Structure of eukaryotic RNA polymerases.

The eukaryotic RNA polymerases Pol I, Pol II, and Pol III are the central multiprotein machines that synthesize ribosomal, messenger, and transfer RNA, respectively. Here we provide a catalog of available structural information for these three enzymes. Most structural data have been accumulated for Pol II and its functional complexes. These studies have provided insights into many aspects of the transcription mechanism, including initiation at promoter DNA, elongation of the mRNA chain, tunability of the polymerase active site, which supports RNA synthesis and cleavage, and the response of Pol II to DNA lesions. Detailed structural studies of Pol I and Pol III were reported recently and showed that the active center region and core enzymes are similar to Pol II and that strong structural differences on the surfaces account for gene class-specific functions.

Impact of vasoactive intestinal polypeptide and gastrin-releasing peptide on small bowel microcirculation and mucosal injury after hepatic ischemia/reperfusion in rats.

BACKGROUND AND AIMS: Alterations in microvascular perfusion of the intestine after hepatic ischemia/reperfusion have been suggested as an important cause of postoperative septic complications. We therefore investigated small bowel microcirculation and mucosal injury after liver ischemia/reperfusion in a rat model. Furthermore, we analyzed the effects of the regulatory peptides vasoactive intestinal polypeptide and gastrin-releasing peptide for their splanchnic vasoactivity. METHODS: Hepatic ischemia was induced by clamping of the left hepatic artery and vein for 40 min, followed by 60 min of reperfusion. The control group was treated similarly, but without clamping of the liver vessels. Ten minutes after clamping of the hepatic vessels, vasoactive intestinal polypeptide or gastrin-releasing peptide, respectively, were continuously infused intravenously in the experimental groups. Small bowel microcirculation and mucosal injury were assessed using intravital microscopy and the Chiu-score, respectively. RESULTS: The functional capillary density of the small intestine following ischemia and reperfusion of the left hepatic lobe significantly decreased compared to normal controls in both the mucosa and the smooth intestinal muscle. Red blood cell velocity decreased, whereas leukocyte-endothelium adherence, stasis index and the mucosal injury score increased. Administration of vasoactive intestinal polypeptide resulted in an increase of functional capillary density in the mucosa and of the red blood cell velocity and a decrease in the stasis index. The mucosal injury score was significantly higher in reperfused animals without treatment. The application of gastrin-releasing peptide resulted in an isolated increase of the red blood cell velocity. Leukocyte adherences could not be altered by the regulatory peptides. CONCLUSION: We conclude that hepatic ischemia/reperfusion injury leads to significant alterations of small bowel microcirculation and mucosal injury. Vasoactive intestinal polypeptide and gastrin-releasing peptide attenuate the damage in a different manner.

Hormonal modifications in patients admitted to an internal intensive care unit for acute hypoxaemic respiratory failure.

To clarify which endocrine modifications can be observed in acute hypoxaemic respiratory failure, 15 severely ill male patients [PAT; median age: 61 (range: 48 years); median height: 173 (range: 12) cm; median mass: 73 (range 31) kg] were investigated immediately upon admission to an intensive care unit (ICU) for this clinical disorder. Before starting treatment, the blood gases were measured and a number of selected hormones with special relevance for an ICU setting were determined. These are known to be modified by acute hypoxaemia in healthy subjects and to possess glucoregulatory properties, or an influence upon cardiocirculation or the vascular volume regulation: insulin, cortisol, adrenaline, noradrenaline, atrial natriuretic peptide, renin, aldosterone, angiotensin converting enzyme, and endothelin-I (ET). To elucidate whether potential endocrine changes resulted from acute hypoxaemia alone, the underlying disease, or unspecific influences connected with the ICU setting, all measurements were compared to those of a completely healthy reference group (REF) with comparable acute experimental hypoxaemia. The latter state was achieved by having the REF breathe a gas mixture with the oxygen content reduced to 14% (H). In the REF, neither the medians nor the distribution of endocrinologic measurements were modified significantly by acute hypoxaemia. In the PAT, the medians were increased considerably, yet with a slight diminution of ET. The distribution of individual values was considerably broader than in the REF with H. In conclusion, considerable increases in the means of the above hormones, with the exception of ET, can be registered in severely ill patients admitted to ICUs with acute hypoxaemic failure. However, such modifications cannot be considered attributable exclusively to acute arterial hypoxaemia. The underlying clinical disorders, such as septicaemia or an unspecific endocrine epiphenomenon, including severe and not only hypoxaemic stress, seem to be predominant.

[Pathogenesis of idiopathic pulmonary fibrosis]. / Pathogenese der idiopathischen Lungenfibrose.

