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R Ziegler

Publications and source records attributed to R Ziegler.

At least 127 records · Page 7Linked to original sources
PubMed1998

Concentration of transforming growth factor beta in human bone tissue: relationship to age, menopause, bone turnover, and bone volume.

Transforming growth factor beta (TGF-beta) is thought to play an important role in bone metabolism, but its relationship to human bone turnover and bone mass has not been examined yet. In this study, we measured the concentration of TGF-beta in 811 samples of male and female bone from four representative sites of the human skeleton and in the supernatants of 72 short-term human bone marrow cultures from the iliac crest. The concentrations of TGF-beta1 and TGF-beta2 in the bone matrix were positively correlated with histomorphometric indices of bone resorption and bone formation and with serum levels of osteocalcin and bone-specific alkaline phosphatase. We also observed a positive association between the release of TGF-beta in the bone marrow cultures and serum osteocalcin. Changes in the rate of cancellous or cortical bone remodeling with age or menopause were accompanied by corresponding changes in skeletal TGF-beta. In contrast, there was no significant relationship between the concentration of TGF-beta and bone volume at any skeletal site. In conclusion, our study supports the hypothesis that TGF-beta plays an important role in human bone remodeling, but fails to demonstrate an association between the skeletal concentration of TGF-beta and human bone mass.

Aging↗
PubMed1998

Leptin concentrations in serum from a randomly recruited sample of 50- to 80-year-old men and women: positive association with plasma insulin-like growth factors (IGFs) and IGF-binding protein-3 in lean, but not in obese, individuals.

OBJECTIVE: The GH/IGF axis is thought to play an important role in the regulation of body composition throughout life. Changes in body fat stores also affect the activity of the GH/IGF axis, but the mechanisms whereby body fat status is signaled to the GH/IGF axis are poorly understood. The newly discovered protein leptin is exclusively produced by adipocytes, and circulating concentrations of leptin closely reflect body fat stores. DESIGN: We here examined whether leptin might be associated with the activity of the GH/IGF axis in a population-based sample. PATIENTS AND METHODS: Circulating concentrations of leptin, IGF-I, IGF-II, and insulin-like growth factor-binding protein-3 (IGFBP-3) were measured in a population-based sample of 50- to 80-year-old men (n=217) and women (n=198) by specific RIA. RESULTS: All three IGF components were significantly positively correlated with leptin in lean women (body mass index (BMI) <25 kg/m2). IGF-II was also positively correlated with leptin in lean men, and positive correlation of leptin with IGF-I in lean men was of borderline statistical significance. In contrast, no correlation was observed in moderately overweight (BMI 25-30kg/m2) and obese individuals (BMI >30 kg/m2). CONCLUSION: Our study shows that serum leptin concentrations are significantly associated with circulating IGF components in lean elderly subjects. The precise mechanism of this interaction between leptin and the GH/IGF system remains to be determined.

Aged↗
PubMed1998

Hyperhomocyst(e)inemia and endothelial dysfunction in IDDM.

OBJECTIVE: Considering that elevated blood levels of homocyst(e)ine represent a known independent risk factor for macrovascular disease, we assessed the link between hyperhomocyst(e)inemia and diabetic microvascular complications. RESEARCH DESIGN AND METHODS: Homocyst(e)ine and thrombomodulin plasma levels, a marker of endothelial cell damage, were measured before and 3 h after oral methionine loading in 75 patients with stable, well-controlled IDDM and 40 healthy control subjects matched for sex and age. Exclusion criteria were hyperlipidemia, hypertension, smoking, or positive family history for cardiovascular disease. RESULTS: IDDM patients had higher pre- and postload homocyst(e)ine plasma levels than did healthy control subjects (12.0 vs. 7.7 mumol/l and 27.6 vs. 16.0 mumol/l; P < 0.001). Of 75 IDDM patients, 26 had homocyst(e)ine plasma levels above the normal range (defined as mean +2 SD of values obtained in the control group). The IDDM patients with hyperhomocyst(e)inemia had higher thrombomodulin plasma levels (62.2 vs. 38.2 ng/ml; P < 0.001), higher albumin excretion rates (485 vs. 115 mg/l; P < 0.005), and a higher prevalence of late diabetic complications (nephropathy, 76 vs. 33%; retinopathy, 69 vs. 51%; neuropathy, 57 vs. 41%; macroangiopathy, 57 vs. 33%) compared with IDDM patients with normal plasma homocyst(e)ine. In vitro experiments with human umbilical vein cells show an increased release of thrombomodulin into the culture supernatant only when endothelial cells were pretreated with advanced glycation end product (AGE)-albumin before L-homocystine was added. A synergistic action of homocyst(e)ine and AGEs might contribute to vascular complications of patients with diabetes. CONCLUSIONS: Hyperhomocyst(e)inemia is common in nephropathic diabetic patients and may contribute to the enhanced morbidity and mortality from cardiovascular diseases characteristically observed in IDDM patients with diabetic nephropathy.

