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Background: Esophageal chemical clearance has been evaluated with the post-reflux swallow-induced peristaltic wave (PSPW) index. The factors triggering PSPW in Gastro-esophageal reflux disease (GERD) have not yet been investigated. This multicenter study was aimed at evaluating the characteristics of reflux episodes associated with PSPW occurrence in patients with typical GERD symptoms., Methods: Impedance-pH tracings from patients with typical reflux symptoms were analyzed. Sixteen healthy subjects were included for comparison. Multivariate analysis was performed to determine predictors of PSPW events., Key Results: Impedance-pH tracings from 60 patients and 16 healthy subjects were evaluated. A total of 3454 refluxes were recorded. In patients, comparing reflux episodes followed with those not followed by a PSPW, significantly higher proportions of acid (79% vs. 74%, p: 0.02), mixed (47% vs. 32%, p: 0.0001) and proximal refluxes (34% vs. 20%, p: 0.0001) were observed. A multivariate analysis, acid (OR: 1.3, 95% CI: 1.05-1.6), mixed (OR: 2, 95% CI: 1.6-2.3), and proximal (OR: 2.1, 95% CI: 1.7-2.5) refluxes were independently associated with PSPWs. Reflux episodes followed by a PSPW were characterized by a significantly higher bolus clearing time [(mean ± SD) 41 s ± 6 s vs. 30 s ± 5 s, p < 0.05] whereas nadir pH value of reflux events preceding PSPWs was tangentially but not significantly lower [(mean ± SD) 2.61 ± 1.22 vs. 2.74 ± 1.26, p: 0.057]., Conclusions and Inferences: Acid, mixed and proximal refluxes, and their duration are key factors in eliciting PSPWs. PSPW represents a response to reflux directly related to the potential harmfulness of reflux contents., (© 2021 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background: Following acid perfusion, esophageal pH is restored by swallowed bicarbonate-containing saliva secreted in response to a vagal esophago-salivary reflex. At impedance-pH monitoring, the post-reflux swallow-induced peristaltic wave (PSPW) index puts into relationship timely post-reflux swallows with the number of reflux events: Low values typify reflux-related heartburn (RRH) and lack of on-therapy improvement characterizes proton pump inhibitor (PPI) failure. Considerable esophageal pH increments associated with PSPWs could demonstrate the occurrence of esophago-salivary reflex in clinical setting, while its relevance could be shown by lower esophageal pH increments in PPI-refractory RRH., Methods: Prospective multicenter study in patients with PPI-refractory or PPI-responsive RRH evaluated with off-PPI impedance-pH monitoring. Increments in pH associated with PSPWs were measured and the mean calculated to obtain the PSPW-associated ∆pH., Key Results: The mean PSPW-associated ∆pH in 294 RRH patients was 1.2 ± 0.7 and was lower in 137 PPI-refractory (1.0 ± 0.6) than in 157 PPI-responsive (1.5 ± 0.6) cases (p < 0.0001). Lower PSPW-associated ∆pH was independently related to PPI failure at multivariable logistic regression analysis (OR 0.16, 95% CI 0.09-0.26). At ROC analysis, comparing PPI-refractory to PPI-responsive cases the AUC for PSPW-associated ∆pH was 0.76 (95% CI 0.71-0.82), the best cutoff value being 1.2., Conclusions and Inferences: Considerable PSPW-associated pH increments demonstrate the occurrence of esophago-salivary reflex in clinical setting. Lower increments in PPI-refractory RRH cases show the clinical relevance of esophago-salivary reflex, confirming that PSPW represents a defense mechanism against reflux. PSPW-associated ∆pH can efficiently predict PPI response in patients undergoing off-therapy impedance-pH monitoring., (© 2021 John Wiley & Sons Ltd.)

Background: Nailfold videocapillaroscopy (NVC) is a feasible method that allows the observation of the microvascular changes that mark the course of systemic sclerosis (SSc). In previous studies, we demonstrated that the NEMO score, i.e. the cumulative number of microhaemorrhages and microthromboses, is a good indicator of the steady-state level and overtime changes of disease activity (DA) in SSc., Objectives: To verify whether high NEMO scores, which mirror a very active microvascular derangement in the fingers, may be associated with the subsequent development of ischaemic digital ulcers (IDUs)., Methods: The NEMO score was assessed at baseline (T0) in 98 patients with SSc, all classified according to the ACR-EULAR criteria. Of them, 90 were females, 48 had the limited and 50 had the diffuse cutaneous variant of SSc. Afterwards, the patients were closely followed up for 2 years, and the appearance of new IDUs recorded at any time of the follow-up. The T0-NEMO score values of patients who developed IDUs were compared to those of patients who did not. A receiver operating curve (ROC) was constructed, and the area under the curve (AUC) calculated by plotting the sensitivity and 1-specificity of the different NEMO score values in predicting the subsequent development of IDUs., Results: During the follow-up, 38 out of 98 patients developed one or more IDUs. The NEMO score at T0 was significantly higher in those who developed IDUs with respect to those who did not [median 14.5 (95% CI 11.0-21.5) and 4.5 (95% CI 4.0-6.0), respectively, p < 0.0001]. The ROC curve derived from different T0-NEMO score values had an AUC of 0.79 (95% CI 0.69-0.86, p < 0.0001). A NEMO score of ≥ 12 had a sensitivity of 83.3% (95% CI 71.5-91.7) and a specificity of 63.2% (95% CI 46.0-78.2), with positive (P) and negative (N) predictive (PV) values of 58.9% (95% CI 44.7-72.2) and 85.6% (71.8-94.4), respectively. A NEMO score of ≥ 16 had a sensitivity of 95.0% (95% CI 86.1-99.0) and a NPV of 93.4% (77.5-99.2)., Conclusions: Being a valid tool to measure DA levels in SSc, the NEMO score also appears to be closely related to the subsequent development of IDUs in this disease.

Background: In previous studies, we demonstrated that the NEMO score, i.e. the cumulative number of microhaemorrhages (MHEs) and microthromboses (MTs), observed in nailfold videocapillaroscopy was a good indicator of the steady state level of disease activity (DA) in patients with systemic sclerosis (SSc) when the European Scleroderma Study Group (EScSG) index was considered the gold standard., Aim of the Study: To verify whether the NEMO score could be (i) a valid tool to assess DA, even when the modified European Scleroderma Trials and Research (EUSTAR) index was considered to be the comparator, and (ii) a sensitive method to capture the DA overtime changes., Patients and Methods: The NEMO score and the EScSG and EUSTAR indices were contemporarily assessed at baseline (T0) and after a follow-up of 4-56 months (T1) in 98 patients with SSc. The differences (Δ) between the T1 and T0 values of the NEMO score and the EScSG and EUSTAR indices were calculated and compared to each other., Results: NEMO score values were very closely correlated with the corresponding values of the EScSG and EUSTAR indices both at T0 and T1 observations (p < 0.0001 in all cases with the exception of the correlation with EScSG values at T1 (p < 0.03)). The values of the two composite DA indices were also strictly related to each other in both T0 and T1 observations (p < 0.0001). Receiver operating characteristic (ROC) curve analysis showed the NEMO score had a good sensitivity and specificity in classifying patients with a predefined level of DA (scores ≥ 3.0 and ≥ 2.5 for the EScSG and EUSTAR indices, respectively, p < 0.0001 in both cases). Δ values of the NEMO score were significantly correlated with the corresponding values of both the EScSG and EUSTAR indices. Weighted Cohen's k level of agreement between Δ values of the NEMO score and those of the EScSG and EUSTAR indices was moderate (0.55 and 0.59, respectively)., Conclusions: NEMO score proves to be a feasible, non-invasive, and valid tool to assess steady state levels and changes over time of DA in patients with SSc. Thus, it can represent an alternative or complementary method to measure this disease status entity in this disorder.

