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Biomedical subjects

S Toth

Publications and source records attributed to S Toth.

At least 19 recordsLinked to original sources
PubMed2005

Inhaled corticosteroids and survival in COPD patients receiving long-term home oxygen therapy.

BACKGROUND: Several observational studies suggest that therapy with inhaled corticosteroids (ICS) is associated with reduced mortality in patients with chronic obstructive pulmonary disease (COPD). However, none of these has reported survival data in COPD patients with respiratory insufficiency who require domiciliary oxygen therapy. The present study was conducted to examine the association between ICS and all-cause mortality in patients with severe COPD and chronic hypoxemia. PATIENTS AND METHODS: From a tertiary referral clinic, we identified 145 consecutive COPD patients who met the criteria for long-term oxygen therapy between 1996 and 2002. We compared the hazard ratio (HR) for all-cause mortality over 1 year between patients who were (n=55) and were not treated with ICS (n=90). RESULTS: In a crude analysis, the use of ICS was associated with a HR of 0.38 (95% confidence interval (CI)=0.18-0.79). After adjustments for age, sex, use of oral steroids, and beta2-agonists, PaO2 and PaCO2, the HR was 0.46 (95% CI=0.21-0.98). CONCLUSIONS: Our findings indicate that ICS may reduce all-cause mortality in patients with severe COPD and chronic hypoxemia, who require long-term domiciliary oxygen therapy. These data suggest that ICS may play an important role in improving clinical outcomes in patients with advanced COPD.

Administration, Inhalation↗
PubMed2001

A novel and rapid prediction assay for the effectiveness of IL-6 receptor specific antisense oligonucleotides by proliferation inhibition of an interleukin-6 dependent cell line.

Interleukin-6 (IL-6) belongs to a family of cytokines that use receptors consisting of a common signal-transducing chain (gp130). Baf/3 cells transfected with the human IL-6 receptor (IL-6R) and gp130 (Baf/3-gp130/IL-6R) can only grow in medium containing IL-6. We attempted to interrupt the signal transducing pathway of IL-6 with the help of antisense oligonucleotides (ASOs) designed against the IL-6R. We used 18 different kinds of antisense oligonucleotides of overlapping sequences around the translational start codon of the human IL-6R. Sense ASOs were used as a control. The proliferation of cells was analysed by H-thymidine incorporation. Cell surface expression of the IL-6R was assessed by FACS analysis. We identified three ASOs which strongly inhibited the proliferation of IL-6 dependent transfected Baf/3 cells. Flow cytometric studies on the suppression of surface expression of IL-6R by ASOs showed a similar pattern. These results should help to clarify the structural requirements of functionally effective ASOs in the inhibition of IL-6R.

Base Sequence↗
PubMed2001

Glucocorticoid receptor signaling in the intestinal epithelial cell lines IEC-6 and Caco-2: evidence of inhibition by interleukin-1beta.

BACKGROUND AND AIMS: Glucocorticoids are potent anti-inflammatory drugs widely used in the treatment of inflammatory bowel disease, but many patients do not benefit from glucocorticoid therapy (glucocorticoid resistance) or need inappropriately high doses to retain remission (glucocorticoid dependency). Because of the role of intestinal epithelial cells in inflammatory bowel disease we examined glucocorticoid receptor signaling and the effect of interleukin-1beta as one of the main proinflammatory cytokines in the intestinal epithelial cell lines IEC-6 and Caco-2. METHODS: Dexamethasone effects on transcriptional activation was measured by reporter gene assay using a construct containing glucocorticoid-responsive elements. The transrepressive effect was monitored by a nuclear factor (NF) kappaB inducible reporter construct. In addition in IEC-6 cells immuncytochemistry was used to monitor glucocorticoid receptor translocation. RESULTS: Dexamethasone induced receptor-mediated reporter gene transcription and receptor translocation, while interleukin-1beta significantly inhibited dexamethasone effects. Dexamethasone inhibited interleukin-1beta induced, NF-kappaB driven gene transcription only in IEC-6 and not in Caco-2 cells. However, in Caco-2 cells glucocorticoid receptor overexpression resulted in a marked decrease in NF-kappaB activity even in absence of dexamethasone. CONCLUSIONS: These studies demonstrate that glucocorticoid receptor driven gene regulation in intestinal epithelial cells may contribute to the anti-inflammatory effects of glucocorticoids in inflammatory bowel disease. Our data are consistent with the notion that interleukin-1beta produced during inflammatory response induces steroid resistance, which is a common clinical problem in treating patients with inflammatory bowel disease.

