Biomedical subjects

I Leigh

Publications and source records attributed to I Leigh.

At least 19 recordsLinked to original sources

PubMed2005

Cytokeratin expression in pili annulati hair follicles.

Pili annulati is a rare autosomal inherited hair shaft abnormality of unknown pathogenesis in which clinical examination reveals alternating light and dark bands leading to a shiny appearance of the hair due to cavities within the cortex of the hair shaft. This is the first investigation of the proposed cytokeratin defect in pili annulati hair follicles. Four cryopreserved pili annulati and four control scalp specimens were analysed using immunohistochemistry for different 'hard' trichocytic and 'soft' epithelial cytokeratins including K1, K6, K10, K14, K16, K17, K18, K19, Ha1 and Hb1. There was no difference in staining intensity and quality of staining pattern seen in pili annulati and control scalp specimens. These results suggest that pili annulati is not caused by a defect of the cytokeratins investigated in this study.

Adult↗

PubMed2003

Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.

Germline mutations of the fumarate hydratase (FH, fumarase) gene are found in the recessive FH deficiency syndrome and in dominantly inherited susceptibility to multiple cutaneous and uterine leiomyomatosis (MCUL). We have previously reported a number of germline FH mutations from MCUL patients. In this study, we report additional FH mutations in MCUL and FH deficiency patients. Mutations can readily be found in about 75% of MCUL cases and most cases of FH deficiency. Some of the more common FH mutations are probably derived from founding individuals. Protein-truncating FH mutations are functionally null alleles. Disease-associated missense FH changes map to highly conserved residues, mostly in or around the enzyme's active site or activation site; we predict that these mutations severely compromise enzyme function. The mutation spectra in FH deficiency and MCUL are similar, although in the latter mutations tend to occur earlier in the gene and, perhaps, are more likely to result in a truncated or absent protein. We have found that not all mutation-carrier parents of FH deficiency children have a strong predisposition to leiomyomata. We have confirmed that renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome, and have shown that these cancers may have either type II papillary or collecting duct morphology. We have found no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients can indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. We conclude that MCUL is probably a genetically homogeneous tumour predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity, with currently unknown functional consequences for the smooth muscle or kidney cell.

Amino Acid Metabolism, Inborn Errors↗

PubMed2003

Vascular patterns in reactive lymphoid tissue and in non-Hodgkin's lymphoma.

The few studies published on angiogenesis in lymphoma have raised the question of whether or not microvessel density (MVD) is associated with more aggressive disease and have reported the observation that in follicular lymphomas, vessels are mature rather than immature. We investigated MVD and the vascular phenotype within follicular or diffuse large B-cell lymphomas, reactive nodes and tonsils. Vascular phenotype was defined by the expression or loss of reactivity to the antibody LH39 (detecting the LH39 laminin epitope of the basement membrane in mature vessels) and by detection of alpha V beta 3 (expressed on immature vessels). In reactive nodes and in follicular lymphomas, MVD was higher in the paracortex than in germinal centres or in neoplastic follicles. However, in neoplastic follicles an increase in alpha V beta 3-positive endothelium suggested the activation of an angiogenic pathway different from that present in the reactive follicles. In large B-cell lymphomas, MVD was higher than in reactive and neoplastic follicles but lower than in the reactive paracortex. The number of immature vessels (LH39 negative) and of alpha V beta 3-positive vessels was higher than in reactive lymph nodes and follicular lymphoma suggesting that a switch to a different angiogenic pathway has occurred. Finally, we have demonstrated that within reactive and neoplastic follicles vascular regression is occurring, perhaps constraining the growth of reactive follicles alongside other phenomena such as apoptosis. Vascular regression was previously believed to occur in adults only in ovarian and endometrial tissue. We conclude that different types of angiogenesis are present in follicular lymphomas and large B-cell lymphomas. This has implications for possible future therapies.

Basement Membrane↗

PubMed2002

Vascular phenotype in angiogenic and non-angiogenic lung non-small cell carcinomas.

