PubMed Health⌕ Search

Biomedical subjects

G Nowak

Publications and source records attributed to G Nowak.

At least 37 records · Page 2Linked to original sources
PubMed2002

Multiple MPEP administrations evoke anxiolytic- and antidepressant-like effects in rats.

Several lines of evidence suggest a crucial involvement of glutamate in the mechanism of action of anxiolytic and antidepressant drugs. The involvement of group I mGlu receptors in anxiety and depression has also been proposed. In view of the recent discovery of anxiolytic- or antidepressant-like effects of acute injections of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective and brain penetrable mGlu5 receptor antagonist, we designed the present study to examine anxiolytic- and/or antidepressant-like effects of multiple administrations of this drug. The anxiolytic-like effects of MPEP were evaluated in rats using the conflict drinking test. The antidepressant-like effect was estimated using the rat olfactory bulbectomy model of depression. Seven subsequent injections of MPEP (1 mg/kg) significantly (by 320%) increased the number of shocks accepted during the experimental session in the Vogel test. MPEP given once daily at a dose of 10 mg/kg, restored the learning deficit of bulbectomized rats after 14 days of treatment, remaining without any effect in the sham-operated animals. N-methyl-D-aspartic acid (NMDA)-induced convulsions in mice were not affected by a single injection of MPEP (30 mg/kg) indicating that at this dose MPEP did not block NMDA receptors. The results indicate that the prolonged blockade of mGlu5 receptors exerts anxiolytic- and antidepressant-like effects in rats. No tolerance to anxiolytic-like action occurs. The previously mentioned results further indicate that antagonists of group I mGlu receptors may play a role in the therapy of both anxiety and depression.

Animals↗
PubMed2002

Influence of room lighting on grey-scale perception with a CRT-and a TFT monitor display.

OBJECTIVES: To determine the influence of ambient lighting on grey-scale perception using a cathode-ray tube (CRT) and a thin film transistor (TFT) computer display. METHODS: A cathode ray tube (Nokia XS 446) and a liquid crystal display (Panasonic LC 50S) were used at reduced room lighting (70 lux) and under conditions recommended for a dental operatory (1000 lux). Twenty-seven observers examined twice a modified SMPTE test pattern [0 to 255; 255 to 0] grey-scale values. The corresponding contrast differences were allocated to four ranges of grey levels (I: 0-63; II: 64-127; III: 128-191; IV: 192-255). The influences of monitor type, grey-scale range and illumination were evaluated by means of repeated measures analysis of variance. RESULTS: Detection of differences in monochromatic intensity was significantly earlier with reduced lighting (P<0.0001). When full ambient lighting was used, the TFT display was superior compared to the CRT monitor in ranges II and III (P<0.0001), whereas no differences could be detected for grey intensities between 0 and 63 (P=0.71) and between 192 and 255 (P=0.36). CONCLUSIONS: Background lighting hampers grey-scale perception on computer displays. In this study of one TFT and one CRT monitor, the TFT in full ambient lighting was associated with earlier detection of grey scale differences than CRT.

Adult↗
PubMed2002

Clinical experience in continuous graft monitoring with microdialysis early after liver transplantation.

BACKGROUND: Early detection of impaired graft function after transplantation is essential. Microdialysis permits continuous monitoring of metabolic changes by mimicking the passive function of a capillary blood vessel by perfusion of a tubular semipermeable membrane introduced into the tissue. Based on the results of animal experiments, a clinical pilot study was undertaken. METHODS: Ten consecutive patients undergoing whole-organ orthotopic liver transplantation were studied. Intrahepatic implantation of a microdialysis catheter was performed at the end of the operation. A reference catheter was placed in the subcutaneous tissue over the right pectoral area immediately after abdominal closure. Consecutive serial samples were collected at 1-h intervals for 3 days after the operation. Glucose, lactate, pyruvate and glycerol concentrations were measured. RESULTS: During the first 24 h, the glucose level was higher in the liver than in reference tissue. Initially, increased mean(s.e.m.) levels of lactate (7.0(1.9) mmol/l) were observed in the liver, with a rapid decrease (to 2.7(0.3) mmol/l) over 24 h. A decrease in, and later stabilization of, the lactate : pyruvate ratio in the liver, from 18.7(4.2) to 10.0(1.1), was observed within 24 h after transplantation. Liver glycerol levels decreased from 62.3(7.4) to 24.3(7.5) micro mol/l within the first 16 h after reperfusion and remained stable thereafter. CONCLUSION: Microdialysis allows continuous monitoring of tissue metabolism in the transplanted liver. The procedure is easy to perform and safe. The specific detection and monitoring of pathological changes in the liver graft (e.g. arterial and portal vein thrombosis, or early rejection) with microdialysis should be addressed in further studies.

