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Biomedical subjects

H Peters

Publications and source records attributed to H Peters.

At least 73 records · Page 4Linked to original sources
PubMed1999

De novo deletion (14)(q11.2q13) including PAX9: clinical and molecular findings.

A 3 year old boy with a de novo deletion (14)(q11.2q13) of paternal origin encompassing the region from D14S264 to D14S70 is described. The patient presented with severe psychomotor retardation, bilateral cleft lip/palate, bilateral colobomas of the optic nerves and retinas, agenesis of the corpus callosum, pes calcaneovarus, reduced oesophageal peristalsis, and swallowing difficulties. This is the first reported case of PAX9 hemizygosity in humans. Haploinsufficiency of the PAX9 gene might be expected to cause some of the developmental defects and the dysphagia. Another haploinsufficiency candidate gene, the bZIP transcription factor gene NRL, which is specifically expressed in neuronal cells and the eye during embryogenesis, was excluded from the deletion interval.

Abnormalities, Multiple↗
PubMed1998

Altered regulation of platelet-derived growth factor receptor-alpha gene-transcription in vitro by spina bifida-associated mutant Pax1 proteins.

Mouse models show that congenital neural tube defects (NTDs) can occur as a result of mutations in the platelet-derived growth factor receptor-alpha gene (PDGFRalpha). Mice heterozygous for the PDGFRalpha-mutation Patch, and at the same time homozygous for the undulated mutation in the Pax1 gene, exhibit a high incidence of lumbar spina bifida occulta, suggesting a functional relation between PDGFRalpha and Pax1. Using the human PDGFRalpha promoter linked to a luciferase reporter, we show in the present paper that Pax1 acts as a transcriptional activator of the PDGFRalpha gene in differentiated Tera-2 human embryonal carcinoma cells. Two mutant Pax1 proteins carrying either the undulated-mutation or the Gln --> His mutation previously identified by us in the PAX1 gene of a patient with spina bifida, were not or less effective, respectively. Surprisingly, Pax1 mutant proteins appear to have opposing transcriptional activities in undifferentiated Tera-2 cells as well as in the U-2 OS osteosarcoma cell line. In these cells, the mutant Pax1 proteins enhance PDGFRalpha-promoter activity whereas the wild-type protein does not. The apparent up-regulation of PDGFRalpha expression in these cells clearly demonstrates a gain-of-function phenomenon associated with mutations in Pax genes. The altered transcriptional activation properties correlate with altered protein-DNA interaction in band-shift assays. Our data provide additional evidence that mutations in Pax1 can act as a risk factor for NTDs and suggest that the PDGFRalpha gene is a direct target of Pax1. In addition, the results support the hypothesis that deregulated PDGFRalpha expression may be causally related to NTDs.

Amino Acid Substitution↗
PubMed1998

Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities.

Pax genes have been shown to play important roles in mammalian development and organogenesis. Pax9, a member of this transcription factor family, is expressed in somites, pharyngeal pouches, mesenchyme involved in craniofacial, tooth, and limb development, as well as other sites during mouse embryogenesis. To analyze its function in vivo, we generated Pax9 deficient mice and show that Pax9 is essential for the development of a variety of organs and skeletal elements. Homozygous Pax9-mutant mice die shortly after birth, most likely as a consequence of a cleft secondary palate. They lack a thymus, parathyroid glands, and ultimobranchial bodies, organs which are derived from the pharyngeal pouches. In all limbs, a supernumerary preaxial digit is formed, but the flexor of the hindlimb toes is missing. Furthermore, craniofacial and visceral skeletogenesis is disturbed, and all teeth are absent. In Pax9-deficient embryos tooth development is arrested at the bud stage. At this stage, Pax9 is required for the mesenchymal expression of Bmp4, Msx1, and Lef1, suggesting a role for Pax9 in the establishment of the inductive capacity of the tooth mesenchyme. In summary, our analysis shows that Pax9 is a key regulator during the development of a wide range of organ primordia.

Animals↗
PubMed1998

Targeted disruption of Pax1 defines its null phenotype and proves haploinsufficiency.

