Biomedical subjects
H Drexler
Publications and source records attributed to H Drexler.
Assignment of skin notation for MAK values and its legal consequences in Germany.
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Occupationally related tumors in tar refinery workers.
BACKGROUND: The study comprised 606 workers with tar-induced dermatosis employed in a German tar refinery. During the period from 1946 to 1996 they were recognized as having an occupational disease. OBJECTIVE: The aim of this study was to characterize the histologic findings and the localization of the occupational dermatosis and to determine the latency period of the carcinomas from the beginning of exposure in the tar refinery to the first occurrence of malignant skin tumors. Furthermore, the study aimed to check whether other skin changes were frequently diagnosed in addition to known tar-induced tumors. METHODS: The data were collected retrospectively from the documents of the Employer's Liability Insurance Association. RESULTS: Surgical removal of 4754 skin tumors was documented up to the end of 1996 in the study. In 90% of cases the histologic diagnosis was confirmed. Among other conditions, this yielded 2490 precancerous stages, 380 squamous cell carcinomas, 218 basal cell carcinomas, and 182 keratoacanthomas. The skin tumors were found mainly in the facial area, as well as on the forearms and hands. Latency from the first exposure in the tar refinery until manifestation of tar-induced dermatosis covered a period of 57 years. CONCLUSION: In comparison to the general population, the ratio of squamous cell to basal cell carcinomas was shifted toward the squamous cell carcinomas (1.7:1). Sunlight is known to be a cofactor in the pathogenesis of keratosis, squamous cell carcinomas, and basal cell carcinomas. However, the difference in location of these tumors shows that the role sunlight plays in the pathogenesis of precancerous lesions and squamous cell carcinomas may be overvalued. The latency period from the beginning of exposure to the manifestation of squamous cell carcinomas could not be evaluated because of an intervention bias as a result of preventive excisions of precancerous lesions. The frequent occurrence of keratoacanthomas (in 18.7% of the workers) and the early age at which this disease became manifest relative to the general population (median, 55 years) indicate that employment in a tar refinery can primarily or secondarily cause keratoacanthomas.
Inducible nitric oxide synthase in skeletal muscle of patients with chronic heart failure.
OBJECTIVES: The expression and localization of inducible nitric oxide (NO) synthase (NOS II) was evaluated as a source of NO which has been shown to affect muscle contraction. BACKGROUND: Advanced stages of chronic heart failure are associated with systemic activation of cytokines which have been shown to stimulate the expression of NOS II in various cell types, including myocytes. We hypothesized that systemic cytokine activation could lead to expression of NOS II in skeletal muscle of patients with chronic heart failure. METHODS: Skeletal muscle specimens were obtained by percutaneous needle biopsy in six normal volunteers and eight patients with heart failure (New York Heart Association class III). Electron microscopy immunocytochemistry (immunogold labeling) with specific anti-NOS antibodies was utilized to elucidate the intracellular localization of NOS II and neuronal NO synthase (NOS I) in myocytes of skeletal muscle. Reverse transcriptase, competitive polymerase chain reaction (PCR) was applied to quantify NOS II mRNA in skeletal muscle. RESULTS: Inducible nitric oxide synthase was readily expressed in the cytosol of skeletal muscle myocytes; NOS I expression was sparse. Polymerase chain reaction results indicated that NOS II gene expression is increased in patients with chronic heart failure. CONCLUSIONS: Inducible NO synthase is expressed in human skeletal muscle and its gene expression is increased in patients with severe heart failure. Given the experimental evidence that NO can attenuate contractile performance of skeletal muscle and can mediate muscle wasting, an increased local production of NO in skeletal muscle by NOS II may have important implications for patients with severe heart failure.
Expression, activity and functional significance of inducible nitric oxide synthase in the failing human heart.
