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Biomedical subjects

H Höger

Publications and source records attributed to H Höger.

At least 19 recordsLinked to original sources
PubMed1997

Dystrophin expression in heterozygous mdx/+ mice indicates imprinting of X chromosome inactivation by parent-of-origin-, tissue-, strain- and position-dependent factors.

Inactivation of one X chromosome (X inactivation) in female mammals results in dosage compensation of X-chromosomally encoded genes between sexes. In the embryo proper of most mammals X inactivation is thought to occur at random with respect to the parental origin of the X chromosome. We determined on the cellular level the expression of the X-chromosomally encoded protein dystrophin in skeletal and cardiac muscle of female mice heterozygous for a null mutation of the dystrophin gene (mdx/+). In all muscles investigated (cardiac, anterior venter of digastric muscle, biceps brachii and tibialis anterior muscle) we found a mosaic expression of dystrophin-expressing versus non-expressing cells and determined their proportion with respect to the parental origin of the X chromosome. In all groups of mdx/+ mice the level and pattern of dystrophin expression were found to be dependent on the parental origin of the mdx mutation. Additionally, the extent of dystrophin expression was clearly dependent on the mouse strains (C57BL/10 and BALB/c) used to produce heterozygous mdx/+ mice. Variable differences and patterns of dystrophin expression in skeletal versus cardiac muscle were found that were strictly dependent on the parental source of the mdx mutation and the strain used to breed mdx/+ mice. Moreover, dystrophin expression was found to be different between the right side and the left side of the body in individual muscles, and this difference was clearly dependent on the parental origin of the X chromosome. Our data provide evidence that in the mouse embryo proper there is a non-random distribution of cells showing inactivation of the paternal versus the maternal X chromosome in skeletal and cardiac muscle, indicating a non-random X-inactivation. Besides gametic imprinting, strain-, tissue and position-dependent factors also appear to bias X inactivation.

Animals↗
PubMed1997

Arginine reduces kidney collagen accumulation, cross-linking, lipid peroxidation, glycoxidation, kidney weight and albuminuria in the diabetic kk mouse.

In diabetic nephropathy a major current concept for pathogenesis is increased collagen accumulation in the glomerulus by increased collagen synthesis and decreased degradation. In the present study, we tested the hypothesis whether arginine is able to influence kidney lipid peroxidation, glycoxidation, collagen accumulation, glucose-mediated cross-linking, hydroxy radical attack, protein oxidation, nitric oxide formation and albuminuria in the diabetic kk mouse. Ten diabetic kk mice were given arginine 50 mg/kg body weight, 10 diabetic kk mice were not treated and used as negative controls and 10 kk mice were kept as healthy controls. Our results show that oral administration of low-dose arginine reduces kidney collagen accumulation as reflected by kidney hydroxyproline, cross-linking as reflected by pentosidine, lipid peroxidation, glycoxidation as reflected by carboxymethyl lysine, kidney weight and albuminuria in the diabetic kk mouse. Albuminuria in untreated animals was closely correlated with lipid peroxidation. Our results in the spontaneously diabetic kk mouse representing type 2 diabetes mellitus therefore confirm and extend recent findings of collagen reduction by arginine in a different animal model. The mechanism of reducing proteinuria can be assigned to the blocking of lipid peroxidation products by L-arginine.

Albuminuria↗
PubMed1995

Oxyradical damage and mitochondrial enzyme activities in the mdx mouse.

A number of studies have already been undertaken to investigate involvement of oxyradicals in muscle diseases by means of measurements of oxyradical protective enzymes. We investigated o-tyrosine, which is a biomarker for OH radical damage in vivo, in 10 mdx and 10 control mice. We also measured mitochondrial enzymes in muscle homogenates of 10 mdx and 10 control mice. Mdx mice had significantly elevated values for o-tyrosine, succinat-phenacinmetosulfat oxidoreductase. NADH O2 oxidoreductase and cytochrome C oxidoreductase. Our findings confirm the suggestion that elevated oxyradical production occurs in muscular dystrophies with lack of dystrophin. Furthermore, our results demonstrate that OH radical damage does not impair mitochondrial enzyme activities in the mdx mouse.

Animals↗
PubMed1994

Coisogenic all-plus-one immunization: a model for identifying missing proteins in null-mutant conditions. Antibodies to dystrophin in mdx mouse after transplantation of muscle from normal coisogenic donor.

