Characteristics of insulin-Naïve people with type 2 diabetes who successfully respond to insulin glargine U100 after 24 weeks of treatment: a meta-analysis of individual participant data from 3 randomized clinical trials.

BACKGROUND: To identify baseline/clinical characteristics associated with clinically meaningful responses to insulin glargine 100 U/mL (IGlar) in insulin-naive people with type 2 diabetes mellitus (T2DM). METHODS: Individual participant data were pooled from 3 randomized trials to compare baseline characteristics and clinical outcomes associated with 24-week response to IGlar in combination with non-insulin antihyperglycemic agents in participants with T2DM. Responders were defined as achieving endpoint HbA1c target < 53 mmol/mol (< 7%) and/or ≥ 11 mmol/mol (≥ 1%) HbA1c reduction from baseline. RESULTS: Differences in baseline characteristics for responders versus nonresponders were higher HbA1c (99 vs 91 mmol/mol [9.1 vs 8.3%]; P < 0.001), higher fasting blood glucose (FBG; 10.4 vs 8.8 mmol/L [187 vs 159 mg/dL; P < 0.001), and fewer participants (94% vs 98%; P = 0.006) taking oral medications targeting postprandial blood glucose (BG). Most participants (80%) achieved one or both components of composite endpoint. 12-week response was a strong predictor of subsequent 24-week response (sensitivity, 85.9%; predictive positive value, 91.4%). At both 12 and 24 weeks, < 40% of responders and nonresponders reached target FBG ≤ 5.6 mmol/L (≤ 100 mg/dL). Responders at 24 weeks had higher incidence of hypoglycemia (total, 82.5% vs 70.4%; P < 0.001; nocturnal, 60.3% vs 50.5%; P = 0.002; documented symptomatic, 65.8% vs 55.6%; P < 0.001) than nonresponders. CONCLUSIONS: Baseline characteristics associated with response were identified. The strong predictability of 12-week response suggests that the magnitude of early HbA1c reduction should be considered when assessing response to IGlar. More aggressive IGlar titration may be reasonable for nonresponders and responders who have not reached FBG and HbA1c targets, taking into account other BG timepoints.

Aspirin in type 2 diabetes, a randomised controlled study: effect of different doses on inflammation, oxidative stress, insulin resistance and endothelial function.

OBJECTIVES: The effect of aspirin upon platelet function is well documented although experimental studies suggest that aspirin may also affect oxidative stress, vascular inflammation, endothelial dysfunction and dysglycaemia. The optimal dose of aspirin for cardiovascular protection in type 2 diabetes is still debated. We examined the effects of different doses of aspirin upon these novel markers of cardiovascular risk and any association between aspirin-mediated changes in these markers. METHODOLOGY: Subjects with type 2 diabetes attended for baseline evaluation including BMI, glycaemic and lipid markers, endothelial function (photoplethysmography), insulin resistance (HOMA), inflammation (sVCAM-1 and Hs-CRP) and markers of oxidative stress [total anti-oxidant status (TAOS and FRAP), whole blood total glutathione (GSH) assays]. Subjects then received in random, sequential, blinded fashion aspirin 75 mg day(-1) , aspirin 300 mg day(-1) , aspirin 3.6 g day(-1) or placebo for 2 weeks with a 2-week washout. The above investigations were repeated after each intervention. Aspirin-related changes compared with placebo were analysed using repeated measures ANOVA. RESULTS: Subjects = 17 (M - 12; F - 5), mean age - 57.4 ± 9.1 years (mean ± 1 SD), HbA1c - 63 ± 13 mmol mol(-1) (7.9 ± 1.2%), total cholesterol 4.57 ± 1.01 mmol l(-1) . At baseline TAOS value was 59.3 ± 9.7 µM AEAC (Ascorbate Equivalent Anti-oxidant Concentration), glutathione 302.2 ± 183.3 mmol l(-1) and FRAP 0.86 ± 0.23 mM FeII. None of the aspirin doses had a significant impact upon BMI, blood pressure, lipid parameters, insulin sensitivity (HOMA), FRAP, TAOS, GSH, endothelial function, glycaemic control (fructosamine) or inflammation (sVCAM-1 and HsCRP). CONCLUSIONS: Aspirin exhibited no significant dose-dependent effect on markers of vascular inflammation, oxidative stress, insulin resistance and endothelial function (photoplethysmography) when used in type 2 diabetes over a 2-week period. ( CLINICAL TRIALS REGISTRATION: NCT00898950, EUDRACT:2004-001418-14).

