Biomedical subjects

A Ziegler

Publications and source records attributed to A Ziegler.

At least 73 records · Page 4Linked to original sources

PubMed2001

Xenon-129 MR imaging and spectroscopy of rat brain using arterial delivery of hyperpolarized xenon in a lipid emulsion.

Hyperpolarized (129)Xe dissolved in a lipid emulsion constitutes an NMR tracer that can be injected into the blood stream, enabling blood-flow measurement and perfusion imaging. A small volume (0.15 ml) of this tracer was injected in 1.5 s in rat carotid and (129)Xe MR spectra and images were acquired at 2.35 T to evaluate the potential of this approach for cerebral studies. Xenon spectra consistently showed two resonances, at 194.5 ppm and 199.0 ppm relative to the gas peak. The signal-to-noise ratio (SNR) obtained for the two peaks was sufficient (ranging from 12 to 90) to follow their time courses. 2D transverse-projection xenon images were obtained with an in-plane resolution of 900 microm per pixel (SNR range 8-15). Histological analysis revealed no brain damage except in two rats that had received three injections.

Animals↗

PubMed2001

Further evidence for linkage of low-mid frequency hearing impairment to the candidate region on chromosome 4p16.3.

We have investigated a three-generation family with an autosomal dominant low-mid frequency hearing loss. Audiograms show consistently a hearing threshold of 50+/-20 db hearing loss (HL) between 250 Hz and 1-2 kHz. Normal hearing level was reached between 3 and 6 kHz in all examined children. Adult patients show an additional hearing impairment (HI) in the mid and higher frequencies that seems to differ from presbyacusis. The HI is always bilateral and symmetrical. Genes causing non-syndromic autosomal-dominant deafness with HI in the low and mid frequencies were previously mapped to chromosome 4p16.3 (DFNA6, DFNA14) and chromosome 5q31 (DFNA1). After exclusion of linkage to DFNA1 on chromosome 5, we mapped the candidate gene region to the DFNA14 and DFNA6 loci, between the genetic markers D4S432 and D4S431, located on chromosome 4. This is a further family in which evident linkage of low-mid frequency HI to the candidate region on chromosome 4p16.3 has been found.

Auditory Threshold↗

PubMed2001

Genesis of the ILT/LIR/MIR clusters within the human leukocyte receptor complex.

The human leukocyte receptor complex (LRC) contains at least 26 genes which belong to the immunoglobulin superfamily The genes include two clusters of immunoglobulin-like transcript (ILT)/leukocyte immunoglobulin-like receptor (LIR)/monocyte-macrophage inhibitory receptor (MIR) loci, a cluster of killer cell inhibitory receptor (KIR) genes, two leukocyte-associated immunoglobulin-like receptor genes, as well as the Fc receptor for IgA and the natural cytotoxicity receptor I loci. It has already been postulated that these genes have evolved by multiple duplications, while the two ILT clusters are likely to have been generated by the inverse duplication of an ancient ILT cluster. To shed more light on the possible origin of the loci within the LRC, we have now investigated the presence of KIR and ILT loci in a variety of vertebrates by hybridizations and compared the genomic sequences of all ILT genes. Our results lead to the following conclusions: 1) the origin of KIR genes dates back to about 100 million years, but only primate and human KIRs are closely related; 2) in contrast, genes which are detectable with human ILT cDNAs are already found in birds, suggesting their presence already about 300 million years ago. Using the sequence data produced by the human genome project, we have developed a hypothesis that reconstructs the genesis of the two human ILT clusters in detail which will help to understand the function of the LRC.

Animals↗

PubMed2001

Systematic screening for mutations in the human necdin gene (NDN): identification of two naturally occurring polymorphisms and association analysis in body weight regulation.

BACKGROUND: NDN, which codes for the human necdin protein, is a candidate gene for Prader-Willi syndrome (PWS). One feature of this neurogenetic disorder is hyperphagia resulting in extreme obesity observed later in development. OBJECTIVE AND DESIGN: In this study we have used single-strand conformation polymorphism (SSCP) analysis to identify sequence variants at the human necdin gene. Furthermore we tested whether these variants were associated with obesity in extremely obese German children and adolescents. RESULTS: Two gene variants could be identified: a g.1352T-->C polymorphism in the putative promotor region and a silent g.2311C-->T polymorphism in the coding region. Genotype and allele frequency distribution of both of the polymorphisms were not significantly different between lower and higher body mass index (BMI) subjects. CONCLUSIONS: Hence, it is unlikely that these polymorphisms play a major role in the emergence of juvenile onset human obesity.

