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Biomedical subjects

M Orth

Publications and source records attributed to M Orth.

At least 73 records · Page 4Linked to original sources
PubMed1998

Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females.

Apolipoprotein E (apoE) mediates the redistribution of lipids among cells and is expressed at highest levels in brain and liver. Human apoE exists in three major isoforms encoded by distinct alleles (epsilon2, epsilon3, and epsilon4). Compared with APOE epsilon2 and epsilon3, APOE epsilon4 increases the risk of cognitive impairments, lowers the age of onset of Alzheimer's disease (AD), and decreases the response to AD treatments. Besides age, inheritance of the APOE epsilon4 allele is the most important known risk factor for the development of sporadic AD, the most common form of this illness. Although numerous hypotheses have been advanced, it remains unclear how APOE epsilon4 might affect cognition and increase AD risk. To assess the effects of distinct human apoE isoforms on the brain, we have used the neuron-specific enolase (NSE) promoter to express human apoE3 or apoE4 at similar levels in neurons of transgenic mice lacking endogenous mouse apoE. Compared with NSE-apoE3 mice and wild-type controls, NSE-apoE4 mice showed impairments in learning a water maze task and in vertical exploratory behavior that increased with age and were seen primarily in females. These findings demonstrate that human apoE isoforms have differential effects on brain function in vivo and that the susceptibility to apoE4-induced deficits is critically influenced by age and gender. These results could be pertinent to cognitive impairments observed in human APOE epsilon4 carriers. NSE-apoE mice and similar models may facilitate the preclinical assessment of treatments for apoE-related cognitive deficits.

Age Factors↗
PubMed1998

K-ras mutations at codon 12 are rare events in chronic pancreatitis.

BACKGROUND/AIMS: The activation of the K-ras gene at codon 12 is thought to be an early genetic event in the multistep pathogenesis of pancreatic cancer. Since the risk of pancreatic cancer is significantly elevated in subjects with chronic pancreatitis, the aim of the present study was to determine the frequency of K-ras mutations in chronic pancreatitis. METHODS: Pancreatic DNA from intraoperatively resected tissues of 60 patients with chronic pancreatitis and 11 patients with histologically confirmed pancreatic carcinoma was evaluated by PCR amplification and restriction fragment length polymorphism analysis. RESULTS: In none of the 60 samples of chronic pancreatitis could K-ras mutations be identified using two independent PCR assays. In 5 of 11 patients with pancreatic carcinoma, K-ras mutations in codon 12 were detected. CONCLUSION: These data indicate that K-ras mutations are rare events in chronic pancreatitis. Alternatively, it is possible that the time span between the occurrence of K-ras mutations and malignant transformation is rather short.

Carcinoma↗
PubMed1998

The diagnostic value of serum homocysteine concentration as a risk factor for coronary artery disease.

Hyperhomocysteinemia is now regarded as an established risk factor for coronary artery disease and is present frequently in the general population. However, the diagnostic value of this risk factor relative to others has only occasionally been investigated. We compared the diagnostic value of classic risk factors and of homocysteine in a retrospective case-control study in 191 cases with angiographically established coronary artery disease and 231 healthy controls. Life style habits were assessed by a detailed questionnaire. Laboratory parameters including lipoproteins and blood lipids, homocysteine, folate, and vitamin B12 were measured and their diagnostic value compared with each other by use of receiver-operator characteristic analysis. Comparison of the receiver-operator characteristic curves revealed that homocysteine significantly discriminated between cases and control subjects. High-density-lipoprotein cholesterol, triglycerides and non-esterified fatty acids also had an area under the curve significantly different from 0.5 (the area under the curve representing no discrimination). Homocysteine was weakly related to folate, vitamin B12, age and serum creatinine concentration. We conclude that hyperhomocysteinemia is at least as important as conventional risk factors for coronary artery disease and that receiver operator characteristic analysis of homocysteine is suitable to determine patients at the highest risk for coronary artery disease. Clinical trials testing the effect of homocysteine lowering by vitamin supplementation in the prevention of coronary artery disease are needed.

Coronary Disease↗
PubMed1998

[Effect of salmeterol in obstructive sleep apnea syndrome].

