Automatic two-channel sleep staging using a predictor-corrector method.

OBJECTIVE: We developed and implemented two predictor-corrector methods for the classification of two-channel EEG data into sleep stages. APPROACH: The sequence of sleep stages over the night is modeled by a Markov chain of first and second order, resulting in an informative prior distribution for the new state, given the distribution of the current one. The correction step is realized by applying a Bayes classifier using the (preprocessed) data and this prior. The preprocessing step consists of a frequency analysis, a log transformation and a dimensionality reduction via principal component analysis. MAIN RESULTS: The software automatically generates sleep profiles in which it detects wakeful phases as well as the different sleep stages with error rates of 16.5%-31.9% (n = 8, healthy subjects, mean age ± SD: 39 ± 8.1 years, five females), where we compared our results to those of a certified polysomnographic technologist, who used a full polysomnograph and rated according to the American Academy of Sleep Medicine (AASM) criteria. SIGNIFICANCE: The method presented relies on considerably less information than visual scoring and is done automatically. Furthermore, the error is comparable to visual scoring, where the inter-rater variability lies around 82%. Therefore, it has the potential to lessen the overheads associated with sleep diagnostics.

Nucleosome serum levels in acute hepatic failure and MARS treatment.

Serum nucleosomes have been suggested to be markers for cell death and apoptosis. Increased hepatocyte apoptosis can be demonstrated in acute liver failure (ALF) as well as acute-on-chronic liver failure (ACLF). We investigated the relevance of nucleosomes in the setting of acute hepatic failure. Further, we studied the effects of the molecular adsorbent recirculating system (MARS) on this marker of cell death. We measured serum nucleosome concentrations with ELISA in 12 patients with ACLF and 7 patients suffering from ALF, with 14 patients experiencing stable chronic hepatic failure (CHF) as controls. In a subset of 8 ACLF and ALF patients treated with MARS, nucleosomes were determined immediately before and after the first MARS session. Baseline nucleosome serum concentrations were significantly increased in ACLF and ALF patients as compared with CHF patients (P = .0161 and P = .0037, respectively). There was no significant difference between the ALF and ACLF groups. Moreover, serum nucleosome levels did not change significantly during MARS treatment in ALF and ACLF patients. Serum nucleosome levels therefore may be useful to discern acute from chronic hepatic failure or to monitor the course and the severity of the disease. Our results, however, warrant further larger clinical studies regarding the clearance of nucleosome in artificial liver-assist devices and to assess their role in acute hepatic failure.

[Working hours and job satisfaction among physicians in hospitals and general practice in Munich. Results of an anonymous questionnaire]. / Arbeitszeit und Arbeitszufriedenheit angestellter und beamteter Arzte in München. Ergebnisse einer anonymen Befragung.

PURPOSE: In autumn 2004 the local association of physicians (Arztlicher Kreis- und Bezirksverband München) performed a survey among employed physicians in Munich on working hours and working conditions. The aim of the study was to assess the extent to which the German law on working hours is actually implemented in employed physicians, and to obtain information about their work satisfaction. METHODS: A questionnaire was sent to all employed physicians in hospitals and medical practices. Participants were asked to give anonymous information and send it back per mail. RESULTS: In total, 2450 out of 5461 physicians took part in the survey. 45% reported that their working hours do not meet the German law on working hours of 1994. 44.4% stated that overtime is not fully recognized by their employers. 43.5% think the job would become more attractive if the law was implemented. 63.3% expect an income loss with the implementation. 53.7% are thinking about quitting their job. For 59.9% the burden of long working hours is an important reason for this. Women are more likely to be given a limited employment contract than men, and their overtime is more rarely recognized in full. CONCLUSION: Many employed physicians in Munich are dissatisfied with their job. The high burden of long working hours is a main reason for this.

Standardized documentation of drug recommendations in discharge letters--a contribution to quality management in cooperative care.

