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Biomedical subjects

M Simon

Publications and source records attributed to M Simon.

At least 163 records · Page 9Linked to original sources
PubMed1998

Receptors of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in fetal and adult human kidney: localization and [125I]VEGF binding sites.

Vascular endothelial growth factor (VEGF) has an important function in renal vascular ontogenesis and is constitutively expressed in podocytes of the adult kidney. The ability of VEGF to be chemotactic for monocytes and to increase the activity of collagenase and plasminogen activator may have implications for renal development and renal disease. In humans, the cellular actions of VEGF depend on binding to two specific receptors: Flt-1 and KDR. The aims of this study were: (1) to localize VEGF receptor proteins in human renal ontogenesis; (2) to quantify VEGF binding in human fetal and adult kidney; and (3) to dissect the binding into its two known components: the KDR and Flt-1 receptors. The latter aim was achieved by competitive binding of VEGF and placenta growth factor-2, which only binds to Flt-1. Quantification of 125I-VEGF binding sites was performed by autoradiography and computerized densitometry. By double-label immunohistochemistry, VEGF receptor proteins were localized solely to endothelial cells of preglomerular vessels, glomeruli, and postglomerular vessels. In developing glomeruli, VEGF receptor protein appeared as soon as endothelial cells were positive for von Willebrand factor. Specific 125I-VEGF binding could be localized to renal arteries and veins, glomeruli, and the tubulointerstitial capillary network in different developmental stages. Affinity (Kd) of adult (aK) and fetal (fK) kidneys was: Kd: glomeruli 38.6 +/- 11.2 (aK, n = 5), 36.3 +/- 7.1 (fK, n = 5); cortical tubulointerstitium 19.4 +/- 2.6 (aK, n = 5), 11.6 +/- 7.0 (fK, n = 5) pmol. Placenta growth factor-2 displaced VEGF binding in all renal structures by approximately 60%. VEGF receptor proteins thus were found only in renal endothelial cells. A coexpression of both VEGF binding sites could be shown, with Flt-1 demonstrating the most abundant VEGF receptor binding sites in the kidney. These studies support the hypothesis of a function for VEGF in adult kidney that is independent of angiogenesis.

Adult↗
PubMed1998

An international dermatological image atlas on the WWW: practical use for undergraduate and continuing medical education, patient education and epidemiological research.

We describe the development of an image database DOIA (Dermatological OnlIne Atlas) and present several spin-off projects using images of the atlas, e.g. student education using the atlas including results of an questionnaire evaluating computer-literacy, prerequisites and interests of students for using computers and the World-Wide-Web (WWW), a patient information system and an experiment to collect epidemiological data from patients with dermatological diseases via WWW. The database, available on the WWW at http:@www.derma.med.uni-erlangen.de, contains about 3,000 clinical images covering more than 540 dermatological diagnoses. It is designed for worldwide use; international submissions are encouraged. One aim of the project is to compile an international reference for dermatological images, containing images of high educational quality and also covering conditions on different skin types and rare diagnoses which are not commonly illustrated in ordinary textbooks. All images were originally mapped to the Erlanger Diagnosis Code, which is a proprietary modified ICD-9 key, later also to the UMLS (Unified Medical Language System). In addition, images are described with keys for the location, physical attributes of the location and clinical and histopathological features of the lesion. In order to facilitate the integration of the atlas into other web-based medical resources and to allow easy access to additional information, the Erlanger Diagnosis Code was mapped to the CUIs (unique concept identifiers) of the UMLS Metathesaurus. One purpose of the UMLS is to allow conversion of terms from one controlled medical vocabulary to another, thus, mapping of our diagnosis code to the UMLS CUIs allows simultaneous search for a given diagnosis in a number of other databases and also access to our image database from other databases. Mapping was successful for 619 out of 1383 dermatological diagnosis terms. For images with these diagnoses we are able to provide a hyperlink to other databases available on the Internet, such as MEDLINE, PDQ and OMIM, with automatic retrieval using the preferred vocabulary of the respective database. By grouping all diagnoses into sets with similar morphologies we further integrated a differential diagnosis mode. In order to educate patients via the Internet, a separate patient information system has been developed, using images of the electronic atlas. As an experiment to explore the feasibility of the Internet to gather epidemiological data from patients, users are asked to complete an electronic questionnaire covering signs for atopy. We conclude that an online image atlas has multiple educational, clinical and research applications.

