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Biomedical subjects

I Molnár

Publications and source records attributed to I Molnár.

At least 19 recordsLinked to original sources
PubMed2000

[Evaluation of medical diagnostic tests: application of Bayes theorem, ROC-curve and Kappa-test] .

With the technical improvement of the sensitivity and specificity of the medical diagnostic tests the principles and methods of statistical analysis of the tests are in developing too. The technical development of the diagnostic tests and the exact statistical evaluation of the data will improve the reliability and effectiveness of the decisions for medical interventions. Application, statistical evaluation and interpretation of the Bayes theorem, ROC curve and Kappa test are presented.

Bayes Theorem↗
PubMed2000

The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium cellulosum So ce90.

BACKGROUND: Epothilones are produced by the myxobacterium Sorangium cellulosum So ce90, and, like paclitaxel (Taxol((R))), they inhibit microtubule depolymerisation and arrest the cell cycle at the G2-M phase. They are effective against P-glycoprotein-expressing multiple-drug-resistant tumor cell lines and are more water soluble than paclitaxel. The total synthesis of epothilones has been achieved, but has not provided an economically viable alternative to fermentation. We set out to clone, sequence and analyze the gene cluster responsible for the biosynthesis of the epothilones in S. cellulosum So ce90. RESULTS: A cluster of 22 open reading frames spanning 68,750 base pairs of the S. cellulosum So ce90 genome has been sequenced and found to encode nine modules of a polyketide synthase (PKS), one module of a nonribosomal peptide synthetase (NRPS), a cytochrome P450, and two putative antibiotic transport proteins. Disruptions in the genes encoding the PKS abolished epothilone production. The first PKS module and the NRPS module are proposed to co-operate in forming the thiazole heterocycle of epothilone from an acetate and a cysteine by condensation, cyclodehydration and subsequent dehydrogenation. The remaining eight PKS modules are responsible for the elaboration of the rest of the epothilone carbon skeleton. CONCLUSIONS: The overall architecture of the gene cluster responsible for epothilone biosynthesis has been determined. The availability of the cluster should facilitate the generation of designer epothilones by combinatorial biosynthesis approaches, and the heterologous expression of epothilones in surrogate microbial hosts.

Anti-Bacterial Agents↗
PubMed1999

[Statistically validated evaluation of clinical trials].

Data of clinical trials of medicinal products must be evaluated in statistically valid models. The statistical validity criteria are defined. Statistically invalid models will result in biased parameter and confidence interval estimations, erroneous statistical inferences and clinical interpretations. Finally, wrong decisions will call forth deleterious consequences in the judgement of the therapeutic effect and the frequency and severity of the adverse reactions of the tested new medicinal, and generic products. Statistically validated analyses will promote the international harmonization of the scientific evaluation of medicinal products according to the idea of the evidence-based-medicine. The study presents examples of clinical trials evaluated with a software checking statistical validity assumptions while performing evaluation of data.

Clinical Trials as Topic↗
PubMed1998

[Iodine deficiency in cardiovascular diseases].

The thyroid hormone deficiency on cardiovascular function can be characterized with decreased myocardial contractility and increased peripheral vascular resistance as well as with the changes in lipid metabolism. 42 patients with cardiovascular disease (mean age 65 +/- 13 yr, 16 males) were investigated if iodine insufficiency can play a role as a risk factor for the cardiovascular diseases. The patients were divided in 5 subgroups on the ground of the presence of hypertension, congestive heart failure, cardiomyopathy, coronary disfunction and arrhythmia. Urine iodine concentration (5.29 +/- 4.52 micrograms/dl) was detected with Sandell-Kolthoff colorimetric reaction. The most decreased urine iodine concentration was detected in the subgroups with arrhythmia and congestive heart failure (4.7 +/- 4.94 micrograms/dl and 4.9 +/- 4.81 micrograms/dl, respectively). An elevated TSH level was found by 3 patients (5.3 +/- 1.4 mlU/l). An elevation in lipid metabolism (cholesterol, triglyceride) associated with all subgroups without arrhythmia. In conclusion, the occurrence of iodine deficiency in cardiovascular disease is frequent. Iodine supplementation might prevent the worsing effect of iodine deficiency on cardiovascular disease.