The murine paired box-containing gene Pax1 is required for normal development of the vertebral column, the sternum, and the scapula. Previous studies have shown that three natural Pax1 mouse mutants, the undulated alleles, exhibit phenotypes of different severity in these skeletal elements. Nevertheless, these analyses have not clarified whether the semidominant Undulated short-tail (Uns) mutation, in which the complete Pax1 locus is deleted, represents a null allele. Moreover, the analyses of the classical undulated mutants did not allow a conclusion with respect to haploinsufficiency of Pax1. To address both questions we have created a Pax1 null allele in mice by gene targeting. Surprisingly, the phenotype of this defined mutation exhibits clear differences to that of Uns. This result strongly indicates the contribution of additional gene(s) to the Uns mutant phenotype. Furthermore, the phenotype of mice heterozygous for the null allele demonstrates that Pax1 is haploinsufficient in some though not all skeletal elements which express Pax1 during embryonic development.

Animals↗
PubMed1998

[Nitric oxide, L-arginine and the kidney. Experimental studies of new therapy approaches].

BACKGROUND: Nitric oxide (NO) is a small gaseous molecule with multiple biological effects. NO is produced from the semi-essential amino acid L-arginine by NO synthases (NOS). In the kidney, neuronal NOS (bNOS), which is localized in the macula densa, and endothelial NOS (ecNOS) are involved in the regulation of glomerular hemodynamics. Dysfunction of these enzymes may cause glomerular hypertension and increased intraglomerular platelet aggregation. NO production in high tissue concentrations can be achieved by activation of an inducible NOS isoform (iNOS) and may act as a potent mediator of inflammation in immune-mediated renal diseases. Selective inhibition of iNOS may, therefore, become a novel anti-inflammatory approach in the treatment of glomerulonephritis. Based on experimental data, the potential importance of NO and other metabolites of L-arginine in the pathophysiology and therapy of renal diseases is summarized in this article. CONCLUSION: Modulation of the renal L-arginine/NO-system represents a promising therapeutic target in the treatment of acute an chronic kidney diseases.

Animals↗
PubMed1998

[Invagination of the vermiform appendix in mucinous cystadenoma].

Intussusception of the appendix vermiformis in adults is an uncommon event. The combination of a mucinous cystadenoma with an intussuscepted appendix is extremely rare. Clinical symptoms are nonspecific; in most cases the correct diagnosis is not made before surgical exploration. With the radiologic and endoscopic presentation of a polypoid lesion of the caecum, a neoplasm is often considered. Endoscopic appendectomy or disinvagination by enema have been described. Thus the definitive therapy is surgery and depends on the histological diagnosis.

Adult↗
PubMed1998

Two novel mutations in exons 19a and 20 and a BsaBI [correction of BsaI] polymorphism in a newly characterized intron of the neurofibromatosis type 1 gene.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder. It is caused by mutations in the NF1 gene, which comprises 60 exons and is located on chromosome 17q11.2. A total of 170 unrelated NF1 patients were screened for mutations in four exons by temperature-gradient gel electrophoresis. Preparatory work revealed the presence of a previously uncharacterized intron (19a) in what was previously designated exon 19; this allowed us to develop assays for genomic mutation screening in the newly defined exons 19a and 19b. Two novel NF1 mutations were detected: a single-base insertion in exon 19a creating a frameshift, and a second mutation affecting the splice donor site of intron 20 and leading to skipping of exon 20. A novel BsaBI polymorphism was identified in intron 19a.

Adult↗
PubMed1998

The effect of the anti-angiogenic agent TNP-470 on tumor growth and vascularity in low passaged xenografts of human gliomas in nude mice.

The effect of the anti-angiogenic agent TNP-470 on tumor growth, vascular area, vascular density and tumor perfusion of two different subcutaneously implanted human glioma xenografts (E98 and E106) in nude mice was evaluated. Vascular parameters were investigated with an image analysis system. For both tumor lines a small but significant tumor growth suppression was observed. However, no differences in vascular parameters between TNP-470 treated tumors and controls could be found after 6 weeks of treatment. It is concluded that although TNP-470 is a promising anti-angiogenic agent in many tumor types, at least 2 glioma lines seem to be partly resistant to its anti-angiogenic effects. Further evaluation of the effects of combination of TNP-470 and cytostatic agents or radiotherapy in human glioma xenografts are required to determine the place of anti-angiogenic therapy in general and treatment with the anti-angiogenic agent TNP-470 more specifically in the treatment of human gliomas.

Animals↗
PubMed1998

Glutaric aciduria type 1: an underdiagnosed cause of encephalopathy and dystonia-dyskinesia syndrome in children.