Idiopathic pulmonary fibrosis or lone cryptogenic fibrosing alveolitis is an interstitial lung disease of unknown origin carrying an unfavorable prognosis. A yet unidentified hazard triggers a chronic inflammatory infiltration of the lung parenchyma characterized by an accumulation of alveolar macrophages, neutrophil and eosinophil granulocytes, and lymphocytes. Cytokines released by the activated cells modulate the inflammatory events. Oxidants and proteases, mainly released by alveolar macrophages and neutrophil granulocytes, mediate the injury to the lung parenchyma, leading to loss of alveolar-capillary units. The ensuing repair process, mesenchymal cell proliferation and up-regulation of synthesis of collagen fibers and other components of connective tissue matrix, replaces lung parenchyma by fibrotic tissue, leading to irreversible pulmonary dysfunction.

[Differential diagnostic significance of complex values of gas exchange during submaximal physical effort in patients with emphysema and pulmonary fibrosis]. / Zur differentialdiagnostischen Bedeutung von komplexen Kenngrössen des Gasaustauschs während submaximaler Körperarbeit bei Patienten mit Emphysem und Lungenfibrose.

The aim of this study was to clarify a) whether the behaviour of functional dead space ratio (VD/VE), alveolo-arterial difference of oxygen tensions (AaDO2) and the venous admixture ratio (QVA/Qt) differed at rest and during submaximal exercise, between patients with pulmonary emphysema and interstitial pulmonary fibrosis as well as from the respective findings in healthy controls, and b) whether a differentiation between these two diseases could be achieved by investigations of complex pulmonary gas exchange. Eleven patients with pulmonary fibrosis (F), which had been diagnosed by pulmonary biopsies, 11 patients with pulmonary emphysema (E) and 11 healthy controls (C) were subjected to conventional pulmonary function tests (PFTs: spirometry, bodyplethysmography, DCO) immediately followed by examinations of pulmonary gas exchange conducted at rest and during an incremental submaximal cycle spiroergometry (ERGO). With normal PFTs for C, vital capacity was diminished in F and the 1" timed vital capacity (FEV1) as well as Tiffeneau's index were reduced in E, while air way resistance and functional residual capacity were augmented in the latter group. In all patients the CO-diffusing capacity was lower compared to C, however, without differences between F and E. In both E and F, the arterial O2 tension were lower at rest as well as during ERGO when compared to C, whereas VD/VE, QVA/Qt and AaDO2 as well as the specific ventilation for O2 were higher, respectively. Alveolar ventilation was similar in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental acute hypoxia in healthy subjects: evaluation of systolic and diastolic function of the left ventricle at rest and during exercise using echocardiography.

To clarify whether or not systolic and diastolic function of the human left ventricle (LV) were decreased during acute hypoxia, at rest and with exercise, 14 healthy male volunteers [age 25.9 (SD 3.0) years, height 182.9 (SD 7.1) cm, body mass 75.9 (SD 6.9)kg] were examined using M-mode and 2D-mode echocardiography to determine the systolic LV function as well as Doppler-echocardiography for the assessment of diastolic LV function on 2 separate test days. In random order, the subjects breathed either air on 1 day (N) or a gas mixture with reduced oxygen content on the other (H; oxygen fraction in inspired gas 0.14). Measurements on either day were made at rest, several times during incremental cycle exercise in a supine position (6-min increments of 50 W, maximal load 150 W) and in 6th min of recovery. Corresponding measurements during N and H were compared statistically. Arterial O2 tension (PaO2) was normal on N-day. All subjects showed a marked acute hypoxia at rest [PaO2, 54.5 (SD 4.6) mmHg], during exercise and recovery on H-day. The latter was associated with tachycardia compared to N-day. All echocardiographic measurements at rest were within the limits of normal values on both test days. Ejection time, end-systolic and end-diastolic left ventricular dimensions as well as the thickness of left posterior wall and of interventricular septum showed no statistically significant influence of H either at rest or during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo assessment of pulmonary oxidant damage: the role of bronchoalveolar lavage.

Oxidants can cause injury and cell death by modifying and/or disturbing the structure and function of any cellular or non-cellular component. There is overwhelming evidence that a variety of lung disorders are mediated, at least in part, by oxidants causing tissue damage, especially since its location, anatomy, and function makes the lung a primary target for oxidant injury. Bronchoalveolar lavage (BAL) is an excellent tool to evaluate these mechanisms in vivo. BAL allows the repetitive sampling of the cellular and non-cellular components of the fluid lining the epithelium of the lower respiratory tract with minimal risk and discomfort for the patient. The analysis of cell numbers, differential cell counts, cellular functions, and concentrations and functional properties of non-cellular components of BAL fluid continuously improves our understanding of the pathogenesis of lung diseases and of the pathogenetic role of oxidants and antioxidants in particular, by "looking into the living lungs." Further, the ready access of the respiratory epithelial surface by BAL provides opportunities to evaluate and monitor therapeutic strategies directed at reducing the oxidant burden and/or augmenting the antioxidant defense mechanisms in the lower respiratory tract, thereby correcting an oxidant-antioxidant imbalance directly at the site of disease.

