A nose for trouble: ecotoxicological implications for climate change and disease in Saiga antelope (S. t. tatarica).

In recent decades, Saiga antelope (Saiga t. tatarica) mass die-offs have become more common. The mass die-off of 2015 in central Kazakhstan, recorded 140,000 individual deaths across multiple herds. Previously, research has shown atmospheric humidity, the bacterium Pasteurella multocida serotype B, and resultant haemorrhagic septicaemia, were the primary cause. However, other synergistic factors may have impacted this process. Here we use a multivariate compositional data analysis (CoDA) approach to assess what other factors may have been involved. We show a pollutant linkage mechanism where relative humidity and dewpoint temperature combine with environmental pollutants, potentially toxic elements (e.g., Hg, As), complex carbon compounds (e.g., Acetone, Toluene), and inorganic compounds (e.g., CHx, SO2) which affected the Saiga during the calving season (start and peak) and at the onset of the mass die-off. We suggest a mechanism for this process. Upon arrival at their carving grounds, the Saiga experienced a sudden precipitation event, a spike in temperatures, and resultant high humidity occurs. The infectious bacterium P. multocida serotype B then spreads. Further, environmental pollutants contained within steppe soils are released to the air, forming localised smog events, these synergistically combine, and mass die-off occurs.

The impact of long haul travel on the sleep of elite athletes.

In order to manage and implement strategies to alleviate the symptoms of jet lag it is essential to assess the impact of jet lag in athletes. The aim of this study was to assess the impact of long haul eastward travel on elite athletes' (n = 7 elite national track cyclists; male n = 3, and female n = 4) sleep. The athletes' sleep was monitored before, during and after travel using both actigraphy and self-report measures. Participants wore an activity monitor for 5 days prior to travel, during the long haul travel and 5 days upon arrival at their destination and completed a daily online sleep diary Actigraphy highlighted significant reductions in time in bed, total sleep time and sleep efficiency (%) due to long haul eastward travel, particularly in the 48 h after travel. Sleep diary data exhibited significant reductions in time in bed, total sleep time, sleep efficiency, sleep quality and a significant increase in fatigue going to bed as a result of long haul eastward travel. In order to facilitate the development of interventions to reduce the symptoms and severity of jet lag objective and subjective assessments of sleep should be coupled with assessments of chronotype and perceived sleep need.

Is there a neuroscience-based, mechanistic rationale for transcranial direct current stimulation as an adjunct treatment for posttraumatic stress disorder?

It is well-known that there is considerable variation in the effectiveness of evidence-based treatments for psychiatric disorders, and a continued need to improve the real-world effectiveness of these treatments. In the last 20+ years the examination of noninvasive brain stimulation techniques for psychiatric treatment has increased dramatically. However, in order to test these techniques for effective therapeutic use, it is critical to understand (a) (what are) the key neural circuits to engage for specific disorders or clusters of symptoms, and (b) (how) can these circuits be reached effectively using neurostimulation? Here we focus on the research toward the application of transcranial direct current stimulation (tDCS) for posttraumatic stress disorder (PTSD). tDCS is a portable and inexpensive technique that lends itself well to be combined with, and thus potentially augment, exposure-based treatment for PTSD. In this review, we discuss the behavioral model of threat and safety learning and memory as it relates to PTSD, the underlying neurobiology of PTSD, as well as the current understandings of tDCS action, including its limitations and opportunities. Through this lens, we summarize the research on the application of tDCS to modulated threat and safety learning and memory to date, and propose new directions for its future research. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Heavy metal (PTE) ecotoxicology, data review: Traditional vs. a compositional approach.

Potentially Toxic Elements (PTEs) otherwise known as heavy metals are ubiquitous in soils and can have a range of negative health and environmental impacts. In terrestrial systems understanding how PTEs move in the environment is made challenging by the complex interactions within soil and the wider environment and the compositional nature of PTEs. PTEs are compositional because data of individual PTEs within in a sample are ratios which may be under a sum constraint, where individual components sum up to a whole. In this study three different scenarios were considered, one using the centred log ratio transformation (clr) a compositional transformation, the more "traditional" log10 transformation (log10) and untransformed data acting as a comparison (unt) were applied to four different datasets. Three were the Liver, Muscle and Kidney tissue of Eurasian Badgers (Meles meles) and the fourth was soil and data were extracted from a regional geospatial survey. Cluster analysis demonstrated that the clr and log10 transformation were able to resolve compositional trends at the point of the individual sample, whilst unt could not and did not meet the preconditions for the next phase of analysis. At the level of compositional trends between PTEs complex heatmaps demonstrated that clr was able to isolate PTE relationships and highlight commonalities between different datasets, whilst log10 could not. In the final phase, principal component analysis (PCA) of the clr transformation showed similarities between the signals in the soft tissues and the disparities they had with soil, whilst the log10 transformation was unable to achieve this. Overall, the clr transformation was shown to perform more consistently under a variety of analytical scenarios and the compositional approach will provide more realistic interpretations about PTEs in both soil and animal soft tissue than the log10 or unt conditions.

