[Treatment of fibromyalgia syndrome with gamma-hydroxybutyrate : A randomized controlled study]. / Die Behandlung des Fibromyalgiesyndroms mit Gamma-Hydroxybuttersäure : Eine randomisierte, kontrollierte Studie.

BACKGROUND: The etiology of fibromyalgia syndrome is not yet fully understood. Current hypotheses suggest a potential role of gamma-hydroxybutyrate (GHB) in influencing endocrinological abnormalities in patients with fibromyalgia. OBJECTIVE: The aim of the study was to investigate whether low dose GHB as a growth-hormone releasing substance reduces pain intensity and improves depressive mood, physical impairment and sleep quality in outpatients with fibromyalgia. Additionally, adverse events were recorded. MATERIAL AND METHODS: The pilot study was conducted in the outpatient clinic for pain at the clinic for anesthesiology and surgical intensive care of the Charité Universitätsmedizin Berlin. In the study 25 female patients with fibromyalgia according to the criteria of the American College of Rheumatology were randomized into 2 groups. Over 15 weeks patients of the intervention group received 25 mg/kg body weight oral GHB before going to bed and were compared with a placebo control group. In addition, all patients participated in operant behavioral pain treatment in a group setting. Dependent variables were pain intensity, depressive mood, physical impairment and quality of sleep. RESULTS: There were no group differences in the course of pain intensity (p = 0.61), depressive mood (p = 0.16), physical impairment (p = 0.25) and quality of sleep (p = 0.44); however, all symptoms improved across the groups from pretherapy to posttherapy. Low dose GHB did not increase growth hormone blood concentrations. The number of adverse events that were reported more than two times was similar in both groups. DISCUSSION: Administration of low dose GHB did not yield clinical improvements in female outpatients with fibromyalgia. General improvement in the course of treatment may have resulted from operant behavioral pain therapy. Future studies on GHB should control hypothetical risk factors for identification of non-responders.

[Diagnosis and therapy of pulmonary embolism prior to death]. / Prämortale Diagnostik und Therapie autoptisch bestätigter Lungenarterienembolien.

BACKGROUND: The study was conducted to assess the rate of suspected pulmonary embolism (PE) prior to death and the diagnostic and therapeutic procedures performed. METHODS: Patients with autopsy-confirmed PE between 1998 and 2002 were included. Autopsy register and medical records were reviewed for history, diagnosis and therapy of PE. Patients were categorised into fatal and non-fatal PE according to the autopsy findings. RESULTS: 102 patients with fatal and 247 patients with non-fatal PE were eligible for analysis (median age 68 years; 24-95). In 58.8% with fatal and in 32% with non-fatal PE, disease was suspected pre-mortal. Clinical suspicion of PE was significantly enhanced in venous thrombosis (Odds Ratio [OR] = 12.17, p=0.004) and significantly decreased for chronic vascular disease (OR = 0.30, p=0.002). Recurrent PE was demonstrated in 31.4% fatal and in 4.5% non-fatal PE (OR = 9.81, p=0.001). 7% of all PE were localised centrally, 19% centrally and peripherally and 74% peripherally. Dyspnoea and tachycardia were the most frequent symptoms in fatal PE. About half of all patients suffered from malignancies. Suspicion of PE decreased after day 14 of hospitalisation (OR = 0.33, p=0.021). CONCLUSION: PE often is not diagnosed pre-mortally. Patients with chronic vascular disease and tumours as well as those hospitalised for over 14 days are at particular risk for PE.

[Sleep disturbances in critically ill patients]. / Schlafstörungen bei kritisch kranken Patienten.

