Biomedical subjects

Nuala Murphy

Publications and source records attributed to Nuala Murphy.

9 recordsLinked to original sources

PubMed2006

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in the Irish population.

OBJECTIVE: To determine the Irish prevalence of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), the AIRE mutations involved and clinical features of this population. METHODS: All patients were identified through paediatricians and endocrinologists in Ireland. Patients were invited to attend a multidisciplinary clinic. RESULTS: Thirty-one patients (2-56 years), 18 female, were identified from 19 families giving an Irish prevalence of 1:130,000. Twenty-six patients had hypoparathyroidism, 21 had adrenal insufficiency (AI) and 10 of 16 had ovarian failure. Three affected patients have died. Many with hypoparathyroidism were resistant to 1-alpha-vitamin D. Two needed daily PTH injections. Mineralocorticoid deficiency as the first manifestation of AI was common. Chronic intra-oral candidiasis affected 25 patients and three had leukoplakia. Two had keratoconjuntivitis. Of 22 with AIRE gene analysis, three different mutations were identified, one of which is novel. CONCLUSION: APECED is rare in Ireland. We saw a significant amount of non-endocrine disease but no ectodermal dystrophy. AIRE gene analysis reassured many siblings and identified individuals with APECED prior to any symptoms.

Adolescent↗

PubMed2005

Dietary antioxidants decrease serum soluble adhesion molecule (sVCAM-1, sICAM-1) but not chemokine (JE/MCP-1, KC) concentrations, and reduce atherosclerosis in C57BL but not apoE*3 Leiden mice fed an atherogenic diet.

Dietary antioxidants are reported to suppress cellular expression of chemokines and adhesion molecules that recruit monocytes to the artery wall during atherosclerosis. In the present study we measured the effect of feeding apoE*3 Leiden mice or their non-transgenic (C57BL) littermates with atherogenic diets either deficient in, or supplemented with, dietary antioxidants (vitamin E, vitamin C and beta-carotene) for 12 weeks, on serum levels of CC (JE/MCP-1) and CXC (KC) chemokines and soluble adhesion molecules (sVCAM-1, sICAM-1) and atherosclerotic lesion size. ApoE*3 Leiden mice developed gross hypercholesterolaemia, and markedly accelerated (10-20 fold; P < 0.0001) atherogenesis, compared with non-transgenic animals. Antioxidant consumption reduced lesion area in non-transgenic, but not apoE*3 Leiden, mice. Serum sVCAM-1 and sICAM-1 levels were significantly (P<0.0001) increased (sVCAM-1 up to 3.9 fold; sICAM-1 up to 2.4 fold) by 4-8 weeks in all groups, and then declined. The initial increase in the concentration of adhesion molecules was reduced by 38%-61% (P < 0.05) by antioxidant consumption, particularly in non-transgenic mice. By contrast, serum chemokine levels tended to increase more rapidly from baseline in apoE*3 Leiden mice, compared with non-transgenic animals, but were unaffected by dietary antioxidants. We conclude that dietary antioxidants reduce circulating soluble adhesion molecules and atherosclerosis in C57BL mice.

Animal Feed↗

PubMed2004

Biochemical diagnosis of Antley-Bixler syndrome by steroid analysis.

Antley-Bixler syndrome (ABS, MIM 207410) is a skeletal abnormality syndrome primarily affecting head and limbs. Little is known of the origin of the condition but inactivating mutations in the fibroblast growth factor receptor (FGFR2) has been found in some patients. Genital ambiguity is seen occasionally in this condition, suggesting possible disordered steroidogenesis in early pregnancy. We report the steroid excretion of eight patients diagnosed with the syndrome and one with a related condition, a mild phenotype of the disorder since skeletal and genital abnormalities were not evident. The steroid excretion pattern was consistent and very distinctive in all nine patients. Metabolites of the two primary precursors of steroid hormones, pregnenolone and progesterone, were elevated as were the classical diagnostic metabolites for 17- and 21-hydroxylase deficiencies. Cortisol production was typically within the normal range but generally had blunted response to ACTH. Androgen metabolite excretion tends to be low in patients over 2 months of age, but may be elevated in the newborn period. The metabolome suggested attenuated steroid hydroxylation (including 17,20-lyase activity) although underlying cause is yet to be established. Mutations in CYP17 and CYP21 have not been found and currently the prime suspect is an abnormality in an essential redox partner (P450 oxidoreductase). This paper proposes use of the distinctive steroid metabolome as the primary biochemical parameter for diagnosis of ABS, at least the form not associated with FGFR2 mutations.

Abnormalities, Multiple↗

PubMed2004

Triglyceride-rich lipoproteins inhibit cholesterol efflux to apolipoprotein (apo) A1 from human macrophage foam cells.

