[Chronobiological aspects of bipolar disorder]. / Chronobiologische Aspekte der bipolaren Störung.

BACKGROUND: Numerous symptoms of bipolar disorder are regulated by the circadian rhythm. Because of this association it is assumed that disruption of the circadian rhythm may be part of the pathomechanism of bipolar disorder. OBJECTIVES: A comparison and subsequent critical discussion of the current data situation on chronobiological aspects of bipolar disorder are presented. METHODS: A narrative literature search was carried out and the main findings are presented in a summarized form. RESULTS: There are a large number of animal and human studies investigating the connection between disorders of the circadian rhythm and bipolar disorder. Especially chronotype, the environmental factor light and sleep disorders seem to be associated with the development of bipolar disorder. CONCLUSIONS: The neurobiology of bipolar disorder shows numerous chronobiological aspects. There is evidence for a direct connection of disruption of the circadian rhythm and development and progression of bipolar disorder; however, at present there is no proof for the specificity of these findings for bipolar disorder. Future studies should consolidate the evidence on the impact of disorders of the circadian rhythm on the pathomechanism of bipolar disorder.

Circadian regulation of hedonic appetite in mice by clocks in dopaminergic neurons of the VTA.

Unlimited access to calorie-dense, palatable food is a hallmark of Western societies and substantially contributes to the worldwide rise of metabolic disorders. In addition to promoting overconsumption, palatable diets dampen daily intake patterns, further augmenting metabolic disruption. We developed a paradigm to reveal differential timing in the regulation of food intake behavior in mice. While homeostatic intake peaks in the active phase, conditioned place preference and choice experiments show an increased sensitivity to overeating on palatable food during the rest phase. This hedonic appetite rhythm is driven by endogenous circadian clocks in dopaminergic neurons of the ventral tegmental area (VTA). Mice with disrupted clock function in the VTA lose their hedonic overconsumption rhythms without affecting homeostatic intake. These findings assign a functional role of VTA clocks in modulating palatable feeding behaviors and identify a potential therapeutic route to counteract hyperphagy in an obesogenic environment.

Impact of adult attention deficit hyperactivity disorder and medication status on sleep/wake behavior and molecular circadian rhythms.

Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric condition that has been strongly associated with changes in sleep and circadian rhythms. Circadian rhythms are near 24-h cycles that are primarily generated by an endogenous circadian timekeeping system, encoded at the molecular level by a panel of clock genes. Stimulant and non-stimulant medication used in the management of ADHD has been shown to potentially impact on circadian processes and their behavioral outputs. In the current study, we have analyzed circadian rhythms in daily activity and sleep, and the circadian gene expression in a cohort of healthy controls (N = 22), ADHD participants not using ADHD-medication (N = 17), and participants with ADHD and current use of ADHD medication (N = 17). Rhythms of sleep/wake behavior were assessed via wrist-worn actigraphy, whilst rhythms of circadian gene expression were assessed ex-vivo in primary human-derived dermal fibroblast cultures. Behavioral data indicate that patients with ADHD using ADHD-medication have lower relative amplitudes of diurnal activity rhythms, lower sleep efficiency, more nocturnal activity but not more nocturnal wakenings than both controls and ADHD participants without medication. At the molecular level, there were alterations in the expression of PER2 and CRY1 between ADHD individuals with no medication compared to medicated ADHD patients or controls, whilst CLOCK expression was altered in patients with ADHD and current medication. Analysis of fibroblasts transfected with a BMAL1:luc reporter showed changes in the timing of the peak expression across the three groups. Taken together, these data support the contention that both ADHD and medication status impact on circadian processes.

[Importance of sleep and circadian rhythm for energy metabolism]. / Bedeutung des zirkadianen Schlafrhythmus für den Energiestoffwechsel.

The circadian clock is a complex and highly specialized network of the human organism and is key for metabolic health. Circadian rhythms are modulated by behavioral patterns, physical activity, food intake as well as sleep loss and sleep disorders. Furthermore, an altered expression of clock genes (e. g. PERIOD1 and 2) can alter circadian rhythms. Chronodisruption, i. e. the alteration of circadian rhythms, is associated with a variety of mental and physical illnesses. Recent studies show a significant association between quantitative and qualitative sleep rhythm disturbances and an increasing prevalence of obesity. Furthermore, reduced sleep quality and duration lead to decreased glucose tolerance and insulin sensitivity, thus increasing the risk of developing type 2 diabetes. In addition to the core components of the metabolic syndrome, there are also changes in hormonal and neuronal signaling pathways impinging on human energy metabolism. This review provides an overview of the current literature highlighting the close link between circadian rhythms and human energy metabolism.

Interaction between circadian rhythms and stress.

