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The aim of this meta-analysis was to derive normal reference values of biventricular size and function estimated by cardiac magnetic resonance (CMR) in competitive athletes. Exercise-induced enlargement of cardiac chambers is commonly observed in competitive athletes. However, ventricular dilatation is also a common phenotypic expression of life-threatening cardiomyopathies. The use of CMR for the exclusion of pathology is growing. However, normal reference values have not been established for athletes. The authors conducted a systematic review of English-language studies in the MEDLINE, Scopus, and Cochrane databases investigating biventricular size and function by CMR in athletes. Athletes were divided into endurance, combined, and mixed groups according to the sport practiced. The potential impact of training volume was also evaluated. Twenty-seven studies and 983 competitive athletes were included for CMR quantification of biventricular size and function. In this review, normal reference values are presented for biventricular size and function to be applied to male competitive athletes according to the disciplines practiced. A significant impact of training volume was demonstrated for the right ventricle: athletes practicing the largest number of training hours per week were those exhibiting the greatest degree of right ventricular remodeling. Notably, biventricular function was not significantly affected by training volume. The present meta-analysis defines the normal limits of biventricular size and function estimated by CMR in competitive athletes. The authors suggest using these normal reference values as an alternative to standard upper limits derived from the general population when interpreting CMR images in athletes. [ABSTRACT FROM AUTHOR]

Abstract Background Pre-participation screening (PPS) of athletes aged over 35 years (master athletes, MA) is a major concern in Sports Cardiology. In this population, sports-related sudden cardiac death is rare but usually due to coronary atherosclerosis (CA). Coronary CT Angiography (CCTA) has changed the approach to diagnosis/management of CA, but its role in this context still needs to be assessed. Methods and results We retrospectively examined 167 MA who underwent CCTA in our hospital since 2006, analyzing symptoms, stress-test ECG, cardiovascular risk profiles (SCORE) and CCTA findings. Among the whole enrolled population, 153 (91.6%) MA underwent CCTA for equivocal/positive stress-test ECG with/without symptoms, 13 (7.8%) just for clinical symptoms, 1 (0.6%) for the family history. The CCTA showed the presence of CA in 69 MA (41.3%), congenital coronary anomalies (anomalous origin or deep myocardial bridge) in 8 (4.8%), both in 7 (4.2%). A negative CCTA was observed in 83 MA (49.7%). The risk-SCORE (age, hypertension, hypercholesterolemia, smoking) was a good indicator for the presence of moderate/severe CA on CCTA. However, mild/moderate CA was present in 17.8% of MA clinically stratified at a low risk-SCORE. Conclusion While coronary angiography is more indicated in athletes with positive stress-test ECG and high clinical risk, the CCTA may be useful in the evaluation of MA with an abnormal stress test ECG and/or clinical symptoms engaged in competitive sports with a high cardiovascular involvement. Age, gender, presence of symptoms and clinical risk-SCORE assessment may help sports physicians and cardiologists to decide whether to request a CCTA or not. Highlights • CCTA documented atherosclerosis (CA) in half of our master athletes (MA) with altered stress ECG. • Risk-SCORE is a good indicator of CA's presence at the CCTA. • However, 17.8% of MA with a low SCORE had equally mild/moderate CA. • We recommend CCTA in MA (males/postmenopausal females) with impaired stress ECG, moderate/high risk-SCORE and/or symptoms. [ABSTRACT FROM AUTHOR]