Thiamine deficiency in diabetes mellitus and the impact of thiamine replacement on glucose metabolism and vascular disease.

Despite the targeting of traditional risk factors for cardiovascular disease, disease burden has not been completely eliminated. Thiamine is an essential cofactor in carbohydrate metabolism and individuals with diabetes are thiamine deficient. The pathophysiology of recognised complications of thiamine deficiency is similar to that underlying atherosclerosis and the metabolic syndrome, namely oxidative stress, inflammation and endothelial dysfunction. This review examines the mechanisms by which thiamine deficiency occurs in individuals with diabetes, how this deficiency leads to hyperglycaemic-induced damage, and the effect of thiamine replacement on vascular disease, endothelial function and oxidative stress. Thiamine administration can prevent the formation of harmful by-products of glucose metabolism, reduce oxidative stress and improve endothelial function. The potential benefit of long-term replacement in those with diabetes is not yet known but may reduce cardiovascular risk and angiopathic complications.

The effect of oral folic acid upon plasma homocysteine, endothelial function and oxidative stress in patients with type 1 diabetes and microalbuminuria.

AIMS: The purpose of this study was to investigate the effect of oral folic acid supplementation upon plasma homocysteine (HCY), endothelial function and oxidative stress on patients with type 1 diabetes and microalbuminuria to test the hypothesis that oral folic acid would lower plasma HCY and thereby improve endothelial function and reduce oxidant stress in this high-risk group of patients. METHODS: We measured plasma HCY, forearm blood flow, total antioxidant status and whole blood glutathione at baseline and after 2 months treatment with oral folic acid or placebo in 16 patients with type 1 diabetes and microalbuminuria. RESULTS: Plasma HCY fell by 25% in the folic acid group but there was no difference in endothelial function or markers of oxidant stress in the treatment group. CONCLUSIONS: Oral folic acid supplementation successfully lowered plasma HCY levels in patients with type 1 diabetes and microalbuminuria, however this was not associated with improvements in endothelial function or markers of oxidant stress.

Plasma homocysteine, oxidative stress and endothelial function in patients with Type 1 diabetes mellitus and microalbuminuria.

AIMS: The purpose of this study was to examine the associations between endothelial function, plasma homocysteine and oxidative stress in patients with Type 1 diabetes mellitus (DM) and microalbuminuria compared with DM patients with normoalbuminuria and non-diabetic control subjects. We wished to test the hypothesis that increased cardiovascular risk in patients with Type 1 diabetes and microalbuminuria may be in part as a result of hyperhomocysteinaemia-mediated oxidative stress leading to impaired endothelial function. METHODS: We measured forearm blood flow, total plasma homocysteine, total antioxidant status (TAOS) and whole blood glutathione in 31 DM patients, 16 with microalbuminuria and 15 with normoalbuminuria, and 15 non-diabetic control subjects. RESULTS: Plasma homocysteine levels were significantly higher in the microalbuminuric diabetic patients compared with the normoalbuminuric patients and the control subjects. TAOS was significantly lower in the micoalbuminuric and normoalbuminuric diabetic patients compared with the control subjects, although TAOS levels were similar in both groups of diabetic patients. There was no difference in forearm blood flow between the groups and no association between measured endothelial function and antioxidant defence/oxidative stress and homocysteine in each group. There was no association between plasma total homocysteine and TAOS or whole blood glutathione within the groups. CONCLUSIONS: We have found mild hyperhomocysteinaemia in microalbuminuric DM patients compared with normoalbuminuric DM patients and non-diabetic subjects and some evidence for reduced antioxidant defence in DM patients. These findings add to our understanding of the increased risk of vascular disease in patients with Type 1 diabetes.

