Treatment of road runoff by coagulation/flocculation and sedimentation.

A laboratory investigation of the treatment potential of a coagulation process in the context of stormwater treatment was undertaken. The initial 25 L road runoff generated from four rain events was collected and subjected to a jar-testing regime with two commercial coagulants. The treatment effect was assessed by analysing the runoff before and after treatment for turbidity, suspended solids and metal content. The coagulation process resulted in particle and total metal reduction of more than 90% compared to 40% for only sedimentation. Up to 40% reduction of dissolved Cr, Cu and Pb was also observed compared to 0% for sedimentation. This study shows that coagulation may be a useful process for stormwater treatment systems when the treatment requirements are high.

Association between serum 25(OH)D3 and cardiovascular morbidity and mortality in people with Type 2 diabetes: a community-based cohort study.

AIM: We aimed to explore the association between vitamin D and cardiovascular morbidity and mortality in people with Type 2 diabetes recruited from a community-based study because there is limited and inconsistent research of this group. METHODS: A prospective community-based cohort study among people aged 55-66 years with Type 2 diabetes as part of The Cardiovascular Risk in Type 2 Diabetes - A Prospective Study in Primary Care (CARDIPP). We analysed serum 25-hydroxyvitamin D3 [25(OH)D3 ] at baseline. Cox regression analyses were used to calculate hazard ratios (HR) for the first myocardial infarction, stroke or cardiovascular mortality according to 25(OH)D3 . RESULTS: We examined 698 people with a mean follow-up of 7.3 years. Serum 25(OH)D3 was inversely associated with the risk of cardiovascular morbidity and mortality: HR 0.98 [95% confidence interval (CI) 0.96 to 0.99, P = 0.001]. Compared with the fourth quartile (Q4) [25(OH)D3 > 61.8 nmol/l], HR (with 95% CI) was 3.46 (1.60 to 7.47) in Q1 [25(OH)D3 < 35.5 nmol/l] (P = 0.002); 2.26 (1.01 to 5.06) in Q2 [25(OH)D3 35.5-47.5 nmol/l] (P = 0.047); and 1.62 (0.70 to 3.76) in Q3 [25(OH)D3 47.5-61.8 nmol/l] (P = 0.26) when adjusting for age, sex and season. The results remained significant after adjusting also for cardiovascular risk factors, physiological variables including parathyroid hormone and previous cardiovascular disease (P = 0.027). CONCLUSIONS: Low 25(OH)D3 is associated with an increased risk of cardiovascular morbidity and mortality in people with Type 2 diabetes independent of parathyroid hormone. Vitamin D could be considered as a prognostic factor. Future studies are needed to explore whether vitamin D deficiency is a modifiable risk factor in Type 2 diabetes.

The impact of using sagittal abdominal diameter to predict major cardiovascular events in European patients with type 2 diabetes.

BACKGROUND AND AIMS: Obesity is associated with diabetes type 2 and one of the most important risk factors for cardiovascular disease. We explored if sagittal abdominal diameter (SAD) is a better predictor of major cardiovascular events than waist circumference (WC) and body mass index (BMI) in type 2 diabetes. METHODS AND RESULTS: The CARDIPP study consists of a cohort of patients with type 2 diabetes. In this study we used data from 635 participants with no previous myocardial infarction or stroke, with a mean follow-up time of 7.1 years. SAD, WC and BMI were measured at baseline and the end-point was first cardiovascular event, measured as a composite of ICD-10 codes for acute myocardial infarction, stroke or cardiovascular mortality. SAD was significantly higher in the major cardiovascular event group compared to participants that did not suffer a major cardiovascular event during follow-up (p < 0.001). SAD >25 cm was the only anthropometric measurement that remained associated with major cardiovascular events when adjusted for modifiable and non-modifiable factors (hazard ratio 2.81, 95% confidence interval 1.37-5.76, p = 0.005). CONCLUSION: SAD with the cut off level of >25 cm, if confirmed in larger studies, may be used as a more independent risk-assessment tool compared with WC in clinical practice, to identify persons with type 2 diabetes at high cardiovascular risk. ClinicalTrials.gov: NCT01049737.