Sleep is an essential part of life with many important roles which include immunologic, cognitive and muscular functions. Of the working population 20% report sleep disturbances and in critically ill patients an incidence of more than 50% has been shown. However, sleep disturbances in the intensive care unit (ICU) population have not been investigated in detail. Sleep disturbances in ICU patients have a variety of reasons: e.g. patient-related pathologies like sepsis, acute or chronic pulmonary diseases, cardiac insufficiency, stroke or epilepsy, surgery, therapeutical interventions like mechanical ventilation, noise of monitors, pain or medication. Numerous scales and questionnaires are used to quantify sleep and the polysomnogramm is used to objectify sleep architecture. To improve sleep in ICU patients concepts are needed which include in addition to pharmacological treatment (pain reduction and sedation) synchronization of ICU activities with daylight, noise reduction and music for relaxation. In order to establish evidence-based guidelines, research activities about sleep and critical illness should be intensified. Questions to be answered are: 1) Which part of sleep disturbances in critically ill patients is directly related to the illness or trauma? 2) Is the grade of sleep disturbance correlated with the severity of the illness or trauma? 3) Which part is related to the medical treatment and can be modified or controlled? In order to define non-pharmacological and pharmacological concepts to improve sleep quality, studies need to be randomized and to include different ICU populations. The rate of nosocomial infections, cognitive function and respiratory muscle function should be considered in these studies as well. This will help to answer the question, whether it is useful to monitor sleep in ICU patients as a parameter to indicate therapeutical success and short-term quality of life. Follow-up needs to be long enough to detect adverse effects of withdrawal symptoms after termination of analgesia and sedation or delirium.

Serum leptin in formerly small-for-gestational-age children during adolescence: relationship to gender, puberty, body composition, insulin sensitivity, creatinine, and serum uric acid.

Serum leptin levels reflect body fat mass (FM), and have been described to be related to serum uric acid levels in adult type 2 diabetic and healthy subjects. We therefore aimed to evaluate the interrelationship between leptin and markers of the metabolic syndrome by studying serum leptin concentration, body mass index (BMI), percent body fat (Fat%), total fat mass (FM), sum of skinfolds (SS), triglycerides (TG), total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glucose, insulin, calculated insulin resistance (HOMA), creatinine (CR), and uric acid (UA) concentration in 50 former small-for-gestational-age (SGA) children and 21 infants born adequate for gestational age (AGA) at the time of mid-puberty. Our data confirm previous results showing a positive association between leptin and body fatness, and female gender. Twelve children with impaired glucose tolerance (IGT) had higher UA levels than subjects with normal glucose tolerance (NGT) (5.1 +/- 1.1 v 4.2 +/- 1.2 mg/dL, P <.05), and showed the strongest relation between serum leptin and UA (r =.76, P <.001). Multiple regression analyses demonstrated that gender, estimates of total body adiposity (Fat% and SS), birth weight (BW), gestational age (GA), stimulated glucose and insulin, and serum UA are independently associated with serum leptin concentration in former SGA children with dysglycemia (R(2) =.89, P <.001). A long-term effect of intrauterine growth restriction on body fatness, metabolic syndrome, and serum leptin levels is suggested.

Lipoprotein(a) levels in formerly small-for-gestational-age children.

Lipoprotein(a) (Lp(a)) is an independent and inherited risk factor for coronary artery disease. Concentrations of Lp(a) have been widely described in adolescents, but little is known about its concentration in children born small for gestational age (SGA). To assess the influence of intrauterine growth on Lp(a) levels we examined 50 children born SGA and 21 children born adequate for gestational age (AGA). Lp(a) blood levels (mean +/- SD) of the SGA children differed significantly (p < 0.05) from AGA children (22.3 +/- 22.1 vs. 10.9 +/- 7.6 mg/dl). 14 out of 50 adolescents of the SGA group but 1 out of 21 of the AGA group had elevated Lp(a) (>30 mg/dl) concentrations (p < 0.05). These children also had higher triglyceride (1.0 +/- 0.6 mmol/l vs. 0.74 +/- 0.38 mmol/l) levels (p < 0.05) compared to children with Lp(a) levels <30 mg/dl. Adolescents with Lp(a) levels >30 mg/dl showed a significant inverse relation between Lp(a) levels and gestational age (r = -0.68, p < 0. 005). We hypothesize that impairment of fetal growth might influence serum Lp(a) levels in later life.

The molecular basis for the natural resistance of the cytochrome bc1 complex from strobilurin-producing basidiomycetes to center Qp inhibitors.

