Development of a Novel Tool To Demystify Drug Distribution at Tissue-Blood Barriers.

Tissue endothelial cells express ABC-transporter enzymes that change the concentration of small molecules within different tissue compartments. These "blood-tissue barriers" have been shown to directly affect the efficacy and toxicity of anticancer, antimicrobial, psychiatric, and anti-epileptic drugs. Currently this phenomenon is best studied for the blood-brain barrier, but remains enigmatic for most other tissues. In addition, canonical pharmacokinetic theory specifically assumes an equal concentration of free drug within all tissue compartments. Inspired by Lipinski's "rule of 5," we here clarify current knowledge on drug-tissue distribution by: 1) curating the in-vivo literature on 73 drugs across 23 tissues and 2) developing two graphical web-based applications to visually describe and interpret data. These curated in-vivo dataset and visualization tools enabled us to achieve new insights into the logic of the barrier-tissue organization and showed remarkable correspondence to whole-body imaging of radiolabeled molecules.

Cell age-specific vulnerability of neurons to anesthetic toxicity.

OBJECTIVE: Anesthetics have been linked to widespread neuronal cell death in neonatal animals. Epidemiological human studies have associated early childhood anesthesia with long-term neurobehavioral abnormalities, raising substantial concerns that anesthetics may cause similar cell death in young children. However, key aspects of the phenomenon remain unclear, such as why certain neurons die, whereas immediately adjacent neurons are seemingly unaffected, and why the immature brain is exquisitely vulnerable, whereas the mature brain seems resistant. Elucidating these questions is critical for assessing the phenomenon's applicability to humans, defining the susceptible age, predicting vulnerable neuronal populations, and devising mitigating strategies. METHODS: This study examines the effects of anesthetic exposure on late- and adult-generated neurons in newborn, juvenile, and adult mice, and characterizes vulnerable cells using birth-dating and immunohistochemical techniques. RESULTS: We identify a critical period of cellular developmental during which neurons are susceptible to anesthesia-induced apoptosis. Importantly, we demonstrate that anesthetic neurotoxicity can extend into adulthood in brain regions with ongoing neurogenesis, such as dentate gyrus and olfactory bulb. INTERPRETATION: Our findings suggest that anesthetic vulnerability reflects the age of the neuron, not the age of the organism, and therefore may potentially not only be relevant to children but also to adults undergoing anesthesia. This observation further predicts differential heightened regional vulnerability to anesthetic neuroapoptosis to closely follow the distinct regional peaks in neurogenesis. This knowledge may help guide neurocognitive testing of specific neurological domains in humans following exposure to anesthesia, dependent on the individual's age during exposure.

A combination of mild hypothermia and sevoflurane affords long-term protection in a modified neonatal mouse model of cerebral hypoxia-ischemia.

BACKGROUND: Infant brain injury from hypoxia-ischemia (HI) can lead to life-long impairment, but protective strategies are lacking. Short-term but not long-term protection has been demonstrated in the Rice-Vannucci neonatal brain ischemia model (RVM) by volatile anesthetic administration before HI, while exposure during HI has not been tested. In the current study, we evaluated a combination of sevoflurane and mild hypothermia as a protective approach during HI, both short- and long-term, by introducing intubation and mechanical ventilation to the RVM. METHODS: The right common carotid artery was ligated in 10-day-old mice during brief sevoflurane anesthesia, followed by a 2-hour recovery with the dam. Littermates were then randomized to either: HI spontaneously breathing 10% oxygen for 60 minutes (the classical RVM); HI-Protect mild hypothermia and orotracheal intubation and mechanical ventilation with 3.5% sevoflurane in 10% oxygen for 60 minutes; or Room Air spontaneously breathing room air for 60 minutes. In a nonsurviving cohort, cerebral oxygenation was monitored in the area at risk and the contralateral hemisphere during HI or HI-Protect using visible-light spectroscopy (Spectros Corp). Mean arterial blood pressure and heart rate were measured. Arterial blood gases were obtained. Right/left brain hemispheric weight ratios and brain damage scores were determined 1 week after HI. In another group, learning and behavior were assessed in young adulthood (9 weeks) using spontaneous locomotion, Morris water maze, and apomorphine injection. RESULTS: During HI, ipsilateral and contralateral brain oxygenation, arterial blood pressures, blood gases, and glucose levels were similar in both ischemic groups, while heart rate was slower in the HI-Protect group. One week after ischemia, brain hemispheric weight ratios and injury scores in several brain regions were significantly worse after HI, compared with HI-Protect. Nine weeks after HI, Morris water maze hidden platform and reversal platform escape latencies, measures of spatial memory function, were superior after HI-Protect, compared with HI (P < 0.0001). HI-Protect animals demonstrated significantly less circling behavior after an apomorphine challenge (P < 0.0001), a measure of striatal integrity. CONCLUSIONS: To test the neuroprotective effects of volatile anesthetics during neonatal brain ischemia, we developed a modification of the RVM. By using mechanical ventilation and endotracheal intubation, sevoflurane administration during HI was survivable. The combination of sevoflurane administration and mild hypothermia during HI conferred not only short-term structural, but also long-term functional protection, compared with littermates treated according to the RVM. These findings warrant further studies to improve neurological outcome in critically ill infants.