Two cases of glutaric aciduria type 1 (GA 1) are presented. GA 1 is probably underdiagnosed and misdiagnosed, and may explain a proportion of cases of extrapyramidal and 'postencephalitic' cerebral palsy. Most cases of GA 1 present with a severe dystonic-dyskinetic syndrome following an acute encephalopathy. Asymptomatic cases have also been described, complicating genetic counselling and prenatal diagnosis. We raise awareness of GA 1 and stress that if clinically suspected, immediate institution of therapy may reduce late morbidity. Moreover, if recognised in the presymptomatic stage, early institution of treatment may prevent the onset of neurological symptoms. GA 1 is an inborn error of lysine and tryptophan catabolism, caused by deficiency of the enzyme, glutaryl coenzyme-A dehydrogenase. Urine organic acid analyses may be negative. Blood acylcarnitine profile has recently been employed as a more sensitive test but was negative in both our patients. Enzyme assay remains the definitive diagnostic test.

Amino Acid Metabolism, Inborn Errors↗
PubMed1998

Targeting TGF-beta overexpression in renal disease: maximizing the antifibrotic action of angiotensin II blockade.

BACKGROUND: Overproduction of transforming growth factor-beta (TGF-beta) is a key mediator of extracellular matrix accumulation in fibrotic diseases. We hypothesized that the degree of reduction of pathological TGF-beta expression can be used as a novel index of the antifibrotic potential of angiotensin II (Ang II) blockade in renal disease. METHODS: One day after induction of Thy 1.1 glomerulonephritis, rats were treated with increasing doses of the Ang I converting enzyme (ACE) inhibitor enalapril and/or the Ang II receptor blocker losartan in the drinking water. Six days after disease induction the therapeutic effect on glomerular TGF-beta overexpression was evaluated. RESULTS: Both enalapril and losartan reduced TGF-beta overproduction in a dose-dependent manner, showing a moderate reduction at doses known to control blood pressure in renal forms of hypertension. A maximal reduction in TGF-beta expression of approximately 45% was seen for both drugs starting at 100 mg/liter enalapril and 500 mg/liter losartan, with no further reduction at doses of enalapril up to 1000 mg/liter or losartan up to 2500 mg/liter. Co-treatment with both drugs was not superior to single therapy. Consistent with our hypothesis that reduction in TGF-beta expression is a valid target, other disease measures, including glomerular matrix accumulation, glomerular production and mRNA expression of the matrix protein fibronectin and the protease inhibitor plasminogen-activator-inhibitor type 1 (PAI-1) closely followed TGF-beta expression. CONCLUSIONS: The data suggest that these therapies act through very similar pathways and that, in order to more effectively treat renal fibrosis, these drugs must be combined with other drugs that act by different mechanisms.

Angiotensin II↗
PubMed1998

Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a common familial tumour syndrome with multiple clinical features such as neurofibromas, café-au-lait spots (CLS), iris Lisch nodules, axillary freckling, optic glioma, specific bone lesions and an increased risk of malignant tumours. It is caused by a wide spectrum of mutations affecting the NF1 gene. Most mutations result in the loss of one allele at the DNA, mRNA or protein level and thus in the loss of any function of the gene product neurofibromin. The idea of the simultaneous loss of several different neurofibromin functions has been postulated to explain the pleiotropic effects of its loss. However, we have identified a novel missense mutation in a family with a classical multi-symptomatic NF1 phenotype, including a malignant schwannoma, that specifically abolishes the Ras-GTPase-activating function of neurofibromin. In this family, Arg1276 had mutated into proline. Based on complex biochemical studies as well as the analysis of the crystal structure of the GTPase-activating protein (GAP) domain of p120GAP in the presence of Ras, we unequivocally identified this amino acid as the arginine finger of the neurofibromin GAP-related domain (GRD)-the most essential catalytic element for RasGAP activity. Here, we present data demonstrating that the mutation R1276P, unlike previously reported missense mutations of the GRD region, does not impair the secondary and tertiary protein structure. It neither reduces the level of cellular neurofibromin nor influences its binding to Ras substantially, but it does completely disable GAP activity. Our findings provide direct evidence that failure of neurofibromin GAP activity is the critical element of NF1 pathogenesis. Thus, therapeutic approaches aimed at the reduction of Ras.GTP levels in neural crest-derived cells can be expected to relieve most of the NF1 symptoms.