Background: Data on the prevalence of hepatitis C virus (HCV) infection in Italy are outdated and usually derived from studying residents in small towns., Methods: To assess prevalence of and risk factors for HCV infection among Italian residents in 5 metropolitan areas, subjects ≥20 years of age were randomly selected from the list of the general practitioners' registers in 2015. Anti-HCV was tested by a salivary test; HCV-RNA, HCV genotypes, and ALT were determined in positive individuals. Logistic regression analysis evaluated independent risk factors for HCV., Results: Of the 4907 enrolled subjects, 112 (2.3%) tested anti-HCV positive. The prevalence of HCV increased with age, from 0.2% in subjects born after the year 1984, to 4.2% in those born before the year 1935 (P < 0.01). The birth-cohort prevalence peaked (7.0%) in elderly. Serum HCV-RNA was detected in 1.7% of the whole population. Nearly 80% of anti-HCV subjects were aware of their status. Age > 70 years, low education level, past use of glass syringes, blood transfusion, intravenous drug use, and cohabitation with an anti-HCV positive subject predicted the HCV positivity., Interpretation: In metropolitan areas in Italy, HCV is prevalent in elderly, reflecting a cohort effect determined by modalities of viral transmission no longer operative. The impact of the infection will further diminish in the years to come due to the natural depletion of the reservoir of the virus. This age pattern and the high proportion of subjects aware of their status do not warrant a policy of screening., (Copyright © 2018. Published by Elsevier B.V.)

Objective: Heartburn is the most specific symptom of reflux disease and is highly responsive to proton pump inhibitor (PPI) therapy. Some patients do not respond to PPIs, but mechanisms of refractoriness have not yet been fully elucidated. Impedance-pH monitoring, allowing comprehensive on-therapy assessment of reflux, represents a valuable test to investigate PPI refractoriness., Methods: Prospective multicenter study comparing endoscopy-negative patients with PPI-refractory and PPI-responsive heartburn. Reflux disease was demonstrated by off-PPI impedance-pH monitoring and mechanisms of refractoriness were studied with on-PPI impedance-pH monitoring. Assessment of impedance-pH tracings comprised conventional parameters, post-reflux swallow-induced peristaltic wave (PSPW) index, and mean nocturnal baseline impedance (MNBI)., Results: Sixty-four patients entered the study, 32 with PPI-refractory and 32 with PPI-responsive heartburn. On PPI, median percentage gastric and esophageal acid exposure time and number of acid refluxes did not differ between the two groups; conversely, number of total and weakly acidic refluxes and percentage bolus exposure were significantly higher while PSPW index and MNBI were significantly lower in PPI-refractory cases. At multivariate logistic regression analysis, PSPW index was the sole independent risk factor for PPI refractoriness (OR 1.082, 95% CI 1.022-1.146, P = 0.007). Comparing off- and on-PPI parameters, median PSPW index did not change in PPI-refractory patients (24% vs. 26%, P = 0.327) but increased significantly in PPI-responsive cases (29% vs. 46%, P < 0.001)., Conclusions: Lack of improvement of impaired chemical clearance is a major determinant of PPI refractoriness. Timely post-reflux salivary swallowing represents a key defensive mechanism and a potential target for future treatment modalities in PPI-refractory reflux-related heartburn.

Transcatheter closure of arterial duct (AD) remains challenging in low-weight patients and using Amplatzer Duct Occluder devices is still considered off-label in infants < 6 kg. This study aimed to report a large, single-center experience of percutaneous AD closure in infants < 6 kg as well as to compare the most frequently used devices, Amplatzer Duct Occluder type I (ADO I) and Amplatzer Duct Occluder type II Additional Sizes devices (ADO II-AS) (St. Jude Medical Corp, St. Paul, MN, USA). From March 2000 to March 2017, among the 762 patients submitted to percutaneous closure of AD at our Institution, 33 were infants < 6 kg (age 4.8 ± 2.1 months; weight 5.0 ± 0.9 kg). Fourteen patients (45%) underwent ADO I (Group I) and 19 patients ADO II-AS (Group II) device implantation. AD diameter was 2.6 ± 0.8 (range 1.5-4.0) mm resulting in QP/QS of 2.6 ± 0.0.9 (range 1.1-4.5). Successful device deployment was achieved in all patients without procedural morbidity or mortality. Procedural and fluoroscopy times were not significantly different between the groups. However, total X-ray absorbed dose was significantly higher in Group I (121 ± 69 vs 29 ± 16 mGy/cm 2 , p < 0.01). Immediate, 24 h, and mid-term (46 ± 37 months, median 39) complete occlusion were recorded in 72.7, 90.9, and 97% of patients, respectively without significant difference between the groups. In conclusion, transcatheter closure of AD with Amplatzer Duct Occluder devices is feasible, safe, and effective also in infants less than 6 kg, without significant difference between the most commonly used devices, namely, ADO I and ADO II-AS.

Significant and balanced PA growth following arterial duct (AD) stenting has already been consistently reported in literature. However, to date, no data are available about the role of this approach as palliation of congenital heart disease with a duct-dependent discontinuous pulmonary artery (dPA). The aim of this study was to evaluate the fate of a dPA of ductal origin following trans-catheter AD stabilization. Angiographic PA evaluation was performed in seven patients submitted to neonatal AD stenting as palliative recruitment of dPA. Five patients showed discontinuity of one PA, while two patients had both PAs served by bilateral ducts. PA growth was evaluated as per the Nakata index, McGoon ratio as well as dPA (n = 9) versus heart-dependent PA (hPA; n = 5) size and z-score changes. AD stabilization was performed using coronary stents dilated to 3.2 ± 0.3 mm (median 3.4), with significant increase of O 2 saturation (from 83 ± 11 to 95 ± 5%, p < 0.02). Control angiography was performed 5.1 ± 2.8 months (median 6 months) after duct stenting, showing significant growth of the dPA (from 3.7 ± 1.0 to 7.6 ± 2.7 mm, p < 0.001; z-score from -0.7 ± 1.4 to 1.7 ± 2.2, p < 0.01). A trend toward better growth of the dPA as compared with the hPA was found (117 ± 87 vs. 54 ± 34%, p = NS). The final vessel size was still significantly different between the groups (dPA 7.6 ± 2.7 vs. hPA 11.9 ± 3.4 mm, p = 0.02), although the final z-score value did not significantly differ (dPA 1.7 ± 2.2 vs. hPA 3.8 ± 0.9 mm, p = NS). In conclusion, percutaneous AD stenting is effective in promoting a significant catch-up growth of duct-dependent dPA, being, therefore, advisable as a reliable alternative to surgical palliation.