OBJECTIVES: The study was designed to evaluate the functional impact of nitric oxide (NO) generation within the myocardium on cardiac contraction in the failing human heart. BACKGROUND: Heart failure is associated with activation of cytokines and expression of inducible nitric oxide synthase (NOS II), which generates NO from L-arginine. Nitric oxide has been shown to modulate myocardial performance, raising the possibility that cardiac generation of NO by NOS II modulates cardiac contraction in the failing human heart. METHODS: Left ventricular (LV) tissue of 24 patients with end-stage heart failure was obtained during cardiac transplantation. Gene expression of NOS II and endothelial NO-synthase (NOS III) was quantified by competitive reverse transcription-polymerase chain reaction and compared to tissues of five nonfailing donor hearts. Nitric oxide synthase II activity was determined by citrulline assay and related to changes in force of contraction induced by the beta-adrenergic agonist isoproterenol, NO-donors and/or N-mono-methyl-L-arginine (L-NMMA), an inhibitor of NOS. RESULTS: While NOS III mRNA was reduced in failing hearts, NOS II mRNA was increased in failing LV tissue and correlated with NOS II activity. High NOS II activity was associated with early relaxation and impaired responsiveness to beta-adrenergic stimulation, that is, the inotropic response to isoproterenol in failing hearts was inversely related to NOS II activity (r=0.61, p < 0.005). Nitric oxide donors or L-NMMA did not affect myocardial performance in failing hearts at baseline. However, L-NMMA enhanced the positive inotropic response to beta-adrenergic stimulation in failing hearts with high NOS II activity. Nitric oxide donors attenuated the isoproterenol-induced increase in force of contraction of failing hearts. CONCLUSIONS: Cardiac production of NO by NOS II attenuates the positive inotropic effects of beta-adrenergic stimulation and hastens relaxation in failing human hearts.
Angiotensin-converting enzyme gene expression in skeletal muscle in patients with chronic heart failure.
BACKGROUND: Skeletal muscle factors may influence functional limitation in patients with heart failure. The renin-angiotensin system is activated in chronic heart failure. Treatment with angiotensin-converting enzyme (ACE) inhibitors improve symptoms and prognosis. The goal of this study was to quantify and localize skeletal muscle ACE-mRNA in patients with chronic heart failure and in control subjects, and to elucidate skeletal muscle fiber area and capillary density. METHODS AND RESULTS: Biopsies from the lateral vastus muscle were taken from 9 patients before and after treatment with enalapril and in 10 control subjects. ACE-mRNA was quantified with reverse transcription polymerase chain reaction. Immunohistochemistry was used to localize ACE within skeletal muscle. No difference in ACE-mRNA transcripts between patients and control subjects was detected, nor did ACE gene expression change after treatment with enalapril. The number of ACE-mRNA transcripts was related to muscle fiber area, whereas an inverse relationship between the number of ACE transcripts and capillary density was found. ACE was detected in the endothelial cells of capillaries in skeletal muscle. CONCLUSION: ACE is expressed in skeletal muscle and is confined to endothelial cells. The close relationship between capillary density and number of ACE transcripts indicate that activation of the renin-angiotensin system has an impact on capillary growth.
Cost and benefit in the choice of ECT schedule. Twice versus three times weekly ECT.
BACKGROUND: We compared the antidepressant and cognitive effects of up to eight sessions of bilateral, brief pulse electroconvulsive therapy (ECT) administered twice (ECT x 2) or three times weekly (ECT x 3), to confirm that ECT x 3 acts more rapidly although the two schedules are equivalent in antidepressant outcome, and to establish whether ECT x 3 is indeed associated with more severe memory impairment. METHOD: Patients with major depression, endogenous subtype were randomly assigned to ECT x 3 or ECT x 2 plus one simulated ECT per week, both up to a maximum of eight real ECT. Depression was evaluated by the Hamilton Depression Scale the day after each treatment and cognitive function by a test battery administered before and after the ECT series and at one month follow-up. RESULTS: Assessed categorically or parametrically, there was no significant difference in antidepressant outcome between the two schedules. Rate of response was significantly more rapid with ECT x 3 but was associated with more severe memory impairment. CONCLUSIONS: Twice weekly administration is an optimum schedule for bilateral ECT unless clinical indications require the more rapid antidepressant effect of three times weekly treatment.
