PubMed Health⌕ Search

Biomedical subjects

J W Gregory

Publications and source records attributed to J W Gregory.

At least 19 recordsLinked to original sources
PubMed2006

A new form of familial multi-nodular goitre with progression to differentiated thyroid cancer.

We report a kindred with euthyroid multi-nodular goitre (MNG) of adolescent onset. Two of the seven subjects with MNG have progressed to papillary thyroid cancer. One affected male had nodular kidney disease, and breast cancer occurred in one affected female. Genes that were candidates on the basis of the associated kidney (PAX8) and breast diseases (sodium iodide symporter (NIS)), were sequenced. No mutations were found in the coding region, intron/exon splice sites or in the promoter sequences (from -1248 relative to the translation initiation codon) of PAX8. Similar results were obtained for NIS. Subsequently, microsatellite analyses were performed on 14 informative family members. We used 2 to 3 markers per locus for 6 loci (on chromosomes 1,2,3,14,19,X) previously reported to predispose to MNG and/or familial non-medullary thyroid cancer (FNMTC). On the basis of non-significant logarithm of the odds ratio (LOD) scores or inheritance of different alleles in affected individuals, all loci have been excluded. Thyroidectomy specimens from three members of the kindred show multiple benign lesions, with papillary cancer in two. The morphological features do not resemble those seen in familial adenomatous polyposis, Cowden syndrome, or in multiple oxyphil lesions. From these findings and from the absence of any linkage to any of the known loci associated with MNG or FNMTC, we suggest that this represents a new form of inherited MNG with a significant risk of progression to papillary carcinoma.

Adolescent↗
PubMed2005

Clinical features, diagnosis and molecular studies of familial central diabetes insipidus.

BACKGROUND: Familial central diabetes insipidus (DI) is rare and is characterised by polydipsia and polyuria with a variable age of onset. The evaluation of arginine vasopressin (AVP) secretion in these individuals has been reported infrequently and only in adulthood. OBJECTIVE: To describe the clinical features, diagnosis and molecular investigation of children affected by familial central DI. METHODS: Functional studies of AVP secretion were undertaken in children from two kindreds with familial central DI. The AVP-neurophysin II (AVP-NPII) gene was also sequenced in symptomatic individuals. RESULTS: In affected individuals, the result of the water deprivation test may be inconclusive. However, the hypertonic saline test identified both the severe and partial forms of AVP deficiency. A novel mutation of the AVP-NPII gene was identified by direct gene sequencing in both families. CONCLUSIONS: This report highlights the progressive decline in AVP secretion with increasing age in this disorder and the usefulness of mutational analysis in these families. In symptomatic individuals, the hypertonic saline test may be a useful second-line investigation for functional studies of AVP secretion where molecular diagnostics are unavailable.

Arginine Vasopressin↗
PubMed2005

Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic beta-cell adenosine triphosphate-sensitive potassium channels.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is clinically and genetically heterogeneous. Hyperinsulinemic hypoglycemia occurs in about 50% of children with BWS and, in the majority of infants, it resolves spontaneously. However, in a small group of patients the hypoglycemia can be persistent and may require pancreatectomy. The mechanism of persistent hyperinsulinemic hypoglycemia in this group of patients is unclear. PATIENTS AND METHODS: Using patch-clamp techniques on pancreatic tissue obtained at the time of surgery, we investigated the electrophysiological properties of ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells in a patient with BWS and severe medically-unresponsive hyperinsulinemic hypoglycemia. RESULTS: Persistent hyperinsulinism was found to be caused by abnormalities in K(ATP) channels of the pancreatic beta-cell. Immunofluorescence studies using a SUR1 antibody revealed perinuclear pattern of staining in the BWS cells, suggesting a trafficking defect of the SUR1 protein. No mutations were found in the genes ABCC8 and KCNJ11 encoding for the two subunits, SUR1 and KIR6.2, respectively, of the K(ATP) channel. Genetic analysis of this patients BWS showed evidence of mosaic paternal isodisomy. CONCLUSIONS: In this novel case of BWS with mosaic paternal uniparental disomy for 11p15, persistent hyperinsulinism was due to abnormalities in K(ATP) channels of the pancreatic beta-cell. The mechanism/s by which mosaic paternal uniparental disomy for 11p15 causes a trafficking defect in the SUR1 protein of the K(ATP) channel remains to be elucidated.

ATP-Binding Cassette Transporters↗
PubMed2005

Bone mass acquisition in healthy children.

