Achievement of behavioral efficacy and improved potency in new heterocyclic analogs of benzofuran H3 antagonists.
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Animals↗
Biomedical subjects
K Drescher
Publications and source records attributed to K Drescher.
Survival of Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus in the terminal ileum of fistulated Göttingen minipigs.
The ability of Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus administered in yogurt to survive the passage through the upper gastrointestinal tract was investigated with Göttingen minipigs that were fitted with ileum T-cannulas. After ingestion of yogurt containing viable microorganisms, ileostomy samples were collected nearly every hour beginning 3 h after food uptake. Living L. delbrueckii subsp. bulgaricus and S. thermophilus were detected in the magnitude of 10(6) to 10(7) per gram of intestinal contents (wet weight) in all animals under investigation. A calculation of the minimum amount of surviving bacteria that had been administered is presented. Total DNA extracted from ileostomy samples was subjected to PCR, which was species specific for L. delbrueckii and S. thermophilus and subspecies specific for L. delbrueckii subsp. bulgaricus. All three bacterial groups could be detected by PCR after yogurt uptake but not after uptake of a semisynthetic diet. One pig apparently had developed an endogenous L. delbrueckii flora. When heat-treated yogurt was administered, L. delbrueckii was detected in all animals. S. thermophilus or L. delbrueckii subsp. bulgaricus was not detected, indicating that heat-inactivated cells and their DNAs had already been digested and their own L. delbrueckii flora had been stimulated for growth.
Animals↗
Biological activity of GLP-1-analogues with N-terminal modifications.
Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and improves glycemic control in type 2 diabetes. In serum the peptide is degraded by dipeptidyl peptidase IV (DPP IV). The resulting short biological half-time limits the therapeutic use of GLP-1. Therefore, various GLP-1 analogues with alterations in cleavage positions were synthesized. GLP-1-receptor binding was investigated in RINm5F cells. Biological activity of the GLP-1 analogues was investigated in vitro by measuring cAMP production in RINm5F cells. GLP-1 analogues with modifications in position 2 were not cleaved by DPP IV and showed receptor affinity and in vitro biological activity comparable to native GLP-1. Analogues with alterations in positions 2 and 8, 2 and 9 or 8 and 9 showed a significant decrease in receptor affinity and biological activity. In vivo biological activity was tested in pigs. GLP-1 analogues were administered subcutaneously followed by an intravenous bolus injection of glucose. Plasma glucose and insulin were monitored over 4 h. Compared to native GLP-1, analogues with an altered position 2 showed similar or increased potency and biological half-time. Other GLP-1 analogues were less active. Despite the lack of degradation of these GLP-1 analogues by DPP IV in vitro, their biological action is as short as that of GLP-1, except for desamino-GLP-1, indicating that other degradation enzymes are important in vivo. Alterations of GLP-1 in positions 8 or 9 result in a loss of biological activity without extending biological half-time.
Cyclic AMP↗
Recovery of 15N-lactoferrin is higher than that of 15N-casein in the small intestine of suckling, but not adult miniature pigs.
