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Biomedical subjects

M Lerch

Publications and source records attributed to M Lerch.

At least 19 recordsLinked to original sources
PubMed2005

Biophysical and biological studies of end-group-modified derivatives of Pep-1.

Pep-1 is a tryptophane-rich cell-penetrating peptide (CPP) that has been previously proposed to bind protein cargoes by hydrophobic assembly and translocate them across cellular membranes. To date, however, the molecular mechanisms responsible for cargo binding and translocation have not been clearly identified. This study was conducted to gain insight into the interaction between Pep-1 with its cargo and the biological membrane to identify the thereby involved structural elements crucial for translocation. We studied three peptides differing in their N- and C-termini: (i) Pep-1, carrying an acetylated N-terminus and a C-terminal cysteamine elongation, (ii) AcPepWAmide, with an acetylated N-terminus and an amidated C-terminus, and (iii) PepW, with two free termini. Thioredoxin (TRX) and beta-galactosidase were used as protein cargoes. To study CPP-membrane interactions, we performed biophysical as well as biological assays. To mimic biological membranes, we used phospholipid liposomes in a dye leakage assay and surfactant micelles for high-resolution NMR studies. In addition, membrane integrity, cell viability, and translocation efficiency were analyzed in HeLa cells. An alpha-helical structure was found for all peptides in the hydrophobic N-terminal region encompassing residues 4-13, whereas the hydrophilic region remained unstructured in the presence of micelles. Our results show that the investigated peptides interacted with the micelles as well as with the protein cargo via their tryptophan-rich domain. All peptides displayed an orientation parallel to the micelle surface. The C-terminal cysteamine group formed an additional membrane anchor, leading to more efficient translocation properties in cells. No membrane permeabilization was observed, and our data were largely compatible with an endocytic pathway for cellular uptake.

Cell Survival↗
PubMed2005

Glycaemic control in type II diabetic tube-fed patients with a new enteral formula low in carbohydrates and high in monounsaturated fatty acids: a randomised controlled trial.

OBJECTIVES: To investigate the effects of long-term treatment with a new enteral formula low in carbohydrates and high in monounsaturated fatty acids (MUFAs), in comparison with a standard formula, on glycaemic control in tube-fed type II diabetic patients. DESIGN: Randomised, double-blind, controlled, multi-centre trial. SETTING: Early rehabilitation centres, primary care and nursing facilities. SUBJECTS: A total of 78 patients with insulin-treated type II diabetes with HbA(1C) > or =7.0% and/or fasting blood glucose >6.66 mmol/l, who required enteral tube feeding due to neurological dysphagia. INTERVENTIONS: Patients received 113 kJ (27 kcal)/kg of body weight of either test feed or an isoenergetic, isonitrogenous enteral formula (control) for 12 weeks. Glycaemic control (total daily insulin dosage (IU), fasting blood glucose, and HbA(1C)) and gastrointestinal tolerance were monitored daily. RESULTS: After 12 weeks, median values for changes from baseline were as follows (test group vs control group, 'data as available' analysis): total daily IUs -6.0 vs 0.0 (P=0.0024), fasting blood glucose (mmol/l) -1.59 vs -0.08 (P=0.0068); HbA(1C) (%) -0.8 vs 0.0 (P=0.0016). Both formulas were tolerated comparably. CONCLUSIONS: This study indicates that in tube-fed insulin-treated type II diabetic patients, the new low-carbohydrate, high MUFA formula results in a more effective glycaemic control than the standard diet, while being comparable in safety.

Adult↗
PubMed2005

Acute generalized exanthematous pustulosis induced by the antifungal terbinafine: case report and review of the literature.

Cutaneous drug reactions occur with a frequency of 1-8% and can be higher for certain classes of drugs. They can range from mild morbilliform eruptions to more severe forms such as drug-hypersensitivity syndrome, toxic epidermal necrolysis or anaphylaxis. Acute generalized exanthematous pustulosis (AGEP) is considered to be a clinical reaction pattern, which is induced in over 90% of the cases by systemic drugs. It is a rare presentation of an adverse drug reaction most frequently triggered by anti-infectious drugs. A high proportion of these cases have been attributed to aminopenicillins and macrolides. We report a terbinafine-induced AGEP in a 68-year-old male confirmed by lymphocyte stimulation in vitro, and review the published cases induced by antimycotic drugs with special emphasis on terbinafine-triggered cases.

