[Pulmonary rehabilitation in asthma bronchiale]. / Rehabilitation bei Asthma bronchiale.

Pulmonary rehabilitation for patients with asthma is designed to achieve and to maintain an optimal daily functioning at a health-related quality of life and to increase participation in social and professional life. In this context, rehabilitation is defined as a time-limited treatment programme which systematically employs scientifically-based diagnostic management and evaluation options to achieve a normal life irrespective of the chronic disease. This requires therapeutic interventions that are characteristic for rehabilitation and complete the regular medical treatment in order to minimise the physical, psychological and social consequences of the chronic disease. Examples of those bio-psycho-social disease consequences which are not sufficiently treated by antiobstructive medication are secondary deconditioning and anxiety, social withdrawal, reduced physical activity and reduced participation in social and professional life. In order to antagonise these secondary consequences of the chronic disease, pulmonary rehabilitation programmes utilise expertise from various health-care disciplines that are integrated into a comprehensive programme tailored to the needs of each individual patient. The interdisciplinary team of health-care professionals in pulmonary rehabilitation includes physicians, respiratory and physical therapists, psychologists, exercise specialists, social workers and others with appropriate expertise for example in nutritional therapy. Therefore, pulmonary rehabilitation programmes are not only an integral part of the current German asthma guidelines with clearly defined tasks within a comprehensive long-time management, but rehabilitative treatment options are also cornerstones of the recently released national disease management programmes for bronchial asthma.

Inhibition of costimulation allows for repeated systemic administration of adenoviral vector in rhesus monkeys.

Immunogenicity of recombinant adenoviral (Ad) vectors severely hampers the clinical development of gene therapy protocols using repeated vector administrations. Inhibition of costimulation by APCs was explored as a strategy to circumvent the immune response against Ad particles. This strategy was tested in rhesus monkeys, treated transiently with chimeric anti-human CD40 and anti-human CD86 antagonist monoclonal antibodies (MAbs) at the time of systemic administration of a recombinant Ad vector. After Ad vector administration in the absence of immunosuppressive treatment, transgene expression in the serum lasted about 3-4 weeks. All control animals developed a strong neutralizing antibody (NAb) response to the Ad particles, which totally prevented efficient administration of a second vector, as shown by the lack of transgene expression. Treatment with anti-CD40 and anti-CD86 chimeric MAbs delayed or blocked the development of a humoral response against Ad and the infiltration of CD8(+) lymphocytes into the liver. This resulted in (i) increased persistence of Ad-transduced cells after injection of a first vector encoding a nonimmunogenic transgene, and (ii) the possibility of readministering a second Ad vector with significant efficacy. In both respects, the combined blockade of CD40 and CD86 was more efficient than treatment with anti-CD40 alone. This study shows for the first time in non-human primates that blocking CD40 and CD86 costimulatory molecules represents a promising strategy to inhibit immune responses against an Ad vector injected systemically.

Blocking B7 and CD40 co-stimulatory molecules decreases antiviral T cell activity.

Inhibition of co-stimulatory signals for T cells by interrupting CD80/CD86-CD28 and CD40-CD154 interactions is a promising approach to prevent transplant rejection and to induce graft tolerance. However, this tolerizing treatment might affect T cell reactivity towards all the antigens to which the immune system is exposed during treatment. We addressed the question whether such inhibition of co-stimulatory ligands on human antigen presenting cells (APC) would affect T cell reactivity against a virus. This was tested in an in vitro system with freshly isolated human monocytes transduced with adenovirus (ad) containing either murine interferon-gamma (mIFN-gamma) or green fluorescent protein (GFP) as marker transgene. T cells co-cultured with transduced monocytes proliferated and produced cytokines. These 'primed' T cells had strong antiviral activity as they subsequently killed ad/GFP-transduced monocytes and reduced mIFN-gamma accumulation in coculture with ad/mIFN-transduced monocytes. However, if priming had occurred in the presence of blocking anti-CD40/CD80/CD86 MoAbs, generation of this antiviral activity was completely prevented. Moreover, T cells primed in the absence of co-stimulatory cells failed to proliferate upon restimulation with adenovirus-transduced monocytes. The results confirm that co-stimulatory signals from APC are required for efficient induction of antiviral T cell activity and point to a potential infectious risk of blocking co-stimulatory signals.

Transient blocking of both B7.1 (CD80) and B7.2 (CD86) in addition to CD40-CD40L interaction fully abrogates the immune response following systemic injection of adenovirus vector.

