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Biomedical subjects

H Peters

Publications and source records attributed to H Peters.

At least 37 records · Page 2Linked to original sources
PubMed2001

Capability of air filters to retain airborne bacteria and molds in heating, ventilating and air-conditioning (HVAC) systems.

The capability of air filters (filterclass: F6, F7) to retain airborne outdoor microorganisms was examined in field experiments in two heating, ventilating and air conditioning (HVAC) systems. At the beginning of the 15-month investigation period, the first filter stages of both HVAC systems were equipped with new unused air filters. The number of airborne bacteria and molds before and behind the filters were determined simultaneously in 14 days-intervals using 6-stage Andersen cascade impactors. Under relatively dry (< 80% R. H.) and warm (> 12 degrees C) outdoor air conditions air filters led to a marked reduction of airborne microorganism concentrations (bacteria by approximately 70% and molds by > 80%). However, during long periods of high relative humidity (> 80% R. H.) a proliferation of bacteria on air filters with subsequent release into the filtered air occurred. These microorganisms were mainly smaller than 1.1 microns therefore being part of the respirable fraction. The results showed furthermore that one possibility to avoid microbial proliferation is to limit the relative humidity in the area of the air filters to 80% R. H. (mean of 3 days), e.g. by using preheaters in front of air filters in HVAC-systems.

Air Conditioning↗
PubMed2001

Molecular characterization of Pax6(2Neu) through Pax6(10Neu): an extension of the Pax6 allelic series and the identification of two possible hypomorph alleles in the mouse Mus musculus.

Phenotype-based mutagenesis experiments will increase the mouse mutant resource, generating mutations at previously unmarked loci as well as extending the allelic series at known loci. Mapping, molecular characterization, and phenotypic analysis of nine independent Pax6 mutations of the mouse recovered in mutagenesis experiments is presented. Seven mutations result in premature termination of translation and all express phenotypes characteristic of null alleles, suggesting that Pax6 function requires all domains to be intact. Of major interest is the identification of two possible hypomorph mutations: Heterozygotes express less severe phenotypes and homozygotes develop rudimentary eyes and nasal processes and survive up to 36 hr after birth. Pax6(4Neu) results in an amino acid substitution within the third helix of the homeodomain. Three-dimensional modeling indicates that the amino acid substitution interrupts the homeodomain recognition alpha-helix, which is critical for DNA binding. Whereas cooperative dimer binding of the mutant homeodomain to a paired-class DNA target sequence was eliminated, weak monomer binding was observed. Thus, a residual function of the mutated homeodomain may explain the hypomorphic nature of the Pax6(4Neu) allele. Pax6(7Neu) is a base pair substitution in the Kozak sequence and results in a reduced level of Pax6 translation product. The Pax6(4Neu) and Pax6(7Neu) alleles may be very useful for gene-dosage studies.

Alleles↗
PubMed2001

Dynamic modeling in medical technology assessment. Fitting hearing aids in The Netherlands.

OBJECTIVES: The main objective of this article is to demonstrate the usefulness of dynamic modeling for an economic assessment of technology in health care. Specifically, this approach is applied to assess the impact of the use of hearing aids in Dutch health care. METHODS: The population is divided into different health classes between which, over time, transitions occur. Transition probabilities are derived from exogenous data. The transitions are associated with economic and societal costs and benefits. People who are satisfied with their hearing aids experience benefits. These benefits are expressed by quality-adjusted life-years (QALYs). Costs are made during transitions (mainly the fitting of hearing aids). A cohort analysis is carried out, starting with people in a particular age group. The starting point is a fixed number of people within this age group, who are followed during their whole lifetime. RESULTS: Costs per QALY ratios are calculated for two health programs. The Fitting Hearing Aid Program describes the present situation in the Netherlands; the Post-purchase Counseling Hearing Aid Program is a hypothetical addition to the first program, where an intervention based on a Dutch study is undertaken to improve satisfaction with hearing aids. Future benefits and costs are discounted at a rate of 5%. CONCLUSIONS: The dynamic modeling approach provides a more realistic picture than a static approach. Particularly, the cost-effectiveness of the Fitting Hearing Aid Program is compared with the Post-purchase Counseling Hearing Aid Program.

Adolescent↗
PubMed2001

Genetic and epigenetic effects on sexual brain organization mediated by sex hormones.

