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Biomedical subjects

T Welte

Publications and source records attributed to T Welte.

At least 91 records · Page 5Linked to original sources
PubMed2000

Evidence of a defective thiol status of alveolar macrophages from COPD patients and smokers. Chronic obstructive pulmonary disease.

In increasing numbers of pulmonary diseases an association with a loss of intracellular thiols, mainly glutathione, is postulated. Therefore, the quantitative measurement of thiols within different viable cells is a possible metabolic parameter for cellular function and defense capacity of all pulmonary immune cells including alveolar macrophages (AM), that are highly compromised by oxidative stress. In this study the cellular thiol content was determined using fluorochrom conjugated chloromethyl derivatives (5-chloromethylfluorescein diacetate, CMFDA) in flow cytometry. The procedure was evaluated in vitro using biochemical techniques for glutathione quantification. Based on this approach, AM obtained from bronchoalveolar lavage (BAL) of smokers and patients with chronic obstructive pulmonary disease (COPD) showed a significant thiol deficiency compared to a nonsmoker/non-COPD group. The cellular thiol expression of AM from smokers and COPD patients reached only 50 and 53% of the control group. Lowest thiol concentrations (47% of control) were detected within the smoker(+)/COPD(+) group. This intracellular thiol deficiency significantly correlated with reduced lung function (FEV(1), PaO(2)). With regard to the tightly regulated thiol metabolism of immune cells, these results imply the onset of functional disturbances in thiol deficient AM. The determination of the cellular thiol content of AM, obtained from BAL by flow cytometry, presents a simple and reliable tool to monitor the effect of therapeutic measures focusing on the stabilization of the cellular thiol status.

Aged↗
PubMed2000

[Noninvasive ventilation in acute respiratory insufficiency].

In many ICU's in these days non-invasive mask ventilation is a technique in addition to the traditional invasive ventilation via endotracheal tube if the patient is able to cooperate. If contraindication (mucus retention, swallowing disorders, acute neurologic disorders, circulatory instability) and definition of interruption criteria are regarded, the method is safe. Besides its use for exacerbation of chronic obstructive pulmonary disease, especially the cardiogenic, pulmonary oedema is an indication which is supported by several studies. Other conditions such as pneumonia and ARDS have only been observed in relatively small studies. According to pathophysiologic pathways the use of non-invasive techniques seems limited to not-so-advanced stages of the disease in these cases. Considering the growing importance of this technique for the weaning procedure after long-term mechanical ventilation should be established at every ICU.

Critical Care↗
PubMed2000

Stat1 as a component of tumor necrosis factor alpha receptor 1-TRADD signaling complex to inhibit NF-kappaB activation.

Activated tumor necrosis factor alpha (TNF-alpha) receptor 1 (TNFR1) recruits TNFR1-associated death domain protein (TRADD), which in turn triggers two opposite signaling pathways leading to caspase activation for apoptosis induction and NF-kappaB activation for antiapoptosis gene upregulation. Here we show that Stat1 is involved in the TNFR1-TRADD signaling complex, as determined by employing a novel antibody array screening method. In HeLa cells, Stat1 was associated with TNFR1 and this association was increased with TNF-alpha treatment. TNFR1 signaling factors TRADD and Fas-associated death domain protein (FADD) were also found to interact with Stat1 in a TNF-alpha-dependent process. Our in vitro recombinant protein-protein interaction studies demonstrated that Stat1 could directly interact with TNFR1 and TRADD but not with FADD. Interaction between Stat1 and receptor-interacting protein (RIP) or TNFR-associated factor 2 (TRAF2) was not detected. Examination of Stat1-deficient cells showed an apparent increase in TNF-alpha-induced TRADD-RIP and TRADD-TRAF2 complex formation, while interaction between TRADD and FADD was unaffected. As a consequence, TNF-alpha-mediated I-kappaB degradation and NF-kappaB activation were markedly enhanced in Stat1-deficient cells, whereas overexpression of Stat1 in 293T cells blocked NF-kappaB activation by TNF-alpha. Thus, Stat1 acts as a TNFR1-signaling molecule to suppress NF-kappaB activation.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Drug-drug interactions in medical patients: effects of in-hospital treatment and relation to multiple drug use.

