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Biomedical subjects

D R Hadden

Publications and source records attributed to D R Hadden.

At least 19 recordsLinked to original sources
PubMed1999

Plasma levels of endothelin-1 in diabetic retinopathy in pregnancy.

PURPOSE: Raised circulating levels of the potent vasoconstrictor endothelin-1 (ET-1) have been demonstrated in diabetes and pregnancy-induced hypertension. Pregnant women with diabetic retinopathy are known to be at a higher risk of developing pregnancy-induced hypertension than those without retinopathy. To examine the association between ET-1, pregnancy, diabetes and diabetic retinopathy, circulating ET-1 levels were measured in each trimester in a cohort of women with and without diabetes during pregnancy. METHODS: A cohort of women with diabetes (n = 13) and normal controls (n = 8) were followed throughout pregnancy. Detailed clinical and fundoscopic examinations were carried out according to ETDRS protocols. Plasma ET-1 levels were measured in each trimester using a sensitive radioimmunoassay. Those with diabetes were further divided into those with retinopathy (n = 7) and those without (n = 6). RESULTS: Plasma levels of ET-1 increased progressively during normal pregnancy and peaked in the third trimester. Women with diabetes had significantly higher levels of plasma ET-1 (14.0 vs 4.6 pg/ml in the first trimester, 14.0 vs 4.8 pg/ml in the second trimester and 15.8 vs 7.2 pg/ml in the third trimester) compared with those without diabetes. These were no significant differences in plasma ET-1 levels between women with diabetes who had pre-existing diabetic retinopathy and those without. CONCLUSION: This study has shown that ET-1 levels rise during normal pregnancy, and are higher in women with diabetes, which may reflect pre-existing endothelial damage. Although no association could be demonstrated between diabetic retinopathy and serum ET-1 levels, this may reflect the small sample size in this study.

Adult↗
PubMed1999

A comparison of the naloxone test with the insulin stress test in patients following transsphenoidal surgery.

OBJECTIVE: To study the reliability of the naloxone test in assessing the hypothalamic-pituitary-adrenal (HPA) axis in patients following transsphenoidal pituitary surgery, by comparison with the insulin stress test (IST). Also, to establish a normal range for the response to naloxone in healthy controls. DESIGN: All patients had the IST performed, soluble insulin 0.1-0.3 U/kg (usually 0.15 U/kg) being administered intravenously, followed by venous sampling for plasma glucose and serum cortisol at 0, 15, 30, 45, 60, 75 and 90 minutes. Naloxone (125 micrograms/kg body weight) was similarly administered to all patients 6 days later, with sampling at -15, 0, 15, 30, 45, 60, 90 and 120 minutes for plasma glucose, serum cortisol and plasma ACTH. The naloxone test was also performed on control subjects using an identical protocol. SUBJECTS: Twenty patients (11F/9M) aged 48.8 +/- 2.8 years (mean +/- SE) 4-6 weeks following transsphenoidal pituitary surgery. Twelve normal healthy control subjects (6F/6M) aged 31.5 +/- 3.0 years. MEASUREMENTS: Serum cortisol was measured by radioimmunoassay and plasma ACTH by immunoradiometric assay. RESULTS: Adequate hypoglycaemia (< or = 2.0 mmol/l) was achieved in all patients. Peak cortisol was > 550 nmol/l in 17 subjects (range: 572-867 nmol/l) and a subnormal response observed in 3 (peak cortisol 163-498 nmol/l). In the 17 patients with a normal cortisol response to hypoglycaemia the response to naloxone was extremely variable, with serum cortisol falling in 4 and an increment of < or = 100 nmol/l in 6 others. In the 3 patients who failed the IST, two responded to naloxone and one did not. In normal controls, 3 of the 12 had little or no response to naloxone. CONCLUSIONS: As the naloxone test fails to produce a response in all normal subjects it is impossible to define a 'normal' response. The numerous discrepancies with the IST in patients are further evidence of the test's lack of reliability in assessing the HPA-axis and it is consequently not a viable alternative to traditional dynamic methods such as the IST.