Computer-Assisted Instruction↗
PubMed1998

Automated high-resolution polymerase chain reaction fragment analysis: a method for detecting T-cell receptor gamma-chain gene rearrangements in lymphoproliferative diseases.

Southern blot analysis and the polymerase chain reaction (PCR) are powerful tools for detecting clonal antigen receptor gene rearrangements. However, a number of limitations restrict the predictive value of the results obtained by these techniques as they are commonly used. We describe a new method, automated high-resolution PCR fragment analysis, that can partially overcome many of the limitations of analyzing the T-cell receptor (TCR) gamma-chain gene. Analysis of TCR-gamma is performed using PCR with four sets of primers, previously described by others, specific for all variable (V) and joining (J) regions of the TCR gamma-chain gene. In addition, the four V region primers are 5' end-labeled with a fluorescent compound, 5-carboxyfluorescein. After amplification, the labeled PCR products are separated with an automated sequencing system, ABI 373 (Applied Biosystems, Weiterstadt, Germany). With the help of the Gene-Scan software ABI 672 (Applied Biosystems) and fluorescent-labeled DNA length markers, the exact size of each peak can be displayed and analyzed. The resolution of this method allows separation of PCR products differing in length by as little as 1 bp. Semiquantitative estimation of specific clones also can be performed. Infiltrate-specific gene rearrangement patterns can be identified and recognized in different tissue specimens at the time of diagnosis or in subsequent biopsy specimens. We conclude that automated high-resolution PCR fragment analysis allows more accurate and convenient analysis of the TCR gamma-chain gene.

Automation↗
PubMed1998

Clinical laboratory test menu changes in the Pacific Northwest: 1994 to 1996.

Laboratory testing services are presently undergoing dynamic changes in response to a wide range of external factors. Government regulations, reimbursement, and managed care are only a few of the influences affecting the availability of testing services and on-site testing capabilities in hospital, independent, and physician office laboratories. Medical practice changes, marketplace influences, test technologies, and costs also play a role in determining where testing is being performed. To better understand the factors influencing clinical laboratory test volumes and menus and to identify on-site testing deemed essential in physician office laboratories, we gathered information from a network of clinical laboratories in the Pacific Northwest. Questionnaires were sent to 257 Laboratory Medicine Sentinel Monitoring Network participants in March 1996. In the past 2 years, changes in on-site test volumes and test menus have been primarily due to medical practice changes and marketplace influences. When laboratories had a decrease in test volumes or test menu choices, the size of the patient workload and the volumes of test orders have had the greatest impact. Laboratory regulations and managed care contracts have played a role in shifting on-site testing to outside sources; however, these factors did not appear to be primary influences. Only 5% of physician office laboratories identified tests that they believed were essential for optimal patient care but did not perform on-site.

Alaska↗
PubMed1998

Immunoblotting detection of autoantibodies to human epidermis filaggrin: a new diagnostic test for rheumatoid arthritis.

OBJECTIVE: We previously reported that so-called antikeratin antibodies (AKA) and antiperinuclear factor (APF) recognize epitope(s) present on human epidermal filaggrin. In the present study, we developed a new diagnostic test for rheumatoid arthritis (RA) based on detection of antifilaggrin autoantibodies (AFA) by immunoblotting. METHODS: We tested 670 serum samples, including 190 RA. AFA titers were estimated by immunoblotting on filaggrin enriched human epidermis extracts, and AKA titers by indirect immunofluorescence (IIF) on rat esophagus epithelium. Diagnostic values of the tests were compared. RESULTS: Each test resulted in diagnosis of more than 40% of RA samples, with a specificity of 0.99. Although the tests were strongly correlated, their association allowed the diagnosis of more than 60% of RA samples, with the same specificity. CONCLUSION: Immunoblot detection of AFA, a simple and standardizable test, may be an alternative or complement to conventional IIF detection of AKA.

Adolescent↗
PubMed1998

The spontaneous aortocaval fistula: a complication of the abdominal aortic aneurysm. Case report and review of the literature.

