Sublethal physiological effects of chlorinated paraffins on the flounder, Platichthys flesus L.
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Animals↗
Biomedical subjects
A Larsson
Publications and source records attributed to A Larsson.
Specificities and binding properties of eight monoclonal antibodies against carcinoembryonic antigen.
Eight different monoclonal antibodies against CEA were derived from fusions with spleen cells of mice immunized with highly purified CEA. All eight antibodies were IgG l, kappa and had isoelectric points between pH 6.5 and 7.5. They reacted strongly with native CEA, Smith degraded CEA (SI-stage) and CEAlow, only marginally with reduced and alkylated CEA and not at all with orosomucoid, indicating that they were directed against conformation dependent protein determinants. Two antibodies cross-reacted strongly with nonspecific cross-reacting antigen (NCA) while none of the antibodies cross-reacted with biliary glycoprotein I (BGP I). At least six different epitopes in the peptide moiety of CEA were recognized by this series of monoclonal antibodies. At least two of these appeared to occur twice in the molecule, possibly indicating that CEA contains two or more homology regions. The affinity constants of three of the CEA-'specific' antibodies were found to be very high, e.g. 1.2, 3.3, and 7.4 X 10(8) M-1, respectively.
Animals↗
Health of children whose parents seek psychiatric care.
The study comprises 69 pre-school children whose parents, mainly mothers, had sought care at a department of psychiatry in Stockholm. The majority of the parents had attended for recurrent ambulatory treatment (58%) or had only come to the emergency room (25%). The children demonstrated a significantly higher frequency of somatic and emotional symptoms than a matched control group. To a large extent, the index children showed failure to thrive without any apparent organic cause. In exceptional cases there had been co-operation between the departments of psychiatry and paediatrics (one case) as well as between the departments of psychiatry and social welfare (five cases). There is an urgent need to develop methods within the scope of psychiatric care whereby the best interests of both the parents and the children are taken into consideration.
Adult↗
TSH and thyroxine in stored neonatal filter-paper blood samples from patients with congenital hypothyroidism.
Filter paper blood samples collected neonatally from infants with congenital hypothyroidism were analysed retrospectively for TSH (n = 41) and thyroxine (n = 16). The patients were detected by clinical signs and symptoms and treatment was started during the first two years of life. Similar blood samples from control infants were analysed for comparison. All CH patients would have been detected neonatally if screening had been based on TSH analyses with a cut-off limit corresponding to 50 mU of TSH/l of plasma. A screening programme involving analyses of thyroxine would require considerably higher recall frequency to yield 100% sensitivity. These results support a nationwide CH screening program based on TSH analyses of PKU filter paper blood samples using 50 mU/l of plasma as the cut-off limit.
Blood Specimen Collection↗
Immunoreactive trypsin screening for cystic fibrosis.
Immunoreactive cationic trypsin (irCT) was measured in 22 cystic fibrosis (CF) and 132 control infants. IrCT was analysed with radioimmunoassay of dried blood samples collected for PKU screening around the 5th day of life and stored on filter paper. The mean +/- 1 SD level of irCT for the control infants was 42 +/- 19 micrograms/1. Sixteen of the 22 CF children had an irCT level above 100 micrograms/1 (mean + 3 SD) while 6 had a level at or below this cut-off limit. A specificity of 99%, which gives a sensitivity of 73%, and an approximative noise: signal ratio of 30:1, suggests that the irCT test may be unsatisfactory as a neonatal screening method for CF.
Child, Preschool↗
Health economic analysis of the Swedish neonatal metabolic screening programme. A method of optimizing routines.
A benefit-cost analysis was carried out to optimize the routines for neonatal metabolic screening. The basis of the study was provided by results of the Swedish neonatal screening programme from 1965 to 1979. During this period over one million infants were screened by the Guthrie test for phenylketonuria and galactosaemia, and for limited periods also for tyrosinaemia, homocystinuria and histidinaemia. The benefit-cost ratio was calculated for combinations of different screening tests, recall routines, and varying degrees of coverage. The largest benefit-cost ratio was obtained with combined screening for phenylketonuria and galactosaemia, using a borderline blood phenylalanine level of 0.50 mmol/L in the Guthrie test for phenylketonuria. However, the inaccuracy of this test necessitated the use of a lower blood phenylalanine level of 0.25 mmol/L and the acceptance of a lower benefit-cost ratio. An increase in the present 98% coverage of newborns by the screening programme was found to be an effective means of improving the benefit-cost ratio in the present programme.
Amino Acid Metabolism, Inborn Errors↗
[Information from the PKU-section - report of activities 1981].
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Humans↗
Importance of the N-terminal sequence in porcine pancreatic colipase.