Characterization and quantification of isoflurane-induced developmental apoptotic cell death in mouse cerebral cortex.

BACKGROUND: Accumulating evidence indicates that isoflurane and other, similarly acting anesthetics exert neurotoxic effects in neonatal animals. However, neither the identity of dying cortical cells nor the extent of cortical cell loss has been sufficiently characterized. We conducted the present study to immunohistochemically identify the dying cells and to quantify the fraction of cells undergoing apoptotic death in neonatal mouse cortex, a substantially affected brain region. METHODS: Seven-day-old littermates (n = 36) were randomly assigned to a 6-hour exposure to either 1.5% isoflurane or fasting in room air. Animals were euthanized immediately after exposure and brain sections were double-stained for activated caspase 3 and one of the following cellular markers: Neuronal Nuclei (NeuN) for neurons, glutamic acid decarboxylase (GAD)65 and GAD67 for GABAergic cells, as well as GFAP (glial fibrillary acidic protein) and S100ß for astrocytes. RESULTS: In 7-day-old mice, isoflurane exposure led to widespread increases in apoptotic cell death relative to controls, as measured by activated caspase 3 immunolabeling. Confocal analyses of caspase 3-labeled cells in cortical layers II and III revealed that the overwhelming majority of cells were postmitotic neurons, but some were astrocytes. We then quantified isoflurane-induced neuronal apoptosis in visual cortex, an area of substantial injury. In unanesthetized control animals, 0.08% ± 0.001% of NeuN-positive layer II/III cortical neurons were immunoreactive for caspase 3. By contrast, the rate of apoptotic NeuN-positive neurons increased at least 11-fold (lower end of the 95% confidence interval [CI]) to 2.0% ± 0.004% of neurons immediately after isoflurane exposure (P = 0.0017 isoflurane versus control). In isoflurane-treated animals, 2.9% ± 0.02% of all caspase 3-positive neurons in superficial cortex also coexpressed GAD67, indicating that inhibitory neurons may also be affected. Analysis of GABAergic neurons, however, proved unexpectedly complex. In addition to inducing apoptosis among some GAD67-immunoreactive neurons, anesthesia also coincided with a dramatic decrease in both GAD67 (0.98 vs 1.84 ng/mg protein, P < 0.00001, anesthesia versus control) and GAD65 (2.25 ± 0.74 vs 23.03 ± 8.47 ng/mg protein, P = 0.0008, anesthesia versus control) protein levels. CONCLUSIONS: Prolonged exposure to isoflurane increased neuronal apoptotic cell death in 7-day-old mice, eliminating approximately 2% of cortical neurons, of which some were identified as GABAergic interneurons. Moreover, isoflurane exposure interfered with the inhibitory nervous system by downregulating the central enzymes GAD65 and GAD67. Conversely, at this age, only a minority of degenerating cells were identified as astrocytes. The clinical relevance of these findings in animals remains to be determined.

