Local injection of a hexametaphosphate formulation reduces heterotopic ossification in vivo.

Heterotopic ossification (HO), the pathological formation of ectopic bone, is a debilitating condition which can cause chronic pain, limit joint movement, and prevent prosthetic limb fitting. The prevalence of this condition has risen in the military population, due to increased survivorship following blast injuries. Current prophylaxes, which aim to target the complex upstream biological pathways, are inconsistently effective â€‹and have a range of side-effects that make them unsuitable for combat-injured personnel. As such, many patients must undergo further surgery to remove the formed ectopic bone. In this study, a non-toxic, U.S. Food and Drug Administration (FDA) -approved calcium chelator, hexametaphosphate (HMP), is explored as a novel treatment paradigm for this condition, which targets the chemical, rather that biological, â€‹bone formation pathways. This approach allows not only prevention of pathological bone formation â€‹but also uniquely facilitates reversal, which current drugs cannot achieve. Targeted, minimally invasive delivery is achieved by loading HMP into an injectable colloidal alginate. These formulations significantly reduce â€‹the length of the ectopic bone formed in a rodent model of HO, with no effect on the adjacent skeletal bone. This study demonstrates the potential of localized dissolution as a new treatment â€‹and an alternative to surgery â€‹for pathological ossification and calcification conditions.

Brain regional vulnerability to anaesthesia-induced neuroapoptosis shifts with age at exposure and extends into adulthood for some regions.

BACKGROUND: General anaesthesia facilitates surgical operations and painful interventions in millions of patients every year. Recent observations of anaesthetic-induced neuronal cell death in newborn animals have raised substantial concerns for young children undergoing anaesthesia. However, it remains unclear why some brain regions are more affected than others, why certain neurones are eliminated while neighbouring cells are seemingly unaffected, and what renders the developing brain exquisitely vulnerable, while the adult brain apparently remains resistant to the phenomenon. METHODS: Neonatal (P7), juvenile (P21), and young adult mice (P49) were anaesthetized with 1.5% isoflurane. At the conclusion of anaesthesia, activated cleaved caspase 3 (AC3), a marker of apoptotic cell death, was quantified in the neocortex (RSA), caudoputamen (CPu), hippocampal CA1 and dentate gyrus (DG), cerebellum (Cb), and olfactory bulb (GrO) and compared with that found in unanaesthetized littermates. RESULTS: After anaesthetic exposure, increased AC3 was detected in neonatal mice in RSA (11-fold, compared with controls), CPu (10-fold), CA1 (three-fold), Cb (four-fold), and GrO (four-fold). Surprisingly, AC3 continued to be elevated in the DG and GrO of juvenile (15- and 12-fold, respectively) and young adult mice (two- and four-fold, respectively). CONCLUSIONS: The present study confirms the findings of previous studies showing peak vulnerability to anaesthesia-induced neuronal cell death in the newborn forebrain. It also shows sustained susceptibility into adulthood in areas of continued neurogenesis, substantially expanding the previously observed age of vulnerability. The differential windows of vulnerability among brain regions, which closely follow regional peaks in neurogenesis, may explain the heightened vulnerability of the developing brain because of its increased number of immature neurones.

Sofosbuvir and daclatasvir combination therapy in a liver transplant recipient with severe recurrent cholestatic hepatitis C.

