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Background Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab—a human IgG1 VEGFR-2 antagonist—or placebo in this patient population. Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125. Findings Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96–4·47] vs 2·76 months [2·60–2·96]; hazard ratio [HR] 0·757, 95% CI 0·607–0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8–30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4–18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1–2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab. Interpretation To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma. Funding Eli Lilly and Company. © 2017 Elsevier Ltd

Due to its high prevalence in patients with heart failure and its negative predictive value concerning morbidity and mortality, Cheyne-Stokes respiration (CSR) is a sleep disorders of major interest. CSR correlates with the degree of heart failure and is characterised by a typical crescendo/decrescendo breathing pattern combined with phases of central sleep apnoea, caused by pulmonary oedema and oscillation of ventilatory control. Thus, CSR is a marker of the severity of heart failure. Treatment of CSR first involves optimisation of heart failure therapy by cardiologists and then application of non-invasive means of ventilatory support. Treatment of patients with severe heart failure with non-invasive positive pressure ventilatory support leads to a significant reduction of CSR, sympathetic activity, and daytime sleepiness and improves cardiac output and 6-minute walking distance. At present, a prospective randomised, controlled intervention-study (Serve-HF study) is being conducted in order to show if therapy of CSR can improve patient survival. This review describes the pathophysiology, epidemiology, and therapeutic options of CSR with a special focus on the elevated cardiovascular risk of patients with CSR.

Within 30 months the diagnosis of drug-induced acute interstitial nephritis was made in ten patients with acute onset of renal failure of clinically unknown cause. Allergenic substances were discovered to be antibiotics, pyrazol and indol derivatives, piromidic acid and chlorazanil. In contrast to the known course of methicillin nephritis the clinical signs were undramatic. Non-oliguric renal failure predominated, sometimes with leucocyturia, microhaematuria and moderate proteinuria. Intermittent haemodialysis was necessary in half the cases. Renal function developed favourably without further specific treatment, however, plasma creatinine did not return to normal levels in most cases. Percutaneous renal biopsy was the definitive diagnostic step. Indications for biopsy in cases of unclear acute renal failure should thus be handled liberally in order to prevent continued drug exposure with the danger of irreversible renal failure.

Sojourns in the high mountains have been recommended to patients with asthma for many decades. It is the aim of this contribution to summarise the published studies about the effects of a stay at > 1500 m above sea level on asthmatic patients. These data from 428 adolescent and adult patients indicate an improvement of asthma symptoms and lung function during sojourns at high altitude. In many patients a reduction of the steroid therapy was achievable. Profound changes in the immune system have been demonstrated at high altitude, with a reduction of B- and T-helper cell activation. Total and mite-specific immunoglobulin E antibodies decrease significantly during longer sojourns. These changes are associated with a reduction of airway inflammation (e. g., reduction of eosinophil activation, NO exhalation and bronchial hyper-responsiveness). The fact that also patients with non-allergic asthma demonstrate a reduction of their airway inflammation at high altitude suggests that the high altitude climate has beneficial effects on asthma beyond the effects of allergen avoidance. High UV exposure and low humidity could be important additional factors, to explain the reductions in asthma severity in the high mountain climate. Larger controlled studies should be performed to prove the positive effects of the high altitude climate on asthma.

Anti-IgE (omalizumab) reduces the allergic airway inflammation by binding of circulating, free immunoglobulin E. This leads to a significant improvement of allergic asthma. Seven Phase III studies in juveniles and adults demonstrate that omalizumab offers an effective and safe, new therapeutic option in the treatment of severe persistent asthma, not sufficiently controlled by standard therapy according to recent guidelines. It appears that even with regard to cost-effectiveness omalizumab could be a valuable new therapeutic option in severe persistent asthma, providing a significant reduction of asthma symptoms, asthma medication, rate of asthma exacerbations and emergency treatment, and improvement of asthma-related quality of life. Severe adverse effects are very rare.

