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Biomedical subjects

H Slater

Publications and source records attributed to H Slater.

At least 19 recordsLinked to original sources
PubMed2000

Chromosome analysis of blastomeres from human embryos by using comparative genomic hybridization.

Karyotypic studies of aborted fetuses have been used to draw the inference that the proportion of conceptuses with chromosome abnormalities is very high. Fluorescent in situ hybridization (FISH) studies of blastomeres from early cleavage embryos have provided some support for this inference but they are limited to the study of a few chromosomes. We describe the novel application of comparative genomic hybridization (CGH) to the study of numerical and structural abnormalities of single blastomeres from disaggregated 3-day-old human embryos. CGH results were obtained for 63 blastomeres from 12 embryos. Identification of all chromosomes with the exception of chromosomes 17, 19, 20 and 22 was possible. The embryos divided into four groups: (1) embryos with a normal CGH karyotype seen in all blastomeres; (2) embryos with consistent aneuploidy suggesting meiotic non-disjunction had occurred; (3) embryos that were mosaic generally with one or more cells showing aneuploidy for one or two chromosomes but some with cells showing extensive aneuploidy; and (4) one embryo with extensive aneuploidy in all blastomeres. The extensive aneuploidy in group 4 is interpreted as corresponding to the random aneuploidy seen in "chaotic" embryos reported by using interphase FISH. Partial chromosome loss and gain following chromosome breakage was observed in one embryo. Our analysis provides basic biological information on the occurrence of constitutional and post-zygotic chromosome abnormalities in early human embryos. Used in conjunction with embryo biopsy, diagnostic CGH should allow the exclusion of a proportion of embryos that appear normal but that have a poor probability of survival and, therefore, may improve the implantation rate after in vitro fertilization.

Base Sequence↗
PubMed1999

Trisomy 20p resulting from inverted duplication and neocentromere formation.

Normal human centromeres contain large tandem arrays of alpha-satellite DNA of varying composition and complexity. However, a new class of mitotically stable marker chromosomes which contain neocentromeres formed from genomic regions previously devoid of centromere activity was described recently. These neocentromeres are fully functional yet lack the repeat sequences traditionally associated with normal centromere function. We report here a supernumerary marker chromosome derived from the short arm of chromosome 20 in a patient with manifestations of dup(20p) syndrome. Detailed cytogenetic, FISH, and polymorphic microsatellite analyses indicate the de novo formation of the marker chromosome during meiosis or early postzygotically, involving an initial chromosome breakage at 20p11.2, followed by an inverted duplication of the distal 20p segment due to rejoining of sister chromatids and the activation of a neocentromere within 20p12. This inv dup(20p) marker chromosome lacks detectable centromeric alpha-satellite and pericentric satellite III sequences, or centromere protein CENP-B. Functional activity of the neocentromere is evidenced by its association with 5 different, functionally critical centromere proteins: CENP-A, CENP-C, CENP-E, CENP-F, and INCENP. Formation of a neocentromere on human chromosome 20 has not been reported previously and in this context represents a new mechanism for the origin of dup(20p) syndrome.

Centromere↗
PubMed1999

Syndromal obesity due to paternal duplication 6(q24.3-q27).

The likelihood of a paternally expressing imprinted gene in chromosome region 6(q23-24) has been highlighted by cases of transient neonatal diabetes mellitus (TNDM) in which paternal uniparental disomy (UPD) for chromosome 6 or paternal duplication 6(q23-qter) was detected. We present the case of a 38-year-old man with moderate to severe intellectual delay, short stature, small hands and feet, eye abnormality, small mouth, and obesity (without hyperphagia) beginning in mid-childhood. The perinatal and neonatal histories were normal. The patient had a duplication within 6q. Fluorescence in situ hybrisation studies were performed with single and dual hybridisations using a chromosome 6 library probe, short and long arm subregional probes, 6q23-24, 6q25.3-6qter locus-specific probes, and a 6q telomere probe. The hybridisation results defined an inverted duplication of 6q24.3 to 6q27. DNA studies with microsatellite markers from 6p and 6q showed regular biparental inheritance of chromosome 6 and confirmed that the duplication was paternal in origin. Our patient appears to be the first one known to have paternal duplication of chromosome area 6(q24-q27) who did not have TNDM as an infant. He has remained nondiabetic, although obesity, without hyperphagia, has been a constant problem since its onset in mid-childhood.