Recurrent HCV infection following liver transplantation can lead to accelerated allograft injury that is difficult to treat with interferon. The aim of this study is to describe the first ever use of an interferon-free, all oral regimen in a liver transplant recipient with severe recurrent HCV. A 54-year-old male with HCV genotype 1b developed severe cholestatic HCV at 6 months posttransplant with ascites, AST 503 IU/mL, alkaline phosphatase of 298 IU/mL, HCV RNA of 12 000 000 IU/mL, and histological cholestasis with pericellular fibrosis. Sofosbuvir, an HCV polymerase inhibitor (400 mg/day), and daclatasvir, an HCV NS5A replication complex inhibitor (60 mg/day), were co-administered for 24 weeks. Within 4 weeks of initiating treatment, serum HCV RNA levels became undetectable and liver biochemistries normalized with concomitant resolution of ascites. The patient achieved a sustained virological response with undetectable HCV RNA at 9 months posttreatment. During and following treatment, the daily dose and blood level of tacrolimus remained stable and unchanged. The rapid and sustained suppression of HCV replication in this liver transplant recipient provides great promise for the use of combination oral antiviral regimens in other immunosuppressed and interferon refractory HCV patients.

Validation of a novel resin-porcine thorax model for chest drain insertion training.

Chest drain insertion in inexperienced hands carries a significant morbidity and mortality. The royal colleges, recognising this, stipulated that chest drain insertion be included as one of the core competences for all core medical trainees. However, there is no formal training in chest drain insertion included in training programmes. Simulation training should, in theory, provide a safe and objective method to overcome the obstacles in chest drain insertion training. There have been a number of attempts to find the ideal simulator for chest drain insertion with varying success. This article describes a model which is practical and affordable in all clinical skills labs, using porcine ribs mounted on a resin cast of a human thorax, and the data about the validation of the porcine-thorax model for chest drain insertion presented.

Short-term effects of screening for cardiovascular risk in the deaf community: a pilot study.

There is limited information on the risk of cardiovascular disease amongst the Deaf community. Given that the access of Deaf people to mainstream health promotion is likely to be hindered by language barriers, we were interested to assess the short-term impact of cardiovascular health promotion within this group. Using a pilot study we investigated changes in cardiovascular risk factors amongst Deaf people identified to be at high cardiovascular risk, who received standard health promotion by a medical team specializing in cardiovascular health promotion. The short-term impact of cardiovascular health promotion in this group did not reduce estimates of cardiovascular risk. The reasons for this are likely to relate to the design and delivery of health promotion to Deaf people, which deserves further study.

Omega-3 polyunsaturated acids and cardiovascular disease: notable ethnic differences or unfulfilled promise?

The consumption of long chain omega-3 polyunsaturated acids (PUFA) is considered to protect against cardiovascular disease and promote longevity following a heart attack. Historically, research in this area was fuelled by compelling reports of the cardiovascular benefits of omega-3 PUFA in select populations and cultures. More recent studies, in wider populations, suggest discordant findings: differences that are difficult to reconcile as the mechanism of action of omega-3 PUFA are poorly understood. As such, the use of this 'natural treatment' for cardiovascular disease is increasingly controversial, and potentially one of unfulfilled promise. To what extent does ethnicity influence the impact that omega-3 PUFA have on cardiovascular disease and its associated complications? We were interested to review the benefits of omega-3 PUFA in the management of cardiovascular risk amongst diverse ethnic groups. Using a systematic review of literature relating to omega-3 PUFA and cardiovascular disease, we found ethnicity to be a factor that accounts for inconsistency between studies. Some of the effects of omega-3 PUFA are limited to cultures with a very high omega-3 intake, and in turn, ethnicity moderates the efficiency with which PUFA are derived from the diet. Moreover, omega-3 PUFA are an important health care intervention in the current climate of globalization, where supplementation is likely to give protection to cultural groups undergoing dietary transition. Future epidemiological research into the efficacy of omega-3 PUFA in cardiovascular disease should consider the influence of ethnicity.

Triglycerides and small dense low density lipoprotein in the discrimination of coronary heart disease risk in South Asian populations.

