Search PubMed⌕ Search

Biomedical subjects

C A Thornton

Publications and source records attributed to C A Thornton.

At least 37 records · Page 2Linked to original sources
PubMed2000

Expanded CUG repeat RNAs form hairpins that activate the double-stranded RNA-dependent protein kinase PKR.

Myotonic dystrophy is caused by an expanded CTG repeat in the 3' untranslated region of the DM protein kinase (DMPK) gene. The expanded repeat triggers the nuclear retention of mutant DMPK transcripts, but the resulting underexpression of DMPK probably does not fully account for the severe phenotype. One proposed disease mechanism is that nuclear accumulation of expanded CUG repeats may interfere with nuclear function. Here we show by thermal melting and nuclease digestion studies that CUG repeats form highly stable hairpins. Furthermore, CUG repeats bind to the dsRNA-binding domain of PKR, the dsRNA-activated protein kinase. The threshold for binding to PKR is approximately 15 CUG repeats, and the affinity increases with longer repeat lengths. Finally, CUG repeats that are pathologically expanded can activate PKR in vitro. These results raise the possibility that the disease mechanism could be, in part, a gain of function by mutant DMPK transcripts that involves sequestration or activation of dsRNA binding proteins.

Base Pairing↗
PubMed2000

Recovery from severe arsenic-induced peripheral neuropathy with 2,3-dimercapto-1-propanesulphonic acid.

CASE REPORT: A 33-year-old female with a 1.5-year history of multisystem illness was diagnosed with arsenic poisoning. Twenty-four-hour urine arsenic was 1030 microg/dL (normal 0-99) and root hair arsenic was 130 microg/g (normal 0-3). Despite treatment with succimer meso-2,3-dimercaptosuccinic acid, her neuropathy progressed to ventilator dependence and quadriplegia. Subsequent intravenous treatment with 2,3-dimercapto-1-propanesulfonic acid sodium salt was associated with arsenic diuresis, marked neuropathic improvement, and extubation. At 1-year follow-up, neuropathy was limited to mild distal lower extremity weakness and sensory loss. The use of 2,3-dimercapto-1-propanesulphonic acid in the treatment of severe arsenic neuropathy was associated with increased urinary elimination of arsenic and dramatic clinical recovery.

Adult↗
PubMed2000

High-abundance mRNAs in human muscle: comparison between young and old.

To gain a better understanding of the potential role of altered gene expression in the diminished muscle function in old age, we performed a broad search for transcripts expressed at quantitatively different levels in younger (21-24 yr) and older (66-77 yr) human vastus lateralis muscle by serial analysis of gene expression (SAGE). Because SAGE was based on RNA pooled from muscle of several different subjects, relative concentrations of selected mRNAs also were determined in individual muscle samples by quantitative RT-PCR. There were 702 SAGE tags detected at least 10 times in one or both mRNA pools, and the detection frequency was different (at P < 0.01) between young and older muscle for 89 of these. The ratio of myosin heavy chain 2a mRNA to myosin heavy chain 1 mRNA was reduced in older muscle. The mRNAs encoding several mitochondrial proteins involved in electron transport (including several subunits of cytochrome-c oxidase and NADH dehydrogenase) and subunits of ATP synthase were approximately 30% less abundant in older muscle. Several mRNAs encoding enzymes involved in glucose metabolism also were less abundant in older muscle. Analysis of individual samples revealed that the differences suggested by SAGE were not artifacts of atypical gene expression in one or a few individuals. These data suggest that some of the phenotypic changes in senescent muscle may be related to altered gene transcription.

Adult↗
PubMed1999

Reduced cerebral blood flow and impaired visual-spatial function in proximal myotonic myopathy.

OBJECTIVE: To compare brain involvement in myotonic dystrophy (DM) with that of proximal myotonic myopathy (PROMM). BACKGROUND: PROMM is a multisystem disease with many features in common with DM. METHODS: Twenty patients with DM (CTGF[500-700), 20 patients with PROMM, and 20 normal control subjects were studied. Neuropsychological testing was performed in 12 patients with PROMM and in 18 patients with DM; brain MRI was performed in 17 of 20 PROMM patients and 15 of 20 DM patients. Ten patients with PROMM and 11 patients with DM were subjected to H2(15)O PET. RESULTS: Two-thirds of the patients with PROMM and one-half of those with DM were impaired on visual-spatial recall, whereas one-third of the patients with PROMM and less than half of those with DM showed an impairment in visual-spatial construction. Brain MRI was normal, or showed only nonspecific white matter abnormalities in both PROMM and DM patients. PET studies in PROMM patients showed a bilateral decrease in regional cerebral blood flow (rCBF) of the orbitofrontal and medial frontal cortex, whereas DM patients had more widespread hypoperfusion that extended to the dorsolateral frontal cortex and subcortical regions. CONCLUSIONS: Impaired visual-spatial function may be present in proximal myotonic myopathy. This correlates best with a reduction in regional cerebral blood flow observed in H2(15)O PET brain scans rather than with specific structural abnormalities observed on brain MRI.

