Variable titin-based stiffness adjustment in heart disease.
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Alternative Splicing↗
Biomedical subjects
Christian Witt
Publications and source records attributed to Christian Witt.
Quantitative Brewster angle microscopy of the surface film of human broncho-alveolar lavage fluid.
The morphology, thickness and surface pressure of the surfactant film of broncho-alveoalar lavage (BAL) fluid from patients with sarcoidosis were investigated during spontaneous adsorption of the BAL's surface active material at the air/aqueous buffer interface at 37 degrees C. The biochemical parameters of the BAL fluid determined were protein (Lowry), total phospholipids (from phosphate after ashing) and the individual phospholipids (HPLC). During the spontaneous adsorption of the pulmonary surfactant the surface pressure increased from initially 26 mN/m to 44 mN/m in the equilibrium state. Simultaneously to the increase of the surface pressure, a continuous increase of the reflectivity signal was observed by quantitative Brewster angle microscopy (BAM). The film thickness is calculated from the reflectivity values using an optical model. The effect of the uncertainty of the refractive index, which has to be estimated, is discussed. The BAM images show the inhomogeneous nature of the surfactant film with three distinct phases of different reflectivity, even at relatively low surface pressures. For the brightest phase, the thickness amounts to approximately 12 nm in the equilibrium state of adsorption. This suggests a multilamellar structure. Additionally, we found visual evidence for an adsorption mechanism involving the spreading of vesicles at the interface, in agreement with published results. Differences in the morphology and thickness of the pulmonary surfactant film reported in the literature are obviously due to the varying experimental conditions and materials. We think that the experimental conditions chosen in our study provide a more realistic view of the structure in the lungs in vivo.
Bronchoalveolar Lavage Fluid↗
Adaptations in titin's spring elements in normal and cardiomyopathic hearts.
The giant elastic protein titin contains an extensible segment that underlies the majority of physiological passive muscle stiffness. The extensible segment comprises mechanically distinct and serially-linked spring elements: the tandem Ig segments, the PEVK and the cardiac-specific N2B unique sequence. Under physiological conditions the tandem Ig segments are likely to largely consist of folded Ig domains whereas the N2B unique sequence and PEVK are largely unfolded and behave as wormlike chains with different persistence lengths. The mechanical characteristics of titin's extensible region may be tuned to match changing mechanical demands placed on muscle, using mechanisms that operate at different time scales and that include post-transcriptional and post-translational processes.
Actins↗
Ultraflex expandable metallic stents: difficulties in benign tracheal stenoses.
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Humans↗
Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease.
BACKGROUND: We compared the efficacy and safety of the low-molecular weight heparin enoxaparin with unfractionated heparin (UFH) for the prevention of venous thromboembolic disease in patients with heart failure or severe respiratory disease. METHODS: This was a multicenter, controlled, randomized, open study in which patients received either enoxaparin (40 mg once daily) or UFH (5000 IU 3 times daily) for 10 +/- 2 days in 64 medical departments in Germany. Patients were stratified and enrolled according to their underlying disease: severe respiratory disease or heart failure. The primary efficacy parameter was a thromboembolic event up to 1 day after the treatment period. RESULTS: Of the 665 patients enrolled, 451 patients were able to be evaluated in the primary efficacy analysis. The incidence of thromboembolic events was 8.4% with enoxaparin and 10.4% with UFH. Enoxaparin was at least as effective as UFH, with a 1-sided equivalence region of -4% (90% CI -2.5-6.5, P =.015). Enoxaparin was associated with fewer deaths, less bleeding, and significantly fewer adverse events (45.8% vs 53.8%, P =.044). CONCLUSIONS: Enoxaparin is at least as effective as UFH in the prevention of thromboembolic events in patients with heart failure or severe respiratory disease. Its beneficial safety profile and once-daily administration is advantageous for inpatient and outpatient use.
Aged↗
Increased spontaneous interleukin-10 release from alveolar macrophages in active pulmonary sarcoidosis.