Background and Aims Symptomatic main pancreatic duct (MPD) strictures secondary to chronic pancreatitis (CP) may benefit from endoscopic insertion of single or multiple plastic stents. MPD stricture resolution after single plastic stent removal is uncommon. The use of removable fully covered, self-expandable metal stents (FC-SEMSs) to dilate MPD strictures secondary to CP was evaluated. Methods Patients with CP and symptomatic MPD stricture located in the head of the pancreas persisting for 3 months or more after placement of a single plastic stent were enrolled in a prospective single-arm trial. A nitinol FC-SEMS was inserted and removed after 6 months. The FC-SEMS diameter and length were chosen according to the stricture anatomy and MPD diameter above the stricture. Our primary objective was FC-SEMS removability. Secondary outcomes were MPD stricture resolution rate and adverse events. Results Between December 2012 and October 2014, 15 patients (10 male, mean age 60 years) were enrolled. Pancreatic calcifications were present in 6 (40%) patients. Four patients (27%) had a history of alcohol abuse. In 10 patients, the FC-SEMS was inserted through the major papilla, whereas 5 patients (3 pancreas divisum, 2 dominant dorsal duct) received the stent through the minor papilla. One patient developed cholangitis after 24 hours due to occlusion of the biliary sphincterotomy from the FC-SEMS; cholangitis resolved after insertion of a plastic biliary stent. Complete distal migration of the FC-SEMS was reported in 7 patients (47%) (5 asymptomatic, 2 symptomatic with recurrence of pancreatitis). All migrations occurred with the 3-cm-long FC-SEMS. Four patients (27%) developed de novo stricture induced by the FC-SEMS at the level of the flared end and were excluded from the follow-up; 1 patient with FC-SEMS migration had failed stricture resolution. One patient was lost to follow-up. Finally, 9 patients with MPD stricture resolution had a mean follow-up of 38.9 months (range, 5.3-55.3 months), and 89% were asymptomatic. Conclusions FC-SEMS removability from the MPD in CP was feasible in all cases, and 90% of the patients were asymptomatic after 3 years. Migration seems more frequent with the 3-cm-long FC-SEMS. Occurrence of FC-SEMS-induced pancreatic strictures is a major issue and deserves further assessment. According to our experience, pancreatic FC-SEMSs have promising results, but a careful evaluation in the setting of clinical trials is needed. Graphical abstract [ABSTRACT FROM AUTHOR]

The gut microbiome, which hosts up to 1000 bacterial species that encode about 5 million genes, perform many of the functions required for host physiology and survival. Consequently, it is also known as “our forgotten organ”. The recent development of next-generation sequencing technologies has greatly improved metagenomic research. In particular, it has increased our knowledge about the microbiome and its mutually beneficial relationships with the human host. Microbial colonization begins immediately at birth. Although influenced by a variety of stimuli, namely, diet, physical activity, travel, illness, hormonal cycles and therapies, the microbiome is practically stable in healthy adults. This suggests that the microbiome plays a role in the maintenance of a healthy state in adulthood. Quantitative and qualitative alterations in the composition of the gut microbiome could lead to pathological dysbiosis, and have been related to an increasing number of intestinal and extra-intestinal diseases. With the increase in knowledge about gut microbiome functions, it is becoming increasingly more possible to develop novel diagnostic, prognostic and, most important, therapeutic strategies based on microbiome manipulation. [ABSTRACT FROM AUTHOR]

Background & Aims: Celiac disease (CD) has been associated with several genetic disorders, but has not been associated with hereditary fructose intolerance (HFI). Methods: We identified CD in 4 female patients affected by HFI from among 38 Italian HFI patients. Results: Three of these patients were children in whom the CD-associated signs were hypertransaminasemia, failure to thrive, low weight, and short stature, whereas the adult patient had protracted diarrhea notwithstanding a fructose-free diet. The incidence of CD in our group of HFI patients was higher (>10%) than in the general population (1%–3%) (P < .02). Conclusions: The possibility of an association between these 2 gastrointestinal disorders is important, particularly in the management of HFI patients with persisting symptoms. [Copyright &y& Elsevier]

