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Biomedical subjects

M Bilban

Publications and source records attributed to M Bilban.

At least 19 recordsLinked to original sources
PubMed2006

Prevention of high-fat diet-induced adipose tissue remodeling in obese diabetic mice by n-3 polyunsaturated fatty acids.

OBJECTIVE: Obesity is associated with reduced insulin sensitivity and extensive reorganization of adipose tissue. As polyunsaturated fatty acids (PUFA) appear to inhibit diabetes development, we investigated PUFA effects on markers of matrix remodeling in white adipose tissue. METHODS AND PROCEDURE: Male obese diabetic (db/db) mice were treated with either a low-fat standard diet (LF), or high-fat diets rich in saturated and monounsaturated fatty acids (HF/S), n-6 PUFA (HF/6) or the latter including marine n-3 PUFA (HF/3). White adipose tissue was analyzed for gene expression, fatty acid composition and by immunofluorescence. RESULTS: HF/S treatment increased adipose tissue expression of a number of genes involved in matrix degradation including matrix metalloproteinase (MMP)-12, -14 and cathepsin K, L and S compared with LF. MMP-12 gene was expressed in macrophages and adipocytes, and MMP-12 protein colocalized with both cell types. In addition, mean adipocyte area increased by 1.6-fold in HF/S-treated mice. Genes essential for collagen production, such as procollagen I, III, VI, tenascin C and biglycan were upregulated in HF/S-treated animals as well. N-3 PUFA supplementation resulted in enrichment of these fatty acids in adipose tissue. Moreover, n-3 PUFA inhibited the HF/S-induced upregulation of genes involved in matrix degradation and production I restored mean adipocyte area and prevented MMP-12 expression in macrophages and adipocytes. CONCLUSION: N-3 PUFA prevent high-fat diet-induced matrix remodeling and adipocyte enlargement in adipose tissue of obese diabetic mice. Such changes could contribute to diabetes prevention by n-3 PUFA in obese patients.

Adipocytes↗
PubMed2006

Adipose tissue inflammation induced by high-fat diet in obese diabetic mice is prevented by n-3 polyunsaturated fatty acids.

AIMS/HYPOTHESIS: Inflammatory alterations in white adipose tissue appear to underlie complications of obesity including diabetes mellitus. Polyunsaturated fatty acids (PUFA), particularly those of the n-3 series, modulate immune responses and may ameliorate insulin sensitivity. In this study, we investigated how PUFA affect white adipose tissue inflammation and gene expression in obese diabetic animals. MATERIALS AND METHODS: We treated db/db mice as well as lean non-diabetic mice (db/+) with either low-fat standard diet (LF) or high-fat diets rich in (1) saturated/monounsaturated fatty acids (HF/S), (2) n-6 PUFA (HF/6) and (3) the latter including purified marine n-3 PUFA (HF/3). RESULTS: Many genes involved in inflammatory alterations were upregulated in db/db mice on HF/S compared with LF in parallel with phosphorylation of c-Jun N-terminal kinase (JNK). In parallel, adipose tissue infiltration with macrophages was markedly enhanced by HF/S. When compared with HF/S, HF/6 showed only marginal effects on adipose tissue inflammation. However, inclusion of n-3 PUFA in the diet (HF/3) completely prevented macrophage infiltration induced by high-fat diet and changes in inflammatory gene expression, also tending to reduce JNK phosphorylation (p<0.1) in diabetic mice despite unreduced body weight. Moreover, high-fat diets (HF/S, HF/6) downregulated expression and reduced serum concentrations of adiponectin, but this was not the case with n-3 PUFA. CONCLUSIONS/INTERPRETATION: n-3 PUFA prevent adipose tissue inflammation induced by high-fat diet in obese diabetic mice, thereby dissecting obesity from adipose tissue inflammation. These data suggest that beneficial effects of n-3 PUFA on diabetes development could be mediated by their effect on adipose tissue inflammation.

Adiponectin↗
PubMed2006

Deregulated expression of fat and muscle genes in B-cell chronic lymphocytic leukemia with high lipoprotein lipase expression.

