Search PubMed⌕ Search

Biomedical subjects

B Persson

Publications and source records attributed to B Persson.

At least 19 recordsLinked to original sources
PubMed2001

Biochemical defects in 11-cis-retinol dehydrogenase mutants associated with fundus albipunctatus.

Mutations in the gene encoding 11-cis-retinol dehydrogenase (RDH5; EC ) are associated with fundus albipunctatus, an autosomal recessive eye disease characterized by stationary night blindness and accumulation of white spots in the retina. In addition, some mutated alleles are associated with development of cone dystrophy, especially in elderly patients. The numbers of identified RDH5 mutations linked to fundus albipunctatus have increased considerably during recent years. In this work, we have characterized the biochemical and cell biological properties of 11 mutants of RDH5 to understand the molecular pathology of the disease. All RDH5 mutants showed decreased protein stability and subcellular mislocalization and, in most cases, loss of enzymatic activity in vitro and in vivo. Surprisingly, mutant A294P displays significant enzymatic activity. Cross-linking studies and molecular modeling showed that RDH5 is dimeric, and co-expression analyses of wild-type and mutated alleles showed that the mutated enzymes, in a trans-dominant-negative manner, influenced the in vivo enzymatic properties of functional variants of the enzyme, particularly the A294P mutant. Thus, under certain conditions, nonfunctional alleles act in a dominant-negative way on functional but relatively unstable mutated alleles. However, in heterozygous individuals carrying one wild-type allele, the disease is recessive, probably due to the stability of the wild-type enzyme.

Alcohol Oxidoreductases↗
PubMed2001

Variations and constant patterns in eukaryotic MDR enzymes. Conclusions from novel structures and characterized genomes.

Medium-chain dehydrogenases/reductases (MDR) alcohol dehydrogenases exhibit multiple forms through a number of gene duplications. A crucial duplication was the one leading from the glutathione-dependent formaldehyde dehydrogenase line to the liver alcohol dehydrogenase (ADH) lines of vertebrates, the first duplication of which can now be further positioned at early vertebrate times. Similarly, screening of MDR forms in recently completed eukaryotic genomes of Caenorhabditis elegans and Drosophila melanogaster suggest that the MDR family may constitute a moderately sized protein family centered around a limited number of enzyme activities of five different structural types.

Alcohol Dehydrogenase↗
PubMed2001

Human type 10 17 beta-hydroxysteroid dehydrogenase: molecular modelling and substrate docking.

17 beta-hydroxysteroid dehydrogenases catalyze the oxidoreduction of hydroxy/oxo groups at position C17 of steroid hormones, thereby constituting a prereceptor control mechanism of hormone action. At present, 11 different mammalian 17 beta-hydroxysteroid dehydrogenases have been identified, catalyzing the cell- and steroid-specific activation and inactivation of estrogens and androgens. The human type 10 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD-10) is a multifunctional mitochondrial enzyme that efficiently catalyzes the oxidative inactivation at C17 of androgens and estrogens. However, it also mediates oxidation of 3 alpha-hydroxy groups of androgens, thereby reactivating androgen metabolites. Finally, it is involved in beta-oxidation of fatty acids by catalyzing the L-hydroxyacyl CoA dehydrogenase reaction of the beta-oxidation cycle. These features and expression profiles suggest a critical role of 17 beta-HSD-10 in neurodegenerative and steroid-dependent cancer forms. Since no three-dimensional structure of 17 beta-HSD-10 is available, homology modelling was carried out to understand the molecular basis of these substrate specificities. The structure obtained displays the properties of a one-domain, alpha/beta fold enzyme of the SDR family. The active site is located within a large, hydrophobic cleft, which forms optimal contacts with the different steroid surfaces. The data provide explanations for the substrate specificities toward the various classes of sex steroid hormones. The model is suitable to explore substrate and inhibitor characteristics that may be used in the development of novel strategies in the treatment of degenerative or malignant diseases.

17-Hydroxysteroid Dehydrogenases↗
PubMed2001

Cadmium exposure and end-stage renal disease.