Adrenocorticotropic Hormone↗
PubMed1999

How to improve prognosis in type 1 diabetic pregnancy. Old problems, new concepts.

OBJECTIVE: To improve the prognosis of pregnancy in type 1 diabetes. RESEARCH DESIGN AND METHODS: This study is an epidemiological analysis of pregnancy outcome in type 1 diabetic mothers attending the combined diabetic antenatal clinic at the Royal Maternity Hospital, Belfast, from 1940 to 1990. Short-term measurement of maternal insulin sensitivity and of intrauterine fetal habituation was taken in selected pregnancies. The article also assesses the European and U.K. recommendations for diabetes in pregnancy, with a goal "to achieve pregnancy outcome in the diabetic woman that approximates that of the non-diabetic woman." RESULTS: Outcomes from 1985 to 1995 in > 800 pregnancies, of which about 60% were delivered at the Regional Centre, suggested that the perinatal mortality was lower for those managed throughout at the center. The highest obstetric risk was in those pregnancies referred to the center at some point later in the pregnancy from a peripheral obstetric clinic. Studies of insulin sensitivity in normal and preeclamptic pregnancy by minimal-model analysis of a frequently sampled intravenous glucose tolerance test and of glycosylated hemoglobin in a large survey of nondiabetic pregnancy indicate that the pregnant state may unmask an increase in insulin resistance, causing both pregnancy-induced hyperglycemia and pregnancy-induced hypertension. Fetal habituation, studied by responses to a variable sound stimulus, was less effective in diabetic pregnancy, which may indicate changes in fetal brain function. CONCLUSIONS: Pregnancy in a type 1 diabetic mother remains a high-risk obstetrical situation, even with presently available intensive diabetic supervision.

Centralized Hospital Services↗
PubMed1999

Basal nitric oxide production is impaired in offspring of patients with essential hypertension.

There is considerable evidence that endothelium-dependent nitric oxide (NO)-mediated vasodilatation in response to acetylcholine is impaired in essential hypertension, whereas the endothelium-independent response to sodium nitroprusside is normal. More limited data have suggested that there is also reduced vasoconstriction in response to N(G)-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of basal NO release. As it is not known whether endothelial dysfunction in hypertension, if indeed present, is a cause or consequence of the condition, we have studied the normotensive offspring of parents with essential hypertension. Both basal and stimulated vascular responses were examined in 12 normotensive offspring [mean age (+/-S.E.M.) 26.1+/-1.4 years] of parents with essential hypertension and compared with those in 12 age-matched offspring (mean age 25.6+/-1.1 years) of normotensive subjects. Forearm blood flow was measured simultaneously in both arms by venous occlusion plethysmography, both at baseline and during intra-arterial brachial infusion of increasing doses of acetylcholine, sodium nitroprusside, noradrenaline and L-NMMA. There were no significant differences between the groups in the responses to acetylcholine, sodium nitroprusside or noradrenaline. In contrast, the vasoconstrictor response to L-NMMA was significantly blunted in the offspring of hypertensive parents compared with that in the offspring of normotensive parents (P=0.005). Thus endothelial dysfunction, as demonstrated by impaired basal production of NO, is present in subjects at high risk of essential hypertension, and does not occur simply as a consequence of the condition.

Acetylcholine↗
PubMed1998

Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: the 10-year follow-up of the Belfast Diet Study.

