[The complex interplay between health services administration, health professionals and patients. A challenge to take up]. / Azienda sanitaria, operatore di salute, paziente. Una interazione complessa, una sfida da raccogliere.

The risk of loss of essential elements of our professionalism, such as sense of duty, altruism and collegiality, contributes to the difficulties in the interplay between health services administration, health professionals and patients. It is not enough to increase salaries or change organization models. It is also insufficient a generic reference to the values of our profession, but it is mandatory to overcome the self-referencing attitude of health professions.

High cardiovascular risk in patients with Type 2 diabetic nephropathy: the predictive role of albuminuria and glomerular filtration rate. The NID-2 Prospective Cohort Study.

BACKGROUND: In Type 2 diabetic patients, clinical diagnosis of diabetic nephropathy (DN) is generally based on the concomitant presence of abnormal albuminuria and severe retinopathy. In this high-risk population, cardiovascular (CV) outcome has never been evaluated. METHODS: A cohort of 742 Type 2 diabetic patients with DN from 17 national centres was selected by the presence of persistent albuminuria ≥ 30 mg/day and severe diabetic retinopathy and was followed prospectively. Time to CV event (CV death, non-fatal myocardial infarction, non-fatal stroke, revascularization, major amputation) was the primary composite end point and it was analysed by multivariable Cox's proportional hazards model. The interaction between albuminuria and glomerular filtration rate (GFR) was specifically investigated. RESULTS: Median follow-up was 4.6 years. Overall 242 events (26% of which fatal) were observed in 202 patients. The proportion of CV events increased from 19 to 40% as GFR declined from the highest (≥ 90 mL/min/1.73 m(2)) to the lowest (<45 mL/min/1.73 m(2)) category and was equal to 25 and 33% in microalbuminuria and macroalbuminuria, respectively. In multivariable analysis, the interaction between albuminuria and GFR was statistically significant (P = 0.012). Albuminuria, indeed, had a remarkable prognostic effect in subjects with high GFR that virtually disappeared as GFR became <30 mL/min/1.73 m(2). Age, smoking habit, previous occurrence of myocardial infarction or stroke and proliferative retinopathy were all found to have a statistically significant prognostic effect on CV outcome. CONCLUSIONS: A clinically based diagnosis of DN in Type 2 diabetes allows the identification of subjects with high CV risk. Albuminuria has a relevant prognostic effect on CV morbidity and mortality; its effect is especially pronounced when GFR is normal or near normal.

SOCS3 and IRS-1 gene expression differs between genotype 1 and genotype 2 hepatitis C virus-infected HepG2 cells.

BACKGROUND: The poor response to antiviral treatment of hepatitis C virus (HCV)-infected patients with genotype 1b has been associated with a higher prevalence of metabolic syndrome. However, the molecular link between these clinical entities is not clear. The goal of this study was to clarify the role of genotype 1b and 2 in the genetic expression of suppressor of cytokine signaling 3 (SOCS3) and insulin receptor substrate 1 (IRS-1). METHODS: We infected human hepatocellular carcinoma cell line (HepG2) cells with human HCV genotype 1b or 2 and measured the gene and protein expression of SOCS3 at various times. We also evaluated impairment in the insulin pathway by analysis of IRS-1 and phospho-AKT. For the control, we used HepG2 cell cultures treated with non-infectious serum. We also demonstrated the occurrence of HCV infection by the detection of both positive and negative strands in the cells and culture medium. To test infection of the HepG2 cells, we performed quantitative real-time polymerase chain reaction (qRT-PCR) of viral load at different time points. We analyzed the viral genotype in the pellet and supernatant. RESULTS: At each time point, we found positive and negative strands in the infected cells, while in the medium we found positive, but no negative strands. We also detected the presence of the correct genotype in the medium. Two weeks following infection when the viral load was higher, we tested genotype 1b and 2 infected cells. SOCS3 gene expression was significantly higher in genotype 1b-infected cells (median 2.56; mean 2.82+/-0.59) compared with genotype 2 (median 1.34; mean 1.46+/-0.31) (p=0.04) and control cells (median 1.09; mean 1.02+/-0.11, p=0.02). There was no difference between cells exposed to genotype 2 and control cells. Conversely, IRS-1 was significantly lower in genotype 1b-infected cells (median 15.97; mean 15.45+/-0.67) compared with genotype 2-infected cells (median 16.45; mean 16.44+/-0.01, p=0.04). Statistically significant differences were seen when comparing the pAKT/AKT ratio in genotype 1b-infected cells (0.19+/-0.034) and not genotype 1b-infected (genotype 2-infected and non-infected) cells (0.253+/-0.004, p=0.03). This inverse regulation is compatible with interactions between the molecular expression of SOCS3, IRS-1 and phospho-AKT mediated by the genotype 1b virus. CONCLUSIONS: Up-regulation of the SOCS3 gene might be one of the mechanisms governing non-response to therapy and expression of insulin resistance mediated via a direct mechanism at this level of genotype 1b HCV.

