Showing papers by "Guy's and St Thomas' NHS Foundation Trust published in 2004"

The Effects of Strontium Ranelate on the Risk of Vertebral Fracture in Women with Postmenopausal Osteoporosis

Abstract: background Osteoporotic structural damage and bone fragility result from reduced bone formation and increased bone resorption. In a phase 2 clinical trial, strontium ranelate, an orally active drug that dissociates bone remodeling by increasing bone formation and decreasing bone resorption, has been shown to reduce the risk of vertebral fractures and to increase bone mineral density. methods To evaluate the efficacy of strontium ranelate in preventing vertebral fractures in a phase 3 trial, we randomly assigned 1649 postmenopausal women with osteoporosis (low bone mineral density) and at least one vertebral fracture to receive 2 g of oral strontium ranelate per day or placebo for three years. We gave calcium and vitamin D supplements to both groups before and during the study. Vertebral radiographs were obtained annually, and measurements of bone mineral density were performed every six months. results New vertebral fractures occurred in fewer patients in the strontium ranelate group than in the placebo group, with a risk reduction of 49 percent in the first year of treatment and 41 percent during the three-year study period (relative risk, 0.59; 95 percent confidence interval, 0.48 to 0.73). Strontium ranelate increased bone mineral density at month 36 by 14.4 percent at the lumbar spine and 8.3 percent at the femoral neck (P<0.001 for both comparisons). There were no significant differences between the groups in the incidence of serious adverse events. conclusions Treatment of postmenopausal osteoporosis with strontium ranelate leads to early and sustained reductions in the risk of vertebral fractures.

Management of the critically ill patient with severe acute pancreatitis.

Abstract: Objective:Acute pancreatitis represents a spectrum of disease ranging from a mild, self-limited course requiring only brief hospitalization to a rapidly progressive, fulminant illness resulting in the multiple organ dysfunction syndrome (MODS), with or without accompanying sepsis. The goal of this c

Widespread sulfenic acid formation in tissues in response to hydrogen peroxide

Abstract: A principal product of the reaction between a protein cysteinyl thiol and hydrogen peroxide is a protein sulfenic acid. Because protein sulfenic acid formation is reversible, it provides a mechanism whereby changes in cellular hydrogen peroxide concentration may directly control protein function. We have developed methods for the detection and purification of proteins oxidized in this way. The methodology is based on the arsenite-specific reduction of protein sulfenic acid under denaturing conditions and their subsequent labeling with biotin–maleimide. Arsenite-dependent signal generation was fully blocked by pretreatment with dimedone, consistent with its reactivity with sulfenic acids to form a covalent adduct that is nonreducible by thiols. The biotin tag facilitates the detection of protein sulfenic acids on Western blots probed with streptavidin–horseradish peroxidase and also their purification by streptavidin–agarose. We have characterized protein sulfenic acid formation in isolated hearts subjected to hydrogen peroxide treatment. We have also purified and identified a number of the proteins that are oxidized in this way by using a proteomic approach. Using Western immunoblotting we demonstrated that a highly significant proportion of some individual proteins (68% of total in one case) form the sulfenic derivative. We conclude that protein sulfenic acids are widespread physiologically relevant posttranslational oxidative modifications that can be detected at basal levels in healthy tissue, and are elevated in response to hydrogen peroxide. These approaches may find widespread utility in the study of oxidative stress, particularly because hydrogen peroxide is used extensively in models of disease or redox signaling.

Vasopressor and inotropic support in septic shock: an evidence-based review.

Abstract: In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for vasopressor and inotropic support in septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and to improve outcome in severe sepsis.

Administration of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002).

Abstract: ObjectiveTo assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was resolution of shock, defined as a mean arterial pressure ≥70 mm Hg in the absence of both conventional vasopressors and study drug, de

Features associated with epilepsy in the antiphospholipid syndrome

Abstract: OBJECTIVE: To assess the frequency of epilepsy in primary and secondary antiphospholipid syndrome (APS); to analyze the clinical and laboratory features characterizing those with epilepsy in a cohort of 538 patients with APS; and to find associated features that would suggest risk factors for epilepsy in APS. METHODS: We analyzed the clinical features of patients with APS who had epilepsy and compared them to the clinical features of non-epileptic APS patients. RESULTS: Of 538 APS patients, 46 (8.6%) had epilepsy. Epilepsy was more prevalent among APS secondary to systemic lupus erythematosus (SLE) compared to primary APS (13.7% vs 6%; p < 0.05). The patients with epilepsy had a higher prevalence of central nervous system (CNS) manifestations including focal ischemic events (strokes or transient ischemic events, 54.3% vs 24.6%; p < 0.0001) and amaurosis fugax (15.2% vs 4.9%; p < 0.05). APS patients with epilepsy had a higher frequency of valvular pathology (30.4% vs 14.6%; p < 0.01), thrombocytopenia (43.5% vs 25%; p < 0.05), and livedo reticularis (26.1% vs 11.5%; p < 0.01). The multivariate logistic regression analysis found CNS thromboembolic events as the most significant factor associated with epilepsy, with an odds ratio (OR) of 4.05 (95% confidence interval, CI: 2.05-8), followed by SLE (OR 1.4, 95% CI 1.2-4.7), and valvular vegetations (OR 2.87, 95% CI 1-8.27). CONCLUSION: Epilepsy is common in APS and most of the risk seems to be linked to vascular disease as manifested by extensive CNS involvement, valvulopathy, and livedo reticularis and to the presence of SLE. These factors, however, explain only part of the increased occurrence of epilepsy in APS and other causes such as direct immune interaction in the brain should be investigated.

