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Context Growth of male genitalia represents an important marker of sexual development. Testicle size is the primary measure and little is known regards penile length changes during puberty. Objective This work aims to assess penis growth and testosterone levels in obese vs normal-weight children and adolescents, to evaluate a possible influence of obesity on genital development in boys, and to establish a new method for measuring penis length that allows comparison of normal-weight and overweight boys. Methods We assessed anthropometric and genital development in 1130 boys from birth to age 20 years. Testosterone levels were also measured. A new method for penile length measurement was employed to minimize errors when comparing obese and nonobese children. Penis length was measured with a gentle, painless, straight positioning on a centimetric ruler without stretching, which is doable from the first years of life until the end of adolescence. Results Penis length and testosterone are strongly related in children during puberty. Penile length growth is significantly decreased (by about 10%) in obese boys when compared to normal-weight boys, with concomitantly reduced testosterone levels, across puberal phases. Conclusion Childhood obesity represents an important determinant of lower testosterone level and reduced penis development. A new method should be employed to improve penis measurement in normal-weight and overweight/obese boys. The possible significance of these observations for adult genital development and reproductive potential will require large longitudinal studies.

The low rate of diagnosis of Klinefelter syndrome in prepubertal age is due to hard data to interpret about hormonal, testicular and penile modifications. About the penis length, the diagnosis seems to be suspected when it is less than 3 cm at the birth date and below 4.2 cm between 2 and 10 years. An impaired testis growth could be identified by ultrasound when the mean volume is under 0.25 mL in the first 6 months of life and below 0.36 mL in children younger than 10 years. At mini-puberty, a testosterone maximum peak under 210 ng/dL may be strongly suspect. Human chorionic gonadotropin (hCG) test may be useful but at now not standardized. About sperm recovery by TESE or micro-TESE in Klinefelter patients, a combination of testosterone above 216 ng/dL and luteinizing hormone (LH) below 17.5 U/L, showed a higher retrieval in both children and adults. Extrapolation from histological damage in cryptorchid children, get to hypotesize a severe germ cell impairment if testosterone rising, after a second 1500 UI hCG injection, is below 101.9 ng/dL. In adults, a possible positive predictive testosterone value could be above 1000 ng/dL after hCG test. The retrieval rate seems to be better after the age of 16 and before 19, when could be maximum the development of germ cell line and before a massive fibrosis of the testis.

Varicocele is a rather common andrological condition in adolescents, which can adversely affect testicular growth and seminal parameters, leading to infertility in about 20% of adults. The aim of this study was to investigate if treating varicocele before the age of 18 is a beneficial option to improve testicular hypotrophy and seminal parameters and if minimally invasive techniques could be an appropriate treatment choice for adolescent varicocele associated with spermatic vein reflux. A percutaneous scleroembolization was performed in sixty-four consecutive young patients (13-19 years old) with left varicocele, preceded by a fluoroscopy. In thirty-four of them, semen samples were also collected. We examined semen samples and testicles dimensions before and after percutaneous varicocelectomy, compared to a nonoperated control group, with a six-month follow-up. Total sperm count and sperm morphology were significantly increased in the intervention group. Left testicular volume significantly increased in both groups, while only correction of varicocele improved spermatozoa release per unit of testis volume. We conclude that early varicocelectomy by percutaneous scleroembolization significantly ameliorates seminiferous tubules activity in the critical adolescent phase of testicular growth. It is suggested that adolescents should be; offered varicocele repair as soon as possible in order to improve reproductive potential.

Precision and personalized medicine is gaining importance in modern clinical medicine, as it aims to improve diagnostic precision and to reduce consequent therapeutic failures. In this regard, prior to use in human trials, animal models can help evaluate novel imaging approaches and therapeutic strategies and can help discover new biomarkers. Breast cancer is the most common malignancy in women worldwide, accounting for 25% of cases of all cancers and is responsible for approximately 500,000 deaths per year. Thus, it is important to identify accurate biomarkers for precise stratification of affected patients and for early detection of responsiveness to the selected therapeutic protocol. This review aims to summarize the latest advancements in preclinical molecular imaging in breast cancer mouse models. Positron emission tomography (PET) imaging remains one of the most common preclinical techniques used to evaluate biomarker expressionin vivo, whereas magnetic resonance imaging (MRI), particularly diffusion-weighted (DW) sequences, has been demonstrated as capable of distinguishing responders from nonresponders for both conventional and innovative chemo- and immune-therapies with high sensitivity and in a noninvasive manner. The ability to customize therapies is desirable, as this will enable early detection of diseases and tailoring of treatments to individual patient profiles. Animal models remain irreplaceable in the effort to understand the molecular mechanisms and patterns of oncologic diseases.

Metabolic syndrome is a complex human disorder characterized by a cluster of conditions (increased blood pressure, hyperglycemia, excessive body fat around the waist, and abnormal cholesterol or triglyceride levels). Any of these conditions increases the risk of serious disorders such as diabetes or cardiovascular disease. Currently, the degree of genetic regulation of this syndrome is under debate and partially unknown. The principal aim of this study was to estimate the genetic component and the common environmental effects in different populations using full pedigree and genomic information. We used three large populations (Gubbio, ARIC, and Ogliastra cohorts) to estimate the heritability of metabolic syndrome. Due to both pedigree and genotyped data, different approaches were applied to summarize relatedness conditions. Linear mixed models (LLM) using average information restricted maximum likelihood (AIREML) algorithm were applied to partition the variances and estimate heritability (h2) and common sib–household effect (c2). Globally, results obtained from pedigree information showed a significant heritability (h2: 0.286 and 0.271 in Gubbio and Ogliastra, respectively), whereas a lower, but still significant heritability was found using SNPs data ( $$h_{\text{SNP}}^{2}$$ : 0.167 and 0.254 in ARIC and Ogliastra). The remaining heritability between h2 and $$h_{\text{SNP}}^{2}$$ ranged between 0.031 and 0.237. Finally, the common environmental c2 in Gubbio and Ogliastra were also significant accounting for about 11% of the phenotypic variance. Availability of different kinds of populations and data helped us to better understand what happened when heritability of metabolic syndrome is estimated and account for different possible confounding. Furthermore, the opportunity of comparing different results provided more precise and less biased estimation of heritability.

