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Biomedical subjects

E Svensson

Publications and source records attributed to E Svensson.

At least 91 records · Page 5Linked to original sources
PubMed1992

Two missense mutations causing mild hyperphenylalaninemia associated with DNA haplotype 12.

The genetic defects responsible for most phenylketonuria (PKU) and hyperphenylalaninemia (HPA) cases are located in the phenylalanine hydroxylase (PAH) gene. Approximately 50-60 mutations have been reported in Caucasians and are reflected in a wide range of clinical severities. Most mutations are linked to specific haplotypes, as defined by eight polymorphic restriction sites in the PAH gene. We hypothesized that there is at least one mild mutation linked to haplotype 12 in the Swedish PKU/HPA population, since 7 of 8 patients carrying haplotype 12 had mild HPA. Sequence analysis revealed a C-to-G transversion at the second base of codon 322, resulting in a substitution of glycine for alanine, in four mutant haplotype 12 genes, and a G-to-A transition at the second base of codon 408, resulting in a substitution of glutamine for arginine, in another three mutant haplotype 12 genes. These mutations segregated with mutant haplotype 12 alleles in nuclear families but were not present on normal or other mutant alleles. Both mutations were tested in a eukaryotic expression system in which enzyme activities of different mutant PAH enzymes reflect the relative severities of the mutations, although these in vitro activities cannot be translated directly into in vivo hepatic activities. The A322G mutant PAH had about 75% and the R408Q mutant PAH about 55% of the wild-type PAH enzyme activity. These in vitro activities are the highest reported for mutant PAH enzymes produced in the same expression system.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Metabolism, Inborn Errors↗
PubMed1992

Multiple origins for phenylketonuria in Europe.

Phenylketonuria (PKU), a disorder of amino acid metabolism prevalent among Caucasians and other ethnic groups, is caused primarily by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). PKU is a highly heterogeneous disorder, with more than 60 molecular lesions identified in the PAH gene. The haplotype associations, relative frequencies, and distributions of five prevalent PAH mutations (R158Q, R261Q, IVS10nt546, R408W, and IVS12n1) were established in a comprehensive European sample population and subsequently were examined to determine the potential roles of several genetic mechanisms in explaining the present distribution of the major PKU alleles. Each of these five mutations was strongly associated with only one of the more than 70 chromosomal haplotypes defined by eight RFLPs in or near the PAH gene. These findings suggest that each of these mutations arose through a single founding event that occurred within time periods ranging from several hundred to several thousand years ago. From the significant differences observed in the relative frequencies and distributions of these five alleles throughout Europe, four of these putative founding events could be localized to specific ethnic subgroups. Together, these data suggest that there were multiple, geographically and ethnically distinct origins for PKU within the European population.

Europe↗
PubMed1991

Polymorphic DNA haplotypes at the phenylalanine hydroxylase locus and their relation to phenotype in Swedish phenylketonuria families.

The genetic heterogeneity at the phenylalanine hydroxylase (PAH) locus was studied in 88 families including 93 of the 105 children with phenylketonuria (PKU) or hyperphenylalaninemia (HPA) detected through the Swedish neonatal screening program from 1966 to the end of 1986. Haplotypes based on eight restriction fragment length polymorphisms (RFLPs) at the PAH locus could be constructed for 132 normal and 136 mutant alleles. The normal alleles were of 27 different RFLP haplotypes, 9 of which have not been described previously, but there was a dominance of a few haplotypes common to many European populations. The distribution of mutant alleles was significantly different from that in neighboring countries, even though over 90% of all mutant alleles were confined to six RFLP haplotypes, also prevalent in other European populations. Allele-specific oligonucleotide hybridization analysis for the Arg408 to Trp408 mutation and for the G to A splicing mutation in intron 12 showed exceptions to the previously reported linkage of these mutations to mutant haplotypes 2 and 3, respectively. Correlation of mutant alleles with clinical phenotypes pointed to the presence of at least two different mutations associated with each of six haplotypes. We argue that PKU/HPA in the Swedish population may be caused by at least 13 different mutations in addition to the 4 already identified. The theoretical informativity of RFLP analysis in heterozygote detection and prenatal diagnosis in PKU/HPA families was estimated at approximately 85%. Carrier detection could, in effect, be accomplished for 88% of the 56 healthy siblings in the families studied.

Alleles↗
PubMed1991

Synergic post-antibiotic effect of mecillinam, in combination with other beta-lactam antibiotics in relation to morphology and initial killing.

