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Biomedical subjects

M Till

Publications and source records attributed to M Till.

At least 37 records · Page 2Linked to original sources
PubMed1999

Tryptanthrins and other tryptophan-derived agonists of the dioxin receptor.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related environmental pollutants exert most of their adverse effects via the aryl hydrocarbon or dioxin receptor (AhR). While most potent agonists of the AhR are of synthetic origin, an increasing number of natural compounds is now recognized as receptor agonists. Our findings demonstrate that some tryptanthrin derivatives biosynthesized in incubations of Candida lipolytica with tryptophan and anthranilic acid or its derivatives activate the AhR measured as induction of cytochrome P4501A1 mRNA and protein in rat hepatocytes in primary culture. The specificity of the inducing effect of tryptanthrins was demonstrated in gel retardation experiments in Hepa-1 mouse hepatoma cells using an oliogonucleotide comprising the sequence of the dioxin-responsive element. Furthermore, unidentified AhR agonists were formed in incubations of rat feces with a minimal medium supplemented with tryptophan. It is suggested that the receptor may be part of a defense system protecting higher organisms from secondary tryptophan-derived metabolites formed by the microflora of the host or its environment.

Animals↗
PubMed1999

Genetic and functional characterization of the alpAB gene locus essential for the adhesion of Helicobacter pylori to human gastric tissue.

In this study, we isolated and characterized a chromosomal locus of Helicobacter pylori previously identified by transposon shuttle mutagenesis as being involved in the adhesion of the pathogen to gastric epithelial cells. Two closely homologous genes were identified, designated as alpA and alpB, encoding outer membrane (OM) proteins of 518 amino acids each. They are members of the outer membrane protein supergene family identified in the H. pylori 26695 complete genome sequence. AlpA carries a functional lipoprotein signal sequence. AlpB carries a putative standard N-terminal signal sequence and shows a strong amino-acid sequence identity to AlpA. Transposon insertion mutagenesis, immunoblotting and primer extension studies indicate that both genes are organized in an operon, but no obvious consensus promoter sequence was found upstream of the transcriptional start site. The C-terminal portion of both proteins is predicted to form a porin-like beta-barrel in the outer membrane, consisting of 14 transmembrane amphipathic beta-strands. Adhesion experiments with defined isogenic mutants indicate that both proteins are necessary for specific adherence of H. pylori to human gastric tissue. The pattern of AlpAB-dependent adherence of H. pylori to the gastric epithelial surface shows a clear difference to the BabA2-mediated adherence to Lewis, suggesting that a different receptor is involved.

Algorithms↗
PubMed1998

Hepatitis C virus infection in Chicago women with or at risk for HIV infection: evidence for sexual transmission.

BACKGROUND AND OBJECTIVES: The importance of sexual transmission of hepatitis C virus (HCV) infection is unclear. We attempted to define its role in women with or at risk for HIV infection. GOAL OF THIS STUDY: To ascertain if high-risk sexual behavior was independently associated with HCV infection. STUDY DESIGN: Risk factors were assessed cross-sectionally in Chicago women newly enrolled in the Women's Interagency HIV Study. Women who had (n = 243) or were at risk for HIV infection (n = 53) were tested for HCV antibodies (Ab). RESULTS: Of 296 women, 123 (42%) were HCV Ab positive; prevalence was 90% in women who injected drugs (IDU) compared with 12% in noninjectors (odds ratio [OR], 64.0, 95% confidence interval [CI], 29.9 to 137.0). A multivariate model showed associations with IDU (OR, 110.3, 95% CI, 33.3 to 365.8), prior gonorrhea (OR, 3.6, 95% CI, 1.4 to 8.9), and sex with a male IDU (OR, 2.7, 95% CI, 1.1 to 7.0). CONCLUSION: Injection drug use is the strongest predictor of HCV infection, but sexual risk factors are also independently associated.

