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Biomedical subjects

O Simell

Publications and source records attributed to O Simell.

At least 181 records · Page 10Linked to original sources
PubMed1988

Lysinuric protein intolerance mutation is not expressed in the plasma membrane of erythrocytes.

We measured mediated fluxes of L-lysine and L-ornithine across the plasma membrane of erythrocytes from control subjects and patients homozygous for the lysinuric protein intolerance (LPI) mutation. We found no differences in net uptake or efflux of cationic amino acids in control and LPI cells, contrary to our findings in cultured skin fibroblasts. We conclude that expression of the LPI (y+) transport system for cationic amino acids varies between tissues and that measurements of fluxes in erythrocytes cannot be used for diagnosis of LPI.

Adult↗
PubMed1988

Venous thrombosis associated with lupus anticoagulant and anticardiolipin antibodies.

We describe deep vein thrombosis associated with lupus anticoagulant and anticardiolipin antibodies in three children aged 10 to 14 years. One of them also had arterial thromboses. None of the patients had systemic lupus erythematosus when the thrombosis first occurred, but one fulfilled the criteria for systemic lupus erythematosus 3 years later. At presentation all had symptoms suggestive of pulmonary embolism and evidence of an autoimmune disease: Addison's disease in one, anti-DNA or antinuclear antibodies in all three, and a positive Coombs' test in two. Two of the three gave a false-positive test for syphilis. In the patient with systemic lupus erythematosus recurrent thrombocytopenia and severe haemolytic anaemia necessitated splenectomy. A child should be tested for lupus anticoagulant or anticardiolipin antibody if venous or arterial occlusion occurs without a known predisposing cause, or if there is pulmonary embolism or symptoms or laboratory findings suggestive of a connective tissue disease.

Adolescent↗
PubMed1988

Morphology, yield and functional integrity of islet-like cell clusters in tissue culture of human fetal pancreata obtained after different means of abortion.

Morphology, yield and function were studied in cultured islet-like cell clusters (ICC) from 140 human fetal pancreata obtained after abortions of different types performed at 11-23 weeks of gestation (12 by hysterotomy, 75 by mechanical dilation and extraction, and 53 induced with prostaglandin). After collagenase digestion and culture in medium supplemented with 10% human serum, up to 2000 free-floating ICC were formed from a single pancreas. Randomly scattered insulin- and glucagon-immunoreactive cells were found in the medullary part of the ICC. More than 100 ICC developed in 100% of the hysterotomies and 87% of the mechanical abortions, but in only 53% of the prostaglandin-induced abortions. Insulin and glucagon levels in the culture medium decreased rapidly during the first 7 days of culture, but then remained stable for at least 31 days. The hysterotomy-derived ICC responded to 10 mmol/l theophylline plus 20 mmol/l glucose by a 12.2 +/- 3.1 (SEM, N = 7) fold increase in insulin release, as compared with a 5.4 +/- 0.9 fold response of the prostaglandin ICC (N = 16; P less than 0.02). Despite the low proportion of B-cells, (pro)insulin biosynthesis accounted for 10% of the total protein biosynthesis in low (2 mmol/l) glucose. In conclusion, the yield and viability of the ICC were clearly better, if prostaglandin had not been used for the induction of the abortion.

Abortion, Induced↗
PubMed1988

Effects of growth hormone and insulin-like growth factor I on endocrine function of human fetal islet-like cell clusters during long-term tissue culture.

