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Some previous studies have suggested that patients with social anxiety disorder (SAD) have a hypoactive central dopaminergic system. Supporting this there have been reports from neuroimaging studies of reduced striatal D2 receptor binding in subjects with SAD. The aim of this study was to investigate D2 receptor sensitivity in patients with SAD compared with a group of matched, healthy controls using a neuroendocrine challenge with the selective D2 antagonist, sulpiride. D2 receptor function was assessed in 23 subjects with generalized SAD and 23 matched, healthy controls using a challenge with 400 mg of a selective D2 antagonist, sulpiride in a randomized, placebo-controlled, crossover design. Response to sulpiride was measured by the change in prolactin level and changes in self-rated measures of social anxiety, mood and the ability to experience pleasure. There was no significant difference in prolactin response to sulpiride between the two groups. Sulpiride resulted in no effect in either the SAD or healthy control group on measures of social anxiety, mood or the ability to experience pleasure. Contrary to our hypothesis, in this study we found no evidence of reduced D2 receptor function in subjects with SAD compared with healthy controls.

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

Objectives: Few studies of neuropsychological function in major depression have examined emotional processing or the impact of gender. Patients have also been compared with highly selected control participants and rarely with other patient groups. The objective of this study was to compare neuropsychological function in a major depressive episode (MDE) with a group of patients with an anxiety disorder, social anxiety disorder (SAD), and healthy controls, to include measures of emotional processing and to analyse the effects of gender on neuropsychological function and emotional processing in these groups., Method: One hundred and one medication-free patients with MDE, 30 patients with SAD and 76 healthy control participants were recruited. The groups were matched for age and estimated premorbid intelligence and education. Subjects performed a battery of neuropsychological tests assessing; verbal learning and memory, visuospatial learning and memory, attention, executive function and psychomotor performance. They also performed a task measuring the accuracy of recognition of facial emotional expressions., Results: Compared with healthy participants and those with SAD, patients with MDE were significantly impaired in verbal learning and spatial working memory. The SAD group misclassified significantly more neutral expressions as angry and fewer as sad, compared with the MDE group and healthy controls, but there were no significant differences between the MDE group and healthy controls. The profile of performance was the same regardless of gender., Conclusions: The study confirms a significant impairment in neuropsychological function in a clinical sample of outpatients with MDE, which is likely to have important implications for day-to-day functioning and treatment.

Background: Obesity is highly associated with elevated serum triglycerides, hepatic steatosis and type 2 diabetes (T2D). The I148M (rs738409) genetic variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is known to modulate hepatic triglyceride accumulation, leading to steatosis. No association between PNPLA3 I148M genotype and T2D in Europeans has been reported. Aim of this study is to examine the relationship between PNPLA3 I148M genotypes and serum triglycerides, insulin resistance and T2D susceptibility by testing a gene-environment interaction model with severe obesity., Methods and Findings: PNPLA3 I148M was genotyped in a large obese cohort, the SOS study (n = 3,473) and in the Go-DARTS (n = 15,448), a T2D case-control study. Metabolic parameters were examined across the PNPLA3 I148M genotypes in participants of the SOS study at baseline and at 2- and 10-year follow up after bariatric surgery or conventional therapy. The associations with metabolic parameters were validated in the Go-DARTS study. Serum triglycerides were found to be lower in the PNPLA3 148M carriers from the SOS study at baseline and from the Go-DARTS T2D cohort. An increased risk for T2D conferred by the 148M allele was found in the SOS study (O.R. 1.09, 95% C.I. 1.01-1.39, P = 0.040) and in severely obese individuals in the Go-DARTS study (O.R. 1.37, 95% C.I. 1.13-1.66, P = 0.001). The 148M allele was no longer associated with insulin resistance or T2D after bariatric surgery in the SOS study and no association with the 148M allele was observed in the less obese (BMI<35) individuals in the Go-DARTS study (P for interaction  = 0.002). This provides evidence for the obesity interaction with I48M allele and T2D risk in a large-scale cross-sectional and a prospective interventional study., Conclusions: Severely obese individuals carrying the PNPLA3 148M allele have lower serum triglyceride levels, are more insulin resistant and more susceptible to T2D. This study supports the hypothesis that obesity-driven hepatic lipid accumulation may contribute to T2D susceptibility.