OBJECTIVES: Adverse drug reactions (ADRs) are a major cause of hospital admissions, thereby leading to significant medical and economical problems. Drug interactions contribute to a major part of ADRs, especially in elderly patients and in patients under polymedication. As a peculiarity of the German health care system the general practitioner is less involved in patient care during hospital stay than in other countries. Consequently, changes in medication at the transition point from out-patient to in-patient care and back may contribute to drug-related problems. PATIENTS: In the present study we investigated potential interactions in 169 consecutive patients with the diagnosis CHD (coronary heart disease) or COLD (chronic obstructive lung disease) who were admitted to the University Hospitals of Hannover and Magdeburg. METHODS: For each patient, potential interactions between prescribed drugs at admission, at discharge, and 3 months after discharge were assessed by using drug interaction data bases. RESULTS: We found that the number of drugs taken per patient as well as the number of interactions per patient are higher during hospitalization than before admission (pre-admission), and fall back after the hospital stay (post-discharge), but not to the pre-admission level. The number of potential interactions was significantly correlated in a polynomial manner to the number of drugs taken by each patient. The number of patients without a potential interaction was 44.4% pre-admission, 39.6% at discharge, and 39.1% post-discharge. Patients with potential interactions had a mean of 2.8, 2.7, and 2.4 interactions at each of the time points. Drug classes mainly involved with potential interactions were kaliuretic diuretics (recorded by 43.3% at discharge), ACE inhibitors (30.3%), anticoagulants and aggregation inhibitors (20.4%) and digitalis glycosides (14.7%). Regarding the frequency of the interaction categories, 68-70% of the potential interactions demand clinical attention, while 1-2% are life-threatening. 17-19% may result in therapeutic benefit; 10-12% are without clinical relevance. CONCLUSIONS: The risk of drug interactions increases exponentially with the number of drugs given to a patient. Although we have no data on the fraction of interactions that became clinically manifest, our study indicates that prescribing fewer drugs can reduce the risk of suffering from sickness secondary to drug interactions. Taking this risk into account may help to improve the quality of drug treatment and to save costs.

Adult↗
PubMed1999

[Cost comparison of hospital and ambulatory i.v. therapy in adult cystic fibrosis patients. Results of a controlled prospective study].

BACKGROUND: The regular i.v.-therapy of adults with cystic fibrosis (CF) on an in-patient basis is regarded as expensive. Home treatment is supposed to be cheaper. During a prospective controlled study to compare in-patient treatment (SIT) with home i.v.-treatment (HIT) in regard to clinical, psychosocial and economic parameters, delivered health services and costs in the German setting were evaluated in a comparable manner. PATIENTS AND METHODS: During the study period 4/95 to 9/96 45 patients with altogether 56 hospital and 40 home i.v.-courses of approximately 14 days were included in the study. Principal instruments to record the resource consumption were documentation sheets kept by the medical staff and the patients. In addition, pharmacy accounts in HIT and patient records and hospital controlling data in SIT were used. RESULTS: The average costs of a course were 14,038 DM for HIT and 18,702 DM for SIT. Striking are the large differences in medication costs. Two main reasons could be identified for the cost difference: 1, the use of a mobile infusion system in HIT and 2, the much higher prices of pharmaceuticals in the ambulatory care sector compared to the hospital sector, where extremely high profits of the home care service firms or the pharmacy can be supposed. The social costs of HIT (when antibiotics are valued to opportunity costs) are estimated at less than 10,500 DM. From a societal perspective HIT is preferable, from the perspective of the statutory health insurance funds hospital therapy is preferable. CONCLUSIONS: 1. The widely accepted hypothesis that ambulatory care is cheaper than hospital care is--at least in the German setting--not a-priori true. 2. In the treatment of CF patients incentive failures exist which induce unnecessary and avoidable hospital stays if the perspective of the statutory sickness funds is dominant. 3. Changes in system conditions as e.g. the permission of mail-order pharmacies might help to implement a more rational allocation of resources.

