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Biomedical subjects

M Simon

Publications and source records attributed to M Simon.

At least 55 records · Page 3Linked to original sources
PubMed1997

[The Clark-Howel-Evans-McConnell syndrome. Observations in one family over 5 generations].

The Clarke-Howel-Evans-McConnell syndrome is a rare hereditary disease characterized by palmoplantar keratoses, squamous cell carcinoma of the esophagus and oral leukoplakia. According to a new classification recently proposed by Stevens and colleagues, the syndrome can also be classified as palmoplantar ectodermal dysplasia type III. We report a family from the Black Forest region of Germany afflicted with the syndrome. The family was traced through five generation. 27 of 46 family members showed tylotic skin changes. In addition, 8 patients showed oral leukoplakia and 5 died from squamous cell carcinoma of the esophagus. Using screening examinations, early changes of the esophageal mucosa could be detected. The responsible gene has been mapped in the family. It is located at 17q23-qter, telomeric to the keratin II gene cluster. Therefore a defect in one of the well known keratin genes can be excluded as a cause of the syndrome.

Adult↗
PubMed1997

Rig2, a RING finger protein that interacts with the Kin28/Ccl1 CTD kinase in yeast.

Kin28/Cell, a cyclin-dependent kinase, is essential for the in vivo phosphorylation of the C-terminal domain of the largest subunit of RNA polymerase II in Saccharomyces cerevisiae. In a search for mutations co-lethal with a thermosensitive kin28 mutation, we have identified genes whose products interact functionally with Kin28. In the present work, we have studied a new complementation group of synthetic lethal mutations. The corresponding gene, RIG2, encodes a predicted RING finger protein. Rig2 is likely to be a homolog of MAT1 of higher eukaryotes which forms a ternary complex with MO15(cdk7) and cyclin H. Our genetic data suggest that Rig2 is a component of transcription factor TFIIH. Transcription activity in a rig2-ts mutant is impeded at restrictive temperature. However, none of the rig2-ts mutants obtained was UV sensitive, suggesting that Rig2 is dispensable for nucleotide excision repair.

Amino Acid Sequence↗
PubMed1997

Ultraviolet-B enhances corneal stromal response to 193-nm excimer laser treatment.

PURPOSE: The purpose of the study was to evaluate the biomicroscopic, light microscopic, and electron microscopic effects of ultraviolet-B (UV-B) exposure on the outcome of photorefractive keratectomy (PRK). METHODS: A total of 24 pigmented rabbits were used in the study. One eye of 16 rabbits received a 193-nm, 45-micron deep (-5.0 diopter) excimer laser PRK. Twenty-one days after PRK, eight of the laser-treated eyes were exposed to 100 mJ/cm2 UV-B (280-315 nm) UV radiation by placing the rabbits in a standard clinically used dermatologic chamber for 7 minutes. Eight PRK-treated rabbits received no further treatment. The remaining eight non-PRK-treated rabbits received 100 mJ/cm2 UV-B only to one eye. Subepithelial haze was assessed before and after UV irradiation. Corneal morphology was assessed 4, 8, 12, and 16 weeks after UV-B exposure, using light microscopic and transmission electron microscopic (TEM) techniques. RESULTS: Untreated eyes exposed to 100 mJ/cm2 UV-B only exhibited photokeratitis for 2 days, but showed no haze and were normal histologically at all intervals. The PRK-treated UV-B irradiated eyes exhibited a significant increase of stromal haze compared to eyes receiving PRK alone. Histologically, the main difference between the UV-B irradiated and nonirradiated post-PRK eyes was the presence of anterior stromal extracellular vacuolization in the UV-B-exposed eyes. The vacuolated foci were confined to the PRK treatment area and showed increased keratocyte density and disorganization of normal collagen lamellae. TEM showed activated keratocytes containing abundant rough endoplasmic reticulum, prominent Golgi zones, and extracellular vacuoles filled with amorphous material. The haze and morphologic changes showed a tendency to incomplete resolution over the period of 16 weeks. CONCLUSIONS: The UV-B exposure during post-PRK stromal healing exacerbates and prolongs the stromal healing response and is manifest biomicroscopically by augmentation of subepithelial haze. The findings suggest that excessive ocular UV-B exposure should be avoided during the period of post-PRK stromal repair and that UV-B may modulate the response of tissues to 193-nm excimer laser and perhaps other laser energy in general.

