Francesco Giugliano

Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans Role of Oxidative Stress

Background—Circulating levels of interleukin-6 (IL-6) and tumor necrosis factor-&agr; (TNF-&agr;) are elevated in diabetic patients. We assessed the role of glucose in the regulation of circulating levels of IL-6, TNF-&agr;, and interleukin-18 (IL-18) in subjects with normal or impaired glucose tolerance (IGT), as well as the effect of the antioxidant glutathione. Methods and Results—Plasma glucose levels were acutely raised in 20 control and 15 IGT subjects and maintained at 15 mmol/L for 5 hours while endogenous insulin secretion was blocked with octreotide. In control subjects, plasma IL-6, TNF-&agr;, and IL-18 levels rose (P <0.01) within 2 hours of the clamp and returned to basal values at 3 hours. In another study, the same subjects received 3 consecutive pulses of intravenous glucose (0.33 g/kg) separated by a 2-hour interval. Plasma cytokine levels obtained at 3, 4, and 5 hours were higher (P <0.05) than the corresponding values obtained during the clamp. The IGT subjects had fasting plasma IL-6 and TNF-&agr; levels higher (P <0.05) than those of control subjects. The increase in plasma cytokine levels during the clamping lasted longer (4 hours versus 2 hours, P <0.01) in the IGT subjects than in the control subjects, and the cytokine peaks of IGT subjects after the first glucose pulse were higher (P <0.05) than those of control subjects. On another occasion, 10 control and 8 IGT subjects received the same glucose pulses as above during an infusion of glutathione; plasma cytokine levels did not show any significant change from baseline after the 3 glucose pulses. Conclusions—Hyperglycemia acutely increases circulating cytokine concentrations by an oxidative mechanism, and this effect is more pronounced in subjects with IGT. This suggests a causal role for hyperglycemia in the immune activation of diabetes.

Modified Supine versus Prone Position in Percutaneous Nephrolithotomy for Renal Stones Treatable with a Single Percutaneous Access: A Prospective Randomized Trial

OBJECTIVES To compare operative time, safety, and effectiveness of percutaneous nephrolithotomy in the supine versus prone position in a prospective randomized trial. MATERIAL AND METHODS From October 2005 to June 2007, 75 patients (33 men, 42 women; mean age, 39.3 yr) were prospectively enrolled and randomly divided into group A (39 patients, supine position) and group B (36 patients, prone position). Inclusion criteria were diagnosis of single or multiple renal stones (pelvic-caliceal) treatable with a single percutaneous access, stone diameter >2.5cm, body mass index (BMI) <30kg/m(2), and no contraindications to perform the operation in the prone position. Exclusion criteria were stones in more than one calyx, complete staghorn stones, and coexisting renal anomalies. RESULTS The two groups were comparable in age, BMI, male-to-female ratio, and stone size. No significant difference was ascertained between the two groups in terms of stone-free rate (group A, 88.7% vs. group B, 91.6%, p=0.12), mean blood loss (group A, Delta hemoglobin -2.3g/dl vs. group B, -2.2g/dl, p=0.23), and mean hospital stay (group A, 4.3 d vs. group B, 4.1 d, p=0.18). The only significant difference reported was mean operative time (group A, 43min vs. group B, 68min, p<0.001). No blood transfusions were needed and no organ injuries were reported. CONCLUSIONS In this carefully selected patient population with uncomplicated renal stones, the supine position was similar to the prone position for percutaneous stone removal.

Erectile dysfunction associates with endothelial dysfunction and raised proinflammatory cytokine levels in obese men

