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R Bender

Publications and source records attributed to R Bender.

At least 19 recordsLinked to original sources
PubMed2001

Long-term, progressive hippocampal cell loss and dysfunction induced by early-life administration of corticotropin-releasing hormone reproduce the effects of early-life stress.

Stress early in postnatal life may result in long-term memory deficits and selective loss of hippocampal neurons. The mechanisms involved are poorly understood, but they may involve molecules and processes in the immature limbic system that are activated by stressful challenges. We report that administration of corticotropin-releasing hormone (CRH), the key limbic stress modulator, to the brains of immature rats reproduced the consequences of early-life stress, reducing memory functions throughout life. These deficits were associated with progressive loss of hippocampal CA3 neurons and chronic up-regulation of hippocampal CRH expression. Importantly, they did not require the presence of stress levels of glucocorticoids. These findings indicate a critical role for CRH in the mechanisms underlying the long-term effects of early-life stress on hippocampal integrity and function.

Animals↗
PubMed2001

[Interpretation of efficacy measures derived from 2 X 2 tables for the evaluation of diagnostic tests and treatment].

BACKGROUND: To describe the efficacy of diagnostic tests and the effect of treatment a number of measures are used, which can be derived from 2 x 2 tables of frequencies. For the comprehension of these measures the knowledge of their properties in the framework of probability theory is necessary. MATERIAL AND METHOD: After an introduction of basic terms such as probability, odds, joint and conditional probability the usual measures sensitivity, specificity, likelihood ratio, positive and negative predictive value, relative risk, odds ratio, relative risk reduction, absolute risk reduction, and number needed to treat are presented and explained. In particular, the importance of disease prevalence and baseline risk for the interpretation of these measures is pointed out by means of examples. CONCLUSION: If the disease prevalence or the baseline risk is not appropriately taken into account, the efficacy of a diagnostic test and the effect of a treatment are overestimated, especially in screening and prevention trials.

Clinical Trials as Topic↗
PubMed2001

Calculating confidence intervals for the number needed to treat.

The number needed to treat (NNT) has gained much attention in the past years as a useful way of reporting the results of randomized controlled trials with a binary outcome. Defined as the reciprocal of the absolute risk reduction (ARR), NNT is the estimated average number of patients needed to be treated to prevent an adverse outcome in one additional patient. As with other estimated effect measures, it is important to document the uncertainty of the estimation by means of an appropriate confidence interval. Confidence intervals for NNT can be obtained by inverting and exchanging the confidence limits for the ARR provided that the NNT scale ranging from 1 through infinity to -1 is taken into account. Unfortunately, the only method used in practice to calculate confidence intervals for ARR seems to be the simple Wald method, which yields too short confidence intervals in many cases. In this paper it is shown that the application of the Wilson score method improves the calculation and presentation of confidence intervals for the number needed to treat. Control Clin Trials 2001;22:102-110

Confidence Intervals↗
PubMed2001

Adjusting for multiple testing--when and how?

Multiplicity of data, hypotheses, and analyses is a common problem in biomedical and epidemiological research. Multiple testing theory provides a framework for defining and controlling appropriate error rates in order to protect against wrong conclusions. However, the corresponding multiple test procedures are underutilized in biomedical and epidemiological research. In this article, the existing multiple test procedures are summarized for the most important multiplicity situations. It is emphasized that adjustments for multiple testing are required in confirmatory studies whenever results from multiple tests have to be combined in one final conclusion and decision. In case of multiple significance tests a note on the error rate that will be controlled for is desirable.

Bias↗
PubMed2001

Low prevalence of cardiac autonomic neuropathy in Type 1 diabetic patients without nephropathy.