Lipoprotein lipase (LPL) is a prognostic marker in B-cell chronic lymphocytic leukemia (B-CLL) related to immunoglobulin V(H) gene (IgV(H))mutational status. We determined gene expression profiles using Affymetrix U133A GeneChips in two groups of B-CLLs selected for either high ('LPL+', n=10) or low ('LPL-', n=10) LPL mRNA expression. Selected genes were verified by real-time PCR in an extended patient cohort (n=42). A total of 111 genes discriminated LPL+ from LPL- B-CLLs. Of these, the top three genes associated with time to first treatment were Septin10, DMD and Gravin (P</=0.01). The relationship of LPL+ and LPL- B-CLL gene expression signatures to 52 tissues was statistically analyzed. The LPL+ B-CLL expression signature, represented by 64 genes was significantly related to fat, muscle and PB dendritic cells (P<0.001). Exploration of microarray data to define functional alterations related to the biology of LPL+ CLL identified two functional modules, fatty acid degradation and MTA3 signaling, as being altered with higher statistical significance. Our data show that LPL+ B-CLL cells have not only acquired gene expression changes in fat and muscle-associated genes but also in functional pathways related to fatty acid degradation and signaling which may ultimately influence CLL biology and clinical outcome.

Cohort Studies↗
PubMed2005

Identification of DLK1 variants in pituitary- and neuroendocrine tumors.

In a gene chip analysis of common pituitary tumor types, one of the genes with the most impressive tissue-specific expression regulation was delta-like 1 (DLK1), which was strongly expressed in GH-secreting (GH-S) pituitary tumors. In addition to pituitary adenomas, various endocrine tumors were subjected to real-time-quantitative PCR revealing high expression of DLK1 in normal pituitary tissue, in GH-S-, in one prolactin-secreting pituitary adenoma and in pheochromocytomas. Additionally, three DLK1 gene-derived subvariants were identified. The first, lacking 204 bp--coding for epidermal growth factor-like domain 6 and parts of the juxtamembrane region--was named Secredeltin. In the other two splice variants (named Brevideltin and Brevideltinin), a stop codon is introduced due to a frame-shift, leading to truncated proteins of 204 and 213 aas, respectively.

Alternative Splicing↗
PubMed2005

Insulin control of placental gene expression shifts from mother to foetus over the course of pregnancy.

AIMS/HYPOTHESIS: The human placenta is a complex organ situated at the interface between mother and foetus that separates maternal from foetal blood. The placental surfaces exposed to the two bloodstreams are different, i.e. trophoblasts and endothelial cells are in contact with the maternal and foetal circulation, respectively. Both cell types produce high insulin receptor levels. The aim of the present study was to test the hypothesis that spatio-temporal changes in insulin receptor expression in trophoblasts from first trimester to the endothelium at term shift the control of insulin-dependent processes from mother to foetus. METHODS: Global microarray analysis of primary trophoblasts from first trimester and term human placentas and endothelial cells from term human placentas cultured under hyperinsulinaemic and control conditions identified different sets of regulated genes in trophoblasts and endothelial cells. RESULTS: Insulin effects on placental gene expression underwent developmental changes from trophoblasts in the first trimester to endothelial cells at term that were paralleled by changes in levels of activated insulin receptors. The changes in gene regulation were both quantitative (i.e. magnitude of effect) and qualitative (i.e. specific genes affected and direction of regulation). CONCLUSIONS/INTERPRETATION: This spatio-temporal shift in insulin sensitivity throughout pregnancy allows maternal and foetal insulin to regulate different processes within the placenta at different gestational stages, facilitated by compartmentalisation of the insulin response. Thus, by altering the levels and function of insulin receptors in space and time, control of insulin-dependent processes in the human placenta will change from mother to foetus throughout gestation. This will be of particular interest in conditions associated with altered maternal or foetal insulin levels, i.e. diabetes mellitus or intrauterine growth restriction.

Blood Circulation↗
PubMed2005

Cytogenetic tests performed on operating room personnel (the use of anaesthetic gases).

