Effect of tolterodine on sleep structure modulated by CYP2D6 genotype

OBJECTIVE: Tolterodine, a drug for the treatment of overactive bladder symptoms, has a limited entry into the brain, which makes cognitive side effects seldom. However, some case reports have described central-nervous side effects such as sleepiness. The aim of this retrospective analysis was to investigate whether tolterodine-related effects on sleep stage parameters could be explained by different CYP2D6 metabolizer characteristics of subjects. METHODS: Data were taken from two randomized, double-blind, placebo-controlled studies conducted in a cross-over design. Forty-eight volunteers underwent 4 two-night attended polysomnographic studies. Subjective quality of sleep and cognitive function were assessed. A single dose of 4 mg tolterodine or placebo was administered before sleep. Forty-four volunteers gave informed consent for genotyping. We found 19 extensive metabolizers (EM), 20 intermediate metabolizers (IM), 4 poor metabolizers (PM) and 1 ultrarapid metabolizer. There were no significant differences between the groups regarding demographic data. RESULTS: Rapid eye movement (REM) sleep duration as a percentage of total sleep time showed significant reduction (p=0.019) in the group carrying one or more deficient alleles (IM+PM). No significant difference was found with two active alleles of CYP2D6 in the EM group. REM latencies under tolterodine displayed a tendency towards prolongation, which was irrespective of the metabolizer status. Subjective sleep parameters did not show statistically significant changes after tolterodine. Cognitive skills were not affected. CONCLUSION: Our retrospective analysis reveals that a decrease of REM sleep under tolterodine is found only in individuals carrying one or two deficient CYP2D6 alleles.     

Risk Perceptions Among Participants Undergoing Lung Cancer Screening: Baseline Results from the National Lung Screening Trial

Background  

Lung cancer screening could present a “teachable moment” for promoting smoking cessation and relapse prevention. Understanding the risk perceptions of older individuals who undergo screening will guide these efforts.     

The role of nitric oxide in innate immunity

Summary: Type 2 nitric oxide synthase (iNOS or NOS2) was originally described as an enzyme that is expressed in activated macrophages, generates nitric oxide (NO) from the amino acid l-arginine, and thereby contributes to the control of replication or killing of intracellular microbial pathogens. Since interferon (IFN)-g is the key cytokine for the induction of NOS2 in macrophages and the prototypic product of type 1 T-helper cells, high-level expression of NOS2 has been regarded to be mostly restricted to the adaptive phase of the immune response. In this review, we summarize data that demonstrate a prominent role of NOS2/NO also during innate immunity. During the early phase of infection with the intra­cellular pathogen Leishmania major , focally expressed NOS2/NO not only exerts antimicrobial activities but also controls the function of natural killer cells and the expression of cytokines such as IFN-g or transforming growth factor-b. Some of these effects result from the function of NOS2/NO as an indispensable co-factor for the activation of Tyk2 kinase and, thus, for interleukin-12 and IFN-a/b signaling in natural killer cells.     

Arsenobenzol (Salvarsan) als Ursache von asthmatischen Anfällen und Dyshidrose

Ohne Zusammenfassung     

Ein Fall von gewerblicher Methylchlorid-Vergiftung

Ohne Zusammenfassung     

Epidural block with ropivacaine and bupivacaine for elective caesarean section: maternal cardiovascular parameters, comfort and neonatal well-being