The study was designed to determine whether alveolar macrophages (AM) in acute pulmonary sarcoidosis release in vitro the anti-inflammatory cytokine interleukin (IL)-10. To learn more about the coherence between IL-10 and proinflammatory cytokines in active sarcoidosis, the release of interferon (IFN)-gamma, macrophage inhibitory protein (MIP)-1alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF) was studied and additionally compared to normal controls and patients with pneumonia and interstitial lung fibrosis. AM were obtained by bronchoalveolar lavage from 13 patients with active sarcoidosis, 8 patients with interstitial lung fibrosis, 10 patients with bacterial pneumonia, and 14 normal controls. The spontaneous and stimulated (tumor necrosis factor [TNF]-alpha, IL-1beta) cytokine release was measured in the supernatant of cultured AM by enzyme-linked immunosorbent assay (ELISA). Unstimulated AM from sarcoidosis patients released more IL-10, IFN-gamma, MIP-1alpha, and GM-CSF than normal controls and patients with pneumonia and interstitial lung disease. Stimulation with TNF-alpha or IL-1beta increased the MIP-1alpha and GM-CSF release from AM of normal controls and patients with pneumonia and interstitial lung disease: however, no further enhancement of MIP-1alpha and GM-CSF production was observed in AM from sarcoidosis patients. Exogenous IL-10 reduced the spontaneous and stimulated MIP-1alpha and GM-CSF release in sarcoidosis to a lesser extent than in controls and patients with fibrosis and pneumonia. The up-regulated IL-10 in active pulmonary sarcoidosis may be a compensatory response to the enhanced expression of proinflammatory cytokines in order to down-regulate the inflammatory process. The results suggest an involvement of the anti-inflammatory cytokine IL-10 in the immunopathogenesis of sarcoidosis.
Adult↗
Distribution of respiratory mucin proteins in human nasal mucosa.
OBJECTIVES/HYPOTHESIS: The upper respiratory tract is involved in many acute and chronic respiratory tract diseases that present with the symptom of mucus hypersecretion. Mucin genes that encode for the backbone of glycoproteins contribute to the viscoelastic property of airway mucus. We examined the cellular expression and distribution of two major respiratory mucus-forming glycoproteins, MUC5AC and MUC5B, in normal human nasal tissues. METHODS: Immunohistochemical analysis using polyclonal antibodies against the mucins MUC5AC and MUC5B was performed in normal human nasal tissues. RESULTS: An abundant staining of submucosal mucus gland and epithelial goblet cells for MUC5B was found. Immunohistochemical analysis of MUC5AC showed staining of surface epithelium goblet cells, whereas there was no staining of glandular cells. Comparison of the expression to lower airways revealed a similar pattern of expression of both mucins. CONCLUSIONS: The data in the present study demonstrated the localization of the two major respiratory mucin proteins in human nasal mucosa with a similar distribution of expression of MUC5AC and MUC5B in normal upper and lower airways. Mucin protein expression parallels that of mucin messenger RNA expression.
Acute Disease↗
Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin.
Tibial muscular dystrophy (TMD) is an autosomal dominant late-onset distal myopathy linked to chromosome 2q31. The linked region includes the giant TTN gene, which encodes the central sarcomeric protein, titin. We have previously shown a secondary calpain-3 defect to be associated with TMD, which further underscored that titin is the candidate. We now report the first mutations in TTN to cause a human skeletal-muscle disease, TMD. In Mex6, the last exon of TTN, a unique 11-bp deletion/insertion mutation, changing four amino acid residues, completely cosegregated with all tested 81 Finnish patients with TMD in 12 unrelated families. The mutation was not found in 216 Finnish control samples. In a French family with TMD, a Leu-->Pro mutation at position 293,357 in Mex6 was discovered. Mex6 is adjacent to the known calpain-3 binding site Mex5 of M-line titin. Immunohistochemical analysis using two exon-specific antibodies directed to the M-line region of titin demonstrated the specific loss of carboxy-terminal titin epitopes in the TMD muscle samples that we studied, thus implicating a functional defect of the M-line titin in the genesis of the TMD disease phenotype.
Amino Acid Sequence↗
Infection of cells with replication deficient adenovirus induces cell cycle alterations and leads to downregulation of E2F-1.