The effects of recombinant human growth hormone (GH, 1 micrograms/ml) and insulin-like growth factor I (IGF-I, 200 ng/ml) on the production of insulin and glucagon by human fetal islet-like cell clusters (ICCs) were studied in tissue culture. ICCs were derived after collagenase digestion and culture of pancreases from 16 fetuses (mean gestational age 15.6 wk). The ICCs were cultured with or without GH or IGF-I for 7 or 31 days. Basal rates of insulin and glucagon production were not altered by GH during the first 17 days of culture, but the release of both hormones was increasingly augmented by GH during the last 2 wk of culture (131% increase in insulin and 85% in glucagon compared with controls). ICCs cultured for 7 days in the presence of GH secreted more insulin when incubated for 120 min in 20 mM than in 2 mM glucose (2.1-fold response, P less than .05), whereas ICCs maintained in basal medium did not respond to glucose. GH had no effect on DNA and insulin content or insulin biosynthesis. Exogenous IGF-I caused a 28% suppression of insulin release (P less than .05) between days 4 and 10 of culture but induced a 49% increase in the mean secretion rate during the last week (days 25-31, P less than .01). Glucagon release was not affected by exogenous IGF-I. In contrast to GH, exogenous IGF-I induced a twofold increase in the DNA content of the 7-day--cultured ICCs. However, insulin biosynthesis and release were markedly suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Culture Techniques↗
PubMed1988

Maturation of insulin response to glucose during human fetal and neonatal development. Studies with perifusion of pancreatic isletlike cell clusters.

The insulin release in response to glucose was studied in perifused isletlike cell clusters (ICCs) obtained from human fetal or neonatal pancreases at various stages of development: 12-15 gestational wk (n = 7), 17-20 wk (n = 13), 22.5 wk (n = 2, 1 diabetic pregnancy), and 26-44 wk (n = 6, postnatal samples). The ICCs were stimulated with 20 mM glucose and subsequently with 10 mM theophylline plus 20 mM glucose as a viability test. Insulin release increased to a detectable level (greater than 0.1 pg.ICC-1.min-1) during glucose stimulation in four of seven of the youngest fetuses. At 17-20 wk the basal rate of insulin release had increased by at least 15-fold above the detection limit (1.5 pg.ICC-1.min-1), and glucose promoted a sustained monophasic response that was on the average 1.6-fold higher than the basal level. The response was significant (P less than .05) in 9 of 13 experiments. With postnatal ICC (gestational age 26-44 wk), an early-phase peak response was observed in 5 of 6 experiments. The mean rates of insulin release after 5-12 min of glucose stimulation were 4.8 pg.ICC-1.min-1 in newborn infants and 2.1 pg.ICC-1.min-1 in 17- to 20-wk fetuses. The corresponding mean relative insulin responses (stimulated to basal) were 3.3-fold (range 1.1-7.5) and 1.6-fold (1.0-3.4), respectively (P less than .05, Mann-Whitney U test). The results suggest that the human fetal pancreas is already responsive to glucose during the first half of gestation, but the biphasic insulin release does not start to mature until the postnatal phase.

Cells, Cultured↗
PubMed1987

Food and guar decrease absorption of trimethoprim.

Absorption of trimethoprim suspension 3 mg/kg has been studied in 12 healthy adult volunteers when given alone, with food or with food and guar, using a randomised Latin-squares study design. Serum and urine trimethoprim concentrations were followed for 24 h. The mean peak serum concentration was higher when fasting subjects were treated (mean: 2.35, 1.84 and 1.97 micrograms/ml for the fasting, food and food + guar groups, respectively; ANOVA p less than 0.001 for the difference between fasting and non-fasting values). The times of the peak serum concentrations did not differ. Food ingestion decreased the area under the curve by 22.2%, as did food + guar. For maximal efficacy trimethoprim should be administered between meals.

Absorption↗
PubMed1987

The effect of ACTH therapy on serum dehydroepiandrosterone, androstenedione, testosterone and 5 alpha-dihydrotestosterone in infants.

Serum concentrations of dehydroepiandrosterone (DHEA), androstenedione, testosterone, 5 alpha-dihydrotestosterone and cortisol were measured in 10 infants (age 5-22 months) before, during and after 6-weeks of ACTH therapy for infantile spasms. During therapy, their mean DHEA concentrations increased 2.3-fold, androstenedione 12.3-fold, testosterone 2.7-fold, 5 alpha-dihydrotesterone 2.5-fold and cortisol 2.9-fold compared to pre-therapy values. Serum dehydroepiandrosterone sulphate (DHEA-S) concentrations were also increased during ACTH therapy above the normal prepubertal range. Three days after the cessation of ACTH treatment, all androgens had returned to the pre-therapy level. We conclude: At least in pharmacologic doses ACTH alone stimulates adrenal androgen secretion in infants, excluding the necessity of a separate adrenal androgen stimulating hormone.

