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Biomedical subjects

J Erdmann

Publications and source records attributed to J Erdmann.

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

Effect of the angiotensin II type 2-receptor gene (+1675 G/A) on left ventricular structure in humans.

OBJECTIVES: Our study goal was to analyze whether gene variants of angiotensin II type 2-receptor (AT2-R) modulate the effects of angiotensin II on the left ventricle (LV). BACKGROUND: Experimental data suggest that angiotensin II modifies ventricular growth responses via angiotensin II type 1-receptors (AT1-R) and AT2-R. METHODS: In 120 white, young male subjects with normal or mildly elevated blood pressure, we assessed plasma angiotensin II and aldosterone concentrations (RIA), 24-h urinary sodium excretion, 24-h ambulatory blood pressure and LV structure (two-dimensional guided M-mode echocardiography). The intronic +1675 G/A polymorphism of the X-chromosomal located AT2-R gene was investigated by single-strand conformational polymorphism analysis and DNA-sequencing. RESULTS: Hypertensive subjects with the A-allele had a greater LV posterior (11.0 +/- 1.3 vs. 9.9 +/- 1.3 mm, p < 0.001), septal (11.8 +/- 1.4 vs. 10.1 +/- 1.2 mm, p < 0.001) and relative wall thickness (0.44 +/- 0.06 vs. 0.39 +/- 0.06, p < 0.01) as well as LV mass index (138 +/- 23 vs. 120 +/- 13 g/m2, p < 0.001) than those with the G-allele. Confounding factors (i.e., body mass index and surface area, plasma angiotensin II, sodium excretion, systolic and diastolic ambulatory blood pressure) were similar between the two genotypes. In normotensive subjects, relative wall thickness (0.36 +/- 0.05 vs. 0.35 +/- 0.05) and LV mass index (115 +/- 21 vs. 112 +/- 17 g/m2) were nearly identical across the two genotypes, with similar confounding variables. CONCLUSIONS: Our data indicate that the X-chromosomal located +1675 G/A-polymorphism of the AT2-R gene is associated with LV structure in young male humans with early structural changes of the heart due to arterial hypertension.

Adult↗
PubMed2001

Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy.

OBJECTIVES: We studied the clinical and genetic features of hypertrophic cardiomyopathy (HCM) caused by mutations in the myosin-binding protein C gene (MYBPC3) in 110 consecutive, unrelated patients and family members of European descent. BACKGROUND: Mutations in the MYBPC3 gene represent the cause of HCM in approximately 15% of familial cases. MYBPC3 mutations were reported to include mainly nonsense versus missense mutations and to be characterized by a delayed onset and benign clinical course of the disease in Japanese and French families. We investigated the features that characterize MYBPC3 variants in a large, unrelated cohort of consecutive patients. METHODS: The MYBPC3 gene was screened by single-strand conformational polymorphism analysis and sequencing. The clinical phenotypes were analyzed using rest and 24-h electrocardiography, electrophysiology, two-dimensional and Doppler echocardiography and angiography. RESULTS: We identified 13 mutations in the MYBPC3 gene: one nonsense, four missense and three splicing mutations and five small deletions and insertions. Of these, 11 were novel, and two were probably founder mutations. Patients with MYBPC3 mutations presented a broad range of phenotypes. In general, the 16 carriers of protein truncations had a tendency toward earlier disease manifestations (33 +/- 13 vs. 48 +/- 9 years; p = 0.06) and more frequently needed invasive procedures (septal ablation or cardioverter-defibrillator implantation) compared with the 9 carriers of missense mutations or in-frame deletions (12/16 vs. 1/9 patients; p < 0.01). CONCLUSIONS: Multiple mutations, which include missense, nonsense and splicing mutations, as well as small deletions and insertions, occur in the MYBPC3 gene. Protein truncation mutations seem to cause a more severe disease phenotype than missense mutations or in-frame deletions.

Adolescent↗
PubMed2000

Tumor necrosis factor receptors types 1 and 2 differentially regulate osteoclastogenesis.

