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Biomedical subjects

Christian Witt

Publications and source records attributed to Christian Witt.

At least 19 recordsLinked to original sources
PubMed2006

Anorexia in chronic obstructive pulmonary disease--association to cachexia and hormonal derangement.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD) weight loss frequently occurs that may ultimately lead to cachexia as a serious co-morbidity, indicating severely impaired functional capacity, health status and increased mortality. Increased energy expenditure due to mechanic and metabolic inefficiency and systemic inflammation are determinants of a hypermetabolic state that is not balanced by dietary intake. Anorexia may importantly contribute to weight loss in COPD, however, the association between immune and hormonal derangement and altered appetite has not been studied in detail. AIM: The aim of the present study was to investigate whether anorexia in COPD is related to inflammation and hormonal derangement in association to weight loss. METHODS: We prospectively enrolled 103 consecutive patients with COPD (age 59.8+/-1.3 years, 35% female, mean FEV1 38.3+/-1.7%) in comparison to healthy controls of similar age (n=15). RESULTS: In 34 patients (33%) cachexia was diagnosed (weight loss >7.5%, BMI < or = 24 kg/m2). Cachectic COPD patients had lower BMI (19.0+/-0.5 vs 25.6+/-0.7 kg/m2) and impaired lung function (FEV1 31+/-2% vs 42+/-2%, FVC 51+/-3 vs 59+/-3%, both p<0.001). Inflammatory immune activation (IL-6 and IL-6/IL-10 ratio) was significantly higher in cachectic COPD patients. Analysis of the extent of anorexia (visual analogue scale) revealed that cachectic COPD patients had significantly decreased subjective desire to eat compared to non-cachectic patients (3.5+/-0.3 vs 6.3+/-0.2, p<0.001). Patients with COPD and cachexia showed evidence of acquired GH resistance (decreased IGF-1/GH ratio) and insulin resistance (HOMA). Anorexia showed a direct correlation with the IGF-1/GH ratio (r=0.34, p<0.05) and was further related to BMI and % weight loss (both p<0.001). CONCLUSION: In COPD anorexia relates to hormonal derangement and inflammatory immune activation. Anorexia contributes to development of cachexia. The concept of appetite stimulating therapy emerges as a novel therapeutic option in cachectic COPD patients.

Anorexia↗
PubMed2006

Expression of distinct classes of titin isoforms in striated and smooth muscles by alternative splicing, and their conserved interaction with filamins.

While the role of titin as a sarcomeric protein is well established, its potential functional role(s) in smooth muscles and non-muscle tissues are controversial. We used a titin exon array to search for which part(s) of the human titin transcriptional unit encompassing 363 exons is(are) expressed in non-striated muscle tissues. Expression profiling of adult smooth muscle tissues (aorta, bladder, carotid, stomach) identified alternatively spliced titin isoforms, encompassing 80 to about 100 exons. These exons code for parts of the titin Z-disk, I-band and A-band regions, allowing the truncated smooth muscle titin isoform to link Z-disks/dense bodies together with thick filaments. Consistent with the array data, Western blot studies detected the expression of approximately 1 MDa smooth muscle titin in adult smooth muscles, reacting with selected Z-disc, I-band, and A-band titin antibodies. Immunofluorescence with these antibodies located smooth muscle titin in the cytoplasm of cultured human aortic smooth muscle cells and in the tunica media of intact adult bovine aorta. Real time PCR studies suggested that smooth muscle titins are expressed from a promoter located 35 kb or more upstream of the transcription initiation site used for striated muscle titin, driving expression of a bi-cistronic mRNA, coding 5' for the anonymous gene FL39502, followed 3' by titin, respectively. Our work showed that smooth muscle and striated muscle titins share in their conserved amino-terminal regions binding sites for alpha-actinin and filamins: Yeast two-hybrid screens using Z2-Zis1 titin baits identified prey clones coding for alpha-actinin-1 and filamin-A from smooth muscle, and alpha-actinin-2/3, filamin-C, and nebulin from skeletal muscle cDNA libraries, respectively. This suggests that the titin Z2-Zis1 domain can link filamins and alpha-actinin together in the periphery of the Z-line/dense bodies in a fashion that is conserved in smooth and striated muscles.

Actinin↗
PubMed2006

Right ventricular function assessed by two-dimensional strain and tissue Doppler echocardiography in patients with pulmonary arterial hypertension and effect of vasodilator therapy.

