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Biomedical subjects

R Goldschmeding

Publications and source records attributed to R Goldschmeding.

At least 37 records · Page 2Linked to original sources
PubMed1998

Expression of connective tissue growth factor in human renal fibrosis.

Chronic renal failure may occur in etiologically diverse renal diseases and can be caused by hemodynamic, immunologic and metabolic factors. Initial damage may evoke irreversible scarring, which involves production of a number of proinflammatory and fibrogenic cytokines, including platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-beta). Connective tissue growth factor (CTGF), a cytokine of the family of growth regulators comprising sef10, cyr61, CTGF and nov, has recently been described in association with scleroderma and other scarring conditions. We investigated CTGF mRNA expression in 65 human renal biopsy specimens of various renal diseases by in situ hybridization. In control human kidney CTFG mRNA was mainly expressed in visceral epithelial cells, parietal epithelial cells, and some interstitial cells. Connective tissue growth factor was strongly up-regulated in the extracapillary and severe mesangial proliferative lesions of crescentic glomerulonephritis, IgA nephropathy, focal and segmental glomerulosclerosis and diabetic nephropathy. An increase in the number of cells expressing CTGF mRNA was observed at sites of chronic tubulointerstitial damage, which correlated with the degree of damage. in the tubulointerstitial area the majority of the CTGF mRNA positive cells coexpressed alpha-smooth muscle actin, and were negative for macrophage markers. Our results indicate that CTGF may be a common growth factor involved in renal fibrosis.

Biopsy↗
PubMed1998

Enalapril prevents imminent and reduces manifest cerebral edema in stroke-prone hypertensive rats.

BACKGROUND AND PURPOSE: Stroke-prone spontaneously hypertensive rats (SHRSP), subjected to high NaCl intake, show severe hypertension, organ damage, and early death. Preventive treatment with an angiotensin-converting enzyme (ACE) inhibitor is known to reduce mortality. Previously we found that proteinuria always precedes cerebral edema in SHRSP. Hence, in this study ACE inhibition was started later, ie, directly after manifestation of either proteinuria or cerebral edema. METHODS: SHRSP were subjected to 1% NaCl intake. Group 1 served as a control. In group 2 early-onset treatment with the ACE inhibitor enalapril was initiated after proteinuria was >40 mg/d. In group 3 late-onset ACE inhibition was started after the first observation of cerebral edema with T2-weighted MRI. Cerebral edema was expressed as the percentage of pixels with an intensity above a defined threshold. RESULTS: In controls median survival was 54 days (range, 32 to 80 days) after start of salt loading. The terminal level of cerebral edema was 19.0+/-3.0%. Under early-onset enalapril, median survival increased to 320 days (range, 134 to 368 days; P<0.01 versus group 1). Cerebral edema was prevented in all but 1 rat. Systolic blood pressure was slightly and transiently reduced at day 14. Proteinuria was markedly reduced (52+/-7 versus 190+/-46 mg/d in group 1 at day 7; P<0.05). Under late-onset enalapril, median survival was 264 days (range, 154 to 319 days; P<0.01 versus group 1). Cerebral edema decreased to baseline levels (9.6+/-2.9 at day 0 to 3.4+/-0.5% at day 3; (P<0.05). Ultimately cerebral edema reoccurred in 6 of the 8 rats. SBP decreased slightly at day 7 only. Proteinuria decreased from 283+/-27 at day 0 to 116+/-22 mg/d at day 7 (P<0.05). Complete remission of the original locus of cerebral edema was confirmed histologically. CONCLUSIONS: In SHRSP with proteinuria, treatment with an ACE inhibitor both prevented the development of cerebral edema and reduced manifest cerebral edema and proteinuria. Survival was markedly prolonged. These findings support the use of ACE inhibition for treatment in hypertensive encephalopathy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Idiopathic granulomatous orbital inflammation.

