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Biomedical subjects

K Kontula

Publications and source records attributed to K Kontula.

At least 145 records · Page 8Linked to original sources
PubMed1989

The gene encoding human low-molecular weight insulin-like growth-factor binding protein (IGF-BP25): regional localization to 7p12-p13 and description of a DNA polymorphism.

The low-molecular weight insulin-like growth-factor binding protein (IGF-BP25) is synthesized by human liver, secretory endometrium and decidua, and is also present in human serum. It binds insulin-like growth factors IGF-I and IGF-II with high affinity, and is proposed to act as a paracrine regulator of cell growth. In situ hybridization studies with a cDNA encompassing the entire protein coding region of IGF-BP25 localized the gene to bands p12-p13 on chromosome 7. Southern blot analysis with the enzyme BglII revealed a common restriction fragment length polymorphism: the presence of the polymorphic BglII site results in the formation of two fragments 4.6 kb and 1.6 kb in size whereas its absence produces a single 6.2 kb fragment. The frequencies of the two alleles were 0.73 and 0.27, respectively. IGF-BP25 constitutes a useful genetic marker for the proximal short arm of chromosome 7.

Blotting, Southern↗
PubMed1989

Lymphocytic beta-adrenergic receptors in X-linked muscular dystrophy.

Lymphocytic beta-adrenoceptor levels, receptor binding affinity, lymphocytic basal and isoproterenol-stimulated cyclic AMP (cAMP) production and plasma catecholamine levels were studied in 49 patients with neuromuscular diseases and in 10 healthy subjects. Patients with X-linked muscular dystrophy (Duchenne, 13 patients; Becker, 4 patients) showed a significant reduction in lymphocytic beta-adrenoceptor densities (35.9 +/- 2.2 fmol/mg protein vs. 49.6 +/- 3.6 fmol/mg, controls; P less than 0.02), whereas the receptor levels for the patients with spinal muscular atrophy (15), polymyositis (10) and for Duchenne carriers (7) did not differ significantly from the corresponding levels for the control subjects. The reduction in the beta-adrenoceptor density was not correlated with the physical disability of the patients. Lymphocytic beta-adrenoceptor affinity (KD) and basal and isoproterenol-stimulated cAMP levels were all comparable to control subjects' values. Catecholamine levels showed mild inconsistent elevations in various patient groups. The results suggest that reduction in cellular beta-adrenoceptors is characteristic of X-linked muscular dystrophies. Its relationship to the basic gene defect is unknown.

Adolescent↗
PubMed1989

Effect of acute ethanol intake and hangover on the levels of plasma and urinary catecholamines and lymphocytic beta-adrenergic receptors.

To determine whether acute ethanol administration affects the function of the adrenergic system the concentrations of plasma catecholamines and cyclic AMP (cAMP), the level of lymphocytic beta-receptors, the concentration of basal and isoproterenol-stimulated lymphocytic cAMP and the excretion of urinary catecholamine metabolites were studied in six healthy men. These parameters were also measured during the hangover, both under resting condition and during an anaerobic ergometer exercise. Acute intake of ethanol (1.5 g/kg body weight) had no statistically significant effect either on plasma adrenaline and noradrenaline concentrations or beta-adrenergic receptor levels. Ethanol consumption did neither change the urinary excretion of catecholamine metabolites (homovanillic acid, normetanephrine, metanephrine, and 3-methoxyhydroxymandelic acid). Exercise was associated with a 6-10-fold elevation in plasma adrenaline and noradrenaline concentrations and with a two- to threefold elevation on beta-adrenergic receptor levels. This effect of exercise was not modified by preceding alcohol intake and resulting hangover. These preliminary findings suggest that acute alcohol intake does not significantly alter the concentration and functioning of human beta-adrenergic receptors.

Adult↗
PubMed1989

Finnish type of low density lipoprotein receptor gene mutation (FH-Helsinki) deletes exons encoding the carboxy-terminal part of the receptor and creates an internalization-defective phenotype.

