Orai3 Surface Accumulation and Calcium Entry Evoked by Vascular Endothelial Growth Factor.

OBJECTIVE: Vascular endothelial growth factor (VEGF) acts, in part, by triggering calcium ion (Ca(2+)) entry. Here, we sought understanding of a Synta66-resistant Ca(2+) entry pathway activated by VEGF. APPROACH AND RESULTS: Measurement of intracellular Ca(2+) in human umbilical vein endothelial cells detected a Synta66-resistant component of VEGF-activated Ca(2+) entry that occurred within 2 minutes after VEGF exposure. Knockdown of the channel-forming protein Orai3 suppressed this Ca(2+) entry. Similar effects occurred in 3 further types of human endothelial cell. Orai3 knockdown was inhibitory for VEGF-dependent endothelial tube formation in Matrigel in vitro and in vivo in the mouse. Unexpectedly, immunofluorescence and biotinylation experiments showed that Orai3 was not at the surface membrane unless VEGF was applied, after which it accumulated in the membrane within 2 minutes. The signaling pathway coupling VEGF to the effect on Orai3 involved activation of phospholipase Cγ1, Ca(2+) release, cytosolic group IV phospholipase A2α, arachidonic acid production, and, in part, microsomal glutathione S-transferase 2, an enzyme which catalyses the formation of leukotriene C4 from arachidonic acid. Shear stress reduced microsomal glutathione S-transferase 2 expression while inducing expression of leukotriene C4 synthase, suggesting reciprocal regulation of leukotriene C4-synthesizing enzymes and greater role of microsomal glutathione S-transferase 2 in low shear stress. CONCLUSIONS: VEGF signaling via arachidonic acid and arachidonic acid metabolism causes Orai3 to accumulate at the cell surface to mediate Ca(2+) entry and downstream endothelial cell remodeling.

Northern Hemisphere summer monsoon intensified by mega-El Nino/southern oscillation and Atlantic multidecadal oscillation.

Prediction of monsoon changes in the coming decades is important for infrastructure planning and sustainable economic development. The decadal prediction involves both natural decadal variability and anthropogenic forcing. Hitherto, the causes of the decadal variability of Northern Hemisphere summer monsoon (NHSM) are largely unknown because the monsoons over Asia, West Africa, and North America have been studied primarily on a regional basis, which is unable to identify coherent decadal changes and the overriding controls on planetary scales. Here, we show that, during the recent global warming of about 0.4 °C since the late 1970s, a coherent decadal change of precipitation and circulation emerges in the entirety of the NHSM system. Surprisingly, the NHSM as well as the Hadley and Walker circulations have all shown substantial intensification, with a striking increase of NHSM rainfall by 9.5% per degree of global warming. This is unexpected from recent theoretical prediction and model projections of the 21st century. The intensification is primarily attributed to a mega-El Niño/Southern Oscillation (a leading mode of interannual-to-interdecadal variation of global sea surface temperature) and the Atlantic Multidecadal Oscillation, and further influenced by hemispherical asymmetric global warming. These factors driving the present changes of the NHSM system are instrumental for understanding and predicting future decadal changes and determining the proportions of climate change that are attributable to anthropogenic effects and long-term internal variability in the complex climate system.

Physical activity and the drive to exercise in anorexia nervosa.

OBJECTIVES: To investigate physical activity (PA) and drive for exercise in anorexia nervosa (AN) in relation to eating disorder (ED) pathology and anxiety. METHOD: Female participants were recruited into four groups: AN outpatients (n = 37), AN inpatients (n = 18), an anxiety group (n = 34), and healthy controls (HCs; n = 30). PA was measured by actigraphy and self-report together with drive/reasons for exercise, ED pathology, anxiety, depression, stress, BMI, and body composition. RESULTS: ED psychopathology, general psychopathology, and physiological measures were consistent with diagnosis. All groups showed a wide range in activity, especially on self-report. No significant group differences were observed in objective PA levels, yet AN groups reported 57-92% higher total activity than HCs. Outpatients reported more walking and moderate exercise than HCs, and inpatients reported more walking but less moderate and vigorous activity than all other groups. AN groups had significantly higher drive to exercise and valued "improving tone" as important and health and enjoyment as less important reasons to exercise. DISCUSSION: Self-perceived activity rather than objective data may partly explain the increased activity reported in AN. Drive to exercise in AN appears to be more related to ED pathology than to anxiety.