Animals↗
PubMed1997

Subcutaneous T-cell lymphoma.

We describe a patient with severe fatal histiocytic phagocytic panniculitis caused by a pleomorphic T-cell lymphoma. Analysis by polymerase chain reaction revealed clonality for both the T-cell receptor gamma-chain gene and the immunoglobulin heavy-chain gene. We also review 44 reported cases of primary or secondary lymphoma affecting the subcutaneous fat.

Adult↗
PubMed1997

Intermediate filament structure: hard alpha-keratin.

Structurally there are four classes of intermediate filaments (IF) with distinct but closely related axial organisations. One of these, hard alpha-keratin IF, has been studied to clarify several apparently exceptional features which include the number of molecules in the IF cross-section and the mode by which the axial organisation of its constituent molecules is stabilised. Using the dark-field mode of the STEM at the Brookhaven National Laboratory (USA) mass measurements were obtained from unstained IF isolated from hair keratin. The data thus obtained show that the number of chains in cross-section is about 30 (+/-3: standard deviation) and is very similar to the numbers determined in previous STEM experiments for the dominant filament type in other classes of IF (about 32). Furthermore, re-analysis of the low-angle equatorial X-ray diffraction pattern reveals, in contrast to earlier work, solutions that are compatible with the number of chains in cross-section indicated by the STEM data. The absence of the head-to-tail overlap between parallel molecules characteristic of most of IF may be compensated in hard alpha-keratin by a network of intermolecular disulfide bonds. It is concluded that native IF of hard alpha-keratin and desmin/vimentin--and probably many other kinds of IF as well--contain about 32 chains in cross-section, and that the axial structures of these various kinds of IF differ in small but significant ways, while generally observing the same basic modes of aggregation.

Animals↗
PubMed1997

Involvement of the yeast DNA polymerase delta in DNA repair in vivo.

The POL3 encoded catalytic subunit of DNA polymerase delta possesses a highly conserved C-terminal cysteine-rich domain in Saccharomyces cerevisiae. Mutations in some of its cysteine codons display a lethal phenotype, which demonstrates an essential function of this domain. The thermosensitive mutant pol3-13, in which a serine replaces a cysteine of this domain, exhibits a range of defects in DNA repair, such as hypersensitivity to different DNA-damaging agents and deficiency for induced mutagenesis and for recombination. These phenotypes are observed at 24 degrees, a temperature at which DNA replication is almost normal; this differentiates the functions of POL3 in DNA repair and DNA replication. Since spontaneous mutagenesis and spontaneous recombination are efficient in pol3-13, we propose that POL3 plays an important role in DNA repair after irradiation, particularly in the error-prone and recombinational pathways. Extragenic suppressors of pol3-13 are allelic to sdp5-1, previously identified as an extragenic suppressor of pol3-11. SDP5, which is identical to HYS2, encodes a protein homologous to the p50 subunit of bovine and human DNA polymerase delta. SDP5 is most probably the p55 subunit of Pol delta of S. cerevisiae and seems to be associated with the catalytic subunit for both DNA replication and DNA repair.

Amino Acid Sequence↗
PubMed1997

Phase II evaluation of cisplatin and WR2721 for refractory metastatic breast cancer.

Cisplatin, as second-line therapy for metastatic breast cancer (MBC), has at best shown only modest response rates. At high doses, the toxicity profile of this drug may outweigh any potential benefits for MBC patients. We performed a phase II study to determine whether the investigational agent WR2721 would mitigate the toxicity of cisplatin in patients with MBC and to assess the antitumor response of cisplatin as salvage therapy. Thirteen women were enrolled in the study. Cisplatin was administered at a dose of 120 mg/m2 together with WR2721 at a dose of 910 mg/m2 intravenously every 21 days. Response was assessed at the end of two cycles, and toxicity was evaluated after each treatment cycle. No objective antitumor responses were noted. Three patients exhibited toxicity from cisplatin in the form of ototoxicity, nephrotoxicity, myelotoxicity, and persistent delayed nausea and vomiting necessitating discontinuation from the study. There was one death from renal failure. WR2721 itself caused significant but transient hypotension in 46% of the patients. In our experience, salvage chemotherapy with cisplatin in pretreated patients with MBC produced no objective responses. WR2721 did not prevent the occurrence of organ toxicity.