Adult↗
PubMed1999

ErbB4 signaling in the mammary gland is required for lobuloalveolar development and Stat5 activation during lactation.

Signaling by members of the epidermal growth factor receptor family plays an important role in breast development and breast cancer. Earlier work suggested that one of these receptors, ErbB4, is coupled to unique responses in this tissue. To determine the function of ErbB4 signaling in the normal mouse mammary gland, we inactivated ErbB4 signaling by expressing a COOH terminally deleted dominant-negative allele of ErbB4 (ErbB4DeltaIC) as a transgene in the mammary gland. Despite the expression of ErbB4DeltaIC from puberty through later stages of mammary development, an ErbB4DeltaIC-specific phenotype was not observed until mid-lactation. At 12-d postpartum, lobuloalveoli expressing ErbB4DeltaIC protein were condensed and lacked normal lumenal lactation products. In these lobuloalveoli, beta-casein mRNA, detected by in situ hybridization, was normal. However, whey acidic protein mRNA was reduced, and alpha-lactalbumin mRNA was undetectable. Stat5 expression was detected by immunohistochemistry in ErbB4DeltaIC-expressing tissue. However, Stat5 was not phosphorylated at Y694 and was, therefore, probably inactive. When expressed transiently in 293T cells, ErbB4 induced phosphorylation of Stat5. This phosphorylation required an intact Stat5 SH2 domain. In summary, our results demonstrate that ErbB4 signaling is necessary for mammary terminal differentiation and Stat5 activation at mid-lactation.

Animals↗
PubMed1999

[Alpha 1-protease inhibitor deficiency. Diagnosis, follow-up and therapy options].

DEFINITION: Alpha-1 antitrypsin (alpha-1 proteinase inhibitor) deficiency is characterized by a marked reduction of alpha-1 antitrypsin, the major antiprotease in man. PREVALENCE: Alpha-1 antitrypsin deficiency is one of the most common hereditary diseases in Caucasians of European descent. Alpha-1 antitrypsin deficiency is the underlying disorder in approximately 2% of all patients with chronic obstructive pulmonary disease and lung emphysema. CLINICAL MANIFESTATIONS: Young adults by the age of 30 to 45 years have a high risk for the development of lung emphysema with cough, sputum expectoration and respiratory insufficiency. There is a moderate risk of liver disease. DIAGNOSTIC PROCEDURES AND TREATMENT: The diagnosis is obtained by measurement of alpha-1 antitrypsin serum levels. Recognition of the disorder is important to prevent deterioration of the pulmonary function by early initiation of preventive measures and treatment. Therapeutic options are physiotherapy, antiobstructive medication and antibiotics. The most direct approach is the intravenous augmentation therapy with purified alpha-1 antitrypsin.

Adult↗
PubMed1999

Generation of carboxy-terminally deleted forms of STAT5 during preparation of cell extracts.

Carboxy-terminally deleted forms of STAT5 have been described to be generated in vivo either by proteolytic processing or by differential splicing mechanisms. By comparing two different cell extraction procedures, we can show that in the mammary gland carboxy-terminally deleted forms are produced in vitro and are not detectable in extracts prepared by SDS lysis.

Alternative Splicing↗
PubMed1999

STAT5 interaction with the T cell receptor complex and stimulation of T cell proliferation.