Two-dimensional strain echocardiography is a new method for the assessment of regional contractility. Thirty-seven patients with pulmonary arterial hypertension (mean age 56.4 +/- 11 years) and 38 normal subjects (mean age 58.3 +/- 12 years) underwent 2-dimensional echocardiography and tissue Doppler echocardiographic evaluation of right ventricular (RV) global function and regional contractility. Patients with pulmonary arterial hypertension additionally underwent 6-minute walking distance tests and right-sided cardiac catheterization before and after (8 +/- 3 months) vasodilator therapy. Moderate or severe RV dysfunction was present in all patients (2-dimensional strain of the basal segment of the RV free wall: -8.8 +/- 4.1% systolic longitudinal deformation) compared with normal subjects (-24.3 +/- 4.7% systolic longitudinal deformation, p < 0.001) and was improved with vasodilator therapy after 6 to 11 months (-13.3 +/- 6.2% systolic longitudinal deformation, p < 0.001).

Adult↗
PubMed2005

Prevalence of anemia in chronic obstructive pulmonary disease: comparison to other chronic diseases.

Chronic obstructive pulmonary disease (COPD) is a multisystemic inflammatory disease characterized by pulmonary and extrapulmonary symptoms. The impaired lung function has long-term implications on metabolism and homeostasis of many organ systems such as the skeleton, heart, brain and skeletal muscle. The occurrence and prevalence of anemia in COPD has rarely been studied. Anemia is such a common and simple clinical finding that we may underestimate its physiological relevance in COPD. The aim of the study was to retrospectively investigate the prevalence of anemia in a large population of COPD patients and to compare it to patients with chronic heart failure, renal insufficiency, cancer and asthma. A population of 7337 patients that was treated in the University Hospital Charité, Berlin, Germany, from 1996 to 2003 was subsetted according to the ICD-9/10 code of the discharge diagnoses into the above-mentioned diagnoses groups. The overall prevalence of anemia in COPD patients was 23.1%. It was comparable to the prevalence of anemia we found in patients with chronic heart failure (23.3%). Patients with renal insufficiency and cancer presented the highest anemia frequencies. The high prevalence of anemia in hospitalised COPD patients that were treated mostly for exacerbations gives evidence that anemia is also a comorbidity in COPD and may contribute to exercise limitation and dyspnoea.

Aged↗
PubMed2005

Fullerene-pyropheophorbide a complexes as sensitizer for photodynamic therapy: uptake and photo-induced cytotoxicity on Jurkat cells.

The main challenge in searching for new photosensitizers is to improve their specificity for target cells to avoid toxicity towards normal cells. New modular drug delivery systems were proposed consisting of a multiplying unit with the property of carrying several drug moieties and an addressing unity with high selectivity for target cells. Following this concept, two new fullerene-bis-pyropheophorbide a derivatives were synthesized: a mono-(FP1) and a hexa-adduct (FHP1). The photophysical characterization of the compounds revealed significantly different parameters related to the number of addends at the fullerene core. In this study, the derivatives were tested with regard to their intracellular uptake and photosensitizing activity towards human leukemia T-lymphocytes (Jurkat cells) in comparison with the free sensitizer, pyropheophorbide a. The C(60)-hexa-adduct FHP1 resulted to have a significative phototoxic activity (58% dead cell, after a dose of 400 mJ/cm(2), 688 nm) while the mono-adduct FP1 had a very low phototoxicity and only at higher light doses. The photosensitizing activity of the fullerene hexa-adduct, FHP1, resulted to be lower than that of pyropheophorbide a. The lesser intracellular concentration reached by the C(60)-hexa-adduct FHP1 is probably the reason for its lower phototoxicity with respect to pyropheophorbide a.

Cell Survival↗
PubMed2005

Adult patients with congenital heart disease and pulmonary arterial hypertension: first open prospective multicenter study of bosentan therapy.

BACKGROUND: Endothelin receptor antagonism has been introduced as an effective oral therapy of patients with idiopathic pulmonary arterial hypertension. In view of the pathophysiologic and histologic similarities between idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD), there is a rationale for treating these patients with the oral dual (ET(A)/ET(B)) endothelin receptor antagonist bosentan. METHODS: Thirty-three patients with PAH-CHD (43 +/- 14 years, 23 with Eisenmenger syndrome) were treated with bosentan for a mean of 2.1 +/- 0.5 years. Efficacy was assessed by a panel of tests, including New York Heart Association functional class, 6-minute walking distance, and echocardiographic and hemodynamic parameters. RESULTS: Mean 6-minute walking distance increased from 362 +/- 105 to 434 +/- 68 m (P = .001). New York Heart Association class also improved significantly (3.1 to 2.4, P = .0001). This was associated with slight trends in improvements of transcutaneous oxygen saturation (86% +/- 7% to 88% +/- 7%, P = .13) and maximum oxygen uptake (13.2 +/- 4.0 to 14.9 +/- 2.5, P = .18). Right ventricular systolic pressure measured by echocardiographic decreased from 111 +/- 32 to 106 +/- 22 mm Hg (P = .001). Bosentan treatment was well tolerated by all patients. CONCLUSIONS: Long-term bosentan treatment in adult patients with PAH-CHD was well tolerated and improved functional status as well as exercise capacity. These findings have to be corroborated by controlled studies that are presently ongoing.