We have previously described a group of non-small cell lung carcinomas without morphological evidence of neo-angiogenesis. In these tumours neoplastic cells fill up the alveoli and the only vessels present appear to belong to the trapped alveolar septa. In the present study we have characterised the phenotype of the vessels present in these non-angiogenic tumours, in normal lung and in angiogenic non-small cell lung carcinomas. The vessels, identified by the expression of CD31, were scored as mature when expressing the epitope LH39 in the basal membrane and as newly formed when expressing alphaVbeta3 on the endothelial cells and/or lacking LH39 expression. In the nine putative non-angiogenic cases examined, the vascular phenotype of all the vessels was the same as that of alveolar vessels in normal lung: LH39 positive and alphaVbeta3 variable or negative. Instead in 104 angiogenic tumours examined, only a minority of vessels (mean 13.1%; range 0--60%) expressed LH39, while alphaVbeta3 (in 45 cases) was strongly expressed on many vessels (mean 55.5%; range 5--90%). We conclude that in putative non-angiogenic tumours the vascular phenotype is that of normal vessels and there is no neo-angiogenesis. This type of cancer may be resistant to some anti-angiogenic therapy and different strategies need to be developed.

Carcinoma, Non-Small-Cell Lung↗

PubMed2000

Linkage and LOH studies in 19 cylindromatosis families show no evidence of genetic heterogeneity and refine the CYLD locus on chromosome 16q12-q13.

Familial cylindromatosis is an autosomal dominant predisposition to multiple neoplasms of the skin appendages. The susceptibility gene has previously been mapped to chromosome 16q12-q13 and has features of a recessive oncogene/tumour suppressor gene. We have now evaluated 19 families with this disease by a combination of genetic linkage analysis and loss of heterozygosity in cylindromas from affected individuals. All 15 informative families show linkage to this locus, providing no evidence for genetic heterogeneity. Recombinant mapping has placed the gene in an interval of approximately 1 Mb. There is no evidence, between families, of haplotype sharing that might be indicative of common founder mutations.

Carcinoma, Adenoid Cystic↗

PubMed2000

Identification of the familial cylindromatosis tumour-suppressor gene.

Familial cylindromatosis is an autosomal dominant genetic predisposition to multiple tumours of the skin appendages. The susceptibility gene (CYLD) has previously been localized to chromosome 16q and has the genetic attributes of a tumour-suppressor gene (recessive oncogene). Here we have identified CYLD by detecting germline mutations in 21 cylindromatosis families and somatic mutations in 1 sporadic and 5 familial cylindromas. All mutations predict truncation or absence of the encoded protein. CYLD encodes three cytoskeletal-associated-protein-glycine-conserved (CAP-GLY) domains, which are found in proteins that coordinate the attachment of organelles to microtubules. CYLD also has sequence homology to the catalytic domain of ubiquitin carboxy-terminal hydrolases (UCH).

Amino Acid Sequence↗

PubMed1999

Development of autologous human dermal-epidermal composites based on sterilized human allodermis for clinical use.

The aim of this study was to identify a sterilization technique for the preparation of human allodermis which could be used as a dermal component in wound healing and as the dermal base for production of dermal-epidermal composites for one-stage grafting in patients. We report that it is possible to produce dermal-epidermal composites which perform well in vitro and in vivo using a standard ethylene oxide sterilization methodology. Prevention of ethylene oxide-induced damage to the dermis was achieved using gentle dehydration of the skin prior to ethylene oxide sterilization. The issue of whether viable fibroblasts are required for composite production was examined in comparative studies using glycerol vs. ethylene oxide sterilized dermis. Where good collagen IV retention was achieved following preparation of acellular de-epidermized dermis there was no advantage to having fibroblasts present in vitro or in vivo; however, where collagen IV retention was poor or where keratinocytes were initially expanded in culture then there was a significant advantage to introducing fibroblasts to the composites during their preparative 10-day period in vitro. The requirement for fibroblasts became less evident when composites were grafted on to nude mice. In conclusion, we report a protocol for the successful sterilization of human allodermis to achieve an acellular dermis with good retention of collagen IV. This acellular dermis would be appropriate for clinical use as a dermal replacement material. It can also be used for the production of dermal-epidermal composites using autologous keratinocytes (with or without fibroblasts).

