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Biomedical subjects

S Szabo

Publications and source records attributed to S Szabo.

At least 19 recordsLinked to original sources
PubMed2001

The thrombolytic paradox.

Thrombolytic drugs do not only stimulate the plasmin system but also induce thrombin activation additionally to the preexisting hypercoagulative state in patients with acute myocardial infarction. Testing the in vitro-derived hypothesis of a plasmin-mediated activation of the contact phase of the coagulation leading to the procoagulant effect, several thrombolytic regimen have been evaluated. Paradoxical thrombin activation (referred to as "thrombolytic paradox") was related to absence of fibrin specificity. Highly fibrin-specific drugs like tenecteplase did not cause additional thrombin activation, while non-fibrin-specific drugs like streptokinase caused a marked additional activation of the contact phase and of thrombin. It could be shown that the thrombolytic paradox was related to the extent of systemic plasmin activation confirming the hypothesis of a plasmin-mediated factor XII/kallikrein system activation as cause of the thrombolytic paradox.

Fibrinolysin↗
PubMed2001

Prognostic influence of delays between exploratory and definitive laparotomy in the treatment of malignant ovarian tumors.

BACKGROUND: The aim of this retrospective study was to evaluate whether a delay between a preliminary exploratory laparotomy and a definitive staging laparotomy and interval chemotherapy between the two operations affected the prognosis of ovarian cancer. METHODS: Of 504 patients with malignant tumors of the ovary who were treated at the Department of Obstetrics and Gynecology between 1980 and 1993, there were 24 who had a delayed definitive staging laparotomy. RESULTS: Sixteen patients did not have chemotherapy between their two operations. After definitive laparotomy, 13 patients (54.2%) were free of disease and 11 patients had residual disease (45.8%). CONCLUSIONS: The value of chemotherapy between preliminary and definitive laparotomy in halting tumor growth was not demonstrated by the results of our analysis.

Adult↗
PubMed2001

The effects of an HIV-1 immunogen (Remune) on viral load, CD4 cell counts and HIV-specific immunity in a double-blind, randomized, adjuvant-controlled subset study in HIV infected subjects regardless of concomitant antiviral drugs.

OBJECTIVE: We examined the activity of an HIV-1 immunogen (Remune) on viral load, CD4 cells and HIV-1 specific immunity. METHODS: Plasma and peripheral blood mononuclear cells were obtained in a predefined random subset of subjects (n = 252) from a multicentre, double-blind, adjuvant-controlled phase III clinical endpoint study. RESULTS: The subjects treated with the HIV-1 immunogen had a significantly greater decline in viral load at multiple time points (P < 0.05), a trend towards increased CD4+ T cell counts and significantly enhanced HIV-1 specific immune responses as measured by HIV-1 lymphocyte proliferation (P < 0.001) compared to the adjuvant control group. Furthermore, in the HIV-1 immunogen treated group, enhanced HIV-1 specific lymphocyte proliferative immune responses were associated with decreased HIV-1 plasma RNA. CONCLUSION: These results suggest that, in a predefined, random subset of subjects, a beneficial effect of the HIV-1 immunogen was observed on viral load, CD4+ T cells, and HIV-specific immunity. These differences were observed in a background of multiple drug therapies. Ongoing trials are evaluating the effect of the combination of this HIV-1 specific, immune-based therapy with potent antiviral drug therapy on virological outcomes.

AIDS Vaccines↗
PubMed2001

Myocardial troponin T release is associated with enhanced fibrinolysis in patients with acute coronary syndromes.

Patients with acute coronary syndromes (ACS) frequently present with signs of disturbed fibrinolysis. The present study investigates the correlation of alterations in the fibrinolytic system and the amount of myocardial damage characterized by troponin release. In 85 patients with ACS markers of plasmin activation, plasminogen activator system and troponin T (TnT) were measured initially and after 48 h. Patients with TnT release (> or = 0.01 microg/l) at admission had higher TPA levels than those without release (10.2+/-0.7 ng/ml vs. 7.6+/-0.5 ng/ml; p <0.01). Additionally, patients with positive TnT had higher D-dimer levels initially (457+/-39 ng/ml vs. 316+/-22 ng/ml; p <0.01) and 48 h later (451+/-42 ng/ml vs. 275+/-37 ng/ml; p <0.01). The association of myocardial damage with a prothrombotic state and an enhanced fibrinolysis may explain the high prognostic value of troponin measurements in respect to future coronary events.

