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P Hess

Publications and source records attributed to P Hess.

At least 37 records · Page 2Linked to original sources
PubMed2000

Combination of non-hypotensive doses of valsartan and enalapril improves survival of spontaneously hypertensive rats with endothelial dysfunction.

There is increasing evidence to suggest endothelial dysfunction as a critical factor in vascular diseases. Genetically predisposed spontaneously hypertensive rats (SHR) treated with inhibitors of nitric oxide (NO) synthase, develop a severe hypertensive nephrosclerosis without the necessity for surgical reduction in renal mass, nephrectomy, renal infarction or nephrotoxic drugs. In these animals, endothelial dysfunction is considered a valid model for assessment of the efficacy of cardiovascular therapy. SHR were treated with either the angiotensin-converting enzyme inhibitor enalapril or the angiotensin II (Ang II) AT(1)-receptor antagonist (AIIA) valsartan at sub-hypotensive doses and the effects on survival rates, cardiac and renal changes were monitored. Rats treated with valsartan, alone or in combination with enalapril, showed markedly higher survival rates (67-85%, respectively) than untreated animals (37%) or those treated with enalapril alone (55%). Valsartan at a dose which attenuated blood pressure increase led to even greater survival rates (95%). Despite these improved survival rates, at non-hypotensive doses the drugs had no effect on histological appearance, nor was kidney function improved. Plasma creatinine levels were reduced by valsartan, alone or in combination with enalapril, but proteinuria persisted with all treatments over the 12 weeks of the study. Aldosterone levels were significantly reduced by all treatments. The results suggest a beneficial role for endothelium in hypertension. Reduced renal perfusion pressure probably underlies the beneficial renal effects of high-dose valsartan.

Aldosterone↗
PubMed1999

Age-dependent hypertension in Mpv17-deficient mice, a transgenic model of glomerulosclerosis and inner ear disease.

The mutant mouse strain Mpv17-/-, carries a retroviral germline integration that inactivates the Mpv17 gene. Mpv17-deficient mice develop progressive glomerulosclerosis and sensineural deafness at early age. Characteristic basement membrane alterations are found in both sites of pathology. Mpv17 is a peroxisomal protein involved in the metabolism of reactive oxygen species, yet its molecular function is unknown. Dysregulation of antioxidant enzymes and basal membrane components has been established in this model and successful therapeutic intervention with antioxidants prove the causal role of reactive oxygen species in the development of the disease phenotype. We here investigated if the Mpv17-/- mice might be hypertensive. Indeed, our study revealed that Mpv17-/- mice developed significant systemic hypertension and tachycardia between 4 weeks and 5 months of age, accompanied by polyuria and elevated natriuresis. Judging from serum and urine parameters, the hypertensive condition develops concomitantly with the renal disease. Biochemical and pharmacological studies that used the endothelin receptor antagonist bosentan and the angiotensin converting enzyme inhibitor cilazapril indicated no involvement of the endothelin and renin-angiotensin systems in this hypertension, suggesting a potential novel mechanism of blood pressure regulation in this new murine hypertension model. Thus, Mpv17-/- mice unravel an intriguing new association between a defect in reactive oxygen metabolism and the age-dependent development of hypertension.

Aging↗
PubMed1999

Impact of pharmacogenomics on the clinical laboratory.

Clinical pharmacogenomics promises to increase the safety and efficacy of drug prescription, decrease the incidence of adverse drug reactions, help improve public health, and presage in an era of personalized, predictive, and prophylactic medicine. Clinical pharmacogenomics stands to be broad based and include the following laboratory components: new and expanded pharmacogenetic tests, disease profiles, chemopredictive testing, and risk profiling. There is a growing body of evidence that variable drug responsiveness is caused by polymorphisms within multiple genes, protein products of which are involved in critical metabolic and/or physiologic pathways relevant for drug action. Different pharmacogenomic approaches will be used to discover a new generation of unique and highly predictive pharmacogenetic tests that the clinical laboratory will employ to help identify patient responder populations. Disease profiling and chemopredictive testing will routinely be applied to accurately screen for disease and help guide therapeutic course of action. A growing number of risk-profiling tests will assist in predicting a patient's predisposition to disease. Clinical pharmacogenomics stands to become the basis for the new millennium's practice of medicine and have a profound impact on the clinical laboratory.

Clinical Laboratory Techniques↗
PubMed1999

[Systematic scientific quality improvement in surgical specialties. The AQS mode].

