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H Schmidt

Publications and source records attributed to H Schmidt.

At least 289 records · Page 16Linked to original sources
PubMed1999

Long-term outcome of paediatric patients with hereditary tubular disorders.

BACKGROUND: An increasing number of children with hereditary tubular disorders (HTD) reach adult life due to diagnostic and therapeutic advances which results in growing need to manage these patients by adult centres. Data on the prevalence and the late clinical problems of these patients are limited. METHODS: We observed 177 paediatric patients with isolated or complex HTD between 1969 and 1994. The median age at the time of diagnosis was 3 (range 0-18) years and the median observation period 10 (range 1-43) years. The long-term outcomes with respect to renal function, bone disease, and body growth were analyzed. RESULTS: The prevalence of HTD was 3.2% of all patients observed in our renal unit and 14% of those patients with chronic renal failure and/ or end-stage renal disease. The three most frequent disorders observed were nephropathic cystinosis (n = 34), X-linked hypophosphataemic rickets (n = 26), and idiopathic hypercalciuria (n = 17). At the last observation, 12% of the patients with isolated HTD and 30% of those with complex HTD had developed preterminal chronic renal failure; end-stage renal disease was observed in 5 and 25%, respectively (p < 0.001). Progressive disease occurred mainly in patients having cystinosis, primary hyperoxaluria, the syndrome of hypomagnesaemia/hypercalciuria, primary Fanconi syndrome, Fanconi-Bickel syndrome, and methylmalonic aciduria. Nephrocalcinosis was found in 42%, urolithiasis in 14%, bone deformities and/or fractures in 28%, and other extrarenal alterations in 29% of all patients. The median body height at last observation was 2.0 SD below the normal mean (range from -10.4 to +2. 6), and the adult height was subnormal in 48% of 67 grown-up patients. Growth retardation was more severe in complex than in isolated HTD. The mortality decreased from 17% in 1969-1981 to 12% in 1982-1994. CONCLUSION: Although HTD are rare nephropathies, their frequently progressive course associated with extrarenal complications requires the attention of nephrologists beyond the paediatric age.

Adolescent↗
PubMed1999

Clonal infection with Actinobacillus actinomycetemcomitans following periodontal therapy.

Mechanical debridement results in a shift of the bacterial composition in the periodontal pocket on the species level. It is unknown, however, whether a clonal change within a species could lead to the emergence of strains with different levels of virulence. Therefore, in the present study, the genetic variability of Actinobacillus actinomycetemcomitans was assessed and strains identified which were associated with periodontal disease progression following periodontal therapy, i.e., refractory periodontitis. Twenty adult patients with untreated periodontitis and subgingival colonization of A. actinomycetemcomitans were randomly assigned to receive full-mouth scaling alone or scaling with an adjunctive antimicrobial therapy. Both groups received supportive periodontal therapy at 3, 6, 9, 12, 18, and 24 months. Subgingival plaque samples were taken at every visit; venous blood was obtained at 24 months only. A. actinomycetemcomitans isolates were typed by the RAPD method, and antibody reactivity against outer membrane proteins was assessed by immunoblot analysis. Eleven distinct RAPD patterns were found in 18 patients completing the study. All patients harbored only one A. actinomycetemcomitans genotype, and within each patient this genotype persisted throughout the 24-month observation period. No differences in the expression of antibody reactivity against outer membrane proteins were found between strains isolated at baseline and at 24 months. Three genotypes were associated with reduced survival rates of teeth without probing attachment loss of 2 mm or more. The results indicated that (i) most patients harbored only one A. actinomycetemcomitans genotype; (ii) the genotype persisted following therapy; and (iii) only some genotypes were associated with refractory periodontitis.

Adult↗
PubMed1999

Assessment of genomic imbalances in malignant fibrous histiocytomas by comparative genomic hybridization.

In order to investigate genomic imbalances, comparative genomic hybridization was applied to 20 malignant fibrous histiocytomas. Deletions were rare and found mainly in chromosomes 2q33-35, 4q32-qter, 8p, 9p21-pter, 12p and 19p, whereas, over-representations frequently affected chromosomes 3, 4q31, 5p, 6, 7, 14q22-ter, 18p, as well as, five distinct amplifications within the regions 12q12-15 and 15q24-qter. The total number of genetic imbalances per tumor was slightly increased in primary tumors when compared to relapses. No relationship was found between the patterns of gain and loss when compared to the histological subtype, tumor grading, the clinical outcome and the p53 mutation status.