Adult↗
PubMed1998

Fetal Smith-Lemli-Opitz syndrome can be detected accurately and reliably by measuring amniotic fluid dehydrocholesterols.

The Smith-Lemli-Opitz syndrome, characterized by limb, face and organ abnormalities, and mental retardation, is caused by an inherited block in the step of cholesterol biosynthesis in which the delta 7 double bond of 7-dehydrocholesterol is reduced. It is diagnosed by the presence of markedly elevated levels of 7-dehydrocholesterol and 8-dehydrocholesterol in plasma and tissue. We measured amniotic fluid sterols in 15 pregnancies in 13 women who had previously carried an affected fetus. Cholesterol, 7-dehydrocholesterol and 8-dehydrocholesterol concentrations averaged 18 +/- 3, 9.8 +/- 2.9 and 5.0 +/- 1.7 micrograms/ml, respectively, in seven pregnancies with an affected fetus or child. In contrast, these levels were 19 +/- 3, 0.05 +/- 0.01 and < 0.005 micrograms/ml, respectively, in eight increased-risk pregnancies with normal outcomes and 16 +/- 2, 0.07 +/- 0.01 and < 0.005 micrograms/ml in normal controls. 7-dehydrocholesterol concentrations, 2.2-26 and 0.05-0.10 micrograms/ml in pregnancies with an affected and unaffected fetus, respectively, did not overlap. Thus, abnormally elevated amniotic fluid dehydrocholesterol concentrations are an accurate predictor of fetal Smith-Lemli-Opitz syndrome. A false-positive or a false-negative result is highly unlikely.

Adult↗
PubMed1997

A gene for FG syndrome maps in the Xq12-q21.31 region.

FG syndrome is an X-linked recessive condition in which mental retardation is associated with congenital hypotonia, macrocephaly, characteristic face, and constipation. This syndrome was mapped by Zhu et al. [Cytogenet Cell Genet 1991;58:2091A] to Xq21.31-q22 by linkage analysis with a max lod score of 1.2 for the DXYS1X, DXS178, DXS101, and DXS94 loci and crossovers at DXS16 (Xp22.31) and DXS287 (Xq22.3). However, this mapping was only provisional and needed to be refined. In this paper, we report the results of a new linkage analysis performed on 10 families including that studied by Zhu et al. [1991]. Two-point analysis demonstrated linkage with DXS441 (Zmax = 3.39 at theta = 0.12) at Xq13. In addition, separate analysis of the lod scores obtained for the Xq13 markers suggested linkage exclusion for three families. Genetic heterogeneity was confirmed by analysis of the linkage results with the HOMOG program (max logL = 4.07, theta = 0, alpha = 0.65). Localization of one FG gene between DXS135 and DXS1066 was suggested by analysis of crossovers found in those three families which were assumed to be linked to Xq13 with a probability of 0.95 or more. This region could be reduced to the DXS135-DXS72 interval after combining our data with those from deletions previously described in males in the Xq13-q21 region.

Abnormalities, Multiple↗
PubMed1997

Molecular mechanisms of contraction-induced translocation of GLUT4 in isolated cardiomyocytes.