Adult↗
PubMed1999

Detection of aneuploidy in single cells using comparative genomic hybridization.

The ability of comparative genomic hybridization (CGH) to detect aneuploidy following universal amplification of DNA from a single cell, or a small number of cells, was investigated with a view to preimplantation diagnosis following in vitro fertilization, and prenatal diagnosis using fetal erythroblasts obtained from maternal blood. The DNA obtained from lysed single cells was amplified using degenerate oligonucleotide-primed PCR (DOP-PCR). This product was labelled using nick translation and hybridized together with normal reference genomic DNA. The CGH fluorescent ratio profiles obtained could be used to determine aneuploidy with cut-off thresholds of 0.75 and 1.25. Deviation in the profiles in the heterochromatic regions was reduced by using, as a reference sample, normal genomic DNA that had also undergone DOP-PCR. Single cells known to be trisomic for chromosomes 13, 18 or 21 were analysed using this technique. The resolution of CGH with amplified DNA from a single cell is of the order of 40 Mb, sufficient for the diagnosis of trisomy 21, and possibly segmental aneuploidy of equivalent size. These results, and those of others, demonstrate that diagnosis of chromosomal aneuploidy in single cells is possible using CGH with DOP-PCR amplified DNA.

Aneuploidy↗
PubMed1998

The fragile X syndrome.

Fragile X syndrome (FXS) is the most common cause known of inherited developmental disability. New and widely available techniques in DNA analysis allow both affected individuals and carriers to be tested from a simple blood sample. It is now recognised that a wide range of clinical severity occurs in both sexes. Specific treatment and interventional strategies are now available and of great benefit to individuals, families and carers. Genetic counselling allows families to make informed decisions. General practitioners can play a central role in detection and management of this syndrome.

Fragile X Syndrome↗
PubMed1997

A novel regulatory system required for pathogenicity of Xanthomonas campestris is mediated by a small diffusible signal molecule.

Mutations in the seven clustered rpf genes cause downregulated synthesis of extracellular enzymes and reduced virulence of Xanthomonas campestris pathovar campestris (Xcc). The phenotype of mutants in one of the genes, rpfF, can be restored by a diffusible extracellular factor (DSF) produced by all Xcc strains tested, apart from rpfF and rpfB mutants. DSF accumulates in early stationary phase (when synthesis of enzymes is maximal), but levels decline subsequently. Addition of DSF to exponentially-growing wild-type bacteria does not cause precocious enzyme synthesis. rpfB and rpfF are expressed throughout growth, but the rate increases in early stationary phase. RpfB is predicted to be a long-chain fatty acyl CoA ligase, and RpfF shows some relatedness to enoyl CoA hydratases. The properties of DSF suggest that it may be a fatty-acid derivative, and certain lipid preparations possess DSF activity at higher concentrations. These include lipid extracts and acid-hydrolysed lipoplysaccharide and lipid A from Xcc, and purified dodecanoic and hydroxydodecanoic acid. DSF production is confined to certain xanthomonads. We propose a model for the DSF system, which represents a novel mechanism for regulating virulence factor synthesis in response to physiological or environmental changes.

Diffusion↗
PubMed1997

"Reduction" of CGG trinucleotide expansion from mother to offspring in seven fragile-X families.

Apparent reduction in the size of the CGG repeat is reported from seven fragile-X mothers to nine offspring in seven extended families. The overall frequency of the reduction amongst 121 fragile-X mother-fragile-X child transmissions was 7.4%, compared with an 18% reduction in fragile-X father-fragile-X daughter transmissions, but ascertainment bias may account for some underestimation of the frequency of reductions, especially between mothers and their offspring. In one mother-son transmission, a premutation present in the son (with a full mutation present in the mother) was unmethylated. This may be the result of either demethylation with reduction, or undetected mosaicism in the mother. There was no obvious increase in the level of intellectual performance in female offspring who received a reduced fragment from their mothers. Several mechanisms leading to apparent reduction, such as germline mosaicism, deletion or replication slippage, should be considered.

Adolescent↗
PubMed1997

Transforming growth factor beta 1 and interleukin 4 induced alpha smooth muscle actin expression and myofibroblast-like differentiation in human synovial fibroblasts in vitro: modulation by basic fibroblast growth factor.