Although 80% of the variance in bone mass is determined genetically, there are many other factors which influence the accumulation of bone in early life and affect future risks of osteoporosis. This review considers the genetic, fetal, and environmental influences on bone mass acquisition in healthy children, and highlights important areas where paediatricians may have a role by counselling children and their families to adopt a healthy lifestyle which promotes bone health.

Adolescent↗
PubMed2005

Are factors at diagnosis of growth hormone deficiency in childhood associated with persistence of growth hormone deficiency into adult life?

A proportion of children with growth hormone deficiency (GHD) have persistence of GHD as young adults. To date, no markers have been shown in childhood to have predictive value in determining persistence of GHD into adult life. We examined the hypothesis in 31 patients that variables present at the time of diagnosis of childhood-onset GHD, or those related to the early response to growth hormone (GH) therapy, are associated with the likelihood of persistence of GHD. The results show that, as previously demonstrated, children with GHD are more likely to have persistent severe GHD in adult life when the diagnosis is associated with other pituitary hormone deficiencies (p = 0.02), abnormal pituitary neuroimaging (p = 0.003), induced puberty (p = 0.001), early age of diagnosis (p = 0.03) and lower peak GH response at the first dynamic GH test in childhood (p = 0.02). However, there are no associations of persistent severe GHD with the pattern of pretreatment growth or growth response to GH treatment in the initial phase.

Adult↗
PubMed2004

Osteopenia, excess adiposity and hyperleptinaemia during 2 years of treatment for childhood acute lymphoblastic leukaemia without cranial irradiation.

OBJECTIVE: Osteopenia and excess adiposity occur following treatment of childhood acute lymphoblastic leukaemia (ALL) and the use of cranial irradiation is thought to be a significant contributory factor. Hyperleptinaemia has also been demonstrated following cessation of treatment for childhood ALL. Therefore a prospective study was undertaken to evaluate serial changes in percentage bone mineral content (BMC), adiposity and serum leptin concentrations during 2 years of treatment of children with ALL with chemotherapy but without cranial irradiation. DESIGN AND PATIENT: Only patients treated using the MRC ALL 97/ALL 97 (modified 99) protocols for childhood ALL were eligible for entry into the study. A total of 14 patients (seven male, with a median age of 7.5 years (range 3.4-16.7 years) were recruited. Serial dual energy X-ray absorptiometry (DEXA) scanning was undertaken at diagnosis and during two years of treatment. Serum leptin concentrations were determined at the same time as the scans. RESULTS: Reductions in %BMC were observed at the hip and lumbar spine by 12 months (P < 0.01) and remained low after 24 months of treatment. Subanalysis of %BMC measurements at the hip demonstrated a greater reduction in %BMC at the trochanteric region compared to the femoral neck. The percentage corrected fat mass increased from 6 months whereas the body mass index (BMI) standard deviation score (SDS) was increased after 24 months of treatment (P < 0.05). Serum leptin concentrations increased following 24 months of therapy (P < 0.05). CONCLUSIONS: Children treated for ALL with contemporary regimens have a predisposition to osteopenia, excess adiposity and hyperleptinaemia during treatment without cranial irradiation administration. We speculate that in addition to glucocorticoid administration, leptin resistance may account in part for these observations.

Adolescent↗
PubMed2004

Childhood diabetes: parents' experience of home management and the first year following diagnosis.

AIMS: To explore parents' experience of having a child diagnosed with Type 1 diabetes, managed at home, and their first year following diagnosis. METHODS: A qualitative, longitudinal study based on 40 in-depth interviews with parents of 20 children with newly diagnosed Type 1 diabetes managed at home from diagnosis in South Wales. RESULTS: Many parents were alarmed by the speed of diagnosis following the gradual progress of their child's symptoms. The provision of timely, adequate information was important to all parents. Although five parents had initial concerns about going home, all parents were subsequently pleased their children had not been hospitalized. Home management enabled parents to integrate diabetes management into the family's normal lifestyle from diagnosis. Professional support, particularly accessible telephone advice, was valued by and reassured parents. Parents experienced a loss of spontaneity, a continuing fear of hypoglycaemia and did not want their child to feel different to other children. Acutely aware of the seriousness of diabetes, they did their utmost to achieve optimal glycaemic control but felt that diabetes could not 'dominate' if they were to lead a 'normal' life. CONCLUSIONS: The experience of parents in this study suggests that parents of children with newly diagnosed diabetes are able to cope successfully when given the opportunity to start treatment at home. Therefore, if children with diabetes are clinically well at diagnosis, this study supports home management as a system of care from the parents' point of view. These findings are relevant to clinicians, policy makers and health service managers involved in planning and providing paediatric diabetes care.