The effect of inhaled long-acting beta 2-agonists on obstructive sleep apnoea syndrome (OSAS) is unknown, though from the pharmacological point of view both therapeutic and adverse effects might be discussed. The purpose of this study was to obtain data on the efficacy and safety of Salmeterol in patients with OSAS. In a randomised, double-blind, placebo-controlled, crossover study effects of Salmeterol were investigated in 20 patients with OSAS: 4 female, 16 male; age 53.0 +/- 7.8 years, body mass index (BMI) 28.0 +/- 3.0 kg.m-2; apnoea hypopnoea index (AHI) 35.6 +/- 17.8 h-1. Patients with asthma, chronic obstructive pulmonary disease (COPD), and left heart failure were excluded. Placebo or verum (50 micrograms Salmeterol) were administered at 7 p.m. by metered dose inhaler and spacer device. All patients underwent full polysomnography during baseline, placebo, and verum night. Statistical analysis was performed by Student's t-test (p < 0.05). Between placebo and verum there were no differences in total sleep time, sleep stages, apnoea index (AI), AHI, and nadir SaO2. There was, however, a significant deterioration of mean SaO2 (placebo 93.1 +/- 2.0 vs Salmeterol 92.5 +/- 2.2%) and of relative time spent with SaO2 < or = 90% (placebo 13.1 +/- 14.5 vs Salmeterol 19.5 +/- 20.8%), as well as a significant increase in heart rate (placebo 63.1 +/- 9.2 vs Salmeterol 65.6 +/- 9.3 h-1). Thus, in patients with OSAS Salmeterol had no adverse effect on quality of sleep, AI or AHI. The slight increase in heart rate and the deterioration of oxygen saturation are clinically irrelevant. The latter might be due to ventilation-perfusion-mismatch. This study demonstrates that Salmeterol has no influence on obstructive sleep apnoea and hypopnoea, but on the other hand provides an acceptable safety profile in OSAS. This might be of special importance in patients suffering from both OSAS and obstructive airway disease.

Adrenergic beta-Agonists↗
PubMed1998

Fluorometric determination of total retinyl esters in triglyceride-rich lipoproteins.

A time-consuming sample preparation and measuring procedure is required for the quantitation of retinyl palmitate by HPLC. We developed a fluorometric method for the determination of total retinyl esters in chylomicrons, chylomicron remnants, and VLDL. This method is precise, sensitive, rapid, simple, and particularly useful for large-scale studies of postprandial lipid metabolism. Because the turbidity of postprandial lipemic samples interferes with the fluorescence measurement, all samples were incubated for 10 min with a clearing buffer containing esterase and detergents. This buffer eliminates the turbidity and hydrolyzes all retinyl esters to retinol. The fluorescence signal (excitation wavelength, 330 nm; emission wavelength, 490 nm) was linear from 0.1 mg/L up to 4 mg/L retinyl palmitate, and the CVs were 3.6% within-run and 5.1% within-series. A first application studied postprandial lipoproteins, which were first separated by ultracentrifugation and then subjected to size exclusion chromatography. Fluorescence analysis revealed that the chylomicron density fraction contains large amounts of chylomicron remnants.

Buffers↗
PubMed1998

[Diagnosis of gallstone ileus].

Gallstone ileus is a rare disorder, which, because it is often misdiagnosed preoperatively, may become life-threatening. The classic triad of Rigler (aerobilia, small bowel ileus and a calcified, dystopic stone) is visualized on abdominal plain films in only 14-35% of cases. Further work-up includes ultrasound, upper gastrointestinal series with water soluble contrast medium and computed tomography (CT). CT is especially reliable in demonstrating all three criteria.

Aged↗
PubMed1997

Nacystelyn, a novel lysine salt of N-acetylcysteine, to augment cellular antioxidant defence in vitro.

