Bazett and Fridericia QT correction formulas interfere with measurement of drug-induced changes in QT interval.

BACKGROUND: The QT interval on the ECG is prolonged by more than 50 marketed drugs, an effect that has been associated with syncope and/or sudden cardiac death due to an arrhythmia. Because changes in heart rate also change the QT interval, it has become standard practice to use a correction formula, such as the Bazett formula, to normalize the QT interval to a heart rate of 60 bpm, that is, the rate-corrected QT or QTc. Numerous other formulas have been devised to make this correction, including the Fridericia, Hodges, and Framingham formulas. OBJECTIVES: The purpose of this study was to investigate how the Bazett formula and three other formulas influence assessment of the QT-prolonging effect of the potassium channel-blocking drug ibutilide. METHODS: Using a standardized physical activity protocol, the QT interval was assessed over a broad range of heart rates before and after an infusion of ibutilide (4.75 microg/kg) that produced a stable 15- to 20-ms QT prolongation in consenting normal subjects (9 men and 9 women). The QT interval was measured digitally over a range of heart rates from 60 to 120 bpm, and then four correction formulas (Bazett, Fridericia, Framingham, or Hodges) were applied. The uncorrected change in QT interval due to ibutilide was compared with the change using each of the formulas by repeated measures analysis of variance. RESULTS: At heart rates from 60 to 120 bpm, the Bazett and Fridericia correction formulas overestimated the change in QT in both men and women (P <.001). However, the Framingham and Hodges formulas did not alter the accuracy of the assessment of QT interval change. CONCLUSION: Rate correction of QT intervals using the standard Bazett and Fridericia formulas can introduce significant errors in the assessment of drug effects on the QT interval. This has implications for the clinical assessment of drug effects and for the safety assessment of new drugs under development.     

The utility of bipolar electrocautery in hereditary hemorrhagic telangiectasia

OBJECTIVE: The surgical treatment of epistaxis associated with hereditary hemorrhagic telangiectasia (HHT) is varied. Laser therapy is often inadequate for larger complex lesions. This study sought to determine if bipolar cautery can be effectively and safely used in treating HHT-associated epistaxis. STUDY DESIGN AND SETTING: Records from all patients with HHT treated surgically over 8 years were reviewed retrospectively. Outcomes or complications were noted in the clinic on follow-up evaluation. RESULTS: Twenty-seven patients with HHT who underwent surgical treatment of epistaxis were evaluated; 18 were treated with bipolar cautery. Forty-two separate bipolar treatments were performed. No new septal perforations or synechiae were noted. Twenty-two of 42 treatments were coupled with ancillary laser treatments. The bipolar was also used as the sole technique in 20 procedures. CONCLUSION: Bipolar electrocautery is a safe and effective tool for the intraoperative control of HHT-related epistaxis. SIGNIFICANCE: Bipolar electrocautery may be used as an adjunct to laser techniques or as a stand-alone technique. EBM RATING: C-4.     

The mitochondrial K(ATP) channel opener BMS-191095 reduces neuronal damage after transient focal cerebral ischemia in rats.

Activation of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels protects the brain against ischemic or chemical challenge. Unfortunately, the prototype mitoK(ATP) channel opener, diazoxide, has mitoK(ATP) channel-independent actions. We examined the effects of BMS-191095, a novel selective mitoK(ATP) channel opener, on transient ischemia induced by middle cerebral artery occlusion (MCAO) in rats. Male Wister rats were subjected to 90 mins of MCAO. BMS-191095 (25 microg; estimated brain concentration of 40 micromol/L) or vehicle was infused intraventricularly before the onset of ischemia. In addition, the effects of BMS-191095 on plasma and mitochondrial membrane potentials and reactive oxygen species (ROS) production in cultured neurons were examined. Finally, we determined the effects of BMS-191095 on cerebral blood flow (CBF) and potassium currents in cerebrovascular myocytes. Treatment with BMS-191095 24 h before the onset of ischemia reduced total infarct volume by 32% and cortical infarct volume by 38%. However, BMS-191095 administered 30 or 60 mins before MCAO had no effect. The protective effects of BMS-191095 were prevented by co-treatment with 5-hydroxydecanoate (5-HD), a mitoK(ATP) channel antagonist. In cultured neurons, BMS-191095 (40 micromol/L) depolarized the mitochondria without affecting ROS levels, and this effect was inhibited by 5-HD. BMS-191095, similar to the vehicle, caused an unexplained but modest reduction in the CBF. Importantly, BMS-191095 did not affect either the potassium currents in cerebrovascular myocytes or the plasma membrane potential of neurons. Thus, BMS-191095 afforded protection against cerebral ischemia by delayed preconditioning via selective opening of mitoK(ATP) channels and without ROS generation.     

