European Stroke Organisation (ESO) guidelines on glycaemia management in acute stroke.

BACKGROUND: Hyperglycaemia is a frequent complication in acute stroke that has been shown to be independently associated with larger infarct size, haematoma growth, poor clinical outcome and mortality. This Guideline Document presents the European Stroke Organisation (ESO) Guidelines for the management of blood glucose levels in patients with acute ischemic or haemorrhagic stroke. METHODS: The working group identified related questions and developed its recommendations based on evidence from randomised controlled trials following the standard operating procedure of the ESO. This Guideline Document was reviewed and approved by the European Stroke Organisation Guidelines Committee and the European Stroke Organisation Executive Committee. RESULTS: We found low-quality evidence from clinical trials in ischemic or haemorrhagic stroke exploring the use of intravenous insulin aimed to achieve a tight glycaemic control with different glucose level targets and several other sources of heterogeneity. None of these trials neither the meta-analysis of them have demonstrated any significant benefit of tight glycaemic control with intravenous insulin in acute ischemic or haemorrhagic stroke patients on functional outcome or in survival and they have shown an increased risk for hypoglycaemia. CONCLUSIONS: We suggest against the routine use of tight glycaemic control with intravenous insulin as a means to improve outcomes. The currently available data about the management of glycaemia in patients with acute stroke are limited and the strengths of the recommendations are therefore weak. Nevertheless, this does not prevent that hyperglycaemia in acute stroke patients could be treated as any other hospitalised patient.

Comparing Risk Factor Profiles between Intracerebral Hemorrhage and Ischemic Stroke in Chinese and White Populations: Systematic Review and Meta-Analysis.

BACKGROUND: Chinese populations have a higher proportion of intracerebral hemorrhage (ICH) in total strokes. However, the reasons are not fully understood. METHODS: To assess the differences in frequency of major risk factors between ICH and ischemic stroke (IS) in Chinese versus white populations of European descent, we systematically sought studies conducted since 1990 that compared frequency of risk factors between ICH and IS in Chinese or white populations. For each risk factor, in Chinese and Whites separately, we calculated study-specific and random effects pooled prevalence and odds ratios (ORs) for ICH versus IS. RESULTS: Six studies among 36,190 Chinese, and seven among 52,100 white stroke patients studied hypertension, diabetes, atrial fibrillation (AF), ischemic heart disease (IHD), hypercholesterolemia, smoking and alcohol. Pooled prevalence of AF was significantly lower in Chinese. Pooled ORs for ICH versus IS were mostly similar in Chinese and Whites. However, in Chinese--but not Whites--mean age was lower (62 versus 69 years), while hypertension and alcohol were significantly more frequent in ICH than IS (ORs 1.38, 95% CI 1.18-1.62, and 1.46, 1.12-1.91). Hypercholesterolemia and smoking were significantly less frequent in ICH in Whites, but not Chinese, while IHD, AF and diabetes were less frequent in ICH in both. CONCLUSIONS: Different risk factor distributions in ICH and IS raise interesting possibilities about variation in mechanisms underlying the different distributions of pathological types of stroke between Chinese and Whites. Further analyses in large, prospective studies, including adjustment for potential confounders, are needed to consolidate and extend these findings.

European Stroke Organisation (ESO) guidelines for the management of temperature in patients with acute ischemic stroke.