Performance of biological functions of lactoferrin in the small intestine requires at least some resistance to degradation. Therefore, we studied prececal digestibility of lactoferrin in comparison to casein both in suckling and adult miniature pigs, applying 15N-labeled proteins. In study 1, 43 piglets (10-d-old), deprived of food for 12 h received 10 mL of sow's milk supplemented with 120 mg of 15N-labeled protein (porcine or bovine lactoferrin or bovine casein). Piglets were anesthetized 150 min later, after which the small intestine was excised, cut into three sections, and chyme was collected. In study 2, nine food-deprived boars fitted with T-canulae at the terminal ileum were given two semisynthetic experimental meals (204 g) in a cross-over design, 2 wk apart. One contained 7.5% (g/100 g) 15N-labeled bovine casein, the other 1.25% 15N-labeled bovine lactoferrin. Both were adjusted to 15% total protein with nonlabeled casein. Ileal chyme was collected from the canula over 33 h postprandially. All diets contained the indigestible marker chromic oxide. 15N-digestibility of lactoferrin, both porcine (84.4 +/- 3.2%) and bovine (82.3 +/- 4.8%), was significantly lower than casein digestibility (97.6 +/- 0.5%) in the distal small intestine of suckling piglets (P < 0.05). Based on immunoblotting after acrylamide electrophoresis, 4.5% of non- and partially digested lactoferrin was found in the last third of the small intestine of piglets. In adult miniature pigs there was no difference in 15N-digestibility of bovine lactoferrin compared to bovine casein (90.7 +/- 1.9% vs. 93.9 +/- 1.0%, P > 0.05). In suckling miniature pigs, the reduced digestibility of lactoferrin may provide the prerequisite for biological actions along the whole intestinal tract. The source of lactoferrin, porcine or bovine, made no difference in this respect.
Aging↗
Estimating the generalized impact fraction from case-control data.
The generalized impact fraction (also called the generalized attributable fraction) was introduced by Walter (1980, American Journal of Epidemiology 112, 409-416) and Morgenstern and Bursic (1982, Journal of Community Health 7, 292-309) as a measure that generalizes the population attributable fraction (attributable risk). It is defined as the fractional reduction of a disease resulting from changing the current distribution of a risk factor to some modified distribution. We show that the point and variance estimator derived by Greenland and Drescher (1993, Biometrics 49, 865-872) for fixed shift functions can be extended to situations where the shift is a probabilistic function of the actual exposure value. The formulas are applicable for case-control designs where the cases are simply randomly selected and the controls are chosen in one of three ways: simple random sampling, stratified random sampling, and frequency matching.
Alcohol Drinking↗
Peritoneal dialysis. An adjunct to pediatric postcardiotomy fluid management.
Patients requiring cardiopulmonary bypass for congenital heart surgery commonly exhibit impaired renal function and extravascular fluid retention. These conditions contribute to early postoperative fluid overload, which may result in significant morbidity and mortality. We examined the safety and efficacy of peritoneal dialysis in removing extravascular fluid from critically ill postcardiotomy patients. A retrospective case review from July of 1995 through April of 1996 was conducted. All patients undergoing peritoneal dialysis achieved a net negative fluid balance. Average urine output increased from 2.1 cc/kg/hr to 3.9 cc/kg/hr (P < 0.01) during the pre-peritoneal dialysis to post-peritoneal dialysis period, and the mean number of inotropic agents decreased from 2.2 to 1.7 (P < 0.05). Controlled comparison revealed that the peritoneal dialysis cohort more rapidly achieved a negative weight-adjusted fluid balance throughout the early postoperative course. The peritoneal dialysis group's illness severity decreased more rapidly within the 24-hour period after initiation of peritoneal dialysis than did that of the control cohort over the same period of time. No difference in postoperative morbidity or mortality existed between the study groups. Complications from the catheter placement were minimal, and no patient experienced peritonitis or metabolic or hemodynamic instability during peritoneal dialysis catheter placement, usage, or removal. Peritoneal dialysis is a safe and effective form of renal replacement therapy, even among critically ill pediatric postcardiotomy patients. Early postsurgical institution of peritoneal dialysis may hasten early postoperative recovery. We speculate that intraoperative catheter placement reduces the complication rate associated with this treatment modality.
Capillary Leak Syndrome↗
Influence of age on the effect of bidirectional cavopulmonary anastomosis on left ventricular volume, mass and ejection fraction.
