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Biomedical subjects

C A Thornton

Publications and source records attributed to C A Thornton.

At least 19 recordsLinked to original sources
PubMed2006

Expression profile of FSHD supports a link between retinal vasculopathy and muscular dystrophy.

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is caused by deletions within a tandem array of D4Z4 repeats on chromosome 4q35. In addition to muscle degeneration, most patients with FSHD develop abnormalities of the retinal vasculature. Previous work has suggested that muscle degeneration in FSHD results from increased expression of genes proximal to the deletion, including FRG1. OBJECTIVES: To reexamine this mechanism and identify pathways that are abnormally regulated early in the disease process. METHODS: We prospectively studied gene expression in skeletal muscle in patients with FSHD (n = 19) vs healthy individuals (n = 30) and patients with myotonic dystrophy type 1 (n = 12). We used oligonucleotide microarrays for global analysis of gene expression and reverse transcriptase-PCR (RT-PCR) to assess expression or alternative splicing for particular genes. RESULTS: Expression of FRG1 was not increased in patients with FSHD, either by microarray analysis or quantitative RT-PCR. Among genes on 4q35, only LRP2BP showed upregulation that was specific to FSHD. However, neither LRP2BP nor FRG1 showed imbalance of allelic expression by RT-PCR. After filtering out genes that showed similar dysregulation in other forms of muscular dystrophy, only 44 genes were specifically upregulated early in FSHD. Among these, 34 genes were characterized or partially characterized, of which 11 (32%) had a role in vascular smooth muscle or endothelial cells. CONCLUSION: Expression of genes on chromosome 4q35 was normally regulated in the early stages of facioscapulohumeral muscular dystrophy. Our results support a possible link between muscular dystrophy and retinal vasculopathy in facioscapulohumeral muscular dystrophy.

Adolescent↗
PubMed2005

Quantitative analysis of the "warm-up" phenomenon in myotonic dystrophy type 1.

To quantitate improvement in hand-grip myotonia and muscle strength (i.e., the "warm-up" phenomenon) in myotonic dystrophy type 1 (DM1), six successive, standardized maximum voluntary isometric contractions (MVICs) were recorded on 2 separate days using a computerized isometric hand-grip myometer in 25 genetically confirmed DM1 patients and in 17 normal controls. An automated computer program placed cursors along the declining (relaxation) phase of the MVICs at 90%, 50%, and 5% of peak force (PF) and calculated relaxation times (RTs) between these points. Mean 90% to 5% RT (a measure of myotonia) rapidly declined from 2.5 s in MVIC 1 to 0.8 s in MVIC 6 (warm-up = 1.7 s) in DM1; in controls, it remained 0.4 s for all six MVICs (warm-up = 0). In DM1, 70% of warm-up occurred between MVIC 1 and 2, almost exclusively in the terminal 50% to 5% phase of muscle relaxation. Day 1 warm-up was highly correlated with the severity of myotonia, and with day 2 warm-up. Improvement in myotonia was not accompanied by either transient paresis or improvement in PF. We conclude that, with this testing paradigm: warm-up of myotonia in DM1 can be reliably measured; is proportional to severity of myotonia; occurs rapidly, being most prominent between the first and second grips; mainly results from shortening of the terminal phase of muscle relaxation; and is not accompanied by significant warm-up in force output.

Adult↗
PubMed2005

Exposure of the fetus and infant to hens' egg ovalbumin via the placenta and breast milk in relation to maternal intake of dietary egg.

