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Biomedical subjects

D Ruppert

Publications and source records attributed to D Ruppert.

At least 19 recordsLinked to original sources
PubMed2001

Simple incorporation of interactions into additive models.

Often, the functional form of covariate effects in an additive model varies across groups defined by levels of a categorical variable. This structure represents a factor-by-curve interaction. This article presents penalized spline models that incorporate factor-by-curve interactions into additive models. A mixed model formulation for penalized splines allows for straightforward model fitting and smoothing parameter selection. We illustrate the proposed model by applying it to pollen ragweed data in which seasonal trends vary by year.

Biometry↗
PubMed1999

Kriging with nonparametric variance function estimation.

A method for fitting regression models to data that exhibit spatial correlation and heteroskedasticity is proposed. It is well known that ignoring a nonconstant variance does not bias least-squares estimates of regression parameters; thus, data analysts are easily lead to the false belief that moderate heteroskedasticity can generally be ignored. Unfortunately, ignoring nonconstant variance when fitting variograms can seriously bias estimated correlation functions. By modeling heteroskedasticity and standardizing by estimated standard deviations, our approach eliminates this bias in the correlations. A combination of parametric and nonparametric regression techniques is used to iteratively estimate the various components of the model. The approach is demonstrated on a large data set of predicted nitrogen runoff from agricultural lands in the Midwest and Northern Plains regions of the U.S.A. For this data set, the model comprises three main components: (1) the mean function, which includes farming practice variables, local soil and climate characteristics, and the nitrogen application treatment, is assumed to be linear in the parameters and is fitted by generalized least squares; (2) the variance function, which contains a local and a spatial component whose shapes are left unspecified, is estimated by local linear regression; and (3) the spatial correlation function is estimated by fitting a parametric variogram model to the standardized residuals, with the standardization adjusting the variogram for the presence of heteroskedasticity. The fitting of these three components is iterated until convergence. The model provides an improved fit to the data compared with a previous model that ignored the heteroskedasticity and the spatial correlation.

Agriculture↗
PubMed1997

The bradykinin B2 receptor antagonist Icatibant (HOE 140) corrects avid Na+ retention in rats with CCl4-induced liver cirrhosis: possible role of enhanced microvascular leakage.

Avid Na+ retention is a hallmark of liver cirrhosis. The aim of this study was to investigate whether and how bradykinin is involved in Na+ retention in rats with CCl4-induced liver cirrhosis. To this end the bradykinin B2 receptor antagonist Icatibant (HOE 140) was used. On one hand, bradykinin has a renal natriuretic action. On the other hand, bradykinin is a potent mediator of both vasodilation and microvascular leakage. Both vascular mechanisms, which are reported for cirrhosis, could cause vascular underfilling and Na+ retention by activating the renin-angiotensin-aldosterone system. Icatibant normalised Na+ retention and reduced the hyperactivity of the renin-angiotensin-aldosterone system, suggesting a bradykinin-induced vascular disturbance. Icatibant had no significant effect on the mild hypotension which developed with CCl4 treatment. However, there was indirect evidence for enhanced microvascular leakage that was strongly inhibited by Icatibant. Our experimental results demonstrate that bradykinin is a key mediator of Na+ retention in liver cirrhosis and suggest that a bradykinin-induced increase in microvascular leakage is mainly responsible.

Animals↗
PubMed1997

Serum levels of folate and cobalamin in women with recurrent spontaneous abortion.

We evaluated the folate and cobalamin status in 29 non-pregnant women with a history of recurrent spontaneous abortion (three or more consecutive) of unknown aetiology in comparison to 29 healthy nulligravidae of similar reproductive age (controls). Serum concentrations of folate and cobalamin showed no significant differences between the two groups. No correlation between age and vitamin concentrations was found. In the study group there was a significant negative correlation of the number of previous abortions and the concentration of serum folate. Patients with at least four previous miscarriages had significantly lower serum values of folic acid than women with three abortions, but not than controls. The underlying cause of this finding remains unclear. In conclusion, the serum concentrations of folic acid and vitamin B12 are not significantly altered in women with unexplained recurrent spontaneous abortions, and an association between a deficiency of these vitamins and an increased risk of pregnancy loss appears to be questionable in the majority of gestations.