Adolescent↗
PubMed1999

Quantitative assessment of motor fatigue and strength in MS.

OBJECTIVE: To determine the test-retest reliability of strength and fatigue measurements in patients with MS and in healthy control subjects, and to examine associations among motor fatigue, strength, and ambulatory impairment in MS patients. BACKGROUND: Motor fatigue, defined as the loss of the maximal capacity to generate force during exercise, and weakness are common in patients with MS. METHOD: Twenty ambulatory MS patients and 20 age- and sex-matched healthy control subjects participated in the study. Test-retest reliability was assessed in two identical testing sessions, separated by 3 to 5 days. Maximal voluntary isometric strength was determined by fixed myometry of seven muscle groups on each side. Motor fatigue was assessed using three exercise protocols: sustained maximal contractions (static fatigue), repetitive maximal contractions, and walking as far as 500 m. Four analysis models for static fatigue were examined for their test-retest reliability and their ability to discriminate between normal fatigue and pathologic fatigue from MS. RESULTS: Test-retest reliability in MS patients was excellent for isometric strength and very good for static fatigue. Test-retest reliability was lower for exercise protocols that involved repetitive contractions or ambulation. Compared with healthy control subjects, MS patients were weak in lower extremity muscles, but upper extremity strength was relatively preserved. Fatigue was greater in MS patients, even in muscles that were not clearly weak. There were no significant associations between strength and fatigue in any of the muscles tested. A fatigue analysis model based on the area under the force-versus-time curve gave the best combination of reliability and sensitivity to detect differences between MS patients and healthy control subjects. CONCLUSIONS: Strength and motor fatigue can be measured reliably in patients with MS. MS patients experience more fatigue than healthy control subjects during sustained contractions, repetitive contractions, and ambulation. Motor fatigue appears to be distinct from weakness because the degree of fatigue was not associated with the degree of weakness in individual muscles. Quantitative assessment of strength and fatigue may be useful to monitor changes in motor function over time in MS patients.

Adult↗
PubMed1999

A comparison of teicoplanin versus cephradine plus metronidazole in the prophylaxis of post-operative infection in vascular surgery.

A total of 272 patients were enrolled into this prospective, unblinded, randomized comparison of single-dose teicoplanin vs three doses of cephradine plus metronidazole as prophylaxis for vascular surgery at St James's and Seacroft Hospitals, Leeds, UK. In all, 71.3% of patients (194/272) were enrolled at St James's University Hospital. Patients received either a single dose of teicoplanin, 6 mg/kg i.v., or cephradine, 1 g i.v. with metronidazole, 1 g rectally, at induction of anaesthesia followed by two further 1 g doses of cephradine and metronidazole 8 and 16 hours later. There were 136 patients in each treatment group. The most common operations were femoropopliteal grafts (96) and aortic aneurysm repairs (47). In the 'intention-to-treat' analysis, primary wound infections were seen in 4.4% of patients (6/136) receiving teicoplanin and 5.9% of patients (8/136) receiving cephradine plus metronidazole (95% CI -6.7%, +3.8%). Other disturbances to wound healing occurred in 23 patients (11 in the teicoplanin and 12 in the cephradine plus metronidazole group). Secondary respiratory tract infections occurred in 17 patients (8 receiving teicoplanin and 9 receiving cephradine plus metronidazole). In the evaluable patients analysis, primary wound infections occurred in 3.5% of patients (4/114) receiving teicoplanin and 5.1% of patients (6/117) receiving cephradine plus metronidazole. Staphylococcus aureus and Proteus sp. were the most common pathogens in primary wound infections. Despite the absence of Gram-negative cover in the teicoplanin group, Gram-negative infections occurred more often in the cephradine plus metronidazole group. Surgery of the lower extremities carried the highest risk of post-operative infection. Rates of infection were significantly higher at Seacroft Hospital (P = 0.001), and significantly higher for cephradine plus metronidazole between the two hospitals (P = 0.0008). Adverse events occurred in 40 patients receiving teicoplanin (29.4%) and 39 patients receiving cephradine plus metronidazole (28.7%). In 19 patients receiving teicoplanin (14%) and 15 receiving cephradine plus metronidazole (11%) these events were considered to be related to the study drugs. The most often reported events were infections, cardiac events and vascular phenomena (haematoma or emboli). Marked changes in haematological parameters and liver function tests were noted seven days after operation in patients in each treatment group, but these resolved quickly as the effects of the operation subsided. ESR remained elevated in both groups at the six-month follow-up assessment. It is concluded from this two-centre study that a single dose of teicoplanin shows similar efficacy to a three-dose regimen of cephradine plus metronidazole as prophylaxis for wound infection in vascular surgery. Both regimens were well tolerated, and there was an equal incidence of adverse events in the two regimens, which reflected the poor general health status of this elderly study population.