AIM: To assess the prevalence of cardiac autonomic neuropathy (CAN) in Type 1 diabetic patients with and without nephropathy. METHODS: Sixty-six consecutive patients without nephropathy (n = 24), with incipient (n = 26) or overt nephropathy (n = 16) and a diabetes duration between 21 and 31 years were examined. Heart rate variability (HRV) as measure for CAN was investigated with short-term spectral analysis in the low-frequency (LF) band (0.06-0.15 Hz), reflecting sympathetic and vagal activity, and high-frequency (HF) band (0.15-0.50 Hz), reflecting vagal activity. HRV was expressed as spectral power (ms2, log-transformed). Normal, age-corresponding reference values were established in 184 controls. QTc intervals and dispersion were measured. RESULTS: After adjustment for age, there was no significant difference between healthy controls and patients without nephropathy. After further adjustment for diabetes duration, HbA1c, hypertension and treatment with beta-blockers, HRV in both frequency bands decreased with evidence of nephropathy. LF band (supine): patients without nephropathy 5.56 (4.89-6.21) (least squares means and 95% confidence interval (CI)), incipient nephropathy 5.72 (5.15-6.29) and overt nephropathy 4.11 (3.27-4.96). HF band (supine): without nephropathy 5.93 (5.26-6.60), incipient nephropathy 5.99 (5.41-6.57) and overt nephropathy 4.84 (4.00-5.68). Significant differences were found for patients without and with incipient nephropathy compared with those with overt nephropathy in the LF band and between patients with incipient nephropathy compared with those with overt nephropathy in the HF band. QTc intervals and QTc dispersion increased significantly with increasing nephropathy. CONCLUSIONS: Long-term Type 1 diabetes without nephropathy was not associated with impaired cardiac autonomic function in our study. However, in those with nephropathy, a loss of both vagal and sympathetic activity was present, and the severity of CAN correlated positively with more advanced nephropathy.

Adult↗
PubMed2000

Granule cell hyperexcitability in the early post-traumatic rat dentate gyrus: the 'irritable mossy cell' hypothesis.

1. Cytochemical and in vitro whole-cell patch clamp techniques were used to investigate granule cell hyperexcitability in the dentate gyrus 1 week after fluid percussion head trauma. 2. The percentage decrease in the number of hilar interneurones labelled with either GAD67 or parvalbumin mRNA probes following trauma was not different from the decrease in the total population of hilar cells, indicating no preferential survival of interneurones with respect to the non-GABAergic hilar cells, i.e. the mossy cells. 3. Dentate granule cells following trauma showed enhanced action potential discharges, and longer-lasting depolarizations, in response to perforant path stimulation, in the presence of the GABAA receptor antagonist bicuculline. 4. There was no post-traumatic alteration in the perforant path-evoked monosynaptic excitatory postsynaptic currents (EPSCs), or in the intrinsic properties of granule cells. However, after trauma, the monosynaptic EPSC was followed by late, polysynaptic EPSCs, which were not present in controls. 5. The late EPSCs in granule cells from fluid percussion-injured rats were not blocked by the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV), but were eliminated by both the non-NMDA glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the AMPA receptor antagonist GYKI 53655. 6. In addition, the late EPSCs were not present in low (0.5 mM) extracellular calcium, and they were also eliminated by the removal of the dentate hilus from the slice. 7. Mossy hilar cells in the traumatic dentate gyrus responded with significantly enhanced, prolonged trains of action potential discharges to perforant path stimulation. 8. These data indicate that surviving mossy cells play a crucial role in the hyperexcitable responses of the post-traumatic dentate gyrus.

2-Amino-5-phosphonovalerate↗
PubMed2000

Species-specific expression of parvalbumin in the entorhinal cortex of the Mongolian gerbil: dependence on local activity but not extrinsic afferents.

Mongolian gerbils are genetically predisposed to develop epileptic seizures in limbic structures. A species-specific property of the Mongolian gerbil is the expression of the calcium-binding protein parvalbumin in the perforant path where it is predominantly concentrated in nerve terminals. To test the hypothesis that this atypical expression of parvalbumin is induced by seizure-correlated hyperactivity in the entorhinohippocampal loop, we investigated whether it is dependent on extrinsic afferents to the entorhinal cortex. We cultivated organotypic slice cultures of neonate gerbil entorhinal cortex, isolated from all regions it is normally connected with in vivo. In these cultures, parvalbumin-expressing neurons demonstrated their characteristic features like in vivo. Blockade of spontaneous local activity with the sodium-channel blocker tetrodotoxin, however, considerably reduced the number of parvalbumin-expressing neurons in culture. These results indicate that spontaneous local activity, but not activity mediated by extrinsic afferents, is an essential factor for the expression of parvalbumin in the entorhinal cortex of the Mongolian gerbil.

Afferent Pathways↗
PubMed2000

Evidence for the existence of non-GABAergic, cholinergic interneurons in the rodent hippocampus.