OBJECTIVES: Personnel exposure to anaesthetic gases in the health sector, whether in the operating room, recovery room, or in the context of outpatient clinics, may entail a health risk. The goal of this research was to study the cytogenetic effects of chronic exposure to small doses of pollutants in operating theatres. METHODS: Results of cytogenetic analyses [structural chromosomal aberrations (SCAs), sister chromatid exchange (SCE) and micronucleus (MN) test] of anaesthetists and other personnel handling anaesthetic gases, who only occasionally work in zones of ionizing radiation, were compared with results from radiologists, occupationally exposed to ionizing radiation only, and with the results obtained from a group of Slovene citizens who were never exposed to genotoxic agents. RESULTS: This study involved 153 workers handling anaesthetic gases. The average frequency of SCAs in the group working with anaesthesia was 2.693. The result was statistically significantly higher than in the group of radiologists and Slovene citizens. The frequency of SCE and MN was also statistically significant. A number of authors, who used the same cytogenetic tests, found similar results in the group of anaesthetist. CONCLUSION: The results of our study indicate that exposure to anaesthetic gases induced changes in human chromosomes.

Adult↗
PubMed2005

Harmful alcohol use of those who died a violent death (the extended region of Ljubljana 1995-1999).

Consumption of alcohol increases the risk of dying a violent death. We wanted to establish a connection between harmful alcohol use and dying a violent death. We analyzed all such victims in the extended region of Ljubljana. The research included 1630 deceased, who were autopsied at the Forensic Institute of the Ljubljana, Faculty of Medicine in the period from 1995 to 1999. Presence of alcohol was established in 76.3% of the cases. From all included in the research, 38.2% of all work accident victims, 28.8% of all murder victims, 25.4% of suicides, 24.6% of victims involved in traffic accidents and 19.3% of those who died in accidents at home. 23.2% of all violent death victims had a concentration of alcohol above 1.5 g/kg; among those, victims of traffic accidents, suicides and accidents at home represent the largest part. The lowest values of alcohol in blood were found in those who died because of accidents at work. The highest values were found in males aged 35-44. The research confirmed that consumption of alcohol in Slovenia was strongly connected to violent deaths. The blood levels of alcohol of the victims are distinctively higher where there are practically no limitations of alcohol consumption and lower in the environment or activities where legal restrictions prohibit or at least explicitly limit harmful use of alcohol (working environment).

Accidents↗
PubMed2005

Presence of alcohol in suicide victims.

A number of studies have established a strong connection between acute inebriation, alcohol addiction and suicides, as the last act of alcoholism or an act of desperation in an alcoholic's family, an act of escape from restraints in state of depression or as a way of self-destruction. In recent years in average 600 people per year committed suicide. Slovenia is a country with extremely high and variable suicide tendencies and harmful alcohol use levels, as well as a high level of alcohol-related troubles. The aim of our research was to ascertain some typical features, especially those connected to the inebriation of suicide victims from a wider Ljubljana region. Autopsies were carried out on the victims in the period between 1995 and 1999. There were 508 (31.2%) suicides among all the analyzed violent deaths; 73.2% of them were men. The average age of the victims was 46.5 years. Most suicides were committed at home (50.0%). 25.4% were completely sober in the moment of the act, while in all other cases inebriation was established, the average value being 9.57 g/kg. Men were drunk in 87.1% of cases, women only in 12.9% and the given alcohol levels were substantially higher with men (0.65:0.26 g/kg). The share of inebriated persons decreases with age-reaching its peak in the 35-54 age group. Regarding the method, the predominant ones are intoxication and the use of firearms, which is a typical way of committing suicide among men, while women rather choose jumping from great heights and drowning. Alcohol was present in as many as 55.7% of suicides with intoxication and in 68.8% of all suicides committed by using firearms, while the highest alcohol levels were found in those who died from cutting their veins (2.01 g/kg). Based on this and on other research, more effort should be focused on alcohol abuse prevention, making all people aware of the consequences of alcohol abuse, the possibilities of treatment and their availability as well as possible co-morbid depressions. Simultaneously, due to an established link, the national alcohol policy and strategy for prevention of suicides should be professionally harmonized.

Adult↗
PubMed2002

Defining signal thresholds in DNA microarrays: exemplary application for invasive cancer.