Knowledge Attainment and Engagement Among Medical Students: A Comparison of Three Forms of Online Learning.

Objective: This study compared knowledge attainment and student enjoyment and engagement between clinical case vignette, patient-testimony videos and mixed reality (MR) teaching via the Microsoft HoloLens 2, all delivered remotely to third year medical students. The feasibility of conducting MR teaching on a large scale was also assessed. Setting & Participants: Medical students in Year 3 at Imperial College London participated in three online teaching sessions, one in each format. All students were expected to attend these scheduled teaching sessions and to complete the formative assessment. Inclusion of their data used as part of the research trial was optional. Primary and Secondary Outcome Measures: The primary outcome measure was performance on a formative assessment, which served to compare knowledge attainment between three forms of online learning. Moreover, we aimed to explore student engagement with each form of learning via a questionnaire, and also feasibility of applying MR as a teaching tool on a large scale. Comparisons between performances on the formative assessment between the three groups were investigated using a repeated measures two-way ANOVA. Engagement and enjoyment were also analysed in the same manner. Results: A total of 252 students participated in the study. Knowledge attainment of students using MR was comparable with the other two methods. Participants reported higher enjoyment and engagement (p<0.001) for the case vignette method, compared with MR and video-based teaching. There was no difference in enjoyment or engagement ratings between MR and the video-based methods. Conclusion: This study demonstrated that the implementation of MR is an effective, acceptable, and feasible way of teaching clinical medicine to undergraduate students on a large scale. However, case-based tutorials were found to be favoured most by students. Future work could further explore the best uses for MR teaching within the medical curriculum.

Comparison of the neuroapoptotic properties of equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in neonatal mice.

BACKGROUND: Volatile anesthetics facilitate surgical procedures and imaging studies in millions of children every year. Neuronal cell death after prolonged exposure to isoflurane in developing animals has raised serious concerns regarding its safe use in children. Although sevoflurane and desflurane are becoming more popular for pediatric anesthesia, their cytotoxic effects have not been compared with those of isoflurane. Accordingly, using newborn mice, the current study established the respective potencies of desflurane, isoflurane, and sevoflurane and then compared equipotent doses of these anesthetics regarding their effects on cortical neuroapoptosis. METHODS: Minimum alveolar concentrations were determined in littermates (aged 7-8 days, n = 42) using tail-clamp stimulation in a bracketing study design. By using equipotent doses of approximately 0.6 minimum alveolar concentration, another group of littermates was randomly assigned to receive desflurane, isoflurane, or sevoflurane or to fast in room air for 6 h. After exposure, animals (n = 47) were euthanized, neocortical apoptotic neuronal cell death was quantified, and caspase 3 activity was compared between the four groups. RESULTS: The minimum alveolar concentration was determined to be 12.2% for desflurane, 2.7% for isoflurane, and 5.4% for sevoflurane. After a 6-h exposure to approximately 0.6 minimum alveolar concentration of desflurane, isoflurane, or sevoflurane, neuronal cell death and apoptotic activity were significantly increased, irrespective of the specific anesthetic used. CONCLUSIONS: In neonatal mice, equipotent doses of the three commonly used inhaled anesthetics demonstrated similar neurotoxic profiles, suggesting that developmental neurotoxicity is a common feature of all three drugs and cannot be avoided by switching to newer agents.

Diabetes Health, Residence & Metabolism in Asians: the DHRMA study, research into foods from the Indian subcontinent - a blinded, randomised, placebo controlled trial.

