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Biomedical subjects

R Bender

Publications and source records attributed to R Bender.

At least 19 recordsLinked to original sources
PubMed1997

Development of cholinergic and GABAergic neurons in the rat medial septum: effect of target removal in early postnatal development.

During normal development of the nervous system, the target fields influence the survival and differentiation of projection neurons, but the factors regulating this interaction remain obscure. In the present study, we have raised the question whether the target region is essential for the postnatal development and maintenance of two different types of central projection neurons, cholinergic and GABAergic septohippocampal cells. In early postnatal rats (P5, P10), the hippocampus was eliminated by unilateral intrahippocampal injections of the excitotoxin N-methyl-D-aspartate. After a long survival time (at P70), we have immunostained serial sections of the septal region with antibodies against choline acetyltransferase (ChAT), the acetylcholine-synthesizing enzyme, or the calcium-binding protein parvalbumin (PARV) which is known to be contained in GABAergic septohippocampal neurons. In the medial septum ipsilateral to the lesioned side, about 60% of ChAT-immunoreactive neurons and 62% of PARV-immunoreactive neurons were found in adulthood even after complete elimination of the hippocampus. Some immunoreactive cells appeared heavily shrunken, but electron microscopic analysis revealed ultrastructural characteristics typical for medial septal neurons obtained from controls. Our results indicate that target elimination during development affected both types of projection cells, although only the cholinergic cells are known to be responsive to target-derived factors.

Animals↗
PubMed1996

Development of cholinergic and GABAergic neurons in the rat medial septum: different onset of choline acetyltransferase and glutamate decarboxylase mRNA expression.

In the present study, we have investigated the developmental expression of the transmitter-synthesizing enzymes choline acetyltransferase (ChAT) and glutamate decarboxylase (GAD) in rat medial septal neurons by using in situ hybridization histochemistry. In addition, we have employed immunostaining for ChAT and the calcium-binding protein parvalbumin, known to be contained in septohippocampal GABAergic neurons. A large number of GAD67 mRNA-expressing neurons were already observed in the septal complex on embryonic day (E) 17, the earliest time point studied. During later developmental stages, there was mainly an increase in the intensity of labeling. Neurons expressing ChAT mRNA were first recognized at E 20, and their number slowly increased during postnatal development of the septal region. The adult pattern of ChAT mRNA-expressing neurons was observed around postnatal day (P) 16. By using a monoclonal ChAT antibody, the first immunoreactive cells were not seen before P 8. Similarly, the first weakly parvalbumin-immunoreactive neurons were seen in the septal complex by the end of the 1st postnatal week. These results indicate that in situ hybridization histochemistry may be an adequate method to monitor the different development of transmitter biosynthesis in cholinergic and GABAergic septal neurons. Moreover, the late onset of ChAT mRNA expression would be compatible with a role of target-derived factors for the differentiation of the cholinergic phenotype.

Animals↗
PubMed1996

Cigarette smoking and progression of retinopathy and nephropathy in type 1 diabetes.

The objective of the present study was to analyse the association between cigarette smoking and progression of retinopathy and nephropathy, respectively, in a prospective multicentre study including 636 people with Type 1 diabetes: 81% of the original cohort of consecutively referred patients, aged 15 to 40 years and free of severe late diabetic complications. At baseline, all patients had participated in a 5-day in-patient group treatment and teaching programme for intensification of insulin therapy. Patients were examined at recruitment, and after 1, 2, 3 and 6 years including assessment of smoking status, blood pressure, metabolic control, and degree of nephropathy. Degree of retinopathy was assessed by ophthalmoscopy or fundus photography at baseline and after 6 years. Several logistic regression analyses were performed by describing the responses retinopathy and nephropathy, respectively, either as progression yes/no or as actual status at the 6-year follow-up and by using different measures for smoking. Adjustments for important covariables were made. While significant associations between smoking, and retinopathy and nephropathy respectively, were found, the relations were variable depending on the statistical model used. The results show that the real associations between smoking and retinopathy and nephropathy are complex and that more emphasis should be put on the complete description of the response variables and the statistical models used in clinical and epidemiological research.

Adult↗
PubMed1996

Prolonged QT interval as a predictor of mortality in diabetic nephropathy.