Pedometer-determined physical activity level and change in arterial stiffness in Type 2 diabetes over 4 years.

AIM: To explore prospectively the correlation between the level of pedometer-determined physical activity at the start of the study and the change in pulse wave velocity from baseline to 4 years later in people with Type 2 diabetes. METHODS: We analysed data from 135 men and 53 women with Type 2 diabetes, aged 54-66 years. Physical activity was measured with waist-mounted pedometers on 3 consecutive days and the numbers of steps/day at baseline were classified into four groups: <5000 steps/day, 5000-7499 steps/day, 7500-9999 steps/day and ≥10 000 steps/day. Pulse wave velocity was measured using applanation tonometry over the carotid and femoral arteries at baseline and after 4 years. RESULTS: The mean (±sd; range) number of steps/day was 8022 (±3765; 956-20 921). The participants with the lowest level of physical activity had a more pronounced increase in the change in pulse wave velocity compared with the participants with the highest. When change in pulse wave velocity was analysed as a continuous variable and adjusted for sex, age, diabetes duration, HbA1c , BMI, systolic blood pressure, pulse wave velocity at baseline, ß-blocker use, statin use, unemployment, smoking and diabetes medication, the number of steps/day at baseline was significantly associated with a less steep increase in change in pulse wave velocity (P=0.005). Every 1000 extra steps at baseline corresponded to a lower increase in change in pulse wave velocity of 0.103 m/s. CONCLUSIONS: We found that a high level of pedometer-determined physical activity was associated with a slower progression of arterial stiffness over 4 years in middle-aged people with Type 2 diabetes.

In type 2 diabetes, randomisation to advice to follow a low-carbohydrate diet transiently improves glycaemic control compared with advice to follow a low-fat diet producing a similar weight loss.

AIMS/HYPOTHESIS: The study aimed to compare the effects of a 2 year intervention with a low-fat diet (LFD) or a low-carbohydrate diet (LCD), based on four group meetings to achieve compliance. METHODS: This was a prospective randomised parallel trial involving 61 adults with type 2 diabetes consecutively recruited in primary care and randomised by drawing ballots. Patients that did not speak Swedish could not be recruited. The primary outcomes in this non-blinded study were weight and HbA(1c). Patients on the LFD aimed for 55-60 energy per cent (E%) and those on LCD for 20 E% from carbohydrate. RESULTS: The mean BMI and HbA(1c) of the participants were 32.7 ± 5.4 kg/m(2) and 57.0 ± 9.2 mmol/mol, respectively. No patients were lost to follow-up. Weight loss did not differ between groups and was maximal at 6 months: LFD -3.99 ± 4.1 kg (n=31); LCD -4.31 ± 3.6 kg (n=30); p < 0.001 within groups. At 24 months, patients on the LFD had lost -2.97 ± 4.9 kg and those on LCD -2.34 ± 5.1 kg compared with baseline (p = 0.002 and p = 0.020 within groups, respectively). HbA(1c) fell in the LCD group only (LCD at 6 months -4.8 ± 8.3 mmol/mol, p = 0.004, at 12 months -2.2 ± 7.7 mmol/mol, p = 0.12; LFD at 6 months -0.9 ± 8.8 mmol/mol, p = 0.56). At 6 months, HDL-cholesterol had increased with the LCD (from 1.13 ± 0.33 mmol/l to 1.25 ± 0.47 mmol/l, p = 0.018) while LDL-cholesterol did not differ between groups. Insulin doses were reduced in the LCD group (0 months, LCD 42 ± 65 E, LFD 39 ± 51 E; 6 months, LCD 30 ± 47 E, LFD 38 ± 48 E; p = 0.046 for between-group change). CONCLUSIONS/INTERPRETATION: Weight changes did not differ between the diet groups, while insulin doses were reduced significantly more with the LCD at 6 months, when compliance was good. Thus, aiming for 20% of energy intake from carbohydrates is safe with respect to cardiovascular risk compared with the traditional LFD and this approach could constitute a treatment alternative. TRIAL REGISTRATION: ClinicalTrials.gov NCT01005498 FUNDING: University Hospital of Linköping Research Funds, Linköping University, the County Council of Östergötland, and the Diabetes Research Centre of Linköping University.

