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Biomedical subjects

R Walter

Publications and source records attributed to R Walter.

At least 55 records · Page 3Linked to original sources
PubMed1998

T-kininogen is a biomarker of senescence in rats.

We have previously reported on the identification of T-kininogen (T-KG) as a gene whose expression is increased during senescence in male Sprague-Dawley (S-D) rats. Serum T-KG levels increase 2.5-4 months before the time of death for any given animal, irrespective of the actual age of the animal at the time of this event. Furthermore, dietary restriction (DR) delays, but does not prevent, the increase in serum T-KG levels. In the present study, we have assessed whether or not the age-related increase in T-KG is a common feature of senescence in other strains of rat. We have analyzed hepatic T-KG mRNA levels in male Fischer 344 rats (F344), as well as in male and female (Fischer 344 x Brown Norway)F1 rats (F1). In both of these strains, we observed a dramatic increase in hepatic T-KG mRNA levels when male rats approach senescence. The mRNA levels behave similarly in F1 and S-D rats, in that the increase occurs late in life, and it is either repressed or delayed by DR. In contrast, the increase in T-KG mRNA levels in F344 rats occurs earlier in life, and is not significantly affected by DR. Young female F1 rats fed ad libitum (AL) show a statistically significant (P = 0.0009) 2.6-fold higher level of T-KG mRNA, as compared to their male counterparts. Thus, while we still observe an age-related increase in this parameter in both AL and DR female F1 rats, the difference is statistically significant (P = 0.0001) only in DR animals. We conclude that the increase in T-KG gene expression is a common feature of senescence and that, at least in males of these commonly used rat strains, T-KG can be used as a reliable biomarker of aging. Since the increase in T-KG gene expression does not appear to correlate with inflammatory processes, and since different strains of animals succumb to different pathologies, these results further suggest that the increase in T-KG expression might be related to the process of aging per se, rather than to any given age-related pathology.

Aging↗
PubMed1998

Induction of tetrahydrobiopterin synthesis in human umbilical vein smooth muscle cells by inflammatory stimuli.

Tetrahydrobiopterin (BH4) is an obligatory cofactor and regulator of nitric oxide synthases (NOS). We evaluated the biosynthesis of BH4 in human umbilical vein smooth muscle cells (HUVSMC). Trace amounts of BH4 were found intra- and extracellularly in untreated cells. When HUVSMC were activated by individual inflammatory stimuli (IL-1beta, TNFalpha, IFNgamma or LPS), both intra- and extracellular levels of BH4 increased significantly, with TNFalpha being the most potent single stimulus. Combined inflammatory cytokines synergized in the induction of an up to 600-fold increase of BH4 synthesis. Addition of LPS to the cytokine mixture led to a further increase of BH4 synthesis. Neopterin, a product of the first intermediate in BH4 biosynthesis, was also raised, but to a much lesser extent. The increase of BH4 synthesis was paralleled by an enhanced expression of isoform-1 (the only isoform coding for the active enzyme) of GTP cyclohydrolase I in cytokine treated cells. Our results show for the first time that BH4 biosynthesis is strongly induced by combinations of inflammatory stimuli in HUVSMC. The importance of BH4-dependent NO synthesis in HUVSMC needs, however, additional detailed studies.

Biopterins↗
PubMed1998

Changes in hepatic DNA binding proteins as a function of age in rats.

The process of aging is accompanied by many changes in gene expression, occurring in virtually all organs of the affected individual. Here we report on the relative changes in DNA binding activity of a panel of 15 different transcription factors in the liver of adult (15-month-old) and old (25-month-old) Sprague-Dawley rats. When expressed as a function of nuclear protein concentration, a great majority of the transcription factors analyzed do not show significant differences in DNA binding activities as a function of age, except activator protein 1 (AP-1) and nuclear factor-kappa B, both of which show increased activities in the older animals, and hepatocyte nuclear factor-3, which undergoes a switch from predominantly alpha and beta subspecies in the adults, to predominantly gamma subspecies in the old animals. Further examination of some of the members of the AP-1 complex using Western blot analysis indicates that the increase in binding activity of this particular complex might be due to an increase in the relative mass of Jun B, presumably resulting in a switch from predominantly c-Fos/Jun D in the young to c-Fos/Jun B complexes in the old animals. Nuclear extracts prepared from the liver of old animals yield less proteins per mass of DNA than similar extracts prepared from younger animals. Accordingly, if the data are analyzed as a function of genomic DNA, our results indicate that aging results in a consistent, but generally not statistically significant decrease in most transcription factor DNA binding activities, with AP-1, nuclear factor-kappa B, and transcription factor II D being the exception to this decline.