Environmental exposure to cadmium may cause kidney damage and tubular proteinuria. We investigated the relationship between low-level cadmium exposure and end-stage renal disease (ESRD), indicated by renal replacement therapy (RRT), in a Swedish population environmentally or occupationally exposed to cadmium. Based on records of all persons in the population previously or presently employed in cadmium-battery production or residing in cadmium-polluted areas near the battery plants, we defined exposure as high (occupational), moderate (domicile < 2 km from a plant), low (domicile 2 to 10 km from a plant), or no exposure (domicile > 10 km from a plant). Comprehensive data were available for all individuals undergoing RRT since 1978. The annual incidence of RRT increased from 41 per million in the age group 20 to 29 years to 243 per million in the age group 70 to 79 years and was greater in a priori-defined populations with cadmium exposure. Adjusting for age and sex gave an increased Mantel-Haenszel rate ratio (MH-RR) of 1.8 (95% confidence interval [CI], 1.3 to 2.3) for RRT in the cadmium-exposed population compared with the unexposed group; the MH-RR was even higher for women (MH-RR, 2.3; 95% CI, 1.5 to 3.5). Directly age-standardized rate ratios for RRT and cadmium exposure increased from 1.4 (95% CI, 0.8 to 2.0) in the low-exposure group to 1.9 (95% CI, 1.3 to 2.5) and 2.3 (95% CI, 0.6 to 6.0) in the moderate- and high-exposure groups, respectively. We conclude that exposure to occupational or relatively low environmental levels of cadmium appears to be a determinant for the development of ESRD.

Adolescent↗
PubMed2001

A case-referent study of cancer mortality among sulfate mill workers in Sweden.

OBJECTIVES: To investigate whether workers in Swedish sulfate mills have an increased risk of death from certain malignancies that have previously been linked to the pulping process. METHODS: Subjects of the study (n=2480) were men aged 40-75 at death during 1960-89 in the parishes surrounding four sulfate mills. Exposure assessment was based on information from the personnel files in the mills- 35% of the subjects were recognised there, and work categories were created. RESULTS: Among all sulfate mill workers, the odds ratio (OR) (90% confidence interval (90% CI)) for death from lung cancer was 1.6 (1.1 to 2.3), pleural mesotheliomas 9.5 (1.9 to 48), brain tumours 2.6 (1.2 to 5.3), and liver or biliary tract cancer 2.3 (1.0 to 5.2). There was an increased mortality from leukaemia among workers in the soda recovery plant (5.9 (2.6 to 13)) and bleaching plant and digester house (2.8 (1.0 to 7.5)). CONCLUSIONS: Sulfate mill workers were at increased risk of dying from lung cancer and pleural mesotheliomas, probably due to exposure to asbestos. Increased risks of brain tumours and cancers of the liver or biliary tract were also found but the aetiology is not obvious.

Adult↗
PubMed2001

Cloning of a novel growth hormone-regulated rat complementary deoxyribonucleic acid with homology to the human alpha1B-glycoprotein, characterizing a new protein family.

A sex-specific secretion of GH prevails in the rat. This has bearings on the expression of target genes, particularly in the liver. We have used suppressive subtractive hybridization to search for genes expressed in response to the female-characteristic, near-continuous secretion of GH. One sequence was particularly abundant among the obtained clones. After isolation of the corresponding full-length complementary DNA using rapid amplification of complementary DNA ends, it was found to be homologous to the human alpha1B-glycoprotein. Sequence comparisons suggest that the human alpha1B-glycoprotein and the rat homolog are members of a new family of proteins, of which at least four additional forms were found in the databases of human and mouse expressed sequence tags. In situ hybridization confirmed the female-specific expression, and by RNase protection analysis a liver-specific expression was indicated. Up-regulation of the messenger RNA by continuous exposure to GH, but not to the male-characteristic intermittent exposure, was demonstrated in hypophysectomized rats and in cultured primary hepatocytes.

Androgen-Insensitivity Syndrome↗
PubMed2000

Prediction of amyloid fibril-forming proteins.

In Alzheimer's disease and spongiform encephalopathies proteins transform from their native states into fibrils. We find that several amyloid-forming proteins harbor an alpha-helix in a polypeptide segment that should form a beta-strand according to secondary structure predictions. In 1324 nonredundant protein structures, 37 beta-strands with > or =7 residues were predicted in segments where the experimentally determined structures show helices. These discordances include the prion protein (helix 2, positions 179-191), the Alzheimer amyloid beta-peptide (Abeta, positions 16-23), and lung surfactant protein C (SP-C, positions 12-27). In addition, human coagulation factor XIII (positions 258-266), triacylglycerol lipase from Candida antarctica (positions 256-266), and d-alanyl-d-alanine transpeptidase from Streptomyces R61 (positions 92-106) contain a discordant helix. These proteins have not been reported to form fibrils but in this study were found to form fibrils in buffered saline at pH 7.4. By replacing valines in the discordant helical part of SP-C with leucines, an alpha-helix is found experimentally and by secondary structure predictions. This analogue does not form fibrils under conditions where SP-C forms abundant fibrils. Likewise, when Abeta residues 14-23 are removed or changed to a nondiscordant sequence, fibrils are no longer formed. We propose that alpha-helix/beta-strand-discordant stretches are associated with amyloid fibril formation.

