Basal insulin therapy is associated with beneficial effects on postoperative infective complications, independently from circulating glucose levels in patients admitted for cardiac surgery.

BACKGROUND: Although hyperglycemia is a strong predictor of postoperative infective complications (PIC), little is known about the effect of basal insulin therapy (BIT) per se on PIC. AIM: To evaluate if there is an association between BIT, independent of glucose levels, and a possible improvement of PIC during the perioperative cardiosurgery period (PCP). METHODS: In 812 patients admitted for cardiac intervention and treated with a continuous intravenous insulin infusion (CIII) for hyperglycemic levels (>130 mg/dl), a retrospective analysis was performed during the PCP (January 2009-December 2011). Upon transfer to the cardiac surgery division, if fasting glucose was ≥130 mg/dl, a basal + premeal insulin therapy was initiated (121 patients, group 1); for <130 mg/dl, a premeal insulin alone was initiated (691 patients, group 2). FINDINGS: Compared with group 2, group 1 showed reductions in PIC (2.48% vs 7.96%, p < 0.049; odds ratio: 0.294; 95% CI: 0.110-0.780), C-Reactive Protein (p < 0.05) and white blood cell (p < 0.05) levels despite glucose levels and CIII that were higher during the first two days after surgery (179.8 ± 25.3 vs 169.5 ± 10.6 mg/dl, p < 0.01; 0.046 ± 0.008 vs 0.037 ± 0.015 U/kg/h, p < 0.05, respectively). Normal glucose levels were achieved in both groups from day 3 before the discharge. The mean length of hospital duration was 18% lower in group 1 than in group 2 (7.21 ± 05.08 vs 8.76 ± 9.08 days, p < 0.007), providing a significant impact on public health costs. CONCLUSIONS: Basal + preprandial insulin therapy was associated with a lower frequency of PIC than preprandial insulin therapy alone, suggesting a beneficial effect of basal insulin therapy on post-surgery outcome.

A multicenter observational study on the management of hyperglycemia in patients with acute coronary syndrome.

AIM: To assess the prevalence, risk and management of hyperglycemia in patients with acute coronary syndrome (ACS). DESIGN: a multicenter prospective observational study of a representative sample of patients with ACS consecutively admitted to intensive cardiac care units (ICCU). SETTING: 31 out of 61 ICCUs in Lombardy, the most heavily populated Italian region. From May 2009 to April 2010 1260 patients (69.4% male; mean age 68 ± 13 years) were included in the study: 301 (23.9%) were known diabetic patients (D) and 265 (21.0%) had hyperglycemia (H) (blood glucose >180 mg/dL) at hospital admission, 174 with a history of diabetes (D+H+) and 91 without (D-H+). On the first day after admission intravenous insulin infusion was prescribed to 72 D+H+ (41.4%) and 10 D-H+ (11.0%), according to different protocols. Approximately one third of D+H+ patients (59) and one fifth (17) of D-H+ maintained mean blood glucose higher than 180 mg/dL during the first day in the ICCU. Patients with diabetes or hyperglycemia had a higher incidence of major adverse cardiovascular events or death in hospital. However, at multivariable analysis neither diabetes nor blood glucose at admission was associated with a poor prognosis whereas mean blood glucose on the first day was an independent negative prognostic predictor (OR 1.010, 95% CI 1.002-1.018, p = 0.016). CONCLUSION: Hyperglycemia is frequent in patients with ACS and is independently associated with a poor in-hospital prognosis if it persists in first day. Unfortunately, however, this condition is still poorly treated, with far from optimal blood glucose control.

Moderate alcohol consumption is associated with improved insulin sensitivity, reduced basal insulin secretion rate and lower fasting glucagon concentration in healthy women.