Aging↗
PubMed1998

Exploring women's experiences: the critical relationship between nursing education, peer mentoring and female friendship.

A research study was conducted in 1995 with seven women nurses from Southern Cross University, Australia. The aim of this research was to investigate the possible relationship between female friendship, mentoring and nursing education. The researchers comprised six second-year nursing degree students and the programme co-ordinator for the Bachelor of Nursing programme. This research was framed in an emancipatory paradigm of critical social science and feminist theory. Reflective journalising and interviewing were used as the research methods. The results indicated that there is an inextricable link between female friendship and peer mentoring. These two 'features' created a productive climate for shared learning, shared caring, reciprocity and commitment to one another's personal and professional growth.

Adult↗
PubMed1998

The revolving door of hospital readmissions.

The elderly comprise a growing percentage of the population. Home care providers find it increasingly important to monitor rates of hospital readmissions and prevent unnecessary readmissions from occurring. This effort requires a conscious, well-thought-out effort on the part of today's providers.

Aged↗
PubMed1998

Interferon- and streptolysin O-induced activation of protein kinases and inhibition of cytochrome P450-dependent monooxygenases in rats.

Immunostimulants known to initiate cytokine production were found to decrease the activity of hepatic microsomal drug oxidative enzymes but to activate protein kinase C (PKC). The present study investigated the effects of immunostimulating doses of rat interferon-gamma (IFN, 670,000 units i.p.) and streptolysin O (SLO, 100 HU/kg i.v. for 5 days) on hepatic soluble, membrane-bound and nuclear PKC, 7-ethylresorufin-O-deethylase (EROD) and 7-pentylresorufin-O-deethylase (PROD) in male Wistar rats. The SLO- and IFN-mediated decrease of EROD and PROD activity was associated with a characteristic activation of the hepatic and spleenic PKC. In SLO- and IFN-treated animals activities of the cytosolic, membrane-bound and nuclear PKC were significantly higher than in respective controls. Our results suggest that a decrease in hepatic cytochrome P450 content as well as the decrease in the EROD and PROD activities are inversely related to the function of PKC.

Animals↗
PubMed1998

Urodynamic verification of noninvasive back-pressure recordings from the urinary bladder.

Obstructive voiding is best evaluated with urodynamics, especially simultaneous measurement of bladder-pressure and urine flow rates. As an alternative to catheterization for urodynamics, noninvasive back-pressure methods using an external condom system have been introduced. This device uses one side tube in the condom for pressure recording and an outlet tube that is clamped for short periods of time during voiding. However, there have been problems with accurate back-pressure recording, including leaking, clamping techniques, hydrostatic pressures associated with pressure recording below the level of the symphysis pubis, and assessment of back pressures in relation to bladder and detrusor pressures. To address these issues, we have modified the condom for passing a catheter into the urethra for simultaneous direct bladder and back-pressure recording. The clamping device on the outlet tube also has been modified to produce back flushing of urine in addition to clamping. Hydrostatic issues have been addressed by making pressure recordings at the level of the symphysis pubis. Seven patients with obstructive symptoms were evaluated using these new devices. Back pressures were not statistically different than detrusor pressures recorded with a urethral catheter. Thus, the modifications have improved back-pressure recording techniques. The use of noninvasive back-pressure recording may be an important adjunct in the evaluation of obstructive uropathy.

Condoms↗
PubMed1998

Morphometric analysis of pancreatic carcinoma by computer-assisted image analysis.

This report describes the results of applying the interactive image analysis system for the measurement of some cytological parameters corresponding to features of adenocarcinoma of the pancreas. The present experiments were carried out by means of the digital cell image analysis of haematoxilyn and eosin stained archival standard glass slides of cancer bearing and healthy patients. Four different parameters describing the morphology of nuclei and nucleoli were selected to quantitate the differences between control and malignant tissues: area, perimeter, elongation, and extension. The parameters that showed the greatest differences between cancerous and normal pancreas were: area and elongation in the case of nuclei as well as area and perimeter for nucleoli. However, the results of this study suggest that none of the four analysed parameters can be selected alone to discriminate neoplastic from normal cells, but could be used all together in diagnosis of pancreatic cancer.

Adenocarcinoma↗
PubMed1997

Untroubled musical judgement of a performing organist during early epileptic seizure of the right temporal lobe.