The impact of diet on liver fibrosis and on response to interferon therapy in patients with HCV-related chronic hepatitis.

BACKGROUND AND AIMS: A deranged metabolic status and alcohol intake may trigger induction and progression of chronic hepatitis C virus (HCV) liver disease. The aim of this study was to evaluate whether dietary composition affects the severity of liver damage and response to therapy in patients with HCV-related chronic hepatitis. METHODS: We enrolled 1,084 patients with biopsy-proven HCV-related chronic hepatitis (432 treated with interferon plus ribavirin) and 2,326 healthy subjects in this prospective study conducted in a university hospital. Dietary habits were recorded in enrolled individuals, and their alcohol consumption was evaluated with a questionnaire (AUDIT). Body mass index, and plasma levels of blood glucose, nitrogen, creatinine, cholesterol, and triglycerides were also measured. All individuals underwent routine liver tests and HCV genotyping. RESULTS: At study onset, there were no differences in metabolic status or alcohol consumption between patients and controls. About 50% of each group was overweight, and about 60% consumed alcohol. Patients and controls had similar dietary habits. Intake of carbohydrates, lipids and polyunsaturated fatty acids, and alcohol consumption were independent factors of liver damage at histology (logistic regression analysis). Some dietary components (unsaturated fatty acids, iron, zinc, vitamin A, and niacin) and alcohol intake differed significantly (P < 0.05 and P 0.01, respectively; univariate analysis) between responders and nonresponders to interferon therapy. Genotype, age, body mass index, steatosis, and fibrosis were independent predictors of therapy outcome (P < 0.02; multivariate analysis). CONCLUSIONS: The severity of HCV-related chronic hepatitis depends on a variety of factors. Our results show that dietary composition is related to the extent of liver damage. Although traditional risk factors independently affected treatment response, some dietary components were associated with nonresponse to therapy in our patients. This suggests that HCV patients may benefit from instructions regarding their diet.

Cardiovascular risk factors and disease management in type 2 diabetic patients with diabetic nephropathy.

OBJECTIVE: The purpose of this study was to assess the prevalence of cardiorenal risk factors, their management in a routine clinical setting, and the actual achievement of international guideline targets in a large cohort of type 2 diabetic patients with diabetic nephropathy. RESEARCH DESIGN AND METHODS: A multicentric cross-sectional study was performed in the Campania region in Italy to evaluate cardiorenal risk factors and their management in light of international guidelines. Overall, 28,550 diabetic patients were screened in the 21 participating centers; 847 (348 male and 449 female) patients with type 2 diabetes and a clinical diagnosis of diabetic nephropathy were recruited. RESULTS: Of these subjects, 749 had microalbuminuria and 98 had macroalbuminuria. Targets for blood pressure, HbA(1c), LDL cholesterol, HDL cholesterol, and triglycerides were reached in, respectively, 17.5, 32.3, 30.7, 47, and 55.2% of the patients. Chronic renal failure (glomerular filtration rate <60 ml/min) was revealed in 41% and anemia in 23.8% of the patients. CONCLUSIONS: This is the first study to investigate a large cohort of type 2 diabetic patients with early and moderate diabetic nephropathy strictu sensu. Notably, impaired renal function can be often diagnosed in these patients even in the presence of microalbuminuria. Thus, clinical diagnosis of diabetic nephopathy allows us to identify a group of patients at very high cardiorenal risk, for whom care is really difficult. We suggest that a correct diagnosis of diabetic nephropathy should always be made and that sodium intake and anemia should be routinely evaluated in these patients.