The potent osteoclastogenic agent, tumor necrosis factor-alpha (TNF), exerts its biological effects via two receptors, namely TNF receptors 1 (p55r) and 2 (p75r), each present on osteoclast precursors. Thus, we asked if p55r and p75r differentially impact the osteoclastogenic process. Marrow derived from mice expressing only p55r generates substantially more osteoclasts, in the basal state, than does wild type, while marrow expressing only p75r, produces substantially fewer. Reflecting its preferential activation of p55r, exogenous TNF stimulates osteoclast formation by p55r(+/+)p75r(-/-), but not p55r(-/-)p75r(+/+), marrow. Consistent with the fact that NF-kappaB is essential for osteoclastogenesis, this transcription complex is activated, relative to wild type, in p55r(+/+)p75r(-/-) osteoclast precursors and suppressed in those expressing only p75r. Because p55r enhances, and p75r suppresses, osteoclastogenesis, we asked if their principal ligands, namely soluble and membrane-residing TNF, respectively, differentially impact basal osteoclast recruitment. We find, in contrast to the significant level of osteoclast formation in wild type marrow, osteoclastogenesis by that derived from mice expressing membrane, but not soluble, TNF, is negligible. Thus, optimal therapeutic inhibition of bone resorption may entail selective TNF receptor modulation and/or arrested cleavage of membrane TNF to its soluble form.

Animals↗
PubMed2000

Investigation of the human serotonin 6 [5-HT6] receptor gene in bipolar affective disorder and schizophrenia.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that mediates a wide range of central nervous functions by activating multiple 5-HT receptor subtypes. A possible irregularity of serotonergic neurotransmission has been implicated in a variety of neuropsychiatric diseases. In the present study, we performed a systematic mutation scan of the complete coding region and splice junctions of the 5-HT(6) receptor gene to explore the contribution of this gene to the development of bipolar affective disorder and schizophrenia. Investigating 137 unrelated individuals (including 45 bipolar affective patients, 46 schizophrenic patients, and 46 unrelated controls), we identified six single base substitutions (126G/T, 267C/T, 873+30C/T, 873+128A/C, 1128G/C, 1376T/G). Comparing frequencies between patients and controls, we observed a significant overrepresentation of the 267C allele among bipolar patients (P=0. 023 not corrected for multiple testing). This finding was followed up in an independent sample of 105 bipolar family trios using a family-based association design. Fifty-one transmissions could be examined. In 30 cases allele 267C and in 21 cases allele 267T were transmitted to the affected offspring. Although this result was far from statistical significance (transmission disequilibrium test=1.59, P=0.208), the limited number of possible transmissions may have prevented detection of smaller effects. Our preliminary data suggest that bipolar affective disorder may be associated with variation in the 5-HT(6) gene. It will be important to extend the present analysis to larger samples. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:217-221, 2000.

Bipolar Disorder↗
PubMed2000

Morphology-related effects on gene expression and protein accumulation of the yeast Arxula adeninivorans LS3.

The dimorphism of the yeast Arxula adeninivorans LS3 is regulated by cultivation temperatures. Up to 42 degrees C the yeast grows as budding cells, which turn to mycelia at higher temperatures. To test whether the dimorphism is exclusively induced by high temperatures or also by other conditions, mutants were selected with an altered behaviour with respect to dimorphism. After mutagenesis with N-methyl-N'-nitro-N-nitrosoguanidine, five of 25,000 colonies formed a very rough surface consisting of mycelia at 30 degrees C, in contrast to the wild-type. These mutants allow temperature-mediated and morphology-related effects on gene expression and protein accumulation to be distinguished. Budding cells and mycelia showed different expression of genes encoding secretory proteins at the same temperature. Mycelia secreted two-fold more protein than budding cells, including the enzymes glucoamylase and invertase. This indicated that morphology, rather than temperature, is the decisive factor in the analysed processes.

Ascomycota↗
PubMed2000

[A 42-year-old patient with the hemolytic-uremic syndrome under gemcitabine therapy for an adenocarcinoma of the liver. The hemolytic-uremic syndrome and gemcitabine].