Nacystelyn (NAL), a recently-developed lysine salt of N-acetylcysteine (NAC), and NAG, both known to have excellent mucolytic capabilities, were tested for their ability to enhance cellular antioxidant defence mechanisms. To accomplish this, both drugs were tested in vitro for their capacity: (1) to inhibit O2- and H2O2 in cell-free assay systems; (2) to reduce O2- and H2O2 released by polymorphonuclear leukocytes (PMN); and (3) for their cellular glutathione (GSH) precursor effect. In comparison with GSH, NAL and NAC inhibited H2O2, but not O2-, in cell-free, in vitro test systems in a similar manner. The anti-H2O2 effect of these drugs was as potent as that of GSH, an important antioxidant in mammalian cells. To enhance cellular GSH levels, increasing concentrations (0-2 x 10(-4) mol l-1) of both substances were added to a transformed alveolar cell line (A549 cells). After NAC administration (2 x 10(-4) mol l-1), total intracellular GSH (GSH + 2GSSG) levels reached 4.5 +/- 1.1 x 10(-6) mol per 10(6) cells, whereas NAL increased GSH to 8.3 +/- 1.6 x 10(-6) mol per 10(6) cells. NAC and NAL administration also induced extracellular GSH secretion; about two-fold (NAC), and 1.5-fold (NAL), respectively. The GSH precursor potency of cystine was about two-fold higher than that of NAL and NAC, indicating that the deacetylation process of NAL and NAC slows the ability of both drugs to induce cellular glut production and secretion. Buthionine-sulphoximine, which is an inhibitor of GSH synthetase, blocked the cellular GSH precursor effect of all substances. In addition, these data demonstrate that NAC and NAL reduce H2O2 released by freshly-isolated cultured blood PMN from smokers with chronic obstructive pulmonary disease (COPD) (n = 10) in a similar manner (about 45% reduction of H2O2 activity by NAC or NAL at 4 x 10(-6) mol l-1). In accordance with the results obtained from cell-free, in vitro assays, O2- released by PMN was not affected. Ambroxol (concentrations: 10(-9)-10(-3) mol l-1) did not reduce activity levels of H2O2 and O2- in vitro. Due to the basic effect of dissolved lysine, which separates easily in solution from NAL, the acidic function of the remaining NAC molecule is almost completely neutralized [at concentration 2 x 10(-4) M: pH 3.6 (NAC), pH 6.4 (NAL)]. Due to their function as H2O2 scavengers, and due to their ability to enhance cellular glutathione levels, NAL and NAC both have potent antioxidant capabilities in vitro. The advantage of NAL over NAC is two-fold; it enhances intracellular GSH levels twice as effectively, and it forms neutral pH solutions whereas NAC is acidic. Concluding from these in vitro results, NAL could be an interesting alternative to enhance the antioxidant capacity at the epithelial surface of the lung by aerosol administration.

Acetylcysteine↗
PubMed1997

Diagnostic pitfalls during therapy for extreme hypertriglyceridaemia.

We report the case of a 34-year-old man with extreme hypertriglyceridaemia (276.6 mmol/l) that was corrected by diet and triple-drug therapy. No primary defect could be found despite an intensive biochemical and genetic evaluation. Early in the time course of triglyceride-lowering therapy, the composition and concentration of different lipoprotein species changed markedly. His lipoprotein profile mimicked type III hyperlipidaemia, then familial hypercholesterolaemia, and finally hyperalphalipoproteinaemia. The increase in LDL cholesterol and apolipoprotein B was paralleled by a sixfold increase in lipoprotein(a). We conclude that these different forms of hypercholesterolaemia disappear solely with a continuation of the triglyceride-lowering therapy.

Adult↗
PubMed1997

[Incidence of cutaneous sensitization to environmental allergens in obstructive sleep apnea syndrome].

A skin prick test was performed in 75 patients with an obstructive sleep apnea syndrome (OSAS) to test allergic skin reactivity to 18 common inhalant allergens. Additionally, anterior rhinomanometry was performed. Results were compared with a group of 21 patients with chronic obstructive pulmonary disease and with 198 workers of the chemical industry. A positive (> or = 4 mm wheal diameter) skin test to at least one allergene was present in 49 per cent of the OSAS patients, compared to 14 per cent in COPD patients and 28 per cent in industrial workers (p < 0.05; chi 2-test)-33 per cent (n = 25) of the OSAS patients with a sleep apnea syndrome showed skin reactivity to house dust mite (D. ph., D. f.) compared to 9.5 per cent in COPD patients and 12.6 per cent in industrial workers (p < 0.05 chi 2-test). No difference was found between anthropometric, polysomnographic, or rhinomanometric data comparing OSAS patients with positive skin reactions against house dust mites (n = 25) and those without any allergic skin reactivity (n = 38).

Adult↗
PubMed1997

The relation between chemically measured total iron-binding capacity concentrations and immunologically measured transferrin concentrations in human serum.

We sought to determine if serum total iron-binding capacity (TIBC) is equivalent to serum transferrin (TRF) so that a low-cost colorimetric chemical assay for unsaturated iron-binding capacity (UIBC) could be substituted for a high-cost immunologic assay for TRF. Our study design included independent and blinded measurements of UIBC, serum iron, and TRF concentrations in human serum samples. Data from five independent correlation studies carried out at three different Quest Diagnostics laboratories were combined into one data set containing 570 paired results for TIBC and TRF. r2 was 0.941 when three outliers were eliminated from the 570-sample data set. Scatter about the regression line was fully accounted for by the CVs for the TIBC and TRF assays. When each test is measured precisely and without bias, the ratio of TIBC (mumol/L) to TRF (g/L) in SI units is close to the theoretically expected value of 25.0.