Blockade of the CD40-CD40L and CD80/CD86-CD28 costimulatory pathways represents a strategy to inhibit the immune response against Ad vectors designed for gene therapy applications. Since most previous studies have used a CTLA4-Ig fusion molecule binding to both CD80 and CD86, the respective roles of these B7 molecules remained undefined. We have studied the effect of blocking monoclonal Abs (mAbs) directed against the costimulatory molecules CD40L, CD80 and CD86, alone or in different combinations, on the humoral and cellular immune responses against Ad. Groups of mice were transiently treated with each combination of blocking mAbs upon systemic injection of a first Ad vector. Combinations of anti-CD80 + anti-CD86 or anti-CD40L + anti-CD86 mAbs resulted in strong inhibition of the immune response against Ad. Using either of these mAb pairs, a second vector could be administered 1 month after the first injection but with lower efficiency than in naive animals. Thus, CD86 stands as the pivotal B7 molecule involved in the development of the immune response against Ad. However, only the blockade of both CD80 and CD86 in addition to CD40L fully inhibited the humoral and cellular responses against the Ad vector, such that readministration after 1 month was as efficient as in naive animals. At the time of readministration, treated animals had regained their ability to mount a normal immune response to the second Ad vector, showing that tolerance was not induced.

Adhesive and/or signaling functions of CD44 isoforms in human dendritic cells.

The regulation and function of the CD44 family of surface glycoproteins were investigated in human monocyte-derived dendritic cells (DCs). Variant CD44 isoform transcripts encoding exons v3, v6, and v9 are differently regulated during the differentiation of monocytes into DCs. TNF-alpha treatment, which induces the maturation of DCs, up-regulates the expression of all v3-, v6-, and v9-containing isoforms examined. CD44 molecules are involved in the adhesion of DCs to immobilized hyaluronate (HA), and v3- and v6-containing variants participate in this function, whereas anti-CD44v9 mAbs were unable to inhibit DC adhesion to HA. The consequences of ligand binding to CD44 were examined by culturing DCs on dishes coated with HA or various anti-CD44 mAbs. HA, the anti-pan CD44 mAb J173, and mAbs directed against v6- and v9-containing (but not v3-containing) isoforms provoked DC aggregation, phenotypic and functional maturation, and the secretion of IL-8, TNF-alpha, IL-1beta, and granulocyte-macrophage CSF. In addition, IL-6, IL-10, and IL-12 were released by DCs stimulated with either J173 or HA, although these cytokines were not detected or were found only at low levels in the culture supernatants of DCs treated with anti-CD44v6 or anti-CD44v9 mAbs. Our study points to distinct capacities of the v3-, v6-, and v9-containing isoforms expressed by human DCs to mediate cell adhesion to HA and/or a signal inducing DC maturation and the secretion of cytokines.

Spirometric gated quantitative computed tomography of the lung in healthy smokers and nonsmokers.

RATIONALE AND OBJECTIVES: The authors investigated the influence of cigarette smoking on healthy, asymptomatic smokers and nonsmokers with the help of spirometric triggered quantitative computed tomography. In our prospective study, the authors compared conventional lung function parameters with the computed tomography values (lung attenuation, lung area). METHODS: The study group comprised 40 healthy volunteers consisting of 20 smokers and nonsmokers (20 females and 20 males). The corresponding groups have been matched concerning their age, height, body mass, (cigarette) pack years. Computer tomography scans were triggered at 35%, 50%, 70% and 95% of vital capacity at a defined apical and a basal level. RESULTS: Functional residual capacity (FRC), total lung capacity and airway resistance showed close correlations to lung parenchymal attenuation values especially at full inspiration and expiration. For example, the authors found a correlation coefficient of r = -0.845 (P < or = 0.001) concerning the FRC and lung attenuation values in the apical lung at 35% of vital capacity in male smokers. Male smokers proved to have a significantly higher pulmonary lung density at all inspiratory states than the other groups (P < or = 0.05; Student's t test). Although male smokers had a higher vital capacity they showed a smaller cross-sectional area increase of the lung during inspiration than nonsmokers. This phenomenon is a result of the decreasing compliance of the smoker's lung, due to small airways disease and hypoxic vasoconstriction. CONCLUSIONS: Spirometric-triggered quantitative computed tomography has proved to be a sensitive diagnostic device for the investigation of early pathomorphologic changes in healthy, asymptomatic cigarette smokers.

A comparison of the germline potential of differently aged ES cell lines and their transfected descendants.

The germline transmission (g.l.t.) of gene trap or gene targeted mutations by ES-cell-derived chimaeric mice is a crucial step in the generation of stable transgenic lines. The wild-type ES cell lines CJ7, D3 and R1 of different passage numbers and their transfected clone-descendants generated in gene targeting or gene trap experiments were tested for their ability to colonize the germline. The maximal g.l.t. age for wild-type ES cells was equal to passage 26 and for transfected clones was equivalent to passage 32 of parental lines. It is shown that wild-type ES cells of less than a passage 15 should be used for effective production of transgenic g.l.t. clones. A simple system is outlined to evaluate the probability of g.l.t. on the basis of the chimaeric progeny obtained.