Alterations of sex hormone levels during pre- or perinatal sexual brain organization - responsible for long-term changes of gonadotropin secretion, sexual orientation, and gender role behavior - can be caused by: 1. Genetic effects, i.e. mutations or polymorphisms of a) 21-hydroxylase genes on chromosome 6, b) 3beta-hydroxysteroid dehydrogenase genes in chromosome 1 or c) X-chromosomal genes, and 2. Epigenetic effects, such as a) stressful situations - especially in combination with mutations - and b) endocrine disrupters, e.g. the pesticide DDT and its metabolites, which display estrogenic, antiandrogenic, and inhibitory effects on the enzyme 3beta-hydroxysteroid dehydrogenase leading to increased levels of dehydroepiandrosterone and its sulfate as precursors of endogenous androgens and estrogens. In connection with the introduction and extensive use of the pesticide DDT, the following findings were obtained in subjects born before as compared to those born during this period: 1. The prevalence of patients with polycystic ovaries (PCO), idiopatic oligospermia (IO), and transsexualism (TS) increased significantly (about 3-4 fold). 2. Partial 21-hydroxylase deficiencies were observed in most patients with PCO and TS and some patients with IO born before this period. 3. In contrast, most patients with PCO and TS and several patients with IO born during the period of massive use of DDT displayed clearly increased plasma levels of dehydroepiandrosterone sulfate (DHEA-S) and DHEA-S/cortisol ratios suggesting partial 3beta-hydroxsteroid dehydrogenase (3beta-HSD) deficiencies. Interestingly enough, geneticists could not find any mutations of 3beta-HSD genes in such subjects. However, o,p'-DDT and/or its metabolite o,p'-DDD are strong inhibitors of 3beta-HSD, indicating their possible co-responsibility for such life-long ontogenetic alterations. Finally, some data suggest that endocrine disrupters may also be able to affect the development of sexual orientation.

Brain↗
PubMed2000

Craniosynostosis in cherubism.

Cherubism is a rare autosomal dominant fibro-osseous disorder that affects almost exclusively maxilla and mandible. Extracranial skeletal involvement is rare. We report on three affected males in three generations. The youngest affected relative was examined at age 4 months. He also had craniosynostosis. His affected father and grandfather had cherubism and clubbing of the fingers. Cherubism was mapped to region 4p16. Because of the associated cranio-synostosis, we excluded the FGFR3 gene as a candidate gene for cherubism.

Adult↗
PubMed2000

[A young woman with neurofibromatosis 1 (Recklinghausen disease), abdominal tumor and hypertension].

HISTORY AND ADMISSION FINDINGS: A 38-year-old woman, known to have type 1 neurofibromatosis (NF1; von Recklinghausen's disease) and recurrence of a malignant haemangiopericytoma in the lower abdomen developed hypertension. She also had headaches and marked perspiration. Physical examination revealed tachycardia and paleness of the distal digits, in addition to multiple neurofibromas and café-au-lait spots. INVESTIGATIONS: A tumour was found in the region of the right adrenal gland, in addition to the known haemangiopericytoma. The levels of epinephrine and dopamine were elevated, suggesting an orthotopic phaeochromocytoma as the cause of the hypertension. Mutation analysis confirmed the neurofibromatosis by demonstrating a splice mutation of the NF1 gene in exon 8. She also was found to have emphysema of the right upper and middle lobes of the lung. TREATMENT AND COURSE: Because of the extensive local changes the recurrent haemangiopericytoma was only partially resected. At the same time a right adrenalectomy was performed without complication. However, the patient's postoperative recovery was slow, but she was now normotensive. Planned radiotherapy was omitted because of her poor general state. Instead she was given weekly palliative chemotherapy with adriamycin, with little improvement. She died several weeks later from the malignancy. CONCLUSION: This case emphasizes that in a patient with NF1 a phaeochromocytoma must be considered as a possible cause of hypertension. It is likely that the patient's emphysema was associated with the NF1, while the haemangiopericytoma was presumably unconnected with the NF1.

Abdominal Neoplasms↗
PubMed2000

Improved production and function of llama heavy chain antibody fragments by molecular evolution.