Acute Disease↗
PubMed2000

Fibrin specificity and procoagulant effect related to the kallikrein-contact phase system and to plasmin generation with double-bolus reteplase and front-loaded alteplase thrombolysis in acute myocardial infarction.

This study was undertaken to compare the effects of reteplase and alteplase regimens on hemostasis and fibrinolysis in acute myocardial infarction (AMI). Thrombolytic treatment in patients with AMI is hampered by paradoxical procoagulant effects that favor early reocclusion. In vivo data comparing this effect and the fibrin specificity of double-bolus reteplase and front-loaded alteplase regimens are not available. In a prospective, randomized study, 50 patients with AMI were either treated with double bolus (10 + 10 U) reteplase or with front-loaded alteplase (up to 100 mg) within 6 hours of symptom onset. Thirty apparently healthy persons served as controls. Molecular markers of coagulation and fibrinolysis were serially examined for up to 5 days. Paradoxical thrombin activation at 3 hours after initiation of therapy was comparable between reteplase and alteplase. Reteplase (65 +/- 5 U/L) and alteplase (72 +/- 8 U/L) caused significantly elevated kallikrein activity at 3 hours after adminstration (p <0.01 vs controls 30 +/- 1 U/L). Fibrin specificity was less for reteplase (p <0.05) with a decrease in fibrinogen at 3 hours to 122 +/- 27 mg/dl versus 224 +/- 28 mg/dl for alteplase (p <0.01 and p <0.05 vs controls). D-Dimer levels at 3 hours were higher (p <0.05) after reteplase (5,459 +/- 611 ng/ml) versus alteplase (3,445 +/- 679 ng/ml) (both p <0.01 vs controls 243 +/- 17 ng/ml). Plasmin generation (plasmin-antiplasmin complexes) was significantly (p <0.01) increased at 3 hours with both regimens to 27,079 +/- 3,964 microg/L (reteplase) and 19,522 +/- 2,381 microg/L (alteplase). The data from 3 hours after start of thrombolytic therapy proved less marked fibrin specificity of the reteplase regimen (in vivo) compared with front-loaded alteplase. Both regimens have a moderate procoagulant effect without differences in activation of the kallikrein system.

Adult↗
PubMed2000

Review article: transcription factors and growth factors in ulcer healing.

This review is focused on recent investigations demonstrating a pharmacological and pathophysiologic role in gastroduodenal ulceration for growth factors such as basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), as well as for transcription factors. Our experiments revealed accelerated healing, without decreased gastric acid secretion, of chronic cysteamine-induced duodenal ulcers in rats treated daily for 3 weeks with intragastric administration of bFGF, PDGF or VEGF. Our recent studies also indicate a pathophysiological role of endogenous growth factors in the natural history of experimental duodenal ulcer development and healing. More recently, we investigated the genetic regulation of these growth factors in experimental duodenal ulceration. Since gene expression is most effectively controlled by transcription factors, proteins that bind to cis-acting elements of DNA and guide the binding of polymerase II to start the transcription of specific mRNA, we tested the hypothesis that the expression of IEGs and their transcription factor products, such as Egr-1 and Sp1, might precede the increased synthesis of bFGF, PDGF and VEGF in duodenal ulcer healing. Indeed, the duodenal ulcerogen cysteamine, but not its nonulcerogen and toxic analogue ethanolamine, rapidly increased duodenal (but not gastric) mucosal levels of ET-1, which was followed by enhanced expression of Egr-1 and a decrease in Sp1 in the preulcerogenic stage of duodenal ulceration. These changes in levels of ET-1 and expression of transcription factors were also accompanied by increased expression of the CDK inhibitor p21. Thus, not only growth factors such as bFGF, PDGF and VEGF, but also transcription factors such as Egr-1 and Sp1 and the cell cycle regulator p21, may play a role in the natural history of experimental duodenal ulceration.

Animals↗
PubMed2000

Investigation of gastroprotective compounds at subcellular level in isolated gastric mucosal cells.