OBJECTIVE: To discover if alpha smooth muscle actin expression and myofibroblastic differentiation are induced in synovial fibroblasts by cytokines found in the inflamed RA joint. METHODS: Immunofluorescent microscopy and western blotting were used to examine different cultures of human synovial fibroblasts for expression of alpha actin in the presence of the cytokines transforming growth factor beta (TGF beta 1), interleukin 1 alpha (IL1 alpha), IL4, IL6, tumour necrosis factor alpha (TNF alpha), and basic fibroblast growth factor (FGF). RESULTS: A small but significant population of cells (14.4 +/- 12.9%) expressed alpha actin under standard culture conditions. Upon treatment with TGF beta 1 there was a pronounced increase in the number of cells expressing alpha actin (68.1 +/- 5.49%), accompanied by a change in morphology to a myofibroblast-like phenotype. Other cytokines found within the inflamed joint such as IL1, TNF alpha, IL6, and basic FGF failed to induce alpha actin expression. However, IL4, which is normally absent or only present at low concentrations in the RA joint had a similar effect to TGF beta 1. It was also found that basic FGF inhibited the induction of alpha actin expression by TGF beta 1 and IL4. CONCLUSION: In the presence of TGF beta 1 or IL4, fibroblasts derived from synovial tissue or synovial fluid are induced to differentiate into myofibroblast-like cells containing the alpha smooth muscle form of actin. This differentiation is inhibited by basic FGF. It is suggested that the balance between these particular cytokines may be important in the modulation of fibroblast behaviour, which could have significant effects on joint repair mechanisms and the generation of fibrous tissue within the rheumatoid joint.

Actins↗
PubMed1997

Screening for diabetic retinopathy in primary care: retinal photography alone can be used efficiently and effectively to exclude those with sight threatening lesions.

BACKGROUND: Good screening performance of retinal photography and ophthalmoscopy together in screening for diabetic retinopathy in primary care have been reported. This study reanalysed the data to evaluate the screening performance of photography alone. METHODS: One thousand and ten patients screened by fundal photography and ophthalmoscopy were studied retrospectively. Fundal photographs were quality graded with poor quality pictures being excluded from the analysis. Each patient was reviewed initially by both retinal photographs and ophthalmoscopy by an ophthalmologist, the "gold standard". Six months later the fundal photographs were reviewed and reported in a blinded manner by the ophthalmologist. RESULTS: Two thousand and fourteen photographs were obtained, of which 162 (8%) had to be excluded because of poor quality. On review of the remaining 1852 photographs in isolation, of 77 cases of severe retinopathy as determined by the "gold standard", 67 had severe changes on photography--detection rate 87%. Of the 1775 cases without sight threatening retinopathy only five were judged to have sight threatening changes on photography--false positive rate 0.3%. Considering sight threatening and background retinopathy together, the detection rate was 69% (257 of 375) and the false positive rate 1.6% (23 of 1477). CONCLUSION: Good quality fundal photographs alone seem specific enough to screen for sight threatening diabetic retinopathy, but will underdetect background retinopathy.

Diabetic Retinopathy↗
PubMed1997

Prader-Willi syndrome.

People with Prader-Willi syndrome (PWS) and their families provide a unique challenge to the general practitioner. This article provides an outline of the key information and management issues for general practitioners who care for people with PWS and their families.

Family Practice↗
PubMed1996

Ophthalmological complications as a manifestation of burn injury.

Facial burns are a frequent component of the presentation of victims who have sustained thermal trauma, reportedly occurring in 20 per cent of burn patients. Even apparently 'f2p4r' facial injuries might well be associated with significant ocular trauma. A retrospective review of 865 patients admitted to our burn centre showed 22 per cent (192) with facial burns. Ocular involvement, defined as globe or eyelid pathology, was present in 15 per cent (127) of these patients. The aetiology and spectrum of ocular injuries is reviewed with lid burns and subsequent lid contractures, accounting for over 50 per cent of ocular complications. Serious ocular pathology necessitating enucleation occurred in only two patients. The difficulties encountered in performing a complete ophthalmological examination in the presence of facial burns are presented in conjunction with a recommended therapeutic plan.

Contracture↗
PubMed1995

Primary cutaneous Ewing's sarcoma/peripheral primitive neuroectodermal tumors in childhood. A molecular, cytogenetic, and immunohistochemical study.