Adult↗
PubMed1998

Insufficient glycemic control increases nuclear factor-kappa B binding activity in peripheral blood mononuclear cells isolated from patients with type 1 diabetes.

OBJECTIVE: The redox-sensitive transcription factor nuclear factor-kappa B (NF-kappa B) is believed to contribute to late diabetic complications. It is unknown whether NF-kappa B is influenced by glycemic control. RESEARCH DESIGN AND METHODS: To determine whether NF-kappa B is activated in patients with insufficient glycemic control (HbA1c > 10%), we developed a tissue culture-independent electrophoretic mobility shift assay (EMSA)-based semiquantitative detection system that allowed us to determine NF-kappa B activation in ex vivo-isolated peripheral blood mononuclear cells (PBMCs). We included 43 patients with type 1 diabetes in this cross-sectional study. 10 of those received the antioxidant thioctic acid (600 mg/day p.o.) for 2 weeks. RESULTS: Monocytes of patients with HbA1c levels > 10% demonstrated significantly higher NF-kappa B binding activity in an EMSA and a stronger NF-kappa B staining in immunohistochemistry than monocytes of patients with HbA1c levels of 6-8%. The increase in NF-kappa B activation correlated with an increase in plasmatic markers of lipid peroxidation. Treatment with the antioxidant thioctic acid decreased NF-kappa B binding activity. CONCLUSIONS: Hyperglycemia induces activation of the transcription factor NF-kappa B in ex vivo-isolated PBMCs of patients with type 1 diabetes. NF-kappa B activation is at least partially dependent on oxidative stress, since the antioxidant thioctic acid significantly lowered the extent of NF-kappa B binding activity.

Adult↗
PubMed1998

Localisation of protein Z in vascular lesions of patients with atherosclerosis.

BACKGROUND: The deposition of protein Z was investigated in atherosclerotic vascular lesions of patients with diabetes mellitus or atherosclerotic vascular disease without diabetes in comparison to controls. PATIENTS AND METHODS: Protein Z antigen was evidenced by immunohistochemistry in arteries of 5 healthy control patients, 11 diabetic patients with arterio-occlusive disease and 7 patients suffering from arterio-occlusive disease without diabetes. For immunohistochemistry, a commercially available antibody was taken as first antibody, and immunopositivity was evaluated independently by two investigators (J.G.; I.K.) as negative (0), positive (+) and strongly positive (++). The results were assessed by the Whitney-Mann-Wilcoxon test. RESULTS: Macrovascular endothelial cells were stained positive for protein Z in all arteries studied. Arteries of controls did not show significant immunopositivity in cells other than macrovascular endothelial cells, while the microvascular endothelial cells of control arteries were largely negative. The proliferating subendothelial space in atherosclerotic vascular lesions showed significant immunopositivity for protein Z. In contrast to control arteries, the microvascular endothelial cells of the proliferating areas stained positive. The staining pattern of the subendothelial space was similar in atherosclerotic vessels independent of the risk factor for atherosclerosis. Plaques were immunopositive for protein Z, too. CONCLUSIONS: Protein Z is present in atherosclerotic vascular lesions of diabetic and non-diabetic patients, but not in the subendothelial space and microvascular endothelial cells of healthy controls. Since protein Z-positivity was detected in microvascular endothelium as well as in extra-vascular deposits around plaques, it may play a role in the development of these lesions.