Adolescent↗
PubMed1999

Stimulation of myofibrillar synthesis by exercise is mediated by more efficient translation of mRNA.

Resistance exercises stimulate protein synthesis in human muscle, but the roles of changes in mRNA concentrations and changes in the efficiency of mRNA translation have not been defined. The present study was done to determine whether resistance exercise affects concentrations of total RNA, total mRNA, actin mRNA, or myosin heavy-chain mRNA (total and isoform specific). Eight subjects, 62-75 yr old, performed unilateral knee extensions at 80% of their one-repetition-maximum capacity on days 1, 3, and 6 of the study. On day 7, biopsies of exercised and nonexercised vastus lateralis muscles were obtained. Myofibrillar synthesis was determined by stable- isotope incorporation, and mRNA concentrations were determined by membrane hybridization and PCR-based methods. The exercise stimulated myofibrillar synthesis [30 +/- 6 (SE)%] without affecting RNA or mRNA concentrations. The effect of exercise on protein synthesis in individual subjects did not correlate with the effect on total RNA and mRNA concentrations. These data suggest that the stimulation of myofibrillar synthesis by resistance exercise is mediated by more efficient translation of mRNA.

Actins↗
PubMed1999

Inventory of high-abundance mRNAs in skeletal muscle of normal men.

G42875rial analysis of gene expression (SAGE) method was used to generate a catalog of 53,875 short (14 base) expressed sequence tags from polyadenylated RNA obtained from vastus lateralis muscle of healthy young men. Over 12,000 unique tags were detected. The frequency of occurrence of each tag reflects the relative abundance of the corresponding mRNA. The mRNA species that were detected 10 or more times, each comprising >/=0.02% of the mRNA population, accounted for 64% of the mRNA mass but <10% of the total number of mRNA species detected. Almost all of the abundant tags matched mRNA or EST sequences cataloged in GenBank. Mitochondrial transcripts accounted for approximately 20% of the polyadenylated RNA. Transcripts encoding proteins of the myofibrils were the most abundant nuclear-encoded mRNAs. Transcripts encoding ribosomal proteins, and those encoding proteins involved in energy metabolism, also were very abundant. The database can be used as a reference for investigations of alterations in gene expression associated with conditions that influence muscle function, such as muscular dystrophies, aging, and exercise.

Expressed Sequence Tags↗
PubMed1998

High-protein meals do not enhance myofibrillar synthesis after resistance exercise in 62- to 75-yr-old men and women.

This study tested the hypothesis that increasing the protein content of isocaloric meals increases the rate of myofibrillar synthesis in muscle of healthy subjects over 60 yr old and enhances the stimulation of myofibrillar synthesis induced by resistance exercise. Myofibrillar synthesis of sedentary and exercised quadriceps muscle was determined by incorporation of L-[1-13C]leucine. During the tracer infusion, subjects consumed meals with a low (7% of energy, n = 6)-, normal (14%, n = 6)-, or high (28%, n = 6)-protein content. In sedentary muscle, the mean (+/- SE) myofibrillar synthesis was 1.56 +/- 0.13%/day in the low-protein group, 1.73 +/- 0.11 %/day in the normal-protein group, and 1.76 +/- 0.10%/day in the high-protein group (P = 0.42). Myofibrillar synthesis was faster in exercised muscle (mean 27%, P < 10(-6) in all groups (2.10 +/- 0.14%/day in low protein; 2.18 +/- 0.10%/day in normal protein; 2.11 +/- 0.09%/day in high protein; P = 0.84). The stimulation of myofibrillar synthesis by exercise was not significantly different among low-protein [0.54 +/- 0.12%/day (37 +/- 9%)], normal-protein [0.46 +/- 0.08%/day (28 +/- 5%)], and high-protein groups [0.34 +/- 0.04%/day (20 +/- 3%); P = 0.31]. We conclude that high-protein meals do not enhance the stimulation of myofibrillar protein synthesis induced by resistance exercise.

Aged↗
PubMed1998

Relative stability of a minimal CTG repeat expansion in a large kindred with myotonic dystrophy.

The genetic basis for myotonic dystrophy (DM) is a CTG trinucleotide repeat expansion. The number of CTG repeats commonly increases in affected individuals of successive generations, in association with anticipation. We identified a large DM family in which multiple members had minimal CTG repeat expansions, and in which the number of CTG repeats remained in the minimally expanded range through at least three, and possibly four, generations. This relative stability of minimal CTG repeat expansions may help to maintain the DM mutation in the population.

Aged↗
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↗