Adult↗
PubMed2002

[Contrast-enhanced intracranial 3 D MR angiography (CE-MRA) in assessing arterial stenoses and aneurysms].

PURPOSE: The aim of this study was to evaluate the diagnostic potential of CE-MR angiography in intracranial arterial stenoses and aneurysms. MATERIAL AND METHODS: Thirteen patients with intracranial arterial stenoses and ten patients with aneurysms, including 6 cases with GDC coil-occluded aneurysms, were examined by both 3 D TOF-MR angiography and CE-MR angiography. In cases of stenoocclusive diseases colour-coded duplex sonography and in cases of aneurysms arterial digital subtraction angiography served as reference method. RESULTS: Both TOF-MRA and CE-MRA could well depict filiform stenosis. In contrast to TOF-MRA, CE-MRA did not show any false positive stenosis or occlusion in regions of turbulent or slow blood flow. Stenoses of the medial cerebral artery could not be graded sufficiently by CE-MRA. In aneurysms the parent vessel was better shown by TOF-MRA. CE-MRA, however, more sensitively detected reperfusion in GDC coil-occluded aneurysms. CONCLUSION: Stenoses of small vessels were graded less exactly by CE-MRA than by TOF-MRA due to lower spatial resolution. CE-MRA, however, seems to be superior in regions of turbulent or slow blood flow. CE-MRA also offers advantages in follow-up examinations of coil-occluded aneurysms.

Aged↗
PubMed2002

[Rationale for an oral thrombin inhibitor from a pharmacological point of view].

Direct thrombin inhibitors are in focus of interest for hereditary or acquired thrombophilic indications. Besides thrombosis prophylaxis in surgery, life-threatening cardiac diseases and stroke are of special interest for this new drug class. For long-term prophylaxis of genetically caused thrombophilia the only drug class currently available are the orally active dicoumarol derivatives. Their application is a time and cost intensive procedure and associated with side effects, too. Active site-directed inhibitors block the catalytic triad of the active centre of thrombin responsible for hydrolytic cleavage. Inhibitor ratios (K(j)) are in the nanomolar or picomolar range. As these substances are eliminated via liver or kidneys with an elimination half-life of 0.3-2 hours, parenteral administration should be used for acute therapy and prophylaxis. For long-term prophylaxis, orally absorbable derivatives of these direct thrombin inhibitors are available with absorption rates of 10-30%. They are converted into their parent substance in blood. Therapeutical range is relatively large so that an oral long-term prophylaxis using standard dose is possible without monitoring. The first representative of this new drug class, Ximelagatran, an orally absorbable variant of Melagatran, is currently undergoing phase III trials for different indications. Using oral administration of two partial doses per day, a good compliance is expected.

Administration, Oral↗
PubMed2001

Evidence for a novel thrombopoietin signalling event: activation of protein kinase A in human megakaryoblastic CMK cells.

Thrombopoietin (TPO) plays a crucial role in megakaryocyte development. TPO signalling, which is mediated by its receptor Mpl, includes Janus kinase, (JAK) signal transducer and activator of transcription (STAT) and Shc/Ras/mitogen-activated protein kinase (MAPK) pathways. The precise nature of these signalling routes has not been clarified in detail up until now. We investigated the effect of TPO on activation of cAMP-dependent protein kinase (PKA) and its involvement in MAPK signalling in human megakaryoblastic leukaemia CMK cells. For estimation of PKA activity, phosphorylation of a PKA-specific peptide substrate was assayed in CMK cell lysates. Since activation of PKA is associated with translocation of its catalytic subunit alpha (C-PKA) into the cell nucleus, Western blot analysis of nuclear fractions with an anti-C-PKA antibody was additionally performed. The activation of TPO-induced MAPK activation and the effect of the PKA inhibitor H-89 was measured using immunoblotting with a monoclonal anti-pERK antibody. TPO enhanced cAMP and induced activation of PKA in CMK cells. In addition, H-89 partly blocked TPO-induced MAPK activation in CMK cells. Our results indicate a novel TPO-triggered signalling event, activation of the cAMP/PKA pathway in human megakaryoblastic CMK cells. This signal transduction route seems to be involved in TPO-induced MAPK signaling.