Patients with diabetic nephropathy face an increased risk of dying due to cardiac causes. The aim of this follow-up trial was to describe the association between the length of the QT interval, as a marker of myocardial electrical stability, and the risk of death in insulin-dependent (IDDM) diabetic patients with overt diabetic nephropathy. A consecutive sample of 85 IDDM patients with overt diabetic nephropathy (i.e. persistent proteinuria > or = 500 mg/24 h) were followed-up until death or for a period of 5-13 years. QT intervals were measured once at baseline in a 12-lead ECG and corrected for heart rate (QTc). During the follow-up period 33 patients (39%) died. In the Cox proportional hazards model independent predictors of death were age (p = 0.0007), the length of the maximum QTc period (p = 0.0049), presence of autonomic neuropathy (p = 0.0068), diabetes duration (p = 0.0163) and RR variation (p = 0.0395). In conclusion, in nephropathic IDDM patients QT prolongation is associated with an increased mortality risk which is independent of the presence of autonomic neuropathy. Further studies are needed to determine whether this risk might be reduced by therapeutic interventions.

Cause of Death↗
PubMed1996

Effects of dietary sodium on blood pressure in IDDM patients with nephropathy.

The objectives of the study were to assess the effects of moderate sodium restriction on blood pressure in insulin-dependent diabetic (IDDM) patients with nephropathy and high normal or mildly hypertensive blood pressure (primary objective), and to document possible associated changes of exchangeable body sodium, body volumes, components of the renin-angiotensin-aldosterone system, atrial natriuretic peptide, and catecholamines (secondary objective). Sixteen patients with untreated systolic blood pressure > or = 140 < 160 mmHg and/or diastolic blood pressure > or = 85 < 100 mmHg were included in a double-blind, randomized, placebo-controlled trial. After a 4-week run-in period on their usual diet and a 2-week dietary training period to reduce sodium intake to about 90 mmol/day, eight patients received 100 mmol/day sodium supplement (group 2) and eight patients a matching placebo (group 1) for 4 weeks while continuing on the reduced-sodium diet. Patients were examined at weekly intervals. Main response variables were mean values of supine and sitting systolic and diastolic blood pressure as measured in the clinic and by the patients at home. The differences in blood pressure between the beginning and the end of the blinded 4-week study period were calculated and the differences in changes between the two patient groups were regarded as the main outcome parameters. During the blinded 4-week study period, average urinary sodium excretion was 92 +/- 33 (mean +/- SD) mmol/day in group 1 and 199 +/- 52 mmol/day in group 2 (p = 0.0002). The differences in blood pressure changes between the two patient groups were 3.9(-1.2 to 9) mmHg [mean (95% confidence intervals)] for systolic home blood pressure, 0.9(-3.7 to 5.5) mmHg for diastolic home blood pressure, 4.9(-3.3 to 13.1) mmHg for clinic systolic blood pressure and 5.3(1 to 9.7 mmHg, p = 0.02) for clinic diastolic blood pressure. Combining all patients, there were relevant associations between changes of urinary sodium excretion and blood volume (Spearman correlation coefficient r = 0.57), blood pressure and angiotensin II (diastolic: r = -0.7; systolic: r = -0.48), and exchangeable body sodium and renin activity (r = -0.5). In conclusion, in this study of IDDM patients with nephropathy and high normal or mildly hypertensive blood pressure, a difference in sodium intake of about 100 mmol/day for a period of 4 weeks led to a slight reduction of clinic diastolic blood pressure. Studies including larger numbers of patients with various stages of nephropathy and hypertension are needed to definitely clarify the effects of sodium restriction in IDDM.

Adolescent↗
PubMed1996

Calculating confidence intervals for summary measures of individual curves via nonlinear regression models.

In biomedical research data are often collected serially over time. Hence, the main outcome is represented by response curves. A suitable approach to analyse such data is given by summary measures describing the main features of the response curves. An important issue is the precision of the estimated summary measures, which can be represented by confidence intervals. However, since summary measures frequently cannot be obtained via linear relationships, the calculation of confidence intervals involves some special considerations. In this paper attention is focused on unimodal response curves. Important summary measures for this type of response curves are the curve maximum (Cmax), the time to curve maximum (tmax), and the area under the curve (AUC). These summary measures can be calculated from the parameters of nonlinear regression models fitted to the data. Since the summary measures are nonlinear functions of the regression coefficients the multivariate delta method is used to derive formulas for the standard errors and confidence intervals of the summary measures. The method is illustrated by application to pharmacodynamic data.

Algorithms↗
PubMed1996

Effects of smoking on blood pressure and proteinuria in patients with diabetic nephropathy.

