Pharmacophore model of drugs involved in P-glycoprotein multidrug resistance: explanation of structural variety (hypothesis)

A general pharmacophore model of P-glycoprotein (P-gp) drugs is proposed that is based on a highly diverse data set and relates to the verapamil binding site of the protein. It is derived from structurally different drugs using the program GASP. The pharmacophore model consists of two hydrophobic points, three hydrogen bond (HB) acceptor points, and one HB donor point. Pharmacophore patterns of various drugs are obtained, and different binding modes are presumed for some of them. It is concluded that the binding affinity of the drugs depends on the number of the pharmacophore points simultaneously involved in the interaction with P-gp. On the basis of the obtained results, a hypothesis is proposed to explain the broad structural variety of the P-gp substrates and inhibitors: (i) the verapamil binding site of P-gp has several points that can participate in hydrophobic and HB interactions; (ii) different drugs can interact with different receptor points in different binding modes.     

Psychophysiological correlates of peritraumatic dissociative responses in survivors of life-threatening cardiac events

The psychophysiological startle response pattern associated with peritraumatic dissociation (DISS) was studied in 103 survivors of a life-threatening cardiac event (mean age 61.0 years, SD 13.95). Mean time period since the cardiac event was 37 (79 IQD) months. All patients underwent a psychodiagnostic evaluation (including the Peritraumatic Dissociative Experiences Questionnaire) and a psychophysiological startle experience which comprised the delivery of 15 acoustic startle trials. Magnitude and habituation to trials were measured by means of electromyogram (EMG) and skin conductance responses (SCR). Thirty-two (31%) subjects were indexed as patients with a clinically significant level of DISS symptoms. High-level DISS was associated with a higher magnitude of SCR (ANOVA for repeated measures p = 0.017) and EMG (p = 0.055) and an impaired habituation (SCR slope p = 0.064; EMG slope p = 0.005) in comparison to subjects with no or low DISS. In a subgroup analysis, high-level DISS patients with severe post-traumatic stress disorder (PTSD; n = 11) in comparison to high-level DISS patients without subsequent PTSD (n = 19) exhibited higher EMG amplitudes during all trials (repeated measures analysis of variance F = 5.511, p = 0.026). The results demonstrate exaggerated startle responses in SCR and EMG measures - an abnormal defensive response to high-intensity stimuli which indicates a steady state of increased arousal. DISS patients without PTSD exhibited balanced autonomic responses to the startle trials. DISS may, therefore, unfold malignant properties only in combination with persistent physiological hyperarousability.     

Peak inspiratory flow rate after methacholine challenge in asthmatic patients and its impact on the effect of formoterol via different inhalers.

The goal of the present study was to investigate the bronchodilating effects of 6 and 12 microg formoterol delivered by the Turbuhaler, in comparison to salbutamol 200 microg (metered dose inhaler) and to controls without treatment. After inducing acute and severe bronchial obstruction by means of methacholine challenge, peak inspiratory mouth flow (PIMF) was measured through a stenosis, simulating the internal resistance of the Turbuhaler, with the in-check device. In addition the relationship was studied between PIMF and clinical response in the 3 treatment groups. In the 176 patients methacholine caused a mean fall in FEV(1) of 37.1 +/- 6.9% compared to baseline. Ten minutes after bronchodilator inhalation, FEV(1) improved significantly in all three treatment groups. At 30 minutes after bronchodilator administration, only the salbutamol 200 microg and the formoterol 12 microg groups had a significantly greater increase in FEV1 than controls (0.69 +/- 0.43 l and 0.66 +/- 0.37 l vs 0.38 +/- 0.32 l, p < 0.0005), whereas the formoterol 6 microg group showed no significant improvement (0.41 +/- 0.38 l, p = 0.74). Thirteen patients (7.4%) did not reach a minimal PIMF of 30 l/min through the in-check device after challenge. In the four patients in the formoterol 6 microg group with a PIMF below 30 l/min inhalation did not cause bronchodilation. In conclusion, the results demonstrate that 6 microg formoterol via Turbuhaler leads to less and slower onset of bronchodilation compared to the other groups in our setting. If patients fail to generate a PIMF of 30 l/min, 6 microg formoterol via Turbuhaler may provide inadequate relief in a severe asthma attack.     