Alzheimer Disease↗
PubMed2000

Consensus predictions of membrane protein topology.

We have explored the possibility that consensus predictions of membrane protein topology might provide a means to estimate the reliability of a predicted topology. Using five current topology prediction methods and a test set of 60 Escherichia coli inner membrane proteins with experimentally determined topologies, we find that prediction performance varies strongly with the number of methods that agree, and that the topology of nearly half of all E. coli inner membrane proteins can be predicted with high reliability (>90% correct predictions) by a simple majority-vote approach.

Bacterial Proteins↗
PubMed2000

The N-terminal domain of 5-lipoxygenase binds calcium and mediates calcium stimulation of enzyme activity.

Human 5-lipoxygenase (5-LO) is a key enzyme in the conversion of arachidonic acid into leukotrienes and lipoxins, mediators and modulators of inflammation. In this study, we localized a stimulatory Ca(2+)-binding site to the N-terminal region of the enzyme. Thus, in a (45)Ca(2+) overlay assay, the N-terminal 128 amino acids of recombinant human 5-LO (fused to glutathione S-transferase) bound radioactive calcium to about the same extent as intact 5-LO. The glutathione S-transferase fusion protein of the C-terminal part of 5-LO (amino acids 120-673) showed much weaker binding. A model of a putative 5-LO N-terminal domain was calculated based on the structure of rabbit reticulocyte 15-LO. This model resembles beta-sandwich C2 domains of other Ca(2+)-binding proteins. Comparison of our model with the C2 domain of cytosolic phospholipase A(2) suggested a number of amino acids, located in the loops that connect the beta-strands, as potential Ca(2+) ligands. Indeed, mutations particularly in loop 2 (N43A, D44A, and E46A) led to decreased Ca(2+) binding and a requirement for higher Ca(2+) concentrations to stimulate enzyme activity. Our data indicate that an N-terminal beta-sandwich of 5-LO functions as a C2 domain in the calcium regulation of enzyme activity.

Amino Acid Sequence↗
PubMed2000

Molecular basis for differential substrate specificity in class IV alcohol dehydrogenases: a conserved function in retinoid metabolism but not in ethanol oxidation.

Mammalian class IV alcohol dehydrogenase enzymes are characteristic of epithelial tissues, exhibit moderate to high K(m) values for ethanol, and are very active in retinol oxidation. The human enzyme shows a K(m) value for ethanol which is 2 orders of magnitude lower than that of rat class IV. The uniquely significant difference in the substrate-binding pocket between the two enzymes appears to be at position 294, Val in the human enzyme and Ala in the rat enzyme. Moreover, a deletion at position 117 (Gly in class I) has been pointed out as probably responsible for class IV specificity toward retinoids. With the aim of establishing the role of these residues, we have studied the kinetics of the recombinant human and rat wild-type enzymes, the human G117ins and V294A mutants, and the rat A294V mutant toward aliphatic alcohols and retinoids. 9-cis-Retinol was the best retinoid substrate for both human and rat class IV, strongly supporting a role of class IV in the generation of 9-cis-retinoic acid. In contrast, 13-cis retinoids were not substrates. The G117ins mutant showed a decreased catalytic efficiency toward retinoids and toward three-carbon and longer primary aliphatic alcohols, a behavior that resembles that of the human class I enzyme, which has Gly(117). The K(m) values for ethanol dramatically changed in the 294 mutants, where the human V294A mutant showed a 280-fold increase, and the rat A294V mutant a 50-fold decrease, compared with those of the respective wild-type enzymes. This demonstrates that the Val/Ala exchange at position 294 is mostly responsible for the kinetic differences with ethanol between the human and rat class IV. In contrast, the kinetics toward retinoids was only slightly affected by the mutations at position 294, compatible with a more conserved function of mammalian class IV alcohol dehydrogenase in retinoid metabolism.