Adolescent↗
PubMed2005

Effects of inhaled HFA beclomethasone on pulmonary function and symptoms in patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease is characterized by progressive airflow limitation and pulmonary inflammation. Inhaled corticosteroids (ICS) have been shown to be effective in the reduction of the number of exacerbations and the rate of deterioration in health status in patients with more advanced chronic obstructive pulmonary disease (COPD). Therefore current international guidelines recommend ICS for patients with severe COPD (FEV1 < 50%) with at least one exacerbation within the last year. We determined the short-term effect of the inhaled corticosteroid beclomethasone in HFA 134 formulation (Ventolair) on Health related Quality of Life (HRQOL), pulmonary function and the release of the cytokines Interleukin-10 (IL-10), Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF), Interferon-gamma (IFN-gamma) and Macrophage Inflammatory Protein-1alpha (MIP-1alpha) from peripheral blood monocytes of patients with COPD (n = 11) in a 12 week double blind cross over placebo-controlled study. Baseline lung function and the St. George Respiratory Questionnaire (SGRQ) were performed at the start and the end of each treatment phase. Monocytes were separated from blood at the end of each treatment phase. The treatment with Ventolair) resulted in an increase of PEF from 4.92 to 5.53 l/s and a decrease of RV% TLC (% predicted) values from 144.52 to 131.36. Inhaled HFA beclomethasone did not affect the cytokine release of IL-10, IFN-gamma, GM-CSF and MIP-1alpha. All cytokines were measured using commercially available Enzyme Linked Immun Sorbent Assay (ELISA) kits. The symptom score of the St. George Respiratory Questionnaire significantly decreased from 55.12 to 47.77 units in the active period compared to the placebo period after the treatment with HFA beclomethasone. The present study shows that a short-term treatment with inhaled steroid beclomethasone in fine particle HFA formulation decreases the hyperinflation and improves the PEF and the COPD symptoms.

Administration, Inhalation↗
PubMed2005

Anemia and inflammation in COPD.

BACKGROUND: Anemia in patients with COPD and its pathophysiology is an understudied issue. METHODS: In a group of 101 COPD patients (FEV(1) percentage of predicted, 37 +/- 2% [mean +/- SEM]; mean age, 61 +/- 1 years; 35% female gender), the prevalence of anemia and its relationship to body mass and weight loss, inflammatory parameters, and erythropoietin levels was determined. Data were compared to a control group (healthy persons with matched age) in order to identify potential factors that may influence the development of anemia in patients with COPD. RESULTS: Anemia was diagnosed in 13 patients (hemoglobin levels < 13.5 mg/dL in male patients and < 12.0 mg/dL in female patients), which represents a prevalence of 13%. Anemic COPD patients showed elevated erythropoietin levels (41.8 +/- 25.4 U/L vs 16.3 +/- 2.9 U/L) and an increased inflammatory response compared to nonanemic patients. A significant inverse correlation of hemoglobin vs erythropoietin (r = - 0.84, p < 0.01) was observed in anemic COPD patients, but not in the nonanemic group. CONCLUSION: Anemic COPD patients show high erythropoietin levels, which may indicate presence of erythropoietin resistance. The latter may be mediated through inflammatory mechanisms, which is typical for anemia of chronic illness.

Anemia↗
PubMed2005

Transcriptional down-regulation of neurotrophin-3 in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) leads to progressive development of airflow limitation and is characterised by cough, mucus hypersecretion and inflammatory changes. These characteristic features of the disease may be modulated by neural mediators such as neurotrophins (NT). Here we examined the expression and transcriptional regulation of neurotrophins in bronchial biopsies of COPD patients and compared the data to control biopsies. Histology revealed characteristic changes in the COPD tissues, including remodelling of the epithelial lining. RT-PCR demonstrated the mRNA expression of neurotrophins in all biopsies. Immunohistochemistry confirmed the expression of different proteins. To assess changes in the transcriptional expression level, quantitative real-time PCR was carried out and revealed differential mRNA expression of neurotrophins, with marked down-regulation of NT-3 mRNA expression and constant levels of nerve growth factor (NGF), brain-derived nerve factor (BDNF), and NT-4/5 mRNA expression. The present data on neurotrophin-specific transcriptional down-regulation of NT-3 in human COPD indicate a pathophysiological role for neurotrophins in COPD.

