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P Itin

Publications and source records attributed to P Itin.

At least 19 recordsLinked to original sources
PubMed1998

Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis.

Erythrokeratodermia variabilis (EKV, OMIM 133200) is an autosomal dominant genodermatosis with considerable intra- and interfamilial variability. It has a disfiguring phenotype characterized by the independent occurrence of two morphologic features: transient figurate red patches and localized or generalized hyperkeratosis. Both features can be triggered by external factors such as trauma to the skin. After initial linkage to the RH locus on 1p, EKV was mapped to an interval of 2.6 cM on 1p34-p35, and a candidate gene (GJA4) encoding the gap junction protein alpha-4 (connexin 31, Cx31) was excluded by sequence analysis. Evidence in mouse suggesting that the EKV region harbours a cluster of epidermally expressed connexin genes led us to characterize the human homologues of GJB3 (encoding Cx31) and GJB5 (encoding Cx31.1). GJB3, GJB5 and GJA4 were localized to a 1.1-Mb YAC in the candidate interval. We detected heterozygous missense mutations in GJB3 in four EKV families leading to substitution of a conserved glycine by charged residues (G12R and G12D), or change of a cysteine (C86S). These mutations are predicted to interfere with normal Cx31 structure and function, possibly due to a dominant inhibitory effect. Our results implicate Cx31 in the pathogenesis of EKV, and provide evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors.

Amino Acid Sequence↗
PubMed1998

Enhanced expression of transforming growth factor-beta type I and type II receptors in wound granulation tissue and hypertrophic scar.

In the present study we have analyzed and compared, by immunohistochemistry and in situ hybridization, the expression pattern of the R4/ALK5 transforming growth factor (TGF)-beta type I receptor (RI) and the TGF-beta type II receptor (RII) in normal human skin, in wounded skin at various stages during the transition of wound granulation tissue to scar, and in long-persisting post-burn hypertrophic scars. In normal human skin, expression of RI and RII was clearly visible in the epidermis, in epidermal appendages, and in vascular cells, although only a small number of dermal fibroblasts revealed detectable levels of TGF-beta receptor expression. In contrast, granulation tissue fibroblasts showed strong expression of both TGF-beta receptor types, although in normal-healing excisional wounds their density decreased during granulation tissue remodeling. However, in post-burn hypertrophic scars, RI- and RII-overexpressing fibroblasts were found in high densities up to 20 months after injury. From these findings we suggest that the repair process of deep wounds involves the transformation of a subset of fibroblastic cells toward an increased TGF-beta responsiveness and a transient accumulation of these cells at the wound site. In addition, our study provides evidence that excessive scarring is associated with a failure to eliminate TGF-beta receptor-overexpressing fibroblasts during granulation tissue remodeling, which leads to a persistent autocrine, positive feedback loop that results in over-production of matrix proteins and subsequent fibrosis.

Actins↗
PubMed1997

Regression of basal cell carcinoma by intralesional interferon-alpha treatment is mediated by CD95 (Apo-1/Fas)-CD95 ligand-induced suicide.

Basal cell carcinoma (BCC) is the most common skin cancer in humans, and although metastasis rarely occurs, the tumor cells are nevertheless able to invade and destroy the surrounding tissue. Intralesional injection of IFN-alpha has been found to be highly effective in inducing BCC regression by an unknown mechanism. We show that in untreated patients, BCC cells express CD95 ligand, but not the receptor, which may allow tumor expansion by averting the attack of activated CD95 receptor-positive lymphoid effector cells. The CD95 ligand of BCC cells is functional as CD95-positive cells incubated on BCC cryosections become apoptotic and are lysed. In IFN-alpha-treated patients BCC cells express not only CD95 ligand but also CD95 receptor, whereas the peritumoral infiltrate that mainly consists of CD4+ T cells predominantly contains CD95 receptor and only few CD95 ligand-positive cells. Thus, in treated patients BCC most likely regresses by committing suicide through apoptosis induction via CD95 receptor-CD95 ligand interaction.