Abstract: Purpose: The aim of this study was to evaluate reproducibility of a fast MRI protocol to measure gastric emptying and motility of the gastric antrum. Methods and materials: Gastric emptying and antral speed were measured in 12 type 1 diabetic patients (mean age 43 years) and 9 healthy volunteers (mean age 31 years). Subjects, fasting from 6h, were evaluated in supine position using a 1.5T MR scanner and a eight-channels phased-array body coil after ingestion of 400ml of a vanillas pudding mixed with 5ml of Gd-DTPA. Axial 3D T1w sequence at 0 and 30min for volume evaluation and cine-steady state acquisition every 5min for a total time of 30min for gastric wave speed assessing were acquired. Two blinded observers extrapolated T½ from gastric volume assessment and speed of gastric waves. Results: All the patients tolerated the examination. The T½ cut-off was of 115min with an accuracy in differentiate controls from diabetics of 96% (95% CI 0.766–0.992; p <0.001), while the antral speed cut-off was of 0.15mm/s with an accuracy of 87% (95% CI 0.628–0.977; p <0.001). The inter-observer agreement for the volumes at time 0 and 30min was respectively 0.983 (95% CI 0.9628–0.9929; p <0.001) and 0.9933 (95% CI 0.9847–0.9971; p <0.001) with an agreement of 0.9918 (95% CI 0.9853–0.9954; p <0.001), while for antral speed it was of 0.935 (95% CI 0.9097–0.9528; p <0.001). Conclusions: MRI is a reproducible technique for the evaluation of gastric emptying and antral motility. [ABSTRACT FROM AUTHOR]

• Evaluation of performances of two different multi-gene panels methodologies. • Identification of genetic variants that may predispose to breast and/or ovarian cancer. • Beyond BRCA1 / BRCA2, novel gene mutations for breast cancer risk. BRCA1 and BRCA2 are the most mutated genes in breast cancer. We analyzed 48 breast cancer subjects using two methods that differ in terms of number of genes investigated and strategy used (primers: Panel A - 12 genes - vs probes: Panel B - 48 genes). Both the panels and procedures identified "pathogenic" or "likely pathogenic" variants in TP53 , ATM , CHEK2 and BARD1 besides BRCA1 and BRCA2. Panel B identified two other putatively pathogenic variants in RNASEL and in RAD50. Identification of variants other than the BRCA genes can be useful in patient management. A total of 121 variants were distributed within the 12 genes and were correctly detected by both panels. However, the number of calls without divergence, namely ± 0.10 difference of allelic frequency, was 78.3%, while calls with a divergence below 0.10 was 16.7%, thus indicating that only 5% (n = 275) of 5,412 calls had a divergence above 0.10. Although these panels differ from each other, both are useful in different situations, particularly when patients should be tested for genes other than BRCA1/2 (as occurs in patients affected by a so called hereditary syndrome) or for therapeutic purposes. [ABSTRACT FROM AUTHOR]

Competitive athletes of all skill levels are at risk of sudden cardiac death (SCD) due to certain heart conditions. Prior to engagement in high-intensity athletics, it is necessary to screen for these conditions in order to prevent sudden cardiac death. Cardiac-CT angiography (CCTA) is a reliable tool to rule out the leading causes of SCD by providing an exceptional overview of vascular and cardiac morphology. This allows CCTA to be a powerful resource in identifying cardiac anomalies in selected patients (i.e. unclear symptoms or findings at ECG or echocardiography) as well as to exclude significant coronary artery disease (CAD). With the advancement of technology over the last few years, the latest generations of computed tomography (CT) scanners provide better image quality at lower radiation exposures. With the amount of radiation exposure per scan now reaching the sub-millisievert range, the number of CT examinations it is supposed to increase greatly, also in the athlete's population. It is thus necessary for radiologists to have a clear understanding of how to make and interpret a CCTA examination so that these studies may be performed in a responsible and radiation conscious manner especially when used in the younger populations. Our work aims to illustrate the main radiological findings of CCTAs and highlight their clinical impact with some case studies. We also briefly describe critical features of state-of-the-art CT scanners that optimize different acquisitions to obtain the best quality at the lowest possible dose. • Describe main causes of Sudden Cardiac Death in athletes worldwide • Illustrate radiological findings on cardiac CT examinations, underlying their clinical impact • Explain key features of state-of-the-art CT scanners in order to optimize acquisitions with lowest dose • Exhaustive visualization and description of cases [ABSTRACT FROM AUTHOR]