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD., Competing Interests: The authors have declared that no competing interests exist.

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

Background: LDL can vary considerably in its cholesterol content; thus, lowering LDL cholesterol (LDLC) as a goal of statin treatment implies the existence of considerable variation in the extent to which statin treatment removes circulating LDL particles. This consideration is particularly applicable in diabetes mellitus, in which LDL is frequently depleted of cholesterol., Methods: Type 2 diabetes patients randomly allocated to 10 mg/day atorvastatin (n = 1154) or to placebo (n = 1196) for 1 year were studied to compare spontaneous and statin-induced apolipoprotein B (apo B) concentrations (a measure of LDL particle concentration) at LDLC and non-HDL cholesterol (non-HDLC) concentrations proposed as statin targets in type 2 diabetes., Results: Patients treated with atorvastatin produced lower serum apo B concentrations at any given LDLC concentration than patients on placebo. An LDLC concentration of 1.8 mmol/L (70 mg/dL) during atorvastatin treatment was equivalent to a non-HDLC concentration of 2.59 mmol/L (100 mg/dL) or an apo B concentration of 0.8 g/L. At the more conservative LDLC targets of 2.59 mmol/L (100 mg/dL) and 3.37 mmol/L (130 mg/dL) for non-HDLC, however, the apo B concentration exceeded the 0.9-g/L value anticipated in the recent Consensus Statement from the American Diabetes Association and the American College of Cardiology., Conclusions: The apo B concentration provides a more consistent goal for statin treatment than the LDLC or non-HDLC concentration.

Women with diabetes experience much greater relative risks of coronary heart disease (CHD) compared with the nondiabetic population than do men with diabetes. In type 2 diabetes, much of the greater elevation in risk in women is explained by a more adverse pattern of known CHD risk factors. In type 1 diabetes the picture is less clear, but current evidence suggests that a cardioprotective lipid profile is found in type 1 diabetic men, thus reducing the effect of diabetes on CHD, but that in women this is not the case. Also, in type 1 diabetic women there is some evidence of altered body fat distribution and a greater elevation in blood pressure. Whether these reflect a greater degree of insulin resistance in type 1 women, and what the origin of this might be, remains controversial. The practical consequence is that clinicians need to be aware that the usual cardioprotective effect of sex does not apply in diabetic women and that risk factor intervention is needed at an early age.

LDL particle size can be measured by gradient gel electrophoresis (GGE) and NMR. The agreement between the two methods has not been extensively evaluated. Therefore, we measured LDL size by NMR and GGE in 324 individuals (152 with type 1 diabetes and 172 controls). The Spearman correlation between both methods was 0.39 [95% confidence interval (CI) = 0.29, 0.48]. The average difference was 5.38 nm (NMR being smaller), but it increased with increasing LDL size. Less than 50% of people classified as pattern B on GGE were classified as pattern B on NMR (kappa = 0.31; 95% CI = 0.17, 0.45). Agreement was lower for diabetic subjects compared with controls, for women compared with men, and for subjects with triglycerides less than 1.30 mmol/l compared with subjects with triglycerides greater than 1.30 mmol/l. External validation showed that cholesteryl ester transfer rate was related to LDL size on GGE in all subgroups and to LDL size on NMR only in men and nondiabetic subjects. Our findings show that agreement between NMR- and GGE-based LDL size is far from perfect and is not consistent across subgroups of patients. In particular, the two methods should not be assumed to be interchangeable in women and diabetic subjects. Whether NMR or GGE predicts cardiovascular disease risk better has not yet been evaluated.

Background: Patients with end-stage renal disease (ESRD) are at increased risk of cardiovascular mortality and morbidity. Many complications arise in ESRD patients as a result of the twin arterial pathologies of atherosclerosis and arteriosclerosis. Part of this latter process is calcification of the arterial media, which is thought significantly to increase vascular stiffness. The aim of our study was to explore the relationship between measures of arterial stiffness-pulse wave velocity (PWV)-and the extent of calcification in the coronary arteries (CAC)., Methods: Over a period of 2 years 82 patients from our renal unit were invited to participate in our study. Sixty-two patients agreed to undergo electron beam computerized tomography (EBCT), and in 55 (38 males and 17 females), PWV measurements were made. EBCT and PWV measurements were done according to previously described protocols., Results: The mean age of the 55 patients was 56.4 years. The mean duration of dialysis was 65.4 months, and the mean CAC score was 2551. The mean PWV was 9.13 m/s. PWV strongly correlated with total CAC even after correction for age, dialysis duration, and time averaged C-reactive protein (CRP) (P= 0.0001). CAC scores were significantly different when compared according to PWV tertiles (P= 0.0001)., Conclusion: We have demonstrated that PWV is strongly related to the degree of EBCT-derived coronary artery calcium score in chronic kidney disease patients.