Aged↗
PubMed2003

MOSFET dosimetry for microbeam radiation therapy at the European Synchrotron Radiation Facility.

Preclinical experiments are carried out with approximately 20-30 microm wide, approximately 10 mm high parallel microbeams of hard, broad-"white"-spectrum x rays (approximately 50-600 keV) to investigate microbeam radiation therapy (MRT) of brain tumors in infants for whom other kinds of radiotherapy are inadequate and/or unsafe. Novel physical microdosimetry (implemented with MOSFET chips in the "edge-on" mode) and Monte Carlo computer-simulated dosimetry are described here for selected points in the peak and valley regions of a microbeam-irradiated tissue-equivalent phantom. Such microbeam irradiation causes minimal damage to normal tissues, possible because of rapid repair of their microscopic lesions. Radiation damage from an array of parallel microbeams tends to correlate with the range of peak-valley dose ratios (PVDR). This paper summarizes comparisons of our dosimetric MOSFET measurements with Monte Carlo calculations. Peak doses at depths <22 mm are 18% less than Monte Carlo values, whereas those depths >22 mm and valley doses at all depths investigated (2 mm-62 mm) are within 2-13% of the Monte Carlo values. These results lend credence to the use of MOSFET detector systems in edge-on mode for microplanar irradiation dosimetry.

Animals↗
PubMed2002

Measurements in radiotherapy beams using on-line MOSFET detectors.

When acquiring data to characterise radiation beams for radiotherapy treatment planning measurements in steep dose gradients such as beam penumbra or dose build-up are often required. A metal oxide semiconductor field effect transistor (MOSFET) with its inherent high spatial resolution was used for penumbra measurements in a 120 kVp X ray beam. The customised MOSFET system features a pulsed readout that allows the acquisition of data points in user defined time intervals of less than 1 s. Using a modified scanning beam data acquisition system the penumbra was acquired on-line in 0.1 mm steps. Measurements were made at different distances behind the beam collimator. From the extrapolation of the penumbra width to a location directly under the block the spatial resolution of the MOSFET system can be estimated to be better than 0.1 mm. This excellent spatial resolution has many potential applications in radiotherapy dosimetry, including the characterisation of multileaf collimator systems.

Equipment Design↗
PubMed2000

Differential regulation of [Ca2+]i oscillations in mouse pancreatic islets by glucose, alpha-ketoisocaproic acid, glyceraldehyde and glycolytic intermediates.

Glucose induces slow oscillations of the cytoplasmic Ca2+ concentration in pancreatic beta-cells. In order to elucidate the mechanisms responsible for the slow [Ca2+]i oscillations the effects of various nutrient insulin secretagogues on glucose-induced [Ca2+]i oscillations in intact mouse pancreatic islets and single beta-cells were studied. These were the glycolytic intermediates, glyceraldehyde and pyruvate, and the mitochondrial substrate, alpha-ketoisocaproic acid (KIC). Glucose, at a 10 or 15 mM concentration, induced the typical slow oscillations of [Ca2+]i (0.4 min(-1)). At higher glucose concentrations the frequency of these oscillations decreased further (0.2 min(-1)). Glyceraldehyde, an insulin secretagogue like glucose, did not cause slow oscillations of [Ca2+]i in the absence of glucose. However, it exhibited a synergistic action with glucose. Glyceraldehyde, at 3 or 10 mM concentration, induced slow [Ca2+]i oscillations at a substimulatory concentration of 5 mM glucose (0.3-0.4 min(-1)) and reduced the frequency of the glucose-induced [Ca2+]i oscillations at stimulatory concentrations of 10 or 15 mM glucose (0.2 min(-1)). KIC (5 or 10 mM) as well as pyruvate (10 mM), the end product of glycolysis, and its ester methyl pyruvate (10 mM), did not cause slow oscillations of [Ca2+]i in the absence of glucose. In contrast to glyceraldehyde, however, all three compounds were capable of preventing the slow [Ca2+]i oscillations induced by glucose. Mannoheptulose (2 mM), an inhibitor of glucokinase and glucose-induced insulin secretion, reversibly blocked any kind of [Ca2+]i oscillation and returned the [Ca2+]i to a basal level through its ability to inhibit glycolytic flux. It can be concluded therefore that only substrates which generate a glucokinase-mediated metabolic flux through glycolysis and produce glycolytic ATP can induce slow [Ca2+]i oscillations in pancreatic beta-cells.

