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Biomedical subjects

O Simell

Publications and source records attributed to O Simell.

At least 217 records · Page 12Linked to original sources
PubMed1981

Lysinuric protein intolerance. Basolateral transport defect in renal tubuli.

In patients with an autosomal recessive diamino acid transport disorder, lysinuric protein intolerance (LPI), we measured plasma and urinary amino acids basally, and during intravenous infusion of citrulline at two rates. Compared with controls, the patients' plasma citrulline concentrations rose similarly, but urinary citrulline excretion increased excessively. Their plasma arginine and ornithine levels rose subnormally, but massive argininuria and moderate ornithinuria appeared. The excretion rates of the third diamino acid lysine and other amino acids remained practically unaltered, thus excluding mutual competition as the cause for the increases. The results suggest that (a) in the normal kidney reabsorption involves partial conversion of citrulline to arginine and ornithine (metabolic run-out), (b) in LPI, the diamino acid transport defect is located at the basolateral cell membrane of the renal tubules; this inhibits the efflux of arginine and ornithine, increasing their cellular concentration, which in turn inhibits the metabolic disposal of citrulline, and causes leakage of arginine, ornithine, and citrulline into the tubular lumen.

Adult↗
PubMed1981

Gyrate atrophy of the choroid and retina with hyperornithinemia: characterization of mutant liver L-ornithine:2-oxoacid aminotransferase kinetics.

Deficient activity of L-ornithine:2-oxoacid aminotransferase is associated with gyrate atrophy of the choroid and retina with hyperornithinemia, an autosomal recessive disease leading to blindness. Liver tissue from two patients contained trace activity of the enzyme. The Michaelis (Km) value of the mutant enzyme for ornithine was 200 mM, 50-fold higher than normal, but increasing the concentrations of alpha-oxoglutarate and pyridoxal 5'-phosphate to 10 times those giving maximal activity of the normal enzyme had no effect on the mutant enzyme. Substrate inhibition of the mutant could not be demonstrated at 1,000 mM ornithine concentration, whereas ornithine concentrations above 70 mM inhibited the normal enzyme. The data suggest that the abnormal L-ornithine:2-oxoacid aminotransferase in the two patients studied has an altered binding site for ornithine.

Adult↗
PubMed1981

Increase in thyroxine-binding globulin (TBG) in lysinuric protein intolerance.

The common occurrence of increased serum PBI concentration in patients with lysinuric protein intolerance (LPI) was elucidated by further studies. The reason was found to be an increase in the concentration of thyroid binding globulin (TBG), concomitantly with an increase in the binding capacity of TBG. The concentrations of serum thyroxine and triiodothyronine were elevated, whereas the free thyroxine index remained normal. The free triiodothyronine index was slightly increased. The binding capacity of thyroid hormone binding pre-albumin (TBPA) was significantly decreased. The concentrations of reverse triiodothyronine (3,3',5'-T3) and of 3,3'-diiodothyronine were normal. In all patients serum lactic acid dehydrogenase activities and ferritin concentrations were elevated. The reason for the almost constant increase in TBG remains obscure. It may be related to the primary disorder of LPI, a defect in diaminoacid transport.

Adolescent↗
PubMed1981

Age dependence of human plasma renin substrate.

Renin substrate (angiotensinogen) was measured with an assay employing exhaustive incubation of plasma with purified human kidney renin and radioimmunoassay of the angiotensin I (AI) generated. Plasma renin substrate concentration was higher at the age of 3 days (females: 2028 +/- 551, males: 1951 +/- 565 micrograms AI/l, mean +/- SD) than in age group 0-15 years (females: 1513 +/- 555, males: 1263 +/- 392 micrograms AI/l). Plasma renin substrate concentration at the age over 15 years (females: 1780 +/- 464, males 1752 +/- 321 micrograms AI/l) was higher than in children 0-15 years. Expectedly, high concentrations of plasma renin substrate were found in pregnant women at term (4127 +/- 1961 micrograms AI/l).

Adolescent↗
PubMed1980

Basolateral-membrane transport defect for lysine in lysinuric protein intolerance.

In lysinuric protein intolerance intestinal, hepatic, and renal diaminoacid transport is defective, causing malnutrition. In patients fed with lysylglycine plasma glycine increased normally, but lysine increased as poorly as with free lysine. This is the first demonstration of defective peptide absorption. The primary defect is suggested to be at the basolateral cell membrane.