Specific antibody response against an alien protein is one of the basic immunologic mechanisms in immunecompetent organisms. They can be used as a first step in various approaches leading to the identification of proteins or even an antigen-encoding gene. Accordingly, we wanted to find out whether a null-mutant immunecompetent organism would produce specific antibodies against the missing gene product. We chose the mouse mutant mdx (X-linked muscular dystrophy) which represents a null-mutant condition for the gene product of the Duchenne muscular dystrophy (DMD) gene, dystrophin. When dystrophin-deficient mdx mice received dystrophin-containing muscle grafts from coisogenic normal mice, high titres of antibodies specific for dystrophin were detected in the transplanted animals' sera. Because dystrophin-containing muscle grafts were not rejected but have properly regenerated even in the presence of high titre antibodies against dystrophin, these findings have important bearings on all therapeutical strategies based on dystrophin supplementation. Using the mdx mouse as null-mutant model we showed that there was no immune tolerance for the missing protein but specific antibodies were produced when the organism came in contact with this protein. This simple approach may serve as a shortcut for identifying missing proteins presumably not only in neuromuscular disorders but in a wide range of diseases where null-mutant animal models and corresponding coisogenic inbred strains exist.

Animals↗
PubMed1994

L-arginine reduces kidney collagen accumulation and N-epsilon-(carboxymethyl)lysine in the aging NMRI-mouse.

BACKGROUND: The aging process leads to glomerular basement membrane (GBM) thickening due to increased collagen accumulation. This mechanism can be explained by the nonenzymatic glycosylation hypothesis of collagen aging. We have published the positive effect of L-arginine on glucose-mediated cross-linking, and if the nonenzymatic glycosylation hypothesis of aging holds, the pharmacological effect of L-arginine on glucose-mediated cross-links in the aging Hannover NMRI mouse can be expected. METHODS: Animals were given L-arginine 50 mg/kg body weight/day orally and compared to a control group without treatment. RESULTS: Electron microscopical measurement of the GBM thickness showed significant differences between controls (4920 +/- 1680 A) and the experimental group (2345 +/- 815 A). Determination of the total kidney collagen content based upon 4-trans hydroxyproline revealed 13.9 +/- 3.9 mg/100 mg kidney weight (kw) in the untreated group versus 7.9 +/- 4.2 mg/100 mg kw in the treated group. For solubility studies based upon hydroxyproline determination, collagen was eluted by pepsin digestion. This revealed 18.7 +/- 3.9 mg/100 mg kw in the controls versus 7.8 +/- 4.8 mg/100 mg kw in the treated group. HPLC analysis of N-epsilon-(carboxymethyl)lysine (CML) showed in the treated group (1.847 +/- 0.247 nM/microM hydroxyproline) significantly lower concentrations than in the untreated group (3.399 +/- 0.349 nM/microM hydroxyproline). On sodium dodecyl sulfate (SDS) polyacrylamidegel electrophoresis, the eluates of the treated animals showed less high molecular weight material than their untreated mates. CONCLUSIONS: We cannot discriminate between the probable mechanisms of cross-linking but we clearly can state that L-arginine reduces cross-linking and collagen accumulation in aging collagen type IV accompanied and strongly associated with decreased CML content.

Aging↗
PubMed1994

Thiaproline reduces glomerular basement membrane thickness and collagen accumulation in the db/db mouse.

Glomerular basement membrane thickening and mesangial expansion are the main pathological features in diabetic nephropathy--glomerulosclerosis with the biochemical correlate of increased collagen accumulation. We studied a new principle to reduce collagen accumulation in the glomerulus: thiaproline, known to inhibit protein synthesis by blocking the elongation, led in our studies to a morphological reduction of the glomerular basement membrane thickening and to a decreased collagen content. As the thiaproline analogue is incorporated into collagen, the mechanism of increased degradation of the modified collagen is being discussed.

Animals↗
PubMed1994

Multiple osteomas in mice.

Osteomas (dense compact neoplasms of mature bone tissue) are rare in nearly all strains and stocks of mice. Of 224 Him:OF1 mice maintained until natural death or until terminally ill, 116 (51.8%) had one or more osteomas. Osteomas had a predilection for the skull and the larger bones of the limbs. Plasma alkaline phosphatase concentrations were elevated significantly in osteoma-bearing mice (446 +/- 153 U/liter versus 206 +/- 65 U/liter in age-matched controls without osteomas). Only very large osteomas resulted in clinical signs, and longevity was not shortened. Histologic examination showed clearly separated dense bony tissue irregularly arranged and forming a mosaic pattern, with distinct cement lines and medullary spaces filled with fibroreticular connective tissue. Electron microscopic examination revealed virus-like structures in osteoblasts, osteocytes, and fibroblasts and in the place of remnants of necrotic cells.