Adult↗
PubMed1997

Early cytokine and chemokine gene expression in lymph nodes of macaques infected with simian immunodeficiency virus is predictive of disease outcome and vaccine efficacy.

Competitive PCR was used to evaluate the expression of cytokine, granzyme B, and chemokine genes in lymph nodes of macaques recently infected with the simian immunodeficiency virus (SIV) pathogenic molecular clone SIVmac239 (n = 16), the nonpathogenic vaccine strain SIVmac239 delta nef (n = 8), and the nonpathogenic molecular clone SIVmac1A11 (n = 8). For both SIVmac239 and its nef-deleted derivative, strong expression was observed as early as 7 days postinfection for interleukin 1beta (IL-1beta), IL-6, tumor necrosis factor alpha, gamma interferon, and IL-13. The levels of gene induction were equally intense for both viruses despite a lower viral load for SIVmac239 deltanef compared with that for SIVmac239. However, the nature of the cytokine network activation varied with the viral inocula. Primary infection with SIVmac239 was characterized by a higher level of IL-4, IL-10, MIP-1alpha, MIP-1beta, MCP-1, and RANTES gene expression and a lower level of IL-12 and granzyme B gene expression compared with infection with SIVmac239 delta nef. Thus, infection with nef-deleted SIV was associated with a preferential Th1 versus Th2 pattern of cytokine production. Infection with SIVmac1A11 was characterized by a delayed immune response for all markers tested. The unique patterns of cytokine and chemokine gene expression in lymph nodes correlated nicely with the pathogenic potential of the SIV strains used as well as with differences in their ability to serve as protective vaccines.

Animals↗
PubMed1997

VE-cadherin antibody accelerates neutrophil recruitment in vivo.

Neutrophils enter sites of inflammation by crossing the endothelial lining of the blood vessel wall. VE-cadherin is an endothelial specific, homophilic adhesion molecule located at the lateral cell surface. We have generated a monoclonal antibody against mouse VE-cadherin which inhibits electrical resistance of endothelial cell monolayers in vitro as well as aggregation of VE-cadherin transfected cells. In vivo, this antibody was found to increase vascular permeability and to accelerate the entry of neutrophils into chemically inflamed mouse peritoneum. Thus, VE-cadherin is essential for the integrity of the endothelial barrier in vivo. Our data suggest that opening of VE-cadherin mediated endothelial cell contacts may be a relevant step during neutrophil extravasation.

Animals↗
PubMed1997

In situ expression and serum levels of tumour necrosis factor alpha receptors in patients with lichen planus.

In lichen planus (LP), an inflammatory skin disease of unknown origin, adhesion molecules and their ligands combined with the local and systemic release of various cytokines are fundamental in regulating inflammation. Therefore, we investigated the expression of tumour necrosis factor alpha receptor (TNF-R) I and II in lesional skin of 15 patients suffering from acute eruptive LP by means of immunohistochemistry. In addition, the serum levels of their soluble forms (sTNF-R) were measured by enzyme-linked immunosorbent assay (ELISA), compared with those of healthy volunteers (n = 10) and correlated with the in situ inflammatory response. In contrast to healthy controls, LP patients showed significantly increased serum levels of sTNF-RI as well as sTNF-RII (p < 0.02). These enhanced serum titres were correlated with a prominent expression of TNF-RI on lesional keratinocytes (basal > suprabasal) and of both receptors on skin-infiltrating lymphocytes. Our data suggest an important role of the TNF ligand/receptor interactions in the induction and/or perpetuation of the pathogenetical and apoptotic events in LP.

