Pulmonary hypertension and the potential of 'drug' repurposing: A case for African medicinal plants.

Abstract: Pulmonary hypertension (PH) is a haemodynamic disorder in which elevated blood pressure in the pulmonary circulation is caused by abnormal vascular tone. Despite advances in treatment, PH mortality remains high, and drug repurposing has been proposed as a mitigating approach. This article reviews the studies that have investigated drug repurposing as a viable option for PH. We provide an overview of PH and highlight pharmaceutical drugs with repurposing potential, based on limited evidence of their mechanisms of action. Moreover, studies have demonstrated the benefits of medicinal plants in PH, most of which are of Indian or Asian origin. Africa is a rich source of many medicinal plants that have been scientifically proven to counteract myriad pathologies. When perusing these studies, one will notice that some African medicinal plants can counteract the molecular pathways (e.g. proliferation, vasoconstriction, inflammation, oxidative stress and mitochondrial dysfunction) that are also involved in the pathogenesis of PH. We review the actions of these plants with actions applicable to PH and highlight that they could be repurposed as adjunct PH therapies. However, these plants have either never been tested in PH, or there is little evidence of their actions against PH. We therefore encourage caution, as more research is needed to study these plants further in experimental models of PH while acknowledging that the outcomes of such proof of-concept studies may not always yield promising findings. Regardless, this article aims to stimulate future research that could make timely contributions to the field. Study synopsis: What the study adds. Pulmonary hypertension (PH) remains a fatal disease, and 80% of the patients live in developing countries where resources are scarce and specialised therapies are often unavailable. Drug repurposing is a viable option to try to improve treatment outcomes.Implications of the findings. We propose that another form of 'drug' repurposing is the use of medicinal plants, many of which have demonstrated benefits against pathological processes that are also key in PH, e.g. apoptosis, tumour-like growth of cells, proliferation, oxidative stress and mitochondrial dysfunction.

Pediatric neurogenic bowel dysfunction: ICCS review document.

INTRODUCTION: The International Children's Continence Society (ICCS) aims to improve the quality of life in children with lower urinary tract dysfunction. A substantial portion of children also have problems with bowel dysfunction. There is a lack of evidence-based information on managing neurogenic bowel dysfunction (NBD) in children. OBJECTIVE/METHODS: The ICCS aimed to provide an up-to-date, selective, non-systematic review of NBD's definitions, assessment, and treatment. RESULTS: Specific definitions and terminology are defined within the document. Recommendations and considerations for physical assessment, history taking, and diagnostic studies are made. Management updates, both surgical and non-surgical, are provided as well as recommendations for follow-up and monitoring of individuals with NBD. CONCLUSION: This review of the current literature will help guide NBD management and research to improve NBD care.

Bone mineral concentration predicted by dual energy X-ray absorptiometry and its relationship with lamb eating quality.

Lumbar bone mineral concentration, as predicted by dual energy x-ray absorptiometry (DEXA), may reflect changes in lamb maturity and eating quality. New season (n = 60) and old season (n = 60) lambs were slaughtered and DEXA scanned at a commercial abattoir across 2 kill groups. The second lumbar vertebra was isolated from the spine for determination of calcium, phosphorus, and magnesium concentration (mg/g). The loin and rack cuts were collected for consumer sensory grilling and roasting analyses. Mineral concentration was significantly higher in old season lambs within kill group 1 (P < 0.05). DEXA was a positive predictor of phosphorus and calcium concentration, but only when DEXA lean % (P < 0.05) was included in the model. Calcium and phosphorus were significant positive predictors of overall liking scores (P < 0.05), but only for the rack roast. These effects became insignificant when DEXA lean % was included. These results suggest that DEXA values likely reflect changes in both DEXA lean % and bone minerals, and that DEXA lean % was the driver of eating quality, rather than maturity.

The potential for dual energy X-ray absorptiometry to predict lamb eating quality.

