[Use of a lung function screening device for identifying patients at risk for COPD in general practice]. / COPD-Screening in der hausärztlichen Praxis mit einem Lungenfunktions-Schnellmessgerät.

BACKGROUND: Screening measures can facilitate the diagnosis of chronic obstructive pulmonary disease (COPD) and help save costs and time. We examined whether use of a lung function screener (Vitalograph copd-6™) can help general practitioners to identify patients at risk for COPD. METHODS: In 17,856 patients aged > 40 years (smokers/ex-smokers with cough and/or exertional dyspnoea) general practitioners measured prebronchodilator FEV1 [% of predicted] and FEV1/FEV6 with the lung function screening device. In addition, the general practitioners completed a questionnaire on symptoms, history and planned measures and estimated whether or not the patient was at risk for COPD. RESULTS: In 2927 patients (16.7 %) an FEV1/FEV6 < 70 % was measured; 88.2 % of these were classed by the doctors as being at risk for COPD. The total number of all patients with suspected COPD was considerably greater (10,000; 56 % of the total population); in only 25.3 % was an FEV1/FEV6 < 70 % documented. Compared with patients without a suspicion of COPD, patients judged to be at risk for COPD in spite of an FEV1/FEV6 ≥ 70 % were more often male, had more cigarette pack years and more often had dyspnoea, but less often cough, as main symptom. They had more concomitant diseases and previous hospitalisations, more prescriptions for bronchodilators, glucocorticoids and antibiotics in the past year and lower FEV1 values. In 61.3 % of the patients with suspected COPD the general practitioners planned further evaluation by spirometry, in 39.9 % referral to a pulmonologist as alternative or additional procedures were suggested. CONCLUSION: Most patients with an FEV1/FEV6 < 70 % measured with the lung function screener Vitalograph copd-6™ were classed by the general practitioners as being at risk for COPD. Even in patients with unremarkable FEV1/FEV6 values the diagnosis of suspected COPD was often made if clinical signs or symptoms or a reduced FEV1 pointed to such a suspicion.

[Early treatment of COPD with tiotropium]. / Evidenz für eine frühzeitige Therapie der COPD mit Tiotropium.

BACKGROUND: In a prespecified subgroup analysis of the 4-year trial "Understanding Potential Long-term Impacts on Function with Tiotropium", the efficacy of tiotropium versus control in patients with moderate COPD (GOLD II) was examined and compared with the pooled results of patients with more severe disease (GOLD III/IV). METHODS: Randomised, multicentre, double-blind, placebo-controlled, parallel-group study in 5993 patients over a period of 4 years. Patients received either tiotropium 18 µg or placebo once-daily. The study endpoints were the annual FEV1 decline as well as lung function parameters, health status, exacerbations and all-cause mortality. RESULTS: 46 % of the patients had moderate disease (GOLD II; tiotropium: n = 1384, control group: n = 1355) with a mean postbronchodilator FEV1 of 1.63 (0.37) L (59 % predicted). In these patients with moderate COPD, tiotropium significantly improved the absolute FEV1 values (pre-bronchodilator FEV1: 101 - 119 ml, post-bronchodilator FEV1: 52 - 82 ml, p < 0.001) and the postbronchodilator FEV1 decline compared with the control patients (43 (2) vs. 49 (2) ml/year; p = 0.024). In addition, there was a statistically significant improvement in the annual exacerbation rate (tiotropium: 0.56, control: 0.7; p < 0.0001), the time to first exacerbation (tiotropium: 23.09, control: 17.47 months; p < 0.0001) and health status (tiotropium vs. control: minus 2.7 - 4 units; p < 0.0001) in the tiotropium group.  CONCLUSIONS: The results of this subgroup analysis support current guideline recommendations and indicate that already patients with moderate COPD (GOLD stage II) benefit clinically from treatment with tiotropium.

Transgenic mouse model of stunned myocardium.