BACKGROUND: Coronary heart disease (CHD) is highly prevalent amongst the South Asian communities in Britain. The reasons for this excess CHD risk are multifactorial, but in part relate to a susceptibility to diabetes mellitus - where the aberrant metabolism of non-esterified fatty acids (NEFA) and glucose are likely to underpin vascular disease in this population. Dietary intervention is an important and first line approach to manage increased CHD risk. However, there is limited information on the impact of the South Asian diet on CHD risk. METHODS/DESIGN: The Diabetes Health, Residence & Metabolism in Asians (DHRMA) study is a blinded, randomised, placebo controlled trial that analyses the efficacy of reduced glycaemic index (GI) staples of the South Asian diet, in relation to cardio-metabolic risk factors that are commonly perturbed amongst South Asian populations - primarily glucose, fatty acid and lipoprotein metabolism and central adiposity. Using a 10-week dietary intervention study, 50 healthy South Asians will be randomised to receive either a DHRMA (reduced GI) supply of chapatti (bread), stone ground, high protein wheat flour and white basmati rice (high bran, unpolished) or commercially available (leading brand) versions chapatti wheat flour and basmati rice. Volunteers will be asked to complete a 75g oral glucose tolerance test at baseline and at 10-weeks follow-up, where blood metabolites and hormones, blood pressure and anthropometry will also be assessed in a standardised manner. DISCUSSION: It is anticipated that the information collected from this study help develop healthy diet options specific (but not exclusive) for South Asian ethnic communities. Trial registration Current Controlled Trials ISRCTN02839188.

Glycemic status underlies increased arterial stiffness and impaired endothelial function in migrant South Asian stroke survivors compared to European Caucasians: pathophysiological insights from the West Birmingham Stroke Project.

BACKGROUND: The pathophysiology of an increased risk of cerebrovascular disease mortality among South Asians (SA) remains unclear. Indices of arterial stiffness and endothelial dysfunction are independent markers of vascular disease, having both prognostic and diagnostic implications. We hypothesized that there are ethnic variations in indices of arterial stiffness and endothelial dysfunction between SA and European Caucasian (EC) stroke patients, which may underline a poorer prognosis in the former, and further investigated promoters of vessel wall abnormalities. METHODS: Using a cross-sectional approach, a total of 100 SA stroke survivors were prospectively recruited from the ongoing West Birmingham Stroke Project. Indices of vessel wall characteristics (arterial stiffness and endothelial function [change in reflective index]) were measured noninvasively using the digital volume pulse analysis technique in a temperature-controlled environment, using a direct standardized approach. SA stroke subjects were compared to 60 EC stroke survivors, 60 SA with risk factors, and 73 healthy controls. RESULTS: Among stroke patients, both ethnic groups were comparable for cardiovascular risk profile, except for more diabetes mellitus in SA (P=0.007) subjects and a higher prevalence of atrial fibrillation in EC (P=0.04) subjects. According to the TOAST and Bamford classifications, SA subjects had more small vessel (P=0.04) and lacunar infarctions (P=0.01). SA subjects had higher measurements of arterial stiffness (P<0.001) and impaired endothelial-dependent vascular function (change in reflective index %; P<0.001). On univariate analysis, endothelial function was negatively correlated with fasting plasma glucose (r=-0.4; P<0.001) and total cholesterol level (r=-0.2; P<0.001). On multivariate analysis, glycemic status was independently associated with impaired endothelial function (P=0.008) and increased arterial stiffness (P<0.001) among SA subjects. CONCLUSIONS: SA stroke survivors had more small vessel disease-related cerebrovascular events compared to EC subjects. Underlying glycemic status in SA subjects had an adverse impact on the vascular system, leading to abnormal vessel wall characteristics.

Ischemic stroke in South Asians: a review of the epidemiology, pathophysiology, and ethnicity-related clinical features.

BACKGROUND AND PURPOSE: Within the United Kingdom, mortality from stroke is higher among South Asians compared to European whites. The reasons for this excess cerebrovascular risk in South Asians remain unclear. The aim of this review is to present a comprehensive and systematic overview of the available literature relating to ischemic stroke among South Asian populations identifying distinct features of stroke epidemiology in this group. SUMMARY OF REVIEW: A high frequency of lacunar strokes is a familiar pattern among South Asians, which suggests a greater prevalence of small-vessel disease in South Asians. This may be a consequence of abnormal metabolic and glycemic processes. In addition, stroke mortality among South Asians appears to be explained by glycemic status, which is an independent predictor of long-term stroke mortality. Within India, there is a perceptible rural-urban gradient in stroke prevalence, underlying the dangers of the rapid transition in socioeconomic circumstances seen across the Indian subcontinent. CONCLUSIONS: This review emphasizes the importance of further research into ischemic stroke for South Asians given their higher cardiovascular disease burden and necessity for targeted healthcare approaches.

