Showing papers by "University of Southern Denmark published in 1996"

Sequence tag identification of intact proteins by matching tanden mass spectral data against sequence data bases.

Abstract: Molecular and fragment ion data of intact 8- to 43-kDa proteins from electrospray Fourier-transform tandem mass spectrometry are matched against the corresponding data in sequence data bases. Extending the sequence tag concept of Mann and Wilm for matching peptides, a partial amino acid sequence in the unknown is first identified from the mass differences of a series of fragment ions, and the mass position of this sequence is defined from molecular weight and the fragment ion masses. For three studied proteins, a single sequence tag retrieved only the correct protein from the data base; a fourth protein required the input of two sequence tags. However, three of the data base proteins differed by having an extra methionine or by missing an acetyl or heme substitution. The positions of these modifications in the protein examined were greatly restricted by the mass differences of its molecular and fragment ions versus those of the data base. To characterize the primary structure of an unknown represented in the data base, this method is fast and specific and does not require prior enzymatic or chemical degradation.

A fluvoxamine-caffeine interaction study.

Abstract: The selective serotonin reuptake inhibitor fluvoxamine is a very potent inhibitor of the liver enzyme CYP1A2, which is the major P450 catalysing the biotransformation of caffeine. Thus, a pharmacokinetic study was undertaken with the purpose of documenting a drug-drug interaction between fluvoxamine and caffeine. The study was carried out as a randomized, in vivo, cross-over study including eight healthy volunteers. In Period A of the study, each subject took 200 mg caffeine orally, and in Period B, the subjects took fluvoxamine 50 mg per day for 4 days and 100 mg per day for 8 days. On day 8 in Period B, the subjects again ingested 200 mg caffeine. After caffeine intake, blood and urine were sampled at regular intervals. Caffeine and its three primary demethylated metabolites, paraxanthine, theobromine and theophylline in plasma and the same four compounds plus 11 more metabolites in urine were assayed by HPLC. During fluvoxamine, the median of the total clearance of caffeine decreased from 107 ml min-1 to 21 ml min-1 and the half-life increased from 5 to 31 h. The N3-demethylation clearance of caffeine to paraxanthine decreased from 46 to 9 ml min-1; the N1- and N7-demethylation clearances decreased from 21 to 9 ml min-1 and from 14 to 6 ml min-1, respectively. The results confirm that CYP1A2 is the main enzyme catalysing the biotransformation of caffeine, in particular the N3-demethylation and partly the N1- and N7-demethylation. The results indicate that intake of caffeine during fluvoxamine treatment may lead to caffeine intoxication. Finally, our study provides additional evidence that fluvoxamine can be used to probe CYP1A2 in drug metabolism.

Karyotypic comparisons of multiple tumorous and macroscopically normal surrounding tissue samples from patients with breast cancer

Abstract: Many tumor tissues are made up of genetically different cell populations, and the study of the causes and consequences of this heterogeneity must play a central role in cancer research We have studied breast cancer clonal heterogeneity by cytogenetic analysis of 4123 cells from 52 successfully short-term-cultured tumorous, metastatic, and macroscopically normal breast tissue samples from 6 women with this disease All 7 carcinomas (one woman had bilateral disease) contained 1 to 9 karyotypically related as well as unrelated clones, unevenly distributed among the tumor quadrants Two clonal chromosome abnormalities were recurrent: interstitial 3p deletions were found in 5 carcinomas, whereas del(1)(q42) was detected in another 2 tumors Both successfully analyzed metastatic lesions (one axillary lymph node and one metastasis in the subcutis) contained only one of several clones present in the primary tumor, thus exemplifying a reduction in overall karyotypic complexity during carcinoma spreading In the case with the cytogenetically abnormal lymph node, another karyotypically unrelated clone was found to invade locally in the surrounding breast; also, histological evidence of carcinoma infiltration was seen in these tissue samples In none of the other cases were clonal karyotypic changes found in macroscopically normal, extratumorous breast tissue We conclude that a large proportion of breast carcinomas are polyclonal with cytogenetically distinct cell subpopulations expanding within separate domains of the growing tumor Karyotypically disparate neoplastic cells may have different capacities to display malignancy-specific features (eg, to grow invasively and set up distant metastases) It is presumed that their synergetic action is required for the full-blown carcinoma phenotype

Risk of retinal detachment following cataract extraction: results from the International Cataract Surgery Outcomes Study.

