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Biomedical subjects

J Seidel

Publications and source records attributed to J Seidel.

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

DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency.

DNA ligase IV functions in DNA nonhomologous end-joining and V(D)J recombination. Four patients with features including immunodeficiency and developmental and growth delay were found to have mutations in the gene encoding DNA ligase IV (LIG4). Their clinical phenotype closely resembles the DNA damage response disorder, Nijmegen breakage syndrome (NBS). Some of the mutations identified in the patients directly disrupt the ligase domain while others impair the interaction between DNA ligase IV and Xrcc-4. Cell lines from the patients show pronounced radiosensitivity. Unlike NBS cell lines, they show normal cell cycle checkpoint responses but impaired DNA double-strand break rejoining. An unexpected V(D)J recombination phenotype is observed involving a small decrease in rejoining frequency coupled with elevated imprecision at signal junctions.

Cell Cycle↗
PubMed2001

Brachytelephalangic dwarfism due to the loss of ARSE and SHOX genes resulting from an X;Y translocation.

Here we report an 8-year-old male patient who had mesomelic shortening of forearms and legs, brachytelephalangia and ichthyotic skin lesions. Chromosomal analysis showed an X;Y translocation involving the short arm of the X chromosome (Xp). Fluorescence in situ hybridization (FISH) and molecular studies localized the breakpoints on Xp22.3 in the immediate vicinity of the KAL gene demonstrating deletions of steroid sulfatase (STS), arylsulfatase E (ARSE), and short stature homeo box (SHOX) genes. It was suspected that the patient was suffering from chondrodysplasia punctata because of a loss of the arylsulfatase E (ARSE) gene. However, no stippled epiphyses were to be seen in the neonatal radiograph. Interestingly, this patient is the first case with a proven loss of the ARSE gene without chondrodysplasia punctata, assuming that chondrodysplasia punctata is not an obligatory sign of ARSE gene loss. Brachytelephalangia was the only result of ARSE gene deletion in this case. The patient's mother also had dwarfism and showed Madelung deformity of the forearms. She was detected as a carrier of the same aberrant X chromosome. The male patient did not show Madelung deformity, demonstrating that Lerri-Weill syndrome phenotype may be still incomplete in children with SHOX gene deletion. The wide clinical spectrum in the male and the Leri-Weill phenotype in his mother are the results of both a deletion involving several sulfatase genes in Xp22.3 and the SHOX gene located in the pseudoautosomal region. Nevertheless, there is no explanation for the absence of chondrodysplasia punctata despite the total loss of the ARSE gene. Further studies are necessary to investigate genotype/phenotype correlation in cases with translocations or microdeletions on Xp22.3, including the ARSE and the SHOX gene loci.

Arylsulfatases↗
PubMed2001

Reduced symptoms and need for antisecretory therapy in veterans 3 years after Helicobacter pylori eradication with ranitidine bismuth citrate/amoxicillin/clarithromycin.

OBJECTIVE: The most effective combination therapy to eradicate Helicobacter pylori has not yet been found. The perfect combination would be effective, relatively free of side effects, and easy to comply with. We studied a 14-day course of three medications taken twice daily by H. pylori-infected patients who were enrolled in the outpatient Veterans Affairs (VA) clinics. The two major objectives were 1) to determine the effectiveness of the combination therapy and 2) to determine the compliance of patients in a VA population. METHODS: Fifty-two male patients were identified with H. pylori infection by positive CLO (Rapid Urease Test) test, positive Giemsa stain, or positive serology. Active infection was confirmed by a positive 13C urea breath test (UBT). Patients were treated for 14 days with open-label triple-combination therapy of ranitidine bismuth citrate (RBC; 400 mg b.i.d.), amoxicillin (1000 mg b.i.d.), and clarithromycin (500 mg b.i.d.). Successful eradication of H. pylori was confirmed by repeat UBT at 6-8 wk after the final dose of therapy. RESULTS: Of the 52 enrolled patients, 49 (94.2%) met the criteria for successful completion of the study (per protocol analysis based on compliance with at least 80% of medication and performance of both UBTs). Of the three patients who did not successfully complete, one was cured (after 6 days of treatment), and two remained infected (after 3 days and 9 days of treatment). Of the 49 completed patients, 45 (91.8%) were cured, and four remained infected. Overall, regardless of compliance (intent-to-treat analysis), 46 of the 52 (88.4%) patients had documented cure of H. pylori infection as determined by the posttreatment UBT. By 3 yr after H. pylori eradication, two of 15 (13.3%) patients who were not on baseline medications had developed the need for antisecretory therapy, but 18 of 31 (58.1%) who were on baseline medications were able to stop therapy. Thus, at 3 yr, successful H. pylori eradication decreased the need for antisecretory therapy from 67.4% of the H. pylori-infected population to 43% of the H. pylori-eradicated population. The effect of H. pylori eradication in improving symptoms at 3 yr was statistically significant in both the ulcer population and the nonulcer population. Adverse events were mild, and included diarrhea (26 patients), bad taste in mouth (24 patients), nausea/upset stomach (nine patients), and headache (two patients). The diarrhea was self-limiting in 25 of the 26 patients. Only two patients discontinued medication because of adverse events. CONCLUSION: The RBC/amoxicillin/clarithromycin combination was, in our VA population, an easily complied with, highly effective, and safe triple therapy with a 90% H. pylori eradication rate. Successful eradication of H. pylori leads to a dramatic decrease in upper-gut symptoms and decreased need for antisecretory therapy.