We report on the case of a 42-year-old man suffering from an irresectable adenocarcinoma of the liver. The patient was treated with 5-fluorouracil for 6 months when the disease progressed and second line therapy with gemcitabine was started. After 4 months diastolic blood pressure increased and edema of the legs as well as vomiting occurred. Laboratory tests revealed anemia and thrombopenia accompanied by an elevation of plasma D-dimer, lactatdehydrogenase, creatinine, and urea levels in the serum. In addition, a pronounced proteinuria as well as renal hematuria were detected and subsequently a hemolytic uremic syndrome was diagnosed. After treatment with high-dose glucocorticoids, anticoagulants and transfusions of packed RBC the course of disease improved. Since Gemcitabine is now widely used for treatment of solid organ cancer (e.g. pancreatic adenocarcinoma, biliary tract cancer, lung cancer etc.), it is necessary to be aware of Gemcitabine-induced hemolytic uremic syndrome as a rare but potentially fatal side effect.

Acute Kidney Injury↗
PubMed2000

Evaluation of three polymorphisms in the promoter region of the angiotensin II type I receptor gene.

BACKGROUND: Angiotensin II induces vasoconstriction and growth via stimulation of the AT1 receptor. A genetic variant (+1166A/C) in the 3' untranslated region of this gene had been found to be associated with arterial hypertension, aortic stiffness and coronary artery disease. OBJECTIVE: In order to evaluate further the potential implications of the genetic variability of the AT1 gene we explored three newly characterized single nucleotide polymorphisms (SNPs) in its promoter in a Caucasian population-based sample (n = 623). One of these (-2228G/A) is in complete linkage disequilibrium with six additional SNPs in the region such that, indirectly, potential functional implications of these sites were assessed as well. For comparison, we genotyped the previously described +1166A/C variant RESULTS: The allele frequencies of the -2228G/A, -1424C/ G and -521 C/T SNPs were 0.82/0.18, 0.963/0.037 and 0.64/0.36, respectively. Statistical analysis by one-factor ANOVA revealed no significant relationship of any allele, genotype or haplotype with age, sex, body mass index, heart rate, systolic or diastolic blood pressure, hypertension, the intake of antihypertensive medication or left ventricular mass. Likewise, renin, angiotensinogen, angiotensin-converting enzyme, aldosterone or atrial natriuretic peptide levels were not found to be associated with any of these SNPs. Surprisingly, the -2228 A allele was found to be overrepresented in subjects with diabetes mellitus (n = 25, P = 0.006). However, this result could not be confirmed when additional individuals with diabetes mellitus (n = 45) were analysed. A weak linkage disequilibrium was observed between the -2228 A allele and the +1166 C allele (chi2 1 3.1; P = 0.010). CONCLUSION: From the present data it is unlikely that any one of the nine newly characterized SNPs in the promoter region of AT1 gene is associated with arterial hypertension.

Aged↗
PubMed2000

Lack of association between polymorphisms of angiotensin II receptor genes and response to short-term angiotensin II infusion.

OBJECTIVES: The physiological effects of polymorphisms of the renin-angiotensin-aldosterone system (RAAS) are poorly understood. Long-term effects of genetic variants can be studied in cross-sectional linkage studies. In this study, we examined the short-term effects of genetic polymorphisms of the angiotensin II AT1 - and AT2-receptor subtypes in humans by means of angiotensin II infusion. METHODS: In 120 male, white, young (26 +/- 3 years) subjects with normal or mildly elevated blood pressure, changes in mean arterial blood pressure, aldosterone levels, glomerular filtration rate (GFR), and renal plasma flow (RPF) were measured in response to angiotensin II infusion (0.5 ng/kg per min and 3.0 ng/kg per min, each over 30 min). The -2228 G/A polymorphism of the AT1-receptor gene, and the +1675 G/A polymorphism of the AT2-receptor gene were determined by restriction digestion and single strand conformation polymorphism analysis, respectively. RESULTS: Infusion of angiotensin II resulted in an increase in mean arterial pressure, serum aldosterone levels and GFR, and in a decrease in RPF (all P< 0.001). However, at similar baseline mean arterial pressure, aldosterone levels, and renal haemodynamics, the response to angiotensin II did not significantly differ across the AT1 - and AT2-receptor genotypes with the sample size of our study being adequate to detect relevant differences across the genotypes with a power of > 90% for all parameters. CONCLUSIONS: The response to angiotensin II infusion does not differ across the the AT1- and AT2-receptor genotypes examined in our study. However, long-term effects of variants of angiotensin II receptor genes cannot be ruled out with this approach.