An aortocaval fistula is a rare complication of the abdominal aortic aneurysm: early diagnosis and appropriate surgery improve survival. We report the case of a patient presenting with abdominal pain and oedema of both lower limbs secondary to an aortocaval fistula. CT-scan confirmed the diagnosis and successful surgery was performed in the emergency room. Immediate haemostasis on the inferior vena cava is easier when preoperative diagnosis of the fistula has been made.

Aortic Aneurysm, Abdominal↗
PubMed1997

Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine.

BACKGROUND: Historically, the acute rejection rates in simultaneous pancreas-kidney (SPK) recipients have been extremely high (50-80%), with many second and third rejection episodes despite the use of quadruple immunosuppression (antibody induction and cyclosporine [CsA]-azathioprine [AZA]-based maintenance immunosuppression). Although this acute rejection has rarely led to graft loss, it has been a great cause of morbidity and of significantly increased cost. In an attempt to decrease the acute rejection rate and related morbidity in SPK transplant recipients, we compared two "state-of-the-art" immunosuppression regimens in a prospective, randomized, single-center study. METHODS: Patients who received SPK transplants were randomized to receive either tacrolimus (TAC) and mycophenolate mofetil (MMF, n=18) or CsA (Neoral formulation) and MMF (n=18). All patients received OKT3 induction and prednisone, which was tapered to 5 mg/day by 6 months after transplantation. All rejection episodes were biopsy proven. In addition, metabolic control (HgbA1C, hypertension, serum cholesterol), drug toxicity, and infection also were measured. Data were compared with that of a historical group (n=18) who received conventional CsA (Sandimmune formulation) and AZA-based immunosuppression. RESULTS: The incidence of biopsy-proven acute rejection was 11% in both the TAC-MMF and CsA-MMF groups with only two patients in each group experiencing a rejection episode. This rejection rate was significantly decreased from that of the CsA-AZA historical group (77%, P<0.01). There were no significant differences in infection rates, including cytomegalovirus, or in metabolic control (HgbA1C, hypertension, and cholesterol levels). All patients remained on their initial immunosuppression regimen for the first 3 months after transplantation. Between 3 and 6 months after transplantation, three patients were switched from TAC to CsA for recurrent migraine headaches, posttransplant diabetes, and chronic cytomegalovirus infection. Two patients in the CsA-MMF group died of nonimmunologic causes (aspiration pneumonia and arrhythmia) between 3 and 6 months after transplantation. CONCLUSIONS: The data from this study show that MMF treatment significantly decreases the incidence of biopsy-proven acute rejection in SPK transplant recipients compared with AZA-treated historical controls. In addition, we conclude that TAC and CsA (Neoral), when combined with MMF, yield similar, low acute rejection rates with similar graft function and metabolic control.

Adult↗
PubMed1997

Characterization and purification of human corneodesmosin, an epidermal basic glycoprotein associated with corneocyte-specific modified desmosomes.

Using monoclonal antibodies, we identified a new protein in mammalian epidermis, which we called corneodesmosin. It is located in the extracellular part of the modified desmosomes in the cornified layer of the tissue, and its proteolysis (from 52-56 to 33 kDa) is thought to be a major prerequisite of desquamation. We have now further characterized human corneodesmosin. Proteolysis of purified cornified cell envelopes produced immunoreactive fragments, confirming the covalent linkage of the protein to these structures. Sequential extraction of epidermal proteins indicated that the 52-56-kDa precursor form of the protein exists in two distinct pools, one extracted with a nondenaturing hypotonic buffer, and the other with urea. Two-dimensional gel analysis and reactivity with phosphoserine-specific antibodies showed that it is a basic phosphoprotein. Deglycosylation experiments, reactivity with lectins, and chromatography on concanavalin A-Sepharose indicated that corneodesmosin is N-glycosylated. Partial sequences, 10 and 15 amino acids long, of the purified 52-56-kDa corneodesmosin showed identity with sequences predicted from a previously cloned gene, proved to be expressed in the epidermis and designated S. This indicates that corneodesmosin is probably encoded by the S gene, the function of which was unknown until now. A model of corneodesmosin maturation during cornification is proposed.

Amino Acid Sequence↗
PubMed1997

The Ca2+-dependent binding of calmodulin to an N-terminal motif of the heterotrimeric G protein beta subunit.