Pedometer-determined physical activity is linked to low systemic inflammation and low arterial stiffness in Type 2 diabetes.

AIMS: The aim of this study was to explore the association between pedometer-determined physical activity versus measures of obesity, inflammatory markers and arterial stiffness in people with Type 2 diabetes. METHODS: We analysed data from 224 men and 103 women with Type 2 diabetes, aged 54-66 years. Physical activity was measured with waist-mounted pedometers during three consecutive days and the number of steps/day were calculated and classified in four groups: < 5000 steps/day, 5000-7499 steps/day, 7500-9999 steps/day and ≥ 10000 steps/day. Blood samples were analysed for lipids, HbA(1c), inflammatory markers including C-reactive protein and interleukin-6. Nurses measured blood pressure and anthropometrics. Aortic pulse wave velocity was measured with applanation tonometry over the carotid and femoral arteries. RESULTS: Mean steps/day was 7683 ± 3883 (median 7222, interquartile range 4869-10,343). There were no differences in age, diabetes duration, blood pressure, lipids or glycaemic control between the four groups of pedometer-determined physical activity. Subjects with higher steps/day had lower BMI (28.8 vs. 31.5 kg/m(2), P < 0.001), waist circumference (101.7 vs. 108.0 cm, P < 0.001), lower levels of C-reactive protein (1.6 vs. 2.6 mg/l, P = 0.007), lower levels of interleukin-6 (1.9 vs. 3.8 pg ml, P < 0.001) and lower pulse wave velocity (10.2 vs. 11.0 m/s, P = 0.009) compared with less physically active people. CONCLUSIONS: We conclude that physical activity measured with pedometer was associated not only with less abdominal obesity, but also with decreased systemic low-grade inflammation as well as with low arterial stiffness, in people with Type 2 diabetes.

Using proximity extension proteomics assay to discover novel biomarkers associated with circulating leptin levels in patients with type 2 diabetes.

We aimed to discover novel associations between leptin and circulating proteins which could link leptin to the development of cardiovascular disease in patients with type 2 diabetes (T2DM). In a discovery phase, we investigated associations between 88 plasma proteins, assessed with a proximity extension assay, and plasma leptin in a cohort of middle-aged patients with T2DM. Associations passing the significance threshold of a False discovery rate of 5% (corresponding to p < 0.0017) were replicated in patients with T2DM in an independent cohort. We also investigated if proteins mediated the longitudinal association between plasma leptin and the incidence of major cardiovascular events (MACE). One protein, adipocyte fatty acid binding protein (A-FABP), was significantly associated with leptin in both the discovery phase [95% CI (0.06, 0.17) p = 0.00002] and the replication cohort [95% CI (0.12, 0.39) p = 0.0003]. Multiplicative interaction analyses in the two cohorts suggest a stronger association between A-FABP and leptin in men than in women. In longitudinal analyses, the association between leptin and MACE was slightly attenuated after adding A-FABP to the multivariate model. Our analysis identified a consistent association between leptin and A-FABP in two independent cohorts of patients with T2DM, particularly in men.Trial registration: ClinicalTrials.gov identifier NCT01049737.

Masked nocturnal hypertension--a novel marker of risk in type 2 diabetes.