Background Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID). Together with fragile X-associated tremor and ataxia (FXTAS) and fragile X-associated premature ovarian failure (POF)/primary ovarian insufficiency (POI), FXS depends on dysfunctional expression of the FMR1 gene on Xq27.3. In most cases, FXS is caused by a > 200 CGG repeats in FMR1 5′-untranslated region (UTR) and by promoter hypermethylation that results in gene silencing. Males and females with unmethylated premutated alleles (repeats between 55 and 200) are at risk for FXTAS and POF/POI. Methods FXS molecular testing relied on PCR and methylation-specific Southern blot analysis of the FMR1 5′UTR. Atypical Southern blot patterns were studied by X-chromosome microsatellite analysis, copy number dosage at DMD locus , amelogenin gender-marker analysis and array-comparative genomic hybridization (array-CGH). Results Six men affected by ID and three women affected by ID and POF/POI underwent FXS molecular testing. They had normal FMR1 CGG repeats, but atypical X chromosome patterns. Further investigations revealed that the six males had Klinefelter syndrome (XXY), one female was a Turner mosaic (X0/XX) and two women had novel rearrangements involving X chromosome. Conclusions Diagnostic investigation of atypical patterns at FMR1 locus can address patients and/or their relatives to further verify the condition by performing karyotyping and/or array-CGH. [ABSTRACT FROM AUTHOR]

This report describes a novel, one-pot synthesis of hybrid nanoparticles formed by a nanostructured inorganic silica core and an organic pH-responsive hydrogel shell. This easy-to-perform, oil-in-water emulsion process synthesizes fluorescently-doped silica nanoparticles wrapped within a tunable coating of cationic poly(2-diethylaminoethyl methacrylate) hydrogel in one step. Transmission electron microscopy and dynamic light scattering analysis demonstrated that the hydrogel-coated nanoparticles are uniformly dispersed in the aqueous phase. The formation of covalent chemical bonds between the silica and the polymer increases the stability of the organic phase around the inorganic core as demonstrated by thermogravimetric analysis. The cationic nature of the hydrogel is responsible for the pH buffering properties of the nanostructured system and was evaluated by titration experiments. Zeta-potential analysis demonstrated that the charge of the system was reversed when transitioned from acidic to basic pH and vice versa . Consequently, small interfering RNA (siRNA) can be loaded and released in an acidic pH environment thereby enabling the hybrid particles and their payload to avoid endosomal sequestration and enzymatic degradation. These nanoparticles, loaded with specific siRNA molecules directed towards the transcript of the membrane receptor CXCR4, significantly decreased the expression of this protein in a human breast cancer cell line (i.e., MDA-MB-231). Moreover, intravenous administration of siRNA-loaded nanoparticles demonstrated a preferential accumulation at the tumor site that resulted in a reduction of CXCR4 expression. [ABSTRACT FROM AUTHOR]

Mannose binding lectin (MBL) is a protein of innate immunity that activates the complement and promotes opsonophagocytosis. The deficiency of MBL due to several common gene polymorphisms significantly enhances the risk of severe infections, particularly in the neonatal age and in childhood. On the contrary, the role of the protein in carcinogenesis and atherogenesis is still debated: MBL has a relevant role against neoplastic cells, but some studies described a protective effect of low levels of MBL toward breast cancer and a longer survival of lung cancer patients with a reduced MBL activity. Similarly, some studies concluded on the protective role of low levels of MBL toward cardiovascular diseases while other focused on a higher risk of myocardial infarction in subjects with a deficient activity of the protein. More recently, a role of MBL in the clearance of senescent cells emerged, and a study in two large cohorts of centenarians demonstrated that a high biological activity of the protein enhances the risk of autoimmune diseases. This body of data strongly suggests that the optimal levels of MBL activity depend on the age and on the environmental context of each subject. [ABSTRACT FROM AUTHOR]