AIMS/HYPOTHESIS: Moderate alcohol consumption is associated with a reduced risk of type 2 diabetes with a stronger effect in women. As the underlying mechanisms remain poorly characterised, we investigated its relationship with insulin resistance, insulin secretion, clearance of insulin and glucagon concentration. METHODS: One-thousand two-hundred and seventy-six non-diabetic individuals from the RISC (relationship between insulin sensitivity and cardiovascular disease) study without high alcohol consumption were studied; all had a euglycaemic-hyperinsulinaemic clamp and an OGTT with assessment of insulin sensitivity, secretion and clearance. RESULTS: Alcohol consumption was positively associated with insulin sensitivity in women (ß = 0.15, p ( trend ) = 0.005) and in men (ß = 0.07, p ( trend ) = 0.07) after controlling for age, centre, waist, smoking and physical activity. In women, this association persisted after adjustment for adiponectin but was attenuated after controlling for HDL-cholesterol, suggesting that part of the protection is related to a higher HDL-cholesterol concentration. Higher alcohol consumption was associated with lower basal insulin secretion in women only (ß = -0.10, p ( trend ) = 0.004) and this association persisted after adjustment for insulin sensitivity. In men, increasing alcohol consumption was associated with enhanced insulin clearance and increased fasting NEFA concentrations, independently of insulin sensitivity. Fasting glucagon decreased with increasing alcohol in women only (abstainers 9.2 ± 4.4; <28 g/week 8.6 ± 4.0; 28-64 g/week 8.1 ± 3.7; >64 g/week 7.5 ± 3.1 pmol/l; p ( trend ) = 0.01). CONCLUSIONS/INTERPRETATION: Light-to-moderate alcohol consumption was associated in healthy women with enhanced insulin sensitivity, reduced basal insulin secretion rate and lower fasting plasma glucagon concentration, providing consistent mechanisms for the reduced risk of diabetes.

Effect of a long-term oral l-arginine supplementation on glucose metabolism: a randomized, double-blind, placebo-controlled trial.

AIM: This study assessed the efficacy of long-term l-arginine (l-arg) therapy in preventing or delaying type 2 diabetes mellitus. METHODS: A mono-centre, randomized, double-blind, parallel-group, placebo-controlled, phase III trial (l-arg trial) was conducted on 144 individuals affected by impaired glucose tolerance (IGT) and metabolic syndrome (MS). l-Arg/placebo was administered (6.4 g/day) on a background structured lifestyle intervention for 18 months plus a 12-month extended follow-up period after study drug termination. Fasting glucose levels and glucose tolerance after oral glucose tolerance test were evaluated throughout the study. RESULTS: After 18 months, l-arg as compared with placebo did not reduce the cumulative incidence of diabetes [21.4 and 20.8%, respectively, hazard ratio (HR), 1.04; 95% confidence interval (CI), 0.58-1.86] while the cumulative probability to become normal glucose tolerant (NGT) increased (42.4 and 22.1%, respectively, HR, 2.60; 95% CI, 1.51-4.46, p < 0.001). The higher cumulative probability to become of NGT was maintained during the extended period in subjects previously treated with l-arg (HR, 3.21; 95% CI, 1.87-5.51; p < 0.001). At the end of the extended period, the cumulative incidence of diabetes in subjects previously treated with l-arg was reduced as compared with placebo (27.2 and 47.1%, respectively, HR, 0.42; 95% CI, 0.24-0.75, p < 0.05). During both periods, l-arg significantly improved insulin sensitivity and ß-cell function. CONCLUSION: Among persons with IGT and MS, the supplementation of l-arg for 18 months does not significantly reduce the incidence of diabetes but does significantly increase regression to NGT.

Plasma sCD36 is associated with markers of atherosclerosis, insulin resistance and fatty liver in a nondiabetic healthy population.