Adolescent↗

PubMed2001

[Comparison of sonographic weight estimation to actual birth weight: a retrospective analysis].

AIM: This retrospective study aims at determining the accuracy of sonographic estimation of birth weight based on ultrasound examinations performed at the department of gynaecology of Philipps University at Marburg, Germany. METHOD: 630 children were born at the university department of gynaecology during the first six months of 1998. 519 babies had been examined sonographically and their birth weight estimated within ten days prior to delivery. 176 (33,91 %) of these examinations were carried out by experienced sonographers complying to the level II standard of performance set out by DEGUM. 343 (66.09 %) of examinations were performed by less experienced junior doctors at the time of the mothers' admission to the delivery room. Two reference tables published by Hansmann und Ferrero were used to estimate birth weight. RESULTS: The lower and upper quartile of deviation between estimated weight and actual weight came to -200 g and + 200 g using the Hansmann method and -180 g and + 220 g respectively based on the method of Ferrero. It has to be noted that even greater differences occurred: the 10 % least exact estimates deviated by 500 g and more. The difference between estimated and actual weight increased with the length of pregnancy. The fully trained physician (DEGUM II) tended to estimate the birth weight more accurately. The average birth weight estimated sonographically was lower in "DEGUM II-babies" than that of children whose weight was estimated at the point of admission to the delivery room (Mann-Whitney p < 0,0001). Junior doctors showed a tendency to over-estimate the birth weight of babies actually being underweight. The opposite happened with babies who presented a relatively higher birth weight: their projected birth weight was underestimated. On the other hand, the regression line of the sonographic estimations of birth weight performed by the expert (level II DEGUM) fit to the expected bisector of the angle (Passing-Bablock p > 0,05). CONCLUSION: When clinical decisions are based on estimated values of birth weight, the possible deviation of this value from the actual weight has to be taken into account. In our study this difference came up to 500 g independent of the level of the examiner's ultrasonographic training.

Birth Weight↗

PubMed2001

No evidence for involvement of alleles of the 825-C/T polymorphism of the G-protein subunit beta 3 in body weight regulation.

The 825-C/T polymorphism of the beta 3 subunit of the heterotrimeric G protein gene (GNB3) has been shown to be associated with essential hypertension in humans. Recently, it was also reported that the 825-T allele has a higher frequency in obese than non-obese hypertensives suggesting that the primary effect of this allele is on body weight. The association to hypertension might merely be a secondary effect of the higher weight of the respective allele carriers. To investigate an involvement of the 825-T allele in body weight regulation in young individuals, we evaluated allele frequencies in 440 extremely obese children and adolescents (82.9% had a body mass index [BMI] > or = 99th percentile), 51 obese students (BMI > or = 90th percentile), 110 normal weight students (BMI between 40th and 60th percentile) and 144 underweight students (BMI < or = 15th percentile). The study groups were genotyped by polymerase chain reaction with subsequent restriction fragment length polymorphism analysis (PCR-RFLP). The one-sided Yates-corrected chi(2)-test and the Cochran-Armitage trend test for association were performed. Tests for association were negative. The 825-T allele frequencies were similar in the four study groups belonging to different weight ranges (extreme early onset obesity: 0.29; obesity: 0.28; normal weight: 0.35; underweight: 0.32). Similarly, genotype frequencies did not differ between the groups. We concluded that the 825-T allele of the GNB3 does not play a major role in weight regulation in German children, adolescents and young adults.

Adolescent↗

PubMed2001

At receptor inhibition affects the noradrenaline sensitivity in isolated portal vein of normotensive rat.