Ultrasound is a noninvasive routine method that allows real-time monitoring of fetal development in utero to determine gestational age and to detect congenital anomalies and multiple pregnancies. To date, the developmental biology of Chinchilla lanigera has not yet been characterized. This species has been found to undergo placentation, long gestation, and fetal dimensions similar to those in humans. The aim of this study was to assess the use of high-frequency ultrasound (HFUS) and clinical ultrasound (US) to predict gestational age in chinchillas and evaluate the possibility of this species as a new animal model for the study of human pregnancy. In this study, 35 pregnant females and a total of 74 embryos and fetuses were monitored. Ultrasound examination was feasible in almost all chinchilla subjects. It was possible to monitor the chinchilla embryo with HFUS from embryonic day (E) 15 to 60 and with US from E15 to E115 due to fetus dimensions. The placenta could be visualized and measured with HFUS from E15, but not with US until E30. From E30, the heartbeat became detectable and it was possible to measure fetal biometrics. In the late stages of pregnancy, stomach, eyes, and lenses became visible. Our study demonstrated the importance of employing both techniques while monitoring embryonic and fetal development to obtain an overall and detailed view of all structures and to recognize any malformation at an early stage. Pregnancy in chinchillas can be confirmed as early as the 15th day postmating, and sonographic changes and gestational age are well correlated. The quantitative measurements of fetal and placental growth performed in this study could be useful in setting up a database for comparison with human fetal ultrasounds. We speculate that, in the future, the chinchilla could be used as an animal model for the study of US in human pregnancy.

«La plus part des fables d’Esope ont plusieurs sens et intelligences: ceux qui les mythologisent, en choisissent quelque visage, qui cadre bien a la fable: mais pour la plupart, ce n’est que le premier visage et superficiel: il y en a d’autres plus vifs, plus essentiels et internes, auxquels ils n’ont sceu penetrer». Cosi Montaigne (Essais, II, 10), che certo ha presenti, oltre agli incunaboli del genere, Esopo e Fedro, anche le riscritture favolistiche rinascimentali, come La moral filosofia...

Introduction Conventional cardiovascular (CV) risk factors identify only half of subjects with incident major adverse CV events (MACE). Hence new markers are needed in high CV risk subjects, as those with erectile dysfunction (ED). A role for dynamic peak systolic velocity (D-PSV) at penile color Doppler ultrasound (PCDU) has been suggested, but it is operator dependent and time consuming. Flaccid penile acceleration (FPA) is a PCDU parameter that reflects PSV, the systolic rise time (SRT), and end diastolic velocity (EDV), arithmetically defined as (PSV−EDV)/SRT. Aim The study aims to verify, in a large series of ED patients, whether FPA has a role in predicting MACE. Methods A selected series of 1,903 patients (aged 54.6 ± 11.7) with a suspected organic component for ED was retrospectively studied from January 2000 until July 2012. A subset of this sample (n = 622) was enrolled in a longitudinal study that ended in December 2007. Main Outcome Measures Several clinical, biochemical, and instrumental (PCDU) parameters were studied. Results Decreased FPA levels were associated with worse metabolic profile and sexual symptoms. In addition, FPA was positively associated with both total and calculated free testosterone. In the longitudinal study, unadjusted incidence of MACE was significantly associated with lower baseline FPA. When FPA was introduced in a multivariate model, along with D-PSV, after adjusting for age and Chronic Disease Score, lower FPA, but not D-PSV, was associated with incident MACE in lower-risk—i.e., younger (HR = 0.48 [0.23–0.99]), nonhypertensive (HR = 0.59 [0.38–0.92]), nonobese (HR = 0.68 [0.49–0.96]), or nondiabetic (HR = 0.67 [0.49–0.96] subjects; all P 2 which showed a threefold increase in incidence of MACE in apparently lower-risk individuals. Conclusions FPA is an easily obtained PCDU parameter and capable of identifying adverse metabolic and CV profiles, particularly in apparently lower-risk individuals with ED. Rastrelli G, Corona G, Lotti F, Aversa A, Bartolini M, Mancini M, Mannucci E, and Maggi M. Flaccid penile acceleration as a marker of cardiovascular risk in men without classical risk factors. J Sex Med 2014;11:173–186 .

This study was aimed at evaluating the association between seminal plasma interleukin-8 (sIL-8) and colour-Doppler ultrasound (CDU) characteristics of the male genital tract in a series of patients fulfilling the criteria of male accessory gland infections (MAGI). Of 250 subjects seeking medical care for couple infertility, 79 (mean age: 36.4 ± 7.5 years) met the criteria of MAGI and scored higher than the rest of the sample on the National Institutes of Health-Chronic Prostatitis Symptom Index score. All patients underwent simultaneous hormone evaluation and seminal analysis (including sIL-8), along with scrotal and transrectal CDU before and after ejaculation. After adjusting for age, sIL-8 in patients with MAGI was significantly related to several abnormal semen and CDU parameters. In particular, leucocytospermia was closely associated with sIL-8. Ejaculate volume, unlike other semen or hormonal parameters, was negatively associated with sIL-8. When scrotal CDU was performed, sIL-8 was positively related to CDU inhomogeneous, hypo-echoic, hyper-echoic epididymis and to epididymal calcifications. In addition, a positive correlation among sIL-8, hyperaemic epididymis and an increased size of epididymal tail was found. When transrectal CDU was performed, an association among sIL-8 and hyper-echoic seminal vesicles, dilated ejaculatory ducts and duct calcifications was also observed. Finally, sIL-8 was positively related to prostate CDU abnormalities such as calcifications, inhomogeneous/hypo-echoic texture, hyperaemia and high arterial blood flow. No association was found with testis parameters. In conclusion, sIL-8 levels in patients with MAGI are associated with several parameters and CDU abnormalities of epididymis, seminal vesicles, ejaculatory ducts and prostate, but not of the testis. Furthermore, sIL-8 positively correlates with CDU signs of ejaculatory duct inflammatory subobstruction.