Regulation of CD44 isoform expression and CD44-mediated signaling in human dendritic cells.

Dendritic cells (DCs) express CD44, a cell surface receptor for the extracellular matrix ligand hyaluronate, involved in cell-cell interactions and cell migration. Besides the "standard" form of CD44, a variety of splice variants contain an additional extracellular region encoded by 10 "variable" exons termed v1 to v10. The standard form of CD44 as well as variants containing exon v6 (CD44v6) are known to play important roles in the immune system, yet largely unexplored in the DC lineage. In this study, we examined the regulation of CD44 isoforms in human DCs derived from monocytes cultivated in the presence of GM-CSF and IL-4. We found that v3, v6 and v9 variants are all up-regulated upon TNF-alpha stimulation of DCs. In addition, we show that stimulation of DCs using anti-CD44 mAbs can induce DC agregation, up-regulation of accessory molecule expression and secretion of cytokines. A mAb directed against CD44v6 variants was shown to mediate some of these effects.

Functions of Fc receptors on human dendritic Langerhans cells.

Immature dendritic cells are antigen presenting cells highly specialized for capturing and processing foreign protein antigens. These cells express Fc gamma RII and Fc epsilon RI which, by their ability to internalize and use the endocytic pathway, increase their capacity to process antigens. Immature dendritic cells, such as epidermal Langerhans cells, also release soluble forms of Fc gamma RII. These latter molecules are likely to compete with the membrane-associated Fc gamma R to diminish or abrogate the capacity of dendritic cells to present immune complexes, as suggested by our in vitro experiments using both human and mouse epidermal Langerhans cells. However, when dendritic cells mature in vitro and become efficient stimulators of resting T cells, they rapidly down-regulate and sometimes completely abolish the expression of their membrane-associated Fc gamma R and Fc epsilon RI. Consequently, they lose or at least strongly diminish their capacity to capture immune complexes. At this stage, the release of soluble Fc gamma R by dendritic cells is also markedly diminished. One can hypothesize that the membrane-associated Fc gamma RII and the soluble Fc gamma RII are molecules expressed when dendritic cells are potent capturing and processing cells, the soluble Fc gamma RII molecule acting by competition as a negative regulatory element on the Fc gamma RII-mediated internalization of IgG-containing immune complexes. Thus, the expression of membrane-associated Fc gamma R and Fc epsilon RI, as well as the release of soluble Fc gamma R, would seem to characterize the immature stage of dendritic cells.

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)

Low-dose almitrine bismesylate in the treatment of hypoxemia due to chronic obstructive pulmonary disease.

STUDY OBJECTIVE: Assessment of acute and chronic effects of low-dose almitrine bismesylate (AB) in stable chronic obstructive pulmonary disease (COPD). STUDY DESIGN: Oral administration of AB, 25 mg three times a day, for 6 months in all patients. Pulmonary function, blood gases, and peripheral nerve conduction velocity were measured at baseline and after long-term administration of AB. In addition, oral pharmacokinetics and effects on pulmonary circulation at rest were studied in half of the patients. Intravenous pharmacokinetics were measured after a single intravenous dose of 60 mg of AB 3 months before the start of oral AB treatment in the other seven patients. SETTING: Outpatient clinic of a community hospital in a coal mining district in southwest Germany. PATIENTS: Fourteen patients with clinically stable COPD and hypoxemia. RESULTS: Acute effects of AB were as follows: a significant increase in arterial oxygen tension (PaO2) from 61 +/- 7 mm Hg to 74 +/- 8 mm Hg (p < 0.001), a decrease in arterial carbon dioxide tension (PaCO2) from 41 +/- 8 mm Hg to 38 +/- 7 mm Hg (p < 0.01), a rise of pH from 7.45 +/- 0.04 to 7.48 +/- 0.04 (p < 0.01), and a transient increase in mean pulmonary artery pressure from 26 +/- 7 to 29 +/- 6 mm Hg (not significant). After long-term treatment, once tissues were saturated with almitrine, improvement in gas exchange persisted with a PaO2 of 70 +/- 10 mm Hg (p < 0.001) and a PaCO2 of 39 +/- 6 mm Hg (not significant) without elevation of pH (7.45 +/- 0.04) or of pulmonary artery pressure (26 +/- 8 mm Hg). The terminal half-life of AB was 56 +/- 45 days after a single intravenous administration, and 55 +/- 16 days after long-term oral dosing. None of the patients developed clinically manifest peripheral neuropathy. Impaired asymptomatic peripheral motor nerve function was prevalent in 4 (29 percent) of the patients and remained unchanged during long-term AB administration. However, asymptomatic impairment of motor nerve conduction velocity developed in two patients with inadequate high AB plasma levels despite low-dose therapy. Both patients were known to have additional conditions predisposing for neuropathy. CONCLUSIONS: Low-dose AB therapy, 75 mg daily, resulted in sustained elevation of arterial oxygen tension in hypoxemic patients with COPD. Although pulmonary artery pressure increased transiently after the first dose, it remained unchanged with long-term treatment despite persistent improvement of pulmonary gas exchange.(ABSTRACT TRUNCATED AT 250 WORDS)