Ca2+ ion concentration changes are critical events in signal transduction. The Ca2+-dependent interactions of calmodulin (CaM) with its target proteins play an essential role in a variety of cellular functions. In this study, we investigated the interactions of G protein betagamma subunits with CaM. We found that CaM binds to known betagamma subunits and these interactions are Ca2+-dependent. The CaM-binding domain in Gbetagamma subunits is identified as Gbeta residues 40-63. Peptides derived from the Gbeta protein not only produce a Ca2+-dependent gel mobility shifting of CaM but also inhibit the CaM-mediated activation of CaM kinase II. Specific amino acid residues critical for the binding of Gbetagamma to CaM were also identified. We then investigated the potential function of these interactions and showed that binding of CaM to Gbetagamma inhibits the pertussis toxin-catalyzed ADP-ribosylation of Galphao subunits, presumably by inhibiting heterotrimer formation. Furthermore, we demonstrated that interaction with CaM has little effect on the activation of phospholipase C-beta2 by Gbetagamma subunits, supporting the notion that different domains of Gbetagamma are responsible for the interactions of different effectors. These findings shed light on the molecular basis for the interactions of Gbetagamma with Ca2+-CaM and point to the potential physiological significance of these interactions in cellular functions.

Adenosine Diphosphate Ribose↗
PubMed1997

New families with von Willebrand disease type 2M (Vicenza).

The variant von Willebrand disease (vWd) variant type 2M (Vicenza) was identified in 13 patients of 7 unrelated families. 11 patients were from different parts of germany and 2 patients from Turkey. Hitherto this variant of vWd has been described only in two families originating from the province of Vicenza in Northern Italy. Characteristically this type of vWd shows the supranormal multimers of von Willebrand factor (vWf) in plasma similar to those seen in normal plasma after desmopressin infusion. Clinically, the patients present with bleeding symptoms. Other laboratory abnormalities include reduced values for vWf antigen (vWf: Ag), factor VIII coagulant activity (VII:C), ristocetin cofactor activity (RiCof) and collagen binding activity (vWf: CBA). The hereditary transmission of this variant is consistent with an autosomal dominant mode of inheritance. The patients with vWd type 2M (Vicenza) could be allocated into two subgroups: type "platelet normal" with normal vWf properties in platelets and type "platelet low" with reduced vWf: Ag levels in platelets.

Adult↗
PubMed1997

BAC and PAC contigs covering 3.5 Mb of the Down syndrome congenital heart disease region between D21S55 and MX1 on chromosome 21.

Chromosome 21 is a model for the study of human chromosomal aneuploidy, and the construction of its physical and transcriptional maps is a necessary step in understanding the molecular basis of aneuploidy-dependent phenotypes. To identify the gene(s) responsible for Down syndrome congenital heart disease (DS-CHD), we constructed a physical map of the D21S55 to MX1 region. A bacterial artificial chromosome (BAC) library was screened using several YACs spanning the interval, and a P1-derived artificial chromosome (PAC) library was screened using radiolabeled STS PCR products and whole BACs in gap-filling initiatives. FISH confirmed the location of all BAC and PAC clones to 21q22.2-q22.3. Overlaps were established using clone-to-clone Southerns and 24 new STSs, generated from the direct sequencing of BAC and PAC ends, along with 35 preexisting STSs. Approximately 3.5 Mb of the 4- to 5-Mb D21S55 to MX1 interval is covered in 85 BACs and 24 PACs, representing fourfold coverage within the contigs. These BAC and PAC contigs are valuable reagents for isolating the genes for DS-CHD.

Base Sequence↗
PubMed1997

Corneodesmosin, a corneodesmosome-specific basic protein, is expressed in the cornified epithelia of the pig, guinea pig, rat, and mouse.