Previous studies have revealed a small number of hippocampal interneurons immunoreactive for choline acetyltransferase, the acetylcholine-synthesizing enzyme. It remained an open question, however, whether these neurons represented a subgroup of inhibitory GABAergic neurons co-localizing acetylcholine. In this study, we have combined immunocytochemistry for choline acetyltransferase and in situ hybridization for glutamate decarboxylase messenger RNA, the GABA-synthesizing enzyme. None of the choline acetyltransferase-immunoreactive neurons in the various layers of the hippocampus proper and fascia dentata were found to co-localize glutamate decarboxylase messenger RNA. The lack of an in situ hybridization signal in these neurons is unlikely to result from the combination of the two labeling techniques. When combining in situ hybridization for glutamate decarboxylase messenger RNA with immunostaining for parvalbumin, a calcium-binding protein expressed by many GABAergic hippocampal interneurons, numerous double-labeled cells were observed. These data provide neurochemical evidence for the existence of non-GABAergic, supposedly cholinergic non-principal cells in the hippocampus.

Animals↗
PubMed2000

Non-linear effects of blood pressure and glycosylated haemoglobin on progression of diabetic nephropathy.

OBJECTIVE: To describe the long-term simultaneous impacts of blood pressure and glycosylated haemoglobin values on the risk of progression of diabetic nephropathy. DESIGN: Prospective, multicentre, 6-year follow-up study. SETTING: One reference centre (university department of internal medicine) and nine general hospitals. SUBJECTS: A total of 601 type 1 diabetic patients on intensive insulin therapy with and without diabetic nephropathy. MAIN OUTCOME MEASURES: Progression of nephropathy was defined as change for the worse within five stages of nephropathy by at least one of these stages during the study period. By the use of logistic regression, the relationship between metabolic and blood pressure control and the risk of nephropathy progression was quantified. RESULTS: The main determinants of nephropathy progression were glycosylated haemoglobin and blood pressure, which were both non-linearly associated with the risk of progression. No significant threshold levels for any of the predictors of progression were identified. CONCLUSIONS: The results of this study underline the importance of optimizing metabolic and blood pressure control to arrest the progression of diabetic nephropathy without the evidence for a clinically relevant threshold effect.

Adult↗
PubMed2000

Effects of on-demand beta2-agonist inhalation in moderate-to-severe asthma. A randomized controlled trial.

BACKGROUND: The appropriate use of short-acting beta2-agonist inhalation in asthma has been the subject of controversy in recent years. Limited information is available for the group of moderate to severe asthmatics with high intake of bronchodilator inhalants and continuous anti-inflammatory protection. OBJECTIVE: To investigate the effects of beta2-agonist reduction in marked asthma treated with multiple asthma medications. DESIGN: Randomized, controlled single-blind, cross-over trial. SETTING: Outpatient clinic at a university medical centre. SUBJECTS: A total of 80 adult patients with moderate-to-severe asthma. INTERVENTIONS: In a 1-year study patients were assigned to on-demand vs. regular beta2-agonist inhalation treatment. MAIN OUTCOME MEASURES: Asthmatic episodes (primary outcome), symptoms, peak expiratory flow rates (PEF) and drug use were recorded daily. Bronchodilator and airway responsiveness, lung function indices and quality of life were assessed during five clinic visits. Also, practicability of beta2-agonist tapering in multimedicated asthmatics was analysed. RESULTS: More than 80% of moderate-to-severe asthmatics were able to reduce their beta2-agonist intake by >/=50%. Puffs per day of active therapy decreased from 7.9 in regular to 3.3 in on-demand treated patients (P = 0.0001). The type of beta2-agonist used (salbutamol/fenoterol) had no significant impact on the study findings. Almost all parameters of control of asthma improved during the on-demand treatment period. CONCLUSION: On-demand inhalation of short-acting beta2-agonists in moderate-to-severe asthma is safe, and even in severe asthma a reduction from regular to on-demand beta2-agonist inhalation is possible, with improved asthma control.

Acute Disease↗
PubMed2000

Prognosis of persons with type 1 diabetes on intensified insulin therapy in relation to nephropathy.