Animals↗
PubMed2000

Local delivery of a low molecular weight heparin following stent implantation in the pig coronary artery.

BACKGROUND: The low molecular weight heparin Reviparin reduces smooth muscle cell proliferation in cell culture experiments. Clinical studies with systemic application of the substance did not show a reduction of the incidence of restenosis following balloon angioplasty. Local delivery, by achieving higher local concentrations of the drug, may have the potential to decrease smooth muscle cell proliferation in the treated arterial segment. OBJECTIVES: The aim of this study was to investigate the effects of local delivery of reviparin following stent implantation in the pig coronary artery. METHODS: A coronary stent was implanted in the LAD of 34 pigs. In the treatment group 5 ml reviparin was injected with the Infusasleeve catheter at a proximal pressure of 80 psi. After 28 days the animals were sacrificed. Quantitative morphometric analysis comprised the intimal area, medial area and the lumen. The extent of vessel injury and the intimal thickness were assessed separately for each stent strut region. The correlation of injury and neointimal thickness was analysed using linear regression. RESULTS: There was no relevant difference in the extent of vessel injury (1.9 +/- 0.7 vs. 1.6 +/- 0.6), the neointimal areas (2.4 +/- 0.9 vs. 2.4 +/- 1.0 mm2) and the resulting stenosis (46 +/- 18 vs. 47 +/- 17%). The medial area was larger in the animals treated with local delivery (2.2 +/- 0.4 vs. 1.6 +/- 0.4 mm2; p < 0.01). The correlation of injury and neointimal thickness was comparable in both groups. In two animals the passage of the stent area with the delivery system resulted in stent dislocation and fatal subacute thrombosis. CONCLUSION: In this animal model, local delivery of reviparin with the Infusasleeve catheter did not result in a reduction of neointimal proliferation following stent implantation. Local delivery after stent implantation carries the risk of stent dislocation as a result of the passage with the delivery system.

Animals↗
PubMed2000

Nephropathy subsequent to hyperlipidemia.

The relationship between lipid abnormalities and the pathogenesis of renal disease is still unclear. Although most patients with primary hyperlipidemia do not develop renal function impairment, experimental and clinical data indicate a possible damaging effect of a disturbed lipid metabolism on the kidney. We report the case history of a patient with hyperlipidemia and mild nephropathy in which an accidentally removed kidney showed intrarenal arteriosclerosis which occured before the development of other cardiovascular risk factors, indicating that primary dyslipidemia induced nephroangiosclerosis.

Arteriosclerosis↗
PubMed1999

Local drug delivery: impact of pressure, substance characteristics, and stenting on drug transfer into the arterial wall.

Injection parameters for local drug delivery are frequently determined by studies with marker substances. However, the pharmacologic properties of the actual drug may influence delivery efficiency and lead to different results. Aim of this study was to assess the delivery capacities of two device-drug combinations in order to verify this approach for further in vivo studies. Tritiated (3H) preparations (5 ml) of the hydrophylic low-molecular-weight heparin reviparin and the lipophilic taxane paclitaxel were injected into the left anterior descending artery of freshly explanted porcine hearts with the Infusasleeve II catheter system. A balloon support pressure of 6 atm and infusion pressures of 40, 60, 80, or 100 psi were used. In three additional groups, reviparin was injected following stent implantation and paclitaxel was injected prior to or following stent implantation. Arteries along with surrounding myocardium were harvested. The artery was carefully dissected, and artery and myocardium were separately homogenized, and activity was measured. Of the totally delivered activity, 0.09%+/-0.03% (40 psi) to 0.17%+/-0.13% (100 psi) of reviparin and 2.03%+/-0.67% (60 psi) to 2.68%+/-1.57% (100 psi) of paclitaxel were found in the vessel wall. The results for different injection pressures were not significantly different for either drug. The percentage activity delivered to the vessel wall was substantially larger in the paclitaxel group as compared to reviparin delivery (P < 0.01 at 60, 80, and 100 psi). The mean concentration of reviparin in the artery was 20 to 33 times higher than in the myocardium. For paclitaxel the factors were 110 to 243. Stent implantation prior to or following local delivery did not result in a different delivery efficiency. The results demonstrate that the characteristics of the delivered drug contribute largely to the delivery efficiency. Using identical injection parameters, drug concentrations in the arterial wall were significantly higher for the lipophilic paclitaxel as compared to the hydrophilic reviparin. Stenting of the artery did not influence delivery efficiency.