Potentially toxic element accumulation in badgers (Meles meles): a compositional approach.

Potentially Toxic Elements (PTEs) in Badgers (Meles meles), otherwise known as heavy metals, are unique amongst environmental pollutants occurring, both naturally and anthropogenically. PTEs have a broad range of negative health and environmental effects, therefore identifying their sources and pathways through the environment is imperative for public health policy. This is difficult in terrestrial systems due to the compositional nature of soil geochemistry. In this study, a compositional statistical approach was used to identify how PTEs accumulate in a terrestrial carnivorous mammal, Eurasian Badgers (Meles meles). Compositional principal component analysis (PCA) was used on geochemical data from the Tellus survey, the soil baseline and badger tissue data to map geo-spatial patterns of PTEs and show accumulative trends measured in time. Mapping PCs identified distinct regions of PTE presence in soil and PTE accumulation in badger tissues in Northern Ireland. PTEs were most elevated in liver, kidney and then muscle tissues. Liver and kidney showed the most distinct geo-spatial patterns of accumulation and muscle was the most depleted. PC1 and 2 for each type were modelled using generalised additive mixed models (GAMM) to identify trends through time. PC1 for the liver and muscle were associated with rainfall and ∂N15 in the liver, showing a link to diet and a bioaccumulation pathway, whilst PC2 for both tissues was associated with mean temperature, showing a link to seasonal activity and a bioaccessibility pathway. However, in kidney tissue these trends are reversed and PC1 was associated with bioaccessibility and PC2 with bioaccumulation. Combined these techniques can elucidate both geo-spatial trends in PTEs and the mechanisms by which they move in environment and in future may be an effective tool for assessing PTE bioavailability in environmental health surveys.

Human placental villi contain stromal macrovesicles associated with networks of stellate cells.

Placental function is essential for fetal development and establishing the foundations for lifelong health. The placental villous stroma is a connective tissue layer that supports the fetal capillaries and villous trophoblast. All the nutrients that cross the placenta must also cross the stroma, and yet little is known about this region. This study uses high-resolution three-dimensional imaging to explore the structural complexity of this region within the placental villi. Serial block-face scanning electron microscopy and confocal microscopy were used to image the placental villous stroma in three-dimensions. Transmission electron microscopy (TEM) was used to generate high resolution two-dimensional images. Stereological approaches were used to quantify volumes of stromal constituents. Three-dimensional imaging identified stromal extracellular vesicles, which constituted 3.9% of the villous stromal volume. These stromal extracellular vesicles were ovoid in shape, had a median length of 2750 nm (range 350-7730 nm) and TEM imaging confirmed that they were bounded by a lipid bilayer. Fifty-nine per cent of extracellular vesicles were in contact with a fibroblast-like stellate cell and these vesicles were significantly larger than those where no contact was observed. These stellate cells formed local networks with adherent junctions observed at contact points. This study demonstrates that the villous stroma contains extracellular macrovesicles which are considerably larger than any previously described in tissue or plasma. The size and abundance of these macrovesicles in the villous stroma highlight the diversity of extracellular vesicle biology and their roles within connective tissues.

The Success and Evolution of a Urological "Boot Camp" for Newly Appointed UK Urology Registrars: Incorporating Simulation, Nontechnical Skills and Assessment.

