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ObjectiveNon-coeliac gluten sensitivity (NCGS) is characterised by intestinal and extraintestinal symptoms related to the ingestion of gluten-containing foods, in the absence of coeliac disease (CD) and wheat allergy. No biomarkers are available to diagnose NCGS and the gold standard double-blind placebo-controlled gluten challenge is clinically impractical. The aim of our work was to investigate the role of serum zonulin as a diagnostic biomarker of NCGS and to develop a diagnostic algorithm.DesignIn a multicentre study, we enrolled 86 patients with either self-reported or double-blind confirmed NCGS, 59 patients with diarrhoea-predominant IBS (IBS-D), 15 patients with CD and 25 asymptomatic controls (AC). Zonulin serum levels were assessed and the associated diagnostic power calculated. Clinical and symptomatic data were recorded. The effect of diet on zonulin levels was evaluated in a subgroup of patients with NCGS.ResultsCompared with ACs, the NCGS, irrespective of modality of diagnosis, and patients with CD had significantly increased levels of zonulin, as did both NCGS and patients with CD compared with participants with IBS-D. Self-reported NCGS showed increased zonulin levels compared with double-blind confirmed and not-confirmed NCGS. Six-month wheat avoidance significantly reduced zonulin levels only in HLA-DQ2/8-positive participants with NCGS. The diagnostic accuracy of zonulin levels in distinguishing NCGS from IBS-D was 81%. After exclusion of CD, a diagnostic algorithm combining zonulin levels, symptoms and gender improved the accuracy to 89%.ConclusionZonulin can be considered a diagnostic biomarker in NCGS and combined with demographic and clinical data differentiates NCGS from IBS-D with high accuracy. Wheat withdrawal was associated with a reduction in zonulin levels only in NCGS carrying HLA genotype.

Hyperandrogenic disorders have been associated with psychological distress, reduced quality of life, anxiety and depression. The hypothalamic–pituitary–adrenal (HPA) axis plays a pivotal role in the adaptive response to stressor events. Salivary cortisol (SalF) and cortisone (SalE) testing have been proven to be useful in the evaluation of HPA-axis activity. This study investigated whether SalF and SalE responses to two putative stressor levels differed between the hyperandrogenic states in late adolescent and young women, thus measuring the HPA-axis adaptive response to acute stress events. We selected 161 drug-free females aged 16–19 years from a large population previously enrolled in a cross-sectional epidemiological study. Saliva was collected in the morning before and after two putative stressor events consisting in a self-filled questionnaire (weaker stressor) and in a structured interview plus physical examination by an endocrinologist (stronger stressor). SalF and SalE, as well as blood steroids, were assessed by liquid chromatography–tandem mass spectrometry. Subjects were subdivided into different groups according to the presence of: isolated menstrual irregularities (MI, oligo-amenorrhea; n = 22), isolated hirsutism (HIR, modified Ferriman–Gallwey score ≥ 8; n = 26), isolated hyperandrogenaemia (HT, testosterone >0.438 ng/mL; n = 14), and polycystic ovary syndrome (PCOS, MI with HIR and/or HT, n = 16). The remaining 83 apparently healthy subjects were used as controls. SalF and SalE significantly decreased after the weaker stressor, following the physiologic diurnal loss, in all the groups except for isolated HIR, where they remained unchanged (P = 0.091 and P = 0.118, respectively). In contrast, SalF and SalE remained unchanged after the stronger stressor in isolated MI, isolated HT and controls, whereas SalF increased significantly in isolated HIR (P = 0.011), and SalE increased significantly both in isolated HIR (P = 0.005) and in PCOS (P = 0.011) groups. SalF percentage variation in response to the stronger stressor was positively associated with systolic blood pressure in PCOS (P = 0.018), and both SalF and SalE percentage variations were positively associated with diastolic blood pressure in the isolated HIR group (P = 0.010 and P = 0.006, respectively). In addition, in the isolated HIR group, the SalF percentage variation was negatively associated with HDL cholesterol levels (P = 0.005). Finally, SalF and SalE percentage variations were positively associated with circulating androstenedione (P = 0.031 and P = 0.011, respectively) and DHEA (P = 0.020 and P = 0.003, respectively) in the isolated HIR group. In conclusion, this study demonstrates that hirsute and PCOS adolescent and young women are characterized by HPA-axis overactivity in response to stressful stimuli, as detectable by salivary glucocorticoid measurements. These data also indicate that the higher the HPA-axis activity, the higher the adrenal androgen output and the worse the metabolic profile.

Background Pathogenesis of acute diverticulitis and diverticular bleeding remains poorly defined, and few data compare directly risk factors for these complications. Aims to assess differences in clinical features, lifestyles factors and concurrent drug use in patients with acute diverticulitis and those with diverticular bleeding. Methods Data were obtained from the REMAD Registry, an ongoing 5-year prospective, observational, multicenter, cohort study conducted on 1,217 patients. Patient- and clinical- related factors were compared among patients with uncomplicated diverticular disease, patients with previous acute diverticulitis, and patients with previous diverticular bleeding. Results Age was significantly lower (OR 0.48, 95% CI: 0.34–0.67) and family history of diverticular disease was significantly higher (OR 1.60, 95% CI: 1.11–2.31) in patients with previous diverticulitis than in patients with uncomplicated diverticular disease, respectively. Chronic obstructive pulmonary disease was significantly higher in patients with previous diverticular bleeding as compared with both uncomplicated diverticular disease (OR 8.37, 95% CI: 2.60–27.0) and diverticulitis (OR 4.23, 95% CI: 1.11–16.1). Conclusion This ancillary study from a nationwide Registry showed that some distinctive features identify patients with acute diverticulitis and diverticular bleeding. These information might improve the assessment of risk factors for diverticular complications.

PURPOSE: The assessment of liver fibrosis is essential in the management of patients with chronic liver diseases. Liver biopsy is considered the gold standard procedure for this purpose, though the recent development of new elastosonographic techniques to measure liver stiffness (LS) noninvasively is promising. Point quantification elastography (PQE) showed good results but less is known about the level of skill needed to obtain reliable results. The aim of the study was to evaluate the reproducibility of PQE in assessing LS in healthy subjects comparing three operators with different expertise. METHODS: Between December 2012 and April 2013, 50 consecutive healthy volunteers (18 males, 32 females), median age 30 years (range 25–66) and BMI 22.4 (range 16.7–33.6) were submitted to PQE (iU22 Philips, Bothell, WA, USA) by three operators: two US and elastography providers (one expert and one with intermediate skill) and a skilled transient elastography (Fibroscan) operator with no expertise in US. Intra- and inter-observer agreements were assessed by intraclass correlation coefficient (ICC). RESULTS: PQE measurement was obtained in all subjects by all evaluators. No significant differences of mean liver stiffness were found among operators (P = 0.980). Intra-observer agreement was excellent 0.918 (0.941 for expert, 0.917 for intermediate and 0.888 for novice). The ICC of the inter-observer agreement among the three ratters was excellent (0.882) and was higher in normal than overweight patients (0.923 vs. 0.603; P = 0.011). CONCLUSION: PQE is a reliable and reproducible non-invasive method for the assessment of LE, and can be performed also by a non-experienced operator.