Caco-2 Cells↗
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↗
PubMed2000

Long-term impact on a closed household of pet cats of natural infection with feline coronavirus, feline leukaemia virus and feline immunodeficiency virus.

A closed household of 26 cats in which feline coronavirus (FCoV), feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV) were endemic was observed for 10 years. Each cat was seropositive for FCoV on at least one occasion and the infection was maintained by reinfection. After 10 years, three of six surviving cats were still seropositive. Only one cat, which was also infected with FIV, developed feline infectious peritonitis (FIP). Rising anti-FCoV antibody titres did not indicate that the cat would develop FIP. The FeLV infection was self-limiting because all seven of the initially viraemic cats died within five years and the remainder were immune. However, FeLV had the greatest impact on mortality. Nine cats were initially FIV-positive and six more cats became infected during the course of the study, without evidence of having been bitten. The FIV infection did not adversely affect the cats' life expectancy.

Animals↗
PubMed2000

Exon-intron organization of the human gp130 gene.

The exon-intron organization and sequences of the exon-intron boundaries of the human gp130 transmembrane receptor gene have been determined using genomic DNAs as samples. The gp130 gene comprises 17 exons and 16 introns. The positions of the exon-intron boundaries show good correlation to the functional/homology regions of gp130. Exons 3-17 code for the gp130 protein, and each subdomain of the receptor is encoded by a set of exons. The coding potential of exons and the intron phasing of the human gp130 gene conform to the patterns observed previously for other cytokine receptor genes. This supports the notions that the gp130 gene evolved from the same ancestral gene that gave rise to other members of the cytokine receptor family.

Antigens, CD↗
PubMed2000

Molecular basis of variant pseudo-hurler polydystrophy (mucolipidosis IIIC)

Mucolipidosis IIIC, or variant pseudo-Hurler polydystrophy, is an autosomal recessive disease of lysosomal hydrolase trafficking. Unlike the related diseases, mucolipidosis II and IIIA, the enzyme affected in mucolipidosis IIIC (N-Acetylglucosamine-1-phosphotransferase [GlcNAc-phosphotransferase]) retains full transferase activity on synthetic substrates but lacks activity on lysosomal hydrolases. Bovine GlcNAc-phosphotransferase has recently been isolated as a multisubunit enzyme with the subunit structure alpha(2)beta(2)gamma(2). We cloned the cDNA for the human gamma-subunit and localized its gene to chromosome 16p. We also showed, in a large multiplex Druze family that exhibits this disorder, that MLIIIC also maps to this chromosomal region. Sequence analysis of the gamma-subunit cDNA in patients from 3 families identified a frameshift mutation, in codon 167 of the gamma subunit, that segregated with the disease, indicating MLIIIC results from mutations in the phosphotransferase gamma-subunit gene. This is to our knowledge the first description of the molecular basis for a human mucolipidosis and suggests that the gamma subunit functions in lysosomal hydrolase recognition.

Amino Acid Sequence↗
PubMed1998

Detection of feline parvovirus in dying pedigree kittens.

Feline parvovirus (FPV) was detected in the intestinal tract contents of 13 pedigree kittens which were fading or died suddenly by the use of a new chromatographic test strip for canine parvovirus (CPV) and FPV. The test appeared to be sensitive and specific for the detection of FPV and was a useful diagnostic aid. In three cases in which virus was grown in cell culture, the isolates were characteristic of FPV and not CPV. Cats in the households in which the kittens were reared were regularly immunised with FPV vaccines. The most likely explanation for the occurrence of FPV-associated disease was exposure of the young kittens to large doses of virus contaminating the environment.

Animals↗
PubMed1996

A prospective risk analysis of contemporary thoracic surgery.

OBJECTIVE: The results of surgical therapy can only be accurately judged if the patients' characteristics and their impact on the outcome are known. The purpose of this study was to identify the risk factors of contemporary thoracic surgery, which could serve as a basis for a risk-matched comparison of different surgical techniques. METHODS: The data of 15 patients' undergoing thoracic surgery were prospectively documented. The outcome of the various operative procedures applied was statistically correlated with the access procedure, sex, age, body mass, dignity of underlying disease and six concomitant diseases. RESULTS: Four patients died within 30 days of surgery (mortality: 2.6%). Morbidity comprising all complications (class I) and morbidity comprising only complications of consequence for postoperative therapy (class II) rose with the number of concomitant diseases (50%/0% with no concomitant disease, 89%/33% with more than three concomitant diseases). Univariate testing identified malignant disease (P = 0.002), male sex (P = 0.003), body mass index of less than 20 and more than 27 kg/m of the expected level according to the Quetelet rule (P = 0.013) and a combination of concomitant respiratory and cardiocirculatory disease (P = 0.022) as being associated with class I morbidity. Male sex was significantly coincident with class II morbidity (P = 0.020). Logistic regression analysis demonstrated that these characteristics also had independent influence on class I morbidity (P = 0.022, P = 0.001, P = 0.023, P = 0.028). CONCLUSION: It is concluded that these characteristics are important predictors of morbidity of thoracic surgery. If a non-randomized comparison of the outcome of thoracic operations or different access strategies like thoracotomy or thoracoscopy is intended, at least these patient features should be documented and used as a basis for matching pairs.