BACKGROUND: Maternally derived allergens may be transferred to the developing infant during pregnancy and lactation. However, it is not known how manipulation of environmental allergen levels might impact on this early-life exposure. OBJECTIVE: To measure dietary egg allergen (ovalbumin (OVA)) in gestation-associated environments, in relation to maternal dietary egg intake. METHOD: OVA was measured by allergen-specific ELISA in maternal blood collected throughout pregnancy, infant blood at birth (umbilical cord) and in breast milk at 3 months post-partum. Samples derived from pregnant women undergoing diagnostic amniocentesis at 16-18 weeks gestation who were not subject to any dietary intervention, and from pregnant women, with personal or partner atopy, randomized to complete dietary egg exclusion or an unmodified healthy diet before 20 weeks gestation as a primary allergy prevention strategy. Maternal dietary egg intake was monitored closely throughout the study period by diary record and serial measurement of OVA-specific immunoglobulin G concentration. RESULTS: Circulating OVA was detected throughout pregnancy in 20% of women and correlated with both presence (P<0.001) and concentration (r=0.754, P<0.001) of infant OVA at birth (umbilical cord). At 3 months post-partum OVA was detected in breast milk samples of 35% women, in higher concentrations than measured in blood. Blood and breast milk OVA were not related to maternal dietary intake or atopic pre-disposition. CONCLUSIONS: Rigorous dietary egg exclusion does not eliminate trans-placental and breast milk egg allergen passage. This early-life exposure could modulate developing immune responses.

Allergens↗
PubMed2004

Leukocyte CTG repeat length correlates with severity of myotonia in myotonic dystrophy type 1.

OBJECTIVE: To quantitate hand muscle myotonia and to assess the relationship between CTG repeat length and myotonia in myotonic dystrophy type 1 (DM1). METHODS: First dorsal interosseous twitch and tetanic contractions evoked by single and 10-Hz ulnar nerve stimulation were recorded with a force transducer in 15 patients with genetically confirmed DM1 and 15 control subjects. An automated computer program analyzed three single and three tetanic recordings per subject on 2 successive days by placing cursors along the declining (relaxation) phase of the force recordings at 90, 50, and 5% of peak force (PF) and calculating relaxation times (RT) between these points. RESULTS: Tetanic and twitch RT was longer and PF lower in patients than subjects. RT (90 to 5%) was above the normal mean + 2.5 SD in 13 tetanic (87%) and 11 (73%) twitch patient recordings. In DM1, prolongation of RT was due mainly to delay in the terminal (50 to 5%), rather than the initial (90 to 50%) phase of relaxation, and was much greater in tetanic than single-twitch recordings. Mean test-retest variability was 19% for tetanic RT and 16% for tetanic PF. In DM1, both tetanic and twitch RT were positively correlated with leukocyte CTG repeat length. CONCLUSIONS: In DM1, myotonia of intrinsic hand muscles can be quantitated reliably by automated analysis of tetanic and twitch RT, targeting, in particular, the terminal phase of muscle relaxation after tetanic stimulation. Severity of hand muscle myotonia depends on CTG repeat length consistent with a "triplet repeat dosage" effect on chloride channel mRNA splicing and function.

Adult↗
PubMed2004

Ovalbumin-specific immunoglobulin G and subclass responses through the first 5 years of life in relation to duration of egg sensitization and the development of asthma.

BACKGROUND: Egg sensitization, particularly persistent sensitization, is a risk factor for later asthma. However, little is known about accompanying IgG and subclass responses and how they might relate to asthmatic outcome. OBJECTIVE: To characterize hen's egg ovalbumin (OVA) IgG and subclass responses through the first 5 years of life in relation to duration of egg sensitization and later asthma. SUBJECTS AND METHODS: The subjects (n=46) formed part of a larger cohort, born to atopic parents, who had been evaluated prospectively for the development of asthma. Egg sensitization was classified as transient (positive egg skin prick test at 1 year only) or persistent (positive skin test for at least 2 years). Plasma OVA IgG, IgG1 and IgG4 concentrations at birth (cord), 6 months, 1 and 5 years of age were measured by ELISA. RESULTS: The kinetics of OVA IgG and IgG1 responses, but not IgG4, differed between egg sensitized and non-egg sensitized (NES) children. Only persistently sensitized children had a rise in OVA IgG1 concentration through the first year of life, and at 1 year of age they had significantly higher OVA IgG and IgG1 than either transiently sensitized or NES children. High OVA IgG1 was associated with later asthma: at 1 year of age, OVA IgG1 greater than 14,500 U predicted asthma with a sensitivity 64% and specificity 74%. CONCLUSION: OVA IgG and subclass responses relate to the duration of egg sensitization. Measurement of OVA IgG1 concentration in infancy might offer a useful adjunct to identify those at an increased risk of asthma.