Stunned myocardium is a syndrome of reversible contractile failure that frequently complicates coronary artery disease. Cardiac excitation is uncoupled from contraction at the level of the myofilaments. Selective proteolysis of the thin filament protein troponin I has been correlated with stunned myocardium. Here, transgenic mice expressing the major degradation product of troponin I (TnI1-193) in the heart were found to develop ventricular dilatation, diminished contractility, and reduced myofilament calcium responsiveness, recapitulating the phenotype of stunned myocardium. Proteolysis of troponin I also occurs in ischemic human cardiac muscle. Thus, troponin I proteolysis underlies the pathogenesis of a common acquired form of heart failure.

Automated classification of celiac disease during upper endoscopy: Status quo and quo vadis.

A large amount of digital image material is routinely captured during esophagogastroduodenoscopies but, for the most part, is not used for confirming the diagnosis process of celiac disease which is primarily based on histological examination of biopsies. Recently, considerable effort has been undertaken to make use of image material by developing semi- or fully-automated systems to improve the diagnostic workup. Recently, focus was especially laid on developing state-of-the-art deep learning architectures, exploiting the endoscopist's expert knowledge and on making systems fully automated and thereby completely observer independent. In this work, we summarize recent trends in the field of computer-aided celiac disease diagnosis based on upper endoscopy and discuss about recent progress, remaining challenges, limitations currently prohibiting a deployment in clinical practice and future efforts to tackle them.

The functional effect of adenoviral Na+/Ca2+ exchanger overexpression in rabbit myocytes depends on the activity of the Na+/K+-ATPase.

OBJECTIVES: The functional consequences of Na+/Ca2+ exchanger (NCX) overexpression in heart failure have been controversially discussed. NCX function strongly depends on intracellular sodium which has been shown to be increased in heart failure. METHODS AND RESULTS: We investigated the Na+/K+-ATPase (NKA) inhibitor ouabain (0.5-16 micromol/l) in electrically stimulated, isotonically contracting adult rabbit cardiocytes overexpressing NCX after adenoviral gene transfer (Ad-NCX-GFP, 48 h culture time). Myocytes transfected with adenovirus encoding for green fluorescent protein (Ad-GFP) served as a control. Contractions were analyzed by video-edge detection. In the Ad-NCX-GFP group, the maximum inotropic response was significantly reduced by 50.7% (P<0.05). This was a result of an enhanced susceptibility to contracture after exposure to the drug (median concentration (25-75%): 4 (4-8) vs. 8 (6-16) micromol/l, P<0.05). When analyzing relaxation before contracture, the maximum relaxation velocity was reduced (0.15+/-0.04 vs. 0.27+/-0.04 microm/s, P<0.05) and the time from peak shortening to 90% of relaxation was increased (298+/-39 vs. 185+/-15 ms, P<0.05). No differences in systolic and diastolic parameters were observed with the Na+ channel modulator BDF9198 (1 micromol/l). CONCLUSIONS: Inhibition of NKA by ouabain induces a combined diastolic and systolic dysfunction in NCX overexpressing rabbit myocytes. This may be the consequence of cytoplasmic Ca2+ overload due to inhibition of forward mode or induction of reverse mode Na+/Ca2+ exchange. In end-stage failing human myocardium and during digitalis treatment this mechanism may be of major importance.

Peptide competition of actin activation of myosin-subfragment 1 ATPase by an amino terminal actin fragment.

The amino-terminal region of actin participates in the binding of myosin subfragment 1 (S1) during cross-bridge cycling, thereby assisting in the activation of the magnesium-dependent myosin ATPase. Effects of three actin fragments on the magnesium-dependent S1 and acto-S1 ATPase activities in solution were studied. One of the peptides, containing residues actin 1-44, mimicked the S1 ATPase-activating properties of actin and in turn inhibited acto-S1 ATPase both in a concentration-dependent manner. This suggests peptide competition for the actin binding site on myosin. The other fragments, residues actin 1-18 and 82-119, respectively, had no detectable effect on S1- and acto-S1 ATPase activity.

FK506 does not affect cardiac contractility and adrenergic response in vitro.