Aims In an observational population study that lasted 20 years, the relationships between mortality trends and changes in cardiovascular risk factor levels were examined. Methods and results In the town of Gubbio, in central Italy, population surveys for measurement of cardiovascular risk factors were performed 20 years apart. In a subset of the initial cohort (1927 men and 2333 women), mortality data were collected for 20 years. Cardiovascular risk factor levels were compared in individuals in the same age range (20–79 years) examined at the initial survey (1927 men and 2333 women) and at the final survey (1761 men and 2055 women). Age-adjusted rates significantly declined, by 28% among men and 51% among women, for all causes of death, and by 50% among men and 71% among women for cardiovascular disease deaths. Declines were observed in the levels of systolic blood pressure, serum cholesterol, resting heart rate, smoking habits, BMI, plasma glucose (the latter two only in women) and the estimated cardiovascular risk, together with increases in serum high-density lipoprotein cholesterol and in the proportion of treated and controlled hypertensive patients. Conclusion Although similar but less impressive changes were recorded in Italy at large, the existence of the observational study in Gubbio might have motivated the general population and the medical profession towards actions promoting general health.

The aim of this study was to compare the results of ultrasound (US), whole-body scintigraphy with iodine-131 (I-131 WBS) and positron emission tomography with fluorine-18 deoxyglucose (FDG-PET) in the follow-up of patients after thyroidectomy for differentiated thyroid carcinoma (DTC). Thirteen patients (3 men, 10 women) were evaluated by neck US, I-131 WBS and FDG-PET. In each patient six anatomical regions (right and left thyroid bed, right and left cervical region, right and left supraclavicular region) were investigated, for a total of 78 regions. Distant metastases were investigated by I-131 WBS and FDG-PET and considered separately in the analysis. Imaging findings were compared with the reference standards, such as fine-needle aspiration cytology (2), biopsy (4) or clinical-radiological studies (7). US, FDG-PET and I-131 WBS showed concordant negative results in most (70, 90%) of the anatomical sites considered. In one patient with left cervical lymph node metastasis, the imaging techniques showed concordant positive results (1%). In the remaining 7 regions (9%), the imaging results were discordant; in particular, tumour lesions, nodal metastases (4) and thyroid bed recurrences (3) were detected by US only (3), by US and I-131 WBS (1) and by FDG-PET only (3). With regard to distant metastases, FDG-PET and I-131 WBS yielded concordant negative results in the majority (77%) of patients (9); in one patient only were the two imaging techniques concordant in their positive result. In the last three patients, the results were discordant; in particular, distant metastases were detected by I-131 WBS only in two patients and by FDG-PET only in one patient. Our work indicates a fundamental role for US in evaluation of the neck after surgery for DTC. WBS is useful to determine differentiation of tumour lesions, to identify thyroid remnants and to look for distant metastases. FDG-PET has an important role in cases of dedifferentiated thyroid carcinoma in which WBS and thyroglobulin measurements are unable to detect tumour lesions.

Myoinositol and D-chiro inositol, which are inositol isomers, have been shown to possess insulin-mimetic properties and to improve insulin resistance, especially in women with polycystic ovary syndrome. However, it has not been determined if this relationship exists also in children. Based on these previous findings, we hypothesized that inositol could be effective in improving insulin sensitivity in children with insulin resistance. To evaluate this hypothesis, we administered both inositol formulations before carrying out an oral glucose tolerance test (OGTT) in a group of obese insulin-resistant male children with high basal insulin levels and compared the values obtained with an OGTT previously conducted without inositol, in the same group, with unchanged BMI. Our results confirm that myoinositol and D-chiro inositol acutely reduce insulin increase after glucose intake mainly in children with high basal insulin level.

BACKGROUND: An increased risk of testicular cancer in men with infertility and poor semen quality has been reported. Our aim was to investigate the prevalence of testicular nodules and cancer in azoospermic subjects with different spermatogenetic patterns. METHODS: A total of 1443 consecutive infertile men were investigated, out of which 145 (10.0%) were found to be azoospermic. By using clinical examination and testicular ultrasound, 11 out of the 145 patients showed testicular nodules (2.8-26 mm). To obtain spermatozoa for assisted reproduction, 97 subjects required testicular sperm extraction (TESE) and biopsy, including the 11 patients with nodules. They were divided into two groups according to biopsy results: Group A (n = 38) with complete Sertoli cell-only syndrome (SCOS) and Group B (n = 59) with varying spermatogenetic patterns. Ten nodules were found in Group A and one in Group B. RESULTS: In azoospermic men, the overall prevalence of nodules was 7.5%. In complete SCOS, the prevalence of nodules and cancer was 10/38 (26.3%) and 4/38 (10.5%), respectively. Amongst the cancers, one embryonal carcinoma, one seminoma and two in-situ carcinomas were found. CONCLUSIONS: The prevalence of testicular nodules and cancer in azoospermic men with complete SCOS is very high. In these subjects, the role of clinical evaluation, ultrasound and biopsy should be emphasized.

Background There is no definite consensus on which indexation of left ventricular mass (LVM) should be used to better identify left ventricular hypertrophy (LVH). Left ventricular mass has been adjusted to height, to height 2.7 (h 2.7 ) and to body surface area (BSA). The aims of the present study were to evaluate the prevalence of LVH according to different indexations and different cut-offs and to identify the most useful indexation of LVM to detect hypertension-related LVH. Methods Echocardiographic LVH was defined as LVM to h 2.7 , LVM to BSA, LVM to height, LVM values in the upper 5th percentile of our gender-related LVM distribution, using different partition values suggested in previous population-based studies. Results Prevalence of LVH in the general population was 32% using the less restrictive criterion (LVH 49.2/46.7 g/m 2.7 ), 15% with the criterion of LVH 116/104 g/m 2 , and 3.8% with the most restrictive one (LVH 134/110 g/m 2 ). Prevalence of LVH in hypertensive subjects was almost twice than in normotensive subjects with all criteria. Only 20 subjects out of the 707 evaluated were found to have LVH with all six criteria. In multiple regression analysis SBP was independently associated with nonindexed LVM and was indexed to both BSA and h 2.7 . On the other hand, fat-free mass was a poweful predictor of nonindexed LVM or of LVM to BSA, whereas body mass index was the strongest predictor of LVM to h 2.7 . Conclusions The indexation of LVM to BSA, possibly with the cut-off of LVH 116/104, is probably the best criterion for identifying blood pressure–related LVH.