Abstract: AIMS: To estimate the risk of retinal detachment (RD) following cataract extraction in Denmark, and to compare the risk with that following cataract extraction in the USA, and with that in a sample of Danish patients who did not have ocular surgery. METHODS: A sample was created from the administrative Danish Hospital Register and included 19,252 patients who underwent first eye cataract surgery between 1985 and 1987, and who were 50 years of age or older. The patients were then followed for 4-6 years using the register data. The design and definition of events were identical to the US National Study of Cataract Outcomes. RESULTS: In Denmark a 4 year cumulative risk of hospitalisation for RD of 0.93% (95% confidence interval (CI) 0.71-1.16) was observed following an extracapsular cataract extraction with a lens implant. A similar cumulative risk of RD was reported from the US study. Thus, no difference in outcomes concerning risk of RD was shown between Denmark and the USA. In a multivariate analysis younger age, male sex, and intracapsular cataract extraction were all associated with higher risk of postoperative RD. A reference group of 7636 people not undergoing any ocular surgery was created and the incidence of RD in this group was calculated. During the sixth year following cataract surgery, the incidence of RD in the cataract group was still 7.5 (95% CI 1.6-22.0) times higher than that observed in the reference group.

Sex and age specific assessment of genetic and environmental influences on body mass index in twins.

Abstract: OBJECTIVE: To assess, by use of a population based twin register, if there are sex and age differences in genetic and environmental influences on inter-individual variation in BMI among middle-aged and elderly subjects DESIGN: Twin study SUBJECTS: 1233 like-sex Danish twin pairs (213 MZ male, 322 DZ male, 280 MZ female, 418 DZ female pairs, age: 46-76 years, BMI: 15-45 kg/m2) MEASUREMENTS: Self-reported height and weight METHODS: Proportions of variance due to genetic and environmental factors were estimated from variance-covariance matrices using the structural equation model approach RESULTS: The most parsimonious explanation of the data was provided by a model that included additive genetic and non-shared environmental factors with the latter fixed to be equal across sex and age The heritability of BMI was estimated to be 046 for males aged 46-59 years, 061 for males aged 60-76 years, 077 for females aged 46-59 years and 075 for females aged 60-76 years CONCLUSION: As in earlier studies, the present one showed a high heritability of BMI throughout adult life, with genetic influences being mainly additive and environmental influences being non-shared, without evidence for major impact of genetic dominance or shared environment Most twin, family and adoption studies do not suggest important sex or age differences in magnitude of genetic effects, but we found that females had greater heritability than males, and that heritability in males increased by age

Inducible metabolism of fluoranthene by the opportunistic polychaete Capitella sp. I

Abstract: The polychaete Capitella sp. I has been described as an enrichment opportunist and is one of very few species able to thrive in highly organic sediments heavily contaminated with polycyclic aromatic hydrocarbons (PAH) and other organic pollutants. We examined 3 plausible explanations for the success of Capitella sp. 1: (1) worms prevent uptake of PAH across body surfaces, (2) worms take up PAH but metabolize them effectively to excretable forms, and (3) worms utilize PAH as a carbon source. We examined the uptake and depuration of sediment-associated fluoranthene by CapiteUa sp. 1 and measured the metabolic loss of ingested 3-[14C] fluoranthene into particulate (POC), dissolved (DOC) and CO2 pools. Our results show that Capitella sp. 1 accumulates fluoranthene from sediment in a concentration-dependent manner, but that body burdens begin to decrease after 2 d and are undetectable by 7 d despite continued exposure to sediment fluoranthene concentrations of up to 360 pg (g dry wt sediment)-' Worms pre-exposed to PAH-contaminated sediment for 1 wk excreted substantially more ingested fluoranthene as DOC than control worms (37 % vs 6 % after 20 h), and retained significantly less fluoranthene in their tissues at the end of the experiment than control worms (33 % vs 56 %). Our results are consistent with the hypothesis that Capitella sp. I metabolize fluoranthene, but contrary to our Hypotheses 1 and 3, worms did take up fluoranthene and did not appear to use it as a carbon source.

