Systematic review of effectiveness of bisphosphonates in treatment of low bone mineral density and fragility fractures in juvenile idiopathic arthritis.

AIMS: To evaluate the currently available evidence for the effectiveness of bisphosphonates in children with low bone mineral density (BMD) and fragility fractures associated with juvenile idiopathic arthritis (JIA), and the safety of bisphosphonates in JIA and other conditions. METHODS: Literature databases were searched using a structured search strategy. The effectiveness review included any studies of children with JIA treated with bisphosphonates. The safety review also included studies of osteogenesis imperfecta. Quantitative data analysis was not undertaken because of the heterogeneity of the studies; findings were summarised using tables and narrative synthesis. RESULTS: Ninety four studies were identified. Sixteen studies (78 JIA children) were included in the effectiveness review: one randomised controlled trial, three controlled cohort studies, 11 case series, and one case report. At baseline, children had low BMD below the expected values for age and sex matched children. In all studies, treatment with bisphosphonates increased BMD compared with baseline: the mean percentage increase in spine BMD ranged from 4.5% to 19.1%. Overall, studies were heterogeneous and of variable quality. A total of 59 papers were included in the safety review; treatment durations were up to three years. The most common side effect was a flu-like reaction with intravenous treatment. This occurred during the first infusion and was transient; the symptoms were managed with paracetamol and did not occur during subsequent cycles. CONCLUSIONS: Bisphosphonates are a promising treatment for low BMD and fragility fractures in children with JIA. However, the quality of the current evidence is variable and better studies are needed to more clearly assess their role.     

Effects of repetitive TMS on visually evoked potentials and EEG in the anaesthetized cat: dependence on stimulus frequency and train duration

Repetitive transcranial magnetic stimulation (rTMS) has been shown to alter cortical excitability that lasts beyond the duration of rTMS application itself. High-frequency rTMS leads primarily to facilitation, whereas low-frequency rTMS leads to inhibition of the treated cortex. However, the contribution of rTMS train duration is less clear. In this study, we investigated the effects of nine different rTMS protocols, including low and high frequencies, as well as short and long applications (1, 3 and 10 Hz applied for 1, 5 and 20 min), on visual cortex excitability in anaesthetized and paralysed cats by means of visual evoked potential (VEP) and electroencephalography (EEG) recordings. Our results show that 10 Hz rTMS applied for 1 and 5 min significantly enhanced early VEP amplitudes, while 1 and 3 Hz rTMS applied for 5 and 20 min significantly reduced them. No significant changes were found after 1 and 3 Hz rTMS applied for only 1 min, and 10 Hz rTMS applied for 20 min. EEG activity was only transiently (<20 s) affected, with increased delta activity after 1 and 3 Hz rTMS applied for 1 or 5 min. These findings indicate that the effects of rTMS on cortical excitability depend on the combination of stimulus frequency and duration (or total number of stimuli): short high-frequency trains seem to be more effective than longer trains, and low-frequency rTMS requires longer applications. Changes in the spectral composition of the EEG were not correlated to changes in VEP size.     

Obesity is Associated with Genetic Variants That Alter Dopamine Availability

Human and animal studies have implicated dopamine in appetite regulation, and family studies have shown that BMI has a strong genetic component. Dopamine availability is controlled largely by three enzymes: COMT, MAOA and MAOB, and by the dopamine transporter SLC6A3, and each gene has a well-characterized functional variant. Here we look at these four functional polymorphisms together, to investigate how heritable variation in dopamine levels influences the risk of obesity in a cohort of 1150, including 240 defined as obese (BMI ≥ 30). The COMT and SLC6A3 polymorphisms showed no association with either weight, BMI or obesity risk. We found, however, that both MAOA and MAOB show an excess of the low-activity genotypes in obese individuals ( MAOA: χ²= 15.45, p = 0.004; MAOB: χ²= 8.05, p = 0.018). Additionally, the MAOA genotype was significantly associated with both weight (p = 0.0005) and BMI (p = 0.001). When considered together, the 'at risk genotype' - low activity genotypes at both the MAOA and MAOB loci - shows a relative risk for obesity of 5.01. These results have not been replicated and, given the experience of complex trait genetics, warrant caution in interpretation. In implicating both the MAOA and MOAB variants, however, this study provides the first indication that dopamine availability (as opposed to other effects of MAOA) is involved in human obesity. It is therefore a priority to assess the associations in replication datasets.     