OBJECTIVES: To analyze the necessity and potential usefulness of a computerized physician order entry (CPOE) system in supporting the writing of pharmacotherapeutic recommendations in discharge letters. METHODS: Systematic analysis of drug recommendations in discharge letters of a hospital providing tertiary care, structured interviews with in-hospital prescribers, and focus groups with general practitioners who admit patients to this hospital. RESULTS: We analyzed 1800 randomly selected discharge letters, 1205 of which contained pharmacotherapeutic recommendations. The frequencies, structure, and quality of these recommendations varied considerably between departments. Nearly 16% of the recommendations contained both proprietary (brand) and non-proprietary names (active ingredient). Interviewed clinicians expressed interest in CPOE systems that check for contraindications and interactions between drugs, suggest cheaper products, and automatically insert active ingredients when omitted. The focus group sessions confirmed that the pharmacotherapeutic recommendations in current discharge letters do not effectively support daily clinical practice. CONCLUSIONS: Documenting active ingredients as well as brand names in drug therapy recommendations is currently not part of clinical practice. Computerized decision support can help to optimise the structure and communication of therapeutic information across interfaces and can be a quality factor with considerable influence on process quality, outcome quality, and costs of cooperative patient care.

Evaluation of oxidative stress measurements in obstructive sleep apnea syndrome.

Assessment of reactive oxygen species (ROS) is highly important in neurodegenerative disorders and neuroleptic treatment. However, conflicting results have been reported, which may arise from methodological difficulties. Obstructive sleep apnea (OSA) syndrome with episodic hypoxia-reoxygenation is proposed as a human model for the investigation of ROS measurements. Despite a broad analytical approach comprising lipid peroxidation and amino acid oxidation products, oxidative DNA damage, and activity of the antioxidant defense, only plasma malondialdehyde (MDA) and urinary o,o'-dityrosine seemed to be appropriate, robust biomarkers of oxidative stress, which are also simple enough for routine clinical use. MDA concentrations correlated with a duration of nocturnal desaturation below 85% (r = 0.77, p<0.0005), and o,o'-dityrosine levels decreased after therapy (p<0.05) as a function of baseline concentrations (r = -0.61, p<0.05). Gender effects in ROS generation also have to be considered. At present, we recommend the application of several oxidative stress measurements at different time points, preferably involving plasma MDA and urinary o,o'-dityrosine.

[Postpolio syndrome. Neurologic and psychiatric aspects]. / Postpolio-Syndrom. Neurologische und psychiatrische Aspekte.

Postpolio syndrome is defined as a clinical syndrome of new pareses in individuals who had been affected by acute paralytic poliomyelitis years before. The objective of this study was to describe neurologic and psychiatric signs of the disease. We evaluated the clinical signs and treatment of 16 patients with postpolio syndrome. Possible symptoms of depression were evaluated by the Hamilton and Geriatric Depression Scales. Postpolio syndrome manifested at a median age of 57.5 years (range 25-73) in a median of 41 years (range 16-70 years) after acute poliomyelitis. Muscles already affected during acute poliomyelitis were affected in all patients with postpolio syndrome. Six of 16 patients (37.5%) developed paresis in muscles formerly not affected by acute poliomyelitis. In eight of 15 patients (53%), depressive episodes were recognized according to the ICD-10 criteria. Symptoms of depression should be recognized in patients with postpolio syndrome and incorporated in therapy based on physiotherapy.

An international course on strategic information management for medical informatics students: aim, content, structure, and experiences.

We report on a course for medical informatics students on hospital information systems, especially on its strategic information management. Starting as course at the Medical Informatics Program of the University of Heidelberg/University of Applied Sciences Heilbronn, it is now organized as international course in the framework of the International Partnership for Health Informatics Education (http:// www.iphie.org) jointly for medical information science students from the University of Amsterdam, medical informatics students, as well as health information management students from the Universities of Heidelberg/Heilbronn. In 2002, medical informatics students from the Master of Science program of the newly founded University for Health Informatics and Technology Tyrol (UMIT) at Innsbruck, Austria, joined. We report about the aim of this course, its audience, and the educational programs involved, about its content and structure, as well as about our experiences gained so far.

Influence of controlled hypoxia and radical scavenging agents on erythropoietin and malondialdehyde concentrations in humans.