Aged↗
PubMed2001

Application of colloidal gold to ultrastructural studies.

Progress in recognition of structure and function in a variety of cells has always been linked to development of new research techniques. Beyond doubt, immunocytochemical techniques belong to such new methods. However, the techniques had not been widely applied to electron microscopy until colloidal gold was introduced as a label. This paper presents the pre-embedding and the post-embedding techniques and the applied markers, which are used in immunocytochemical techniques at the ultrastructural level. The potential of colloidal gold techniques is discussed. Particular attention is paid to methods of reaction amplification. Application of gold is illustrated with our own results.

Animals↗
PubMed2001

Cellular expression of TNF-alpha in human cytomegalovirus (HCMV) infection.

Human cytomegalovirus (HCMV) belongs to the most frequent human pathogens. Even if the respective pathomorphological patterns are known in detail, the mechanisms which lead to persistence of the virus in its latent form, its reactivation as well as mechanisms of cell death in the symptomatic infection remain to be clarified. It is postulated that HCMV controls expression of TNF-alpha gene and the associated secondary inflammatory response. On the other hand, TNF-alpha has been shown in in vitro studies to represent a potential stimulator of HCMV major IE promoter. The present studies have been aimed at evaluation of TNF-alpha expression in HCMV-infected brain, liver, kidney and pancreas, obtained upon autopsy from children deceased due to an inborn HCMV infection. In situ hybridisation using digoxigenin-labelled oligonucleotide probe demonstrated the expression of TNF-alpha transcript in the liver (in macrophages and endothelial cells) and in pancreatic islets of Langerhans (in beta cells). Immunocytochemical studies aimed at detection of TNF-alpha protein in the material yielded negative results.

Child↗
PubMed2001

Immunocytochemical localization of PTHrP in human and rat salivary glands.

Parathyroid hormone-related protein (PTHrP) was isolated from tumours and is thought to represent the main factor responsible for humoral hypercalcaemia, which accompanies neoplastic diseases. At present, the protein is known to reside in multiple tissues and organs of both humans and animals. Our study was aimed at demonstrating the presence of PTHrP in normal salivary glands (parotid and submandibular) of rats and humans. Application of immunocytochemical techniques permitted to document the presence of PTHrP in the human and in the rat salivary glands. In all cases, an intense reaction was observed in intra- and interlobular ducts. In rat salivary glands, PTHrP was also present in cells of mucous acini. In our opinion, the presence of PTHrP in the ducts indicates participation of the protein in electrolyte transport across the epithelial cells. The positive reaction noted in mucous acini of rat salivary glands may indicate accessory role of PTHrP in the secretory processes in the glands.

Animals↗
PubMed2001

Immunolocalization of PTHrP in the submandibular glands of three rodent species.

