[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.

[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.

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.

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.

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.

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.

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.

Olfactory identification deficits in Down's syndrome and idiopathic mental retardation.

We investigated olfactory identification in children and adults with Down's syndrome (DS) and idiopathic mental retardation (IMR) and in age-matched normal controls (NC). Identification was assessed with a four alternative-forced-choice task modified from the University of Pennsylvania Smell Identification Test (M-UPSIT) and a yes/no task yielding measures of discrimination and response bias for the same stimulus material. Control tactile identification tasks were also administered. Results were that odor identification performance on both tasks was specifically impaired in DS compared to IMR and NC. Accuracy of identification on the M-UPSIT correlated inversely with age in DS only. When uncertain, DS and IMR subjects guessed "yes" more often than "no" on the Yes/No task (liberal decision bias) and guessed the last response alternative on the M-UPSIT (recent position bias), whereas the normal subjects had neutral decision bias on the Yes/No task and matched the objective position presentation probabilities on the M-UPSIT. Decision bias correlated with accuracy of identification in both tasks for the DS subjects only.

Thrombus generation within the artificial heart.

The sites of thrombus formation in the Jarvik III artificial heart were studied in 20 consecutive calf experiments. Identical design and implantation procedures were used with two different surfaces. The 10 anticoagulated calves receiving Dacron-fibrilized silicone rubber surfaces survived an average of 296 hours. In contrast, the 10 nonanticoagulated calves with smooth poyurethane hearts survived 545 hours. The polyurethane surfaces were constantly clean. However, the rough surfaces were coated with variable amounts of thrombi. The sharp angle between the diaphragm and housing contained varying amounts of thrombi deposits in 75 per cent of the cases. Thrombe deposition occurred on 41 per cent of the valves. These thrombe were the source of emboli into the kidney, brain, and lungs. Turbulences and stagnation areas generated thrombus formation. Anticoagulation did not prevent thrombus formation. It would appear that heart free of turbulence and stagnation areas must be designed to eliminate thromboembolism.

Survival for 18 days with a Jarvik-type artificial heart.

This is a report of an experiment wherein a calf had its natural heart replaced with an artificial heart and survived for 18 days and 20 hours. All measured physiologic parameters remained normal until the fourteenth day. Thereafter a gradual persistent rise in venous pressure and signs of a decreased cardiac output occurred. However, the animal outwardly appeared normal until the eighteenth day. During the nineteenth day it became comatose and was killed. At autopsy large thrombi were found in both atria, impairing ventricular filling, resulting in venous congestion and diminished cardiac output. This extended survival time and our ability to understand and eliminate the problems associated with artificial heart implantation give support to our hope that artificial hearts for man will be possible in the not too distant future.

Multiple-dose safety study of ibuprofen/codeine and aspirin/codeine combinations.

This multiple-dose, double-blind, placebo-controlled, randomized, normal volunteer study compared formulations of ibuprofen/codeine and aspirin/codeine for systemic safety. Vital signs, hematologic, biochemical and urinary parameters, side effects, mood and mental alertness, were monitored. The placebo group had less gastrointestinal side effects and more frequent stools than the active treatment groups. There was statistical evidence for greater adverse effects of aspirin/codeine on mood and mental alertness in comparison to ibuprofen/codeine and placebo. Ibuprofen/codeine had a more favorable adverse effect profile than aspirin/codeine. A mild respiratory and cardiac depressant effect attributable to codeine was evident in all active treatment groups after 7 days of frequent therapy. More work needs to be done to elucidate the factors regulating the development of tolerance to the respiratory and cardiovascular depressant effects of opiates in general, and for codeine in particular.

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.

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.

Surgical treatment of double-outlet left ventricle in 2 patients with D-position and L-position of the aorta.