ABSTRACT. Erectile and endothelial dysfunction may have some shared pathways through a defect in nitric oxide activity. We evaluated associations between erectile function, endothelial function and markers of systemic vascular inflammation in 80 obese men, aged 35–55 yr, divided into two equal groups according to the presence/absence of erectile dysfunction. Compared with non-obese age-matched men [no.=50, body mass index (BMI)=24±1], obese men (all) had impaired indices of endothelial function as suggested by the reduced mean blood pressure and platelet aggregation responses to L-arginine, and higher circulating concentrations of the proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin- 18 (IL-18), as well as C-reactive protein (CRP). The mean erectile function score was 14±4 (range 7–19) in obese men with erectile dysfunction and 23.5±1 (range 22–25) in obese men without erectile dysfunction. Endothelial function showed a greater impairment in impotent obese men as compared with potent obese men. The mean blood pressure and platelet aggregation decreases following Larginine were -1.5±1.1 mmHg and -1.1±1.2%, respectively, in obese men with erectile dysfunction, and -3.4±1.2 mmHg and -5.6±2.1%, respectively, in obese men without erectile dysfunction (p<0.01). Circulating CRP levels were significantly higher in obese men with erectile dysfunction as compared with obese men without erectile dysfunction (p<0.05). Erectile function score was positively associated with mean blood pressure responses to L-arginine and negatively associated with BMI, waist-to-hip ratio (WHR), and CRP. Erectile and endothelial dysfunction associate in obese men and may contribute to their raised cardiovascular risk through impaired nitric oxide availability elicited by a low-grade inflammatory state.

Determinants of female sexual dysfunction in type 2 diabetes

Studies assessing sexual dysfunction in type 2 diabetic women are scanty. This study was designed to evaluate the prevalence and correlates of female sexual function in a quite large population of diabetic women. A total of 595 women with type 2 diabetes completed a questionnaire of self-report measures of sexual dysfunction and were analyzed in this study. Their age was 57.9±6.9 (mean and s.d.), duration of diabetes was 5.2±1.5 years and mean hemoglobin A1c (HbA1c) level was 8.3±1.3%. Female sexual dysfunction (FSD) was assessed by the Female Sexual Function Index instrument with a cut-off score of 23. The overall prevalence of FSD among the diabetic women was 53.4%, significantly higher in menopausal women (63.9%), as compared with nonmenopausal women (41.0%, P<0.001). There was no association between HbA1c, duration of diabetes, hypertension, or cigarette smoking status and FSD; on the contrary, age, metabolic syndrome and atherogenic dyslipidemia were significantly associated with FSD. Both depression and marital status were independent predictors of FSD, while physical activity was protective. Further studies are needed to elucidate in full the mechanisms underlying the evident differences between male and female sexual function. In the meantime, evaluation of female sexuality should become a routine evaluation in women with type 2 diabetes, such as other diabetic complications.

Determinants of erectile dysfunction in type 2 diabetes

This study was designed to evaluate the prevalence and correlates of ED in a population of diabetic men. Consecutive patients with type 2 diabetes were recruited among outpatients regularly attending Diabetes Clinics. Inclusion criteria for the initial selection of patients were a diagnosis of type 2 diabetes for at least 6 months but less than 10 years, age 35–70 years, body mass index (BMI) of 24 or higher, HbA1c of 6.5% or higher: a total of 555 (90.8%) of the 611 men were analyzed in this study. ED was assessed by the IIEF-5 instrument. Approximately, 6 in 10 men in our sample of diabetic men had varying degrees of erectile dysfunction: mild 9%, mild to moderate 11.2%, moderate 16.9% and severe 22.9%. The prevalence of severe ED increased with age. Higher hemoglobin A1c (HbA1c) levels were associated with ED; similarly, the presence of metabolic syndrome, hypertension, atherogenic dyslipidemia (low levels of HDL-cholesterol and high levels of triglycerides) and depression was associated with ED. Physical activity was protective of ED; men with higher levels of physical activity were 10% less likely to have ED as compared with those with the lowest level. In conclusion, among subjects with type 2 diabetes glycemic control and other metabolic covariates were associated with ED risk, whereas higher level of physical activity was protective. These results encourage the implementation of current medical guidelines that place intensive lifestyle changes as the first step of the management of type 2 diabetes.

Effects of Intensive Lifestyle Changes on Erectile Dysfunction in Men

INTRODUCTION Limited data are available supporting the notion that treatment of lifestyle risk factors may improve erectile dysfunction (ED). AIM In the present study, we analyzed the effect of a program of changing in lifestyle designed to improve erectile function in subjects with ED or at increasing risk for ED. METHODS Men were identified in our database of subjects participating in randomized controlled trials evaluating the effect of lifestyle changes. A total of 209 subjects were randomly assigned to one of the two treatment groups. The 104 men randomly assigned to the intervention program received detailed advice about how to reduce body weight, improve quality of diet, and increase physical activity. The 105 subjects in the control group were given general information about healthy food choices and general guidance on increasing their level of physical activity. MAIN OUTCOME MEASURES Changes in erectile function score (International Index of Erectile Function-5 [IIEF-5]; items 5, 15, 4, 2, and 7 from the full-scale IIEF-15) and dependence of the restoration of erectile function on the changes in lifestyle that were achieved. RESULTS Erectile function score improved in the intervention group. At baseline, 35 subjects in the intervention group and 38 subjects in the control group had normal erectile function (34% and 36%, respectively). After 2 years, these figures were 58 subjects in the intervention group and 40 subjects in the control group, respectively (56% and 38%, P = 0.015). There was a strong correlation between the success score and restoration of erectile function. CONCLUSIONS It is possible to achieve an improvement of erectile function in men at risk by means of nonpharmacological intervention aiming at weight loss and increasing physical activity.

