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Biomedical subjects

J Forejt

Publications and source records attributed to J Forejt.

At least 19 recordsLinked to original sources
PubMed2004

Life-threatening renal failure caused by vasomotor nephropathy associated with nonsteroidal anti-inflammatory drugs.

The purpose of this study was to evaluate the prevalence of life-threatening renal failure (RF) caused by vasomotor nephropathy associated with nonsteroidal anti-inflammatory drug (NSAID) treatment (NSAID-RF) and risk factors for this renal impairment in an inception cohort of patients with recently diagnosed uremia treated by emergency hemodialysis in a prospective regional study. There are few published data on this phenomenon. Two hundred fifty-six patients (137 men, 119 women, mean age 68 years [22-95 years]) with acute uremia were treated with emergency hemodialysis in the intensive care unit over a period of 70 months. The patients were from an area of 231,000 inhabitants. Of the 256 patients, clinical data from a group of 79 patients with medical-type renal failure were analyzed in detail. The prevalence of NSAID-RF was 8%. This prevalence decreased to 4% when patients without any other medication affecting compensatory renal hemodynamics were considered. Moreover when nonpharmacological insults were not taken into account the prevalence decreased to only 1.6%. In 80% of the patients with NSAID-RF, nonpharmacological insults contributed to renal impairment. Both hypotension of cardiac etiology and dehydration/hypovolemia were present in 25% of the patients with this type of RF while urinary tract obstruction was seen in 1%. In 75% patients with NSAID-RF the underlying nephropathies were identified. NSAID-RF was not frequent. The population at greatest risk for renal functional alteration associated with NSAID therapy included patients with dehydration/hypovolemia, hypotension of cardiac etiology and those with pre-existing renal impairment, especially with vascular and analgesic nephropathy.

Acute Disease↗
PubMed2001

Expression profiles and intergenic structure of head-to-head oriented Brca1 and Nbr1 genes.

Mouse and human Brca1/BRCA1 and Nbr1/NBR2 genes lie head-to-head, being transcribed from the opposite strands. The normal function of Brca1 is associated with DNA damage-related responses and the maintenance of genome integrity. Mutations of this gene are major risk factors for developing breast and ovarian cancers. The function of Nbr1 is unknown. Here we analyzed expression profiles of Brca1 and a newly identified, evolutionary conserved isoform of Nbr1(1a) transcript. In adult testis, the Nbr1(1a) mRNA showed an 18-fold higher steady-state level than the ubiquitous Nbr1(1b) form and its expression was confined mainly to spermatids. The expression profile of Brca1 paralleled that of Nbr1(1b). The Nbr1(1a) mRNA was not significantly expressed in normal somatic tissues, but was found on a list of cDNA clones from a human myeloblast cell line. The newly defined intergenic region (289 bp) between Nbr1 and Brca1 in the mouse and rat corresponds well to that of human BRCA1-NBR2 region.

Animals↗
PubMed2001

Synteny of orthologous genes conserved in mammals, snake, fly, nematode, and fission yeast.

Four mouse genes, programmed cell death 2 (Pdcd2 or Rp8), brain protein 44-like (Brp441), bystin-like (Bysl), and uncoordinated-93-like (Unc931) genes were mapped to Chromosome (Chr) 17. The orthologs of these and other mouse Chr 17 genes are localized on Chr III of Caenorhabditis elegans, thus defining a syntenic group conserved between vertebrates and nonvertebrates. In human, mouse, and snake, the PDCD2-, and TATA-binding protein (TBP)-encoding genes are adjacent tail-to-tail. The TBP- and PDCD2-encoding genes are linked also in Drosophila, and, together with proteasomal subunit C5 gene, they are syntenic in human, mouse, C. elegans, and Schizosaccharomyces pombe. The orthologs of tightly linked C. elegans genes, coding for BRP44L and PDCD2, map to about 2-Mb interval on human region 6q27 and on mouse Chr 17. Hitherto, 13 members of synteny conserved between C. elegans and vertebrates have been detected, of which six are located on Drosophila Chr X. Such a distribution of transcription units is nonrandom and could indicate a long-range cis-acting relationship among the genes within the conserved syntenic group.

Animals↗
PubMed2001

Identification of a mutation in ADD1/SREBP-1 in the spontaneously hypertensive rat.