The distinction between active inflammation and fibrosis of the bowel wall is essential for therapeutic decisions in stricturing Crohn's disease. We aimed to assess whether real-time elastography (RTE) with strain ratio measurement could be useful in differentiating fibrotic from inflamed bowel strictures and to evaluate the possible relationship between US techniques and the histology of the stenotic bowel wall.Bowel ultrasonography (including RTE, color-Doppler and CEUS examination) was prospectively evaluated in 26 patients with symptomatic stricturing Crohn's disease, before surgery. RTE was adopted to evaluate bowel stiffness: five loops of 20 RTE frames were recorded for each stenotic segment and the mean strain ratio (MSR) was obtained. Histology scoring systems both for inflammation and fibrosis were established for surgical specimens.No significant correlation was found between MSR and fibrosis score (MSR detection was not able to distinguish fibrotic from inflammatory tissue in our selected population. This result could be influenced by the presence of the superimposed inflammation. Larger cohort of patients, further analysis with shear wave elastography, and validated histopathology classification systems for fibrosis and inflammation are necessary to assess if intestinal fibrosis could be reliably detected on the basis of bowel elastic properties.la distinzione tra infiammazione attiva e fibrosi nella parete intestinale è essenziale nel proceso decisionale della terapia nella malattia di Crohn stenosante. Lo scopo del nostro studio era di stabilire se l’elastografia real-time (RTE) con la misurazione dello strain ratio potesse essere utile nel differenziare il tessuto fibrotico da quello infiammatorio nella parete intestinale stenotica, e di valutare la presenza di correlazioni tra le tecniche ecografiche di studio delle anse intestinali e le caratteristiche istologiche dei segmenti analizzati.Lo studio ecografico delle anse intestinali che comprendeva anche RTE, valutazione color-Doppler e CEUS, è stato eseguito in maniera prospettica in 26 pazienti con malattia di Crohn stenosante sintomatica, prima dell’ intervento chirurgico resettivo. La RTE è stata utilizzata per valutare la rigidità della parete intestinale: 5 filmati di 20 frames di elastografia sono stati registrati per ogni segmento stenotico, per ogni frame è stato calcolato lo strain ratio e quindi ne è stata ottenuta la media (MSR). E’ stato poi stabilito uno score istologico per l’ infiammazione e la fibrosi per i pezzi operatori analizzati.non è stata rilevata alcuna correlazione significativa tra MSR e score istologico della fibrosi (P = 0877). Il Color-doppler correlava significativamente con lo spessore di parete e l’ispessimento della sottomucosa (P = 0006 e P = 0032, rispettivamente). Non è stata trovata una correlazione significativa tra il numero di vasi rilevato sul pezzo istologico e gli score color-Doppler e CEUS (P = 0170 e P = 0302, rispettivamente).il calcolo del MSR non si è rivelato un parametro efficace nel distinguere tra tessuto fibrotico ed infiammatorio nella nostra popolazione. Questo risultato è influenzato da vari fattori, tra cui probabilmente la compresenza di infiammazione. Coorti di pazienti più ampie, ulteriori analisi con l’ausilio eventualmente dell’ elastografia shear-wave, e sistemi di classificazione istopatologici validati sia per la fibrosi che per l’infiammazione, risultano necessari per stabilire se la fibrosi intestinale possa essere rilevata in maniera affidabile sulla base delle proprietà elastiche della parete intestinale.

Objective The endocannabinoid system hypertonicity features obesity. Excess circulating 2-arachidonoylglycerol was variously associated with obesity-related metabolic impairment; however, unstandardized experimental and analytical settings have clouded its usefulness as a dysmetabolism biomarker. We aimed at assessing the influence of body mass index (BMI), menopause in women, and aging in men on 2-arachidonoylglycerol relationship with metabolic parameters. Methods Adult, unmedicated women (premenopausal (preMW): n = 103; menopausal (MW): n = 81) and men (n = 144) were stratified in normal weight (NW; BMI: 18.5–24.9 kg/m2), overweight (OW; BMI: 25.0–29.9 kg/m2), and obese (OB; BMI ≥ 30.0 kg/m2) classes. Anthropometric and metabolic parameters were determined. Plasma 2-arachidonoylglycerol was measured by a validated liquid chromatography-mass spectrometry assay. Results 2-arachidonoylglycerol level was raised by menopause (P, Highlights • Plasma 2AG is a biomarker of dysmetabolism rather than obesity. • Menopause is a major determinant of plasma 2AG levels in females. • Increased plasma 2AG level features obese premenopausal females and obese males. • 2AG is a biomarker of dyslipidemia and insulin resistance in lean menopausal women. • 2AG is a biomarker of dyslipidemia and age-related insulin resistance in lean men.

Objective: This study was designed to assess the steroid profiling by liquid chromatography coupled with tandem mass spectrometry in PCOS women with different phenotypes. Design: Cross-sectional study. Setting: University hospital of Bologna, Italy. Patients and Methods: A total of 156 PCOS women and 141 controls comparable for age were investigated. All underwent a steroid profiling by liquid chromatography coupled with tandem mass spectrometry. Metabolic parameters were also investigated and hirsutism was measured by the modified Ferriman-Gallwey (mF-G) score. Results: Three distinct phenotypes were initially defined according to the combination of hirsutism (mF-G ≥ 8) and/or high testosterone (T) (HA), oligo-amenorrhea (OA), and polycystic ovarian morphology (PCOm); OA + PCOm (n = 43), HA + OA (n = 65), and HA + OA + PCOm (n = 45). T, androstenedione (A), and free androgen index (FAI) levels progressively increased in the 3 PCOS phenotypes with respect to the controls, with the highest values in the HA + OA + PCOm phenotype. The various combinations of hirsutism, high T, high A, and high FAI made it possible to categorize the 3 original phenotypes into 8 hyperandrogenic subgroups, characterized by divergent additional steroid profile and metabolic pattern. A total of 90% of patients with PCOS thus proved hyperandrogenic. Interestingly, half the PCOS women originally classified as having the OA-PCOm phenotype were categorized in a hyperandrogenic subgroup. No significant correlation was found between T, A, and the mF-G score. In contrast, significant correlation was found between A and both T and FAI. Conclusions: This study provides evidence that, by including a steroid profile in the definition of hyperandrogenemia, the majority of women with PCOS are hyperandrogenic, although a clinical and biochemical heterogeneity exists. In addition, these data demonstrate that hirsutism and high androgen levels cannot be used indifferently to define hyperandrogenism.

Objective N-acylethanolamines play different roles in energy balance; anandamide (AEA) stimulates energy intake and storage, N-palmitoylethanolamide (PEA) counters inflammation, and N-oleoylethanolamide (OEA) mediates anorectic signals and lipid oxidation. Inconsistencies in the association of plasma N-acylethanolamines with human obesity and cardiometabolic risk have emerged among previous studies, possibly caused by heterogeneous cohorts and designs, and by unstandardized N-acylethanolamine measurements. We aimed to characterize changes in the plasma profile, including N-acylethanolamine levels and ratios associated with obesity, menopause in women, and ageing in men, and to define the significance of such a profile as a biomarker for metabolic imbalance. Methods Adult, drug-free women (n = 103 premenopausal and n = 81 menopausal) and men (n = 144) were stratified according to the body mass index (BMI) into normal weight (NW; BMI: 18.5–24.9 kg/m2), overweight (OW; BMI: 25.0–29.9 kg/m2), and obese (OB; BMI ≥30.0 kg/m2). Anthropometric and metabolic parameters were determined. Validated blood processing and analytical procedures for N-acylethanolamine measurements were used. We investigated the effect of BMI and menopause in women, and BMI and age in men, as well as the BMI-independent influence of metabolic parameters on the N-acylethanolamine profile. Results BMI and waist circumference directly associated with AEA in women and men, and with PEA in premenopausal women and in men, while BMI directly associated with OEA in premenopausal women and in men. BMI, in both genders, and waist circumference, in women only, inversely associated with PEA/AEA and OEA/AEA. Menopause increased N-acylethanolamine levels, whereas ageing resulted in increasing OEA relative abundance in men. AEA and OEA abundances in premenopausal, and PEA and OEA abundances in lean menopausal women, were directly associated with hypertension. Conversely, PEA and OEA abundances lowered with hypertension in elderly men. Insulin resistance was associated with changes in N-acylethanolamine ratios specific for premenopausal (reduced PEA/AEA and OEA/AEA), menopausal (reduced OEA/AEA) women and men (reduced OEA/AEA and OEA/PEA). PEA and OEA levels increased with total cholesterol, and OEA abundance specifically increased with HDL-cholesterol. Elevated triglyceride levels were associated with increased N-acylethanolamine levels only in menopausal women. Conclusions Obesity-related N-acylethanolamine hypertone is characterized by imbalanced N-acylethanolamine ratios. The profile given by a combination of N-acylethanolamine absolute levels and ratios enables imbalances to be identified in relationship with different metabolic parameters, with specific relevance according to gender, menopause and age, representing a useful means for monitoring metabolic health. Finally, N-acylethanolamine system appears a promising target for intervention strategies., Highlights • Obesity is featured by plasma N-acylethanolamine excess and imbalanced ratios. • AEA excess is a biomarker of abdominal fat irrespectively of sex and menopause/age. • PEA and OEA protect from hypertension in gender and menopause/age specific fashion. • AEA excess in women and OEA deficiency in men are biomarkers of insulin resistance. • High AEA in men and low OEA in men and menopausal women reflect low HDL-cholesterol.