The acceptability and safety of video triage for ambulance service patients and clinicians during the COVID-19 pandemic.

INTRODUCTION: In response to anticipated challenges with urgent and emergency healthcare delivery during the early part of the COVID-19 pandemic, Yorkshire Ambulance Service NHS Trust introduced video technology to supplement remote triage and 'hear and treat' consultations as a pilot project in the EOC. We conducted a service evaluation with the aim of investigating patient and staff acceptability of video triage, and the safety of the decision-making process. METHODS: This service evaluation utilised a mixture of routine and bespoke data collection. We sent postal surveys to patients who were recipients of a video triage, and clinicians who were involved in the video triage pilot logged calls they attempted and undertook. RESULTS: Between 27 March and 25 August 2020, clinicians documented 1073 triage calls. A successful video triage call was achieved in 641 (59.7%) cases. Clinical staff reported that video triage improved clinical assessment and decision making compared to telephone alone, and found the technology accessible for patients. Patients who received a video triage call and responded to the survey (40/201, 19.9%) were also satisfied with the technology and with the care they received. Callers receiving video triage that ended with a disposition of 'hear and treat' had a lower rate of re-contacting the service within 24 hours compared to callers that received clinical hub telephone triage alone (16/212, 7.5% vs. 2508/14349, 17.5% respectively). CONCLUSION: In this single NHS Ambulance Trust evaluation, the use of video triage for low-acuity calls appeared to be safe, with low rates of re-contact and high levels of patient and clinician satisfaction compared to standard telephone triage. However, video triage is not always appropriate for or acceptable to patients and technical issues were not uncommon.

Seven centuries of reconstructed Brahmaputra River discharge demonstrate underestimated high discharge and flood hazard frequency.

The lower Brahmaputra River in Bangladesh and Northeast India often floods during the monsoon season, with catastrophic consequences for people throughout the region. While most climate models predict an intensified monsoon and increase in flood risk with warming, robust baseline estimates of natural climate variability in the basin are limited by the short observational record. Here we use a new seven-century (1309-2004 C.E) tree-ring reconstruction of monsoon season Brahmaputra discharge to demonstrate that the early instrumental period (1956-1986 C.E.) ranks amongst the driest of the past seven centuries (13th percentile). Further, flood hazard inferred from the recurrence frequency of high discharge years is severely underestimated by 24-38% in the instrumental record compared to previous centuries and climate model projections. A focus on only recent observations will therefore be insufficient to accurately characterise flood hazard risk in the region, both in the context of natural variability and climate change.

Optimal management of malignant left-sided large bowel obstruction: do international guidelines agree?

Background: Approximately 20% of patients diagnosed with colorectal cancer will present with left-sided large bowel obstruction. The optimal management of this cohort of patients remains unclear. We aimed to review international guidelines to see if there was a consensus on the treatment of this surgical emergency. Methods: The PubMed and Medline databases were searched for guidelines on the management of left-sided, malignant large bowel obstruction (MBO) between 2010 and 2018. Results: Nineteen guidelines were identified spanning a range of continents. There was no clear consensus on the management of potentially resectable disease. Eight guidelines (42%) suggested primary surgery, two guidelines (11%) suggested stenting as a bridge to surgery and nine guidelines (47%) suggested surgery or stenting could be performed. Primary resection with or without anastomosis was the most frequently recommended procedure (n = 6 35%), but over a third of guidelines gave no operative recommendations. There was very limited detail on the stenting procedure and how long elective surgery should be deferred. In the palliative situation, there was general agreement that stents should be offered in preference to surgery. Conclusion: International guidelines offer limited and contrasting recommendations on the management of left-sided MBO. There is a lack of high-quality evidence to support whether emergency surgery or stenting as a bridge to surgery is the optimal procedure in terms of morbidity, mortality and long-term oncological outcome.

