Quantification of the Effect of Inhaled Budesonide on Airway Inflammation in Intermittent Asthma by Bronchitis Index

The bronchitis index (BI) is a scoring system for the visual quantification of airway inflammation by flexible bronchoscopy. A prospective study was carried out to determine whether patients with intermittent asthma present a considerable visible airway inflammation. Ten steroid-naive patients with intermittent asthma taking only inhaled β₂-agonists were enrolled and received budesonide (800 μg/day) over a period of 4 weeks. The airway inflammation was assessed by flexible electronic videobronchoscopy before and after the steroid treatment phase and quantified using the BI. Despite normal pulmonary function, all patients with intermittent asthma showed a marked visible airway inflammation that was reversed by a 4-week treatment with the inhaled steroid budesonide. The present study demonstrates that the BI may be useful as a clinical research tool for the assessment and quantification of airway inflammation in asthma. Furthermore, our results support the widely recognized theory that airway inflammation is present even in patients with mild asthma, and emphasize the necessity of an early therapy with inhaled steroids.     

Sequence Analysis Using Logic Regression

Logic Regression is a new adaptive regression methodology that attempts to construct predictors as Boolean combinations of (binary) covariates. In this paper we use this algorithm to deal with single‐nucleotide polymorphism (SNP) sequence data. The predictors that are found are interpretable as risk factors of the disease. Significance of these risk factors is assessed using techniques like cross‐validation, permutation tests, and independent test sets. These model selection techniques remain valid when data is dependent, as is the case for the family data used here. In our analysis of the Genetic Analysis Workshop 12 data we identify the exact locations of mutations on gene 1 and gene 6 and a number of mutations on gene 2 that are associated with the affected status, without selecting any false positives. © 2001 Wiley‐Liss, Inc.     

Investigation of polyesters of adipic acid and sebacinic acid with hydroquinone by pyrolysis-mass spectrometry

The structure and thermal degradation behaviour of polyesters of adipic acid and sebacinic acid with hydroquinone were investigated by direct pyrolysis in the ion source of a mass spectrometer. Poly(oxyadipoyloxy-1,4-phenylene) ( 1 ) and poly(oxyebacoyloxy-1,4-phenylene) ( 2 ) undergo a cleavage of the ester bond as a very selective thermal degradation reaction (Eq. (iii)). In order to differentiate the thermal and electron impact induced degradation reactions of these polyesters the fragmentation pathways of corresponding low molecular weight esters were followed.     

Acute effects of N-acetylcysteine on skeletal muscle microcirculation following closed soft tissue trauma in rats.

Trauma-induced microcirculatory dysfunction, formation of free radicals and decreased endothelial release of nitric oxide (NO) contribute to evolving tissue damage following skeletal muscle injury. Administration of N-acetylcysteine (NAC) known to scavenge free radicals and generate NO is considered a valuable therapeutic approach. Thus, the objective of this study was to quantitatively analyze the acute effects of NAC on skeletal muscle microcirculation and leukocyte-endothelial cell interaction following severe standardized closed soft tissue injury (CSTI). Severe CSTI was induced in the hindlimbs of 14 male anesthetized Sprague-Dawley rats using the controlled impact injury technique. Rats were randomly assigned (n = 7) to high-dose intravenous infusion of NAC (400 mg/kg body weight) or isovolemic normal saline (NS). Non-injured, sham-operated animals (n = 7) were subjected to the same surgical procedures but did not receive any additional fluid. Creatin kinase (CK) activity was assessed at baseline, 1 h before and 2 h following posttraumatic NAC or NS infusion. Microcirculation of the extensor digitorum longus (EDL) muscle was analyzed using intravital microscopy and Laser-Doppler flowmetry (LDF). Edema index (EI) was calculated by measuring the EDL wet-to-dry weight ratio (EI=injured/contralateral limb). EDL-muscles were analyzed for desmin immunoreactivity and granulocyte infiltration. Microvascular deteriorations observed following NS-infusion were effectively reversed by NAC: Functional capillary density was restored to levels found in sham-operated animals and leukocyte adherence was significantly (p < 0.05) reduced compared to the NS group. NAC significantly (p < 0.05) increased erythrocyte flux determined by Laser-Doppler flowmetry. Posttraumatic serum CK levels and EI were significantly (p < 0.05) decreased by NAC. During the posttraumatic acute phase, single infusion of NAC markedly reduced posttraumatic microvascular dysfunction, attenuated both leukocyte adherence and tissue infiltration. NAC also decreased CSTI-induced edema formation and myonecrosis as reflected by attenuated serum CK levels and attenuated loss of desmin immunoreactivity. NAC may serve as an effective therapeutic strategy by supporting microvascular blood supply and tissue viability in the early posttraumatic period. Additional studies aimed at long-term analysis and investigation of injury severity--or dosage dependency are needed.     

Structural Decomposition and Heterogeneity of Commercial Lipoteichoic Acid Preparations

Fractionation of commercial preparations of lipoteichoic acids (LTA) by hydrophobic interaction chromatography (HIC) and nuclear magnetic resonance spectroscopy revealed very inhomogeneous compositions and decomposition of the LTA structure: LTA content of the preparations averaged 61% for Streptococcus pyogenes, 16% for Bacillus subtilis, and 75% for Staphylococcus aureus. The decomposition was characterized by a loss of glycerophosphate units as well as alanine and N-acetylglucosamine substituents. All preparations contained-to varying degrees-non-LTA, non-lipopolysaccharide (LPS) immunostimulatory components as indicated by their elution profile in HIC, lack of phosphate, and negative Limulus amoebocyte lysate (LAL) test results. After purification, the commercial LTA from Bacillus subtilis and S. pyogenes but not LTA from S. aureus induced the release of tumor necrosis factor alpha, interleukin 1 beta (IL-1beta), IL-6, and IL-10 in human blood. While pure LTA are negative in the LAL assay, endotoxin equivalents of more than 10 ng of LPS/mg of LTA were found in the commercial preparations. Taken together, these data indicate that these crude preparations with relatively high endotoxin contamination are not suitable for characterizing the activation of immune cells by LTA.     