OBJECTIVES: To investigate the effects of smoking on blood pressure and proteinuria in hypertensive diabetic patients with nephropathy. DESIGN: Controlled, randomized, cross-over study. SETTING: Tertiary care centre, University Hospital of Düsseldorf, Germany. SUBJECTS: A total of 25 subjects were recruited, each of whom smoked at least 20 cigarettes a day: 10 normotensive healthy volunteers and 15 hypertensive type 1 (insulin-dependent) diabetic outpatients with diabetic retinopathy and persistent micro- or macroalbuminuria; 10 diabetic patients had normal autonomic function test, whilst five patients showed signs of autonomic neuropathy. INTERVENTIONS: Controlled smoking or nonsmoking over a period of 8 h on separate days. MAIN OUTCOME MEASURES: Blood pressure was measured every 10 min with an automatic device and urine samples were collected every 3 h. RESULTS: Systolic blood pressure increased during smoking in controls (mean) (11.5 mmHg, P = 0.0001) and in diabetic patients without autonomic neuropathy (7.9 mmHg; P = 0.018), but not in patients with autonomic neuropathy (-2.4 mmHg; P = 0.792). Diastolic blood pressure increased during smoking in controls (6.2 mmHg; P = 0.019) but not in diabetic patients (2.5 mmHg; P = 0.204. 0.2 mmHg; P = 0.956). During smoking, median proteinuria and albuminuria increased in diabetic patients without autonomic neuropathy (8.1 mg mmol-1 creatinine, P = 0.002; and 2.6 mg mmol creatinine, P = 0.084). No significant changes in albuminuria or proteinuria occurred in the other two groups. CONCLUSIONS: Smoking increases blood pressure values in healthy subjects and in hypertensive patients with diabetic nephropathy and without autonomic neuropathy. This effect of smoking may be partly responsible for the faster progression of diabetic nephropathy in smoking diabetic patients.

Adult↗
PubMed1996

Effects of enalapril and nitrendipine on exercise albuminuria in normotensive type I diabetic patients with incipient nephropathy.

Based on animal experiments it has been proposed that antihypertensive agents may differentially influence albuminuria through their divergent effects on glomerular haemodynamics or glomerular sieving properties and may beneficially influence the progression of diabetic nephropathy even without an effect on blood pressure. However, to date this hypothesis has not been tested in normotensive patients with diabetic nephropathy. The main aim of this study was therefore to investigate the effects of the administration of two antihypertensive agents on albuminuria during rest and exercise. The study consisted of 3 x 3 randomised, cross-over periods with five days double blind administration of enalapril (E: 2.5 mg bid), nitrendipine (N: 5 mg bid) and placebo (P) on 18 Type 1 normotensive (blood pressure < 140/90 mmHg) diabetic patients with incipient diabetic nephropathy (albuminuria 30-300 mg/24 h, normal glomerular filtration rate, diabetes duration > 6 years and presence of diabetic reinopathy. The aim of this study was to investigate the effect of enalapril and nitrendipine on blood pressure values and albuminuria during exercise challenge (bicycle ergometry: 20 min at 75 W and 20 min at 100 W) in comparison to the placebo. Albumin excretion rates during pre-exercise rest (mean +/- SD; E: 6.2 +/- 6.0; N: 7.1 +/- 8.0; P: 7.7 +/- 7.0 mg/mmol creatinine) and during exercise (E: 8.7 +/- 9.4; N: 8.2 +/- 8.2; P: 11.1 +/- 11.4 mg/mmol creatinine) were comparable between the drugs and not significantly different after administration of placebo. Blood pressure values were significantly different between the medications (systolic blood pressure: p = 0.0269; diastolic blood pressure: p = 0.0021, ANOVA for repeated measurements). There were no significant correlations between blood pressure values and albuminuria at any time. In normotensive patients with incipient diabetic nephropathy low-dose administration of enalapril, nitrendipine and placebo does not result in clear cut differences in albuminuria.

Adolescent↗
PubMed1995

Fate of GABAergic septohippocampal neurons after fimbria-fornix transection as revealed by in situ hybridization for glutamate decarboxylase mRNA and parvalbumin immunocytochemistry.