AZD1775 induces toxicity through double-stranded DNA breaks independently of chemotherapeutic agents in p53-mutated colorectal cancer cells.

AZD1775 is a small molecule WEE1 inhibitor used in combination with DNA-damaging agents to cause premature mitosis and cell death in p53-mutated cancer cells. Here we sought to determine the mechanism of action of AZD1775 in combination with chemotherapeutic agents in light of recent findings that AZD1775 can cause double-stranded DNA (DS-DNA) breaks. AZD1775 significantly improved the cytotoxicity of 5-FU in a p53-mutated colorectal cancer cell line (HT29 cells), decreasing the IC50 from 9.3 µM to 3.5 µM. Flow cytometry showed a significant increase in the mitotic marker pHH3 (3.4% vs. 56.2%) and DS-DNA break marker γH2AX (5.1% vs. 50.7%) for combination therapy compared with 5-FU alone. Combination therapy also increased the amount of caspase-3 dependent apoptosis compared with 5-FU alone (4% vs. 13%). The addition of exogenous nucleosides to combination therapy significantly rescued the increased DS-DNA breaks and caspase-3 dependent apoptosis almost to the levels of 5-FU monotherapy. In conclusion, AZD1775 enhances 5-FU cytotoxicity through increased DS-DNA breaks, not premature mitosis, in p53-mutated colorectal cancer cells. This finding is important for designers of future clinical trials when considering the optimal timing and duration of AZD1775 treatment.

Piezo1 channels sense whole body physical activity to reset cardiovascular homeostasis and enhance performance.

Mammalian biology adapts to physical activity but the molecular mechanisms sensing the activity remain enigmatic. Recent studies have revealed how Piezo1 protein senses mechanical force to enable vascular development. Here, we address Piezo1 in adult endothelium, the major control site in physical activity. Mice without endothelial Piezo1 lack obvious phenotype but close inspection reveals a specific effect on endothelium-dependent relaxation in mesenteric resistance artery. Strikingly, the Piezo1 is required for elevated blood pressure during whole body physical activity but not blood pressure during inactivity. Piezo1 is responsible for flow-sensitive non-inactivating non-selective cationic channels which depolarize the membrane potential. As fluid flow increases, depolarization increases to activate voltage-gated Ca2+ channels in the adjacent vascular smooth muscle cells, causing vasoconstriction. Physical performance is compromised in mice which lack endothelial Piezo1 and there is weight loss after sustained activity. The data suggest that Piezo1 channels sense physical activity to advantageously reset vascular control.The mechanisms that regulate the body's response to exercise are poorly understood. Here, Rode et al. show that the mechanically activated cation channel Piezo1 is a molecular sensor of physical exercise in the endothelium that triggers endothelial communication to mesenteric vessel muscle cells, leading to vasoconstriction.

Upregulated WEE1 protects endothelial cells of colorectal cancer liver metastases.

Surgical resection of colorectal cancer liver metastases (CLM) can be curative, yet 80% of patients are unsuitable for this treatment. As angiogenesis is a determinant of CLM progression we isolated endothelial cells from CLM and sought a mechanism which is upregulated, essential for angiogenic properties of these cells and relevant to emerging therapeutic options. Matched CLM endothelial cells (CLMECs) and endothelial cells of normal adjacent liver (LiECs) were superficially similar but transcriptome sequencing revealed molecular differences, one of which was unexpected upregulation and functional significance of the checkpoint kinase WEE1. Western blotting confirmed that WEE1 protein was upregulated in CLMECs. Knockdown of WEE1 by targeted short interfering RNA or the WEE1 inhibitor AZD1775 suppressed proliferation and migration of CLMECs. Investigation of the underlying mechanism suggested induction of double-stranded DNA breaks due to nucleotide shortage which then led to caspase 3-dependent apoptosis. The implication for CLMEC tube formation was striking with AZD1775 inhibiting tube branch points by 83%. WEE1 inhibitors might therefore be a therapeutic option for CLM and could be considered more broadly as anti-angiogenic agents in cancer treatment.