OBJECTIVES: Insulin resistance is associated with increased CD36 expression in a number of tissues. Moreover, excess macrophage CD36 may initiate atherosclerotic lesions. The aim of this study was to determine whether plasma soluble CD36 (sCD36) was associated with insulin resistance, fatty liver and carotid atherosclerosis in nondiabetic subjects. METHODS: In 1296 healthy subjects without diabetes or hypertension recruited from 19 centres in 14 European countries (RISC study), we determined the levels of sCD36, adiponectin, lipids and liver enzymes, insulin sensitivity (M/I) by euglycaemic-hyperinsulinaemic clamp, carotid atherosclerosis as intima-media thickness (IMT) and two estimates of fatty liver, the fatty liver index (FLI) and liver fat percentage (LF%). RESULTS: IMT, FLI, LF%, presence of the metabolic syndrome, impaired glucose regulation, insulin and triglycerides increased across sCD36 quartiles (Q2-Q4), whereas adiponectin and M/I decreased (P ≤ 0.01). sCD36 was lower in women than in men (P = 0.045). Log sCD36 showed a bimodal distribution, and amongst subjects with sCD36 within the log-normal distribution (log-normal population, n = 1029), sCD36 was increased in subjects with impaired glucose regulation (P = 0.045), metabolic syndrome (P = 0.006) or increased likelihood of fatty liver (P < 0.001). sCD36 correlated significantly with insulin, triglycerides, M/I and FLI (P < 0.05) after adjustment for study centre, gender, age, glucose tolerance status, smoking habits and alcohol consumption. In the log-normal population, these relationships were stronger than in the total study population and, additionally, sCD36 was significantly associated with LF% and IMT (P < 0.05). CONCLUSIONS: In this cross-sectional study of nondiabetic subjects, sCD36 was significantly associated with indices of insulin resistance, carotid atherosclerosis and fatty liver. Prospective studies are needed to further evaluate the role of sCD36 in the inter-relationship between atherosclerosis, fatty liver and insulin resistance.

Food selection based on high total antioxidant capacity improves endothelial function in a low cardiovascular risk population.

BACKGROUND AND AIMS: Oxidative stress has been advocated as a major cause for cardiovascular disease (CVD), and low plasma antioxidant concentrations are associated with endothelial dysfunction, the first step towards atherosclerosis. However, although the antioxidant content in fruits and vegetables may explain at least in part their protective effect against CVD, supplementation with antioxidant vitamins fails to improve endothelial function and reduce CVD risk. The aim of this study was to investigate the impact of a diet rich in antioxidants on endothelial function measured by flow-mediated dilatation (FMD) in volunteers at low cardiovascular risk. METHODS AND RESULTS: In a crossover trial, 24 subjects (13 women, mean age 61 ± 3 years), received, in a randomised order, a 14-day high (HT) and a 14-day low (LT) antioxidant diets, with a 2-week wash-out (WO) in between. Both diets were comparable in daily portions of fruits and vegetables, and in alcohol, fibre and macronutrient intake, but differed in their total antioxidant capacity. Before and after each diet, anthropometrics, blood pressure, fasting plasma glucose, lipid profile, hepatic enzymes, circulating antioxidant concentrations, high sensitivity C-reactive protein (hs-CRP) and FMD were assessed. FMD increased significantly during the HT diet compared to the LT (p < 0.000). FMD values were 2.3% higher after HT compared with LT (p < 0.001) after adjustment for age, gender and diet order. α-tocopherol increased significantly (p < 0.05) and hs-CRP and of γ-glutamyltranspeptidase decreased significantly (p < 0.05 and p < 0.01, respectively) during the HT diet, compared with the LT diet. CONCLUSIONS: A short-term HT diet improves endothelial function in volunteers at low cardiovascular risk, which may further reduce their risk of CVD.

Effects of chronic elevation of atrial natriuretic peptide and free fatty acid levels in the induction of type 2 diabetes mellitus and insulin resistance in patients with mitral valve disease.