Adult↗
PubMed2000

Functional gene testing of the Glu298Asp polymorphism of the endothelial NO synthase.

OBJECTIVES: To test whether the Glu298Asp polymorphism of the endothelial nitric oxide synthase (eNOS) gene is of functional relevance in humans by altering endothelium-dependent vasodilation. BACKGROUND: The Asp298 variant of the eNOS gene product has been associated with arterial hypertension, coronary artery disease and myocardial infarction. The pathogenetic mechanism has not yet been elucidated. Since endothelium-dependent vasodilation has been shown to be impaired in these disorders, we hypothesized that the Glu298Asp polymorphism of the eNOS gene influences endothelium-dependent vasodilation. METHODS: In 80 patients with normal or elevated cholesterol, endothelium-dependent and -independent vasodilation was assessed. Forearm blood flow was measured by plethysmography in response to intra-arterial (i.a.) infusion of 12 and 48 microg/min acetylcholine and 3.2 and 12.8 microg/min nitroprusside, respectively. NG-monomethyl-L-arginine (L-NMMA) in doses of 4, 8 and 16 micromol/min was infused to test basal nitric oxide (NO) production and release. Genomic DNA was extracted from blood samples to determine the Glu298Asp polymorphism of the eNOS gene at position 1917 G/T after BanII restriction. RESULTS: Baseline parameters (age, gender, blood pressure, body mass index, cholesterol level) were similar across the genotypes. Genotype frequencies did not deviate from the Hardy-Weinberg equilibrium. No differences in forearm blood flow to i.a. acetylcholine (average increase: + 554 +/- 371%), nitroprusside or L-NMMA infusion were found across the eNOS genotypes, neither for endothelium-dependent or endothelium-independent vasodilation, nor for basal NO production and release. Our sample size of n = 80 had a power of > 80% (beta = 0.20) with a P value < 0.05 (alpha = 0.05) to detect a 200% difference in forearm blood flow response to 48 microg/min acetylcholine. CONCLUSIONS: At a power of 80%, we can exclude a relevant effect on endothelium-dependent vasodilation due to the eNOS Glu298Asp polymorphism. Thus, our functional genetic study does not suggest any biological effect of the eNOS Glu298Asp genotype on the cardiovascular system via an influence on endothelium-dependent vasodilation.

Adult↗
PubMed1999

Age-associated changes in the stimulatory effect of transforming growth factor beta on human osteogenic colony formation.

Previous studies have indicated that the mitogenic responsiveness of human bone cells may change with age. In the present study, we examined whether aging affects the capacity of transforming growth factor beta (TGF-beta) to stimulate the colony formation of human osteoprogenitor cells. Outgrowths of bone cells from 98 iliac crest biopsies were plated at a density of 25 cells/cm2 and cultured for 3 weeks in the presence of 10% fetal calf serum. Approximately 5% of the plated cells gave rise to clonal colonies. TGF-beta (10(-11) M) significantly increased the estimated number of cells per colony. However, the stimulatory effect of TGF-beta significantly declined with donor age (r = -0.26, P = 0.01). Whereas TGF-beta raised the average number of cells per colony in cultures from donors below the age of 50 years by 136+/-50%, the average increase was only 43+/-16% in donors older than 60 years. These data raise the possibility that aging may be associated with a declining capacity of TGF-beta to enlarge the pool of bone cells that can be generated from a single human osteoblast progenitor cell.

Adult↗
PubMed1999

Expression of ACE mRNA in the human atrial myocardium is not dependent on left ventricular function, ACE inhibitor therapy, or the ACE I/D genotype.