The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory.

BACKGROUND: Volatile anesthetics, such as isoflurane, are widely used in infants and neonates. Neurodegeneration and neurocognitive impairment after exposure to isoflurane, midazolam, and nitrous oxide in neonatal rats have raised concerns regarding the safety of pediatric anesthesia. In neonatal mice, prolonged isoflurane exposure triggers hypoglycemia, which could be responsible for the neurocognitive impairment. We examined the effects of neonatal isoflurane exposure and blood glucose on brain cell viability, spontaneous locomotor activity, as well as spatial learning and memory in mice. METHODS: Seven-day-old mice were randomly assigned to 6 h of 1.5% isoflurane with or without injections of dextrose or normal saline, or to 6 h of room air without injections (no anesthesia). Arterial blood gases and glucose were measured. After 2 h, 18 h, or 11 wk postexposure, cellular viability was assessed in brain sections stained with Fluoro-Jade B, caspase 3, or NeuN. Nine weeks postexposure, spontaneous locomotor activity was assessed, and spatial learning and memory were evaluated in the Morris water maze using hidden and reduced platform trials. RESULTS: Apoptotic cellular degeneration increased in several brain regions early after isoflurane exposure, compared with no anesthesia. Despite neonatal cell loss, however, adult neuronal density was unaltered in two brain regions significantly affected by the neonatal degeneration. In adulthood, spontaneous locomotor activity and spatial learning and memory performance were similar in all groups, regardless of neonatal isoflurane exposure. Neonatal isoflurane exposure led to an 18% mortality, and transiently increased Paco(2), lactate, and base deficit, and decreased blood glucose levels. However, hypoglycemia did not seem responsible for the neurodegeneration, as dextrose supplementation failed to prevent neuronal loss. CONCLUSIONS: Prolonged isoflurane exposure in neonatal mice led to increased immediate brain cell degeneration, however, no significant reductions in adult neuronal density or deficits in spontaneous locomotion, spatial learning, or memory function were observed.

Impact of mean arterial blood pressure on higher arterial stiffness indices in South Asians compared to white Europeans.

BACKGROUND: The pathophysiology of excessive premature coronary heart disease mortality among South Asians living in Britain remains unclear. We hypothesized that higher measures of arterial stiffness among South Asians compared with their white European counterparts would reflect an earlier progression of atherosclerosis, even in the absence of established coronary heart disease risk indices. METHODS: Arterial stiffness was measured by digital volume pulse photoplethysmography in 90 healthy South Asians and compared with 62 matched white Europeans in a temperature-controlled environment using a direct, standardized approach. RESULTS: Both ethnic groups were comparable for coronary heart disease risk profiles and had similar 10-year coronary heart disease risk estimates, but South Asians had a greater mean (SD) stiffness index compared with white Europeans [9.39 (0.22) vs. 8.43 (0.23) m/s; P = 0.007]. On linear regression analysis, mean arterial blood pressure (beta = 0.06; P = 0.03) and age (beta = 0.11; P = 0.002) were independent predictors of arterial stiffness in South Asians. Among white Europeans, age was an independent predictor of arterial stiffness (beta = 0.05; P = 0.01). CONCLUSION: Healthy South Asians have increased systemic arterial stiffness measured by stiffness index compared with white Europeans. There was an adverse and disproportional impact of age and mean arterial pressure on the vascular system in South Asians. Increased indices of arterial stiffness may explain their increased susceptibility to coronary heart disease.

Measurement of stiffness index by digital volume pulse analysis technique: clinical utility in cardiovascular disease risk stratification.