[Long-term follow-up of pulmonary emphysema]. / Langzeitverläufe bei Lungenemphysem.

Definition of lung emphysema is based on morphologic criteria (irreversible destruction of alveolar space). In advanced stages of the disease, emphysema may be suspected clinically, by lung auscultation, lung function tests, and radiology. In early stages, there are characteristic functional findings, such as an irreversible decrease in forced expiratory volumes or flows. These simple tests are easily available. In this article, the natural course of lung emphysema is described, based on long term changes in lung function. The typical discrepancy between normal airway resistance and a decrease in FEV1 allows suspicion of early emphysema. In the further development of emphysema, an increase of airway resistance together with hypercapnia indicates severe functional disturbances and cor pulmonale.

Quantitative skin prick and bronchial provocation tests with platinum salt.

Occupational asthma due to platinum salts is a frequent disease in platinum refineries. The diagnosis is based upon a history of work related symptoms and a positive skin prick test with platinum salts. Bronchial provocation tests have not been performed in epidemiological studies because the skin test is believed to be highly specific and sensitive. As no reliable data about this issue currently exist, this study assesses the use of skin prick and bronchial provocation tests with methacholine and platinum salt in platinum refinery workers. Twenty seven of 35 workers, who were referred to our clinic with work related symptoms and nine control subjects with bronchial hyperreactivity underwent a skin prick test and bronchial provocation with methacholine and platinum salt. For skin prick and bronchial provocation tests with platinum salt a 10(-2)-10(-8) mol/l hexachloroplatinic acid solution, in 10-fold dilutions was used. Four of the 27 subjects and all controls showed neither a bronchial reaction nor a skin reaction. Twenty three subjects were considered allergic to platinum salt; 22 of these showed a fall of 50% or more in specific airway conductance after inhalation of the platinum salt solution. Four workers experienced a positive bronchial reaction despite a negative skin prick test. No correlation of responsiveness to methacholine with responsiveness to platinum salt was found, but the skin prick test correlated with the bronchial reaction to platinum salt (rs = 0.50, p less than 0.023, n = 22). One dual reaction was seen in bronchial provocation tests. Side effects of both skin tests and bronchial provocation tests with platinum salt were rare and were not encountered in workers without a skin reaction to platinum salt. It is concluded that bronchial provocation tests with platinum salts should be performed on workers with work related symptoms but negative skin tests with platinum salts.

[The status of pneumonology in German medicine at present]. / Der Stellenwert der Pneumologie in der deutschen Medizin der Gegenwart.

The status and ranking of pneumology in Germany is discussed in relation to the historical development, the current structure, the performance and the future tasks of this discipline. Obvious deficiencies are listed. It is concluded that pneumology is a fundamental part of internal medicine. Sufficient possibilities to specialize in pneumology are missing, and the representation of the discipline at university level is inadequate. Research aspects are not discussed.

[Para-pleural lung lesions: diagnostic value of sonography versus computerized tomography]. / Pleuranahe Lungenprozesse: Diagnostische Wertigkeit Sonographie versus Computertomographie (CT).

UNLABELLED: 45 patients with pleural and/or peripheral lung lesions detected by chest radiography were examined by chest ultrasound. A chest CT-scan was obtained as a reference method afterwards. In 43 pleural or peripheral lung lesions we found corresponding results comparing size, invasivity and nature comparing the two diagnostic methods. In 35 of 41 cases an ultrasound (US)-guided needle biopsy confirmed the preliminary diagnosis suspected after sonography of the chest. Six needle biopsies allowed no definite diagnosis. Two patients developed a pneumothorax that required drainage after US-guided needle biopsy. CONCLUSION: Real-time sonography of the chest and chest CT-scans are complementary methods examining pleural and peripheral lung lesions, corresponding results are demonstrated in respect of location, size, invasivity and nature of the lesions.

[Drug-induced disseminated lung diseases]. / Arzneimittelverursachte disseminierte Lungenerkrankungen.

Disseminated pulmonary diseases sensu stricto are interstitial lung disorders, pulmonary edema, diffuse pulmonary bleeding as well as bronchiolitis obliterans and thrombo-embolic disorders. Three important pathogenetic mechanisms are direct toxicity, allergy/immunology and idiosyncrasy; however, unfrequently essential elements of pathogenesis are unknown. The multitude of potential noxious agents implies that the clinician principally has to consider the possibility of drug-toxicity in all cases of disseminated pulmonary diseases. In order to give a complete presentation summaries organized as tables could not be avoid. The most sensible measure for disseminated lung diseases is the functional parameter DLCO; it is more sensible than the conventional X-ray. The drug of choice for a treatment are corticosteroids.