The present study deals with immunohistochemical localization of PTHrP in bank vole, pine vole and white mouse submandibular glands. PTHrP immunoreactivity was observed in epithelial cells of all ductal segments (intercalated, striated, interlobular and main excretory ducts) of the salivary glands in all the three animal species tested. We also found PTHrP expression in myoepithelial cells surrounding the mucous alveoli of submandibular glands in those animals. The reaction was less intense than that found in the epithelial cells of excretory ducts. We occasionally observed a very slight positive reaction for PTHrP in smooth muscle cells of small blood vessels. We also found PTHrP expression in the neurons of ganglion in the submandibular gland.

Animals↗
PubMed2001

Disturbed copper transport in humans. Part 1: mutations of the ATP7A gene lead to Menkes disease and occipital horn syndrome.

Mutations of the ATP7A gene (OMIM 300011) lead to the Menkes disease (MD, OMIM 309400) involving impaired brain development, neurological degeneration, connective tissue abnormalities, and high lethality in early infancy. Occipital horn syndrome (OHS, OMIM 304150), a milder phenotype, is also caused by ATP7A gene mutations. In MD patients, an early copper-histidine treatment may prevent the neurological impairment and prolong survival leading to an OHS phenotype. To demonstrate the genotype/phenotype correlation, two male patients are reported with different ATP7A gene mutations and several phenotypes. In the first patient with the MD phenotype, a mutation within the exon 20 (Gln1288Ter) was found producing a stop codon just prior to the highly conserved ATP binding domain. The OHS phenotype of the second patient was caused by a splice site mutation involving the position +6 of intron 6 within a copper binding domain. Small amounts of correctly spliced ATP7A transcript were sufficient to develop the milder OHS phenotype in this patient (OMIM 30001.0006). In conclusion, mutations of the copper transporting P-type ATPase ATP7A gene cause distinct human diseases showing some genotype/phenotype correlation and implications for treatment.

Adenosine Triphosphatases↗
PubMed2001

Disturbed copper transport in humans. Part 2: mutations of the ATP7B gene lead to Wilson disease (WD).

Mutations in the Wilson disease gene ATP7B, a P-type ATPase, are responsible for copper accumulation in the liver and other organs leading to Wilson disease (WD, OMIM 277900). Clinical manifestations of Wilson disease (WD) include chronic liver disease, acute hepatic failure or neuropsychiatric diseases. Since potent medical treatments are available to prevent disabling residual symptoms, early diagnosis is crucial. To demonstrate the clinical course and genetic findings, a male patient with a novel mutation in the ATP7B gene, a 10 base pair insertion in exon 6 (1927ins 10), and a second missense mutation in exon 13 (P992L) is reported. The patient presented with signs of chronic liver disease at the age of 10 years. Clinical findings included hepatomegaly, elevated liver enzymes and coagulopathy. A combination treatment with the copper chelating agent D-penicillamine and zinc acetate was started leading to normalization of liver function and no appearance of neurological signs or Kayser-Fleischer ring after 7 years follow-up. Truncating mutations of the ATP7B gene (insertions, deletions, nonsense mutations) leading to gross loss of C-terminal parts of the protein, thereby probably completely destroying the protein function, may correlate with a hepatic phenotype and early onset as seen in the patient presented.

Adenosine Triphosphatases↗
PubMed2000

Formation of unexpected substitution patterns in sulfonylbutylation of cyclomaltoheptaose promoted by host-guest interaction.

The distribution of substituents in sulfonylbutylethers of cyclomaltoheptaose (beta-cyclodextrin) formed in aqueous medium has been determined by gas chromatography after hydrolysis and formation of the permethylated sulfonylfluoride derivatives. In contrast to other etherification reactions of beta-cyclodextrin, preferred substitution in position 3 of the glucose units has been detected. From 1H NMR and microcalorimetric experiments, the formation of host-guest complexes by beta-cyclodextrin and the reagent 1,4-butane sultone in water became evident. This spatial preorganization presumably favors the reaction with the O-3. In contrast, in methyl sulfoxide preferred 2-O-alkylation was obtained, indicating that host-guest interaction does not influence regioselectivity in this solvent.

Alkanesulfonates↗
PubMed2000

Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome.