AIMS/HYPOTHESIS: This study was designed to evaluate the prevalence of masked nocturnal hypertension (MNHT) and its impact on arterial stiffness and central blood pressure in patients with type 2 diabetes. METHODS: Middle-aged patients (n = 414) with type 2 diabetes underwent clinic and ambulatory BP measurements and applanation tonometry. RESULTS: MNHT (clinic BP < 130/80 mmHg and night-time BP > or = 120/70 mmHg) was found in 7.2% of patients (n = 30). Compared with patients with both clinical and nocturnal normotension (n = 70), patients with MNHT had higher aortic pulse wave velocity (PWV) (10.2 +/- 1.8 m/s vs 9.4 +/- 1.7 m/s; p = 0.03) and higher central BP (117.6 +/- 13.9/74.0 +/- 9.1 mmHg vs 110.4 +/- 16.4/69.7 +/- 9.6 mmHg, p = 0.04). In patients with clinical normotension, night-time systolic BP correlated significantly with PWV. CONCLUSIONS/INTERPRETATION: Thirty per cent of patients with clinical normotension had nocturnal hypertension. This was accompanied by increased arterial stiffness and higher central BP. We conclude that in clinically normotensive patients with type 2 diabetes, ambulatory BP measurement may help clinicians to identify patients with increased cardiovascular risk.

Carotid intima-media thickness and apolipoprotein B/apolipoprotein A-I ratio in middle-aged patients with Type 2 diabetes.

AIMS: To explore the association between carotid intima-media thickness (IMT) and the apolipoprotein B (apoB)/apolipoprotein A-I (apoA-I) ratio compared with conventional lipids in middle-aged patients with Type 2 diabetes. METHODS: We analysed data from 247 patients with Type 2 diabetes, aged 55-66 years, in the Cardiovascular Risk factors in Patients with Diabetes-a Prospective study in Primary care (CARDIPP-1) study. Primary care nurses measured blood pressure and anthropometric characteristics. Blood samples were taken for laboratory analyses. The carotid IMT was determined by ultrasonography at the University Hospital in Linköping and at the County Hospital Ryhov, Jönköping, Sweden. RESULTS: The ApoB/apoA-I ratio (r = 0.207, P = 0.001), apoB (r = 0.166, P = 0.009) and non-high-density lipoprotein cholesterol (non-HDL-c) (r = 0.129, P = 0.046) correlated with IMT. Conventional lipids, high-sensitivity C-reactive protein (hsCRP), glycated haemoglobin (HbA(1c)) and systolic blood pressure were not significantly correlated to IMT. A stepwise logistic regression analysis was conducted with IMT as the dependent variable and the apoB/apoA-I ratio, HbA(1c), hsCRP, low-density lipoprotein cholesterol (LDL-c), total cholesterol, non-HDL-c and treatment with statins as independent variables. Following adjustment for age and gender, only the apoB/apoA-I ratio remained significantly associated with IMT (odds ratio 4.3, 95% confidence intervals 1.7-10.8, P = 0.002). CONCLUSIONS: We conclude that there was a significant association between the apoB/apoA-I ratio and IMT in middle-aged patients with Type 2 diabetes. The association was independent of conventional lipids, hsCRP, glycaemic control and use of statins.

Fluid therapy and the use of albumin in the treatment of severe traumatic brain injury.

BACKGROUND: Evidence-based guidelines for severe traumatic brain injury (TBI) do not include strategies for fluid administration. The protocol used in this study includes albumin administration to maintain normal colloid osmotic pressure and advocates a neutral to slightly negative fluid balance. The aim of this study was to analyze the occurrence of organ failure and the mortality in patients with severe TBI treated by a protocol that includes defined strategies for fluid therapy. METHODS: Ninety-three patients with severe TBI and Glasgow Coma Score or=3 was evident only for respiratory failure, which was observed in 29%. None developed renal failure. After 28 days, mortality was 11% and, after 18 months, it was 14%. CONCLUSIONS: A protocol including albumin administration in combination with a neutral to a slightly negative fluid balance was associated with low mortality in patients with severe TBI in spite of a relatively high frequency (29%) of respiratory failure, assessed with the SOFA score.