Antibody Specificity↗
PubMed2004

Serum ovalbumin-specific immunoglobulin G responses during pregnancy reflect maternal intake of dietary egg and relate to the development of allergy in early infancy.

BACKGROUND: The value of allergen elimination diets during pregnancy for primary prevention of infant allergy has been questioned. However, dietary compliance may influence effectiveness. OBJECTIVES: To monitor egg intake during a randomized controlled trial of egg avoidance throughout pregnancy and lactation by serial measurements of serum ovalbumin (OVA) IgG concentration in conjunction with dietary diary record and also, to analyse specific IgG concentrations at birth in relation to infant allergic outcome. METHODS: Pregnant women, with personal or partner atopy, were randomized to complete dietary egg exclusion or an unmodified healthy diet before 20 weeks gestation. The infants were evaluated for atopy at 6 months of age. Serum food-specific IgG concentrations were determined by ELISA in maternal samples collected at study recruitment and during labour, and in infant samples at birth (umbilical cord). RESULTS: Serum-specific IgG to OVA, but not the unrelated allergen, cow's milk beta-lactoglobulin, decreased over pregnancy in egg-avoiding women only (P<0.001). Cord OVA IgG concentration correlated with maternal IgG at delivery (r=0.944; P<0.001), and for infants born to atopic women, cord concentration was higher than that of their mother's (P<0.001). Infants with the lowest and highest cord IgG concentrations were the least likely, and those with mid-range concentrations were the most likely, to be atopic by 6 months of age (P=0.008). CONCLUSION: Serum OVA IgG concentration reflects egg consumption, thereby indicating dietary allergen doses to which the developing immune system might be exposed. Trans-placental maternal IgG must be considered among early life factors that regulate infant atopic programming.

Adult↗
PubMed2003

Fetal exposure to intact immunoglobulin E occurs via the gastrointestinal tract.

BACKGROUND: Consideration of the evolutionary significance of IgE might provide insight into the immunological interactions occurring in utero and during early post-natal life that regulate later atopic disease. OBJECTIVE: We postulated that the fetal gut is exposed to intact amniotic fluid IgE that might interact with local IgE receptors. METHODS: IgE levels in matched maternal blood and amniotic fluid (n = 47) or breast milk (n = 15) collected from pregnant women in the UK (Southampton) and Brazil (Sao Paulo) were studied. Expression of IgE receptors, Fc epsilon RI and Fc epsilon RII (CD23), in fetal gastrointestinal tract (n = 19) and skin (n = 11) was examined immunohistochemically. RESULTS: Human amniotic fluid at 16-18 weeks' gestation contained intact IgE at levels that increased as maternal circulating levels increased (Spearman's rho = 0.897; P < 0.001). Circulating IgE levels from women in Sao Paulo, Brazil, associated positively not only with term (> 37 weeks' gestation) amniotic fluid (rho = 0.993; P < 0.001) but also breast milk IgE levels (rho = 0.785; P = 0.001). Maternal levels of IgE did not change significantly over pregnancy and fetal circulating levels of IgE were very low (< 0.6 IU/mL). Low-affinity IgE receptors (CD23) were expressed in lymphoid follicles of the fetal gut from 16 weeks of gestation (6/8), but not from 11 to 16 weeks (0/11) or in the skin. CONCLUSION: Amniotic fluid contains intact IgE that might bind to CD23+ cells within the lymphoid follicles of the fetal gastrointestinal tract. The evolutionary significance of these interactions might be to prepare the immune system for helminthic parasite exposure at birth via IgE-mediated antigen focusing, or "education" of the developing immune system about the prevailing extrauterine environment. However, at present in societies where helminthosis is not a significant health issue, this pathway may still be operational and associated with the development of atopic disease.

Amniotic Fluid↗
PubMed2003

Neonatal interleukin-12 capacity is associated with variations in allergen-specific immune responses in the neonatal and postnatal periods.

