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S Lindstedt

Publications and source records attributed to S Lindstedt.

At least 37 records · Page 2Linked to original sources
PubMed1993

Human 4-hydroxyphenylpyruvate dioxygenase. Primary structure and chromosomal localization of the gene.

We report the primary structure of 4-hydroxyphenylpyruvate dioxygenase [4-hydroxyphenyl-pyruvate:oxygen oxidoreductase (hydroxylating, decarboxylating)]. The work is based on the isolation of cDNA clones from human liver lambda gt11 libraries. Several overlapping clones covering the coding sequence were characterized. In parallel, peptides from four different digests of the purified protein were analysed for their amino-acid sequence. These peptide sequences covered 86% of the cDNA-derived amino-acid sequence. This gives the sequence for a polypeptide of 392 amino acids with a calculated molecular mass of 44.8 kDa. There is more than 80% identity between the human and the pig enzymes and also between these enzymes and the F antigen from rat and the two allelic forms of this antigen from mouse. The enzyme has 53% conserved amino acids and 27% identical amino acids in common with 4-hydroxyphenylpyruvate dioxygenase from Pseudomonas sp. P.J. 874 and 52% conserved and 28% identical residues, with a protein from Shewanella colwelliana. At the C-terminus there is 61% identity between the seven proteins. These results indicate that these proteins are all 4-hydroxyphenylpyruvate dioxygenases. The identity of the C-terminus makes this part of the molecule a candidate for a functional role in the catalytic process. At conserved positions in all seven enzymes, there are two tyrosine residues and three histidine residues, i.e. amino acids which have been implicated as ligands for iron in 2-oxoacid-dependent dioxygenases. The gene encoding the enzyme was localized to chromosome 12q14-->qter by Southern-blot analysis of human-rodent somatic-cell hybrids.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1993

Peripheral neuropathy as the presenting feature of tyrosinaemia type I and effectively treated with an inhibitor of 4-hydroxyphenylpyruvate dioxygenase.

A 21 month old girl presented with a short history of frequent falls and a right sided foot drop. She went on to suffer recurrent episodes of distal weakness in her arms and legs with hyporeflexia. Electrophysiological studies were consistent with inflammatory demyelinating polyradiculoneuropathy (IDP) and treatment with corticosteroids appeared to lead to an improvement. However, the development of hypertension, evidence of tubulopathy, and hepatomegaly led to re-evaluation. A diagnosis of type I tyrosinaemia was made, based on increased urinary excretion of succinylacetone and decreased activity of fumarylacetoacetase in her cultured skin fibroblasts. A low tyrosine diet did not prevent life-threatening exacerbations of neuropathy but intravenous haemarginate appeared to aid her recovery from one exacerbation. An immediate improvement in strength was seen after starting treatment with 2-(2-nitro-4-trifluoro-methyl-benzoyl)-1,3-cyclohexanedione (NTBC), an inhibitor of 4-hydroxy-phenylpyruvate dioxygenase. A liver transplant was performed but the patient died of immediate postoperative complications. Tyrosinaemia needs to be considered in a child with recurrent peripheral neuropathy because (i) the signs of liver disease and renal tubular dysfunction may be subtle; (ii) acute exacerbations may be life threatening; (iii) specific forms of treatment are available.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1993

Adrenocortical carcinoma--diagnostic and therapeutical implications.

OBJECTIVE: To evaluate the results of treatment of a consecutive series of patients with adrenocortical carcinoma who presented during the six year period 1985 to 1991. DESIGN: Open study. SETTING: Departments of Surgery, Pathology, Endocrinology, and Clinical Chemistry, Sahlgren Hospital, Göteborg, Sweden. SUBJECTS: 10 consecutive patients, two with recurrent and eight with primary adrenocortical carcinoma. INTERVENTIONS: All patients were treated surgically. Two required preoperative embolisation of the tumour vessels to facilitate excision of particularly large tumours, and eight were given adjuvant treatment with mitotane (o,p'-DDD). RESULTS: At a median follow up of 1.5 years (range 3 months, to 21 years) 6 patients were alive with no radiological or biochemical signs of disease; 2 were alive, but with signs of recurrence (at 3 months and 6 years, respectively); and two had died of their disease (at 4 and 8 months, respectively). For the past two years all patients have had their urinary steroid profiles monitored by gas chromatography and mass spectrometry to detect recurrence of the tumour at the earliest possible stage. CONCLUSION: Operation is the treatment of choice for patients with adrenocortical carcinoma, particularly stages I-III. The role of mitotane as adjuvant treatment can be evaluated only in multicentre studies.

Adrenal Gland Neoplasms↗
PubMed1993

Swedish obese subjects (SOS)--an intervention study of obesity. Baseline evaluation of health and psychosocial functioning in the first 1743 subjects examined.