Abortion, Habitual↗
PubMed1996

ACE inhibition decreases postoperative mortality in rats with left ventricular hypertrophy and myocardial infarction.

UNLABELLED: In male Sprague Dawley rats with left ventricular hypertrophy (LVH) and hypertension induced by aortic constriction (AC) and subsequent myocardial infarction (MI) by occlusion of the left coronary artery the effects of ACE inhibition with ramipril (RA 1 mg/kg/day via the drinking water during 6 weeks) on survival as well as cardiac function and metabolism were investigated. Respective groups (sham AC; AC; AC + sham MI; normotensive animals with sham MI; MI; MI + RA) served as comparisons. Following MI hypertensive rats with AC and LVH revealed an increased postoperative mortality (68%) when compared to normotensives without AC (28%). ACE inhibition with ramipril significantly reduced mortality in hypertensive rats by 26%. Untreated hypertensive animals with LVH clearly showed reduced MI size (6.2 +/- 2.3%) in comparison with untreated normotensive animals and MI (31.0 +/- 3.3%). In hypertensive rats with MI which died during the study a significant increase in infarct size was found compared to those which survived MI. In normotensive animals ramipril reduced infarct size by 50%. Due to the quite small infarct size observed in hypertensive rats, ACE inhibition did not further reduce MI in these animals. LVH as well as hydroxyproline/proline ratio was diminished by ACE inhibitor treatment. In the isolated hearts of ramipril treated rats contractility was improved when compared to the respective untreated groups with MI. In the coronary effluent of isolated hearts from rats with AC and MI lactate dehydrogenase and creatine kinase activities as well as lactate levels were increased. Ramipril treatment starting one week before MI normalized these parameters and in addition increased prostacyclin output. Hearts with MI from treated normotensive animals contained increased energy rich phosphates when compared to hearts from untreated rats with MI. CONCLUSIONS: Hypertensive rats with LVH undergoing MI experience increased postoperative mortality probably due to a reduced tolerance to myocardial ischemia and occurrence of arrhythmias. In these animals ACE inhibition with ramipril increased survival. Both, increased survival in hypertensive and reduction in infarct size in normotensive rats by ACE inhibition with ramipril was accompanied by an improved myocardial metabolism.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

HIV protease inhibitor HOE/BAY 793, structure-activity relationships in a series of C2-symmetric diols.

A detailed structure-activity relationship of C2-symmetric diol inhibitors of HIV-1 protease leads to inhibitor 6 (HOE/BAY 793) which is outstanding in the inhibition of the enzyme and in the inhibition of viral replication in HIV infected cell culture (IC50: 0.3 nM; EC50: 3 nM). There are well defined steric requirements for the design of the side chains P1-P3 of the inhibitors. In addition, all three side chains need to be lipophilic. While the enzyme tolerates hydrophilic substituents in some cases, drastic reductions in anti-HIV activity are observed in cell culture, most likely due to insufficient cell penetration.

Carbon↗
PubMed1995

[The computed tomographic morphology of Crohn's disease and ulcerative colitis].

PURPOSE: To assess the value of computed tomography for the diagnosis of Crohn's disease and ulcerative colitis. METHOD: We analysed the CT examinations of 109 patients with 197 involved bowel locations. 81 patients suffered from Crohn's disease, 28 from ulcerative colitis. Diagnosis was based on the combination of clinical, endoscopic and histopathologic findings. Three radiologists evaluated the CT series concerning the presence of morphologic changes analogous to conventional radiographic findings. RESULTS: In Crohn's disease, we found irregular outer contours in 26% of cases. The bowel wall was thickened in 82%. In acute phases, the bowel wall was thickened in 100%. Abscess and fistula as complications of inflammatory disease were present in 26 and 14% respectively. In ulcerative colitis, a target sign of the bowel wall was present in 40%, whereas in Crohn's disease a homogeneous wall density was present in all but two cases. Reduced attenuation due to submucosal fat deposits was found in 16% and mucosal tunneling in 27% of cases with ulcerative colitis. Even if severe mucosal destructions were found, the outer contour of the gut was smooth and regular in 95% of the ulcerative colitis cases. CONCLUSION: CT can provide additional information on acuity, extent and complications in inflammatory bowel disease. In combination with conventional radiographic findings a three-step classification for Crohn's disease and ulcerative colitis (early changes, acute and chronic phase) can be proposed.