Objective: The revascularization of critical limb ischemia (CLI) in hemodialysis (HD) patients features poor results in terms of patient survival and limb salvage. Recent predictive models in CLI revascularization did not specifically address HD patients. The aim of this study was to define risk factors for clinical success (CS) after revascularization of CLI in HD patients and to transform findings in a prognostic score. Methods: A retrospective study was conducted of prospectively gathered data, including consecutive HD patients treated for CLI from January 2004 to December 2012. Patients' demographics, comorbidities, CLI stage (Rutherford classification), tissue loss (Texas University Wound classification [TUWC]), and type of revascularization were assessed. End points were CS after revascularization (amputation-free and reintervention-free survival) and a prognostic score for CS based on significant risk factors (multivariable analysis). Results: In the study period, 131 patients (mean age, 70.2 ± 9.9 years; male, 76.3%) with a total of 180 limbs were treated. Endovascular (52.8%), surgical (28.9%), or hybrid (10.6%) revascularization was performed in 163 (90.6%) limbs in 117 patients. The mean (± standard deviation) follow-up was 20.8 ± 21.1 months. Considering revascularized patients, CS was 47.9%, 30.8%, and 17.8% at 6, 12, and 24 months, respectively. On multivariable analysis, age (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.01-1.05; P =.005), coronary artery disease (CAD; HR, 1.55; 95% CI, 1.04-2.32; P =.032), and TUWC stage D (HR, 1.80; 95% CI, 1.22-2.67; P =.003) were independent negative factors. Type of revascularization had no influence on CS. The score for predicting CS was 0.026 × age (years) + 0.441 × CAD + 0.59 × TUWC stage D. CAD and TUWC stage D were 1 in the presence of disease and 0 in the absence of disease. The score has a significant discrimination power of 75.5% (P =.036), with a best cutoff value of 2.07. Patients with a CS score 2.07 would have a high risk. There were 31 (26.5%) cases of low-risk score and 86 (73.5%) cases of high-risk score. Cases with low-risk score had a CS at 1 year of 51.6% compared with 23.3% in cases with high-risk score. Conclusions: CS after revascularization in HD patients remains poor independent of the type of revascularization. A prognostic model based on age, history of CAD, and severity of CLI (TUWC stage D lesion) can estimate an individual's chances of CS and may help in the decision-making process.

OBJECTIVE: To explore the characteristics of diabetes mellitus in adults with Turner syndrome. DESIGN: Observational study consisting of a prospective phase after the access of adults with Turner syndrome to the Endocrinology Unit (median period of follow-up 15.6, interquartile range: 12.0-24.5 months) and a retrospective collection of data from the diagnosis of Turner syndrome until the time of access to the Endocrinology Unit. A total of 113 Italian Turner syndrome patients were included in the study. During the prospective phase of the study, each patient underwent physical examination, fasting blood sampling, and an oral glucose tolerance test on a yearly basis. Oral glucose tolerance test was used to perform the diagnosis of diabetes mellitus. RESULTS: Before access to the Endocrinology Unit, diabetes mellitus was diagnosed in two Turner syndrome patients. Another five cases of diabetes mellitus were diagnosed at the first access to the Endocrinology Unit, whereas seven new cases of diabetes mellitus were diagnosed during the prospective phase of the study. At the diagnosis of diabetes mellitus, only one patient had fasting glucose above 126 mg/dL, and only two had an HbA1c value >6.5% (48 mmol/mol). When compared to normo-glucose tolerant patients, the diabetic patients had a significantly lower insulin-to-glucose ratio at 30 and 60 min of the oral glucose tolerance test. In the regression analyses, only age was associated with the development of diabetes mellitus. CONCLUSIONS: This study confirms that diabetes mellitus is frequent in Turner syndrome and suggests that it is specific to the syndrome. In addition, this study demonstrates that oral glucose tolerance test is a more sensitive test than HbA1c for the diagnosis of diabetes mellitus in Turner syndrome.

Context: Low testosterone (T) levels are often found in obese men with impaired glucose tolerance (IGT) and overt type 2 diabetes (T2DM); however, the mechanisms underlying this condition and its correct therapy are still under debate. Objective: To evaluate the effectiveness of clomiphene citrate (CC) in increasing endogenous T levels in obese men with low serum T and with IGT or T2DM treated with metformin (MET). Design: Cross-over, randomized, double-blind, placebo-controlled study. Methods: 24 obese men, aged 47.3 ±. 6.3 (range 35–55 years), with low T level (≤3 ng/mL) and naïve diagnosis of IGT or T2DM were included. Subjects were randomized to CC 25 mg/day or placebo (Plac) with MET 2 g/day for 3 months. After a 6-week wash-out period, subjects were moved to the alternative arm for additional 3 months. Clinical evaluation and blood exams performed prior to and at the end of treatment. Results Of 24 randomized, 21 were evaluable, classified as IGT (n = 11) or T2DM (n = 10). Compared to baseline levels, T levels increased significantly after 3 months of CC treatment (3.03±0.80 to 5.99±1.67 ng/mL P

OBJECTIVE. The aim of this study is to determine whether any correlation between CT findings and functional parameters exists to predict subclinical glucocorticoid secretion. MATERIALS AND METHODS. This is a retrospective database study of 55 patients with incidentally discovered adenomas, investigated through CT with an adrenal protocol, assessing diameters and attenuation values on the unenhanced and contrast-enhanced phases. Patients underwent blood cortisol and corticotropin evaluation and overnight dexamethasone suppression test (DST), in accordance with clinical recommendations. Cortisol levels higher than 50 nmol/L after DST identified subclinical cortisol secretion. We identified 28 subjects with lipid-rich nonsecreting adenomas, nine with lipid-rich secreting adenomas, 11 with lipidpoor nonsecreting adenomas, and seven with lipid-poor secreting adenoma. RESULTS. Cortisol levels after DST were significantly and positively related to mass diameters. At univariate analysis, maximum and minimum diameters and attenuation in the delayed phase were significantly related to the presence of secreting or nonsecreting adenoma; at multivariate analysis, only the minimum diameter and the attenuation in the venous phase entered the stepwise logistic regression. Similarly, minimum diameter and attenuation in the venous phase emerged also at the multivariate stepwise regression between radiologic parameters and cortisol levels after DST. The formula of the radiologic score computed by using the coefficients of the multivariate regression was as follows: (0.1914 × minimum diameter) + (0.0308 × enhanced attenuation). The diagnostic accuracy of this discriminatory score in differentiating secreting from nonsecreting adenomas was 84.9%, the sensitivity was 81.3%, and the specificity was 87.2%. Adenomas with scores greater than 7.59 were considered as secreting adenomas, and adenomas with scores less than 7.36 were considered as nonsecreting adenomas. CONCLUSION. This study shows that imaging parameters can predict subclinical cortisol hypersecretion in patients with adrenal adenomas.

Obstructive sleep apnoea syndrome is the periodic reduction or cessation of airflow during sleep together with daytime sleepiness. Its diagnosis requires polysomnographic evidence of 5 or more episodes of apnoea or hypopnoea/hour of sleep (apnoea/hypopnoea index, AHI). Volumetric 3-dimensional computed tomographic (CT) reconstruction enables the accurate measurement of the volume of the airway. Nasal continuous positive airway pressure (CPAP) is the conventional non-surgical treatment for patients with severe disease. Operations on the soft tissues that are currently available give success rates of only 40%-60%. Maxillomandibular advancement is currently the most effective craniofacial surgical technique for the treatment of obstructive sleep apnoea in adults. However, the appropriate distance for advancement has not been established. Expansion of the air-flow column volume did not result in an additional reduction in AHI, which raises the important issue of how much the maxillomandibular complex should be advanced to obtain an adequate reduction in AHI while avoiding the risks of overexpansion or underexpansion. We have shown that there is a significant linear relation between increased absolute upper airway volume after advancement and improvement in the AHI (p=0.013). However, increases in upper airway volume of 70% or more achieved no further reduction in the AHI, which suggests that the clinical improvement in AHI reaches a plateau, and renders further expansion unnecessary. This gives a new perspective to treatment based on the prediction of changes in volume, so the amount of sagittal advancement can be tailored in each case, which replaces the current standard of 1cm.