Alanine↗
PubMed2000

Interaction between hammerhead ribozyme and RNA substrates measured by a surface plasmon resonance biosensor.

Dynamic interactions between hammerhead ribozymes and RNA substrates were measured using the surface plasmon resonance (SPR) technology. Two in vitro transcribed substrates (non-cleavable and cleavable) were immobilised on streptavidin-coated dextran matrices and subsequently challenged with non-related yeast tRNA or two hammerhead ribozymes, both of which had previously been shown to exhibit functional binding and cleavage of complementary target RNAs. The target-binding domain of one of the ribozymes was fully complementary to a 16-ribonucleotide stretch on the immobilised substrates, while the other ribozyme had a nine-ribonucleotide complementarity. The two ribozymes could readily be differentiated with regard to affinity. Cleavage could be measured, using the ribozyme with full target complementarity to the cleavable substrate. In contrast, the ribozyme with lower affinity lacked cleavage activity. We suggest that SPR will be useful for investigations of ribozyme-substrate interactions.

Base Pairing↗
PubMed2000

Pulmonary surfactant protein B: a structural model and a functional analogue.

Surfactant proteins B and C (SP-B and SP-C), together with phospholipids, are important constituents of pulmonary surfactant and of preparations used for treatment of respiratory distress syndrome (RDS). SP-B belongs to the saposin family of homologous proteins, which include other lipid-interacting proteins, like the membranolytic NK-lysin. SP-B, in contrast to other saposins, is hydrophobic and a disulfide-linked dimer, and its mechanism of action is not known. A model of the three-dimensional structure of one SP-B subunit was generated from the structure of monomeric NK-lysin determined by nuclear magnetic resonance, and the SP-B dimer was formed by joining two subunits via the intersubunit disulfide bond Cys48-Cys48'. After energy minimization, intersubunit hydrogen bonds/ion pairs were formed between the strictly conserved residues Glu51 and Arg52, which creates a central non-polar region located in between two clusters of positively charged residues. The structural features support a function of SP-B in cross-linking of lipid membranes. Mixtures of phospholipids, an SP-C analogue and polymyxin B (which cross-links lipid vesicles but is structurally unrelated to SP-B) exhibit in vitro surface activity which is indistinguishable from that of analogous mixtures containing SP-B instead of polymyxin B. This suggests an avenue for identification of SP-B analogues that can be used in synthetic surfactants for treatment of RDS.

Amino Acid Sequence↗
PubMed2000

Comparative study using oral solutions of bambuterol once daily or terbutaline three times daily in 2-5-year-old children with asthma. Bambuterol Multicentre Study Group.

The aim of this study was to compare safety and efficacy of bambuterol hydrochloride (10 mg) oral solution administered once daily in the evening with terbutaline sulphate (0.075 mg/kg body weight) oral solution administered three times daily in 2-5-year-old children with asthma. There were two treatment groups: (2/3) of the patients received bambuterol and (1/3) received terbutaline. The study was double-blind, randomized, and of a parallel group design, and it lasted for 3 months after a 2-week run-in period. The primary objective was to evaluate safety (adverse events, and changes in blood pressure, pulse rate, hematology, and clinical chemistry parameters). Plasma concentrations of terbutaline and/or bambuterol were also measured. Evaluation of efficacy (diary card data) was a secondary objective. A total of 155 patients (range, 2-6 years; 3 patients were 6 years old at randomization) were treated with the study drugs; 104 patients received bambuterol and 51 patients received terbutaline. Both treatments showed a good safety profile with respect to clinical and laboratory tests, and they were generally well tolerated. Reported adverse events were mild to moderate. There were no statistically significant differences between treatment groups in any of the efficacy variables (diary variables: peak expiratory flow (PEF), asthma symptoms, restlessness, other reported symptoms, use of inhaled bronchodilators, and nighttime awakenings). For morning PEF, the mean increase from run-in to treatment was 16.9 L/min in the terbutaline group and 23.3 L/min in the bambuterol group. For evening PEF, the mean increase was 20.2 L/min in the terbutaline group and 20.6 L/min in the bambuterol group. In conclusion, once-daily bambuterol is as safe and effective as terbutaline given three times daily. The study also confirmed that bambuterol has a 24-hr duration of action, and therefore its once daily administration, makes it a preferred bronchodilator agent. Pediatr Pulmonol. 2000:29:194-201.

Administration, Oral↗
PubMed2000

One-year safety study with bambuterol once daily and terbutaline three times daily in 2-12-year-old children with asthma. The Bambuterol Multicentre Study Group.