Data were obtained from 120 lambs which were slaughtered, scanned using dual energy X-ray absorptiometry (DEXA) and underwent eating quality assessment. DEXA images were used to determine R values, reflecting atomic mass, to predict carcass lean %. Additionally, bone regions (humerus, lumbar, femur and "all carcass bone") were isolated from images to determine bone specific R values (DEXA R Mean and SDev). Prediction of overall liking of cuts across the carcass (scored between 0 and 100) using lean % and bone DEXA was variable. Loin grill overall liking demonstrated significant associations with lumbar DEXA R Mean and SDev, decreasing by 8.6 and 7.6 units across the increasing range of these bone DEXA measures. This association is somewhat independent of carcass lean % and intramuscular fat % of the loin. Given the association of DEXA with eating quality, there are potential benefits for the lamb industry with respect to carcass sorting and marketing during routine processing and DEXA scanning.

Ab Initio Neutrinoless Double-Beta Decay Matrix Elements for

We calculate basis-space converged neutrinoless ßß-decay nuclear matrix elements for the lightest candidates: ^{48}Ca, ^{76}Ge, and ^{82}Se. Starting from initial two- and three-nucleon forces, we apply the ab initio in-medium similarity renormalization group to construct valence-space Hamiltonians and consistently transformed ßß-decay operators. We find that the tensor component is non-negligible in ^{76}Ge and ^{82}Se, and the resulting nuclear matrix elements are overall 25%-45% smaller than those obtained from the phenomenological shell model. While a final matrix element with uncertainties still requires substantial developments, this work nevertheless opens a path toward a true first-principles calculation of neutrinoless ßß decay in all nuclei relevant for ongoing large-scale searches.

Structural development of cortical lobes during the first 6 months of life in infant macaques.

This study mapped the developmental trajectories of cortical regions in comparison to overall brain growth in typically developing, socially-housed infant macaques. Volumetric changes of cortical brain regions were examined longitudinally between 2-24 weeks of age (equivalent to the first 2 years in humans) in 21 male rhesus macaques. Growth of the prefrontal, frontal, parietal, occipital, and temporal cortices (visual and auditory) was examined using MRI and age-specific infant macaque brain atlases developed by our group. Results indicate that cortical volumetric development follows a cubic growth curve, but maturational timelines and growth rates are region-specific. Total intracranial volume (ICV) increased significantly during the first 5 months of life, leveling off thereafter. Prefrontal and temporal visual cortices showed fast volume increases during the first 16 weeks, followed by a plateau, and significant growth again between 20-24 weeks. Volume of the frontal and temporal auditory cortices increased substantially between 2-24 weeks. The parietal cortex showed a significant volume increase during the first 4 months, whereas the volume of the occipital lobe increased between 2-12 weeks and plateaued thereafter. These developmental trajectories show similarities to cortical growth in human infants, providing foundational information necessary to build nonhuman primate (NHP) models of human neurodevelopmental disorders.

Malignant transformation of tailgut cysts is significantly higher than previously reported: systematic review of cases in the literature.

AIM: The best treatment for tailgut cysts has not been firmly established. We report a systematic review of the cases in the available literature in order to provide an evidence base for treatment. METHOD: A systematic search of articles wholly or partly in English was made of PubMed, Embase and Google Scholar; additional studies were discovered by searching reference lists and contacting authors directly. Search terms 'tailgut cyst', 'tail gut cyst', 'retrorectal hamartoma' and 'retrorectal tumour' were used for case reports or case series; no publication date restrictions were imposed. Only studies with histological confirmation of diagnosis and reporting the age and gender of patients were included. Papers were excluded by consensus between the first two authors. RESULTS: A total of 196 individual cases were analysed in detail including 51 cases of neoplasia. The overall rate of neoplastic transformation was 26.6%. Although the male:female cyst incidence ratio was 1:4, men over 18 had a significantly greater relative risk of neoplasm at 1.94 (P = 0.0055). Radiological evidence of nodular thickening of the cyst wall significantly increased the relative risk of the presence of cancer (P = 0.0023). CONCLUSIONS: Current orthodoxy that these are not dangerous embryological remnants is unfounded and may be false. The available data suggest the risk of malignant transformation is high and will apply to any residual tissue after excision. The same rationale behind total mesorectal excision in rectal cancer applies to tailgut cysts. Consequently they should be resected with similar oncological margins.

The discovery and optimization of benzimidazoles as selective NaV1.8 blockers for the treatment of pain.