Animals↗
PubMed1994

Reduced tumour incidence in mice with inherited seborrhoeic dermatitis.

121 mice homozygous for the gene seb (inherited seborrhoeic dermatitis) and their 142 unaffected heterozygous littermates were kept for their natural lifespan. Heterozygotes showed 84.1% total tumour incidence in males and 95.9% in females. The most common neoplasms were lymphomas, osteomas, lung tumours and neoplasms of the female genital tract. Homozygotes showed a tumour incidence of 36.1% in males and 45.0% in females. The reduction in incidence included all types of neoplasms except epithelial tumours of the skin: skin tumours were detected in 11 homozygous but only in one heterozygous animal. Life expectancy was not affected significantly by genotype. Homozygous mice showed rough and greasy fur and became alopecic with age. Energy intake was increased but growth and depository fat was reduced compared with heterozygous mice. Higher heat loss may incompletely be compensated by higher metabolic rate and thus 'dietary restriction' results in decreased tumour rates. As females show small gonads and a higher increase in food consumption hormonal factors may also be involved.

Animals↗
PubMed1993

Evidence for the existence of differential O-glycosylated alpha 5-subunits of the gamma-aminobutyric acidA receptor in the rat brain.

Polyclonal antibodies were raised to synthetic peptides having amino acid sequences corresponding with the N- or C-terminal part of the gamma-aminobutyric acidA (GABAA) receptor alpha 5-subunit. These anti-peptide alpha 5(2-10) or anti-peptide alpha 5(427-433) antibodies reacted specifically with GABAA receptors purified from the brains of 5-10-day-old rats in an enzyme-linked immunosorbent assay and were able to dose-dependently immunoprecipitate up to 6.3 or 13.1% of the GABAA receptors present in the incubation, respectively. In immunoblots, each of these antibodies reacted with the same two protein bands with apparent molecular mass of 53 or 57 kDa. After exhaustive treatment of purified GABAA receptors with N-Glycanase, each of these antibodies identified two proteins with apparent molecular masses of 46 and 48 kDa. Additional treatment of GABAA receptors with neuraminidase and O-Glycanase resulted in an apparently single protein with molecular mass of 47 kDa, which again was identified by both the anti-peptide alpha 5(2-10) and the anti-peptide alpha 5(427-433) antibody. These results indicate the existence of at least two different alpha 5-subunits of the GABAA receptor that differ in their carbohydrate content. In contrast to other alpha- or beta-subunits of GABAA receptors so far investigated, at least one of these two alpha 5-subunits contains O-linked carbohydrates.

Animals↗
PubMed1992

L-arginine reduces glomerular basement membrane collagen N epsilon-carboxymethyllysine in the diabetic db/db mouse.

The present study was carried out to examine the effect of L-arginine on advanced stage nonenzymatic glycosylation end products in glomerular basement membrane (GBM) as represented by carboxymethyllysine (CML). Twelve db/db mice were given a solution containing a daily dosage of L-arginine of 50 mg/kg body weight orally. Twelve db/db mice served as controls. At the end of the 4-months study period treated animals had significantly lower concentrations of CML (0.084 +/- 0.008, 0.071-0.098 nmol/mumol OH-proline; mean +/- SD, range, p less than 0.01) compared to untreated controls (0.11 +/- 0.018, 0.095-0.152 nmol/mumol OH-proline). In addition, there was a significant positive correlation between GBM thickness and concentrations of CML (r = 0.86, p less than 0.001). We conclude that reduction of CML concentrations in treated db/db mice possibly reflects a beneficial effect of L-arginine on advanced stage nonenzymatic glycosylation end-products in GBM. In addition, measuring CML concentrations might have future clinical implications as a noninvasive parameter for basement membrane thickening.

Administration, Oral↗
PubMed1992

Genetic drift in an outbred stock of mice.