Arterial Occlusive Diseases↗
PubMed1998

[Drug treatment of osteoporosis (in the woman)].

In women, osteoporosis with fractures can happen between 50 years, the age of the menopause, and 80 years. Over these three decades, the condition of bone metabolism is not the same. The years after menopause present with high bone turnover. During these years, the administration of antiresorptive drugs is promising: Estrogens (plus progestagens), calcitonins, bisphosphonates. About 10 years after the menopause bone turnover slows down to low turnover. Now the administration of bone-formation stimulating agents is to be preferred: fluorides in the first line, perhaps anabolics in single cases. The prominent fracture of women older than 75 years is the hip fracture (type II osteoporosis). Bone turnover mostly is accelerated again, now due to secondary hyperparathyroidism as a consequence of long-lasting calcium and vitamin D deficiency. For treatment, calcium plus vitamin D is recommended. The exact diagnosis of the metabolic status of the skeleton is a prerequisite for the choice of the optimal therapeutic principle.

Aged↗
PubMed1997

[Prevalence of thyroid gland dysfunctions in 50- to 80-year-old patients. An epidemiologic cross-sectional study in a southwestern community].

BACKGROUND: Thyroid dysfunctions in the elderly are common in iodine deficient Germany. However, the exact prevalence of hypo- and hyperthyroidism is unknown and differs according to the composition of the screened population. In this study we examined the prevalence of thyroid disorders in a population based sample of non-hospitalized elderly people living in a community in southwestern Germany. PATIENTS AND METHODS: In the context of an epidemiological study on the prevalence of osteoporosis and associated factors, 288 men and 271 women between the age of 50 and 80 years were screened for plasma levels of thyreotropin, free T3 and free T4. Participants received an interview on medical conditions including a history on thyroid disorders. RESULTS: 6.7% of the women and 1.7% of the men had a history of thyroid surgery. Manifest or treated hyperthyroidism was observed in 3.5% of the women (n = 10) and 0.7% of the men (n = 2). In 2 of 12 patients with manifest hyperthyroidism the condition was previously unknown. 70- to 80-year old women tended to have a higher prevalence of hyperthyroidism (6.3%) than 50- to 59-year old women (2.9%), or 60- to 69-year old women (3.4%). Subclinical hyperthyroidism was observed in 7.3% of the men (n = 21) and 5.9% of the women (n = 16). We observed no cases of over hypothyroidism in men but in 1.8% of the women (n = 5). Four of 5 manifest states of hypothyroidism were previously unknown. CONCLUSION: The prevalence of thyroid dysfunction in older women and men living in southwestern Germany is high. In view of the often nonspecific clinical symptoms of hypo- and hyperthyroidism in elderly individuals, thyroid disorders should be early included to the list of the differential diagnosis of clinical complaints in this age group.

Aged↗
PubMed1997

Advanced glycation end product (AGE)-mediated induction of tissue factor in cultured endothelial cells is dependent on RAGE.

BACKGROUND: Binding of advanced glycation end products (AGEs) to the cellular surface receptor (RAGE) induces translocation of the transcription factor NF-kappaB into the nucleus and NF-kappaB-mediated gene expression. This study examines the role of RAGE in the AGE albumin-mediated induction of endothelial tissue factor, known to be partly controlled by NF-kappaB. METHODS AND RESULTS: Endothelial cells (ECs) were incubated in the presence of an 18-mer phosphorothioate oligodeoxynucleotide antisense to the 5'-coding sequence of the RAGE gene (antisense RAGE; 0.1 micromol/L). Sense oligonucleotides (sense RAGE, 0.1 micromol/L) of the same region served as control. The cellular uptake of oligonucleotides was controlled by immunofluorescence microscopy. RAGE transcription was suppressed by antisense RAGE, as demonstrated by RT-PCR reactions. AGE albumin-mediated activation of cultured ECs was studied after 48 hours of preincubation of ECs with antisense or sense RAGE. Electrophoretic mobility shift assays and Western blot analysis demonstrated that the AGE albumin-induced translocation of NF-kappaB from the cytoplasm into the nucleus was suppressed in the presence of antisense RAGE but not by sense RAGE. In parallel, AGE albumin-mediated tissue factor transcription, activity, and antigen were significantly reduced in ECs exposed to antisense RAGE, whereas sense RAGE (and nonspecific oligonucleotides) did not influence tissue factor expression. CONCLUSIONS: Activation of ECs and induction of tissue factor by AGE albumin in ECs is dependent on RAGE.