This part of an on-going intervention trial analyses impacts of obesity on psychosocial factors and health. The study sample comprised 800 obese men (BMI > or = 34 kg/m2) and 943 women (BMI > or = 38 kg/m2) ranging in age from 37 to 57 years. All participants completed standardized health-related quality of life measures, a validated obesity-specific eating inventory and study-specific questionnaires on current and past health status, use of medical care and medications, socioeconomic status, dietary habits, physical activity habits, weight history and familial history of obesity. Chronic patients and population samples were used as reference. The obese reported distinctly poorer current health and less positive mood states than the reference subjects, women being worse than men. Anxiety and/or depression on a level indicating psychiatric morbidity were more often seen in the obese and again women reported more affliction than men. Furthermore, the average poor mental well-being was worst than in chronically ill or injured patients, such as rheumatoid, cancer survivors and spinal cord injured persons. Predictors of perceived health and psychosocial functioning could be discerned using a comprehensive system of statistical analyses (16-28% explained variance). A background of both somatic and psychiatric morbidity was decisive for the health and psychosocial functioning in the obese; joint symptoms and angina pectoris dominated among somatic variables. Physical inactivity was the most prominent of traditional risk factors. The number of dieting attempts and body image were important weight correlates. Our results provide further evidence to the effect that severe obesity is a crippling condition.

Adult↗
PubMed1992

Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase.

Liver transplantation is the only effective treatment for hereditary tyrosinaemia type I (McKusick 276700). We have treated one acute and four subacute-chronic cases with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27), to prevent the formation of maleylacetoacetate and fumarylacetoacetate and their saturated derivatives. The oral daily dose was 0.1-0.6 mg/kg. The excretion of succinylacetoacetate and succinylacetone decreased from 15-103 mmol/mol creatinine to the detection limit or slightly above (ie, to 20-150 mumol/mol creatinine). The concentration of succinylacetone in plasma decreased from 5.8-43 mumol/l to the detection limit (0.1 mumol/l) over 2-5 months of treatment. The almost complete inhibition of porphobilinogen synthase in erythrocytes was abolished and the excretion of 5-aminolevulinate decreased to within or slightly above the reference range. The concentration of alpha-fetoprotein decreased in four patients to 1.3-7.5% of initially high values over 6-8 months. Improved liver function was reflected by normal concentrations of prothrombin complex and in decreased activities of alkaline phosphatase and gamma-glutamyltransferase in serum. Computed tomography revealed regression of hepatic abnormalities in three patients. One patient developed rickets 6 months before treatment and had excreted high concentrations of markers of tubular dysfunction--after 3 weeks of treatment, this excretion had disappeared. No side-effects were encountered. Inhibition of 4-hydroxyphenylpyruvate dioxygenase may prevent the development of liver cirrhosis and abolish or diminish the risk of liver cancer. Normalisation of porphyrin synthesis will eliminate the risk of porphyric crises. This type of treatment may thus offer an alternative to liver transplantation in hereditary tyrosinaemia.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1992

Characterization of 4-hydroxyphenylpyruvate dioxygenase. Primary structure of the Pseudomonas enzyme.

The primary structure of Pseudomonas 4-hydroxyphenylpyruvate dioxygenase was determined. Sequence degradation of the intact protein and of peptides from three different digests of the carboxymethylated protein established a 357-residue polypeptide chain with a free alpha-amino group. Hydroxylamine cleavage at a single Asn-Gly sequence was useful. Comparisons with known structures in data banks revealed no close relationship with other characterized proteins. The human enzyme has a related composition, suggesting that also the eukaryotic form belongs to this protein type, but with a blocked N-terminus like in many other eukaryotic intracellular proteins. Secondary structure predictions suggest an alpha/beta mixed structure, fairly typical of globular proteins, without long segments of hydrophobicity or charge, although a region in the middle of the C-terminal third of the subunit appears to have the most extreme properties. A ferric centre, correlating with enzyme activity and absorbance at 595 nm, has previously been assigned to tyrosinate coordination. The Tyr and His distributions, and the position of a single Cys residue, all suggest a few likely sites, outside the C-terminal segment, for this centre.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1992

Mitochondrial ATP-synthase deficiency in a child with 3-methylglutaconic aciduria.

We report the finding of mitochondrial ATP-synthase deficiency in a child with persistent 3-methylglutaconic aciduria. The child presented in the neonatal period with severe lactic acidosis, which was controlled by Na-HCO3 and glucose infusions. During the 1st y of life, there were several episodes of lactic acidosis precipitated by infections or prolonged intervals between meals. The excretion of lactate in urine was variable, but there was a persistent high excretion of 3-methylglutaconic acid. The activity of 3-methylglutaconyl-CoA hydratase in fibroblasts was normal. The child had a hypertrophic cardiomyopathy and magnetic resonance images revealed hypoplasia of corpus callosum. The gross motor and mental development was retarded, but there were no other neurologic signs. Investigation of muscle mitochondrial function at 1 y of age revealed a severe mitochondrial ATP-synthase deficiency (oligomycin-sensitive, dinitrophenol-stimulated Mg2+ ATPase activity: 27 nmol x min-1 x (mg protein)-1, control range 223-673 nmol x min-1 x (mg protein)-1. The mitochondrial respiratory rate was low and tightly coupled. The respiratory rate was normalized by the addition of an uncoupler. Low Mg2+ ATPase activity was also demonstrated by histochemical methods. Morphologic examination revealed ultrastructural abnormalities of mitochondria. There was no deletion of mitochondrial DNA. The sequences of the ATP synthase subunit genes of mitochondrial DNA were in accordance with published normal sequences.