Aged↗
PubMed1998

[How to proceed in the age of increasing antibiotic resistance?].

The authors examined the infection control activity, the quality of basic health care of 6906 patients in 44 praxis. The mass of accomplished treatments was compared with the virtual mass of desirable treatments according to up-to-date considerations. The presumptive purposivity and expectable efficiency of the realised treatments didn't satisfy the justly expected professional claims. The decrease in quality was basically due to the cognitive dissonance (deficiencies of cognition and/or erroneous adoptation of theoretical and practical knowledge) of physicians. The unnecessarily prescribed (polypragmatic) and simultaneously purposeless broad spectrum of antibiotic treatments ran to two-third of the total--mainly in the cases or viral and beta-hemolytic Streptococcal infections; the number of antibacterial treatments was three times more than needed. Better compromise could be reached by the introduction of quality control in the field of infection treatments in the basic health care system. Spreading of the antibiotic resistance cannot be prevented without of quality assurance in the field of infection control and without the wide use of a more reasonable kind of treatment practice.

Bacterial Infections↗
PubMed1997

[Immunomodulatory effect of pentoxifylline in Graves ophthalmopathy].

In the pathomechanism of the thyroid associated ophthalmopathy (TAO) the inflammatory cytokines produced by infiltrating lymphocytes of the retroorbital tissues are involved. The activated lymphocytes have been shown to secrete a number of cytokines including tumour necrosis factor-alpha, interleukin-1 and interferon-gamma. The widely used immunosuppressive therapies have potential serious side effects. The pentoxifylline (Ptx) is known to have effect on production of cytokines. The aim of this study was to investigate the effect of Ptx on expression of HLA-DR molecules and production of glycosaminoglycan of human retroorbital tissue cultures and potential efficacy in patients with TAO. It was found that pentoxifylline (Ptx) was able to inhibit significantly the HLA-DR expression and glycosaminoglycan synthesis induced by inflammatory cytokines including TNF-alpha, IFN-gamma and IL-1. Ten patients with untreated moderate severe ophthalmopathy (8 female and 2 male) were excluded from steroid treatment due diabetes mellitus and psychiatric disease. Classification of eye changes was made by NOSPECS categories and total eye score. All patients were euthyroid during the study and was no remarkable difference in thyroid function and eye symptoms. Before and during Ptx therapy the laboratory parameters were also determined including glycosaminoglycan. TNF-alpha, anti-TSH-receptor, anti-eye muscle, anti-thyroglobulin and anti-thyroid peroxidase antibodies in the patients'sera. It was found a remarkable improvement in the eye symptoms in eight of ten patients. The levels of glycosaminoglycan (uronic acid) and TNF-alpha gradually decreased in eight patients who considered to be responders. The levels of uronic acid in plasma of the responders were found to be significantly lower after Ptx treatment. Before Ptx therapy the TNF-alpha in the sera was not different remarkably in non-responders and responders. After 4 weeks Ptx treatment the TNF-alpha decreased significantly in responders compared to non-responders (20.9 +/- 4.8 pg/ml v. s. 28.3 +/- 6.1 pg/ml) (p < 0.01). The titre of anti-eye muscle antibodies were found to be lower at the end of observation, however, the anti-thyroid antibodies were not changed remarkably. It was concluded that Ptx in the majority of patients (8/10) has a beneficial effect on inflammatory symptoms of TAO and laboratory parameters and suggested to use as an additive therapy, however, further comparative studies are required for final evaluation of Ptx in the treatment of TAO.

Adjuvants, Immunologic↗
PubMed1997

High circulating IL-6 level in Graves' ophthalmopathy.