The effect of statin therapy on subclasses of LDL, VLDL and HDL lipoproteins is unclear. We compared changes in serum lipids, apolipoproteins and nuclear magnetic resonance (NMR) spectroscopy measured lipoprotein subclass concentration and average particle size over a minimum 6 months treatment period of atorvastatin 10 mg vs. placebo in 122 men and women. All subjects had type 2 diabetes and a modest dyslipidaemia (mean LDL-cholesterol 3.2 mmol/l and median triglycerides 1.8 mmol/l) and had a previous myocardial infarction. Compared with placebo, atorvastatin therapy was associated with a greater decrease in medium VLDL (median within person change -13.4 vs. -5.9 nmol/l, P<0.001 adjusted for baseline level), small VLDL (median change -17.8 vs. -8.1 nmol/l, P=0.002), large LDL (mean within person change -167.9 vs. -48.6 nmol/l, P<0.001) and medium LDL (median within person change -101.8 vs. -22.3 nmol/l, P=0.017). Atorvastatin therapy was also associated with a greater increase in large HDL than placebo (median change 1.40 vs. 0.80 micromol/l, P=0.02) and there was little change in small HDL so that average HDL particle size increased significantly with atorvastatin (P=0.04). In addition to reducing levels of (enzymatically measured) triglyceride, LDL-cholesterol and apolipoprotein B in diabetic patients, atorvastatin significantly reduces NMR measured medium and small VLDL and large and medium LDL, and increases large HDL.

Background: Baroreflex sensitivity (BRS) and heart rate variability (HRV) are attenuated in cardiovascular disease and can give important prognostic information. Conventional measures of BRS require expensive or invasive equipment for the beat-to-beat measure of blood pressure (BP). We examined the possibility of developing a simple protocol that would provide a relatively standardized BP stimulus, which might obviate the need to measure BP beat-by-beat., Methods and Results: Fifty-five patients with chronic heart failure (mean age 59 [SD 11] years) and 20 healthy control subjects (mean age 53 [SD 14] years, P not significant) underwent 5-minute recordings of BP (by photoplethysmograph) and R-R interval during 0.1-Hz controlled breathing. The size of the oscillations in BP was the same in the 2 groups (3.6 mm Hg vs 4.1 mm Hg, P =.5). There was, however, a significant difference in the amplitude of the R-R interval oscillations (77 ms vs 31 ms, P <.0001). The amplitude of the R-R interval oscillations correlated strongly with BRS (r = 0.81, P <.0001 with controlled breathing BRS, and r = 0.51, P <.0001 with alpha index). There was no correlation with the size of BP oscillations (r = -0.13, P not significant with controlled breathing BRS, and r = -0.15, P not significant with alpha index). In a separate study, a group of 22 young patients (mean age 36 years) with type I diabetes mellitus and 28 healthy control subjects (mean age 39 years) underwent measurement of resting HRV and amplitude of R-R interval oscillations during 0.1-Hz breathing. There was no significant difference in triangular index or low-frequency R-R interval power between the 2 groups. There was, however, a significant difference in the amplitude of R-R interval oscillations during controlled breathing between patients with diabetes and healthy control subjects. Total and high-frequency RR interval variability was also significantly different between the 2 groups., Conclusion: During 0.1-Hz breathing, the marked difference in BRS between patients with CHF and age-matched control subjects is the result of smaller R-R interval oscillations. In young patients with diabetes, these R-R interval oscillations are significantly smaller than age-matched control subjects, even when some measures of spontaneous HRV are not different between groups. Breathing at 0.1 Hz provides a standard BP stimulus and concentrates spectral power of heart rate at one frequency, enabling simple evaluation of BRS even when BP measurement is not available.