Animals↗
PubMed1999

[Is there a need for treatment in subclinical hypo- and hyperthyroidism?].

Subclinical thyroid dysfunction is characterized by normal levels of thyroid hormones but abnormal values of thyrotropin (TSH) in an asymptomatic individual. Subclinical hypothyroidism is a common disorder with a prevalence of about 7 to 8% in women (most frequently in females over 50 years), and about 3% in men. It is characterized by elevated serum TSH in the presence of normal concentrations of serum thyroxine. Patients with TSH levels about 12 mU/L (and with positive antithyroidal antibodies) have the highest risk for developing overt hypothyroidism. Therefore, these patients will require L-thyroxine treatment. In patients with TSH < 12 mU/L, the indication for therapy depends on the etiology, on risk factors and concomitant diseases (e.g. strumectomy, coronary heart disease, depression, infertility). Subclinical hyperthyroidism (TSH suppression syndrome) is characterized by normal thyroid hormone concentrations but diminished serum TSH. Most frequently, this disorder is caused by exogenous L-thyroxine treatment. The endogenous form of subclinical hyperthyroidism mainly caused by nodular goiter has a prevalence of up to 20% in patients with large goiters. In patients with subclinical hyperthyroidism, there is an increased risk for development of atrial fibrillation and for a decrease in bone mass in postmenopausal women. In the majority of patients measurable TSH levels can be detected before or after stimulation with TRH. This formally excludes overt hyperthyroidism in such patients. Frequently, there is no need for treatment but follow-up is important. However, in patients with subclinical hyperthyroidism associated with atrial fibrillation a therapy with antithyroid drugs, beta-blockers or radioiodine must be considered.

Diagnosis, Differential↗
PubMed1999

Metabolic effects of temocapril in hypertensive patients with diabetes mellitus type 2.

Compared with other angiotensin-converting enzyme (ACE) inhibitors, the elimination of temocapril is less dependent on renal function. To investigate the metabolic and antihypertensive effects of temocapril in diabetic hypertensives, 30 patients with diabetes mellitus type 2 and mild to moderate hypertension [diastolic blood pressure (BP) 90-115 mm Hg] and without azotemia (plasma creatinine < 180 microM) were evaluated in a prospective randomized double-blind placebo-controlled study. After a 4-week placebo run-in, they received temocapril, 20 mg daily (n = 19), or placebo (n = 11) for 6 weeks. Insulin sensitivity index (SI), determined by the Minimal Model method of Bergman, serum lipoproteins, plasma renin activity, fibrinogen, and microalbuminuria were assessed at the end of the placebo run-in phase and the double-blind treatment phases. Temocapril but not placebo administration produced a significant decrease in supine BP (152/92+/-5/3 vs. 162/98+/-5/2 mm Hg; p < 0.01) and increase in plasma renin (p < 0.05). Variation of SI during temocapril treatment did not reach statistical significance (0.95+/-0.2 before vs. 1.44+/-0.4 x 10(-4)/min/mU/L after treatment). During administration of temocapril or placebo, no significant changes in fasting plasma glucose, insulin, and serum levels of total triglycerides, cholesterol, lipoprotein cholesterol fractions, or fibrinogen were observed. Microalbuminuria decreased significantly on temocapril treatment (49+/-10 vs. 79+/-17 mg/24 h; p < 0.01) but not on placebo. These findings demonstrate that in hypertensive patients with diabetes mellitus type 2, short-term treatment with temocapril is neutral to insulin sensitivity, lipoprotein metabolism, and fibrinogen, and significantly reduces microalbuminuria.

Adult↗
PubMed1998

Negative cooperativity between alpha 3 beta 1 and alpha 2 beta 1 integrins in human mammary carcinoma MDA MB 231 cells.