IL-6 is a paracrine and autocrine cytokine, which acts in the regulation of immunological and inflammatory processes. Its production can be observed in different cell types, as well as thyrocytes. The purpose of the study was to examine the serum IL-6 levels between the patients with Graves' disease (N = 47) and without (N = 29) ophthalmopathy in respect of the presence of inflammatory eye signs and thyroiditis, thyroid function and radioiodine or medical treatments. The serum IL-6 levels were greater (P < 0.025) in the patients with ophthalmopathy (440 +/- 32.4 pg/ml) than in those without eye disease (81.6 +/- 25.2 pg/ml). An elevated serum IL-6 levels could be detected in 22 out of 47 patients with ophthalmopathy with longer manifestation of thyroid disease than one year in comparison with those who had shorter (694 +/- 35.3 pg/ml vs 215.8 +/- 27.9 pg/ml, P < 0.05). The increase showed a strong association with the inflammatory signs of eye disease in the patients with Graves' hyperthyroidism compared with those without ophthalmopathy (513.3 +/- 33.7 pg/ml vs 96.9 +/- 12.1 pg/ml, P < 0.025). Euthyroid function and the presence of thyroiditis did not influence the serum IL-6 levels. Radioiodine and medical treatments did not lead to a remarkable decrease in the serum IL-6 levels. The results supported that IL-6 cytokine may be an important factor in the inflammatory events of Graves' ophthalmopathy.

Adolescent↗
PubMed1997

Effect of anti-thyroid peroxidase (TPO) antibodies on TPO activity measured by chemiluminescence assay.

A chemiluminescence method was developed to measure thyroid peroxidase (TPO) activity and the inhibitory effect of anti-TPO antibodies in purified porcine TPO. The TPO preparation was characterized kinetically and controlled by Western-blotting technique. The chemiluminescence method proved to be reproducible and much more sensitive than the widely used guaiacol method, being able to detect TPO concentrations of 2.21 x 10(-5) g/L vs 6.63 x 10(-2) g/L with the latter. Otherwise, the determinations with the two methods correlated well (r = 0.76). Investigating the effect of IgGs from 23 hypothyroid patients on measured TPO activity, we detected inhibition in 19 cases with the chemiluminescence technique (15 with the guaiacol method). Anti-TPO antibodies showed competitive inhibition of TPO activity with respect to the substrate guaiacol. In both systems, the inhibition is present in the IgG F(ab')2 fragment. We conclude that the high sensitivity of chemiluminescence detection allows routine determination of the inhibition of TPO activity by anti-TPO antibodies.

Animals↗
PubMed1996

Detectable serum IgE levels in Graves' ophthalmopathy.

Graves' ophthalmopathy is an organ-specific autoimmune disorder in which the target organs are infiltrated by T lymphocytes and polymorphonuclear neutrophils that release immunoregulatory cytokines in the thyroid and retrobulbar tissues. Th2-type cytokines (IL-4, IL-5, IL-6) support the inflammatory symptoms and immunoglobulin production, e.g. IgE isotype. IgE is thought to play a part not only in allergy but also in the normal immune responses, antigen processing and presentation. Since studies report IgE accumulation around the extraocular muscles in ophthalmopathy and a correlation between the total IgE levels and the severity of ophthalmopathy in Graves' disease, we measured the total IgE levels in 56 patients with Graves' disease (associated with ophthalmopathy in 47 patients) and in 42 healthy subjects as controls to determine if IgE plays a part in the autoimmune or the local inflammatory processes. For detection we used the Enzymun-Test IgE, which was a two-step ELISA sandwich assay. Elevated circulating IgE levels could be demonstrated in non-treated hyperthyroid Graves' patients in comparison with the controls (51.02 +/- 113.16 IU/ml vs 34.95 +/- 54.91 IU/ml, P < 0.01). The IgE levels were higher in patients with active inflammatory eye signs (63.65 +/- 130.41 IU/ml) than in controls (P < 0.007). The anti-thyroid drug and glucocorticoid management decreased the total IgE levels, and the difference was significant after the treatment compared with the values at the beginning of the therapy in the Graves' patients without ophthalmopathy (17.34 +/- 6.34 IU/ml vs 13.01 +/- 9.86 IU/ml, P < 0.03). In conclusion, since the results suggested that IgE plays a role in the inflammatory eye signs in Graves' ophthalmopathy, we propose administering antihistamines for medical management.

