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S Thibodeau

Publications and source records attributed to S Thibodeau.

15 recordsLinked to original sources
PubMed1998

Evidence for a prostate cancer susceptibility locus on the X chromosome.

Over 200,000 new prostate cancer cases are diagnosed in the United States each year, accounting for more than 35% of all cancer cases affecting men, and resulting in 40,000 deaths annually. Attempts to characterize genes predisposing to prostate cancer have been hampered by a high phenocopy rate, the late age of onset of the disease and, in the absence of distinguishing clinical features, the inability to stratify patients into subgroups relative to suspected genetic locus heterogeneity. We previously performed a genome-wide search for hereditary prostate cancer (HPC) genes, finding evidence of a prostate cancer susceptibility locus on chromosome 1 (termed HPC1; ref. 2). Here we present evidence for the location of a second prostate cancer susceptibility gene, which by heterogeneity estimates accounts for approximately 16% of HPC cases. This HPC locus resides on the X chromosome (Xq27-28), a finding consistent with results of previous population-based studies suggesting an X-linked mode of HPC inheritance. Linkage to Xq27-28 was observed in a combined study population of 360 prostate cancer families collected at four independent sites in North America, Finland and Sweden. A maximum two-point lod score of 4.60 was observed at DXS1113, theta=0.26, in the combined data set. Parametric multipoint and non-parametric analyses provided results consistent with the two-point analysis. Significant evidence for genetic locus heterogeneity was observed, with similar estimates of the proportion of linked families in each separate family collection. Genetic mapping of the locus represents an important initial step in the identification of an X-linked gene implicated in the aetiology of HPC.

Adult↗
PubMed1998

[Rectal carcinomas in HNPCC].

The true incidence of rectal cancer in HNPCC is still unknown. In our retrospective series analyzing 42 probands from HNPCC families, we found rectal cancer primaries in 29% of our probands. Patients with a first cancer diagnosed in the rectum developed metachronous colon cancer in 54% of the cases. These numbers indicate a requirement to discuss the most appropriate surgical procedure for preventive intervention (ileorectal anastomosis versus ileoanal pouch procedure).

Adult↗
PubMed1997

Different mechanisms underlie DNA instability in Huntington disease and colorectal cancer.

Two recent lines of evidence raise the possibility that instability in germ-line or somatic cells arises by a common mechanism that involves defective mismatch repair. Mutations in mismatch-repair proteins are known to cause instability in hereditary nonpolyposis colorectal cancer, instability that is physically similar to germ-line instability observed in Huntington disease (HD). Furthermore, both germ-line and somatic-cell instability are likely to be mitotic defects, the former occurring early in embryogenesis. To test the hypothesis that defective repair is a common prerequisite for instability, we have utilized two disease groups that represent different instability "conditions." Germ-line instability within simple tandem repeats (STR) at 10 loci in 29 HD families were compared with somatic instability at the same loci in 26 colon cancer (CC) patients with identified or suspected defects in mismatch-repair enzymes. HD is known to be caused by expansion within the CAG repeat of the locus, but the extent or pattern of STR instability outside this region has not been examined systematically. We find a distinctly different pattern of STR mutation in the two disease groups, suggesting different mechanisms. Instability in HD is generally confined to a single locus, whereas instability is widespread for the same loci in CC. Our data do not support a causative role for defective mismatch-repair enzymes in instability associated with HD; rather, our data are consistent with a model in which DNA structure may inhibit normal mismatch repair at the expansion site.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed1996

Segregation of the fragile X mutation from a male with a full mutation: unusual somatic instability in the FMR-1 locus.

Fragile X syndrome is associated with an unstable CGG-repeat in the FMR-1 gene. There are few reports of affected males transmitting the FMR-1 gene to offspring. We report on a family in which the propositus and his twin sister each had a full mutation with abnormal methylation. Their mother had an FMR-1 allele in the normal range and a large premutation, with normal methylation. The maternal grandmother had two normal FMR-1 alleles. The maternal grandfather had an unusual somatic FMR-1 pattern, with allele size ranging from premutation to full mutation. No allele was detectable by PCR analysis. Multiple Southern blot analyses identified a hybridization pattern that originated at a distinct premutation band and extended into the full mutation range. Methylation studies revealed a mosaic pattern with both unmethylated premutations and methylated full mutations. This individual declined formal evaluation but did not finish high school and has difficulty in reading and writing. The size of the premutation FMR-1 allele passed to his daughter is larger than his most prominent premutation allele. This is most likely due to gonadal mosaicism similar to that in his peripheral lymphocytes. Alternatively, this expansion event may have occurred during his daughter's early embryonic development and this large premutation allele is mitotically unstable. This pattern of FMR-1 alleles in a presumably mildly affected male is highly unusual. These findings are consistent with the absence of transmission of a full fragile X mutation through an expressing male. Studies of tissue specific FMR-1 allele expansion and FMR-1 protein expression on this individual should help to determine the correlation of the molecular findings with the phenotypic effects.