Amino Acid Sequence↗
PubMed1998

Pax genes and organogenesis: Pax9 meets tooth development.

Pax genes encode a family of transcription factors that play key roles during embryogenesis. They are required for the development of a variety of organs including the nervous and muscular system, skeleton, eye, ear, kidney, thymus, and pancreas. Whereas the developmental roles of many of the nine known Pax genes have been analyzed in great detail, a functional analysis of Pax9 has just begun. During mouse embryogenesis, Pax9 exhibits a highly specific expression pattern in derivatives of the foregut endoderm, somites, limb mesenchyme, midbrain, and the cephalic neural crest. In the mandibular arch mesenchyme, the expression of Pax9 marks the prospective sites of tooth development prior to any morphological signs of odontogenesis and is maintained in the developing tooth mesenchyme thereafter. To understand the function of Pax9 during mouse embryogenesis, we recently have created a null allele by gene targeting. Preliminary analyses show that Pax9 is essential for the formation of teeth, and we conclude that Pax9 is required for tooth development to proceed beyond the bud stage. Here, we briefly summarize our current knowledge about Pax genes and introduce Pax9 to the growing family of factors which are involved in tooth development.

Animals↗
PubMed1998

Impact of strain heterogeneity on Lyme disease serology in Europe: comparison of enzyme-linked immunosorbent assays using different species of Borrelia burgdorferi sensu lato.

For the standardization of serological tests for Lyme borreliosis (LB) in Europe, the influence of the heterogeneity of Borrelia burgdorferi sensu lato must be assessed in detail. For this study four immunoglobulin M (IgM) and IgG enzyme-linked immunosorbent assays (ELISAs) with octyl-beta-D-glucopyranoside extracts of strains PKo (Borrelia afzelii), PBi (Borrelia garinii), and PKa2 and B31 (both B. burgdorferi sensu stricto) were compared. Strains PKo, PBi, and PKa2 at the passages used for antigen preparations abundantly expressed outer surface protein C (OspC), whereas strain B31 at the passage used for antigen preparation did not express OspC. Sera (all from Germany) from 222 patients with clinically defined LB of all stages, 133 blood donors, and 458 forest workers were tested. None of the forest workers had symptoms consistent with LB at the time that the samples were collected. For IgM tests, receiver operating characteristic curves demonstrated that discrimination between sera from patients and blood donors was best with strain PKo and worst with strain B31. The discriminatory abilities of the four IgG ELISAs were similar in a diagnostically reasonable specificity range (90 to 100%). More than 20% of the sera from forest workers reacted strongly in the PKo IgG ELISA (optical density value, >1.5; other assays, less than 8%). Western blots of the sera with the most discrepant ELISA results revealed almost exclusive reactivity with p17. This highly immunogenic antigen is only expressed by strain PKo. This observation might be important for the development of assays enabling discrimination between asymptomatic or previous infection and active disease.

Agricultural Workers' Diseases↗
PubMed1998

Immunogenicity of a combined hepatitis B and Haemophilus influenzae type b conjugate vaccine in Alaska Native infants.

UNLABELLED: Hepatitis B and Haemophilus influenzae b (Hib), prevalent diseases in Alaska Native infants, have been reduced 95% following universal vaccination. Therefore, we were interested in studying a new combined Hib and hepatitis B vaccine in this population. METHOD: Healthy Alaska Native infants free from Hib and hepatitis B exposure were randomized into four groups, three with different lots of bivalent Hib and hepatitis B vaccine, and one with Hib and hepatitis B monovalent controls. The Hib component had 7.5 micrograms of polyribosylribitol phosphate polysaccharide (PRP) bound to 125 micrograms of Neisseria meningitidis outer membrane protein complex (OMP); the hepatitis B component was 5 micrograms of recombinant hepatitis B surface antigen. The vaccines were given at 2 months, 4 months, and 12-15 months of age. RESULTS: There were no differences in the responses to the bivalent compared to the monovalent controls except for a lower Hib anti-PRP level at 12-15 months in the bivalent recipients; this did not persist after the booster. CONCLUSION: A combined Hib and hepatitis B vaccine appears immunogenic. The recommended schedule for the Hib component (PRP-OMP) of 2 months, 4 months, and 12-15 months appears to promote an optimal response to the hepatitis B component as well.