Childhood cutaneous and subcutaneous malignancies are rare and include metastatic tumors of diverse histogenesis as well as primary lesions, such as sweat gland carcinomas. Some cutaneous malignancies exhibit a small round cell tumor morphology with few definitive differentiating features; they can thus pose a significant diagnostic problem. We describe two primary malignancies of the skin and superficial subcutis, which were originally diagnosed as sweat gland carcinomas on the basis of their morphological features. A cytogenetic analysis performed on one of these lesions showed the t(11;22)(q24;q12) rearrangement, believed to be unique to the Ewing's sarcoma/peripheral primitive neuroectodermal tumor (ES/pPNET) group of neoplasms. In view of this unexpected result, reverse transcriptase-polymerase chain reaction analysis was performed on both lesions and showed that they expressed EWS/FLI-1 fusion gene mRNA transcripts, the molecular equivalent of t(11;22)(q24;q12). The two tumors also had an immunohistochemical profile suggesting ES/pPNET, including strong expression of the MIC2 antigen. Both patients were treated with wide local excision, and one was given a course of chemotherapy. Neither patient showed evidence of tumor elsewhere after follow-up periods of 2 years and 16 years. These findings suggest that these tumors are indeed a form of primary ES/pPNET arising in the skin or superficial subcutis, which may be of low-grade malignancy and curable by local surgery.

Base Sequence↗
PubMed1995

Expansion of the CGG repeat in fragile X in the FMR1 gene depends on the sex of the offspring.

Analysis of 139 mother-to-offspring transmissions of fragile X CGG triplet repeats revealed that the repeat expansion is enhanced in mother-to-son transmissions compared with mother-to-daughter transmissions. Evidence has been based on analysis of mother-offspring differences in the size of repeat (in kb), as well as on comparisons between proportions of male and female offspring with premutations, and full mutations, inherited from mothers carrying a premutation. Mean difference in the repeat size from mother-son transmissions was 1.45 kb, compared with mother-daughter transmissions of 0.76 kb. The difference is due primarily to a greater proportion of male than female offspring with full mutation from the premutation mothers and also to a higher frequency of reduction in repeat size from mothers to daughters than from mothers to sons. Our findings suggest the possibility of an interaction of the normal X homologue in a female zygote with the FMR1 sequence on the fragile X during replication to account for the lower level of expansion in mother-to-daughter transmissions relative to mother-to-son transmissions.

Female↗
PubMed1994

Maternal uniparental disomy of chromosome 13 in a phenotypically normal child.

A case of maternal uniparental disomy of chromosome 13 is described. The subject is a phenotypically normal male who inherited a t(13;13)(p11.2;p11.2) from his mother who is a carrier of this translocation. The mother was ascertained through a history of recurrent abortion and is phenotypically normal. The translocation in both subjects was studied by cytogenetic and DNA analysis and appears to be a true dicentric isochromosome. These findings show that maternal uniparental disomy of chromosome 13 has had no pathological consequences and suggests that there is no imprinting of genes on maternally derived chromosome 13.

Abortion, Habitual↗
PubMed1992

Absence of satellite III DNA in the centromere and the proximal long-arm region of human chromosome 14: analysis of a 14p- variant.

Cytogenetic methods and molecular probes derived from the centromere and short arm of chromosome 14 were used to investigate the structural properties of a chromosome 14 variant. Results of GTL, CBG, Ag-NOR, and non-banded Giemsa staining of the chromosomes suggested the complete absence of the short arm and possibly a large part of the centromere. Negative in situ hybridisation with an alpha satellite III probe confirmed the absence of the arm; the detection of normal amounts of alpha satellite DNA, however, indicated retention of the centromeric domain. The natural occurrence of a human acrocentric variant lacking a short arm was thus established. Within the detection limits of the methods used, the results demonstrate that satellite III DNA is not essential for normal centromeric activity and allow us to exclude the presence of this satellite DNA within the centromere and proximal long-arm region of human chromosome 14.

Centromere↗
PubMed1992

Chondritis of the burned ear: a review.

Seventy-six patients with burns of the ears presented to the Western Pennsylvania Hospital Burn Trauma Center over a three year period. To prevent chondritis, all ears were treated prophylactically with periauricular hair shaving, daily cleaning, avoidance of pressure dressings and Sulfamylon Burn Cream. Chondritis developed in two patients. Aspects of auricular chondritis prevention and treatment are reviewed. Biology of the disease is discussed.

Burns↗