Search

Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases. [ABSTRACT FROM AUTHOR]

Objective: To report four foetal cases of the Binder phenotype associated with maternal autoimmune disorders. Patients and Methods: In three mothers with autoimmune diseases, 2D and 3D ultrasonographic measurements were made on four foetuses with the Binder profile, and were compared with postnatal phenotypes. Results: The Binder phenotype can be detected in early pregnancy (14.5 WG). All foetuses had verticalized nasal bones and midfacial hypoplasia. Punctuate calcifications were found in almost all the cases. No specific maternal auto-antibody has been associated with foetal Binder phenotype. Conclusion: Since the Binder phenotype can be diagnosed at ultrasound examination during pregnancy, it is important to establish the underlying cause so as to assess the foetal prognosis. This study stresses the importance of systematic checks for maternal autoimmune disease in cases of prenatally diagnosed Binder phenotypes. [ABSTRACT FROM AUTHOR]

Objectives. – Recent investigations showed a high prevalence of Y chromosome microdeletions in men with severely impaired spermatogenesis. Screening for these men is recommended prior to assisted reproduction techniques. The aim of this study was to set up a simple method to detect Y deletion in infertile men. First, we tested the feasibility of cytobrush to collect oral cells as source of DNA. Second, we compared a classic PCR corresponding to European recommendations to the Promega kit®.Patients and methods . – Seventeen infertile male patients with previously characterized deletions were included in the present study, after fully informed written consent. Both oral cells and blood were used for DNA extraction. A specific DNA extraction protocol was carried out on the buccal cells. The DNAs were tested for Y deletion screening by two different methods.Results. – We retrieved between 4 and 10 μg of DNA per brush from buccal cells, allowing several multiplex PCR. The Promega kit® detected all the deletions but one: an AZFa deletion was not detected by the two markers of the kit covering this region. In addition, sY130, sY133 and SY153, included in the kit, are not reliable.Discussion and conclusions. – Buccal cells represent a convenient substitute for blood in testing for Y microdeletions. Both false negative and false positive results were obtained with Promega Kit®. On the opposite, PCR according to the European recommendations allow the accurate detection of Y microdeletion in our 17 cases, at a lower cost. [Copyright &y& Elsevier]

The bystander effect (BSE) is an interesting and important property of the herpes thymidine kinase/ganciclovir (hTK/GCV) system of gene therapy for cancer. With the BSE, not only are the hTK expressing cells killed upon ganciclovir (GCV) exposure but also neighboring wild-type tumor cells. On testing a large number of tumor cell lines in vitro, a wide range of sensitivity to bystander killing was found. Since transfer of toxic GCV metabolites from hTK-modified to wild-type tumor cells via gap junctions (GJ) seemed to be a likely mechanism of the BSE, we tested GJ function in these various tumors with a dye transfer technique and pharmacological agents known to affect GJ communication. We confirmed that mixtures of tumor cells resistant to the BSE did not show dye transfer from cell to cell while bystander-sensitive tumor cells did. Dieldrin, a drug known to decrease GJ communication, diminished dye transfer and also inhibited the BSE. Forskolin, an upregulator of cAMP did increase GJ, but directly inhibited hTK and therefore its effect on BSE could not be determined. We conclude that these observations further support the concept that functional GJ play an important role in the BSE and further suggest that pharmacological manipulation of GJ may influence the outcome of cancer therapy with hTK/GCV. [ABSTRACT FROM AUTHOR]