The synergic in-vitro post-antibiotic effect (PAE) of mecillinam, in combination with either ampicillin, aztreonam, ceftazidime or piperacillin, on a reference strain of Escherichia coli was evaluated by bioluminescence assay of bacterial ATP. Ampicillin, ceftazidime and mecillinam alone induced a concentration dependent PAE (greater than 3 h) on E. coli, whereas aztreonam and piperacillin alone induced a short (less than 1 h) non-dose dependent PAE. At most concentrations, the combination of mecillinam and ampicillin, aztreonam, ceftazidime or piperacillin induced longer PAEs on E. coli than the sum of the individual antibiotics' PAEs. Long PAEs were seen concomitantly with the presence of spheroplasts. In addition to the synergistic PAE, the decrease in colony counts and changes in ATP values after a 2 h exposure to mecillinam, in combination with the other beta-lactam antibiotics, were more prominent than the respective values after exposure to the individual antibiotics. The change in ATP was generally less pronounced than the decrease in colony counts. This could be due to lysis of spheroplasts on agar plates, leading to an over-estimation of the initial killing when assayed by viable counting. Mecillinam, which induced long PAEs on E. coli at almost all concentrations in this study, has a high affinity for penicillin binding protein 2 (PBP 2) and induced spheroplast formation at all concentrations. However, mechanisms other than the affinity for PBP 2 and spheroplast formation are involved in the PAE of beta-lactam antibiotics on Gram-negative bacteria; since the PAE was prolonged when mecillinam was combined with ampicillin, aztreonam, ceftazidime or piperacillin, which bind preferentially to PBP 1 and 3.

Adenosine Triphosphate↗
PubMed1990

Two mutations within the coding sequence of the phenylalanine hydroxylase gene.

Two previously unidentified mutations at the phenylalanine hydroxylase locus were found during a study of the relationship between genotype and phenotype in phenylketonuria and hyperphenylalaninemia. One mutation eliminates the BamHI site in exon 7 and the other eliminates the HindIII site in exon 11 of the phenylalanine hydroxylase gene. They were suspected because of deviating restriction fragment patterns and confirmed by amplification, via the polymerase chain reaction, of exon 7 and exon 11, respectively, followed by digestion with the appropriate restriction enzyme. Direct sequencing of amplified mutant exon 7 revealed a G/C to T/A transversion at the first base of codon 272, substituting a GGA glycine codon for a UGA stop codon. Direct sequencing of amplified mutant exon 11 revealed a deletion of codon 364, a CTT leucine codon. The exon 7 mutation can be expected to result in a truncated protein and the exon 11 mutation in the elimination of an amino acid in the catalytic region of the enzyme. A patient who is a compound heterozygote for these two mutations has classical phenylketonuria. It is concluded that each of the two mutations leads to a profound loss of enzymatic activity. The segregation of these mutations with disease alleles in 4 and 2 families, respectively, supports the hypothesis that multiple mutations at the phenylalanine hydroxylase locus explain the variable phenylalanine tolerance in patients with phenylalanine hydroxylase deficiency.

Alleles↗
PubMed1989

Effect of viscosity on the pharmacokinetics and biological response to intranasal desmopressin.

The effect of viscosity on the nasal absorption and biological response to desmopressin was studied in humans. Nasal solutions of desmopressin with and without the addition of 0.25% (w/v) methylcellulose were administered by a precompression nasal spray pump to 10 volunteers. Plasma levels of desmopressin were assayed by radioimmunoassay and the biological response was measured by determination of the antihemophilia factors (Factor VIII and von Willebrand factor). The results showed that the addition of methylcellulose produced a more sustained and slower absorption, with a longer time to maximum plasma concentration (tmax). However, the areas under the plasma concentration-time curve were not different, indicating a similar total bioavailability. The biological response showed a similar effect. Peak Factor VIII activity was not different, but the presence of methylcellulose produced a slower onset of activity. These findings indicate that although the addition of a viscous agent to nasal formulations may produce a more sustained effect, it delays the onset of activity and no enhancement is achieved in the total bioavailability.

Administration, Intranasal↗
PubMed1988

Effect of viscosity on particle size, deposition, and clearance of nasal delivery systems containing desmopressin.

The effect of methylcellulose on the particle size distribution and dosing accuracy of pre-metered spray pump devices containing the peptide desmopressin (DDAVP) was investigated. Using gamma scintigraphy, the influence of methylcellulose on the in vivo deposition and clearance of nasal solutions administered as drops or spray was studied. Nasal formulations containing 0, 0.25, and 0.50% methylcellulose produced a dose-related increase in average particle size from 51 micron for 0% to 81 and 200 micron for 0.25 and 0.50% methylcellulose, respectively. However, no effect was observed on the dosing accuracy of the spray pumps. The addition of methylcellulose gave a more localized in vivo deposition in the anterior region of the nasal vestibule. However, the net effect on clearance followed a biphasic pattern which showed an increase in retention time for the 0.25% solution, followed by a decrease in retention time and faster clearance time for the 0.50% solution. The spray delivers well-controlled doses to the nasal cavity. These findings show that viscosity, particle size, and nasal clearance are important parameters in the design of nasal delivery systems.

Administration, Intranasal↗
PubMed1988

Neonatal screening for congenital adrenal hyperplasia using 17-hydroxyprogesterone assay in filter paper blood spots.