FK506 (tacrolimus) is a new immunosuppressant being used in cardiac allograft transplantation. While cyclosporine A has been shown to exert an acute negative inotropic effect on isolated heart muscle preparations, little is known of the inotropic influence of FK506. The Ca(2+) release channel of human skeletal muscle and cardiac muscle is associated with FK506 binding proteins (FKBP), FKBP12 and FKBP12.6, respectively. FKBPs can be dissociated by treatment with FK506. As a consequence of FK506 exposure, isolated skeletal muscle and cardiac muscle ryanodine receptors show altered gating characteristics. Therefore, we analyzed the direct inotropic effect of FK506 exposure to isolated, intact heart muscle preparations from the human and rabbits. Experiments were performed on isolated, electrically stimulated right atrial auricular muscle strips obtained from human myocardium during elective open heart surgery and on intact right ventricular trabeculae from rabbit hearts. The human preparations were exposed to concentrations of 8 x 10(-9), 8 x 10(-8) and 8 x 10(-6) M FK506 followed by a cumulative dose-response curve with isoprenaline as a non-selective beta-adrenoceptor agonist. Our data suggest that FK506 does not exert any positive or negative inotropic effect in either human or rabbit myocardium.

Arthrichitin. A New Cell Wall Active Metabolite from Arthrinium phaeospermum.

Arthrichitin (1), C(33)H(46)N(4)O(9), is a new cell wall active depsipeptide isolated from the fermentation broth of Arthrinium phaeospermum (HIL Y-903022). Its structure was elucidated on the basis of spectroscopic and chemical degradation studies. Arthrichitin consists of serine, beta-keto tryptophan, glutamic acid, and 2,4-dimethyl-3-hydroxydodecanoic acid units.

Mulundocandin, a new lipopeptide antibiotic. II. Structure elucidation.

The structure of a new antifungal antibiotic, mulundocandin, C48H77N7O16, was elucidated by high field NMR experiments e.g., homo- and heteronuclear correlation spectra, distortionless enhancement by polarization transfer (DEPT) spectra as well as nuclear Overhauser effect. The compound is a lipopeptide antibiotic belonging to the echinocandin class.

Friulimicins: novel lipopeptide antibiotics with peptidoglycan synthesis inhibiting activity from Actinoplanes friuliensis sp. nov. II. Isolation and structural characterization.

Four novel lipopeptide antibiotics, friulimicins A, B, C, and D, were isolated from cultures of Actinoplanes friuliensis HAG 010964 after fermentation in different nutrient media. The new compounds were separated by ion-exchange chromatography from the acidic lipopeptides of the amphomycin type also present in the culture fluid, compounds A-1437 A, B, E, and G. The principal constituent friulimicin B, C59H94N14O19, was structurally characterized by mass spectrometric investigations of its hydrolysis and partial degradation products and by sequencing of the cyclic acyl peptide. The NMR data of friulimycin B and the amphomycin constituent A-1437 B were completely assigned by a variety of 2-D experiments, and confirmed the structures determined by mass spectrometry. All 8 lipopeptides possess an identical peptide macrocycle as their central element, linked via a diaminobutyric acid N-terminal either to an acylated asparagine residue or, in the case of the amphomycin series, to an acylated aspartic acid residue. The structures of the amphomycins have now been revised to take account of the peptide framework described herein and the determined cis-configuration of the exocyclic double bond. As a consequence of their higher isoelectric points, the new compounds friulimicin A, B, C, and D have different properties than the amphomycins.

Memnopeptide A, a novel terpene peptide from Memnoniella with an activating effect on SERCA2.

The terpene peptide memnopeptide A (1), C76H108N16O18S, MW 1564, was isolated from a culture of the fungus Memnoniella echinata FH 2272 on casein peptone. The structure of the novel compound was elucidated with the aid of 2D NMR experiments and from amino acid analysis and mass spectrometric sequencing of the peptide. The compound consists of a known phenylspirodrimane subunit linked to the decapeptide Met-His-Gln-Pro-His-Gln-Pro-Leu-Pro-Pro. This proline-rich peptide is a subsequence of beta-casein. From the observed absence in the literature of any other highly significant sequence homologues, memnopeptide A can be assumed to arise from metabolic products of the fungus with direct incorporation of constituents of the nutrient medium. The formation of memnopeptide A suggests this may be a mechanism for storage of amines by the fungus. Memnopeptide A has weak antibacterial activity against gram-positive bacteria and effects half-maximal activation of sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2) at a concentration of 12.5 microM.