Objectives: We examined to what extent the variation in risk factors for coronary heart disease (CHD) and the Framingham risk score (FRS) explain the variation in vascular reactivity in adults aged 30 to 53 years., Background: The role of risk factors in determining vascular reactivity in the general population has not been quantified., Methods: Risk factors for CHD were measured, and the FRS was calculated in 69 healthy volunteers. Lipoprotein particle size was measured using proton-nuclear magnetic resonance spectroscopy. Forearm plethysmography was used to assess blood flow responses to acetylcholine (ACh), bradykinin (BK), glyceryl trinitrate (GTN), noradrenaline and N(G)-monomethyl-L-arginine (L-NMMA)., Results: Lower ACh and BK responses were associated with a higher body mass index (BMI), a higher total cholesterol to high-density lipoprotein (HDL) cholesterol ratio, lower HDL cholesterol and a cigarette smoking habit (all p < 0.05). Higher low-density lipoprotein (LDL) cholesterol was also associated with a lower BK response (p = 0.001). A decreased GTN response was associated with a higher BMI and total cholesterol to HDL cholesterol ratio (both p < 0.05). A decreased L-NMMA response was associated with a smoking habit (p < 0.001). Lipoprotein particle sizes did not independently predict any vascular response. A high FRS was associated with a reduced response to ACh (p = 0.07), BK (p = 0.003) and L-NMMA (p = 0.003), and the relationship was stronger in women than in men. Altogether, risk factors explained 13%, 9%, 8% and 15% of the response to ACh, BK, GTN and L-NMMA, respectively., Conclusions: Lipids, BMI and smoking are important determinants of vascular reactivity. The FRS is predictive of agonist-stimulated, endothelium-dependent vasodilation and basal NO release. However, much of the variation in the vascular responses to these drugs, at this age, remains unexplained.

During the menstrual cycle, changes in endothelium-dependent vasodilatation have been demonstrated in conduit vessels in vivo, but responses in resistance vessels have not been studied. The aim of this study was to examine endothelium-dependent vasodilatation, the effects of local nitric oxide synthesis, and alpha-adrenergic constriction in resistance vessels during the menstrual cycle in 15 healthy female volunteers (mean age, 28.07 +/- 2.1 yr). Forearm blood flow in response to intrabrachial infusion of bradykinin (10, 30, and 100 pmol/min; endothelium-dependent vasodilator), glyceryl trinitrate (4, 8, and 16 nmol/min; endothelium-independent vasodilator), noradrenaline (60, 120, and 240 pmol/min; alpha-adrenergic receptor agonist), and N(G)-monomethyl-L-arginine (1, 2, and 4 micromol/min; nitric oxide synthase inhibitor) was assessed by venous occlusion plethysmography. All subjects were studied in early menstrual phase (days 1--4) and midcycle (days 10-13). Vasodilator response to bradykinin, expressed as the within-subject mean difference in the area under the dose-response curve between phases, was significantly increased at midcycle compared with that in the early menstrual phase (486.5 +/- 165.0; P = 0.01), whereas there was no significant difference in response to glyceryl trinitrate (185.8 +/- 239.0; P = 0.45). The vasoconstrictor response to noradrenaline was significantly greater at midcycle (97.1 +/- 39.4; P = 0.027), but the response to N(G)-monomethyl-L-arginine was not significantly different (17.5 +/- 35.2; P = 0.63). Serum estradiol was approximately 3-fold higher at midcycle, with a mean difference of 252.3 +/- 56.0 pmol/L (P = 0.0005). Progesterone concentrations were not significantly different (-0.11 +/- 0.1 nmol/L; P = 0.28). Differences in endogenous estrogen levels between menstrual phases may underlie changes in bradykinin and noradrenaline responses. If exogenous estrogens have similar effects, the balance of these two opposing actions may determine whether estrogen replacement in postmenopausal women has beneficial or harmful effects on the vasculature.