Many septohippocampal neurons are GABAergic and are affected by transection of the fimbria-fornix, like the septohippocampal cholinergic cells. Here we have studied the changes that occur in GABAergic septohippocampal neurons following fimbria-fornix transection. For labeling of septohippocampal projection neurons, adult Sprague-Dawley rats received injections of the fluorescent tracer Fluoro-Gold into the hippocampus 1 week prior to bilateral transection of the fimbria-fornix. After axotomy, rats were allowed to survive for varying periods ranging from 3 weeks to 18 months. Following fixation of the animals, sections through the septal region were either stained by in situ hybridization for glutamate decarboxylase (GAD) mRNA or immunostained for parvalbumin (PARV), which is known to be present in GABAergic septohippocampal neurons. In situ hybridization for GAD mRNA revealed no statistically significant changes in cell number 3 weeks and 6 months postlesion. In contrast, PARV-immunoreactive neurons were reduced to 35% of control 3 weeks postlesion. This value increased to 66% after 6 months of survival. As seen in the electron microscope, axotomized PARV-positive neurons exhibited characteristics of vital cells. Most neurons contained lysosomes associated with Fluoro-Gold, resulting from retrograde labeling prior to fimbria-fornix transection. We conclude that mainly PARV-containing GABAergic neurons in the medial septal nucleus (MS) project to the hippocampus and are thus heavily affected by the lesion but are able to survive and restore the synthesis of PARV. The lack of significant changes in the number of GAD mRNA-expressing cells is explained by the presence of numerous GABAergic MS neurons not projecting to the hippocampus.

Animals↗
PubMed1995

Fitting nonlinear regression models with correlated errors to individual pharmacodynamic data using SAS software.

Nonlinear regression is widely used in pharmacokinetic and pharmacodynamic modeling by applying nonlinear ordinary least squares. Although the assumption of independent errors is frequently not fulfilled, this has received scant attention in the pharmacokinetic literature. As in linear regression, leaving correlation of errors out of account leads to an underestimation of the standard deviations of parameter estimates. On the other hand, the use of models that accommodate correlated errors requires more care and more computation. This paper describes a method to fit log-normal functions to individual response curves containing correlated errors by means of statistical software for time series. A sample computer program is given in which the SAS/ETS procedure MODEL is used. In particular, the problem of finding appropriate starting values for nonlinear iterative algorithms is considered. A linear weighted least squares approach for initial parameter estimation is developed. The adequacy of the method is investigated by means of Monte Carlo simulations. Furthermore, the statistical properties of nonlinear least squares with and without accommodating correlated errors are compared. Time action profiles of a long-acting insulin preparation injected subcutaneously in humans are analyzed to illustrate the usefulness of the method proposed.

Dose-Response Relationship, Drug↗
PubMed1995

Intensified antihypertensive therapy is associated with improved survival in type 1 diabetic patients with nephropathy.

OBJECTIVE: To determine the prognosis of treated hypertensive type 1 (insulin-dependent) diabetic patients with overt nephropathy. DESIGN: A controlled, prospective, parallel, 5-year follow-up trial. SETTING: The tertiary care centre of the Heinrich Heine University Hospital in Dusseldorf, Germany. PATIENTS AND INTERVENTIONS: A sequential sample of 91 hypertensive patients with overt diabetic nephropathy participated in a diabetes treatment programme. Thereafter 45 patients received intensified antihypertensive therapy including blood pressure self-monitoring and self-adjustment of antihypertensive drug treatment with the goal of permanent normalization of blood pressure values below 140/90 mmHg. The remaining 46 patients were administered routine antihypertensive therapy and formed the control group. At baseline both groups were comparable in age, sex, metabolic control and renal function. The groups differed at baseline in their duration of diabetes and blood pressure values, which were higher in the intensified antihypertensive therapy group. OUTCOME MEASURES: Total mortality and the need for renal replacement therapy. MAIN RESULTS: Blood pressure control was significantly improved in patients who were subjected to intensified antihypertensive therapy, whereas it deteriorated in the group of patients who received routine antihypertensive therapy. At follow-up, primary end points of the study occurred in five (11%) patients of the intensified therapy group and in 19 (41%) patients of the routine therapy group. According to life table analysis, intensified antihypertensive therapy was associated with less frequent primary end points (P = 0.0058) and longer survival (P = 0.01). The differences between the groups remained significant after adjustment for covariates in the proportional hazards model. CONCLUSION: Participation in a treatment programme aimed at intensification of antihypertensive therapy is associated with a reduction of mortality in hypertensive type 1 diabetic patients with overt nephropathy.

Adult↗
PubMed1995

Liberalized diet in patients with type 1 diabetes.