Adrenocorticotropic Hormone↗
PubMed1987

Lysinuric protein intolerance mutation is expressed in the plasma membrane of cultured skin fibroblasts.

Lysinuric protein intolerance (LPI) is an autosomal recessive phenotype consistent with impaired transport of cationic amino acids at the basolateral membrane of intestinal and renal epithelia. On the assumption that the basolateral membrane of epithelial cells and plasma membrane of parenchymal cells are functional analogues, we studied transport of cationic amino acids by cultured skin fibroblasts from LPI and control subjects matched for age, sex, and site of biopsy. We measured Na+-independent transport of radiolabeled lysine, arginine, ornithine, and homoarginine on system y+, the carrier with preference for cationic amino acids, and leucine transport on system L (as the internal control). LPI cells had increased net uptake of cationic amino acids (nmol/mg of protein) relative to leucine. LPI cells also maintained increased steady-state intracellular pools of cationic amino acids. Neither increased metabolic utilization nor increased pool size were responsible for high uptake of cationic amino acids in LPI cells. We then measured trans-stimulated efflux of homoarginine as a specific test of system y+ activity. Homoarginine efflux was significantly impaired in LPI cells (P less than 0.05), whereas leucine efflux was similar in LPI and control cells. Percent trans-stimulation of homoarginine efflux was 1.0 +/- 0.5% in homozygous LPI cells, 10 +/- 0.5% in heterozygous cells, and 22 +/- 0.5% in control cells indicating a gene-dosage effect. The LPI mutation affects system y+ asymmetrically, selectively impairing efflux in fibroblast plasma membrane. To our knowledge, this appears to be the first demonstration that the skin fibroblast can be used to study a corresponding transport defect in intestinal and renal membranes.

Amino Acids, Diamino↗
PubMed1987

Beneficial effects of palatable guar and guar plus fructose diets in diabetic children.

This randomized cross-over study evaluates the effects of extended, guar and guar + fructose diets on the metabolic balance of children with insulin-dependent diabetes mellitus (IDDM). We studied 22 children; mean age 12.2 years, mean duration of diabetes 4.4 years. The diet was supplement for three weeks with guar in palatable form (5% of daily carbohydrate intake) and with guar + fructose (1 g of fructose/kg body weight, max 30 g/d) for another three weeks. A control group (8 children, mean age 12.3, duration of diabetes 4.3 years) followed the same experimental protocol without guar supplementation. The metabolic balance was assessed by glucosuria index (per cent of tests with less than 1% glucosuria from all urine tests) and measurements of red cell glycohaemoglobin A1c (HbA1c). Serum total and HDL-cholesterol, C-peptide, pancreatic and enteroglucagon were also measured. HbA1c decreased during guar (p less than 0.001) and guar + fructose diet (p less than 0.001). The glucosuria index improved (p less than 0.02) and the serum total cholesterol concentration decreased (p less than 0.02) during the experimental guar diets. Guar in acceptable form and quantity in the diet appears to improve metabolic control of diabetic children.

Adolescent↗
PubMed1987

Cystine fluxes across the isolated jejunal epithelium in cystinuria: increased efflux permeability at the luminal membrane.