The voltage gated sodium channel NaV1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole NaV1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.

Understanding and managing fish populations: keeping the toolbox fit for purpose.

Wild fish populations are currently experiencing unprecedented pressures, which are projected to intensify in the coming decades. Developing a thorough understanding of the influences of both biotic and abiotic factors on fish populations is a salient issue in contemporary fish conservation and management. During the 50th Anniversary Symposium of The Fisheries Society of the British Isles at the University of Exeter, UK, in July 2017, scientists from diverse research backgrounds gathered to discuss key topics under the broad umbrella of 'Understanding Fish Populations'. Below, the output of one such discussion group is detailed, focusing on tools used to investigate natural fish populations. Five main groups of approaches were identified: tagging and telemetry; molecular tools; survey tools; statistical and modelling tools; tissue analyses. The appraisal covered current challenges and potential solutions for each of these topics. In addition, three key themes were identified as applicable across all tool-based applications. These included data management, public engagement, and fisheries policy and governance. The continued innovation of tools and capacity to integrate interdisciplinary approaches into the future assessment and management of fish populations is highlighted as an important focus for the next 50 years of fisheries research.

The effects of traffic light labelling versus cartoon labelling on food and beverage purchases in a children's hospital setting.

This study's purpose was to examine changes in healthy and unhealthy items purchased following the implementation of traffic light and cartoon labelling in a small retail food venue (Café Bay) in a children's hospital in eastern North Carolina. Between October 2015 and March 2016, daily food and beverage sales from Café Bay were obtained during baseline, traffic light labelling, a washout period, cartoon labelling (on healthy foods only) and a final washout period. Pearson chi-squared tests and multiple linear regressions were used to examine effects of labelling strategies, controlling for the holidays. In unadjusted analyses, traffic light labelling was associated with significant decreases in purchases of unhealthy items purchased, while cartoon labelling was associated with increases in unhealthy items purchased. In adjusted linear regression analysis, traffic light labelling was associated with fewer unhealthy purchases and thus may have potential to decrease the amount of unhealthy items purchased in a children's hospital food retail venue.

Highly potent and selective NaV1.7 inhibitors for use as intravenous agents and chemical probes.

The discovery and selection of a highly potent and selective NaV1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed. A proposed protein-ligand binding mode for this compound is also provided to rationalise the high levels of potency and selectivity over inhibition of related sodium channels. To further support the proposed binding mode, potent conjugates are described which illustrate the potential for development of chemical probes to enable further target evaluation.

Achieving assessor accuracy on the International Standards for Neurological Classification of Spinal Cord Injury.

STUDY DESIGN: A retrospective audit of assessor accuracy using the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) in three multicentre randomised controlled trials (SCIPA: Spinal Cord Injury and Physical Activity) spanning 2010-2014 with standards revised in 2011. OBJECTIVES: To investigate assessor accuracy of neurological classification after spinal cord injury. SETTING: Australia and New Zealand. METHODS: ISNCSCI examinations were undertaken by trained clinicians prior to randomisation. Data were recorded manually and ISNCSCI worksheets circulated to panels, consensus reached and worksheets corrected. An audit team used a 2014 computerised ISNCSCI algorithm to check manual worksheets. A second audit team assessed whether the 2014 computerised algorithm accurately reflected pre- and post-2011 ISNCSCI standards. RESULTS: Of the 208 ISNCSCI worksheets, 24 were excluded. Of the remaining 184 worksheets, 47 (25.5%) were consistent with the 2014 computerised algorithm and 137 (74.5%) contained one or more errors. Errors were in motor (30.1%) or sensory (12.4%) levels, zone of partial preservation (24.0%), motor/sensory scoring (21.5%), ASIA Impairment Scale (AIS, 8.3%) and complete/incomplete classification (0.8%). Other difficulties included classification when anal contraction/sensation was omitted, incorrect neurological levels and violation of the 'motor follows sensory rule in non-testable myotomes' (7.4%). Panel errors comprised corrections that were incorrect or missed or incorrect changes to correct worksheets. CONCLUSION: Given inaccuracies in the manual ISNCSCI worksheets in this long-term clinical trial setting, continued training and a computerised algorithm are essential to ensure accurate scoring, scaling and classification of the ISNCSCI and confidence in clinical trials.