The role of STAT (signal transducer and activator of transcription) proteins in T cell receptor (TCR) signaling was analyzed. STAT5 became immediately and transiently phosphorylated on tyrosine 694 in response to TCR stimulation. Expression of the protein tyrosine kinase Lck, a key signaling protein in the TCR complex, activated DNA binding of transfected STAT5A and STAT5B to specific STAT inducible elements. The role of Lck in STAT5 activation was confirmed in a Lck-deficient T cell line in which the activation of STAT5 by TCR stimulation was abolished. Expression of Lck induced specific interaction of STAT5 with the subunits of the TCR, indicating that STAT5 may be directly involved in TCR signaling. Stimulation of T cell clones and primary T cell lines also induced the association of STAT5 with the TCR complex. Inhibition of STAT5 function by expression of a dominant negative mutant STAT5 reduced antigen-stimulated proliferation of T cells. Thus, TCR stimulation appears to directly activate STAT5, which may participate in the regulation of gene transcription and T cell proliferation during immunological responses.

Animals↗
PubMed1999

The use of noninvasive pressure support ventilation for severe respiratory insufficiency due to pulmonary oedema.

OBJECTIVE: Experimental use of noninvasive pressure support ventilation (NIPSV) in patients with severe pulmonary oedema who would have been intubated if noninvasive ventilation were not available. DESIGN: Open, prospective, within patients non comparative study. SETTING: Internal intensive care unit (11 beds) at a university hospital. PATIENTS: 29 patients with severe respiratory distress and confirmed pulmonary oedema. INTERVENTIONS: NIPSV was applied via a tight fitting face mask delivering between 13 and 24 cm H2O inspiratory airway pressure and 2 to 8 cm H2O expiratory airway pressure. MEASUREMENTS AND RESULTS: One patient required endotracheal intubation. Mean plethysmographic oxygen saturation rose significantly within 30 min from 73.8+/-11 to 90.3+/-5%, while the oxygen supply was reduced from 7.3+/-3.7 to 5.1+/-3 l/min. Mean pH increased significantly (p<0.01) from 7.22+/-0.1 before NIPSV to 7.31+/-0.07 after 60 min of NIPSV. Partial pressure of carbon dioxide was 62+/-18.5 mmHg but decreased significantly within 60 min to 48.4+/-11.5 mm Hg. Heart rate and-blood pressure stabilised continuously during the observation time. Mean duration of NIPSV was 6 h 9 min (range 60 min to 24 h). There were no serious side effects. Four patients died from underlying diseases between 1 and 28 days after NIPSV. CONCLUSION: NIPSV is a highly effective technique with which to treat patients with severe cardiogenic pulmonary oedema.

Aged↗
PubMed1999

In human and rat lung membranes [35S]GTPgammaS binding is a tool for pharmacological characterization of G protein-coupled dinucleotide receptors.

The P2Y receptor family is activated by extracellular nucleotides such as ATP and UTP. P2Y receptors regulate physiological functions in numerous cell types. In lung, the P2Y2 receptor subtype plays a role in controlling Cl- and fluid transport. Besides ATP or UTP, also diadenosine tetraphosphate (Ap4A), a stable nucleotide, seems to be of physiological importance. In membrane preparations from human and rat lung we applied several diadenosine polyphosphates to investigate whether they act as agonists for G protein-coupled receptors. We assessed this by determining the stimulation of [35S]GTPgammaS binding. Stimulation of [35S]GTPgammaS binding to G proteins has already been successfully applied to elucidate agonist binding to various G protein-coupled receptors. Ap(n)A (n = 2 to 6) enhanced [35S]GTPgammaS binding similarly in human and rat lung membranes, an indication of the existence of G protein-coupled receptor binding sites specific for diadenosine polyphosphates. Moreover, in both human and rat lung membranes comparable pharmacological properties were found for a diadenosine polyphosphate ([3H]Ap4A) binding site. The affinity for Ap2A, Ap3A, Ap4A, Ap5A, and Ap6A was also comparable. 8-Diazido-Ap4A and ATP were less potent, whereas the pyrimidine nucleotide UTP showed hardly any affinity. Thus, we present evidence that different diadenosine polyphosphates bind to a common G protein-coupled receptor binding site in membranes derived either from human or rat lung.