Survey in protein polymorphism in the nucleus colony of the Him: OF 1-mouse outbred stock showed that 8 of 53 loci were variable in the stock. Allele frequencies of these eight loci (Idh-1, Mup-1, Pgm-1; Ldr-1, Gpi-1s, Hbb, Mod-1, Ce-2) changed between generations investigated. The average percentage of heterozygote animals for these loci decreased with generation. These suggested that genetic drift occurred in the breeding stock. Examination in the breeding record sheets showed that genetic drift was caused by mistakes in mating probably due to repeated personnel changes and insufficient training of the animal technicians. Mice had not been paired according to the schemes prescribed, pairing among relatives and reduction of the number of litters used for mating occurred. The increase in homozygosity showed only little effect on breeding parameters: The interval between pairing and first and second litter increased significantly.

Animals↗
PubMed1991

[The tumor spectrum of Him:OFA rats].

The longevity and incidence of spontaneous tumors was investigated in 92 male and 182 female rats of the Sprague-Dawley (SD) derived stock Him: OFA. The overall tumour incidence was 85.9% in males and 97.8% in females with 32 different types of tumors in males and 30 in females. The most frequent neoplasms were mammary tumours in females with 84.6% incidence, followed in this sex by adrenal (36.8%), pituitary (32.9%) and thyroid neoplasms (10.9%). The incidence of all neoplasms in female genital tract was 12.6%. In male rats tumours of the adrenals have the highest incidence (53.2%, most of them cortical) followed by pituitary tumours (31.5%) and neoplasm of the mesenteric lymph nodes (14.1%, which is uncommonly high compared with other Sprague-Dawley stocks). All other tumours are below 10% incidence. The mean lifespan of females is with 719 +/- 142 d shorter than that of males with 752 +/- 108 d because of the high incidence of mammary tumours between 16 to 18 months of age.

Adrenal Gland Neoplasms↗
PubMed1990

The effect of substance L on glucose-mediated cross-links of collagen in the diabetic db/db mouse.

Genetically diabetic mice (db/db) were given 50 mg/kg body weight/day substance L, a nontoxic basic amino acid and compared to control diabetic mice without treatment. The oral administration of the compound was started at the age of 3 months and the animals were sacrificed at the age of 7 months. No adverse effects were observed in animals given the substance L. Total food consumption, drinking water intake and body weight were comparable between the groups. Nonenzymatic glycosylation of serum proteins and hemoglobin was not significantly different in the groups. Renal pathological lesions in the control diabetic mice showed glomerular mesangial expansion and on electron microscopy thickened glomerular basement membranes with a mean thickness of 3,204 +/- 186 A. Treated animals showed significantly less mesangial crescents and thinner glomerular basement membrane thickness of 2,520 +/- 252 A (p less than 0.01). The experimental animals showed in addition a lower mean kidney weight. Glomerular but not tubular proteinuria was reduced in the treated group. Basement membrane collagen type IV isolated from kidneys of experimental animals was more soluble in acidity and showed a lower degree of cross-linking as evaluated by SDS-polyacrylamide gel electrophoresis. We conclude that substance L is beneficial to diabetic renal changes. We suggest that this positive effect could be due to the inhibition of glucose-mediated abnormal cross-linking of collagenous structures by the interaction of substance L with reactive carbonyl residues of glycosylation adducts of collagen. Other possible mechanisms are discussed.

Administration, Oral↗
PubMed1987

Inherited seborrheic dermatitis--a new mutant in mice.

A new mutation, affecting skin and hair, occurred in an expansion colony of Him:OF1 mice. Test crosses showed that a single autosomal recessive gene was responsible for this trait. Homozygotes have sparse greasy fur and lower viability and fertility than normal littermates. Histological observations showed hypertrophy of sebaceous glands, hyperkeratosis, parakeratosis, acanthosis and signs of inflammation. The disease was named 'inherited seborrheic dermatitis' and the gene name seb is proposed.

Animals↗
PubMed1986

Induction of arthritic processes by synovial fluids of rheumatoid arthritis patients in long-term experiments with mice.

Diluted synovial fluids derived from three patients with rheumatoid arthritis (RA) and applied subcutaneously once as a single dose in Swiss mice caused arthritic processes after a long period of latency (10 months). The arthritis-inducing effect was enhanced by storing the original synovial fluids at 4 degrees C for three months. The effects were followed histologically for at least 18 months. In contrast to the theory that RA is based on immunological processes, these preliminary observations support the finding of other authors that a transmissible agent which is rather slow-acting exists in the synovial fluid of RA patients.

Animals↗