The case of a professional musician with a right temporal lobe epilepsy is presented. Whilst playing an organ concert (John Stanley's Voluntary VIII, Op. 5), he suffered a complex partial seizure. The recorded concert performance (with the seizure) was analysed and compared with other available exercise records and with the composition. The musical analysis of the seizure-induced variations reveals that at the beginning of the seizure, the left hand started to become unprecise in time and deviated from the score, whereas the right hand remained faultless at this time. With increasing duration of the seizure discharge, the dissociation of both hands from the score increased but the right hand compensated for the errors of the left hand in a musically meaningful way, i.e. with the aim to compensate for the seizure-induced errors of the left hand. The case illustrates untroubled musical judgement during epileptic activity in the right temporal lobe at the beginning of the seizure. Whereas the temporal formation of the performance was markedly impaired, the ability of improvisation-in the sense of a 'perfect musical solution' to errors of the left hand-remained intact.

Adult↗
PubMed1997

N,N-dimethyldioncophyllinium A iodide: synthesis, stereoanalysis, and antimalarial activity of the first N-quaternary naphthylisoquinolinium salt.

The first synthesis of an N-quaternary salt of a naphthylisoquinoline alkaloid, N,N-dimethyldioncophyllinium A iodide, is described. For this potential natural product, a degradative procedure for the unambiguous stereoanalysis of the stereogenic centers has been elaborated. It shows enhanced anti-plasmodial activity in vitro towards Plasmodium falciparum erythrocytic forms, as compared to its less methylated precursors.

Animals↗
PubMed1997

Nitrite generation in interleukin-4-treated human macrophage cultures does not involve the nitric oxide synthase pathway.

The search continues for high-output nitric oxide biosynthesis in human macrophages analogous to murine phagocytes. Recently, generation of nitrite in culture supernatants of human macrophages exposed to interferon-gamma and interleukin-4 (IFN-gamma/IL-4) was reported. The present study reproduces these findings and shows that L-arginine is not consumed and L-citrulline is not produced during this process. Furthermore, the biosynthesis of the obligatory cofactor tetrahydrobiopterin is not coinduced. These biochemical data provide support against a nitric oxide synthase contribution to nitrite accumulation. Nitrite was generated from nitrate salts even in cell-free media. Nitric oxide synthase activity but not nitrate reduction depended on molecular oxygen. Nitrite accumulation in experiments with IFN-gamma/IL-4 in human monocytes appears to be an in vitro artifact produced by nitrate-reducing activities contained in cytokine preparations.

Amino Acids↗
PubMed1997

Inhalation of the nitric oxide synthase cofactor tetrahydrobiopterin in healthy volunteers.

Pulmonary endothelial dysfunction is the hallmark of acute lung injury. Impaired pulmonary endothelial nitric oxide (NO) production in this event has been described. Tetrahydrobiopterin (BH4) is an essential cofactor for NO synthase and modulator of its activity. At high local concentrations, BH4 provokes local vasodilation in vivo in healthy individuals. At lower concentrations, BH4 selectively and locally restores disturbed NO-dependent vasodilation in patients with endothelial dysfunction. In this preliminary study, we therefore investigated the feasibility of BH4 inhalation in five healthy human volunteers. Inhalation of buffered, aqueous BH4-dihydrochloride solution was well tolerated; despite the buffer, BH4 stability was completely preserved. Resorption of inhaled BH4 was demonstrated by significantly increased BH4 levels in plasma and urine. Inhaled BH4 did not alter pulmonary function and had no effect on systemic hemodynamic values. Our data demonstrate that inhalation is a novel method for local BH4 administration, offering a basic therapeutic tool for investigation of restoration of impaired NO-dependent vasodilation due to pulmonary endothelial dysfunction.

Administration, Inhalation↗
PubMed1996

Effects of activating and deactivating cytokines on the functionally linked tetrahydrobiopterin. No pathways in vascular smooth muscle cells.

The functional relationship of nitric oxide (NO) production and synthesis of tetrahydrobiopterin (BH4), the requisite cofactor for NO synthase, was investigated in rat aortic smooth muscles cells (SMC). Inflammatory cytokines induced BH4 and NO synthesis in different ratios, IL-1 beta induced mainly NO synthesis with concomitant but limiting amounts of BH4 for maximal NO production. TNF alpha did not induce NO synthesis but induced BH4 synthesis. IFN gamma was ineffective on both the induction of NO and BH4 synthesis. TGF beta downregulated NO production but did not affect BH4 biosynthesis. IL-4 and IL-10 had no effect on both BH4 and NO synthesis. Activating cytokines strongly synergized in induction of NO production, whereas endogenous BH4 production became insufficient for maximal NO synthesis. Exogenous cofactor in the form of sepiapterin or authentic BH4, but not the natural isomer 7-BH4, enhanced NO production twofold. Inhibition of BH4 synthesis with dicumarol abolished NO production that could be restored in the presence of BH4.