BACKGROUND: How can the new legal requirements (Law on Statistics 1992 with its corresponding regulations of 1993: minimum data record of the Federal Department of Statistics (BFS) with ICD codification and the law on medical insurance 1995 with its corresponding regulations of 1996: necessity of documenting quality and efficiency) be integrated into the daily hospital routine with reasonable expenditure of time and costs? METHOD: The BFS minimum data record was combined with additional information on quality improvement on one single questionnaire. The surgical departments of the Hospital Limmattal in Schlieren and the Regional Hospital Bienne founded the Association for Quality Improvement in Surgery (AQC) in 1995 and have tested the AQC system for two years. RESULTS: Until the end of 1997 data from 15,115 surgical procedures were collected in our database. In addition to the more time consuming collection of the "minimal data set of the Federal Department of Statistics (BFS)" which requires between 3 to 10 minutes, the collection of the additional AQC-data will take 1 to 3 minutes. DISCUSSION: There is an increasing expenditure of time and costs as a result of legal requirements. Expenditure may, however, be kept within manageable limits if a single questionnaire serves several purposes simultaneously. The AQC system does not only meet the legal requirements as to systematic quality improvement and BFS statistics, but can also be used for the annual statistics of the clinic, the statistics of individual surgeons, and for hospital comparisons provided other clinics adopt the system as well. There are no standards, reference areas or indicators as yet, but such tools may now be developed much more easily with comprehensive data available through the AQC system. CONCLUSIONS: The AQC system has proved to be a manageable tool in the hospital routine; it could thus be implemented as a wide-area system to provide systematic quality improvement and to meet other statistical requirements.

Humans↗
PubMed1999

Pharmacology of tezosentan, new endothelin receptor antagonist designed for parenteral use.

Tezosentan (Ro 61-0612) [5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-+ ++pyri din-4-yl)-pyrimidin-4-ylamide] is a new endothelin (ET) receptor antagonist specifically designed for parenteral use. Tezosentan competitively antagonizes the specific binding of (125)I-labeled ET-1 and of the selective ET(B) receptor ligands (125)I-labeled ET-3 and (125)I-labeled sarafotoxin S6c on cells and tissues carrying ET(A) and ET(B) receptors, with inhibitory constants in the nanomolar range, and has high water solubility. Tezosentan exhibits high functional inhibitory potency for inhibiting contraction induced by ET-1 on isolated rat aorta (ET(A) receptors; pA(2) = 9.5) and by sarafotoxin S6c on rat trachea (ET(B) receptors; pA(2) = 7.7). In vivo, tezosentan inhibits the pressor effect of big ET-1 in pithed rats and increases ET-1 plasma concentrations in conscious rats in a dose-dependent fashion. In spontaneously hypertensive rats, i.v. injection of tezosentan has acute hemodynamic effects and decreases blood pressure. Tezosentan is also able to prevent the acute renal failure that complicates rhabdomyolysis in a rat model of myoglobinuric nephropathy. Finally, tezosentan exhibits an apparent elimination half-life of less than 1 h in rabbits and primates and of 2 h in rats. In conclusion, tezosentan, a potent mixed ET receptor antagonist with a short half-life, may offer a novel medical approach for the i.v. treatment of acute pathological conditions.

Acute Kidney Injury↗
PubMed1997

Gene Therapy Monitoring: Clinical Monitoring for Efficacy and Potential Toxicity.

Since the first human clinical trial was initiated in 1990, the field of gene therapy has gone through a period explosive growth. Building on a sound foundation of many years of basic and clinical research this novel therapeutic approach has the potential to revolutionize medicine. As gene therapy moves from a research setting, however, clinical monitoring for efficacy and potential toxicity will become increasingly important, perhaps becoming as commonplace as therapeutic drug monitoring is today.

Journal Article↗
PubMed1996

The detection and evaluation of aneugenic chemicals.