Apoptosis↗
PubMed1997

[Erythema nodosum: 112 cases. Epidemiology, clinical aspects and histopathology].

In a retrospective study we analyzed the cases of 112 patients with erythema nodosum treated during the period 1983-1993 in the Department of Dermatology, University Hospital of Basel, Switzerland. The aim of the study was to investigate the epidemiology, incidence of different etiologies, relevance of laboratory investigations and the histopathologic features in our patients, 83% of whom were females. The peak incidence occurred between the ages of 18 and 34 years. The commonest cause of erythema nodosum was infection. Other etiologic factors were adverse drug reactions, sarcoidosis, Crohn's disease, non-Hodgkin lymphoma, pregnancy, discoid lupus erythematosus, Sharp syndrome and aspartame. Only 47% of patients showed the classic bilateral distribution of the nodes on the extensor surface of the lower extremities. 77% of infection-induced erythema nodosum healed after 7 weeks, the longest course being 18 weeks. In contrast, 30% of idiopathic erythema nodosum lasted more than 6 months. Patients in whom erythema nodosum was associated with non-Hodgkin lymphoma had an extremely protracted course. Erythema nodosum associated with non-Hodgkin lymphoma may precede the diagnosis of lymphoma by months. In 4 cases erythema nodosum was the initial sign of sarcoidosis. In 30% of biopsies we found single vessels with leukocytoclastic vasculitis. The histologic pattern failed to provide etiologic pointers.

Adolescent↗
PubMed1997

Linkage studies in erythrokeratodermias: fine mapping, genetic heterogeneity and analysis of candidate genes.

Erythrokeratodermias are a clinically heterogeneous group of rare autosomal dominant disorders of cornification with overlapping features including hyperkeratosis and erythema. We ascertained five extended pedigrees with different phenotypes for a linkage study. Three families presented with localized erythrokeratodermia variabilis, and one with erythrokeratodermia and ataxia. Another family had Greither disease associated with variable hyperkeratotic plaques. Despite their phenotypic differences, both erythrokeratodermia variabilis and erythrokeratodermia with ataxia map to a common region in 1p34-p35. Multipoint linkage and haplotype analyses place erythrokeratodermia variabilis between the marker D1S496 and D1S186 with a maximum LOD score of 12.88. Our linkage results provide compelling evidence for genetic homogeneity among families of mixed European and French-Canadian origin. In contrast, results excluded Greither's disease from the established erythrokeratodermia variabilis gene region indicating genetic heterogeneity of erythrokeratodermias. Based on recombinations, two genes assigned to 1p34-p35 were excluded: cartilage matrix protein and avian myelocytosis viral oncogene. Connexin-37 (GJA4), a member of the connexin gene family, maps within the erythrokeratodermia variabilis region and is an attractive candidate gene. Direct sequencing of the coding region of GJA4 in four patients revealed several variations, including a novel polymorphism within the 5' cytoplasmic domain, but no pathogenic mutations were found, thus excluding Connexin-37 as a candidate. There is evidence, however, that other epidermally expressed connexins cluster in this region, and one may yet be determined to play a role in the pathogenesis of erythrokeratodermia variabilis.

Chromosome Mapping↗
PubMed1996

[Epidemiology of skin diseases in HIV-infected patients: a prospective cohort study].

Along with the rising AIDS epidemic, the recognition of mucocutaneous lesions indicating HIV infection is important not only for dermatologists but also for general practitioners. During 36 months we prospectively followed 357 HIV-1-infected patients on a regular base, and all the dermatologic findings were evaluated statistically. Several skin problems such as seborrheic dermatitis, may occur early in HIV infection. Mollusca contagiosa, oral hairy leukoplakia and Kaposi's sarcoma are often clinical signs of marked disease progression with very low CD4-cell counts.

AIDS-Related Opportunistic Infections↗
PubMed1996

Molecular cloning of a human melanoma-associated chondroitin sulfate proteoglycan.