Increased vascular endothelial growth factor expression but impaired vascular endothelial growth factor receptor signaling in the myocardium of type 2 diabetic patients with chronic coronary heart disease.

OBJECTIVES: The aim of the present study was to evaluate the expression and the activity of vascular endothelial growth factor (VEGF) in the hearts of diabetic patients with chronic coronary heart disease (CHD). BACKGROUND: Diabetes is characterized by a decreased collateral vessel formation in response to coronary ischemic events, although the role of VEGF in human diabetic macroangiopathy has not been fully investigated. METHODS: Biopsies of left ventricular (LV) myocardium were obtained from 10 patients with type 2 diabetes and 10 non-diabetic patients with chronic CHD, all undergoing surgical coronary revascularization. Right ventricle myocardial samples taken from normal hearts were used as control specimens. Vascular endothelial growth factor and VEGF-receptors (flt-1 and flk-1) were evaluated by Western blot, reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time RT-PCR. Akt and endothelial nitric oxide synthase (eNOS) protein expression and their phosphorylated forms were also evaluated by Western blot. RESULTS: Vascular endothelial growth factor, flt-1, and flk-1 messenger ribonucleic acid (mRNA) and protein expressions were increased in non-diabetic patients with CHD compared with control subjects. Remarkably, in diabetic patients, VEGF mRNA and protein levels were significantly higher, whereas flt-1, flk-1 mRNA, and protein were lower when compared with non-diabetic patients. Interestingly, phospho-flk-1 was reduced in diabetic patients compared with non-diabetic patients. As a consequence, Akt phosphorylation, eNOS protein and its phosphorylated form were significantly higher in the samples from non-diabetic patients compared with diabetic patients. CONCLUSIONS: Chronic CHD in diabetic patients is characterized by an increased VEGF myocardial expression and a decreased expression of its receptors along with a down-regulation of its signal transduction. The latter could be partially responsible for the reduced neoangiogenesis in diabetic patients with ischemic cardiomyopathy.

Management of cardiovascular risk factors in advanced type 2 diabetic nephropathy: a comparative analysis in nephrology, diabetology and primary care settings.

OBJECTIVES: Advanced diabetic nephropathy (DN) is characterized by a marked development of cardiovascular and renal disease. These patients are frequently managed by different health professionals with the consequence that the quality of care may differ substantially. To compare the management of cardiovascular risk factors in patients with type 2 DN and an estimated glomerular filtration rate (GFR) of 15-60 ml/min per 1.73 m2 followed in nephrology, diabetology and primary care. METHODS: This multicentre cross-sectional study verified the control of blood pressure (BP), total cholesterol, triglycerides, glycosylated haemoglobin A1c (HbA1c) and haemoglobin in patients exclusively followed in either nephrology (n = 266), diabetology (n = 246) or primary care (n = 195) of the same metropolitan area for at least 1 year. RESULTS: Primary care patients were older and had a greater prevalence of previous cardiovascular events. The GFR was lower in nephrology than in diabetology and primary care (33 +/- 13 versus 47 +/- 9 and 40 +/- 12 ml/min per 1.73 m2, P < 0.0001). The prevalence of BP target (< 130/80 mmHg) was similarly low in nephrology, diabetology and primary care (14, 13 and 10%, P = 0.421) probably because of insufficient prescription of diuretics and low-salt diet. Whereas the prevalence of the triglycerides target was similar, that of total cholesterol (< 200 mg/dl) was larger in diabetology (63%) than in nephrology and primary care (59 and 46%, P = 0.003) because of greater statin prescription in hypercholesterolemic individuals (70, 50 and 41%, respectively, P = 0.002). The attainment of HbA1c less than 7% was less frequent in diabetology (32%) than in nephrology and primary care (61 and 46%, P = 0.0003) despite a more frequent prescription of insulin/oral agents in diabetology. The control of anaemia was better in diabetology. Multivariate analysis adjusted for the patient case-mix and physician-level clustering confirmed these differences except for anaemia. CONCLUSION: Patients with advanced DN, despite the worst renal and cardiovascular prognosis, are at high risk of being under-treated independently of the type of clinical setting.