BACKGROUND: Hyperthermia is a frequent complication in patients with acute ischemic stroke. On the other hand, therapeutically induced hypothermia has shown promising potential in animal models of focal cerebral ischemia. This Guideline Document presents the European Stroke Organisation guidelines for the management of temperature in patients with acute ischemic stroke. METHODS: A multidisciplinary group identified related questions and developed its recommendations based on evidence from randomized controlled trials elaborating the Grading of Recommendations Assessment, Development, and Evaluation approach. This Guideline Document was reviewed within the European Stroke Organisation and externally and was approved by the European Stroke Organisation Guidelines Committee and the European Stroke Organisation Executive Committee. RESULTS: We found low-quality evidence, and therefore, we cannot make any recommendation for treating hyperthermia as a means to improve functional outcome and/or survival in patients with acute ischemic stroke and hyperthermia; moderate evidence to suggest against routine prevention of hyperthermia with antipyretics as a means to improve functional outcome and/or survival in patients with acute ischemic stroke and normothermia; very low-quality evidence to suggest against routine induction of hypothermia as a means to improve functional outcome and/or survival in patients with acute ischemic stroke. CONCLUSIONS: The currently available data about the management of temperature in patients with acute ischemic stroke are limited, and the strengths of the recommendations are therefore weak. We call for new randomized controlled trials as well as recruitment of eligible patients to ongoing randomized controlled trials to allow for better-informed recommendations in the future.

Risk factors for ischemic stroke and its subtypes in Chinese vs. Caucasians: Systematic review and meta-analysis.

BACKGROUND: Chinese populations are reported to have a different distribution of ischemic stroke subtypes compared with Caucasians. AIMS: To understand this better, we aimed to evaluate the differences in prevalence of risk factors in ischemic stroke and their distributions among ischemic stroke subtypes in Chinese vs. Caucasians. SUMMARY OR REVIEW: We systematically sought studies conducted since 1990 with data on frequency of risk factors among ischemic stroke subtypes in Chinese or Caucasians. For each risk factor, we calculated study-specific and random effects pooled estimates in Chinese and Caucasians separately for: prevalence among ischemic stroke; odds ratios, comparing prevalence for each ischemic stroke subtype vs. all others. We included seven studies among 16,199 Chinese, and eleven among 16,189 Caucasian ischemic stroke patients. Risk factors studied were hypertension, diabetes, atrial fibrillation, ischemic heart disease, hypercholesterolemia, smoking and alcohol. Chinese ischemic stroke patients had younger onset of stroke than Caucasians, similar prevalence of hypertension, diabetes, smoking and alcohol, and significantly lower prevalence of atrial fibrillation, ischemic heart disease and hypercholesterolemia. Risk factor associations with ischemic stroke subtypes were mostly similar among Chinese and Caucasian ischemic stroke patients. Compared with all other ischemic subtypes, diabetes was more common in large artery stroke, atrial fibrillation and ischemic heart disease in cardioembolic stroke, and hypertension and diabetes in lacunar stroke. CONCLUSION: Our study showed a lower prevalence of atrial fibrillation, ischemic heart disease and hypercholesterolemia in Chinese, and mostly similar risk factor associations in Chinese and Caucasian ischemic stroke patients. Further analyses of individual patient data to allow adjustment for confounders are needed to confirm and extend these findings.

European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) accounted for 9% to 27% of all strokes worldwide in the last decade, with high early case fatality and poor functional outcome. In view of recent randomized controlled trials (RCTs) of the management of ICH, the European Stroke Organisation (ESO) has updated its evidence-based guidelines for the management of ICH. METHOD: A multidisciplinary writing committee of 24 researchers from 11 European countries identified 20 questions relating to ICH management and created recommendations based on the evidence in RCTs using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: We found moderate- to high-quality evidence to support strong recommendations for managing patients with acute ICH on an acute stroke unit, avoiding hemostatic therapy for acute ICH not associated with antithrombotic drug use, avoiding graduated compression stockings, using intermittent pneumatic compression in immobile patients, and using blood pressure lowering for secondary prevention. We found moderate-quality evidence to support weak recommendations for intensive lowering of systolic blood pressure to <140 mmHg within six-hours of ICH onset, early surgery for patients with a Glasgow Coma Scale score 9-12, and avoidance of corticosteroids. CONCLUSION: These guidelines inform the management of ICH based on evidence for the effects of treatments in RCTs. Outcome after ICH remains poor, prioritizing further RCTs of interventions to improve outcome.

Increased uptake and new therapies are needed to avert rising hepatitis C-related end stage liver disease in England: modelling the predicted impact of treatment under different scenarios.