A human melanoma-associated chondroitin sulfate proteoglycan (MCSP), recognized by mAb 9.2.27, plays a role in stabilizing cell-substratum interactions during early events of melanoma cell spreading on endothelial basement membranes. We report here the molecular cloning and nucleotide sequencing of cDNA encoding the entire core protein of human MCSP and provide its deduced amino acid sequence. This core protein contains an open reading frame of 2322 aa, encompassing a large extracellular domain, a hydrophobic transmembrane region, and a relatively short cytoplasmic tail. Northern blot analysis indicated that MCSP cDNA probes detect a single 8.0-kb RNA species expressed in human melanoma cell lines. In situ hybridization experiments with a segment of the MCSP coding sequence localized MCSP mRNA in biopsies prepared from melanoma skin metastases. Multiple human Northern blots with an MCSP-specific probe revealed a strong hybridization signal only with melanoma cells and not with other human cancer cells or a variety of human fetal and adult tissues. These data indicate that MCSP represents an integral membrane chondroitin sulfate proteoglycan expressed by human malignant melanoma cells. The availability of cDNAs encoding MCSP should facilitate studies designed to establish correlations between structure and function of this molecule and help to establish its role in the progression of human malignant melanoma.

Adult↗
PubMed1996

Evidence for genetic heterogeneity in monilethrix.

Monilethrix is a rare inherited defect of the hair shaft resulting in hair fragility and dystrophic alopecia. In contrast to recent reports mapping monilethrix to the type II epithelial and trichocyte keratin gene cluster on 12q13, we strongly excluded these candidate genes in another family with autosomal dominant monilethrix. Moreover, there was no evidence for linkage of the disease to the keratin gene cluster on chromosome 17q12-q21, thus excluding defects in all known trichocyte and epithelial keratins as the cause of monilethrix in this family. Likewise, several other genes known to play an important role in hair shaft formation (trichohyalin and involucrin, ultra-high sulfur matrix proteins, and transglutaminases 1, 2, and 3) did not provide any evidence for linkage. Our results indicate genetic heterogeneity in monilethrix and suggest that aberrations in at least one other gene result in a similar phenotype.

Age Factors↗
PubMed1996

Vitiligo associated with lichen planus. Is there a pathogenetic relationship?

We report the case of a 13-year-old boy with vitiligo who developed lichen planus involving both vitiliginous skin and normally pigmented skin. Biopsy of lichen planus surrounded by a depigmented halo revealed a dermal infiltrate composed of CD3 + T cells and macrophages. The association of these skin diseases may indicate a pathogenetic relationship.

Adolescent↗
PubMed1996

In situ analysis of transforming growth factors-beta (TGF-beta 1, TGF-beta 2, TGF-beta 3) and TGF-beta type II receptor expression in basal cell carcinomas.

Transforming growth factor-beta (TGF-beta) consists of a highly homologous family of multifunctional peptides which are differentially expressed and function in a wide range of target cells. Aberrant expressions of TGF-beta s have been implicated in a number of disease processes, particularly those involving fibrotic and inflammatory lesions, and loss of TGF-beta growth inhibition may play a part in the progression of certain neoplasms. In the present study, we have analysed and compared, by in situ hybridization, mRNA expression of transforming growth factors-beta (TGF-beta 1, TGF-beta 2, TGF-beta 3) and TGF-beta type II receptor (T beta R II), and, by immunohistochemistry, the distribution of TGF-beta 3 protein in normal human skin and in basal cell carcinoma (BCC). The stroma of most BCCs revealed enhanced TGF-beta 1 and T beta R II mRNA expression when compared with normal dermis. A minority of BCCs also showed stromal overexpression of TGF-beta 2 and/or TGF-beta 3 mRNA. However, tumour tissues of all BCCs revealed weaker TGF-beta 3 mRNA and protein expression than normal interfollicular epidermis and hair follicle epithelia, whereas expression of TGF-beta 1 mRNA was comparably weak in tumour tissues and normal skin epithelia. Expression of TGF-beta 2 mRNA, which was clearly detectable in distinct hair follicle epithelia, was only barely detectable in normal interfollicular epidermis and in tumour tissues. In contrast, abundant T beta R II mRNA expression was observed both in normal skin epithelia and tumour tissues. From these findings, we suggest that increased stromal TGF-beta activity induces fibrotic alterations which promote tumour survival and/or progression via paracrine mechanisms, whereas lack of TGF-beta 3 expression by tumour cells may contribute to an autocrine growth control defect in BCCs.