Endoskopische Bursektomie und Traktopexie am Trochanter major

Zusammenfassung Operationsziel Minimal invasive Entfernung der Bursa trochanterica, gegebenenfalls mit Exostosenresektion und/oder Traktopexie am Trochanter major. Indikationen Chronische, konservativ ausbehandelte Bursitis trochanterica. Bursitis bei Coxa saltans oder infolge Spornbildung am Trochanter major. Kontraindikationen Bakterielle oder rheumatische Bursitis trochanterica. Operationstechnik Über je eine Stichinzision proximal, distal und leicht dorsal der Trochanterspitze wird Spülflüssigkeit (Purisole^®) epitrochantär eingebracht; die Fascia lata wird unter endoskopischer Sicht gespalten. Subtotale Bursektomie mit dem Synovialisresektor. Bedarfsweise Erweiterung des Eingriffs um eine Traktopexie mit resorbierbaren "Ankern" ist möglich. Ergebnisse Insgesamt 34 Patienten (28 weiblich, sechs männlich, Durchschnittsalter 57,8 Jahre) wurden seit 1995 operiert. Die ersten 20 Patienten (18 weiblich, zwei männlich, Durchschnittsalter 52,6 Jahre) konnten nach 20 (zwölf bis 36) Monaten nachuntersucht werden. 15 Patienten waren mit dem Resultat zufrieden. Der Schmerzwert sank in der visuellen Analogskala von 8,9 Punkten präoperativ (10 = stärkster Schmerz) auf 5,2 Punkte postoperativ und 4,3 zum Zeitpunkt der Nachkontrolle. Komplikationen: eine sekundäre Heilung im Bereich einer Stichinzision. Summary Objectives Minimally invasive surgical procedure for removal of the trochanteric bursa and, if necessary, exostosectomy and/or fixation of the iliotibial tract at the greater trochanter. Indications Chronic, unsuccessfully treated trochanteric bursitis. Bursitis caused by snapping hip or due to exostosis at the greater trochanter. Contraindications Infected bursitis or bursitis in rheumatoid patients. Surgical Technique Through 2 approaches, cranial and caudal and slightly posterior to the tip of the trochanter, infiltration of the epitrochanteric area with saline (Purisole^®); the iliotibial tract is divided under endoscopic control. Subtotal removal of the trochanteric bursa using a synovial resector. If necessary, the procedure can be extended to include a fixation of the tract with resorbable suture anchors. Results Since June 1995, we performed an endoscopic bursectomy in 34 patients (28 women and 6 men, average age 57.8 years). The first 20 patients (18 women and 2 men, average age 52.6 years) had an average follow-up of 20 (12 to 36) months. Fifteen patients were satisfied with the result. The degree of pain and functional handicap was assessed using a visual analog scale (10 points for intense pain). This pain score amounted to 8.9 points before surgery, to 5.2 postoperatively, and to 4.3 at follow-up. One instance of secondary healing was seen in a stab incision.     

Systematic review of diagnostic tests for vaginal trichomoniasis

OBJECTIVE: To review critically and to summarize the evidence of diagnostic tests and culture media for the diagnosis of Trichomonas vaginitis. METHODS: We performed a systematic review of literature indexed in MEDLINE of studies that used Trichomonas culture as the reference standard (9,882 patients, 35 studies). Level I studies (5,047 patients, 13 studies) fulfilled at least two of three criteria: 1) consecutive patients were evaluated prospectively, 2) decision to culture was not influenced by test results, and 3) there was independent and blind comparison to culture. RESULTS: The sensitivity of the polymerase chain reaction technique (PCR) was 95% (95% CI 91% to 99%), and the specificity was 98% (95% CI 96% to 100%). One study was classified as Level I evidence (52 patients). The sensitivity of the enzyme-linked immunosorbent assay was 82% (95% CI 74% to 90%), and the specificity was 73% (95% CI 35% to 100%). The sensitivity of the direct fluorescence antibody was 85% (95% CI 79% to 90%), and the specificity was 99% (95% CI 98% to 100%). Sensitivities of culture media were 95% for Diamond's, 96% for Hollander, and 95% for CPLM. CONCLUSIONS: The sensitivity and specificity of tests to diagnose trichomoniasis vary widely.     