Cell Nucleus↗
PubMed2001

Antidepressant-like properties of zinc in rodent forced swim test.

The effects of zinc, the N-methyl-D-aspartate glutamate receptor inhibitor, were studied in mice and rats using the forced swim test. Zinc (ZnSO4) in a dose of 30 mg/kg and imipramine (30 mg/kg), reduced the immobility time in the forced swim test in both species. Moreover, combined treatment in this test with zinc and imipramine at their ineffective doses (1 and 5 mg/kg, respectively) induced a statistically significant effect in rats. The doses active in the forced swim test reduced (in mice) or did not affect (in rats) locomotor activity. The results obtained indicate that zinc induces an antidepressant-like effect and enhances the effect of imipramine in the forced swim test, suggesting a potential antidepressant activity of zinc in humans.

Animals↗
PubMed2001

Analysis of the toxic effects of linoleic acid, 12,13-cis-epoxyoctadecenoic acid, and 12,13-dihydroxyoctadecenoic acid in rabbit renal cortical mitochondria.

P450 epoxidation of linoleic acid has been associated with many pathological conditions that often lead to acute renal failure. However, there is only suggestive evidence that linoleic acid monoepoxides and/or linoleic diols directly induce mitochondrial dysfunction. Using isolated rabbit renal cortical mitochondria (RCM), we found that linoleic acid (50 microM) and the linoleic acid monoepoxide, cis-12,13-epoxy-9-octadecenoic acid (12,13-EOA, 50 microM) increased state 4 and oligomycin-insensitive respiration and reduced state 3 and oligomycin-sensitive respiration. Concomitant with these effects, linoleic acid and 12,13-EOA decreased mitochondrial membrane potential (DeltaPsi). In contrast, the hydrolyzed product of 12,13-EOA, 12,13-dihydroxyoctadecenoic acid (12,13-DHOA, 50 microM), had no effect on state 3, state 4, oligomycin-sensitive, and oligomycin-insensitive respiration, and DeltaPsi. Neither linoleic acid or its metabolites altered uncoupled respiration, which suggests that these compounds have no affect on electron transport chain in RCM. Nucleotides such as ATP (0.5 mM) and GDP (0.5 mM) partially prevented the decrease in DeltaPsi but did not attenuate the increase in oligomycin-insensitive respiration after exposure to linoleic acid (50 microM) and 12,13-EOA (50 microM). These results demonstrate that linoleic acid metabolism to the 12,13-DHOA is a detoxification pathway that prevents mitochondrial dysfunction in RCM. The increase in state 4 respiration concomitant with decreases in state 3 respiration and DeltaPsi suggest that, in addition to uncoupling effects, linoleic acid and 12,13-EOA may have other effects, such as alterations of mitochondrial membranes. The inability of ATP and GDP to fully attenuate the uncoupling effects of linoleic acid and 12,13-EOA suggests that these effects are mediated through a nucleotide-independent mechanism.

Adenosine Triphosphate↗
PubMed2001

A novel PAR-1-type thrombin receptor signaling pathway: cyclic AMP-independent activation of PKA in SNB-19 glioblastoma cells.

Cellular effects of thrombin are mediated by members of a new subfamily of G protein-coupled receptors designated proteinase-activated receptors (PARs) with the prototype PAR-1. Investigation of PAR-1-induced signaling has been shown to be very important in clarifying thrombin's role in cell metabolism, differentiation, and growth. We evaluated connection of PAR-1 with the cAMP/PKA pathway in SNB-19 glioblastoma cells. Alpha-thrombin and the synthetic PAR-1 agonist SFLLRN stimulated PKA as shown by increased PKA activity and translocation of the catalytic PKA alpha subunits (PKA(cat)alpha) into the nucleus. However, no effect on cAMP could be observed. PKA(cat)alpha was found to be associated with nuclear factor-kappa B (NF-kappaB) p65 and its inhibitor protein IkappaB in SNB-19 cells. After PAR-1 stimulation, this association was markedly diminished. We conclude that PAR-1 mediates PKA activation without altering cAMP levels but includes NF-kappaB-associated PKA(cat)alpha in SNB-19 glioblastoma cells. This is the first evidence for a cAMP-independent PKA signaling by a G protein-coupled receptor.

Active Transport, Cell Nucleus↗
PubMed2001

Synthesis and antifeedant properties of N-benzoylphenylisoserinates of Lactarius sesquiterpenoid alcohols.