Basal Cell Carcinoma↗
PubMed1995

[Multiple familial glomangiomas].

Multiple glomus tumours represent a special variant of glomangiomatosis. Based on our observation, the clinical features, diagnosis and differential diagnosis are presented and possible therapeutic approaches are discussed.

Diagnosis, Differential↗
PubMed1995

In situ analysis of transforming growth factor-beta s (TGF-beta 1, TGF-beta 2, TGF-beta 3), and TGF-beta type II receptor expression in malignant melanoma.

We have analysed, by in situ hybridization, mRNA expression of TGF-beta 1, TGF-beta 2, TGF-beta 3, and of TGF-beta type II receptor in benign melanocytic naevi, primary melanomas, and in skin metastases of malignant melanomas. Our results show that melanoma progression correlates with overexpression of TGF-beta. All skin metastases and most primary melanomas invasive to Clark's level IV-V revealed specific TGF-beta 2 mRNA and protein expression. However, expression of this cytokine was not observed in benign melanocytic lesions and was detected only in one of five early primary melanomas investigated. Some primary melanomas and skin metastases also revealed specific TGF-beta 1 mRNA signals although expression of this isoform was not found in benign naevi. TGF-beta 3 expression, which was only barely detectable in benign melanocytic lesions, was enhanced in some skin metastases. Interestingly, the epidermis overlaying melanomas revealed lower levels of TGF-beta 3 mRNA expression than epidermis of healthy skin or epidermis adjacent to benign naevi, thereby suggesting that paracrine mechanisms between tumour cells and keratinocytes may influence melanoma development. In primary melanomas TGF-beta type II receptor mRNA signals were much more heterogeneously distributed when compared to benign melanocytic naevi, suggesting variable degrees of TGF-beta resistance among melanoma cells within individual lesions. However, melanoma progression appeared not to be correlated with a complete loss of TGF-beta type II receptor gene expression, since all skin metastases revealed clearly detectable although heterogeneous levels of TGF-beta type II receptor mRNA expression.

Disease Progression↗
PubMed1995

Lymphoproliferative responses to Borrelia burgdorferi in patients with erythema migrans, acrodermatitis chronica atrophicans, lymphadenosis benigna cutis, and morphea.

BACKGROUND AND DESIGN: Specific humoral and cell-mediated immune responses play an important role in the pathogenesis of Lyme borreliosis. Several previous studies demonstrated that a specific cellular immune response to Borrelia burgdorferi can occur independently of a diagnostic humoral response. Little is known about T-cell reactivities against B burgdorferi in early and late cutaneous manifestations of Lyme borreliosis. We studied the lymphoproliferative response of peripheral blood mononuclear cells to B burgdorferi antigen from 99 patients (25 with erythema migrans, 16 with acrodermatitis chronica atrophicans, 13 with lymphadenosis benigna cutis, and 45 with localized scleroderma) and 21 control subjects. The results are expressed as a stimulation index (SI) (mean count per minute of triplicate cultures with stimulant divided by mean count per minute without stimulant). The serum samples from all patients and control subjects were tested for antibodies to B burgdorferi by indirect immunofluorescence assay. RESULTS: The 21 healthy seronegative controls had an SI of 3.3 +/- 2.0 (mean +/- SD). Compared with that of control subjects, the SIs were significantly elevated in patients with erythema migrans (9.8 +/- 9.1), acrodermatitis chronica atrophicans (11.8 +/- 8.2), and lymphadenosis benigna cutis (7.2 +/- 6.2). The 45 patients with localized scleroderma had elevated proliferative responses, with an SI of 6.5 +/- 7.3, but these responses did not significantly differ from those of controls. Elevated titers of antibodies to B burgdorferi were present in six (24%) of 25 patients with erythema migrans, five (38%) of 13 patients with lymphadenosis benigna cutis, and 13 (29%) of 45 patients with localized scleroderma. All 16 patients with acrodermatitis chronica atrophicans had markedly elevated antibody titers. CONCLUSIONS: Our findings show that a significant lymphoproliferative response to B burgdorferi occurs in the majority of patients with cutaneous manifestations of Lyme borreliosis. The lymphocyte proliferation assay may be of diagnostic value in patients in whom Lyme borreliosis is strongly clinically suspected and who have nondiagnostic levels of antibodies against B burgdorferi.