BACKGROUND: Genome-wide or application-targeted microarrays containing a subset of genes of interest have become widely used as a research tool with the prospect of diagnostic application. Intrinsic variability of microarray measurements poses a major problem in defining signal thresholds for absent/present or differentially expressed genes. Most strategies have used fold-change threshold values, but variability at low signal intensities may invalidate this approach and it does not provide information about false-positives and false negatives. RESULTS: We introduce a method to filter false-positives and false-negatives from DNA microarray experiments. This is achieved by evaluating a set of positive and negative controls by receiver operating characteristic (ROC) analysis. As an advantage of this approach, users may define thresholds on the basis of sensitivity and specificity considerations. The area under the ROC curve allows quality control of microarray hybridizations. This method has been applied to custom made microarrays developed for the analysis of invasive melanoma derived tumor cells. It demonstrated that ROC analysis yields a threshold with reduced missclassified genes in microarray experiments. CONCLUSIONS: Provided that a set of appropriate positive and negative controls is included on the microarray, ROC analysis obviates the inherent problem of arbitrarily selecting threshold levels in microarray experiments. The proposed method is applicable to both custom made and commercially available DNA microarrays and will help to improve the reliability of predictions from DNA microarray experiments.

Journal Article↗
PubMed2002

Methadone maintenance treatment and drugs.

The mental and physical capabilities of drivers in traffic are often seriously challenged these days. Not only do they need to concentrate on driving, predict connections between various phenomena, take appropriate judgements in current situations and foresee the sequence of measures to be taken, but they are also expected to be emotionally stable, etc. The problem with drugs in traffic is often encountered when assessing the actual safe driving capability of a person in a given moment, for example after a car accident or a police check, or medical check-ups that are required for a driving license. The Road Traffic Safety Law considers methadone a drug. Drug addicts do not meet the health standards required of drivers. This research program deals with the attitude of drivers who are in methadone maintenance treatment programs with respect to the driving ability as well as the effects of methadone use in combination with other drugs on driving. It has been established that drivers undergoing the methadone maintenance program, regularly drive not only under the influence of methadone but also under the influence of marijuana (20%) and heroin (18%) and sometimes under the influence of marijuana (58.6%), heroin (55.7%), and alcohol (48.6%). Certain initiatives have been taken by some therapists to give, under certain circumstances, a clean bill of health to responsible methadone maintenance patients who have an adequate level of responsibility for themselves and their deeds, in order to help them obtain a driving license. Since it has been established that methadone maintenance patients use methadone quite commonly in combination with illegal drugs and/or alcohol, the classification of this type of addicts among possible driving candidates remains disputable. Long term interdisciplinary research is still required to determine the basic principles required to asses and possibly admit this type of drivers to participate in traffic, as well as to determine which professional therapists can participate and evaluate the driving capabilities of these patients.

Adolescent↗
PubMed2001

Genotoxic effects of radiotherapy and chemotherapy on circulating lymphocytes in patients with Hodgkin's disease.

PURPOSE: The aim of this study was to find out the structural chromosomal changes in somatic cells after chemotherapy (CT) with or without radiotherapy (RT). METHODS AND MATERIALS: This prospective study included 30 Hodgkin's disease (HD) patients. The patients of Group I(1) had only MOPP/ABV CT. The patients of Group II(2) also had irradiation. Group III(3) (control group) consisted of healthy subjects without any reported malignant disease. Mutagenetic testing was performed at the time of diagnosis and was repeated immediately after treatment and again 6 months later. The following tests were applied: structural chromosomal aberrations (CA), sister chromatid exchange (SCE) and micronucleus (MN) tests. RESULTS: Prior to treatment, the chromosome damage in our patients was not higher than that in the control group. Immediately after the complete treatment, we observed a strong inhibition of the mitotic activity of lymphocytes as well as a significant increase in the frequency of CA, MN and SCE in the Groups I and II. In patients treated by RT, we found statistically significant differences between the Groups I and II in MN (P<0.005) and CA frequencies (P<0.005), and an increased number of dicentrics (P=0.021). Six months after the complete treatment, the mitotic activity was found to be nearly normal, but chromosome damage occurred. CA and SCE values did not differ much from the values measured immediately after treatment, whereas MN values decreased without returning to the baseline levels. The chromosome damage persisted even 6 months after combined RT and CT. The damage in the genome of individual cells was in some cases even greater than immediately after treatment. The possible risk of neoplastic transformation posed by these heavily damaged cells, if viable, due to the changes in the expression of oncogenes or tumour suppresser genes, is discussed.