Introduction: Recent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS., Methods and Analyses: Protocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial., Ethics and Dissemination: The study protocol was approved by the Ethics Committee of IRCCS 'Carlo Besta Foundation' of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Distributions of 137 Cs, 239,240 Pu, Δ 14 C and δ 13 C measured in sediments indicated low 137 Cs and 239,240 Pu activities in the Curonian Lagoon and higher levels in the open Baltic Sea. Depleted δ 13 C TOC values were found in the Curonian Lagoon as compared with the open Baltic Sea, while the most depleted Δ 14 C TOC values were found in the Gotland Deep. The global fallout Pu dominated in the deeper zones of the Baltic Sea, while higher 240 Pu/ 239 Pu atom ratios were characteristic of the coastal regions., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Some abnormalities in nailfold videocapillaroscopy (NVC), such as the presence of micro-haemorrhages (MHEs), micro-thromboses (MTs), giant capillaries (GCs) and reduction in the number of capillaries (nCs), suggest a disease activity (DA) phase in systemic sclerosis (SSc). In a previous paper, we showed that the number of micro-haemorrhages and micro-thromboses (the so-called NEMO score) was the NVC feature more closely associated with DA. The present study was aimed at validating the NEMO score as a measure of DA in patients with SSc., Methods: Two cohorts of 122 and 97 patients with SSc who were referred to two different rheumatology units, one in Milan and one in Naples, respectively, constituted the validation cohorts. The NEMO score, the total number of GCs and the mean nCs per digit were the parameters defined in each patient by eight-finger NVC. An expert operator analysed the NVCs in each of the participating units. The European Scleroderma Study Group (ESSG) index was used to define the DA level in each patient at the time of NVC examination., Results: The NEMO score was the NVC parameter more strictly correlated with the ESSG score in both the Milan and Naples cohorts (p < 0.0001), and it was the only one among the NVC variables that gave a significant contribution in a logistic model where the ESSG score represented the dependent variable. ROC curve analysis confirmed that the NEMO score had the best performance in measuring DA. The AUC of the NEMO score was significantly greater than the AUCs obtained by plotting the sensitivity and specificity of the number of GCs and the mean nCs (p < 0.0001 in all cases). The NEMO score values that showed the best sensitivity-specificity balance in capturing patients with a relevant DA level were slightly higher in the Naples cohort than in the Milan cohort., Conclusions: This study confirms that the presence of a certain number of MHEs and MTs in NVC may be considered a strong warning signal of a current phase of DA in patients with SSc.

Objective: To report our experience on novel, off-label use of Amplatzer Duct Occluder type II additional sizes (ADO II-AS) device (St. Jude Medical, Inc.; St. Paul, Minnesota, USA) to manage nonduct shunt lesions., Methods and Results: Among the 114 patients submitted to ADO II-AS implantation at our institution, 12 received this device as off-label treatment of paravalvular leak (n = 5), sinus of Valsalva fissuration (n = 2), accessory atrial septal defect (n = 2), muscular ventricular septal defect (n = 1), bleeding bronchial artery aneurysm (n = 1) and reverse shunt due to abnormal origin of left subclavian artery from pulmonary artery (n = 1). Age and body weight of these patients ranged from 3 to 74 years and from 15 to 80 kg, respectively. All procedures were completed without anatomical, functional or ECG complications and without residual shunt. In one patient with mitral paravalvular leak, mild restriction of the posterior disc excursion after device deployment was recorded., Conclusion: In our case series, ADO II-AS was well tolerated, versatile and cost-effective in treatment of different types of nonduct shunt lesions, mainly in young children and in older patients with comorbidities.

With an eye on the sequence of two Indian papers concurrently published in Diabetes Therapy, this paper analyzes skin differences among races and points to a lack of organized structured education sessions as the main cause of the high prevalence of lipodystrophy (LD) and consequent poor metabolic control. Only half of all insulin-treated patients reach their therapeutic targets worldwide. The factors involved in this are manifold, including the choice of overlong and repeatedly reused needles, as well as a failure to systematically rotate injection sites, all of which lead to skin LD. Regularly issued guidelines and expert recommendations provide suggestions about how to correct poor injection techniques, but LD still occurs at a high rate and is associated with poor metabolic control, a high risk of complications, frequent severe hypoglycemic episodes, and huge health and social costs. Poor knowledge of subcutaneous tissue anatomy and the physiological response to insulin injection by both health care personnel and patients may contribute to this problem. Moreover, differences in body structure among the races present in our multiethnic societies must be taken into account when choosing needle length and shooting technique in order to avoid accidental intramuscular injections.

Objectives: This study aimed to report a large, single-center experience of percutaneous arterial duct (AD) closure using Amplatzer Duct Occluder II Additional Sizes device (ADO II-AS)(St. Jude Medical Corp, St. Paul, MN, USA)., Background: Transcatheter closure of AD remains challenging in low body weight patients and those who have a persisting shunt following a previous attempt at interventional closure. Recent technical advances in device design may address these issues., Methods: From May 2011 to April 2016, 109 patients underwent attempted percutaneous closure of AD with ADO II-AS at our Institution. Mean age and weight were 4.8 ± 8.1 years (range 0-48) and 21.4 ± 20.6 kg (range 3-93), respectively. Fifteen patients (13.8%) were ≤6 kg (age 3.5 ± 2.0 months; weight 4.7 ± 1.1 kg). Arterial duct morphology was type A in 62 (57%), type B in 1 (1%), type C in 32 (29%), type D in 7 (6%) and type E in 6 patients (6%), respectively. Arterial approach was used to negotiate and deploy the occluding device in 103 patients (94.5%)., Results: AD diameter was 2.2 ± 0.6 (range 1.5-4.5) resulting in QP/QS of 1.9 ± 0.7 (range 1-3.3). Mean pulmonary artery pressure and PA/aortic pressure ratio were 19.3 ± 5.0 mm Hg (range 12-38) and 0.34 ± 0.14 (range 0.14-0.95), respectively. Successful device deployment was achieved in 107 patients (98.2%). Neither procedural morbidity nor mortality was recorded. Immediate, 24h and mid-term (30 ± 17 months) complete occlusion was recorded in 71%, 98.1%, and 100% of patients, respectively., Conclusion: In our experience, trans-catheter closure of AD of different sizes and morphologies using ADO II-AS is highly feasible, safe and effective also in challenging anatomic/clinical settings. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

: A 56-year-old patient was referred because of refractory heart failure and mild haemolysis caused by multiple, severe paravalvular leaks of a Starr-Edwards valve implanted in mitral position 23 years before. Owing to perceived high risk of surgical re-valving, percutaneous paravalvular leak occlusion was performed by implantation of multiple, simultaneously deployed Amplatzer Vascular Plugs.

Pediatric T-ALL patients have a worse outcome compared to BCP-ALL patients and they could benefit from new prognostic marker identification. Alteration of CRLF2 gene, a hallmark correlated with poor outcome in BCP-ALL, has not been reported in T-ALL.We analyzed CRLF2 expression in 212 T-ALL pediatric patients enrolled in AIEOP-BFM ALL2000 study in Italian and German centers.Seventeen out of 120 (14.2%) Italian patients presented CRLF2 mRNA expression 5 times higher than the median (CRLF2-high); they had a significantly inferior event-free survival (41.2%±11.9 vs. 68.9%±4.6, p=0.006) and overall survival (47.1%±12.1 vs. 73.8%±4.3, p=0.009) and an increased cumulative incidence of relapse/resistance (52.9%±12.1 vs. 26.2%±4.3, p=0.007) compared to CRLF2-low patients. The prognostic value of CRLF2 over-expression was validated in the German cohort. Of note, CRLF2 over-expression was associated with poor prognosis in the high risk (HR) subgroup where CRLF2-high patients were more frequently allocated.Interestingly, although in T-ALL CRLF2 protein was localized mainly in the cytoplasm, in CRLF2-high blasts we found a trend towards a stronger TSLP-induced pSTAT5 response, sensitive to the JAK inhibitor Ruxolitinib.In conclusion, CRLF2 over-expression is a poor prognostic marker identifying a subset of HR T-ALL patients that could benefit from alternative therapy, potentially targeting the CRLF2 pathway.