Adult↗
PubMed1996

Organisation of the biosynthetic gene cluster for rapamycin in Streptomyces hygroscopicus: analysis of genes flanking the polyketide synthase.

Analysis of the gene cluster from Streptomyces hygroscopicus that governs the biosynthesis of the polyketide immuno-suppressant rapamycin (Rp) has revealed that it contains three exceptionally large open reading frames (ORFs) encoding the modular polyketide synthase (PKS). Between two of these lies a fourth gene (rapP) encoding a pipecolate-incorporating enzyme that probably also catalyzes closure of the macrolide ring. On either side of these very large genes are ranged a total of 22 further ORFs before the limits of the cluster are reached, as judged by the identification of genes clearly encoding unrelated activities. Several of these ORFs appear to encode enzymes that would be required for Rp biosynthesis. These include two cytochrome P-450 monooxygenases (P450s), designated RapJ and RapN, an associated ferredoxin (Fd) RapO, and three potential SAM-dependent O-methyltransferases (MTases), RapI, RapM and RapQ. All of these are likely to be involved in 'late' modification of the macrocycle. The cluster also contains a novel gene (rapL) whose product is proposed to catalyze the formation of the Rp precursor, L-pipecolate, through the cyclodeamination of L-lysine. Adjacent genes have putative roles in Rp regulation and export. The codon usage of the PKS biosynthetic genes is markedly different from that of the flanking genes of the cluster.

Amino Acid Sequence↗
PubMed1996

Organization of the biosynthetic gene cluster for rapamycin in Streptomyces hygroscopicus: analysis of the enzymatic domains in the modular polyketide synthase.

The three giant multifunctional polypeptides of the rapamycin (Rp)-producing polyketide synthase (RAPS1, RAPS2 and RAPS3) have recently been shown to contain 14 separate sets, or modules, of enzyme activities, each module catalysing a specific round of polyketide chain extension. Detailed sequence comparison between these protein modules has allowed further characterisation of aa that may be important in catalysis or specificity. The acyl-carrier protein (ACP), beta-ketoacyl-ACP synthase (KS) and acyltransferase (AT) domains (the core domains) have an extremely high degree of mutual sequence homology. The KS domains in particular are almost perfect repeats over their entire length. Module 14 shows the least homology and is unique in possessing only core domains. The enoyl reductase (ER), beta-ketoacyl-ACP reductase (KR) and dehydratase (DH) domains are present even in certain modules where they are not apparently required. Four DH domains can be recognised as inactive by characteristic deletions in active site sequences, but for two others, and for KR and ER in module 3, the sequence is not distinguishable from that of active counterparts in other modules. The N terminus of RAPS1 contains a novel coenzyme A ligase (CL) domain that activates and attaches the shikimate-derived starter unit, and an ER activity that may modify the starter unit after attachment. The sequence comparison has revealed the surprisingly high sequence similarity between inter-domain 'linker' regions, and also a potential amphipathic helix at the N terminus of each multienzyme subunit which may promote dimerisation into active species.

Amino Acid Sequence↗
PubMed1995

The adaptive advantage of phenotypic memory in changing environments.

The adaptive value of carry-over effects, the persistence of induced phenotypes for several generations despite the change in the conditions that first induced these phenotypes, is studied in the framework of a simple model. Three different organismal strategies-non-inducible (genetic), completely inducible (plastic), and intermediate (carry-over)-are compared in fitness terms within three different environments. Analytical results and numerical simulations show that carry-over effects can have an advantage in stochastic environments even over organisms with high adaptive plasticity. We argue that carry-over effects represent an adaptive mechanism on the ecological timescale that fills the gap between short-term individual adaptations and long-term evolutionary adaptations. An extension of the concept of plasticity to incorporate the time dimension and include the stability of induced phenotypes through both clonal and sexual generations, is suggested.

Adaptation, Biological↗
PubMed1995

Divergent sequence motifs correlated with the substrate specificity of (methyl)malonyl-CoA:acyl carrier protein transacylase domains in modular polyketide synthases.