Acute pressor and hormonal effects of beta-endorphin at high doses in healthy and hypertensive subjects: role of opioid receptor agonism.

CONTEXT: The opioid system is involved in blood pressure regulation in both normal humans and patients with essential hypertension. OBJECTIVE: The objective of the study was to investigate the effects of a high-dose infusion of beta-endorphin, an opioid peptide, on blood pressure and on the hormonal profile in healthy subjects and in hypertensive patients and the mediation played by opioid receptor agonism. DESIGN, SETTING, AND PARTICIPANTS: According to a randomized double-blind design, 11 healthy subjects (controls) and 12 hypertensive inpatients (mean age, 38.9 and 40.4 yr, respectively) received 1-h iv infusion of beta-endorphin (250 mug/h) and, on another occasion, the same infusion protocol preceded by the opioid antagonist naloxone (8 mg). MAIN OUTCOME MEASURES: Hemodynamic and hormonal measurements were performed at established times during the infusion protocols. RESULTS: At baseline, circulating beta-endorphin, norepinephrine, and endothelin-1 in hypertensive patients were significantly (P < 0.05) higher than in controls. In controls, beta-endorphin reduced blood pressure (P < 0.01) and circulating norepinephrine (P < 0.02) and increased plasma atrial natriuretic factor (P < 0.003) and GH (P < 0.0001). In hypertensive patients, beta-endorphin decreased systemic vascular resistance (P < 0.0001), blood pressure (P < 0.0001), and plasma norepinephrine (P < 0.0001) and endothelin-1 (P < 0.0001) and raised circulating atrial natriuretic factor (P < 0.0001), GH (P < 0.0001), and IGF-I (P < 0.0001). These hemodynamic and hormonal responses to beta-endorphin in hypertensive patients were significantly (P < 0.0001) greater than in controls but were annulled in all individuals when naloxone preceded beta-endorphin infusion. CONCLUSIONS: High doses of beta-endorphin induce hypotensive and beneficial hormonal effects in humans, which are enhanced in essential hypertension and are mediated by opioid receptors.

Red wine consumption improves insulin resistance but not endothelial function in type 2 diabetic patients.

Epidemiological studies have shown that red wine consumption is associated with less cardiovascular mortality in the general population and in the diabetic patients. To determine whether red wine improves insulin resistance in diabetic patients and to explore the relation between insulin sensitivity and endothelial function, we studied vascular reactivity and insulin-mediated glucose uptake in 9 type 2 diabetic patients before and after 2 weeks of red wine consumption (360 mL/d, wine-treated diabetics) and 8 type 2 diabetic patients who did not consume wine (control diabetics). Vascular reactivity was evaluated by plethysmography during intraarterial infusion of acetylcholine (Ach), sodium nitroprusside, and L-N-monomethylarginine. Forearm nitrite balance was measured during Ach infusion. Insulin sensitivity was measured by euglycemic hyperinsulinemic clamp at 1 mU/kg per minute. The basal forearm blood flow and the response to Ach, to sodium nitroprusside, and to L-N -monomethylarginine were unchanged both in the wine-treated and in the control diabetics. In contrast, insulin-mediated whole body glucose disposal improved by 43% after red wine consumption (from 2.79 +/- 0.4 to 4.02 +/- 0.5 mg/kg of lean body mass per minute, P = .02), but did not change in the control group. In conclusion, red wine consumption for 2 weeks markedly attenuates insulin-resistance in type 2 diabetic patients, without affecting vascular reactivity and nitric oxide production.