Animals↗
PubMed1996

Crystal structure of soybean lipoxygenase L-1 at 1.4 A resolution.

Lipoxygenases, which are widely distributed among plant and animal species, are Fe-containing dioxygenases that act on lipids containing (Z,Z)-pentadiene moieties in the synthesis of compounds with a variety of functions. Utilizing an improved strategy of data collection, low temperature, and synchrotron radiation of short wavelength, the structure of ferrous soybean lipoxygenase L-1, a single chain protein of 839 amino acid residues, has been determined by X-ray crystallography to a resolution of 1.4 A. The R-factor for the refined model is 19.7%. General features of the protein structure were found to be consistent with the results of prior crystallographic studies at lower (2.6 A) resolution. In contrast to the prior studies, the binding of a water molecule to the active site Fe was established. The octahedral coordination sphere of the Fe also includes the side chains of His499, His504, His690, and Asn694 as well as the terminal carboxylate of Ile839, which binds as a monodentate ligand. Asn694 is involved in a number of labile polar interactions with other protein groups, including an amide-aromatic hydrogen bond, and appears to be a weak ligand. Several possible access routes for dioxygen and fatty acids to the internal active site and substrate binding cavity are described. The protein structure restricts access to the Fe site such that the formation of an organo-Fe intermediate seems improbable. Structural restrictions pertinent to other proposed reaction intermediates, such as planar pentadienyl and nonplanar allyl radicals, are also discussed.

Crystallography, X-Ray↗
PubMed1996

Effects of interferon-gamma and streptolysin O on hepatic procainamide N-acetyltransferase and various microsomal cytochrome P450-dependent monooxygenases in rats.

Immunostimulants known to initiate cytokine production were found to inhibit processes of microsomal drug oxidation but to activate arylamine N-acetylation. The present study investigated the effects of immunstimulating doses of rat interferon-gamma (IFN gamma, 670,000 units ip) and streptolysin O (SLO, 100 HU/kg iv for 5 days) on hepatic cytosolic N-acetyltransferase (NAT) and microsomal cytochrome P450 (CYP)-dependent monooxygenases in male Wistar rats. Both IFN gamma and SLO activated NAT to 120% (P < 0.05) and 135% (P < 0.05), respectively. As expected, monooxygenases were depressed by IFN gamma (P < 0.05) and SLO, the ethylresorufin O-deethylase being the most susceptible enzyme. The results suggested that not only the toxin of gram-positive streptococcal bacteria SLO, but also the cytokine IFN gamma can stimulate NAT activity in rat hepatic cytosol. While the enhancing SLO effect on NAT could not be neutralized by the inhibitor of transcription actinomycin D, NAT stimulation by IFN gamma was abolished by actinomycin D and by the inhibitor of translation, cycloheximide. Obviously, SLO activated NAT independent of protein synthesis and different from IFN gamma-mediated pathways. Posttranslational processes might be involved in NAT stimulation in the rats.

Animals↗
PubMed1996

Influence of H2-receptor- and proton pump inhibitors on some functions of the oxydative and conjugative drug metabolism.

There are numerous investigations describing the influence of histamine H2-receptor antagonists and proton pump inhibitors on cytochrome P450-mediated hepatic oxydative and conjugative drug metabolizing enzymes. The aim of this study was to investigate the influence of the H2-receptor blockers cimetidine, ranitidine, famotidine, nizatidine and of the proton pump inhibitors omeprazole and lansoprazole on the acetylation capacity and on different microsomal monooxygenases of the rat liver. The experiments were performed in two randomized studies with male Wistar rats after a 7-day pretreatment of the animals with antisecretory, equipotent doses of the investigational products. The activities of the arylamine N-acetyltransferase (NAT) and the microsomal enzymes were determined in vitro. Cimetidine and ranitidine decreased the activity of NAT significantly, no effect on this enzyme was observed after nizatidine. Small doses of famotidine tended to lower, high doses of famotidine tended to enhance the NAT activity. The proton pump inhibitor omeprazole significantly increased the NAT activity, lansoprazole evoked a small increase of the enzyme activity. Ethyl-resorufin O-deethylase (EROD) and penthlresorufin O-depentylase (PROD) were sensitive to cimetidine, ranitidine and famotidine. Only omeprazole and lansoprazole treatment inhibited the detromethorphan O-demethylase (DXDM) activity.

Acetylation↗