Randomized, placebo controlled trial of withdrawal of slow-acting antirheumatic drugs and of observer bias in rheumatoid arthritis

Abstract: Patients with rheumatoid arthritis, in stable treatment with methotrexate, penicillamine, or sulfasalazine, were randomized in a double-blind fashion either to continuation of their usual treatment or to placebo. 112 patients were included; 52 patients who refused participation had no more severe disease than the others. The patients felt worse on placebo than on active drug (p = 0.002). The mean differences in number of tender, painful and swollen joints after one month were 2.4 (p=0.08), 3.0 (p = 0.I2) and 2.2 (p = 0.03), respectively. Treatment failure occurred for 42 patients of whom 33 received placebo (p = 0.000,001). There was no difference in the severity of side effects (p=0.91). The patients guessed their treatment correctly more often than expected (p=0.02) because of the perceived effect. None of the two observers guessed better than chance, and there were no differences between the observers' evaluations of the joints. The effect of slow-acting antirheumatic drugs was unequivocal and no obser...

Simulations at conducting interfaces: Boundary conditions for electrodes and electrolytes

Abstract: The purpose of this paper is to derive a set of boundary conditions appropriate for simulating a wide variety of electrochemical and biophysical systems which are not necessarily electrically neutral. This is done by using the method of Green’s function, a generalization of the method of images, for solving the Poisson equation to provide boundary conditions for simulating electrochemical reactions involving ions confined between metal electrodes as well as ions in membranes enclosed between regions of aqueous electrolytes.

Quasiperiodicity in a detailed model of the peroxidase–oxidase reaction

Abstract: Quasiperiodicity in models of the peroxidase–oxidase reaction has previously been reported in ‘‘abstract’’ or phenomenological models which sacrifice chemical realism for tractability. In the present paper, we discuss how such behavior can arise in a detailed model (BFSO) of the reaction which has previously been shown to be consistent with experimental findings. We distinguish two types of quasiperiodic behavior. Regions of what we here refer to as ‘‘primary’’ quasiperiodicity are delimited by supercritical secondary Hopf bifurcations at one end of the relevant range of parameter values and by heteroclinic transitions at the other. Regions of so‐called ‘‘secondary quasiperiodicity’’ are delimited by supercritical Hopf bifurcations at both ends of the parameter range. The existence of a quasiperiodic route to chaos in a modified version of BFSO is also described. This paper emphasizes the experimental circumstances under which quasiperiodic dynamics may be detected in the lab and offers specific prescriptions for its observation.

Clonal chromosome aberrations in myeloid leukemia after styrene exposure

Abstract: Objectives The purpose of the study was to determine the risk of myeloid leukemia subclassified according to clonal chromosome aberrations in styrene-exposed workers. Methods A nested case-referent study was carried out on 19 myeloid leukemia patients, of which 12 showed clonal chromosome aberrations, and 57 referents ascertained within the Danish reinforced plastics industry and similar industries with no styrene exposure. Results A 2.5-fold increased risk for myeloid leukemia with clonal chromosome aberrations (95% confidence interval 0.2--25.0) was found among workers of companies with styrene exposure. Conclusions The results suggest that styrene may cause leukemia through a clastogenic effect. But similar findings could also have been found if the exposure was associated with a specific subtype of leukemia prone to develop the chromosome aberrations in question. Due to the few observations and the lack of detailed exposure data, additional studies are needed to corroborate or refute the present suggestive findings.

Severe hypothyroidism masquerading as renal impairment.

Abstract: A case of severe hypothyroidism in a 51-year old male is presented. The patient was especially complaining of weakness, stiffness and moderate pain in the proximal muscle groups together with rhinorrhea and nasal stenosis. Because of severely elevated S-creatine-kinase combined with reduced creatinine clearance and proteinuria, polymyositis with secondary glomerulopathy was suspected. Meanwhile, biopsies from skin, muscle, and kidney were normal. All symptoms disappeared 3 months after thyroid replacement therapy was initiated. S-TSH should be considered when evaluating patients with renal impairment of unknown etiology.