[Large mediastinal mass of heterotopic thyroid tissue: a case report and review of literature]. / Voluminosa massa mediastinica di tessuto tiroideo eterotopico: caso clinico e review della letteratura.

Incidental detection of a mediastinal mass in a asymptomatic patient poses a not easy diagnostic problem. For solid masses or cysts, histology or cytology is often necessary. Although substernal extension of a cervical goiter is common, totally intrathoracic primary thyroidal mass is unusual. We describe a rare case of heterotopic accessory mediastinal thyroid in a patient completely asymptomatic both for signs of thyroid dysfunction and mechanical compression. Radiological and hormonal 6 and 12 months follow-up is reported.

Irbesartan reduces the albumin excretion rate in microalbuminuric type 2 diabetic patients independently of hypertension: a randomized double-blind placebo-controlled crossover study.

OBJECTIVE: ACE inhibitors delay the progression from incipient to overt diabetic nephropathy and reduce albumin excretion rate (AER), independently of blood pressure. Angiotensin II type 1 receptor antagonists produce similar effects on microalbuminuria and mean arterial pressure. The aim of this study was to evaluate the effect of irbesartan on microalbuminuria and blood pressure in hypertensive and normotensive type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Sixty-four microalbuminuric hypertensive (group 1) and 60 microalbuminuric normotensive (group 2) type 2 diabetic male patients, matched for age, BMI, HbA(1c), and diabetes duration, were enrolled. Each group was divided into two subgroups receiving either irbesartan (150 mg b.i.d. orally) or placebo for 60 days. After 15 days of washout, irbesartan was given to the subgroups who had received the placebo, and vice versa, in a randomized double-blind crossover study. RESULTS: In microalbuminuric hypertensive type 2 diabetic subjects, irbesartan reduced 24-h mean systolic and diastolic pressure and AER. In microalbuminuric normotensive type 2 diabetic patients, irbesartan reduced AER. CONCLUSIONS: These results indicate the beneficial effects of irbesartan on AER in type 2 diabetic subjects, independently of its antihypertensive effects.

Lack of effect of aspirin in primary CV prevention in type 2 diabetic patients with nephropathy: results from 8 years follow-up of NID-2 study.

The risk-to-benefit ratio for the use of low dose of aspirin in primary cardiovascular (CV) prevention in patients with diabetes mellitus remains to be clarified. We assessed the effect of aspirin on risk of CV events in type 2 diabetic patients with nephropathy, in order to verify the usefulness of Guidelines in clinical practice. We carried out a prospective multicentric study in 564 patients with type 2 diabetic nephropathy free of CV disease attending outpatient diabetes clinics . A total of 242 patients received antiplatelet treatment with aspirin 100 mg/day (group A), and 322 were not treated with antiplatelet drugs (group B). Primary end point was the occurrence of total major adverse cardio-vascular events (MACE). Secondary end points were the relative occurrence of fatal MACE. The average follow-up was 8 years. Total MACE occurred in 49 patients from group A and in 52 patients from group B. Fatal MACE occurred in 22 patients from group A and in 20 from group B; nonfatal MACE occurred in 27 patients from group A and in 32 patients from group B. Kaplan-Meier analysis did not show a statistically significant difference of cumulative MACE between the two groups. A not statistically significant difference in the incidence of both fatal (p = 0.225) and nonfatal CV events (p = 0.573) between the two groups was observed. These results were confirmed after adjustment for confounders (HR for MACE 1.11, 95 % CI 0.91-1.35). These findings suggest that low dose of aspirin is ineffective in primary prevention for patients with nephropathy.