Flavonoid-rich grapeseed extracts: a new approach in high cardiovascular risk patients?

The management of traditional risk factors such as hypertension and dyslipidaemia has been successful in reducing the development of cardiovascular disease. However, this has not resulted in the amelioration of complications; prompting attention to be focused on novel markers of vascular risk such as endothelial dysfunction (a determinant of vascular tone), vascular inflammation, oxidative stress and insulin resistance. With an ever-growing interest in plant-derived products, agents that could have a beneficial effect on this complex web of pathophysiology have thus been a major area of research and interest. Flavonoids have been a major focus of attention since the days of the French paradox and the presence of high quantity of flavonoids in grapeseed extracts has prompted research looking at its effects on novel markers of vascular risk. This review briefly summarises mechanisms implicated in the development of vascular disease and then focuses upon the potential role of the antioxidant properties of flavonoid-rich grapeseed extracts in the reversal of these processes.

Diabetic erectile dysfunction--an indicator of generalised endothelial function per se?

Erectile dysfunction (ED) affects up to 70% of men with diabetes. However, the pathophysiology of ED in diabetes remains uncertain with both neuronal and vascular factors cited. We examined whether ED is an indicator of generalized endothelial dysfunction. A unique group of diabetic patients free from established conventional cardiac risk factors were investigated. Forearm bloodflow responses to nitroprusside and acetylcholine on 11 diabetic men with ED and 11 potent diabetic men were measured by venous plethysmography. Patient characteristics between the impotent and potent patients were similar except for Hba1c which was higher in the group with ED (8.35% vs. 7.03%: p = 0.003). Both groups showed increases in FBF to incremental infusions of nitroprusside and acetylcholine but the area under curve (AUC) were similar in the ED and the non-ED groups (p = 0.16 and p = 0.17, respectively). We demonstrated that ED in patients with type 2 diabetes is not associated with additional generalized endothelial dysfunction.

A double-blind randomised trial to evaluate the effect of anastrozole for the treatment of non-toxic multinodular goitre.

Multinodular goitre (MNG) is a common clinical finding, particularly in females and is usually asymptomatic. When symptoms occur because of local pressure-related effects the only treatment is surgical involving partial or total thyroidectomy. A number of epidemiological observations and experimental data have suggested that oestrogen aromatase activity may be involved in the pathogenesis of MNG. This study examines the effect of anastrozole, a non-steroidal aromatase inhibitor that inhibits the peripheral conversion of testosterone to oestradiol, in reducing the size of MNG. Thirty-two post-menopausal female patients, median age 63 years (range 42-84) were randomised in a double-blind fashion to receive either anastrozole 1 mg daily or placebo for 3 months. Ultrasonographic measurement of each thyroid lobe and isthmus together with complete biochemical and hormone profiles were performed at the start and end of treatment. There was no significant reduction in the goitre size for patients in the anastrozole group (p = 0.246) or the placebo group (p = 0.418). There were no significant changes in hormone profiles (including throglobulin concentration) within each group between the start and end of the study. We conclude that the use of anastrozole in the treatment of MNG does not appear to have any effect in reducing the size of MNG.

Angiotensin II does not affect endothelial tone in Type 1 diabetes-results of a double-blind placebo controlled trial.