Animals↗
PubMed1997

Role of NFkappaB in the mortality of sepsis.

Binding activity for nuclear factor kappa B (NFkappaB) consensus probes was studied in nuclear extracts from peripheral blood mononuclear cells of 15 septic patients (10 surviving and 5 not surviving). Nonsurvivors could be distinguished from survivors by an increase in NFkappaB binding activity during the observation period (P < 0.001). The increase in NFkappaB binding activity was comparable to the APACHE-II score as a predictor of outcome. Intravenous somatic gene transfer with an expression plasmid coding for IkappaBalpha was used to investigate the role of members of the NFkappaB family in a mouse model of endotoxemia. In this model, increased NFkappaB binding activity was present after injection of LPS. Intravenous somatic gene transfer with IkappaBalpha given before LPS attenuated renal NFkappaB binding activity and increased survival. Endothelial cells and monocytes/macrophages were the major target cells for somatic gene transfer, transfected with an average transfection efficiency of 20-35%. Tissue factor, a gene under regulatory control of NFkappaB, was induced by LPS. Somatic gene transfer with a reporter plasmid containing the functional tissue factor promoter demonstrated NFkappaB-dependent stimulation by LPS. Intravenous somatic gene transfer with IkappaBalpha reduced LPS-induced renal tissue factor expression, activation of the plasmatic coagulation system (decrease of thrombin-antithrombin III complexes) and renal fibrin/fibrinogen deposition. Somatic gene transfer with an expression plasmid with tissue factor cDNA in the antisense direction (in contrast to sense or vector alone) also increased survival. Furthermore, antisense tissue factor decreased renal tissue factor expression and the activation of the plasmatic coagulation system.

Adult↗
PubMed1997

[Secondary resistance to coumarin derivatives in a patient with a hypercoagulability syndrome].

HISTORY AND CLINICAL FINDINGS: A 23-year-old woman with deep (leg) vein thrombosis was hospitalised because the Quick value had not decreased despite administration of phenprocoumon. Two years previously she had sustained an anterior wall myocardial infarction and a scar on her right kidney had been an incidental sonographic finding. There was bluish, fine reticular discoloration over the toes of both legs. Physical examination was otherwise unremarkable except for obesity. INVESTIGATIONS: The concentration of creatine kinase was raised to 250 U/l and that of lactate dehydrogenase to 300 U/l. The platelet count was decreased to 75/nl. The level of IgG anti-cardiolipin antibodies was raised (204 U/l) and the test for lupus anticoagulant positive. A biopsy of the skin from a toe revealing livedoid vasculitis, primary antiphospholipid syndrome (PAPS) was diagnosed. TREATMENT AND COURSE: Noncompliance, excessive vitamin K ingestion, drug interaction and malabsorption were excluded as cause of the lacking action of phenprocoumon. Despite anti-coagulation with high-dosage low-molecular heparin and inhibition of platelet aggregation with ticlopidine and finally also immunosuppressive treatment with cyclophosphamide, skin necroses developed on the toes and she had recurrent pulmonary embolisms of which she died. CONCLUSION: Standard treatment of PAPS is effective anti-coagulation with coumarin derivatives. Secondary resistance to coumarin is a rare occurrence: its cause remains unknown.

Adult↗
PubMed1997

[Hypercalcemia].

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Diagnosis, Differential↗
PubMed1997

Characterization of the solubilized oocyte membrane receptor for insecticyanin, a biliprotein of the hawkmoth, Manduca sexta.