BACKGROUND & AIMS: Hepatitis C (HCV) related disease in England is predicted to rise, and it is unclear whether treatment at current levels will be able to avert this. The aim of this study was to estimate the number of people with chronic HCV infection in England that are treated and assess the impact and costs of increasing treatment uptake. METHODS: Numbers treated were estimated using national data sources for pegylated interferon supplied, dispensed, or purchased from 2006 to 2011. A back-calculation approach was used to project disease burden over the next 30 years and determine outcomes under various scenarios of treatment uptake. RESULTS: 5000 patients were estimated to have been treated in 2011 and 28,000 in total from 2006 to 2011; approximately 3.1% and 17% respectively of estimated chronic infections. Without treatment, incident cases of decompensated cirrhosis and hepatocellular carcinoma were predicted to increase until 2035 and reach 2290 cases per year. Treatment at current levels should reduce incidence by 600 cases per year, with a peak around 2030. Large increases in treatment are needed to halt the rise; and with more effective treatment the best case scenario predicts incidence of around 500 cases in 2030, although treatment uptake must still be increased considerably to achieve this. CONCLUSIONS: If the infected population is left untreated, the number of patients with severe HCV-related disease will continue to increase and represent a substantial future burden on healthcare resources. This can be mitigated by increasing treatment uptake, which will have the greatest impact if implemented quickly.

Epidemiology of stroke and its subtypes in Chinese vs white populations: a systematic review.

OBJECTIVE: We aimed to systematically assess the evidence for differences in the incidence of stroke and distribution of its subtypes in Chinese compared with white populations. METHODS: We comprehensively sought studies conducted since 1990 in Chinese populations of 1) first-ever stroke incidence (community-based studies only), and 2) pathologic types/subtypes of stroke (hospital- or community-based studies of first-ever or recurrent strokes). We identified community-based studies in white populations from a recent systematic review. For each study, we calculated age-standardized stroke incidence and the proportions of each pathologic type and ischemic subtype, using random-effects meta-analysis to pool proportions of stroke types/subtypes in Chinese and in white populations. RESULTS: Age-standardized annual first-ever stroke incidence in community-based studies was higher among Chinese than white populations (for ages 45-74 years, range 205-584 vs 170-335 per 100,000, respectively). Intracerebral hemorrhage accounted for a larger, more variable proportion of strokes in China than Taiwan (range 27%-51% vs 17%-28%), in Chinese community-based than hospital-based studies (27%-51% vs 17%-30%), and in community-based Chinese than white studies (pooled proportion 33% vs 12%). Although the overall proportion of lacunar ischemic stroke appeared higher in Chinese than white populations, variable study methodologies precluded reliable comparisons. CONCLUSIONS: There is good evidence for a slightly higher overall stroke incidence and higher proportion of intracerebral hemorrhage in Chinese vs white populations, but no clear evidence for different distributions of ischemic stroke subtypes. Studies using comparable, population-based case ascertainment and similar classification methods are needed to address this.

A systematic review of the utility of 1.5 versus 3 Tesla magnetic resonance brain imaging in clinical practice and research.