The aim of this study was to compare bambuterol oral solution (10 mg) administered once daily in the evening with terbutaline oral solution (0.075 mg/kg body weight) administered three times daily in 2-5-year-old children and to compare bambuterol tablets (10 mg or 20 mg) administered once daily in the evening with terbutaline tablets (2.5 mg) administered three times daily in 6-12-year-old children with asthma. The study was of an open, randomized, parallel-group design, and lasted 1 year. The primary objective was to evaluate safety (pulse rate, blood pressure, adverse events, hematology, and clinical chemistry). Plasma terbutaline concentrations were also measured. Evaluation of efficacy (FEV(1)) was a secondary objective. A total of 141 patients (83 boys, 58 girls) were randomized and treated with the study drugs, i.e., 43 patients in the terbutaline group (30 on oral solution and 13 on tablets) and 98 patients in the bambuterol group (62 on oral solution and 36 on tablets). A total of 11 patients discontinued the study: 3 were on terbutaline, and 8 were on bambuterol. There were no clinically important differences between treatment groups regarding pulse rate, or systolic or diastolic blood pressure. There were no clinically important findings in the laboratory tests (hematology and clinical chemistry). Both terbutaline and bambuterol were well-tolerated, and the reported adverse events were mostly mild or moderate. Mean steady state plasma terbutaline concentrations at the visits ranged between 8.0-11.5 nmol/L in the bambuterol tablet group and between 10.6-15.2 nmol/L in the terbutaline tablet group. The corresponding values in children on oral solution were 10.3-11.3 nmol/L in the bambuterol group and 7.5-9.7 nmol/L in the terbutaline group. FEV(1) measured in the 6-12-year-old children increased by more than 0.2 L in both treatment groups during the year in the study. In conclusion, bambuterol tablets or oral solution once daily and terbutaline tablets or oral solution three times daily showed a comparable and favorable safety profile.

Administration, Oral↗
PubMed2000

Bioinformatics in protein analysis.

The chapter gives an overview of bioinformatic techniques of importance in protein analysis. These include database searches, sequence comparisons and structural predictions. Links to useful World Wide Web (WWW) pages are given in relation to each topic. Databases with biological information are reviewed with emphasis on databases for nucleotide sequences (EMBL, GenBank, DDBJ), genomes, amino acid sequences (Swissprot, PIR, TrEMBL, GenePept), and three-dimensional structures (PDB). Integrated user interfaces for databases (SRS and Entrez) are described. An introduction to databases of sequence patterns and protein families is also given (Prosite, Pfam, Blocks). Furthermore, the chapter describes the widespread methods for sequence comparisons, FASTA and BLAST, and the corresponding WWW services. The techniques involving multiple sequence alignments are also reviewed: alignment creation with the Clustal programs, phylogenetic tree calculation with the Clustal or Phylip packages and tree display using Drawtree, njplot or phylo_win. Finally, the chapter also treats the issue of structural prediction. Different methods for secondary structure predictions are described (Chou-Fasman, Garnier-Osguthorpe-Robson, Predator, PHD). Techniques for predicting membrane proteins, antigenic sites and postranslational modifications are also reviewed.

Computational Biology↗
PubMed2000

Intrapartum tocolysis has no effect on fetal lactate concentration.

OBJECTIVE: To assess the fetal metabolic effects of intrapartum maternal tocolysis with terbutaline in the presence of fetal heart rate abnormalities, with a special emphasis on lactate concentration, in view of its potential use as a marker of fetal condition. DESIGN: Descriptive study. SETTING: Two labour wards, National University Hospital, Singapore, and Ostersund Hospital, Sweden. METHODS: Eight parturients with abnormal intrapartum fetal heart rate recordings were given bolus i.v. injection of 0.25 mg terbutaline and monitored both before and 20 minutes after treatment. RESULTS: Maternal venous glucose increased from 5.0 (0.9) (mean (SD)) to 5.6 (1.2) mmol/l (p=0.002) and fetal scalp blood glucose rose from 4.1 (1.8) to 4.7 (1.4) mmol/l (p=0.009) 20 minutes after the injection. No significant change was found in maternal or fetal lactate concentrations. CONCLUSION: Terbutaline tocolysis for "intrauterine resuscitation" does not affect fetal lactate concentration 20 minutes after treatment.

Acid-Base Equilibrium↗