The alpha 3 beta 1 integrin has been implicated as a receptor for several matrix components, including collagen, fibronectin, and laminins. The function of alpha 3 beta 1 seems to be very versatile involving cell adhesion to or migration on ECM, establishment of cell-cell contacts in aggregates, as well as linkage to intracellular tyrosine phosphorylation cascades. Here we report a strong induction of attachment of alpha 3 beta 1 integrin expressing human breast carcinoma cell line MDA MB 231 to matrix proteins by two alpha 3 integrin subunit function-blocking monoclonal antibodies (P1B5 and ASC-1). In contrast, stimulation of adhesion to ECM by inhibitory alpha 3 integrin-specific antibodies was not observed in the alpha 3 beta 1 integrin-expressing nonmalignant human mammary epithelial cell line MCF-10A or the human breast carcinoma cell line MDA MB 468 that expressed relatively low amounts of alpha 3 beta 1 integrin at the cell surface. This increase was specific for collagens and not observed on fibronectin or laminin. Physiological concentrations of bivalent cations were not required. MAb P1B5 did not induce homotypic aggregation of MDA MB 231 cells. The P1B5-induced increase in cell attachment to collagens could be prevented but not reduced below control levels by blocking mAb to the alpha 2 integrin subunit. Function blocking anti-alpha 5 integrin subunit mAb was without effect while anti-beta 1-mAb completely abolished adhesion. Our data indicate that negative cooperativity between integrins results in transdominant inhibition of alpha 2 beta 1 function by alpha 3 beta 1 in human MDA MB 231 but not MDA MB 468 tumor cells or nonmalignant MCF-10A cells.

Antibodies, Monoclonal↗
PubMed1998

Endothelin-1 infusion inhibits plasma insulin responsiveness in normal men.

OBJECTIVES: Elevated plasma endothelin (ET)-1 levels have been described in insulin-resistant states such as syndrome X, obesity, non-insulin-dependent diabetes mellitus, and in some studies in essential hypertension. To investigate whether increases in circulating ET-1 to levels observed in insulin-resistant states can modulate insulin levels and/or insulin sensitivity in humans, we assessed these variables during low, non-pressor-dose ET-1 compared with placebo infusion. DESIGN: In a randomized, single blind, crossover design, 10 lean normotensive male subjects received either an intravenous infusion of subpressor doses of ET-1 dissolved in polygeline or a control infusion of polygeline only (placebo). Using dynamic assessment by the minimal model approach with the modified frequent sampling intravenous glucose tolerance test (FSIGT) the following and other parameters were measured: insulin sensitivity; acute insulin response to glucose (AIR(G)) calculated as the average of the three peak values between 2 and 5 min after injection of glucose from which the basal insulin levels were subtracted; the initial area under the curve (AUC(1-19)) from insulin values between time 0 and 19 min and the first-phase insulin secretion (phi1) from insulin kinetics parameters. RESULTS: ET-1 infusion reduced AIR(G) (to 34.85 +/- 4.27 compared with 49.3 +/- 6.9 microU/ml during placebo, P=0.017) and the acute C-peptide response to glucose (to 2.33 +/- 0.41 compared with 3.1 +/- 0.44 ng/ml, P=0.018), decreased plasma insulin levels during the FSIGT compared with placebo (analysis of variance P<0.0001) and decreased the AUC(1-19) (to 2.1 +/- 0.2 compared with 2.9 +/- 0.3 U/l per 20 min, P<0.01) while phi1 tended to be lower. S1 measured during ET-1 infusion was unaltered (11.11 +/- 1.91 x 10(-4) versus 10.88 +/- 2.11 10(-4)/min per mU per l, NS). CONCLUSIONS: These findings demonstrate that an increase in circulating ET-1 to levels observed in insulin-resistant states acutely diminishes the insulin secretory response but does not significantly modify insulin sensitivity.

Adult↗
PubMed1998

Effects of angiotensin II-receptor blockade with losartan on insulin sensitivity, lipid profile, and endothelin in normotensive offspring of hypertensive parents.