Proteolysis of corneodesmosin, a 52- to 56-kDa basic protein located in the extracellular part of the modified desmosomes (corneodesmosomes) of human cornified epithelia, is thought to be a key event of desquamation. Three monoclonal antibodies specific for human corneodesmosin were used to search for the expression of the protein in other mammals. Cryosections of pig, guinea pig, rat, and mouse cornified tissues and proteins sequentially extracted from the corresponding epithelia were analyzed by immunofluorescence and immunoblotting, respectively. Two of the antibodies (F28-27 and B17-21) showed, on the epidermis of the four species and on the cornified epithelia of the rat tongue and esophagus, the same labeling as on human epidermis. Cytoplasmic in the lower granular layer, then pericellular microgranular, the labeling progressively disappeared in the lower cornified layer. By contrast, it persisted up to the surface in the rat tail epidermis. The two antibodies immunodetected basic proteins extracted with isotonic buffer from the epidermis of the pig (50 kDa), guinea pig (52 kDa), and mouse (75 kDa) and from the cornified epithelia of the rat (75 kDa). Immunoreactive proteins of lower Mr were also extracted partly with urea and partly with a reducing agent. The third antibody (G36-19) presented the same reactivities except on murine tissues, where it was unreactive. Our results show that the location, the biochemical characteristics, and the processing of corneodesmosin are similar in five mammals, including humans, suggesting an important role for this protein. They open the way to studies of its function in desquamation using various animal models.

Animals↗
PubMed1997

Altered erythrocytes and a leaky block in B-cell development in CD24/HSA-deficient mice.

The heat stable antigen (HSA, or murine CD24) is a glycosyl phosphatidylinositol-linked surface glycoprotein expressed on immature cells of most, if not all, major hematopoietic lineages, as well as in developing neural and epithelial cells. It has been widely used to stage the maturation of B and T lymphocytes because it is strongly induced and then repressed again during their maturation. Terminally differentiated lymphocytes, as well as most myeloid lineages, are negative for HSA. Erythrocytes are an exception in that they maintain high levels of HSA expression. HSA on naive B cells has been shown to mediate cell-cell adhesion, while HSA on antigen-presenting cells has been shown to mediate a costimulatory signal important for activating T lymphocytes during an immune response. Here, we characterize mice that lack a functional HSA gene, constructed by homologous recombination in embryonic stem cells. While T-cell and myeloid development appears normal, these mice show a leaky block in B-cell development with a reduction in late pre-B and immature B-cell populations in the bone marrow. Nevertheless, peripheral B-cell numbers are normal and no impairment of immune function could be detected in these mice in a variety of immunization and infection models. We also observed that erythrocytes are altered in HSA-deficient mice. They show a higher, tendency to aggregate and are more susceptible to hypotonic lysis in vitro. In vivo, the mean half-life of HSA-deficient erythrocytes was reduced. When infected with the malarial parasite Plasmodium chabaudi chabaudi, the levels of parasite-bearing erythrocytes in HSA-deficient mice were also significantly elevated, but the mice were able to clear the infection with kinetics similar to wild-type mice and were immune to a second challenge. Thus, apart from alterations in erythrocytes and a mild block in B-cell development, the regulated expression of HSA appears to be dispensable for the maturation and functioning of those cell lineages that normally express it.

Animals↗
PubMed1997

Molecular and cellular characterization of CRP1, a Drosophila chromatin decondensation protein.

CRP1, a Drosophila nuclear protein that can catalyze decondensation of demembranated Xenopus sperm chromatin was cloned and its primary structure was deduced from cDNA sequence. Alignment of deduced amino acid sequence with published sequences of other proteins revealed strong homologies to Xenopus nucleoplasmin and NO38. CRP1 is encoded by one or several closely related genes found at a single locus, position 99A on the right arm of chromosome 3. CRP1 mRNA is expressed throughout Drosophila development; it is highest during oogenesis and early embryogenesis. mRNA levels correlate closely with levels of protein expression measured previously. Results of chemical crosslinking indicate that CRP1 is either tetrameric or pentameric; similar ambiguity was revealed by direct visualization using scanning transmission electron microscopy. Consistent with previously published results, parallel crosslinking studies of Xenopus nucleoplasmin suggested a pentameric structure. Scanning transmission electron microscopic examination after negative staining revealed that CRP1 and Xenopus nucleoplasmin are morphologically similar. CRP1 is able to substitute for nucleoplasmin in Xenopus egg extract-mediated sperm chromatin decondensation. In vitro, CRP1-induced decondensation is accompanied by direct binding of CRP1 to chromatin.

Amino Acid Sequence↗
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↗