INTRODUCTION: Coronary heart disease (CHD) is exceptionally prevalent amongst globally dispersed migrant groups originating from the Indian subcontinent, but the contribution of dyslipidaemia to their increased risk remains poorly defined. METHODS: Fasting lipids and lipoproteins, apolipoproteins (Apo), low density lipoprotein (LDL) diameter and oxidised LDL were measured amongst rural Indians in India (n=294) and their migrant contemporaries in the UK (n=242). The performance of qualitative and quantitative measures of lipid metabolism were compared in the discrimination of WHO defined metabolic risk and raised Framingham CHD risk scores (>15%) using Receiver Operating Characteristic (ROC) curves. RESULTS: LDL diameter was correlated with triglycerides (R(2)=0.12, P<0.001) and with high density lipoprotein (HDL) cholesterol levels (R(2)=0.15, P<0.001) in both groups. Migrants had less small dense LDL (95% CI: 12.5-14.2%) vs. rural Indians (15.7-17.2, P<0.05). On ROC analysis, triglycerides were the only consistent discriminators of metabolic and CHD risk scores (all P< or =0.001). Apo B was also a strong indicator of raised CHD risk scores. Irrespective of site, individuals with raised triglycerides also had higher total cholesterol and Apo B, denser LDL, lower HDL and more oxidised LDL (all P< or =0.01). DISCUSSION: Fasting triglycerides reflect both qualitative and quantitative aspects of lipid metabolism, and are a comprehensive discriminator of CHD risk in this South Asian population.

Circulating biomarkers of angiogenesis as indicators of left ventricular systolic dysfunction amongst patients with coronary artery disease.

BACKGROUND: Patients with coronary artery disease (CAD) and left ventricular systolic dysfunction (LVSD) are often asymptomatic. Angiogenesis is implicated in the physiology of vascular repair and cardiac remodelling, and is one of many pathophysiological processes implicated in heart failure. We hypothesized that plasma indices associated with angiogenesis [angiogenin, vascular endothelial growth factor (VEGF), and angiopoietin (Ang)-1 and Ang-2] would be abnormal in CAD patients with LVSD, being correlated with EF and wall motion abnormalities (wall motion score) independently of underlying CAD (coronary atheroma score). We also evaluated the specificity of angiogenic 'biomarkers' in their detection of LVSD [ejection fraction (EF) <40%] amongst CAD patients. METHODS: Using a cross sectional approach, we measured angiogenin, VEGF, Ang-1 and Ang-2 by ELISA in 194 CAD patients (aged 34-81 years) undergoing elective coronary angiography. RESULTS: Levels of angiogenin were inversely related with EF (r = -0.17, P = 0.02) and positively with coronary atheroma scores (r = 0.15, P = 0.04, but not independently of EF). Other angiogenic markers were unrelated to objective measures of LVSD but VEGF (P = 0.008) and Ang-2 (P = 0.015) were lower amongst those patients with heart failure. Angiogenin levels were related to wall motion scores (r = 0.16, P = 0.024). CONCLUSION: Heart failure has a modest impact on biomarkers of angiogenesis, in patients with CAD. Further research is warranted into the diagnostic and prognostic utility of biomarkers of angiogenesis, in this common cardiac condition.

Circulating serum adiponectin levels in patients with coronary artery disease: relationship to atherosclerotic burden and cardiac function.

BACKGROUND: Abnormal adipocyte function is implicated in both the pathophysiology of coronary heart disease (CHD) and cardiac function, where adiponectin provides a putative link. However, the utility of adiponectin as a discriminator of CHD severity is unclear and may be confounded by cardiac function. We hypothesized that plasma adiponectin would relate to indices of coronary artery disease severity (coronary atheroma scores, CAS), ejection fraction (EF) and regional wall motion abnormalities (RWMA) therein. METHOD: We measured adiponectin using a cross-sectional approach, we measured plasma adiponectin enzyme-linked immunosorbent assay in 204 consecutive patients (aged 34-81 years) undergoing elective coronary angiography. RESULTS: Levels of adiponectin decreased in an ordinal fashion across tertiles of increasing CAS (P = 0.047), but were nonsignificantly correlated to absolute values of CAS (P = 0.06). Adiponectin levels were unrelated to left ventricular dysfunction related measures of RWMA or EF. On multivariate analysis, (including factors relating to CHD risk, history and medication) adiponectin levels were independently inversely associated with triglycerides (P = 0.001), CAS tertiles (P = 0.01) and positively with age (P < 0.001). CONCLUSION: Levels of adiponectin decreased with coronary artery disease severity, without impact from systolic dysfunction, but levels may be moderated through established CHD risk factors such as smoking and triglycerides. Further work is warranted as to the clinical prognostic utility of this marker amongst CHD patients.