Effect of ACE inhibition on endothelial dysfunction in patients with chronic heart failure.
The endothelium controls vascular smooth muscle tone by secreting relaxing and contracting factors. There is a constant release of endothelium-derived relaxing factors(s) (EDRF) under basal conditions. In addition, the endothelium can increase the release of EDRF in response to humoral stimulation by vasoactive substances such as acetylcholine or bradykinin. Under physiological conditions the most important stimulus to the release of EDRF is an increase in blood flow, leading to increased shear stress on endothelial cells. Recent experimental studies have raised the possibility that bradykinin plays an important role in the regulation of vascular tone at rest and during flow-stimulated conditions. Bradykinin is a very potent vasodilator that exerts its vasodilatory actions by causing endothelial release of nitric oxide, prostacyclin and/or endothelium-derived hyperpolarizing factor. Recent studies in humans have demonstrated that bradykinin contributes to the regulation of coronary vascular tone under resting and flow-stimulated conditions. This mechanism has been shown to be important in humans in both peripheral and coronary arteries. Angiotensin-converting enzyme (ACE) inhibitors not only decrease angiotensin II but also increase bradykinin levels, since ACE is identical to kininase II, which degrades bradykinin. The beneficial vascular effects of ACE inhibitors may therefore be related to increased availability of bradykinin. Indeed, we have recently shown that ACE inhibition improves flow-dependent, endothelium-mediated vasodilation and that this beneficial effect is bradykinin-dependent. Our preliminary data also indicate that ACE inhibition improves endothelium-mediated vasodilation in patients with heart failure and coronary artery disease due to an enhanced availability of nitric oxide. These findings suggest that the beneficial vascular effects of ACE inhibition in heart failure may be due in part to improved endothelial function.
Left ventricular contractile effects of inducible nitric oxide synthase in the human allograft.
BACKGROUND: Myocardial expression of inducible (i) nitric oxide (NO) synthase (iNOS) gene has been reported in transplant recipients and in dilated cardiomyopathy. NO derived from NO donor or from coronary endothelium has previously been shown in the human heart to reduce end-systolic left ventricular (LV) pressure, especially during beta-adrenoreceptor stimulation, because of earlier onset of LV relaxation. The present study investigated in transplant recipients whether a similar cardiodepressant effect could be attributed to NO derived from iNOS. METHODS AND RESULTS: In 16 transplant recipients who were free of rejection or graft vasculopathy, microtip LV pressure recordings, LV angiograms, and endomyocardial biopsies were obtained at annual coronary angiography. In 8 transplant recipients, microtip LV pressure recordings were obtained during intravenous dobutamine (5 microg x kg(-1) x min(-1)). Competitive reverse transcription-polymerase chain reaction of iNOS mRNA was performed on the endomyocardial biopsies, and the intensity of iNOS mRNA expression was quantified on a scale ranging from 0 to 5+. All measures of baseline LV function were comparable in transplant recipients with low (< or = 2+) or high myocardial iNOS mRNA. During intravenous dobutamine infusion, there was a significant correlation between the abbreviation of LV electromechanical systole time (LVEST is the time from onset of QRS to dP/dt(min)) and the rise of LV dP/dt(max) (r=.79; P<.02). By use of a multiple regression analysis, addition of the intensity of iNOS mRNA expression as an independent variable significantly (P<.005) improved the correlation between deltaLVEST and deltaLV dP/dt(max) (P<.001; r=.97), implying a larger abbreviation of LV contraction for a similar rise in LV dP/dt(max), when myocardial iNOS mRNA was higher. The larger abbreviation of LV contraction in-patients with high iNOS mRNA was associated with a decrease in LV end-systolic pressure (-31+/-16 mm Hg). CONCLUSIONS: Myocardial iNOS gene expression in the human allograft influences the LV contractile response to beta-adrenergic stimulation through earlier onset of LV relaxation and reduction of LV end-systolic pressure. These effects are similar to the LV contractile effects of NO derived from NO donor or from coronary endothelium.