The aim of this study was to improve production level of llama heavy chain antibody fragments (V(HH)) in Saccharomyces cerevisiae while retaining functional characteristics. For this purpose, the DNA shuffling technique was used on llama V(HH) fragments specific for the azo-dye reactive red-6. In the DNA shuffling process, three parental llama V(HH) with high amino acid sequence identity with significant differences in production and functional characteristics were used. From these parental sequences, a S. cerevisiae library was created and 16 antigen specific shuffled V(HH) fragments were selected. We found that these shuffled V(HH) fragments were, (i) unique in sequence; (ii) composed of two or three parental sequences; (iii) in three V(HH)s point mutations occurred; and (iv) antigen specificity was not changed. The four highest producers in the yeast S. cerevisiae were selected and production, affinity, and antigen binding at 90 degrees C were compared with parental V(HH)s. One shuffled V(HH) was enhanced both in production (3.4-fold) and affinity (four-fold). A second shuffled V(HH) displayed increased production (1.9-fold), and improved stability (2.4-fold) in antigen binding at 90 degrees C. Structural analysis suggested that improved antigen binding is associated with the A24 --> V24 substitution, which reduces the size of the hydrophobic pit at the llama V(HH) surface. We demonstrate that it is possible to improve desired characteristics of the same V(HH) fragment simultaneously using DNA shuffling. Finally, this is one of the first examples of DNA shuffling improving temperature stability of an antibody fragment.

Amino Acid Sequence↗
PubMed2000

Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation.

The composite structure of the mammalian skull, which forms predominantly via intramembranous ossification, requires precise pre- and post-natal growth regulation of individual calvarial elements. Disturbances of this process frequently cause severe clinical manifestations in humans. Enhanced DNA binding by a mutant MSX2 homeodomain results in a gain of function and produces craniosynostosis in humans. Here we show that Msx2-deficient mice have defects of skull ossification and persistent calvarial foramen. This phenotype results from defective proliferation of osteoprogenitors at the osteogenic front during calvarial morphogenesis, and closely resembles that associated with human MSX2 haploinsufficiency in parietal foramina (PFM). Msx2-/- mice also have defects in endochondral bone formation. In the axial and appendicular skeleton, post-natal deficits in Pth/Pthrp receptor (Pthr) signalling and in expression of marker genes for bone differentiation indicate that Msx2 is required for both chondrogenesis and osteogenesis. Consistent with phenotypes associated with PFM, Msx2-mutant mice also display defective tooth, hair follicle and mammary gland development, and seizures, the latter accompanied by abnormal development of the cerebellum. Most Msx2-mutant phenotypes, including calvarial defects, are enhanced by genetic combination with Msx1 loss of function, indicating that Msx gene dosage can modify expression of the PFM phenotype. Our results provide a developmental basis for PFM and demonstrate that Msx2 is essential at multiple sites during organogenesis.

Abnormalities, Multiple↗
PubMed2000

Tandem antifibrotic actions of L-arginine supplementation and low protein diet during the repair phase of experimental glomerulonephritis.

BACKGROUND: Based upon the central role transforming growth factor-beta (TGF-beta) overexpression appears to play in renal fibrotic diseases, we have recently advocated reduction of TGF-beta as a therapeutic target. As part of efforts to determine the strength of this approach, we have undertaken studies to quantitate the effects of currently used and promising therapies in terms of their potential to reduce markers of disease in anti-thymocyte-serum (ATS)-glomerulonephritis in the rat. Here we assess the therapeutic effect of L-arginine supplementation, which has been shown to reduce fibrosis in a number of hypertensive models, given alone or in combination with low protein diet and started 24 hours after disease induction. METHODS: Glomerulonephritis was induced by intravenous injection of OX-7 monoclonal antibody into 200 g Sprague-Dawley rats. Twenty-four hours later animals were placed in groups that were either untreated, treated with 1% L-arginine in drinking water or 6% protein diets or both. On the fifth day of disease 24-hour urine specimens were collected and systemic blood pressure was measured. On the sixth day rats were anesthetized. Kidneys were perfused, tissue was taken for PAS staining and glomeruli were isolated. Aliquots of glomeruli were used for RNA preparation and for culture to determine 72-hour production of TGF-beta, fibronectin and plasminogen activator-type 1 (PAI-1), which were assayed by ELISA on culture supernatants. Measures of nitrate and nitrite (NOx) production included plasma NOx, urinary NOx and glomerular production of NOx in culture. RESULTS: All disease measures except proteinuria and including matrix accumulation, TGF-beta, fibronectin and PAI-1 production and mRNA expression for TGF-beta, fibronectin and PAI-1 were significantly and similarly reduced by about 50% in groups treated with L-arginine or with low protein diet. Proteinuria was reduced in low protein treated but not in L-arginine supplemented rats. Neither systemic blood pressure nor measures of NO synthesis showed differences between groups that could be attributed to L-arginine supplementation. In contrast, disease-related increases in glomerular production of NOx were markedly reduced by low protein. Combined therapy resulted in small, but statistically significant decreases in most measures of disease. CONCLUSIONS: L-arginine supplementation reduces fibrotic disease in ATS-induced glomerulonephritis if started after disease induction. The absence of evidence for increased NO production related to L-arginine supplementation suggests that L-arginine is acting here through different pathways from those demonstrated in hypertensive models of disease. The data support the ideas that TGF-beta reduction is a valid therapeutic target and that quantitation of TGF-beta reduction is a useful approach for comparing antifibrotic drug candidates.

