report the first comparison of in vitro steady-state kinetic profiles for erCYP2E1 and mtCYP2E1 oxidation of probe substrate 4-nitrophenol and pollutants styrene and aniline using subcellular fractions from rat liver. For all substrates, metabolic efficiency changed with substrate concentration for erCYP2E1 reflected in non-hyperbolic kinetic profiles but not for mtCYP2E1. Hyperbolic kinetic profiles for the mitochondrial enzyme were consistent with Michaelis-Menten mechanism in which metabolic efficiency was constant. By contrast, erCYP2E1 metabolism of 4-nitrophenol led to a loss of enzyme efficiency at high substrate concentrations when substrate inhibited the reaction. Similarly, aniline metabolism by erCYP2E1 demonstrated negative cooperativity as metabolic efficiency decreased with increasing substrate concentration. The opposite was observed for erCYP2E1 oxidation of styrene; the sigmoidal kinetic profile indicated increased efficiency at higher substrate concentrations. These mechanisms and CYP2E1 levels in mitochondria and endoplasmic reticulum were used to estimate the impact of CYP2E1 subcellular localization on metabolic flux of pollutants. Those models showed that erCYP2E1 mainly carries out aniline metabolism at all aniline concentrations. Conversely, mtCYP2E1 dominates styrene oxidation at low styrene concentrations and erCYP2E1 at higher concentrations. Taken together, subcellular localization of CYP2E1 results in distinctly different enzyme activities that could impact overall metabolic clearance and/or activation of substrates and thus impact the interpretation and prediction of toxicological outcomes.

The multiple bottle effect is overridden in male and female rats by simultaneous presentation of two oral nicotine solutions.

BACKGROUND: Studies on the oral route of nicotine administration in rodents make important contributions to our understanding of human nicotine use, and alternative approaches to smoking cessation. While environmental availability of oral nicotine contributes to voluntary intake and appears to drive consumption initially, solution concentration may exert more control over intake with continued exposure. Further, it is believed that female rodents consume more nicotine and show greater motivation to obtain it than males. OBJECTIVES: The purpose of our study was to determine voluntary oral nicotine intake patterns following continuous exposure to relatively high concentrations in male and female rats, employing a multiple bottle approach, and to describe the relationship between oral nicotine consumption and sera cotinine. METHODS: Using five bottles, adult Sprague-Dawley rats were given continuous access to water and 15 µg/ml nicotine solutions or water and 15 and 30 µg/ml nicotine solutions for 2 weeks; blood serum was analyzed for cotinine. RESULTS: Rats consistently consumed oral nicotine and female rats ingested more nicotine than males, even at relatively high concentrations. Yet, when both concentrations were presented simultaneously, oral nicotine intake did not exceed that of water, thus overriding an environmental, or multiple-bottle, effect. Cotinine was systemically circulated following first-pass hepatic metabolism of nicotine at early, but not at later stages of nicotine exposure. CONCLUSIONS: Our findings suggest rats will readily and voluntarily ingest considerably higher doses of nicotine than previously reported resulting in initial systemic cotinine, and trends toward sex differences are mitigated by solution concentration.

Volunteerism is Key to Offering Successful Neuroscience Outreach with Limited Resources.

As sponsors of a university Society for Neuroscience (SfN) organization, we and our student members are committed to neuroscience outreach but with limited resources, it is not feasible for us to host a week-long program during National Brain Awareness Week (BAW). Hence, we decided on a half-day program wherein attendees are provided with information about the workings of the nervous system and current research in the field in a fun and interactive environment. Our volunteers - mostly undergraduate students - select hands-on activities, gather required materials, and actively engage participants of all ages. We coined the event Brain Awareness Day (BAD) and organize the annual program on a budget between $100-$300.

Solution concentration influences voluntary consumption of nicotine under multiple bottle conditions.

Female Sprague Dawley rats were given a choice between two concentrations of nicotine solution (5 microg/ml and 8 microg/ml) and water in a 5-bottle arrangement for 25 days. Rats developed clear bottle discrimination, drinking more of the 5 microg/ml nicotine solution than water or the higher concentration nicotine solution. Further, intake patterns were sensitive to exposure. Differences in consumption of the three solutions (5 microg/ml vs. 8 microg/ml vs. water) were minimal during initial exposure days but became clear and stable with chronic exposure. Control rats given 5 bottles of water drank equally from all bottles and showed no development of preference for bottle position. Results suggest that both environmental availability and post-ingestional effects of nicotine contribute to the voluntarily oral consumption of nicotine solutions by rats. The influence of these two factors, however, is modulated by exposure. Availability appears to drive consumption initially, but the impact of concentration exerts more control over consumption with continued exposure. These data support the utility of oral methods of nicotine self-administration in the laboratory rat and suggest the need for further investigations into the biological impact of nicotine consumed orally.

The first thalamocortical synapses are made in the cortical plate in the developing visual cortex of the wallaby (Macropus eugenii).

The time course of development and laminar distribution of thalamocortical synapses in the visual cortex of the marsupial mammal the wallaby (Macropus eugenii) has been studied by electron microscopy from the time of afferent ingrowth to the appearance of layer 4, the main target for thalamic axons. Axons were labeled from the thalamus by a fluorescent carbocyanine dye in fixed tissue or by transneuronal transport of horseradish peroxidase conjugated to wheat germ agglutinin from the eye. Thalamic axons first reached the cortex 2 weeks after birth and grew into the developing cortical plate without a waiting period in the subplate. The first thalamocortical synapses were detected 2 weeks later solely throughout the loosely packed zone of the cortical plate, where layer 6 cells previously have been shown to reside. As the thickness of the cortex increased with age, thalamocortical synapses were increasingly prevalent in the loosely packed zone of the cortical plate. With the appearance of layer 4, thalamocortical synapses were found there as well as in the marginal zone and layer 6. There was no evidence for an early population of thalamocortical synapses in the subplate. The first synapses made by thalamic axons were in a region containing layer 6 cells, one of their normal targets in the mature cortex.