Background and Aims: We sought to correlate hepcidin levels in inflammatory bowel disease [IBD] children with disease activity, inflammatory markers, and iron load test [ILT] and to compare IBD patients with coeliac and healthy patients., Methods: Between December 2012 and June 2013, 145 subjects [50 IBD patients, 45 coeliac patients and 50 healthy controls] were included in the study. All patients underwent the following examinations: blood count, iron status, erythropoiesis parameters, serum hepcidin, C-reactive protein [CRP], and erythrocyte sedimentation rate [ESR]. In order to evaluate the efficacy of iron absorption, ILT was performed in IBD patients. Disease activity indexes and IBD duration, localisation, and therapy were also evaluated, and a faecal sample for calprotectin collected., Results: Serum hepcidin was significantly higher in IBD patients with active disease compared with both coeliac and healthy patients [p = 0.005, p = 0.003 respectively]. In a multivariate logistic regression model, having a Paediatric Crohn's Disease Activity Index [PCDAI] / Paediatric Ulcerative Colitis Activity Index [PUCAI] ≥ 30 resulted in the only variable independently associated with a positive serum hepcidin (odds ratio [OR] = 6.87; 95% confidence interval [CI] 1.4-33, p = 0.01]]. Patients with iron malabsorption [IM] showed higher values of ESR, CRP, and hepcidin [p = 0.02, p = 0.001, and p = 0.06, respectively]. Eight out of 12 [66.7%] children with IM showed an active disease compared with 6/31 [19.3%] children with normal ILT [p = 0.01]. Hepcidin levels correlated negatively with ILT [r = -0.451, p = 0.002], and positively with ferritin and CRP [r = 0.442, p = 0.0001; r = 0.243, p = 0.009, respectively], Conclusions: Our study demonstrates that serum hepcidin is increased in IBD children with active disease and it is responsible for IM., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Neurological disorders can be associated with protein glycosylation abnormalities. Rett syndrome is a devastating genetic brain disorder, mainly caused by de novo loss-of-function mutations in the methyl-CpG binding protein 2 (MECP2) gene. Although its pathogenesis appears to be closely associated with a redox imbalance, no information on glycosylation is available. Glycoprotein detection strategies (i.e., lectin-blotting) were applied to identify target glycosylation changes in the whole brain of Mecp2 mutant murine models of the disease. Remarkable glycosylation pattern changes for a peculiar 50kDa protein, i.e., the N-linked brain nucleotide pyrophosphatase-5 were evidenced, with decreased N-glycosylation in the presymptomatic and symptomatic mutant mice. Glycosylation changes were rescued by selected brain Mecp2 reactivation. Our findings indicate that there is a causal link between the amount of Mecp2 and the N-glycosylation of NPP-5., (Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Aims: To compare metabolic control under lispro and recombinant regular human insulin (RHI) in people with diet-unresponsive type 2 diabetes mellitus (T2DM) and compensated non-alcoholic liver disease (CLD)., Methods: 108 people with T2DM and CLD were randomly allocated to RHI or lispro according to a 12+12 week cross-over protocol. A 1-week continuous glucose monitoring (CGM) session was performed at the end of each treatment period followed by a standard meal test with a 12IU lispro or RHI shot ahead., Results: CGM showed higher glycemic excursions under RHI than under lispro (p<0.01) with lower glucose levels in the late post-absorption phase (p<0.05) and even more during the night (p<0.01). Post-challenge incremental areas under the curve (ΔAUC) were undistinguishable for insulin but lower for glucose, while insulin peaked higher and earlier and glycemic excursions were lower with lispro than with RHI (0.05

Objective: Significant and balanced pulmonary artery (PA) growth following arterial duct (AD) stenting has already been reported in literature. However, no data are so far available about the role of this percutaneous approach in promoting PA growth in the case of congenital heart disease (CHD) with completely duct-dependent pulmonary blood flow (CDD-PBF). Aim of this study was to evaluate the effect of AD stenting in this pathophysiological setting., Methods: PA growth was evaluated as Nakata index and McGoon ratio as well as individual PA z-score changes in 49 patients submitted to neonatal AD stenting according to their pathophysiology (CDD-PBF (n=15) versus multiple PBF sources (n=34))., Results: Control angiography was performed 7.2±6.4 months (range 1-8, median 6) after AD stenting. In the whole population, significant and balanced PA growth was recorded (Nakata index+122±117%; left pulmonary artery (LPA) z-score +84±52%; right pulmonary artery (RPA) z-score +92±53% versus preprocedure, p<0.0001 for all comparisons). Percentage increase of global and branch vessel size was not significantly different in patients with CDD-PBF compared with those with multiple PBF sources (Nakata index 89±90% vs 144±124%; LPA z-score 63±40% vs 89±58%; RPA z-score 74±35% vs 100±57%, p=NS for all comparisons) as was final absolute PA size (Nakata index 237±90 vs 289±80 mm(2)/m(2), p=NS)., Conclusions: Percutaneous AD stenting was associated with significant and balanced PA growth in CHD with completely duct-dependent pulmonary circulation over a short-term follow-up. Thus, it may be considered as an alternative to surgical palliation in this subset of patients., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

In the setting of acute pulmonary embolism (PE), pulmonary infarction is deemed to occur primarily in individuals with compromised cardiac function.The current study was undertaken to establish the prevalence of pulmonary infarction in patients with acute PE, and the relationship between infarction and: age, body height, body mass index (BMI), smoking habits, clot burden, and comorbidities.The authors studied prospectively 335 patients with acute PE diagnosed by computed tomographic angiography (CT) in 18 hospitals throughout central Italy. The diagnosis of pulmonary infarction on CT was based on Hampton and Castleman's criteria (cushion-like or hemispherical consolidation lying along the visceral pleura). Multivariable logistic regression was used to model the relationship between covariates and the probability of pulmonary infarction.The prevalence of pulmonary infarction was 31%. Patients with infarction were significantly younger and with significantly lower prevalence of cardiovascular disease than those without (P < 0.001). The frequency of infarction increased linearly with increasing height, and decreased with increasing BMI. In logistic regression, the covariates significantly associated with the probability of infarction were age, body height, BMI, and current smoking. The risk of infarction grew with age, peaked at approximately age 40, and decreased afterwards. Increasing body height and current smoking were significant amplifiers of the risk of infarction, whereas increasing BMI appeared to confer some protection.Our data indicate that pulmonary infarction occurs in nearly one-third of the patients with acute PE. Those with infarction are often young and otherwise healthy. Increasing body height and active smoking are predisposing risk factors.