BACKGROUND: Urological training has dramatically changed in recent years. Training durations are shorter and a drive toward consultant led care has reduced trainees experience. Within the UK, approximately 50 registrars annually embark on a 5-year Urology training programme, with variable levels of basic urological experience. OBJECTIVE: To describe a simulation programme aimed at delivering the knowledge and skills necessary to safely and effectively start working as a registrar in Urology by intensive training with a 1:1 faculty to delegate ratio. DESIGN, SETTING, AND PARTICIPANTS: Our course content mirrors the UK training syllabus for junior Urology registrars. We delivered 8 modules over a 4-day programme with a fifth day of assessments. Delegates level of urological knowledge, operative competency and confidence pre-, immediately post-training and at 3-months postcourse were assessed. Objective delegate and faculty feedback was also collected. Technical skills modules include; inguinoscrotal surgery, ureteroscopy, transurethral resection, urodynamics, and Botox administration as well as basic reconstructive and laparoscopic operative skills. "Nontechnical" skills included simulated ward round, out-patient, and emergency scenarios. RESULTS: Feedback from delegates and faculty members has been overwhelmingly positive. We have used this feedback to tailor the content of the course for following years. An increased knowledge level (based on mean examination scores [precourse 55.5%, postcourse 70.1%]) and operative competency was observed in all skills assessed (transurethral resection of the prostate, transurethral resection of bladder tumor, Ureteroscopy, laparoscopic skills, and instrument assembly). Operative confidence was increased immediately and at 3-months postcourse. CONCLUSIONS: Our "boot camp" course provides a realistic introduction and foundation to begin Urological practice. Being delivered at the beginning of the training scheme, prior to intensive patient exposure, registrars are in an optimum position to develop their newly acquired knowledge and skills to enhance training and intends to improve patient safety and satisfaction.

Optimal remediation design and simulation of groundwater flow coupled to contaminant transport using genetic algorithm and radial point collocation method (RPCM).

The simulation-optimisation models of groundwater and contaminant transport can be a powerful tool in the management of groundwater resources and remediation design. In this study, using Multiquadratic Radial Basis Function (MRBF) a coupled groundwater flow and reactive transport of contaminant and oxidant was developed in the framework of the Meshfree method. The parameter analysis has determined the optimum shape parameter (0.97), and the results of the model were compared with a physical sandbox model which were in good agreement. The genetic algorithm approach was used to find the optimum design of the remediation using permanganate as an oxidant. To find the optimum design we considered two objectives and two constraints. The results revealed that the breakthrough of contaminant to the downstream area of interest and the concentration of the contaminant in this area is reduced significantly with optimisation.

Maternal Mortality in Women with Epilepsy.

It is estimated that, in Ireland, there are 10,000 women with epilepsy of childbearing potential1. In this paper the maternal mortality rate for women with epilepsy attending the Rotunda Hospital Epilepsy Clinic 2004 - 2013 was determined. There were 3 maternal deaths in women with epilepsy during this time, which represents a mortality rate of 0.8%. In those women who died, there were concerns in relation to risks to the foetus by taking Anti-Epileptic Drugs (AED) and also issues with access to neurology services before pregnancy, acceptance of specialist support and lack of consistency in advice from health care professionals outside of Ireland. Implementing the nationally agreed care plan for women with epilepsy will improve the quality of care given and potentially we will see a reduction in maternal mortality in these women.

Neuroendocrine tumours of the small bowel: interpretation of raised circulating chromogranin A, urinary 5 hydroxy indole acetic acid and circulating neurokinin A.

BACKGROUND: Neuroendocrine tumours (NETs) of the small bowel are difficult to diagnose as symptoms are non-specific and more often found in common gastrointestinal diseases. Chromogranin A (CGA), urinary 5 hydroxy indole acetic acid (U-5HIAA) and Neurokinin A (NKA) are used as laboratory diagnostic tests but results may be misleading or confusing. AIM: To clarify the relevance of NET biomarkers for diagnosis of small bowel NETs. DESIGN: A review of laboratory test results. METHODS: We reviewed 500 consecutive raised plasma CGA, U-5HIAA and plasma NKA, results from patients in N Ireland. The diagnosis of NET was confirmed by the Northern Ireland Cancer Registry. RESULTS: In 500 specimens recording raised CGA, 52.2% were from patients with NETs, 13.6% being small bowel tumours, 5.4% of specimens from patients with auto-immune atrophic gastritis and 15.4% from patients taking proton pump inhibitors. In 500 specimens with raised U-5HIAA, 87.8% were from patients with NETs, 68.2% being small bowel tumours. Lung NETs contributed 12.2% and NETs from other sites, 7.4%. Of 500 specimens with raised NKA (reference range (RR) > 20 ng/L), 72.6% were from patients with small bowel NETs and 6% specimens from patients with other NETs. In 20% of specimens NKA concentrations were 21-23 ng/L, within limits of assay precision. CONCLUSION: CGA remains the best general circulating marker for NETs although only half of raised test results are due to an NET. U-5HIAA is an excellent marker for small bowel and lung NETs with 80% of high test results confirming these diagnoses. NKA is the most specific biomarker for small bowel NETs.

Epigenetic regulation of the innate immune response to LPS in bovine peripheral blood mononuclear cells (PBMC).