Anti-52 kDa Ro, anti-60 kDa Ro, and anti-La antibody profiles in neonatal lupus.

Abstract: OBJECTIVE: Studies suggest that anti-52 kDa Ro antibodies are more sensitive and specific than anti-60 kDa Ro antibodies for neonatal lupus. However, these studies mainly used immunoblot or ELISA using recombinant protein, which have poor sensitivity for anti-60 kDa Ro antibodies. In addition, the control patients were not disease matched. We reassessed the sensitivity and specificity of anti-52 kDa Ro, anti-60 kDa Ro, and anti-La, addressing these limitations. METHODS AND RESULTS: To assess sensitivity, 125 mothers of children with neonatal lupus (NLM) were recruited. All maternal sera were assessed using a commercial line immunoassay that uses natural 60 kDa Ro protein (Inno-Lia ANA Update, Innogenetics NV, Gent, Belgium). By this method, 96% of the sera had antibodies to 60 kDa Ro, 86% to 52 kDa Ro, and 78% to 48 kDa La. Immunoblot of 65 NLM showed significantly fewer positive results for anti-60 kDa Ro (p < 0.001) and anti-52 kDa Ro (p < 0.05). Sensitivity of the 3 antibodies was assessed in the symptomatic mothers of children with congenital heart block (CHB) (78 women) and disease matched controls with unaffected children (65 women) using Inno-Lia ANA Update. The sensitivity of each antibody was compared by multiple logistic regression to adjust for maternal disease. There was no significant difference between the groups for 60 kDa Ro or for anti-52 kDa Ro antibody. However, there was a significant difference for the anti-La antibody (p = 0.001), with an odds ratio of 3.59. This translates to an increase in risk from a published 2% for CHB in an anti-Ro-positive mother to 3.1% if the woman is also anti-La antibody-positive, and to a decrease in risk to 0.9% if anti-La-negative. CONCLUSION: Contrary to previous reports, 52 kDa Ro as detected by Inno-Lia ANA Update is not more specific for or frequent in CHB than 60 kDa Ro. However, the presence of anti-La antibodies significantly increases the risk for CHB.

Bimolecular interaction of insulin-like growth factor (IGF) binding protein-2 with alphavbeta3 negatively modulates IGF-I-mediated migration and tumor growth.

Abstract: Both the integrin and insulin-like growth factor binding protein (IGFBP) families independently play important roles in modulating tumor cell growth and progression. We present evidence for a specific cell surface localization and a bimolecular interaction between the alpha v beta 3 integrin and IGFBP-2. The interaction, which could be specifically perturbed using vitronectin and alpha v beta 3 blocking antibodies, was shown to modulate IGF-mediated cellular migration responses. Moreover, this interaction was observed in vivo and correlated with reduced tumor size of the human breast cancer cells, MCF-7 beta 3, which overexpressed the alpha v beta 3 integrin. Collectively, these results indicate that alpha v beta 3 and IGFBP-2 act cooperatively in a negative regulatory manner to reduce tumor growth and the migratory potential of breast cancer cells.

A multicenter Phase I gene therapy clinical trial involving intraperitoneal administration of E1A-lipid complex in patients with recurrent epithelial ovarian cancer overexpressing HER-2/neu oncogene.

Abstract: Purpose: HER-2/ neu oncogene is overexpressed in 10–30% of epithelial ovarian cancers and is associated with a poor prognosis. The E1A gene product of adenovirus type 5 down-regulates HER-2/ neu and causes tumor regression in animal models. In the current study, we sought to determine the toxicity and biological activity of E1A-lipid complex in ovarian cancer patients. Experimental Design: A Phase I trial involving intraperitoneal (i.p.) administration of E1A-lipid complex was initiated in ovarian cancer patients to assess biological activity (E1A gene transfer/transcription/translation and HER-2/ neu expression) and to determine the maximum tolerated dose. Successive cohorts received E1A-lipid complex at doses of 1.8, 3.6, and 7.2 mg DNA/m 2 , given as weekly i.p. infusions for 3 of 4 weeks (each cycle) up to a maximum of six cycles. Peritoneal fluid was sampled at baseline and twice monthly for cellularity, cytology, CA-125, and biological activity Results: Fifteen patients, with a median age of 57 years (range, 43–81) were recruited. Three (1.8 mg DNA/m 2 ), 4 (3.6 mg DNA/m 2 ), and 8 patients (7.2 mg DNA/m 2 ) received i.p. E1A. A total of 91 infusions (range, 1–18) was administered. Abdominal pain was the dose-limiting toxicity, and the maximum-tolerated dose was 3.6 mg DNA/m 2 . E1A gene transfer and expression was observed in all of the patients and at all of the dose levels. HER-2/ neu down-regulation could be demonstrated in the tumor cells of 2 patients (18%). There was no correlation between dose and biological activity. Conclusions: I.P. EIA-lipid complex gene therapy is feasible and safe. Future studies, either alone or in combination with chemotherapy, particularly in patients with minimal residual disease, should be evaluated.