Aneuploidy↗
PubMed1999

C1-esterase inhibitor and its effects on endotoxin-induced leukocyte adherence and plasma extravasation in postcapillary venules.

BACKGROUND: C1-esterase inhibitor (C1-INH) has been shown to have beneficial effects in patients with sepsis. However, the microcirculatory effects of C1-INH during sepsis are unknown. This study investigated the influence of C1-INH on leukocyte-endothelial cell adhesion, vascular leakage, and venular microhemodynamics in postcapillary venules of rat mesentery during endotoxemia. METHODS: Thirty-two anesthetized Wistar rats randomly received 1 of 4 treatments: pretreatment with infusion of C1-INH in a concentration of 7.5 U.kg-1 body weight (C1-INH-7.5 group, n = 8) or in a concentration of 15 U.kg-1 body weight (C1-INH-15 group, n = 8) followed by continuous infusion of Escherichia coli lipopolysaccharide (LPS). The LPS group (n = 8) was pretreated with saline solution 30 minutes before LPS infusion. The control group (n = 8) received equivalent amounts of saline infusion. Leukocyte adherence, red blood cell velocity, and vessel diameters in postcapillary venules of rat mesentery were determined every 60 minutes during a period of 120 minutes using in vivo videomicroscopy. Vascular permeability was determined by measuring the extravasation of fluorescence-labeled albumin. Venular wall shear rate was calculated from mean red blood cell velocity and vessel diameter. RESULTS: LPS infusion induced a decrease in venular wall shear rate and an increase in leukocyte adherence and vascular permeability in postcapillary venules of rat mesentery. All microcirculatory disturbances were attenuated by pretreatment with C1-INH, showing no significant difference between the 2 concentrations. CONCLUSIONS: Pretreatment with C1-INH attenuates endotoxin-induced leukocyte adherence and macromolecular leakage in postcapillary venules of rat mesentery, indicating that complement inhibition might be a therapeutic tool in the treatment of sepsis.

Animals↗
PubMed1999

[Evaluation of a newly discovered LDL receptor mutation (exon 10, GAC>AAC, D271N, "FH Graz-1") in familial hypercholesterolemia-- a familystudy].

Heterozygous familial hypercholesterolemia (FH, prevalence 1:500) is a major cause of early atherosclerotic disease. Little is known about possible co-factors influencing individual patient's risk. We investigated this question in a large family carrying a new LDL-receptor-mutation. Genetic analysis of all exons of the LDL-receptor gene in the index case using polymerase chain reaction (PCR) and Denaturing Gradient Gel Electrophoresis (DGGE) revealed a previously unknown mutation in exon 10 (GAC > ACC, D471N, "FH Graz-1"). Investigation of 21 family members (15 females, 6 males), aged 17 to 86 years, revealed 9 female and 4 male carriers of the mutation. 7 female carriers aged 17 to 58 years show no clinical signs of macrovascular disease. An 86-year old female patient, who was asymptomatic until 85, recently suffered a transient cerebral ischemic attack. All these females were normotensive. The only hypertensive 76-year old patient (ex-smoker with a history of 15 pack years) suffers from angina pectoris. 2 male carriers of the mutation (32 and 38 years old) are asymptomatic. A 65-year old patient suffers from cardiovascular disease. A 49-year old patient had a coronary artery bypass graft after a myocardial infarction at the age of 37. Additionally he has a history of bilateral thrombendarterectomy of the carotid arteries and suffers from bilateral peripheral artery disease. This patient also carries the apoE-genotype 4/3, which might be responsible for his poor response to stain therapy, and needs extracorporal lipid elimination (LDL-C > 200 mg/dl under drug therapy). Both of his daughters are homozygous for the apoE-allele 3 and and responded well to stain therapy. Genetic analysis in patients with FH assures diagnosis, but is not sufficient to determine the individual patient's risk. A precise clinical examination remains the gold standard for individual risk evaluation.