[Salazosulfapyridine-induced eosinophilic pneumonia with pulmonary and cutaneous epithelioid cell granulomatosis in Sjögren syndrome]. / Salazosulfapyridin-induzierte eosinophile Pneumonie mit pulmonaler und kutaner epitheloidzellige Granulomatose bei Sjögren-Syndrom.

A 68-year old woman suffering from Sjögren's syndrome for the last 30 years took sulphasalazine (SSP) for severe signs and symptoms at the joints. Soon after the start of this medication she developed progressive cough and shortness of breath. After two years she was referred for evaluation of a hemoptysis and a reddish skin lesion. The chest radiograph showed wide spread interstitial infiltrates in the lower lobes and some fibrotic changes. FVC was slightly reduced, DLCO markedly reduced. There was a high percentage of eosinophils in the bronchoalveolar lavage (55.2%). Transbronchial lung biopsy and skin biopsy demonstrated epitheloid granulomata. SSP was discontinued. After a short period of prednisone treatment the patient's condition improved considerably. After two months of followup neither pulmonary infiltrates nor any skin lesions were found. History and the clinical course after discontinuation of SSP indicate the relation of these infiltrates to SSP treatment. The previously published case reports of SSP-related lung disorders are reviewed. Three of these case reports included bronchoalveolar lavage. Our data suggest that patients with SSP related pulmonary infiltrates may have a marked increase of eosinophils in the bronchoalveolar lavage fluid.

[Quantitative skin test and inhalation provocation test in asthma using platinum salts]. / Quantitativer Hauttest und inhalativer Provokationstest bei Asthma durch Platinsalze.

In this article, the in vivo test results obtained from workers of two platinum separating plants are described. A total of 30 out of 102 workers in two platinum separating plants and 0/40 control subjects showed a positive skin reaction on being provoked with platinum compounds. Twelve out of 15 workers and none of 5 control subjects showed a positive reaction to the bronchial provocation test; this indicates that both tests are highly specific. Three workers with negative skin test reactions showed a clearly positive immediate reaction to the bronchial provocation test with platinum compounds.

[Results of a questionnaire survey of pulmonary complaints of dental technicians: effect of the duration of occupational activity (total exposure time)]. / Ergebnisse einer Fragebogenerhebung zu pulmonalen Beschwerden von Zahntechnikern: Einfluss der beruflichen Tätigkeitsdauer (Gesamt-Expositionszeit).

UNLABELLED: With the aid of a questionnaire survey conducted among 3,415 dental laboratories in Hesse and North Rhine Westphalia, the incidence of pulmonary symptoms among dental technicians, and their relationship to dust (exposure time: ET) was established. A total of 5,100 questionnaires were evaluable. The median age of the participants was 29 years, the ET 8 years. A total of 49.1% smoked cigarettes, 15.8% were ex-smokers, and 38% non-smokers. SYMPTOMS: 33.9% had unproductive cough, 25.4% experienced dyspnoea on effort, 18.9% had a productive cough, 5.7% episodic apnoea, 5.2% apnoea with audible wheezing, 3.6% apnoea at rest. In order to eliminate the "overlapping" influence of smoking habits, age and sex, in a matched-pair analysis, a comparison of short exposure time groups (SET: ET less than 5 years), and long exposure time groups (LET: ET greater than or equal to 5 years) was made for each symptom. The median ET for all SET was 3 (range: 0-4); for all LET 10 (range: 5-40) years. The frequency of the symptoms was generally greater in the LET group than in the sET group. Statistically significant differences were found for unproductive cough, productive cough, apnoea of effort, and episodic dyspnoea. No differences were found for apnoea at rest and dyspnoea with audible wheezing. Since such confounding factors as sex, age and smoking habits were excluded, our results point to a causal relationship between the pulmonary symptoms of dental technicians and occupational exposure to dust in the dental laboratory. These results are supported by the results of clinical and radiological study.

[Clinical aspects and diagnosis of chronic berylliosis--a case report]. / Klinik und Diagnostik der chronischen Berylliose--Eine Kasuistik.

Three case reports of patients with chronic berylliosis are presented. The examination findings of these three cases are all unspecific. Merely the lymphocyte transformation test (LTT), which has, in the meantime, become an established procedure, is capable of demonstrating, at a high level of sensitivity and specificity, the presence of sensitisation towards beryllium, a condition that accompanies the disease itself. All three patients showed a positive LTT. A modification of the diagnostic criteria worked out by Sprince, is proposed, which takes into account the LTT performed in blood and bronchoalveolar fluid.