Mitochondria from the strobilurin A producing basidiomycetes Strobilurus tenacellus and Mycena galopoda exhibit natural resistance to (E)-beta-methoxyacrylate inhibitors of the ubiquinol oxidation center(center Qp) of the cytochrome bc1 complex. Isolated cytochrome bc1 complex from S. tenacellus was found to be highly similar to that of Saccharomyces cerevisiae with respect to subunit composition, as well as spectral characteristics and midpoint potentials of the heme centers. To understand the molecular basis of natural resistance, we determined the exon/intron organization and deduced the sequences of cytochromes b from S. tenacellus, M. galopoda and a third basidiomycete, Mycena viridimarginata, which produces no strobilurin A. Comparative sequence analysis of two regions of cytochrome b known to contribute to the formation of center Qp suggested that the generally lower sensitivity of all three basidiomycetes was due to the replacement of a small amino acid residue in position 127 by isoleucine. For M. galopoda replacement of Gly143 by alanine and Gly153 by serine, for S. tenacellus replacement of a small residue in position 254 by glutamine and Asn261 by aspartate was found to be the likely causes for resistance to (E)-beta-methoxyacrylates. The latter exchange is also found in Schizosaccharomyces pombe, which we found also to be naturally resistant to (E)-beta-methoxyacrylates.

What information do inhibitors provide about the structure of the hydroquinone oxidation site of ubihydroquinone: cytochrome c oxidoreductase?

The Q cycle mechanism of the bc1 complex requires two quinone reaction centers, the hydroquinone oxidation (QP) and the quinone reduction (QN) center. These sites can be distinguished by the specific binding of inhibitors to either of them. A substantial body of information about the hydroquinone oxidation site has been provided by the analysis of the binding of QP site inhibitors to the bc1 complex in different redox states and to preparations depleted of lipid or protein components as well as by functional studies with mutant bc1 complexes selected for resistance toward the inhibitors. The reaction site is formed by at least five protein segments of cytochrome b and parts of the iron-sulfur protein. At least two different binding sites for QP site inhibitors could be detected, one for the methoxyacrylate-type inhibitors binding predominantly to cytochrome b, the other for the chromone-type inhibitors and hydroxyquinones binding predominantly to the iron-sulfur protein. The interactions with the protein segments, between different protein segments, and between protein and ligands (substrate, inhibitors) are discussed in detail and a working model of the QP pocket is proposed.

Significance of the "Rieske" iron-sulfur protein for formation and function of the ubiquinol-oxidation pocket of mitochondrial cytochrome c reductase (bc1 complex).

The binding of specific inhibitors to the ubiquinol oxidation pocket ("QP center") of cytochrome c reductase was analyzed before and after removal of bound phospholipid and the "Rieske" iron-sulfur protein using optical spectroscopy and fluorescence quench binding assays. The enzyme lacking iron-sulfur protein showed almost unchanged, tight binding of the E-beta-methoxyacrylate inhibitors oudemansin A and MOA-stilbene, whereas binding of the chromone inhibitor stigmatellin was almost completely abolished. The affinity of the weak inhibitor 3-undecyl-2-hydroxy-naphthoquinone was decreased. Oudemansin A binding to the defective pocket of the iron-sulfur protein-depleted enzyme was lowered by added phospholipid. It was deduced from these results that the QP center is a spacious pocket formed by domains of cytochrome b, bearing the E-beta-methoxcyacrylate binding site, and the iron-sulfur protein, bearing the stigmatellin binding site. Moreover, removal of the iron-sulfur protein leaves this pocket defective but essentially unchanged in its remaining binding capability. The affinity of three preparations of cytochrome c reductase, the complete, the delipidated, and the iron-sulfur depleted enzyme for E-beta-methoxyacrylate-stilbene, was analyzed for different redox states of the catalytic centers of cytochrome c reductase. The apparent Kd values for the different redox states were interpreted in terms of two conformational states. It is suggested that these changes reflect the two states of the "catalytic switch" proposed recently for the QP pocket of cytochrome c reductase (Brandt, U., and von Jagow, G. (1991) Eur. J. Biochem. 195, 163-170). According to the refined model presented in this work, changeover to the "b" state is triggered by reduction of the iron-sulfur cluster, and changeover back to the "FeS" state is triggered by electron transfer from the low potential onto the high potential heme b center. Our interpretation implies that the stability of the two states is affected by the redox states of the enzyme, but that additionally changing the redox states of the two centers is required for "switching" on a catalytic time scale.