BACKGROUND AND AIMS: The relationship between atrial natriuretic peptide (ANP), increased free fatty acid (FFA) and insulin resistance in patients with mitral valve disease (MVD), a group characterised by elevated atrial pressure and increased ANP levels, is not defined. The present study was performed to evaluate, in MVD patients, the relationship between increased ANP and FFA levels and insulin resistance and the role of mitral valve replacement/repair in ameliorating these metabolic alterations. Conversely, coronary heart disease (CHD) patients were evaluated before and after coronary artery bypass grafting (CABG), since they are known to be insulin resistant in the presence of chronic FFA increase. METHODS AND RESULTS: Fifty MVD patients and 55 CHD patients were studied before and 2 months after surgery and compared with 166 normal subjects. Before surgery, 56% of MVD patients had impaired glucose tolerance or newly diagnosed type 2 diabetes after a standard oral glucose load and this percentage decreased to 46% after surgery. In CHD, impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetic patients were 67% of patients before and after CABG. In MVD, left atrial (LA) volume, ANP, FFA incremental area and insulin levels were higher and Insulin Sensitivity (IS) index significantly reduced while after surgery, LA volume, ANP and FFA significantly decreased and IS index significantly improved. In CHD, insulin resistance and hyperinsulinaemia were present both before and after surgery with increased tumour necrosis factor (TNF)-α and interleukin (IL)-6 levels. CONCLUSION: In MVD, a higher degree of abnormal glucose tolerance and insulin resistance are associated to increased levels of ANP and FFA, while these metabolic alterations are improved by mitral valve replacement/repair surgery. Clinical Trial.gov registration number NCT 00520962.

Consensus on: Screening and therapy of coronary heart disease in diabetic patients.

The screening and best treatment for coronary heart disease in diabetic patients is still a matter of debate. For this reason the main Italian scientific societies dealing with diabetes and cardiovascular diseases have tried to finalize a document providing shared recommendations based on the available evidence on : 1) how and who to screen for coronary heart disease, 2) methodologies for the characterization of existing coronary heart disease 3) evaluation of the optimal treatment of cardiovascular risk factors and 4) appropriate revascularization procedures. For each of these points, the levels of evidence and strength of recommendations used in the Italian Standard of Care were adopted.

Detecting impaired glucose tolerance or type 2 diabetes mellitus by means of an oral glucose tolerance test in HIV-infected patients.

OBJECTIVE: As a proactive diagnosis of diabetes mellitus (DM) may prevent the onset of severe complications, we used an oral glucose tolerance test (OGTT) to check for impaired glucose tolerance (IGT) and DM in patients with long-standing HIV infection and long durations of exposure to antiretroviral drugs with normal fasting plasma glucose (FPG) levels. METHODS: This was a cross-sectional, single-centre study. The homeostatic model assessment for insulin resistance (HOMA-IR) and 2-h post-load glucose levels were used to evaluate patients with known HIV-1 infection since before 1988 and no previous diagnosis of DM for whom data on hepatitis C virus (HCV) and hepatitis B virus (HBV) infection were available. RESULTS: Eighty-four Caucasian patients [67 (80%) male; median age 45.7 years; range 43.8-49.1 years] were able to be evaluated; 65 (77%) were coinfected with HCV, and seven (8%) were coinfected with HBV. Median (interquartile range [IQR]) exposure to antiretrovirals was 12.8 (10.4-16.5) years. Fifteen patients (18%) had a previous AIDS-defining event, 64 (76%) had HIV RNA<50 copies/mL, and the median (IQR) CD4 count was 502 (327-628) cells/µL. The median [IQR] FPG was 81 mg/dL (4.5 mmol/L) [75-87 mg/dL (4.2-4.8 mmol/L)], and the median (IQR) HOMA-IR was 2.82 (1.89-4.02). After OGTT, nine patients (11%) were diagnosed as having IGT (6) or DM (3). A first multivariable analysis showed that CD4 cell count (P=0.038) and HOMA-IR (P=0.035) were associated with IGT or DM, but a second model including only the variables with a P-value of <0.2 in the univariable analysis (CD4 cell count, HBV coinfection, and HOMA-IR) found that only HOMA-IR independently predicted IGT or DM. CONCLUSIONS: In patients with long-standing HIV infection and normal FPG levels, an OGTT can reveal IGT or DM.