Alleles↗
PubMed1992

A study of aqueous humor formation in patients with cystic fibrosis.

The circadian pattern of aqueous formation and the effect of timolol on aqueous flow was studied in 12 patients with cystic fibrosis. Cystic fibrosis is a disease characterized by a defect in a chloride channel-associated regulatory protein found in epithelial cells. Improper regulation of these chloride channels, causes abnormal composition of exocrine secretions, including respiratory tract, gastrointestinal tract, exocrine pancreas, and sweat glands. Ocular findings previously reported include abnormal endothelial cell permeability, decreased tear secretion, and abnormal tear composition. In this study, aqueous humor flow was measured by fluorophotometry. No statistically significant difference was found when flow rates measured during the morning, during the afternoon, at night, and after topical timolol treatment were compared to normal values. The conclusion is that the beta adrenergically regulated chloride selective channels defective in patients in cystic fibrosis do not play a major role in the formation of aqueous humor or they are not regulated by the cystic fibrosis transmembrane conductance regulator (CFTR).

Administration, Topical↗
PubMed1989

Third-party-mediated graft rejection and graft-versus-host disease after T-cell-depleted bone marrow transplantation, as demonstrated by hypervariable DNA probes and HLA-DR polymorphism.

Graft rejection after marrow transplantation is generally thought to be mediated by alloreactive immune effector cells of host origin. Transfused blood products also contain immune cells capable of alloreactivity against both donor graft and host. To reduce the risk of transfusion-associated graft-versus-host disease (GVHD) and graft rejection, standard procedure is to irradiate all blood products with at least 1,500 rad before transfusion. We report a patient with chronic myelogenous leukemia who developed graft rejection and GVHD after receiving a T-cell-depleted transplant from a serologically HLA-A, B, DR/DQ matched and mixed lymphocyte culture (MLC) nonreactive unrelated donor. Cytogenetic analysis of marrow cells collected at the time of graft rejection revealed a PH1-negative female karyotype that was not consistent with donor cells. Use of specific minisatellite DNA probes (YNH 24, H-RAS, and 3' HVR) revealed the exclusive presence of third-party (neither donor nor recipient) restriction-fragment-length polymorphisms (RFLP) in both peripheral blood and marrow. Repeat RFLP analysis 3 days later showed persistence of this unique third-party banding pattern. DNA-based HLA-typing, using polymerase chain reaction (PCR) and oligonucleotide probe hybridization, also showed these cells to be derived from an individual whose HLA-DR type was distinct from donor and recipient. Together, these findings suggested the presence of a proliferating population of transfused cells possessing alloreactivity against both donor graft and host, despite prior irradiation of all blood products with 2,000 rad. Limiting dilution analysis to assess the frequency of irradiated lymphocytes able to respond to mitogen revealed an approximate 5- to 6-log reduction at 1,500 to 2,000 rad as compared with unirradiated controls. These data indicate that a small percentage of lymphocytes can survive irradiation at these doses and suggest that existing blood-product irradiation guidelines may require reassessment, especially in T-cell-depleted transplant recipients.

Bone Marrow Transplantation↗
PubMed1989

Neonatal hyperbilirubinemia at high altitude.

A previous retrospective study showed an increased frequency of neonatal hyperbilirubinemia at high altitude in Colorado. In a prospective study we found that 39% of newborns at 3100 m altitude vs 16% at 1600 m exhibited hyperbilirubinemia, defined as a day 3 serum bilirubin level of 205 mumol/L or higher. Increased bilirubin production at 3100 m vs 1600 m was shown by increased levels of corrected carboxyhemoglobin. This finding was supported by increased erythropoietin and bilirubin values in cord blood and increased hematocrit values at day 3 among infants at 3100 m vs 1600 m. The sustained elevation in bilirubin for breast-fed vs formula-fed infants at 1600 m was observed for both feeding types at 3100 m. The findings suggested that there is a hematologic response to decreased oxygen availability at high altitude, resulting in increased bilirubin production accompanied by delayed bilirubin clearance.

Adult↗
PubMed1989

An intronic region within the human factor VIII gene is duplicated within Xq28 and is homologous to the polymorphic locus DXS115 (767).

The genomic sequences recognized by the anonymous probe 767 (DXS115) are localized to two sites within Xq28. One site lies within intron 22 of the factor VIII gene (FBC). Physical mapping suggests that the second site lies within 1.2 megabases of the F8C gene. The RFLPs detected by 767 are located within the second site. Genetic data suggest that F8C and DXS115 are tightly linked (theta max = .04; Zmax = 8.30). Recombination events in meioses informative for DXS52 (St14), DXS115, and F8C suggest that DXS115 and F8C lie distal to DXS52.