BACKGROUND AND OBJECTIVES: A reduced capacity of antigen presenting cells (APC) to provide pro-T helper 1 (Th1) signals, such as IL-12, to T cells during early life may be implicated in the development of T helper 2 (Th2)-mediated allergic disease. In this study we examined the relationships between the capacity for IL-12 responses in the neonatal period and atopic risk (family allergy), in vitro T cell responses to allergens, and the subsequent development of allergic disease at 6 years. METHODS: The capacity of circulating neonatal (and maternal) APC to produce IL-12 p70 in response to LPS (and IFN-gamma) stimulation was assessed in a group of 60 children with previously well-characterized immune responses to allergens and atopic outcomes. The IL-12 responses were compared with allergen-induced lymphoproliferation (to house dust mite (HDM) ovalbumin (OVA), cat and beta-lactoglobulin (BLG)) and IL-13 and IFN-gamma cytokine responses (to OVA, HDM and phytohaemaglutinin (PHA)) in the neonatal and postnatal periods. IL-12 responses were also compared according to atopic risk and atopic outcomes (doctor-diagnosed asthma, eczema, food allergies and sensitization as evidenced by skin prick testing) at 6 years clinical follow-up. RESULTS: Maternal peripheral blood mononuclear cells (PBMC) synthesized significantly greater amounts of IL-12 than neonatal PBMC, though within maternal-infant pairs IL-12 responses were significantly correlated (r = 0.4, P = 0.019). Moreover, neonatal IL-12 responses were positively correlated with neonatal allergen proliferation for HDM (r = 0.6, P < 0.0001), OVA (r = 0.55, P < 0.0001), cat (r = 0.5, P = 0.003) and BLG (r = 0.55, P = 0.001), but negatively correlated with neonatal IL-13 responses to both allergens tested (HDM: r = - 0.4, P = 0.03 and OVA: r = - 0.5, P = 0.001). Both neonatal and maternal IL-12 responses were positively correlated with postnatal IFN-gamma responses to HDM at 12, 18 and 24 months of age (responses after age of 2 years were not assessed). There was no relationship between atopic risk and IL-12 capacity in the neonatal period, but there was a (non-significant) trend for neonatal IL-12 responses to be lower in the high-risk children who developed clinical allergy at 6 years (compared with the low risk group) although the number in this analysis was small. CONCLUSIONS: Reduced APC IL-12 production in the perinatal period was associated with reduced T cell activation (lymphoproliferation), stronger neonatal Th2 responses, and weaker Th1 responses to allergen in the postnatal period. This supports the notion that variations in APC function in early life may contribute to altered allergen-specific cytokine responses associated with later allergy.

Allergens↗
PubMed2002

Proximal myotonic myopathy: a syndrome with a favourable prognosis?

Cardiac involvement in myotonic dystrophy type 1 (DM1) is well known. In contrast, the severity and frequency of cardiac abnormalities in proximal myotonic myopathy (PROMM) are still unclear. To identify similarities and differences in the rate of progression of muscle weakness and cardiac disturbances in these two disorders, 16 patients with PROMM (3q-unlinked PROMM: n=10; uniformative for linkage: n=6) were compared to 33 patients with moderately severe myotonic dystrophy type 1 (DM1). There was no significant difference in disease duration between PROMM and DM1. Patients underwent serial manual muscle strength testing, EKG, 24-h Holter monitoring, 2D-echocardiography. Muscle weakness progressed slowly in both groups. Most DM1 patients developed conduction defects. No significant atrioventricular disturbances on initial and follow-up examinations were found in PROMM patients. One patient developed right bundle branch block. Many families with PROMM appear to have more benign cardiac manifestations and less severe prognosis compared to DM1. Further studies of subgroups of PROMM (linked to the 3q21 locus and without linkage) are necessary to determine whether the cardiac conduction disturbances are more common in a specific genotype of PROMM.

Adult↗
PubMed2002

Personal exposure monitoring of particulate matter, nitrogen dioxide, and carbon monoxide, including susceptible groups.