Adolescent↗
PubMed1994

Effects of the renin inhibitor N-[N-(3-(4-amino-1-piperidinyl-carbonyl)-2(R)-benzylpropionyl)-L- histid inyl] -(2S,3R,4S)-1-cyclohexyl-3,4-dihydroxy-6(2-pyridyl)-hexane-2-amide acetate in anesthetized rhesus monkeys.

The renin inhibitory effect of the non-peptide renin inhibitor S 2864 (N-[N-(3-(4-Amino-1-piperidinyl-carbonyl)-2(R)-benzylpropionyl)-L- histidinyl]-(2S,3R,4S)-1-cyclohexyl-3,4-dihydroxy-6(2-pyridyl)-hexane-2- amide acetate, CAS 135683-92-0) was characterized in vitro and in vivo in primates. In vitro, S 2864 inhibited the activity of purified human plasma renin with an IC50 of 3.8 x 10(-10) mol/l and did not affect related human aspartyl proteases like human cathepsin E, cathepsin D or pepsin. In vivo, in anesthetized sodium depleted rhesus monkeys S 2864 decreased mean arterial blood pressure after intraduodenal (i.d.) administration of 2 mg/kg significantly by 27% from 94 +/- 8 to 62 +/- 6 mmHg for 90 min. Heart rate was not changed. Cumulative intravenous (i.v.) administration of S 2864 or remikiren in doses of 1, 10 and 30 micrograms/kg significantly decreased systemic blood pressure, dP/dtmax and cardiac output while heart rate was not changed. Plasma angiotensin II (ANG II) levels as well as renin activity were dose dependently reduced after 10, 30 and 60 min. It is concluded that S 2864 is an effective specific inhibitor of human renin eliciting marked blood pressure lowering activities in primates.

Anesthesia↗
PubMed1993

Renin inhibitors containing a pyridyl amino diol derived C-terminus.

Based on the concept of transition-state analogs, a series of nonpeptide renin inhibitors with the new (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)hexane moiety at the C-terminal functionality were synthesized and evaluated for inhibition of renin both in vitro and in vivo. All compounds exhibited potencies in the nanomolar or even subnanomolar range when tested versus human renin in vitro. Selected inhibitors were evaluated in anesthetized, sodium-depleted rhesus monkeys and produced a marked reduction in mean arterial blood pressure (MAP) upon intraduodenal administration of a dose of 2 mg/kg. Compound 38 (S 2864) containing an amino piperidyl succinic acid derived N-terminal is the most promising member in this series. 38 inhibited human renin with an IC50 of 0.38 nM, did not affect other human aspartic proteinases, and decreased mean arterial blood pressure significantly by 27% with a duration of action of 90 min after administration of 2 mg/kg id in anesthetized, sodium-depleted rhesus monkeys.

Amino Acids↗
PubMed1992

Inhibition of HIV-1 protease by short peptides derived from the terminal segments of the protease.

The active HIV-1 protease is a homodimeric enzyme. A beta-sheet consisting of N- and C-terminal segments provides the main driving force for dimerization of the inactive protomers. Several short peptides with sequences derived from the N- and C-termini of the protease were tested for inhibition of protease activity and for inhibition of HIV-1 replication in lymphocytes. Medium inhibitory activity was found with each of the peptides in the enzyme test and no inhibition of the lymphocytes was found up to 200 micrograms/ml. The enzyme tests indicate that HIV-1 protease is the target of the inhibitory action. Synergistic action could not be found with pairs of the peptides derived from the two different termini. Prolonged incubation with one of the peptides increased inhibition indicating a slow dissociation of the protease dimers. No cytotoxic effect of the inhibitors could be found below 200 micrograms/ml.

Amino Acid Sequence↗
PubMed1992

Renin inhibitory pentols showing improved enteral bioavailability.

Incorporation of a C-terminal pentahydroxy functionality led to potent, low molecular weight hydrophilic renin inhibitors lacking the P1' side chain. As these compounds are easy to synthesize and have sufficient water solubility, they were chosen for further study. Compound 33 was transported across rabbit intestinal brush border membrane vesicles and yielded a hypotensive effect in sodium-depleted rhesus monkeys which lasted for 90 min when dosed at 2 mg/kg id.