Colipase exists in pancreatic juice in a pro-form which is activated by limited trypsin hydrolysis. During this activation, the N-terminal pentapeptide 1Val-Pro-Asp-Pro-5Arg is cleaved. The new N-terminal sequence formed, 6Gly-Ile-Ile-Ile-10Asn, contains three isoleucine residues. The importance of these for stimulating lipase activity has been investigated by successive Edman degradation of epsilon-acetimidolysine residues followed by limited trypsin hydrolysis. The epsilon-amidinated colipase obtained was fully active both with a phospholipid-covered triacylglycerol (Intralipid) and tributyrin as substrate. After removal of the three isoleucine residues, the activity of colipase was lost with Intralipid but not with tributyrin as substrate. The shortened colipases regained their Intralipid activity upon addition of long-chain fatty acids. The binding of colipase to lipase was not affected by removal of the isoleucine residues.
Amino Acid Sequence↗
The identity and properties of two forms of activated colipase from porcine pancreas.
Colipase is excreted as a procolipase, colipase101. It is activated by low concentrations of trypsin, hydrolyzing the N-terminal pentapeptide. With higher concentrations of trypsin or in the presence of Ca2+ a smaller form of colipase containing 85 amino acids, appears. It has glycine as the N-terminal and arginine as the C-terminal amino acid residue and has lost 11 amino acids in the C-terminal chain. The ability of colipase85 to activate lipase with tributyrin as substrate is about the same as for colipase96 and procolipase. With fenfluramine, an anoretic agent, added to the tributyrin colipase assay system, the specific activities of colipase96 and colipase85 are similar and about five times higher than that of colipase101. With intralipid as substrate colipase85 enables lipase to reach the triacylglycerol substrate more rapidly than colipase96, having about six times shorter lagtime for a given concentration. Colipase84, obtained by splitting off the C-terminal arginine from colipase85, has a lagtime somewhere between colipase85 and colipase96, pointing to the importance of arginine85 for Intralipid activity. The binding between lipase and colipase has about the same strength for procolipase, colipase96 and for colipase85, Kd being about 10(-6) M either in buffer or in the presence of 2 mM taurodeoxycholate at pH 7. Addition of long chain fatty acids in the presence of bile salts increases the binding strength between colipase and lipase 100-fold, both for colipase96 and colipase85.
Animals↗
Antiherpes activity of [E]-5-(1-propenyl)-2'-deoxyuridine and 5-(1-propenyl)-1-beta-D-arabinofuranosyluracil.
5-(1-Propenyl)-1-beta-D-arabinofuranosyluracil has been synthesized, and this compound and [E]-5-(-propenyl)-2'-deoxyuridine have been tested for inhibition of herpes virus multiplication. Only [E]-5-(1-propenyl)-2'-deoxyuridine was found to be an active inhibitor reducing by 50% the plaque formation of herpes simplex virus type 1 (HSV-1) at about 1 muM. A comparison to the bromovinyl derivatives showed the following order of descending activity; [E]-5-(2-bromovinyl)-2'-deoxyuridine greater than 5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil greater than or equal to [E]-5-(1-propenyl)-2'-deoxyuridine greater than 5-(1-propenyl)-1-beta-arabinofuranosyluracil. HSV-1 mutants lacking thymidine kinase or resistant against acycloguanosine were resistant against [E]-5-(1-propenyl)-2'-deoxyuridine. All compounds seemed to be phosphorylated by HSV-1 thymidine kinase in a cell-free assay. The compounds were phosphorylated to a lower extent by cellular or HSV-2 thymidine kinase, and the HSV-2 strains tested were inhibited by less than 50% at 100 muM in plaque assays. A selective inhibition of HAV-1 DNA synthesis by [E]-5-(1-propenyl)-2'-deoxyuridine was observed in infected cells indicating an effect on viral DNA polymerase. [E]-5-(1-Propenyl)-2'-deoxyuridine had a low cellular toxicity and a therapeutic effect when applied topically to HSV-1-infected guinea pig skin.
Animals↗
Induction and repair of single-strand DNA breaks after X-irradiation of human fibroblasts deficient in glutathione.