Objectives: This study sought to evaluate the impact of arterial duct (AD) stenting in promoting catch-up growth of hypoplastic pulmonary artery (PA) tree in congenital heart disease with duct-dependent pulmonary circulation (CHD-DPC)., Background: Significant and balanced PA growth following AD stenting has already been consistently reported in the literature. However, no data are so far available about the role of this approach in severe PA hypoplasia, which significantly impacts the risk of surgical repair., Methods: Pre-surgical angiographic PA evaluation was performed in 45 patients with confluent PAs submitted to neonatal AD stenting as palliation of CHD-DPC. PA growth was evaluated as Nakata Index and McGoon ratio as well as individual PA z-score changes, both in the whole population and according to the original vessel size (Nakata Index <100 mm(2)/m(2), Group I [n = 15] vs. Nakata Index >100 mm(2)/m(2), Group II [n = 30])., Results: Control angiography was performed 7.5 ± 6.5 months (median 6 months) after duct stenting, showing significant and balanced PA growth. The Nakata Index increased from 143 ± 73 mm(2)/m(2) to 270 ± 88 mm(2)/m(2) (124 ± 118%, p < 0.0001); left PA z-score from -0.7 ± 1.7 to 1.0 ± 1.4; right PA z-score from -0.6 ± 1.3 to 1.2 ± 1.3 (p < 0.0001 for both comparisons). Group I showed a greater increase of global PA growth (Nakata Index increase 227 ± 141% vs. 72 ± 57%, p < 0.001) as compared with Group II. Final PA size did not significantly differ between the groups (246 ± 105 mm(2)/m(2) vs. 282 ± 78 mm(2)/m(2), p = NS)., Conclusions: Percutaneous AD stenting is highly effective in promoting a significant and balanced catch-up growth of diminutive PAs, being therefore advisable in this subset of patients as a reliable alternative to surgical palliation., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Chronic kidney disease (CKD) entails a worse cardiovascular outcome. The aim of our work was to study the relationship between CKD and the achievement of recommended targets for glycated haemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-c) and blood pressure (BP) in a real-life sample of patients with type 2 diabetes mellitus (T2DM)., Methods: We analysed a sample of 116 777 outpatients from the Network of the Italian Association of Clinical Diabetologists; all patients had T2DM and at least one measurement of HbA1c, LDL-c, BP, serum creatinine and albuminuria in the year 2010. The outcome was the achievement of HbA1c, LDL-c and BP values as recommended by International Guidelines., Results: In the entire sample, the mean value of HbA1c was 7.2 ± 1.2%, of LDL-c was 102 ± 33 mg/dL and of BP was 138/78 ± 19/9 mmHg. CKD and its components were associated with poor glycaemic and BP control, notwithstanding greater use of glucose and BP-lowering drugs, while no association was found with LDL-c values. Factors independently related to unsatisfactory glycaemic control included female gender, body mass index, duration of disease and high albuminuria. Men, older people and those taking statins were more likely to reach LDL-c target levels. Male gender, age and high albuminuria strongly affected the achievement of BP targets., Conclusions: CKD or its components, mainly high albuminuria, are associated with failure to reach therapeutic targets, especially for HbA1c and BP, despite a greater use of drugs in patients with T2DM., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Objectives: To evaluate early results, learning-curve changes, and mid-term outcome of arterial duct (AD) stenting in congenital heart disease with duct-dependent pulmonary circulation (CHD-DPC) in a high-volume, tertiary referral center., Background: In spite of wide acceptance as cost-effective alternative to surgical palliation, AD stenting indications, results and mid-term outcome still largely depend on small series, experiences in particular subsets of patients or multicenter series with different approaches and interventional philosophy., Methods: Between April 2003 and December 2013, 119 patients underwent AD stenting as lower-risk palliation of CHD-DPC at our Institution. Procedural and mid-term follow-up data of these patients are reported., Results: The procedure was successfully completed in 93.3% of cases, with a complication rate and in-hospital mortality of 17.6% and 3.6%, respectively. No patient underwent rescue surgical shunt but elective Blalock-Taussig shunt was needed in 15 patients (13.5%). Over time, favorable trends toward higher feasibility and efficacy in complex ductal anatomy as well as lower procedural risk were recorded. Presurgical cardiac catheterization (n = 36) showed significant and balanced pulmonary artery (PA) growth (Nakata Index +113 ± 101%; left PA z-score +87 ± 52%; right PA z-score +97 ± 53%, P < 0.001 for all comparisons), without significant changes of left-to-right PA diameter ratio. PA growth was significantly better in patients with severely hypoplastic PAs at the time of duct stabilization (Nakata Index increase 194 ± 115 vs. 75 ± 61%, P < 0.001)., Conclusions: AD stenting is feasible and effective at low-risk in a high percentage of patients with CHD-DPC, promoting significant and balanced PA growth mainly in patients with hypoplastic main PAs at duct stabilization., (© 2015 Wiley Periodicals, Inc.)

Objective: To assess the efficacy of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS)., Methods: Patients with probable laboratory-supported, probable or definite ALS were enrolled by 25 Italian centres and randomly assigned (1:1) to receive intravenous rhEPO 40,000 IU or placebo fortnightly as add-on treatment to riluzole 100 mg daily for 12 months. The primary composite outcome was survival, tracheotomy or >23 h non-invasive ventilation (NIV). Secondary outcomes were ALSFRS-R, slow vital capacity (sVC) and quality of life (ALSAQ-40) decline. Tolerability was evaluated analysing adverse events (AEs) causing withdrawal. The randomisation sequence was computer-generated by blocks, stratified by centre, disease severity (ALSFRS-R cut-off score of 33) and onset (spinal or bulbar). The main outcome analysis was performed in all randomised patients and by intention-to-treat for the entire population and patients stratified by severity and onset. The study is registered, EudraCT 2009-016066-91., Results: We randomly assigned 208 patients, of whom 5 (1 rhEPO and 4 placebo) withdrew consent and 3 (placebo) became ineligible (retinal thrombosis, respiratory insufficiency, SOD1 mutation) before receiving treatment; 103 receiving rhEPO and 97 placebo were eligible for analysis. At 12 months, the annualised rate of death (rhEPO 0.11, 95% CI 0.06 to 0.20; placebo: 0.08, CI 0.04 to 0.17), tracheotomy or >23 h NIV (rhEPO 0.16, CI 0.10 to 0.27; placebo 0.18, CI 0.11 to 0.30) did not differ between groups, also after stratification by onset and ALSFRS-R at baseline. Withdrawal due to AE was 16.5% in rhEPO and 8.3% in placebo. No differences were found for secondary outcomes., Conclusions: RhEPO 40,000 IU fortnightly did not change the course of ALS., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Purpose: To evaluate long-term keratoconus stability after corneal crosslinking (CXL) with riboflavin., Methods: In this prospective study, 57 eyes of 55 patients with progressive keratoconus, consecutively treated with ultraviolet A (UVA) - riboflavin CXL, were examined with the corneal topographer Pentacam, the biometer IOLMaster and the analyzer of corneal biomechanics Ocular Response Analyzer before and during a 24 months follow-up after CXL., Results: Twenty-four months after CXL, there was a significant improvement in best corrected visual acuity (BCVA) (P<0.01), a significant decrease in corneal thinnest point (CTP), keratometry readings at the keratoconus apex (K max), and corneal volume (CV) (P<0.01), and a significant increase in axial eye length (AL) (P=0.01). No significant changes in anterior chamber volume (ACV) and depth (ACD), (P=0.8), corneal hysteresis (CH) (P=0.16) and corneal resistance factor (CRF) (P=0.06) were found. However, in the subgroup of patients with decreased K max readings 24 months after treatment, both CH and CRF showed a significant reduction (P<0.01)., Conclusion: In the first month after the procedure, CXL induces a reduction in corneal volume. During the 24 months follow-up the cornea tends to recover its original volume with a persistence of the CXL efficacy., (Copyright © 2013 Spanish General Council of Optometry. Published by Elsevier Espana. All rights reserved.)