Mersacidin, a new antibiotic from Bacillus. Fermentation, isolation, purification and chemical characterization.

Mersacidin (1) is a new peptide antibiotic containing beta-methyllanthionine. It is classified as a member of the proposed lantibiotic group of antibiotics, and is produced by a species of Bacillus. Mersacidin has a molecular weight of 1,824 (C80H120N20O21S4). The antibiotic is active against Gram-positive organisms including methicillin-resistant Staphylococcus aureus, but has no activity against Gram-negative bacteria or fungi.

Kodaistatins, novel inhibitors of glucose-6-phosphate translocase T1 from Aspergillus terreus thom DSM 11247. Isolation and structural elucidation.

Two novel compounds, kodaistatin A, C35H34O11, molecular weight 630, and kodaistatin C, C35H34O12, molecular weight 646, have been isolated from cultures of Aspergillus terreus Thom DSM 11247 by solid-phase extraction, size-exclusion chromatography, and various preparative HPLC steps. The use of a range of 2D NMR measurements, in particular 13C-13C correlation measurements, has led to the clarification of the structure of kodaistatin A. Kodaistatin C is a hydroxylated derivative of kodaistatin A. Both natural products contain hydroxylated aspulvinones and identical highly substituted polyketide units. An X-ray single crystal structure analysis of aspulvinon E demonstrated the z-configuration at the central double bond. The kodaistatins are effective inhibitors of the glucose-6-phosphate translocase component of the glucose-6-phosphatase system (EC 3.1.3.9), an enzyme system which is important for the control of blood glucose levels. The IC50 is 80 nM for kodaistatin A and 130 nM for kodaistatin C.

Aranorosin, a novel antibiotic from Pseudoarachniotus roseus. II. Structure elucidation.

Aranorosin, a new antifungal antibiotic, has been isolated from the culture filtrate and mycelium of a strain of Pseudoarachniotus roseus Kuehn. The antibiotic, C23H33NO6, contains a novel 1-oxaspiro[4,5]decane ring system. The structure (I) has been elucidated on the basis of spectroscopic and chemical analysis.

Deoxymulundocandin--a new echinocandin type antifungal antibiotic.

A new echinocandin type antifungal antibiotic, deoxymulundocandin, C48H77N7O15, was isolated from the culture filtrate and mycelia of a fungal culture, Aspergillus sydowii (Bainier and Sartory) Thom and Church var. nov. mulundensis Roy (Culture No. Y-30462). The structure was established by comparative GC-MS analyses of the derivatized acid hydrolysates of deoxymulundocandin and mulundocandin as well as by the high field NMR experiments (COSY, NOESY and DEPT).

Swalpamycin, a new macrolide antibiotic. II. Structure elucidation.

A new antibiotic swalpamycin (1) has been isolated from the culture broth of Streptomyces sp. Y-84,30967. The antibiotic has the molecular formula of C37H56O14 and belongs to the class of 16-membered neutral macrolide antibiotics. Its structure has been elucidated by an analysis of its spectral properties. It contains a novel aglycone herein called swalpanolide.

Ala(0)-actagardine, a new lantibiotic from cultures of Actinoplanes liguriae ATCC 31048.

The actagardine-producing strain Actinoplanes liguriae ATCC 31048, forms an additional lantibiotic when it is cultured on mannitol and soya meal. The new compound, Ala(0)-actagardine (1), has been isolated by solid-phase extraction followed by a two-step chromatographic separation. The molecular formula of 1 is C84H129N21O25S4. Its chemical structure was determined by 2D-NMR analysis and was further confirmed by an amino acid analysis, Edman degradation, and partial synthesis from actagardine. 1 exhibits a slightly higher biological activity than the parent compound actagardine. The synthetic analogs Lys(0)-actagardine (2) and Ile(0)-actagardine (3) demonstrate also antibacterial activities and emphasize the importance of the N-terminus for further derivatization.