OBJECTIVE: MRI at 3 T is said to be more accurate than 1.5 T MR, but costs and other practical differences mean that it is unclear which to use. METHODS: We systematically reviewed studies comparing diagnostic accuracy at 3 T with 1.5 T. We searched MEDLINE, EMBASE and other sources from 1 January 2000 to 22 October 2010 for studies comparing diagnostic accuracy at 1.5 and 3 T in human neuroimaging. We extracted data on methodology, quality criteria, technical factors, subjects, signal-to-noise, diagnostic accuracy and errors according to QUADAS and STARD criteria. RESULTS: Amongst 150 studies (4,500 subjects), most were tiny, compared old 1.5 T with new 3 T technology, and only 22 (15 %) described diagnostic accuracy. The 3 T images were often described as "crisper", but we found little evidence of improved diagnosis. Improvements were limited to research applications [functional MRI (fMRI), spectroscopy, automated lesion detection]. Theoretical doubling of the signal-to-noise ratio was not confirmed, mostly being 25 %. Artefacts were worse and acquisitions took slightly longer at 3 T. CONCLUSION: Objective evidence to guide MRI purchasing decisions and routine diagnostic use is lacking. Rigorous evaluation accuracy and practicalities of diagnostic imaging technologies should be the routine, as for pharmacological interventions, to improve effectiveness of healthcare. KEY POINTS : • Higher field strength MRI may improve image quality and diagnostic accuracy. • There are few direct comparisons of 1.5 and 3 T MRI. • Theoretical doubling of the signal-to-noise ratio in practice was only 25 %. • Objective evidence of improved routine clinical diagnosis is lacking. • Other aspects of technology improved images more than field strength.

Direct vasoactive effects of the chromogranin A (CHGA) peptide catestatin in humans in vivo.

Catestatin is a bioactive peptide of chromogranin A (CHGA) that is co-released with catecholamines from secretory vesicles. Catestatin may function as a vasodilator and is diminished in hypertension. To evaluate this potential vasodilator in vivo without systemic counterregulation, we infused catestatin to target concentrations of approximately 50, approximately 500, approximately 5000 nM into dorsal hand veins of 18 normotensive men and women, after pharmacologic venoconstriction with phenylephrine. Pancreastatin, another CHGA peptide, was infused as a negative control. After preconstriction to approximately 69%, increasing concentrations of catestatin resulted in dose-dependent vasodilation (P = 0.019), in female subjects (to approximately 44%) predominantly. The EC(50) (approximately 30 nM) for vasodilation induced by catestatin was the same order of magnitude to circulating endogenous catestatin (4.4 nM). No vasodilation occurred during the control infusion with pancreastatin. Plasma CHGA, catestatin, and CHGA-to-catestatin processing were then determined in 622 healthy subjects without hypertension. Female subjects had higher plasma catestatin levels than males (P = 0.001), yet lower CHGA precursor concentrations (P = 0.006), reflecting increased processing of CHGA-to-catestatin (P < 0.001). Our results demonstrate that catestatin dilates human blood vessels in vivo, especially in females. Catestatin may contribute to sex differences in endogenous vascular tone, thereby influencing the complex predisposition to hypertension.

A systematic review of clinical trials of pharmacological interventions for acute ischaemic stroke (1955-2008) that were completed, but not published in full.

BACKGROUND: We assessed the prevalence, and potential impact of, trials of pharmacological agents for acute stroke that were completed but not published in full. Failure to publish trial data is to be deprecated as it sets aside the altruism of participants' consent to be exposed to the risks of experimental interventions, potentially biases the assessment of the effects of therapies, and may lead to premature discontinuation of research into promising treatments. METHODS: We searched the Cochrane Stroke Group's Specialised Register of Trials in June 2008 for completed trials of pharmacological interventions for acute ischaemic stroke, and searched MEDLINE and EMBASE (January 2007 - March 2009) for references to recent full publications. We assessed trial completion status from trial reports, online trials registers and correspondence with experts. RESULTS: We identified 940 trials. Of these, 125 (19.6%, 95% confidence interval 16.5-22.6) were completed but not published in full by the point prevalence date. They included 16,058 participants (16 trials had over 300 participants each) and tested 89 different interventions. Twenty-two trials with a total of 4,251 participants reported the number of deaths. In these trials, 636/4251 (15.0%) died. CONCLUSIONS: Our data suggest that, at the point prevalence date, a substantial body of evidence that was of relevance both to clinical practice in acute stroke and future research in the field was not published in full. Over 16,000 patients had given informed consent and were exposed to the risks of therapy. Responsibility for non-publication lies with investigators, but pharmaceutical companies, research ethics committees, journals and governments can all encourage the timely publication of trial data.

Matrix metalloproteinases: discrete elevations in essential hypertension and hypertensive end-stage renal disease.