Adolescent↗
PubMed2004

Management of newly diagnosed diabetes: home or hospital?

Type 1 diabetes is one of the most common chronic childhood disorders, occurring with increasing frequency. Diabetes management involves the child and family learning how to inject insulin and monitor blood glucose, and adhere to a diet containing healthy food choices. Medical interventions necessary to stabilise newly diagnosed diabetes depend upon the clinical condition of the child at presentation. Hospital admission is necessary if intravenous therapy is required to correct dehydration, electrolyte imbalance, and ketoacidosis, with progression to oral fluids and subcutaneous insulin administration as the child's condition improves. If the child is mildly to moderately symptomatic and clinically well, subcutaneous insulin and oral diet and fluids may be begun from the time of diagnosis, and stabilisation at diagnosis does not necessarily require hospital admission. This article reviews the evidence concerning hospital or home based treatment at diagnosis for children with type 1 diabetes. The Cardiff approach to home management is briefly described, and the benefits and disadvantages of different approaches to initial management are discussed.

Diabetes Mellitus, Type 1↗
PubMed2004

The investigation of short stature: a survey of practice in Wales and suggested practical guidelines.

AIM: To survey the investigation of short stature in Wales and suggest guidelines to improve practice. METHODS: Questionnaires were circulated to paediatricians and consultant clinical biochemists or consultant chemical pathologists at 13 Welsh hospitals where children with short stature are investigated. RESULTS: A 100% response was obtained from laboratory and clinical staff. Clinicians screened 1-50 patients each year (median, 10). Growth hormone (GH) deficiency was subsequently diagnosed in 0-30% (median, 10%) and GH treatment started in 30-100% (median, 100%) of patients. Five paediatricians and eight laboratories had written investigative protocols. Investigation of GH secretion was initiated in some centres before a complete clinical evaluation was carried out. Various screening tests for GH deficiency, including insulin-like growth factor 1 (IGF-1), random GH, and exercise tests were used. The clonidine stimulation test was used to assess the GH axis in most centres but eight different protocols were described. GH was measured in four Welsh laboratories using two automated immunoassay methods. However, nine different ranges of cutoff values for defining abnormal GH responses were quoted, and in three centres laboratories and paediatricians quoted different cutoffs. CONCLUSION: This survey demonstrates the need for practical guidelines for the investigation and management of short stature in children, agreed by paediatricians and their laboratory colleagues. The guidelines should encompass the initial clinical investigation, assessment of the GH-IGF-1 axis (using standardised protocols), and provision for the transition to adult management. This article presents practical guidelines based on published points for good practice.

Child↗
PubMed2004

Pitfalls in the assessment of body composition in survivors of acute lymphoblastic leukaemia.

BACKGROUND: Body fat mass (FM) and fat free mass (FFM) in childhood are often estimated by conversion of a measured variable into compartmental body composition using constants or regression equations that have been previously derived in healthy individuals. Application of such constants or equations to children with disease states may lead to inappropriate conclusions since the "normal" relationships may become altered. AIMS AND METHODS: To test this hypothesis by taking measurements of body composition using dual energy x ray absorptiometry (DEXA) as a "gold standard" method and calculating hydration and body potassium constants using isotopic water dilution and whole body potassium counting. Measurements of bioelectrical impedance (BIA) by two different analysers (RJL and Holtain) were also performed to allow comparison with body water measurements. RESULTS: Measurements were performed in 35 children treated for acute lymphoblastic leukaemia (ALL) and compared to those in 21 children treated for a variety of other malignancies and 32 healthy sibling controls. The mean hydration and potassium content of FFM was significantly reduced in the ALL group compared to both other malignancies and controls. Application of equations derived from controls for the measurement of FFM derived from bioelectrical impedance led to an underestimation of 1.15 kg when compared to that derived from DEXA in children treated for ALL but not in other malignancies. For all groups combined, BIA was significantly different in the two analysers. CONCLUSION: Care needs to be taken in the application of equations derived from the normal population to body composition measurement in children treated for ALL.

Absorptiometry, Photon↗
PubMed2003

Hypoparathyroidism and 22q11 deletion syndrome.