UNLABELLED: The present study was carried out to evaluate a model of a hypoxic stimulus of erythropoietin (EPO) production in humans and to investigate the role of free oxygen radicals in human EPO production. The study was conducted as an open, randomized, parallel, placebo-controlled trial. Thirty-six healthy male volunteers received a hypoxic treatment (13% O(2)) with a respiration mask for 6 h. During the period of hypoxia, the volunteers received as a short-term treatment either 1200 mg thioctic acid, or N-acetylcysteine 600 mg or placebo (0.9% sodium chloride). The EPO concentration in plasma increased up to 290% of the baseline level in all three groups. No statistically significant differences of AUC(EPO(0-48 h)) could be demonstrated between the groups. The malondialdehyde (MDA) concentration in plasma increased significantly (P < 0.001) 2 h after termination of hypoxia (mean 129.8 +/- 6.8% of the baseline) in all three groups. CONCLUSIONS: Taken together, our in-vivo results do not support a gross modulatory effect of a short-term treatment with radical scavenging agents on EPO-production during or after hypoxia in humans, as derived from the detected changes of MDA-concentrations in peripheral plasma.

Multimodal online monitoring in middle cerebral artery territory stroke.

BACKGROUND AND PURPOSE: Patients with large middle cerebral artery infarction and elevated intracranial pressure (ICP) who are undergoing invasive intensive care therapy require technical monitoring. However, the effectiveness of the current gold standard, measurement of ICP, is limited. Furthermore, the effects of what is considered to be standard antiedema medical treatment are not fully understood. We studied whether multimodal monitoring can help to overcome this problem. METHODS: ICP, cerebral perfusion pressure (CPP), and partial brain tissue oxygen pressure (PbrO(2)) were continuously measured within the white matter of the frontal lobe unilaterally or bilaterally. We analyzed the effects of antiedema drugs and looked for pattern changes in the PbrO(2) before transtentorial herniation in patients in whom this could not be prevented. Furthermore, complications were registered. RESULTS: We performed 27 measurements in 21 patients. A total of 297 antiedema drug administrations were analyzed in 11 patients. Hyper-HAES and mannitol were most often associated with an increase in CPP and PbrO(2), whereas the use of thiopental and tromethamine led to negative or contrary effects, although ICP was decreased in every case. Pattern changes in the PbrO(2) curve could be observed between 6 to 18 hours before transtentorial herniation. No bleeding complication or infections were observed. CONCLUSIONS: Multimodal monitoring can be used to monitor antiedema drug effects. Our data suggest that with multimodal monitoring, pathophysiological changes could be predicted considerably in advance. ICP alone is of questionable use. Furthermore, this method might help to optimize the timing of invasive therapy in space-occupying infarction.

[Cortisol in night-urine: Introduction of a research method in psychoneuroendocrinology]. / Cortisolbestimmung im Nachturin - Vorstellung einer Methode für die psychoneuroendokrinologische Forschung.

Cortisol is one of the major parameters investigated in psychoneuroendocrinological research, but the methods employed for sample collecting are often unsatisfactory. A suitable method of sample collection should allow for the integrative assessment of long-term changes of the HPA-system, should be non-invasive, and should not exceed the subject's compliance. The assessment of cortisol in night-urine fulfils these demands; although this method has been occasionally employed, it has not yet been described systematically. For the first time a detailed description is given here that allows for a standardized replication. In ten previous studies and three investigations of our own this method has been successfully applied to detect changes in the cortisol excretion of patients with endocrinological and psychiatric disorders as well as in subjects under conditions of psychosocial stress. The determination of cortisol in night-urine represents an ideal method for the assessment of changes in the basal HPA-activity in numerous areas of psychoneuroendocrinological research, e.g. field and screening studies in natural environment, clinical studies in psychiatry and especially follow-up studies in psychotherapy research.

Creutzfeldt-Jakob disease and oxidative stress.