It has recently been proposed that primary mutations in genes involved in fatty acid and lipid metabolism may contribute to the pathogenesis of insulin resistance and dyslipidemia often observed in spontaneous forms of hypertension. In the current study in the spontaneously hypertensive rat (SHR), we mapped and sequenced the gene encoding a key transcription factor known as ADD1 (adipocyte determination and differentiation factor 1) or SREBP-1c (sterol regulatory element binding protein- c) that has recently been identified as a master regulator of genes involved in the hepatic control of lipid and carbohydrate metabolism. We found that (1) the gene for ADD1/SREBP-1c maps to a region of rat Chromosome 10 previously reported to contain a quantitative trait locus involved in the regulation of hepatic cholesterol levels and (2) the SHR harbors a valine-to-methionine substitution in the COOH terminal portion of the ADD1/SREBP-1 protein that is not present in 44 other strains of laboratory rats. These findings, together with previous studies showing that transgenic expression of SREBP-1 isoforms has major effects on hepatic fatty acid and cholesterol biosynthesis, suggest that naturally occurring variation in the gene encoding the SREBP-1 isoforms might contribute to inherited variation in lipid metabolism in the SHR versus other strains of rats. These results should serve to motivate future transfection studies of the effect of the SHR mutant on SREBP-1 expression and activation in vitro, as well as the development of congenic and transgenic strains of SHR to investigate the effects of different variants of SREBP-1 on carbohydrate and lipid metabolism in vivo.

Amino Acid Sequence↗
PubMed2001

Accumulation of the proteolytic marker peptide ubiquitin in the trophoblast of mammalian blastocysts.

Ubiquitination is a universal protein degradation pathway in which the molecules of 8.5-kDa proteolytic peptide ubiquitin are covalently attached to the epsilon-amino group of the substrate's lysine residues. Little is known about the importance of this highly conserved mechanism for protein recycling in mammalian gametogenesis and fertilization. The data obtained by the students and faculty of the international training course Window to the Zygote 2000 demonstrate the accumulation of ubiquitin-cross-reactive structures in the trophoblast, but not in the inner cell mass of the expanding bovine and mouse blastocysts. This observation suggests that a major burst of ubiquitin-dependent proteolysis occurs in the trophoblast of mammalian peri-implantation embryos. This event may be important for the success of blastocyst hatching, differentiation of embryonic stem cells into soma and germ line, and/or implantation in both naturally conceived and reconstructed mammalian embryos.

Animals↗
PubMed2001

Expression of BRCA1, NBR1 and NBR2 genes in human breast cancer cells.

BRCA1 is a tumour suppressor gene with a caretaker function in the DNA-damage repair and the maintenance of genome integrity. The human BRCA1 and NBR2 genes and the homologous Brcal and Nbr1 mouse genes are situated head-to-head on human chromosome 17q21 and on mouse chromosome 11, respectively. Their transcription start sites, located on opposite DNA strands, are separated by 218 bp in humans, and by 289 bp in mice. Because of this intimate contact and because of our previous observation of a quasi-reciprocal expression pattern of Brca1 and Nbr1 in mouse spermatogenesis, we estimated here the relative mRNA expression of BRCA1, NBR1 (next-to-BRCA1) and NBR2 genes in a panel of permanent cell lines and primary cell cultures derived from human breast cancer or normal mammary tissue. The analysis revealed highly significant downregulation of BRCA1 in 11 out of 12 examined tumour cell lines and primary cell cultures as compared to non-malignant mammary cells. Two isoforms of NBR1(1A) and the classical NBR1(1B) transcripts were found in cells from malignant mammary tissues, all of them downregulated in respect to normal cells. The expression of NBR2 differed, being increased in three permanent tumour cell lines and slightly decreased in all primary breast cancer cell cultures. The in silico analysis revealed two new putative domains of the predicted NBR1 protein, suggesting its role in the ubiquitin pathway. The recent identification of the ubiquitin protein ligase activity of BRCA1 implies a possible functional connection between both genes.

Alternative Splicing↗
PubMed2001

[Central salt-wasting diuresis syndrome as a cause of hyponatremia in patients at the internal medicine department].

Hyponatremia is a common electrolyte disorder related to central nervous system diseases and is often attributed to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and on the other hand to the cerebral salt wasting syndrome (CSWS). This syndrome is characterized by hyponatremia due to excessive renal sodium excretion resulting from a centrally mediated process. Given the divergent nature of the treatment it is of paramount importance for a clinician to be able to recognize and differentiate between these two entities. Thus the monitoring of renal function tests, which are needed for earlier diagnosis of effective osmolality disorders, is important to do in intensive care units, which are caring for patients with central nervous system lesons. Two patients successfully treated for CSW due to ischemic stroke caused by arterial embolism from heart cavities are described.