In cystinuria, renal clearance of cystine frequently exceeds creatinine clearance, suggesting net cystine secretion; and absorption of the (di)basic amino acid is impaired at the luminal membrane of the jejunal and probably also renal tubular epithelium. We studied cystine transport in vitro in jejunal biopsy specimens of eight subjects with homozygous cystinuria and in 12 controls. Cellular/medium cystine distribution ratio was reduced in cystinuria (1.36 +/- 0.36 versus 5.36 +/- 0.61, p less than 0.001). Cystine influx across the luminal membrane was normal (221 +/- 48 versus 261 +/- 79 pmol X h-1 cm-2). Measurement of transepithelial cystine fluxes showed net absorption in controls but secretion in cystinuria. Apparent permeability coefficients were close to normal in cystinuria except that the efflux permeability at the luminal membrane was significantly increased (0.839 +/- 0.22 versus 0.186 +/- 0.12 X h-1 cm-2), and, accordingly, at the luminal membrane, the influx over efflux permeability ratio was small (1.01 +/- 0.50 versus 4.95 +/- 0.80, p less than 0.001). The defect in cystine transport in cystinuria is apparently not caused by decreased influx but increased efflux of cystine (or cystine) from the cell to the lumen across the luminal membrane.

Adult↗
PubMed1987

Gyrate atrophy of the choroid and retina. The ocular disease progresses in juvenile patients despite normal or near normal plasma ornithine concentration.

Hyperornithinemia disappeared in three children with Gyrate atrophy of the choroid and retina during a low-arginine diet for 3 to 4 1/2 years. Because of the young age of the patients, we had an exceptional opportunity to follow the progression of the disease during this period. Despite the excellent biochemical control, electroretinographic changes progressed in two patients, and the chorioretinal atrophy progressed steadily in all the patients throughout the diet. Dark adaptation and color vision remained stable. In these patients, the normo-ornithinemia has not been able to halt the progression of the chorioretinal degeneration.

Amino Acid Metabolism, Inborn Errors↗
PubMed1986

Celiac disease in insulin-dependent diabetes mellitus.

Jejunal biopsy was performed without selection in 110 of 201 children with insulin-dependent diabetes mellitus; serum reticulin antibody, antigliadin antibody by enzyme-linked immunosorbent assay, and serum IgA were studied in all 201 children. Seven children had severe jejunal villous atrophy, giving a prevalence of celiac disease of at least 3.5%. Of the serum tests used, antigliadin antibody with ELISA was the most sensitive. Four patients adhered to a gluten-free diet, and their jejunal structure became normal; three had subsequent gluten provocation, and the jejunal mucosa relapsed in every one. Six had HLA-B8 and -DR3 antigens, and one had B15 and -DR4 phenotypes. In most patients, a gluten-free diet had little effect on insulin dosage, urinary excretion of glucose, or serum level of hemoglobin A1.

Antibodies↗
PubMed1986

Abnormal immune responses during hypozincaemia in acrodermatitis enteropathica.

Immune responses were characterized in six patients with acrodermatitis enteropathica during a break in zinc supplementation and during resupplementation. During hypozincaemia the number of T-cells increased but the amount of B-cells and the responses of T- and B-lymphocytes to phytohaemagglutinin, concanavalin A-, pokeweed mitogen- and Staphylococcus aureus stimulations in vitro were subnormal. Cell counts and stimulation results both normalized when serum zinc values improved. One patient was anergic to tuberculin while showing signs of acrodermatitis enteropathica; she converted during supplementation whereas the others were continuously positive. Three females had antibodies against nuclear antigens and slightly elevated serum IgE concentrations; these values were not affected by the break in supplementation. Four females were continuously rheumatoid factor positive. Our findings suggest that zinc deficiency is closely associated with impaired immune responses in patients with acrodermatitis enteropathica, and laboratory markers of autoimmunity occur in a considerable number of the acrodermatitis enteropathica patients, irrespective of their zinc status.

Acrodermatitis↗
PubMed1986

Disturbed calcium and phosphate homeostasis during treatment with ACTH of infantile spasms.