Adolescent↗
PubMed2001

Cooperative interactions of laminin 5 gamma2 chain, matrix metalloproteinase-2, and membrane type-1-matrix/metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma.

Vasculogenic mimicry describes a process where aggressive tumor cells in three-dimensional matrices mimic embryonic vasculogenesis by forming extracellular matrix (ECM)-rich, patterned tubular networks. Microarray gene chip analyses revealed significant increases in the expression of laminin 5 (Ln-5, gamma2 chain) and matrix metalloproteinases (MMP)-1, -2, -9, and MT1-MMP (MMP-14) in aggressive compared with poorly aggressive melanoma cells. These components colocalized with developing patterned networks and antisense oligonucleotides to the Ln-5 gamma2 chain (but not sense oligonucleotides), and antibodies to MMP-2 or MT1-MMP (but not MMP-9) inhibited the formation of these networks. Cultures which did not receive antibodies to either MMPs-2 or -14 contained the Ln-5 gamma2 chain promigratory cleavage fragments. Poorly aggressive melanoma cells seeded on collagen I matrices preconditioned by the aggressive cells formed tubular networks along the Ln-5 gamma2 chain-enriched tracks deposited by the aggressive cells. These results suggest that increased expression of MMP-2 and MT1-MMP, along with matrix deposition of the Ln-5 gamma2 chain and/or its cleavage fragments, are required for vasculogenic mimicry by aggressive melanoma cells. Furthermore, the apparent recapitulation of laminin-rich, patterned networks observed in aggressive melanoma patients' tissue sections by aggressive melanoma tumor cells in three-dimensional culture may also serve as a model to help identify specific molecular targets which could function as templates for the coordinated migration of aggressive tumor cells and their proteolytic remodeling of the ECM and may have profound implications for the development of novel therapies directed at the ECM to alter tumor progression.

Cell Adhesion Molecules↗
PubMed2001

Chromosome aberrations study of pupils in high radon level elementary school.

The ICRP Publication 65 recommends 200-600 Bq x m(-3) as the indoor radon action level for the general public. In Slovenia, a value of 400 Bq x m(-3) has been proposed but not yet approved. In a nation-wide radon project financed by the Health Inspectorate of Slovenia, it was discovered that the elementary school named "S3" belongs to a group of schools with elevated winter indoor radon concentrations up to 7,000 Bq x m(-3). Opening windows and doors during classes substantially decreased radon concentrations, but very seldom below 1,000 Bq x m(-3). Yearly effective doses for pupils, estimated according to ICRP 65, ranged from 7 to 11 mSv. Because the pupils have been subjected to the elevated radon concentrations, special preventive health checks have been performed. The examination protocol included mutagenetic tests, one for structural chromosomal aberrations and the other a micronucleus test. Altogether 85 pupils (37 girls and 48 boys) from the first four grades between the ages of 9 and 12 y were examined. An increase in cytogenetic damage was found for these pupils, compared to the control group, composed of pupils of the same age from another area with indoor radon concentrations in their school of below 400 Bq x m(-3). The incidence of structural chromosomal aberrations reached 2.0% (0.5-4) and micronucleus test was 6.52 per 500 cells with a maximum of 15 in some cases. In the control group structural chromosomal aberrations varied from 0.5 to 2.5%, while the maximum incidence of micronucleus was 9 micronucleus per 500 CB cells. The results obtained are preliminary and suggest a need to expand the study. A long-term radon survey, at least over a year, of the homes and wider residential environment of the pupils would be necessary to assess the correlation between radon exposure and both structural chromosomal aberrations and micronucleus findings.

Air Pollution, Indoor↗
PubMed2001

Location and incidence of chromosome and chromatid breaks in patients with Hodgkin's disease or testicular tumors.