Alaska↗
PubMed1998

Demonstration of the efficacy of ginkgo biloba special extract EGb 761 on intermittent claudication--a placebo-controlled, double-blind multicenter trial.

BACKGROUND: A multicentric, randomized, placebo-controlled double-blind study on ginkgo biloba special extract EGb 761 (Tebonin forte) in patients suffering from peripheral occlusive arterial disease (POAD) in Fontaine stage II b was carried out in order to prove its clinical efficacy in this indication according to guidelines of European Community authorities and the German Angiological Society and to confirm the results of former clinical studies with EGb 761. PATIENTS AND METHODS: In total, 111 patients with angiographically proven POAD in Fontaine stage II b and intermittent claudication (pain-free walking distance < 150 m on the treadmill) were recruited in 5 centers and treated with either EGb 761 or placebo at a daily dose of 3 times 1 film-coated tablet over a duration of 24 weeks following a 2-week placebo run-in period. The primary response variable was the difference of the pain-free walking distance between the start of treatment and after 8, 16 and 24 weeks as measured on the treadmill (walking speed 3 km/h and slope of 12%) under standardized conditions. RESULTS: At the start of the treatment period, the mean pain-free walking distances were very similar with 108.5 m in the EGb 761 group and 105.2 m in the placebo group. At the end of the treatment period these values increased to 153.2 m and 126.6 m, respectively. The group differences were statistically significant at all three control visits with p = 0.017, p = 0.007, and p = 0.016. The differences for the maximum walking distance and the relative increases of the pain-free walking distance and the maximum distance were also significantly higher in the EGb 761 group with p-values < 0.05 each. In both groups Doppler indices remained nearly unchanged during therapy. The subjective assessment of the patients demonstrated an amelioration of complaints in both groups. Tolerability was very good with no adverse events under EGb 761 and one case of heartburn and gastric pain in the placebo group. CONCLUSIONS: It can be concluded from the results of this study that treatment with EGb 761 in POAD patients with Fontaine stage II b is very safe and causes a significant and therapeutically relevant prolongation of the patients' walking distance.

Aged↗
PubMed1997

Antagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation.

Vertebrate organogenesis is initiated at sites that are often morphologically indistinguishable from the surrounding region. Here we have identified Pax9 as a marker for prospective tooth mesenchyme prior to the first morphological manifestation of odontogenesis. We provide evidence that the sites of Pax9 expression in the mandibular arch are positioned by the combined activity of two signals, one (FGF8) that induces Pax9 expression and the other (BMP2 and BMP4) that prevents this induction. Thus it appears that the position of the teeth is determined by a combination of two different types of signaling molecules produced in wide but overlapping domains rather than by a single localized inducer. We suggest that a similar mechanism may be used for specifying the sites of development of other organs.

Animals↗
PubMed1997

[Treatment of euthyroid struma. Comparable volume reduction with 400 micrograms iodine, 100 micrograms levothyroxine combined with 100 micrograms iodine or individually dosed levothyroxine].

AIM: In patients with euthyroid goitre, the efficacy of treatment with 400 micrograms iodine and 100 micrograms levothyroxine combined with 100 micrograms iodine was compared to that of the previous standard of therapy, individually dosed levothyroxine. PATIENTS AND METHODS: A total of 78 patients presenting with euthyroid diffuse goitre (> or = 25 ml) were prospectively enrolled, randomised and treated for 6 months. The course of thyroid volume was followed using thyroid volumetry. RESULTS: Data of 69 patients were included in the final evaluation (57 women, 12 men, age 31 +/- 1 years, thyroid volume 31.5 +/- 1.4 ml, 23 per treatment group). In the patients treated with individually dosed levothyroxine, the thyroid volume decreased by about 39% (95%-confidence limit [CL]-31% to -41%). However, the volume reductions achieved in the patients treated with 400 micrograms iodine or 100 micrograms levothyroxine/100 micrograms iodine were not significantly different (p = 0.35, variance analysis, mono-iodine -34%, 95%-CL -29% to -43%, 100 micrograms levothyroxine/100 micrograms iodine -39%, 95%-CL -32% to -45%). CONCLUSIONS: In patients with euthyroid diffuse goitre, treatment with mono-iodine or combination of levothyroxine with iodine should have principally the same status as the previous standard of therapy, individually dosed levothyroxine. In the view of the authors, its preferential treatment with mono-iodine appears most reasonable.

Adult↗