Bronchi↗
PubMed2004

Quantification of free RNA in serum and bronchial lavage: a new diagnostic tool in lung cancer detection?

Circulating cell-free nucleic acids have been detected in serum. In cancer patients levels of free DNA seem to be higher than in non-tumor controls and the detectable nucleic acids are partly of tumor origin. We asked whether free RNA can be detected as well in cell-free bronchial lavage fluid (BLF) supernatant, and whether quantification of free RNA allows to discriminate between tumor and non-tumor patients. 73 patients with lung cancer (NSCLC n=62, SCLC n=11) and 56 patients with non-malignant lung diseases were included. The RNA was isolated from 1 mL serum and lavage, respectively with the Quiamp MinElute Virus Vacuum Kit (Qiagen, Germany). A real-time quantitative RT-PCR assay was used for transcript quantification of the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene. Intact RNA was detectable in cell-free supernatants of BLF from 126/129 patients and was investigated in all 64 serum samples. RNA levels were higher in the cell-free supernatant of BLF than in serum. RNA concentration in the BLF from tumor patients was higher than in patients with a benign lung disease (p=0.009). In conclusion, quantification of intact RNA isolated from BLF supernatant and from serum might become a valuable tool for differentiation between tumor and non-tumor patients.

Adult↗
PubMed2004

Substance P expression in TRPV1 and trkA-positive dorsal root ganglion neurons innervating the mouse lung.

In the present study, the co-localisation of substance P (SP) with the vanilloid receptor TRPV1 and the neurotrophin receptor tyrosine kinase trkA was analysed in airway-specific murine dorsal root ganglion (DRG) neurons. DRG neurons labelled with Fast Blue were predominantly found at the segmental levels T2-T5. Immunoreactivity for the receptor TRPV1 was localized to 12% of Fast Blue labelled DRG neurons. Double-labelling immunohistochemistry revealed that a substantial number of them also co-express SP (7.6 +/- 1.1% (mean +/- S.E.M.)), whereas neurons with immunoreactivity for TRPV1 only were found in 4.4 +/- 1.3% of the retrogradely labelled neuronal population. Further analysis of retrogradely labelled neurons showed that their majority expressed trkA (62.8 +/- 1.4%), neurofilament protein 68-kDa (64.8 +/- 1.5%) or glutamate alone (19.5 +/- 1.9%). SP was always expressed in trkA-positive neurons. Based on the extent of co-localization of SP with the receptors TRPV1 and trkA in DRG airway neurons, the present study indicates that the DRG pathway may have effects on the magnitude of neurogenic inflammation in airway diseases such as asthma.

Animals↗
PubMed2004

Hepatotoxic effects of polidocanol in a model of autologously perfused porcine livers.

Polidocanol is an effective sclerosing agent that consists of 95% hydroxypolyethoxydodecane and 5% ethyl alcohol and is known to have a low risk of complications. However, since the compound has been proposed for the local treatment of liver diseases, the potential for topical hepatic side effects should be examined. Therefore, the new model of normothermic-hemoperfused isolated porcine slaughterhouse livers was used to examine polidocanol-hepatotoxicity encompassing the advantages of slaughterhouse organs to reduce animal experiments and autologous blood as an optimal perfusate. Polidocanol was administered via the hepatic artery and portal vein and the effects of the sclerosant on organ function parameters were compared with those in an untreated control group. In contrast to the untreated control organs, significant differences were found in the polidocanol group for parameters such as alanine aminotransferase or organ weight after perfusion. The most striking differences were found for hepatic bile flow, which dropped in the polidocanol group to 0.24+/-0.02 ml/min per 1000 g after administration of the compound compared with 3.80+/-1.08 ml/min per 1000 g in the control group. In summary, the present observations indicate a risk of hepatotoxic effects of polidocanol. Clinicians should be aware of this problem and the use of polidocanol for intrahepatic sclerosing should be restricted to specialized centers.

Animal Testing Alternatives↗
PubMed2004

Inhibition of chemokine production from human airway smooth muscle cells by fluticasone, budesonide and beclomethasone.