Humans genetically predisposed to hypertension tend to develop at a prehypertensive stage subtle metabolic and hormonal dysregulations, and certain of these could potentially be angiotensin II dependent. Therefore the aim of this study was to investigate the effects of the angiotensin II-receptor antagonist losartan on insulin sensitivity, lipid profile, and plasma endothelin-1 (ET-1) levels in normotensive offspring of hypertensive parents with a randomized, double-blind, placebo- controlled, crossover design. Insulin sensitivity index (SI), determined by the Minimal Model Method of Bergman, fasting plasma insulin and glucose concentrations, serum total and HDL cholesterol, serum triglycerides, and plasma ET-1 levels were assessed in 19 young (26.2 +/- 0.7 years, mean +/- SEM), healthy, lean [body mass index (BMI), 22.6 +/- 0.7 kg/m2] normotensive male offspring of essential hypertensive parents after 14 days of losartan, 50 mg, and 14 days of placebo, respectively. Compared with placebo, losartan administration did not significantly modify SI (12.2 +/- 1.7 vs. 12.7 +/- 1.5 x 10(-4)/min/microU/ml on placebo), fasting plasma insulin and glucose, as well as the areas under the insulin and glucose curves. Plasma ET-1 levels also did not differ significantly between the placebo and losartan administration phases (1.1 +/- 0.06 vs. 1.2 +/- 0.06 pg/ml). However, serum total cholesterol and triglycerides decreased significantly with losartan treatment (3.8 +/- 0.2 vs. 4.1 +/- 0.2 mM and 0.9 +/- 0.1 vs. 1.1 +/- 0.1 mM, respectively; p < 0.01). Body weight, BMI, heart rate (HR), blood pressure (BP), and 24-h urinary sodium, potassium, and creatinine values were stable throughout the study. These findings demonstrate that angiotensin II-receptor blockade with losartan, administered in the therapeutic dose of 50 mg daily, does not alter insulin sensitivity determined by the Minimal Model Method of Bergman and does not affect ET-1 in normotensive offspring of essential hypertensive parents. The normal insulin sensitivity in the subjects studied might explain why losartan did not improve it. However, losartan significantly reduced serum total cholesterol and total triglyceride levels.

Adult↗
PubMed1996

Metabolic neutrality of combined verapamil-trandolapril treatment in contrast to beta-blocker-low-dose chlortalidone treatment in hypertensive type 2 diabetes.

OBJECTIVE: To investigate the metabolic, antihypertensive and albuminuria-modifying effects of a heart rate-modulating calcium antagonist-angiotensin converting enzyme inhibitor combination compared with those of a beta-blocker-low-dose diuretic combination in non-insulin-dependent diabetic hypertensives. DESIGN: A prospective randomized double-blind study. SUBJECTS AND METHODS: Twenty-four diabetics with diastolic blood pressure 90-115 mmHg without azotemia (plasma creatinine level < 150 mumol/l) were evaluated after 4 weeks receiving placebo and 12 weeks receiving treatment either with combined slow-release verapamil (retard formulation) and trandolapril (mean maintenance doses, 180 and 1.6 mg daily) or with atenolol and chlortalidone (71 and 18 mg daily). Insulin sensitivity (by the minimal model method of Bergman), additional metabolic variables, clinic blood pressure, ambulatory blood pressure profile and renal indices were assessed at the end of the placebo and active treatment phases. RESULTS: Compared with placebo, the two therapies produced similar decreases in mean supine clinic blood pressure [10 +/- 3 versus 11 +/- 3% (means +/- SEM)], upright clinic blood pressure (10 +/- 4 versus 11 +/- 4%) and ambulatory daytime blood pressure (9 +/- 2 versus 12 +/- 3%). However, although the verapamil-trandolapril combination was found to be metabolically neutral, the atenolol-chlortalidone combination aggravated insulin resistance [insulin sensitivity index, from (0.8 +/- 0.2) to (0.3 +/- 0.1) x 10(-4)/min per U per ml], increased the serum triglycerides level and decreased the high-density lipoprotein cholesterol and plasma potassium levels. Although both therapies tended to reduce 24 h albuminuria, this was significant for the verapamil-trandolapril treatment only. CONCLUSIONS: Because the effect of any antihypertensive drug, including diuretics and beta-blockers, on cardiovascular morbidity and on mortality in non-insulin-dependent diabetic patients is not known, rational treatment selection can presently be based only on surrogate end-points. Therefore, the triad of metabolic neutrality with antihypertensive and antiproteinuric efficacy supports combined verapamil-trandolapril as a potentially valuable therapy for hypertension accompanying diabetes mellitus.

Adrenergic beta-Antagonists↗