OBJECTIVES: We sought to identify age-related differences in the ventricular response of patients after bidirectional cavopulmonary anastomosis (CPA) and to compare changes in the ventricular response among children < 3 years of age who underwent CPA with that of age-matched control subjects who had a systemic to pulmonary artery shunt alone. BACKGROUND: Pre-Fontan CPA has been advocated over a systemic to pulmonary artery shunt alone in patients with a single ventricle to facilitate ventricular volume unloading and minimize risk of the Fontan operation. METHODS: Our study evaluated 23 patients who initially received a systemic to pulmonary artery shunt as an initial procedure before subsequent Fontan palliation. In eight of these patients (group I), bidirectional CPA was performed before age 3 years, and in four (group II), it was performed after age 10 years. The remaining 11 patients (group III, age and weight control group for group I) were maintained with their initial shunt until they underwent Fontan palliation. Serial echocardiographic analysis was used retrospectively to evaluate left ventricular volume and mass and systolic pump function (ejection fraction) before and after bidirectional CPA. RESULTS: Through 10 months of follow-up, group I patients showed significant decreases in indexed end-diastolic volume both after CPA (120 ml/m1.5 body surface area vs. 78 ml/m1.5, p = 0.001) and in comparison with values in patients in group II and III, who showed no changes in end-diastolic volume (p < 0.001). Indexed ventricular mass decreased moderately after bidirectional CPA in group I (from 228 g/m1.5 body surface area to 148 g/m1.5) but remained unchanged in groups II and III. The differences in trends between groups I and III were significant (p = 0.03). Ejection fraction decreased significantly in group II versus group I patients (0.48 to 0.27 vs. 0.51 to 0.52, p < 0.05) after CPA. Oxygen saturation measurements before and after bidirectional CPA revealed a significant increase in group I (73% to 86%, p < 0.001) and a decrease in group II (82% to 73%, p < 0.01). CONCLUSIONS: Bidirectional CPA facilitates ventricular volume unloading and promotes regression of left ventricular mass in younger children (< 3 years) in preparation for a Fontan operation. In contrast, bidirectional CPA is of questionable value in older children as a staging procedure for Fontan palliation.
Aging↗
Competing Anisotropies in the Ferromagnetic Kondo-Lattice Compound YbNiSn: Observation of a Complex Magnetic Ground State under High Pressure.
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Journal Article↗
Maximum likelihood estimation of the attributable fraction from logistic models.
Bruzzi et al. (1985, American Journal of Epidemiology 122, 904-914) provided a general logistic-model-based estimator of the attributable fraction for case-control data, and Benichou and Gail (1990, Biometrics 46, 991-1003) gave an implicit-delta-method variance formula for this estimator. The Bruzzi et al. estimator is not, however, the maximum likelihood estimator (MLE) based on the model, as it uses the model only to construct the relative risk estimates, and not the covariate-distribution estimate. We here provide maximum likelihood estimators for the attributable fraction in cohort and case-control studies, and their asymptotic variances. The case-control estimator generalizes the estimator of Drescher and Schill (1991, Biometrics 47, 1247-1256). We also present a limited simulation study which confirms earlier work that better small-sample performance is obtained when the confidence interval is centered on the log-transformed point estimator rather than the original point estimator.
Biometry↗
Smoking cessation and nonsmoking intervals: effect of different smoking patterns on lung cancer risk.
A case-control study of lung cancer was conducted in northwestern Germany in 1985-86. The study included 194 lung cancer cases and the same number of hospital controls and population controls who were matched to the cases by sex and age. Personal interviews were conducted by trained interviewers. We report here the effect of different smoking patterns--such as nonsmoking intervals, and time since quitting smoking--on lung cancer risk. Both quitting smoking and having a nonsmoking interval are seen to reduce lung cancer risk significantly. For a nonsmoking interval of three years or more, relative risk (RR) = 0.21, 95 percent confidence interval (CI) = 0.08-0.52; for quitting smoking for 10 years or more, RR = 0.23, CI = 0.11-0.48). A dose-response relationship was estimated for cigarette dose, length of nonsmoking interval, and time since stopped smoking.
Adult↗
Attributable risk estimation from case-control data via logistic regression.