PURPOSE: Granulomatous orbital inflammation may occur as an isolated condition of unknown origin. These idiopathic granulomatous lesions are believed to belong to the orbital pseudotumor group by some authors, whereas others consider them sarcoidosis limited to the orbit. The aim of this study is to define the clinicotherapeutic aspects of these lesions. METHODS: The records of all patients with diagnosis of orbital pseudotumor and orbital sarcoidosis from the Orbital Center Amsterdam in the period between 1976 and 1994 were reviewed to define those with idiopathic granulomatous orbital inflammation. The authors studied the clinicotherapeutic aspects and histopathology of idiopathic granulomatous orbital inflammation by analysis of their own series and the literature. RESULTS: Their study group encompassed seven patients with idiopathic granulomatous orbital inflammation. The mean follow-up was 9.5 years (range, 3.5-16.0 years). All had unilateral orbital presentation, with localization in the lacrimal gland in three patients. The lesions clinically presented with signs of mass effect or inflammation or both and were treated successfully with surgery, systemic corticosteroids, a combination of surgery and systemic corticosteroids, or systemic corticosteroids followed by irradiation. Histopathologic analysis showed a spectrum of granulomatous inflammation, admixed with nongranulomatous inflammation and fibrosis. There have been 30 similar cases described in the literature with comparable clinicotherapeutic characteristics. CONCLUSIONS: Based on this study and the literature, it appears that idiopathic granulomatous orbital inflammation is more related to orbital pseudotumor than to orbital sarcoidosis.

Acute Disease↗
PubMed1996

The surgical management of lacrimal gland pseudotumors.

PURPOSE: Lacrimal gland pseudotumors belong to the group of orbital pseudotumor. Systemic corticosteroids are advocated as the primary treatment of choice in orbital pseudotumor, but recurrent and refractory cases are commonly described. In this retrospective study, the authors evaluate alteerative treatment options such as surgical excision or debulking of lacrimal gland pseudotumors. METHODS: The records of 26 patients referred to the Orbital Center of Amsterdam between 1976 and 1994 with a diagnosis of lacrimal gland pseudotumor were reviewed with special reference to computed tomography scans, histopathologic specimens (in 23 patients), treatment regimens, and final clinical outcome. RESULTS: Histopathologic review showed 15 nonsclerosing (classic) and 8 sclerosing lacrimal gland pseudotumors. Initial treatment consisted of corticosteroids alone (9/26), surgery alone (7/26), a combination of surgery and irradiation (5/26), a combination of surgery and corticosteroids (4/26), or indomethacin alone (1/26). Surgery comprised tumor excision or tumor debulking. Of the patients treated with corticosteroids alone, 55% (5/9) responded initially but only 22% (2/9) obtained a cure. However, all patients treated with surgery combined with corticosteroids/irradiation (9/9), with surgery alone (7/7), or with indomethacin alone (1/1) responded well without recurrences. The main complication of therapy was dry eye syndrome, the incidence being highest in patients who received surgery of the palpebral lobe or irradiation. The mean follow-up was 4.9 years. CONCLUSION: Surgical excision or debulking is a safe and effective treatment option in lacrimal gland pseudotumors, even in the histopathologic sclerosing variant.

Adult↗
PubMed1996

Are systemic corticosteroids useful in the management of orbital pseudotumors?