Two cases of double-outlet left ventricle (DOLV) are described, 1 with D-position and 1 with L-position of the aorta. Both patients had situs solitus, atrioventricular concordance with D-relationship of the two ventricles, a ventricular septal defect, and subpulmonary stenosis. The patient with D-position of the aorta was operated on using a technique similar to that for repair of Fallot's tetralogy but including emergency implantation of a bioprosthesis into the pulmonary artery position on the eighth postoperative day. Surgical correction in the patient with L-position of the aorta required the implantation of a composite valved conduit between the right ventricle and the pulmonary artery. The various surgical techniques for correction of DOLV are described, and the literature is reviewed. Postoperative right heart failure in both patients is explained by the impaired function of the right ventricle being exposed to gross pulmonary incompetence or by the persistence of elevated right ventricular pressure.

Treatment of ocular fungal infections with oral fluconazole.

PURPOSE: We treated five patients who had ocular fungal infections with oral fluconazole to determine its safety and effectiveness. METHODS: We reviewed the case histories of the five patients. One patient had coccidioidomycosis and four had endogenous Candida endophthalmitis. RESULTS: The intraocular fungal infection resolved in all patients. CONCLUSION: Fluconazole appears to be a safe and effective antifungal agent that can be administered orally and may be a useful agent for treating some intraocular fungal infections.

The electrocardiographic inverse problem.

Using the boundary element method in conjunction with Tikhonov zero-order regularization, we have computed epicardial potentials from body surface potential data in a realistic geometry heart-torso system. The inverse-reconstructed epicardial potentials were compared to the actual measured potentials throughout a normal cardiac cycle. Potential features (maxima, minima) were recovered with an accuracy better than 1 cm in their location. In this chapter, we use these data to illustrate and discuss computational issues related to the inverse-reconstruction procedure. These include the boundary element method, the choice of a regularization scheme to stabilize the inversion, and the effects of incorporating a priori information on the accuracy of the solution. In particular, emphasis is on the use of temporal information in the regularization procedure. The sensitivity of the solution to geometrical errors and to the spatial and temporal resolution of the data is discussed.

Hearing loss in Turner syndrome.

A retrospective study was undertaken to answer the following questions: Is the sensorineural hearing loss (SNHL) in Turner syndrome progressive? Can the occurrence of hearing loss be explained by the parental origin of the intact X chromosome? Twenty-four individuals recruited through the Turner Syndrome Society completed a questionnaire and submitted sufficient medical records to determine their otologic status. The majority (21/24) have had problematic otitis media (OM), and two thirds (16/24) have SNHL. In seven of the Turner subjects (age range: 12 to 51 years), gradual progressive SNHL began in late childhood or early adulthood. Molecular techniques showed no correlation between parental origin of the retained X chromosome and hearing status in 17 Turner subjects and at least one of their parents. SNHL and frequent OM appear to be independent variables that are both present in Turner syndrome. It is postulated that the presence of unpaired genes on the X chromosome may account for hearing loss and other phenotypic abnormalities seen in this syndrome.

The use of temporal information in the regularization of the inverse problem of electrocardiography.

The inverse problem of electrocardiography is solved in order to reconstruct electrical events within the heart from information measured noninvasively on the body surface. These electrical events can be deduced from measured epicardial potentials; therefore, a noninvasive method of recovering epicardial potentials from body surface data is useful in clinical and experimental work. The ill-posed nature of this problem necessitates the use of regularization in the solution procedure. Inversion using Tikhonov zero-order regularization, a quasi-static method, had been employed previously and was able to reconstruct, with relatively good accuracy, important events in cardiac excitation (maxima, minima, etc.). Taking advantage of the fact that the process of cardiac excitation is continuous in time, one can incorporate information from the time progression of excitation in the regularization procedure using the Twomey technique. Methods of this type were tested on data obtained from a human-torso tank in which a beating canine heart was placed in the correct human anatomical position. The results show a marked improvement in the inverse solution when these temporal methods are used, and demonstrate that important physiological events (e.g., right ventricular breakthrough) not detected by the quasi-static approach, are reconstructed using these methods. In addition, the results indicate that as the time interval between sampled maps is reduced, the quality of the solutions that use this temporal regularization is greatly improved.