Amino Acid Metabolism, Inborn Errors↗
PubMed1980

Lysinuric protein intolerance: a two-year trial of dietary supplementation therapy with citrulline and lysine.

In lysinuric protein intolerance, a disease resulting from an autosomal recessive disorder of diamino acid transport, citrulline, unlike arginine and lysine, is absorbed normally from the intestine. In 19 patients with LPI, the status after 2 years of treatment with citrulline or citrulline + lysine was compared with that during the preceding period of treatment with arginine. Administration of citrulline led to improved protein nutrition, as indicated by increases in daily protein intake, blood hemoglobin values, and plasma albumin and valine concentrations. Normal excretion of orotic acid indicated adequate urea cycle function. Seven of the nine stunted children had marked catch-up growth. Of four patients biopsied twice and having initially severe fatty degeneration of the liver, two had improved histology. However, hepato- and splenomegaly, and several biochemical abnormalities in the serum remained unchanged. Giving additional lysine did not enhance the favorable effect, but in some patients provoked abdominal cramps and diarrhea. Citrulline is the most valuable agent for treatment of LPI. Although not curative, it corrects the deficiency of the urea cycle intermediates and protects the patients from hyperammonemia and its consequences.

Adolescent↗
PubMed1980

Endogenous clearance rate and synthesis of alphafoetoprotein during and after blood exchange transfusion in hyperbilirubinaemic newborns.

Plasma alphafoetoprotein (AFP) concentration was monitored in 22 hyperbilirubinaemic infants during blood exchange transfusion at the age of 0-4 days, in order to determine the endogenous clearance rate and demonstrate possible postnatal synthesis of AFP. The rapid fall in plasma AFP during the transfusion to 19 +/- 4% (mean +/- S.D.) was followed by an increase to 81 +/- 15% of the initial concentration; only a 68% rise was expected after the establishment of a new equilibrium between the intra- and extravascular pools of AFP. Repeated transfusion in the same individuals gave similar findings. In two infants the total amount of AFP in these pools increased by 4.0-7.4 mg after the transfusions. The results could be accounted for by postnatal AFP synthesis. Because of the diffusion of AFP from the extravascular compartment to the intravascular pool the actual turnover rate of AFP could not be measured. The estimated magnitude of endogenous turnover rate of AFP, 0.02-0.09 min-1, gave a mean half-life of about 20 min, which is distinctly shorter than that of AFP in plasma (3-5 days); this could be due to either continuous synthesis of AFP or transfer of presynthesized AFP from the liver cells to extracellular pool. We postulate that either the synthesis or the turnover rate of AFP is controlled by the plasma AFP concentration via a negative feedback mechanism.

Birth Weight↗
PubMed1980

Changes in peripheral blood cells and serum ferritin in lysinuric protein intolerance.

Twenty-seven patients with lysinuric protein intolerance, an autosomal recessive disorder of diamino acid transport, have been followed at our hospital since 1965. Many of the patients had recurrent mild normochromic anaemia without apparent iron deficiency, and leuko- and/or thrombocytopenia. Serum ferritin concentrations were inappropriately high. Serum ferritin concentration appears to be a valuable index of the control of this disease.

Amino Acid Metabolism, Inborn Errors↗
PubMed1980

Intestinal absorption in lysinuric protein intolerance: impaired for diamino acids, normal for citrulline.

Lysinuric protein intolerance (LPI) is an autosomal recessive defect of diamino acid transport characterised by massive diaminoaciduria, especially lysinuria, with hyperammonaemia after heavy nitrogen intake. The defect has previously been demonstrated in the kidney, and is probably present in the liver cells. To evaluate the effect of the LPI gene on the net intestinal absorption of the diamino acids and citrulline, separate oral loads of each were given to controls, and to subjects heterozygous and homozygous for LPI. In the affected subjects the plasma concentrations of the loaded diamino acids showed lower increments after the loads than in the controls, the difference being marked in the homozygotes and moderate in the heterozygotes. Urinary excretion failed to explain these differences. Thus, the diamino acid transport defect of LPI is also present in the intestine. After citrulline loads, in contrast, plasma citrulline levels rose similarly in controls and homozygotes. Thus, LPI is associated with intact citrulline absorption. The ornithinopenic hyperammonaemia of LPI is probably preventable by supplementing dietary protein with the ornithine precursor citrulline.