Intake of the plant lignans matairesinol, secoisolariciresinol, pinoresinol, and lariciresinol in relation to vascular inflammation and endothelial dysfunction in middle age-elderly men and post-menopausal women living in Northern Italy.

BACKGROUND AND AIMS: It has been suggested that lignan intake may decrease the risk for cardiovascular disease (CVD) by modifying traditional risk factors as well as aortic stiffness. However, the role of dietary lignans on the vascular system is largely unknown. The objective was to investigate whether dietary intake of plant lignans in a free-living population was associated with markers of vascular inflammation and function. METHODS AND RESULTS: We performed a cross-sectional study in 242 (151 males) men and post-menopausal women. Anthropometric characteristics and lignan intake were evaluated. Soluble intercellular adhesion molecule-1 (sICAM-1), insulin, high-sensitive C-reactive protein, glucose, total cholesterol, HDL-cholesterol and triacylglycerols were measured in fasting blood samples. Brachial flow-mediated dilation (FMD) measurements were available for 101 subjects (56 males). Median (interquartile range) daily intake of matairesinol (MAT), secoisolariciresinol (SECO), pinoresinol (PINO), lariciresinol (LARI), and total lignans was 20.9 microg (17.4), 335.3 microg (289.1), 96.7 microg (91.1), 175.7 microg (135.8), and 665.5 microg (413.7), respectively, as assessed by 3-day weighed food record. Plasma concentrations of sICAM-1 (whole sample) significantly decreased (mean (95%CI) = 358 microg/L (320-401), 276 microg/L (252-303), 298 microg/L (271-326), and 269 microg/L (239-303), P per trend 0.013) and FMD values (FMD sub-group) significantly increased (4.1% (2.2-6.0), 5.7% (4.3-7.2), 6.4% (4.9-7.8), and 8.1% (6.3-10.0), P per trend 0.016) across quartiles of energy-adjusted MAT intake, even after adjustment for relevant clinical and dietary variables. Intake of SECO was also inversely related to plasma sICAM-1 (P per trend 0.018), but not to FMD values. No relationship between intake of PINO, LARI or total lignans and either sICAM-1 or FMD values was observed. CONCLUSIONS: Higher MAT intakes in the context of a typical Northern Italian diet are associated to lower vascular inflammation and endothelial dysfunction, which could have some implications in CVD prevention.

Beneficial role of L-arginine in cardiac matrix remodelling in insulin resistant rats.

BACKGROUND: The study was performed to determine whether sucrose-induced insulin resistance could increase the expression of cardiac matrix metalloproteinases (MMPs), indices of matrix remodelling, and whether the addition of 1.25 g day(-1) of L-arginine (ARG) to a sucrose diet could prevent both the sucrose-induced metabolic abnormalities and elevated cardiac expression of matrix metalloproteinases in an insulin resistant stage that precedes frank type 2 diabetes. MATERIALS AND METHODS: Experiments were performed on 38 male Sprague-Dawley rats, 16 rats maintained a standard chow diet (ST), 12 rats were switched to a sucrose enriched diet (SU) and 10 rats to a sucrose plus L-arginine (1.25 g day(-1)) enriched diet (SU + ARG) for a period of 8 weeks. After 8 weeks of different diets, an intravenous glucose tolerance test (IVGTT) was performed and samples were drawn for the measurements of insulin, glucose, triglycerides, free fatty acids (FFA), plasma cyclic guanosine-monophosphate (c-GMP) and retroperitoneal, omental, epididymal fat pad and heart were dissected and weighed. RESULTS: At the end of the study, retroperitoneal fat, heart weight/body weight ratio, fasting plasma glucose, serum insulin, and serum triglyceride levels and integrated insulin area after IVGTT were significantly higher in SU than in SU + ARG and ST. All these parameters were comparable between SU + ARG and ST animals. FFA levels were significantly different among groups, with highest levels in SU and lowest levels in ST. Fasting plasma c-GMP levels and the integrated c-GMP area after IVGTT, an index of nitric oxide activity, were significantly lower in SU than in SU + ARG and ST, the result was similar in SU + ARG and in ST MMP-9 protein expression increased 10.5-fold, MMP-2 protein expression increased 2.4-fold and the expression of tissue inhibitors of metalloproteinase (TIMP-1) increased 1.7-fold in SU rats as compared to ST animals. This was accompanied with a significant increase of cardiac triglyceride concentrations. In contrast, cardiac MMP-9, MMP-2, and TIMP-1 protein expressions were not different between SU + ARG and ST animals. Cardiac triglyceride levels were not significantly different between SU + ARG and ST rats. CONCLUSIONS: SU rats developed insulin resistance and hyperlipidaemia, accompanied with increased fat deposition in the heart and enhanced MMP protein expression. Conversely, ARG supplementation prevents these metabolic abnormalities and restored MMP/TIMP-1 balance.