OBJECTIVE: To study the prognosis of persons with type 1 diabetes in relation to the degree of nephropathy at initiation of intensified insulin therapy. DESIGN: Ten years follow-up of a cohort of 3674 patients who had participated in a 5-day group treatment and teaching programme for intensification of insulin therapy between September 1978 and December 1994. SETTING: Ten diabetes centres in Germany. SUBJECTS: A total of 3674 patients (insulin treatment before age 31), age at baseline 27 +/- 10 years, with a diabetes duration of 11 +/- 9 years. Patients were divided into three groups according to baseline renal parameters (group I, normal proteinuria, n = 1829; group II, microproteinuria, n = 1257; group III, at least macroproteinuria, n = 367). MAIN OUTCOME MEASURES: End-stage diabetic complications (blindness, amputations, renal replacement therapy, standardized mortality ratios (SMR) and causes of death. RESULTS: Outcome measures were documented for 97% of patients; 251 (7%) had died. During follow-up, 1% of patients in group I, 4% in group II and 47% in group III had at least one end-stage diabetic complication. SMR for men: nephropathy group I, 2.2 (95% CI = 1.5-3); group II, 3.2 (2.3-4.3); group III, 11.5 (8.8-14.7). SMR for women: group I, 2.5 (1.5-3.8); group II, 3.5 (2.2-5.3); group III, 27 (19.8-35.9). Causes of death for men and women combined: group I (total 58 deaths)--cardiovascular, 21 (36%); hypoglycaemia, 1; ketoacidosis, 3; violent deaths, 17 (29%); others, 16; group II (66 deaths)--cardiovascular, 25 (38%); hypoglycaemia, 2; ketoacidosis, 2; violent deaths, 14 (21%); others, 23; group III (114 deaths)--cardiovascular, 68 (60%); hypoglycaemia, 2; ketoacidosis, 5; infections, 15 (13%); violent deaths, 5 (4%); others, 19. CONCLUSIONS: Patients with microproteinuria have only a slightly worse prognosis than patients with normal proteinuria during the first 10 years after initiation of intensified insulin therapy. Excess mortality amongst patients who started intensified insulin therapy is mainly due to those with manifest clinical nephropathy.

Adult↗
PubMed2000

Predictors of mortality and end-stage diabetic complications in patients with Type 1 diabetes mellitus on intensified insulin therapy.

AIMS: To assess predictors of mortality and end-stage diabetic complications in patients with Type 1 diabetes mellitus on intensified insulin therapy. METHODS: A cohort of 3,674 patients (insulin treatment before age 31) who had participated in a 5-day in-patient group treatment and teaching programme for intensification of insulin therapy between 9/1978 and 12/1994 were reassessed after 10 +/- 3 (mean +/- SD) years. RESULTS: Vital status and data on blindness, amputations, and renal replacement therapy were documented for 97% patients; 7% patients had died, 1.3% had become blind, 2% had amputations and 4.6% started renal replacement therapy. Using the Cox proportional hazards model, the following risk factors of mortality as assessed at baseline were identified: nephropathy (at least macroproteinuria), hazard ratio 3.8 (95% confidence interval 2.6-5.6); smoking, 1.9 (1.4-2.6); diabetes duration, 1.5 (1.2-1.8) for a difference of 10 years; serum cholesterol, 1.1 (1.0-1.2) for a difference of 1 mmol/l; lower social status, 1.4 (1.1-1.8) for a difference of 1 out of 3 levels; age, 1.3 (1.1-1.6) for a difference of 10 years; male sex, 1.4 (1.1-1.9); systolic blood pressure, 1.1 (1-1.2) for a difference of 10 mmHg. For the combined endpoint - blindness or amputations or renal replacement therapy - predictors were: nephropathy, foot complications, HbA1c, smoking, cholesterol, systolic blood pressure, retinopathy, hypertension, and social status. CONCLUSION: In Type 1 diabetic patients who start intensified insulin therapy, nephropathy remains the strongest predictor of mortality and end-stage complications. Glycosylated haemoglobin is a risk factor of end-stage complications but not of mortality. Conventional risk factors comparable to the general population, particularly smoking become operative as predictors of both mortality and end-stage complications.

Adult↗
PubMed2000

A cross-over evaluation of different methods and devices to measure blood pressure in type 1 diabetic patients with nephropathy.