The activity of the cardiac renin-angiotensin system is altered in human heart failure, but the regulatory mechanisms are unknown. We analyzed whether angiotensin-converting enzyme (ACE) mRNA expression in heart failure is altered in the atrial myocardium, and whether a correlation exists between atrial ACE mRNA expression and the parameters of left ventricular function. We also investigated whether the use of ACE inhibitors or the ACE I/D genotype modulates the atrial ACE mRNA content. For this purpose patients who were to undergo routine cardiac surgery were selected in a prospective manner according to left ventricular function and ACE inhibitor therapy. Samples of atrial myocardium were taken, and ACE mRNA expression was determined by internally standardized reverse transcription polymerase chain reaction. Atrial ACE mRNA expression did not differ in patients with left ventricular ejection fraction higher than 55% (2423+/-199 copies/ng RNA) and those with a value less than 45% (2661+/-143 copies/ng RNA, n.s.). ACE mRNA expression also did not differ in patients using ACE inhibitors (2585+/-175 copies/ng RNA) and those not using ACE inhibitors (2476+/-185 copies/ng RNA). Furthermore, atrial ACE mRNA expression was not affected by the ACE genotype (DD 2573+/-203, ID 2472+/-215, II 2563+/-249 copies/ng RNA). We conclude that the regulation of atrial ACE mRNA expression occurs predominantly by local mechanical or para- or autocrine factors.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Changes in the concentration of insulin-like growth factor I and transforming growth factor beta1 in rat femoral bone during growth.

Our knowledge of the concentration of growth factors in growing bone is limited. In the present study, we examined the developmental changes in the concentrations of insulin-like growth factor I (IGF-I) and transforming growth factor beta (TGF-beta) in the rat femur between weanling and maturity. We show that during the rapid growth phase there is a continuous rise in bone matrix IGF-I and TGF-beta in all compartments of the femoral bone. The association between IGF-I and TGF-beta is not only temporal, but with few exceptions is also observed within the animals of each age class. These data support the hypothesis that IGF-I and TGF-beta play an important role in the growth-associated accumulation of bone mass.

Aging↗
PubMed1999

Characterization of polymorphisms in the promoter of the human angiotensin II subtype 1 (AT1) receptor gene.

In this study eight sequence variants in the functional promoter of the human angiotensin II subtype 1 (AT1 or AGTR1) receptor gene are reported. Six of these variants are in nearly total linkage disequilibrium with each other and occur with a frequency of 15.7%. By haplotype estimation this group of eight sequence variants is characterized by only five haplotypes. There is no linkage disequilibrium between one of these haplotypes and the AT1 + 1166A/C variant. The finding of polymorphic sites in the functional promoter of the human AT1 locus will be beneficial to the study of the role of the AT1 receptor gene in hypertension and other cardiovascular diseases.

Base Sequence↗
PubMed1998

Screening the human bradykinin B2 receptor gene in patients with cardiovascular diseases: identification of a functional mutation in the promoter and a new coding variant (T21M).

To elucidate if genetic variants in the bradykinin B2 receptor (B2) gene occur that could affect receptor expression and function, we screened for mutations in the promoter and in the coding region of the human B2 gene. In our initial study we analyzed 92 consecutive, unrelated subjects (including 25 patients with hypertrophic cardiomyopathy, 18 patients with dilated cardiomyopathy (DCM), 25 patients with hypertension, 18 patients with coronary heart disease, and 6 patients with valvular heart disease) using nonradioactive polymerase chain reaction-single-strand conformation polymorphism analysis as mutation screening method. We detected eight as yet unknown polymorphic sites in the promoter region of the B2 gene (-845 C/T, -704 C/T, -649 insG, -640 T/C, -536 C/T, -412 C/G, -143 C/T and -78 C/T) with allele frequencies between 0.5 and 13%. One of them (-412 C/G) destroys a Sp1 binding site and abolishes protein binding to this Sp1 site in human umbilical vein endothelial cells and human vascular smooth muscle cells. In the protein-coding region one new coding variant (T21M) with the potential to create a truncated receptor isoform was detected. We determined the frequency of the promoter variant at position -412 (C --> G) and the newly identified coding variant (T21M) in extended samples of 69 patients with HCM, 163 patients with DCM, 109 patients with hypertension, and 173 healthy anonymous blood donors. The promoter variant (-412 C/G) was found in one blood donor and the T21M mutation was not found in the control population. Therefore, it appears that these mutations are rare events and the determination of clinical significance will be a demanding task in the future.

Cardiovascular Diseases↗