PURPOSE: Systemic corticosteroids are the established primary treatment for orbital pseudotumors, but patients with recurrent and refractory pseudotumors commonly are observed. In this retrospective study, the authors aimed to assess the value of corticosteroids in the management of orbital pseudotumor. METHODS: The clinical notes, computed tomography scans, and histologic specimens of patients with orbital pseudotumor seen at the Orbital Center, Amsterdam, between 1976 and 1994 were analyzed with particular regard to the clinical and visual outcome. The patients were categorized according to the anatomic location of the pseudotumor within the orbit. Patients with pseudotumors restricted to the lacrimal gland or an extraocular muscle were excluded. RESULTS: The authors studied 32 patients with orbital pseudotumor, 20 of whom had histopathologic confirmation. Twenty-seven of these 32 patients received systemic corticosteroids as an initial treatment. Of these 27 patients, 21 (78%) showed an initial response and 10 (37%) obtained a cure. After the initial response, 11 (52%) of the 21 patients recurred. Optic nerve involvement was present in 13 (41%) of the 32 patients, and all except 1 patient recovered with corticotherapy. The mean follow-up of therapy was 4.3 years (range, 5.3 months-21.5 years). CONCLUSION: The authors found a moderate response, a high recurrence, and a low cure rate in patients treated with corticosteroids for orbital pseudotumor, and they therefore challenge the value of corticosteroids in both diagnosing and treating this condition. However, in patients with pseudotumor-induced optic neuropathy, corticosteroids remain of value.

Adolescent↗
PubMed1995

Platelet satellitism is Fc gamma RIII (CD16) receptor-mediated.

Platelet satellitism (PS), the phenomenon of platelet rosetting around polymorphonuclear neutrophils (PMN), which is observed in ethylenediamineetetraacetic acid (EDTA)-anticoagulated blood at room temperature, is caused by the presence of IgG autoantibodies in the serum. Fourteen patients with PS were studied, and the presence of both EDTA-dependent antiplatelet and EDTA-dependent antineutrophil IgG (auto)antibodies were found in their sera. Anti-neutrophil activity was completely abolished when the sera were absorbed on normal platelets, which suggests that a single antibody is involved. Inhibition studies with monoclonal antibodies indicated that this IgG autoantibody is directed against the glycoprotein IIb/IIIa complex of the platelet membrane, as well as the neutrophil Fc gamma receptor III (Fc gamma RIII). In addition, the antibody did not react with platelets from a patient with type I Glanzmann's disease, nor with neutrophils from a patient with congenital Fc gamma RIII absence (NAnull phenotype), thus confirming both specificities. As in other literature cases, a clear correlation between the presence of this IgG and a specific clinical situation, disease, or use of drugs could not be shown. Therefore, these antibodies, which are present in some normal individuals, might occur naturally. Because of the exposure of particular cryptoantigenic structures present on EDTA-modified platelet and PMNs, they may manifest themselves by triggering the PS phenomenon.

Antibodies, Monoclonal↗
PubMed1995

Proteolysis of classic anti-neutrophil cytoplasmic autoantibodies (C-ANCA) by neutrophil proteinase 3.

C-ANCA, which are directed against neutrophil proteinase 3 (PR3), are specific markers for the diagnosis of active Wegener's granulomatosis (WG). The correlation between C-ANCA titre and WG disease activity suggests that these autoantibodies are involved in the development of WG. We have previously observed that C-ANCA interfere with PR3 proteolytic activity and with complexation of PR3 with its major physiologic inhibitor alpha 1-antitrypsin (alpha 1-AT). The possible pathogenic importance of C-ANCA may be related to the stability of C-ANCA IgG-PR3 complexes. In the present study we tested proteolysis by PR3 of human IgG and proteolysis of C-ANCA IgG complexed to the enzyme. All human IgG subclass proteins were cleaved by PR3. Digestion products were compared with those obtained by human neutrophil elastase (HNE)-mediated proteolysis of human IgG subclass proteins. Although cleavage products of similar size could be identified, the proteolytic activity of both enzymes towards human IgG differed. Furthermore, inhibiting C-ANCA IgG were cleaved into small peptides when complexed to PR3. The possible pathogenic consequences of these findings will be discussed.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1994

Human platelet antigen-1 (Zw) typing of fetuses by analysis of polymerase chain reaction-amplified genomic DNA from amniocytes.