Adult↗

PubMed1999

Parent bonding in clinically depressed deaf and hard-of-hearing adults.

This study assessed the relationships between parent communication variables and the parent bonding factors of care and overprotection using a sample of 38 deaf and hard-of-hearing individuals connected with mental health services who had DSM-III-R or DSM-IV diagnoses of depression-related disorders. The 22 therapists working with these individuals also contributed to data collection. Results based on revised depression (BDI-R) and parent bonding (PBI-R) questionnaires, together with background data from both clients and therapists, indicate that higher ratings of depression are associated with less perceived care by mother and greater perceived overprotection by both mother and father. Paternal care and overprotection were negatively correlated, as were maternal care and overprotection. In comparison to hard-of-hearing counterparts, deaf participants were less depressed and had more positive ratings of communication with their parents. The BDI-R scores positively and significantly correlated with coded severity of diagnosis. Due to the small sample size, findings are suggestive. Further study is warranted.

Journal Article↗

PubMed1999

Inclusive education and personal development.

Open-ended questionnaires covering mainstream educational experiences and personal development of deaf and hard-of-hearing adults were analyzed. Half of the 34 deaf and hard-of-hearing respondents altered self-labels based on changes in personal definitions rather than audiological changes. Supportive school environments and coping skills contributed to positive perceptions; nonsupportive school environments and being treated as 'different' were viewed negatively. Everyone valued contact with hearing peers. Contact with deaf peers depended on finding those with similar values. Identification with Deaf culture was nonexistent. Most noteworthy, 24 of 34 participants felt caught between the deaf and hearing worlds, indicating the need for niches in both. Implications for educators are that development of self-confidence and comfort with identity may be enhanced by validating the deafness dimension through opportunities for contact with deaf adults and positive relationships with both deaf and hearing peers.

Journal Article↗

PubMed1998

Infantile myofibromatosis: a rare presentation with intussusception.

Infantile myofibromatosis (IM) is a distinct but rare clinicopathological entity occurring in neonates and infants. It probably represents a rare soft-tissue tumour made up of undifferentiated myofibroblasts. Its recognition is important since it can be mistaken for a malignancy when, in fact, it has a generally benign prognosis with spontaneous regression. We describe the first case of an infant with IM presenting with acute intussusception due to gastrointestinal as well as the typical skin involvement.

Acute Disease↗

PubMed1998

Deaf/hearing cultural identity paradigms: modification of the deaf identity development scale.

The Deaf Identity Development Scale (Glickman, 1993) was modified to include hearing individuals and examine how hearing and deaf adults identify themselves. Statistical analysis based on 244 deaf, hard-of-hearing, and hearing respondents revealed a significant interaction between hearing status of self and parents on the hearing, marginal, and immersion scales of the modified version but not on the bicultural scale. Codas are more marginalized, less immersed, and similarly 'hearing' in comparison to deaf persons with deaf parents. Hard-of-hearing respondents with deaf parents endorse more hearing values and fewer deaf values in comparison to deaf counterparts and also appear to be more marginalized. There were no significant differences between deaf and hard-of-hearing individuals with hearing parents. Compared to hearing respondents with hearing parents, deaf counterparts were more marginalized, more 'hearing,' and equally 'deaf.' Strong professional affiliation with the deaf community resulted in scores that differed significantly from those for individuals not as strongly affiliated. We discuss implications for identity development.

Journal Article↗

PubMed1998

Activated keratinocytes in the epidermis of hypertrophic scars.