The esterification of various sesquiterpenoid alcohols of Lactarius origin with N-benzoyl-[2R,3S]-phenylisoserine (side chain of Taxol) produced compounds whose antifeedant properties against storage pests Tribolium confusum, Trogoderma granarium and Sitophylus granarius were measured. The introduction of the taxol side chain in these molecules, in comparison to original compounds, moderately enhanced their antifeedant activities, as well as changed their selectivity of activity towards the test insects.

Agaricales↗
PubMed2001

Implementation of similarity model in the CSB system for chemical reaction predictions.

A new algorithm for predicting the course of chemical reactions, implemented in the CSB system is presented. It allows to use of four various models for reaction generation, that lead to create different solution space according to the needs of the user. Depending on the chosen model one can expect solutions featuring great completeness or great reliability.

Journal Article↗
PubMed2001

Evidence for functionally active protease-activated receptor-4 (PAR-4) in human vascular smooth muscle cells.

1. This study investigates, whether in addition to the protease-activated receptor-1 (PAR-1), PAR-4 is present in vascular smooth muscle cells (SMC) of the human saphenous vein and whether this receptor is functionally active. PAR-1 and PAR-4 are stimulated by thrombin and by the synthetic peptides SFLLRN and GYPGQV, respectively. 2. mRNAs for both, PAR-1 and PAR-4, were detected in the SMC by using reverse transcriptase polymerase chain reaction (RT - PCR). 3. Treatment of the SMC with GYPGQV (200 microM) resulted in a transient increase in free intracellular calcium. This calcium signal was completely abolished after a preceding challenge with thrombin (10 nM), indicating homologous receptor desensitization. 4. Stimulation of the SMC with 10 nM thrombin or 200 microM SFLLRN caused a time-dependent activation of the extracellular signal-regulated kinases-1/2 (ERK-1/2) with a maximum at 5 min. In contrast, 100 nM thrombin as well as 200 microM of GYPGQV induced a prolonged phosphorylation of ERK-1/2 with a maximum at 60 min. These data suggest that PAR-1 and PAR-4 are activated by thrombin at distinct concentrations and with distinct kinetics. 5. GYPGQV stimulated [(3)H]-thymidine incorporation in SMC. At 500 microM, the peptide increased DNA synthesis 2.5 fold above controls. A comparable mitogenic effect was obtained after stimulation of the SMC by 10 nM thrombin or 100 microM SFLLRN, respectively. 6. These data indicate that a functionally active PAR-4 is present in SMC and, in addition to PAR-1, might contribute to thrombin-induced mitogenesis.

Amino Acid Sequence↗
PubMed2001

Clinical monitoring of hirudin and direct thrombin inhibitors.

In addition to heparin, the standard medication for prophylaxis and therapy of thromboembolism, several other substances have been developed and tested for clinical use with the aim of decreasing or eliminating side effects. Most of all, hirudin, a direct antithrombin (AT), has proved to be effective. To define the therapeutic range and to avoid underdosage or overdosage, clinical monitoring is necessary. For monitoring of hirudin, thrombin time (TT) is not suited because of the missing linearity of the standard curve. Activated partial thromboplastin time (aPTT) can be used only in the lower hirudin level range, where the standard curve is quite linear. However, high and toxic hirudin levels cannot be determined using aPTT. Another drawback is a high variation in single measurements and in the normal value of patients. Methods using chromogenic substrates are suited for determination of hirudin in plasma but cannot be used at bedside. Especially for monitoring of hirudin, the ecarin clotting time (ECT) was developed. The standard curve is linear over the entire concentration range. There are no influences by other coagulation parameters or anticoagulants. For both acute clinical situations and long-term monitoring, this method capable of point-of-care therapy (POCT) will be the method of choice.

Antithrombins↗
PubMed2001

Twenty colloid cysts--comparison of endoscopic and microsurgical management.