Fast-food-based hyper-alimentation can induce rapid and profound elevation of serum alanine aminotransferase in healthy subjects.

OBJECTIVE: To study the effect of fast-food-based hyper-alimentation on liver enzymes and hepatic triglyceride content (HTGC). DESIGN: Prospective interventional study with parallel control group. SETTING: University Hospital of Linköping, Sweden. PARTICIPANTS: 12 healthy men and six healthy women with a mean (SD) age of 26 (6.6) years and a matched control group. INTERVENTION: Subjects in the intervention group aimed for a body weight increase of 5-15% by eating at least two fast-food-based meals a day with the goal to double the regular caloric intake in combination with adoption of a sedentary lifestyle for 4 weeks. MAIN OUTCOME MEASURES: Weekly changes of serum aminotransferases and HTGC measured by proton nuclear magnetic resonance spectroscopy at baseline and after the intervention. RESULTS: Subjects in the intervention group increased from 67.6 (9.1) kg to 74.0 (11) kg in weight (p<0.001). Serum ALT increased from 22.1 (11.4) U/l at study start to an individual mean maximum level of 97 (103) U/l (range 19.4-447 U/l). Eleven of the 18 subjects persistently showed ALT above reference limits (women >19 U/l, men >30 U/l) during the intervention. Sugar (mono- and disaccharides) intake during week 3 correlated with the maximal ALT/baseline ALT ratio (r = 0.62, p = 0.006). HTGC increased from 1.1 (1.9)% to 2.8 (4.8)%, although this was not related to the increase in ALT levels. ALT levels were unchanged in controls. CONCLUSION: Hyper-alimentation per se can induce profound ALT elevations in less than 4 weeks. Our study clearly shows that in the evaluation of subjects with elevated ALT the medical history should include not only questions about alcohol intake but also explore whether recent excessive food intake has occurred.

Weight gain restriction for obese pregnant women: a case-control intervention study.

OBJECTIVE: To minimise obese women's total weight gain during pregnancy to less than 7 kg and to investigate the delivery and neonatal outcome. DESIGN: A prospective case-control intervention study. SETTING: Antenatal care clinics in the southeast region of Sweden. POPULATION: One hundred fifty-five pregnant women in an index group and one hundred ninety-three women in a control group. METHODS: An intervention programme with weekly motivational talks and aqua aerobic classes for obese pregnant women. MAIN OUTCOME MEASURES: Weight gain in kilograms, delivery and neonatal outcome. RESULTS: The index group had a significantly lower weight gain during pregnancy compared with the control group (P < 0.001). The women in the index group weighed less at the postnatal check-up compared with the weight registered in early pregnancy (P < 0.001). The percentage of women in the index group who gained less than 7 kg was greater than that of women in the control group who gained less than 7 kg (P= 0.003). The percentage of nulliparous women in this group was greater than that in the control group (P= 0.018). In addition, the women in the index group had a significantly lower body mass index at the postnatal check-up, compared with the control group (P < 0.001). There were no differences between the index group and the control group regarding birthweight, gestational age and mode of delivery. CONCLUSION: The intervention programme was effective in controlling weight gain during pregnancy and did not affect delivery or neonatal outcome.

The association between endostatin and kidney disease and mortality in patients with type 2 diabetes.