We tested the hypothesis that recognized gastroprotective agents exert direct protection against ethanol-induced injury in isolated rat gastric mucosal cells in vitro. If protection exists, we also wanted to identify subcellular targets in the reversible and/or irreversible stages of cell injury. Ethanol-induced cell injury was quantified by measuring plasma membrane leakage (trypan blue exclusion and lactate dehydrogenase release), mitochondrial integrity (succinic dehydrogenase), and nuclear damage (ethidium bromide-DNA fluorescence). Initial cell viability and responsiveness were estimated by the effects of carbachol, carbachol + atropine, or 16,16-dimethyl-PGE(2) on chief cell pepsinogen secretion. Enriched parietal cells were stimulated by histamine, carbachol, or histamine + IBMX. Preincubation of cells with PG, sucrose octasulfate, or the sulfhydryl compounds N-acetylcysteine, taurine, or cysteamine increased cell resistance </=21% against ethanol. Similar protection was found with low histamine concentrations, but a higher concentration aggravated ethanol toxicity. Other naturally occurring or synthetic gastroprotective agents offered partial protection or aggravated ethanol-induced cell injury. Only a few in vivo gastroprotective agents demonstrated in vitro direct cytoprotection, which involved mainly the reversible stage of cell injury (e.g., plasma membrane changes) and, less often, irreversible (e.g., mitochondrial and nuclear) damage. Our findings also indicate that a major part of the beneficial effect of gastroprotective agents is expressed at the tissue level.

1-Methyl-3-isobutylxanthine↗
PubMed1999

Activation of VEGF and Ras genes in gastric mucosa during angiogenic response to ethanol injury.

Our previous studies demonstrated that ethanol injury triggers the angiogenic response in gastric mucosa bordering necrosis. The present study was aimed to determine whether vascular endothelial growth factor (VEGF) (a potent angiogenic peptide selectively acting on endothelial cells) and Ras (a mediator of cell proliferation and a putative regulator of VEGF expression) are involved in gastric angiogenesis after ethanol injury. We studied the angiogenic response and expression of VEGF and Ras in gastric mucosa after ethanol injury. Ethanol damage triggered 1) angiogenesis in the gastric mucosa bordering necrosis, 2) significant increases in VEGF mRNA and protein expression, and 3) significant increases in the expression of Ki-ras mRNA and Ras proteins. Neutralizing anti-VEGF antibody significantly reduced (by greater than threefold) the angiogenic response to ethanol-induced injury. Moreover, mevastatin, an inhibitor of Ras activation, completely blocked the induction of VEGF expression in cultured primary endothelial cells. Because, in other tissues, VEGF is one of the most potent angiogenic factors and VEGF expression is dependent on Ras, our data indicate that Ras and VEGF are involved in gastric mucosal angiogenesis after ethanol injury.

Animals↗
PubMed1999

Perception of the form of stimulus increment as a method in assessment of the psychophysical relationship.

Among numerous procedures for determination of the psychophysical relation, one approach has seldom been applied. Essential in this method is to present a set of stimuli whose intensity increases in fixed time following different forms. The objective stimulus increment, which the subjects perceive as linear growth directly, represents the inverse psychophysical relation. In this paper the method was tested in the fields of click frequency and sound pressure. This procedure was named "Perception of the Form of Stimulus Increment in Time". In comparison to other psychophysical approaches, this one has several advantages. The principal ones are the following: (1) In assessing the psychophysical relation it is not necessary to try to measure the perceptual magnitude; and (2) the psychophysical relation is directly determined by its dynamic pattern. In this paper modifications to the method are reported which facilitate the subject's task and avoid some differences in subjects' individual approaches to the task. The modified procedure leads to results satisfactory independent of the influence of the factors irrelevant to the psychophysical relationship.

Acoustic Stimulation↗
PubMed1998

Thrombolytic therapy in acute myocardial infarction: comparison of procoagulant effects of streptokinase and alteplase regimens with focus on the kallikrein system and plasmin.