AIMS: Previously, we have demonstrated that patients with normoalbuminuric Type 1 diabetes are characterized by impaired nitric oxide bioavailability compensated for by increased vasodilatory prostanoid-mediated vasodilation. Experimental evidence suggests vascular responses to endogenous angiotensin II involve the nitric oxide and prostaglandin pathways. We examined whether selective blockade of angiotensin II influences endothelial tone with particular reference to the nitric oxide/prostaglandin pathways in patients with Type 1 diabetes free from vascular complications. METHODS: At baseline, we studied changes in forearm blood flow in response to brachial arterial infusions of acetylcholine, l-NMMA, a combination of l-NMMA and the cyclo-oxygenase inhibitor indomethacin and nitroprusside in 30 patients with normoalbuminuric Type 1 diabetes [21 male, 9 female; age 38.5 +/- 1.9 years (mean +/- sem)]. Patients were randomized to 2 weeks' treatment with placebo or the selective angiotensin II receptor blocking agent irbesartan, 300 mg, prior to forearm vasoactive responses being re-examined. RESULTS: The forearm responses to nitroprusside and acetylcholine were unchanged by both placebo (P = 0.23 and P = 0.36, respectively) and irbesartan (P = 0.41 and P = 0.36). Similarily, dose-response curves to acetylcholine in the presense of l-NMMA alone (P = 0.42) and a combination of l-NMMA and indomethacin (P = 0.44) were not altered by angiotensin II blockade. CONCLUSION: This study demonstrated that physiological blockade of endogenous angiotensin II in Type 1 diabetes does not augment agonist-evoked vasodilation or the contribution of nitric oxides and prostanoids to endothelial tone.

The contribution of nitric oxide and vasodilatory prostanoids to bradykinin-mediated vasodilation in Type 1 diabetes.

AIMS: To investigate the effect of bradykinin on endothelial tone in normoalbuminuric Type 1 diabetic patients and specifically whether any changes are mediated through nitric oxide or prostaglandins. METHODS: Forearm blood flow was measured using venous occlusion plethysmography at baseline and after brachial artery infusions of incremental doses of bradykinin (50, 100 and 200 ng/min) in 15 patients with Type 1 diabetes and 13 non-diabetic controls. Forearm blood flow at baseline and following bradykinin was then re-examined after local infusion of L-NMMA, a nitric oxide synthase inhibitor, and L-NMMA with indomethacin, a cyclo-oxygenase inhibitor. RESULTS: Baseline blood flow in the diabetic and control groups were similar (4.46 +/- 1.11 vs. 3.41 +/- 1.23 ml/min/100 ml, respectively; P = 0.07). After infusion of L-NMMA and L-NMMA with indomethacin, there was a similar reduction in blood flow responses to bradykinin in both groups. There was no significant difference between the diabetic patients and control subjects in the percentage reduction in forearm blood flow following L-NMMA (16.55 vs. 18.12%, respectively, P = 0.94) and L-NMMA with indomethacin (47.1 vs. 37.3%, respectively, P = 0.14). CONCLUSIONS: This study demonstrates that bradykinin-stimulated vasodilation is mediated by both nitric oxide and prostaglandin release from the endothelium in patients with Type 1 diabetes and normoalbuminuria, and in healthy control subjects. We have also shown that the relative contributions of nitric oxide and prostaglandin to bradykinin-mediated vasodilation are similar in these diabetic patients compared with non-diabetic subjects.

Recurrent severe hyperandrogenism during pregnancy: a case report.

This report describes the case of a 28 year old woman with virilisation occurring in two successive pregnancies. Recurrent maternal virilisation is rare (seven previous reports) and this case is unique in its severity. Differential diagnoses include ovarian disease and fetal aromatase deficiency. New techniques to exclude a fetal cause were used in this case. This patient presented during the third trimester of her first pregnancy with rapid onset of hirsuitism, increased musculature, and deepening voice. A blood hormone profile revealed significant hyperandrogenism (testosterone, 72.4 nmol/litre; normal range, 0.5-3.0). She delivered a normal boy and maternal androgen concentrations returned rapidly to normal (testosterone, 0.8 nmol/litre). She presented two years later, during her second pregnancy, with similar symptoms and biochemistry (testosterone, 47.5 nmol/litre). Again, she delivered a healthy normal boy and androgens returned immediately to normal (serum testosterone, 2.0 nmol/litre). Ultrasonography revealed no evidence of ovarian (or adrenal) masses in either pregnancy. Umbilical cord venous blood sampling and placental assays revealed no evidence of fetal aromatase deficiency. Recurrent hyperandrogenism during pregnancy is rare. Ovarian luteoma rarely recurs and hyperreactio luteinalis does not lead to such pronounced androgen concentrations. Therefore, this patient has a unique ovarian condition that could be harmful to offspring and mother.