[Long-term effect of the beta 2-sympathomimetic formoterol in young smokers--study of duration and site of effect of bronchodilatation using conventional methods of lung function and monodispersed aerosols]. / Langzeitwirkung des beta 2-Sympathomimetikums Formoterol bei jungen Rauchern--Untersuchung von Wirkdauer und Wirkort der Bronchodilatation mittels konventioneller Lungenfunktionsmethoden und monodisperser Modellaerosole.

Formoterol is a novel selective beta 2-sympathomimetic inducing bronchodilatation after inhalation or oral application. Compared to other beta 2-sympathicomimetics the substance begins to act very rapidly even at a much lower dosage level, while it remains effective for at least 12 hours. In the present study the bronchodilatory effect of 24 micrograms MDI formoterol was investigated in 18 healthy smokers between 20 and 30 years of age means. Measurement was effected by means of conventional lung function diagnostics (body plethysmography, spirometry) and an biophysical aerosol measurement method for determining the effective airways dimensions (EAD). This method is based on the gravitational losses of a previously inspired monodisperse model aerosol during apnoea periods of different duration. It enables determination of the EAD as a function of the volumetric lung depth (VLT). A marked and universally measurable bronchodilatation is detectable directly after formoterol has been inhaled. The longterm action of formoterol was confirmed for more than 15 hours after application, using the conventional lung function test and the EAD method. Over and above this the EAD determination showed that the bronchodilatory effect was much more marked in the central airways than in the periphery of the lungs, thus confirming the effect generally described for beta 2-sympathomimetics as being mainly directed towards the central airways region.

Unspecific bronchial reactivity to carbachol in healthy subjects--effect of age and smoking habits.

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 (p < 0.05, both comparisons). In young smokers and nonsmokers (age: 20-30 years) pulmonary function tests were not different (p > 0.28, 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 (p > 0.05, both comparisons) and did not correlate with the age of the subjects (p > 0.2). No correlations between baseline values of pulmonary function tests and PD50sRaw were observed (p > 0.34, all comparisons). The observations confirm that the distribution profile of BHR is unimodal and apparently not affected by age and smoking habits.

[The value of studies of pulmonary gas exchange during exercise for evaluation of reduced arterial oxygenation at rest in asymptomatic long-term smokers]. / Zur Bedeutung von Untersuchungen des Gasaustauschs unter Belastung für die Bewertung einer reduzierten arteriellen Oxygenierung in Ruhe bei asymptomatischen Langzeit-Rauchern.

The aim of this study was to elucidate extent and nature of an impairment of gas exchange after long time cigarette-smoking. Pulmonary gas exchange at rest as well as during steady state exercise and conventional lung function tests (LFTs) were studied in 32 clinically healthy, asymptomatic severe cigarette-smokers (S; 48.1 +/- 15.7 pack-years) and 32 healthy lifetime nonsmokers (N) between 40 and 60 years of age, respectively, individually matched for age, body height, body weight and gender. Pulmonary function tests of all subjects were within the limits of normal values. Except for a slight reduction of MEF25 in S (p < 0.05) and a slight increase of FRC (p < 0.05), the groups did not differ with respect to LFTs. At rest, however, S had markedly lower values for PaO2, TLO2, DCO and KCO, and higher values for AaDO2 and QVA/Qt. Resting measurements for VD/VE and PaCO2 did not differ between N and S. During ergometry PaO2 and TLO2 increased respectively; AaDO2 and QVA/Qt fell concomitantly with VD/VE and PaCO2. On termination of exercise no significant difference between N and S for the above variables could be discerned any longer. Our findings confirm that even in clinically healthy asymptomatic cigarette-smokers a distinct impairment of gas exchange is present. Their improvement during physical exercise primarily indicates the presence of reversible ventilation-perfusion mismatching and excludes relevant morphologic changes in the lung in these cases.

[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.

[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.