Colorimetry↗
PubMed1996

Clearance of postprandial lipoproteins in normolipemics: role of the apolipoprotein E phenotype.

The hepatic clearance of triglyceride-rich lipoproteins is mediated via apolipoprotein (apo) E which occurs in three common isoforms, apoE2, apoE3 and apoE4. To study the importance of the apoE isoforms on the response curves of different triglyceride-rich lipoproteins and the effect of chylomicron remnants on the composition of HDL, 37 normolipemics were investigated after a standardized fatty meal (8 apoE2/E2, 8 apoE2/E3, 8 apoE3/E3, 7 apoE3/E4 and 6 apoE4/E4). These individuals were matched for age, body mass index, fasting triglycerides, HDL-cholesterol, and apoA-I. A delayed chylomicron remnant clearance was observed only in apoE2 homozygotes, and this delay was neither correlated with fasting lip ds nor with peak lipoprotein concentrations. In apoE2/E3 heterozygotes, in contrast, the defective isoform E2 appears to be compensated for by the normal apoE isoform E3. In non-apo-E2/E2 individuals, the chylomicron remnant response was highly correlated with the magnitude of chylomicron and VLDL responses, with fasting triglycerides, and with the triglycerides enrichment and cholesterol depletion of HDL. These correlations were not observed in apoE2/E2. From these results we conclude that the chylomicron remnant response curve is an indicator of the extent of postprandial lipemia in non-apoE2/E2 individuals only.

Adult↗
PubMed1996

[Incidence of chronic obstructive respiratory tract disease in patients with obstructive sleep apnea].

Data concerning the occurrence of chronic-obstructive pulmonary disease (COPD) in patients with obstructive sleep apnea syndrome (OSAS) vary between 11 and 20% due to the underlying definition of COPD. We investigated the frequency of COPD in 202 patients with OSAS. The obstructive pattern was defined by bodyplethysmography (Rt > 0.35 kPa x 1(-1) x s(-1)), flow-volume-curve (MEF50 < 50% pred.), Tiffeneau-index (FEV1/IVC < 70% pred.) and anamnesis (cough and/or sputum). Prevalence of COPD in our 202 patients with OSAS was 16.3%. Patients with OSAS and COPD had a higher body-mass-index (BMI), lower PaO2 and spent more time in an oxygen saturation < or = 90% in relation to total recording time (t90). Polysomnographically there was no difference between the two groups with regard to the ventilatory parameters apnea-index (AI) and apnea-hypopnea-index (AHI). As there is a high risk of developing hypercapnia, pulmonary arterial hypertension and cor pulmonale in patients with OSAS and COPD there is need for early diagnosis of the combination of both diseases.

Adult↗
PubMed1996

[Anamnestic and polygraphic parameters in obstructive sleep apnea syndrome patients with reduced nasal respiration during the day in comparison with obstructive sleep apnea patients with normal nasal respiration].

Nasal obstruction is a predictive factor for snoring and may contribute to the development of an obstructive sleep apnea syndrome (OSAS). The aim of this study was to further evaluate the impact of nasal obstruction in OSAS. Therefore, we investigated 2 groups of OSAS-patients, matched pairs concerning gender, age, and BMI: OSAS-patients with nasal obstruction (N, n = 28), total nasal airflow < 500 ccm/s (referred to 150 pa pressure of difference or unilateral nasal resistance > 1 pa/ccm/s), and 28 OSAS-patients without nasal obstruction (control-group K, total nasal airflow > 700 ccm/s [referred to 150 pa pressure of difference or unilateral nasal resistance > 1 pa/ccm/s]). We performed anterior rhinomanometry, lung-function testing, cardio-respiratory polygraphy, and patients answered a standardized questionnaire. We found the following significant differences: 1) N complained more often (n = 17) about dyspnea at night than K (n = 7, p < 0.05, Chi2-test). 2) N had a higher apnea index (20.4 +/- 19.0/h) than K (9.6 +/- 10.0/h, p < 0.05, Student's t-test). There were, however, no significant differences concerning lung function, number of nocturnal hypopneas, nocturnal SaO2 and heart rate. Our results underline the importance of nasal ventilation in the pathogenesis of OSAS. At least in moderate cases of OSAS a therapy of nasal obstruction might be of success in order to abolish nCPAP-therapy or might reduce nasal problems during nCPAP-therapy and thus ameliorate patient's therapy compliance.