The contribution of inflammation to hypertension and target organ damage is under investigation. The matrix metalloproteinase (MMP) enzymes are inflammatory mediators that may contribute to hypertension and its target organ consequences. Here we probe MMPs as inflammatory mediators in hypertension, by studying all three MMP classes in uncomplicated hypertension as well hypertension with profound renal damage, such as hypertensive end-stage renal disease (ESRD). We assayed plasma levels of five MMPs: one collagenase (MMP-1), two gelatinases (MMP-2, MMP-9), and two stromelysins (MMP-3, MMP-10). In hypertension, MMP-9 was elevated versus normotensive controls. Systolic blood pressure (SBP) in all three subject groups positively correlated with MMP-9. In hypertensive-ESRD, MMP-2 and MMP-10 were elevated compared to both hypertensive and normotensive subjects. Several correlations occurred across MMPs, suggesting coordinate biosynthetic control. Our results suggest discrete patterns of MMP overexpression in hypertension, with MMP-9 elevated early, and MMP-2 and MMP-10 linked to target organ damage.

Genetic variation within adrenergic pathways determines in vivo effects of presynaptic stimulation in humans.

BACKGROUND: Catecholamines govern stress blood pressure responses. Catecholaminergic responses may be partially genetic and contribute to the complex heritability of hypertension. METHODS AND RESULTS: To evaluate catecholaminergic responses without systemic counterregulation, we infused graded concentrations of tyramine, an indirect presynaptic norepinephrine releaser, into dorsal hand veins of 49 normotensive men and women of 5 ethnicities. Vascular responses were coupled to common (minor allele frequency >10%) single-nucleotide polymorphisms at adrenergic target loci within presynaptic pathways. Significance was set at P<0.003 after Bonferroni correction. Generalized analysis of molecular variance (GAMOVA) was performed to determine whether genetic admixture contributed to results. Venoconstriction progressed to 47% with increasing concentrations of tyramine (0.129 to 25.8 mmol/L; P<0.001). Family history of hypertension (P<0.001) and female sex (P=0.02) predicted blunted tyramine responses. Two genetic loci significantly predicted vascular response: chromogranin B, which encodes a protein that catalyzes catecholamine vesicle formation (CHGB, exon 4, Glu348Glu; P=0.002), and cytochrome b-561 (CYB561, intron 1, C719G; P<0.001), an electron shuttle for catecholamine synthesis. Stepwise regression suggested important effects for the CHGB locus, with polymorphisms for the vacuolar-ATPase beta-subunit (ATP6V1B1, exon 1, Ile30Thr) and flavin-containing monooxygenase-3 (FMO3, exon 3, Lys158Glu, P=0.002). GAMOVA did not show a significant relationship between overall genetic profile and hand-vein constriction (P=0.29), which indicates that population stratification did not contribute to this phenotype. CONCLUSIONS: Locally infused tyramine produced dose-dependent pressor responses, predicted by family history of hypertension, sex, and genetic variants at loci, particularly CHGB, that encode the biosynthesis, storage, and metabolism of catecholamines. Such variants may influence the complex heritability of adrenergic responses and perhaps hypertension.

Development and evaluation of a real-time PCR assay for rapid identification and semi-quantitation of measles virus.

A real-time PCR assay for measles virus was designed and validated using clinical samples including oral fluids, sera, urines, throat swabs, blood samples, and nasopharyngeal aspirates. The test was specific for measles virus, with a slightly higher sensitivity compared to the conventional nested PCR. Calculation of viral genome number in these samples, by comparison with a standard curve prepared from dilutions of cloned measles virus H gene, indicated that, overall, serum samples tended to have a lower viral load than oral fluid samples, and that the viral load decreased with increasing time after onset of symptoms. The real-time PCR is considered to be a sensitive and specific alternative to the conventional measles PCR, especially in situations where early and rapid diagnosis are important.

Application of molecular and serological assays to case based investigations of rubella and congenital rubella syndrome.