Although aneuploidy makes a significant contribution to both somatic and inherited disease the mechanisms by which environmental chemicals may induce numerical chromosome aberrations are only poorly defined. The European Union Project was aimed to further our understanding of those chemical interactions with the components of the mitotic and meiotic cell division cycle which may lead to aneuploidy and to characterise the parameters such as cellular metabolism which may influence the activity of aneugenic chemicals. C-mitosis can be induced by the highly lipophilic polychlorinated biphenyl and the completion of mitosis and cleavage can be modified by agents which deplete cellular levels of reduced glutathione. Modifications of the fidelity of chromosome segregation were produced by inhibiting the functioning of topoisomerase II during chromatid separation. In contrast, the modification of centromere integrity resulted in chromosome breakage as opposed to disturbance of segregation. Modifiers of tubulin assembly and centriolar functioning in somatic cells such as acrylamide, vinblastine and diazepam reproduced their activity in rodent bone marrow and male germ cells. The analysis of chromosome malsegregation in Aspergillus nidulans by a structurally related series of halogenated hydrocarbons was used to develop a QSAR model which had high predictive value for the results of fungal tests for previously untested related chemicals. Metabolic studies of potential aneugens in genetically engineered human lymphoblastoid cells demonstrated the detoxification of the aneugenic activity of chloral hydrate and the activation of 2,3-dichlorobutane, 1,1,2-trichloroethane and trichloroethylene by Phase I biotransforming enzymes. Cell transformation studies in Syrian hamster dermal cultures using a panel of 22 reference and or potential aneugens indicated that 15 of the 22 produced positive results following single exposures. Five of the aneugens which were negative following single exposures produced positive results where cultures were continuously exposed for up to 6 weeks to low concentrations following a single non-transforming exposure to the mutagen dimethyl sulphate. The transformation studies indicate that a significant proportion of chemical aneugens are potential complete carcinogens and/or co-carcinogens. To optimise the enumeration of chromosomes following exposure to potential chemical aneugens whole chromosome paints and centromere specific probes suitable for use in fluorescence in situ hybridisation (FISH) were developed for the rat, mouse and Chinese hamster and selected human probes evaluated for their suitability for routine use. Molecular chromosome probes were used to develop protocols for enumerating chromosomes in metaphase cells and centromeres and micronuclei in interphase cells. The analysis of segregation of specific centromeres in binucleate cells following cytochalasin B treatment was shown to be a potentially valuable system for characterising non-disjunction following chemical exposure. Whole chromosome paints and centromere specific probes were used to demonstrate the presence of dose-response thresholds following treatment with a reference panel of spindle inhibiting chemicals. These data indicate that the FISH technology is suitable for evaluating the relative hazards of low-dose exposures to aneugenic chemicals.

Aneuploidy↗
PubMed1996

Telemetry monitoring of pulmonary arterial pressure in freely moving rats.

Several rat models of pulmonary hypertension have been developed. However, up until now it has been difficult to monitor pulmonary arterial pressure for long periods of time. The goal of the present study was to develop a telemetry system allowing chronic monitoring of pulmonary arterial pressure in freely moving rats. For this purpose, while animals were under anesthesia, a sensing catheter was implanted into the pulmonary arterial trunk through the right ventricle. This catheter was connected to an emitter implanted in the abdomen. Validation of the system was performed in three steps. First, acutely, we controlled that the pressure signal transmitted by the telemetry system was accurate and corresponded to a signal obtained with a high-fidelity Millar catheter. Second, we evaluated the chronic consequences of implantation of the system. Third, we used the system to monitor pulmonary arterial pressure in a model of monocrotaline-induced hypertension in which the effects of bosentan, an endothelin-receptor antagonist, were evaluated. The telemetry system was reliable and did not lead to damage of the right ventricle and/or to chronic pulmonary embolism. After a recovery period of 8-10 days, mean pulmonary arterial pressure was stable. With the use of this telemetry system, it was possible to follow the increase of pulmonary arterial pressure induced by monocrotaline. In this model, bosentan decreased mean pulmonary arterial pressure by 13% (P = 0.07), suggesting a role of endothelin in this model of pulmonary hypertension. We conclude that it is possible to use this telemetry system to monitor pulmonary arterial pressure in freely moving conscious rats.

Animals↗
PubMed1996

[Thoracic sympathectomy in palmar hyperhidrosis: comparison of open with thorascopic procedure].

Between 1976 and 1994 we performed 26 thoracic sympathectomies for treatment of therapy-resistant palmar hyperhidrosis. Until the end of 1992 the operation was performed using an open transaxillary approach, since 1993 sympathectomy was done by video-assisted thoracoscopy. Both procedures consisted in excision of the thoracic ganglia T2 to T5. The only complication was a pneumothorax in the open surgery group (successfully treated by drainage). Compensatory sweating occurred in 70% of our patients, compared to results in the literature of 60-90%. We did not note further complications, e.g. no Horner's syndrome. All of our patients were satisfied with the result of the operation. Comparison of the two collectives shows significant advantages for video-assisted thoracoscopic surgery. the procedure is easier to perform, exposure is better, cosmetic results are favourable, operation-time and hospital stay are reduced.

Adult↗
PubMed1996

Respective role of humoral factors and blood pressure in cardiac remodeling of DOCA hypertensive rats.