Cardiovascular risk in women with polycystic ovarian syndrome (PCOS).

AIMS: Studies have suggested that polycystic ovary syndrome (PCOS) is associated with increased cardiovascular risk. The aim of this study was to examine cardiovascular risk profiles in women with PCOS compared with healthy age and weight matched control subjects using novel biochemical and biophysical markers. METHODS: After ethics committee approval, 11 women with PCOS and 12 controls were recruited (mean age, 32; SD, 6.5 years; mean body mass index (BMI), 33.1; SD, 5.9 kg/m2). Serum was analysed for lipid and lipoprotein profile (total and high density lipoprotein cholesterol, triglycerides, apolipoprotein B-100, apolipoprotein A1, lipoprotein (a)), and sialic acid, fibrinogen, homocysteine, and C reactive protein (CRP) concentrations. Endothelial function was also assessed by a standard venous occlusion plethysmography technique to measure reactive hyperaemic forearm blood flow (RH), and expressed as per cent increase from baseline. RESULTS: There were no significant differences in glucose, lipid, or lipoprotein concentrations between the two groups. Furthermore, sialic acid (PCOS: mean, 70.5; SD, 149 mg/litre; controls: mean, 71.3; SD, 112 mg/litre), fibrinogen (PCOS: mean, 3.1; SD, 1.0 g/litre; controls: mean, 3.3; SD, 0.7 g/litre), CRP (PCOS: mean, 4.6; SD, 4.2 mg/litre; controls: mean, 5.41 SD, 5.5 mg/litre), and RH (PCOS: mean, 158.7; SD, 135.5%; controls: mean, 200.1; SD, 114.2%) were similar. CONCLUSIONS: There were no differences in surrogate markers of the processes linked to enhanced cardiovascular risk between patients with PCOS and weight matched controls.

Reduced forearm reactive hyperaemia in normoalbuminuric subjects with Type 1 diabetes and retinopathy.

AIM: To determine whether the forearm vasodilatory response to reactive hyperaemia (RH) is reduced in normoalbuminuric subjects with Type 1 diabetes mellitus and retinopathy compared with subjects with no retinopathy. METHODS: Forearm RH, an indicator of endothelial function, was measured, using strain-gauge plethysmography, in 39 normoalbuminuric subjects (22 with retinopathy) with long-standing Type 1 diabetes mellitus. RESULTS: were evaluated in relation to conventional risk factors for atherosclerosis, and C-reactive protein (CRP), which we have recently determined to be an independent correlate of forearm RH. RESULTS: Forearm RH was decreased in subjects with retinopathy compared with those with no retinopathy (219 +/- 182 vs. 473 +/- 355, P < 0.01). Both retinopathy and CRP proved to be independent and negative predictors, and explain 27% of the variance, in forearm RH. CONCLUSION: Retinopathy in subjects with Type 1 diabetes mellitus may reflect a generalized process of endothelial dysfunction, even in the absence of microalbuminuria.

Effects of growth hormone (GH) replacement therapy on low-density lipoprotein apolipoprotein B100 kinetics in adult patients with GH deficiency: a stable isotope study.