Summary background There is substantial but not conclusive evidence that insulin resistance is related to left ventricular mass (LVM) in hypertensive individuals. To what extent this association is mediated by the relationship between plasma insulin and body size and build is still debated, and is poorly explored in nonhypertensive people. objective To explore the relationship between insulin or insulin resistance and LVM in a population-based sample of nonhypertensive participants of the Gubbio Study. method Echocardiographic LVM was determined in 91 nondiabetic, nonhypertensive individuals aged 45–54 years, participating in a population-based screening. LVM normalized for height2·7 was used in the analyses; LV hypertrophy was defined as a value of ≥ 50 g/m2·7 in men or ≥ 47 g/m2·7 in women. Fasting plasma insulin and glucose were measured and the Homeostasis Model Assessment (HOMA) index was used as a measure of insulin resistance. results LVM was positively and significantly correlated with body mass index (BMI) (P

Background and objectives Demonstration of antihypertensive beneficial role in population settings is difficult. Relationships of antihypertensive treatment, blood pressure control, risk factors and cardiovascular outcomes were investigated in the Gubbio study. Material and methods Among 2248 cardiovascular disease-free men and women aged 35-74 years, individuals were classified as nonhypertensive, controlled hypertensive, uncontrolled hypertensive and untreated hypertensive based on cut-off limits of 140/90 mmHg for SBP/DBP and/or the use of antihypertensive drugs. End-point was the first major coronary, cerebrovascular or peripheral hard event [cardiovascular disease (CVD)] during a 15-year average. Univariate and multivariate analyses were run. Results Nonhypertensive individuals were about 10 years younger and had lower risk factor levels than the other categories. The relative risk (and 95% confidence interval) for CVD versus nonhypertension was 1.78 (1.02-3.10) for controlled hypertension, 3.76 (2.79-5.06) for uncontrolled hypertension and 3.30 (2.59-4.21) for untreated hypertension (UTH). After adjusting for covariates, such as sex, age, achieved blood pressure and other risk factors, the CVD risk of controlled hypertension was practically equal to that of nonhypertension, and remained unchanged even when blood pressure was excluded from the model (1.03, 0.58-1.82). The higher cardiovascular risk of uncontrolled hypertension and UTH was reduced after adjusting for covariates, but remained significantly higher than in nonhypertension, with no significant differences between uncontrolled hypertension and UTH. Conclusions A higher level of baseline risk is not due to treatment per se, the risk being similar in uncontrolled hypertension and UTH. Adjustment for risk factors reduces the risk only in controlled hypertension, suggesting that there may be structural alterations scarcely reversible by antihypertensive treatment.

Background: The association between overweight, high blood pressure (BP), and insulin resistance is well established, but the role of body fat distribution in this association has yet to be fully elucidated. The aim of this study was to investigate the role of central adiposity in the association between overweight, high BP, and insulin resistance. Methods: A total of 1079 men participated in the follow-up of the Olivetti Heart Study from 1994 to 1995. The present analysis includes 768 men, after the exclusion of 184 participants on pharmacological treatment for hypertension. In 65 men fasting blood glucose was 7 mmol/L; in 48, age was below or above 2 standard deviations from the mean of the population ; and in 14 the data set was incomplete. Anthropometric indices of adiposity, metabolic variables (including fasting serum insulin and homeostasis model assessment [HOMA] index of insulin sensitivity), and BP were measured. Results: In univariate analysis, waist circumference was the anthropometric index that best correlated with BP (P .001). In multiple regression analysis, waist circumference remained the strongest independent predictor of BP after adjustment for confounders. Significant increase of systolic (P value for trend analysis .001) and diastolic (P .001) pressure, heart rate (P .003), fasting and postload serum insulin (P .001), and HOMA index of insulin sensitivity (P .001) were observed across ageadjusted quintiles of waist circumference. Greater degrees of central adiposity were associated with higher prevalence of elevated BP values and insulin resistance (P value .001, 2 for linear trend). Conclusions: In middle-aged men, a central distribution of body fat is associated with increased BP, independently of body mass index and insulin resistance, thus suggesting a key role of central adiposity in the full expression of the “metabolic syndrome.” Am J Hypertens 2002;15:780 ‐786 © 2002 American Journal of Hypertension, Ltd.

Background: The hypothesis that intravenous L-arginine infusion improves the vasodilatory response to ischemia in the resistance vessels of human lower limbs in relatively young coronary heart disease patients taking vasodilating drugs was tested. Methods: Twenty patients with onset of symptoms of coronary artery disease before age 50, operated for aortocoronary bypass and taking vasodilating drugs, were compared with 20 control subjects of comparable age and gender; neither group included heavy smokers (>10 cigarettes/day). Blood flow in the lower limbs was measured noninvasively with strain-gauge plethysmography, both at rest and during a reactive hyperemia test. Intravenous infusion of L-arginine was performed in nine coronary heart disease patients and in nine control subjects. Results: Resting blood flow to the lower limbs was 2.3 mI,/minIlO0 mL in control subjects vs 3.4 mL/minIlO0 mL in patients (difference not statistically significant). Peak blood flow measured after a 3-minute arterial occlusion was 24.0 mL/min/lO0 mL in control subjects vs 20.3 mL/min/lO0 mL in coronary heart disease patients (P Conclusions: Hemodynamic responses in the skeletal muscle are impaired during a reactive hyperemia test in relatively young coronary heart disease patients taking vasodilating drugs. Intravenous L-arginine infusion corrects the impaired vasodilatory response of the lower limbs to an acute increase in flow following a cuff thigh occlusion.