Gender differences of symptom reporting and medical health care utilization in the German population

Aim: Gender differences in morbidity have been widely confirmed in representative health surveys in North America and Europe. Significantly more women than men suffer from somatic complaints. It is less clear whether differences in symptom reporting provide an impact on health care utilization and to which degree psychosocial factors exhibit confounding influence. Methods: We analyzed data from a representative health examination survey in Germany with 7466 participants in the age range of 25 to 69 years. Results: The analysis confirmed an overall excess in female symptom reporting, both in the total sample (n = 7460; p 0.001) and in the healthy subsample (n = 906, p 0.01). Also, female utilization of medical services was higher (p 0.0001). A simultaneous age related increase in the prevalence of symptom reporting in both groups peaked in the age group of 55–59 years followed by a subsequent slight decrease in higher age groups whereas utilization steadily increased over the adult life span in both sexes. As expected, more medical utilization was associated with higher symptom reporting levels. Nevertheless, females constantly exhibited more medical utilization than males in all symptom reporting groups. Age and marital status had no univariate influence on symptom reporting whereas low social class status (p = 0.001), poor perceived/self assessed health (p < 0.0001), and high levels of chronic distress (p < 0.0001) were associated with more symptom reporting. In multivariate analysis, the female gender lost its significance on heightened symptom reporting. Poor perceived/self assessed health had the most pronounced impact on symptom count (F-value 59.1; p < 0.001). Conclusions: The present study confirms a female excess of symptom reporting and utilization of medical services. Nevertheless, symptom reporting and utilization are not closely related. The gender gap in symptom reporting may be largely explained by low social class status, high levels of chronic distress and poor perceived/self assessed health.     

Branched-chain amino acids and respiration.

A series of investigations suggest a specific role for BCAA in the regulation of respiration. In vitro incubation studies have shown that BCAAs improve the recovery of muscle force after fatigue. Further investigations revealed that leucine plays a key role in this action and acts in a manner not dependent on its use as an energy substrate. In humans, solutions enriched with BCAA have decreased PCO2 and stimulated the ventilatory response to hypercapnia, thereby corresponding to an enhanced ventilatory sensitivity with the administration of BCAA. The mechanisms for these actions are unknown. The most viable hypothesis is based on the ability of BCAA to decrease the synthesis of serotonin due to altered transport of AAs, including tryptophan, to the brain. Clinical studies have suggested a potency of BCAA in the treatment of respiratory dysfunction of preterm infants, as well as of patients with sleep apnea related to various disease states. The clinical applications of BCAA-enriched mixtures in respiratory diseases are still experimental, and many controversies exist concerning the validity of BCAA in clinical practice. Most TPN regimens contain BCAA approximating the average intake of BCAA in the Western diet. The question therefore remains whether additional BCAA supplementation is useful to achieve the suggested metabolic and pharmacological effects. Meticulous future studies are needed to establish the therapeutic value of BCAA in the treatment of various respiratory functions.     

Der zellstoffwechsel von candida unter prednisolon-wirkung

Zusammenfassung Die Stoffwechselwirksamkeit von 2 wasserlöslichen Prednisolon-Verbindungen wurde an je 10 Candida albicans- und Candida tropicalis-Stämmen in vitro geprüft. Die Versuche erfolgten im Ruhestoffwechsel und in der Proliferationsphase. Der Einfluß auf den Zellstoffwechsel wurde anhand des O₂-Verbrauchs im Warburg-Apparat gemessen.Sowohl im nährstofffreien Milieu als auch in Gegenwart von Nährsubstraten ergab sich eine mit steigenden Corticosteroidmengen von 10–10000ml dosisabhängige Zunahme der Zellatmung. Während der 3stündigen Versuchsdauer konnte auch im Bereich hoher Konzentrationen ein antimetabolischer Effekt nicht nachgewiesen werden.Ein unterschiedliches Verhalten der beiden geprüften Candidaarten war nicht zu beobachten.

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Effect of prednisolon on cell metabolism of candida

Summary In vitro effects of 2 water-soluble prednisolon-derivatives on 10 Candida albicans and 10 Candida tropicalis species were investigated. Tests were performed during resting and proliferation phases. Changes of cell metabolism were measured by O₂-consumption by the Warburg technique.With increasing corticosteroid concentrations (10–10000ml) a dose dependent increase of cell respiration was found with and without addition of nutritive substrates. Even high concentrations of corticosteroid did not cause an antimetabolic effect. The tests did not yield different results for the two Candida species examined.