We studied interrelationships between maternal and neonatal thyroid function, TSH receptor binding inhibiting immunoglobulins (TBII), and dose of thionamide antithyroid drugs in 44 women with active Graves' disease presenting during 46 pregnancies, and their 48 infants. The women were treated with propylthiouracil (PTU) or carbimazole (CBZ). In 30 pregnancies (30 infants) treatment was withdrawn from 3 to 18 weeks before delivery (Group A). Drug treatment (PTU, n = 10, dose 50-400 mg/day or CBZ, n = 6, dose 5-45 mg/day) was continued throughout pregnancy and delivery in 16 pregnancies producing 18 infants (Group B). The maternal TBII at delivery was well correlated with maternal free thyroxine index (FTI) averaged over the third trimester (r = 0.603, P less than 0.001) and umbilical venous serum TBII (r = 0.940, P less than 0.001). Neonatal FTI was independently related to umbilical vein TBII (t = 2.29, P = 0.03) and maternal dose of antithyroid drug (t = -2.21, P = 0.03). Neonatal thyrotoxicosis was seen in all four infants (8% of births) of women whose TBII levels at delivery exceeded 70%. No child was born with a subnormal FTI but 7/18 infants in group B had raised TSH at birth. This was more likely to occur (P = 0.05) if maternal TBII was less than 30% (6/10) than if maternal TBII was greater than 30% (1/8). Four Group B women with FTI in the lower half of the reference range delivered infants with raised TSH compared with 3/14 (21%) women whose FTI was in the upper half of the reference range or above (P = 0.05). In pregnant women with active Graves' disease TBII levels reflect stimulatory TSH receptor antibody activity. TBII measurements are of use in the prediction of neonatal thyrotoxicosis and impaired neonatal thyroid function in infants of women treated with antithyroid drugs.
We report a novel activating mutation (E604K) of the calcium-sensing receptor in a family with autosomal dominant hypocalcemia. Whereas all affected individuals exhibited marked hypocalcemia, some cases with untreated hypocalcemia exhibited seizures in infancy, whereas others were largely asymptomatic from birth into adulthood. The missense mutation E604K (G2182A; GenBank accession no. U20759), which affects an amino acid residue in the C terminus of the cysteine-rich domain of the extracellular head, cosegregated with hypocalcemia in all seven individuals for whom DNA was available. Two unaffected, normocalcemic members of the family did not exhibit the mutation. The molecular impact of the mutation on two key components of the signaling response was assessed in HEK-293 cells transiently transfected with cDNA corresponding to either the wild-type calcium-sensing receptor or the E604K mutation derived by site-directed mutagenesis. There was a significant leftward shift in the concentration response curves for the effects of extracellular Ca(2+) on both intracellular Ca(2+) mobilization (determined by aequorin luminescence) and MAPK activity (determined by luciferase expression). The C terminus of the cysteine-rich domain of the extracellular head may normally act to suppress receptor activity in the presence of low extracellular Ca(2+) concentrations.
Opposite associations between alanine aminotransferase and γ-glutamyl transferase levels and all-cause mortality in type 2 diabetes: analysis of the fenofibrate intervention and event lowering in diabetes (FIELD) study Kathryn H. Williams, David R. Sullivan, Geoffrey C. Nicholson, Jacob George, Alicia J. Jenkins, Andrzej S. Januszewski, Val J. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (2) 9562 5304; E-mail: fieldtrial@ctc.usyd.edu.au. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT3 Abstract AimsReported associations between liver enzymes and mortality may not hold true in type 2 diabetes, owing to a high prevalence of non-alcoholic fatty liver disease, which has been linked to cardiovascular disease and mortality in its own right. Our study aimed to determine whether alanine aminotransferase (ALT) or γ-glutamyl transferase (GGT) levels predict mortality in type 2 diabetes, and to examine possible mechanisms. MethodsData from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were analysed to examine the relationship between liver enzymes and all-cause and cause-specific mortality over 5 years. ResultsOver 5 years, 679 (6.9%) individuals died. After adjustment, for every standard deviation increase in ALT (13.2U/L), the HR for death on study was 0.85 (95% CI 0.78-0.93), p<0.001.Conversely, GGT >70 U/L, compared with GGT ≤70 U/L, had HR 1.82 (1.48−2.24), p<0.001.For cause-specific mortality, lower ALT was associated with a higher risk of cardiovascular death only, whereas GGT >70 U/L was associated with higher risks of death due to cardiovascular disease, cancer and non-cancer/non-cardiovascular causes. The relationship for ALT persisted after adjustment for indirect measures of frailty but was attenuated by elevated hsCRP. ConclusionsAs in the general population, ALT has a negative, and GGT a positive, correlation with mortality in type 2 diabetes when ALT is less than two times the upper limit of normal. The relationship A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT4 for ALT appears specific for death due to cardiovascular disease. Links of low ALT with frailty, as a potential mechanism for relationships seen, were neither supported nor conclusively refuted by our analysis and other factors are also likely to be important in those with type 2 diabetes.
The current review failed to find any completed randomised clinical trials with results. Therefore we are unable to conclude whether intensive glycaemic control when compared to conventional glycaemic control has a positive or detrimental effect on the treatment of foot ulcers in people with diabetes. Previous evidence has however highlighted a reduction in risk of limb amputation (from various causes) in people with type 2 diabetes with intensive glycaemic control. Whether this applies to people with foot ulcers in particular is unknown. The exact role that intensive glycaemic control has in treating foot ulcers in multidisciplinary care (alongside other interventions targeted at treating foot ulcers) requires further investigation.
This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effects of intensive glycaemic control compared to conventional control on the outcome of foot ulcers in patients with type 1 and type 2 diabetes
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