Hypophosphatasia is an inherited disorder characterised by defective bone mineralisation and deficiency of serum and tissue liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity. We report the characterisation of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 13 European families affected by perinatal, infantile or childhood hypophosphatasia. Eighteen distinct mutations were found, only three of which had been reported previously in North American and Japanese populations. Most of the 15 new mutations were missense mutations, but we also found two mutations affecting donor splice sites and a nonsense mutation. A missense mutation in the last codon of the putative signal peptide probably affects the final maturation of the protein. Despite extensive sequencing of the gene and its promotor region, only one mutation was identified in two cases, one of which was compatible with a possible dominant effect of certain mutations and the putative role of polymorphisms of the TNSALP gene. In 12 of the 13 tested families, genetic diagnosis was possible by characterisation of the mutations or by use of polymorphisms as genetic markers. Hypophosphatasia diagnosis was assigned in two families where clinical, laboratory and radiographic data were unclear and prenatal diagnosis was performed in one case. The results also show that severe hypophosphatasia is due to a very large spectrum of mutations in European populations with no prevalent mutation and that genetic diagnosis of the disease must be performed by extensive analysis of the gene. [ABSTRACT FROM AUTHOR]

Presents letters to the editor regarding articles published in the previous issues of the "British Journal of Dermatology." "Lichen sclerosus et atrophicus in non-identical female twins," which discusses the development of perineal lichen sclerosus et atrophicus in female twins; "Influence of containers on the quantities of topical preparations used," which was about the dispensing of topical agents; "Laser, dermal fibroblasts and psoriasis," which was about psoriasis.

Extensive lesions on 36 patients with psoriasis were treated by Tigason, 1 mg kg/day plus PUVA until skin clearance. A clinical score was calculated for each body area, and erythema, scaling, thickness and pruritus of the lesions were scored from 0 to 3. Skin clearing was defined as a clinical score < 10% of the initial score. Double-blind maintenance treatment was then started. This was Tigason at half of the maximal dose tolerated during the clearing phase of the treatment v. placebo. Relapse of the disease was defined as the occurrence of a clinical score > 50% of the initial score. Among the 36 patients randomized, 20 received placebo and 16 received Tigason. Relapses increased quickly in the patients on placebo, but occurred in few patients treated by Tigason with 60% remaining clear after i year (P < 0.05). Surprisingly, the kinetics of disappearance of the most frequent side effect, cheilitis, was the same in the Tigason group and in the placebo group. This double-blind randomized clinical trial shows that Tigason at low doses is an efficient and well-tolerated maintenance treatment of psoriasis. [ABSTRACT FROM AUTHOR]

The initiating event of several immune effector functions in the skin is the presentation of antigens to lymphoid immunocornpetent cells. Two kinds of antigen-presenting cells have been identified in normal human epidermis: Langerhans cells (LC) and indeterminate cells (Rowden, Phillips & Lewis, 1979). They display a dendritic morphology, bear class II HLA-DR molecules, and are necessary for T-cell activation and proliferation. The role of these epidermal dendritic cells in epidermal cell-lymphocyte interactions and their antigen-presenting proper- tics have been studied in vitro in the mixed epidermal cell-lymphocyte reaction (MECLR). [ABSTRACT FROM AUTHOR]

Until recently, changes in cell physiology following application of pharmacological agents have been studied in vivo or in vitro using monolayered cells. Although both approaches have unique advantages, both have shortcomings. Now the development of a skin-equivalent model has provided a system for studying cell responses at the tissue and organ levels in vitro (Bell, Ivarsson & Merrill, 1979; Bell et at, 1981a, b). The in vitro tissue model can he made simple or complex with respect to cell type heterogeneity and matrix constitution; ideally, however, it should resemble skin as closely as possible. It has the special advantage, unlike skin, of being able to survive for long periods in vitro. In this paper we compare the model morphologically with skin arid review some aspects of the biosynthetic output of cells in the tissue equivalent with that of monolavered cells. Finally we illustrate in a pharmacological study that the model can be used to provide new information that in vivo studies or monolayer cell studies cannot yield. [ABSTRACT FROM AUTHOR]