Animals↗
PubMed2000

Angiotensin II blockade and low-protein diet produce additive therapeutic effects in experimental glomerulonephritis.

BACKGROUND: Transforming growth factor-beta (TGF-beta) overexpression plays a key role in the accumulation of extracellular matrix in acute and chronic renal diseases. Recent studies have suggested that the degree of reduction in pathological TGF-beta overexpression can be used as a therapeutic index to evaluate the antifibrotic potential of pharmacological angiotensin II (Ang II) blockade in renal disease. Using this target, we found that treatment with the angiotensin I-converting enzyme inhibitor enalapril or the Ang II type 1 receptor antagonist losartan reduced TGF-beta overexpression more effectively at doses clearly higher than those required to control blood pressure. However, both forms of Ang II blockade were only partially effective in normalizing TGF-beta expression. This study investigated whether a greater antifibrotic, TGF-beta-reducing benefit can be achieved when Ang II blockade is combined with dietary protein restriction. METHODS: Mesangioproliferative glomerulonephritis was induced in male Sprague-Dawley rats on a normal-protein diet. Treatment with a low-protein diet and/or maximally effective doses of enalapril or losartan was started one day after disease induction. On the fifth day, 24-hour urine protein excretion was measured. On the sixth day, cortical kidney tissue was taken for periodic acid-Schiff staining. Isolated glomeruli were used for mRNA extraction or were placed in culture for determination of production of TGF-beta1, the matrix protein fibronectin, and the protease inhibitor plasmin activator inhibitor type 1 (PAI-1) by enzyme-linked immunosorbent assay. RESULTS: Compared with untreated nephritic animals on a normal-protein diet, a single treatment with enalapril, losartan, or low-protein diet significantly reduced glomerular TGF-beta production, albeit to a similar degree of approximately 45%. A moderate, but significant further reduction in pathological TGF-beta expression of a total of 65% for enalapril and 60% for losartan was achieved when these drugs were combined with low-protein feeding. This reduction in TGF-beta overexpression paralleled decreased proteinuria, glomerular matrix accumulation, and overproduction of fibronectin and PAI-1. CONCLUSIONS: Ang II blockade and low-protein diet have additive effects on disease reduction, suggesting that disease progression in humans with chronic renal failure may be slowed more effectively when Ang II blockade and low-protein diet are combined. Since maximal pharmacological Ang II inhibition was used, it is likely that dietary protein restriction further reduces pathological TGF-beta overexpression by mechanisms different from those of enalapril or losartan.

Angiotensin II↗
PubMed2000

Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain.

More than 500 unrelated patients with neurofibromatosis type 1 (NF1) were screened for mutations in the NF1 gene. For each patient, the whole coding sequence and all splice sites were studied for aberrations, either by the protein truncation test (PTT), temperature-gradient gel electrophoresis (TGGE) of genomic PCR products, or, most often, by direct genomic sequencing (DGS) of all individual exons. A total of 301 sequence variants, including 278 bona fide pathogenic mutations, were identified. As many as 216 or 183 of the genuine mutations, comprising 179 or 161 different ones, can be considered novel when compared to the recent findings of Upadhyaya and Cooper, or to the NNFF mutation database. Mutation-detection efficiencies of the various screening methods were similar: 47.1% for PTT, 53.7% for TGGE, and 54.9% for DGS. Some 224 mutations (80.2%) yielded directly or indirectly premature termination codons. These mutations showed even distribution over the whole gene from exon 1 to exon 47. Of all sequence variants determined in our study, <20% represent C-->T or G-->A transitions within a CpG dinucleotide, and only six different mutations also occur in NF1 pseudogenes, with five being typical C-->T transitions in a CpG. Thus, neither frequent deamination of 5-methylcytosines nor interchromosomal gene conversion may account for the high mutation rate of the NF1 gene. As opposed to the truncating mutations, the 28 (10.1%) missense or single-amino-acid-deletion mutations identified clustered in two distinct regions, the GAP-related domain (GRD) and an upstream gene segment comprising exons 11-17. The latter forms a so-called cysteine/serine-rich domain with three cysteine pairs suggestive of ATP binding, as well as three potential cAMP-dependent protein kinase (PKA) recognition sites obviously phosphorylated by PKA. Coincidence of mutated amino acids and those conserved between human and Drosophila strongly suggest significant functional relevance of this region, with major roles played by exons 12a and 15 and part of exon 16.