Adolescent↗
PubMed1996

Structural Organization of the WD repeat protein-encoding gene HIRA in the DiGeorge syndrome critical region of human chromosome 22.

The human gene HIRA lies within the smallest critical region for the DiGeorge syndrome (DGS), a haploinsufficiency developmental disorder associated with instertitial deletions in most patients in a juxtacentromeric region of chromosome 22. The HIRA protein sequence can be aligned over its entire length with Hir1 and Hir2, two yeast proteins with a regulatory function in chromatin assembly. The HIRA transcription unit was found to spread over approximately 100 kb of the DGS critical region. The human transcript is encoded from 25 exons between 59 and 861 bp in size. Domains of highest conservation with Hir1 and Hir2 are encoded from exons 1-11 and 13-25, respectively. The amino- and carboxy-terminal regions of homology are separated from each other by a domain unique to HIRA that is encoded from a single exon. Seven WD repeats are conserved between yeast and man in the amino-terminal region of the HIR proteins. Individual repeats were found to be encoded from one, two, or three exons of the HIRA gene. End sequences have been obtained for all 24 introns, opening the way to PCR amplification of the entire coding sequence starting from genomic DNA. Point mutations can also be sought in 16 of the 24 introns that are readily PCR-amplifiable.

Amino Acid Sequence↗
PubMed1995

Risk of feline infectious peritonitis in cats naturally infected with feline coronavirus.

A longitudinal survey of 820 cats in 73 households was conducted over a period of 6 years to establish the fate of pet cats that were seropositive after natural exposure to feline coronavirus (FCoV). In particular, their risk of developing feline infectious peritonitis (FIP) was determined. The seropositive cats were assigned to 1 of 3 groups: cats from households in which FIP had recently been diagnosed; cats from households in which FIP had not been diagnosed, but from which kittens had been relocated and subsequently died of FIP; and cats from households in which FIP had not been diagnosed. Cats in the first group were not at greater risk of developing FIP than were cats in the other 2 groups. Consequently, any household in which seropositive cats live must be considered a potential source of FCoV that can cause FIP. There was no evidence that the enhanced disease, which has been described after experimentally induced infection of seropositive cats, exists in nature. Thus, analysis of the survival of the seropositive cats over periods of up to 36 months indicated that their risk of developing FIP decreased with time, suggesting the development of immunity rather than increased susceptibility to disease. In addition, of 56 cats deemed to have been naturally reinfected because their anti-FCoV antibody titers decreased and subsequently increased, only 3 developed FIP.

Animal Feed↗
PubMed1993

Conditional expression and oncogenicity of c-myc linked to a CD2 gene dominant control region.

Over-expression of the c-myc gene is widely implicated in the genesis of lymphoid neoplasia, including tumours of the T-cell lineage. To study the effects of deregulated c-myc expression on T-cell development and oncogenesis, we sought to generate a transgenic mouse model in which c-myc expression was targeted specifically to the T-cell lineage. A plasmid construct containing a dominant control region (DCR) from the human CD2 locus linked 5' to the human c-myc gene was used to generate 2 lines of transgenic mice. Both strains developed thymic lymphoma at low frequency, but thymic development and peripheral T-cell numbers were otherwise apparently normal. Low tumour penetrance was consistent with the observed lack of stable CD2-myc transgene mRNA in tissues of healthy transgenic mice. In contrast, transgene RNA was detected in all malignant tumours as well as in early lymphomatous lesions. RNase protection analyses confirmed these findings and showed that the PI human c-myc promoter was active in all neoplastic tissues but not in the thymus or other tissues of healthy transgenic mice. Despite the low spontaneous tumour incidence, the presence of the transgene markedly and uniformly accelerated the onset of tumours after neonatal infection with Moloney murine leukaemia virus. All tumours were rearranged for T-cell receptor beta-chain genes and were of T-cell origin from their surface phenotype (Thy-1+, CD3+, CD4+/-, CD8+, sIg-). Virus-accelerated tumours contained clonal integrations of Moloney murine leukaemia virus, suggesting that proviral insertional mutagenesis may have played a role in tumour development. Analysis of several candidate myc-cooperating genes failed to reveal any rearrangements apart from a low frequency involving proviral insertion at the pim-1 locus. The CD2-myc mouse should therefore be a valuable system in screening for novel myc-collaborating genes involved in T-cell lymphoma.