The possible role of epidermal serine proteases in the genesis of psoriatic lesions was investigated by sequential biopsies of the epidermal damage induced by topical cantharidin. In the skin of normal subjects, epidermal damage was followed by the transient appearance of proteolytic activity in the upper epidermis accompanied by temporary hyperacanthosis and perivascular inflammatory cells in the superficial dermis. In the uninvolved skin of five patients with psoriasis this proteolysis persisted longer, for more than 7 days. Thereafter, in three of the patients, the proteolysis abated, and this was followed by disappearance of the hyperacanthosis and the dermal infiltrate; in the other two psoriatics the proteolysis and hyperacanthosis increased, and a typical Koebner phenomenon ensued. Migration of neutrophils into the epidermis occurred as a later event. Thus the abnormal persistence of proteolytic activity in the upper epidermis after cantharidin application distinguishes the normal from the psoriatic skin injury response and might initiate the psoriatic lesion. [ABSTRACT FROM AUTHOR]

A new diagnostic technique is describe, in which 0·7 mm thick slices of skin are freshly cut, thoroughly washed, slightly fixed and directly incubated in peroxidase-labelled antibodies. This easy technique allows routine immuno-electron microscopic diagnosis of subepidermal auto-immune bullous diseases, with excellent morphological results. [ABSTRACT FROM AUTHOR]

By using a very sensitive and reproducible skin chamber technique we have shown that the aromatic retinoid etretinate (Ro 10–9359) and its main metabolite (Ro 10–1670) significantly inhibit the migration of neutrophils from the blood to tissues when applied into skin chambers (0·1 mg/ml) or when given orally (1 mg/kg/day for 8 days) to normal volunteers. This pharmacological property could be closely linked to the antipsoriatic properties of these drugs. [ABSTRACT FROM AUTHOR]

Incubation of unfixed and unfrozen slices of skin in diaminobenzidine allows visualization of peroxidatic activity in the perinuclear envelope and endoplasmic redculum of normal human Langerhans cells. A similar peroxidatic activity is observed in supra-basal keratinocytes undergoing orthokeratotic differentiation. Basal keratinocytes and melanocytes are always negative. This enzyme is absent in mucous and parakeratotic (psoriatic) differentiation. A peroxidatic activity was also found in the endoplasmic reticulum of normal resident skin macrophages. Mitochondria are also strongly stained by this technique and it was shown that the number of epidermal mitochondria is greatly increased in psoriatic lesions. [ABSTRACT FROM AUTHOR]

Incubation of unfixed slices of skin for t h at 37°C in Hanks' medium allowed the expression of proteolytic activity in the upper keratinocyte layers in psoriatic lesions and, in some cases, in uninvolved skin of psoriatics, but never in normal skin. This proteolysis was inhibited by DFP and TLCK, known inhibitors of the neutral proteinase previously described as increased in psoriatic lesions. The topographical analysis of this proteolytic activity suggests that a disturbance of the protease-antiprotease equilibrium in human epidermis may be implicated in the appearance of psoriatic lesions. [ABSTRACT FROM AUTHOR]

Cellular events occurring in eight patients with bullous pemphigoid were studied by light and electron microscopy. Sections (0.5 μm) of large surface area, overlapping blisters and surrounding skin, were examined and correlated ultrastructural studies were performed on selected areas. The peroxidase contained in granules of neutrophils, eosinophils and young macrophages was visualized by incubation with diaminobenzidine and hydrogen peroxide. This cytochemical reaction was used as a marker to study the release of granule enzymes from these inflammatory cells. The release of such enzymes from eosinophils and occasionally from macrophages on the epidermal basement membrane (more precisely in the lamina lucida) was demonstrated in the skin surrounding the blisters in four patients. The release of these enzymes was also observed in the floor of the blisters in all eight patients. It is well known that these granules contain several proteolytic enzymes. These observations are therefore consistent with the proposal that proteolytic enzymes of eosinophils play a pathogenic role during the initial stages of blister formation in bullous pemphigoid. [ABSTRACT FROM AUTHOR]

The visualization of peroxidase positive lysosomes by diaminobenzidine plus H2O2 allowed easy identification of neutrophils, eosinophils, monocytes and young tissue macrophages in 0.2 μm to 0.5 μm skin plastic sections of large surface area. Evaluation of the lysosomal functions of these phagocytic cells was greatly improved by the possibility of correlating observations on the same cell at light and electron microscopic levels. [ABSTRACT FROM AUTHOR]