The etiology of hypertrophic scarring, a pathological end point of wound healing, is unknown. The scars most commonly occur when epithelialization has been delayed during, for example, the healing of deep dermal burn wounds. Hypertrophic scars are conventionally described as a dermal pathology in which the epidermis has only a passive role. In this study, the expression of keratin intermediate filament proteins and filaggrin has been investigated in the epidermis of hypertrophic scars and site-matched controls from the same patients. Hypertrophic scar epidermis was found to express the hyperproliferative keratins K6 and K16 in interfollicular epidermis in association with K17 and precocious expression of filaggrin. K16 mRNA was localized by in situ hybridization using a highly specific cRNA probe. In contrast to the immunohistochemical location of K16 protein, the K16 mRNA was found to be expressed in the basal cell layer of normal skin. In hypertrophic scars the mRNA distribution corroborated the abnormal K16 protein distribution. These results suggest the keratinocytes in hypertrophic scar epidermis have entered an alternative differentiation pathway and are expressing an activated phenotype. Activated keratinocytes are a feature of the early stages of wound healing producing growth factors that influence fibroblasts, endothelial cells, and the inflammatory response. We propose that cellular mechanisms in the pathogenesis of hypertrophic scarring are more complex than isolated dermal phenomena. The persistence of activated keratinocytes in hypertrophic scar epidermis implicates abnormal epidermal-mesenchymal interactions.

Adult↗

PubMed1995

Expression of type VII collagen, the major anchoring fibril component, in normal and neoplastic human nervous system.

The distribution of type VII collagen was examined in the normal human nervous system, in brain tumour biopsies and in glioma cell lines by immunohistochemistry and western blotting. In normal tissue, positivity was observed beneath choroid plexus epithelial cells and around pineal gland and pituitary gland cell nests, while other brain regions and peripheral nerves were negative. Expression was preserved in most related tumours (choroid plexus papilloma, pineoblastoma, pituitary adenoma). Scattered abnormal vessels showed neo-expression of type VII collagen in about half of the astrocytic and ependymal tumours. Glioma cells in situ were consistently negative for type VII collagen, whereas the glioblastoma cell lines were positive. Our results suggest that anchoring fibrils or at least epitopes of their major structural component are present in normal and pathological cerebral structures, indicating a unique distribution of type VII collagen in the nervous system.

Adult↗

PubMed1995

Transplantation of keratinocytes in the treatment of wounds.

BACKGROUND: Keratinocyte grafting can be used to treat acute traumatic and chronic non-healing wounds. The keratinocyte sheets are fragile and clinical "take" is difficult to assess, especially as activated keratinocytes secrete many growth factors, which have effects on wound healing apart from take. We have developed animal models of grafting that allow us to examine factors influencing autologous keratinocyte graft take. Results show clearly that pretreatment of the wound bed with viable dermis greatly increases the take of keratinocyte grafts. DATA SOURCES: International literature. CONCLUSIONS: As a greater understanding of the complex interactions of cell and matrix evolve, so will potential therapeutic maneuvers, not just in the field of cultured keratinocyte grafts, but clearly in that of benign tumors, for example, keloids, and that of oncology. There is now overwhelming evidence of the requirement for a dermal substitute for cultured keratinocyte autografts, and the sheet complexity of the situation demands that this should approximate live human dermis as closely as possible. The stumbling blocks relate to avoiding the risks of viral transmission, tissue matching of host and donor, providing early epithelial cover, and improving delivery systems for fragile keratinocyte grafts.

Animals↗

PubMed1995

Cutaneous squamoproliferative lesions in renal transplant recipients. Differentiation from lesions in immunocompetent patients.

