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Biomedical subjects

C A Thornton

Publications and source records attributed to C A Thornton.

18 recordsLinked to original sources
PubMed1997

Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene.

Myotonic dystrophy, or dystrophia myotonica (DM), is a highly variable multisystem disease in which the classic adult-onset form displays progressive muscle wasting, cataracts, heart block, gonadal atrophy, insulin resistance and neuropsychiatric impairment. Its genetic basis is an expansion of CTG trinucleotide repeats in the DMPK protein kinase gene. Among the triplet repeat expansion disorders, DM is distinguished by the extended length of the repeat tract (5-13 kb in postmortem tissue) and its location in the 3' untranslated region of the gene that contains it. The pathophysiological mechanism for multisystem degeneration in DM is not understood. In contrast to the profound muscle wasting that characterizes advanced DM, only minor histopathological abnormalities have occurred in DMPK knockout mice or in mice that overexpress a human DMPK transgene, making it unlikely that changes in DMPK activity provide a unitary explanation for the disease. A DNAse hypersensitive site that maps 0.7 kb downstream (centromeric) from the CTG repeats is eliminated on DM chromosomes. This finding indicates that the repeat expansion may alter the adjacent chromatin structure and raises the possibility that it may also affect the expression of flanking genes. An interesting candidate flanking gene is DMAHP, a recently discovered homeodomain-encoding gene. We show here that DMAHP expression in myoblasts, muscle and myocardium is reduced by the DM mutation is cis, and the magnitude of this effect depends on the extent of CTG repeat expansion. These observations support the hypothesis that DMAHP participates in the pathophysiology of DM.

Animals↗
PubMed1996

Human IgG production in vivo: determination of synthetic rate by nonradioactive tracer incorporation.

Exposure of Ab-secreting cells to selected hormones, cytokines, and drugs alters the rate of Ig production in vitro. Whether these effects are important clinically is unknown because there are no safe, reproducible, and appropriate techniques for measuring Ig synthesis in vivo. We developed a stable isotope tracer method to measure IgG secretion into plasma. L-[1-13C]Leucine was given as a priming dose followed by a constant i.v. infusion over 8 h. Tracer accrual in IgG, determined by mass spectrometry, was linear from 2 to 8 h of the infusion. The normal rate of IgG synthesis into plasma assessed in 21 healthy subjects was 860 +/- 310 mg/day (mean +/- SD). The synthetic rate measurements were remarkably reproducible (coefficient of variation = 10.5 %). Simultaneous analysis of leucine kinetics allows, for the first time, Ig secretion to be studied in the context of whole body protein economy. IgG secretion into plasma accounts for 0.3% of whole body protein synthesis. Experimental support for a key metabolic assumption, that tracer enrichment in plasma and that at the site of IgG synthesis were similar, came from a comparison of synthetic rates derived from low dose and high dose tracer infusions. Measurement of Ig secretion by tracer incorporation is rapid and reproducible. In contrast to older methods that rely on radioisotope disappearance, the tracer incorporation method is safe for serial measurements in an individual and will be useful for quantitative studies of treatment effects and immune regulation in vivo.

Adult↗
PubMed1995

Ragged red fibers in normal aging and inflammatory myopathy.

Ragged red fibers are an important marker for mitochondrial disease. To evaluate the hypothesis that mitochondrial dysfunction may play a role in the pathogenesis of aging and inclusion body myositis, we studied the frequency of ragged red fibers in muscle biopsy specimens from 15 young and 13 old normal adults, and from 27 patients with inclusion body myositis, polymyositis, or dermatomyositis. Serial transverse cryostat sections were stained with modified Gomori trichrome, modified succinic dehydrogenase, and cytochrome c oxidase. The frequency of ragged red fibers, determined by measuring the percent number of succinic dehydrogenase-positive ragged red fiber equivalents, was significantly higher in old compared to young normal subjects (0.33 vs. 0.02%, p < 0.0001). With the exception of a single polymyositis biopsy specimen showing a large number of ragged red fibers, the frequency of ragged red fibers in patients with polymyositis or dermatomyositis was similar to that of age-matched normal control subjects. The frequency of ragged red fibers was more than 1% in 7 of 8 patients with inclusion body myositis (maximum, 15%). The modified succinic dehydrogenase stain was more sensitive than the modified Gomori trichrome in detecting accumulation of mitochondria in muscle fibers. Cytochrome c oxidase activity was deficient in most ragged red fibers. We conclude that the number of ragged red fibers increases with normal aging and may reflect an age-related decline in muscle mitochondrial oxidative metabolism. The frequent occurrence of ragged red fibers in inclusion body myositis suggests that mitochondrial function may be impaired in this disease.