Background and objective N-acetylcysteine (NAC) is known to have direct antioxidant properties due to its thiol-group on the one hand as well as indirect antioxidant capacity as cysteine-donor to cellular glutathione-synthesis on the other hand. Therefore NAC appears to be attractive in antioxidant therapy of inflammatory disorders of the lung. This study aimed to investigate the use of antioxidant therapy with NAC in chronic bronchitis. Patients and methods In this randomized, double-blinded and placebo-controlled trial 100 patients divided into four groups were observed over a period of 3 months. The treatment consisted of either 600 mg NAC bid, 500 mg Vitamin C bid, a combination of those two substances using the same dosage or a placebo-preparation. The release of reactive oxygen species from isolated neutrophilic granulocytes and mononuclear cells was quantified before treatment and after three months using chemiluminescence (primary outcome parameter). Furthermore cellular glutathione content of these inflammatory cells was quantified spectrometrically. In addition, leukocyte-count and erythrocyte sedimentation rate as well as spirometry and a standardized symptom-based questionnaire were used to monitor the clinical efficacy. Results None of the above substances were able to significantly reduce the release of reactive oxygen species from the examined population of inflammatory cells. They also failed to increase intracellular glutathione-levels. Concordantly, no changes in spirometry and the results of the symptom-based questionnaire were found. Conclusion In summary NAC, Vitamin C and the NAC/ Vitamin C-combination did neither enhance antioxidant protection in the blood nor is it of any clinical benefit in chronic bronchitis. Possible reasons may be a lack of antioxidant deficiency in these patients and negative feedback mechanisms of the glutathione-system.

Zusammenfassung Virale Atemwegsinfektionen stellen die größte infektiöse Einzelursache für pulmonale Morbidität dar. Berufliche Ausfallzeiten und daraus folgende Krankenhausaufenthalte tragen erheblich zu den Kosten der Gesundheitsfürsorge bei. Rhinoviren, Influenzavirus A und B, Adenoviren, Parainfluenza, RSV und Coronaviren sind die häufigsten auslösenden Agenzien in diesem Zusammenhang. Trotz dieser enormen Bedeutung ist eine Therapie der virusbedingten Atemwegsinfektionen nur in einem geringen Teil der Infektionen möglich. Einen erheblichen Fortschritt in diesem Zusammenhang hat die Einführung der Neuraminidaseinhibitoren gebracht, die zumindest mit einer Verkürzung der Symptomdauer bei Influenza assoziiert sind. Unter den zur Zeit verfügbaren antiviral wirksamen Substanzen, stellen die Neuraminidasehemmer jedoch nur einen kleinen Teil dar. Im vorliegenden Artikel werden daher die aktuell oder in Kürze verfügbaren Substanzen mit ihrem Wirkmechanismus und dem Stand der klinischen Forschung dargestellt.

Diseases of the upper and lower respiratory tract are often combined in daily practice requiring compelling concepts in both diagnosis and therapy. The following paper covers epidemiologic studies on the concomitant onsetof rhinitis, sinusitis and asthma with special focus on predisposition and prognostic value. Based on anatomic considerations various aspects of the mutual influence of the lower and upper respiratory tract system concerning the pathogenetic mechanisms are described including neurogenic actions, the aerogenic transmission and overlapping effects of mediators and inflammatory cells. In the clinical point of view special emphasize is laid on different therapeutic options for their effect on rhinitis and asthma symptoms such as rhinitis and sinusitis therapy, specific immunotherapy, leucotriene antagonists, and functional endonasal sinus surgery.

The evolution of the health care marketplace in the nineties in Southern California is described, including the dominance of managed care at the decade's end. The marketplace, especially in Los Angeles, is now one of the most complex, competitive, and challenging medical marketplaces in the country. The University of California, Los Angeles (UCLA) Medical Center and the academic health center of which it is a part have had to respond appropriately and vigorously to survive and to position themselves for the future. This article focuses on the responses of the medical center to these marketplace pressures. The center has recognized single-signature contracting, cost containment, and an emphasis on ambulatory care as fundamental success factors for survival in a complex, organized managed care environment. Data on the medical, financial, and educational performances of the medical center are presented in terms of its responses to the marketplace. Preliminary information about quality of care is presented for three patient-population groups that have been heavily affected by managed care. The need for emphasis on quality and service for future success and the attendant need for emphasis on information systems are discussed. The importance of fundamental understanding of markets is also reviewed. The concomitant approaches to securing the center's academic missions are described, including changes in institutional governance for the entire health sciences center of which the medical center is a part and the establishment of priorities in research, clinical care, and teaching programs, especially teaching programs in primary care.