Objectives: To examine whether the gender difference in coronary artery calcification, a measure of atherosclerotic plaque burden, is lost in type 1 diabetic patients, and whether abnormalities in established coronary heart disease risk factors explain this., Background: Type 1 diabetes abolishes the gender difference in coronary heart disease mortality because it is associated with a greater elevation of coronary disease risk in women than men. The pathophysiological basis of this is not understood., Methods: Coronary artery calcification and coronary risk factors were compared in 199 type 1 diabetic patients and 201 nondiabetic participants of similar age (30 to 55 years) and gender (50% female) distribution. Only one subject had a history of coronary disease. Calcification was measured with electron beam computed tomography., Results: In nondiabetic participants there was a large gender difference in calcification prevalence (men 54%, women 21%, odds ratio 4.5, p < 0.001), half of which was explained by established risk factors (odds ratio after adjustment = 2.2). Diabetes was associated with a greatly increased prevalence of calcification in women (47%), but not men (52%), so that the gender difference in calcification was lost (p = 0.002 for the greater effect of diabetes on calcification in women than men). On adjustment for risk factors, diabetes remained associated with a threefold higher odds ratio of calcification in women than men (p = 0.02)., Conclusions: In type 1 diabetes coronary artery calcification is greatly increased in women and the gender difference in calcification is lost. Little of this is explained by known coronary risk factors.

The prevention and treatment of coronary heart disease is a major challenge in the overall management of the patient with type 2 diabetes. Diabetic dyslipidaemia is an important risk factor and is open to therapeutic intervention. However, as yet there are no primary or secondary coronary heart disease prevention trials of lipid-lowering therapy reported in diabetic populations. In this review, on-going clinical trials of lipid-lowering therapy in specific diabetic populations will be described.

Aims/hypothesis: To examine whether the HDL-cholesterol:apoA-I + apoA-II ratio and the epsilon2 allele are related to albuminuria at baseline and whether they are risk factors for progression of albuminuria in a cohort study of patients with Type I (insulin-dependent) diabetes mellitus., Methods: At baseline, the study cohort comprised 617 patients, aged 15-60 years, from seven European diabetic centres of the EURODIAB study. Albumin excretion rate, measured in a central laboratory, was categorised as normoalbuminuria at 20 microg/min or less, microalbuminuria between 20 and 200 microg/min or macroalbuminuria at 200 microg/min or over. Of the 250 patients who were normoalbuminuric at baseline and had follow-up albuminuria measurements, 34 patients were defined as early progressors., Results: At baseline, the mean HDL-cholesterol:apoA-I + apoA-II ratio was lower in macroalbuminuric patients (0.79, 95 % CI:0.74-0.83) compared with normoalbuminuric (0.88, 95 % CI:0.87-0.90) patients (p = 0.0002, adjusted for age and sex). At follow-up, 34 patients who progressed from normoalbuminuria to microalbuminuria or macroalbuminuria also had a slightly lower baseline ratio (0.85, 95% CI:0.80-0.89) than those 216 who remained normoalbuminuric (0.89, 95 % CI:0.87-0.92) (adjusted p = 0.08). Neither of these relations were independent of LDL-cholesterol or fasting triglyceride. There was no association of the epsilon2 allele with albuminuria either at baseline (OR = 1.4, 95% CI:0.7-2.8) or with progression of albuminuria (OR = 0.4, 95 % CI:0.1-3.5)., Conclusion/interpretation: There is an inverse relation of HDL-cholesterol:apoA-I + apoA-II ratio with albuminuria at baseline. This lower ratio in microalbuminuric or macroalbuminuric patients could contribute to the increased risk of cardiovascular disease associated with nephropathy. There is weak evidence that HDL-composition is a risk factor for progression of albuminuria and no association of the epsilon2 allele with diabetic nephropathy.

Vascular complications are major causes of morbidity and mortality in patients with diabetes mellitus. The mechanisms underlying the development of microvascular and macrovascular angiopathy in Type I (insulin-dependent) diabetes mellitus are complex and incompletely understood. The discovery of endothelium-derived nitric oxide has greatly improved our understanding of vascular biology. Nitric oxide has an important role in the regulation of vascular tone and impaired nitric oxide activity could be implicated in the development of diabetic vasculopathy. Vascular studies of endothelial function in Type I diabetes have produced conflicting results. The role of nitric oxide in diabetic vasculopathy is still not clear.