By fitting an unconditional logistic regression model to unmatched case-control data, an estimate of the joint population attributable risk for the factor included is obtained. This estimate and its asymptotic variance can easily be computed from the intercept parameter and its asymptotic variance. A generalization to the analysis of stratified data with large strata enables the calculation of stratum-specific attributable risks and their variances via stratum-specific intercept parameters. If sampling of cases is independent of strata, an estimate of the summary attributable risk and its asymptotic variance may be obtained as a weighted sum of the stratum-specific attributable risks.
Biometry↗
The design of case-control studies: the effect of confounding on sample size requirements.
This paper considers the extent to which confounding effects of covariates, which are not controlled for by matching in the design, may influence the sample size necessary for case-control studies. The quantitative calculations are performed for an age-matched case-control study on lung cancer and air pollution, and are based on different evaluation methods. For illustrative purposes attention is confined to a dichotomous risk factor and a single dichotomous covariate. By using the numerical values of a pilot study investigating lung cancer and air pollution, it turns out that the sample size required for detecting a relative risk as close as 1.15 to 1 is only slightly influenced by the strength of the association between confounder and risk factor for reasonable variations around our empirical values. On the other hand, sample size considerably increases with increasing relative risk of a confounder even when the association remains small. The sample size required for an individually matched analysis practically equals that for an age-stratified analysis when the relative risk of the covariate is one. With a relative risk greater than one, however, the size for a matched analysis exceeds that for a stratified analysis and the ratio between them increases with increasing relative risk.
Air Pollutants↗
[Results of the epidemiology of lung cancer in females].
In the context with an extensive pilot study investigating risk factors for lung cancer, aetiological and clinical questions were analysed for lung cancer mortality in women. In a first step all available data sources about the prevalence of smoking in the FRG were used to determine the correlation between the prevalence of smoking and lung cancer mortality. 88% of the variance (R2) of lung cancer mortality for women could be explained by smoking. In a second step medical records of 133 female lung cancer patients from three hospitals were analysed with regard to the histological types of lung cancer and smoking. Small cell lung cancers were more frequent among female smokers while adenocarcinoma was more prevalent among non-smokers. Survival analysis for 421 men and 97 women showed a significantly longer survival time for women as compared to men, taking into account other relevant prognostic factors. The association between smoking and lung cancer is discussed and analysed in greater detail.
Cause of Death↗
Influence of antipsychotics and serotonin antagonists on presynaptic receptors modulating the release of serotonin in synaptosomes of the nucleus accumbens of rats.
In the nucleus accumbens of rats the release of [3H]serotonin (5-HT) from superfused synaptosomes stimulated by 30 mM K+ was investigated. In the presence of 40 microM of the uptake inhibitor cocaine the release of [3H]5-HT was inhibited by 5-HT in a concentration-dependent manner (IC50 = 0.45 microM). The maximum inhibitory effect of 5-HT was 54% of controls. The inhibition of K+-stimulated release of [3H]5-HT induced by 5-HT was antagonized completely by methiothepine and clozapine, respectively, whereas methysergide had only a weak antagonizing effect in a concentration of 20 microM or less, haloperidol was ineffective. Furthermore, the synaptosomal K+-stimulated release of [3H]5-HT was also inhibited by dopamine (DA) in a concentration-dependent manner (IC50 = 0.1 microM). This inhibitory effect was antagonized by antipsychotic drugs, the rank order of antagonistic potencies was sulpiride greater than haloperidol greater than clozapine; methiothepine was ineffective. The experimental system (the K+-stimulated synaptosomal release of [3H]5-HT seems to be a suitable model for differentiating dopaminergic and/or serotonergic components of antipsychotics or other drugs on presynaptic receptors.
Animals↗
Influence of antipsychotics on presynaptic receptors modulating the release of dopamine in synaptosomes of the nucleus accumbens of rats.