Acidosis, Lactic↗
PubMed1991

Serum cobalamins in the elderly: a longitudinal study of a representative population sample from age 70 to 81.

In a representative population sample (n = 973) born 1901-1902 and examined at the ages of 70, 75, 79, and 81, the change in serum cobalamins with increasing age was studied by trend analysis using values obtained in single individuals at all four examinations. In subsamples without definable disorders, the mean annual decline was: among men 3.4 pmol/l (p less than 0.05), among women 3.2 pmol/l (n.s.). The decline was possibly more pronounced among individuals with low and intermediate concentrations. The health-related lower reference limits (the 2.5 percentile values of subsamples without definable disorders) did not differ significantly between sexes and age groups, but low concentrations or ongoing cobalamin medication became more common with advancing age. The results indicate a slight fall in serum cobalamins between age 70 and 81 but do not call for age-related lower reference limits.

Aged↗
PubMed1989

Carnitine deficiency induced by pivampicillin and pivmecillinam therapy.

Short-term administration of pivampicillin and pivmecillinam resulted in a reduction of serum carnitine concentration and an increase in excretion of acylcarnitine in urine. These changes persisted for more than ten days after cessation of therapy. In seven girls on long-term treatment with a mixture of pivampicillin and pivmecillinam the mean total serum carnitine concentration fell to 15% (7-27%) of pretreatment values. The acylcarnitine fraction was 11-57% of total carnitine, compared with less than 2% before treatment. Muscle carnitine concentrations in two girls treated with the antibiotics for 22 and 30 months were only 10% of the mean reference value. These concentrations in serum and muscle are in the range encountered in patients with carnitine deficiencies of other aetiologies in which life-threatening metabolic crises may arise. The risk of adverse effects from prodrugs that give rise to pivalic acid should be seriously considered, particularly in patients under metabolic stress.

Adolescent↗
PubMed1989

Transport of carnitine into cells in hereditary carnitine deficiency.

Carnitine uptake has been studied in fibroblasts from a case of hereditary carnitine deficiency and in relatives. There was no evidence for carrier-dependent uptake in cells from the patient. The mother and probably the healthy sister had an impaired uptake. The results show that the defect in this form of carnitine deficiency is an inability to establish a concentration gradient over the cell membrane.

Biological Transport↗
PubMed1989

Hydroxylation of aspartic acid in domains homologous to the epidermal growth factor precursor is catalyzed by a 2-oxoglutarate-dependent dioxygenase.

3-Hydroxyaspartic acid and 3-hydroxyasparagine are two rare amino acids that are present in domains homologous to the epidermal growth factor precursor in vitamin K-dependent plasma proteins as well as in proteins that do not require vitamin K for normal biosynthesis. They are formed by posttranslational hydroxylation of aspartic acid and asparagine, respectively. The first epidermal growth factor-like domain in factor IX (residues 45-87) was synthesized with aspartic acid in position 64, replacing 3-hydroxyaspartic acid. It was used as substrate in a hydroxylase assay with rat liver microsomes as the source of enzyme and reaction conditions that satisfy the requirements of 2-oxoglutarate-dependent dioxygenases. The synthetic peptide stimulated the 2-oxoglutarate decarboxylation in contrast to synthetic, modified epidermal growth factor (Met-21 and His-22 deleted and Glu-24 replaced by Asp) and synthetic peptides corresponding to residues 60-71 in human factor IX. This indicates that the hydroxylase is a 2-oxoglutarate-dependent dioxygenase with a selective substrate requirement.

Amino Acid Sequence↗
PubMed1989

The population study of women in Gothenburg 1980-81--the third phase of a longitudinal study. Comparison between participants and non-participants.

A representative population sample comprising 1,462 women was studied in Gothenburg, Sweden in 1968-69, and a third follow-up study was carried out in 1980-81. The participation rates in the baseline study and during the follow-up studies were high. In 1980-81 women in two new age strata, aged 26 and 38, were added. Women who had moved to or from Gothenburg during the study period were not found to differ from those who were living in Gothenburg during the total study period, while there were a few differences of statistical significance between refusers and participants in 1980-81. The mortality among initial refusers was about doubled compared to that of those who participated in the baseline study.

Adult↗