Isolated adult rat ventricular cardiomyocytes were used to investigate the effects of contractile activity on 3-O-methylglucose transport on the translocation of the insulin-responsive glucose transporter GLUT4, and the possible activation of intermediates of the insulin signaling cascade. When elicited by field stimulation, contraction at 1 Hz did not significantly affect the adenosine triphosphate (ATP) content of cardiac cells, even after 60 min. At 5 Hz, a stable ATP level was observed until 15 minutes with a rapid decline at later time points. Stimulation of cardiomyocytes at 5 Hz for 5 minutes induced a 2-3 fold increase of 3-O-methylglucose transport with no additional stimulation in the presence of insulin (10[-7] M). Subcellular fractionation and immunoblotting analysis of GLUT4 distribution indicated that both contraction and insulin induced an identical increase (8-9-fold) of GLUT4 in the plasma membrane with a concomitant decrease (one third) in the microsomal fraction. Treatment of cardiomyocytes with wortmannin produced a complete inhibition of insulin- and contraction-induced glucose uptake. However, immunoprecipitation of insulin receptor substrate-1 (IRS-1) showed that the p85 regulatory subunit of phosphatidylinositol-3 kinase did not associate with IRS-1 upon contraction but with a marked stimulated association in response to insulin. These data suggest the existence of identical insulin- and contraction-recruitable GLUT4 pool. Contraction-induced signaling may use a limited part of the insulin-signaling cascade, possibly involving IRS-2. We further suggest that insulin resistance at the level of IRS-1 will not affect contraction-regulated glucose uptake by the heart.

3-O-Methylglucose↗
PubMed1997

Tryptanthrins: a novel class of agonists of the aryl hydrocarbon receptor.

2,3,7,8-Tetrachlorodibenzo-p-dioxin and related environmental pollutants exert most of their adverse effects such as immunosuppression, induction of endocrine dysfunction, tumor promotion, and teratogenicity via the aryl hydrocarbon or dioxin receptor. While most potent agonists of the aryl hydrocarbon receptor are of synthetic origin, an increasing number of natural compounds are now recognized as receptor agonists. Our findings demonstrated that some tryptanthrin derivatives biosynthesized in incubations of Candida lipolytica with tryptophan and anthranilic acid or its derivatives were agonists of the aryl hydrocarbon receptor. The biosynthetic products 8-methyltryptanthrin, 8-chlorotryptanthrin, and 8-bromotryptanthrin induced cytochrome P4501A1 mRNA and protein in rat hepatocytes in primary culture, characteristic features of aryl hydrocarbon receptor agonists. Log-probit analysis of the catalytic activity of cytochrome P4501A1, 7-ethoxyresorufin O-deethylase (EROD), revealed EC50 induction values of 1.7, 0.25, and 0.17 microM for 8-methyltryptanthrin, 8-chlorotryptanthrin, and 8-bromotryptanthrin, respectively. Interestingly, the nonsubstituted tryptanthrin molecule, biosynthesized from the common physiological precursors tryptophan and anthranilic acid, was also active as an inducer. The specificity of the inducing effect of tryptanthrins was demonstrated in gel retardation experiments in Hepa-1 mouse hepatoma cells, showing the characteristic interaction of the activated aryl hydrocarbon receptor with an oligonucleotide containing a xenobiotic-responsive element. It is suggested that the receptor may be part of a defense system protecting higher organisms from secondary metabolites formed by the microflora of the host or its environment.

Animals↗
PubMed1997

Dioxinlike components in incinerator fly ash: a comparison between chemical analysis data and results from a cell culture bioassay.

Potent polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxinlike polychlorinated biphenyls (PCBs) are among the most relevant toxic emissions from incinerators. Induction of cytochrome P450 1A1-catalyzed 7-ethoxyresorufin O-deethylase (EROD) activity in mammalian cell culture (EROD bioassay) is thought to be a selective and sensitive parameter used for the quantification of dioxinlike compounds. Fly ash extracts from municipal waste incinerators (MWI), a crematorium, wood combustors, and a noble metal recycling facility were analyzed in the EROD bioassay using rat hepatocytes in primary culture. Fractions containing 2,3,7,8-substituted PCDDs/PCDFs, dioxinlike PCBs, and 16 major polycyclic aromatic hydrocarbons (PAHs) were isolated from the extract and analyzed by gas chromatography-mass spectrometry (GC-MS) and by the EROD bioassay. It was found that with MWI samples the bioassay of the extract resulted in a two- to fivefold higher estimate of TCDD equivalents (TEQ) than the chemical analysis of PCDDs/PCDFs and PCBs. However, the outcome of both methods was significantly correlated, making the bioassay useful as a rough estimate for the sum of potent PCDDs/PCDFs and dioxinlike PCBs in extracts from MWI fly ash samples and in a fly ash sample from a crematorium. In noble metal recycling facility and wood combustor samples, higher amounts of PAHs were found, contributing to more pronounced differences between the results of both methods. The remaining unexplained inducing potency in fly ash samples probably results from additional dioxinlike components including certain PAHs not analyzed in this study. The hypothesis that emissions from MWI of hitherto unidentified dioxinlike compounds are higher by orders of magnitude than emissions of potent PCDDs/PCDFs and dioxinlike PCBs could not be confirmed. We found no indication for a marked synergistic interaction of dioxinlike fly ash components in the bioassay.