The Carotid Atherosclerosis Italian Ultrasound study (CAIUS), a multicenter, double-blind clinical trial, performed in 305 asymptomatic, moderately hypercholesterolemic patients, clearly demonstrated beneficial effects of pravastatin on the carotid intima-media thickness (IMT) progression. The database of the CAIUS study was examined in order to investigate the presence of a relationship, if any, between the activity of pravastatin on IMT progression rate and its hypocholesterolemic effect. Quantitative B-mode ultrasound imaging was used to quantify the individual mean maximum IMT progression rate in 3 years. In the overall group of patients (placebo and pravastatin) covariance analysis showed that while the variable 'treatment' (0 = placebo, 1 = pravastatin) was significantly related to the reduction of IMT progression (F= 6.6, P = 0.01), the IMT progression did not correlate with the extent of LDL-C lowering (F= 0.00, P = 0.98). To further investigate this issue. the pravastatin treated group was stratified into quartiles of LDL-C reduction. In contrast to what was observed in the placebo group, in which a positive mean IMT progression rate was observed, independent of the extent of LDL-C reduction, no IMT progressionwas observed in any subgroup treated with pravastatin. No significant difference was found among quartiles and no trend could be identified. In conclusion, the effect of pravastatin treatment on carotid IMT progression rate is beneficial; however the CAIUS study demonstrated that lowering LDL-C by itself, does not explain the variability of beneficial changes in IMT.

SummaryWe studied the effects of fluvastatin and bezafibrate in monotherapy and in combination on plasma fibrinogen, t-plasminogen activator inhibitor (PAI-1) and C reactive protein (CRP) in patients with coronary artery disease (CAD) and mixed hyperlipidaemiaIn this randomised, double blind, multicentre trial 333 patients with stable angina pectoris or previous myocardial infarction or coronary revascularisation and mixed hyperlipidaemia (LDL-cholesterol 135-250 mg/dl and triglycerides (TG) 180-400 mg/dl) were randomised to fluvastatin 40 mg, bezafibrate 400 mg, fluvastatin 20 mg + bezafibrate 400 mg or fluvastatin 40 mg + bezafibrate 400 mg treatments for 24 weeks.Plasma fibrinogen significantly decreased after treatment with the combinations fluvastatin+bezafibrate (−14 and −16%) and with bezafibrate monotherapy (−9%). No significant reduction was observed after fluvastatin monotherapy (−4%). No significant changes were observed in PAI-1 and CRP plasma levels. Combination therapy significantly decreased both LDL-C and TG, and significantly increased HDL-C.The combined effects on fibrinogen and plasma lipids achieved by fluvastatin and bezafibrate combination treatment might be more useful than the simple reduction of cholesterol in preventing ischaemic cardiovascular disease.

Worldwide, cardiovascular diseases are now the most common cause of death and a substantial source of chronic disability and health costs. In the light of new data from clinical trials and a fuller understanding of risk factors, the International Task Force for the Prevention of Coronary Heart Disease, in cooperation with the International Atherosclerosis Society, prepared a revised and comprehensive statement regarding the scientific basis of the primary and secondary prevention of cardiovascular disease. The following is a short account of the clinical implications of this statement. It is best read in conjunction with the full document, which can be found at http://www.chd-taskforce.com Assessing a patient’s overall or global risk of cardiovascular disease is the first step in preventive care, for it enables the physician to identify and provide the appropriate level of treatment for risk factors. Much can be learned from measuring even a few risk factors. The fuller the knowledge of the patient’s risk status, the sounder the treatment decisions. Initial costs may be offset by long-term rational treatment. The goals of treatment and, hence, the extent of dietary change and the need for (and choice and dosage of) drug treatment all depend on global risk assessment. Two methods for determining global risk follow. Note and tabulate the following risk factors, including those laboratory investigations that are available. ### Age, Sex, and Menopausal Status Risk increases progressively with adult age, and coronary heart disease (CHD) is most common after the age of 60 years. In premenopausal women, CHD is rare (except in those who use oral contraceptives and smoke). After menopause, risk increases steeply, approaching that of men after the age of 70 years. ### History of Cardiovascular Disease The risk of further CHD events or stroke is much higher in persons with a history of myocardial infarction, angina, stroke, or intermittent claudication and in those who have ischemic …

Objective To examine whether hypertension predicts the incidence of kidney stone disease. Design Prospective cohort study (the Olivetti Prospective Heart Study). Setting The Olivetti factory in Southern Italy. Subjects Five hundred and three male workers, aged 21 - 68 years, with no evidence of kidney stone disease at baseline. Follow-up 8 years. Main outcome measures Anthropometry, blood pressure, biochemistry and history of kidney stone disease were evaluated at the baseline examination in 1987. Occurrence of kidney stone disease was evaluated again in 1994-1995. Hypertension was defined as systolic blood pressure > or = 160 or diastolic blood pressure, > or = 95 mmHg or both, or being on drug therapy for hypertension. Occurrence of kidney stone disease was defined as radiological or echographic evidence of calculi or documented passage of one or more stones. Results At baseline, 114/503 men (22.7%) had hypertension and 32 were on drug treatment. After 8 years, 52 (10.3%) incident cases of kidney stone disease were detected. The majority (n = 45) had a documented passage of one or more stones. The incidence of kidney stone disease was higher in hypertensive than in normotensive men (19/114 (16.7%) versus 33/389 (8.5%); P = 0.011). Hypertensive men had a greater risk of developing kidney stones than normotensive ones (RR 1.96; 95% confidence interval 1.16-3.32). The risk was unaffected by the exclusion of treated hypertensives (2.01; 1.13-3.59) and after adjustment for age (1.89; 1.12-3.18), body weight (1.78; 1.05-3.00) or height (2.00; 1.19-3.38). Conclusions Hypertension in middle-aged men is a significant predictor of kidney stone disease rather than a consequence of renal damage caused by the kidney stones.

