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Biomedical subjects

I D Young

Publications and source records attributed to I D Young.

At least 19 recordsLinked to original sources
PubMed1995

Long-term survival in the Wolf-Hirschhorn (4p-) syndrome.

The clinical features of Wolf-Hirschhorn syndrome are described in a 29-year-old woman who shows severe retardation of growth and development. It is important for health care professionals involved with families in which this condition is present to realize that long-term survival may occur.

Adult↗
PubMed1995

A clinical and genetic study of campomelic dysplasia.

Campomelic dysplasia (CMD) is a rare skeletal disorder that is usually lethal. It is characterised by bowing of the lower limbs, severe respiratory distress, and many of the chromosomal (XY) males show sex reversal. Because of a number of reports of familial campomelic dysplasia it is considered to be inherited in an autosomal recessive manner. In this study, details of 36 patients with campomelic dysplasia were collected from genetic centres, radiologists, and pathologists in the United Kingdom. The chromosomal sex ratio was approximately 1:1. There was a preponderance of phenotypic females owing to sex reversal. Three quarters of the chromosomal males were sex reversed or had ambiguous genitalia. Three cases are still alive, two with chromosomal rearrangements involving chromosome 17q. The majority of the others died in the neonatal period. The 36 index cases had 41 sibs of whom only two were affected. Formal segregation analysis gave a segregation ratio of 0.05 (95% CI approximately 0.00 to 0.11). This excludes an autosomal recessive mode of inheritance. The data suggest a sporadic, autosomal dominant mode of inheritance. Patients with a chromosomal rearrangement involving 17q (q23.3-q25.1) show a milder phenotype. The molecular mechanism for the difference is still unknown.

Adolescent↗
PubMed1995

Mutations in SOX9, the gene responsible for Campomelic dysplasia and autosomal sex reversal.

Campomelic dysplasia (CD) is a skeletal malformation syndrome frequently accompanied by 46,XY sex reversal. A mutation-screening strategy using SSCP was employed to identify mutations in SOX9, the chromosome 17q24 gene responsible for CD and autosomal sex reversal in man. We have screened seven CD patients with no cytologically detectable chromosomal aberrations and two CD patients with chromosome 17 rearrangements for mutations in the entire open reading frame of SOX9. Five different mutations have been identified in six CD patients: two missense mutations in the SOX9 putative DNA binding domain (high mobility group, or HMG, box); three frameshift mutations and a splice-acceptor mutation. An identical frameshift mutation is found in two unrelated 46,XY patients, one exhibiting a male phenotype and the other displaying a female phenotype (XY sex reversal). All mutations found affect a single allele, which is consistent with a dominant mode of inheritance. No mutations were found in the SOX9 open reading frame of two patients with chromosome 17q rearrangements, suggesting that the translocations affect SOX9 expression. These findings are consistent with the hypothesis that CD results from haploinsufficiency of SOX9.

Base Sequence↗
PubMed1994

Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene.

Induction of testis development in mammals requires the presence of the Y-chromosome gene SRY. This gene must exert its effect by interacting with other genes in the sex-determination pathway. Cloning of a translocation chromosome breakpoint from a sex-reversed patient with campomelic dysplasia, followed by mutation analysis of an adjacent gene, indicates that SOX9, an SRY-related gene, is involved in both bone formation and control of testis development.

Amino Acid Sequence↗
PubMed1994

Holt-Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q.

Holt-Oram syndrome (HOS) is an autosomal dominant condition affecting the heart and upper limbs. We have sought to identify the location of this gene using microsatellite DNA markers in a linkage study. Of seven families analysed, five show linkage between HOS and markers on chromosome 12q. But the two remaining families, phenotypically indistinguishable from the others, do not show this linkage. Analysis with the computer program HOMOG indicates that HOS is a heterogeneous disease. Our analysis places one HOS locus in a 21 cM interval in the distal region of chromosome 12q. The localization of a gene for HOS, reported here, represents an important step towards a better understanding of limb and cardiac development.

Abnormalities, Multiple↗
PubMed1994

Severe microphthalmia, diaphragmatic hernia and Fallot's tetralogy associated with a chromosome 1;15 translocation.

A 9-year-old boy with multiple abnormalities including severe bilateral microphthalmia, diaphragmatic hernia and Fallot's tetralogy is presented. He has also been shown to have an apparently balanced de novo reciprocal translocation, 46,XY,t(1;15)(q41;q21.2), which suggests that one of those breakpoints may be the locus for a gene which is important in morphogenesis.