Ethnic differences in myocardial infarction in patients with hypertension: effects of diabetes mellitus.

BACKGROUND: It has been reported that hypertension carries a greater risk of myocardial infarction (MI) in South Asians living in the UK than in the indigenous British population. This has been attributed to some specifically Asian susceptibility factor. DESIGN: Using a longitudinal approach, we investigated the relationship between coronary heart disease (CHD) risk factors amongst hypertension patients attending Sandwell and City Hospitals, and the onset of cardiovascular events over a 5-year follow-up period. RESULTS: A total of 350 Caucasian (83.7% male) and 104 South Asian (66.3% male) patients with hypertension [age 63.7 (7.6) years and 57.1 (11.1) years respectively, P < 0.001] were followed-up for a mean (SD) period of 64.7(12.1) months. There were 11 (6.4/1000 patient years) cases of MI in Caucasian patients vs. 11 (17.8/1000 patient years) in South Asians, with event-free survival times being significantly lower amongst South Asians (log-rank test P = 0.04). The prevalence of diabetes mellitus was 22.9% higher amongst South Asians (P < 0.001), whilst mean serum cholesterol and fasting triglyceride levels were higher amongst Caucasians (P = 0.001). There were no ethnic differences in HDL cholesterol concentrations, the use of tobacco, statin therapy or anti-platelet therapies (all P = NS), or in composite endpoint (MI, angina, peripheral vascular disease, stroke, revascularization or death; P = 0.74). On Cox regression analysis of all independent cardiovascular risk variables, associated treatments and ethnicity, MI risk was associated with diabetes mellitus (odds ratio 3.77, 95%CI 1.55-9.15, P = 0.003) but not ethnicity per se (P = 0.26). CONCLUSION: Increased risk of MI in hypertensive South Asians in the United Kingdom appears to be the result of a higher prevalence of diabetes mellitus. Further work is required to understand the pathophysiological basis with which diabetes increases CHD risk in this ethnic group.

Secular trends in the cardiovascular risk profile and mortality of stroke admissions in an inner city, multiethnic population in the United Kingdom (1997-2005).

Our objective was to study ethnic differences in the cardiovascular risk profile and mortality of stroke admissions to an inner city teaching hospital serving a multiethnic population in Birmingham, UK, over a 9-year period (1997-2005). Hospital case notes and registry data of 3083 patients admitted with a first onset stroke were reviewed. Secular trends in the prevalence of risk factors (hypertension, diabetes, hyperlipidaemia, atrial fibrillation and myocardial infarction), hospital admission rates and 30-day mortality among Afro-Caribbean, European Caucasian and South Asian ethnic groups were analysed. Between 1997 and 2005, there were 3083 first onset strokes, of whom 47.6% (1595) were men, 9.3% Afro-Caribbean, 57.8% European Caucasian and 15.1% South Asian. There was a significant trend towards a reduction in non-haemorrhagic stroke admissions over the study period (P<0.001), with no ethnic variation (P=0.07). Increases in hypertension and hyperlipidaemia were observed (P<0.001), whereas myocardial infarction showed a decline (P<0.001). Compared to other ethnic groups, South Asian patients were younger on admission (P<0.001), had more hyperlipidaemia (P<0.05) and poorer survival at 30 days (P=002). We conclude that cardiovascular risk profiles among patients admitted with non-haemorrhagic stroke have changed over the last decade. In particular, hyperlipidaemia has increased, especially among South Asians. The reduced decline in stroke admissions and 30-day survival of stroke in South Asians in recent years warrants further investigation and highlights the importance of a targeted health-care approach in the migrant ethnic minorities.