Gene products of recombinant replication-deficient adenovirus vectors of the first generation (Ad vector) can induce cell cycle dysregulation and apoptosis after infection in eukaryotic cells. The mechanisms underlying this complex process are largely unknown. Therefore, we investigated the regulation of the pRb/E2F-1 complex, which controls transition from G(0)/G(1) to S phase of the cell cycle. As Ad vector infection results in a decrease in the number of cells in G(0)/G(1) phase of the cell cycle, we observed a decline of the pRb protein level and, surprisingly, also a decrease of the E2F-1 protein and mRNA level in infected cell lines. Furthermore, in contrast to the reduction of cells in the G(0)/G(1) phase we observed increased protein levels of p53 and p21 proteins. However, as experiments in p53 deficient cell lines indicated, the decrease of pRb and E2F-1 is independent of p53 and p21 expression. Moreover, results obtained with Rb deficient cell lines indicated that the reduced E2F-1 expression is independent of pRb. These results suggest that Ad vector-induced cell cycle dysregulation is associated with a specific downregulation of E2F-1 independent of Rb and p53 genomic status of cells.
Adenoviridae↗
Innervation of human nasal mucosa in environmentally triggered hyperreflectoric rhinitis.
Hyperreflectoric rhinitis is related to an unspecific hyperreactivity probably caused by chemical irritants. As a major modulatory role may be attributed to the mucosal innervation, the present study was carried out to examine possible changes in the nasal mucosa innervation. Immunohistochemistry for the neuropeptides vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), substance P (SP) and neuropeptide tyrosine (NPY) revealed abundant staining of nerve fibers. Neuropeptide-contents in mucosal nerves was then quantitatively assessed and significant increases were found for SP (3.00 +/- 0.37 vs. 1.64 +/- 0.34 control group staining intensity) and VIP (2.33 +/- 0.42 vs. 0.82 +/- 0.33). In conclusion, these findings demonstrated differences in human nasal mucosa innervation between nonrhinitic and hyperreflectoric rhinitic subjects and provide evidence for a modulatory participation of neuropeptide-specific subpopulations of nerve fibers in hyperreflectoric rhinitis.
Adolescent↗
Automated analysis of data is inferior to visual analysis of ambulatory sleep apnea monitoring.
BACKGROUND: Many ambulatory sleep apnea monitoring devices are equipped with software which allows an automated analysis of data as well as a visual analysis. OBJECTIVE: The Merlin system which records heart rate, snoring sound, efforts, oronasal flow, body position and oxygen saturation was investigated to identify proper parameter settings for the automated analysis and to compare the automated with the visual analysis in patients with mild obstructive sleep apnea syndrome (OSAS). Sensitivity and specificity of the visual and automated analysis of ambulatory monitoring in comparison with visual polysomnographic (PSG) analysis were determined. METHODS AND RESULTS: First, we tried to find the optimal parameters for the automated analysis, using 7 different settings in 17 OSAS patients. Furthermore, we applied the optimized setting to 66 OSAS patients who were admitted (age 50.9 +/- 9.9 years, BMI 32.9 +/- 5 kg/m(2)), and compared the results with the visual analysis of raw data. The patients slept for one night in the sleep laboratory with Merlin and PSG simultaneously to compare the visual and automated analysis of Merlin data with results from the visual analysis of PSG. Automated analysis leads to an underestimation of the respiratory disturbance index (RDI; p < 0.001) compared with both the visual analysis and results of PSG. Using a cutoff level of 5 apneas and hypopneas/h for the diagnosis of OSAS, the sensitivity of Merlin with the automated analysis is 40.6% and the specificity is 100%. With a cutoff level of 15/h, sensitivity and specificity rose to 91.3 and 100%, respectively, which is comparable to the visual analysis. CONCLUSION: Merlin is a reliable device for detection of sleep-related breathing disorders, but recordings should be analyzed visually, especially in patients with a low RDI.
Adult↗
Increased production of matrix metalloproteinase-2 in alveolar macrophages and regulation by interleukin-10 in patients with acute pulmonary sarcoidosis.