Short term treatments of normotensive Wistar Kyoto rats with angiotensin II (ANGII) or in combination with the AT1 receptor antagonist, losartan or PD123319, the AT2 receptor antagonist on systemic arterial blood pressure (MABP) and their influence on noradrenaline sensitivity in isolated mesenteric portal vein were evaluated. ANGII increased MABP as well as the contractile response to noradrenaline in vessels from ANGII-treated animals. MABP and the maximal effect of the concentration response curve for noradrenaline were prevented by losartan. However, PD123319 did not influence the blood pressure, but completely removed the vessels sensitivity to noradrenaline. ANGII combined with the AT1 and/or AT2 receptors blockade completely prevented the pressure response to ANGII, but the concentration response curve for noradrenaline did not differ from the vehicle-treated control curve. In conclusion both AT1- and AT2 receptor activation seems to be important in controlling noradrenaline sensitivity of rat portal vein smooth muscle.

Angiotensin Receptor Antagonists↗

PubMed2001

Identification of human epidermal differentiation complex (EDC)-encoded genes by subtractive hybridization of entire YACs to a gridded keratinocyte cDNA library.

The epidermal differentiation complex (EDC) comprises a large number of genes that are of crucial importance for the maturation of the human epidermis. So far, 27 genes of 3 related families encoding structural as well as regulatory proteins have been mapped within a 2-Mb region on chromosome 1q21. Here we report on the identification of 10 additional EDC genes by a powerful subtractive hybridization method using entire YACs (950_e_2 and 986_e_10) to screen a gridded human keratinocyte cDNA library. Localization of the detected cDNA clones has been established on a long-range restriction map covering more than 5 Mb of this genomic region. The genes encode cytoskeletal tropomyosin TM30nm (TPM3), HS1-binding protein Hax-1 (HAX1), RNA-specific adenosine deaminase (ADAR1), the 34/67-kD laminin receptor (LAMRL6), and the 26S proteasome subunit p31 (PSMD8L), as well as five hitherto uncharacterized proteins (NICE-1, NICE-2, NICE-3, NICE-4, and NICE-5). The nucleotide sequences and putative ORFs of the EDC genes identified here revealed no homology with any of the established EDC gene families. Whereas database searches revealed that NICE-3, NICE-4, and NICE-5 were expressed in many tissues, no EST or gene-specific sequence was found for NICE-2. Expression of NICE-1 was up-regulated in differentiated keratinocytes, pointing to its relevance for the terminal differentiation of the epidermis. The newly identified EDC genes are likely to provide further insights into epidermal differentiation and they are potential candidates to be involved in skin diseases and carcinogenesis that are associated with this region of chromosome 1. Moreover, the extended integrated map of the EDC, including the polymorphic sequence tag site (STS) markers D1S1664, D1S2346, and D1S305, will serve as a valuable tool for linkage analyses.

Amino Acid Sequence↗

PubMed2001

Characterization of clustered MHC-linked olfactory receptor genes in human and mouse.

Olfactory receptor (OR) loci frequently cluster and are present on most human chromosomes. They are members of the seven transmembrane receptor (7-TM) superfamily and, as such, are part of one of the largest mammalian multigene families, with an estimated copy number of up to 1000 ORs per haploid genome. As their name implies, ORs are known to be involved in the perception of odors and possibly also in other, nonolfaction-related, functions. Here, we report the characterization of ORs that are part of the MHC-linked OR clusters in human and mouse (partial sequence only). These clusters are of particular interest because of their possible involvement in olfaction-driven mate selection. In total, we describe 50 novel OR loci (36 human, 14 murine), making the human MHC-linked cluster the largest sequenced OR cluster in any organism so far. Comparative and phylogenetic analyses confirm the cluster to be MHC-linked but divergent in both species and allow the identification of at least one ortholog that will be useful for future regulatory and functional studies. Quantitative feature analysis shows clear evidence of duplications of blocks of OR genes and reveals the entire cluster to have a genomic environment that is very different from its neighboring regions. Based on in silico transcript analysis, we also present evidence of extensive long-distance splicing in the 5'-untranslated regions and, for the first time, of alternative splicing within the single coding exon of ORs. Taken together with our previous finding that ORs are also polymorphic, the presented data indicate that the expression, function, and evolution of these interesting genes might be more complex than previously thought.