Of 291 immunosuppressed renal transplant recipients (RTRs) with surviving allografts attending the Royal London Hospital, 171 patients (59%) were found to have warty keratoses. On histological analysis, the lesions in 50 patients (17%) showed partial-thickness dysplasia, and 34 (12%) had one or more invasive squamous cell carcinoma (SCC) and/or one or more in situ SCC or full-thickness dysplasia. We examined the claim that squamoproliferative lesions in RTRs possess distinctive histopathological features that differ from those of similar lesions occurring sporadically in the nonimmunosuppressed population. We compared 40 squamoproliferative lesions from RTRs with 40 matched squamoproliferative lesions from nonimmunosuppressed patients; lesions were coded and their source was unknown to the assessors. Two dermatopathologists independently assessed the cases and gave scores for 11 histological features that have been reported to be characteristic of such lesions in the immunosuppressed population. These included a warty architecture, koilocytes, and multinucleate giant cells. Using these criteria, it was not possible to distinguish lesions of immunosuppressed patients from those of immunocompetent people.

Carcinoma in Situ↗

PubMed1995

Generation and selection of monoclonal antibodies, single-chain Fv and antibody fusion phage specific for human melanoma-associated antigens.

A panel of 13 murine monoclonal antibodies (mAbs) recognizing antigens on human melanoma cells but not on melanocytes was generated. Two mAbs (LHM3 and LHM5) stained sections of melanoma but not normal tissues. mAbs LHM2 and LHM8 stained only a minority of normal tissues. The mAbs differed further in their staining patterns on melanoma cell lines HMB2, DX3 and SK23 in FACS. The mAbs recognize antigens of 34, 38, 57, 94, 190-200 and > 200 kD. One mAb each bound to each of the antigens HLA DR (LHM4) and high molecular weight proteoglycan (LHM2). The high molecular weight proteoglycan-specific mAb was used to construct a single-chain Fv (scFv) antibody fragment and an antibody fusion phage in Escherichia coli. Both the scFv and the fusion phage were shown to bind specifically to melanoma cells. A method for the selection of melanoma cell-binding phages from phage libraries is described.

Animals↗

PubMed1995

Development and characterization of a novel xenograft model permissive for human papillomavirus DNA amplification and late gene expression.

Human papillomaviruses (HPVs) are important human pathogens associated with a range of epithelial neoplasia. The rising incidence of HPV infection and association of HPV with malignancy has led to increased interest in appropriate management of these infections. Development of new therapies for viral warts has been frustrated by the lack of availability of models permissive for viral replication. Here we describe the development of HPV-severe combined immunodeficient mouse model which reproduces mature HPV-infected epithelia. Grafting of anogenital and laryngeal papillomas harbouring either HPV-6 or HPV-11 resulted in the formation of a differentiated neo-epithelium exhibiting the hallmark features of HPV infection including basal hyperplasia, acanthosis and koilocytosis. The reformed warty epithelium contained amplified HPV DNA and expressed capsid protein in the differentiated layers. A striking feature is the production of macroscopic papillomata in an anatomically relevant and accessible site, providing a system of particular relevance for the temporal evaluation of developing lesions and selection of antiviral agents.

Animals↗

PubMed1994

Comparative analysis of normal and psoriatic skin both in vivo and in vitro.

The morphological and biochemical characteristics of psoriasis are well documented, but the pathogenesis of this disease is not clearly understood. A variety of in vitro models of psoriasis have been developed in attempts to identify the trigger factors, but no model so far reproduces the stable psoriatic phenotype accurately. In the present work, we initially checked the immunohistochemical distribution of proliferation/differentiation markers in psoriatic skin in vivo, and our results largely confirm previously reported data. However the study was performed using a new series of monoclonal antibodies to keratin. Subsequently we took normal or psoriatic skin biopsies, reconstructed skin equivalents using a recently described model and analysed the proliferation/differentiation status of the resulting epidermis. Dramatic morphological and antigenic differences were found between normal and psoriatic skin in vivo, but whatever the source of the initial biopsy, a unique in vitro phenotype was obtained in the reconstructed epidermis. This phenotype was marked by mild hyperproliferation and an altered distribution of differentiation-associated antigens suggesting a need for extracutaneous stimuli to maintain the psoriatic phenotype in vitro.

Antibodies, Monoclonal↗