Life on earth has adapted to the day-night cycle by evolution of internal, so-called circadian clocks that adjust behavior and physiology to the recurring changes in environmental conditions. In mammals, a master pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus receives environmental light information and synchronizes peripheral tissues and central non-SCN clocks to geophysical time. Regulatory systems such as the hypothalamus-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS), both being important for the regulation of stress responses, receive strong circadian input. In this review, we summarize the interaction of circadian and stress systems and the resulting physiological and pathophysiological consequences. Finally, we critically discuss the relevance of rodent stress studies for humans, addressing complications of translational approaches and offering strategies to optimize animal studies from a chronobiological perspective.

Time-of-day-dependent adaptation of the HPA axis to predictable social defeat stress.

In modern societies, the risk of developing a whole array of affective and somatic disorders is associated with the prevalence of frequent psychosocial stress. Therefore, a better understanding of adaptive stress responses and their underlying molecular mechanisms is of high clinical interest. In response to an acute stressor, each organism can either show passive freezing or active fight-or-flight behaviour, with activation of sympathetic nervous system and the hypothalamus-pituitary-adrenal (HPA) axis providing the necessary energy for the latter by releasing catecholamines and glucocorticoids (GC). Recent data suggest that stress responses are also regulated by the endogenous circadian clock. In consequence, the timing of stress may critically affect adaptive responses to and/or pathological effects of repetitive stressor exposure. In this article, we characterize the impact of predictable social defeat stress during daytime versus nighttime on bodyweight development and HPA axis activity in mice. While 19 days of social daytime stress led to a transient reduction in bodyweight without altering HPA axis activity at the predicted time of stressor exposure, more detrimental effects were seen in anticipation of nighttime stress. Repeated nighttime stressor exposure led to alterations in food metabolization and reduced HPA axis activity with lower circulating adrenocorticotropic hormone (ACTH) and GC concentrations at the time of predicted stressor exposure. Our data reveal a circadian gating of stress adaptation to predictable social defeat stress at the level of the HPA axis with impact on metabolic homeostasis underpinning the importance of timing for the body's adaptability to repetitive stress.

Acute sleep deprivation delays the glucagon-like peptide 1 peak response to breakfast in healthy men.

OBJECTIVE: Previous experiments have demonstrated that acute sleep loss impairs glucose homeostasis and increases food intake in humans. The incretin hormone glucagon-like peptide 1 (GLP-1) enhances postprandial insulin secretion and promotes satiety. Hypothesizing that the detrimental metabolic effects of sleep curtailment imply alterations in GLP-1 signaling, we investigated 24-h serum total GLP-1 concentrations during total sleep deprivation (TSD) and a normal sleep/wake cycle (comprising ∼8 h of sleep) in 12 healthy young men. METHODS: Sessions started at 1800 h, and subjects were provided with standardized meals. Assessments of serum GLP-1 took place in 1.5- to 3-h intervals, focusing on the response to breakfast intake (3.8 MJ). RESULTS: Across conditions, 24-h concentration profiles of GLP-1 were characterized by the expected postprandial increases (P<0.001). Although there were no differences in magnitude between conditions (P>0.11), the postprandial GLP-1 peak response to breakfast intake was delayed by ∼90 min following sleep loss in comparison with regular sleep (P<0.02). CONCLUSIONS: RESULTS indicate that acute TSD exerts a mild, but discernible effect on the postprandial dynamics of circulating GLP-1 concentrations in healthy men.

[Biological role and clinical relevance of central and peripheral circadian clocks]. / Zirkadiane Uhren in Gehirn und Peripherie: biologische Funktion und Relevanz für die Klinik.

In most species--from cyanobacteria to humans--genetically encoded circadian clocks have evolved to adapt behavioral and physiological processes to environmental changes brought about by the Earth's rotation. Clock disruption, e. g. by shift work, can lead to circadian misalignment, promoting the development of metabolic, immune and cognitive dysfunction. In mammals, a central circadian pacemaker residing in the suprachiasmatic nuclei of the hypothalamus resets subordinate, but semi-independent cellular clocks in tissues such as liver, kidney, adrenal, and many brain areas. Peripheral clocks regulate various endocrine, metabolic and immune processes, whereas central oscillators modulate basic as well as higher brain functions. For the clinical practice it is of major importance to be aware of these physiological rhythms in order to correctly interpret laboratory data and other disease symptoms. Chronomedical therapies can reduce side effects and increase efficacy by optimizing the timing of treatment or directly affect disease state by restoring internal circadian synchrony.

Clinical efficacy of short-term treatment with extra-fine HFA beclomethasone dipropionate in patients with post-infectious persistent cough.