Amino Acid Sequence↗

PubMed2001

Update of familial pancreatic cancer in Germany.

BACKGROUND/AIMS: The prevalence of familial pancreatic cancer (FPC) and the characteristics of FPC have not yet been well investigated in the German population. Therefore, a German case collection for FPC was established in July 1999 to collect and evaluate data on FPC families. METHODS: The prevalence of pancreatic cancer (PC) as well as other tumours and diseases was studied in families with at least 2 first-degree relatives with histologically confirmed PC, and in families of patients with PC and a first-degree relative with malignant melanoma. All participating family members were genetically counselled and evaluated by a standardised questionnaire. RESULTS: In an 18-month period, 73 independent kindreds with potential FPC contacted the national case collection. So far, 20 kindreds have fulfilled the criteria for FPC and have undergone complete workups. Most families revealed an autosomal dominant pattern of inheritance. Twelve families revealed an isolated accumulation of PC. Importantly, in 8 of 20 (35%) families, additional tumour types such as melanoma, breast and prostate cancer occurred. CONCLUSION: The observed phenotypic heterogeneity indicates an association with predisposing tumour suppressor genes p16 and BRCA2 in up to 30% of FPC families. Mutation analysis of these candidate genes might lead to the identification of the predisposing gene defect in a proportion of FPC families.

Genetic Counseling↗

PubMed2001

Lack of association between endoglin intron 7 insertion polymorphism and intracranial aneurysms in a white population: evidence of racial/ethnic differences.

BACKGROUND AND PURPOSE: Endoglin is a component of the transforming growth factor-beta receptor complex and is predominantly expressed on cell surfaces of endothelial cells. A polymorphism of the endoglin gene has previously been found to be associated with the occurrence of intracranial aneurysms in a Japanese population. In our study, we investigated whether this polymorphism is associated with the development of cerebral aneurysm in a white population. METHODS: The study population consisted of 121 white patients who had been treated for intracranial aneurysms, 124 healthy white blood donors, and 15 Japanese volunteers. Exon 7 of the endoglin gene and adjacent intronic sequences were amplified by polymerase chain reaction and analyzed by using an automated laser fluorescence detection system. RESULTS: A well-known insertion polymorphism (5'-TCCCCC-3', starting 23 bp distal from the 3' end of exon 7) was identified. The allele frequencies of the polymorphism were 35 (14.5%) of 242 alleles in the aneurysm group and 35 (14.1%) of 248 alleles in the white control group, which does not represent a statistically significant difference (P>0.85). The sequence of the polymorphism is complementary to that reported in the previously mentioned Japanese study. However, the 2 polymorphisms are identical. Under this assumption, the allele frequencies differ significantly among the Japanese controls in that particular study and the white controls in our study (27.8% versus 14.1%, respectively; P=0.0003). CONCLUSIONS: The genetic polymorphism in the vicinity of 3' end of exon 7 in the endoglin gene was not significantly associated with the occurrence of intracranial aneurysms in the white population. There are ethnic-related differences of allele frequencies between our white controls and the previously reported Japanese controls.

Adult↗

PubMed2001

Pharmacological investigation on nigrescigenin-a cardenolide from Parquetina nigrescens (Afzel.) Bullock: comparative studies on cardiotonic effects of Parquetina nigrescens, g-strophanthin and noradrenaline in guinea-pig isolated atria.

The cardiotonic and catecholamine-like effects of Parquetina nigrescens extract-induced contractile force of guinea-pig left and right atria were investigated in-vitro. Isometric contractions were recorded. P. nigrescens extract, 5-150 microg mL(-1), increased the force of contraction dose dependently in electrically driven left atria. The concentration of P. nigrescens extract producing 50% of the maximal effect (EC50 value) was 7.5 microg mL(-1). The positive inotropic response differed from that of g-strophanthin by its high rate of onset and its complete reversibility upon removal of the extract from the incubation medium. In spontaneously beating right atrial muscle, P. nigrescens extract increased the rate of contractions. Its positive chronotropic and inotropic effects were partly antagonized by propranolol and atenolol indicating the presence of an adrenergic acting principle in P. nigrescens extract. In contrast, the inotropic response to P. nigrescens extract could not be completely suppressed by beta-blocking agents, suggesting that the force of contraction is not only increased by a sympathomimetic ingredient of P. nigrescens extract but also by the cardenolides known to be present in P. nigrescens.