The kallikrein-kinin system in post-myocardial infarction cardiac remodeling.
Angiotensin converting-enzyme (ACE) inhibitors attenuate cardiac hypertrophy and prolong survival in animal models and patients after myocardial infarction (MI). Considering the dual function of the ACE, the therapeutic efficacy of ACE inhibitors after MI implicates the renin-angiotensin system and/or the kallikrein-kinin system in the pathophysiology of postinfarction cardiac remodeling. We evaluated the role of kinins, and their potential contribution to the antiremodeling effects of ACE inhibition in this setting. Rats underwent coronary artery ligation followed by chronic B2 kinin receptor blockade with icatibant (HOE 140). Additional groups of MI rats were treated with the ACE inhibitor lisinopril, alone or in combination with icatibant. B2 kinin receptor blockade enhanced the deposition of collagen (morphometric analysis) in the left ventricular interstitial space after MI, whereas markers of cardiomyocyte hypertrophy (left ventricular weights and prepro-atrial natriuretic factor [ANF] expression) were not affected. Chronic ACE inhibition reduced collagen deposition and cardiomyocyte hypertrophy after MI. The inhibitory action of ACE inhibition on interstitial collagen was partially reversed by B2 kinin receptor blockade. However, B2 kinin receptor blockade did not attenuate the effects of ACE inhibition on cardiomyocyte hypertrophy. In conclusion, kinins inhibit the interstitial accumulation of collagen, but do not modulate cardiomyocyte hypertrophy after MI. Kinins contribute to the reduction of myocardial collagen accumulation by ACE inhibition; however, the effects of ACE inhibition on cardiomyocyte hypertrophy are related to reduced generation of angiotensin II.
Differential effects of kinins on cardiomyocyte hypertrophy and interstitial collagen matrix in the surviving myocardium after myocardial infarction in the rat.
BACKGROUND: Left ventricular remodeling after myocardial infarction (MI) involves the hypertrophic growth of cardiomyocytes and the accumulation of fibrillar collagen in the interstitial space. We evaluated the role of kinins in postinfarction ventricular remodeling and their potential contribution to the antiremodeling effects of ACE inhibition and angiotensin II type 1 (AT1) receptor blockade. METHODS AND RESULTS: Rats underwent coronary artery ligation followed by chronic B2 kinin receptor blockade with icatibant. Additional groups of infarcted rats were treated with the ACE inhibitor lisinopril or the AT1 receptor antagonist ZD7155, each separately and in combination with icatibant. B2 kinin receptor blockade enhanced the interstitial deposition of collagen after MI, whereas morphological and molecular markers of cardiomyocyte hypertrophy (cardiac weight, myocyte cross-sectional area, prepro-atrial natriuretic factor mRNA expression) were not affected. Chronic ACE inhibition and AT1 receptor blockade reduced collagen deposition and cardiomyocyte hypertrophy after MI. The inhibitory action of ACE inhibition and AT1 receptor blockade on interstitial collagen was partially reversed by B2 kinin receptor blockade. However, B2 kinin receptor blockade did not attenuate the effects of ACE inhibition and AT1 receptor blockade on cardiomyocyte hypertrophy. CONCLUSIONS: (1) Kinins inhibit the interstitial accumulation of collagen but do not modulate cardiomyocyte hypertrophy after MI. (2) Kinins contribute to the reduction of myocardial collagen accumulation by ACE inhibition and AT1 receptor blockade. (3) The effects of ACE inhibition and AT1 receptor blockade on cardiomyocyte hypertrophy are related to a reduced generation/receptor blockade of angiotensin II.
Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans.
BACKGROUND: The angiotensin-converting enzyme (ACE) not only generates angiotensin II but is also the main enzyme that destroys bradykinin. It has been hypothesized, therefore, that bradykinin is involved in the vascular effects of ACE inhibitors. However, its contribution has never been demonstrated in humans because of the lack of specific bradykinin receptor antagonists. METHODS AND RESULTS: High-resolution ultrasound and Doppler were used to measure radial artery diameter and blood flow in 10 healthy volunteers. The vascular effects of the ACE inhibitor quinaprilat, the selective bradykinin B2-receptor antagonist icatibant, and their combination were determined at rest, during reactive hyperemia (with increased flow causing endothelium-mediated, flow-dependent dilation), and during sodium nitroprusside, causing endothelium-independent dilation. Neither icatibant nor quinaprilat affected arterial diameter or blood flow at rest. However, icatibant reduced flow-dependent dilation by 33%, and quinaprilat increased flow-dependent dilation over baseline by 46%. After coinfusion of quinaprilat and icatibant, flow-dependent dilation was reduced to a similar extent as after infusion of icatibant alone. CONCLUSIONS: ACE inhibition enhances flow-dependent, endothelium-mediated dilation in humans by a bradykinin-dependent mechanism. This observation indicates that accumulation of endogenous bradykinin is involved in the vascular effects of ACE inhibitors in humans.
Expression and function of the cardiac Na+/Ca2+ exchanger in postnatal development of the rat, in experimental-induced cardiac hypertrophy and in the failing human heart.
The diastolic and systolic dysfunction in the failing heart appear to be related to the altered Ca2+ handling of the cardiac myocyte. Disturbed Ca2+ handling might also affect influx and efflux of other ions, including Na+. In this context, the cardiac sarcolemmal Na+/Ca2+ exchanger represents an important exchange mechanism of Ca2+ versus Na+ transport across the sarcolemma. Expression and function of cardiac Na+/Ca2+ exchanger is highest in newborn rats and declines gradually in postnatal development. In pressure overload-induced hypertrophy, expression of cardiac Na+/Ca2+ exchanger is increased and translated into increased Na+/Ca2+ exchanger activity similar to the early phase of postnatal development in the rat. This suggests a common underlying mechanism in the control of Na+/ Ca2+ exchanger expression in the immature and the hypertrophied myocardium. Similar to experimental-induced hypertrophy, mRNA, protein and activity of Na+/ Ca2+ exchanger is increased in the failing human heart suggesting an increase in the number of functional exchanger molecules rather than an enhanced exchange rate by preexisting exchanger molecules. The potential functional implications of an increased cardiac Na+/Ca2+ exchanger activity in human heart failure may be limitation of diastolic intracellular Ca2+ overload. However, this may increase the arrhythmogenic potential of the failing heart, since additional Na+ influx via Na+/Ca2+ exchanger may affect the membrane potential.
[Therapy of chronic cardiac insufficiency with ACE inhibitors versus AT1 receptor antagonists. Is there a difference?].
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Neurotoxicity of long-term low-level exposure to carbon disulphide: results of questionnaire, clinical neurological examination and neuropsychological testing.