Post-infectious persistent cough may be caused by an underlying inflammation in the airways. Due to its antiinflammatory properties, inhaled corticosteroids (ICS) may be a rational therapeutic approach to reduce cough symptoms. In this randomized, double-blind study, the efficacy of treatment with inhaled extra-fine HFA beclomethasone diproprionate (HFA-BDP) was compared with placebo in patients with post-infectious persistent cough. A total of 72 patients with persistent cough lasting at least 3 days (max. 14 days) following an acute respiratory tract infection were randomized to treatment with extra-fine HFA-BDP (400 microg twice daily for 7 days followed by 200 microg twice daily for 4 days) or placebo. The efficacy was measured by tussometry. The primary endpoint was defined as a reduction of frequency of cough epochs/h at the end of treatment (Day 11) in relation to the baseline level and in comparison to placebo, calculated as the area under the curve (AUC). The treatment with extra-fine HFA-BDP resulted in a greater reduction of cough frequency in patients with post-infectious persistent cough in comparison to placebo. The AUC from Day 1 to Day 11 for the frequency of cough epochs/h between 7:00 am and 11:00 pm was calculated as 605.8 for HFA-BDP and 847.9 for placebo, respectively (P<0.05). There is evidence that extra-fine HFA-BDP leads to a more rapid reduction of cough frequency at the beginning of treatment. A short-term treatment with extra-fine HFA-BDP could be an effective and well tolerated therapeutic option in the treatment of post-infectious persistent cough.

Efficacy and safety of once or twice daily inhalation of extrafine HFA beclomethasone dipropionate in patients with mild to moderate asthma.

The relatively new chlorofluorocarbon-free solution preparation of beclomethasone dipropionate in hydrofluoroalkane (HFA-BDP) (Qvar, 3M Pharmaceuticals) generates an extra fine aerosol with a smaller particle size (mean mass aerodynamic diameter of 1.1 microm), drug deposition in the lung is more uniformly distributed, thus improving efficacy even at a low dose. This might be also important for the use of a new fixed combination containing HFA-BDP plus formoterol in one inhaler for basic therapy and for an as-need application. Further, inhalation once a day might considerably enhance patients' adherence to maintenance therapy. The aim of this study was to test clinical efficacy and safety of twice daily inhalation (b.i.d.) vs. once daily inhalation (o.d.). In a double-blind, randomised, multicenter, parallel-group study, the efficacy and safety of 200 microg HFA-BDP o.d. (evenings) was compared with 100 microg HFA-BDP b.i.d., and with placebo. The trial included 201 patients with mild to moderately severe asthma. FEV1 was the primary endpoint and treatment duration was eight weeks. The improvement of FEV1 (20.4% o.d. vs. 12.9% b.i.d. vs. 7.9% placebo) was comparable in the two BDP groups. Both were more effective than placebo (P=0.014). The efficacy of o.d. dose was also equivalent to b.i.d. dose in secondary endpoints (peak flow, beta2-sympathomimetic drug use, asthma symptom score, and nocturnal awakenings). The treatment was well tolerated. A single evening dose (200 microg HFA-BDP) is as equivalently effective as the twice daily inhalation (2x100 microg HFA-BDP) in mild to moderate asthma.

The genetic basis of circadian behavior.

In most species, an endogenous timing system synchronizes physiology and behavior to the rhythmic succession of day and night. The mammalian circadian pacemaker residing in the suprachiasmatic nuclei (SCN) of the hypothalamus controls peripheral clocks throughout the brain and the body via humoral and neuronal transmission. On the cellular level, these clockworks consist of a set of interwoven transcriptional/translational feedback loops. Recent work emphasizes the tissue specificity of some components of these molecular clockworks and the differential regulation of their rhythmicity by the SCN.

Biological clock in total darkness: the Clock/MOP3 circadian system of the blind subterranean mole rat.

Blind subterranean mole rats retain a degenerated, subcutaneous, visually blind but functionally circadian eye involved in photoperiodic perception. Here we describe the cloning, sequence, and expression of the circadian Clock and MOP3 cDNAs of the Spalax ehrenbergi superspecies in Israel. Both genes are relatively conserved, although characterized by a significant number of amino acid substitutions. The glutamine-rich area of Clock, which is assumed to function in circadian rhythmicity, is expanded in Spalax compared with that of humans and mice, and is different in amino acid composition from that of rats. We also show that MOP3 is a bona fide partner of Spalax Clock and that the Spalax Clock/MOP3 dimer is less potent than its human counterpart in driving transcription. We suggest that this reduction in transcriptional activity may be attributed to the Spalax Clock glutamine-rich domain, which is unique in its amino acid composition compared with other studied mammalian species. Understanding Clock/MOP3 function could highlight circadian mechanisms in blind mammals and their unique pattern as a result of adapting to life underground.