OBJECTIVES: Substantial evidence supports the hypothesis that oxygen free radicals are involved in various neurodegenerative disorders. To assess the presence of oxidative stress in Creutzfeldt-Jakob disease (CJD) we examined the concentrations of malondialdehyde (MDA) as an established marker of lipid peroxidation. MATERIAL AND METHODS: MDA was quantified by high performance liquid chromatography (HPLC) in cerebrospinal fluid (CSF; n=12) and in serum (n=11) samples of CJD patients and healthy controls (n = 15). RESULTS: Mean values in healthy controls: 2.56 nmol/ml +/- 0.46 (CSF) and 1.94 nmol/ ml +/- 0.67 (serum); mean values in CJD patients: 2.64 nmol/ml +/- 0.67 (CSF) and 1.68 nmol/ml +/- 0.79 (serum). No significant (P>0.05) difference between CJD patients and controls was observed. CONCLUSIONS: The results indicated that the CSF and serum of CJD patients showed no higher endogenous levels of MDA as compared to normal healthy controls. These findings provide no evidence for an additional role of oxidative stress in the pathogenetic mechanism underlying CJD neurodegeneration.

Measurement of free and bound malondialdehyde in plasma by high-performance liquid chromatography as the 2,4-dinitrophenylhydrazine derivative.

We established a method for the detection of free and total (free and bound) malondialdehyde (MDA) in human plasma samples after derivatisation with 2,4-dinitrophenylhydrazine (DNPH). Free MDA was prepared by perchloric acid deproteinisation whereas an alkaline hydrolysation step for 30 min at 60 degrees C was introduced prior to protein precipitation for the determination of total MDA. Derivatisation was accomplished in 10 min at room temperature subsequently chromatographed by HPLC on a reversed-phase 3 microm C(18) column with UV detection (310 nm). The detection limit was 25 pmol/ml for free and 0.3 nmol/ml for total MDA. The recovery of MDA added to different human plasma samples was 93.6% (n=11; RSD 7.1%) for the hydrolysation procedure. In samples from 12 healthy volunteers who underwent a hypoxic treatment (13% O2 for 6 h) we estimated a baseline value of total MDA of 2.16 nmol/ml (SD 0.29) (ambient air) with a significant increase to 2.92 (nmol/ml, SD 0.57; P=0.01) after the end of this physiological oxidative stress challenge. Plasma values of free MDA in these samples were close to our detection limit. The presented technique can easily performed with an isocratic HPLC apparatus and provides highly specific results for MDA as do sophisticated GC-MS methods.

Rifampin reduces production of reactive oxygen species of cerebrospinal fluid phagocytes and hippocampal neuronal apoptosis in experimental Streptococcus pneumoniae meningitis.

Bacterial compounds induce the production of reactive oxygen species (ROS) in meningitis. Rifampin releases smaller quantities of proinflammatory compounds from Streptococcus pneumoniae than do beta-lactam antibiotics. Therefore, rabbits infected intracisternally with S. pneumoniae were treated intravenously either with rifampin 5 mg/kg/h or ceftriaxone 10 mg/kg/h (n=9 each). Before initiation of antibiotic treatment, a strong positive correlation between ROS production of cerebrospinal fluid (CSF) phagocyte populations and bacterial CSF titers was observed (granulocytes: rs=.90, P<.0001; monocytes: rs=.81, P<.0001). CSF leukocytes from rifampin-treated rabbits produced less ROS (monocytes at 2 h after initiation of treatment: P=.045; at 5 h: P=.014; granulocytes at 5 h: P=.036) than did leukocytes from animals receiving ceftriaxone. The CSF malondialdehyde concentrations and the density of apoptotic neurons in the dentate gyrus were lower in rifampin- than in ceftriaxone-treated animals (P=.002 and.005). The use of rifampin to reduce the release of ROS and to decrease secondary brain injury appears promising.

Sleep disorders and portal-systemic encephalopathy following transjugular intrahepatic portosystemic stent shunt in patients with liver cirrhosis. Relation to plasma tryptophan.