OBJECTIVE: To document that strict dietary regimen are not necessary in the context of intensified insulin therapy. DESIGN: German multicentre, prospective cohort study; 6 years follow-up. SETTING: Ambulatory examination using a mobile ambulance. SUBJECTS: A total of 636 type 1 diabetic patients (age 33 +/- 7 years, diabetes duration 15 +/- 7 years; mean +/- SD), who had participated in a structured, 5-day, in-patient, group treatment and teaching programme for intensification of insulin therapy and liberalization of the diabetes diet 6 years prior to follow-up. MAIN OUTCOME MEASURES: Relations between the extent to which patients practise a liberalized diet, the degree of metabolic control (HbA1c, severe hypoglycaemia, body mass index, cholesterol), and the patients' perceived burden through dietary treatment. RESULTS: In the total patient group, HbA1c was 7.9 +/- 1.6%, and the incidence of severe hypoglycaemia was 0.17 cases per patient during the preceding year; 31% patients injected insulin < or = 3 times per day, 58% 4-7 times per day, and 11% used insulin pump therapy. Only 11% patients reported following a meal plan, whereas 89% continually changed timing and amount of carbohydrate intake; only 5% had the same number of meals every day, whereas as many as 20% varied the number of meals per day by four or more; 53% skipped main meals; 85% habitually consumed sugar or sugar containing foods. Patients with a higher degree of diet liberalization injected insulin or used an insulin pump therapy more frequently, and perceived their dietary treatment to be less burdensome. No clinically significant associations were found between the extent of diet liberalization and metabolic control. CONCLUSIONS: Under the conditions where type 1 diabetic patients have the opportunity to participate in an intensified insulin treatment and teaching programme, liberalization of the diabetes diet is not associated with adverse effects on glycaemic control, but is associated with less perceived burden through dietary treatment.

Adult↗
PubMed1995

Mortality and morbidity in treated hypertensive type 2 diabetic patients with micro- or macroproteinuria.

In order to describe the natural history of high risk diabetic patients treated for hypertension we have followed a sequential sample of 100 hypertensive Type 2 diabetic patients with elevated urinary protein excretion ( > or = 60 mg 24 h-1) for a period of 1-7 years. Antihypertensive treatment was instituted in all patients and, in addition, the patients were offered the possibility of participation in an intensified antihypertensive therapy programme. After a mean follow-up of 4 years overall mortality was 13%. Nineteen percent of all patients experienced a cardiovascular event and 7% a cerebrovascular event. In conclusion, in this study the overall mortality was lower that previously reported in proteinuric Type 2 diabetic patients. Antihypertensive treatment may account for this outcome.

Age Factors↗
PubMed1995

Preclinical evaluation of HBY 097, a new nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 replication.

HBY 097 [(S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3, 4-dihydroquinoxaline-2(1H)-thione] was selected from a series of quinoxalines as a nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (NNRTI). HBY 097 was shown to be a highly potent inhibitor of HIV-1 induced cell killing and HIV-1 replication in a variety of human cell lines as well as in fresh human peripheral blood lymphocytes and macrophages. The compound was also active against a variety of clinical isolates of HIV-1 including different HIV-1 subtypes and viruses resistant to 3'-deoxy-3'-azidothymidine. Mutant reverse transcriptases which arise as a consequence of treatment with other nonnucleoside inhibitors of HIV-1 reverse transcriptase were still inhibited by HBY 097 at relatively low concentrations. An HIV-1MN variant resistant to inhibition by HBY 097 displayed in the reverse transcriptase gene a mutation causing a substitution at position 190 of a glutamic acid for a glycine residue (G190 --> E), which is characteristic for quinoxaline derivatives. The drug was demonstrated to possess a favorable toxicity profile and to show good oral bioavailability in both mice and dogs. As a consequence of its outstanding properties, HBY 097 was selected for further development and is at present undergoing clinical trials.

Animals↗
PubMed1995

Impact of new population estimates on health and vital statistics.

Changes in Statistics Canada's annual population estimates, introduced in 1993, have an impact on a wide range of social, economic and demographic indicators. Any indicator that relies on population estimates will be affected by the new figures. This article describes the adjustment and examines its impact on health and vital statistics rates. With rare exceptions, all rates decrease as the denominators are adjusted upward. For example, accident rates, suicide rates, and age-specific fertility rates based on the adjusted population are lower than those previously calculated. The extent of the adjustment, however, depends on the geographic and demographic characteristics of the population at risk. Analysts whose work concentrates on special subgroups for whom the adjustment is particularly great (such as young adult men) may wish to pay closer attention to the new population figures. Although the new rates are lower than before, underlying trends and patterns over time or across subcategories are quite similar. The revised series incorporates estimates of net census undercoverage, and for the first time, includes non-permanent residents. In 1991, net census undercoverage and non-permanent residents together amounted to about one million persons, or 3.6% of the revised Canadian population of 28,120,100.

Adolescent↗