AIMS: To investigate the relation between personal exposures to nitrogen dioxide, carbon monoxide, and PM(10), and exposures estimated from static concentrations of these pollutants measured within the same microenvironments, for healthy individuals and members of susceptible groups. METHODS: Eleven healthy adult subjects and 18 members of groups more susceptible to adverse health changes in response to a given level of exposure to nitrogen dioxide, carbon monoxide, and/or PM(10) than the general population (six schoolchildren, six elderly subjects, and six with pre-existing disease-two with chronic obstructive pulmonary disease (COPD), two with left ventricular failure (LVF), and two with severe asthma) were recruited. Daytime personal exposures were determined either directly or through shadowing. Relations between personal exposures and simultaneously measured microenvironment concentrations were examined. RESULTS: Correlations between personal exposures and microenvironment concentration were frequently weak for individual subjects because of the small range in measured concentrations. However, when all subjects were pooled, excellent relations between measured personal exposure and microenvironment concentration were found for both carbon monoxide and nitrogen dioxide, with slopes of close to one and near zero intercepts. For PM(10), a good correlation was also found with an intercept of personal exposure (personal cloud) of 16.7 (SD 10.4) micro g/m(3). Modelled and measured personal exposures were generally in reasonably good agreement, but modelling with generic mean microenvironment data was unable to represent the full range of measured concentrations. CONCLUSIONS: Microenvironment measurements of carbon monoxide and nitrogen dioxide can well represent the personal exposures of individuals within that microenvironment. The same is true for PM(10) with the addition of a personal cloud increment. Elderly subjects and those with pre-existing disease received generally lower PM(10) exposures than the healthy adult subjects and schoolchildren by virtue of their less active lifestyles.

Adult↗
PubMed2001

Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2.

The phenotypes in myotonic dystrophy types 1 and 2 (DM1 and DM2) are similar, suggesting a shared pathophysiologic mechanism. DM1 is caused by expansion of a CTG repeat in the DMPK gene. Pathogenic effects of this mutation are likely to be mediated, at least in part, by the expanded CUG repeat in mutant mRNA. The mutant transcripts are retained in the nucleus in multiple discrete foci. We investigated the possibility that DM2 is also caused by expansion of a CTG repeat or related sequence. Analysis of DNA by repeat expansion detection methods, and RNA by ribonuclease protection, did not show an expanded CTG or CUG repeat in DM2. However, hybridization of muscle sections with fluorescence-labeled CAG-repeat oligonucleotides showed nuclear foci in DM2 similar to those seen in DM1. Nuclear foci were present in all patients with symptomatic DM1 (n = 9) or DM2 (n = 9) but not in any disease controls or healthy subjects (n = 23). The foci were not seen with CUG- or GUC-repeat probes. Foci in DM2 were distinguished from DM1 by lower stability of the probe-target duplex, suggesting that a sequence related to the DM1 CUG expansion accumulates in the DM2 nucleus. Muscleblind proteins, which interact with expanded CUG repeats in vitro, localized to the nuclear foci in both DM1 and DM2. These results support the idea that nuclear accumulation of mutant RNA is pathogenic in DM1, suggest that a similar disease process occurs in DM2, and point to a role for muscleblind in the pathogenesis of both disorders.

Adult↗
PubMed2001

A prospective natural history study of inclusion body myositis: implications for clinical trials.

Eleven patients with untreated inclusion body myositis (IBM) were prospectively studied during a 6-month period that included muscle strength, lean body mass, and muscle mass measurements. There was an overall quantifiable mean decline in percent of predicted normal muscle strength of 4% from baseline in a 6-month period, but one third of patients showed no change or slight improvements in strength. Short-term treatment trials in IBM will require large numbers of patients to detect slowing, arrest, or even slight improvement in muscle strength.

Aged↗
PubMed2001

Senescence-related changes in gene expression in muscle: similarities and differences between mice and men.

A microarray study of the effect of senescence in mice on gene expression in muscle has been published recently. The present analysis was done to evaluate the extent to which the age-related differences in gene expression in murine muscle are also evident in human muscle. RNA extracted from muscle of young (21-24 yr) and old men (66-77 yr) was studied both by serial analysis of gene expression (SAGE) and by oligonucleotide microarrays. SAGE tags were detected for 61 genes homologous to genes reported to be differentially expressed in young and old murine muscle. The microarray had probe sets for 70 homologous genes. For 17 genes, there was evidence for a similar age-related change in expression in muscles of mice and men. For 32 other genes, there was evidence that the effect of age on the level of expression is not the same in mice and men. There was no evidence that older human muscle has increased expression of the stress response genes that are increased in old murine muscle.