GH replacement therapy has been shown to improve the dyslipidemic condition in a substantial proportion of patients with adult GH deficiency. The mechanisms are not yet fully elucidated. Low-density lipoprotein (LDL) apolipoprotein B100 (apoB) formation and catabolism are important determinants of plasma cholesterol concentrations. This study examined the effect of GH replacement therapy on LDL apoB metabolism using a stable isotope turnover technique. LDL apoB kinetics was determined in 13 adult patients with GH deficiency before and after 3 months GH/placebo treatment in a randomized, double-blind, placebo-controlled study. LDL apoB (13)C-leucine enrichment was determined by isotope-ratio mass spectrometry. Plasma volume was assessed by standardized radionuclide dilution technique. GH replacement therapy significantly decreased LDL cholesterol, LDL apoB concentrations, and LDL apoB pool size compared with placebo. Compared with baseline, GH replacement therapy resulted in a significant increase in plasma volume and fractional catabolic rate, whereas LDL formation rate remained unchanged. LDL lipid content did not significantly change after GH and placebo. This study suggests that short-term GH replacement therapy decreases the LDL apoB pool by increasing removal of LDL particles without changing LDL composition or LDL apoB production rate. In addition, it is possible that the beneficial effects of GH on the cardiovascular system contribute to these findings.

Long-term predictors of coronary artery disease and mortality in type 1 diabetes.

We assessed clinical and biochemical predictors of death and/or cardiovascular disease in 147 type 1 diabetes mellitus (DM) patients followed-up for 14 years. At follow-up, 28 of patients (19%) had died, and 25 patients (18%) had developed or died of coronary artery disease (CAD). At baseline, those who died had significantly higher serum creatinine (p=0.001) and urine albumin/creatinine ratio (p=0.016), greater prevalence of retinopathy (p=0.006), lower serum apolipoprotein A1 (p=0.046), and lower daily insulin dose (p=0.024) than those who survived. CAD patients had a longer duration of diabetes (p<0.001), were older at the onset of diabetes and at presentation (p=0.001), and had higher prevalences of retinopathy (p=0.005) and neuropathy (p=0.016). The CAD group also had higher baseline serum creatinine (p=0.02), lower HDL cholesterol (p=0.004) and apolipoprotein A1 (p=0.007) and higher LDL cholesterol (p=0.028) and apolipoprotein B concentrations (p=0.027). Under logistic regression analysis (adjusted for age and sex), baseline urine albumin/creatinine ratio (p=0.003), presence of retinopathy (p=0.004), serum creatinine (p=0.028), and serum urea (p=0.034) were the most powerful predictors of mortality, while duration of diabetes (p<0.0001), baseline HDL cholesterol (p=0.012), serum creatinine (p=0.02), apolipoprotein B (p=0.038), LDL cholesterol (p=0.039), and systolic blood pressure (p=0.055) were the strongest predictors of CAD. These findings emphasize the role of abnormal lipoprotein metabolism in the development of CAD in type 1 DM. Indicators of renal impairment and the presence of retinopathy seem to be of greater importance in predicting overall mortality.

Effects of cyclo-oxygenase inhibition on vasodilatory response to acetylcholine in patients with type 1 diabetes and nondiabetic subjects.

OBJECTIVE: Studies examining vasodilatory responses to acetylcholine (ACh) and its derivatives have been conflicting. Enhanced activation of the cyclo-oxygenase pathway and increased availability of vasodilatory prostanoids may occur in type 1 diabetes, and this may compensate for the observed reduction in nitric oxide (NO) activity We examined the role of cyclo-oxygenase inhibition on vasodilatory responses in 12 healthy normotensive type 1 diabetic adults and 12 nondiabetic control subjects of similar age, sex, and BMI. RESEARCH DESIGN AND METHODS: Forearm blood flow was measured using a venous occlusion plethysmography technique at baseline and after brachial artery infusions of ACh (7.5, 15, and 30 microg/min). Forearm blood flow at baseline and after ACh was then reexamined after local intra-arterial infusion of indomethacin (0.3 mg/100 ml forearm volume), a cyclo-oxygenase inhibitor. RESULTS: Baseline blood flow in the diabetic and control groups were similar (2.65 +/- 0.26 vs. 2.59 +/- 0.20 ml/min per 100 ml, respectively; P = 0.4). After indomethacin infusion, the vasodilatory responses to all doses of ACh were reduced in both the diabetic (by 25.30 +/- 4.90%) and control group (by 11.23 +/- 5.45%). However, the reduction in blood flow response to ACh after indomethacin was greater in diabetic patients compared with control subjects (P = 0.03). CONCLUSIONS: Our findings suggest that vasodilatory, prostanoids are important in determining endothelial response to ACh in diabetic and nondiabetic subjects. Increased prostaglandin-mediated vasodilation may compensate for attenuated responses to NO previously reported in diabetic subjects. These findings may partly explain the conflicting reports of endothelial dysfunction in patients with type 1 diabetes.