Acrodermatitis↗
PubMed1994

Oral hairy leukoplakia in a patient with ulcerative colitis.

A 30-year-old man with ulcerative colitis developed oral hairy leukoplakia (OHL). Serological examination for human immunodeficiency virus (HIV)-1 and HIV-2 infection showed no abnormalities. Biopsy specimen of the lateral tongue showed ballooned prickle cells, and electron microscopy revealed herpes-type viruses. Immunologic investigation of the patient showed a marked decrease in T-helper cells as a result of immunosuppressive regimen. The present report appears to be the first well-documented case of OHL in an HIV-negative patient with ulcerative colitis. OHL may be a marker for severe immunosuppression but is not necessarily associated with HIV infection. Patients with iatrogenic immunosuppression should be monitored for OHL. Concerning the marked decrease in T-helper cells in this case, the presence of OHL may imply the examination of T-lymphocyte subsets in patients such as HIV-infected individuals or in organ transplant recipients.

Adult↗
PubMed1994

The type I interferon system is locally activated in psoriatic lesions.

The expression of mRNAs encoding interferons (IFNs) and IFN-inducible proteins has been studied in psoriatic lesions and in noninvolved skin. The specific mRNAs have been detected by in situ hybridization using antisense RNAs. Signals for the expression of IFN-gamma mRNA have been found exclusively in cells of psoriatic lesions, and most likely represent a subpopulation of infiltrating leukocytes. Weak signals of IFN-alpha mRNA have been detected throughout the hyperkeratotic epidermis, although specific signals for IFN-beta mRNA expression were not detectable. The expression of two IFN-alpha-inducible gene products, namely the MxA protein and the 2'-5' oligoadenylate (2-5A) synthetase, have been studied as markers for the local activation of the IFN-alpha system. Expression of MxA mRNA and protein was observed in psoriatic keratinocytes, but not in normal appearing keratinocytes adjacent to the lesions. Similarly, 2-5A synthetase expression was markedly elevated in psoriatic keratinocytes. The results of the present study indicate that the IFN-alpha system is selectively activated in psoriatic lesions, although it remains silent in noninvolved skin. The implications of this finding are discussed within the boundaries of current understanding of the cytokine network.

2',5'-Oligoadenylate Synthetase↗
PubMed1993

In situ hybridization analysis of cytokine, proto-oncogene and tumour suppressor gene expression in psoriasis.

The purpose of this study was to investigate and to compare, by in situ hybridization, gene expression of IL-1 beta, IL-8, TGF-beta 1, TGF-beta 2, TGF-beta 3, TGF-alpha, p53 and c-myc in lesions and in non-involved skin of patients with psoriasis. All lesional skin biopsies showed overexpression of IL-1 beta, IL-8 TGF-alpha mRNAs. IL-1 beta hybridization signals were strong in a small number of cells localized predominantly in the dermal papillae and in the suprapapillary epidermis. Overexpression of TGF-alpha was observed in all suprabasal keratinocytes, whereas strongly elevated IL-8 mRNA expression was found to be restricted to clusters of suprabasal keratinocytes. TGF-beta 3, p53 and c-myc transcripts were clearly detected in the epidermis of all biopsies, although expression levels were comparable in lesional and non-lesional skin.

Cytokines↗