Circulating CD34+KDR+ Endothelial Progenitor Cells Correlate with Erectile Function and Endothelial Function in Overweight Men

INTRODUCTION Bone marrow-derived endothelial progenitor cells (EPCs) circulate in the peripheral blood and are involved in endothelial homeostasis and repair. AIM The aim of this study was to assess the circulating levels of different EPC phenotypes in overweight men with or without erectile dysfunction (ED). As endothelial dysfunction is considered a necessary link with ED, endothelium-dependent vasodilation and its relation with EPCs were also investigated. METHODS We studied 30, otherwise healthy, overweight subjects with symptomatic ED for at least 6 months, and 30 age- and weight-matched subjects without ED. Erectile function was assessed by completing the International Index of Erectile Function (IIEF-5), which consists of items 5, 15, 4, 2, and 7 from the full-scale IIEF-15. MAIN OUTCOME MEASURES Seven subpopulations of EPCs were determined by flow cytometry on the basis of the surface expression of CD34, CD133, and KDR antigens: CD34(+), CD133(+), KDR(+), CD34(+)CD133(+), CD34(+)KDR(+), CD133(+)KDR(+), and CD34(+)CD133(+)KDR(+). Endothelium-dependent flow-mediated dilation (FMD) was evaluated in the right brachial artery with a high-resolution ultrasound machine following reactive hyperemia. RESULTS CD34(+)KDR(+) cell count was significantly lower in men with ED as compared with men without ED (63.1 +/- 4 vs. 92.4 +/- 6 cells/10(6) events, mean +/- standard error, P < 0.01). There was a significant direct correlation between circulating CD34(+)KDR(+) cells and the IIEF score (r = 0.44; P = 0.01): men with the severe form of ED presented the lowest level of circulating EPC CD34(+)KDR(+) cells. No significant correlation was found between the circulating levels of the other EPC phenotypes and the IIEF score. There was a significant correlation between CD34(+)KDR(+) cell count and FMD (r = 0.45; P = 0.01), but not between FMD and the other phenotypes. CONCLUSIONS Circulating levels of CD34(+)KDR(+) EPC are reduced in overweight subjects with ED and correlate with the severity of ED. Other EPC phenotypes are not related to ED, suggesting that the CD34(+)KDR(+) phenotype of EPCs may be preferred in future studies.

Health related quality of life after radical cystectomy: Comparison of ileal conduit to continent orthotopic neobladder

AIMS To compare health related quality of life (HRQOL) between patients with two different types of urinary diversion, ileal conduit and orthotopic neobladder, and between them and an age-matched population of healthy subjects. MATERIALS AND METHODS Eighty eight patients treated with radical cystectomy for bladder cancer at our institutions between 2002 and 2007 were contacted for this survey. All of them had a follow-up of more than 12 months after surgery and were recurrence free. The SF-36 questionnaire was provided to each patient during a follow-up visit at outpatient clinics. Overall, 79 patients (90%) returned the questionnaire and were included in this analysis. They were divided into two groups: group 1 comprised 44 patients with an ileal conduit diversion, and group 2 included 35 patients with a neobladder. As a control, normative values of an age-matched healthy Italian population were considered. RESULTS No significant difference was found in scale scores between the neobladder and ileal conduit groups. Scale scores for role-physical functioning, social functioning and role-emotional functioning in both the neobladder and ileal conduit groups were significantly below the Italian population norm. Patients with a neobladder 65 years old or older (n=18) had significantly lower scores for role-physical functioning and role-emotional functioning than those younger than 65 years (n=17; p<0.05). CONCLUSION Few differences between ileal conduit and orthotopic bladder substitution have been detected. Thus, the assumption that continent reconstruction provides better HRQOL than ileal conduit diversion cannot be supported. Patient education and active participation in treatment decisions seem to be the key to postoperative satisfaction.