Airway Resistance↗
PubMed1996

[Signs of right heart stress in diurnal normoxemic patients with chronic obstructive lung disease and nocturnal hypoxemia].

Nocturnal hypoxemia in daytime normoxemic patients with COPD may lead to an increased right ventricular afterload due to pulmonary hypertension. We investigated the frequency of clinical, electrocardiographical, and radiological signs of right cardiac insufficiency (SRCI) in 178 consecutive COPD-patients [71 bronchitis, 25 emphysema, 82 bronchitis plus emphysema; PaO2 = 60 mm Hg]. Patients with asthma, left ventricular impairment, obstructive sleep apnea syndrome, primary pulmonary hypertension, and neuromuscular diseases were excluded. Polysomnography was performed in all patients. They were divided into 3 groups concerning SRCI: missing, doubtful, and secure SRCI. Parameters of nocturnal pulse oximetry were analyzed within the three groups (Student's t-Test. Chi2-Test. p < 0.05). 25.8% of the patients had secure SRCI without a significant frequency difference between patients with bronchitis and/or emphysema. Patients with secure SRCI had a significant lower mean nocturnal SaO2 than those with missing SRCI (92.7 +/- 2.5 vs. 90.3 +/- 3.5%). With regard to the high prevalence of SRCI in association with nocturnal hypoxemia routine control of nocturnal oxygenation is recommended in daytime normoxemic COPD-patients for the early decision for nocturnal oxygen therapy.

Adult↗
PubMed1996

[Sex-specific sleep anamnesis in obstructive sleep apnea syndrome?].

Although the prevalence of obstructive sleep apnea syndrome (OSAS) is about 4% in men and 2% in women, women are underrepresented in clinical routine. The aim of this study was to determine whether differences in clinical features of OSAS may in part explain the bias observed. 224 men and 24 women with polysomnographically confirmed OSAS filled in a symptom-focussed multiple-choice questionnaire. Polysomnographical results were comparable in both groups. With regard to snoring, daytime sleepiness and tendency of falling asleep there were no differences between both groups. Women more frequently complained about difficulties of initiating and maintaining sleep and about apneas. Further investigations have to concentrate on the pathomechanisms of OSAS in women which may in part explain the gender differences in sleep apnea associated symptoms.

Adult↗
PubMed1995

Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth.

Previously, we demonstrated in cultured dorsal root ganglion neurons that, in the presence of beta-migrating very low density lipoproteins (beta-VLDL), apolipoprotein (apo) E4, but not apoE3, suppresses neurite outgrowth. In the current studies, murine neuroblastoma cells (Neuro-2a) were stably transfected with human apoE3 or apoE4 cDNA, and the effect on neurite outgrowth was examined. The stably transfected cells secreted nanogram quantities of apoE (44-89 ng/mg of cell protein in 48 h). In the absence of lipoproteins, neurite outgrowth was similar in the apoE3- and apoE4-secreting cells. The apoE4-secreting cells, when incubated with beta-VLDL, VLDL, cerebrospinal fluid lipoproteins (d < 1.21 g/ml), or with triglyceride/phospholipid (2.7:1 (w/w)) emulsions, showed a reduction in the number of neurites/cell, a decrease in neurite branching, and an inhibition of neurite extension, whereas in the apoE3-secreting cells in the presence of a lipid source, neurite extension was increased. Uptake of beta-VLDL occurred to a similar extent in both the apoE3- and apoE4-secreting cells. With low density lipoproteins or with dimyristoylphosphatidylcholine emulsions, either alone or complexed with cholesterol, no differential effect on neurite outgrowth was observed. A slight differential effect was observed with apoE-containing high density lipoproteins. The differential effect of apoE3 and apoE4 in the presence of beta-VLDL was blocked by incubation of the cells with heparinase and chlorate, with lactoferrin, or with receptor-associated protein, all of which prevent the uptake of lipoproteins by the low density lipoprotein receptor-related protein (LRP). The data suggest that the secreted and/or cell surface-bound apoE interact with the lipoproteins and facilitate their internalization via the heparan sulfate proteoglycan-LRP pathway. The mechanism by which apoE3 and apoE4 exert differential effects on neurite outgrowth remains speculative. However, the data suggest that apoE4, which has been shown to be associated with late onset familial and sporadic Alzheimer's disease, may inhibit neuronal remodeling and contribute to the progression of the disease.

Alzheimer Disease↗