AIM: Circulating endostatin, a biologically active derivate of collagen XVIII, is considered to be a marker of kidney disease and a risk factor for its related mortality. However, less is known of the role of endostatin in diabetes and the development of diabetic nephropathy. For this reason, our study investigated the associations between circulating endostatin and the prevalence and progression of kidney disease, and its mortality risk in patients with type 2 diabetes (T2D). METHODS: This was a cohort study of 607 patients with T2D (mean age: 61 years, 44% women). Estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, was used to assess the patients' kidney function decline and mortality. RESULTS: Of the total study cohort, 20 patients declined by ≥20% in eGFR over 4 years, and 44 died during the follow-up (mean duration: 6.7 years). At baseline, participants with diabetic nephropathy (defined as eGFR<60mL/min/1.73m2) and/or microalbuminuria [defined as a urinary albumin-to-creatinine ratio (ACR)>3g/mol] had higher median levels of endostatin than those without nephropathy (62.7µg/L vs 57.4µg/L, respectively; P=0.031). In longitudinal analyses adjusted for age, gender, baseline eGFR and ACR, higher endostatin levels were associated with a higher risk of decline (≥20% in eGFR, OR per 1 SD increase: 1.73, 95% CI: 1.13-2.65) and a higher risk of mortality (HR per 1 SD increase: 1.57, 95% CI: 1.19-2.07). CONCLUSION: In patients with T2D, circulating endostatin levels can predict the progression of kidney disease and mortality independently of established kidney disease markers. The clinical usefulness of endostatin as a risk marker in such patients merits further studies.

Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells.

BACKGROUND: Previously, we demonstrated that insulin stimulates production of nitric oxide (NO) in endothelial cells. However, specific insulin-signaling pathways mediating production of NO have not been elucidated. METHODS AND RESULTS: We developed methods for transfection of human umbilical vein endothelial cells (HUVECs) and direct measurement of NO to begin defining insulin-signaling pathways related to NO production. HUVECs were cotransfected with enhanced Green Fluorescent Protein (eGFP) and another gene of interest. Transfection efficiencies >95% were obtained by selecting cells expressing eGFP. Overexpression of insulin receptors in HUVECs resulted in an approximately 3-fold increase in production of NO in response to insulin. In contrast, HUVECs overexpressing a tyrosine kinase-deficient mutant insulin receptor had a dose-response curve similar to that of control cells. Overexpression of inhibitory mutants of either phosphatidylinositol 3-kinase (PI3K) or Akt resulted in nearly complete inhibition of insulin-stimulated production of NO. Overexpression of an inhibitory mutant of Ras had a much smaller effect. CONCLUSIONS: Receptor kinase activity is necessary to mediate production of NO through the insulin receptor. Both PI3K and Akt contribute importantly to this process, whereas the contribution of Ras is small.

Insulin signalling: metabolic pathways and mechanisms for specificity.

Biological actions of insulin are mediated by the insulin receptor, a member of a large family of receptor tyrosine kinases (RTK). Signal transduction by the insulin receptor follows a paradigm for RTK signalling. Many intracellular signalling molecules contain multiple modular domains that mediate protein-protein interactions and participate in the formation of signalling complexes. Phosphorylation cascades are also a prominent feature of RTK signalling. Distal pathways are difficult to dissect because branching paths emerge from downstream effectors and several upstream inputs converge upon single branch points. Thus, insulin action is determined by complicated signalling networks rather than simple linear pathways. Interestingly, many signalling molecules downstream from the insulin receptor are also activated by a plethora of RTKs. Therefore, mechanisms that generate specificity are required. In this review we discuss recent advances in the elucidation of specific metabolic insulin signalling pathways related to glucose transport, one of the most distinctive biological actions of insulin. We also present examples of potential mechanisms underlying specificity in insulin signalling including interactions between multiple branching pathways, subcellular compartmentalization, tissue-specific expression of key effectors and modulation of signal frequency and amplitude.

Caveolin-1 interacts with the insulin receptor and can differentially modulate insulin signaling in transfected Cos-7 cells and rat adipose cells.