Background: Beckwith-Wiedemann syndrome (BWS) is a rare pediatric overgrowth disorder with a variable clinical phenotype caused by deregulation affecting imprinted genes in the chromosomal region 11p15. Alterations of the imprinting control region 1 (ICR1) at the IGF2/H19 locus resulting in biallelic expression of IGF2 and biallelic silencing of H19 account for approximately 10% of patients with BWS. The majority of these patients have epimutations of the ICR1 without detectable DNA sequence changes. Only a few patients were found to have deletions. Most of these deletions are small affecting different parts of the ICR1 differentially methylated region (ICR1-DMR) removing target sequences for CTCF. Only a very few deletions reported so far include the H19 gene in addition to the CTCF binding sites. None of these deletions include IGF2., Case Presentation: A male patient was born with hypotonia, facial dysmorphisms and hypoglycemia suggestive of Beckwith-Wiedemann syndrome. Using methylation-specific (MS)-MLPA (Multiplex ligation-dependent probe amplification) we have identified a maternally inherited large deletion of the ICR1 region in a patient and his mother. The deletion results in a variable clinical expression with a classical BWS in the mother and a more severe presentation of BWS in her son. By genome-wide SNP array analysis the deletion was found to span ~100 kb genomic DNA including the ICR1DMR, H19, two adjacent non-imprinted genes and two of three predicted enhancer elements downstream to H19. Methylation analysis by deep bisulfite next generation sequencing revealed hypermethylation of the maternal allele at the IGF2 locus in both, mother and child, although IGF2 is not affected by the deletion., Conclusions: We here report on a novel large familial deletion of the ICR1 region in a BWS family. Due to the deletion of the ICR1-DMR CTCF binding cannot take place and the residual enhancer elements have access to the IGF2 promoters. The aberrant methylation (hypermethylation) of the maternal IGF2 allele in both affected family members may reflect the active state of the normally silenced maternal IGF2 copy and can be a consequence of the deletion. The deletion results in a variable clinical phenotype and expression.

Background and Aim: There is uncertainty regarding the prevention of migraine crises by changing the lifestyle of patients. The aim of this randomized, crossover intervention trial was to evaluate the effects of a low lipid intake on the incidence and severity of migraine crises, in comparison to a diet with moderate lipid intake., Methods and Results: After a 2-month run-in when patients received preventive medication but were left on their habitual diet, a low-lipid or a normal-lipid diet was randomly prescribed for 3 months and thereafter diets were crossed over for the following 3 months. Headache was diagnosed based on the International Classification of Headache Disorders (IHCD) III criteria. The number and severity of attacks were assessed using a self-reported calendar. Adherence to the diet was assessed by a food frequency questionnaire. An analysis was performed on the 83 episodic or chronic migraineurs (63 female and 20 male), in the age range of 18-57 years, who completed both intervention periods. Obese subjects had a significantly higher number of attacks than those overweight or with normal body weight (24.7 ± 8, 16.3 ± 12, and 15.6 ± 11, respectively, p < 0.03) with a significant relationship between the body mass index (BMI) and the number of monthly attacks (r = 0.238, p < 0.03). The number (2.9 ± 3.7 vs. 6.8 ± 7.5, p < 0.001) and severity (1.2 + 0.9 vs. 1.7 ± 0.9, p < 0.01) of attacks significantly decreased during both intervention periods, with a significant difference in favour of the low-lipid diet., Conclusions: In this group of patients, the low-lipid diet significantly affected the number and severity of migraine attacks in comparison to a normal-lipid diet. ClinicalTrials.gov Identifier: NCT 01917474., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objectives: Self-injury (SI) is defined as a behavioral disturbance consisting of a deliberate harm to one's own body without suicidal intent, it is not uncommon and ranges in severity from simple nail-biting to more extreme forms of self-mutilation. The head neck region may be the target of such lesions. SI is associated with several medical conditions, of which it can represent the first clinical sign. Aim of this paper is to describe a series of oral SI, giving special emphasis to the clinical findings, etiology and the management of lesions., Material and Methods: A total of 19 patients with oral SI were prospectively examined; attention was paid to the occurrence and characterization of oral lesions. The management of the lesion also varied depending on the patient medical history, on the etiology of the psychiatric behavior, and on the severity, frequency, and method of inflicting injury. Periodic examinations were performed (after two weeks, three months and six months) and registered., Results: All the patients healed gradually and healing was conditioned by the disease underlying. The treatment consisted of behavior modification in 11 cases, pharmacological treatment in 11 cases, psychotherapy in 2 cases, mouth guard in 9 cases, surgery in 2 cases, extractions in 1 case., Conclusions: Oral SI are uncommon in the clinical practice. They may be associated with a known disease or may be the consequence of this, but often they may be the first sign of a psychiatric disorder.

Asthma is a phenotypically heterogeneous chronic disease of the airways, characterized by either predominant eosinophilic or neutrophilic, or even mixed eosinophilic/neutrophilic inflammatory patterns. Eosinophilic inflammation can be associated with the whole spectrum of asthma severity, ranging from mild-to-moderate to severe uncontrolled disease, whereas neutrophilic inflammation occurs mostly in more severe asthma. Eosinophilic asthma includes either allergic or nonallergic phenotypes underlying immune responses mediated by T helper (Th)2 cell-derived cytokines, whilst neutrophilic asthma is mostly dependent on Th17 cell-induced mechanisms. These immune-inflammatory profiles develop as a consequence of a functional impairment of T regulatory (Treg) lymphocytes, which promotes the activation of dendritic cells directing the differentiation of distinct Th cell subsets. The recent advances in the knowledge of the cellular and molecular mechanisms underlying asthmatic inflammation are contributing to the identification of novel therapeutic targets, potentially suitable for the implementation of future improvements in antiasthma pharmacologic treatments.

Purpose: To evaluate keratoconus biomechanical changes after transepithelial corneal collagen cross linking (TE CXL) using riboflavin and ultraviolet A (UVA)., Setting: Second University of Naples, Naples, Italy., Design: Prospective non comparative case series study., Methods: Patients with progressive keratoconus were examined, before and during a 6 months follow up after TE CXL, with a Pentacam, an Ocular Response Analyzer and an IOLMaster. Best corrected visual acuity (BCVA), refraction, corneal thinnest point (CTP), keratometry readings at the keratoconus apex (Kmax), axial eye length (AL), corneal volume (CV) anterior chamber volume (ACV), anterior chamber depth (ACD), corneal hysteresis (CH) and corneal resistance factor (CRF) were evaluated., Results: Thirty-six eyes of 36 patients with progressive keratoconus were analyzed. Six months after treatment there was a significant improvement in BCVA (p<0.01), no significant changes in refraction (p=0.57), CTP (p=0.07), Kmax (p=0.88), AL (p=0.07), CV (p=0.38), ACV (p=0.07), ACD (p=0.7), CH (p=0.1) and CRF (p=0.3)., Conclusions: According to our results TE CXL stabilizes most of the patients with progressive keratoconus, without affecting in negative way the corneal elasticity., (Copyright © 2014 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Locus minoris resistentiae (lmr) refers to a body region more vulnerable than others. This ancient concept, which is also present in Achilles' and Siegfried's old epic myths, weaves through many fields of medicine. In any internal organ or external body region with a congenital or acquired altered defense capacity, a disease process may occur more easily than elsewhere. Illustrative instances are the appearance of hepatocarcinoma on a cirrhotic liver, the onset of lung carcinoma in a tuberculosis scar, cases of osteosarcoma arising in chronic osteomyelitis, and carcinoma complicating chronic cholelithiasis, just to name a few. In dermatology there are countless reports of privileged localization of cutaneous lesions on injured skin which, therefore, represents a typical condition of lmr. The Köbner phenomenon itself features the oldest, simplest, and most common example of lmr, because it denotes the appearance of new lesions pertaining to a previously present skin disorder at the sites of trauma or other insult. The modern transposition of this old but still valid way of thinking in medicine is the reading key of this issue, devoted to lmr in dermatology., (Copyright © 2014. Published by Elsevier Inc.)