Epigenetic regulation of gene expression could help explain variation in responses to infection and differences in disease susceptibility in cattle. The aim of this study was to examine epigenetic mechanisms in the regulation of LPS-induced innate immune gene expression in peripheral blood mononuclear cells (PBMCs) from five healthy calves. Firstly, epigenetic enzyme gene expression (histone deacetylase (HDAC) and DNA methyltransferase (DNMT)) was measured after LPS stimulation. Secondly, the effect of the histone deacetylase inhibitor Trichostatin A (TSA) on histone H3 acetylation and on innate immune gene expression was also measured. Results showed differential expression of HDAC6, HDAC7 and DNMT3A genes in response to LPS in cells from all animals, while TSA significantly inhibited pro-inflammatory cytokine (TNF, IL2 and IFNG) expression (P<0.05), presumably by histone acetylation. These results suggest an important role for the HDAC family of enzymes in the regulation of bovine innate immune gene expression.

New St. Jude Medical Portico™ transcatheter aortic valve: features and early results.

Patients with symptomatic aortic valve disease who are inoperable or have high surgery-related risks may be treated with transcatheter aortic valve implantation devices. With this method increasingly applied, device innovations are aimed at achieving improved procedural results and therapeutic outcome. This paper describes the innovations implemented in the St. Jude Medical Portico™ system for transcatheter aortic valve implantation, the application of this system and initial clinical experience.

Aldehyde dehydrogenase activity selects for the holoclone phenotype in prostate cancer cells.

Aldehyde dehydrogenase 1 (ALDH) activity is considered to be a marker of cancer stem cells (CSCs) in many tumour models, since these cells are more proliferative and tumourigenic than ALDH(Lo) cells in experimental models. However it is unclear whether all CSC-like cells are within the ALDH(Hi) population, or whether all ALDH(Hi) cells are highly proliferative and tumourigenic. The ability to establish a stem cell hierarchy in vitro, whereby sub-populations of cells have differing proliferative and differentiation capacities, is an alternate indication of the presence of stem cell-like populations within cell lines. In this study, we have examined the interaction between ALDH status and the ability to establish a stem cell hierarchy in PC3 prostate cancer cells. We demonstrate that PC3 cells contain a stem cell hierarchy, and isolation of ALDH(Hi) cells enriches for the most primitive holoclone population, however holoclone formation is not restricted to ALDH(Hi) cells. In addition, we show that ALDH activity undergoes phenotypic plasticity, since the ALDH(Lo) population can develop ALDH(Hi) populations comparable to parental cells within 2 weeks in culture. Furthermore, we show that the majority of ALDH(Hi) cells are found within the least primitive paraclone population, which is circumvented by culturing PC3 cells as spheroids in defined medium favouring stem cell characteristics. Although ALDH(Hi) status enriches for holoclone formation, this activity may be mediated by a minority of ALDH(Hi) cells.

Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study.

OBJECTIVE: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS: Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (± 5 years) who were negative for the familial mutation. RESULTS: In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47·6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS: The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.

Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models.

BACKGROUND AND AIMS: Increased efficiency of energy harvest, due to alterations in the gut microbiota (increased Firmicutes and decreased Bacteroidetes), has been implicated in obesity in mice and humans. However, a causal relationship is unproven and contributory variables include diet, genetics and age. Therefore, we explored the effect of a high-fat (HF) diet and genetically determined obesity (ob/ob) for changes in microbiota and energy harvesting capacity over time. METHODS: Seven-week-old male ob/ob mice were fed a low-fat diet and wild-type mice were fed either a low-fat diet or a HF-diet for 8 weeks (n=8/group). They were assessed at 7, 11 and 15 weeks of age for: fat and lean body mass (by NMR); faecal and caecal short-chain fatty acids (SCFA, by gas chromatography); faecal energy content (by bomb calorimetry) and microbial composition (by metagenomic pyrosequencing). RESULTS: A progressive increase in Firmicutes was confirmed in both HF-fed and ob/ob mice reaching statistical significance in the former, but this phylum was unchanged over time in the lean controls. Reductions in Bacteroidetes were also found in ob/ob mice. However, changes in the microbiota were dissociated from markers of energy harvest. Thus, although the faecal energy in the ob/ob mice was significantly decreased at 7 weeks, and caecal SCFA increased, these did not persist and faecal acetate diminished over time in both ob/ob and HF-fed mice, but not in lean controls. Furthermore, the proportion of the major phyla did not correlate with energy harvest markers. CONCLUSION: The relationship between the microbial composition and energy harvesting capacity is more complex than previously considered. While compositional changes in the faecal microbiota were confirmed, this was primarily a feature of high-fat feeding rather than genetically induced obesity. In addition, changes in the proportions of the major phyla were unrelated to markers of energy harvest which changed over time. The possibility of microbial adaptation to diet and time should be considered in future studies.

Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype.

There is a high and rising prevalence of prostate cancer (PRCA) within the male population of the United Kingdom. Although the relative risk of PRCA is higher in male BRCA2 and BRCA1 mutation carriers, the histological characteristics of this malignancy in these groups have not been clearly defined. We present the histopathological findings in the first UK series of BRCA1 and BRCA2 mutation carriers with PRCA. The archived histopathological tissue sections of 20 BRCA1/2 mutation carriers with PRCA were collected from histopathology laboratories in England, Ireland and Scotland. The cases were matched to a control group by age, stage and serum PSA level of PRCA cases diagnosed in the general population. Following histopathological evaluation and re-grading according to current conventional criteria, Gleason scores of PRCA developed by BRCA1/2 mutation carriers were identified to be significantly higher (Gleason scores 8, 9 or 10, P=0.012) than those in the control group. Since BRCA1/2 mutation carrier status is associated with more aggressive disease, it is a prognostic factor for PRCA outcome. Targeting screening to this population may detect disease at an earlier clinical stage which may therefore be beneficial.

Inhibition or deletion of the lipopolysaccharide receptor Toll-like receptor-4 confers partial protection against lipid-induced insulin resistance in rodent skeletal muscle.

AIMS/HYPOTHESIS: A role for increased activity of the innate immune system in the pathogenesis of insulin resistance is supported by a number of studies. The current study assessed the potential role of the lipopolysaccharide receptor known as Toll-like receptor-4 (TLR-4), a component of the innate immune system, in mediating lipid-induced insulin resistance in skeletal muscle. METHODS: The effects of TLR-4 inhibition/deletion on lipid-induced insulin resistance was determined in skeletal muscle of TLR-4 null mice in vivo and in rat L6 myotubes in vitro. RESULTS: In mice, acute hyperlipidaemia induced skeletal muscle insulin resistance, but a deletion of TLR-4 conferred significant protection against these effects. In L6 myotubes, inhibition of TLR-4 activity substantially reduced the capacity of the saturated fatty acid palmitate to induce insulin resistance. Importantly, palmitate activated the nuclear factor kappaB (NFkappaB) pathway in L6 myotubes and mouse skeletal muscle, and these effects were blocked by inhibition of TLR-4 in L6 myotubes and absence of TLR-4 in skeletal muscle. Furthermore, inhibition of the NFkappaB pathway downstream of TLR-4 in L6 myotubes also protected against the induction of insulin resistance by palmitate. CONCLUSIONS/INTERPRETATION: Inhibition or absence of TLR-4 confers protection against the detrimental effects of lipids on skeletal muscle insulin action, and these effects are associated with a prevention of the activation of the NFkappaB pathway by lipids. Importantly, inhibition of the NFkappaB pathway in myotubes downstream of TLR-4 also protects against lipid-induced insulin resistance, suggesting a mechanism by which reduced TLR-4 activity confers beneficial effects on insulin action.

Delivery of cancer genetics services: The Royal Marsden telephone clinic model.

We have conducted a telelink telephone-led cancer genetic counselling model at The Royal Marsden NHS Foundation Trust. The study commenced in March 2004 and evaluation of the clinic was conducted over 17 months from March 2005 to the end of July 2006. A total of 612 patients had telephone consultations during this time, 228 of whom were referred from primary care with a median of 30 patients counselled per month (range of 19-63, depending on staff availability with average of two staff per clinic). Waiting times were measured for General Practitioner referrals and all 228 were counselled within the national target-stipulated 13 weeks (median 6 weeks, range 1-12). An additional 132 patients who were sent appointment letters after receipt of their family history questionnaires did not attend their appointments (18% of all potential referrals) and required recontacting by letter. After telephone counselling, 42% of patients were able to be discharged from the telephone clinic without a subsequent face-to-face appointment, thereby saving resources. The telephone clinic also had a short set-up time with flexibility on timing and day of administration, which would be an advantage in centres where outreach clinic facilities are scarce. The telelink telephone counselling model is highly efficient in triaging high risk individuals for face-to-face counselling as per the Kenilworth model, in effecting concentration of resources and in providing a flexible individual-centred approach to cancer genetic counselling delivery.