ADMA is independently related to flow-mediated vasodilation in subjects at low cardiovascular risk.

BACKGROUND: Increased plasma concentrations of asymmetric dimethylarginine (ADMA) contribute to impair endothelial function in patients with established cardiovascular disease (CVD) and/or individuals with clinical syndromes known to increase CVD. However, the impact of ADMA on endothelial function in apparently healthy individuals has not been determined. MATERIALS AND METHODS: To address this issue, we measured endothelial-dependent vasodilatation in response to forearm ischaemia (flow-mediated vasodilatation, FMD) in 111 non-smoking, healthy volunteers with low CVD risk by the Framingham risk equation. Measurements were also made of multiple anthropometric, metabolic, and dynamic variables related to FMD. l-arginine and its methylated derivates (ADMA and SDMA) were quantified by high-liquid pressure chromatography. RESULTS: After adjustment by gender, lower values for FMD were significantly associated with increases in plasma ADMA concentrations (anova linear trend by FMD tertiles, P < 0.05) as well as in brachial artery diameter (partial r = -0.352, P = 0.001), body mass index (-0.337, P = 0.001), fasting insulin (-0.368, P < 0.001) and high-sensitivity C-reactive protein (-0.283, P = 0.007) plasma concentrations, and with decreased HDL cholesterol (0.233, P = 0.026). Multiple linear regression analysis indicated that the only statistically significant predictors of FMD were brachial artery diameter (P < 0.001), ADMA (P < 0.05) and fasting plasma insulin (P < 0.001) concentrations. CONCLUSIONS: In conclusion, a significant relationship between increases in plasma ADMA concentration and lower values of FMD is not limited to patients with clinical syndromes related to CVD, but can also be seen in healthy subjects at low global CVD risk.

The total antioxidant capacity of the diet is an independent predictor of plasma beta-carotene.

OBJECTIVE: To investigate the contribution of the total antioxidant capacity (TAC) of the diet to plasma concentrations of beta-carotene. DESIGN: Cross-sectional study. SETTING: Department of Public Health and Department of Internal Medicine and Biomedical Sciences, University of Parma. SUBJECTS: A total of 247 apparently healthy adult men (n=140) and women (n=107). METHODS: A medical history, a physical exam including height, weight, waist circumference and blood pressure measurements, a fasting blood draw, an oral glucose tolerance test and a 3-day food record. RESULTS: We observe a negative trend across quartiles of plasma beta-carotene for most biological variables clustering in the insulin resistance syndrome, as well as for traditional and new risk factors for type II diabetes and cardiovascular disease (CVD), including C-reactive protein and gamma-glutamyltranspeptidase (P<0.05). Regarding dietary characteristics, energy-adjusted intake of fat, fiber, fruits, vegetables, beta-carotene, vitamin C, vitamin E and dietary TAC significantly increased with increasing plasma beta-carotene (P<0.05), whereas alcohol intake decreased (P=0.013). Adjusted geometric means (95% confidence interval) of plasma beta-carotene significantly increased across quartiles of dietary TAC, even when single dietary antioxidants were considered in the model (QI=0.087 mg/dl (0.073-0.102); QII=0.087 mg/dl (0.075-0.103); QIII=0.114 mg/dl (0.098-0.132) and QIV=0.110 mg/dl (0.093-0.130); P for linear trend=0.026). When the population was divided on the basis of alcohol consumption, this trend was also observed in subjects drinking <20 g alcohol/day (P=0.034), but not in those with higher alcohol intake (P=0.448). CONCLUSIONS: Dietary TAC is an independent predictor of plasma beta-carotene, especially in moderate alcohol drinkers. This may explain, at least in part, the inverse relationship observed between plasma beta-carotene and risk of chronic diseases associated to high levels of oxidative stress (i.e., diabetes and CVD), as well as the failure of beta-carotene supplements alone in reducing such risk.