Rubella and congenital rubella syndrome continue to be important health problems worldwide. The detection of rubella RNA directly in clinical specimens is a critical factor in early laboratory diagnosis of recent or congenital infection, in addition to detection of rubella-specific IgM. In order to comply with recent WHO recommendations for establishing uniform genetic analysis protocols for rubella virus we have developed a new block based PCR assay (PCR-E317), which extends the sequence generated by the block based PCR-E592 currently in use, to cover the minimum acceptable 739 nucleotides (nt) window at the E1 gene. In addition, a real-time PCR assay has been developed to allow rapid detection of the virus in the laboratory. The assays were applied to a number of clinical specimens collected from patients including recent rubella incidences in the UK, Ethiopia and Turkey, two prenatal and two congenital rubella syndrome cases. Rubella RNA was detected in specimens from two patients that were collected too early for IgM detection, in two amniotic fluids for prenatal diagnosis and in the follow up specimens from the two infant with congenital rubella syndrome tested for viral secretion. At least four genotypes were identified among these patients. The results showed that molecular assays are important tools in the early diagnosis of rubella and congenital rubella syndrome, in the provision of molecular epidemiological information for tracking transmission pathways and in adding to the knowledge of rubella strain distribution worldwide.

Antibodies to Chlamydia trachomatis heat-shock protein 60 kDa and detection of Mycoplasma genitalium and ureaplasma urealyticum are associated independently with chronic nongonococcal urethritis.

BACKGROUND: Chronic nongonococcal urethritis (NGU) is a well-recognized clinical problem in genitourinary medicine clinics, but its etiology and optimal management are poorly understood. GOAL: The authors showed previously that antibody to chlamydial hsp60 is associated with urethritis 30 to 92 days after treatment of acute NGU (chronic NGU) and that the detection of ureaplasmas or is associated with chronic NGU in which symptoms or signs are present. The aim was to determine whether these associations are independent of each other. STUDY DESIGN: This was a longitudinal prospective follow-up study over a 3-month period of 86 men with acute NGU. Men were tested for, ureaplasmas, and antibody to chlamydia hsp60 at presentation and during follow-up. RESULTS: The detection of either ureaplasmas or (OR, 29.45; 95% CI, 1.78-487) and the occurrence of hsp60 antibody at 30 to 92 days' follow-up (OR, 26.45; 95% CI, 1.34-523) were associated independently with the development of chronic NGU 30 to 92 days after treatment of acute NGU. The presence of chlamydial hsp60 antibody at 30 to 92 days was not associated with the development of chronic NGU in which symptoms or signs were present (P= 0.363). Chlamydial hsp60 antibody associated, however, with chronic NGU in which there were no symptoms or signs (P = 0.01). CONCLUSION: The results suggest that the immune response to chlamydial hsp60 may have a role in the etiology of chronic NGU in asymptomatic men who have no discharge on examination. The clinical relevance of this is unknown.

Detection of Chlamydia trachomatis infection in early pregnancy using self-administered vaginal swabs and first pass urines: a cross-sectional community-based survey.

A cross-sectional survey of 1216 newly pregnant women (mean age = 31 years) from 32 general practices and five family planning clinics was conducted to find the prevalence of chlamydial infection and to evaluate self-administered vaginal swabs and first-pass urines for detection of Chlamydia trachomatis by ligase chain reaction assay. Overall prevalence of infection was 2.4% (95% CI = 1.5 to 3.3) but in women aged less than 25 years it was 8.6% (95% CI = 4.1 to 12.9) and in pregnant teenagers it was 14.3% (95% CI = 3.7 to 24.9). In 1161 women with both swab and urine results, 25 women were positive on both specimens three on swab alone, and one on urine alone. When asked which they preferred to provide, 47% said urine, 59 swab and 48% preferred both equally. This is the first study to show that non-invasive screening in early pregnancy is feasible in the community. Although swabs detected 10% more infections, nearly half the women preferred providing urine specimens.