From the Editor

Sexuality and Disability -     

The effect of postural changes on body temperatures and heat balance

Early studies have demonstrated that rectal temperature (T _re) decreases and mean skin temperature (T _sk) increases in subjects changing their posture from standing to supine, and vice versa. Such changes have important implications insofar as thermal stress experiments are conducted and interpreted. However, the extent of these changes between steady-state conditions is not known. In addition, it is not known whether thermal balance is also affected by postural changes. To examine these questions, 11 healthy males were exposed to a thermoneutral air environment (28.2–28.5°C and 40% relative humidity) in various postures at rest. Body temperatures, heat losses, and metabolic rate were measured. Subjects wore shorts only and began in an upright posture (standing or sitting at an inclination of 7.5°) on a customized tilt-table. They were tilted twice, once into a supine position and then back to the original upright position. Each tilt occurred after steady state was satisfied based on the subject's circadian variation of T _re determined previously in a 4.25 h control supine trial. Times to supine steady state following the first tilt were [mean (SE)] 92.6 (6.4) and 116.6 (5.1) min for the standing and sitting trials, respectively. Times to upright steady state following the second tilt were 107.9 (11.4) and 124.1 (9.0) min. Mean steady-state T _re and T _sk were 36.87 (0.07) and 34.04 (0.14), 37.47 (0.09) and 33.48 (0.14), and 37.26 (0.05) and 33.49 (0.10) °C for supine, standing, and sitting, respectively. Thermal balance was attained in all steady-state conditions, and allowing for a decrease in the weighting factor of T _re for mean body temperature in the upright postures, it also appears that thermal balance was preserved between changes in posture. These results are consistent with no perceived changes by the subjects in their thermal comfort and skin wetness.     

Identification of CYP3A4 and CYP2C8 as the major cytochrome P450 s responsible for morphine N -demethylation in human liver microsomes

1. The aim was to identify the cytochrome P450 (CYP) enzymes responsible for the N -demethylation of morphine in vitro. 2. In human liver microsomes, normorphine formation followed Michaelis-Menten kinetics with mean K m and V max of 12.4 ± 2.2 mM and 1546 ± 121 pmol?min ? 1?mg ? 1, respectively. In microsomes from a panel of 14 human livers phenotyped for 10 CYP enzymes, morphine N -demethylation correlated with testosterone 6 β -hydroxylation (r = 0.91, p <0.001) and paclitaxel 6- α hydroxylation (r = 0.72, p <0.001), two specific markers of CYP3A4 and CYP2C8, respectively. Normorphine formation decreased when incubated in the presence of troleandomycin or quercetin (by 46 and 33-36%, respectively), which further corroborates the contribution of CYP3A4 and CYP2C8. 3. Among eight recombinant human CYP enzymes tested, CYP3A4 and CYP2C8 exhibited the highest intrinsic clearance. More than 90% of morphine N -demethylation could be accounted for via the action of both CYP3A4 and CYP2C8. 4. The in vitro findings suggest that hepatic CYP3A4, and to a lesser extent CYP2C8, play an important role in the metabolism of morphine into normorphine.     

Atrial fibrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction: results from the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program.

OBJECTIVES: We assessed the risk of adverse cardiovascular (CV) outcomes associated with atrial fibrillation (AF) in the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program, which enrolled patients with chronic heart failure (CHF) and a broad range of ejection fractions (EFs). BACKGROUND: Atrial fibrillation is associated with an increased risk of adverse CV outcomes in patients with CHF and reduced EF. The risk of AF in patients with CHF and preserved left ventricular ejection fraction (PEF) is unknown. METHODS: A total of 7,599 patients with symptomatic CHF were randomized to candesartan or placebo. Patients were divided by baseline EF (< or =40% or >40%) in low or preserved EF groups. Major outcomes were cardiovascular death or hospitalization for worsening heart failure, and all-cause mortality. Median follow-up was 37.7 months. RESULTS: A total of 670 (17%) patients in the low EF group and 478 (19%) in the PEF group had AF at baseline. Atrial fibrillation predicted a high risk of cardiovascular morbidity and mortality regardless of baseline EF. Patients with AF and low EF had the highest absolute risk for adverse CV outcomes. However, AF was associated with greater relative increased risk of the major outcomes in patients with PEF than in patients with low EF: hazard ratio 1.72 (95% confidence interval [CI] 1.45 to 2.06) versus 1.29 (95% CI 1.14 to 1.46), respectively. The same was true for the risk of all-cause mortality. Candesartan was associated with similar treatment effects regardless of baseline rhythm. CONCLUSIONS: Atrial fibrillation is associated with an increased risk of CV outcomes in patients with CHF and either reduced EF or PEF. Candesartan improved outcomes similarly regardless of baseline rhythm.     

Simulation Study of the Effect of Influenza and Influenza Vaccination on Risk of Acquiring Guillain-Barré Syndrome

It is unclear whether seasonal influenza vaccination results in a net increase or decrease in the risk for Guillain-Barré syndrome (GBS). To assess the effect of seasonal influenza vaccination on the absolute risk of acquiring GBS, we used simulation models and published estimates of age- and sex-specific risks for GBS, influenza incidence, and vaccine effectiveness. For a hypothetical 45-year-old woman and 75-year-old man, excess GBS risk for influenza vaccination versus no vaccination was −0.36/1 million vaccinations (95% credible interval −1.22 to 0.28) and −0.42/1 million vaccinations (95% credible interval, –3.68 to 2.44), respectively. These numbers represent a small absolute reduction in GBS risk with vaccination. Under typical conditions (e.g. influenza incidence rates >5% and vaccine effectiveness >60%), vaccination reduced GBS risk. These findings should strengthen confidence in the safety of influenza vaccine and allow health professionals to better put GBS risk in context when discussing influenza vaccination with patients.