We report the solubilization and characterization of the oocyte membrane receptor for insecticyanin, a blue biliprotein of the hawkmoth Manduca sexta. The insecticyanin receptor was solubilized using 40 mM CHAPS. Strong binding affinity of [125I]insecticyanin to its solubilized receptor was demonstrated to be heat-labile, pH-dependent, Ca2+-dependent, and saturable. The binding was inhibited by excess unlabeled insecticyanin, but not by two other major hemolymph and oocyte proteins, vitellogenin and lipophorin. The receptor for insecticyanin showed tissue specificity: it was present only in oocyte membranes, not in membranes of fat body, midgut or ovariole sheath. The equilibrium data for the solubilized receptor, K(d) and B(max), were estimated to be 17 nM and 11.4 pmol/mg solubilized proteins, respectively. The results from co-immunoprecipitation showed that the apparent molecular mass for the insecticyanin receptor is approximately 185 kDa while chemical crosslinking of the insecticyanin-receptor complex revealed a product with a molecular mass near 10(3) kDa. This suggests that the insecticyanin receptor has a multimeric structure, or that four receptor molecules can bind to one insecticyanin tetramer.

Animals↗
PubMed1997

[Mutations of ret-proto-oncogene in thyroid medullary carcinoma].

OBJECTIVE: To determine the importance of the molecular-genetic demonstration of germ-line mutation in the ret protooncogene for therapeutic measures in sporadic and hereditary medullary thyroid carcinoma (MTC). PATIENTS AND METHODS: Several molecular-genetic tests were performed on DNA of 35 families with hereditary and 81 patients with the sporadic form of MTC (isolation of genomic DNA; PCR amplification; DNA sequencing: demonstration of mutation in codon 918 with restriction enzyme FOK 1). RESULTS: A disease risk was demonstrated in 178 individuals among the 35 families, 159 of whom were investigated by molecular-genetic tests: 84 family members were found to be gene carriers. Germ-line mutation had already been suspected on clinical grounds in 76% of the carriers, 24% being discovered in a presymptomatic stage. Six children among the latter were treated prophylactically by thyroidectomy, histological evidence of C-cell hyperplasia being found in all of them, microcarcinomas in three of the older children. There were four patients among the non-carriers on whom thyroidectomy had been performed previously because of a false-positive pentagastrin-test; but germ-line mutation was now excluded. In one family, with familial MTC in two brothers, no mutation in ret-proto-oncogene has been demonstrated. The members of this family must now, as used to be routine, undergo a pentagastrin-test. Three of the 81 patients with "sporadic" MTC had a germ-line mutation, presumably a new one. CONCLUSION: Molecular-genetic tests have further improved the management of families with hereditary MTC and they thus take first place among essential diagnostic procedures. The diagnosis of sporadic MTC can be confirmed by excluding germ-line mutation in the ret-proto-oncogene.

Adolescent↗
PubMed1997

[The Wolfram syndrome: diabetes mellitus, hypacusis, optic atrophy and short stature in STH deficiency].

HISTORY AND CLINICAL FINDINGS: A 43-year-old man was known for 3 years to have diabetes mellitus. For 2 months before admission he had symptoms of hyperglycaemia with polyuria, polydipsia, weight loss, as well as impairment of vision and declining fitness. In addition to bilateral deafness he was clearly of normally proportioned short stature (150 cm). INVESTIGATIONS: The levels of blood sugar (221 mg/dl), HbA1c(10.2%), triglycerides (496 mg/dl) and cholesterol (323 mg/dl) were raised, while the concentration of somatotropic hormone was diminished, both before and after arginine administration. Fundoscopy revealed concentric diminution of the visual fields with left amblyopia. Visual evoked potentials and colour sense testing revealed bilateral optical atrophy, and the audiogram demonstrated deafness. These findings provided the diagnosis of Wolfram syndrome, namely insulin-dependent diabetes mellitus, deafness, optical atrophy and small stature with somatotropic hormone deficiency. TREATMENT AND COURSE: On insulin treatment the metabolic state became normal (HbA1c 7.5%, normal lipid profile). It was decided that the deficiency in somatotropic hormone regulation did not require treatment. CONCLUSION: Cardinal symptoms of the autosomally recessive Wolfram syndrome are insulin-dependent diabetes and optic nerve atrophy. Several types of hormonal abnormalities are associated with it, including a deficiency in the somatotropic axis. To obtain early and adequate hormonal substitution requires extensive endocrinological diagnosis of a disease which frequently becomes manifest in childhood or adolescence.

Adult↗