Aged↗
PubMed2001

[Pharmacologic insult as a cause of acute kidney failure with a need for acute hemodialysis therapy].

Acute renal failure is a heterogeneous disease. In advanced countries the incidence of acute renal failure is rising steadily in the elderly population. One of the serious causes of renal failure in this age group are pharmacological preparations and iodine radiocontrast diagnostic substances. It was revealed that also commonly used drugs may have a nephrotoxic potency in subjects with pre-existing renal disease and/or in certain clinical risk situations. In a group of 133 acutely haermodialyzed patients at the medical department we made a detailed clinical and economic analysis of treatment in a group of patients haemodialyzed on account of acute drug induced renal failure. These patients accounted for 28% of all acutely haemodialyzed patients and 65% of them were older than 65 years. The drugs which were involved as the cause or partial cause of renal failure had a negative effect on intrarenal haemodynamics. They comprised in the first place inhibitors of the angiotensin converting enzyme and non-steroid antirheumatic drugs, frequently in combination with diuretics or an iodine contrast substance. A risk factor was preexisting nephropathy defined by the presence of renal perfusion depending on increased formation of angiotensin II and renal vasodialatating prostaglandins. Risk is ascribed also to pathological conditions associated with systemic hypotension and a reduced effective circulating volume. Costs of treatment per patient with drug induced renal failure were calculated as 127,000 Czech crowns. The sum was calculated as the cost of the diagnosis related group.

Acute Kidney Injury↗
PubMed2000

PWD/Ph and PWK/Ph inbred mouse strains of Mus m. musculus subspecies--a valuable resource of phenotypic variations and genomic polymorphisms.

PWD/Ph and PWK/Ph (abbreviated PW*) are highly inbred mouse strains (F66 and F70) derived from wild mice of Mus musculus musculus subspecies. When compared with laboratory inbred strains, they display a plethora of differences in many complex phenotypes such as body weight, fat distribution pattern, blood levels of intermediary metabolites, sensitivity to type-1 diabetes or behaviour patterns. The PWD/Ph genes can rescue the lethal effect of lack of the Igf2 receptor. The male-limited hybrid sterility of (PWD/Ph x laboratory strain)F1 hybrids is a specific phenotype controlled by three or four unlinked loci. These complex phenotypic traits can be genetically dissected by QTL analysis using microsatellite markers of known genetic location. The PW strains are particularly useful for such genome-wide scans since 70-80% of randomly chosen microsatellite markers are polymorphic in (PW x laboratory strain) crosses compared to 35-45% in crosses between two laboratory strains. The list of polymorphic microsatellite loci is included in this report. The high degree of sequence polymorphism allows easier distinction between paternal and maternal mRNA transcripts in PW hybrids, which makes the PW* strains a useful tool also in molecular studies of genomic imprinting. The high frequency of phenotypic differences together with the high degree of sequence polymorphism and the relatively easy breeding of PW strains make them a valuable mammalian model organism for the functional genomics of the traits of biomedical importance.

Alleles↗
PubMed1999

Monoallelic expression of reactivated imprinted genes in embryonal carcinoma cell hybrids.

Though DNA methylation is necessary to maintain monoallelic expression of imprinted genes, it is still unclear whether it represents the primary mark. Here we ask whether the imprinting mark is still present in terminally differentiated somatic cells in which the transcription of embryo-specific imprinted genes was shut off. For such analysis H19 and Igf2 genes were activated by inducing differentiation of (mouse embryonal carcinoma cell x mouse lymphocyte) hybrid cell clones. Although lymphocytes do not express H19 and Igf2, both genes are reactivated in a proper monoallelic manner in hybrid cells. Analysis of the upstream region of the H19 gene confirmed maintenance of differential methylation of the active and inactive H19 genes of lymphocyte origin, although a tendency toward in vitro induced hypermethylation was apparent. We conclude that the imprints of the H19, U2af1-rs1, and Igf2 genes are maintained in lymphocytes in adult mice.

Alleles↗
PubMed1999

Transcription and RNA processing of mammalian genes in Saccharomyces cerevisiae.