Air Pollutants↗
PubMed1996

Idiopathic genital ulcers in women infected with human immunodeficiency virus.

A national survey of investigators caring for human immunodeficiency virus (HIV)-infected women was undertaken to describe the clinical presentation of idiopathic genital ulcer disease. Patients with negative syphilis and herpes simplex testing and/or negative genital ulcer biopsy were included in this study. Study participants (n = 29) were generally severely immunocompromised (median CD4 cell count was 50/mm3, and 68% had an acquired immunodeficiency syndrome [AIDS]-defining opportunistic process). Thirty-seven percent had coexistent oral ulcers and 19% had their genital ulcer progress to fistula formation (four rectovaginal and one vaginal-perineal). There was generally a favorable response to topical, systemic, and intralesional steroid treatment. This study suggests that idiopathic or probable aphthous genital ulcers in women have similar clinical characteristics to aphthous oroesophageal ulcers. Although infrequent, these genital ulcers can cause severe morbidity. Further research is warranted to better define the pathophysiology and optimal management.

Adult↗
PubMed1996

Waardenburg-Hirschsprung disease in two sisters: a possible clue to the genetics of this association?

A Tunisian infant of consanguineous parents had pigmentary disorders, congenital deafness and long-segment Hirschsprung disease. Her elder sister had the same disorders but with short-segment aganglionosis. Their father, mother and two brothers are healthy without history of deafness, constipation or pigmentary disorder. We confirm that this Waardenburg-Hirschsprung association seems to be a distinct clinical entity with a possible autosomal recessive mode of inheritance. Linkage analyses performed in this family support the view that neither the RET locus (candidate for familial dominant Hirschsprung disease) nor the HuP2 locus (candidate for Waardenburg syndrome type I) are involved in the disease phenotype. We suggest that Waardenburg-Hirschsprung complex is a distinct genetic entity and at least one additional locus altering cranial neural crest cell development is responsible for pleiotropic features observed in this association.

Hirschsprung Disease↗
PubMed1996

Optimized BlaM-transposon shuttle mutagenesis of Helicobacter pylori allows the identification of novel genetic loci involved in bacterial virulence.

Helicobacter pylori is an important etiologic agent of gastroduodenal disease in humans. In this report, we describe a general genetic approach for the identification of genes encoding exported proteins in H. pylori. The novel TnMax9 mini-blaM transposon was used for insertion mutagenesis of a H. pylori gene library established in Escherichia coli. A total of 192 E. coli clones expressing active beta-lactamase fusion proteins (BlaM+) were obtained, indicating that the corresponding target plasmids carry H. pylori genes encoding putative extracytoplasmic proteins. Natural transformation of H. pylori P1 or P12 using the 192 mutant plasmids resulted in 135 distinct H. pylori mutant strains (70%). Screening of the H. pylori collection of mutant strains allowed the identification of mutant strains impaired in motility, in natural transformation competence and in adherence to gastric epithelial cell lines. Motility mutants could be grouped into distinct classes: (i) mutant strains lacking the major flagellin subunit FlaA and intact flagella (class I); (ii) mutant strains with apparently normal flagella, but reduced motility (class II), and (iii) mutant strains with obviously normal flagella, but completely abolished motility (class III). Two independent mutations that exhibited defects in natural competence for genetic transformation mapped to different genetic loci. In addition, two independent mutant strains were isolated by their failure to bind to the human gastric carcinoma cell line KatoIII. Both mutant strains carried a transposon in the same gene, 0.8 kb apart, and showed decreased autoagglutination when compared to the wild-type strain.