OBJECTIVE: Carbon disulphide (CS2) is highly neurotoxic. There is ample evidence of damage to the peripheral and central nervous system. The air concentration at which such adverse effects can first be observed is presently a subject of controversy. METHODS: In a cross-sectional study of CS2-exposed workers from the viscose industry and healthy controls, data on neurological complaints, basic laboratory diagnosis, clinical neurological examination and neuropsychological testing were evaluated. Data were from 222 workers in the viscose industry exposed to CS2 and 191 employees from the same factory with similar physical and psychological stress factors but without occupational contact with neurotoxic substances. Multiple linear or multiple logistic regression analysis was used to check for statistical differences. RESULTS: The median of the CS2-measurements using personal air sampling was below the current maximum concentration permissible (MAK value) in Germany (10 ppm) in all departments. The threshold limit value was, however, exceeded in almost 10% of the persons investigated. Exposure fluctuated between < 0.2 and 65.7 ppm (median of all departments was 4.02 ppm). As a parameter of internal exposure, CS2-metabolite 2-thio-1,3-thiazolidine-4-carboxylic acid (TTCA) concentrations in the urine of the exposed persons were between < 0.16 and 10.9 mg/g creatinine (median 1.43 mg/g). CONCLUSIONS: Neither an increase in subjective complaints nor an increase in pathological findings in clinical-neurological and neuropsychological examination could be found in persons exposed to CS2 at the exposure levels described.
Electrophysiological investigation of central, peripheral and autonomic nerve function in workers with long-term low-level exposure to carbon disulphide in the viscose industry.
OBJECTIVE: Neurotoxicity of carbon disulphide (CS2) is well known. The air concentration at the workplace at which such adverse effects can first be observed is the subject of controversial discussion. METHODS: In a cross-sectional study on CS2-exposed workers peripheral motor and sensory nerve conduction studies, somatosensory evoked potentials, thermotesting and investigation of forced respiration sinus arrythmia have been carried out. The data from 222 workers exposed to CS2 in the viscose industry were evaluated and compared with data from 191 employees from the same factory with similar physical and psychological stress factors but without detectable occupational contact to neurotoxic substances. Median exposure to CS2 was below the currently valid occupational-medical threshold limit value (MAK-value) of 10 ppm. Multiple linear or multiple logistic regression analysis was used to check for statistical differences. RESULTS: Binary evaluation (comparison of exposed persons versus controls after multiple linear regression) revealed a slightly lower value in the exposed group for the motor nerve conduction velocity (MNCV, -0.76 m/s, median 48 m/s), but a long way from pathological thresholds. No dose-response relationship could be found within the exposed group for any evaluation criteria of CS2-exposure. Somatosensory evoked potentials, thermotesting and analysis of heart rate variability yielded no indication of a neurotoxic effect of CS2. CONCLUSION: Isolated decrease of MNCV in binary evaluation is, with regard to the known mechanism of CS2-neurotoxicity and the lack of a dose-response relationship, obviously not due to toxic effects. We interpret our results as showing that an adverse effect of carbon disulphide at the exposure ranges found was not detectable in the exposed group.
Effects of alpha-adrenergic stimulation on the sarcolemmal Na+/Ca(2+)-exchanger in adult rat ventricular cardiocytes.
OBJECTIVE: The cardiac sarcolemmal Na+/Ca(2+)-exchanger (NCX) plays an important role in the maintenance of the myocardial Ca2+ homeostasis which is altered in cardiac hypertrophy and failure. The aim of the present study was to investigate whether alpha-adrenergic stimulation known to induce cardiac hypertrophy might be involved in the regulation of the sarcolemmal NCX. METHODS: Adult rat ventricular cardiocytes (ARC) were isolated from male Sprague-Dawley rats. Phenylephrine, an alpha-adrenergic agonist, was used as hypertrophic agent. NCX expression was measured by competitive RT-PCR and Western blot analysis. RESULTS: alpha-Adrenergic stimulation of ARC with 10 microM phenylephrine for 24 h resulted in a significant increase of the NCX mRNA (2.5-fold) and the NCX protein level (1.8-fold). The changes on the expression level were blocked by the alpha 1-adrenoceptor antagonist prazosin. CONCLUSIONS: The data demonstrate that the NCX expression level is up-regulated by the activation of the alpha-adrenergic signal transduction pathway. The increased NCX mRNA level induced by alpha-adrenergic stimulation appeared to be translated into increased NCX protein level.