Abnormalities, Multiple↗
PubMed1994

Modulation of glomerular structure and function in murine lupus nephritis by methylprednisolone and cyclophosphamide.

The effects of methylprednisolone and cyclophosphamide were examined in a murine model of lupus nephritis (MRL-1pr/1pr). Animals were assigned to four groups at 12 weeks of age. Mice in the control group received intraperitoneal saline solution either daily or weekly. Animals in the low-dose methylprednisolone (MPLD) group received 6 mg/kg/day intraperitoneal methylprednisolone; those in the high-dose methylprednisolone (MPHD) group received 12 mg/kg/day intraperitoneal methylprednisolone. Animals in the cyclophosphamide group received 50 mg/kg/wk intraperitoneal cyclophosphamide. Animals surviving to 24 weeks were examined. MPHD and cyclophosphamide treatments were associated with maintenance of normal glomerular filtration rates and the development of only minimal proteinuria. However, detailed morphometric evaluation of the glomerulus revealed glomerular enlargement and mesangial matrix expansion in both groups. Unlike MPHD-treated mice, cyclophosphamide-treated animals demonstrated a marked reduction in the number of osmophilic dense deposits along the glomerular capillary walls. MPLD had little effect on function, despite significant reductions in cell proliferation and anti-double-strand DNA antibodies. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels were dramatically increased in plasma of control animals. Treatment with methylprednisolone and cyclophosphamide dramatically reduced TNF-alpha but not IL-6. Treatment also reduced renal IL-1 beta, TNF-alpha and transforming growth factor-beta mRNA levels compared with untreated mice. Despite minimal serologic activity and preservation of renal function, neither cyclophosphamide nor methylprednisolone was able to completely suppress disease activity, as measured by increased cytokine production and glomerular structural injury. The inability of treatment to reduce IL-6 levels may explain the resistance to treatment in this model.

Animals↗
PubMed1994

Increased expression of the 72-kd type IV collagenase in prostatic adenocarcinoma. Demonstration by immunohistochemistry and in situ hybridization.

The expression of the 72-kd type IV collagenase has been implicated as an important factor in determining the invasive potential of malignant tumors. Using immunohistochemistry and nonisotopic in situ hybridization, type IV collagenase expression was assessed in benign and malignant prostatic tissue obtained from 117 surgical and autopsy specimens. Diffuse strong staining for type IV collagenase mRNA and protein was identified in the malignant cells of more than 85% of prostatic adenocarcinomas and the dysplastic cells of high grade prostatic intraepithelial neoplasia. Benign hyperplastic epithelium showed moderate expression in basal cells and mild expression in secretory cells. The qualitative patterns of type IV collagenase expression in prostatic epithelium at the protein and mRNA levels in individual cases were identical. There was no correlation between the level of type IV collagenase expression and either tumor grade or stage. In 10% of adenocarcinomas, focal mild to moderate stromal cell immunoreactivity was present but mRNA was not detectable in the stromal compartment in any case. The enhanced expression of type IV collagenase in dysplastic epithelium and prostatic adenocarcinoma suggests it contributes to the development of the invasive phenotype. The vast majority of the enzyme present in these tumors is synthesized by malignant cells and its production by stromal cells is negligible.

Adenocarcinoma↗
PubMed1993

Synthesis of digoxigenin-labeled cRNA probes for nonisotopic in situ hybridization using reverse transcription polymerase chain reaction.

Nonisotopic methods of mRNA in situ hybridization have distinct advantages over isotopic techniques. Nonisotopically labeled probes are stable and nontoxic, have short detection times, demonstrate excellent spatial resolution of their signals and have sensitivities comparable to radiolabeled probes. We developed a simple method of generating nonisotopically labeled cRNA probes which is based on the reverse transcription polymerase chain reaction (RT-PCR) and used it to synthesize a panel of probes for various murine extracellular matrix genes. Engelbreth-Holm-Swarm (EHS) tumor RNA was reverse transcribed and PCR was used to amplify defined regions of multiple extracellular matrix protein genes from the resulting first strand cDNAs. Bacteriophage promoters which had been incorporated into the PCR products were then used to generate digoxigenin-conjugated antisense and sense cRNAs. The antisense probes were employed to detect the specific extracellular matrix protein mRNAs in the EHS tumor by in situ hybridization. This technique provides a rapid and efficient alternative to conventional transcription systems which use plasmid vectors for the synthesis of digoxigenin-labeled cRNA probes.

Animals↗