Context: Surgery represents the mainstay of treatment for pelvic organ prolapse (POP). Among different surgical procedures, abdominal sacrocolpopexy (SC) is the gold standard for apical or multicompartmental POP. Research has recently focused on the role of robot-assisted sacrocolpopexy (RASC)., Objective: To conduct a systematic review on the outcomes of RASC., Evidence Acquisition: PubMed, Scopus, and Web of Science databases as well as ClinicalTrials.gov were searched for English-language literature on RASC. A total of 509 articles were screened; 50 (10%) were selected, and 27 (5%) were included. Studies were evaluated per the Grading of Recommendations, Assessment, Development, and Evaluation system and the European Association of Urology guidelines., Evidence Synthesis: Overall, data on 1488 RASCs were collected from 27 studies, published from 2006 to 2013. Objective and subjective cures ranged from 84% to 100% and from 92% to 95%, respectively. Conversion rate to open surgery was <1% (range: 0-5%). Intraoperative, severe postoperative complications, and mesh erosion rates were 3% (range: 0-19%), 2% (range: 0-8%), and 2% (range: 0-8%), respectively. Surgical-related outcomes have improved with increased experience, with an estimated learning curve of about 10-20 procedures. Laparoscopic SC is less costly than RASC, although the latter has lower costs than abdominal SC., Conclusions: RASC is a safe and feasible procedure for POP; it allows the execution of complex surgical steps via minimally invasive surgery without medium- and long-term anatomic detriments. Further prospective studies are needed to confirm these findings., Patient Summary: We looked at the outcomes of robotic sacrocolpopexy for prolapse. We found that the use of robotic technology is safe and effective for the treatment of prolapse in women., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Many asthmatic women complain of symptom exacerbations in particular periods, i.e. during pregnancy and menstrual cycles (perimenstrual asthma: PMA)". The goal of this study was to study the effect of the luteal and follicular phases of the menstrual cycle on bronchial reactivity (BR) in a group of asthmatic women., Methods: For this purpose, 36 pre-menopausal women were enrolled and underwent testing for resting pulmonary function, measurement of the diffusing capacity of the lung for carbon monoxide (DLCO), and airway responsiveness to methacholine in the follicular and luteal phases of their menstrual cycles. We also measured plasma hormone levels and levels of cyclic adenosine monophosphate (cAMP; a mediator of bronchial smooth muscle contraction) and testosterone in induced sputum samples., Results: Our study showed that about 30% of the asthmatic women had decreased PC20FEV1.0 in the follicular phase of menstrual cycle with a significant correlation between PC20FEV1.0 and serum testosterone levels. Moreover, marked increases in sputum testosterone levels (mean=2.6-fold increase) together with significant increases in sputum cAMP concentrations (mean=3.6-fold increases) were observed during the luteal phase of asthmatic patients, suggesting that testosterone contributes to the pathophysiology of PMA. We excluded the possibility that testosterone directly inhibits phosphodiesterase (PDE) activity as incubating PDE with testosterone in vitro did not reduce PDE catalytic activity., Conclusions: In conclusion, our data show that PC20FEV1.0 was decreased in the follicular phase of the menstrual cycle in about 30% of women and was associated with lower cAMP levels in sputum samples, which may contribute to bronchoconstriction. Our results also suggest a link between PMA and testosterone levels. However, whether these findings are of clinical significance in terms of the management of asthma or asthma worsening during the menstrual cycle needs further investigation.

Objective: To test the hypothesis that the simultaneous administration of GLP-1 and insulin may increase their vasodilatory, antiinflammatory, and antioxidant action in type 2 diabetes., Research Design and Methods: In two groups of persons with type 2 diabetes, two sets of experiments were performed. The first group had two normoglycemic-normoinsulinemic clamps with or without GLP-1 and two normoglycemic-hyperinsulinemic clamps with or without GLP-1. The second group had two hyperglycemic-normoinsulinemic clamps and two hyperglycemic-hyperinsulinemic clamps with or without GLP-1., Results: During the normoglycemic-hyperinsulinemic clamp, flow-mediated dilatation (FMD) increased, while soluble intercellular adhesion molecule (sICAM-1), plasma 8-iso-prostaglandin F2α (8-iso-PGF2α), nitrotyrosine, and interleukin (IL)-6 decreased compared with normoglycemic-normoinsulinemic clamp. Similar results were obtained with the infusion of GLP-1 during the normoglycemic-normoinsulinemic clamp. The combination of hyperinsulinemia and GLP-1 in normoglycemia was accompanied by a further FMD increase and sICAM-1, 8-iso-PGF2α, nitrotyrosine, and IL-6 decrease. During the hyperglycemic-normoinsulinemic clamp, FMD significantly decreased, while sICAM-1, 8-iso-PGF2α, nitrotyrosine, and IL-6 significantly increased. When hyperglycemia was accompanied by hyperinsulinemia or by the simultaneous infusion of GLP-1, these phenomena were attenuated. The simultaneous presence of hyperinsulinemia and GLP-1 had an increased beneficial effect., Conclusions: Our results show that the combination of insulin and GLP-1 is more effective than insulin or GLP-1 alone in improving endothelial dysfunction, inflammation, and oxidative stress in type 2 diabetes., (© 2014 by the American Diabetes Association.)