Adult↗
PubMed1994

Myotonic dystrophy patients have larger CTG expansions in skeletal muscle than in leukocytes.

The genetic basis of myotonic dystrophy is an unstable expansion of CTG repeats located in a gene on chromosome 19 that encodes a putative serine/threonine protein kinase. We studied the somatic mosaicism of the (CTG)n expansion in myotonic dystrophy patients. (CTG)n expansions were 2- to 13-fold greater in DNA isolated from skeletal muscle than in DNA from leukocytes in 10 of 11 patients with myotonic dystrophy. Different muscles of the same individual showed similar (CTG)n expansions. In postmortem tissues from an adult patient, (CTG)n expansions in brain, skeletal muscle, cardiac muscle, testes, and liver were all greater than in leukocytes. Normal myotonic dystrophy gene alleles from 7 healthy subjects had the same number of CTG repeats in leukocytes and muscle. The myotonic dystrophy mutation displays pronounced heterogeneity in somatic cells. The (CTG)n expansion observed in peripheral blood leukocytes is not necessarily representative of the repeat expansion in affected tissues, such as skeletal muscle and myocardium. In some patients with myotonic dystrophy, the predictive value of genetic analysis based on leukocyte DNA may be limited.

Adult↗
PubMed1994

Plasma exchange and intravenous immunoglobulin treatment of neuromuscular disease.

Removal of immunoglobulin by plasma exchange and administration of immunoglobulin by intravenous infusion each improve selected neuromuscular diseases. Both treatments are expensive and relatively brief in their duration of action, but they benefit both self-limited neuromuscular diseases such as the Guillain-Barré syndrome and acute exacerbations of more chronic neuromuscular diseases including myasthenia gravis and chronic inflammatory demyelinating polyneuropathy. It is likely that plasma exchange acts by removing pathogenic antibodies. The mechanism by which intravenous immunoglobulin acts is less clear. Possibilities include (1) antiidiotypic antibody effect, (2) complement absorption, (3) downregulation of immunoglobulin production, (4) receptor blockade, (5) virus neutralization, (6) enhancement of suppressor cells, and (7) inhibition of lymphocyte proliferation. Although plasma exchange and intravenous immunoglobulin have major side effects, severe reactions are uncommon with plasma exchange and rare with intravenous immunoglobulin. Because of their low incidence of life-threatening complications, both treatments have major appeal to clinicians. Because of their brief action and high cost as well as the uncertainty as to whether either or both should be employed, their role in the therapeutic armamentarium of the neurologist requires further study.

Blood Proteins↗
PubMed1994

Myotonic dystrophy with no trinucleotide repeat expansion.

We report 3 patients from 2 families with myotonic dystrophy who do not show an abnormal expansion of CTG trinucleotide repeats within the myotonic dystrophy gene. Characteristic features of myotonic dystrophy in these patients were frontal balding, cataracts, cardiac conduction abnormalities, and testicular atrophy with myotonia and muscle weakness. Results of muscle histopathology were consistent with myotonic dystrophy. Genetic analysis of leukocyte and muscle DNA showed a normal number of CTG repeats. The demonstration of normal CTG repeat number for the myotonic dystrophy gene does not exclude the diagnosis of myotonic dystrophy.

Adult↗
PubMed1992

Neurocysticercosis and human immunodeficiency virus infection. A possible association.

We present four patients with active neurocysticercosis and human immunodeficiency virus type 1 infection. In three patients, symptoms of neurocysticercosis brought the patient to medical attention and led to the diagnosis of human immunodeficiency virus infection. Neurocysticercosis should be considered in human immunodeficiency virus-infected persons who have been in areas where cysticercosis is endemic.

Adult↗
PubMed1992

Teicoplanin vs cephradine and metronidazole in the prophylaxis of sepsis following vascular surgery: an interim analysis of an ongoing trial.

This paper presents further preliminary results of a trial of the prophylaxis of sepsis in 165 patients undergoing vascular surgery. The efficacy and safety of a single dose of teicoplanin was examined and compared with three doses of cephradine plus metronidazole. No significant differences were detected in the prophylactic efficacy in either group. The first interim report indicated abnormalities in liver function, maximum at 7 days, in both groups. These findings are confirmed in this second interim report. Raised levels of GGT and alkaline phosphatase are more prominent in patients receiving teicoplanin. Liver function improved by 28 days, however, suggesting that any abnormality is transient.