Das Asthma bronchiale gehort zu den haufigsten chronischen Krankheiten mit einer Pravalenz von 5% im Erwachsenenalter und 10% im Kindesalter. Die bislang nicht geklarten Ursachen der Haufigkeitszunahme des Asthma bronchiale sind Gegenstand einer breit angelegten internationalen Forschung. Die Asthmamortalitat ist trotz therapeutischer Fortschritte unverandert ein bedeutendes Problem. Umso wichtiger sind Verbesserungen des Therapiestandards dieser Erkrankung. 1998 veroffentlichte die Deutsche Atemwegsliga ihre „Empfehlungen zum Asthmamanagement bei Erwachsenen und bei Kindern”, die zur Zeit als aktuelle nationale Therapieempfehlungen zu gelten haben. Fur Erwachsene und Kinder wurden in jeweils 4-stufigen Schemata Empfehlungen fur die medikamentose Therapie der unterschiedlichen Asthmaschweregrade vorgelegt. Daruber hinaus wurden Empfehlungen fur die Therapie im Sauglingsalter, fur die Schulung und Selbstbehandlung, fur geeignete Inhalationssysteme in den unterschiedlichen Altersstufen sowie fur die Behandlung des schweren Asthmaanfalls bei Kindern und bei Erwachsenen gegeben. Diese Ubersicht basiert auf den Therapieempfehlungen der Atemwegsliga und stellt die Fortschritte der Pharmakotherapie des Asthma bronchiale im Erwachsenenalter in den vergangenen Jahren dar.

Diese Ubersicht beschreibt den Stand der Diskussion uber die medikamentose Therapie des Asthma bronchiale beim Erwachsenen. Es liegen zahlreiche nationale und internationale Empfehlungen zur Asthmatherapie bei Erwachsenen vor, die sich im Grundsatz gleichen. Danach sind inhalative Kortikosteroide und langwirksame inhalative Beta-2-Agonisten als Dauertherapie sowie kurzwirksame inhalative Beta-2-Agonisten als Bedarfstherapie Standard der Asthmabehandlung. Die Position der weiteren Antiasthmatika ist weniger gut definiert. Dies gilt sowohl fur die herkommlichen Substanzen, wie Theophyllin, Anticholinergika, Cromoglicinsaure und Nedocromil, als auch fur neuere Entwicklungen, wie Leukotrien-Antagonisten.

A total of 701 adults living in the USA or Western Europe who had symptoms of allergic respiratory disease were skin prick tested with extracts prepared from eight basidiomycetes species and four Fungi Imperfecti species. In these subjects, the presence of asthma, rhinitis, or both was determined by questionnaire. Overall, 178/701 (25.4%) of the participants reacted to at least one basidiomycete extract. There was no difference in the prevalence of reactivity detected in the USA and Europe (P < 0.005); however, the prevalence of reactors in individual centers from both areas varied significantly. Psilocybe cuhensis was the most potent allergen source in both the USA (12.3% reacted) and Europe (16.0%). Pleurotus ostreatus was second overall (10.6%) and in the USA (10.7%), and third in Europe (10.3%). Pisolithus tinctorius and Coprinus quadrifidus produced the least potent allergens, with only 5.4% of the population reacting. There was a significant relationship (P < 0.005) between basidiospore reactivity and the presence of atopy, asthma, and asthma and rhinitis. Basidiospore reactivity was not associated with the presence of rhinitis alone (P= 0.312). These results suggest that basidiomycetes are important sources of aeroallergens in geographically disparate regions and may be particularly important in patients with asthma. Lehrer SB, Hughes JM, Altman LC, Bousquet J, Davies RJ, Gell L, Li J, Lopez M, Mailing HJ, Mathison DA, Sastre J, Schultze-Werninghaus G, Schwartz HJ. Prevalence of basidiomycete allergy in the USA and Europe and its relationship to allergic respiratory symptoms.