Caveolae may function as microdomains for signaling that help to determine specific biological actions mediated by the insulin receptor (IR). Caveolin-1, a major component of caveolae, contains a scaffolding domain (SD) that binds to a caveolin-1 binding motif in the kinase domain of the IR in vitro. To investigate the potential role of caveolin-1 in insulin signaling we overexpressed wild-type (Cav-WT) or mutant (Cav-Mut; F92A/V94A in SD) caveolin-1 in either Cos-7 cells cotransfected with IR or rat adipose cells (low and high levels of endogenous caveolin-1, respectively). Cav-WT coimmunoprecipitated with the IR to a much greater extent than Cav-Mut, suggesting that the SD is important for interactions between caveolin-1 and the IR in intact cells. We also constructed several IR mutants with a disrupted caveolin-1 binding motif and found that these mutants were poorly expressed and did not undergo autophosphorylation. Interestingly, overexpression of Cav-WT in Cos-7 cells significantly enhanced insulin-stimulated phosphorylation of Elk-1 (a mitogen-activated protein kinase-dependent pathway) while overexpression of Cav-Mut was without effect. In contrast, in adipose cells, overexpression of either Cav-WT or Cav-Mut did not affect insulin-stimulated phosphorylation of a cotransfected ERK2 (but did significantly inhibit basal phosphorylation of ERK2). Furthermore, we also observed a small inhibition of insulin-stimulated translocation of GLUT4 when either Cav-WT or Cav-Mut was overexpressed in adipose cells. Thus, interaction of caveolin-1 with IRs may differentially modulate insulin signaling to enhance insulin action in Cos-7 cells but inhibit insulin's effects in adipose cells.

Reduction of ACE activity is insufficient to decrease microalbuminuria in normotensive patients with type 1 diabetes.

OBJECTIVE: To study whether administration of 1.25 and 5.0 mg ramipril daily, compared with placebo treatment, reduces the urinary albumin excretion rate (UAER) in normotensive patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Ramipril was administered double blind at two different doses (1.25 [n = 19] and 5.0 mg [n = 18]), and compared with placebo (n = 18) after a single-blind placebo period of 1-4 weeks. The patients (total, n = 55; women, n = 14) were followed for 2 years. To document an effect on the renin-angiotensin system, ACE activity and plasma-renin activity (PRA) were measured. In addition, 24-h ambulatory blood pressure (BP) was recorded at baseline and repeated after 1 and 2 years using a Spacelab 90207 ambulatory BP recording device (Spacelab, Redmont, CA). RESULTS: Both doses of ramipril were sufficient to reduce ACE activity and to increase PRA significantly as compared with placebo (P < 0.05 for both). On the other hand, neither ambulatory nor clinic BP was affected by either dose of ramipril compared with the placebo group. There was no progression of UAER in the placebo group during the 2 years of the study. Analysis of covariance showed no differences in UAER between the three treatment groups at year 1 (P = 0.94) or year 2 (P = 0.97), after adjusting for baseline. Furthermore, there were no statistically significant changes from baseline UAER within any of the three treatment groups. CONCLUSIONS: Treatment with ramipril did not affect microalbuminuria or clinic or ambulatory BP in this study. On the basis of the present study, we question the clinical use of ACE inhibitors in stably normotensive patients with type 1 diabetes and microalbuminuria in whom a concomitant reduction in BP is not demonstrated.

Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients.

OBJECTIVES: To determine whether polymorphisms in the renin-angiotensin system can predict blood pressure-lowering response to antihypertensive treatment; more specifically, in response to treatment with irbesartan or atenolol. DESIGN AND METHODS: Eighty-six patients with hypertension were randomized to double-blind treatment with either the angiotensin II type 1 receptor antagonist irbesartan or the beta1 adrenergic receptor blocker atenolol and followed for 3 months. We analysed angiotensinogen T174M and M235T, angiotensin converting enzyme (ACE) I/D and angiotensin II type 1 receptor A1166C polymorphisms and related them to blood pressure reduction. RESULTS: The mean reductions in blood pressure were similar for both treatments. In the irbesartan group, individuals homozygous for the ACE gene I allele showed a greater reduction in diastolic blood pressure, exceeding those with the D allele (-18 +/- 11 SD versus -7 +/- 10 mmHg, P = 0.0096). This was not the case during treatment with atenolol, and the interaction term between type of treatment and ACE II genotype was significant (P = 0.0176). The angiotensinogen and angiotensin II type 1 receptor polymorhisms were not related to the response to treatment. CONCLUSIONS: ACE genotyping predicted the blood pressure-lowering response to antihypertensive treatment with irbesartan but not atenolol. Thus, specific genotypes might predict the response to specific antihypertensive treatment.