Acute effects of beta-endorphin on cardiovascular function in patients with mild to moderate chronic heart failure.

BACKGROUND: Cardiomyocytes produce opioid peptides and receptors. beta-Endorphin is increased in the plasma of patients with congestive heart failure (CHF). We evaluated whether an intravenous infusion of beta-endorphin exerted any effect on cardiovascular function and on the neurohormonal milieu in patients with mild to moderate CHF. METHODS: According to a double-blind, placebo-controlled design, 10 patients (5 men, age 46.9 +/- 8.2 years [mean +/- SD]) with CHF and New York Heart Association functional class II to III received, in random order, 1-hour intravenous infusion of beta-endorphin (500 microg/h) and, on a separate occasion, received placebo and underwent echocardiographic and laboratory measurements at baseline and during infusions. RESULTS: beta-Endorphin significantly increased left ventricular ejection fraction (LVEF) (P =.0001) and stroke volume (P =.0001), and reduced systemic vascular resistance (P =.031) in patients with CHF. These changes were paralleled by a significant increase in plasma levels of glucagon (P =.0001), GH (P =.0001), and IGF-1 (P =.0001), and a significant decrease in plasma levels of endothelin (P =.0001) and catecholamines (P =.01). No hemodynamic and neurohormonal changes were observed during the placebo study in any patient. CONCLUSIONS: We conclude that a short-term, high dose infusion of beta-endorphin improves LVEF, reduces systemic vascular resistance, blunts the neurohormonal activation, and stimulates the GH/IGF-1 axis in patients with mild to moderate CHF.

Solitary plasmacytoma of the jaw occurring in an elderly woman affected by hepatitis C virus infection: a case report.

Solitary plasmacytoma accounts for a small percentage of plasma cell neoplasms. The disease often affects older people and is potentially curable. Only a few cases of solitary jaw plasmacytoma have been described in the literature. Here we report the case of a 76-year-old woman affected by chronic hepatitis C infection and isolated plasmacytoma of the left jaw. Plasmacytoma was diagnosed in January 2001, but the swelling of the mandible had been present since 1993. Two different pathologists made the diagnosis on the basis of biopsy material from the mandibular swelling.

Internal jugular vein thrombosis as first sign of metastatic lung cancer.

We describe a case of spontaneous internal jugular vein thrombosis occurring as the first sign of occult lung cancer. The peculiarity of the case was the unusual site of thrombosis and the lack of risk factors for DVT (only a moderated reduction of protein S without inherited thrombophilia) as well as the absence of clinical signs of cancer. This report shows once again the strong association between idiopathic venous thromboembolism and cancer. Hypercoagulation tests confirmed the association between cancer and thrombophilia. Reduction of protein S has been discovered recently in patients with lung cancer but further data are required to confirm this finding. Combined treatment (chemotherapy and radiotherapy) associated with oral anticoagulation therapy was started in our patient at the moment of diagnosis.

Glucose metabolism and coronary heart disease in patients with normal glucose tolerance.