The aim of this study was to evaluate the safety of pancreatic resections in patients 80 years or older.A systematic search of the literature was carried out that compared perioperative outcomes after pancreatic resection in patients 80 years or older with patients younger than 80 years. The primary end points were postoperative mortality and morbidity. The secondary end points were incidence of postoperative pancreatic fistula, delayed gastric emptying, bile leak, pneumonia, postoperative infection, cardiologic complications, reoperation, and length of hospital stay.Nine studies were found to be suitable for the meta-analysis. The postoperative mortality and morbidity were significantly higher in the group 80 years or older (P0.00001 and P = 0.003, respectively) except for patients in whom there were no differences in preoperative comorbidities (P = 0.56 and P = 0.36, respectively). Postoperative cardiac complications were significantly more frequent in patients 80 years or older (P0.0001), and the length of hospital stay was significantly longer in octogenarian patients (P = 0.008).Patients 80 years or older have an increased incidence of postoperative mortality, morbidity, and cardiac complications and a longer length of hospital stay than do younger patients. Thus, pancreatic resection can be recommended only in a selected group of patients 80 years or older.

OBJECTIVES: Contrast-enhanced ultrasound (CEUS) has been developed to better characterize the microvasculature of solid masses in several organs, including the pancreas. In this study, we assessed CEUS accuracy in differentiating exocrine from endocrine pancreatic tumors. METHODS: A total of 127 patients with single, undetermined pancreatic masses were prospectively examined with transabdominal ultrasound and CEUS, before surgical resection or percutaneous biopsy. RESULTS: Exocrine and endocrine pancreatic tumors showed different intralesional vascularization patterns: 98.9% (90/91) of exocrine tumors were hypoenhancing, whereas 95.8 % (23/24) of endocrine tumors had a hypervascular supply. A hypoenhancing pattern, indicative of ductal adenocarcinoma, had a significant (P < 0.001) diagnostic accuracy of 91.3% with a sensitivity of 96.8%, a specificity of 85.3%, a positive predictive value and a negative predictive value of 94.7% and 90.6%, respectively. The hyperenhancing pattern, indicative of endocrine tumors, had a significant (P = 0.031) diagnostic accuracy of 73.8% with a sensitivity of 83.3%, a specificity of 60.0%, a positive predictive value and negative predictive value of 83.3% and 60.0%, respectively. CONCLUSIONS: Contrast-enhanced ultrasound has a valuable diagnostic accuracy in differentiating exocrine from endocrine pancreatic tumors, which is a fundamental step to address appropriate histological evaluation, therapeutic approach, and follow-up.

Context An increase in enzyme lactate dehydrogenase (LDH) in serum is a negative prognostic factor for survival in cats affected by lymphoma. Measuring LDH at the time of diagnosis has been studied for differentiating neoplastic disease from non-neoplastic disease in dogs. Inflammatory bowel disease (IBD) and alimentary lymphoma are common diseases in cats. Objective The aim of this study was to determine whether elevation of total LDH occurred in cats with alimentary lymphoma and non-neoplastic gastrointestinal disease, such as IBD, and to evaluate whether this enzyme is useful in supporting the differential diagnosis of these specific diseases. Materials and Methods A prospective non-randomized controlled study was carried-out in a real world setting of three Italian private veterinary clinics. Seventy-one client-owned cats with a history of chronic gastrointestinal symptoms were enrolled; 33 cats were histologically diagnosed as having alimentary lymphoma and 38 cats as having IBD. Serum samples of total LDH analysis were measured. Results Gender (P = 0.016) and age (P = 0.046) were found to be significant factors influencing the differentiation of serum total LDH between cats with alimentary lymphoma and those with IBD. Despite low diagnostic accuracy in the overall population (63%), a cut-off value of serum total LDH ranging from 0.85- to 1.04-times the upper reference limit showed good capability (accuracy >80%) of differentiating these two conditions in neutered males and cats younger than 8 years of age (AUC: 0.805, 0.833; sensitivities: 76.9%, 83.3%; specificities: 80.0%, 76.5%; PPV: 76.9%, 55.6%; NPV: 80.0%, 92.9%; respectively). Conclusions Although our study showed that gender and age are significant factors in differentiating serum total LDH between cats with alimentary lymphoma and those with IBD, this test had poor diagnostic accuracy in differentiating between these two conditions in the overall population.

Background Subclinical inflammation and atrial stretch have been recognized as important contributors to atrial fibrillation (AF) onset and perpetuation. The aim of the study was to compare the predictive role of serum inflammatory markers (serum amyloid A [SAA], and C-reactive protein [CRP]) and N-terminal pro brain natriuretic peptide (NT-proBNP) an indice of atrial strain in relation to subacute arrhythmic recurrence rate in patients with persistent AF and normal left ventricular ejection fraction (LVEF). Methods We studied 57 patients with a mean LVEF of 58.7 ± 6%. NT-proBNP, SAA and CRP levels were determined few hours before electrical cardioversion and 3 weeks after cardioversion. Results Subacute AF recurrences were documented in 19 (33 %) patients. Whereas NT-proBNP levels did not predict arrhythmic outcome, higher SAA (> 6.16-6.19 mg/L) and CRP levels (> 2.99-3.10 mg/L) were significantly associated with AF recurrences (odds ratio [OR], 5.39; 95% confidence interval [CI], 1.59-18.26; P = 0.007 and OR, 14.93; 95% CI, 3.90-57.19; P P = 0.009) and high sensitivity CRP (OR, 42.03; 95% CI, 4.83-365.45; P = 0.001) through the multivariate logistic regression analysis show an independent role in predicting the AF recurrence with a sensitivity of 100% (38/38) and a specificity of 52.6% (10/19). Conclusions The present study demonstrates that in patients with persistent AF and preserved LVEF, SAA and CRP levels are independent predictors of AF subacute recurrence rate, whereas NT-proBNP, not associated with arrhythmic outcome, reflects the hemodynamic alterations secondary to arrhythmia presence. The simultaneous determination of SAA and high sensitivity CRP has a very high sensitivity (100%) in predicting the AF recurrence.

BackgroundSubclinical Cushing's syndrome (SCS) is defined as alterations in hypothalamic–pituitary–adrenal axis without classic signs/symptoms of glucocorticoid excess. Whether SCS leads to metabolic and cardiovascular diseases is still controversial.AimTo evaluate the prevalence of hypertension, type 2 diabetes (T2D), coronary heart disease (CHD), ischemic stroke, osteoporosis, and fractures, and their relationship to increasing patterns of subclinical hypercortisolism, in patients with nonsecreting adrenal adenomas (NSA) and SCS.MethodsUsing the 1 mg dexamethasone suppression test (DST), 348 patients were classified as follows: 203 were defined as NSA and 19 SCS, using the most stringent cutoff values (138 nmol/l respectively). Patients with cortisol post-DST (50–138 nmol/l) were considered as intermediate phenotypes and classified as minor (n=71) and major (n=55) using plasma ACTH and/or urinary free cortisol as additional diagnostic tools.ResultsSCS patients showed higher prevalence of T2D, CHD, osteoporosis, and fractures with respect to NSA. Intermediate phenotypes also showed higher prevalence of CHD and T2D with respect to NSA. The prevalence of all clinical outcomes was not different between intermediate phenotype patients, which were therefore considered as a single group (IP) for multivariate logistic regression analysis: both IP and SCS-secreting patterns showed a significant association with CHD (odds ratio (OR), 4.09; 95% confidence interval (CI), 1.47–11.38 and OR, 6.10; 95% CI, 1.41–26.49 respectively), independently of other potential risk factors. SCS was also independently associated with osteoporosis (OR, 5.94; 95% CI, 1.79–19.68).ConclusionsPatterns of increasing subclinical hypercortisolism in adrenal adenomas are associated with increased prevalence of adverse metabolic and cardiovascular outcomes, independently of other potential risk factors.