OBJECTIVES: Recent studies have shown that beside elevated arterial blood pressure, humoral factors such as angiotensin II, aldosterone, endothelin or bradykinin might play a role in the cardiac hypertrophy and fibrosis secondary to hypertension. In addition, it seems that perivascular fibrosis and interstitial fibrosis are controlled by independent mechanisms. Therefore, the goal of our study was to evaluate the respective role of the increased arterial pressure and of humoral factors on cardiac remodeling in an experimental hypertension model. METHODS: Uninephrectomized rats received DOCA, a high salt diet, and when hypertension was installed, they were treated for 6 weeks with either a long-acting calcium antagonist, mibefradil (30 mg/kg day-1), an ACE inhibitor, enalapril (3 mg/kg day-1), or a mixed ETA-ETB endothelin receptor antagonist, bosentan (100 mg/kg day-1). A group of hypertensive rats was left untreated and a sham-operated group of normotensive rats was used for control. At the end of treatment, maximal coronary blood flow was measured in isolated perfused hearts. Cardiac hypertrophy and interstitial as well as perivascular fibrosis were evaluated by quantitative morphometry. RESULTS: DOCA-salt hypertensive rats exhibited a marked cardiac hypertrophy associated with a decrease of maximal coronary blood flow and interstitial and perivascular fibrosis. The calcium antagonist nearly normalized arterial pressure and suppressed all these changes. Enalapril had no effect on arterial pressure and perivascular fibrosis but decreased subendocardial fibrosis. Bosentan had a very small effect on arterial pressure but decreased cardiac hypertrophy and both perivascular and subendocardial fibrosis. CONCLUSIONS: We conclude that in DOCA salt hypertension, humoral factors such as endothelin may play a role beside high blood pressure in cardiac remodeling. In addition, the different components of this remodeling (decrease of vascular reserve, cardiac hypertrophy and cardiac fibrosis) are controlled independently.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Gene therapy: a brief review.

Gene therapy is no longer defined simply as gene replacement; today, it is better defined as any treatment involving genetic alteration of cells. As a result, its applications have grown enormously and continue to do so. The purpose of gene therapy--treatment of the underlying cause of disease--represents a fundamental break with all previous forms of therapy in the history of medicine. Within a relatively short period, gene therapy promises to be a major pharmacologic force, revolutionizing the practice of medicine.

Clinical Medicine↗
PubMed1995

A mutator phenotype characterizes one of two complementation groups in human cells tolerant to methylation damage.

Sixty % of clones isolated from HeLa cells treated with toxic concentrations of a methylating carcinogen showed increased resistance to the cytotoxicity of N-methyl-N-nitrosourea. D37 values were 6- to 100-fold higher than in the parental cell population. The absence of detectable levels of the repair enzyme O6-methylguanine-DNA methyltransferase indicated that the resistant clones were able to tolerate the presence of O6-methylguanine in their DNA. Analysis of N-methyl-N-nitrosourea survival in the hybrids between tolerant clones and HeLa cells showed that tolerance can be either recessive or codominant. Fusion between tolerant clones indicated two complementation groups. We measured spontaneous mutation rates at microsatellites and at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus in several tolerant clones. All the clones of Complementation Group I showed unstable microsatellites and 4-8-fold increases in mutation rates at hprt. No significant alterations in spontaneous mutation rates were found in clones of Complementation Group II. The data indicate that tolerance to methylation damage can be conferred by alterations in at least two different gene products and that one of the two groups has the mutator phenotype typical of mismatch correction defective cells.

Cell Survival↗
PubMed1994

A mismatch recognition defect in colon carcinoma confers DNA microsatellite instability and a mutator phenotype.

We have analyzed spontaneous mutations in the adenine phosphoribosyltransferase gene of Chinese hamster clone B cells that exhibit a mutator phenotype because of defective mismatch binding. The mutator phenotype conferred increases in a limited number of mutational classes. The rates of transitions and most transversions were not significantly increased. The rates of A to T transversions and -2 frameshifts were strikingly elevated. These mutations were in repeated elements and 5 of 9 of the frameshifts were dinucleotide deletions in DNA sequences resembling microsatellites. The mismatch binding protein that is defective in the mutator line is a G-T mismatch recognition factor. Band-shift analysis indicated that the preferred substrate for the mismatch recognition protein is duplex DNA containing an extrahelical mono- or dinucleotide within repeated sequences. In agreement with a role in preventing minus frameshifts, a defective binding protein conferred an instability in clone B microsatellite DNA. A mismatch binding defect was also detected in Lo Vo, a human colorectal carcinoma cell line. Extracts of clone B or a second mismatch binding-deficient line, Raji-F12, did not complement Lo Vo extracts, indicating that these lines share a common defect. Our data provide a mechanistic explanation for the relation between defective mismatch recognition and the microsatellite instability of human colon cancer.

Adenine Phosphoribosyltransferase↗