CONTEXT: Several investigations as well as prospective studies have shown a significant correlation between glucose metabolism and atherosclerosis in patients without diabetes, but differences in parameters of glucose metabolism among the various degrees of coronary disease in such patients have not been specifically evaluated. OBJECTIVE: To investigate glucose metabolism in patients with normal glucose tolerance (NGT) and coronary heart disease (CHD). DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of 234 men (mean [SD] age, 56.2 [6.1] years) with NGT and suspected CHD who were admitted from January 1 through June 30, 2001, to an academic medical center in Italy for coronary angiography. MAIN OUTCOME MEASURES: Correlation of glucose metabolic factors and extent of atherosclerosis determined by coronary angiography. Factors included levels of fasting and postload glucose and insulin, glycosylated hemoglobin (HbA1c), and lipids, as well as insulin resistance measured by homeostasis model assessment (HOMA-IR). RESULTS: Patients were divided into 4 groups based on coronary angiography: no significant stenosis (n = 42), 1-vessel disease (n = 72), 2-vessel disease (n = 64), and 3-vessel disease (n = 56). Simple correlation analysis showed that the factors correlated with the extent of atherosclerosis were levels of postload glucose (r = 0.667), HbA1c (r = 0.561), postload insulin (r = 0.221), and fasting insulin (r = 0.297), as well as HOMA-IR (r = 0.278) (P<.001 for all). Multiple stepwise regression analysis suggested that the factors independently associated with the number of stenosed coronary arteries were levels of postload plasma glucose (r = 0.572), HbA1c (r = 0.413), postload insulin (r = 0.267), and fasting insulin (r = 0.174), as well as HOMA-IR (r = 0.250) (P<.001 for all). Similar results were obtained after grouping patients by Duke Myocardial Jeopardy Score. CONCLUSIONS: For patients with NGT and different extents of atherosclerotic disease, postload glycemia and HbA1c level are not equally distributed but are significantly higher in those with more severe disease. This suggests that the glycemic milieu correlates with the cardiovascular risk according to a linear model.

Carbonic anhydrase activation is associated with worsened pathological remodeling in human ischemic diabetic cardiomyopathy.

BACKGROUND: Diabetes mellitus (DM) has multifactorial detrimental effects on myocardial tissue. Recently, carbonic anhydrases (CAs) have been shown to play a major role in diabetic microangiopathy but their role in the diabetic cardiomyopathy is still unknown. METHODS AND RESULTS: We obtained left ventricular samples from patients with DM type 2 (DM-T2) and nondiabetic (NDM) patients with postinfarct heart failure who were undergoing surgical coronary revascularization. Myocardial levels of CA-I and CA-II were 6- and 11-fold higher, respectively, in DM-T2 versus NDM patients. Elevated CA-I expression was mainly localized in the cardiac interstitium and endothelial cells. CA-I induced by high glucose levels hampers endothelial cell permeability and determines endothelial cell apoptosis in vitro. Accordingly, capillary density was significantly lower in the DM-T2 myocardial samples (mean±SE=2152±146 versus 4545±211/mm(2)). On the other hand, CA-II was mainly upregulated in cardiomyocytes. The latter was associated with sodium-hydrogen exchanger-1 hyperphosphorylation, exaggerated myocyte hypertrophy (cross-sectional area 565±34 versus 412±27 µm(2)), and apoptotic death (830±54 versus 470±34 per 10(6) myocytes) in DM-T2 versus NDM patients. CA-II is activated by high glucose levels and directly induces cardiomyocyte hypertrophy and death in vitro, which are prevented by sodium-hydrogen exchanger-1 inhibition. CA-II was shown to be a direct target for repression by microRNA-23b, which was downregulated in myocardial samples from DM-T2 patients. MicroRNA-23b is regulated by p38 mitogen-activated protein kinase, and it modulates high-glucose CA-II-dependent effects on cardiomyocyte survival in vitro. CONCLUSIONS: Myocardial CA activation is significantly elevated in human diabetic ischemic cardiomyopathy. These data may open new avenues for targeted treatment of diabetic heart failure.

Coronary artery disease is detectable by multi-slice computed tomography in most asymptomatic type 2 diabetic patients at high cardiovascular risk.