Adolescent↗
PubMed1999

Predictive value of flow cytometry for metastatic potential in breast cancer.

Breast cancer is the leading malignancy in women in the United States. Tumor size and nodal metastases have been the most important predictors of patient outcome and determinants of treatment, but have also been used to predict metastatic potential. This study was undertaken to ascertain the predictive value of flow cytometry for lymph node or systemic metastases. From 1994 through 1997, surgical specimens from 106 women who underwent treatment for invasive breast cancer were reviewed. Epidemiological data, tumor stage, nodal metastases, and flow cytometric data were collected. Analysis of variance and Student's t test were used to determine whether the presence of nodal metastases or distant metastases correlated with high S phase values and aneuploidy. Of the 106 patients studied, the mean age was 57 years; tumor size consisted of 35 per cent T1, 48 per cent T2, 8 per cent T3, and 9 per cent T4. Node status was found in the following distribution: 56 per cent node negative, 38 per cent N1, and 6 per cent N2. Distant metastases were present in four patients. Elevated S phase (defined as >9.0%) was present in 72 per cent of the population. Fifty-six per cent of these tumors were aneuploid. Node-negative patients had an elevated S phase in 66 per cent of cases, whereas node-positive patients had an elevated S phase in 71 per cent of cases. Neither S phase (P = 0.91) nor DNA index (P = 0.99) proved to be statistically significant in determining axillary node status. Neither did S phase (P = 0.87) nor DNA index (P = 0.48) consistently predict the presence of distant metastases. There is no statistical correlation between axillary node status and flow cytometric data. Breast cancers with high S phase values and aneuploid features do not reliably have axillary nodal metastases, and this data cannot replace that information provided by axillary node dissection. Synchronous systemic metastatic disease is also not predicted by flow cytometry.

Axilla↗
PubMed1999

Genomic imbalances of 7p and 17q in malignant peripheral nerve sheath tumors are clinically relevant.

We investigated 31 malignant peripheral nerve sheath tumors (MPNSTs) from 23 patients by means of comparative genomic hybridization (CGH) in order to study quantitative genomic aberrations of these tumors. Twenty-one of the 23 patients revealed changes, with a mean value of 11 aberrations per sample (range 2-29). The minimal common regions of the most frequent gains were 8q23-q24.1 (12 cases), 5p14 (11 cases), and 6p22-pter, 7p15-p21, 7q32-q35, 8q21.1-q22, 8q24.2-qter, and 17q22-qter (10 cases each). Seventeen high-level amplifications were detected in eight of the 21 samples. In three cases, the high-level amplifications involved 8q24.1-qter, and in two cases each the high-level amplifications involved regions 5p14, 7p14-pter, 8q21.1-q23, and 13q32-q33. The minimal common region of frequent losses was 14q24.3-qter (five cases). The gain of 8q as a single common change in the primary tumor, the recurrence, and the metastasis from the same patient suggests that this aberration is an early change in the tumorigenesis of MPNSTs. Comparable aberrations were observed in separate tumors of the same patients affected by Recklinghausen's disease, indicating a limited number of accidental secondary changes. In sporadic MPNSTs, the most frequent gains were narrowed down predominantly to 5p, 6, 8q, and 20q, whereas in MPNSTs from patients with Recklinghausen's disease, there was most often a gain in 7q, 8q, 15q, and 17q. The occurrence of gain of both 7p15-p21 and 17q22-qter was associated with a statistically significant poor overall survival rate (P = 0.0096).

Adolescent↗
PubMed1999

[Rothmund-Thomson syndrome and osteosarcoma].

Until now less than 200 cases of Rothmund Thomson syndrome (RTS) also called Poikiloderma atrophicans have been reported. RTS is an autosomal recessive dermatosis characterized by athropy and teleangiectasia of the skin, juvenile cataract, hypogonadism and sceletal abnormalities. These osseous disorders include cortical hyperostosis mimicking rickets or chondrodysthropy and may mask early signs of malignant disorders. This seems to be a problem due to the fact that there is an association between osteosarcoma and RTS. The radiologic findings of both RTS and osteosarcoma in a 7 year old female are discussed.