Kidney histology of five infants who died during or immediately after treatment with adrenocorticotrophic hormone (ACTH) showed severe tubular and interstitial calcinosis. We therefore studied serum concentrations of calcium, inorganic phosphate, and parathormone, serum activities of alkaline phosphatase, and urinary excretion of calcium, inorganic phosphate, and cyclic adenosine monophosphate (cAMP) in 16 other children with infantile spasms before, during, and after 6 weeks of treatment with ACTH. During the treatment the following observations were made: hypocalcaemia developed in three infants; the mean daily urinary excretion of calcium in the group increased threefold and seven infants had hypercalciuria; the excretion of phosphate increased but its tubular reabsorption remained stable; and in most infants serum parathormone and urinary cAMP excretion increased, and in four infants they increased to supranormal concentrations. These biochemical changes were reversible in most infants. Radiographs suggested loss of bone mass by 3-4 weeks of treatment, with rapid recovery after treatment. We conclude that infants treated with ACTH for infantile spasms are at risk of suffering disturbance in calcium and phosphate homeostasis, which leads to nephrocalcinosis.

Adrenocorticotropic Hormone↗
PubMed1986

Adrenocortical hyporesponsiveness after treatment with ACTH of infantile spasms.

The hypothalamic-pituitary-adrenocortical axis was studied in 10 infants before and during a six week period of treatment with adrenocorticotrophic hormone (ACTH) and three days and one and two weeks after its stopping. During the treatment 24 hour urinary cortisol excretion increased 20 to 350-fold (mean 100) above the basal value. Mean morning serum cortisol concentration, measured 24 hours after the preceding ACTH dose, did not increase. After the treatment mean urinary cortisol excretion was subnormal and mean morning serum cortisol concentration was below the pretreatment value. The mean serum cortisol response to a vasopressin test was reduced and shortened throughout the post-treatment observation period. The mean serum cortisol response to an intravenous ACTH test was not significantly different from the pretreatment response three days after treatment but was clearly reduced thereafter. At one and two weeks after treatment the basal concentrations of serum cortisol of one third of the patients and the post-ACTH concentrations of two thirds were subnormal. We conclude that in infants treatment with ACTH may cause adrenocortical hyporesponsiveness.

Adrenocorticotropic Hormone↗
PubMed1986

Waste nitrogen excretion via amino acid acylation: benzoate and phenylacetate in lysinuric protein intolerance.

Benzoate and phenylacetate improve prognosis in inherited urea cycle enzyme deficiencies by increasing waste nitrogen excretion as amino acid acylation products. We studied metabolic changes caused by these substances and their pharmacokinetics in a biochemically different urea cycle disorder, lysinuric protein intolerance (LPI), under strictly standardized induction of hyperammonemia. Five patients with LPI received an intravenous infusion of 6.6 mmol/kg L-alanine alone and separately with 2.0 mmol/kg of benzoate or phenylacetate in 90 min. Blood for ammonia, serum urea and creatinine, plasma benzoate, hippurate, phenylacetate, phenylacetylglutamine, and amino acids was obtained at 0, 120, 180, and 270 min. Urine was collected in four consecutive 6-h periods. Alanine caused hyperammonemia: maximum increase 107, 28-411 microM (geometric mean, 95% confidence interval); ammonia increments were nearly identical after alanine + benzoate (60, 17-213 microM) and alanine + phenylacetate (79, 13-467 microM) (NS). Mean plasma benzoate was 6.0 mM when extrapolated to the end of alanine + benzoate infusions; phenylacetate was 4.9 mM at the end of alanine + phenylacetate. Transient toxicity (dizziness, nausea, vomiting) occurred in four patients at the end of combined infusions, and we suggest upper therapeutic plasma concentrations of 4.5 mM for benzoate and 3.5 mM for phenylacetate. Benzoate and phenylacetate then decreased following first-order kinetics with t1/2S of 273 and 254 min, respectively. Maximal plasma hippurate (0.24, 0.14-0.40 mM) was lower than maximal phenylacetylglutamine (0.48, 0.22-1.06 mM, p = 0.008).(ABSTRACT TRUNCATED AT 250 WORDS)

Acylation↗