The amino acid sequences of a large number of polyketide synthase domains that catalyse the transacylation of either methylmalonyl-CoA or malonyl-CoA onto acyl carrier protein (ACP) have been compared. Regions were identified in which the acyltransferase sequences diverged according to whether they were specific for malonyl-CoA or methylmalonyl-CoA. These differences are sufficiently clear to allow unambiguous assignment of newly-sequenced acyltransferase domains in modular polyketide synthases. Comparison with the recently-determined structure of the malonyltransferase from Escherichia coli fatty acid synthase showed that the divergent region thus identified lies near the acyltransferase active site, though not close enough to make direct contact with bound substrate.

Acyl Carrier Protein↗
PubMed1995

The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin.

The macrocyclic polyketides rapamycin and FK506 are potent immunosuppressants that prevent T-cell proliferation through specific binding to intracellular protein receptors (immunophilins). The cloning and specific alteration of the biosynthetic genes for these polyketides might allow the biosynthesis of clinically valuable analogues. We report here that three clustered polyketide synthase genes responsible for rapamycin biosynthesis in Streptomyces hygroscopicus together encode 14 homologous sets of enzyme activities (modules), each catalyzing a specific round of chain elongation. An adjacent gene encodes a pipecolate-incorporating enzyme, which completes the macrocycle. The total of 70 constituent active sites makes this the most complex multienzyme system identified so far. The DNA region sequenced (107.3 kbp) contains 24 additional open reading frames, some of which code for proteins governing other key steps in rapamycin biosynthesis.

Acyltransferases↗
PubMed1995

Secretory overproduction of Arthrobacter simplex 3-ketosteroid delta 1-dehydrogenase by Streptomyces lividans with a multi-copy shuttle vector.

The gene for 3-ketosteroid delta 1-dehydrogenase (ksdD) of Arthrobacter simplex was expressed in Streptomyces lividans and the secreted enzyme was overproduced by using a multi-copy shuttle vector composed of pIJ702 and pUC19. Deletional analysis of the recombinant plasmid showed that the entire coding sequence of the ksdD gene was located within a 7-kb segment of the chromosomal DNA obtained from the enzyme-producing strain of A. simplex. When S. lividans carrying the recombinant plasmid was grown in an appropriate medium, the cells produced about 100-fold more 3-ketosteroid delta 1-dehydrogenase than the original strain. Although the percentage of enzyme secreted was changed during cultivation, a maximum 55% of the enzyme was secreted into the cultured medium of S. lividans, while A. simplex did not produce the enzyme extracellularly. Secretory overproduction of 3-ketosteroid delta 1-dehydrogenase in S. lividans was also identified by sodium dodecyl sulfate/polyacrylamide gel electrophoresis and on native gel, and the enzyme reaction was confirmed by reverse-phase HPLC using 4-androstene-3,17-dione as a substrate.

Androstadienes↗
PubMed1995

IgA autoantibodies against human eye muscle antigen detected by western blotting and immunohistochemical methods in Graves' disease.

The presence of IgA autoantibodies against human eye muscle was investigated in 40 patients with Graves' disease (33 had ophthalmopathy). IgA anti-eye muscle antibodies could be demonstrated in sera of patients using western blotting and immunohistochemical methods. For the detection of sera possessing autoantibodies against eye muscle antigen the indirect immunosorbent assay had been used. IgA anti-eye muscle antibodies could be demonstrated in 25 cases and IgG types in 16 cases out of 40 patients. These anti-muscle autoantibodies were associated with eye muscle rather than skeletal muscle, the number of positive cases with the latter being 5/40 for IgG and 2/40 for IgA. Immunoreactive bands of IgA autoantibodies against eye cytosol were found at 84, 64, 45, 40 and 25-23 kDa in 22, 2, 16, 2 and 18 cases, respectively. A difference was observed in the staining of IgG and IgA types of autoantibodies by immunohistochemical analysis of eye muscle tissue. The IgA anti-eye muscle antibodies reacted with muscle fibers and the IgG types showed staining on endomysium. No sera of Graves' disease patients gave staining on skeletal muscle tissue. The results supported the presence of IgA anti-human eye muscle antibodies in patients with Graves' ophthalmopathy, which might play a relevant role in the development of eye disease.

Adult↗