Unfavorable wake and separated flow from the hull might cause a dramatic decay of the propeller performance in single-screw propelled vessels such as tankers, bulk carriers and containers. For these types of vessels, special attention has to be paid to the design of the stern region, the occurrence of a good flow towards the propeller and rudder being necessary to minimize fuel consumption and avoid excessive vibratory shaft loads and risk for cavitation erosion. The present work deals with the analysis of the propeller inflow in a single-screw chemical tanker vessel affected by massive flow separation in the stern region. Detailed flow measurements by Laser Doppler Velocimetry (LDV) were performed in the propeller region at model scale, in the large Circulating Water Channel of CNR-INSEAN. These tests were undertaken with and without the propeller in order to investigate its effect on the inflow characteristics and the separation mechanisms. In this context, the study also concerned a phase locked analysis of the propeller perturbation at different distances upstream of the propulsor. The study shows the effectiveness of the 3rd order statistical moment (i.e., skewness) for describing the topology of the wake and accurately identifying the portion affected by the detached flow. The skewness coefficient also suggests that a better physical representation of the propeller inflow is provided by the mode value of the velocity, which is the maximum of the probability density function, rather than the mean velocity. [ABSTRACT FROM AUTHOR]

Background Accurate and sensitive detection of BRCA 1/2 germ-line mutations is crucial for the clinical management of women affected by breast cancer, for prevention and, notably, also for the identification of at-risk healthy relatives. The most widely used methods for BRCA1 / 2 molecular analysis are Sanger sequencing, and denaturing high performance liquid chromatography (dHPLC) followed by the Sanger method. However, recent findings suggest that next-generation sequencing (NGS)-based approaches may be an efficient tool for diagnostic purposes. In this context, we evaluated the effectiveness of NGS for BRCA gene analysis compared with dHPLC/Sanger sequencing. Methods Seventy women were screened for BRCA1/2 mutations by both dHPLC/Sanger sequencing and NGS, and the data were analyzed using a bioinformatic pipeline. Results Sequence data analysis showed that NGS is more sensitive in detecting BRCA 1/2 variants than the conventional procedure, namely, dHPLC/Sanger. Conclusion Next-generation sequencing is more sensitive, faster, easier to use and less expensive than the conventional Sanger method. Consequently, it is a reliable procedure for the routine molecular screening of the BRCA 1/2 genes. [ABSTRACT FROM AUTHOR]

End-stage hypertrophic cardiomyopathy (ES-HC) has an ominous prognosis. Whether genotype can influence ES-HC occurrence is unresolved. We assessed the spectrum and clinical correlates of HC-associated mutations in a large multicenter cohort with end-stage ES-HC. Sequencing analysis of 8 sarcomere genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, and ACTC1) and 2 metabolic genes (PRKAG2 and LAMP2) was performed in 156 ES-HC patients with left ventricular (LV) ejection fraction (EF) <50%. A comparison among mutated and negative ES-HC patients and a reference cohort of 181 HC patients with preserved LVEF was performed. Overall, 131 mutations (36 novel) were identified in 104 ES-HC patients (67%) predominantly affecting MYH7 and MYBPC3 (80%). Complex genotypes with double or triple mutations were present in 13% compared with 5% of the reference cohort (p = 0.013). The distribution of mutations was otherwise indistinguishable in the 2 groups. Among ES-HC patients, those presenting at first evaluation before the age of 20 had a 30% prevalence of complex genotypes compared with 19% and 21% in the subgroups aged 20 to 59 and ⩾60 years (p = 0.003). MYBPC3 mutation carriers with ES-HC were older than patients with MYH7, other single mutations, or multiple mutations (median 41 vs 16, 26, and 28 years, p ⩽0.001). Outcome of ES-HC patients was severe irrespective of genotype. In conclusion, the ES phase of HC is associated with a variable genetic substrate, not distinguishable from that of patients with HC and preserved EF, except for a higher frequency of complex genotypes with double or triple mutations of sarcomere genes. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated a patient, born after a normal 38-week pregnancy, with psychomotor retardation, poor coordination of ocular movements, recurrent vomiting and severe lactic acidosis. The patient was admitted to hospital at 2months of age because of a mitochondrial-like syndrome and died at the age of 4.5months. Array-comparative genomic hybridization (a-CGH) analysis revealed a homozygous deletion in 5q11.2 involving NADH dehydrogenase (ubiquinone) Fe–S protein 4, 18kDa (NADH-coenzyme Q reductase; NDUFS4). Both parents were heterozygous for the mutation. The array revealed a deletion of ~32kb that includes exon 2 of NDUFS4 subsequently confirmed by real time-PCR and multiplex PCR. NDUFS4 was previously correlated to Leigh syndrome since mutations in this gene block the assembly of complex I. This result demonstrates the relevance of a-CGH screening in patients affected by metabolic disorders of unknown etiology. [Copyright &y& Elsevier]