Chronic inflammatory processes of the airways induced by long-time cigarette consumption are a crucial factor in the pathogenesis of chronic obstructive pulmonary disease. In contrast, the role of cigarette smoking in the pathogenesis of bronchial hyperreactivity (BHR) is still unclear. The aim of this study was to assess the effect of chronic cigarette consumption on pulmonary function tests and BHR in healthy subjects. 63 healthy smokers and 63 lifetime nonsmokers matched for sex, age, height and weight were evaluated. Pulmonary function was determined by body plethysmography and spirometry. Bronchial provocation was performed by inhalation of increasing doses of carbachol (up to 25 g/l) in isotonic NaCl solution. Pulmonary function tests were within normal limits in all subjects. Nevertheless, midexpiratory flow at 25% of forced vital capacity was significantly smaller, and functional residual capacity was significantly greater in middle-aged smokers (age: 40-60 years) compared to middle-aged nonsmokers (p0.05, both comparisons). In young smokers and nonsmokers (age: 20-30 years) pulmonary function tests were not different (p0.28, all comparisons). Importantly, the carbachol concentration that provoked a 50% rise in specific airway resistance (PD50sRaw) was similar in smokers and nonsmokers of both age groups (p0.05, both comparisons) and did not correlate with the age of the subjects (p0.2). No correlations between baseline values of pulmonary function tests and PD50sRaw were observed (p0.34, all comparisons). The observations confirm that the distribution profile of BHR is unimodal and apparently not affected by age and smoking habits.

Salmonella serology is used for classifying pig herds in risk categories in several national quality programs. Meat juice is used as test matrix in most of these programs. Two studies were done to compare the salmonella ELISA test results from meat juice with blood serum as a reference. Pig blood and meat samples for these studies were collected in one slaughterhouse. ELISA tests were done with a commonly applied commercial test. In the first study paired blood serum and meat juice samples from 182 pigs were collected and tested in two different laboratories. In the second study meat and blood samples were collected from 470 herds, over 20.000 samples for each matrix. The first study showed a linear relation between all matrices, but the OD values in meat juice were significantly lower than in blood serum. To obtain comparable outcomes in serum and meat juice, the blood serum OD%-values had to be reduced with 20 to 40%, depending on the lab that applied the test. This underestimation was confirmed in the second study. When the diagnostic cut off, OD10%, was applied on the blood samples, over 57% of the tested pigs showed antibodies and none of the slaughtered herds had fully negative serology, whereas with meat juice and a cut off at OD40% only 7,5% pigs were positive. It is concluded that meat juice testing for Salmonella antibodies can heavily underestimate the proportion of pigs that have encountered a salmonella infection. Consequently, pigs from herds that are categorised as low risk may be infected with salmonella. These pigs may therefore contaminate the lairage and the slaughter line. Monitoring results based on blood serology can not be compared with results based on meat juice, without taking care of the observed differences.

The paper deals with the behaviour of parameters of wood rays over stem's transverse section as to be found in selected publications as well as in their continuance over the stem length according to own additional investigations. Considered are height, number and portion of uniseriate rays in peripherical wood of the mature tree species Pinus silvestris L., Picea abies, (L.) KARST., Pseudotsuga menziesii (MIRB.) FRANCO, Larix deciduaMILL., and Taxodium distichumRICH. With increasing tree height ray height decreases, number of rays more or less increases, and ray portion decreases only with Pinus silvestris and Picea abies. Die Arbeit beschaftigt sich sowohl mit dem Verhalten von Holzstrahlparametern uber dem Stammquerschnitt, wie es aus ausgewahltem Schrifttum zu entnehmen war, als auch mit ihrer Verfolgung uber die Stammhohe gemas eigenen zusatzlichen Untersuchungen. Betrachtet werden die Hohe, die Anzahl und der Anteil einreihiger Strahlen an peripherem Holz erwachsener Baume der Arten Pinus silvestris L., Picea abies (L.) KARST., Pseudotsuga menziesii (MIRB.) FRANCO, Larix deciduaMILL. und Taxodium distichumRICH. Mit steigender Baumhohe nimmt die Strahlhohe ab, die Strahlenanzahl mehr oder weniger zu und der Strahlenanteil nur bei Pinus silvestris und Picea abies ab.

A 73-year-old female patient was admitted to our clinic for further clarification of a suspicious mediastinal lesion. Endosonographically, we performed a fine-needle aspiration biopsy. Clinical and radiological findings as well as cytology hardened the suspicion of a paraganglioma as being the cause of the mediastinal lesion. Finally, this diagnosis was confirmed histologically after complete surgical resection of the lesion. This case report on a mediastinal paraganglioma includes a concise summary of diagnostic procedures and therapeutic options for this rare disease.