More than 150 point mutations have now been identified in the ATP7A gene. Most of these mutations lead to the classic form of Menkes disease (MD), and a few lead to the milder occipital horn syndrome (OHS). To get a better understanding of molecular changes leading to classic MD and OHS, we took advantage of the unique finding of three patients with similar mutations but different phenotypes. Although all three patients had mutations located in the splice-donor site of intron 6, only two of the patients had the MD phenotype; the third had the OHS phenotype. Fibroblast cultures from the three patients were analyzed by reverse transcriptase (RT)-PCR to try to find an explanation of the different phenotypes. In all three patients, exon 6 was deleted in the majority of the ATP7A transcripts. However, by RT-PCR amplification with an exon 6-specific primer, we were able to amplify exon 6-containing mRNA products from all three patients, even though they were in low abundance. Sequencing of these products indicated that only the patient with OHS had correctly spliced exon 6-containing transcripts. We used two different methods of quantitative RT-PCR analysis and found that the level of correctly spliced mRNA in this patient was 2%-5% of the level found in unaffected individuals. These findings indicate that the presence of barely detectable amounts of correctly spliced ATP7A transcript is sufficient to permit the development of the milder OHS phenotype, as opposed to classic MD.

Adenosine Triphosphatases↗
PubMed2000

Phenylketonuria and hyperphenylalaninemia in eastern Germany: a characteristic molecular profile and 15 novel mutations.

Phenylketonuria (PKU) is an important error of amino acid metabolism which results in most patients from phenylalanine hydroxylase (PAH) deficiency. PKU displays a marked genotypic heterogeneity both within and between different populations. The aim of this study was to establish the genotypic spectrum of PKU in eastern Germany, and to compare this to the distribution of mutations in western Germany. The study population included 302 patients in 290 families who were followed at treatment centers in Berlin, Leipzig and Jena. The study showed marked genotypic variability with a total of 75 mutations, including 15 that have so far not been described (eleven missense mutations, one splicing mutation, and three small deletions). One of these novel mutations, E183Q, occurred in cis to a R408W mutation. In the non-immigrant eastern German population, the frequency of R408W accounted for 40.1% of the PKU alleles. In the immigrant Turkish population of the former West Berlin, the most prevalent mutation was IVS10-11G>A (57%). There was a marked difference of the genotypic spectrum between the population studied here and the data reported from the western part of the country.

Amino Acid Substitution↗
PubMed2000

Spatial distribution of in-patient service use of psychiatric patients: somatic departments versus psychiatric units.

BACKGROUND: It has long been recognized that a high proportion of psychiatric patients are admitted to emergency, medical and surgical wards. However, until now no assessment has been made of which urban general hospitals would be most appropriate for the establishment of specific psychiatric facilities. METHOD: Our study concerned Germany's second largest city, Hamburg (population 1.7 million), and involved an evaluation of psychiatric principal diagnoses in general and psychiatric hospitals. The research was based on data collected between 1988 and 1994 embracing approximately 77% of all psychiatric patients (n = 64,000) in 41 hospitals. The evaluation was carried out using the statistics programs SPSS and DismapWin. RESULTS: We established that the proportion of male patients discharged from somatic wards, mainly internal medicine, with alcohol and drug abuse as well as with neuroses and personality disorders or illegal drug abuse was surprisingly high (70%, 34% and 24% respectively). For female patients the figures were 67%, 40% and 35% respectively. A geographical analysis of spatial heterogeneity of hospitalization risks showed that general hospitals admit a disproportionately high number of patients from areas of lower social status - both male and female from the above-mentioned diagnostic categories. A rank correlation between the classification of areas based on the heterogeneity model and the social status of the areas supports this hypothesis, at least for males. CONCLUSION: Our findings lead us to the conclusion that the establishment of new psychiatric services should focus on internal wards in hospitals located in areas of low social status.

Adult↗
PubMed2000

Phenotypic variation and genetic heterogeneity in Léri-Weill syndrome.