Introduction: To evaluate the applicability of a modified Clavien classification system (CCS) in grading postoperative complications of transurethral resection of bladder tumours (TURB)., Materials and Methods: A series of patients undergoing monopolar TURB from April 2011 to March 2012 at five Italian centers were enrolled. All complications occurring within the first 30-day postoperative period were prospectively recorded and graded according to the CCS., Results: Overall, 275 patients were included. Median age was 71 (63/78) years; median BMI was 28 (25.4/30.8) Kg/m(2), median tumour size was 2 (1-3) cm; median number of tumour lesions was 1 (1-3). Median operative time was 30 (20/45) min. Fifty-seven complications were recorded in 43 patients. Overall postoperative morbidity rate was 16%. Most of the complications were not serious and classified as Clavien type I (42 cases; 74%) or II (8 cases, 14%). Higher grade complications were scarce: CCS IIIa in 1 case (2%) and CCS IIIb in six cases (10%). No TURB related death was reported. Six patients were re-operated due to significant bleeding or clot retention on postoperative days 2-7. On univariate (73.5 ± 38 versus 36.7 ± 21.6 min) and multivariate analysis longer operative time was an independent predictor of complications (OR: 1.06 per min, 95%CI 1.04-1.08, p = 0.001)., Conclusions: A modified CCS can be used as a standardized tool to objectively define the complications of TURB which confirms to be a safe procedure with a low surgical morbidity. This tool can be used to aid in patient counselling and to facilitate scientific assessment., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: To compare 3T elliptical-centric CE MRA with 3T TOF MRA for the detection and characterization of unruptured intracranial aneurysms (UIAs), by using digital subtracted angiography (DSA) as reference., Materials and Methods: Twenty-nine patients (12 male, 17 female; mean age: 62 years) with 41 aneurysms (34 saccular, 7 fusiform; mean diameter: 8.85 mm [range 2.0-26.4mm]) were evaluated with MRA at 3T each underwent 3D TOF-MRA examination without contrast and then a 3D contrast-enhanced (CE-MRA) examination with 0.1mmol/kg bodyweight gadobenate dimeglumine and k-space elliptic mapping (Contrast ENhanced Timing Robust Angiography [CENTRA]). Both TOF and CE-MRA images were used to evaluate morphologic features that impact the risk of rupture and the selection of a treatment. Almost half (20/41) of UIAs were located in the internal carotid artery, 7 in the anterior communicating artery, 9 in the middle cerebral artery and 4 in the vertebro-basilar arterial system. All patients also underwent DSA before or after the MR examination., Results: The CE-MRA results were in all cases consistent with the DSA dataset. No differences were noted between 3D TOF-MRA and CE-MRA concerning the detection and location of the 41 aneurysms or visualization of the parental artery. Differences were apparent concerning the visualization of morphologic features, especially for large aneurysms (>13 mm). An irregular sac shape was demonstrated for 21 aneurysms on CE-MRA but only 13/21 aneurysms on 3D TOF-MRA. Likewise, CE-MRA permitted visualization of an aneurismal neck and calculation of the sac/neck ratio for all 34 aneurysms with a neck demonstrated at DSA. Conversely, a neck was visible for only 24/34 aneurysms at 3D TOF-MRA. 3D CE-MRA detected 15 aneurysms with branches originating from the sac and/or neck, whereas branches were recognized in only 12/15 aneurysms at 3D TOF-MRA., Conclusion: For evaluation of intracranial aneurysms at 3T, 3D CE-MRA is superior to 3D TOF-MRA for assessment of sac shape, detection of aneurysmal neck, and visualization of branches originating from the sac or neck itself, if the size of the aneurysm is greater than 13 mm. 3T 3D CE-MRA is as accurate and effective as DSA for the evaluation of UIAs., (Copyright © 2013. Published by Elsevier Ireland Ltd.)

Background: Hormones and growth factors influence the proliferation and invasiveness of human mesenchymal tumors. The highly aggressive human fibrosarcoma HT1080 cell line harbors classical androgen receptor (AR) that responds to androgens triggering cell migration in the absence of significant mitogenesis. As occurs in many human cancer cells, HT1080 cells also express epidermal growth factor receptor (EGFR)., Findings: We report that the pure anti-androgen Casodex inhibits the growth of HT1080 cell xenografts in immune-depressed mice, revealing a novel role of AR in fibrosarcoma progression. In HT1080 cultured cells EGF, but not androgens, robustly increases DNA synthesis. Casodex abolishes the EGF mitogenic effect, implying a crosstalk between EGFR and AR. The mechanism underlying this crosstalk has been analyzed using an AR-derived small peptide, S1, which prevents AR/Src tyrosine kinase association and androgen-dependent Src activation. Present findings show that in HT1080 cells EGF induces AR/Src Association, and the S1 peptide abolishes both the assembly of this complex and Src activation. The S1 peptide inhibits EGF-stimulated DNA synthesis, cell matrix metalloproteinase-9 (MMP-9) secretion and invasiveness of HT1080 cells. Both Casodex and S1 peptide also prevent DNA synthesis and migration triggered by EGF in various human cancer-derived cells (prostate, breast, colon and pancreas) that express AR., Conclusion: This study shows that targeting the AR domain involved in AR/Src association impairs EGF signaling in human fibrosarcoma HT1080 cells. The EGF-elicited processes inhibited by the peptide (DNA synthesis, MMP-9 secretion and invasiveness) cooperate in increasing the aggressive phenotype of HT1080 cells. Therefore, AR represents a new potential therapeutic target in human fibrosarcoma, as supported by Casodex inhibition of HT1080 cell xenografts. The extension of these findings in various human cancer-derived cell lines highlights the conservation of this process across divergent cancer cells and identifies new potential targets in the therapeutic approach to human cancers.

Percutaneous closure currently is widely considered to be the first-choice therapeutic option in the treatment of ostium secundum atrial septal defect (ASD). The Amplatzer Septal Occluder (ASO) device is the most used prosthesis, although its influence on cardiac function still is under active investigation. This study aimed to evaluate the impact of the ASO device size on left ventricular (LV) function in pediatric patients using the speckle-tracking strain imaging technology. The study enrolled 43 nonobese pediatric patients submitted to percutaneous ASD closure with the Amplatzer Septal Occluder device and grouped them according to the size of the occluding prosthesis into three groups: a small-device group (≤ 10 mm, group 1), a medium-size-device group (11-16 mm, group 2), and a large-device group (≥ 17 mm, group 3). Echocardiographic data were compared among the groups and with the data of an age-, weight-, and gender-matched control group (50 patients). The large-device group showed a significant impairment in the strain rate value of the basal LV segments. In particular, the mean basal circumferential and radial strain rate values were lower than either normal or the values of the small- and medium-device groups. However, only the absolute device diameter reached statistical significance in the multivariate analysis. The large Amplatzer Septal Occluding device significantly impaired LV systolic function, particularly that of juxtaprosthetic segments, as shown in the strain rate analysis.

Several studies suggest that the N/OFQ (nociceptin/orphanin FQ)-NOP (N/OFQ peptide) receptor pathway is involved in airway physiology. We previously demonstrated a modulation of the endogenous N/OFQ levels in allergen-sensitized mice. Here, we investigated the effects of NOP receptor activation in allergen sensitization using a murine model of allergen-induced airway hyperresponsiveness (AHR). BALB/c mice were intraperitoneally treated with the NOP receptor agonist UFP-112, either during the sensitization phase (30 min before ovalbumin administration) or at the end of sensitization process (15 min before bronchopulmonary reactivity evaluation). At day 21 from the first allergen exposure, bronchopulmonary reactivity and total and differential cell count in bronchoalveolar lavage fluid were evaluated. In a separate set of experiments cell proliferation in lymphocytes, cytokine levels, IgE serum levels, and the effect of UFP-112 on IL-13-induced AHR were evaluated. Pretreatment with UFP-112, during the sensitization phase, caused a significant reduction in allergen-induced AHR and total cell lung infiltration. No effect on allergen-induced AHR was observed when the treatment was performed at the end of sensitization process, on tissues harvested from OVA-sensitized mice and on IL-13-induced AHR. The in vitro proliferative response of lymphocytes was significantly reduced by pretreatment during the sensitization phase with UFP-112. This effect was paralleled by a significant modulation of cytokine secretion in pulmonary tissues and lymphocytes. In conclusion, we demonstrated a role for the NOP receptor and N/OFQ pathway in the AHR induced by allergen, probably through a modulation of the immune response that triggers the development of AHR that involves pro- and anti-inflammatory cytokines.