Prenatal typing for the human platelet antigens-1 (HPA) permits identification of a fetus at risk for neonatal alloimmune thrombocytopenia (NAITP) in cases of HPA-1 incompatibility in which the father is heterozygous for the HPA-1a antigen. Diagnostic cordocentesis and phenotyping of the fetal platelets are used for this purpose. We applied allele-specific restriction enzyme analysis on polymerase chain reaction (PCR)-amplified DNA purified from amniocytes. This assays allows early second trimester typing for HPA-1 alleles. We were able to determine the genotype of three fetuses at risk. Iatrogenic fetal loss is lower with amniocentesis than with cordocentesis. Therefore, this technique is a welcome addition to the antenatal management of NAITP.

Alleles↗
PubMed1994

A new private platelet antigen, Groa, localized on glycoprotein IIIa, involved in neonatal alloimmune thrombocytopenia.

The serum of a Caucasian woman who gave birth to a child with neonatal alloimmune thrombocytopenia contained antibodies directed against a platelet antigen of the newborn. There was no incompatibility for the known platelet alloantigens HPA-1 to HPA-7 or for the private or low-frequency antigens Sra and Vaa, between the platelets of the parents. However, crossmatching with the serum of the mother and the platelets of the child and the father was strongly positive, suggesting a new platelet antibody specificity. To investigate the inheritance of the 'Groa' antigen involved, the available family members were tested in the platelet immunofluorescence test (PIFT) and the monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay. The Groa antigen was found to be inherited in an autosomal-codominant fashion. In the MAIPA, we localized the Groa antigen on the glycoprotein IIb/IIIa complex (alpha IIb beta 3). The GP IIb/IIIa localization was confirmed in immunoprecipitation studies. In Western blotting experiments, we further localized the Groa antigen on the GP IIIa (beta 3) subunit of the GP IIb/IIIa complex. Until now we have tested approximately 400 unrelated donors. None of these appeared to be positive for the Groa antigen, suggesting a phenotype frequency in the Dutch population of less than 0.01.

Adult↗
PubMed1994

Sequence analysis of cDNA derived from reticulocyte mRNAs coding for Rh polypeptides and demonstration of E/e and C/c polymorphisms.

RNA derived from enriched reticulocytes of Rh-phenotyped donors was isolated, reversely transcribed into cDNA and amplified with Rh-specific primers by polymerase chain reaction. Nucleotide sequence analysis of the entire coding region of the Rh cDNAs was carried out. Four types of cDNAs were identified, tentatively designated as RhSCI, RhSCII, RhSCIII and RhSCIV. Comparison of RhSCII with RhSCI (identical to the previously reported RhIXb/30A cDNA), showed single base pair difference. Since RhSCI and RhSCII were found to be related to the presence of E or e antigen, respectively, the P226A amino acid polymorphism appears to be the genetic basis of the E/e polymorphism. RhSCIII was demonstrated to be a transcript derived from the RhD gene, with 35 amino acid substitutions as compared to RhSCI. RhSCIV was found to be present only in RhC-positive individuals, indicating that RhSCIV encodes a polypeptide carrying the C antigen. Six nucleotide changes, resulting in four amino acid substitutions W16C, L60I, N68S and P103S, were observed between RhSCII and RhSCIV, probably representing the C/c polymorphism.

Amino Acid Sequence↗
PubMed1994

Neutrophil cytoplasmic antibodies (p-ANCA) in ulcerative colitis.