Bone Development↗
PubMed1999

Up-regulation of LDL-receptor expression by LDL-immunoapheresis in patients with familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is characterized by an autosomal dominantly inherited deficiency of LDL-receptor expression on the cell surface, leading to excess plasma LDL-cholesterol and severe premature atherosclerosis. In patients with heterozygous FH, a major therapeutic objective of conventional drug therapy is to stimulate maximally the residual cellular capacity to produce LDL-receptors via inhibition of endogenous cholesterol synthesis. In contrast, LDL-immunoapheresis aims at reducing the plasma LDL-cholesterol level by extracorporeal elimination of LDL particles. The present study investigates whether LDL-immunoapheresis applied in addition to conventional drug therapy is able to further stimulate residual LDL-receptor expression capacity in patients with heterozygous FH via the withdrawal of external cholesterol supply, thereby exerting a second accessory lipid lowering effect. METHODS: LDL-receptor expression--calculated by transforming mean fluorescence intensities into numbers of antibody binding sites per cell (S/C)--was determined flow-cytometrically on peripheral blood monocytes before and after LDL-apheresis. For a comparison with the maximum obtainable receptor expression capacity, in vitro stimulation experiments under completely LDL deficient conditions were performed. RESULTS: Prior to LDL-apheresis, LDL-receptor density was comparable in patients (N = 7; 2014 +/- 359 S/C) and controls (N = 10; 1782 +/- 252 S/C). Under in vitro conditions LDL-receptor expression of controls exceeded that of patients with FH by 1.6 times. Immediately after apheresis, LDL-receptor expression significantly increased to almost the same level as obtained by in vitro stimulation (3640 +/- 423 S/C and 3632 +/- 572 S/C). The LDL-receptor expression in FH subsequent to LDL-apheresis exhibited two patterns of kinetics [Type 1: maximal receptor stimulation (288 +/- 70%; P < 0.07) already during apheresis; Type 2: highest receptor density 24 hours after treatment (149 +/- 11%; P < 0.01)]. CONCLUSIONS: These results demonstrate that despite drug therapy, LDL-apheresis significantly stimulates the residual LDL-receptor expression in FH via the reduction of available extracellular cholesterol resulting in delayed reappearance of hypercholesterolemia in between treatments.

Adult↗
PubMed1999

Influence of C1-esterase inhibitor on tissue oxygenation of jejunal mucosa during endotoxemia.

BACKGROUND: The complement system has been shown to play an important role in the pathogenesis of microcirculatory disturbances in trauma and sepsis. The intestinal mucosa is the most susceptible portion of the gut to impaired perfusion and oxygen delivery. The objective of this study was to investigate the effects of C1-esterase inhibitor (C1-INH) on arterial oxygenation (PaO2) and tissue oxygenation (PtiO2) of jejunal mucosa during endotoxemia. METHODS: Eighteen anesthetized and ventilated rats were laparotomized and a jejunal portion was exteriorized and fixed on a plexiglass stage. The jejunum was punctured and a Clark type microcatheter PO2 probe and a micro thermocouple were placed on the mucosa in order to measure PtiO2. The animals were randomly assigned to receive one of the three treatments: infusion of Escherichia coli lipopolysaccharides (LPS) without C1-INH pretreatment (LPS group); or infusion of LPS with C1-INH pretreatment (C1-INH group); the control group (n = 6) without treatment of either C1-INH or LPS. The mean arterial pressure (MAP), heart rate (HR), PaO2 and PtiO2 were measured at baseline, 60 and 120 min after induction of endotoxemia. RESULTS: Hemodynamic parameters (MAP, HR) in all the three groups showed no significant changes during the study period. PaO2 significantly decreased in the LPS group. This decrease could be attenuated by pretreatment with C1-INH. The mucosal PtiO2 of the jejunum in the control group remained stable. It significantly decreased in the LPS and in the C1-INH groups without showing a significant difference after 120 min of endotoxemia. CONCLUSIONS: Pretreatment with C1-INH was able to diminish a decrease in PaO2 during endotoxemia, indicating that pulmonary injury was attenuated. Endotoxin-induced tissue hypoxia of the intestinal mucosa could not be prevented suggesting a minor involvement of complement activation in this pathophysiological process.