A multiplex PCR assay for the identification of animal species in feedstuffs.

A multiplex Polymerase Chain Reaction (PCR) assay was applied to feedstuff analysis for the identification of the most used species in rendering plants (ruminant, poultry, fish and pork materials). Primers were designed in different regions of mitochondrial DNA (12S rRNA, tRNA Val and 16S rRNA) after alignment of the available sequences in the GenBank database. The primers generated specific fragments of 104-106, 183, 220-230 and 290 bp length for ruminants, poultry, fish and pork, respectively. The detection limit was 0.004% for fish primers and 0.002% for ruminants, poultry and pork primers. The multiplex PCR proposed in this study can be considered a valid alternative to the microscopic method for the detection of animal derived materials banned by a European Union Regulation as a preventive measure against the spread of Bovine Spongiform Encephalopathy.

An Italian Multicentric Phase II study on peritonectomy and intra peritoneal hyperthermic perfusion (IPHP) to treat patients with pseudomyxoma peritonei.

Pseudomyxoma peritonei (PMP) is a rare disease with a poor prognosis when not adequately treated. It is characterized by a complete redistribution of mucin within the peritoneal cavity. The aim of this multicentric study was to evaluate the survival, morbidity, toxicity and mortality of patients with PMP treated by cytoreductive surgery (CRS) with intraperitoneal hyperthermic perfusion (IPHP). Seventy patients with PMP (31 males and 39 females) were enrolled onto a Phase II clinical trial. One patient was operated on twice because of disease recurrence. CRS was performed with peritonectomy procedures. The closed, opened and semi-closed abdomen techniques were employed for IPHP using cisplatin plus mitomycin-C for 60 minutes under hyperthermic conditions (42.5 degrees C). Sixty two (87%) patients were optimally cytoreduced. Five-year overall survival, progression-free survival and locoregional progression-free survival were 91%, 54% and 69%, respectively. Thirteen Grade III complications occurred in 10 (14%) patients and the most frequent one was gastrointestinal fistula/perforation (11%). There was one case (1.4%) of treatment-related mortality 21 days after treatment. CRS associated with IPHP permitted complete tumour removal with an acceptable morbidity and mortality in patients with PMP. This study confirms the efficacy of the combined treatment on long-term survival and local disease control.

Triglycerides impair postischemic recovery in isolated hearts: roles of endothelin-1 and trimetazidine.