The recognition of mammalian genes encoded within a mouse yeast artificial chromosome (YAC) by the yeast transcription and RNA processing machinery was investigated. Transcripts from five genes known to be encoded by the YAC were all found in the total yeast RNA. Of 12 mouse introns assayed, six were correctly spliced by the yeast. However, an abnormal transcription of mouse DNA was also observed. Three genes of three tested were transcribed both from their sense and antisense strands and all tested microsatellite, inter-repetitive and anonymous mouse loci were detected in the YAC clone RNA. An RNA transcript from a well defined intergenic region of two head-to-head oriented mouse genes was detected by RT-PCR and by RNase protection assay. These results indicate the presence of multiple yeast-specific transcription sites in the mouse DNA. 3' RACE experiments demonstrated the inability of the yeast to use the mouse polyadenylation signals. Thus, a method for isolation of mammalian exons based on a YAC clone RNA is likely to produce a high background, because the enrichment with mammalian exons in the YAC RNA is low. Nevertheless, YAC clones can serve as in vivo test tubes to study the conservation of RNA processing sequences.

Animals↗
PubMed1999

Lymphoid specificity of a copy number-related expression of the H2-Kb transgene.

Transcriptional regulation of the MHC class I genes leading to their developmental and tissue specific expression is still poorly understood in spite of the recovery of a large variety of cis-controlling sequences and trans-acting factors pertaining to the 5' enhancer and the downstream regulatory element. Here we produced a series transgenic lines of mice with a genomic subclone of the H2-Kb gene consisting of 367 bp of the 5' upstream region, the coding region and 1.5 kb of the 3' downstream region and carrying all hitherto known regulatory sequences. The comparison of nine transgenic lines carrying the same H2-Kb transgene made it possible to ask whether the cis-information present in the transgene was sufficient for the tissue- and developmental-specific expression and its copy number dependence. We found the proper developmental onset of expression of the transgene at day 13 p.c. and correct tissue specific mRNA levels in adult mice. While in lymphoid tissues and in lung the number of transgene copies still correlated with RNA levels, the copy number dependence was completely lost in liver, kidney and embryonic tissues. Comparison with previously published H2-Kb transgenes indicates that the H2-Kb locus-controlling region is composed of more than one element.

Animals↗
PubMed1997

Linkage of TATA-binding protein and proteasome subunit C5 genes in mice and humans reveals synteny conserved between mammals and invertebrates.

The TATA-binding protein (TBP) is a factor required for the transcription of all classes of eukaryotic genes. Here, we demonstrate that in the mouse the TBP-encoding gene (Tbp) resides next to the proteasomal subunit C5-encoding gene (Psmb1). The genes are located on mouse chromosome 17 in the t complex within the Hybrid sterility 1 (Hst1) region. We demonstrate that the homologous human genes (TBP AND PSMB1) are tightly linked on the long arm of chromosome 6, in a region syntenic with the proximal part of mouse chromosome 17. The mouse Tbp and Psmb1 and the human TBP and PSMB1 genes are transcribed in the opposite orientation. The TATA-binding protein and proteasomal subunit C5 genes are also linked on chromosome III of Caenorhabditis elegans, and together they are linked to other genes whose homologs map to human chromosome 6 and mouse chromosome 17. In the Drosophila genome, the housekeeping TATA-binding protein gene maps close to two other genes with homologs in the mammalian major histocompatibility complex. There thus exists conserved synteny of unrelated genes between mammals and invertebrates.

Animals↗
PubMed1997

Isolation of candidate hybrid sterility 1 genes by cDNA selection in a 1.1 megabase pair region on mouse chromosome 17.

The Hybrid sterility 1 (Hst1) gene causes male infertility in crosses between certain inbred strains of the laboratory and wild mouse, Mus musculus. To identify the causative gene, we have searched YAC clones encompassing the Hst1 region for testis-expressed sequences, using the cDNA selection method. We isolated 12 non-overlapping cDNA clones, sequenced them, and placed them on a physical map based on the analysis of YAC clones and total genomic DNA. The cDNA clones map to ten loci. Three cDNA sequences correspond to the proteasome subunit C5 (locus Psmb1), ornithine decarboxylase (Odc-rs15), and penta-zinc finger (Zfp91-rs1) transcripts. Three of the ten testis-expressed loci described in this report (D17Ph4e, Psmb1, and Zfp91-rs1) co-segregate with all Hst1 recombinants and, together with the Tbp gene, are therefore potential candidates for the Hst1 gene. The presented physical and genetic mapping data indicate there are no gross rearrangements distinguishing the Hst1(f) and Hst1(s) alleles.

Animals↗