Amino Sugars↗
PubMed1989

Fitting heteroscedastic regression models to individual pharmacokinetic data using standard statistical software.

In the analysis of individual pharmacokinetic data by nonlinear regression it is important to allow for possible heterogeneity of variance in the response. Two common methods of doing this are weighted least squares with appropriate weights or data transformation using a suitable transform. With either approach it is appealing to let the data determine the appropriate choice of weighting scheme or transformation. This article describes two methods of doing this which are easy to compute using standard statistical software. The first method is a generalized least squares scheme for the case where the variance is assumed proportional to an unknown power of the mean. The second involves applying a power transformation to both sides of the regression equation. It is shown that both techniques may be implemented using only nonlinear regression routines. Sample code is provided for their implementation using the SAS software package. However, the proposed methods are feasible using any software package that incorporates a nonlinear least squares routine, and are thus well suited to routine use.

Humans↗
PubMed1984

Hoe 263, a new substance with calcium channel antagonistic activity.

Hoe 263 inhibited the contraction of the potassium-depolarized pulmonary artery of the guinea pig. In this experiment it was slightly more active than verapamil. The calcium uptake of the potassium-depolarized pulmonary artery was inhibited by Hoe 263 more effectively than by prenylamine. The upstroke velocity of the potassium-depolarized papillary muscle of the guinea pig was depressed with similar concentrations of Hoe 263 and verapamil. In the (3H)-nitrendipine binding test, Hoe 263 was effective at similar concentrations as prenylamine and verapamil. The positive inotropic effect of K-strophanthin was depressed by Hoe 263 at concentrations which were comparable with those necessary for verapamil.

Animals↗
PubMed1982

HL 725, an extremely potent inhibitor of platelet phosphodiesterase and induced platelet aggregation in vitro.

The new pyrimido-isoquinoline compound HL 725 is an extremely potent inhibitor of the aggregation of human platelets induced in vitro by ADP, collagen, thrombin and epinephrine. The aggregation induced by 0,5 mM arachidonic acid is inhibited about 50% with 50 pM HL 725. Thus the potency of HL 725 is higher than that of prostacyclin, the most active natural inhibitor of aggregation. We hypothesize that HL 725 inhibits the enzymatic degradation of cyclic adenosine 3', 5'-monophosphate (cAMP) in the platelets. In accordance with this proposal is the strong inhibitory action on cAMP phosphodiesterase extracted from human platelets. About 250 pM HL 725 inhibited 50% of the activity of this enzyme at a substrate concentration of 0.5 microM. A marked elevation of cAMP levels in human platelets could be demonstrated after incubation in vitro with 100 nM HL 725.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1982

Effects of calcium antagonists on coronary spasm and pulmonary artery contraction in comparison to their antagonistic action against K-strophanthin in isolated guinea pig atria.

The contraction of the potassium depolarized pulmonary artery of the guinea pig was diminished by the calcium antagonists nifedipine, gallopamil, diltiazem, verapamil and prenylamine. The drugs are listed here in order of activity. The uptake of 45Ca of the depolarized pulmonary artery was reduced by nifedipine, verapamil and prenylamine in this order of activity. The depression of the coronary flow of the isolated guinea pig heart, which was brought about by barium chloride, antigenic rabbit serum or vasopressin plus oxytocin was reduced by infusion of prenylamine. The positive inotropic effect of K-strophanthin on the isolated, electrically stimulated left atrium of the guinea pig heart was reduced by gallopamil, verapamil, prenylamine, diltiazem and nifedipine in this order of activity.

Animals↗
PubMed1976

Sources of variance in the measurement of intrapulmonary killing of bacteria.

Sources of variability are described for a method used for the quantitative measurement of pulmonary resistance to inhaled bacteria in individual animals. Factors contributing significantly to variability include aerosol exposure chamber design, bacterial species used for aerosol challenge, location of animals in the chamber, and individual intrapulmonary bacterial killing rates. Laboratory error accounted for a small portion of the variance. The data demonstrate that with appropriate modifications in protocol, statistical design and analysis experiments can be performed with increased accuracy, thereby reducing the number of animals needed for each experiment.

Aerosols↗