Statins, fenofibrate, and quinapril increase clot permeability and enhance fibrinolysis in patients with coronary artery disease

BACKGROUND: Aspirin increases fibrin clot porosity and susceptibility to lysis. It is unknown whether other drugs, in combination with aspirin, used in the treatment of coronary artery disease (CAD) might affect clot structure and resistance to lysis. AIM: The aim of the study was to assess the effects of statins, fibrates, or angiotensin-converting enzyme inhibitors (ACEIs) on fibrin clot properties. PATIENTS AND METHODS: In a randomized double-blind study, men with advanced CAD taking low-dose aspirin were assigned to receive one of the four drugs: simvastatin 40 mg day(-1) (n = 13), atorvastatin 40 mg day(-1) (n = 12), fenofibrate 160 mg day(-1) (n = 12), and quinapril 10 mg day(-1) (n = 11) for 28 +/- 2 days. Moreover, CAD patients (n = 13) taking aspirin (75 mg day(-1)) for 8 weeks were studied after additional 4 weeks on an open-label basis. Thirty men served as healthy controls. Plasma clot permeability and tissue plasminogen activator-induced fibrinolysis were evaluated at baseline and after drug administration. RESULTS: Permeability increased following the administration of simvastatin (by 20%; P = 0.01), atorvastatin (by 22%; P = 0.001), fenofibrate (by 16%; P = 0.02), and quinapril (by 13%; P = 0.04) like for aspirin (P < 0.001). Turbidity analysis showed that administration of any of the drugs was associated with higher maximum absorbancy, suggesting thicker fibers, and shorter fibrinolysis time (P < 0.001). Post-treatment reduction in lysis time correlated with an increase in clot porosity in all the groups (r from 0.42 to 0.61; P from 0.01 to 0.001). CONCLUSIONS: Statins, fibrates, and ACEIs may increase plasma clot permeability and susceptibility to fibrinolysis in CAD patients receiving aspirin. This novel antithrombotic mechanism might contribute to clinical benefits of the drugs tested.     

Determinants of left ventricular systolic function recovery after an acute coronary syndrome.

INTRODUCTION: Ischemic heart disease is a major cause of heart failure in western societies. However, the factors that may influence left ventricular function (LVF) recovery after an acute coronary syndrome (ACS) are still unclear. OBJECTIVE: To identify variables that may influence LVF evolution one year after ACS. METHODS: 104 patients hospitalized with ACS between 7/1/2001 and 12/31/2002 and with systolic dysfunction--defined as an echocardiographic ejection fraction (EF) < or = 45%--were randomly allocated to a planned coronary follow-up program (FUP) or a general cardiology clinic (GC); patients from both groups were also randomly referred to a structured cardiac rehabilitation program (CRP). EF was re-assessed at one year. We compared differences between patients who recovered left ventricular function (EF > 45%; group 1) and those who did not (group 2). RESULTS: One year after discharge, 44.2% of the patients had recovered function. There were no significant differences between the groups in gender (77.7 vs. 76.5% male), age (56 vs. 59 years), hypertension, diabetes, dyslipidemia, smoking habits or family history. A previous history of cardiovascular events was more frequent in group 2 (11.1% vs. 35.3%, p = 0.03). Cardiac catheterization was performed before discharge in 88.8% and 88.2% in groups 1 and 2 respectively (p = NS); no differences were found in coronary anatomy between the two groups. Angioplasty was performed in 54.2% in group 1 and 50% in group 2 (p = NS). There were no differences in the use of angiotensin-converting enzyme inhibitors (83.3% vs. 87.5%), beta-blockers (87.5% vs. 87.5%), nitrates (37.5% vs. 33.3%), aspirin (95.8% vs. 95.8%), statins (79.1% vs. 75%) or diuretics (20.8% vs. 45.8%). There was no significant difference in LVF recovery between patients randomized to FUP or GC (38.5% vs. 54.5%). 87.5% of patients who completed the CRP had normal EF at one year compared to 32.7% of patients not referred to the program (p = 0.009). Although EF improved in both groups, this improvement was greater in patients who completed a CRP (EF 8% vs. 5%, p = 0.003). CONCLUSION: A previous cardiovascular event and completion of a CRP were the only variables that influenced LVF recovery. Thus, enrollment in a CRP, in addition to standard therapy, could be an important therapeutic measure in patients with systolic dysfunction after ACS; our data suggest that these programs should be more widely used.