BACKGROUND: Thrombolytic therapy in patients with acute myocardial infarction (AMI) is hampered by procoagulant effects. In vitro studies have indicated that plasmin stimulation activates the kallikrein-contact-phase system, resulting in thrombin activation. This prospective comparative study was designed to examine the procoagulant effects of streptokinase or alteplase in AMI. METHODS AND RESULTS: Sixty-one patients with AMI received 1.5 million U of streptokinase or front-loaded alteplase (up to 100 mg) and systemic heparin. Twenty-four patients with AMI and no thrombolytic therapy and 30 control subjects were examined for comparison. Molecular markers of thrombin, plasmin activation, and coagulation activities were determined before therapy and serially for up to 10 days. Moderate thrombin (initial thrombin-antithrombin [TAT] complex 18+/-5 versus 4+/-0.3 microg/L, P<0.05) and kallikrein (up to 45+/-4 versus 30+/-1 U/L at 3 hours, P<0.01) activation occurs in patients with AMI. D-Dimers are increased (P<0.01), and plasmin is stimulated (P<0.01). Streptokinase and alteplase increase TAT to 50+/-17 and 51+/-18 microg/L at 3 hours and to 50+/-17 and 33+/-14 microg/L at 6 hours, respectively (P<0.01). Kallikrein activity is elevated (P<0. 01) to 76+/-5 and 71+/-7 U/L at 3 hours and 64+/-6 and 47+/-5 U/L by streptokinase and alteplase, respectively, at 6 hours. Reductions in fibrinogen and increases in D-dimers and plasmin-antiplasmin complexes are more marked (P<0.05 and 0.01) after streptokinase versus alteplase. Correlations were found among TAT, kallikrein activity, and plasmin activation (P<0.01). CONCLUSIONS: The data indicate a more marked procoagulant action of the streptokinase regimen compared with front-loaded alteplase, thus supporting the hypothesis of a plasmin-mediated kallikrein activation with consecutive procoagulant action in vivo.

Acute Disease↗
PubMed1998

Hans Selye and the development of the stress concept. Special reference to gastroduodenal ulcerogenesis.

Hans Selye has a historic role in the development of the stress concept. Before his short article in Nature in 1936, the neuroendocrine response to nonspecific injury was thought to be restricted to the release of catecholamines, as recognized by Cannon. Selye was the first to appreciate the crucial role of the adrenal cortex/hypophysis axis in the stress response. He also insisted on the nonspecificity of this neuroendocrine response, and he named the stress-causing agent "stressors". His last major contribution was the distinction between negative, that is, distress, and positive, that is, eustress reactions. The "triad of stress" (adrenal hypertrophy, gastrointestinal ulcers, thymolymphatic atrophy) was also first described by Selye, who was fascinated by the fact that in stressed rodents only gastric and not duodenal ulcers would develop. It was not until the recognition of duodenal ulcerogenic properties of propionitrile and cysteamine as well as the subsequent quantitative structure-activity studies predicting the duodenal ulcerogenic action of complex molecules that pathogenetic investigations allowed a molecular and mechanistic approach for studying the etiology and pathogenesis of duodenal ulceration. Recent studies on the role of sulfhydryls, TRH, ET, and growth factors provide new insights into central and peripheral pre-ulcer pathways. We were surprised to learn that an organ-specific ET-1 release may play a role both in ulcer induction and healing, which seems to start with the expression of immediate early genes such as egr-1 and stimulation of the local synthesis of growth factors such as bFGF and PDGF. Thus, a historic review originating with Hans Selye and extending through the next 60 years allows a cellular and molecular approach to the better understanding of stress-related disorders such as gastroduodenal ulceration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Gastroprotection by 4-methylpyrazole against ethanol in humans.

4-Methylpyrazole (4-MP), a specific inhibitor of alcohol dehydrogenase, exerts gastroprotection of unusually long duration in rats. We tested the hypothesis that pretreatment with 4-MP might protect the human gastric mucosa against alcohol-induced acute injury. Fourteen healthy volunteers received pretreatment with either 4-MP, 15 mg/kg body weight dissolved in 50 ml of orange juice, or placebo and 2 hr later 100 ml of 40% ethanol. The endoscopic appearance of the gastric mucosa was evaluated and scored (scale 0-5) and mucosal biopsies were obtained just before pretreatment and 30 min after ethanol for histologic examination and prostaglandin E2 measurement. In the 4-MP group the mean endoscopic injury score was significantly lower than that in placebo group, in both the body and the antrum. Histologically, 4-MP significantly reduced disruption of surface epithelium and completely prevented the deep hemorrhagic mucosal lesions. In the 4-MP group no changes in gastric mucosal PGE2 levels were detected. In rats, 4-MP did not inhibit gastric acid output, whereas it markedly increased the adherent gastric mucus evaluated by the alcian blue recovery method. When lipid peroxidation was induced by carbon tetrachloride in hepatic microsomes, 4-MP caused significant inhibition of malondialdehyde generation. We conclude that 4-MP provides significant protection of the human stomach against alcohol-induced acute mucosal injury. 4-MP, besides inhibiting the conversion of alcohol to acetaldehyde, might protect the gastric mucosa by increasing adherent gastric mucus and by scavenging free radicals.