Antigens, CD↗
PubMed1997

Normal human epidermal keratinocytes express in vitro specific molecular forms of (pro)filaggrin recognized by rheumatoid arthritis-associated antifilaggrin autoantibodies.

BACKGROUND: The so-called antikeratin antibodies and the antiperinuclear factor are the most specific serological markers of rheumatoid arthritis (RA). They were recently shown to be largely the same autoantibodies and to recognize human epidermal filaggrins and profilaggrin-related proteins of buccal epithelial cells (collectively referred to as (pro)filaggrin). MATERIALS AND METHODS: To further characterize the target antigens, we investigated their expression by normal human epidermal keratinocytes cultured in differentiating conditions, using immunofluorescence and immunoblotting with RA sera and three different monoclonal antibodies to (pro)filaggrin. RESULTS: On the cornified, stratified epithelial sheets obtained in vitro, RA sera with anti(pro)filaggrin autoantibodies (AFA) produced granular staining of the stratum granulosum and diffuse staining of the stratum corneum. The antigens recognized by RA sera strictly colocalized with (pro)filaggrin in keratohyalin granules. Following sequential extraction of the proteins from the epithelial sheets, the RA sera and the three monoclonal antibodies to (pro)filaggrin, recognized a series of low-salt-soluble molecules, including a neutral/acidic isoform of filaggrin and several proteins with sizes and pI intermediates between this isoform and profilaggrin. They also recognized urea-soluble high-molecular-weight profilaggrin-related molecules. CONCLUSIONS: These results show that in vitro epidermal keratinocytes express various molecular forms of (pro) filaggrin that bear epitopes targeted by AFA of RA sera, and that some of these are absent from epidermis. Moreover, these epitopes, which are present on the keratohyalin granules of buccal epithelial cells but not on those of epidermal cells, are present on the granules of the cultured keratinocytes. This work completes the molecular characterization of the proteins targeted by AFA.

3T3 Cells↗
PubMed1997

Metabolism of all-trans-retinoic acid by cultured human epidermal keratinocytes.

The uptake and metabolism of exogenous all-trans-retinoic acid by human epidermal keratinocytes in submerged culture was examined. Retinoic acid presented to keratinocytes in physiological form bound to albumin was rapidly taken up. Peak cellular concentrations were achieved within 1 h and were 50- to 100-fold higher than that in medium. Retinoic acid metabolism was less rapid but was vigorous, exhibiting a half-life of 6 h. Neither uptake nor metabolism was saturable at medium retinoic acid concentrations up to 1 microM. Eighty-five percent of retinoic acid was metabolized to unidentified polar compounds which were excreted from cells to the medium. The production and clearance of the polar metabolites was inhibited 60% by 10 microM ketoconazole. Fifteen percent of intracellular retinoic acid was converted to 3,4-didehydroretinoic acid, was proportional to cellular retinoic acid concentration, and was not affected by ketoconazole. Cellular retinyl ester content, which is sensitive to exogenous retinoic acid, was correlated with both the concentration and the quantity, of retinoic acid in the culture system. These results suggest that the metabolism of retinoic acid in keratinocytes is substrate limited and has potential to limit the availability of exogenous retinoic acid for retinoid signaling.

Albumins↗
PubMed1997

[Primary peritonitis caused by Streptococcus pneumoniae].

Primary peritonitis caused by Streptococcus pneumoniae is a rare but serious complication of childbirth. We present here three cases of young women who developed abdominal pain after childbirth. All of the patients had fever with abdominal pain, diarrhea and clinical signs of peritonitis. In two cases a laparotomy was performed to remove pus. Cultures taken were positive for Streptococcus pneumoniae. Culture of vaginal swabs and blood cultures were also positive for the same pathogen. For the third patient, both vaginal swabs and blood cultures were positive for Streptococcus pneumoniae, antibiotic therapy only was administered. Outcome was favorable for all. We discuss the pathogenesis, clinical presentation, management and the usefulness for systematic search "for" Streptococcus pneumoniae in vaginal swabs.

Abdominal Pain↗
PubMed1997

Expression of corneodesmosin in the granular layer and stratum corneum of normal and diseased epidermis.