Neuropsychiatric symptoms due to any type of dysfunction and/or portal-systemic shunting are summarized as hepatic encephalopathy (HE). HE in the presence of liver cirrhosis and/or portal-systemic shunting has been termed portal-systemic encephalopathy (PSE). PSE is most frequent among the HE syndromes and is almost exclusively seen in patients with advanced cirrhosis and portal hypertension. Portal-systemic shunting either spontaneous due to portal hypertension, following surgical portocaval anastomosis, or subsequent to transjugular intrahepatic portosystemic stent-shunt (TIPSS) is regarded as the primary causative condition for PSE, not hepatic dysfunction per se. PSE may be considered as a disorder of multiple neurotransmitter systems among which derangements of the serotonergic system have been documented most consistently. Incipient PSE is frequently paralleled by the occurrence of sleep disorders, however, their relation to PSE remains unclear. We observed a transient increase of sleep disorders post-TIPSS, which were only in part correlated to other symptoms of PSE. Among the biochemical parameters studied only an association between arterial ammonia levels and sleep disorders became apparent, whereas no significant relation was observed for peripheral tryptophan.

Serotonergic hyperinnervation of the frontal cortex in an animal model of depression, the bulbectomized rat.

We studied the influence of olfactory bulbectomy in rats on three different parameters of serotonin (5-HT) presynapses, 5-HT transporter density, tryptophan hydroxylase apoenzyme concentration, and the levels of 5-HT and 5-hydroxyindole acetic acid (5-HIAA) in various brain regions. Compared with sham-operated controls, the Bmax values of [3H]paroxetine binding, the apoenzyme concentration of tryptophan hydroxylase and the level of 5-HIAA, and, therefore, the 5-HIAA/5-HT ratio were significantly and selectively increased in the frontal cortex of bulbectomized rats, measured 12 weeks after surgery. The most likely explanation of the concomitant increase in levels of all three markers of 5-HT presynapses in the frontal cortex is an increased density of 5-HT innervation in this remote projection field of the raphe nuclei. It is suggested that the bulbectomy-associated axotomy of 5-HT fibers projecting to the bulb stimulates collateral sprouting and synaptogenesis, especially in the frontal cortex. The resulting 5-HT hyperinnervation must be expected to alter global neuronal activity in this region and to impair the balance of information flow between this and other brain regions, resulting in a multitude of secondary behavioral and neurochemical changes. The frontocortical abnormalities observed by brain imaging studies in the brains of depressed patients may also be explained by a selective 5-HT hyperinnervation of this brain region.

Sex differences in endocrine and psychological responses to psychosocial stress in healthy elderly subjects and the impact of a 2-week dehydroepiandrosterone treatment.

Evidence from animal as well as human studies has suggested that significant sex differences exist in hypothalamus-pituitary-adrenal axis (HPA) activity. As gonadal steroids could be important modulators of HPA sex differences, stress responses were investigated in subjects of advanced age after dehydroepiandrosterone (DHEA) or placebo treatment. After a 2-week treatment with 50 mg DHEA daily or placebo, 75 men and women (mean age, 67.6 yr) were exposed to the Trier Social Stress Test (TSST). The TSST is a brief psychosocial stress that consists of a free speech and mental arithmetic task in front of an audience. The results show that the TSST induced significant increases in ACTH, salivary free cortisol, total plasma cortisol, norepinephrine, and heart rates (all P < 0.0001) as well as decreased positive affect in the elderly (P = 0.0009). Men showed larger stress responses in ACTH (P = 0.004), salivary free cortisol (P = 0.044), and plasma total cortisol (P = 0.076) compared to women. No sex differences were observed in norepinephrine, epinephrine, or heart rate responses. In contrast to ACTH and cortisol response differences, women reported that they were significantly more stressed by the TSST than men (P = 0.0051). Women treated with DHEA showed ACTH stress responses similar to those of men, but significantly enhanced compared to those of women taking placebos (P < 0.009). No other stress response differences emerged between DHEA and placebo groups. Finally, DHEA treatment did not result in an improvement of subjective well-being. We conclude that elderly men show larger HPA responses than women to psychosocial stress, as studied in the TSST. Estrogen effects on hypothalamic CRF-producing neurons might be responsible for these sex differences.