Animals↗
PubMed1999

Retinoic acid modulates prolactin receptor expression and prolactin-induced STAT-5 activation in breast cancer cells in vitro.

Two recent papers demonstrate that prolactin plays an important role in the induction and progression of mammary tumours. Retinoids have been shown to be potent inhibitors of breast carcinogenesis. We studied expression of prolactin receptor mRNA in human breast cancer cell lines MCF-7, SKBR-3, T47D and BT-20 treated with and without retinoids using Northern blot and a quantitative polymerase chain reaction (PCR) method. In all cell lines, all-trans- and 9-cis-retinoic acid, as well as the retinoic acid receptor gamma (RAR-gamma) selective agonists CD2325 and CD437 (1 microM), were able to down-regulate prolactin receptor. After 1 h, a significant reduction was detectable and maximal effect was achieved after 24 h of treatment. Pretreatment with retinoic acid also reduced the prolactin-/prolactin receptor-dependent signal transduction and activation of transcription 5 (STAT-5) activation in T47D cells. Cycloheximide failed to abrogate the retinoic acid-induced decline in prolactin receptor mRNA levels, indicating that this effect was not dependent upon continuing protein synthesis. Similarly, no change in the stability of prolactin receptor mRNA was observed during 12 h of retinoic acid treatment. In conclusion, our results demonstrate that retinoids are able to inhibit the expression of prolactin receptor message, which encodes an important growth factor receptor in breast cancer cells. This action could be responsible for the anti-tumour effects of retinoids.

Alitretinoin↗
PubMed1999

Increased release of transforming growth factor (TGF)-beta1, TGF-beta2, and chemoattractant mediators in pneumonia.

Transforming growth factor-beta (TGF-beta), interleukin-8 (IL-8), and leukotrienes are potent neutrophil chemoattractants that are released in several lung diseases. There is limited information about the release of TGF-beta in bronchoalveolar lavage fluid (BALF) of patients with pneumonia. Furthermore, it is not clear if TGF-beta is differentially expressed in different lung diseases. The aim of our study was to compare the concentrations of TGF-beta1 and TGF-beta2 in the BALF of patients with pneumonia and other lung diseases. Furthermore, correlation of the TGF-beta levels with the concentration of chemoattractant mediators as well as with indicators of macrophage and granulocyte activation should be investigated. Patients with pneumonia, interstitial lung disease (ILD), or chronic obstructive pulmonary diseases (COPD) were included. Patients with ischemic heart disease without pulmonary involvement served as controls. The concentrations of TGF-beta1 and TGF-beta2, of the chemoattractant cytokine IL-8, of leukotriene B4, and of the leukotrienes C4, D4, and E4 were measured. Neutrophil elastase and granulocyte content (PMN) were used as markers for granulocyte activation, and neopterin was used as a marker for the activation of macrophages. Significantly elevated levels of TGF-beta1 (mean = 0.216 ng/ml, p < 0.01) were found in patients with microbiologically positive pneumonia but not in patients with ILD or COPD. A significant (p < 0.001) correlation was found between the TGF-beta1 concentrations and the IL-8 levels and the percentage of granulocytes (r = 0.76, and r = 0.44, respectively). Elevated TGF-beta2 concentrations were measured in the BALF of patients with pneumonia (mean = 1.4 ng/ml, p < 0.01) and with ILD. Pneumonia was also associated with increased concentrations of leukotrienes C4, D4, and E4 (mean = 91.61 pg/ml, p < 0.05) and leukotriene B4 (mean = 203.9 pg/ml, p < 0.01), significantly elevated levels of PMN elastase (mean = 2958.26 ng/ml, p < 0.01), and neopterin (mean = 0.42 nmol/L). Our results strongly suggest that different lung diseases do differ with regard to the released cytokines. TGF-beta1 probably plays a key role in regulation of pulmonary inflammation, particularly in pneumonia.

Bronchoalveolar Lavage Fluid↗