Increased 5-year mortality in the migrant South Asian stroke patients with diabetes mellitus in the United Kingdom: the West Birmingham Stroke Project.

BACKGROUND: Stroke is a major cause of premature mortality in Britain, but its burden is markedly greater amongst South Asians. Because of the paucity of data in this area, we investigated the magnitude and impact of risk from cardiovascular comorbidities on survival amongst South Asian stroke patients. METHODS: We reviewed hospital case records of consecutive first in life time ischaemic stroke patients [self reported ethnicity and International Classification of Disease (ICD) 10th revision, codes 430-438] admitted to an inner city hospital in the UK between 1997 and 2001. In-hospital mortality data and CVD risk factors were analysed. Five-year mortality data was obtained from the National Health Tracing Services. RESULTS: Of 1474 ischaemic stroke patients, 242 (16%) were South Asian of whom, 143 (59.1%) were male. The prevalence of hypertension was 70.2%, followed by diabetes 56.2%, hyperlipidaemia 7% and myocardial infarction 10.3%. At 5 years follow-up, 40.5% had died. Cumulative event-free survival at 5 years was significantly poorer in patients with diabetes (log-rank test, p=0.009). On Cox regression analysis, incorporating age, gender and other CVD risk factors, diabetes mellitus was an independent predictor of mortality odds ratio=1.65 (1.02-2.6, p=0.039). Hypertension and dyslipidaemia did not discriminate survival amongst South Asian patients. CONCLUSION: Stroke mortality in South Asians is associated with presence of diabetes mellitus. This highlights the significance of early and intensive CVD risk modification strategies in ethnic minorities particularly in patients with diabetes. Further research is warranted in South Asians to examine the underlying basis and related pathophysiological abnormalities.

Elevated lipoprotein (a) and apolipoprotein B to AI ratio in South Asian patients with ischaemic stroke.

BACKGROUND: Stroke is a continuing cause of excess cardiovascular disease (CVD) mortality amongst migrants from the Indian subcontinent (South Asians) living in Britain. However, little is known about the dyslipidaemia associated with stroke in South Asians. In particular, the highly atherogenic lipoprotein (a) [Lp(a)] and high apolipoprotein (Apo) B to AI ratio are emerging risk factors for CVD. METHODS: Using a case-control study, we investigated features of the dyslipidaemia in South Asian patients with stroke compared with South Asian subjects with no history of clinically detectable stroke. We studied 55 consecutive South Asian patients with ischaemic stroke (confirmed on computerised scan of the brain) and 85 controls. RESULTS: The stroke patients were significantly older than controls (65.2 vs. 59.8 years, p = 0.001), but were similarly matched for male gender (63.6 vs. 61.2%), smoking habit (20.7 vs. 18.1%) and presence of type 2 diabetes (25.5 vs. 19.3%). There were no differences between serum total cholesterol (p = 0.07) and high-density lipoprotein cholesterol (p = 0.08) between the groups, but stroke patients had higher serum triglycerides (p = 0.005). Mean [95% confidence interval (CI)] Apo B to AI ratio was higher amongst stroke patients [1.0 (0.9-1.0) vs. 0.7 (0.7-0.75), p < 0.001]. Similarly, geometric mean serum Lp(a) was significantly higher (p = 0.037) in stroke patients [19.9 mg/dl (14.0-28.5)] vs. controls [15.1 mg/dl (11.4-20.1)]. On logistic regression, stroke was independently associated with age and Apo B to AI ratio (p < 0.01). CONCLUSION: The present study suggests that Lp(a) and the Apo B to AI ratio are associated with ischaemic stroke in South Asians. A prospective analysis is needed to elucidate the role of Lp(a), Apo B and AI as risk factors for ischaemic stroke in this population, as well as the effects of intervention.