Alkaline Phosphatase↗
PubMed1991

Guillain-Barré syndrome associated with human immunodeficiency virus infection in Zimbabwe.

We studied the clinical features and human immunodeficiency virus (HIV) serology of 32 consecutive adults with inflammatory demyelinating polyneuropathy (IDP) admitted to the teaching hospitals in Harare, Zimbabwe. Twenty-nine of the IDP patients had Guillain-Barré syndrome (GBS), and the other three had chronic IDP. Sixteen of 29 (55%) GBS patients were HIV-seropositive, a higher frequency of HIV infection than in blood donors drawn from the population served by these hospitals. All three chronic IDP patients were HIV-seronegative. In all HIV-seropositive patients, GBS was the initial illness that brought the patient to medical attention and led to the diagnosis of HIV infection. Compared with seronegative patients, the HIV-seropositive GBS patients were more likely to have generalized lymphadenopathy, CSF pleocytosis, coexistent CNS disturbance, and prior sexually transmitted disease. GBS in this region of Africa is frequently associated with HIV infection.

Adolescent↗
PubMed1987

Locomotor activity and contracture of isolated ileum precipitated by naloxone following treatment of guinea-pigs with a single dose of morphine.

Guinea-pigs treated with a single dose of morphine, 15 mg kg-1 s.c., exhibited an increase in locomotor activity 2 h later on injection of naloxone, 4 mg kg-1 i.p. At the same time, contracture of ileal preparations isolated from morphine-treated guinea-pigs occurred on addition of naloxone 1 microM. Contracture of the ileum was inhibited by the tachykinin antagonist, spantide, and was therefore presumably mediated by a substance P-like agent. This study has established a useful model for the parallel investigation of central and enteric nervous system mechanisms of opiate dependence.

Animals↗
PubMed1977

Factor VIII-related antigen and factor VIII coagulant activity in normal and pre-eclamptic pregnancy.

The changes in the ratio between factor VIII-related antigen and factor VIII activity were compared in ten patients with normal pregnancies and in ten patients with severe pre-eclampsia. In the patients with pre-eclampsia, a highly significant increase in the ratio was observed during the third trimester. No difference in the ratio between the two groups was found on day 7 of the puerperium. In the pre-eclamptic patients, the highest ratios for factor VIII-related antigen to factor VIII activity were associated with either a perinatal death or with the delivery of a severely growth retarded infant. These findings are in keeping with an increased rate of thrombin production in women with pre-eclampsia, and suggest that the ratio of factor VIII-related antigen to factor VIII activity may reflect the severity of the effect of the disease process on the fetus.

Antigens↗
PubMed1976

A comparison of the effect of extradural and parenteral analgesia on maternal plasma cortisol concentrations during labour and the puerperium.

Maternal plasma levels of cortisol were measured serially by radioimmunoassay in two groups of 12 patients during induced labour and in the puerperium. One group was given continuous extradural analgesia throughout labour, the other group received pethidine and promazine in response to pain. Pre-induction cortisol levels were significantly higher in patients who were to have extradural analgesia but the percentage increase in plasma cortisol during labour was considerably less than in patients with parenteral analgesia; in second stage labour, mean cortisol levels were the same in the two groups. This study suggests that patients who had chosen to have extradural analgesia may have been more anxious before labour than the other patients but continuous, extradural analgesia suppressed to some extent the percentage increase in mean cortisol levels found during labour in patients given parenteral analgesia. In the puerperium, there was no difference in mean cortisol levels in the two groups.

Anesthesia, Epidural↗
PubMedDate not supplied

Mathematics instruction for elementary students with learning disabilities.

Recent research in mathematics instruction requires educators to rethink long-established beliefs about teaching, learning, and assessment. In particular, this research underscores the need for problem solving and higher level thinking in mathematics. Consistent with these recommendations, this article presents and illustrates four promising themes for mathematics instruction that have emerged from research involving students with learning disabilities. These themes-(a) providing a broad and balanced mathematics curriculum; (b) engaging students in rich, meaningful problem tasks; (c) accommodating the diverse way in which children learn; and (d) encouraging students to discuss and justify their problem-solving strategies and solutions-suggest ways for rethinking the teaching and learning of mathematics in relation to students with learning disabilities.

Achievement↗