‘‘Beet-ing’’ the Mountain: A Review of the Physiological and Performance Effects of Dietary Nitrate Supplementation at Simulated and Terrestrial Altitude

Exposure to altitude results in multiple physiological consequences. These include, but are not limited to, a reduced maximal oxygen consumption, drop in arterial oxygen saturation, and increase in muscle metabolic perturbations at a fixed sub-maximal work rate. Exercise capacity during fixed work rate or incremental exercise and time-trial performance are also impaired at altitude relative to sea-level. Recently, dietary nitrate (NO3-) supplementation has attracted considerable interest as a nutritional aid during altitude exposure. In this review, we summarise and critically evaluate the physiological and performance effects of dietary NO3- supplementation during exposure to simulated and terrestrial altitude. Previous investigations at simulated altitude indicate that NO3- supplementation may reduce the oxygen cost of exercise, elevate arterial and tissue oxygen saturation, improve muscle metabolic function, and enhance exercise capacity/ performance. Conversely, current evidence suggests that NO3- supplementation does not augment the training response at simulated altitude. Few studies have evaluated the effects of NO3- at terrestrial altitude. Current evidence indicates potential improvements in endothelial function at terrestrial altitude following NO3- supplementation. No effects of NO3- supplementation have been observed on oxygen consumption or arterial oxygen saturation at terrestrial altitude, although further research is warranted. Limitations of the present body of literature are discussed, and directions for future research are provided

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: A comparative risk assessment

Background: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. Methods: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. Findings: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. Interpretation: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. Funding: UK Medical Research Council, US National Institutes of Health. © 2014 Elsevier Ltd

Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has an exceedingly low median overall survival of only 15 months. Current standard-of-care for GBM consists of gross total surgical resection followed by radiation with concurrent and adjuvant chemotherapy. Temozolomide (TMZ) is the first-choice chemotherapeutic agent in GBM; however, the development of resistance to TMZ often becomes the limiting factor in effective treatment. While O6-methylguanine-DNA methyltransferase repair activity and uniquely resistant populations of glioma stem cells are the most well-known contributors to TMZ resistance, many other molecular mechanisms have come to light in recent years. Key emerging mechanisms include the involvement of other DNA repair systems, aberrant signaling pathways, autophagy, epigenetic modifications, microRNAs, and extracellular vesicle production. This review aims to provide a comprehensive overview of the clinically relevant molecular mechanisms and their extensive interconnections to better inform efforts to combat TMZ resistance

Laparoscopic adrenalectomy of pheochromocytoma following management of severe aortic stenosis with transcatheter aortic valve replacement under monitored anesthesia care sedation: a case report

Abstract Background Management of a patient with an active pheochromocytoma and severe aortic stenosis remains controversial. Adrenalectomy for a pheochromocytoma poses a high risk for stroke, hypertensive emergency, and mortality, compounded by the cardiovascular instability of severe aortic stenosis. In this case report, successful management of an active pheochromocytoma with concomitant severe aortic stenosis was accomplished by performing transcatheter aortic valve replacement under monitored anesthesia care prior to laparoscopic adrenalectomy. Case presentation An 84-year-old woman with severe aortic stenosis (valve area 0.53 cm2) presented with a symptomatic pheochromocytoma. Transcatheter aortic valve replacement was performed under monitored anesthesia care using a judicious approach of 100 mcg fentanyl total, 4 mg total of midazolam, and a background dexmedetomidine infusion. Alpha-blockade was maintained with 10 mg total of phentolamine mesylate. Laparoscopic adrenalectomy was performed after an uncomplicated postoperative course. The perioperative course for the adrenalectomy was unremarkable and the patient was hemodynamically stable. Postoperative course was uncomplicated and the patient was discharged from the hospital after 5 days. Conclusion This case report demonstrated the successful approach of managing severe aortic stenosis through a transcatheter aortic valve replacement using monitored anesthesia care sedation prior to laparoscopic adrenalectomy of a symptomatic pheochromocytoma

Managing acute ischaemic stroke in a small island developing state: meeting the guidelines in Barbados

Abstract Background We describe hospital-based management of acute ischaemic stroke patients in 2010–2013 in Barbados, by comparing documented treatment given in the single tertiary public hospital with international guideline recommendations. Methods Evidence-based stroke management guidelines were identified through a systematic literature search. Comparisons were made between these guidelines and documented diagnostic practice (all strokes) and prescribed medication (ischaemic stroke only), using a combination of key informant interviews and national stroke registry data for 2010–2013. Results Several published international guidelines for the acute management of ischaemic stroke recommended patient management in a dedicated stroke unit or nearest hospital specialised in stroke care. Further, patients should receive clinical diagnosis, CT brain scan, specialist evaluation by a multidisciplinary team and, if eligible, thrombolysis with alteplase within 3–3.5 h of symptom onset. Subsequent secondary prophylaxis, with a platelet aggregation inhibitor and a statin was advised. Barbados had no stroke unit or stroke team, and no official protocol for acute stroke management during the study period. Most of the 1735 stroke patients were managed by emergency physicians at presentation; if admitted, they were managed on general medical wards. Most had a CT scan (1646; 94.9%). Of 1406 registered ischaemic stroke patients, only 6 (0.4%) had been thrombolysed, 521 (37.1%) received aspirin within 24 h of admission and 670 (47.7%) were prescribed aspirin on discharge. Conclusions Acute ischaemic stroke diagnosis was consistent with international recommendations, although this was less evident for treatment. While acknowledging the difficulty in implementing international guidelines in a low-resource setting, there is scope for improvement in acute ischaemic stroke management and/or its documentation in Barbados. A stroke unit was established in August 2013 and written clinical protocols for acute stroke care were in development at the time of the study; future registry data will evaluate their impact. Our findings have implications for other low-resource settings with high stroke burden

The Global Cardiovascular Risk Transition Associations of Four Metabolic Risk Factors with National Income, Urbanization, and Western Diet in 1980 and 2008

Background-It is commonly assumed that cardiovascular disease risk factors are associated with affluence and Westernization. We investigated the associations of body mass index (BMI), fasting plasma glucose, systolic blood pressure, and serum total cholesterol with national income, Western diet, and, for BMI, urbanization in 1980 and 2008