Adrenergic alpha-Agonists↗

PubMed2001

Molecular characterization of V-type H(+)-ATPase (B-subunit) in gills of euryhaline crabs and its physiological role in osmoregulatory ion uptake.

The vacuolar-type H(+)-ATPase (V-ATPase) has been implicated in osmoregulatory ion uptake across external epithelia of a growing variety of species adapted to life in fresh water. In the present study, we investigated whether the V-ATPase may also function in a euryhaline species that tolerates brackish water (8 salinity) but not fresh water, the shore crab Carcinus maenas. cDNA coding for the regulatory B-subunit of the V-ATPase was amplified and sequenced from C. maenas gills and partially sequenced from four other crab species. Two isoforms differing in the 3'-untranslated region were found in C. maenas. In this species, the abundance of B-subunit mRNA was greater in the respiratory anterior gills than the ion-transporting posterior gills and was not increased by acclimation to dilute salinity. Immunocytochemical analysis showed that the B-subunit protein is not targeted to the apical membrane but is distributed throughout the cytoplasmic compartment. Physiological studies of isolated perfused gills indicated that the V-ATPase inhibitor bafilomycin had no effect on transepithelial potential difference. Thus, in contrast to the freshwater-tolerant Chinese crab Eriocheir sinensis, in which the V-ATPase appears to play an important osmoregulatory role, the V-ATPase in C. maenas probably functions in acidification of intracellular organelles but not in transbranchial NaCl uptake.

3' Untranslated Regions↗

PubMed2001

Pharmacokinetics of morphine 3-esters after oral administration in rabbits.

Pharmacokinetics of three morphine 3-esters-3-(2,2-dimethylvaleroyl) morphine (A), 3-(2-phenylbenzoyl) morphine (B), and 3-(2,2-diphenylpropionyl) morphine (C) was characterized after single oral administration in rabbits. Blood was sampled up to 24 h and cerebro-spinal fluid (CSF) was collected with the last blood sample. The concentration of the morphine 3-esters, morphine, morphine 3-glucuronide and morphine 6-glucuronide were determined in plasma and CSF using HPLC UV-detection. The morphine 3-esters were suggested to be a subject to marked presystemic elimination, since, in comparison to the administration of the un-esterified morphine, relatively low concentrations of morphine and morphine glucuronides were detected in plasma. The rate of disposition of morphine was dependent on the hydrolytic stability of the esters. The mean (+/- S.E.) plasma half-life of morphine was 0.9 +/- 0.2 h, 2.5 +/- 0.6 h and 3.5 +/- 3.5 h after the administration of A, B and C, respectively, compared to 0.9 +/- 0.2 h as estimated after the administration of non-esterified morphine. An analgesic effect will be achieved, since morphine was detected in CSF even 24 h after the application of the ester pro-drugs. It is concluded that esterification at the 3-position may be adapted to obtain sustained plasma levels of morphine.

Administration, Oral↗

PubMed2001

[Determination of pravastatin in rat liver by RP-HPLC].

AIM: To establish a reverse-phase high performance liquid chromatographic method for the determination of pravastatin in rat liver. METHODS: An aliquot of 5 g liver homogenates, spiked with triamcinolone acetonide (internal standard), was extracted by solid-phase extraction with Bond Elut C18 columns. Chromatography was performed using a C18 reverse-phase column with mobile phase of Na2HPO4 buffer sdution (0.035 mmol.L-1, pH 3.0)-acetonitrile (155:42). RESULTS: The linear equation was Y = 0.1843X-4.238 x 10(-3) (gamma = 0.9934) in the range of 0.05-10 micrograms.g-1 liver. The limit of detection for pravastatin was 13 ng.mL-1 (signal-to-noise ratio of 3), and the limit of quantification for pravastatin in liver homogenate was 50 ng.g-1 liver (RSD < 20%). The average extraction recovery of pravastatin from liver at different concentrations was 80.8%, and the average inter-day precision was 11%. This procedure was applied to assay pravastatin in rat liver which were collected from Lewis rats at different times after administration of pravastatin (ig 20 mg.kg-1). CONCLUSION: The method was sensitive and is feasible for the pharmacokinetic and distribution study of pravastatin.

