Risk Factors for Voriconazole Hepatotoxicity at 12 Weeks in Lung Transplant Recipients

Voriconazole is commonly used for prophylaxis and treatment of invasive aspergillosis in lung transplant recipients. However, the use of voriconazole may at times be limited by the development of hepatotoxicity. Our goal is to determine predictors of voriconazole‐associated hepatotoxicity in lung transplant recipients. We conducted a single center retrospective cohort study of lung transplant recipients from 2006 to 2010 who received voriconazole therapy. We compared characteristics of patients who developed hepatotoxicity and those who did not. One hundred five lung transplant recipients received voriconazole. Hepatotoxicity occurred in 51% (54/105) of patients and lead to discontinuation in 34% (36/105). In univariate analysis, age less than 40 years, cystic fibrosis, use of azathioprine, history of liver disease and early initiation of voriconazole were associated with hepatotoxicity. In multivariable logistic regression analysis, perioperative initiation of voriconazole (within 30 days of transplantation) was independently associated with hepatotoxicity (OR 4.37, 95% CI: 1.53–12.43, p = 0.006). The five risk factors identified in the univariate analysis were used to build a K‐nearest neighbor algorithm predictive model for hepatotoxicity. This model predicted hepatotoxicity with an accuracy of 70%. Voriconazole therapy initiated within the first 30 days of transplantation is associated with a greater risk of developing hepatotoxicity.     

Characteristics of individuals meeting criteria for new onset panic attacks following exposure to a typhoon

The association between trauma exposure and panic attacks has received increased attention over the past decade, with mounting evidence suggesting an overlapping etiologic pathway. This study examined the incidence of new onset panic attacks in 775 Vietnamese individuals in the 2–3 months following Typhoon Xangsane. Pre-typhoon (Wave 1) and post-typhoon (Wave 2) assessments were conducted, allowing for consideration of factors occurring prior to the typhoon in addition to typhoon-relevant responding. Of the 775 participants, 11.6% (n=90) met criteria for lifetime panic attack pre-typhoon and 2.8% (n=22) met post-typhoon panic attack criteria. Individuals with pre-typhoon panic were significantly older and reported less education compared to the no-panic group. Individuals in both panic groups were more likely to screen positive on a Wave1 psychiatric screening measure, endorse greater typhoon exposure and prior traumatic event exposure and were significantly more likely to meet DSM-IV criteria for posttraumatic stress disorder (PTSD) and major depression (MDD) post-typhoon compared with persons reporting no history of panic attacks. Pre and post-typhoon panic exhibited similar patterns across variables and both panic conditions were associated with the development of PTSD and MDD, suggesting that persons experiencing panic attacks may represent a vulnerable population in need of early intervention services.     

Very low concentrations of ethanol suppress excitatory synaptic transmission in rat visual cortex

Ethanol is one of the most commonly used substances in the world. Behavioral effects of alcohol are well described, however, cellular mechanisms of its action are poorly understood. There is an apparent contradiction between measurable behavioral changes produced by low concentrations of ethanol, and lack of evidence of synaptic changes at these concentrations. Furthermore, effects of ethanol on synaptic transmission in the neocortex are poorly understood. Here, we set to determine effects of ethanol on excitatory synaptic transmission in the neocortex. We show that 1–50 mm ethanol suppresses excitatory synaptic transmission to layer 2/3 pyramidal neurons in rat visual cortex in a concentration‐dependent manner. To the best of our knowledge, this is the first demonstration of the effects of very low concentrations of ethanol (from 1 mm ) on synaptic transmission in the neocortex. We further show that a selective antagonist of A₁ adenosine receptors, 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX), blocks effects of 1–10 mm ethanol on synaptic transmission. However, the reduction in excitatory postsynaptic potential amplitude by 50 mm ethanol was not affected by DPCPX. We propose that ethanol depresses excitatory synaptic transmission in the neocortex by at least two mechanisms, engaged at different concentrations: low concentrations of ethanol reduce synaptic transmission via A₁R‐dependent mechanism and involve presynaptic changes, while higher concentrations activate additional, adenosine‐independent mechanisms with predominantly postsynaptic action. Involvement of adenosine signaling in mediating effects of low concentrations of ethanol may have important implications for understanding alcohol's effects on brain function, and provide a mechanistic explanation to the interaction between alcohol and caffeine.     

Effect of Interleukin-6 promoter polymorphisms in survivors of myocardial infarction and matched controls in the North and South of Europe. The HIFMECH Study

Elevated plasma IL-6 levels have been implicated in the pathogenesis of coronary heart disease. We have investigated the association of two polymorphisms in the promoter of IL-6 (-572G>C and -174G>C) with levels of inflammatory markers and risk of myocardial infarction (MI) in a European study of MI survivors and age-matched controls from two high-risk centres in the North of Europe, and two low risk centres in the South. IL-6 and CRP levels were similar in controls in both regions, but were higher in cases. For the -174G>C polymorphism the rare -174C allele showed a regional difference in allele frequency, being more common in the North European group (0.43 vs 0.28; p < 0.0005), where -174C allele carriers showed an apparent reduced risk of MI compared to -174GG homozygotes (OR 0.53, 95%CI 0.32, 0.86). No such effect was observed in the South or with the -572G>C in either group. Neither genotype was associated with a significant effect on plasma IL-6 levels in either cases or controls. Furthermore, no regional difference was observed in the frequency of the -572G>C SNP, suggesting that these polymorphisms are unlikely to be contributing to the observed increased risk of cardiovascular disease in Northern Europe.     

Dose effect relationship of reviparin in chronic hemodialysis: a crossover study versus nadroparin

Low molecular weight heparins (LMWHs) are used for prevention of clotting in the dialysis circuit. The aim of this trial was to define the optimal dose of a new LMWH and to test the efficiency of a single dose at the start of the session. Fifteen patients were treated according to a double blind and crossover design during 4 blocks of 5 consecutive reviparin doses assigned randomly as 50, 60, 70, 85, and 100 IU anti-Xa/kg. Assessment was carried out on screening of fibrin rings or clots in the arterial and venous air traps and on visual detection of fiber in the dialyzer after rinsing. These clinical results were compared to plasmatic anti-Xa activity and thrombin-antithrombin (TAT) complex generation. A standard dose of 70 IU anti-Xa/kg of nadroparin was used as the control. After a bolus of 50 to 100 IU anti-Xa/kg, the occurrence of fibrin rings and clots in the air traps was dependent on three factors: dose of LMWH, time of the session, and patient status. A bolus of 85 IU anti-Xa/kg of reviparin was effective and safe for sessions of 4 h. For this dose, plasmatic anti-Xa activity was 0.96 +/- 0.28 IU/ml at Hour 2 and 0.82 +/- 0.22 IU/ml at Hour 4. TAT complexes are good markers of the activation of the coagulation. They did not increase during a 4 h session after a reviparin bolus of 100 IU/kg. For the same LMWH dose, the trial shows a great variability of the clinical effect and anti-Xa activities from one patient to another. A single dose of 85 IU anti-Xa/kg of reviparin can be used at the start of the dialysis session as a loading dose. We advise adapting the dose during the subsequent sessions according to the appearance of the blood circuit. The benefit of monitoring anti-Xa activity and TAT complexes could be tested in a further trial.