Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis

BACKGROUND AND AIMS: Cyclosporine A is highly effective in severe attacks of ulcerative colitis (UC) but is associated with important adverse effects that are mainly dose dependent. Our single center, randomized, double-blind, controlled trial aimed to evaluate the additional clinical benefit of 4 mg/kg over 2 mg/kg IV cyclosporine in the acute treatment of severe UC. METHODS: Primary end point was the proportion of patients with a clinical response. Secondary end points included time to response, colectomy rate, and adverse effects. RESULTS: Seventy-three patients were included. Day-8 response rates were 84.2% (32 of 38, 4 mg/kg) and 85.7% (32 of 35, 2 mg/kg) after a median of 4 days in both groups. Short-term colectomy rates were 13.1% (4 mg/kg) and 8.6% (2 mg/kg). Mean cyclosporine blood levels were 237 +/- 33 in the 2-mg/kg group and 332 +/- 43 ng/mL in the 4-mg/kg group. Active smoking was inversely correlated with clinical response (odds ratio, 0.06), but concomitant azathioprine or steroids were not predictive. A trend toward a higher incidence of hypertension was observed in the 4-mg/kg group (23.7% vs. 8.6%, 2 mg/kg, P < 0.08). CONCLUSIONS: High-dose IV cyclosporine has no additional clinical benefit over low dose in the treatment of severe UC. Although we did not observe differences in adverse effects on the short term, the use of 2 mg/kg IV cyclosporine should provide an improved toxicity profile for medical treatment of severe UC.     

Evidence for Aggressive Blood Pressure–Lowering Goals in Patients with Coronary Artery Disease

Lowering blood pressure (BP) reduces the risk of major cardiovascular mortality and morbidity. Current consensus targets for BP reduction are less than 140/90 mm Hg in uncomplicated hypertension and less than 130/80 mm Hg in those patients with diabetes, chronic kidney disease, and coronary artery disease or in those who are at high risk for developing coronary artery disease (defined as a Framingham risk score of ≥ 10%). There is solid epidemiologic evidence for lower BP targets, supported by some clinical studies with surrogate end points. On the other hand, there are meager data from clinical trials using hard end points, and there is a concern that overly aggressive BP lowering, especially of diastolic BP, may impair coronary perfusion, particularly in patients with left ventricular hypertrophy and/or coronary artery disease. This review evaluates the evidence for the benefit of lower BP targets in hypertension management.     

Time course of the response to navigated repetitive transcranial magnetic stimulation at 10 Hz in chronic neuropathic pain

Objective This prospective study evaluated the time to response and outcomes of navigated repetitive transcranial magnetic stimulation (TMS) at a frequency of 10 Hz in patients with chronic neuropathic pain.

Methods This prospective study included patients with unilateral chronic neuropathic pain. All patients received motor cortex stimulation at 10 Hz over nine consecutive days using repetitive TMS. Outcome was evaluated over a six-week follow-up period using the visual analogue scale, the German Pain Questionnaire and time to pain reduction.

Results Fifty patients (23 female, 27 male) were recruited. Two patients were excluded from analysis owing to premature discontinuation of treatment and follow-up. 31/48 patients in the cohort suffered from atypical facial pain. The pain duration ranged approximately from six months to 27 years. After six weeks, 28/46 patients reported a significant level of pain relief (P < 0.001).

Conclusion Navigated repetitive TMS for chronic pain is a non-invasive modality with demonstrable clinical benefit. In particular, patients with atypical facial pain with a clear clinicoanatomical correlate responded well to high-frequency stimulation. Patients with a mean pain history of less than five years benefited significantly from this treatment, so early treatment with repetitive TMS should be encouraged.     

Ethanol inhibits long‐term potentiation in hippocampal CA1 neurons,irrespective of lamina and stimulus strength,through neurosteroidogenesis

Ethanol inhibits memory encoding and the induction of long‐term potentiation (LTP) in CA1 neurons of the hippocampus. Hippocampal LTP at Schaffer collateral synapses onto CA1 pyramidal neurons has been widely studied as a cellular model of learning and memory, but there is striking heterogeneity in the underlying molecular mechanisms in distinct regions and in response to distinct stimuli. Basal and apical dendrites differ in terms of innervation, input specificity, and molecular mechanisms of LTP induction and maintenance, and different stimuli determine distinct molecular pathways of potentiation. However, lamina or stimulus‐dependent effects of ethanol on LTP have not been investigated. Here, we tested the effect of acute application of 60 mM ethanol on LTP induction in distinct dendritic compartments (apical versus basal) of CA1 neurons, and in response to distinct stimulation paradigms (single versus repeated, spaced high frequency stimulation). We found that ethanol completely blocks LTP in apical dendrites, whereas it reduces the magnitude of LTP in basal dendrites. Acute ethanol treatment for just 15 min altered pre‐ and post‐synaptic protein expression. Interestingly, ethanol increases the neurosteroid allopregnanolone, which causes ethanol‐dependent inhibition of LTP, more prominently in apical dendrites, where ethanol has greater effects on LTP. This suggests that ethanol has general effects on fundamental properties of synaptic plasticity, but the magnitude of its effect on LTP differs depending on hippocampal sub‐region and stimulus strength. © 2014 Wiley Periodicals, Inc.     

Mycobacterial Esx-3 is required for mycobactin-mediated iron acquisition

The Esx secretion pathway is conserved across Gram-positive bacteria. Esx-1, the best-characterized system, is required for virulence of Mycobacterium tuberculosis, although its precise function during infection remains unclear. Esx-3, a paralogous system present in all mycobacterial species, is required for growth in vitro. Here, we demonstrate that mycobacteria lacking Esx-3 are defective in acquiring iron. To compete for the limited iron available in the host and the environment, these organisms use mycobactin, high-affinity iron-binding molecules. In the absence of Esx-3, mycobacteria synthesize mycobactin but are unable to use the bound iron and are impaired severely for growth during macrophage infection. Mycobacteria thus require a specialized secretion system for acquiring iron from siderophores.     

Low dose (renal dose) dopamine in the critically ill patient

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether low dose (renal dose) dopamine in the critically ill patient prevents acute renal failure. Altogether 141 papers were found using the reported search, of which three presented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of these papers are tabulated. We conclude that there is no evidence to support the use of low-dose dopamine to treat acute renal failure in critically ill patients.     

Should the pericardium be closed in patients undergoing cardiac surgery?

A best evidence topic in Cardiothoracic Surgery was written according to a structured protocol. The question addressed was in open heart surgery is there any adverse effect to closing the pericardium? Altogether 240 publications were found using the reported search of which 8 were deemed to be relevant to answer the clinical question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of these papers are tabulated. We conclude that the adverse haemodynamic impact of pericardial closure is confirmed in several studies, however, no study has yet reported an adverse clinical outcome due to the closure of the pericardium.