High circulating levels of triglyceride-rich lipoproteins (TGRL) represent an independent risk factor for coronary artery disease. Here, we show that TGRL inhibit the efflux of cholesterol from 'foam cell' macrophages to lipid-poor apolipoprotein (apo) A1, and may thereby inhibit arterial reverse cholesterol transport and promote the formation of atherosclerotic lesions. Human (THP-1) monocyte-derived macrophages were pre-incubated (48 h) with acetylated low-density lipoprotein (AcLDL) to provide a foam cell model of cholesterol efflux to apoA1. Pre-incubation of macrophage 'foam cells' with TGRL (0-200 microg/ml, 0-24 h) inhibited the efflux of exogenously radiolabelled ([3H]), endogenously synthesised ([14C]) and cellular cholesterol mass to lipid-poor apoA1, but not control medium, during a (subsequent) efflux period. This inhibition is dependent upon the length of prior exposure to, and concentration of, TGRL employed, but is independent of changes in intracellular triglyceride accumulation or turnover of the cholesteryl ester pool. Despite the negative impact of TGRL on cholesterol efflux, major proteins involved in this process--namely apoE, ABCA1, SR-B1 and caveolin-1--were unaffected by TGRL pre-incubation, suggesting that exposure to these lipoproteins inhibits an alternate, and possibly novel, anti-atherogenic pathway.

Analysis of Variance↗

PubMed2004

The hypothalamic-pituitary-thyroid axis in preterm infants; changes in the first 24 hours of postnatal life.

The purpose of this study was to measure serum T4, free T4, TSH, T3, rT3, T4 sulfate, and thyroxine binding globulin at four time points within the first 24 h of life (cord and 1, 7, and 24 h) in infants between 24 and 34 wk gestation. The infants were subdivided into gestational age groups: 24-27 wk (n = 22); 28-30 wk (n = 26); and 31-34 wk (n = 24). The TSH surge in the first hour of postnatal life was markedly attenuated in infants of 24-27 wk gestation [8 compared with 20 (28-30 wk) and 23 mU/liter (31-34 wk)]. T4 levels in the most immature group declined over the first 24 h, whereas levels increased in the more mature groups [mean cord and 24-h levels: 65 and 59 (NS) vs. 70 and 84 (P < 0.002) vs. 98 and 125 (NS) nmol/liter]. Free T4 and T3 showed only small, transient increases in the most immature group and progressively larger and sustained increases in the other gestational groups. rT3 and T4 sulfate levels in cord serum were higher in the most immature infants, and in all groups levels decreased initially and then variably increased. The features of a severely attenuated or failed hypothalamic-pituitary-thyroid response to delivery critically define this 24- to 27-wk group as distinct from more mature preterm infants.

Humans↗

PubMed2004

Developmental trends in cord and postpartum serum thyroid hormones in preterm infants.

The purpose of this study was first to clarify postnatal trends in sera T(4), free T(4) (FT(4)), T(4)-binding globulin, TSH, T(3), rT(3), and T(4) sulfate levels in cord and at 7, 14, and 28 d in groups of preterm infants at 23-27 wk (n = 101), 28-30 wk (n = 196), and 31-34 (n = 253) wk gestation, and second to compare these trends to those of term infants and also with cord sera levels of equivalent gestational ages (n = 812; 23-42 wk gestation). In all preterm groups, TSH and rT(3) decrease to below, T(4)-binding globulin increases to within, and T(3) and T(4) sulfate increase to above cord levels of equivalent gestational age. Term infants are hyperthyroxinemic relative to cord and nonpregnant adult levels of T(4). Postnatal T(4) increases are attenuated in 31- to 34-wk infants, absent in 28- to 30-wk infants (although levels are equivalent to gestational age), and crucially reversed in 23- to 27-wk infants. This immature group is hypothyroxinemic relative to other groups and to cord levels of equivalent gestational age. Compared with term infants, postnatal FT(4) increases are lower in 31- to 34-wk infants, attenuated in 28- to 30-wk infants, and absent in 23- to 27-wk infants. The 23- to 27-wk group is distinctive; they are hypothyroxinemic on T(4) levels, yet FT(4) levels are within the cord levels of equivalent gestational age.

Fetal Blood↗

PubMed2003

Temporal relationships between circulating levels of CC and CXC chemokines and developing atherosclerosis in apolipoprotein E*3 Leiden mice.