Secondary failure of plasma glucose control following initial successful response to diet therapy may be due to dietary indiscretion, or to progression of the intrinsic diabetic condition. We report a 10-year prospective natural history study of 432 newly diagnosed diabetic patients aged 40-69 years undertaken to assess the effect of intensive dietary management, where patients were transferred to insulin, or oral hypoglycaemic therapy (tolbutamide, metformin) by predetermined criteria of weight and plasma glucose. Secondary failure to diet therapy occurred in 41 patients in years 2-4, 67 patients in years 5-7, and 51 patients in years 8-10; 173 patients remained on diet alone until death or the end of the study. Continuation on diet alone was associated with a lower ongoing fasting plasma glucose, greater beta-cell function assessed by an oral glucose tolerance test at 6 months, and increasing age. The rate of rise of fasting plasma glucose was inversely related to the duration of successful dietary therapy, but mean weight remained constant in all groups while on diet alone. The ongoing fall in beta-cell function assessed by HOMA modelling closely mirrored the progressive rise in fasting plasma glucose: there was no change in mean insulin sensitivity in any of the groups.

Adult↗
PubMed1998

Evidence for a second genetic locus in Carney complex.

Carney complex (MIM no. 160980) is an autosomal dominant condition of lentiginosis, cutaneous and cardiac myxomas and multiple endocrine neoplasia. A locus for Carney complex has recently been mapped to chromosome 2p16. We have studied two Northern Irish families with this disorder. Linkage analysis was performed on the families using five highly informative dinucleotide repeat markers covering this area. Negative logarithm of the odds scores were obtained for all markers at all recombination fractions. We conclude that Carney complex is genetically as well as clinically heterogeneous.

Breast Neoplasms↗
PubMed1998

Insulin sensitivity in pre-eclampsia.

OBJECTIVE: To investigate whether pre-eclampsia is associated with an exaggeration of the insulin resistance seen in normotensive pregnancy. DESIGN: Minimal model analysis of a frequently sampled intravenous glucose tolerance test to assess insulin sensitivity. SETTING: Royal Maternity Hospital, Belfast. PARTICIPANTS: Eleven women with pre-eclampsia and 11 matched normotensive pregnant women. RESULTS: Insulin sensitivity (S(I)) was increased in the group with pre-eclampsia compared with the normotensive women (mean [+/-SEM]: 2.6 [0.4] vs 1.6 [0.2] 10(-4) min(-1) per mU/L; P = 0.028). This was accompanied by a decrease in glucose effectiveness (SG) (1.1+/-0.1 vs 1.7+/-0.1 10(-2)min(-1), P = 0.006) in the pre-eclamptic women. In the normotensive group there was a significant inverse correlation between S(I)and mean arterial blood pressure (r = -0.65; P = 0.03), but no such relation existed in the group with pre-eclampsia. CONCLUSIONS: As with other forms of secondary hypertension, and unlike essential hypertension, the pathophysiology of pre-eclampsia is not associated with insulin resistance.

Adult↗
PubMed1998

Glycosylated haemoglobin and hypertension arising in pregnancy.

We analysed a database of glycosylated haemoglobin (HbA1) in nondiabetic pregnant women to investigate the relation between glucose metabolism in the first and second trimesters and hypertensive complications of pregnancy. From a total of 1334 women, 13 had pre-existing hypertension, 225 developed gestational hypertension and 51 developed pre-eclampsia. At 28 weeks of gestation, the women who subsequently developed gestational hypertension had a significantly higher mean HbA1 than those who remained normotensive (6.33 vs 6.17%, P < 0.02). This difference remained significant after correcting for the effects of age and body mass index (regression coefficient 0.11, SE 0.06, P = 0.05). In contrast, there were no significant differences in HbA1 between the women with pre-eclampsia and their normotensive counterparts. This provides indirect evidence to support our hypothesis that gestational hypertension is associated with insulin resistance but pre-eclampsia is not.

Adolescent↗
PubMed1998

A neurological evaluation of adult phenylketonuria in Northern Ireland.

To investigate the extent of neurological disease in adults with phenylketonuria and also their requirement for specialist medical services, we assessed 27 such patients in Northern Ireland. Most had been diagnosed early and with one exception had dietary relaxation by early adolescence. Abnormal neurological features were elicited in 21/27 cases with significant delay of visual evoked potentials and somatosensory evoked potentials occurring in 63.6 and 13.6% of cases respectively. Periventricular white matter abnormalities were observed in 5/12 patients undergoing magnetic resonance imaging, whilst phenylalanine levels were high (mean 1,226 micromol/l). These data accord with the observation that even early treated patients with phenylketonuria can have significant neurological morbidity in adulthood, although the correlation with current or recent dietary control is unclear and requires further study.