Background Unlike chronic idiopathic intestinal pseudo-obstruction (CIIP), severe digestive syndromes that are not characterized by episodes resembling mechanical obstruction remain poorly characterized. The present study compared clinical features, small bowel motility, and quality of life (QoL) in patients with CIIP or severe functional gastrointestinal disorders (SFGID), compared to irritable bowel syndrome (IBS). Methods We enrolled 215 consecutive patients: 70 CIIP, 110 malnourished SFGID [body mass index (BMI) 17.8 ± 1.8 kg m−2] and 35 non-malnourished SFGID (BMI 22.8 ± 3.6 kg m−2). Key Results Abnormal motor patterns that fulfilled diagnostic criteria for small bowel dysmotility were virtually absent in IBS patients, but were recorded in69 CIIP patients (98.6%), 82 malnourished SFGID patients (74.5%;), and 23 SFGID patients without malnutrition (65.7%) (P

Background: The aim of the study was to evaluate the circulating concentrations of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR-2), vascular endothelial growth factor-D (VEGF-D) and endostatin in patients with intraductal papillary mucinous neoplasm (IPMN), and in those with ductal adenocarcinomas. Methods: Sixty patients (32 males, 28 females, mean age 69.3±11.3 years) were enrolled: 31 (51.7%) had IPMNs and 29 (48.3%) had histologically confirmed pancreatic adenocarcinomas. Thirty blood donors were also studied as controls. In all study subjects, the concentrations of VEGF, VEGF-D, VEGFR-2, and endostatin were determined using enzyme-linked immunosorbent assays. Results: Serum concentrations of VEGF, VEGF-D, and VEGFR-2 were significantly higher in patients with pancreatic ductal adenocarcinoma and those with IPMNs compared with healthy subjects, while endostatin was significantly higher only in patients with pancreatic ductal adenocarcinoma compared with healthy subjects. Within the group of patients, VEGFR-2 was significantly higher in patients with ductal adenocarcinoma compared to those with IPMNs. The sensitivity and the specificity of VEGFR-2 in differentiating patients with ductal adenocarcinomas from those with IPMN at a cut-off range of 4003–4034 pg/mL was 86.2% and 54.8%, respectively. Conclusions: IPMNs have serum VEGFR-2 concentra-tions different from those in patients with ductal adenocarcinomas. However, serum VEGFR-2 cannot be routinely utilized to differentiate IPMNs from pancreatic ductal adenocarcinomas.

Acute pancreatitis, chronic pancreatitis and pancreatic cancer are responsible for most of the burden of exocrine pancreatic disease. Glandular damage from recurrent bouts of acute pancreatitis can lead to irreversible changes characteristic of chronic pancreatitis. In recent decades accumulating evidence has defined longstanding pre-existing chronic pancreatitis as a strong risk factor for pancreatic cancer. The lag period between diagnosis of chronic pancreatitis and pancreatic cancer is usually one or two decades: pancreatitis appearing a year or two before the diagnosis of pancreatic cancer is often the result of tumour-related ductal obstruction. The risk of developing pancreatic cancer appears to be highest in rare types of pancreatitis with an early onset, such as hereditary pancreatitis and tropical pancreatitis. Even though there is a strong link between chronic pancreatitis and pancreatic cancer, over a 20 year period only around five percent of patients with chronic pancreatitis will develop pancreatic cancer. Until the development of more sophisticated screening procedures, screening is not recommended for patients with chronic pancreatitis.

The resulting pain is the main symptom of acute pancreatitis and it should be alleviated as soon as possible. NSAIDs are the first line therapy for pain and they are generally administered to acute pancreatitis patients upon admission to the hospital. In addition, these drugs have also been used to prevent post-endoscopic cholangiopancreatography (ERCP) acute pancreatitis. On the other hand, there are several reports indicating that NSAIDs may be the actual cause of acute pancreatitis. We carried out a literature search on PubMed/MEDLINE; all full text papers published in from January 1966 to November 2009 on the use of NSAIDs in acute pancreatitis were collected; the literature search was also supplemented by a review of the bibliographies of the papers evaluated. Thus, in this article, we will systematically review the current literature in order to better illustrate the role of NSAIDs in acute pancreatitis, in particular: i) NSAIDs as a cause of acute pancreatitis; ii) their use to prevent post-retrograde ERCP pancreatitis and iii) their efficacy for pain relief in the acute illness of the pancreas.

OBJECTIVE: Serum leptin and adiponectin determinations have been proposed as markers for distinguishing pancreatic cancer and chronic pancreatitis from autoimmune pancreatitis; however, no studies exist in patients with autoimmune pancreatitis and in those with intraductal papillary mucinous tumors of the pancreas. The aim of this paper was to evaluate the circulating concentrations of receptor for advanced glycation end products (RAGE), leptin and adiponectin in patients with chronic pancreatic diseases. MATERIAL AND METHODS: Seventy-five consecutive patients with chronic pancreatic diseases (47 males, 28 females; mean age 67.0 +/- 13.2 years; range 37-97 years) were studied: six (8.0%) had autoimmune pancreatitis, 23 (30.7%) had chronic pancreatitis, 34 (45.3%) had pancreatic cancer and the remaining 12 (16.0%) had intraductal papillary mutinous tumors of the pancreas. Leptin, adiponectin and RAGE were determined in serum using commercially available kits. The leptin concentrations were normalized to the lower and upper reference limits because of the different gender reference ranges. RESULTS: Normalized leptin concentrations were significantly lower in chronic pancreatitis patients (0.53 +/- 1.28; p = 0.008) and in those with pancreatic cancer (0.12 +/- 0.33; p < 0.001) compared to the overall population (0.58 +/- 1.23), whereas autoimmune pancreatitis patients had significantly higher concentrations of this protein (2.18 +/- 2.56; p = 0.004) compared to the overall population. RAGE and adiponectin concentrations were similar among the four groups of patients studied. Among the clinical variables considered, only pain was significantly related to leptin concentrations (patients with pain 0.18 +/- 0.54, patients without pain 1.07 +/- 1.64; p = 0.001). CONCLUSION: Serum leptin seems to be a good serum marker for differentiating autoimmune pancreatitis patients from those with chronic pancreatitis and pancreatic cancer.

Alcoholic pancreatitis continues to stir up controversy. One of the most debated points is whether from onset it is a chronic disease or whether it progresses to a chronic form after repeated episodes of acute pancreatitis. Histological studies on patients with alcoholic pancreatitis have shown that the disease is chronic from onset and that alcoholic acute pancreatitis occurs in a pancreas already damaged by chronic lesions. Genetic factors may also play a role in the pathogenesis of alcoholic disease. The incidence of chronic alcoholic pancreatitis seems to have decreased in the last twenty years. Finally, recent therapeutic studies which have shown medical or surgical approaches capable of reducing the pain episodes in chronic pancreatitis patients will be described.

none 4 Chronic nonpathological pancreatic hyperenzymemia is characterized by a chronic, abnormal increase in the serum concentrations of the pancreatic enzymes including amylase, pancreatic isoamylase, lipase and trypsin. The diagnostic work-up that the physicians should recommend to subjects with hyperenzymemia to definitively assess this syndrome is still an open question. A 72-year-old female was admitted to our Pancreas Unit in December 2008 for the presence of long-standing pancreatic hyperenzymemia of 42 years duration. On admission, serum amylase activity was 160 IU/l (reference range 8-78 IU/l), serum pancreatic isoamylase activity was 91 IU/l (reference range 13-53 IU/l) and serum lipase activity was 127 IU/l (reference range 8-78 IU/l). Other laboratory examinations revealed normal blood tests except for total serum cholesterol, HDL cholesterol and serum triglycerides that was slight elevated. Abdominal ultrasonography demonstrated no alteration of the pancreatic gland. A magnetic resonance cholangiopancreatography was carried out according to our diagnostic work-up of patients with unexplained pancreatic hyperenzymemia. This examination revealed two small cystic lesions: one of 6 mm in diameter in the head of the pancreas and the other one of 9 mm in diameter in the body of the pancreatic gland. The duct of Wirsung was normal and the two cystic lesions were diagnosed as branch-type intrapapillary mucinous tumors of the pancreas. All patients with pancreatic hyperenzymemia should be strictly followed in high volume centers for pancreatic disease in order to early diagnose the possible appearance of morphological pancreatic alterations Pezzilli R; Morselli-Labate AM; Calculli L; Casadei R. Pezzilli R; Morselli-Labate AM; Calculli L; Casadei R.

High circulating serum immunoglobulin G4 (IgG4) levels have been proposed as a marker of autoimmune pancreatitis (AIP). The aim of the present study was to review the data existing in the English literature on the usefulness of the IgG4 serum levels in the diagnosis and follow up of patients with AIP. A total of 159 patients with AIP and 1099 controls were described in seven selected papers reporting the usefulness of serum IgG4 in diagnosing AIP. In total, 304 controls had pancreatic cancer, 96 had autoimmune diseases, and the remaining 699 had other conditions. The summary receiver-operating characteristic curve analysis was carried out by means of Meta-DiSc open-access software. Serum IgG4 showed good accuracy in distinguishing between AIP and the overall controls, pancreatic cancer and other autoimmune diseases (area under the curve [+/- SE]: 0.920 +/- 0.073, 0.914 +/- 0.191, and 0.949 +/- 0.024, respectively). The studies analyzed showed significantly heterogeneous specificity values in each of the three analyses performed. The analysis of the four studies comparing AIP and pancreatic cancers also showed significantly heterogeneous values of sensitivities and odds ratios. Regarding the usefulness of IgG4 as a marker of efficacy of steroid treatment, a decrease in the serum concentrations of IgG4 was found in the four available studies. The serum IgG4 subclass is a good marker of AIP, and its determination should be included in the diagnostic workup of this disease. However, the heterogeneity of the studies published until now means that more studies are necessary in order to better evaluate the true accuracy of IgG4 in discriminating AIP versus other autoimmune diseases.