Use of Coronary Calcification Scores to Predict Coronary Heart Disease

Abstract: To the Editor: Dr Greenland and colleagues reported that both the Framingham Risk Score (FRS) and the coronary artery calcium score (CACS) were predictive of coronary artery disease. The authors also reported that across categories of FRS, CACS was predictive of risk among patients with an FRS higher than 10%, but not with an FRS less than 10%. Furthermore, the CACS was less predictive than the FRS (hazard ratio, 3.9 vs 14.3), and only added slightly to the area under the receiver operating characteristic (ROC) curve using FRS alone. We point out that the FRS has a wide confidence interval (5.1%-6.9%) depending on the number of initial measurements in this type of patient and so it is possible that no significant difference exists given the size of the ROC envelope for the FRS and the small numbers of events that occurred in the study. The original cohort for the FRS included a larger proportion of smokers (40%) than is currently present in the population, and it is likely that the performance of the FRS was better than that observed now due to risk-factor drift away from smoking and toward diabetes. Modification of the FRS by the addition of inflammatory markers (eg, high-sensitivity Creactive protein [hsCRP]) has been suggested as a way to improve performance, but this may be limited by large biological variation. While the combination of FRS and hsCRP levels might have been superior to the combination of FRS and CACS, the authors did not measure hsCRP levels. Finally, we suspect that this study did not include patients with diabetes, given the National Cholesterol Education Program guidelines. However, the FRS used in many countries does include diabetes as a variable. The high rate of arterial calcification in this group may further confound estimates of risk determined by CACS scores.

Developing an analytical toxicology service: principles and guidance.

Abstract: Many acutely poisoned patients are treated with no laboratory help other than general clinical chemistry and haematology. Emergency toxicological analyses (24-hour availability) that could influence immediate patient management such as iron, lithium and paracetamol (acetaminophen), are relatively few in number and are remarkably similar worldwide. These assays should be provided at hospitals with large accident and emergency departments. More complex, less frequently needed clinical toxicological assays that can often be offered on a less urgent basis are usually provided from regional or national centres because of the need to make best use of resources. Recommendations as to the assays that should be provided locally and at regional centres are available for the UK and US, and are generally applicable. Regional centres normally diversify into specialised therapeutic drug monitoring, urine screening for drugs of abuse, metals analysis and sometimes forensic work in order to widen the repertoire of tests available and to increase funding. Whatever the type and quantity of work undertaken and the instrumentation used, guidelines are now available delineating staff training, method validation, assay operation, quality control/quality assurance, and indeed virtually all other aspects of laboratory operation. These considerations notwithstanding, clinical interpretation of analytical results remains a difficult area and is the responsibility of the reporting laboratory, at least in the first instance.

Administration of nitric oxide synthase inhibitor 546C88 in septic shock [1] (multiple letters)

Abstract: To the Editor: We read with interest the article reporting on a large phase III trial concerning the use of the nitric oxide synthase inhibitor 546C88 in septic shock in Critical Care Medicine (1). Although a smaller phase II study (2) showed no untoward adverse events, this result could not be confirmed in the larger phase III study. Considering the causes of death in both study arms in the phase III study, all excess mortality is apparently caused by refractory shock. Unfortunately, the authors do not specify the specific nature of the type of refractory shock. Their study and the previous one show a consistent increase in mean arterial pressure after the administration of 546C88, which is accompanied by an approximately 20% decrease in cardiac output. The dismissal of a minimum cardiac index as a requirement for inclusion in the phase III trial is one of the key differences between these studies. Is the excess mortality explained by forward failure possibly in the patient category with a low cardiac index from the onset? The authors state in their discussion that a post hoc analysis seemed to indicate that a lower prescribed dose rate of 546C88 was associated with an improved survival. Do the authors also find a higher cardiac output in this patient category? Also, as noted in the accompanying editorial (3) in the same issue, there are some data indicating that lower perfusion pressures are not associated with increased organ failure (4). Treatment was directed at maintaining mean arterial pressure between 70 and 90 mm Hg. Albeit a post hoc analysis, could the authors provide any data on the outcome of the patients in the lower ranges of perfusion pressure? Were these patients treated with lower dose rates of 546C88? Furthermore, we are curious what prompted the investigators to allow for a more rapid dose escalation in the phase III trial when it is already apparent from the phase II trial that any effect from 546C88 on mean arterial pressure occurs rapidly after the first administration and is sustained long after the last dose? This also could have led to treating patients with higher dose rates of 546C88 compared with the earlier study.