Using the unwinding technique in weak alkali, the induction and repair of DNA single-strand breaks was determined after aerobic and anerobic X-irradiation of human fibroblasts, obtained from a patient suffering from 5-oxoprolinuria, and from a clinically healthy control. The metabolic disorder associated with 5-oxprolinuria is a deficiency in glutathione synthetase activity resulting in a greatly reduced glutathione content in the cells. A small dose-modifying effect of oxygen (o.e.r. = 1.1) was found for these cells in comparison to an o.e.r. of 2.5 for control cells with normal glutathione content. No significant difference was found between the repair capacity of cells with normal and deficient glutathione content, and repair was nearly completed within 60 min of anoxic irradiation in each case. In contrast, after aerobic irradiation of glutathione-deficient cells repaired less than 70 per cent of the breaks during the same period. When the glutathione-deficient cells were incubated with either dithiothreitol or mercaptopropionylglycine directly after aerobic irradiation, almost complete repair was obtained within 60 Min. The data are interpreted as indicating that the repair mechanism for oxically and anoxically induced single-strand breaks is qualitatively different, and requires glutathione in the former case.
Adult↗
Regulation of effector functions of human K-cells and monocytes by antigen density of the target cells.
Antibody-dependent cytolysis and phagocytosis mediated by human K-cells or monocytes against chicken erythrocytes (ChRBC) were studied. The antigen density of the target cells was varied by coating the cells with different amounts of 3H-labelled dinitrophenyl (DNP) hapten. The degree of antigenicity thus acquired by the target cells was assessed on the basis of their uptake of the isotope. Anti-DNP serum was used to induce lysis or phagocytosis. Below 500 antigenic determinants per ChRBC the target cells were not affected. However, at the density, lysis and/or phagocytosis was seen when the antibody concentration was high (2 X 10(-9) M). With less antibody present (2 X 10(-11) M) only monocyte-mediated phagocytosis was induced. The estimated lowest number of target-cell-bound antibodies required for K-cell-mediated lysis was approximately 50. The corresponding number for monocyte-mediated phagocytosis was approximately 20 IgG per ChRBC. The result suggests that interaction of several Fc receptors on the effector cells with IgG molecules bound to adjacent sites on the target cell membrane is an important factor in the regulation of these antibody-dependent cell-mediated effector functions.
Animals↗
Substituent effects on the ionization step regulating desorption and catalytic oxidation of alcohols bound to liver alcohol dehydrogenase.
1. Transient-state kinetic methods, based on the use of pyrazole as a displacing reagent and reporter ligand, have been applied to examine the pH dependence of rate and equilibrium constants for 2-chloroethanol and 2,2-dichloroethanol binding to the binary complex formed between liver alcohol dehydrogenase and NAD+. 2. The apparent affinity of the enzyme . NAD+ complex for the examined alcohols is dependent on two proton dissociation equilibria. One of these equilibria affects the rate of alcohol association to the binary complex with a ligand-independent pKa value of 7.6, attributable to ionization of zinc-bound water in the enzyme . NAD+ complex. The second proton dissociation equilibrium regulates the rate of alcohol desorption from the enzyme . NAD+ . alcohol complex and exhibits a pKa value of 5.4 and 4.5, respectively, with 2-chloroethanol and 2,2'-dichloroethanol as the ligand. Steady-state kinetic data are reported which indicate that the pKa-5.4-equilibrium controls also the apparent rate of enzymic hydride transfer from 2-chloroethanol to NAD+. 3. These results lend strong support to the mechanism of enzyme action proposed by Kvassman and Pettersson according to which the enzyme . NAD+ . alcohol complex participates in an obligatory proton dissociation step which regulates both desorption and catalytic oxidation of the alcohol ligand. The corresponding pKa value is shown to be lineary dependent on the pKa of the free alcohol ligand with a regression coefficient (Brönstedt alpha value) of about 0.6. The latter observation provides direct evidence that the effect of pH on the reactivity of the enzyme . NAD+ . alcohol complex reflects an alcohol/alcoholate ion equilibration of the enzyme-bound substrate. 4. The particular mode of binding and properties of the active-site zinc ion in liver alcohol dehydrogenase suggest that the catalytic function of the metal ion can be related primarily to facilitation of the process of alcohol oxidation through facilitation of the alcoholate ion formation step now established to precede hydride transfer to NAD+.
Alcohol Oxidoreductases↗
Screening for congenital hypothyroidism. I. Laboratory results of a pilot study based on dried blood samples collected for PKU screening.
A pilot study was performed to establish optimal conditions for nation-wide screening for congenital hypothyroidism in Sweden. The levels of T4 and TSH were determined by automated radioimmunoassay in the dried blood spots, routinely collected for PKU screening on the fifth postnatal day, from all 19 792 infants born in the Stockholm area during a 14-month period. To identify safe minimum recall criteria for routine use, infants were recalled if the TSH level was more than 30 mU/l of plasma or--if they were not preterm--the T4 concentration was less than -2 S.D. of the mean. Altogether 160 infants were recalled. Seven newborns with congenital hypothyroidism were identified, 6 with primary and one with secondary hypothyroidism. Five infants had decreased levels of thyroxine-binding globulin. The results of the follow-up analyses from recalled infants showed that determination of the reverse-T3 level may be of diagnostic value around the 23rd day of life. The results of the clinical investigation of recalled infants are reported in a subsequent paper and a programme for nation-wide screening for congenital hypothyroidism is proposed.