BACKGROUND: Indices of arterial stiffness are accepted as independent markers of cardiovascular disease (CVD), having both positive prognostic and diagnostic implications. The utility of stiffness index (SI) derived from digital volume pulse (DVP) analysis in CVD risk screening is not established. METHODS: Using a representative sample of individuals from local communities (West Midlands, UK), we determined the performance of SI in the discrimination of increasing CVD risk. Arterial stiffness was measured by DVP photoplethysmography (PCA 2; Micro Medical) using a direct, standardized approach. CVD risk assessment was performed in accordance with the Joint British Society guidelines (JBS2). RESULTS: Of our cohort of 247 individuals (51% male; mean age 55.2 (s.d. 10.3) years), 187 were apparently healthy and 60 had established CVD risk factors (diabetes mellitus: 33%, hypertension: 77.8%, hypercholesteremia: 61%). On univariate analysis, SI was strongly associated with CVD risk (the European Society of Cardiology (ESC) based HeartScore) (Pearson correlation coefficient (R): 0.56, P < or = 0.001) and increased in an ordinal fashion from "low risk" to "medium risk" to "high risk" to "very high risk" (pseudo R2 = 0.30; P < 0.001). In receiver operator characteristic curve analysis, SI was the best discriminator between low to medium risk and high-risk categories (area under curve (AUC): 0.76 (95% CI 0.64-0.88), P < 0.001) when compared to total cholesterol, plasma glucose, systolic blood pressure, and waist-to-hip ratio and had the utility to discriminate the individuals with known CVD risk factors such as diabetes and hypertension. CONCLUSION: Noninvasive measurements of arterial stiffness may aid the optimal stratification of CVD risk in an apparently healthy population.

Evaluation of B-type natriuretic peptide for validation of a heart failure register in primary care.

BACKGROUND: Diagnosing heart failure and left ventricular systolic dysfunction is difficult on clinical grounds alone. We sought to determine the accuracy of a heart failure register in a single primary care practice, and to examine the usefulness of b-type (or brain) natriuretic peptide (BNP) assay for this purpose. METHODS: A register validation audit in a single general practice in the UK was carried out. Of 217 patients on the heart failure register, 56 of 61 patients who had not been previously investigated underwent 12-lead electrocardiography and echocardiography within the practice site. Plasma was obtained for BNP assay from 45 subjects, and its performance in identifying echocardiographic abnormalities consistent with heart failure was assessed by analysing area under receiver operator characteristic (ROC) curves. RESULTS: 30/217 were found to have no evidence to suggest heart failure on notes review and were probably incorrectly coded. 70/112 who were previously investigated were confirmed to have heart failure. Of those not previously investigated, 24/56 (42.9%) who attended for the study had echocardiographic left ventricular systolic dysfunction. A further 8 (14.3%) had normal systolic function, but had left ventricular hypertrophy or significant valve disease. Overall, echocardiographic features consistent with heart failure were found in only 102/203 (50.2%). BNP was poor at discriminating those with and without systolic dysfunction (area under ROC curve 0.612), and those with and without any significant echocardiographic abnormality (area under ROC curve 0.723). CONCLUSION: In this practice, half of the registered patients did not have significant cardiac dysfunction. On-site echocardiography identifies patients who can be removed from the heart failure register. The use of BNP assay to determine which patients require echocardiography is not supported by these data.

Widening access to cardiovascular healthcare: community screening among ethnic minorities in inner-city Britain - the Healthy Hearts Project.

BACKGROUND: The burden of cardiovascular disease (CVD) in Britain is concentrated in inner-city areas such as Sandwell, which is home to a diverse multi-ethnic population. Current guidance for CVD risk screening is not established, nor are there specific details for ethnic minorities. Given the disparity in equitable healthcare for these groups, we developed a 'tailored' and systematic approach to CVD risk screening within communities of the Sandwell locality. The key anticipated outcomes were the numbers of participants from various ethnic backgrounds attending the health screening events and the prevalence of known and undiagnosed CVD risk within ethnic groups. METHODS: Data was collected during 10 health screening events (September 2005 and July 2006), which included an assessment of raised blood pressure, overweight, hyperlipidaemia, impaired fasting glucose, smoking habit and the 10 year CVD risk score. Specific features of our approach included (i) community involvement, (ii) a clinician who could deliver immediate attention to adverse findings, and (iii) the use of an interpreter. RESULTS: A total of 824 people from the Sandwell were included in this study (47% men, mean age 47.7 years) from community groups such as the Gujarati Indian, Punjabi Indian, European Caucasian, Yemeni, Pakistani and Bangladeshi. A total of 470 (57%) individuals were referred to their General Practitioner with a report of an increased CVD score - undetected high blood pressure in 120 (15%), undetected abnormal blood glucose in 70 (8%), undetected raised total cholesterol in 149 (18%), and CVD risk management review in 131 (16%). CONCLUSION: Using this systematic and targeted approach, there was a clear demand for this service from people of various ethnic backgrounds, of whom, one in two needed review from primary or secondary healthcare. Further work is required to assess the accuracy and clinical benefits of this community health screening approach.