Animals↗
PubMed1998

Differential distribution of alternatively spliced somatostatin receptor 2 isoforms (sst2A and sst2B) in rat spinal cord.

We have recently shown that the cytoplasmic tail of the somatostatin receptor sst2 undergoes alternative splicing giving rise to two isoforms, SSt2A and sst2B. In the present study, we have raised polyclonal antibodies that specifically detect either sst2A or sst2B and used these antisera for immunocytochemical localization of the receptor proteins in the rat spinal cord. sst2A-immunoreactivity formed a dense network consisting of neuronal perikarya and dendrites in the superficial layers of the dorsal horn. In contrast, prominent sst2B-immunoreactivity was found on neuronal perikarya and proximal dendrites throughout the gray matter of the spinal cord. Taken together, we show that alternative carboxy-terminal splicing is involved in cell-specific expression of somatostatin receptor sst2 isoforms in rat spinal cord, and that sst2A and sst2B mediate effects of somatostatin at different cellular sites.

Amino Acid Sequence↗
PubMed1998

Inhibition of Fc epsilon RI-mediated activation of mast cells by 2,3,4-trihydropyrimidino[2,1-a]isoquinolines.

Assays based on reporter gene technology represent today an important tool in the pharmaceutical industry for discovering novel compound classes interfering with the activation and signaling of target cells after stimulation. Here we describe a reporter gene assay targeting mast cell activation of IgE plus antigen, established in an attempt to identify substances preventing type I allergy (allergic rhinitis, allergic conjunctivitis, allergic asthma, and acute and chronic urticaria). The assay is based on a murine mast cell line designated CPII, stimulation by IgE plus antigen, and a reporter gene construct with the TNF alpha promoter linked to luciferase as a read-out system. Via screening about 50,000 substances, compound 2 was found to inhibit the reporter gene induction in the submicromolar range in this assay. Analogues of compound 2 of the 2,3,4-trihydropyrimidino[2,1-a]isoquinoline type were synthesized starting from 2-alkyl-substituted benzonitriles via aminolysis with 1,3-diaminopropane, dimetalation of 2-substituted 2-phenyl-1,4,5,6-tetrahydropyrimidines with n- and sec-butylithium, reaction with carboxylic acid methyl esters, and finally acidic dehydration. From about 50 derivatives, compound 41 was selected as a lead structure with an IC50 of 0.2 microM and a TC50 of 2.7 microM. In a first profiling in secondary assays, it effectively interfered with the production of mediators such as TNF alpha, IL-4, IL-6, IL-13, and leukotriene synthesis as measured by the corresponding ELISAs. In addition, a passive cutaneous anaphylaxis in mice (a typical type I reaction) is inhibited to more than 90% by compound 41, when administered intradermally 90 min before challenge.

Animals↗
PubMed1998

High prognostic significance of Mdm2/p53 co-overexpression in soft tissue sarcomas of the extremities.

Soft tissue sarcomas are a heterogeneous group of neoplasms with various histological subtypes. Up to now, no individual causal molecular markers for prognosis and therapeutic success have been identified. A tumorigenic connection between the oncogene product Mdm2 and tumor suppressor p53 is generally accepted, but their possible clinical relevance has not yet been investigated sufficiently in soft tissue sarcoma. In 86 primary soft tissue sarcoma of the extremities (RO-resected, T1/2 N0 M0), Mdm2 and p53 overexpression were investigated by immunohistochemistry. The results were adjusted to clinico-pathological characteristics and evaluated for their prognostic relevance by multivariate analysis. In Cox's multivariate analysis with stratification of Mdm2 to p53 results, we determined four groups which had different prognostic values for relapse-free and overall survival (Mdm2-/p53- < Mdm2-/p53+ < Mdm2+/p53- < Mdm2+/p53+). The most striking finding was a relative risk (rr) for overall survival of 18.77 (P=0.006) for patients with Mdm2/p53 co-overexpression (n=40). It is noticeably higher than the additive risk from both factors. Coincident Mdm2/p53 overexpression is an independent molecular marker with the highest prognostic relevance described for soft tissue sarcoma. Thus, a high risk sarcoma group has been defined which we believe requires alternative therapeutic approaches.