BACKGROUND: In type 1 diabetic patients with nephropathy, tight blood pressure control has been shown to prevent the progression of the disease. Up until now, self-monitoring, ambulatory and office blood pressure values have not been compared in these patients. Thus, we have evaluated blood pressure values obtained in the office by a physician and at home by self-monitoring with those measured under ambulatory conditions in these patients. Additionally, for blood pressure self-monitoring, three different devices (the sphygmomanometer, upper-arm oscillometer and wrist oscillometer) were compared. METHODS: Twenty-one treated hypertensive type 1 diabetic patients [age 45+/-9 years, duration of diabetes 33+/-12 years (mean+/-SD)] with overt diabetic nephropathy participated in this study. At both baseline and the end of the study, daytime ambulatory blood pressure measurement was performed. Office blood pressure was measured at baseline. Additionally, all the patients measured their blood pressure over a 3-week period using each of the three different devices, in random order, for 1 week. RESULTS: The mean office blood pressure values (135+/-21/85+/-12mmHg) were higher than both the ambulatory (131+/-23/80+/-12, P<0.05) and self-monitoring values (130+/-14/78+/-10; P<0.05 for systolic and P<0.02 for diastolic values). The difference between the ambulatory and self-monitoring values were not statistically significant. Diastolic blood pressure values measured with the oscillometric wrist device showed a trend towards higher values when compared to those measured with the sphygmomanometer and with the oscillometric upper-arm device (P=0.065 for diastolic values). CONCLUSION: Office blood pressure measurements may over-estimate blood pressure in patients with type 1 diabetes and diabetic nephropathy. Because the oscillometric wrist device tends to over-estimate diastolic values, upper-arm devices should be preferred for blood pressure self-monitoring in these patients.

Arm↗
PubMed2000

Improving the calculation of confidence intervals for the number needed to treat.

The number needed to treat has gained much attention in the past years as a useful way of reporting the results of randomised controlled trials with a binary outcome. Defined as reciprocal of the absolute risk reduction the number needed to treat is the estimated number of patients who need to be treated to prevent an adverse outcome in one additional patient. As with other estimated effect measures, it is important to document the uncertainty of the estimation by means of an appropriate confidence interval. Confidence intervals for the number needed to treat can be obtained by inverting and exchanging the confidence limits for the absolute risk reduction. Unfortunately, the only method used in practice for calculating a confidence interval for the absolute risk reduction seems to be the usual asymptotic method, which yields confidence intervals which are too short in many cases. In this paper it is shown that the application of the Wilson score method improves the calculation and presentation of confidence intervals for the number needed to treat.

Bias↗
PubMed1999

Effect of age on excess mortality in obesity.

CONTEXT: The effect of age on excess mortality from all causes associated with obesity is controversial. Few studies have investigated the association between body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters), age, and mortality, with sufficient numbers of subjects at all levels of obesity. OBJECTIVE: To assess the effect of age on the excess mortality associated with all degrees of obesity. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: A total of 6193 obese patients with mean (SD) BMI of 36.6 (6.1) kg/m2 and mean (SD) age of 40.4 (12.9) years who had been referred to the obesity clinic of Heinrich-Heine University, Düsseldorf, Germany, between 1961 and 1994. Median follow-up time was 14.8 years. MAIN OUTCOME MEASURE: All-cause mortality through 1994 among 6053 patients for whom follow-up data were available (1028 deaths) analyzed as standardized mortality ratios (SMRs) using the male-female population of the geographic region (North Rhine Westphalia) as reference. RESULTS: The cohort was grouped into approximate quartiles according to age (18-29, 30-39, 40-49, and 50-74 years) and BMI (25 to <32, 32 to <36, 36 to <40, and > or =40 kg/m2) at baseline. The SMRs showed a significant excess mortality with an SMR for men of 1.67 (95% confidence interval, 1.51-1.85; P<.001) and an SMR for women of 1.45 (95% confidence interval, 1.34-1.57; P<.001). The excess mortality associated with obesity declined with age. For men, the SMRs of the 4 age groups were 2.46, 2.30, 1.99, and 1.31, respectively; for women, they were 1.81, 2.10, 1.70, and 1.26, respectively (Poisson trend test, P<.001). The SMRs increased with BMI but, within each BMI group, the SMRs decreased with age. The lowest SMRs (for men, 1.01; for women, 0.91) were obtained for patients older than 50 years with BMIs of 25 to less than 32 kg/m2. Thus, older men and women at a BMI range of 25 to less than 32 kg/m2 had no excess mortality. The highest SMRs (for men, 4.22; for women, 3.79) were calculated for the patients aged 18 to 29 years with a BMI of 40 kg/m2 or higher. CONCLUSIONS: In this large cohort of obese persons, risk of death increased with body weight, but obesity-related excess mortality declined with age at all levels of obesity.

Adult↗