Objectives There are no data available that evaluate the possible modifications of the quality of life during the clinical course of chronic pancreatitis. To evaluate the outcome for patients with chronic pancreatitis in a 2-year follow-up study. Methods The Short Form 12 Health Survey Italian version questionnaire was used for the purpose of the study. The questionnaire generates 2 summary scores: the physical component summary (PCS-12) and the mental component summary (MCS-12). Eighty-three patients with chronic pancreatitis were studied with a mean (+/-SD) interval time of 2.3 +/- 0.2 years between the first and the second evaluation. Results There was a significant increase in the frequency of diabetes mellitus (P = 0.008), nonpancreatic surgery (P = 0.016), and comorbidities (P = 0.004). The PCS-12 (44.7 +/- 10.7) and MCS-12 (44.1 +/- 13.3) were not significantly different in comparison with the baseline evaluation (PCS-12, 43.7 +/- 9.8; MCS-12, 44.3 +/- 11.4). The PCS-12 score worsened in 17 (20.5%) patients, 44 (53.0%) had a stable PCS-12 score, and the remaining 22 (26.5%) improved their PCS-12 score. Regarding the mental score, 15 (18.1%) patients worsened, 52 (62.7%) had a stable MCS-12 score, and the remaining 16 (19.3%) improved their MCS-12 score. Only age at diagnosis was significantly related to the change of the MCS-12 score (P = 0.028, positive relationship). Conclusions The information given by quality-of-life assessment should be routinely included in the work-up of patients affected by chronic pancreatitis to select those patients with severely impaired physical and mental scores, and to plan an intensive program of medical and psychological follow-up.

Background Since the incidence of myocardial infarction and other cardiovascular ischaemic events is highest in early morning, on account of a relative hypercoagulable state occurring in this time period, an attempt was made to test whether reperfusion of the hepatic artery at this time of the day, at liver transplantation, produces an increased risk of early thrombosis. Methods The records of 255 consecutive patients receiving a first transplant for chronic liver disease were retrospectively analysed. As possible risk factors, for early post-operative thrombosis ( Results Logistic regression identified donor age (OR for age >60: P = 0.017), bench reconstruction of the artery (OR: 5.06, P = 0.013) and time of high coagulability at reperfusion (OR 2.93, P = 0.087), as independently associated with early hepatic artery thrombosis. Conclusions The present findings identified three independent predictors of early hepatic thrombosis, warranting stricter post-surgical follow-up of patients presenting such conditions. Interestingly, these factors are consistent with arterial reperfusion in the early morning being associated with an increased risk of early hepatic artery thrombosis, suggesting relative coagulative imbalances to provide a contribution in the pathogenesis of this severe complication of liver transplantation.

Background. The effectiveness of a homeopathic syrup on cough has been demonstrated in an adult population in a previous double-blind randomized study. The present prospective observational study investigated children affected by wet acute cough caused by non-complicated URTIs, comparing those who received the homeopathic syrup versus those treated with the homeopathic syrup plus antibiotic. Objectives. The aims were: 1) to assess whether the addition of antibiotics to a symptomatic treatment had a role in reducing the severity and duration of acute cough in a pediatric population, as well as in improving cough resolution; 2) to verify the safety of the two treatments. Methods. Eighty-five children were enrolled in an open study: 46 children received homeopathic syrup alone for 10 days and 39 children received homeopathic syrup for 10 days plus oral antibiotic treatment (amoxicillin/clavulanate, clarithromycin, and erythromycin) for 7 days. To assess cough severity we used a subjective verbal category-descriptive (VCD) scale. Results. Cough VCD score was significantly (P

Background.Evidence is accumulating in favour of a link between erectile dysfunction (ED) and coronary artery diseases. We investigated the presence of cardiac injury in patients who have had arteriogenic and nonarteriogenic ED using the hs-Tn levels.Methods.The diagnosis of ED was based on the International Index of Erectile Function 5-questionnaire (IIF-5) and patients were classified as arteriogenic (A-ED,n=40), nonarteriogenic (NA-ED,n=48), and borderline (BL-ED,n=32) patients in relation to the results of echo-color-Doppler examination of cavernous arteries. The level of hs-TnT and hs-TnI was measured in 120 men with a history of ED of less than one year with no clinical evidence of cardiac ischemic disease.Results.The levels of both hs-TnT and hs-TnI were within the reference range and there was no significant (P>0.05) difference between patients of the three groups. The hs-CRP values were higher in A-ED men compared with NA-ED (P=0.048) but not compared with BL-ED (P=0.136) and negatively correlated with IIF-5 (r=-0.480;P=0.031).Conclusions.In ED patients of the three groups the measurement of hs-Tn allows us to exclude the presence of cardiac involvement at least when the history of ED is less than one year and the men are without atherosclerotic risk factors.

BACKGROUND: A few studies have assessed the short-term effects of low-dose nicotine e-cigarettes, while data about nicotine-free e-cigarettes (NF e-cigarettes) are scanty. Concerns have been expressed about the use of NF e-cigarettes, because of the high concentrations of propylene glycol and other compounds in the e-cigarette vapor. METHODS: This laboratory-based study was aimed to compare the effects of ad libitum use of a NF e-cigarette or and a traditional cigarette for 5 min in healthy adult smokers (n = 10) and non-smokers (n = 10). The main outcome measures were pulmonary function tests, fraction of exhaled nitric oxide (FeNO) and fractional concentration of carbon monoxide (FeCO) in exhaled breath. RESULTS: The traditional cigarette induced statistically significant increases in FeCO in both smokers and non-smokers, while no significant changes were observed in FeNO. In non-smokers, the traditional cigarette induced a significant decrease from baseline in FEF75 (81 % ± 35 % vs 70.2 % ± 28.2 %, P = 0.013), while in smokers significant decreases were observed in FEF25 (101.3 % ± 16.4 % vs 93.5 % ± 31.7 %, P = 0.037), FEV1 (102.2 % ± 9.5 % vs 98.3 % ± 10 %, P = 0.037) and PEF (109.5 % ± 14.6 % vs 99.2 % ± 17.5 %, P = 0.009). In contrast, the only statistically significant effects induced by the NF e-cigarette in smokers were reductions in FEV1 (102.2 % ± 9.5 % vs 99.5 ± 7.6 %, P = 0.041) and FEF25 (103.4 % ± 16.4 % vs 94.2 % ± 16.2 %, P = 0.014). DISCUSSION: The present study demonstrated that the specific brand of NF e-cigarette utilized did not induce any majoracute effects. In contrast, several studies have shown that both traditional cigarettes and nicotine-containing e-cigarettes have acute effects on lung function. Our study expands on previous observations on the effects of NF e-cigarettes, but also for the first time describes the changes induced by smoking one traditional cigarette in a group of never smokers. CONCLUSIONS: The short-term use of the specific brand of NF e-cigarette assessed in this study had no immediate adverse effects on non-smokers and only small effects on FEV1 and FEF25 in smokers. The long-term health effects of NF e-cigarette use are unknown but worthy of further investigations. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02102191.

PURPOSE: Delayed diarrhea is the most important side effect of irinotecan. The aim of this study was to investigate the role of intestinal microflora on the induction of systemic and intestinal toxicity and diarrhea, studying germ-free and holoxenic mice i.p. injected with irinotecan. EXPERIMENTAL DESIGN: To evaluate the lethal dose, starting with 100 mg/kg/4 d, we treated the holoxenic mice with 100, 80, and 60 mg/kg/4 d and germ-free mice with 60, 80, 100, and 150 mg/kg/4 d. We recorded the percentage of dead animals, diarrhea, and the epithelial damage to the jejunum, ileum, cecum, and colon at optical and scanning electron microscopy. RESULTS: Germ-free mice were more resistant to irinotecan than the holoxenic group. The lethal dose was between 60 and 80 mg of irinotecan for holoxenic mice and > or =150 mg for the germ-free. The intestinal damage score was higher in holoxenic than germ-free mice at 100 mg and equally diffuse in the small and large bowel. The damage in germ-free mice was less severe (8 of 40 samples) prevailing in the ileum. The differences were significant for all sites (jejunum, P < 0.001; ileum, P = 0.012; cecum, P = 0.001; colon, P < 0.001). No damage was found in germ-free mice at 60 mg. Diarrhea was present in all 100 and 80 mg holoxenic mice and in 19 of 20 cases at 60 mg whereas it was absent in 60 mg or sporadic in 80 and 100 mg germ-free mice. CONCLUSIONS: The intestinal microflora plays a key role in the intestinal toxicity of irinotecan.

