Mortality Risk of Hypnotics: Strengths and Limits of Evidence

Sleeping pills, more formally defined as hypnotics, are sedatives used to induce and maintain sleep. In a review of publications for the past 30 years, descriptive epidemiologic studies were identified that examined the mortality risk of hypnotics and related sedative-anxiolytics. Of the 34 studies estimating risk ratios, odds ratios, or hazard ratios, excess mortality associated with hypnotics was significant (p < 0.05) in 24 studies including all 14 of the largest, contrasted with no studies at all suggesting that hypnotics ever prolong life. The studies had many limitations: possibly tending to overestimate risk, such as possible confounding by indication with other risk factors; confusing hypnotics with drugs having other indications; possible genetic confounders; and too much heterogeneity of studies for meta-analyses. There were balancing limitations possibly tending towards underestimates of risk such as limited power, excessive follow-up intervals with possible follow-up mixing of participants taking hypnotics with controls, missing dosage data for most studies, and over-adjustment of confounders. Epidemiologic association in itself is not adequate proof of causality, but there is proof that hypnotics cause death in overdoses; there is thorough understanding of how hypnotics euthanize animals and execute humans; and there is proof that hypnotics cause potentially lethal morbidities such as depression, infection, poor driving, suppressed respiration, and possibly cancer. Combining these proofs with consistent evidence of association, the great weight of evidence is that hypnotics cause huge risks of decreasing a patient's duration of survival

Effects of circadian disruption on physiology and pathology: from bench to clinic (and back)

Nested within the hypothalamus, the suprachiasmatic nuclei (SCN) represent a central biological clock that regulates daily and circadian (i.e., close to 24 h) rhythms in mammals. Besides the SCN, a number of peripheral oscillators throughout the body control local rhythms and are usually kept in pace by the central clock. In order to represent an adaptive value, circadian rhythms must be entrained by environmental signals or zeitgebers, the main one being the daily light?dark (LD) cycle. The SCN adopt a stable phase relationship with the LD cycle that, when challenged, results in abrupt or chronic changes in overt rhythms and, in turn, in physiological, behavioral, and metabolic variables. Changes in entrainment, both acute and chronic, may have severe consequences in human performance and pathological outcome. Indeed, animal models of desynchronization have become a useful tool to understand such changes and to evaluate potential treatments in human subjects. Here we review a number of alterations in circadian entrainment, including jet lag, social jet lag (i.e., desynchronization between body rhythms and normal time schedules), shift work, and exposure to nocturnal light, both in human subjects and in laboratory animals. Finally, we focus on the health consequences related to circadian/entrainment disorders and propose a number of approaches for the management of circadian desynchronization.Fil: Chiesa, Juan José. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Duhart, José Manuel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Casiraghi, Leandro Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Paladino, Natalia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bussi, Ivana Leda. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Golombek, Diego Andrés. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Jet lag syndrome and circadian disorders of the sleep-wake cycle

Circadian rhythm sleep disorders (CRSDs) are related to alterations in circadian timekeeping system or misalignment between endogenous circadian rhythm and exogenous factors, such as desidered or socially required time schedules, that affect sleep timing or duration. The most commonly observed are jet lag disorder, advanced and delayed sleep phase disorder, free-running disorder, and irregular sleep-wake disorder. The clinical picture may include sleep loss, fatigue, cognitive and vigilance deterioration and hormonal and gastrointestinal distress. Therapeutic management involves interventions aimed at mitigating symptoms affecting sleep and vigilance, and facilitating adaptation to the desired circadian schedule. Appropriately, scheduled bright and dim light exposure and melatonin administration are the main therapeutic tools together with sleep hygiene and chronotherapy. Excessive daytime sleepiness may benefit from short strategic naps and caffeine, whereas bedtime hypnotics may have favorable effect on sleep latency and maintenance. Melatonin and appropriately timed bright light exposure are effective in enhancing new time zone adaption, particularly for stays longer than 3-5 days, whereas short stopover may not benefit

The role of calcification in carbonate compensation

The long-term recovery of the oceans from present and past acidification is possible due to neutralization by the dissolution of biogenic CaCO3 in bottom sediments, that is, carbonate compensation. However, such chemical compensation is unable to account for all features of past acidification events, such as the enhanced accumulation of CaCO3 at deeper depths after acidification. This overdeepening of CaCO3 accumulation led to the idea that an increased supply of alkalinity to the oceans, via amplified weathering of continental rocks, must accompany chemical compensation. Here we discuss an alternative: that changes to calcification, a biological process dependent on environmental conditions, can enhance and modify chemical compensation and account for overdeepening. Using a simplified ocean box model with both constant and variable calcification, we show that even modest drops in calcification can lead to appreciable long-term alkalinity build-up in the oceans and, thus, create overdeepening; we term this latter effect biological compensation. The chemical and biological manifestations of compensation differ in terms of controls, timing and effects, which we illustrate with model results. To better predict oceanic evolution during the Anthropocene and improve the interpretation of the palaeoceanographic record, it is necessary to better understand biological compensation