A specific type of gene mutation affecting the LDL receptor has been found in many Finnish patients with familial hypercholesterolemia (FH). The mutant allele is characterized by a 9.5-kb deletion extending from intron 15 to exon 18. Molecular cloning and sequencing of a cDNA segment corresponding to the deleted allele indicated that the mutant receptor differs radically from the normal one because of loss of the domains encoded by exons 16, 17, and 18. The carboxy-terminal portion of the normal receptor, comprising the amino acids 750-839, has been replaced by an unrelated stretch of 55 amino acids. The mutant allele was found to occur in 23 (50%) of 46 unrelated FH patients with an established functional defect in the LDL receptor. In cultured fibroblasts from the FH patients with the 9.5-kb deletion, both receptor-mediated binding and internalization of 125I-LDL were lower than normal, the former, on average, by 25%, and the latter, on average, by 50%. This combined functional defect probably results from both impaired attachment and impaired internalization of the mutated receptor. It remains to be investigated whether this Finnish type of LDL receptor gene mutation, here designated FH-Helsinki, occurs in other ethnic groups.

Adult↗
PubMed1988

Primary structure of human insulin-like growth factor-binding protein/placental protein 12 and tissue-specific expression of its mRNA.

The low-molecular-mass insulin-like growth factor-binding protein (IGF-BP) and placental protein 12 (PP12) are identical proteins that are present in human serum, amniotic fluid, secretory endometrium and decidua. IGF-BP/PP12 is believed to act as an autocrine or paracrine regulator of cell growth. A cDNA clone encompassing the entire protein coding region of this protein was isolated from a human decidual cDNA library. The authenticity of the cDNA was verified by in vitro transcription/translation experiments and by the identity of the 10 N-terminal amino acids deduced for the mature peptide with those obtained by direct protein sequencing. The amino acid sequence indicates that pre-IGF-BP/PP12 consists of 259 amino acid residues. The putative signal peptide is 25 residues long, and the mature protein thus contains 234 amino acids and has a molecular mass of 25293 Da. The sequence is very cysteine-rich at the N-terminus after which there are regions of clustered Pro, Glu, Ser and Thr residues (so-called PEST regions), which exist in proteins with short half-lives. The amino acid sequence also includes an Arg-Gly-Asp tripeptide that may function as a cell recognition signal. The IGF-BP/PP12 gene encodes a single 1.6 kb mRNA species that is expressed in decidua, secretory endometrium, liver and a human hepatoma cell line (HepG2). Southern blot analysis suggests that there is a single IGF-BP/PP12 gene in the human genome.

Amino Acid Sequence↗
PubMed1988

Identification of a deletion in the LDL receptor gene. A Finnish type of mutation.

A cDNA probe for the low density lipoprotein (LDL) receptor gene was used to screen DNA samples from 52 unrelated Finnish patients with the heterozygous form of familial hypercholesterolemia (FH) and 51 healthy controls. Southern blot analysis using the restriction enzyme PvuII revealed an abnormal 11 kb (kilo base-pair) restriction fragment in 16 (31%) of the patients but none of the controls. A more detailed restriction enzyme analysis of the DNA from patients revealed a mutation which apparently is due to an 8 kb deletion extending from intron 15 to exon 18 of the LDL receptor gene. Co-segregation of FH with the mutated gene was demonstrated in three families. These data are consistent with a 'founder gene effect' and support the assumption that recombinant DNA methods may have great impact on the diagnostics of FH in genetically homogeneous populations.

Adolescent↗
PubMed1988

XbaI and c/g polymorphisms of the apolipoprotein B gene locus are associated with serum cholesterol and LDL-cholesterol levels in Finland.