Approximately 30% of diabetic patients develop nephropathy, the appearance of which is partially under genetic control. Atrial natriuretic peptide (ANP) has associated physiologic effects on the kidney. This study was conducted to examine the relationship between a newly identified and known polymorphism at the pronatriodilatin (PND) gene locus and renal involvement in type 1 diabetic subjects. Of 454 type 1 diabetic patients (219 men, 235 women), 323 showed no sign of nephropathy, 79 had incipient renal involvement, and 52 established nephropathy; 58 healthy control subjects were examined for comparison. Allele frequencies (C708 versus T708) were: 0.95 and 0.05 in normoalbuminuric patients, respectively; 0.88 and 0.12 in microalbuminuric patients; 0.96 and 0.04 both in those with overt nephropathy and in healthy control subjects (P = 0.011). Patients with incipient nephropathy were in disequilibrium compared with the total diabetic cohort (P = 0.02). In the same populations, an additional genotype for ScaI polymorphism of the PND gene was tested. The A1 and A2 allele frequencies were: 0.21 and 0.79 in normoalbuminuric patients; 0. 13 and 0.87 in microalbuminuric patients; 0.06 and 0.94 in type 1 diabetic subjects with overt nephropathy; and 0.20 and 0.80 in healthy control subjects, respectively (P < 0.0001). A subset of 55 normotensive patients with type 1 diabetes, well matched for clinical features, plasma ANP levels, and microvascular permeability to macromolecules, was investigated on the basis of the C708/T and A2/A1 polymorphisms. Both transcapillary escape rate of albumin (TERalb) and plasma ANP levels were significantly lower in patients with the T708 than with C708 allele, as well as in the A1 than in A2 allele (TERalb: T708 versus C708: 5.5+/-1.7 versus 7.8+/-2.0%/h, P = 0.0001; plasma ANP levels: 8.3+/-3.9 versus 15.3+/-7.7 pg/ml, P = 0.0003; A1 versus A2: 6.05+/-2.2 versus 7.3+/-2.1%/h, P = 0.044; 8.53+/-4.6 versus 14.5+/-7.4 pg/ml, P = 0.0024, respectively). Thus, in a large ethnically homogeneous cohort of diabetic subjects, our data show: (1) a significant association of C708/T polymorphism with microalbuminuria in long-term diabetes and with both lower plasma ANP levels and widespread albumin leakage; and (2) a strong association between ScaI polymorphism and both diabetic nephropathy and plasma ANP concentrations. These results suggest a possible role of PND gene in conferring protection from nephropathy and microvascular damage in type 1 diabetes.

Diabetic nephropathy clusters in families, suggesting an inherited predisposition. Parental history of hypertension and of Type 2 diabetes mellitus have been associated with nephropathy in offspring with Type 1 diabetes in some studies but not in others. The associations of parental history of hypertension and of diabetes with both albuminuria and proliferative retinopathy were studied in a large cross-sectional study of 3250 patients with Type 1 diabetes, from 16 European countries. Albuminuria was associated with hypertension in a parent (p < 0.01 in men, p < 0.05 in women), adjusted for age. Patients with a parental history of hypertension had a higher prevalence of hypertension (p < 0.001 in men, p < 0.01 in women) and a higher prevalence of parental diabetes (p < 0.001 in men, p < 0.001 in women). The association of albuminuria with parental hypertension was independent of parental diabetes in men but not women (OR = 1.28 in men p = 0.04, OR = 1.25 in women p = 0.09) and was not independent of hypertension in the patient him/herself in either sex. Albuminuria was associated with parental diabetes in women only (OR = 1.36, p = 0.04). This association was independent of both parental hypertension and hypertension in the patient herself. Proliferative retinopathy was not associated with parental hypertension or diabetes. The implications of these data are that both candidate genes for hypertension and Type 2 diabetes should be considered in the search for the genetic determinants of diabetic nephropathy.

To 31st December 1989, 71 persons are known to have attended medical practitioners in Northern Ireland with a diagnosis of Human Immunodeficiency Virus (HIV) infection. Twenty-one of these persons have had the diagnosis of Acquired Immune Deficiency Syndrome (AIDS) and 11 have died. The distribution of reports in the "at risk" categories of homosexual/bisexual males, injecting drug users, heterosexual males and females was significantly different (p less than 0.001) from those reported in the United Kingdom as a whole. Of tests for HIV infection carried out in patients attending the genitourinary medicine department of the Royal Victoria Hospital between 1987-1989, 0.16% have been positive. The prognostic value of the T4 lymphocyte count at presentation for the subsequent development of AIDS was significant (p = 0.0011). The commonest AIDS indicator disease diagnosed was Pneumocystis carinii pneumonia which was seen in seven of the 21 patients (33%).