OBJECTIVE: To determine cardiovascular effects and neonatal outcome of ropivacaine 0.75% and bupivacaine 0.5% for elective epidural caesarean section. RESEARCH DESIGN AND METHODS: Healthy pregnant women, scheduled for elective caesarean section, were enrolled in this randomised, double-blind study. Epidural block was obtained with 20-30 ml of ropivacaine 0.75% (Group R) or bupivacaine 0.5% (Group B) and surgery did not commence until anaesthesia was achieved bilaterally to T6. MAIN OUTCOME MEASURES: Maternal heart rate and blood pressure were assessed before the main dose of local anaesthetic and at 5-min intervals until 35 min. Neonatal umbilical pH and Apgar scores were determined after delivery. Ten, twenty and thirty minutes after the main dose, sensory and motor block characteristics were determined. Quality of analgesia was assessed by the anaesthetist, surgeon and the patient. Adverse events were recorded. RESULTS: Sixty-two patients were enrolled and the data of 60 of them were eligible for analysis: 31 in Group R and 29 in Group B. The area under the curve (AUC) for maternal heart rate decreased significantly less in Group B than in Group R (p = 0.038). Twenty-five and thirty minutes after administration of the main local anaesthetic dose, heart rate decreased significantly less in Group B than in Group R (p = 0.006 and p = 0.007). There was no difference in AUC for maternal blood pressure (p = 0.32). Repeated measurement analysis showed no difference between groups in motor block (p = 0.78) and in spread of the sensory block (lower level: p = 0.83, upper level: p = 0.88). There was no statistical difference in neonatal umbilical pH (p = 0.22) and Apgar score (p = 0.59). Multiple linear regression analysis showed a significant influence of maternal body mass index on neonatal pH (p = 0.004), but not of maternal blood pressure (p = 0.323), nor of maternal heart rate (p = 0.12). The quality of analgesia and incidence of adverse events were similar in both groups. CONCLUSIONS: Both drugs produced equally satisfactory epidural block. Although ropivacaine 0.75% resulted in a greater decrease of maternal heart rate, this effect did not influence neonatal well-being. Both ropivacaine 0.75% and bupivacaine 0.5% can therefore be recommended for epidural anaesthesia in elective caesarean section.     

Poly(ADP-ribosyl)ation inhibitors: promising drug candidates for a wide variety of pathophysiologic conditions

Poly(ADP-ribose) polymerases are involved in many aspects of regulation of cellular functions. Using NAD+ as a substrate, they catalyse the covalent transfer of ADP-ribose units onto several acceptor proteins to form a branched ADP-ribose polymer. The best characterised and first discovered member of this multiprotein family is PARP-1. Its catalytic activity is markedly stimulated upon binding to DNA strand interruptions, and the resulting polymer is thought to function in chromatin relaxation as well as in signalling the presence of damage to DNA repair complexes and in regulating enzyme activities. Moderate activation of PARP-1 facilitates the efficient repair of DNA damage arising from monofunctional alkylating agents, reactive oxygen species or ionising radiation, but severe genotoxic stress leads to rapid energy consumption and subsequently to necrotic cell death. The latter aspect of PARP-1 activity has been implicated in the pathogenesis of various clinical conditions such as shock, ischaemia-reperfusion and diabetes. Inhibition of ADP-ribose polymer formation has been shown to be effective, on the one hand, in the treatment of cancer in combination with alkylating agents by suppressing DNA repair and thus driving tumour cells into apoptosis, and on the other hand it appears to be a promising drug target for the treatment of pathologic conditions involving oxidative stress. In view of the existence of several members of the PARP family in mammalian cells, one has to be aware of possible side effects but also of a wide spectrum of potential clinical applications, which calls for the development of more specific inhibitors.     

Stimulus history alters behavioral responses of neuronal growth cones.

Generally, it is assumed that growth cones respond to a specific guidance cue with a single, specific, and stereotyped behavior. However, there is evidence to suggest that previous exposure to a given cue might alter subsequent responses to that cue (Snow and Letourneau, 1992; Shirasaki et al., 1998). We therefore tested the hypothesis that growth cone responses to stimuli are dependent on the history of previous stimulation. Growth cones of chick dorsal root ganglion neurons were exposed to well characterized stimuli: (1) contact with a laminin-coated bead, which causes growth cone turning, or (2) electrical stimulation, which causes growth cone collapse. Although the expected behavioral responses were observed after the initial stimulation, strikingly different responses to a subsequent stimulation were observed. Growth cones that had recovered from electrical stimulation-induced collapse rapidly developed insensitivity to a second identical electrical stimulation. Growth cones that previously turned in response to contact with a laminin-coated bead responded to a second bead with a "stall" or cessation in outgrowth. This stimulus history dependence of growth cone behavior could be generalized across dissimilar stimuli: after contact with a laminin-coated bead, growth cones failed to collapse in response to electrical stimulation. The calcium/calmodulin-dependent protein kinase II (CaMKII) was implicated in this history dependence by pharmacological experiments. Together, these results demonstrate that growth cones can alter their behavioral response rapidly to a given stimulus in a manner dependent on previous history and that knowledge of past events in growth cone navigation may be required to predict future growth cone behavior.