The release of preloaded [3H]dopamine (DA) from superfused synaptosomes stimulated by 30 mM K+ was investigated in the nucleus accumbens of rats. Under conditions preventing the uptake of DA (presence of 40 microM cocaine) release of [3H]DA was inhibited by DA and apomorphine in a concentration-dependent manner (IC50s 0.65 and 0.3 microM, respectively). The maximal inhibitory effects of DA, as well as of apomorphine, were about 50% of the controls. The DA-induced inhibition was antagonized by antipsychotics completely; the rank order of antagonistic potencies was haloperidol greater than clozapine greater than sulpiride; methiothepine was ineffective. Furthermore, the K+-stimulated release of [3H]DA was inhibited by serotonin in a concentration-dependent manner (IC50 = 0.9 microM). This inhibitory effect was antagonized by methiothepine with a high efficiency, by clozapine and methysergide with moderate efficiencies; haloperidol and sulpiride were ineffective. The experimental system demonstrated appears to be suitable for characterizing the DA- and serotonin-antagonistic potencies of antipsychotics and other drugs on presynaptic autoreceptors as well as receptors modulating release of DA in the nucleus accumbens.
Animals↗
Chemoattraction and chemotaxis in Dictyostelium discoideum: myxamoeba cannot read spatial gradients of cyclic adenosine monophosphate.
Myxamoebae of the morphogenetic cellular slime mold Dictyostelium discoideum are thought to be able to accurately read and respond to directional information in spatial gradients of cyclic AMP. We examined the spatial and temporal mechanisms proposed for chemotaxis by comparing the behavior of spreading or evenly distributed cell populations after exposure to well-defined spatial gradients. The effects of gradient generation on cells were avoided by using predeveloped gradients. Qualitatively different responses were obtained using (a) isotropic, (b) static spatial, or (c) temporal (impulse) gradients in a simple chamber of penetrable micropore filters. We simulated models of chemotaxis and chemokinesis to aid our interpretations. The attractive and locomotory responses of populations were maximally stimulated by 0.05 microM cyclic AMP, provided that cellular phosphodiesterase was inhibited. But a single impulse of cyclic AMP during gradient development caused a greater and qualitatively different attraction. Attraction in spatial gradients was only transient, in that populations eventually developed a random distribution when confined to a narrow territory. Populations never accumulated nor lost their random distribution even in extremely steep spatial gradients. Attraction in spatial gradients was inducible only in spreading populations, not randomly distributed ones. Thus, spatial gradients effect biased-random locomotion: i.e., chemokinesis without adaptation. Cells cannot read gradients; the reaction of the cells is stochastic. Spatial gradients do not cause chemotaxis, which probably requires a sharp stimulant concentration increase (a temporal gradient) as a pulse or impulse. The results also bear on concepts of how embryonic cells might be able to decipher the positional information in a morphogen spatial gradient during development.
3',5'-Cyclic-AMP Phosphodiesterases↗
Phase response curves obtained by perturbing different variables of a 24 hr model oscillator based on translational control.
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Animals↗
Kinetics and models of the Drosophila heat-shock system.
The puffing of Drosophila heat-shock genes after (1) a step-wise temperature increase ("heat-shock"); (2) recovery from anaerobiosis; and (3) incubation with uncoupling reagents was expressed as percent of the maximal size and normalized to the time scale. Data were taken from the literature and new measurements. In addition, puffing was measured after a 30-min temperature pulse and after two 30-min pulses. The latter experiment revealed a second, smaller increase in puff-size. Data on RNA and protein synthesis in Drosophila cells were collected from the literature and also normalized. From the available data, a feed-back control system is derived that consists of a controlled variable x, possibly a metabolic function of the mitochondria, interacting with an activator molecule which exists in an active (A+) and an inactive (A-) configuration. A+ activates the heat-shock genes which in turn produce their mRNA (y) and proteins (z) which then change the controlled variable x into a new steady state. A modified version of this model assumes a feed-back control of the heat-shock proteins on the activator molecule. A mathematical model of this system (Goodwin, 1965) was simulated by computer and compared with the experimental results.
2,4-Dinitrophenol↗