Animals↗
PubMed1993

An aggressive philosophy in controlled ovarian stimulation cycles increases pregnancy rates.

To assess the effect of timing of human chorionic gonadotrophin (HCG) administration in ovarian stimulation cycles, the serum oestradiol concentration and follicle profile were compared with the clinical pregnancy rate in 582 ovarian stimulation-intra-uterine insemination (OS-IUI) cycles and 3917 in-vitro fertilization-embryo transfer (IVF-ET) cycles. The pregnancy rates increased exponentially with increasing oestradiol in both OS-IUI and IVF-ET cycles (R2 = 0.720, P < 0.001) but then decreased in OS-IUI cycles when the oestradiol concentration exceeded 5000 pmol/l (R2 = 0.936, P < 0.004) at HCG administration. In OS-IUI cycles the percentages of cycles with three or more mature follicles (> or = 18 mm diameter) increased up to an oestradiol concentration of 5000 pmol/l then declined, mirroring the pregnancy rate (R2 = 0.900, P = 0.01). The exponential increase in pregnancy rate with increasing oestradiol concentration in IVF-ET cycles suggests that high oestradiol concentration does not have a deleterious effect on endometrial receptivity. The decrease in pregnancy rate in OS-IUI cycles when oestradiol concentration exceeded 5000 pmol/l reflected fewer mature follicles, resulting from premature administration of HCG to avoid severe ovarian hyperstimulation syndrome (OHSS). We recommend that HCG administration be delayed until multiple follicles have reached maturity, and reducing the risk of severe OHSS by converting high risk OS-IUI cycles to IVF-ET, or if funds or facilities are unavailable, transvaginally draining all but four or five mature follicles.

Chorionic Gonadotropin↗
PubMed1992

Subtentorial subdural empyema: case report.

We present a case of an extensive subtentorial subdural empyema of otorhinological origin. Although 3%-6% of all intracranial suppurations are infratentorial, there is no report on extensive multiloculated subtentorial empyema so far.

Empyema, Subdural↗
PubMed1990

Differentiation inhibiting activity is produced in matrix-associated and diffusible forms that are generated by alternate promoter usage.

The differentiation of embryonic stem (ES) cells is controlled by the regulatory factor differentiation inhibiting activity/leukemia inhibitory factor (DIA/LIF). Examination of feeder cell-mediated suppression of ES cell differentiation revealed that DIA/LIF is produced both as a diffusible protein and in an immobilized form associated with the extracellular matrix. This alternative localization arises from the expression of alternate transcripts that diverge throughout exon 1. The effect of alternate first exon usage is to change the amino terminus of the primary translation product and to direct incorporation of mature, biologically active DIA/LIF into the extracellular matrix. The production of a potent regulatory factor in both diffusible and immobilized forms may be an important element of developmental control mechanisms.

Amino Acid Sequence↗
PubMed1990

Developmentally programmed induction of differentiation inhibiting activity and the control of stem cell populations.

Differentiation inhibiting activity/leukemia inhibitory factor (DIA/LIF) is a glycoprotein that controls differentiation of pluripotential stem cells. Alternative transcription generates both diffusible and matrix-associated forms of DIA/LIF. Transcriptional analysis using a sensitive ribonuclease protection assay revealed that the two messages are expressed independently, consistent with the proposition that the two forms of DIA/LIF have distinct biological roles. DIA/LIF expression was found to be activated early during differentiation of embryonic stem (ES) cells, providing a mechanism for feedback regulation of stem cell renewal. Expression of DIA/LIF by mesenchymal cells was shown to be controlled in a paracrine manner by polypeptide regulatory factors. Specific expression of the two forms of DIA/LIF was also demonstrated in the egg cylinder-stage mouse embryo. The combination of cell type-specific and signal-specific regulation enables very precise control over DIA/LIF expression and may represent an important component of the regulatory networks that govern stem cell proliferation and differentiation during mammalian development.

Animals↗