Amino Acid Sequence↗
PubMed1995

The value of cervical cytology in HIV-infected women.

The purpose of this study was to assess the ability of cytology to predict the results of colposcopically directed cervical biopsies in HIV-infected women. We performed a case-control study of 52 HIV(+), 31% of whom had AIDS, and 57 HIV(-) women referred to two tertiary care centers for colposcopy from July 1991 to November 1993. All 57 HIV(-) controls and 27 HIV (+) cases underwent colposcopy for evaluation of an abnormal Pap smear. The remaining HIV(+) cases (n = 25) had colposcopy as part of their routine assessment. In women with abnormal Pap smears, colposcopic biopsy agreed with the Pap smear results in 83% of 24 HIV(+) women and 65% of 37 controls (chi 2; P = 0.34). For patients with low-grade SIL on Pap smear, 14% of HIV(+) and 11% of HIV(-) women had moderate or severe dysplasia on biopsy (P = 0.52). The positive predictive value of an abnormal Pap smear was 96% in HIV(+) women vs 78% in noninfected patients (P = 0.05). In the overall series of 52 HIV(+) women, the Pap smear did not match the biopsy in 44% of patients and was less severe than the cervical biopsy results in 91% of these mismatches. The Pap smear had a sensitivity of 57%, a specificity of 92%, a positive predictive value of 96%, and a negative predictive value of 39%, when compared to biopsy results in HIV-seropositive patients. Pap smears missed 43% of biopsy-proven intraepithelial lesions in this series of HIV (+) women. However, when abnormal, the Pap smear was no worse in predicting the presence and degree of an intraepithelial lesion in HIV(+) women than in noninfected women. These characteristics may justify immediate treatment of HIV(+) women at the time of colposcopy after an abnormal Pap smear given its high positive predictive value.

Adult↗
PubMed1995

Exclusion of RET and Pax 3 loci in Waardenburg-Hirschsprung disease.

The RET and the Pax 3 genes have recently been shown to account for autosomal dominant Hirschsprung's disease (HSCR) and Waardenburg syndrome type 1 (WS1) respectively, which led us to consider them as candidate genes in the WS/HSCR association. Linkage analyses performed in a consanguineous WS/HSCR family support the view that neither the RET locus nor the Pax 3 locus are involved in the disease phenotype. Hence, at least one further locus altering neural crest cell development is responsible for the pleiotropic features observed in the WS/HSCR association.

Consanguinity↗
PubMed1994

Apparent genetic homogeneity of the Treacher Collins-Franceschetti syndrome.

The Treacher Collins-Franceschetti syndrome (TCOF) or mandibulofacial dysostosis (MFD) is an autosomal dominant disorder characterized by craniofacial abnormalities and hearing loss. A refined genetic linkage map of the TCOF locus was established in 8 independent families, using 12 microsatellite DNA markers of the distal 5q. Positive lod score values were obtained for all markers with a maximum at the D5S413 locus (Zmax = 3.79 at theta = 0%). Multipoint linkage analysis and haplotype analysis supported the location of the gene between loci D5S434 and D5S412. These results are consistent with previous linkage analyses [Dixon et al.: Am J Hum Genet 49:17-22, 1991, Am J Hum Genet 52:907-914, 1993; Jabs et al.: Genomics 11:193-198, 1991, Genomics 18:7-13, 1993] and provide further evidence of genetic homogeneity in this syndrome.

Chromosomes, Human, Pair 5↗