The discovery of a potent Nav1.3 inhibitor with good oral pharmacokinetics.

In this article, we describe the discovery of an aryl ether series of potent and selective Nav1.3 inhibitors. Based on structural analogy to a similar series of compounds we have previously shown bind to the domain IV voltage sensor region of Nav channels, we propose this series binds in the same location. We describe the development of this series from a published starting point, highlighting key selectivity and potency data, and several studies designed to validate Nav1.3 as a target for pain.

Are edible insects more or less 'healthy' than commonly consumed meats? A comparison using two nutrient profiling models developed to combat over- and undernutrition.

BACKGROUND/OBJECTIVES: Insects have been the subject of recent attention as a potentially environmentally sustainable and nutritious alternative to traditional protein sources. The purpose of this paper is to test the hypothesis that insects are nutritionally preferable to meat, using two evaluative tools that are designed to combat over- and under-nutrition. SUBJECTS/METHODS: We selected 183 datalines of publicly available data on the nutrient composition of raw cuts and offal of three commonly consumed meats (beef, pork and chicken), and six commercially available insect species, for energy and 12 relevant nutrients. We applied two nutrient profiling tools to this data: The Ofcom model, which is used in the United Kingdom, and the Nutrient Value Score (NVS), which has been used in East Africa. We compared the median nutrient profile scores of different insect species and meat types using non-parametric tests and applied Bonferroni adjustments to assess for statistical significance in differences. RESULTS: Insect nutritional composition showed high diversity between species. According to the Ofcom model, no insects were significantly 'healthier' than meat products. The NVS assigned crickets, palm weevil larvae and mealworm a significantly healthier score than beef (P<0.001) and chicken (P<0.001). No insects were statistically less healthy than meat. CONCLUSIONS: Insect nutritional composition is highly diverse in comparison with commonly consumed meats. The food category 'insects' contains some foods that could potentially exacerbate diet-related public health problems related to over-nutrition, but may be effective in combating under-nutrition.

Mechanism of the biomolecular synthesis of PEDOT:PSS: importance of heme degradation by hydrogen peroxide.

The use of biomolecules as oxidants for the synthesis of conducting polymers provides an important tool for the control of polymer properties. Using PEDOT: PSS as a representative conducting polymer, we compare a set of heme proteins (soybean peroxidase, cytochrome c, and horseradish peroxidase) used as oxidants. The resulting PEDOT: PSS was characterized with visible and near IR spectroscopy, Fourier transform infrared spectroscopy, electron spin resonance spectroscopy, and four point probe conductivity measurements. We find that the relative concentrations of bipolarons and polarons vary as a function of the protein used for polymerization. We then show that heme degradation by hydrogen peroxide plays a critical role in determining polymer properties.

Translation research: 'Back on Track', a multiprofessional rehabilitation service for cancer-related fatigue.

OBJECTIVES: To assess the effectiveness and acceptability of an individually tailored rehabilitation intervention for patients with cancer-related fatigue (CRF). METHODS: Eighteen individuals, (16 female, two male, aged 40-83 years), who self-reported CRF (above four on a 10-point Likert scale) took part in an 8 week physical activity intervention weekly review and optional gym-based support. Fifteen participants had a primary diagnosis of breast cancer and along with the other participants had multiple myeloma, colorectal or prostate cancer. All participants took part in a goal-oriented walking and muscle strengthening programme with dietary advice and psychological support based on the Transtheoretical Model (TTM) of behaviour change. Effectiveness was assessed by physical and psychological outcomes. Focus groups with participants and individual interviews with the professionals delivering the intervention explored the feasibility and acceptability of the intervention. RESULTS: Statistically significant improvements were seen in the primary outcome of fatigue and on the secondary outcomes of physical function, depression and in triceps skin fold thickness reduction. Participants endorsed the intervention as being highly acceptable, holistic and as important as medical treatments for cancer. The importance of team working was highlighted as key to service delivery and success. CONCLUSIONS: A multidisciplinary home-based tailored intervention with optional weekly gym attendance is acceptable to people with CRF, improving physical and psychosocial outcomes. Study limitations and suggestions for further research are discussed.