Arterial hypertension is frequently associated with metabolic abnormalities. An abnormal activity of the erythrocyte sodium/lithium countertransport (Na/Li CT), an ion transport system under strong genetic control, is also found in people with hypertension and concomitant metabolic abnormalities. However, little information exists with regard to these clinical associations in different racial groups. The aim of this international collaborative study was to investigate Na/Li CT and the metabolic correlates of hypertension in two comparable samples of normotensive and hypertensive populations in the cities of Naples, Italy, and Shanghai, China, using identical, carefully standardized techniques. Blood pressure, anthropometric and metabolic variables, Na/Li CT, and 24-h urinary Na and K excretion were measured in untreated essential hypertensive (HPT) and normotensive (NT) individuals selected by age (35–60 years), body mass index (BMI; These results indicate that essential hypertension is associated with a higher prevalence of obesity, impaired glucose tolerance, and hyperinsulinemia in Naples than in Shanghai; and Na/Li CT is linked to both high blood pressure and metabolic abnormalities in the Italian sample, whereas it is an isolated marker of hypertension in the Chinese sample.

n-3 Fatty acids in the form of ethyl esters (EE) allow lower daily doses and improved compliance. Administration of n-3 fatty acids to patients with glucose intolerance has led to controversial findings, some studies indicating worsening of the disorder, others no effect, or an improvement. A total of 935 patients with hypertriglyceridemia, associated with additional cardiovascular risk factors, i.e. glucose intolerance, NIDDM and/or arterial hypertension were entered a double blind (DB) protocol lasting 6 months with n-3 EE versus placebo, followed by a further 6 months of open study (n = 868) on 2 g a day of n-3 EE. At the end of the DB period, triglyceridemia in the total group was reduced significantly more by n-3 EE, without alterations in glycemic parameters. In the 6 months open follow up, patients on n-3 EE with type IIB hyperlipoproteinemia showed a significant reduction of total cholesterol, both in cases with (-4.15% vs. the 6 month levels) and without NIDDM (-3.8%). HDL-cholesterol had an overall mean rise of 7.4%, maximal in type IV patients with (+9.1%) and without (+10.1%) NIDDM. No alterations in glycemic parameters were detected in treated patients. Administration of n-3 EE to patients with hypertriglyceridemia associated with NIDDM or impaired glucose tolerance appears safe and effective.

Primary and secondary prevention trials in individuals with high plasma cholesterol levels have proven that cholesterol-lowering drug treatment significantly reduces the risk of coronary heart disease (CHD) morbidity and mortality, and prolongs life. The degree of clinical benefit derived from such treatment appears to be proportional to the percentage reduction in plasma cholesterol. Regression and reduced progression of atherosclerosis may partially account for the clinical gains derived from lipid-lowering drug therapy; however, other direct mechanisms may be operative, including reduced atherogenicity of macrophages, improved vascular vasodilation, and reduced thrombogenesis. Specific treatment is determined on the basis of LDL cholesterol levels and overall global risk for CHD, that is, the presence of CHD and/or other CHD risk factors. Angiographic and clinical data support intensive lipid-lowering therapy in all hypercholesterolemic patients with CHD and those with high CHD risk, particularly those with ultrasonographic evidence (but no symptoms) or clinical signs of extracoronary atherosclerosis. Selection criteria for monotherapy include LDL-cholesterol lowering efficacy, CHD morbidity/mortality and overall survival benefits, no adverse effect on concomitant metabolic diseases (e.g., diabetes), tolerability, long-term safety, simple dose schedule, and cost effectiveness. However, in refractory hypercholesterolemia combination therapy may be required. Secondary prevention and primary prevention in individuals at high CHD risk are cost effective.

Background and objectives: Prospective investigations on cardiovascular risk factors in populations provide a unique opportunity to dissect time-dependent quantitative complex traits, such as arterial blood pressure (BP), into their polygenic and environmental components. BP heritability analyses were carried out on 2620 patients belonging to 711 nuclear pedigrees that could be followed up throughout 25 years in the Gubbio Population Study. Methods: Each patient's BP serial measurements were summarized into individual intercepts (expected values at baseline) and slopes (time-related changes), which were predicted through latent curve models. These models considered either age in years or waves (times from the first survey) as time axis and were linked at a family level in the heritability analyses using additive polygenic-common environment-unique error models adjusted for sex, age and clinical variables. Results: The additive genetic effect explained 32-49% of the variance of SBP values at baseline, the wave-dependent analysis with nuclear pedigrees and the sibs-household matrix accounting for higher heritability values. Heritability of DBP baseline value was lower than that of SBP in analyses by age (5-15%), but fell in the same heritability range as SBP on the analysis by waves (36-37%). The BP variation over time (slope) explained by an additive genetic effect ranged from 33 to 43% and from 24 to 25% for SBP and DBP, respectively, in the analysis by age. Shared environment also exerted a significant influence, but explained a smaller portion of the variances (4-17%) for both traits. Conclusion: Longitudinal data from the Gubbio population show strong to moderate genetic influences on SBP and DBP baseline values and changes over time with a smaller, though significant, effect of environment.

Serum uric acid (SUA) and estimated glomerular filtration rate (eGFR) were separately assessed as risk factors for incident coronary hard (CHDH), cardiovascular disease (CVDH) or all-cause (ALL) deaths but never concomitantly in a residential cohort.Men and women aged 35-74years, totaling 2888 subjects were followed 13.5-19.5years for incident CVDH, CHDH and ALL deaths. Systematic comparisons among different end-points were based on: age, gender, systolic blood pressure (SBP), total and HDL cholesterol, cigarette consumption, body mass index, blood glucose, SUA, eGFR from the Chronic Kidney Disease Prognosis Consortium (eGFR_CKDEPI) and (eGFR_CKDEPI)(2).Significant (p0.00001) differences in SUA quintiles were seen for SBP, total and HDL cholesterol, body mass index and eGFR_CKDEPI whereas cigarettes and blood glucose were not statistically different. There were increasingly larger proportions of all events in SUA quintiles (0.05p0.0001). Among 4 major continuous variables, SUA was largely accurate (ROC0.610) to predict all end-points whereas eGFR_CKDEPI was the worse univariate predictor. Multivariately, age, gender, SBP and cigarettes were significant predictors for all end-points. Total cholesterol was a significant predictor only for CHDH events. Blood glucose and SUA were contributors for CVDH events (RR, for 1mg/dl of SUA, 1.09, 95%CI 1.01-1.17), CVD deaths (RR 1.11, 95%CI 1.03-1.20) and ALL deaths (RR 1.08, 95%CI 1.03-1.14) whereas (eGFR_CKDEPI)(2) was for ALL deaths only (RR 1.02, 95%CI 1.00-1.04).SUA is a predictor of long-term incidence of cardiovascular events and deaths and all-cause mortality and should be considered for risk predictive purposes and instruments whereas eGFR_CKDEPI only predicts all-cause mortality by a U-shaped relation.