Abnormal soluble CD40 ligand and C-reactive protein concentrations in hypertension: relationship to indices of angiogenesis.

BACKGROUND: Abnormal inflammation, platelets and angiogenesis are involved in the pathophysiology of cardiovascular disease (CVD). OBJECTIVE: To test the hypothesis that concentrations of high sensitive C-reactive protein (CRP, an index of inflammation) and soluble CD40 ligand (sCD40L, an index of platelet activation) would be abnormal in hypertension, and in turn, be related to plasma indices of angiogenesis, the angiopoietins-1 and -2, and vascular endothelial growth factor (VEGF), in addition to the presence or absence of CVD. METHODS: Using a cross-sectional approach, we measured plasma concentrations of CRP, sCD40L, VEGF, and angiopoietins-1 and -2 in 147 patients with hypertension (85 with a history of CVD event/s, 62 CVD event-free) and 68 age- and sex-matched healthy controls. RESULTS: Concentrations of sCD40L (P = 0.039), CRP (P < 0.001), angiopoietin-1 (P < 0.001), angiopoietin-2 (P = 0.003) and VEGF (P < 0.001) were all greater amongst hypertensive patients than in controls. There were no significant differences in sCD40L and VEGF concentrations between hypertensive individuals with and without CVD events, but CRP and angiopoietin-1 concentrations were significantly greater amongst those with CVD events. On multiple regression analysis, sCD40L was associated with angiopoietin-2 (P = 0.01) and VEGF (P = 0.007) in hypertensive individuals, but no such associations were found within the healthy control group. CONCLUSION: In patients with hypertension, sCD40L was associated with increased circulating markers of abnormal angiogenesis (angiopoietin-2, VEGF). The interaction between sCD40L and angiogenesis may contribute to the pathophysiology of CVD in hypertension.

Role of metabolically active hormones in the insulin resistance associated with short-term glucocorticoid treatment.

BACKGROUND: The mechanisms by which glucocorticoid therapy promotes obesity and insulin resistance are incompletely characterized. Modulations of the metabolically active hormones, tumour necrosis factor alpha (TNF alpha), ghrelin, leptin and adiponectin are all implicated in the development of these cardiovascular risk factors. Little is known about the effects of short-term glucocorticoid treatment on levels of these hormones. RESEARCH METHODS AND PROCEDURES: Using a blinded, placebo-controlled approach, we randomised 25 healthy men (mean (SD) age: 24.2 (5.4) years) to 5 days of treatment with either placebo or oral dexamethasone 3 mg twice daily. Fasting plasma TNFalpha, ghrelin, leptin and adiponectin were measured before and after treatment. RESULTS: Mean changes in all hormones were no different between treatment arms, despite dexamethasone-related increases in body weight, blood pressure, HDL cholesterol and insulin. Changes in calculated indices of insulin sensitivity (HOMA-S, insulin sensitivity index) were strongly related to dexamethasone treatment (p < 0.001). DISCUSSION: Our data do not support a role for TNF alpha, ghrelin, leptin or adiponectin in the insulin resistance associated with short-term glucocorticoid treatment.

Corrigendum to "Ferritin as a Risk Factor for Glucose Intolerance amongst Men and Women Originating from the Indian Subcontinent".

[This corrects the article DOI: 10.1155/2015/924387.].

Comparison of brain natriuretic peptide and left ventricular diastolic function determined by tissue Doppler in patients with diabetes mellitus, patients with hypertension without diabetes, and in healthy subjects.