Several restriction fragment length polymorphisms (RFLPs) have been identified within or adjacent to the gene locus for apolipoprotein B (apo B), the major protein component of serum low density lipoprotein (LDL). One of these, detected with the restriction enzyme XbaI, has been suggested to be involved in the determination of serum lipid levels in some but not all populations. We determined the XbaI genotypes and serum lipoprotein levels of 176 apparently healthy unrelated Finns. Subjects homozygous (genotype X2X2) or heterozygous (genotype X1X2) for the presence of the XbaI restriction site within the apolipoprotein B gene (n = 113) had, on the average, an 11% higher serum total cholesterol (P = 0.01) level than those homozygous for the absence of this site (genotype X1X1, n = 63). In addition, the X2 allele was significantly associated with apo B(c), another allele reportedly associated with elevated serum cholesterol levels. The combined genotype (both X2 and apo B(c) alleles present) resulted in a greater elevation of total cholesterol (P = 0.004, when compared to subjects with neither allele) and LDL-cholesterol (P = 0.02) than the presence of either allele alone. The results suggest that both the XbaI and apo B(c/g) sites are in linkage disequilibrium with a functionally important DNA alteration within or adjacent to the apo B gene but the XbaI locus may be in stronger linkage disequilibrium.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Propranolol attenuates exercise-induced increment in human lymphocytic beta-adrenergic receptors.

The effect of peroral propranolol administration on the level of lymphocytic beta-adrenergic receptors was studied in six healthy volunteers using an acute exercise test. When no drug was used, a 15-min ergometer exercise period induced a significant increase in the receptor density (from 42 +/- 5 to 117 +/- 14 fmol/mg protein; mean +/- SEM), followed by a return to the pre-exercise level after a 1-hr rest. During propranolol administration (40 mg, three times daily), the basal receptor level (49 +/- 4 fmol/mg protein) did not change but the exercise-induced increment of the receptor density was significantly inhibited (peak value 79 +/- 5 fmol/mg protein, p less than 0.05). This effect could not be explained by direct competition for receptor binding sites by propranolol nor by differences in the plasma adrenalin and noradrenaline concentrations during the two tests. The fact that propranolol interferes with the normal adaptation of the beta-adrenergic receptor level to acute exercise may explain some of the adverse effects of beta-blocking drugs on physical performance.

Adult↗
PubMed1988

Aseptic necrosis of the femoral head during pregnancy.

Two patients are presented with rare aseptic osteonecrosis of the femoral head appearing during the last trimester of pregnancy. Both patients suffered from increasing pain in one hip joint, beginning about one month before parturition. Radiographs demonstrated local osteoporotic changes of the femoral head on the painful side. Needle aspiration of the hip joint yielded a scant amount of clear, sterile synovial fluid and gave prompt relief of pain in both cases. The patients' history did not demonstrate any predisposing factors to osteonecrosis other than pregnancy. Treatment comprised omission of weight-bearing on the affected lower extremity for a month or two. The patients had completely recovered one year postpartum, and radiographs were normal.

Adult↗
PubMed1987

DNA polymorphisms of apolipoprotein A-I/C-III and insulin genes in familial hypertriglyceridemia and coronary heart disease.

Two DNA polymorphisms adjacent to the apolipoprotein A-I/C-III and insulin genes have been suggested to be associated with hypertriglyceridemia and increased risk of coronary heart disease. Using cloned apolipoprotein A-I and insulin gene probes, we determined the genotypes of 39 subjects from six different kindreds with familial clustering of hypertriglyceridemia, 20 additional unrelated subjects with hypertriglyceridemia, 39 patients with angiographically confirmed coronary heart disease (CHD) and 61 normolipemic control subjects. The S2 allele bearing an additional SstI restriction site in the apo A-I/C-III complex was found in 16% of healthy controls, 23% of patients with CHD and 62% (P less than 0.001 when compared to controls) of unrelated subjects with hypertriglyceridemia. Among CHD patients the S2 allele was present in 6 out of 14 hypertriglyceridemic patients but only 3 out of 25 normotriglyceridemic patients (P less than 0.05). The S2 allele was present in 64% of subjects from kindreds with hypertriglyceridemia but this allele did not determine the occurrence of hyperlipidemia. The frequencies of the large size or U allele of the polymorphic DNA region flanking the 5' end of the insulin gene in CHD patients (33%) and in controls (24%) were not significantly different. Neither of the polymorphisms studied was associated with changes in serum LDL or HDL cholesterol levels in patients with CHD or unrelated subjects with hypertriglyceridemia. The data suggest that, at least in the Finnish population, the S2 allele of the apolipoprotein A-I/C-III gene complex may serve as a genetic marker for hypertriglyceridemia, whereas both DNA polymorphisms studied are probably useless in determining individual risks of atherosclerosis.