AIMS: To study ulcerative colitis associated neutrophil cytoplasmic antibodies (p-ANCA) in respect of class and subclass distribution, antigen specificity, and (sub)cellular localisation of the antigen(s) to which these antibodies are directed. METHODS: p-ANCA positivity was determined using the standard indirect immunofluorescence test (IIFT). The immunoglobulin (Ig) subclass distribution of p-ANCA was investigated using monoclonal antibodies directed against IgG1, IgG2, IgG3, and IgG4. Intracellular antigen localisation studies were performed on (fractionated) neutrophils using antigen-specific antibodies. RESULTS: In contrast to vasculitis associated ANCA, ulcerative colitis p-ANCA are mainly of IgG1 and IgG3 subclass and lack IgG4. Ulcerative colitis p-ANCA are myeloid specific. IIFT data indicate that the related antigen(s) seem(s) to be located not in the cytosol, but in the granules (most likely the azurophil granules) of the neutrophil. CONCLUSIONS: p-ANCA in ulcerative colitis have a different immunoglobulin subclass distribution than the ANCA of systemic necrotising vasculitis and necrotising and crescentic glomerulonephritis. This may point to differences in immune regulation between these diseases. Both cathepsin G and lactoferrin are recognised by a subpopulation of ulcerative colitis p-ANCA. In our series, eight out of 36 (22%) of ulcerative colitis associated p-ANCA react with lactoferrin and seven (19.5%) other sera with cathepsin G. None of them recognised both antigens. The main target antigen(s) of ulcerative colitis p-ANCA still remain(s) to be identified.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1993

Vasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy.

Vasculitis is a rare complication of propylthiouracil therapy. Antineutrophil cytoplasmic antibodies (ANCA) have been described in association with several vasculitic disorders. We report detection of ANCA against human neutrophil elastase, proteinase 3, and myeloperoxidase in serum from six patients who developed evidence of vasculitis during propylthiouracil treatment of hyperthyroidism. On withdrawal of the drug ANCA concentrations fell and clinical symptoms resolved completely.

Adult↗
PubMed1993

Glanzmann's thrombasthenia caused by homozygosity for a splice defect that leads to deletion of the first coding exon of the glycoprotein IIIa mRNA.

Glanzmann's thrombasthenia (GT) is the result of the absence or of an altered and dysfunctional expression on the platelet membrane of the fibrinogen receptor (glycoprotein [GP] IIb/IIIa complex). Various molecular genetic mechanisms have been found to be responsible for this inherited disease. In a patient with a severe type of GT, we have found a splice variant in the GP IIIa gene that leads to premature chain termination. Immunoprecipitation experiments, using monoclonal antibodies specific for GP IIb/IIIa, showed that GP IIb/IIIa was not detectable on the platelet membrane. Amplification of reversely transcribed platelet GP IIIa mRNA by the polymerase chain reaction and subsequent sequence analysis showed a 86-bp deletion, which corresponds to exon i of the GP IIIa gene. This deletion results in a shift of the reading frame leading to eight altered amino acids followed by a premature termination codon. Analysis of the corresponding genomic DNA fragments showed three mutations in the exon i-intron i boundary region of the GP IIIa gene. One of these mutations is a G-->T transition that eliminates the GT splice donor site in the wild type. This base pair change creates a restriction site for the enzyme Mse I. Allele-specific restriction enzyme analysis (ASRA) with Mse I of amplified genomic DNA of the parents and the proposita showed that both parents (who are first cousins) are heterozygous, whereas the proposita is homozygous for the G-->T substitution.

Adult↗
PubMed1993

Determination of human platelet antigen frequencies in the Dutch population by immunophenotyping and DNA (allele-specific restriction enzyme) analysis.

Platelets from 200 random Dutch blood donors were typed for the human platelet alloantigens HPA-1 to -5 recognized at present and for Naka. Naka is an epitope on glycoprotein IV, not expressed on the platelet of individuals with hereditary GP IV deficiency. Platelet immunofluorescence and monoclonal antibody-specific immobilization of platelet antigens (MAIPA) were applied for this purpose. The observed phenotype frequencies were 97.86% and 28.64% for HPA-1a and -1b, 100% and 13.15% for HPA-2a and -2b, 80.95% and 69.84% for HPA-3a and -3b, 100% and 0% for HPA-4a and -4b, 100% and 19.7% for HPA-5a and HPA-5b, respectively. Platelets from all donors reacted with the anti-Naka antibodies. To determine the gene frequencies for the HPA-1, HPA-2 and HPA-3 systems directly, DNA from 98 of these donors was isolated from peripheral blood mononuclear leucocytes and specific fragments were amplified by polymerase chain reaction (PCR). The fragments were analyzed using allele-specific restriction enzymes (ASRA). In all amplified PCR products an "internal control" for each assay, ie, a restriction site for the applied enzyme independent from the phenotype of the donor was present. In all donors tested, phenotypes, as determined by serological methods and genotypes, directly determined by the ASRA, were identical. Thus, the PCR-ASRA described in this report is a practical and reliable technique for the determination of alleles that code for platelet antigen allotypes, at least in the Dutch population.