Animals↗

PubMed2000

Familial associations of lipid profiles: a generalized estimating equations approach.

Elevated plasma levels of apolipoproteins A1 (apoA1) and B (apoB) are important protective factors and risk factors, respectively, for atherosclerosis and coronary heart disease. It is well known that both apoA1 and apoB reveal strong familial aggregation. Our goal was to investigate whether exogenous variables influence these associations. We used marginal regression models for the mean and association structure (generalized estimating equations 2; GEE2) to analyse data from 1435 family members within 469 families of different sizes included in the Donolo-Tel Aviv Three-Generation Offspring Study. The usual robust variance matrix was approximated by extensions of jack-knife estimators of variance to GEE2 models. Estimation of standard errors in models with quite complex correlation structures was possible using this approach. All analyses were easily carried out using a menu-driven stand-alone software tool for marginal regression modelling. We demonstrate that a variety of hypotheses can be tested using Wald statistics by modelling regression matrices for the association structure. We show that correlation for apoB between parent-offspring pairs increased with decreasing age difference and that pairs with individuals of the same gender had more similar apoA1 levels than individuals of different gender. Associations between different relative pairs did not all agree with those expected from differences in kinship coefficients. The analysis using GEE2 models revealed structures that would not have been detected by other models and should therefore be used in addition to traditional approaches of analysing family data. GEE2 should be considered a standard method for the investigation of familial aggregation.

Apolipoproteins A↗

PubMed2000

Proximal myotonic myopathy: evidence for anticipation in families with linkage to chromosome 3q.

OBJECTIVE: To investigate anticipation in proximal myotonic myopathy (PROMM). BACKGROUND: PROMM is a recently described autosomal dominantly inherited disorder similar to but distinct from myotonic dystrophy (DM). DM belongs to the group of inherited disorders with anticipation caused by an unstable trinucleotide repeat expansion. In PROMM, no mutation has been identified, although PROMM has recently been mapped to a gene locus on chromosome 3q. METHODS: We investigated 10 German families with the PROMM phenotype and linkage to chromosome 3q. We based our analysis of anticipation on the age of disease onset. Anticipation was assumed if the offspring had first symptoms earlier in life than his or her affected parent. For statistical analysis Independence Estimating Equations (IEE) and a Monte-Carlo bootstrap were used. RESULTS: In 27 affected living parent-offspring pairs from these 10 families, the mean difference of disease onset was 18.8 years with either statistical analysis (p < 10-14 and p < 10-15). The mean disease onset interval in years was greater in father-offspring as compared to the mother-offspring pairs (p < 0.05; IEE). CONCLUSION: Our findings suggest the occurrence of anticipation in parent-offspring pairs from families with the PROMM phenotype and linkage to chromosome 3q. The different disease onset intervals in mother-offspring and father-offspring pairs could indicate a mild parent-of-origin effect. These observations are compatible with the suggestion that PROMM, like DM, may be a trinucleotide repeat associated disorder. In contrast to DM, anticipation in PROMM is milder, a congenital form does not seem to occur, and fertility does not appear to be affected.

Adolescent↗

PubMed2000

Transcription factor GATA-2 gene is located near 3q21 breakpoints in myeloid leukemia.

Rearrangements affecting chromosome band 3q21 are observed in a subgroup of patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). However, little is known about the molecular consequences of such aberrations. We therefore established a PAC contig in the 3q21 breakpoint region and identified potential protein coding sequences by exon trapping. One of the exons isolated was from the human GATA-2 gene, which we showed to be transcribed from telomere to centromere. The majority of 3q21 breakpoints are located telomeric to the transcribed portion of this gene in a region that in mice appears to be necessary for proper promoter function. Results of GATA-2 expression analyses in leukemic cell lines as well as primary patient samples are compatible with the hypothesis that 3q21 aberrations contribute to leukemogenesis through deregulation of the hematopoietic transcription factor GATA-2.

Acute Disease↗