Congenital Hypothyroidism↗
Screening for congenital hypothyroidism. II. Clinical findings in infants with positive screening tests.
In a pilot screening programme for congenital hypothyroidism, PKU filter paper blood samples from 20 000 infants born in Stockholm were analysed for TSH and T4 to identify optimal conditions for routine nationwide screening. Among 160 infants with positive screening tests, 7 infants (group I) had true-positive results, 6 had primary and one secondary hypothyroidism. The 153 infants with false-positive tests were divided into group II:74 infants with an isolated increased TSH level; group III: 71 infants with an isolated decreased T4 concentration; and group IV: 8 infants with increased TSH and decreased T4 levels. In group I the clinical signs and symptoms of hypothyroidism varied when the diagnosis was made at 3 weeks of age. The median hypothyroid index score was 8 (range 0--18). In groups II-IV most infants showed very few signs of hypothyroidism. The median hypothyroid index scores were 1, 1, and 0, respectively. Clinical findings were of little value in the individual case for distinguishing true from false positive screening tests. We suggest that nation-wide screening should be based on TSH analyses of PKU blood samples, with a cut-off level corresponding to 50 mU/l of plasma. Recall frequency will be less than 0.1%.
Congenital Hypothyroidism↗
Evaluation of a nation-wide neonatal metabolic screening programme in Sweden 1965-1979.
In Sweden, neonatal screening for phenylketonuria was started in 1965 and a total of 1 326 000 infants were studied up to 1979. During various periods of time, screening was also carried out for galactosaemia, hereditary tyrosinaemia, histidinaemia, and homocystinuria. In screening for phenylketonuria and galactosaemia no false-negative results were obtained and the incidences were 1/30 850 and 1/81 100, respectively. In screening for hereditary tyrosinaemia only 1 out of 6 patients was identified by screening and the incidence was 1/106 710. Two cases of histidinaemia were detected, which corresponds to an incidence of 1/36 840. Both children developed normally without any treatment. No child with homocystinuria was detected in the screened population of more than 300 000 newborn infants. A screening programme involving phenylketonuria and galactosaemia was considered to be optimal among the tested disorders.
Evaluation Studies as Topic↗
Placental transfer of maternal anti-rabbit IgG causing falsely elevated TSH levels in neonates.
Two infants were found to have markedly increased TSH levels, 104 and 154 mU/l of plasma, respectively, in a routine screening programme for congenital hypothyroidism. THe recall limit used was 50 mU/l of plasma. On follow-up, both infants were clinically euthyroid and had normal serum T4 and T3. The elevated TSH levels were confirmed only with some commercial radioimmunoassay kits--but not with others. Similar results were obtained in TSH assays of samples from their mothers, who had no other biochemical or clinical evidence of thyroid dysfunction. Both mothers had intense contact with rabbits over long periods. The apparent TSH activity was found to be associated with the IgG fraction. It was neutralized by the addition of normal rabbit serum to the samples and was caused by antibodies to rabbit immunoglobulin. The activity was eliminated from the circulation of both infants with a half-life of approximately one month. Apparently, the heterophilic antibodies were of maternal origin and were transferred to the foetus via the placenta. Infants with so-called transient hyperthyrotropinaemia identified in screening programmes have to be reevaluated to exclude false TSH elevations of this type.
Animals↗
Congenital hypothyroidism in Sweden. Psychomotor development in patients detected by clinical signs and symptoms.
Thirty-nine children at 7 to 9 years of age with congenital hypothyroidism have been studied with respect to their intellectual, neurological and social functions. Their intellectual achievement as assessed by the WISC test, was significantly lower than in a reference population (mean IQ 88, range 50-113). In children who showed signs and symptoms of hypothyroidism during their first four weeks of life, there was a negative correlation between the age when therapy was started and intellectual development. No such correlation was found in children who showed signs and symptoms after the first four weeks of life. Nine children of 26 with signs of hypothyroidism in the neonatal period, were found to have neurological abnormalities consisting of fine and gross motor disturbances. The neurological abnormalities seriously affected daily life in only the two most severely mentally retarded. No correlation was found between the age when the therapy was started and neurological abnormalities. Three children attended special schools because of mental retardation and six attended normal schools but required additional teaching assistance for learning disabilities. Our results suggest that the risk of future intellectual handicaps may be reduced by early treatment in children with hypothyroidism presenting during the neonatal period.
Age Factors↗