Alleles↗
PubMed1993

Single point mutation in human glycoprotein IIIa is associated with a new platelet-specific alloantigen (Mo) involved in neonatal alloimmune thrombocytopenia.

Here we describe a new platelet-specific alloantigen that was identified in a case of neonatal alloimmune thrombocytopenia. This antigen has provisionally been called "Mo." By studying the Mo family, it was shown to be inherited in an autosomal dominant manner. Immunoprecipitation and Western blot analysis showed that the antigen resides on platelet glycoprotein IIIa (GP IIIa). Genomic analysis, performed by applying polymerase chain reaction and sequencing, showed a C-->G substitution of base pair 1267 of the coding region of the DNA for GP IIIa, resulting in a substitution of Proline407 by Alanine407. That this substitution is associated with the antigen could be demonstrated by restriction fragment length polymorphism analysis of cDNA, prepared from platelet RNA, and of genomic DNA. It was confirmed by dot-blot hybridization with allele-specific oligonucleotides. All family members, also those being Mo antigen-positive, were healthy. None of them appeared to suffer from increased tendency of bleeding or thrombosis. Thus, the Mo mutation does not lead to significant platelet dysfunction in vivo with heterozygous carriers. One of 450 random healthy blood donors who were tested was positive for the Mo antigen. Typing was performed by the classical serologic methods as well as by DNA analysis.

Base Composition↗
PubMed1993

Proteinase 3: substrate specificity and possible pathogenetic effect of Wegener's granulomatosis autoantibodies (c-ANCA) by dysregulation of the enzyme.

Reactivity of proteinase 3 (PR3) was tested against various amino acid and thioester substrates. The best substrate is Boc-Ala-Ala-Nva-SBzl with a kcat/Km value of 1.0 x 10(6) M-1.s-1. We also studied the effect of C-ANCA on PR3 proteolytic activity towards elastin and inactivation by alpha 1-antitrypsin (alpha 1AT). C-ANCA IgG from 8 patients with active Wegener's granulomatosis were tested and found to inhibit elastin degradation by PR3 and to prevent the inactivation of PR3 by alpha 1AT.

Amino Acid Sequence↗
PubMed1993

A novel specificity of anticytoplasmic autoantibodies directed against eosinophil peroxidase.

Vasculitis associated anticytoplasmic autoantibodies (ANCA) are directed against enzymes in the granules of both neutrophils and monocytes. These autoantibodies can be detected by indirect immunofluorescence technique (IIFT) using ethanol-fixed cytospins. We here report the identification of a novel specificity of autoantibodies, present in the sera of eight patients, that reacted only with eosinophils in the IIFT. By immunoprecipitation and ELISA experiments it was shown that the autoantibodies in these sera were directed against eosinophil peroxidase (EPO). There was no apparent influence on initial substrate conversion rate, but reduced plateau levels suggested increased inactivation of the enzyme in the course of the peroxidase reaction. Flow cytometry studies demonstrated the presence of EPO on the surface of primed eosinophils. Anti-EPO sera and purified anti-EPO immunoglobulins significantly increased the release of reactive oxygen species from primed eosinophils. The patients with anti-EPO antibodies suffered from clinically diverse disorders, with more or less generalized manifestations involving the kidneys, blood vessels, lungs and/or joints.

Adolescent↗