Objective To evaluate insulin sensitivity of essential hypertensive patients with different salt sensitivities of blood pressure in the absence of confounding factors such as obesity, glucose intolerance and the inclusion both of normotensive and of hypertensive subjects that have affected most previous studies. Patients Ninety-nine patients with untreated mild or moderate essential hypertension, World Health Organization class I-II, participated in the study. Methods Salt sensitivity was estimated using the Weinberger protocol with minor modifications and the patients were classified into tertiles of salt sensitivity. Results Patients with high NaCI sensitivities were slightly older and had somewhat higher blood pressures than did subjects with low salt sensitivities. Plasma renin activity significantly decreased with increasing salt sensitivity. There were no differences among the three groups in terms of body mass index, fasting blood glucose and insulin plasma levels. There were no differences among the groups in the integrated glucose and insulin response to a standard oral-glucose tolerance test However, there was a significant difference in insulin sensitivity between two subgroups of the upper and lower tertile of salt sensitivity, the salt-sensitive hypertensives having a markedly lower utilization of glucose than did the salt-resistant ones, with a minor overlap (5.4 ± 0.6 versus 7.4 ± 0.3 mg/kg per min, P< 0.01). Conclusions This study showed that essential hypertensive patients with high NaCI sensitivities were relatively insulin resistant compared with those with low NaCI sensitivities, independently of confounding factors such as age, obesity and glucose intolerance. Insulin resistance was not associated with overt hyperinsulinaemia among these patients.

The Seven Countries Study showed that fatal coronary heart disease (CHD) with only chronic heart failure, arrhythmia or blocks (atypical CHD, A-CHD) may represent a distinct disease as compared to fatal CHD cases with angina pectoris, acute myocardial infarction (AMI) or sudden death (typical CHD, T-CHD). We aimed at validating this, using identical diagnostic criteria, in a separate residential cohort first examined in 1983-85 in Gubbio, central Italy.Forced Cox's models were run to assess 9 classic risk factors and their 20-year predictivity of A-CHD versus T-CHD, in the entire cohort or separately for men and women.There were 3229 subjects aged 30-79 years. Entry mean age was slightly higher in women than men although age at death was lower in men than in women for both T-CHD (71.99 ± 11.38 versus 81.20 ± 9.35 years, p0.0001) and A-CHD (80.22 ± 9.44 versus 84.98 ± 8.13 years, p0.0001). T-CHDs were predicted by male gender, age, continued smoke, systolic blood pressure (SBP), blood glucose, total and HDL-cholesterol (protective). A-CHDs were predicted by age, continued smoke, SBP, body mass index and blood glucose but neither total nor HDL-cholesterol or gender was significant. In the entire cohort and in men there were predictive differences of T-CHD versus A-CHD fatalities only in relation to age (p0.01), SBP (p0.05) and total cholesterol (p0.01).As age, SBP and total cholesterol had a different predictive role of T-CHD versus A-CHD fatalities also in the Gubbio cohort, the possibility is reinforced that a different etiology exists between these entities.

The Gubbio Study is a prospective epidemiological study on the population residing in the city of Gubbio, Italy. Original objectives of the Study were the control of hypertension and the role of cellular electrolyte handling in hypertension. Other objectives were added during the 30-year activity of the Study. The original target cohort consists of individuals with age ≥ 5 years residing within the medieval walls of the city. To complete family genealogies, individuals residing outside the walls were also included. Three active screenings (exam) were conducted. A total of 5,376 individuals (response rate = 92%) participated in exam 1 which was performed in 1983-86. Follow-up exams were performed in 1989-92 and 2001-2007. Data categories included demographics, personal and family medical history, lifestyle habits, education, type of work, anthropometry, blood pressure, pulse rate, blood biochemistry, urine biochemistry, and special investigations on cellular electrolyte handling. Electrocardiogram, echocardiogram, 24-hour ambulatory blood pressure, and uroflowmetry were performed in selected subgroups defined by age and/or sex. Data about hospitalizations, mortality, and causes of death were collected starting from completion of exam 1. The Study shared the data with other studies. Data are not an open access. Please contact mlaurenzi@comcast.net for information about data sharing.

The Carotid Atherosclerosis Italian Ultrasound Study (CAIUS) was performed to test the effects of lipid lowering on the progression of carotid intima-media thickness (IMT) in 305 asymptomatic patients from a Mediterranean country.Eligibility included hypercholesterolemia (baseline means: low-density lipoprotein [LDL] = 4.68 mmol/L, high-density lipoprotein [HDL] = 1.37 mmol/L), and at least one 1.3IMT3.5 mm in the carotid arteries. Patients (mean age 55 years, 53% male) were assigned to pravastatin (40 mg/day, n = 151) or placebo (n not equal to 154). Ultrasound imaging was used to quantify IMT at baseline, and semiannually thereafter for up to 3 years. The mean of the 12 maximum IMTs (MMaxIMT), was calculated for each patient visit, and used to determine each patient's longitudinal progression slope. The intention-to-treat group difference in the MMaxIMT progression was chosen a priori as the primary end point.Five serious cardiovascular events (1 fatal myocardial infarction), and 7 drop-outs for cancer were registered. In the pravastatin group, LDL decreased -0.22 after 3 months versus -0.01 in the placebo group, and remained substantially unchanged afterward (-0.23 versus +0.01 at 36 months, respectively). Progression of the MMaxIMT was 0.009 +/- 0.0027 versus -0.0043 +/- 0.0028 mm/year (mean +/- SE, P0.0007) in the placebo and pravastatin groups, respectively. IMT progression slopes diverged after 6 months of treatment.Pravastatin stops the progression of carotid IMT in asymptomatic, moderately hypercholesterolemic men and women. This finding extends the beneficial effects of cholesterol lowering to the primary prevention of atherosclerosis in a population with relatively low cardiovascular event rates, and suggests that this benefit is mediated by specific morphological effects on early stages of plaque development.