APOE epsilon3 gene transfer attenuates brain damage after experimental stroke.

Apolipoprotein E (apoE, protein; APOE, gene) is the major lipid-transport protein in the brain and plays an important role in modulating the outcome and regenerative processes after acute brain injury. The aim of the present study was to determine if gene transfer of the epsilon3 form of APOE improves outcome in a murine model of transient focal cerebral ischaemia. Mice received an intrastriatal injection of vehicle, a second-generation adenoviral vector containing the green fluorescent protein gene (Ad-GFP) or a vector containing the APOE epsilon3 gene (Ad-APOE) 3 days before 60 mins focal ischaemia. Green fluorescent protein expression was observed in cells throughout the striatum and subcortical white matter indicating successful gene transfer and expression. ApoE levels in the brain were significantly increased after Ad-APOE compared with Ad-GFP or vehicle treatment. Ad-APOE treatment reduced the volume of ischaemic damage by 50% compared with Ad-GFP or vehicle treatment (13+/-3 versus 29+/-4 versus 27+/-5 mm(3)). The extent of postischaemic apoE immunoreactivity was enhanced in Ad-APOE compared with Ad-GFP or vehicle treated mice. These results show the ability of APOE gene transfer to markedly improve outcome after cerebral ischaemia and suggest that modulating apoE levels may be a potential strategy in human stroke therapy.     

Characteristics of pollinosis caused by Betula in patients from Ourense (Galicia, Spain).

A retrospective study was performed to describe the features of the pollinosis caused by Betula in the area of Ourense, Spain. The pollen count was carried out with a Lanzoni volumetric Hirts spore trap (1993-2000). The Betula pollen represented 5% over the annual total (annual mean quantity: 965 grains). It was present in the air from March to mid-May. The highest peaks took place in April (maximum values mean: 131 grains/m3). The medical records of 222 patients (mean age 25.66 years) diagnosed with pollinosis (1998-2000), who lived at less than 30 km. from the spore trap, were reviewed. In all of them, the skin-prick test (SPT) was carried out with pollen allergens. The percentages of positive SPT were: Lolium perenne, 91.89% (16.6% monosensitized); Plantago lanceolata, 71.17% (1.26% monosensitized); Betula alba, 41.89% (10.75% monosensitized); Platanus hybrida, 34.95%; Olea europea, 10.36%; and Parietaria judaica, 6.3%. The mean age of Betula monosensitized patients was 44.7 years. The majority of them had symptoms in March-April, 40% had asthma symptoms, 80% had lived in Central Europe, and 30% of them presented an oral allergy syndrome to fruits. There were 41.93% of the patients with positive SPT to Betula pollen who had asthma symptoms, in comparison with 23.25% of the patients with negative SPT to Betula (p = 0.0034). There were 20.28% of the patients with positive SPT to Betula pollen, who had lived in Central Europe, in comparison with 4.27% of the patients with negative SPT to Betula, p: 0.00049. The relative risk of sensitization was 2.05. CONCLUSIONS: Betula pollen was the second cause of clinical pollinosis in our patients, after grass, being responsible of the symptoms in the early spring, in a small number of the patients in their forties. The presence of asthma was higher in Betula sensitized patients, and the residence in Central Europe was a sensitization risk factor.