Adolescent↗
PubMed1998

A historical perspective on gestational diabetes.

Extreme fetal macrosomia occurred in the first recorded case of diabetes in pregnancy in 1823. The belief that the diabetic condition was in some way a symptom of the pregnancy, which dates to that first report, has led to the more recent concept of gestational diabetes. Lesser degrees of maternal hyperglycemia were also recognized to be a risk to the baby, and early studies of carbohydrate intolerance in pregnancy in Boston and Los Angeles have set the stage for the worldwide interest in this maternal/fetal interaction.

Diabetes, Gestational↗
PubMed1997

Macrovascular disease and hyperglycaemia: 10-year survival analysis in Type 2 diabetes mellitus: the Belfast Diet Study.

The relationship between macrovascular disease and blood glucose control in long-term follow-up of Type 2 (non-insulin-dependent) diabetes mellitus is difficult to study because of the gradual rise in fasting plasma glucose due to ongoing beta-cell failure. We used time-dependent covariates in Cox's proportional hazards model to allow variables measured annually during a 10-year prospective follow-up to be related to risk of myocardial infarction or cerebrovascular accident. Data for 432 newly diagnosed diabetic patients were available, 112 of whom suffered myocardial infarction (fatal or non-fatal). Analysis of baseline measurements only gave relative hazards (95% CL) of 1.04 (0.99, 1.09) per mmol l(-1) increase in fasting plasma glucose, 1.43 (1.12, 1.83) per decade increase in age and 1.07 (0.98, 1.17) per 10 % increase in percentage of ideal weight. Analysis incorporating ongoing measurements gave corresponding figures of 1.07 (1.02, 1.12) for fasting plasma glucose, 1.64 (1.23, 2.20) for age and 1.06 (0.95, 1.18) for percentage of ideal weight. The risk of myocardial infarction while on insulin treatment 1.09 (0.58, 2.06) or oral agents 1.41 (0.86, 2.31) was not significantly elevated relative to dietary treatment. Baseline smoking status, systolic blood pressure, and previous myocardial infarction were also significant predictors of myocardial infarction. Similar relationships were found for cerebrovascular accident and total mortality. Increasing fasting plasma glucose is a significant independent predictor of macrovascular disease in diabetes.

Adult↗
PubMed1997

Diagnosing diabetes mellitus--do we need new criteria?

The current classification and diagnostic criteria for diabetes mellitus were introduced by the United States National Data Group in 1979 and endorsed by the World Health Organization in 1980, with modifications in 1985 and 1994. The criteria, chosen to reflect the risk of complications, were the synthesis of considerable thought and expertise and represented a consensus which, it was hoped, would prove helpful to all those involved with diabetes-practising clinician, research scientist and epidemiologist alike. The inconvenience, variability and non-physiological nature of the oral glucose tolerance test (OGTT) are well-recognised. In spite of these limitations the 2-h post-load plasma glucose has remained the standard against which all other tests have been evaluated. This article reviews the original justification for the OGTT, and in the light of more recent epidemiological research seeks to place the current diagnostic criteria for diabetes into a pathophysiological, diagnostic and prognostic perspective.

Blood Glucose↗
PubMed1997

Metformin.

Metformin, a dimethylbiguanide, was first synthesized in 1929 and was shown to be a potent hypoglycemic agent. It was rediscovered in 1957 and was widely used in Europe to treat obese type II patients. Metformin resurfaced in the 1980s and was shown to increase insulin sensitivity; this has led to its introduction to clinical practice in the United States for the first time. The small risk of lactic acidosis is now well documented and appropriate therapeutic guidelines have been established. Metformin is a sage and effective drug for management of non-insulin-dependent diabetes mellitus.