Screening of infants for congenital adrenal hyperplasia (CAH) using filter paper blood samples collected on the 5th day of life was performed with a radioimmunoassay for 17-hydroxyprogesterone without extraction with organic solvents. A total of 153,000 newborns were screened and 12 cases of CAH were detected (1:12,800). With recall levels related to gestational age, the recall rate could be lowered to 0.05%.

17-alpha-Hydroxyprogesterone↗
PubMed1988

Military flight experience and sympatho-adrenal activity.

Urine excretion levels of adrenaline (A) and noradrenaline (NA) were determined, and achievement, commitment to the task, difficulty, risk, activation, and tension were rated after the preparation or planning and after the performance of 245 missions by 21 attack pilots. The catecholamine excretion levels increased and the ratio NA/A decreased as a function of condition (lesson, preparation, and mission). From a confirmatory factor analysis it was found that the catecholamine reactivity during preparation (values corrected for basal activity) was affected by the perceived challenge potential of the mission. The reference A activity covaried with the total A reactivity during the missions, i.e., the higher the basal excretion levels the higher the reactions to the missions. A positive relationship was found between former flight experience (hours) and mean activity of A. The rate of increase of A was potentiated by nicotine. Potential explanations of the increase of A are discussed.

Adolescent↗
PubMed1987

Effects of exposure to vehicle exhaust on health.

Exposure to combustion engine exhaust and its effect on crews of roll-on roll-off ships and car ferries and on bus garage staff were studied. The peak concentrations recorded for some of the substances studied were as follows: total particulates (diesel only) 1.0 mg/m3, benzene (diesel) 0.3 mg/m3, formaldehyde (gasoline and diesel) 0.8 mg/m3, and nitrogen dioxide (diesel) 1.2 mg/m3. The highest observed concentration of benzo(a)pyrene was 30 ng/m3 from gasoline and diesel exhaust. In an experimental study volunteers were exposed to diesel exhaust diluted with air to achieve a nitrogen dioxide concentration of 3.8 mg/m3. Pulmonary function was affected during a workday of occupational exposure to engine emissions, but it normalized after a few days with no exposure. The impairment of pulmonary function was judged to have no appreciable, adverse, short-term impact on individual work capacity. In the experimental exposure study, no effect on pulmonary function was observed. Analyses of urinary mutagenicity and thioether excretion showed no sign of exposure to genotoxic compounds among the occupationally exposed workers or among the subjects in the experimental study.

Air Pollutants↗
PubMed1984

The development of simple acoustic reaction time in normal children.

Normative data on the simple acoustic reaction time were obtained from 56 children without neurological or psychiatric symptoms aged between four and 14 years, and the results were compared with those for an adult reference group. Mean reaction times declined precipitously from 465 msec at age five to 190 msec at 15 years. The relationship between reaction time and age during childhood can be described by a linear equation in a log-log system. The adult level is achieved at 16 years.

Acoustic Stimulation↗
PubMed1980

Mood effects of diazepam and caffeine.

Changes in mood after administration of Diazepam and Caffeine were analyzed. Six aspects were studied: pleasantness, activation, extraversion, calmness, social orientation and control. In addition to this check list, mood ratings using magnitude estimation of selected adjectives were obtained. It was found that Diazepam decreased feelings of activation and extraversion and increased calmness. Caffeine had no clear effects on the check list, but on the magnitude estimation scale some effects opposite to those of Diazepam were observed. Men reported a higher degree of pleasantness than women after administration of Diazepam. No differences in heart rate were found. Few distinct scale values were utilized on the magnitude estimation scale and the discriminative power was found to be larger for the check list than for the magnitude estimation scale.

Adult↗
PubMed1980

Mood effects of alcohol.

Doses of 0.41, 0.63, and 0.85 g alcohol/kg body weight were administered using a double-blind Latin square design to subjects who made mood ratings at seven points in time during 3h subsequent to administration. The subjects felt more euphoric and extraverted and less tense at mainly the highest dose levels. Lower dose levels tended to induce more negative feelings. Frequent consumers of alcohol derived greater affective benefit than rare drinkers. Intercorrelations between ratings of subjective intoxication and mood variables indicated that the meaning of the variable "subjective intoxication" was different for the three dose levels and for different points in time.

Adult↗
PubMed1978

Light inhibits the production of alternariol and alternariol monomethyl ether in Alternaria alternata.

Alternaria alternata (Fr.) Keissler, grown in drop culture, produced alternariol and alternariol monomethyl ether in late growth phase. Production was almost completely inhibited when the fungal cultures were exposed to white light (180 W/m2), although mycelial dry weight was not significantly affected. The fungus was most sensitive to light during the exponential growth phase. Twelve hours of light exposure was sufficient to decrease significantly the production of the secondary metabolites. In light the fungus produced a red-brown pigment of unknown nature.

Alternaria↗