For 130 years transverse dimensions of softwood tracheids have been the subject of study. Selected references show that diameter and wall thickness of the cells have been more thoroughly studied than lumen diameter. An attempt was made to correlate these three anatomical parameters among each of them and with wood density in 15 coniferous tree species and Ginkgo biloba L. In the case of an old Scots pine (Pinus sylvestris L.) it will be emphasized besides juvenile and mature wood the so-called »overmature wood«, by which is assumed its formation being due to symptoms of senescence. Seit uber 130 Jahren sind Querschnittsmessungen von Nadelholz-Tracheiden Gegenstand der Forschung. Die ausgewahlten Schriftumsangaben zeigen, das Durchmesser und Wanddicke der Zellen mehr Beachtung fanden als der Lumen-Durchmesser. Es wurde versucht, fur 15 Nadelbaumarten und Ginkgo biloba L. diese drei Strukturparameter miteinander und mit der Dichte in Beziehung zu setzen. Im Falle einer alten Kiefer (Pinus sylvestris L.) wird neben dem jugendlichen und reifen Holz ein sogenanntes »uberaltes Holz« ausgeschieden. dessen Bildung einer Seneszenzerscheinung zugeschrieben wird.

Scleroderma is a generic term for autoimmunological diseases having thickened sclerotic skin lesions in common. Scleroderma belongs to a group of connective tissue diseases. The systemic form of scleroderma is called progressive systemic sclerosis (PSS) or systemic sclerosis (SSc). Lung impairments, namely interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH), are one of the most common manifestations in SSc. This article summarises the forms of lung impairment in SSc with special emphasis on interstitial lung diseases and draws attention to the so far identified pathogenetic mechanisms and the presently accepted therapeutic options.

Due to its high prevalence in patients with heart failure and its negative predictive value concerning morbidity and mortality, Cheyne-Stokes respiration (CSR) is a sleep disorders of major interest. CSR correlates with the degree of heart failure and is characterised by a typical crescendo/decrescendo breathing pattern combined with phases of central sleep apnoea, caused by pulmonary oedema and oscillation of ventilatory control. Thus, CSR is a marker of the severity of heart failure. Treatment of CSR first involves optimisation of heart failure therapy by cardiologists and then application of non-invasive means of ventilatory support. Treatment of patients with severe heart failure with non-invasive positive pressure ventilatory support leads to a significant reduction of CSR, sympathetic activity, and daytime sleepiness and improves cardiac output and 6-minute walking distance. At present, a prospective randomised, controlled intervention-study (Serve-HF study) is being conducted in order to show if therapy of CSR can improve patient survival. This review describes the pathophysiology, epidemiology, and therapeutic options of CSR with a special focus on the elevated cardiovascular risk of patients with CSR.

A standard outcome parameter for pharmacological trials in COPD has not yet been defined. Therefore, it is the aim of this review to evaluate frequently used parameters for their eligibility as assessment and outcome parameters in COPD.A review of the actual scientific literature was performed.It is recommended to continue to rely primarily on the FEV (1), which has been used as a primary variable in the vast majority of trials. In addition, further parameters, such as FVC and IC/TLC should be determined. If available, additional information is provided by RV/TLC, K (co), PaO (2) and PaCO (2). FEV (1) is not a surrogate parameter for dyspnoea, quality of life, and exercise tolerance, which should therefore be assessed separately. Frequency and severity of exacerbations and mortality are important outcome parameters in long-term trials. Complex indices, such as the BODE index, may be superior to single variables.No single additional parameter has been evaluated sufficiently in order to substitute FEV (1) as the standard parameter for the assessment and outcome in COPD.

COPD is a heterogenous disease caused by the interaction of genetic susceptibility and environmental influences. The best example to support this is tobacco smoke. Although cigarette smoking is the most important aetiological factor, only up to half of chronic smokers develop significant COPD. There are three main themes within the pathogenesis of COPD: 1) imbalance between proteases and anti-proteases, 2) oxidative stress, 3) inflammation. Disparity between levels of exogeneous oxidants, e. g., tobacco smoke, and endogeneous antioxidants leads to oxidative stress which, in turn, causes an inflammatory response involving pro-inflammatory mediators. The activated inflammatory cells release further proteases and oxidants, leading to chronic inflammation and irreversible destruction of connective tissue in the lung. Individual genetic variations influence these processes in many ways. This article summarises the results of recent candidate gene studies for COPD.

Respiratory viruses trigger the majority of common colds, acute respiratory illnesses in children during the cold season as well as acute exacerbations of asthma and chronic obstructive pulmonary disease. They also play a role in community acquired pneumonia. Unfortunately their detection is still difficult. The aim of this review is therefore to introduce the methods of detection and to present the current knowledge of the clinical role of respiratory viruses in different diseases.