Prognostic value of plasma soluble P-selectin and von Willebrand factor as indices of platelet activation and endothelial damage/dysfunction in high-risk patients with hypertension: a sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial.

BACKGROUND: Abnormal levels of prothrombotic markers have been described in hypertension, but no such marker has yet been shown to reliably predict cardiovascular outcomes in hypertension. We hypothesized that raised circulating levels of soluble P-selectin (sP-sel, an index of platelet activation) and/or von Willebrand factor (vWF, an index of endothelial damage/dysfunction) would predict vascular events in patients treated for cardiovascular risk. METHODS: We measured vWF and sP-sel levels by an ELISA in 234 hypertensive participants with no prior cardiovascular events who were participating in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Plasma vWF and sP-sel levels were related to the subsequent cardiovascular events over a mean (SD) follow-up period of 59.6 (19) months. RESULTS: Plasma sP-sel was a significant predictor of myocardial infarction (P = 0.03), with the greatest risk amongst those with the highest sP-sel levels. sP-sel did not predict cerebrovascular events (P = 0.53) or composite cardiovascular events (P = 0.06). No significant relationships were found between vWF levels and outcomes. There was no relationship to the presence or absence of diabetes mellitus (DM) at baseline or subsequent development of DM during the follow-up period. CONCLUSIONS: Among 'high-risk' patients with hypertension, raised levels of sP-sel (platelet activation) were predictive of myocardial infarction. Levels of vWF (endothelial damage/dysfunction) were not associated with coronary events and neither marker predicted cerebrovascular or composite cardiovascular endpoints. Platelets (or P-selectin) might represent a target for novel therapies or an adjunctive aid to risk stratification in the setting of hypertension.

Efficacy, safety and LDL-C goal attainment of ezetimibe 10 mg-simvastatin 20 mg vs. placebo-simvastatin 20 mg in UK-based adults with coronary heart disease and hypercholesterolaemia.

It is increasingly accepted that more intensive lipid-lowering treatment is associated with greater cardiovascular risk reductions in patients with coronary heart disease (CHD), thus providing a rationale for more aggressive LDL-cholesterol (LDL-C) targets. Ezetimibe in combination with statin therapy provides an additional approach to lipid management by utilising the additive action of two different mechanisms of LDL-C reduction. In this multicentre, randomised, double-blind, placebo-controlled study, a total of 98 men and 55 women with CHD and primary hypercholesterolaemia, naïve to statin therapy, were randomised to receive treatment for 6 weeks with either ezetimibe 10 mg-simvastatin 20 mg (n = 77) or placebo-simvastatin 20 mg (n = 75). At 6 weeks, ezetimibe 10 mg-simvastatin 20 mg provided a mean additional LDL-C reduction of 14.6% (95% CI 10.1-19.1) compared with simvastatin monotherapy (p < 0.0001). Moreover, a higher proportion of patients on ezetimibe/simvastatin achieved the National Standard Framework LDL-C standard (<3.0 mmol/l; 93% vs. 75%, p < 0.001) or the new Joint British Societies (JBS 2) goal of LDL-C < 2.0 mmol/l (49.3% vs. 11.1%, p < 0.001). On logistic regression analysis, the odds ratio of achieving target LDL-C with ezetimibe 10 mg-simvastatin 20 mg was 5.1 (95% CI 1.8-15.0) times higher than with simvastatin monotherapy (p = 0.003). Clinical chemistry profiles and proportions of adverse events were similar in both groups at baseline and follow-up. In conclusion, ezetimibe 10 mg-simvastatin 20 mg is a practical, effective and safe option for the treatment of primary hypercholesterolaemia in CHD patients, and brings more patients to new aggressive cholesterol targets compared with simvastatin 20 mg monotherapy.