Direkte Thrombinhemmung Ein neues Therapieprinzip bei Vorhofflimmern und akutem Koronarsyndrom?

Die direkte Inhibition von Thrombin ist ein vielversprechender neuer therapeutischer Ansatz in der Behandlung kardiovaskulärer Erkrankungen und der Prävention thromboembolischer Ereignisse. Zugelassen sind derzeit drei intravenös applizierbare Substanzen (Lepirudin, Bivalirudin und Argatroban) und ein oral verfügbarer direkter Thrombininhibitor (Ximelagatran). Die direkten Thrombininhibitoren (DTI) können in bivalente (Lipirudin und Bivalirudin) und monovalente Moleküle (Argatroban und Ximelagatran) unterschieden werden. Die bivalenten DTI binden an zwei Stellen des Thrombinmoleküls. Lepirudin und Argatroban sind zur Antikoagulation von Patienten mit heparininduzierter Thrombozytopenie (HIT) zugelassen. Für den DTI Bivalirudin konnten in den REPLACE-1- und -2-Studien eine sichere Antikoagulation und im Vergleich zu Heparin eine geringere Rate an Blutungskomplikationen eindrucksvoll belegt werden. Bivalirudin ist aufgrund dieser Daten zur Antikoagulation von Patienten während perkutaner koronarer Angioplastie (PTCA) zugelassen. Die orale Inhibition von Thrombin mit Ximelagatran ist zur Prävention eines thromboembolischen Insults bei Patienten mit Vorhofflimmern genauso effektiv wie eine orale Antikoagulation mit Warfarin/Phenprocoumon. Dies ist das Ergebnis der SPORTIF-III- und -V-Studien. In dieser Übersicht werden die pharmakologischen Grundlagen der DTI und deren Einsatz zur Prävention thromboembolischer Ereignisse sowie zur Antikoagulation beim akuten Koronarsyndrom diskutiert.     

Prophylaxis, Diagnosis and Therapy of Surgery-Related Complications in Orthopedic and Trauma Surgery An Observational Survey (CHANGE)

Background and Purpose:   

Selective factor Xa inhibition by the synthetic pentasaccharide fondaparinux is an efficient way of preventing venous thrombosis. Fondaparinux has been shown to reduce the incidence of venous thromboembolism (VTE) by 50% compared with the low-molecular-weight heparin enoxaparin. The aim of the CHANGE study was to evaluate the management of thrombosis prevention with fondaparinux, and the diagnosis and treatment of complications following major orthopedic surgery.     

Quantification of D2-like dopamine receptors in the human brain with 18F-desmethoxyfallypride.

Substituted benzamides such as (11)C-raclopride or (123)I-iodobenzamide are selective radiotracers for PET and SPECT imaging of D(2)-like dopamine (DA) receptors. (18)F-Desmethoxyfallypride ((18)F-DMFP) is a benzamide tracer with the advantage of an (18)F label. We optimized the synthesis and evaluated (18)F-DMFP in PET studies on healthy human volunteers. METHODS: The affinity of DMFP for D(2)-like DA receptors was characterized in vitro using membrane preparations from rat striatum and the DA receptor ligand (3)H-spiperone. PET studies on 10 healthy human volunteers were performed using a whole-body PET scanner after injection of 214 +/- 54 MBq (mean +/- SD) (18)F-DMFP. Brain images were acquired dynamically over 124 min, and metabolite-corrected plasma activity was used as the input function. Data analysis was performed using several different approaches (compartmental, graphical, equilibrium methods). RESULTS: The mean inhibition constant (K(i)) of DMFP was 15 +/- 9 nmol/L. In human brain, the striatum-to-cerebellum ratio reached a maximum of about 4 between 60 and 120 min. When specific binding in the striatum was expressed as the difference between binding in the striatum and the cerebellum, it reached a maximum at approximately 60 min after injection and remained almost constant until the end of data acquisition. The ratio of specific striatal to nonspecific cerebellar binding was about 3:1 at 120 min after injection. A small, but significant specific tracer binding could also be detected in the thalamus. Treatment of a schizophrenic patient with a high dose (1,000 mg/d) of another substituted benzamide, amisulpride, resulted in a reduction of specific tracer uptake of about 90% in striatal regions. With regard to measured distribution volumes and binding potentials, there was an excellent agreement between all applied analytic methods. CONCLUSION: Our study demonstrates that (18)F-DMFP is a highly reliable tracer for PET imaging of D(2)-like DA receptors. It offers the major advantage that it can be used independently of an on-site cyclotron within a PET satellite network. Noninvasive analytic methods without blood sampling provide valid measurements of receptor quantities in human striatum. Because of the (18)F label and the favorable imaging properties, (18)F-DMFP could become an efficient substitute for (11)C-raclopride in a clinical context.     

ARVC with left ventricular involvement in a young woman

A 22-year-old patient was sent to our institution with recurrentpalpitations and echocardiographic findings of an isolated rightventricular (RV) dilation. Holter-ECG demonstrated frequent,polymorphic ventricular ectopia and an