Background: The aim of this study was to evaluate the survival rate of patients with endocrine tumors of the pancreas, functioning or non-functioning, associated or not with MEN 1 syndrome. Patients and methods: Eighty-three patients with pancreatic endocrine tumors diagnosed in our department from 1978 to 2003 were studied. Results: The study included 37 men (44.6%) and 46 women (55.4%). The median age of patients at diagnosis was 55 years (range 19–81 years). Fifty-two patients (62.7%) had non-functioning endocrine tumors, 16 (19.3%) had functioning endocrine tumors and 15 (18.1%) had MEN 1 disease with pancreatic involvement. Twenty-seven patients (32.5%) had liver metastases at the time of diagnosis, involvement of the lymph nodes was found in 47 out of 79 patients (59.5%). Forty patients (48.2%) had radical surgery, 20 (24.1%) had palliative surgery and 53 were treated medically. The survival rate was significantly related to the presence of metastases, lymph node involvement, and the type of tumor and treatment. Conclusions: Tumor resection, the absence of liver and lymph node metastases, and the presence of MEN 1 syndrome are related to a better survival rate. Radical surgery continues to have a central role in the therapeutic approach to endocrine tumors of the pancreas.

Background Oxidative stress contributes to the pathogenesis of hepatic ischemia-reperfusion injury. This study aimed to determine whether fatty degeneration affects the oxidative damage during warm ischemia reperfusion and whether mitochondria, the major intracellular site of energy synthesis, represent a preferential target of this injury. Materials and methods Fed rats with control or fatty liver induced by choline deficiency underwent 60′ lobar ischemia and reperfusion. Oxidative damage was assessed by measuring in whole liver tissue and in isolated mitochondria the thiobarbituric acid-reactive substances (TBARs), protein carbonyls (PC), and total and oxidized glutathione (GSH and GSSG) concentrations. The mitochondrial F0-F1-ATPase content and the oxidative phosphorylation activity were also determined. Rat survival and ALT release were assessed as parameters of liver injury. Results In the whole liver tissue, with the exception of TBARs, no differences were observed for GSH, GSSG, and PC between the two groups throughout all of the experiment. In contrast, in isolated mitochondria, fatty infiltration was associated with a mild oxidative imbalance already under basal conditions. The preischemic differences in the mitochondrial TBARs, PC, and GSSG levels were significantly amplified by reperfusion in the presence of steatosis. The enhanced oxidative damage was associated to a reduced F0-F1-ATPase content and oxidative phosphorylation activity in fatty liver mitochondria. Finally, serum ALT levels were significantly greater and survival significantly lower in rats with steatotic liver. Conclusions Fatty infiltration exacerbates mitochondrial oxidative injury during warm ischemia reperfusion. The increased oxidative stress can alter mitochondrial functions, including key processes for ATP synthesis, thus, contributing to the reduced tolerance to reperfusion injury.

Objectives To evaluate the clinical value of a new direct and competitive immunoassay for trypsinogen activation peptide (TAP) determination in acute pancreatitis (AP). Methods The subjects were 34 patients with AP (22 mild, 12 severe), 12 patients with nonpancreatic acute abdominal pain (AA), 11 healthy subjects (HS), and 16 consecutive patients who underwent therapeutic ERCP (ERCP). Serum TAP, amylase, and lipase levels were determined in AP, AA, and HS at their initial observation; the AP patients were also studied for 6 consecutive days after admission. In the ERCP patients, serum TAP, amylase, and lipase levels, as well as urine TAP and amylase levels, were determined before and 6 hours after endoscopy. Results Serum TAP levels on admission were 0.35 +/- 1.60 OD (mean +/- SD) in AP patients and 0.005 +/- 0.001 OD in AA patients, while HS patients had no detectable serum TAP levels. ERCP patients had no detectable serum TAP levels before and 6 hours after the ERCP, whereas urine TAP concentrations were 1.72 +/- 3.43 OD and 0.75 +/- 1.49 OD before and 6 hours after the execution of the endoscopy, respectively (P = 0.249). The sensitivities and specificities of serum TAP, amylase, and lipase levels in discriminating between AP and AA were 23.5% and 91.7%, 94.1% and 100%, and 97.1% and 100%, respectively, while those used in the assessment of the severity of AP were 29.9% and 73.5%, 38.8% and 81.2%, and 28.4% and 83.6%, respectively. Conclusion TAP is of limited value in assessing the diagnosis and the severity of acute pancreatic damage.

The aim of this study was to investigate the phenotypic parameters and associated factors characterizing the development of glucose intolerance in polycystic ovary syndrome (PCOS). Among the 121 PCOS female subjects from the Mediterranean region, 15.7 and 2.5% displayed impaired glucose tolerance and type 2 diabetes, respectively. These subjects were included in a single group of overweight or obese subjects presenting with glucose intolerance (GI) states. PCOS women with normal glucose tolerance (81.8%) were subdivided into two groups: those who were overweight or obese and those of normal weight. Metabolic and hormonal characteristics of the GI group included significantly higher fasting and glucose-stimulated insulin levels, more severe insulin resistance, hyperandrogenemia, and significantly higher cortisol and androstenedione responses to 1–24 ACTH stimulation. One important finding was that lower birth weight and earlier age of menarche were associated with GI in PCOS women. Frequency of hirsutism, oligomenorrhea, acne, and acanthosis nigricans did not characterize women with GI. Our findings indicate that PCOS patients with GI represent a subgroup with specific clinical and hormonal characteristics. Our observations may have an important impact in preventative and therapeutic strategies.

In this study we evaluated whether testosterone undecanoate (TU), alone or combined with low dose cyproterone acetate (CPA), can maintain spermatogenic suppression induced by higher doses of CPA plus TU. Twenty-four men received for 12 wk 20 mg/d CPA plus 1000 mg/6 wk TU and then 1000 mg/8 wk TU plus 20 mg/d CPA (n = 8), 2 mg/d CPA (n = 8), or plus placebo (n = 8) for 32 wk. Blood samples, physical examinations, hormones, chemistry, hematology, semen analysis, and sexual/behavioral assessments were performed throughout the study. Sperm counts decreased to less than 1 million/ml in all subjects by wk 12, and 54% of them achieved azoospermia. Suppression of sperm counts was maintained until wk 44. Serum LH and FSH levels were suppressed by wk 12 of hormone administration and remained suppressed until wk 44. No significant changes in any biochemical parameters were detected at wk 44 in any group. There was a slight increase in total prostate volume to within the normal range at wk 44 that returned to baseline 1 yr after stopping hormone administration. In conclusion, TU alone or combined with lower doses of CPA maintains sperm suppression induced by higher dose CPA plus TU for 32 wk. This prototype regimen represents a promising male contraceptive regimen.

An association has been found between CFTR gene mutations and chronic pancreatitis; however, there is a lack of information about the frequency of CFTR gene mutations in acute pancreatitis and in pancreatic cancer.To prospectively evaluate the prevalence of CFTR gene mutations in acute pancreatitis, chronic pancreatitis, and pancreatic cancer.Ninety-eight consecutive patients were studied and divided into 3 groups: 34 patients with acute pancreatitis, 46 patients with chronic pancreatitis, and 18 patients with pancreatic cancer. The mutation analysis of the CFTR gene was carried out using diagnostic commercial kits for the simultaneous detection of 29 mutations and Tn polymorphism.Among the 98 patients studied, 12 (12.2%) had CFTR gene mutations: 2 of the 34 patients (5.9%) with acute pancreatitis, 9 of the 46 (19.6%) with chronic pancreatitis, and 1 of the 18 (5.6%) with pancreatic cancer. All the mutations were found in heterozygosis (2 DeltaF508, 1 W1282X, and 9 T5 allele).Our prospective study adds further information about the frequency of CFTR mutations in patients with a single episode of acute pancreatitis. Furthermore, our results suggest an association of CFTR gene mutations with chronic alcoholic pancreatitis and emphasize the need for a multicenter study, possibly multinational, to conclusively establish the role of CFTR mutations as a genetic susceptibility factor for this disease.