Endocrine and hemodynamic effects of stress versus systemic CRF in alcoholics during early and medium term abstinence.

In alcoholics, disturbances of the autonomic nervous system as well as of the hypothalamic-pituitary-adrenal axis (HPA) are known. However, these two systems have never been analyzed, under stimulated conditions, in parallel in the same patients. Moreover, studies using intravenous (i.v.) corticotropin releasing factor (CRF) to assess neuroendocrine function bypass the hypothalamic component of the HPA axis. Therefore, i.v. human (h) CRF (pituitary stimulation/exogenous CRF) and a multifaceted stress test (hypothalamic activation/endogenous CRF) were compared with respect to their effects on hemodynamics as well as plasma norepinephrine (NE), epinephrine (E), ACTH, and cortisol in abstinent alcoholics (n = 11) versus healthy men (n = 10). Each stimulus was tested twice, 12 weeks apart, in two separate experimental blocks (I and II). Alcoholics entered block 18 days after the last ethanol ingestion and were controlled for abstinence up to block II. hCRF caused a fall in mean arterial pressure (MAP), most pronounced in alcoholics, particularly in block II. In contrast, stress testing raised MAP in both groups and blocks. A sustained increase in ACTH, cortisol, and NE occurred after hCRF, although the ACTH response in alcoholics was blunted in both blocks. Stress testing elevated NE in both groups and blocks, while raising plasma ACTH and cortisol during block I only in controls. However, unlike the persistently blunted ACTH response to i.v. CRF, a normalization of the stress-induced ACTH output occurred in alcoholics after 12 weeks of abstinence. During block I, basal E levels were elevated in alcoholics whereas NE levels tended to be lower than in controls, resulting in a significantly decreased NE/E ratio that returned to near control values in block II. Neither CRF nor stress had any effect on circulating E in either group or block. To conclude: (1) Normalization of the ACTH response to stress, but not to i.v. CRF, after 12 weeks of abstinence, suggests that other ACTH secretagogues may be compensating for CRF dysfunction in alcoholics. (2) Despite the dramatically lowered plasma NE/E ratio in alcoholics, the NE response to stimuli was unaffected. (3) The exaggerated hypotensive reaction and blunted ACTH response to i.v. CRF may reveal a long-term dissociative dysregulation of CRF actions in alcoholics.

Urinary excretion of cortisol, norepinephrine, testosterone, and melatonin in panic disorder.

Nocturnal urinary cortisol, norepinephrine, epinephrine, testosterone, and melatonin secretion patterns were studied in male patients with DSM IV/ICD-10 panic disorder (n = 16) over two series of 5 consecutive nights each. Night-time urinary excretion of cortisol, norepinephrine, and epinephrine was significantly elevated in drug-free patients compared to normal individuals (n = 13). Measurements were repeated after 4 weeks, and the same differences were found again. There were high correlations between the first and the second series of measurements. Testosterone and melatonin levels did not differ between panic patients and controls.

Endocrine correlates of personality traits: a comparison between emotionally stable and emotionally labile healthy young men.

An initial sample of 120 healthy young men was screened by a personality questionnaire and 15 subjects each with highest and lowest scores respectively on emotionality (emotionally labile, EL subjects and emotionally stable, ES subjects) were recruited for a study on the relationship between the degree of emotionality and the basal secretion of stress-sensitive hormones during night-time. The nocturnal urinary excretion of cortisol, testosterone, adrenaline, noradrenaline and melatonin was measured over a period of 5 consecutive nights. The average amounts of each hormone excreted per night were not different between the two extreme groups. The variability of the excretion during the 5 nights of cortisol and testosterone, but not of adrenaline, noradrenaline and melatonin, was significantly higher in EL compared to ES subjects. The larger fluctuations in the nocturnal secretion of these two (and no other) hormones in EL subjects indicate that emotional lability is associated with a more labile regulation of cortisol and testosterone secretion. The observed intraindividual variability of basal stress hormone secretion may contribute to the vast interindividual variability noticed in psychoneuroendocrine stress research, especially in emotionally labile subjects.