AIMS: To investigate a population of individuals with 22q11 deletion syndrome for hypocalcaemia. METHODS: A detailed clinical history enquiring into symptoms of hypocalcaemia and blood sampling to assess for hypocalcaemia and hypoparathyroidism, of patients outside the neonatal period known to have the 22q11 microdeletion from fluorescent in situ hybridisation studies was taken. RESULTS: Sixty one individuals were identified, of whom 23 were untraceable and one was unable to give informed consent. Biochemical investigations were performed on 27 subjects. Ten subjects had review of notes only. Four subjects had previously identified hypoparathyroidism. A new case of hypoparathyroidism was identified. Three subjects had borderline hypocalcaemia. DISCUSSION: In this population of patients with 22q11 deletion syndrome, 13% of the total or 30% of those biochemically assessed had evidence of reduced serum calcium concentrations. It is likely that 13-30% of patients with 22q11 deletion syndrome have possible hypoparathyroidism outside the neonatal period. Reported symptoms of hypocalcaemia did not correlate with biochemical evidence of persisting hypocalcaemia. We have shown that previously undiagnosed asymptomatic hypoparathyroidism occurs in patients with 22q11 deletion syndrome and conclude that screening of this population should be considered.

Adolescent↗
PubMed2003

A pilot study of motivational interviewing in adolescents with diabetes.

AIMS: To obtain preliminary data on the impact of motivational interviewing, a counselling approach to behaviour change, on glycaemic control, wellbeing, and self-care of adolescents with diabetes. METHODS: Twenty two patients aged 14-18 years participated in motivational interviewing sessions during a six month intervention. The effects of the intervention on HbA1c and a range of psychological factors were assessed. RESULTS: Mean HbA1c decreased from 10.8% to 9.7% during the study and remained significantly lower after the end of the study. Fear of hypoglycaemia was reduced and diabetes was perceived as easier to live with. There were no other significant changes in the psychological measures. By contrast no reduction in HbA1c values was observed in a comparison group who did not receive the motivational interviewing intervention. CONCLUSION: The findings of this pilot study indicate that motivational interviewing may be a useful intervention in helping adolescents improve their glycaemic control. A larger, longer term randomised controlled study is indicated to clarify the mechanisms and extent of these benefits.

Adolescent↗
PubMed2003

The W546X mutation of the thyrotropin receptor gene: potential major contributor to thyroid dysfunction in a Caucasian population.

Congenital hypothyroidism (CH) occurs in approximately 1 in 3000 births and can be caused by mutations in 9 known genes, including that encoding the TSH receptor (TSHR). We report on two Welsh siblings, detected by neonatal screening, who had normal sized and placed glands but negative isotope uptake. Genomic DNA was obtained from both siblings and parents, the TSHR amplified using pairs of intronic and/or overlapping exonic primers and the PCR products sequenced automatically. Both siblings were homozygous for a previously described G to A transition producing a missense mutation, W546X, in the fourth membrane spanning region of the TSHR, rendering it unresponsive to TSH. Both parents were heterozygous and unrelated; furthermore, the W546X has been described in three further families (one of which is Welsh), suggesting that it may be a relatively common mutation. We genotyped 368 euthyroid Welsh individuals using single nucleotide primer extension, and found 366 homozygous wild-type (G:G) and 2 heterozygous (G:A) for the mutation. In conclusion, CH in the siblings is due to the missense mutation, W546X, in their TSHR gene. The W546X allele was detected in approximately 1 in 180 individuals and may be a major contributor to hypothyroidism in the Welsh population.

Alleles↗
PubMed2003

Effects of chemotherapeutic agents on the function of primary human osteoblast-like cells derived from children.

Studies in children treated with chemotherapy suggest that chemotherapeutic agents have deleterious effects on bone metabolism. We therefore evaluated the in vitro effects of clinically relevant concentrations of chemotherapeutic agents on the synthesis of type I collagen, alkaline phosphatase (AP) activity, and mineralization by primary human osteoblast-like (HOB) cells derived from children. Because serum 1,25-dihydroxyvitamin D(3) concentrations may be reduced during treatment with chemotherapy, the effect of chemotherapeutic agents on HOB cells cultured in the presence or absence of 1,25-dihydroxyvitamin D(3) was also evaluated. Type I collagen synthesis was reduced by all agents (P < 0.01) other than methotrexate, whereas the relative AP activity was increased (P < 0.01) by all agents. The relative number of cells staining intensely for AP after culture with agents increased (P < 0.05), and AP mRNA expression was increased (P < 0.01) with vincristine. 1,25-Dihydroxyvitamin D(3) ameliorated (P < 0.01) the depletion of HOB cell numbers by chemotherapeutic agents. Furthermore, vincristine and daunorubicin inhibited 1,25-dihydroxyvitamin D(3)-mediated AP activity (P < 0.01). We conclude that chemotherapeutic agents can adversely affect HOB cell function, and we speculate that this observation may account, in part, for the osteopenia observed during and after treatment of children with chemotherapy.

Adolescent↗