OBJECTIVE: CC and CXC chemokines are implicated in leukocyte recruitment during development of atherosclerotic lesions, suggesting circulating levels of chemokines may be useful serum markers of atherogenesis. Serum chemokine concentrations were measured in apolipoprotein (apo) E*3 Leiden mice and their nontransgenic littermates and related to the differing rates of atherogenesis in these animals. METHODS AND RESULTS: Mice were fed a high-fat, high-cholesterol/cholate (HFC/C) diet for 18 weeks. Circulating levels of JE/monocyte chemotactic protein-1 increased (P<0.05) after 2 to 4 weeks, coincident with development of diet-induced hypercholesterolemia, and remained elevated throughout the study. Circulating KC concentrations increased (P<0.05) after consumption of HFC/C diet; however, unlike JE, serum KC concentrations increased more rapidly in apoE*3 Leiden mice than their nontransgenic littermates. Hepatic expression of JE and KC mRNA were detected by in situ hybridization in all mice fed HFC/C diet. Aortic expression of JE mRNA was seen only in apoE*3 Leiden mice within macrophage-rich atherosclerotic lesions. By contrast, no aortic expression of KC mRNA was detected by in situ hybridization. CONCLUSIONS: Increases in serum chemokine concentrations did not reflect temporal aortic production of these molecules and proved less predictive than serum cholesterol of the markedly different extent of atheroma in apoE*3 Leiden and nontransgenic mice.

Animals↗

PubMed2002

Hypercholesterolaemia and circulating levels of CXC chemokines in apoE*3 Leiden mice.

Hyperlipidaemia may accelerate the development of atherosclerosis by enhancing the expression of chemokines by cells within the arterial wall. Chemokines of the CC subfamily are clearly implicated in atherogenesis; however, recent reports suggest that CXC chemokines may play a hitherto unrecognised role in monocyte recruitment into atheromatous lesions expressing these molecules. Here, we examine whether circulating levels of CXC chemokines may reflect the pathogenic changes occurring during early atherogenesis. ApoE*3 Leiden mice developed marked hypercholesterolaemia, and early Type I 'fatty streak' lesions, following consumption of an atherogenic diet high in saturated fat and cholesterol, and containing sodium cholate, for up to 4 weeks. By contrast, their non-transgenic littermates (C57BL/6J) exhibited a much less pronounced hypercholesterolaemia and did not develop fatty streak lesions, when fed the same diet. Under these conditions, serum concentrations of CXC chemokines, KC and Macrophage Inflammatory Protein-2 (MIP-2) were significantly (P<or=0.0005) elevated in apoE*3 Leiden mice consuming HFC/C diet, compared with apoE*3 Leiden mice consuming a chow diet. Further, serum concentrations of KC were significantly (P<0.02) higher at 4 weeks in apoE*3 Leiden mice fed HFC/C diet compared with their non-transgenic littermates consuming the same diet. Expression of KC mRNA was detected in both aortic and hepatic tissues of apoE*3 Leiden mice, and the non-transgenic controls. Thus, hypercholesterolaemia is associated with elevated serum concentrations of CXC chemokines, KC and MIP-2 that probably reflect chronic inflammation during atherogenesis.

Animals↗

PubMed2002

A longitudinal study of the effects of a gluten-free diet on glycemic control and weight gain in subjects with type 1 diabetes and celiac disease.

OBJECTIVE: To describe the longitudinal growth characteristics and glycemic control in type 1 diabetic children diagnosed with celiac disease and started on a gluten-free diet (GFD). RESEARCH DESIGN AND METHODS: Data on growth and glycemic control for 11 case subjects diagnosed with celiac disease (cd(+) group) and started on a GFD were collected prospectively, and two control subjects without celiac disease matched for age, sex, and duration of diabetes (cd(-) group) were selected for comparison. RESULTS: In the period between diagnosis of type 1 diabetes and start of a GFD in the cd(+) compared with the cd(-) group, BMI standard deviation score (SDS) was lower (-0.2 vs. 0.7, P = 0.015), as was HbA(1c) (8.9 vs. 9.8%, P = 0.002). In a regression model the cd(+) group had lower BMI SDS (P < 0.001) and lower HbA(1c) (P = 0.04), independent of other variables. On a GFD, BMI SDS increased by 12 months in the cd(+) group and then was no different than the cd(-) group (1.1 vs. 1.0, P = 0.11), whereas HbA(1c) improved further within case subjects compared with pre-GFD (8.9 vs. 8.3%, P = 0.002). On a GFD, case subjects in contrast to control subjects showed no deterioration in HbA(1c) during the years of puberty (8.3 vs. 10.0%, P = 0.022) CONCLUSIONS: In children with type 1 diabetes, untreated celiac disease resulted in lower BMI SDS and lower HbA(1c). Recovery of BMI SDS with a GFD was associated with further improvement in HbA(1c) as compared with pre-GFD, with no expected deterioration in glycemic control during puberty. These apparent clinical benefits need confirming by larger studies.

Adolescent↗