Léri-Weill syndrome (LWS) or dyschondrosteosis represents a short stature syndrome characterised by the mesomelic shortening of the forearms and lower legs and by bilateral Madelung deformity of the wrists. Recently, mutations in the pseudoautosomal homeobox gene SHOX have been shown to be causative for this disorder. This gene has previously been described as the short stature gene implicated in Turner syndrome (TS). We studied 32 Léri-Weill patients from 18 different German and Dutch families and present clinical, radiological and molecular data. Phenotypic inter- and intrafamilial heterogeneity is a frequent finding in LWS, and phenotypic manifestations are generally more severe in females. In males, muscular hypertrophy is a frequent finding. To test for SHOX mutations we used FISH, Southern blot and SSCP analysis as well as long-range PCR and sequencing. We identified (sub)microscopic deletions encompassing the SHOX gene region in 10 out of 18 families investigated. Deletion sizes varied between 100 kb and 9 Mb and did not correlate with the severity of the phenotype. We did not detect SHOX mutations in almost half (41%) the LWS families studied, which suggests different genetic etiologies.

Adolescent↗
PubMed2000

Interior-point methodology for 3-D PET reconstruction.

Interior-point methods have been successfully applied to a wide variety of linear and nonlinear programming applications. This paper presents a class of algorithms, based on path-following interior-point methodology, for performing regularized maximum-likelihood (ML) reconstructions on three-dimensional (3-D) emission tomography data. The algorithms solve a sequence of subproblems that converge to the regularized maximum likelihood solution from the interior of the feasible region (the nonnegative orthant). We propose two methods, a primal method which updates only the primal image variables and a primal-dual method which simultaneously updates the primal variables and the Lagrange multipliers. A parallel implementation permits the interior-point methods to scale to very large reconstruction problems. Termination is based on well-defined convergence measures, namely, the Karush-Kuhn-Tucker first-order necessary conditions for optimality. We demonstrate the rapid convergence of the path-following interior-point methods using both data from a small animal scanner and Monte Carlo simulated data. The proposed methods can readily be applied to solve the regularized, weighted least squares reconstruction problem.

Algorithms↗
PubMed2000

Performance characteristics of the 3-D OSEM algorithm in the reconstruction of small animal PET images. Ordered-subsets expectation-maximixation.

Rat brain images acquired with a small animal positron emission tomography (PET) camera and reconstructed with the three-dimensional (3-D) ordered-subsets expectation-maximization (OSEM) algorithm with resolution recovery have better quality when the brain is imaged by itself than when inside the head with surrounding background activity. The purpose of this study was to characterize the dependence of this effect on the level of background activity, attenuation, and scatter. Monte Carlo simulations of the imaging system were performed. The coefficient of variation from replicate images, full-width at half-maximum (FWHM) from point sources and image profile fitting, and image contrast and uniformity were used to evaluate algorithm performance. A rat head with the typical levels of five and ten times the brain activity in the surrounding background requires additional iterations to achieve the same resolution as the brain-only case at a cost of 24% and 64% additional noise, respectively. For the same phantoms, object scatter reduced contrast by 3%-5%. However, attenuation degraded resolution by 0.2 mm and was responsible for up to 12% nonuniformity in the brain images suggesting that attenuation correction is useful. Given the effects of emission and attenuation distribution on both resolution and noise, simulations or phantom studies should be used for each imaging situation to select the appropriate number of OSEM iterations to achieve the desired resolution-noise levels.

Algorithms↗
PubMed2000

Molecular cytogenetic characterisation of partial trisomy 9q in a case with pyloric stenosis and a review.

Partial trisomy 9q represents a rare and heterogeneous group of chromosomal aberrations characterised by various clinical features including pyloric stenosis. Here, we describe the case of a 1 year old female patient with different dysmorphic features including pyloric stenosis and prenatally detected partial trisomy 9q. This partial trisomy 9q has been analysed in detail to determine the size of the duplication and to characterise the chromosomal breakpoints. According to the data gained by different molecular cytogenetic techniques, such as fluorescence in situ hybridisation (FISH) with whole and partial chromosome painting probes, yeast artificial chromosome (YAC) probes, and comparative genomic hybridisation (CGH), the derivative chromosome 9 can be described as dup(9)(pter-->q22. 1::q31.1-->q22.1::q31.1--> q22.1::q31.1-->qter). Four breakpoint spanning YACs have been identified (y806f02, y906g6, y945f5, and y747b3) for the proximal breakpoint. According to this new case and previously published data, the recently postulated putative critical region for pyloric stenosis can be narrowed down to the subbands 9q22.1-q31.1 and is the result of either partial trisomy of gene(s) located in this region or a gene disrupted in 9q31.

Chromosome Banding↗