Acidosis, Lactic↗
PubMed1997

Antioxidant status and lipid peroxidation in diabetic pregnancy.

Pregnancy in insulin-dependent diabetes mellitus is associated with a greater incidence of fetal abnormality. Animal studies suggest that increased free-radical production and antioxidant depletion may contribute to this risk. The aim of the present study was, therefore, to assess nutritional antioxidant status and lipid peroxidation in diabetic mothers in comparison with a control group. A 7 d dietary history and a food-frequency questionnaire were performed and venous blood collected for biochemical analyses from thirty-eight diabetic mothers and matched control subjects before 12 weeks gestation. Protein intake was significantly greater in diabetic patients (81.4 (SE 14.8) v. 72.7 (SE 15.8) g/d, P = 0.015), while total sugar intake was less (79.5 (SE 13.2) v. 104.8 (SE 28.8) g/d, P < 0.001). There were no significant differences in the intake of the major antioxidant vitamins (retinol, vitamin C or vitamin E) or beta-carotene. However, intakes of a number of other micronutrients (including Se, Zn, Mg, Mn, riboflavin, thiamin, niacin and folate) were greater in diabetic patients. Among the nutritional chain-breaking antioxidants, serum levels of alpha-tocopherol (21.6 (SE 5.7) v. 17.3 (SE 4.7) mumol/, P = 0.0013), beta-carotene (0.27 (SE 0.18) v. 0.14 (SE 0.11) mumol/l, P = 0.003) and lycopene (0.23 (SE 0.17) v. 0.16 (SE 0.13) mumol/l, P = 0.03) were greater in diabetic patients. There was no evidence of greater lipid peroxidation in diabetic patients, and total antioxidant capacity was similar in the two groups. Overall, these results indicate that nutritional antioxidant status is better in this group of diabetic mothers than in control pregnant non-diabetic subjects attending the same maternity hospital.

Adult↗
PubMed1997

Treatment of diabetic ketoacidosis using normalization of blood 3-hydroxybutyrate concentration as the endpoint of emergency management. A randomized controlled study.

OBJECTIVE: To compare the efficacy of an extended insulin regimen using correction of hyperketonemia as endpoint with a more conventional regimen in the treatment of diabetic ketoacidosis. RESEARCH DESIGN AND METHODS: A total of 22 patients admitted to a Belfast teaching hospital with clinical and biochemical features of diabetic ketoacidosis (pH < 7.25 and/or bicarbonate < 16 mmol/l) were randomized to either conventional or extended insulin regimens. In the conventional regimen, insulin was administered at 5 U/h until near-normoglycemia (blood glucose < or = 10 mmol/l) and then administered at a reduced rate until clinical recovery. In the extended regimen, administration of insulin at 5 U/h was continued beyond attainment of normoglycemia, until resolution of hyperketonemia (3-hydroxybutyrate < 0.5 mmol/l). Main outcome measures were 3-hydroxybutyrate and bicarbonate levels during the 24 h after attainment of near-normoglycemia. RESULTS: After near-normoglycemia, correction of hyperketonemia was achieved earlier with the extended treatment (5.9 +/- 0.8 vs. 21.8 +/- 3.4 h, P = 0.0004 [mean +/- SD]). The area under the curve of 3-hydroxybutyrate against time for 24 h after near-normoglycemia was reduced with the extended treatment (24.9 +/- 3.8 vs. 55.9 +/- 6.7 mmol.l-1.h-1, P = 0.001). These differences remained statistically significant after adjustment for higher baseline levels of 3-hydroxybutyrate at near-normoglycemia in the extended treatment group. Bicarbonate levels at 6 and 12 h after near-normoglycemia were not significantly different between groups. CONCLUSIONS: The extended insulin regimen, which was easy to implement at ward level, produced a more rapid resolution of ketosis than the conventional regimen.

3-Hydroxybutyric Acid↗