OBJECTIVE The aim of this study was to evaluate the long-term (6-month) effects of moderate fish oil supplementation on insulin sensitivity and plasma lipoproteins in NIDDM patients with hypertriglyceridemia. RESEARCH DESIGN AND METHODS The study has been performed according to a randomized double-blind placebo-controlled design with a parallel group sequence. After a washout period of 4 weeks and a run-in period of 3 weeks, 16 NIDDM patients with hypertriglyceridemia (triglyceride [TG], 2.25–5.65 mmol/l) were randomly assigned to either fish oil (2.7 g/day eicosapentaenoic plus docosahexaenoic acid for 2 months, then 1.7 g/day for 4 more months) (n = 8) or placebo (n = 8). Diet and hypoglycemic drugs remained unchanged throughout the whole experiment. At baseline and after 6 months, insulin sensitivity was measured by euglycemic hyperinsulinemic clamp (insulin infused, 2.0 mIU · kg−1 body wt · min−1). At the same time, blood glucose control, fasting and postprandial serum insulin and nonesterified fatty acid (NEFA) concentrations, and fasting plasma lipoprotein concentrations were evaluated. RESULTS In the group treated with ffish oil compared with the baseline, there was: 1) a significant reduction in both plasma TG (2.92 ± 0.23 vs. 3.85 ± 0.32 [mean ± SE] mmol/l, P < 0.001) and VLDL-TG (2.35 ± 0.24 vs. 4.25 ± 0.66 mmol/l, P < 0.01), without significant changes in blood glucose control; 2) a significant reduction in fasting NEFA concentrations (572 ± 100 vs. 825 ± 131 μmol/l, P < 0.01); and 3) a significant enrichment in long-chain ω-3 fatty acids of erythrocyte membrane phospholipids. In the placebo group, there were no changes in any of the variables analyzed. The insulin-mediated glucose uptake was unchanged in both groups (fish oil, 4.04 ± 0.82 mg · kg−1 · min−1 at baseline and 3.96 ± 0.50 mg · kg−1 · min−1 at 6 months; placebo, 3.51 ± 0.62 mg · kg−1 · min−1 at baseline and 4.09 ± 0.49 mg · kg−1 · min−1 at 6 months). CONCLUSIONS In NIDDM patients with hypertriglyceridemia, moderate amounts of fish oil induce a long-term significant reduction in plasma triglycerides, VLDL triglycerides, and NEFA and a significant enrichment in the erythrocyte phospholipid content of long-chain ω-3 fatty acids, without deteriorating blood glucose control. However, this amount of ω-3 fatty acids was unable to improve insulin sensitivity in this group of patients.

Purpose: We retrospectively assessed the number and histology of testicular lesions diagnosed clinically and by ultrasonography in a population of infertile men. Materials and Methods: From October 2000 to January 2003, 560 infertile men underwent physical examination, hormonal assessment (follicle-stimulating hormone, luteinizing hormone, testosterone) and scrotal ultrasonography. Eight men were diagnosed with focal testicular ultrasonographic lesions. In 4 cases there was a palpable lesion and in the other 4 cases the lesion was not palpable, diagnosed by ultrasonography (1 was cryptorchid). Only cases of lesions with clear-cut ultrasonographic edges and no history of recent genital infections were considered for explorative surgery through the groin. Microcalcifications were reported if present. The testicle was only preserved when frozen section examination revealed a benign lesion and the margins were negative. Results: Gynecomastia was not present in any patient. No microcalcifications were observed. Follicle-stimulating hormone was high in all patients (range 19.8 to 66.0 mUI/ml, mean 34.4). Luteinizing hormone levels were variable (range 1.32 to 28 mUI/ml, mean 12.3). Testosterone was normal in all cases (range 2.82 to 6.25 ng/ml, mean 4.2). Ultrasonographic features of the lesions were hypoechoic area (6 patients) and mixed hyper-hypoechoic area (2 patients). Histological outcomes of Leydig cell tumor (in 3 patients), focal Leydig cell hyperplasia (1 patient), fibrosis (1 patient), diffuse Leydig cell hyperplasia (1 patient), classic seminoma (1 patient) and embryonal carcinoma (in 1 patient) were observed. Conclusions: Of 560 infertile patients 8 (1.4%) showed focal testicular lesions, 2 (0.4%) were diagnosed with germ cell tumors and 3 (0.5%) with interstitial cell neoplasms. The malignant tumors were both palpable and in 2 of 3 cases Leydig cell tumors were diagnosed only with ultrasonography.

An association has been demonstrated between the extent of atherosclerotic involvement and vasodilatory capacity in coronary and cerebral circulation. Impairment of endothelium-dependent relaxation is inversely related to HDL concentrations in plasma. Angiographic studies in humans have shown improved vasodilation capacity of the coronary arteries after lipid-lowering treatment.

objectives: Previous studies concerning ultrasound evaluation of the seminal vesicles (SV) were performed on a limited series of subjects, and considered few parameters, often only before ejaculation and without assessing the patients’ sexual abstinence. The aim of this study was to evaluate the volume and the emptying characteristics of the SV and their possible correlations with scrotal and transrectal ultrasound features. methods: The SV of 368 men seeking medical care for couple infertility were evaluated by ultrasound. All patients underwent, during the same ultrasound session, scrotal and transrectal evaluation, before and after ejaculation, and the ejaculate was subjected to semen analysis. A new parameter, SV ejection fraction, calculated as: [(SV volume before ejaculation 2 SV volume after ejaculation)/SV volume before ejaculation] × 100, was evaluated. results: After adjusting for sexual abstinence and age, both pre-ejaculatory SV volume and SV ejection fraction were positively associated with ejaculate volume. As assessed by receiver operating characteristic curve, a cut-off for SV ejection fraction of 21.6% discriminates subjects with normal ejaculate volume (≥1.5 ml) and pH (≥7.2 ml) with both sensitivity and specificity equal to 75%. Subjects with SV ejection fraction of ,21.6% more often had a higher post-ejaculatory SV volume and ejaculatory duct abnormalities. Furthermore, a higher post-ejaculatory SV volume was associated with a higher prostate volume and SV abnormalities. Higher epididymal and deferential diameters were also detected in subjects with a higher post-ejaculatory SV volume or reduced SV ejection fraction. No association between SV and testis ultrasound features or sperm parameters was observed. Associations with SV ejection fraction were confirmed in nested 1:1 case– control analysis. conclusions: The SV contribute significantly to the ejaculate volume. A new parameter, SV ejection fraction, could be useful in assessing SV emptying. A SV ejection fraction of ,21.6% was associated with prostate –vesicular and epididymal ultrasound abnormalities.