Adult↗
PubMed1987

Plasma concentrations and receptor binding of RU 486 and its metabolites in humans.

Using Chromosorb chromatography and HPLC, we measured the plasma concentrations of RU 486, and its monodemethylated (RU 42633), didemethylated (RU 42848) and alcoholic nondemethylated (RU 42698) metabolites up to 72 h following oral ingestion of 100 mg of RU 486 by five female volunteers. The peak plasma level of RU 486 (4.5 mumol/l) occurred within 1 h after ingestion of the compound; at this point significant amounts of the metabolites were also present in the plasma. After the initial redistribution within 6 h the plasma concentrations of RU 486 and three of its metabolites measured remained stable for 24 h. Concentrations of the monodomethylated metabolite exceeded those of the parent steroid during the time period measured, whereas the concentrations of the didemethylated and alcoholic metabolites were lower than those of RU 486, but still notable. At 72 h the concentrations of all the four steroids were still in the micromolar range. The relative binding affinities of these metabolites to human endometrial and myometrial progesterone receptors as well as to human placental glucocorticoid receptors were determined in vitro. The affinity of RU 486 for the human uterine progesterone receptor (Kd = 1.3 X 10(-9) M for RU 486) was higher than that of progesterone but lower than that of ORG-2058, a potent synthetic progestin. The relative binding affinities of the monodemethylated, alcoholic and didemethylated metabolites to the progesterone receptor were 21, 15 and 9%, respectively, compared with the parent compound RU 486; each was lower than that of progesterone (43%). RU 486 had an approx. 4-fold higher relative binding affinity to the glucocorticoid receptor than dexamethasone. Interestingly, the relative binding affinities of the metabolites studied to the human glucocorticoid receptor exceeded those of dexamethasone or cortisol. Compared with the parent compound RU 486, they were 61, 48 and 45% for the monodemethylated, alcoholic and didemethylated metabolites, respectively; each was higher than that of dexamethasone (23%). The affinity of dexamethasone to the human glucocorticoid receptor was 1.6 X 10(-9) M. These data indicate that the pool of certain metabolites of RU 486 may contribute to a significant extent to the antiprogestagenic (23-33%) and even greater extent to the antiglucocorticoid (47-61%) effects of RU 486.

Binding, Competitive↗
PubMed1987

Beta-adrenergic receptors of human lymphocytes in physically active and immobilized subjects: characterization by a polyethylene glycol precipitation assay.

To investigate the role of physical conditioning in the regulation of cellular beta-adrenergic responsiveness in man, a simple and accurate method for the determination of lymphocytic beta-adrenergic receptors was developed and subsequently utilized for the characterization of these receptors in subjects with varying degrees of physical fitness. This method combines the advantages of the use of [125I]iodocyanopindolol as the radioligand and polyethylene glycol (PEG) precipitation for the separation of bound and unbound radioligand. The assay is quick and easy to perform and allows several samples to be processed simultaneously. The concentration of beta-adrenergic receptors in lymphocytic membrane particulates in 16 healthy subjects was 58 +/- 4 fmol/mg protein (mean +/- SEM) and the Kd of the interaction between [125I]iodocyanopindolol and the receptor was 4 X 10(-11) mol/l. The receptor level was similar in both sexes. As compared with the controls, the cellular concentration of beta-adrenergic receptors was higher in eight regularly competing long-distance runners (73 +/- 4 fmol/mg protein; p less than 0.025), whereas the corresponding receptor level in six sprinters (62 +/- 9 fmol/mg protein) did not differ from that of controls. The concentration of lymphocyte beta-adrenergic receptors in seven patients undergoing supine immobilization for weeks because of neck fracture or dislocation showed a wide range from 44 to 155 fmol/mg protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