Chromosome Deletion↗
PubMed1989

The bcr gene in Philadelphia chromosome positive acute lymphoblastic leukemia.

In chronic myelogenous leukemia (CML) and in a percentage of childhood and adult acute lymphoblastic leukemia (ALL) the Philadelphia (Ph') chromosome is present in the leukemic cells of patients. This chromosome is the result of a reciprocal translocation between chromosomes 9 and 22. In CML the break on chromosome 22 occurs within the major breakpoint cluster region (Mbcr) of the bcr gene. In this study, we report on the examination of DNAs from nine Ph'-chromosome positive ALL patients for rearrangements within the bcr gene using Southern blot analysis. Of nine patients having a karyotypically identifiable Ph'-chromosome, only five exhibited rearrangements of the bcr gene. This could indicate that in ALL, chromosome 22 sequences other than the bcr gene are involved in the Ph'-translocation. Within the group of Ph'-positive ALL patients having a bcr gene breakpoint, a correlation appears to exist between the age of the patient and the location of the breakpoint within the gene: all or the vast majority of pediatric patients analyzed to date do not have a Mbcr breakpoint as found in CML and in adult ALL.

Adolescent↗
PubMed1988

Multilocus analysis of the fragile X syndrome.

A multilocus analysis of the fragile X (fra(X] syndrome was conducted with 147 families. Two proximal loci, DXS51 and F9, and two distal loci, DXS52 and DXS15, were studied. Overall, the best multipoint distances were found to be DXS51-F9, 6.9%, F9-fra(X), 22.4%; fra(X)-DXS52, 12.7%; DXS52-DXS15, 2.2%. These distances can be used for multipoint mapping of new probes, carrier testing and counseling of fra(X) families. Consistent with several previous studies, the families as a whole showed genetic heterogeneity for linkage between F9 and fra(X).

Chromosome Mapping↗
PubMed1987

Mapping of DNA markers close to the fragile site on the human X chromosome at Xq27.3.

We report the identification of a new RFLP detected by the DNA probe MN12, which is linked to both the fragile site on the X chromosome at Xq27.3 and the highly polymorphic locus detected by St14 (DXS52). In situ mapping confirms the localisation of MN12 distal to the fragile site. A detailed physical analysis of this region of the X chromosome using pulsed-field gel electrophoresis has shown that MN12, St14 and DX13 (DXS15) are physically linked within a region of 470kb. A long range restriction map around the MN12 locus reveals at least two candidate HTF islands, suggesting the existence of expressed sequences in this region.

Base Sequence↗
PubMed1986

Optimized calcium/phosphorus solubility in a parenteral nutrition solution containing dicarboxylic amino acids and cysteine.

The solubility of calcium and phosphorus was studied in neonatal parenteral nutrition solutions containing dicarboxylic amino acids and cysteine. Experimental amino acid solutions containing aspartic acid, glutamic acid, and cysteine in concentrations from 0.5% to 2.0% were studied with dextrose concentrations of 5-20% plus standard electrolyte, vitamin, and trace element additives. Solutions were held at room temperature for 24 hr prior to incubation in a 37 degrees C water bath for 30 min. The pH of each solution was determined. Precipitation was detected by light scattering on a Cobas Bio centrifugal analyzer. An absorbance greater than 0.015 at 600 nm was considered evidence of precipitation. The pH of test solutions ranged between 5.7 and 6.4. Increasing amino acid concentration produced an improvement in calcium/phosphate solubility. Change in dextrose concentration had a lesser effect. Solutions of 10% dextrose with 2% amino acids contained 40 mEq/liter calcium and 17 mmol/liter phosphorus without precipitation. Administered at 150 ml/kg/day, such a solution would provide 120 mg/kg body weight/day calcium and 80 mg/kg/day phosphorus, approximately the daily in utero accretion rates during the last trimester. This is not readily achieved in comparable solutions of previous amino acid formulations.

Amino Acids, Dicarboxylic↗
PubMedDate not supplied

Fragile X syndrome: linkage analysis in black and white populations.

Eleven white families and 10 black families have been studied to detect racial differences in the linkage of DNA markers flanking the fragile X site (FRAXA). The differences in the recombination fractions for F9-FRAXA and DX13-FRAXA were not significant. The pair St14-FRAXA exhibited no difference between the two groups. Although the sample size was small, it would appear that these DNA markers can be used in black persons for prenatal diagnosis and genetic counseling. A larger group of families would be necessary to determine if 4D8 and cX55.7 will be equally useful since these appear to have lower heterozygote frequencies in the black population.

Black People↗