In this study, it was found that increased plasma B-type natriuretic peptide (BNP) levels in patients with diabetes may be related to left ventricular (LV) diastolic relaxation, independent of LV mass and atherosclerosis (using common carotid intima-media thickness as a surrogate index). A "package of care" of glycemic control and cardiovascular risk management was not associated with reduction in BNP levels.

Plasma matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-2, and CD40 ligand levels in patients with stable coronary artery disease.

Endogenous matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitor of metalloproteinases (TIMPs), are important mediators of extracellular matrix remodeling, which is integral to plaque progression in coronary artery disease. In addition, high levels of the soluble fragment of CD40 ligand (sCD40L) have previously been associated with adverse cardiovascular outcomes. We hypothesized that circulating levels of MMP-9, TIMP-1, TIMP-2, and sCD40L were abnormal in patients who had stable coronary artery disease, and these levels were compared with those in matched controls. We also hypothesized correlations of MMPs, TIMPs, and sCD40L to each other and to high-sensitivity C-reactive protein (a proinflammatory marker), white blood cell count, severity of coronary artery disease (based on angiographic measurements of atherosclerotic burden), and coronary collateralization. We studied 204 adult patients who attended our unit for outpatient diagnostic cardiac catheterization for the investigation of suspected coronary artery disease. Coronary angiograms were scored for atheroma burden and stenosis by 2 independent observers. Circulating levels of MMP-9, TIMP-1, TIMP-2, and sCD40L were measured by enzyme-linked immunosorbent assay. Plasma levels of MMP-9 (p = 0.0099), TIMP-2 (p = 0.0019), and sCD40L (p <0.001), but not TIMP-1 (p = 0.463) were high in patients compared with healthy controls. In patients who had coronary artery disease, MMP-9 and high-sensitivity C-reactive protein levels were significantly higher in women than in men. Only MMP-9 correlated modestly with total white blood cell count (Spearman's correlation, r = 0.274, p = 0.002). Logistic regression of cardiovascular risk factors showed that only white blood cell count was independently associated with MMP-9 (p = 0.02). After standardizing for atheroma and stenosis scores, there were no statistically significant differences in our research indexes in patients who had angiographic collaterals compared with those who did not. In conclusion, stable coronary artery disease is associated with abnormal circulating levels of MMP-9, TIMP-2, and sCD40L, which do not appear to related to each other or to severity of coronary artery disease or collateralization. The gender difference in high-sensitivity C-reactive protein and MMP-9 levels may provide insight into the pathophysiology of coronary artery disease in men and women, and further studies are warranted to explore this potential link.

Efficacy and safety of atorvastatin in South Asian patients with dyslipidemia: an open label noncomparative pilot study.

BACKGROUND: Rates of coronary heart disease (CHD) mortality are 40% higher amongst South Asian men and women living in the UK compared with the general UK population. Despite an established excess CHD risk, little is known of the efficacy and safety of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) amongst South Asian migrants. METHODS AND RESULTS: Hyperlipidemic South Asian patients (raised or uncontrolled low-density lipoprotein cholesterol [LDL-C]) were recruited from two UK centers (n = 33). After a five-week period, which included dietary advice, patients received atorvastatin 10 mg/d for five weeks to achieve a target LDL-C goal of < 3.0 mmol/L, titrated to 20 mg, 40 mg, or 80 mg for a further 12 weeks as required. Significant reductions in LDL-C levels from baseline were observed after 4 weeks' and 17 weeks' treatment with atorvastatin (> or = 33.6%; 26.0, 41.2). Overall, 81% (95% confidence interval [CI]: 62.5, 92.6%) achieved the target LDL-C after 4 weeks' treatment with 10 mg atorvastatin. Titration to a dose of more than 20 mg was required in only one patient (40 mg) at any point during the study. Nineteen patients reported at least one adverse event during the study; the majority were mild in severity and considered unrelated to atorvastatin. CONCLUSIONS: Atorvastatin was effective in achieving target lipid levels and was well tolerated. Statin therapy for high-risk South Asian individuals is likely to benefit CHD outcomes, although further and larger prospective trials are required.