Matrix metalloproteinases (MMPs) and cathepsins have been implicated in the pathogenesis of several interstitial lung diseases by their effects on inflammatory processes and extracellular matrix remodelling. The aim of this study was to investigate whether macrophage-derived MMPs and cathepsins are involved in the pathogenesis of sarcoidosis. Therefore the release of MMP-2, MMP-9, and cathepsins B and L from alveolar macrophages (AM) in active pulmonary sarcoidosis was studied and compared to normal controls and patients with pneumonia and fibrosis. Patients with sarcoidosis (n = 11), pulmonary fibrosis (n = 7), and pneumonia (n = 9) and normal controls (n = 10) were enrolled in the study. AM were obtained by bronchoalveolar lavage and cultured without stimulation and in presence of tumor necrosis factor alpha (TNFalpha) and interleukin-10 (IL-10). The release of cathepsins and MMPs as well as IL-10 and TNFalpha was measured in the supernatant of cultured AM by fluorimetric assays and zymography. AM of patients with sarcoidosis and pneumonia spontaneously released more MMP-2 than normal controls. Stimulation with TNFalpha showed no effects on MMP-2 and MMP-9 production. Exogenous IL-10 led partially to an inhibition of the MMP-2 and MMP-9 release. Patients with sarcoidosis produced significantly more IL-10 and TNFalpha than normal controls. This was not observed in patients with fibrosis and pneumonia. The spontaneous release of cathepsins B and L did not differ between the patient groups and normal controls and was not affected by TNFalpha and IL-10. The data show that AM of patients with sarcoidosis and pneumonia release significant amounts of MMP-2. The endogenous production of IL-10 in AM of patients with sarcoidosis and the MMP downregulation by exogenous IL-10 suggest an involvement of IL-10 in MMP regulation. Furthermore the results suggest that the production of MMP-2 is more specific for acute lung injury, rather than for a single lung disease such as sarcoidosis.
Adult↗
Isolated hemoperfused slaughterhouse livers as a valid model to study hepatotoxicity.
Different models of isolated and perfused livers and precision cut liver slices have been developed for studies on liver toxicology the past years. As most of these models were limited by nonphysiologic settings, a new model of normothermic hemoperfused isolated porcine slaughterhouse livers to examine hepatotoxicity was established encompassing the advantages of slaughterhouse organs to reduce animal experiments and autologous blood as an optimal perfusate. As model compound, the analgesic substance diclofenac was used and the effects of this drug on organ function parameters were compared to an untreated control group. Using an amount of 2,000 ml, the organs were perfused over 180 minutes, metabolically controlled via a dialysis and oxygenation system and various hematological and hepatic parameters were examined. In contrast to the untreated control organs, significant differences were found in the diclofenac group for parameters such as lactate, creatinine, ALT, bicarbonate, or bile flow. In summary, the presently established model of isolated hemoperfused slaughterhouse livers displays a useful new approach to assess hepatotoxicity of different substances on the organ level. As a major economic advantage in comparison to setups using laboratory animals, the new model can be run with blood and organs obtained from slaughterhouse animals.
Animals↗
Toxic rhinitis-induced changes of human nasal mucosa innervation.
Irritative toxic rhinitis is a nasal disorder induced by chemical compounds like ozone, formaldehyde, nickel, chrome, solvents and tobacco smoke. These noxious stimuli may have effects on the nasal innervation leading to a cascade of neuro-immune interactions and an augmentation of the symptoms. Here we examined changes in the neuropeptide content of mucosal parasympathetic, sympathetic and sensory nerves of patients with toxic rhinitis caused by chronic cigarette smoke exposure. Semiquantitative immunohistochemistry using antibodies against calcitonin gene-related peptide (CGRP), substance P (SP), neuropeptide tyrosine (NPY), and vasoactive intestinal peptide (VIP) was carried out on cryostat sections of human nasal mucosa obtained from normal subjects and patients with toxic rhinitis and revealed significant differences between both groups. Toxic rhinitis patients had significantly elevated expression scores for VIP (2.83 +/- 0.31 vs 1.27 +/- 0.47 control group) and NPY (3.17 +/- 0.31 vs 0.91 +/- 0.37 control group) revealing an increase of mediators in distinct subpopulations of airway nerves. In summary, the present studies indicate a differential participation of subclasses of mucosal nerves in the pathophysiology of toxic rhinitis. Airway innervation may have a major role in the pathophysiology of toxic rhinitis associated with chronic cigarette smoke exposure.
Adolescent↗