Cohort Studies↗
PubMed2000

Purification and reconstitution of an integral membrane protein, the photoreaction center of Rhodobacter sphaeroides, using synthetic sugar esters.

Detergents are indispensable reagents for the extraction and solubilization of integral membrane proteins, but their removal from a reconstituted phospholipid-protein complex is usually desirable. In this paper, we describe a novel method in which the synthetic sugar esters 6-O-octanoyl-beta-D-glucose (OG) or 6-O-octanoyl-beta-D-mannose (OM) are used as detergents for both the isolation and the rapid reconstitution of the photosynthetic reaction center protein of Rhodobacter sphaeroides. Following solubilization of the reaction center with OG or OM and reconstitution of this protein in liposomes, a convenient removal of these detergents was achieved within less than two hours by hydrolytic cleavage of the sugar esters using immobilized lipases. Best results were achieved with lipase from Bacillus sp. immobilized on silica gel.

Detergents↗
PubMed2000

Hypoxia in a human intracerebral glioma model.

OBJECT: The development of hypoxia in human gliomas is closely related to functional vasculature and the presence of hypoxia has important biological and therapeutic consequences. Assessment of hypoxia is necessary to understand its role in treatment response and to evaluate treatment strategies to improve tumor oxygenation. In this study, the authors report findings of their analysis of the degree of hypoxia in relation to other vascular parameters in a human intracerebral glioma xenograft. METHODS: In sections of tumor, hypoxic regions were identified immunohistochemically by using the hypoxic marker pimonidazole. The S-phase marker bromodeoxyuridine was used to detect cell proliferation, and the perfusion marker Hoechst 33342 was used to delineate perfused vessels. Vascular structures were stained with an endothelial marker. Hypoxic tumor regions were clearly present in this human intracerebral glioma model. Hypoxic areas were usually found in nonperfused regions, whereas tumor cell proliferation was especially marked in perfused tumor areas. Furthermore, by using in situ hybridization the authors identified infiltrating tumor cells in the normal brain. This feature is often observed in gliomas in patients. CONCLUSIONS: This model is a representative human glioma model that provides the researcher with the opportunity to analyze the relationship between the degree of hypoxia and vascular parameters, as well as to examine the effects of treatments aimed at modification of the oxygenation status of a tumor.

Animals↗
PubMed1999

Risk stratification of sudden cardiac death and malignant ventricular arrhythmias in right ventricular dysplasia-cardiomyopathy.

UNLABELLED: Arrhythmogenic right ventricular dysplasia-cardiomyopathy is in most cases a benign cause of ventricular arrhythmias in young patients. The major reason of mortality is sudden arrhythmic death with an annual rate of 2-3% as the first manifestation of the disease in most cases. Little is known about risk factors of sudden arrhythmic death so far. The purpose of the retrospective study was to classify risk factors from invasive and non-invasive examinations. METHODS: In a cohort of 121 consecutive patients sampled from 1986 to 1998 the value of right ventricular dilatation, left ventricular involvement analysed by angiocardiography or echocardiography and standard ECG parameters such as precordial T wave inversions, right precordial ST elevation, precordial QRS dispersion, left precordial JT interval prolongation and complete right bundle branch block were determined. The whole cohort of patients were divided into two groups with high arrhythmic risk (aborted or non-aborted sudden death, recurrent ventricular tachycardia despite medical treatment, recurrent syncopes) and low risk (frequent ventricular premature beats, non sustained ventricular tachycardia, uneventful course under medical therapy). RESULTS: From angiocardiography or echocardiography in a quantitative approach right ventricular dilatation (p<0.0001) and additional left ventricular abnormalities (p<0.0001) could be identified as major risk factors. From an ECG point of view increased precordial QRS dispersion > or =50 ms (p<0.01) with complete right bundle branch block and right ventricular dilatation in most cases and precordial T wave inversions beyond V3 (p<0.0001) and the phenomenon of left precordial JT interval prolongation (JT dispersion > or =30 ms) in cases of additional left ventricular abnormalities represented non-invasive predictors of recurrent arrhythmic events. Right precordial ST segment elevation could be excluded as risk factor of sudden arrhythmic death. CONCLUSIONS: Right ventricular dilatation with ECG depolarisation abnormalities and additional left ventricular involvement with striking ECG repolarisation abnormalities could be identified as strong risk factors of recurrent arrhythmic events in ARVD with unfavorable prognosis.

Adult↗