There is growing evidence that hypertriglyceridemia exacerbates ischemic injury. We tested the hypothesis that triglycerides impair myocardial recovery from low-flow ischemia in an ex vivo model and that such an effect is related to endothelin-1. Hyperglycemic (glucose concentration = 12 mmol/l) and hyperinsulinemic (insulin concentration = 1.2 micromol/l) isolated rat hearts were perfused with Krebs-Henseleit buffer (PO(2) = 670 mmHg, pH 7.4, 37 degrees C) added with increasing triglycerides (0, 1,000, 2,000, and 4,000 mg/dl, n = 6-9 rats/group). Hearts were exposed to 60 min of low-flow ischemia (10% of basal coronary flow), followed by 30 min of reperfusion. We found that increasing triglycerides impaired both the diastolic (P < 0.005) and systolic (P < 0.02) recovery. The release of endothelin-1 during reperfusion increased linearly with triglyceride concentration (P = 0.0009). Elevated triglycerides also increased the release of nitrite and nitrate (NO(x)), the end products of nitric oxide, up to 6 micromol/min. Trimetazidine (1 micromol) further increased NO(x) release, blunted endothelin-1 release, and protected myocardial function during recovery. We conclude that high triglyceride levels impair myocardial recovery after low-flow ischemia in association with endothelin-1 release. The endothelium-mediated effect of triglycerides on both contractile recovery and endothelin-1 release is prevented by 1 microM trimetazidine.

Long-term oral L-arginine administration improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients.

UNLABELLED: The aim of this study was to evaluate whether long-term administration of arginine acting through a normalization of NO/cyclic-guanosine-3' 5'-cyclic monophosphate (cGMP) pathway was able to ameliorate peripheral and hepatic insulin sensitivity in 12 lean type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A double-blind study was performed for 3 months. In the first month, patients were treated with their usual diet. Then they were randomly allocated into to groups. In group 1, patients were treated with diet plus placebo (orally three times per day) for 2 months. In group 2 patients were treated for 1 month with diet plus placebo orally, three times per day) and then for 1 month with diet plus L-arginine (3 g three times per day). At the end of the first and the second month of therapy, patients underwent a euglycemic-hyperinsulinemic clamp combined with [6,6-2H2] glucose infusion. A total of 10 normal subjects underwent the same test as control subjects. RESULTS: In group 1, no changes in basal cGMP levels, systolic blood pressure, forearm blood flow, glucose disposal, and endogenous glucose production were observed throughout. In group 2, L-arginine normalized basal cGMP levels and significantly increased forearm blood flow by 36% and glucose disposal during the clamp by 34% whereas it decreased systolic blood pressure and endogenous glucose production by 14 and 29%, respectively. However, compared with normal subjects, L-arginine treatment was not able to completely overcome the defect in glucose disposal. CONCLUSIONS: L-Arginine treatment significantly improves but does not completely normalizc peripheral and hepatic insulin sensitivity in type 2 diabetic patients.

In middle-aged siblings of patients with type 2 diabetes mellitus normal glucose tolerance is associated with insulin resistance and with increased insulin secretion. The SPIDER study.

OBJECTIVES: To evaluate the frequency of impaired glucose tolerance (IGT) and of Type 2 diabetes mellitus (Type 2 DM) in siblings of patients with Type 2 DM, and to assess insulin release and insulin sensitivity in siblings with normal glucose tolerance (NGT), compared with NGT spouses of probands without family history of Type 2 DM. DESIGN AND METHODS: We evaluated 87 families including 103 Type 2 DM patients (87 probands), and we carried out an oral glucose tolerance test (OGTT) in 130 siblings and in 60 spouses. Among NGT subjects, 12 siblings and 16 spouses underwent a low-dose insulin-glucose infusion test (LDIGIT) to evaluate C-peptide release and insulin sensitivity. RESULTS: After the OGTT, 24 siblings were classified as having Type 2 DM, 31 as IGT, and only 14 spouses as IGT (P=0.0012 vs siblings). NGT siblings (n=75) showed higher insulin levels at 120 min than NGT spouses (n=46) at OGTT, in spite of identical blood glucose levels; at LDIGIT, NGT siblings secreted more C-peptide and showed a lower insulin sensitivity than NGT spouses. CONCLUSIONS: These data indicate that middle-aged siblings of probands with Type 2 DM have a high frequency of IGT and Type 2 DM, and that NGT siblings have increased insulin resistance and increased insulin secretion when compared with adequate controls.