Fine-needle aspiration of the thyroid.

BACKGROUND: Although fine-needle aspiration (FNA) of the thyroid is the key preoperative investigation of thyroid lesions, there are overlaps in the criteria for diagnosis of certain lesions, particularly important among which are those for follicular neoplasms. A proposal for a 5-category working system for thyroid FNA diagnosis is presented, devised using clearly defined diagnostic guidelines with a prospective 2-year evaluation in 1 center. METHODS: The results of FNA of 156 patients with nodular thyroid lesions are presented. All patients were observed over a 2-year period in a multidisciplinary thyroid clinic. In some cases, the aspirates were repeated before excision of the lesion. The results of the FNA are classified by worst category for each patient, according to a 5-category scheme: THY1: inadequate; THY2: benign; THY3: indeterminate; THY4: suspicious lesion; THY5: malignant. RESULTS: Seventy-five of the 156 patients (48.1%) proceeded to excision, of these 50 (67%) showed multinodular goiter or adenomatoid nodule within a goiter, 7 (9.3%) showed evidence of Hashimoto thyroiditis or lymphocytic thyroiditis alone, 1 (1.3%) showed evidence of Reidel thyroiditis, and 1 (1.3%) showed evidence of a parathyroid cyst. Eight patients (11%) showed evidence of follicular adenoma, and 5 patients (6.6%) showed papillary carcinoma; 1 (1.3%) showed follicular carcinoma, and 2 (2.7%) showed lymphoproliferative disease. There was a significant difference in the number of benign as compared with neoplastic thyroid lesions excised in the indeterminate (THY3) (2 of 13 [15%]) as compared with the suspicious categories (THY4) (10 of 24 [42%]), (P = 0.05). Although no false-negative FNAs were identified in this series, there was 1 false-positive (THY5) FNA. CONCLUSIONS: The use of an indeterminate (THY3) category is helpful because it improves the diagnostic efficacy of thyroid FNA. The indeterminate (THY3) category is clinically useful and may markedly reduce or eliminate false-negative FNA in many patients with thyroid nodules. Cancer (Cancer Cytopathol)

Comparison of vasodilator effects of substance P in human forearm vessels of normoalbuminuric Type 1 diabetic and non-diabetic subjects.