Adult↗
PubMed2001

Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVE: To determine the efficacy of IV immunoglobulin (IVIg) given patients with untreated chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: A randomized, double-blind, multicenter, investigator-initiated study compared IVIg (Aventis Behring LLC, King of Prussia, PA) with placebo (5% albumin). On days 1, 2, and 21, IVIg (1 g/kg) or placebo was given. The primary outcome measure was the change in muscle strength from baseline to day 42, using the average muscle score (AMS). Secondary outcome measures included change from baseline AMS at days 10 and 21, the Hughes' functional disability scale, forced vital capacity (FVC), and nerve conduction studies (NCS) of four motor nerves (median, ulnar, peroneal, and tibial). RESULTS: The patients (n = 33) were randomized. Of these, 30 (14 women, 16 men, aged 54 +/- 20 years, range 13 to 82) received IVIg and 23 were given placebo (12 women, 11 men, aged 50 +/- 18 years, range 23 to 73). Baseline AMS values of the groups were similar (IVIg 7.06 +/- 1.31 versus placebo 7.28 +/- 1.18, p = 0.53). There were two dropouts in placebo group and one in the IVIg group. Mean AMS improved at day 42 comparing IVIg with placebo (0.63 versus -0.1, p = 0.006). Improved strength was seen by day 10. The placebo group lost strength over this same interval. In the IVIg, 11 subjects improved by the functional disability scale; none worsened. This differed (p = 0.019) from those in the placebo-treated group (two improved, two got worse, remainder unchanged). Forced vital capacity did not improve with IVIg treatment. IVIg improved ulnar motor distal latency (p = 0.005), tibial distal compound muscle amplitude (p = 0.003), and peroneal nerve conduction velocity (p = 0.03). CONCLUSIONS: IVIg improves strength in patients with untreated CIDP by day 10 with continued benefit through day 42; more than one third improve by at least a functional grade on a disability scale. This study provides data supporting IVIg as the initial treatment for CIDP.

Adolescent↗
PubMed2000

Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat.

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adult humans, results from expansion of a CTG repeat in the 3' untranslated region of the DMPK gene. The mutant DMPK messenger RNA (mRNA) contains an expanded CUG repeat and is retained in the nucleus. We have expressed an untranslated CUG repeat in an unrelated mRNA in transgenic mice. Mice that expressed expanded CUG repeats developed myotonia and myopathy, whereas mice expressing a nonexpanded repeat did not. Thus, transcripts with expanded CUG repeats are sufficient to generate a DM phenotype. This result supports a role for RNA gain of function in disease pathogenesis.

3' Untranslated Regions↗
PubMed2000

Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy.

Myotonic dystrophy (DM1) is an autosomal dominant neuromuscular disorder associated with a (CTG)(n) expansion in the 3'-untranslated region of the DM1 protein kinase (DMPK) gene. To explain disease pathogenesis, the RNA dominance model proposes that the DM1 mutation produces a gain-of-function at the RNA level in which CUG repeats form RNA hairpins that sequester nuclear factors required for proper muscle development and maintenance. Here, we identify the triplet repeat expansion (EXP) RNA-binding proteins as candidate sequestered factors. As predicted by the RNA dominance model, binding of the EXP proteins is specific for dsCUG RNAs and proportional to the size of the triplet repeat expansion. Remarkably, the EXP proteins are homologous to the Drosophila muscleblind proteins required for terminal differentiation of muscle and photoreceptor cells. EXP expression is also activated during mammalian myoblast differentiation, but the EXP proteins accumulate in nuclear foci in DM1 cells. We propose that DM1 disease is caused by aberrant recruitment of the EXP proteins to the DMPK transcript (CUG)(n) expansion.

Amino Acid Sequence↗