Bread of heaven or wines of light: entheogenic legacies and esoteric cosmologies.

This is an article in two parts. The first part discusses current research in psychoactive preparations of ergot in various religious systems with a particular emphasis on Persian, Greek, Jewish and Islamic sources. Certain poems, hadith, and scriptural writings suggest an entheogenic heritage to various ancient sects that exerted and received philosophical and ritual influences over large distances and over time. Particularly, some esoteric Shia and Sufi writings are highly suggestive of a "celestial botany" that employed psychoactive plants for initiatory and ritual purposes. The second part will address current research methods that render ergot alkaloids nontoxic and entheogenic, a most crucial part of the discussion in the absence of a modern bioassay. This is essential, as without a chemical reality to support that such a preparation of entheogenic ergot is possible, all ergot theories concerning mystery traditions would remain largely speculative.

Rethinking Indian monsoon rainfall prediction in the context of recent global warming.

Prediction of Indian summer monsoon rainfall (ISMR) is at the heart of tropical climate prediction. Despite enormous progress having been made in predicting ISMR since 1886, the operational forecasts during recent decades (1989-2012) have little skill. Here we show, with both dynamical and physical-empirical models, that this recent failure is largely due to the models' inability to capture new predictability sources emerging during recent global warming, that is, the development of the central-Pacific El Nino-Southern Oscillation (CP-ENSO), the rapid deepening of the Asian Low and the strengthening of North and South Pacific Highs during boreal spring. A physical-empirical model that captures these new predictors can produce an independent forecast skill of 0.51 for 1989-2012 and a 92-year retrospective forecast skill of 0.64 for 1921-2012. The recent low skills of the dynamical models are attributed to deficiencies in capturing the developing CP-ENSO and anomalous Asian Low. The results reveal a considerable gap between ISMR prediction skill and predictability.

Are top journals biased against eating disorders topics?

OBJECTIVE: This study investigated whether there is a bias against eating disorders research among the leading psychiatric, psychological, and medical journals. METHOD: The authors performed a comparison between the number of empirical articles published about anorexia nervosa and/or bulimia nervosa and the number of articles published about panic disorder and/or agoraphobia (i.e., disorders of comparable disease burden) in 29 high-impact journals over a 5-year period (1996-2001). RESULTS: There were almost twice as many published empirical articles about panic disorder and/or agoraphobia (N=365) as there were about anorexia nervosa and/or bulimia nervosa (N=169). CONCLUSIONS: The findings indicate a possible bias against eating disorders research among some leading psychiatric journals. Alternative explanations and implications are discussed.

Perforated jejunal diverticula secondary to a large faecolith: a rare cause of the acute abdomen.

Jejunal diverticula are uncommon and usually asymptomatic. Very rarely, they can lead to acute complications such as bleeding, obstruction, and perforation. This report describes our experience of a case of jejunal diverticula perforation secondary to a large faecolith, with particular focus on the aetiology and management of this rare condition.

Development and implementation of South Asia's first heat-health action plan in Ahmedabad (Gujarat, India).

Recurrent heat waves, already a concern in rapidly growing and urbanizing South Asia, will very likely worsen in a warming world. Coordinated adaptation efforts can reduce heat's adverse health impacts, however. To address this concern in Ahmedabad (Gujarat, India), a coalition has been formed to develop an evidence-based heat preparedness plan and early warning system. This paper describes the group and initial steps in the plan's development and implementation. Evidence accumulation included extensive literature review, analysis of local temperature and mortality data, surveys with heat-vulnerable populations, focus groups with health care professionals, and expert consultation. The findings and recommendations were encapsulated in policy briefs for key government agencies, health care professionals, outdoor workers, and slum communities, and synthesized in the heat preparedness plan. A 7-day probabilistic weather forecast was also developed and is used to trigger the plan in advance of dangerous heat waves. The pilot plan was implemented in 2013, and public outreach was done through training workshops, hoardings/billboards, pamphlets, and print advertisements. Evaluation activities and continuous improvement efforts are ongoing, along with plans to explore the program's scalability to other Indian cities, as Ahmedabad is the first South Asian city to address heat-health threats comprehensively.