Adult↗
PubMed1998

How is the mutational status for tumor suppressors p53 and p16(INK4A) in MFH of the bone?

Both tumor suppressor genes p53 and p16(INK4A) play a crucial role in the control of cell cycle and tumor development. In this study 19 malignant fibrous histiocytomas of the bone (MFH-b), a very rare sarcoma entity, were investigated for mutations in p53 and p16 genes by a PCR-SSCP-sequencing analysis. In the tumor samples two p53 mutations and two polymorphisms (one in the p53 gene and one in the p16 gene) were found. The occurrence rate for p53 mutations and the absence of p16 mutations in MFH-b are comparable to the findings for MFH of soft tissues (MFH-st) and osteosarcomas, suggesting that p53 rather than p16 may play a role in tumorigenesis of MFH-b.

Bone Neoplasms↗
PubMed1998

Cytogenetic characterization of ten malignant fibrous histiocytomas.

We examined 10 malignant fibrous histiocytomas (MFHs) using metaphase preparations. Six tumors showed clonal structural and/or numerical chromosomal aberrations, and four tumors had normal karyotypes. For the most part, chromosomes 1, 3, 6, 9, 12, 16, 18, and 20 were involved in structural aberrations. The breakpoint regions most frequently were in 1p32, 3p25, and the centromeric region of chromosomes 1 and 16. There was a conspicuous loss in chromosome 18. We detected ring chromosomes in two tumors. One tumor showed a high percentage of near-haploid cells. Our results show many parallels to data which have already been published. MFHs include a broad spectrum of tumors of widely different histology and clinical course. So it is not surprising to find a cytogenetic diversity of chromosomal aberrations in this study.

Aged↗
PubMed1998

LDLR Database (second edition): new additions to the database and the software, and results of the first molecular analysis.

Mutations in the LDL receptor gene (LDLR) cause familial hypercholesterolemia (FH), a common autosomal dominant disorder. The LDLR database is a computerized tool that has been developed to provide tools to analyse the numerous mutations that have been identified in the LDLR gene. The second version of the LDLR database contains 140 new entries and the software has been modified to accommodate four new routines. The analysis of the updated data (350 mutations) gives the following informations: (i) 63% of the mutations are missense, and only 20% occur in CpG dinucleotides; (ii) although the mutations are widely distributed throughout the gene, there is an excess of mutations in exons 4 and 9, and a deficit in exons 13 and 15; (iii) the analysis of the distribution of mutations located within the ligand-binding domain shows that 74% of the mutations in this domain affect a conserved amino-acid, and that they are mostly confined in the C-terminal region of the repeats. Conversely, the same analysis in the EGF-like domain shows that 64% of the mutations in this domain affect a non-conserved amino-acid, and, that they are mostly confined in the N-terminal half of the repeats. The database is now accessible on the World Wide Web at http://www.umd.necker.fr

Computer Communication Networks↗
PubMed1998

No p16INK4A/CDKN2/MTS1 mutations independent of p53 status in soft tissue sarcomas.

The p16INK4A/CDKN2/MTS1 gene encodes a specific inhibitor of cyclin-dependent kinases (CDKs) 4 and 6. This study investigates p16INK4A gene status and expression in mesenchymal tumours, in particular soft tissue sarcomas (STSs). Employing non-radioactive polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) sequencing, no p16INK4A mutation was found in 86 samples taken from 74 mesodermal tumours with known p53 gene status. This suggests that p16INK4A gene alterations, inc contrast to p53, are not involved in the progression of STS. This finding is supported by the reports of a low frequency of deletions and intragenic mutations in STS. Furthermore, by immunohistochemistry (IHC), an inverse correlation was established between p16INK4A and RB positivity for 62 per cent of the frozen tumour samples investigated. However, alterations in other components of the pRh/p16INK4A/ CDK4/cyclin D1/E2F pathway have been proven crucial for tumourigenesis in human sarcomas.

Cyclin-Dependent Kinases↗