ADMA: A key player in the relationship between vascular dysfunction and inflammation in atherosclerosis

Atherosclerosis is a chronic cardiovascular disease which increases risk of major cardiovascular events including myocardial infarction and stroke. Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) have long been recognised as a hallmark of cardiovascular disease and are associated with cardiovascular risk factors including hypertension, obesity and hypertriglyceridemia. In this review, we discuss the clinical literature that link ADMA concentrations to increased risk of the development of atherosclerosis. The formation of atherosclerotic lesions relies on the interplay between vascular dysfunction, leading to endothelial activation and the accumulation of inflammatory cells, particularly macrophages, within the vessel wall. Here, we review the mechanisms through which elevated ADMA contributes to endothelial dysfunction, activation and reactive oxygen species (ROS) production; how ADMA may affect vascular smooth muscle phenotype; and finally whether ADMA plays a regulatory role in the inflammatory processes occurring within the vessel wall

Economics of Tourism and Transport: An Introduction

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Effects of ramadan intermittent fasting on sports performance and training: A review

The month-long diurnal Ramadan fast imposes a major challenge to Islamic athletes. Sporting events are programmed throughout the year, with the result that training and competition are often scheduled during Ramadan. The small numbers of well-controlled studies that have examined the effects of Ramadan on athletic performance suggest that few aspects of physical fitness are negatively affected, and only modest decrements are observed. Whereas subjective feelings of fatigue and other mood indicators are often cited as implying additional stress on the athlete throughout Ramadan, most studies show these measures may not be reflected in decreases in performance. The development and early implementation of sensible eating and sleeping strategies can greatly alleviate the disruptions to training and competitiveness, thus allowing the athlete to perform at a high level while undertaking the religious intermittent fast. Nevertheless, further research is required to understand the mechanisms and energy pathways that allow athletes to maintain their performance capacities during Ramadan, and which factors are responsible for the observed decrements in performance of some individuals. © Human Kinetics, Inc

ORIGINAL COMMUNICATION Effects on health of fluid restriction during fasting in Ramadan

During the 9th month (Ramadan) of the Islamic calendar (Hijra) many millions of adult Muslims all over the world fast during the daylight hours. Since Hijra is a lunar calendar, Ramadan occurs at different times in the seasonal year over a 33-year cycle. Fasting during Ramadan is partial because the abstention from food, fluid, tobacco and caffeine is from sunrise to sunset. Several categories of people are exempt or can postpone the Ramadan fast. The effect on health and well being of the month-long intermittent fast and fluid restriction has been studied in various potentially vulnerable groups in addition to normal healthy individuals in many countries. The majority of the studies have found significant metabolic changes, but few health problems arising from the fast. A reduction in drug compliance was an inherent negative aspect of the fast. Common findings of the studies reviewed were increased irritability and incidences of headaches with sleep deprivation and lassitude prevalent. A small body mass loss is a frequent, but not universal, outcome of Ramadan. During the daylight hours of Ramadan fasting, practising Muslims are undoubtedly dehydrating, but it is not clear whether they are chronically hypohydrated during the month of Ramadan. No detrimental effects on health have as yet been directly attributed to negative water balance at the levels that may be produced during Ramadan

Evaluation of low temperature waste heat as a low carbon heat resource in the UK

The capture and transport of waste heat represents a great opportunity for the decarbonisation of heat supply in buildings. To date, mostly high temperature waste heat has been reused and reported. However, with the recent advent of low and ambient temperature (4th and 5th generation) district energy networks, there is scope for the recovery and utilisation of heat from a range of novel, low temperature sources. The current study represents one of the first attempts to quantify the size of this opportunity, with particular focus in the UK, and complements the few previous attempts at estimating low temperature waste heat by focussing on a range of novel sources. The approach used was to evaluate a number of low temperature waste heat sources to determine: (a) the annual quantity of waste heat generated; and (b) the temperature(s) of the waste heat, for each heat source. In many cases, this was achieved using methodology and assumptions derived from the authors’ earlier investigations. The relative merits and potential of each heat source are also discussed, with respect to location, proximity to end users, need for upgrade using a heat pump, continuity of supply and distribution options for reuse, for example by using district energy networks with different operating temperatures. The total quantity of waste heat energy identified from the heat sources considered in this study, for England, Wales and Northern Ireland, was estimated to be 572 TWh.a−1, which would represent 132% of the total energy consumption for heat in these countries (432 TWh.a−1). Although this study focused on the UK potential for low temperature waste heat, the estimation methods developed and resulting analysis are generic and could also be applied in the context of other countries

A Novel Pathway for Metabolism of the Cardiovascular Risk Factor Homoarginine by alanine:glyoxylate aminotransferase 2

Low plasma concentrations of L-homoarginine are associated with an increased risk of cardiovascular events, while homoarginine supplementation is protective in animal models of metabolic syndrome and stroke. Catabolism of homoarginine is still poorly understood. Based on the recent findings from a Genome Wide Association Study we hypothesized that homoarginine can be metabolized by alanine:glyoxylate aminotransferase 2 (AGXT2). We purified human AGXT2 from tissues of AGXT2 transgenic mice and demonstrated its ability to metabolize homoarginine to 6-guanidino-2-oxocaproic acid (GOCA). After incubation of HepG2 cells overexpressing AGXT2 with isotope-labeled homoarginine-d4 we were able to detect labeled GOCA in the medium. We injected wild type mice with labeled homoarginine and detected labeled GOCA in the plasma. We found that AGXT2 knockout (KO) mice have higher homoarginine and lower GOCA plasma levels as compared to wild type mice, while the reverse was true for AGXT2 transgenic (Tg) mice. In summary, we experimentally proved the presence of a new pathway of homoarginine catabolism - its transamination by AGXT2 with formation of GOCA and demonstrated that endogenous AGXT2 is required for maintenance of homoarginine levels in mice. Our findings may lead to development of novel therapeutic approaches for cardiovascular pathologies associated with homoarginine deficiency