The circadian clock and behavior.

Temporal organization is a fundamental feature of all living systems. Timing is essential for development, growth and differentiation and in the mature organism, it is essential to maintain normal physiology and behavior. The biological entity that permits an organism's day/night organization is the circadian system. In the following, we describe how daily or circadian activity is measured in mice, and what such activity measurements can tell us about the state of the animal.

A surgical gauze appearing as a retrocardiac mass in a patient after coronary artery bypass surgery.

Five years after open chest surgery because of three vessel coronary artery disease a patient was referred for progressing dyspnea and recent onset of atrial fibrillation. A retrocardiac mass was detected on chest X-ray and echocardiography. On CT-scan, the inhomogenous tumor made the diagnosis of a retained surgical gauze likely. Through a left incision the sponge was removed uneventfully and the dyspnea resolved.

Minimally invasive coronary revascularization in elderly patients.

BACKGROUND: Internal mammary artery to left anterior descending coronary artery anastomosis can be done without extracorporeal circulation on the beating heart. This method seems to have particular advantages for elderly patients, those 70 years old or older. METHODS: From January 1, 1997, to October 31, 1997, 27 patients have been operated on with a minimally invasive approach through a left-sided minithoracotomy. Twelve patients had up to four previous percutaneous interventions with percutaneous transluminal coronary angioplasty (3) or percutaneous transluminal coronary angioplasty and stent implantation (9). The remainder showed stenosis not suitable for percutaneous transluminal coronary angioplasty or an occluded vessel. In all patients the internal mammary artery was anastomosed with the left anterior descending coronary artery, and in 2 patients additionally with the first diagonal. In 1 patient the operation had to be converted to a sternotomy because it was impossible to identify the left anterior descending coronary artery. RESULTS: All patients survived the operation. There was no perioperative infarction. All patients were extubated within 4 hours. Mean stay in the intensive care unit was 20.3 hours; postoperative stay was 7.4 days. Nine patients had elective repeat angiography within 10 days postoperatively and all showed a patent graft. CONCLUSIONS: We believe that minimally invasive coronary revascularization of the anterior wall can be done in elderly patients with low risk and good results.

[The anti-inflammatory action of an oral sustained-release theophylline preparation. Results of a clinical pilot study with low dosages]. / Untersuchungen zur antiinflammatorischen Wirkung eines oralen retardierten Theophyllin-Präparates. Ergebnisse einer Klinischen Pilotstudie mit niedriger Dosierung.

A pilot study in 14 patients with mild asthma was performed to study the anti-inflammatory efficacy of theophylline (CAS 58-55-9). At the start, during and at the end of a 3 months' treatment with oral sustained release theophylline and during 1 week thereafter, the influence on airway hyperreactivity and ECP (eosinophil cationic protein) serum levels was investigated. Airway responsiveness was expressed as the cumulative provocative dose of methacholine necessary to decrease FEV1 by 20% (PD20-FEV1). Data of 8 patients were suitable for evaluation. At a mean predose serum concentration of 6.5 mg/l, theophylline increased the mean PD20-FEV1 for methacholine from 151 micrograms (at start) to 332 micrograms (at the end of medication), and reduced the mean ECP serum concentration from 34.6 to 24.5 micrograms/l. Up to 1 week after theophylline treatment, the improvement of airway hyperreactivity compared to the baseline was maintained, whereas ECP-serum levels tended to increase. Thus, theophylline markedly attenuated airway hyperreactivity in patients with bronchial asthma at "subtherapeutic" serum theophylline concentrations as well as ECP serum concentrations, suggesting the anti-inflammatory efficacy of theophylline. These observations may have therapeutic implications in the treatment of patients with mild asthma. A slight improvement of lung function and dyspnoea, and a reduction of additional beta 2-bronchodilator use was also observed. Two patients only complained of slight nausea, tremor and restlessness.

Production of emotional facial expressions in European American, Japanese, and Chinese infants.

European American, Japanese, and Chinese 11-month-olds participated in emotion-inducing laboratory procedures. Facial responses were scored with BabyFACS, an anatomically based coding system. Overall, Chinese infants were less expressive than European American and Japanese infants. On measures of smiling and crying, Chinese infants scored lower than European American infants, whereas Japanese infants were similar to the European American infants or fell between the two other groups. Results suggest that differences in expressivity between European American and Chinese infants are more robust than those between European American and Japanese infants and that Chinese and Japanese infants can differ significantly. Cross-cultural differences were also found for some specific brow, cheek, and midface facial actions (e.g., brows lowered). These are discussed in terms of current controversies about infant affective facial expressions.