The stratum corneum (SC) has long been considered as a sort of inert membrane destined to be shed at the surface of the epidermis. During the last two decades, however, several lines of evidence have been reported, suggesting that active physical and chemical changes take place in the horny layer despite the absence of intracytoplasmic organelles. In particular, processing of filaggrin, replacement of the plasma membrane by a ceramide envelope and constant, progressive modification of extracellular lipid multilayers have been put forward. Recently, attention has focused on the intercellular junctions, which may be involved in the regulation of SC desquamation. Corneodesmosin, a newly discovered protein of s.c. desmosomes (corneodesmosomes), is synthesized at the latest stages of keratinocyte differentiation and persists between the horny cells until desquamation occurs. In the present study, we performed immunohistochemical and immuno-ultrastructural investigations on corneodesmosin expression in various skin lesions characterized by abnormal production and/or retention of the horny layer. Our results suggest that corneodesmosin expression is independent from profilaggrin synthesis. We found corneodesmosin in almost all morphologically recognizable corneodesmosomal structures and specifically those which persisted up to the SC surface. Hyperkeratotic lesions which are characterized by an increased number of junctions showed intense immunoreactivity with anticorneodesmosin antibody. A complete absence of corneodesmosin was not observed in any disease. This finding, together with our previous biochemical studies, suggests that corneodesmosin may exert a protective function against proteolytic degradation of corneodesmosomes both in normal skin and in the pathological horny layer.

Antibodies, Monoclonal↗
PubMed1997

An optimization study on unprogrammed cryopreservation of human CD34+ bone marrow cells and their subsequent storage in an -80 degrees C mechanical freezer.

Among the factors which enable successful bone marrow transplantation, the ability to store and subsequently recover sufficient viable marrow cells to reestablish hematopoiesis is crucial. In most centers, marrow is typically prepared for long term storage by programmed, controlled rate freezing with subsequent placement into the vapor phase of liquid nitrogen. Though clearly effective, this procedure is time consuming and equipment intensive. Since cost containment is an important issue for all medical procedures, we evaluated the utility of a faster and less costly method to accomplish the same purpose. We found that when CD34+ bone marrow cells are immediately frozen and stored at -80 degrees C, the number and quality of stem/progenitor cells recovered after thawing was comparable to those reported recovered after conventional processing. Herein we report optimized conditions for cryopreserving and storing CD34+ bone marrow cells at -80 degrees C and for subsequent thawing of the stored product. With these methods post-thaw recovery of CFU-Mix, for example, equaled or exceeded 80% of predicted numbers, even after six months of storage. Further, though progenitor cell recovery does not necessarily correlate with speed of engraftment, these results nonetheless suggest that storage of human CD34+ cells at -80 degrees C in a mechanical freezer is a convenient, inexpensive, and reliable method for storing marrow for transplantation.

Antigens, CD34↗
PubMed1996

Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system.

We studied the survival of 195 patients with agnogenic myeloid metaplasia (AMM) diagnosed between 1962 and 1992 in an attempt to stratify patients into risk groups. Median survival was 42 months. Adverse prognostic factors for survival were age > 60 years, hepatomegaly, weight loss, low hemoglobin level (Hb), low or very high leukocyte count (WBC), high percentage of circulating blasts, male sex, and low platelet count. A new scoring system based on two adverse prognostic factors, namely Hb < 10 g/dL and WBC < 4 or > 30 x 10(9)/L, was able to separate patients in three groups with low (0 factor), intermediate (1 factor), and high (2 factors) risks, associated with a median survival of 93, 26, and 13 months, respectively. An abnormal karyotype (32 cases of 94 tested patients) was associated with a short survival, especially in the low-risk group (median survival of 50 v 112 months in patients with normal karyotype). The prognostic factors for acute conversion were WBC > 30 x 10(9)/L and abnormal karyotype. Thus, hemoglobin level and leukocyte count provide a simple prognostic model for survival in AMM, and the adverse prognostic value of abnormal karyotype may be related to a higher rate of acute conversion.

Adult↗