Asymmetric dimethylarginine enables depolarizing spikes and vasospasm in mesenteric and coronary resistance arteries

BACKGROUND: Increased vasoreactivity due to reduced endothelial NO bioavailability is an underlying feature of cardiovascular disease, including hypertension. In small resistance arteries, declining NO enhances vascular smooth muscle (VSM) reactivity partly by enabling rapid depolarizing Ca2+-based spikes that underlie vasospasm. The endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) is metabolized by DDAH1 (dimethylarginine dimethylaminohydrolase 1) and elevated in cardiovascular disease. We hypothesized ADMA might enable VSM spikes and vasospasm by reducing NO bioavailability, which is opposed by DDAH1 activity and L-arginine. METHODS: Rat isolated small mesenteric arteries and myogenic rat-isolated intraseptal coronary arteries (RCA) were studied using myography, VSM intracellular recording, Ca2+ imaging, and DDAH1 immunolabeling. Exogenous ADMA was used to inhibit NO synthase and a selective DDAH1 inhibitor, NG-(2-methoxyethyl) arginine, to assess the functional impact of ADMA metabolism. RESULTS: ADMA enhanced rat-isolated small mesenteric arteries vasoreactivity to the α1-adrenoceptor agonist, phenylephrine by enabling T-type voltage-gated calcium channel-dependent depolarizing spikes. However, some endothelium-dependent NO-vasorelaxation remained, which was sensitive to DDAH1-inhibition with NG-(2-methoxyethyl) arginine. In myogenically active RCA, ADMA alone stimulated depolarizing Ca2+ spikes and marked vasoconstriction, while NO vasorelaxation was abolished. DDAH1 expression was greater in rat-isolated small mesenteric arteries endothelium compared with RCA, but low in VSM of both arteries. L-arginine prevented depolarizing spikes and protected NO-vasorelaxation in rat-isolated small mesenteric artery and RCA. CONCLUSIONS: ADMA increases VSM electrical excitability enhancing vasoreactivity. Endothelial DDAH1 reduces this effect, and low levels of DDAH1 in RCAs may render them susceptible to endothelial dysfunction contributing to vasospasm, changes opposed by L-arginine

Risk of Injury in Royal Air Force Training: Does Sex Really Matter?

IntroductionMusculoskeletal injuries are common during military and other occupational physical training programs. Employers have a duty of care to reduce employees’ injury risk, where females tend to be at greater risk than males. However, quantification of principle co-factors influencing the sex–injury association, and their relative importance, remain poorly defined. Injury risk co-factors were investigated during Royal Air Force (RAF) recruit training to inform the strategic prioritization of mitigation strategies.Material and MethodsA cohort of 1,193 (males n = 990 (83%); females n = 203 (17%)) recruits, undertaking Phase-1 military training, were prospectively monitored for injury occurrence. The primary independent variable was sex, and potential confounders (fitness, smoking, anthropometric measures, education attainment) were assessed pre-training. Generalized linear models were used to assess associations between sex and injury.ResultsIn total, 31% of recruits (28% males; 49% females) presented at least one injury during training. Females had a two-fold greater unadjusted risk of injury during training than males (RR = 1.77; 95% CI 1.49–2.10). After anthropometric, lifestyle and education measures were included in the model, the excess risk decreased by 34%, but the associations continued to be statistically significant. In contrast, when aerobic fitness was adjusted, an inverse association was identified; the injury risk was 40% lower in females compared with males (RR = 0.59; 95% CI: 0.42–0.83).ConclusionsPhysical fitness was the most important confounder with respect to differences in males’ and females’ injury risk, rather than sex alone. Mitigation to reduce this risk should, therefore, focus upon physical training, complemented by healthy lifestyle interventions

Assessment of the direct effects of DDAH I on tumour angiogenesis in vivo

Nitric oxide (NO) has been strongly implicated in glioma progression and angiogenesis. The endogenous inhibitors of NO synthesis, asymmetric dimethylarginine (ADMA) and N-monomethyl-l-arginine (l-NMMA), are metabolized by dimethylarginine dimethylaminohydrolase (DDAH), and hence, DDAH is an intracellular factor that regulates NO. However, DDAH may also have an NO-independent action. We aimed to investigate whether DDAH I has any direct role in tumour vascular development and growth independent of its NO-mediated effects, in order to establish the future potential of DDAH inhibition as an anti-angiogenic treatment strategy. A clone of rat C6 glioma cells deficient in NO production expressing a pTet Off regulatable element was identified and engineered to overexpress DDAH I in the absence of doxycycline. Xenografts derived from these cells were propagated in the presence or absence of doxycycline and susceptibility magnetic resonance imaging used to assess functional vasculature in vivo. Pathological correlates of tumour vascular density, maturation and function were also sought. In the absence of doxycycline, tumours exhibited high DDAH I expression and activity, which was suppressed in its presence. However, overexpression of DDAH I had no measurable effect on tumour growth, vessel density, function or maturation. These data suggest that in C6 gliomas DDAH has no NO-independent effects on tumour growth and angiogenesis, and that the therapeutic potential of targeting DDAH in gliomas should only be considered in the context of NO regulation