Adult↗
PubMed1998

Radiation-induced enterocolitis: basic and applied science.

We adapted and introduced in our laboratory a simplified animal model of radiation-induced enterocolitis. After a shielding of the parenchymatous organs, our dose-response studies revealed that 20 Gy x-ray radiation resulted in about 20% mortality and reproducible lesions in the terminal ileum and proximal colon. These changes are optimal for pharmacologic studies since they may be decreased or aggravated by drugs. Sucralfate dose-dependently decreased the clinical signs of enterocolitis (e.g., lethargy, diarrhea) as well as the number and area of ileal and colonic erosions and ulcers. The wet weight of the ileum and colon were also decreased by sucralfate. bFGF at the small doses used exerted a beneficial effect only on a few of the parameters of enterocolitis. Thus sucralfate, and maybe bFGF, might decrease the severity and accelerate the healing of radiation-induced enterocolitis.

Animals↗
PubMed1998

The diagnostic and prognostic value of tumor angiogenesis.

The "angiogenic switch" and tumor angiogenesis play a critical role in the growth and metastasis of solid tumors. Tumor angiogenesis is regulated by a balance of stimulators (e.g., VEGF, bFGF) and inhibitors of angiogenesis (e.g., angiostatin, endostatin, angiostatic steroids). Measuring angiogenesis (blood vessel density) and/or its main regulators such as VEGF and bFGF in solid tumors, or the levels of these growth factors in the serum or urine provides new and sensitive markers for tumor progression, metastasis and prognosis.

Endothelial Growth Factors↗
PubMed1998

Quality of life following a change in therapy for diabetes mellitus.

OBJECTIVE: The study objective was to evaluate and compare quality-of-life (QOL) parameters between patients with type 2 (non-insulin-dependent) diabetes mellitus who changed therapy from an oral hypoglycaemic agent (OHA) to insulin and those who remained on an OHA. DESIGN: The World Health Organization Quality of Life Questionnaire (WHOQOL) was used to assess quality of life among 2 groups of patients with type 2 diabetes mellitus at baseline and after a 2-month follow-up period. SETTING: The study was conducted in the outpatient department of the Vuk Vrhovac Clinic, a referral centre for registration, treatment and follow-up of patients with diabetes mellitus in Zagreb, Croatia. PARTICIPANTS AND INTERVENTIONS: 32 consecutively recruited patients with type 2 diabetes mellitus who were switched from an OHA to insulin therapy (group 1) were compared with 28 patients who remained on OHA (group 2) with respect to QOL issues. The patient groups were comparable in terms of gender, age, duration of disease, education and family status. However, patients in group 1 had glycosylated haemoglobin (HbA1c) values greater than 9.5% on average during a period of approximately 6 months, which was the criterion used for switching to insulin therapy. MAIN OUTCOME MEASURES AND RESULTS: At baseline, various QOL ratings were higher among patients in group 2 than group 1, indicating better quality of life with respect to overall quality of life (t = -2.31, p = 0.03), physical health (t = -2.36, p = 0.02), psychological state (t = -2.01, p = 0.05) and level of independence (t = -2.75, p = 0.001), while no differences were found between groups with respect to the social domain, personal beliefs and environmental QOL aspects. After the follow-up period, the groups were comparable in all QOL aspects other than overall quality of life (t = -2.18, p = 0.03) and level of independence (t = -3.49, p = 0.001), both of which remained higher for patients in group 2. No changes in QOL parameters were detected within group 2 from baseline to the end of the 2-month follow-up period, whereas patients in group 1 showed significant improvement in psychological QOL determinants (t = -2.14, p = 0.04). CONCLUSION: Results of the study indicate that introducing insulin therapy in patients with type 2 diabetes mellitus and sustained elevated HbA1c levels might positively affect their quality of life.

Adult↗