Adolescent↗
PubMed1980

Gyrate atrophy of the choroid and retina with hyperornithinemia. Deficient formation of guanidinoacetic acid from arginine.

Patients with gyrate atrophy of the choroid and retina have 10- to 20-fold increased ornithine concentrations in body fluids and significantly reduced activity of ornithine aminotransferase in lymphocytes and cultured fibroblasts. We administered intravenous arginine to six patients and six controls to study in vivo inhibition by high ornithine concentrations of arginine-glycine transamidinase, the rate-limiting enzyme in creatine synthesis. Serum arginine concentrations curves after administration were similar for the two groups. The increment in serum ornithine was more than three times as great in patients as in controls. The mean half-times in plasma ornithine were 360 and 97 min, respectively. In the patients, the metabolic clearance of ornithine from the extracellular fluid was significantly delayed. Urinary guanidinoacetate excretion rose markedly in all controls, the excretion rate being higher in females. The patients always excreted less than the controls, the differences within the sexes being highly significant. Differences in creatine excretion after administration were less marked. We conclude that in gyrate atrophy patients, formation of guanidinoacetate, creatine, and possibly phosphocreatine is inhibited at the transaminidation step by the high concentrations of ornithine. Deficiency of the high-energy phosphates may underlie the pathogenesis of the eye and muscle atrophies.

Adolescent↗
PubMed1979

Gyrate atrophy of the choroid and retina with hyperornithinemia: tubular aggregates and type 2 fiber atrophy in muscle.

We studied 21 patients with gyrate atrophy of the choroid and retina and hyperornithinemia. Although the patients were not weak, type 2 muscle fibers were almost universally atrophic and had tubular aggregates. Gyrate atrophy is the first disease in which females are shown to have tubular aggregates; the sexes were affected equally. In gyrate atrophy the number of type 2 fibers decreases with age. The muscle and eye changes are probably related to abnormal creatine synthesis, caused, in gyrate atrophy, by the increased body pool of ornithine; muscle abnormalities may also be present in other tapetoretinal dystrophies.

Adolescent↗
PubMed1975

Lysinuric protein intolerance.

Lysinuric protein intolerance (LPI), an autosomal recessive defect of diamino acid transport, is characterized chemically by renal hyperdiaminoaciduria, especially lysinuria, and by impaired formation of urea with hyperammonemia after protein ingestion. Our 20 patients thrived during breast-feeding, but ingestion of cow's milk caused diarrhea and vomiting. When able to select their diet, they rejected all protein-rich foods. They were short staturated and had weak atrophic muscles, osteoporosis, hepatomegaly and often splenomegaly. Four patients were mentally retarded. Fifteen patients had leukocyte counts below 4,000/mm3, and 17 patients had platelet counts below 150,000/mm3. Serum lactate dehydrogenase activity was constantly increased, and transaminase and aldolase activities were often increased. In the infants' livers, changes were only revealed by electron microscopy: increased and vesicular smooth endoplasmic reticulum, and abundance of glycogen particles in the hepatocytes. In the older patients, light microscopy demonstrated clearly limited areas where hepatocytes had large pale cytoplasm and small pyknotic nuclei. The diamino acids lysine, arginine and ornithine had plasma concentrations only one-third to one-half the normal mean; the renal clearances were clearly increased. Oral diamino acid loading tests suggested impaired intestinal absorption. Urea is built in the liver through transformation of ornithine to arginine, and cleavage of arginine to ornithine and urea. The addition of ornithine to an intravenous I-alanine loading prevented the hyperammonemia and normalized the urea production. Therefore, the diet has been supplemented with arginine, and more protein has been added. This therapy has lead to a remarkable catch-up growth in some patients. The pathophysiology of LPI is explained. Because of defective intestinal absorption and incrased renal loss, the diamino acids have a low plasma concentration. Their transport from plasma to hepatocytes is also impaired, and the liver becomes deficient in ornithine. This retards the urea cycle, and leads to postprandial hyperammonemia and protein aversion. The presence of the transport defect in the hepatocytes distinguishes LPI from other hyperdibasicaminoacidurias.

Adolescent↗