Human airway smooth muscle cells (HASMC) contribute to the process of airway wall remodelling in asthma by virtue of their secretory functions. This study was performed to investigate the effectiveness of the commonly used steroids beclomethasone, budesonide and fluticasone in downregulating HASMC production of RANTES and IL-8. HASMC (n=5) were cultured from dissected bronchi using collagenase digestion. Confluent HASMC were exposed to TNFalpha and IL-1beta (10 ng/ml) for 24 h. All stimulations were set with and without pre-treatment with beclomethasone, budesonide or fluticasone for 2 h at concentrations of 10(-9)-10(-6)M. IL-8 and RANTES mRNA expression was assessed by RT-PCR and protein secretion was determined by ELISA. Pre-treatment with beclomethasone, budesonide or fluticasone reduced TNFalpha- and IL-1beta-stimulated IL-8 and RANTES release from HASMC in a dose dependent manner. However, beclomethasone was 22-28% less effective than fluticasone and budesonide in inhibiting chemokine production. TNFalpha- and IL-1beta-induced RANTES and IL-8 expression was reduced on the transcriptional level by pre-treatment with fluticasone and budesonide. The results suggest that the topical steroids fluticasone, budesonide and to a lesser extent beclomethasone may have beneficial effects on airway inflammation in asthma by reducing RANTES and IL-8-induced leukocyte infiltration into the airway wall.

Androstadienes↗
PubMed2004

Detection of cell-free DNA in bronchial lavage fluid supernatants of patients with lung cancer.

Recently, it was shown that it is possible to isolate free circulating DNA from plasma/serum of patients with benign and malignant diseases. In addition, several groups were able to detect tumor-associated alterations in these nucleic acids. We wondered whether any nucleic acids are detectable in cell-free bronchial lavage supernatants, which until now have been discarded after cell harvest. Additionally, we wanted to find out if it is possible to detect tumor-associated alterations in these DNA molecules. DNA was isolated from cell-free lavage supernatants from 30 lung cancer patients, and the DNA was examined for microsatellite alterations. Intact DNA could be isolated from all cell-free bronchial lavage supernatants. Microsatellite alterations were found in lavage supernatants of 12 of 30 patients and in lavage cells of 6 of 30 patients. Altogether, alterations were found in 14 of 30 patients. Thus, we could demonstrate for the first time that it is possible to isolate intact DNA from cell-free bronchial lavage supernatants. Their quantity and quality are sufficient for further amplification via polymerase chain reaction. Altogether, tumor-associated changes were detected in the DNA of 47% of the patients that were analyzed.

Aged↗
PubMed2003

Effects of positive-pressure ventilation on the spontaneous baroreflex in healthy subjects.

To determine the short-term effects of noninvasive positive-pressure ventilation (PPV) on spontaneous baroreflex sensitivity, we acquired time series of R-R interval and beat-to-beat blood pressure in 55 healthy volunteers (mean age 46.5 +/- 10.5 yr) who performed breathing on four occasions at frequencies of 12 and 15 breaths/min without positive pressure (control) and also using PPV of 5 mbar. By using spectral and cross-spectral analysis, R-R interval variability and systolic blood pressure variability as well as the gain (alpha-index) of the baroreceptor reflex were estimated for the low-frequency and high-frequency (HF) bands. Compared with control breathing, PPV at 12 breaths/min and 15 breaths/min led to an increase in mean R-R (P < 0.001) and blood pressure (P < 0.05). The alpha-index of the HF band increased significantly for both respiratory frequencies (P < 0.05) due to PPV. These results indicate that short-term administration of PPV in normal subjects elicits a significant enhancement in the HF index of the baroreflex gain. These findings may contribute to understanding the mechanisms, indications, and effectiveness of positive pressure breathing strategies in treating cardiorespiratory and other disease conditions.

Adult↗
PubMed2003

Calcium-dependent molecular spring elements in the giant protein titin.

Titin (also known as connectin) is a giant protein with a wide range of cellular functions, including providing muscle cells with elasticity. Its physiological extension is largely derived from the PEVK segment, rich in proline (P), glutamate (E), valine (V), and lysine (K) residues. We studied recombinant PEVK molecules containing the two conserved elements: approximately 28-residue PEVK repeats and E-rich motifs. Single molecule experiments revealed that calcium-induced conformational changes reduce the bending rigidity of the PEVK fragments, and site-directed mutagenesis identified four glutamate residues in the E-rich motif that was studied (exon 129), as critical for this process. Experiments with muscle fibers showed that titin-based tension is calcium responsive. We propose that the PEVK segment contains E-rich motifs that render titin a calcium-dependent molecular spring that adapts to the physiological state of the cell.

Amino Acid Motifs↗