Background. Data concerning the usefulness and type of drugs employed to treat patients with primary sclerosing cholangitis are controversial. Ursodeoxycholic acid has been shown to be a useful agent, however the drug dosage and its effect on the clinical course are still under debate. Aim. To evaluate the efficacy of low-dose ursodeoxycholic acid in the treatment of primary sclerosing cholangitis. Methods. We retrospectively analysed data from 86 patients with primary sclerosing cholangitis from eight centres in Italy between 1987 and 1997: 69 were treated with ursodeoxycholic acid (8–13 mg/kg/day), while 17 received symptomatic treatment and served as controls. The effect of therapy was evaluated by standard liver function tests and symptom analysis. Results. Ursodeoxycholic acid treatment was associated with significant improvement in serum alkaline phosphatase (735±833 vs. 519±448 U/l, p

In this study we compared the effects of high-dose and low-dose testosterone enanthate (TE) administered with the same dose of cyproterone acetate (CPA). Eighteen men aged 21-45 were treated with CPA 5 mg/day and with TE 100 mg/week (n = 9; CPA-5-100) or TE 200 mg/week (n = 9; CPA-5-200) for 16 weeks. Semen analyses were performed every 2 weeks; physical examination and chemistry, hematology, gonadotropin, and testosterone measurements were performed every 4 weeks. At week 16 of treatment, sperm counts were significantly more suppressed in the CPA-5-100 group than in the CPA-5-200 group. Sperm counts returned to baseline in all subjects after hormone administration ceased. No difference in gonadotropin levels was found at any time between the 2 groups. During the treatment phase, testosterone levels were significantly higher in the CPA-5-200 group than in the CPA-5-100 group. The present study confirms that CPA/TE administration induces profound sperm suppression. An increase in the dose of androgen resulted in less profound sperm suppression despite no difference in gonadotropin suppression. These data suggest that high testosterone levels can maintain sperm production in men.

Background & aims: The epidemiology of bone disease in home parenteral nutrition (HPN) is unknown. The aim of this paper is to evaluate the prevalence and severity of reduced bone mineral density (BMD) in long-term HPN. Design: Cross-sectional, multicentre study including patients who within the last 12 months had their BMD assessed by dual-energy-X-ray absorptiometry after at least 6 months of HPN. Data on bone pain and fractures, the primary gastrointestinal diseases, nutritional and rehabilitation status and HPN regimen were reviewed. Both the T -score (no. of SD below mean BMD of young subjects) and the Z -score (no. of SD from normal BMD values corrected for sex and age) were analysed. Results: A T -score

Cough is a frequent symptom associated to upper respiratory tract infections (URTIs) and, although being self-limiting, it might deeply affect the quality of life. Homeopathic products are often employed by patients to treat cough, but the evidence on their efficacy is scarce. Thus, we tested the efficacy of a homeopathic syrup in treating cough arising from URTIs with a randomized, double blind, placebo controlled clinical trial. Patients were treated with either the homeopathic syrup or a placebo for a week, and recorded cough severity in a diary by means of a verbal category-descriptive score for two weeks. Sputum viscosity was assessed with a viscosimeter before and after 4 days of treatment; patients were also asked to provide a subjective evaluation of viscosity. Eighty patients were randomized to receive placebo (n = 40) or the homeopathic syrup (n = 40). All patients completed the study. In each group cough scores decreased over time, however, after 4 and 7 days of treatment, cough severity was significantly lower in the homeopathic group than in the placebo one (p < 0.001 and p = 0.023, respectively). Sputum was collected from 53 patients: in both groups its viscosity significantly decreased after 4 days of treatment (p < 0.001); however, viscosity was significantly lower in the homeopathic group (p = 0.018). Instead, the subjective evaluation did not significantly differ between the two groups (p = 0.059). No adverse events related to any treatment were reported. We concluded that the homeopathic syrup employed in the study was able to effectively reduce cough severity and sputum viscosity, thereby representing a valid remedy for the management of acute cough induced by URTIs.

In the present study we evaluated the relation among histology, H. pylori, IgG to H. pylori, gastric emptying, and acid secretion in 43 patients with fundic atrophic gastritis. On the basis of gastric acid secretion, patients were divided into three subgroups: patients with preserved acid secretion (Group 1), patients with hypochlorhydria (Group 2), and patients with achlorhydria (Group 3). Fundic glandular atrophy was more severe in hypoachlorhydric patients than in those with preserved acid secretion (P < 0.05 vs Group 2, P < 0.005 vs Group 3). H. pylori colonization was found in 94% of patients in Group 1, in 61% of patients in Group 2, and in only 8% of patients in Group 3 (P < 0.001 vs Group 1, P < 0.05 vs Group 2). Conversely, serological positivity to H. pylori was high in all three subgroups of patients (100% in Group 1, 77% in Group 2, 92% in Group 3). Gastric emptying was delayed in atrophic patients, particularly in those with hypoachlorhydria. Our data suggest that fundic atrophic gastritis represents a possible end stage of H. pylori infection, characterized by a progressive disappearance of the bacterium and a progressive deterioration of gastric functions.

Amyloid A (SAA) and procalcitonin (PCT) have been reported as useful indicators of inflammation. Our aim was to assess the utility of SAA and PCT in establishing the severity of acute pancreatitis in comparison to C-reactive protein (CRP): Thirty-one patients with acute pancreatitis enrolled within 24 hr from the onset of pain and 31 healthy subjects were studied. Nineteen patients had mild acute pancreatitis, and 12 had severe pancreatitis. Serum SAA, PCT, and CRP were measured in all subjects at admission and, in acute pancreatitis patients, during the following five days. Patients with acute pancreatitis had serum concentrations of SAA, PCT, and CRP significantly higher (P < 0.001) than those of healthy subjects during the entire study period. Using cutoff values ranging from 240 to 250 mg/liter for SAA, from 0.252 to 0.255 ng/ml for PCT, and from 12.8 to 12.9 mg/dl for CRP, the sensitivity (calculated on patients with severe pancreatitis), the specificity (calculated on patients with mild pancreatitis), and the efficiency (calculated as the percentage of correct classifications) were 76.8%, 69.3%, and 72.4% for SAA; 21.7%, 83.2%, and 58.2% for PCT; and 60.9%, 89.1%, and 77.6% for CRP. In conclusion, the sensitivity of SAA is significantly higher than that of PCT and CRP in assessing the severity of pancreatitis, whereas PCT and CRP had a specificity significantly higher than SAA. The accuracy and efficiency were similar for SAA and CRP, and both these markers had an accuracy and efficiency significantly higher than those of PCT.

Although the etiology of liver disease affects the features of hepatocellular carcinoma (HCC) diagnosed during surveillance, it is not known whether it influences patients' survival. We analyzed the impact of etiology on the characteristics and outcome of HCC detected during surveillance.In this cohort study, 742 patients with HCC detected during semiannual or annual surveillance were selected from the ITA.LI.CA database, including 1,834 consecutive patients observed in three primary and seven tertiary care settings for HCC. Patients were grouped according to etiology: hepatitis B virus (HBV, 87), hepatitis C virus (HCV, 461), alcohol (59), and multietiology (135).In all etiologic groups, most HCCs were unifocal (51-68%) and most of them wereor=3 cm (60-69%). Unifocal HCCs were less common in the multietiology group (P=0.050) and slightly more frequent in the HCV group (P=0.087). Besides etiology, only age was associated with gross pathology (P=0.023). About two-thirds of HCCs in all groups were discovered at Cancer of the Liver Italyn Program (CLIP) stage 0 or 1. The 1-, 3-, and 5-yr survival rates were comparable among groups (HBV 81%, 47%, and 22%; HCV 86%, 49%, and 24%; alcohol 76%, 41%, and 25%; multietiology 75%, 37%, and 24%; P=0.446). The surveillance interval did not influence survival, which was independently predicted by serum alpha-fetoprotein, Child-Pugh class, gross pathology, cancer size, vascular invasion, and treatment.In patients with HCC diagnosed during surveillance: (a) single nodules are less common in multietiology cases and (b) prognosis is independent of etiology, being dictated by liver function, oncologic features, and treatment.