Hyperlipidemia and Sexual Function in Premenopausal Women

INTRODUCTION No reported studies exist assessing the relationship between sexual function and hyperlipidemia in women. AIM In this study, we assessed the domains of sexual function in a representative sample of sexually active premenopausal women with hyperlipidemia, but without cardiovascular disease, as compared with an age-matched female population without hyperlipidemia. METHODS To be enrolled in the study, women had to meet at least one of the following criteria for the diagnosis of hyperlipidemia: low-density lipoprotein (LDL) cholesterol levels >160 mg/dL; high-density lipoprotein (HDL) cholesterol levels <50 mg/dL; or triglyceride levels >150 mg/dL. Lipid parameters were assessed and verified on blood taken at least twice in the hospital during the screening phase. Four hundred forty-one premenopausal women with hyperlipidemia were compared with 115 age-matched premenopausal women without hyperlipidemia. MAIN OUTCOME MEASURES We used the Female Sexual Function Index (FSFI) for assessing the key dimensions of female sexual function. RESULTS The two groups were well matched for age and smoking prevalence. Compared with women of the control group, women with hyperlipidemia had reduced mean global FSFI score (22.8 +/- 6.8 vs. 29.4 +/- 4.9, P < 0.001). Individual analysis of the different domains showed that women with hyperlipidemia reported significantly lower arousal, orgasm, lubrication, and satisfaction scores than control women. Based on the total FSFI score, 51% of women with hyperlipidemia had scores of 26 or less, indicating sexual dysfunction, as compared with 21% of women without hyperlipidemia (P < 0.001). Based on a more conservative analysis including women under the lower quartile of the distribution of FSFI score, 32% of women with hyperlipidemia had scores of 23 or less, as compared with 9% of women without hyperlipidemia (P < 0.001). Multiple regression analysis identified age, body mass index, HDL-cholesterol and triglycerides as independent predictors of FSFI score. CONCLUSIONS Women with hyperlipidemia have significantly lower FSFI-domain scores as compared with age-matched women without hyperlipidemia. HDL cholesterol and triglyceride levels were independently associated with the FSFI score.

Phenotypic Assessment of Endothelial Microparticles in Diabetic and Nondiabetic Men with Erectile Dysfunction

INTRODUCTION Endothelial microparticles (EMPs) may play a role as biomarkers of vascular injury. EMPs are higher in men with diabetes diabetic men with erectile dysfunction (ED) than in nondiabetic potent men. AIM The aim of this study was to quantize different phenotypic circulating EMP levels among diabetic and nondiabetic patients with ED, and to determine whether EMPs are released as a result of activation or apoptosis. METHODS We studied 30 type 2 diabetic and 24 nondiabetic subjects with symptomatic ED from at least 6 months, and 20 nondiabetic men without ED matched for age and weight with diabetic and nondiabetic subjects. Erectile function was assessed by completing the International Index of Erectile Function (IEEF)-5, which consists of Items 5, 15, 4, 2, and 7 from the full-scale IIEF-15. A score of 21 or less indicates the presence of ED. MAIN OUTCOME MEASURES EMP levels in plasma were quantified by flow cytometry. Markers for apoptosis (platelet/endothelial cell adhesion molecule 1/CD31 antigen) and activation (E-selectin/CD62E antigen) were compared. Endothelium-dependent flow-mediated dilation (FMD) was evaluated in the right brachial artery with a high-resolution ultrasound machine following reactive hyperemia. RESULTS Diabetic patients were found to have the highest levels of EMP31+; diabetic and nondiabetic men with ED were found to have significantly higher levels of EMP62+ than nondiabetic men without ED. The EMP62/EMP31 ratio, an index of endothelial activation (high ratio) or apoptosis (low ratio), was lowest in diabetic men with ED (0.20). In the whole group of 54 men with ED (diabetic and nondiabetic), there was an inverse correlation between FMD and the number of circulating EMPs (P < 0.05). CONCLUSIONS The presence of diabetes in subjects with ED is associated with a different pattern of endothelial cell injury. The phenotypic assessment of EMPs in diabetic patients with ED is consistent with increased apoptotic activity.