The management of colloid cyst remains controversial, evaluation of the competing methods seems to be necessary. We report on our experience with colloid cysts in the last decade: ten were managed solely endoscopically, 10 were resected microsurgically (9 via a transcortical/transventricular, 1 via a transcallosal approach). The outcome in the endoscopic group was excellent in 9 cases and unsatisfying in 1 case (recurrence). In the microsurgical group we achieved a good outcome in 5 of 10 cases, a fair outcome in 4 cases and 1 lethal outcome (caused by pulmonary embolism). Complications in the endoscopic group: one intraoperative bleeding, 1 stitch granuloma, 1 mispuncture of the ventricle, and 1 meningitis. Complications in the microsurgical group: 1 subdural effusion, 1 flap infection, 1 mild hemiparesis, 1 transient impairment of consciousness and 1 pulmonary embolism. Mean operative time and length of hospitalization of the endoscopic group were clearly shorter than in the microsurgical group: 91 min versus 267 min time of surgery, 5.1 days versus 18.9 days of hospitalization. Complete resection was achieved in 8 of 10 cases of microsurgery, and in 3 of 10 cases in endoscopy. Endoscopic management results in lower costs and superior patients' comfort. The reduced number of total resections in the endoscopic group may lead to a higher recurrence rate in long-term follow-up, which might be a serious disadvantage of endoscopy. However, more experience in the endoscopic techniques may result in a higher rate of total resection of colloid cysts.

Adult↗
PubMed2001

Collagen IV promotes repair of renal cell physiological functions after toxicant injury.

Collagen IV is found in the renal proximal tubular cell (RPTC) basement membrane and is a mediator of renal development and function. Pharmacological concentrations of L-ascorbic acid phosphate (AscP) promote the repair of physiological functions in RPTC sublethally injured by S-(1,2-dichlorovinyl)-L-cysteine (DCVC). We hypothesized that AscP promotes RPTC repair by stimulating collagen IV synthesis and/or deposition. RPTC exhibited increased synthesis but decreased deposition of collagen IV after DCVC exposure. In contrast, RPTC cultured in pharmacological concentrations of AscP maintained collagen IV deposition. The activity of prolyl hydroxylase was decreased in RPTC after DCVC injury, an effect that was partially attenuated in injured RPTC cultured in pharmacological concentrations of AscP. The addition of exogenous collagen IV to the culture media of DCVC-injured RPTC promoted the repair of mitochondrial function and Na(+)-K(+)-ATPase activity. However, neither collagen I, laminin, nor fibronectin promoted cell repair. These data demonstrate an association between AscP-stimulated deposition of collagen IV and exogenous collagen IV and repair of physiological functions, suggesting that collagen IV plays a specific role in RPTC repair after sublethal injury.

Animals↗
PubMed2000

A myosin I isoform in the nucleus.

A nuclear isoform of myosin I beta that contains a unique 16-amino acid amino-terminal extension has been identified. An affinity-purified antibody to the 16-amino acid peptide demonstrated nuclear staining. Confocal and electron microscopy revealed that nuclear myosin I beta colocalized with RNA polymerase II in an alpha-amanitin- and actinomycin D-sensitive manner. The antibody coimmunoprecipitated RNA polymerase II and blocked in vitro RNA synthesis. This isoform of myosin I beta appears to be in a complex with RNA polymerase II and may affect transcription.

3T3 Cells↗
PubMed2000

Ascorbic acid promotes recovery of cellular functions following toxicant-induced injury.

We have shown that renal proximal tubular cells (RPTC) recover cellular functions following sublethal injury induced by the oxidant t-butylhydroperoxide but not by the nephrotoxic cysteine conjugate dichlorovinyl-L-cysteine (DCVC). This study investigated whether L-ascorbic acid phosphate (AscP) promotes recovery of RPTC functions following DCVC-induced injury. DCVC exposure (200 microM; 100 min) resulted in 60% RPTC death and loss from the monolayer at 24 h independent of physiological (50 microM) or pharmacological (500 microM) AscP concentrations. Likewise, the DCVC-induced decrease in mitochondrial function (54%), active Na(+) transport (66%), and Na(+)-K(+)-ATPase activity (77%) was independent of the AscP concentration. Analysis of Na(+)-K(+)-ATPase protein expression and distribution in the plasma membrane using immunocytochemistry and confocal laser scanning microscopy revealed the loss of Na(+)-K(+)-ATPase protein from the basolateral membrane of RPTC treated with DCVC. DCVC-injured RPTC cultured in the presence of 50 microM AscP did not proliferate nor recover their physiological functions over time. In contrast, RPTC cultured in the presence of 500 microM AscP proliferated, recovered all examined physiological functions, and the basolateral membrane expression of Na(+)-K(+)-ATPase by day 4 following DCVC injury. These results demonstrate that pharmacological concentrations of AscP do not prevent toxicant-induced cell injury and death but promote complete recovery of mitochondrial function, active Na(+) transport, and proliferation following toxicant-induced injury.

Animals↗