In 90 patients aged 17 to 35 who suffered from Hodgkin's disease (HD) or had testicular tumors (TT), the location of chromosome and chromatid breaks on individual chromosome segments was reviewed using an adapted Funes-Cravioto scheme, in addition to examining the percentage of structural chromosomal aberrations. On the basis of an analysis of 1121 breaks in patients with HD or TT, the results were presented graphically as multiples of the expected number of breaks for the normal population. Before the beginning of treatment, the number of structural chromosomal aberrations (SCA) in patients with TT or HD was equal to that in a control group of subjects with malignant diseases. This, however, does not apply to the location of chromosome and chromatid breaks. In patients with HD, the dominant unstable sites are located on group A2 chromosomes, segments 2 and 5, and on group B chromosomes, segment 5. In patients with TT, the number of chromosome and chromatid breaks is also increased on group A2 chromosomes, segments 2 and 5, and in addition, also on group B chromosomes, segment 4.

Adolescent↗
PubMed2001

Incidence of chromosomal aberrations and micronuclei in cave tour guides.

An analysis of structural chromosomal aberrations (SCA) and micronucleus tests (MN) were performed in 38 subjects, cave tour guides and in appropriate control group. The dominant type of chromosomal aberrations in tourist guides were chromosomal breaks (0.013 per cell) and acentric fragments (0.011 per cell). In the control group, these aberrations were present up to 0.008 on cells. Considering the analysed cells of the guides in total (33,556), the incidence of dicentric and rings range is below 0.0008 on cells, even though three dicentric and ring chromosoms were found already in the first 1000 in vitro metaphases of some guides. Only 0.0003 dicentrics and neither other translocations were found in control group (ambiental exposure). The incidence of micronuclei in cytokinesis blocked lymphocytes ranged from 12-32 per 500 CB cells in the cave tour guides and from 4-11 per 500 CB cells in control group. Measurements of radon and its daughters were performed at different locations in the cave. Annual doses from 40-60 mSv were estimated per 2000 work hours for cave guides. The changes found in the genome of somatic cells may be related to the exposure doses of radon and its daughters, although smoking should not be ignored.

Cells, Cultured↗
PubMed2000

Differential regulation of endothelin secretion and endothelin receptor mRNA levels in JAR, JEG-3, and BeWo choriocarcinoma cell lines and in human trophoblasts, their nonmalignant counterpart.

Endothelin (ET) secretion and expression of both ET-A and ET-B receptor subtypes have been found in a number of primary cancers. The present study tested (1) whether choriocarcinoma cells and their nonmalignant counterpart, the trophoblast, secrete ET-1 and express ET-A and ET-B receptors; (2) whether ET-1 secretion and receptor mRNA levels are regulated by the same factors in nonvascular tissues as in vascular tissues; and (3) whether such regulation is similar in malignant and nonmalignant cells. All cells secreted ET-1 in similar amounts (approximately 0.8 fmol/10(6) cells per 24 h) and secretion was unaffected by culture and treatment. Whereas ET-B accounted for almost all (>98%) ET receptor transcripts in the choriocarcinoma cells, the trophoblasts expressed about 20% ET-A receptor mRNA. During control cultures, ET-B mRNA levels rose in choriocarcinoma, with the greatest relative increase (6-fold; P < 0.05 vs 0 h) in BeWo, whereas in trophoblasts, ET-A mRNA transiently changed after 24 and 48 h. Treatment with dexamethasone and glucose did not alter the mRNA levels in all cells. Insulin induced changes (P < 0.05) in ET-B mRNA levels in BeWo (+90 and +60% after 24 and 48 h, respectively) and JEG-3 (-70%), but not in JAR and trophoblast cells. We conclude that malignant transformation affects the responsiveness of the endothelin receptor system to external stimuli and that the regulation of the endothelin system differs in vascular and nonvascular tissues.

Base Sequence↗
PubMed2000

New fluorogenic substrate for the first continuous steroid sulfatase assay.

The screening for new inhibitors of steroid sulfatase requires an efficient test system. To overcome the shortcomings of the available discontinuous fluorimetric assay, several coumarin-type compounds were investigated as potential new substrates. 3,4-Benzocoumarin 7-O-sulfate was found to have appropriate substrate properties for the establishment of the first direct continuous assay of steroid sulfatase.

Arylsulfatases↗