AIMS: To compare the vasodilatory responses to substance P in human forearm vessels in Type 1 normoalbuminuric diabetic and non-diabetic subjects. METHODS: Forearm blood flow (FBF) was measured using a plethysmography technique in 12 normoalbuminuric Type 1 diabetic subjects (six males, six females) (HbA(1c) 8.2 +/- 0.3% (mean +/- SEM)) and 12 non-diabetic healthy control subjects in response to the infusion of the vasodilators substance P (SP), acetylcholine (ACh) and nitroprusside. RESULTS: There was no significant difference in baseline FBF between the two groups (2.80 +/- 0.29 ml/min per 100 ml forearm tissue (diabetic group) vs. 2.85 +/- 0.37 ml/min per 100 ml (non-diabetic group), P = 0.45). Infusion of SP was associated with an incremental increase in FBF in the diabetic (0.6, 2 and 6 ng/min - 6.08 +/- 1.07, 7.82 +/- 1.08 and 9.48 +/- 1.14 ml/min per 100 ml, respectively) and the non-diabetic group (0.6, 2 and 6 ng/min - 5.41 +/- 0.80, 6.93 +/- 0.96 and 9.25 +/- 1.11 ml/min per 100 ml, respectively). Similarly, an incremental rise in FBF was observed during infusion of ACh (diabetic group: 7.5, 15 and 30 microg/min - 7.14 +/- 1.22, 8.91 +/- 1.40 and 11.67 +/- 1.93 ml/min per 100 ml, respectively; non-diabetic group: 7.5, 15 and 30 microg/min - 5.87 +/- 0.81, 7.49 +/- 0.96 and 10.74 +/- 1.29 ml/min per 100 ml, respectively). When FBF was expressed as percentage change from baseline, there was no significant difference in vasodilatory responses between the two groups for SP (0.6 ng/min, P = 0.21; 2 ng/min, P = 0.19; 6 ng/min, P = 0.19) or ACh (7.5 microg/min, P = 0.20; 15 microg/min, P = 0.20; 30 microg/min, P = 0.35). CONCLUSIONS: This study suggests that endothelium-dependent vasodilatory responses to SP (and ACh) are not impaired in Type 1 diabetic subjects with normal urinary albumin excretion.

Endothelial dysfunction in Type 2 diabetic subjects with and without microalbuminuria.

AIMS: The primary aim of this study was to determine whether microalbuminuria is associated with endothelial dysfunction in Type 1 diabetes mellitus. The secondary aim was to determine whether any reported biochemical markers of cardiovascular risk are associated with endothelial dysfunction in this group. METHODS: Measurements were made of the vasodilatory responses of the brachial artery to post-ischaemic hyperaemia and to sublingual glyceryl trinitrate (GTN) (causing endothelium-dependent and endothelium-independent dilation, respectively) using a high-resolution ultrasound technique in 18 Type 1 diabetic patients with microalbuminuria, 18 age and sex-matched normoalbuminuric Type 1 diabetic patients and 18 non-diabetic control subjects. RESULTS: There was a significant reduction in flow-mediated dilation (FMD) in microalbuminuric and normoalbuminuric diabetic patients compared with control subjects (2.4% (95% confidence interval (CI) 1.0-3.8%) and 2.3% (95% CI 0.7-3.9%) respectively vs. 6.3% (95% CI 5.1-7.5%), P<0.0001) but no difference in GTN-mediated dilation (14.7% (95% CI 10.7-18.7%) and 15.2% (95% CI 11.2-19.2%) vs. 18.7% (95% CI 16.1-21.3%), P = 0.09). There was no significant difference in FMD, however, between the microalbuminuric group and normoalbuminuric group (P=0.45). FMD was not significantly associated with urinary albumin-creatinine ratio, glycosylated haemoglobin, plasma glucose, lipid or lipoprotein concentrations in diabetic patients. There was a positive correlation between active transforming growth factor (TGF)-beta concentration, a novel biochemical marker of macrovascular disease, and FMD in diabetic patients (r=0.36, P<0.05). GTN-mediated dilation was positively associated with HDL-cholesterol concentration (r = 0.49, P = 0.002) but not with other biochemical variables (including active TGF-beta concentration). Active TGF-beta concentration was not associated with degree of microalbuminuria or other biochemical parameters. CONCLUSIONS: These data suggest that endothelial dysfunction occurs in Type 1 diabetic patients regardless of urine albumin status. Endothelial dysfunction appears therefore to predate the development of microalbuminuria as a marker for the development of coronary artery disease. It is also concluded that low plasma levels of active TGF-beta are associated with an impaired endothelial response and this may provide a useful tool for identifying Type 1 diabetic patients at a greater risk of coronary artery disease.