OBJECTIVE: Non-invasive testing often does not identify coronary artery disease (CAD) in diabetic subjects. This study was designed in order to examine the prevalence of CAD in a cohort of asymptomatic type 2 diabetic patients at high cardiovascular risk and negative nuclear imaging, using multi-slice computed tomography (MSCT) angiography. METHODS: In total, 770 type 2 diabetic patients were screened from January 2008 through July 2010. Of these, 132 Caucasians with diabetic nephropathy and asymptomatic for angina were eligible for a cross-sectional study. Patients underwent MSCT after ischaemia was excluded by myocardial Single Photon Emission Computed Tomography (SPECT) at rest and after dynamic exercise. When obstructive plaques were found (≥ 50% lumen narrowing), patients were sent to conventional coronary angiography (CCA). RESULTS: Six subjects were not included in the analysis because of motion artefacts. MSCT was positive for CAD in 114 patients (90%). Within patients with positive MSCT, 60 (48% of all) showed one or more obstructive plaques. CCA confirmed significant stenosis (≥ 50%) in 48 of these 60 patients (80%). Some 21 (35%) showed stenosis ≥ 75% and were submitted to the revascularisation procedure. CONCLUSION: MSCT seems to better identify CAD than myocardial SPECT in asymptomatic patients with type 2 diabetes and diabetic nephropathy.

Kidney in diabetes: from organ damage target to therapeutic target.

Despite the growing of pharmacological options for the treatment of diabetes, epidemiological studies suggest that a substantial proportion of patients does not achieve glycemic goals and so suffers from the risk of chronic complications. This review explores the inhibition of renal glucose reabsorption as a novel approach to treat hyperglycemia. Sodium-glucose cotransporter 2 (SGLT2), a low-affinity high-capacity transporter located in the brush-border membrane of the early segment (S1) of the proximal renal tubule, accounts for about 90% of the reabsorption of glucose from tubular fluid. Competitive inhibitors of SGLT2 that are responsible for renal excretion of glucose provide a unique mechanism to potentially lower the elevated blood glucose levels in patients with diabetes. They act independently of insulin secretion, thereby minimizing the risk of hypoglycemia and weight gain, to control energy balance in a negative direction, a distinctive advantage of this class of drugs over existing oral hypoglycemic agents. Although this group of medications is still under investigation, it appears to be safe and generally well tolerated and it would be expected to improve the treatment of type 2 diabetes as monotherapy or in combination with other oral or parenteral agents. Dapagliflozin is the first agent within this class, which induces clinically meaningful reductions in FPG, PPG, HbA1c, and body weight in type 2 diabetes.

Effects of a mixed meal on hemodynamics and autonomic control of the heart in patients with type 1 diabetes.

CONTEXT: Food intake induces relevant cardiovascular changes together with parallel increases in cardiac sympathetic activity and insulin plasma levels in man. OBJECTIVE: We evaluated hemodynamics, neurohormones, and cardiac autonomic control after eating in patients with type 1 diabetes, a disease characterized by the absence of basal and stimulated insulin production. DESIGN AND SETTING: Fifteen type 1 diabetic patients and 15 healthy controls underwent blood sampling, electrocardiogram, blood pressure and respiration recordings, and heart rate variability analysis while recumbent, during the 70 degrees head-up tilt, and 20 min after a mixed meal; on another occasion, diabetic patients were also studied 20 min after a mixed meal preceded by their scheduled bolus of exogenous insulin. Spectrum analysis of RR interval provided the indices of sympathetic (LF(RR)) and vagal (HF(RR)) modulation of the sinoatrial node. RESULTS: At baseline, no significant differences were found between groups, except for metabolic parameters. Compared with baseline, heart rate, plasma catecholamines, and LF(RR) significantly (P < 0.005) increased, whereas HF(RR) significantly (P < 0.0001) decreased during the tilt in all subjects. Compared with baseline, plasma norepinephrine, heart rate, and LF(RR) significantly (P < 0.05) increased, whereas HF(RR) significantly (P < 0.02) decreased after eating in controls but not in diabetic patients (with and without insulin administered before eating). In both controls and diabetic patients, no relationship between postprandial changes of insulin and LF(RR) and HF(RR) was found. CONCLUSIONS: Hemodynamic, neurohormonal, and cardiac neural responses to eating are abnormal in type 1 diabetic patients, independently of insulin.