Methotrexate-induced pulmonary toxicity.

Methotrexate is a widely used medication with an array of recognized side effects. The present report describes a case of methotrexate-induced pneumonitis in a patient with psoriasis, and demonstrates the hallmark clinical and investigational findings that support this infrequently encountered diagnosis. The ensuing discussion reviews the pathogenesis, management and prevention of this adverse drug reaction.

Evaluation of a blended learning model in geriatric medicine: a successful learning experience for medical students.

BACKGROUND: Despite the increasingly ageing population, teaching geriatric medicine at medical schools is a challenge due to the particularities of this subspecialty and the lack of student interest in this subject. METHODS: We assessed a blended system that combines e-learning and person-to-person interaction. Our program offered the students a hands-on learning experience based on self-reflection, access to technology, interactive learning, frequent interaction with the multidisciplinary team, more exposure to patients, and regular feedback. RESULTS: Our results indicate that the students appreciate this system as a rich and effective learning experience demonstrated by their positive feedback and by their significant improvement in knowledge assessed at the end of their rotation. CONCLUSION: Implementing an interactive blended system is a beneficial approach to teaching geriatric medicine in medical schools and to motivating medical students' interest in this important medical subspecialty.

Environmental prediction, risk assessment and extreme events: adaptation strategies for the developing world.

The uncertainty associated with predicting extreme weather events has serious implications for the developing world, owing to the greater societal vulnerability to such events. Continual exposure to unanticipated extreme events is a contributing factor for the descent into perpetual and structural rural poverty. We provide two examples of how probabilistic environmental prediction of extreme weather events can support dynamic adaptation. In the current climate era, we describe how short-term flood forecasts have been developed and implemented in Bangladesh. Forecasts of impending floods with horizons of 10 days are used to change agricultural practices and planning, store food and household items and evacuate those in peril. For the first time in Bangladesh, floods were anticipated in 2007 and 2008, with broad actions taking place in advance of the floods, grossing agricultural and household savings measured in units of annual income. We argue that probabilistic environmental forecasts disseminated to an informed user community can reduce poverty caused by exposure to unanticipated extreme events. Second, it is also realized that not all decisions in the future can be made at the village level and that grand plans for water resource management require extensive planning and funding. Based on imperfect models and scenarios of economic and population growth, we further suggest that flood frequency and intensity will increase in the Ganges, Brahmaputra and Yangtze catchments as greenhouse-gas concentrations increase. However, irrespective of the climate-change scenario chosen, the availability of fresh water in the latter half of the twenty-first century seems to be dominated by population increases that far outweigh climate-change effects. Paradoxically, fresh water availability may become more critical if there is no climate change.

Impact of shifting patterns of Pacific Ocean warming on North Atlantic tropical cyclones.

Two distinctly different forms of tropical Pacific Ocean warming are shown to have substantially different impacts on the frequency and tracks of North Atlantic tropical cyclones. The eastern Pacific warming (EPW) is identical to that of the conventional El Niño, whereas the central Pacific warming (CPW) has maximum temperature anomalies located near the dateline. In contrast to EPW events, CPW episodes are associated with a greater-than-average frequency and increasing landfall potential along the Gulf of Mexico coast and Central America. Differences are shown to be associated with the modulation of vertical wind shear in the main development region forced by differential teleconnection patterns emanating from the Pacific. The CPW is more predictable than the EPW, potentially increasing the predictability of cyclones on seasonal time scales.