Regression of left ventricular hypertrophy in human hypertension with irbesartan.

BACKGROUND: The Swedish irbesartan left ventricular hypertrophy investigation versus atenolol (SILVHIA). OBJECTIVE: Angiotensin II induces myocardial hypertrophy. We hypothesized that blockade of angiotensin II subtype 1 (AT1) receptors by the AT1-receptor antagonist irbesartan would reduce left ventricular mass (as measured by echocardiography) more than conventional treatment with a beta blocker. DESIGN AND METHODS: This double-blind study randomized 115 hypertensive men and women with left ventricular hypertrophy to receive either irbesartan 150 mg q.d. or atenolol 50 mg q.d. for 48 weeks. If diastolic blood pressure remained above 90 mmHg, doses were doubled, and additional medications (hydrochlorothiazide and felodipine) were prescribed as needed. Echocardiography was performed at weeks 0, 12, 24 and 48. RESULTS: Baseline mean blood pressure was 162/ 104 mmHg, and mean left ventricular mass index was 157 g/m2 for men and 133 g/m2 for women. Systolic and diastolic blood pressure reductions were similar in both treatment groups. Both irbesartan (P < 0.001) and atenolol (P< 0.001) progressively reduced left ventricular mass index, e.g. by 26 and 14 g/m2 (16 and 9%), respectively, at week 48, with a greater reduction in the irbesartan group (P = 0.024). The proportion of patients who attained a normalized left ventricular mass (i.e. < or = 131 g/m2 for men and < or = 100 g/m2 for women) tended to be greater with irbesartan (47 versus 32%, P = 0.108). CONCLUSIONS: Left ventricular mass was reduced more in the irbesartan group than in the atenolol group. These results suggest that blocking the action of angiotensin II at AT1-receptors may be an important mechanism, beyond that of lowering blood pressure, in the regulation of left ventricular mass and geometry in patients with hypertension.

Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes.

OBJECTIVE: To study plasma concentrations of insulin-like growth factor-I (IGF-I) in adults with type 1 diabetes (IDDM) in comparison with a reference population, and the influence of glycaemic control, dose of insulin, and sex on the concentration of circulating IGF-I in IDDM. DESIGN AND METHODS: Patients with type 1 diabetes were recruited consecutively from our outpatient diabetes unit. In all, 79 men and 55 women aged 20-60 years with a disease duration >/=6 years (range 6-51 years) took part in the study. A reference population of 80 men and 83 women aged 20-60 years was randomly obtained from the population registry. IGF-I was measured with radioimmunoassay after acid-ethanol extraction. RESULTS: Mean +/- s. d. values of IGF-I were lower in patients with diabetes (146+/-66 microg/l) than in controls (238+/-83 microg/l, P<0.001). Those with diabetes had lower IGF-I concentrations in all age groups and the differences were highly significant in all decades except in women aged 50-59 years. IGF-I was negatively correlated with age in patients and controls. No correlation was found between IGF-I and glycaemic control measured as haemoglobin A(1c) (HbA(1c)) in the patients. IGF-I was positively associated with the dose of insulin/kg body weight in male patients independently of age, HbA(1c) and body mass index (P<0.03), but not in female patients (P=0.14). CONCLUSIONS: Our data show that IGF-I concentrations are low in adult patients with type 1 diabetes with a disease duration >/=6 years, independently of glycaemic control. This suggests that subcutaneous insulin substitution is inadequate to normalize circulating IGF-I concentrations in patients without endogenous insulin secretion.