Abstract: Fragile X syndrome (FXS) is the main cause of heritable mental retardation. In most patients, it is associated with an increased number of CGG repeats (>200) within the 5′-untranslated region of the FMR1 gene, and with methylation of the expanded repeats and of the promoter. FXS female carriers and transmitting males have expansions of between 55 and 200 repeats (premutated alleles). Alleles with premutations are unstable in female meioses. Normal and premutated repeats are unmethylated in males and subject to lyonization in females. Here, we report the postnatal and prenatal molecular diagnoses of FXS made with conventional PCR and Southern blotting in a cohort of Italian patients and their families over a period of 15years. Moreover, we tested two novel high-performance PCR procedures (PCR with a chimeric primer, and the AmplideX™ FMR1 kit) in our patients and compared the results with our previous observations. We concluded that the high-performance PCR assays complement the results obtained by conventional methods, but they cannot replace the Southern blot procedure. Consequently, also based on cost–benefit considerations, our FXS diagnostic flowchart now consists of conventional PCR and Southern blotting plus the chimeric primer PCR procedure, whereas the AmplideX™ procedure is reserved for doubtful cases. [Copyright &y& Elsevier]

Abstract: Objective: Inflammation is a pivotal process in atherosclerosis development and progression, but the underlying molecular mechanisms remain largely obscure. We have conducted an extensive expression study of atherosclerotic plaques to identify the inflammatory pathways involved in atherosclerosis. Methods: We studied 11 human carotid plaques, their respective adjacent regions and 7 control arteries from different subjects. Expression of 92 genes was studied by TaqMan low-density array human inflammation panel. Human aortic endothelial and smooth muscle cells were used for in vitro experiments. Results: The mRNA levels of 44/92 genes (48%) differed significantly between the tissues examined (13 up-regulated and 31 down-regulated). Dysregulated genes encode molecules belonging to different functional classes although most of them encode enzymes involved in the eicosanoid synthesis pathway. The expression of PTGIS and PTGIR genes was decreased in human aortic endothelial and smooth muscle cells stimulated with oxLDL and TNF-α. Conclusions: This study not only reveals several dysregulated genes in human lesions but also focuses the role played by the genes involved in the eicosanoid synthesis pathway during atherosclerotic development. The decrease of PTGIS and PTGIR expression after oxLDL treatment mirrors the decreased mRNA levels in atherosclerotic lesions versus control arteries, which suggests that oxidation is important for PTGIS and PTGIR regulation in human vessel cells during atherosclerosis development. [Copyright &y& Elsevier]

Abstract: Hyperphenylalaninemias are genetic diseases prevalently caused by mutations in the phenylalanine hydroxylase (PAH) gene. The wild-type PAH enzyme is a homotetramer regulated by its substrate, cofactor and phosphorylation. We reproduced a full-length wild-type protein and seven natural full-length PAH variants, p.I65M, p.N223Y, p.R297L, p.F382L, p.K398N, p.A403V, and p.Q419R, and analyzed their biochemical and biophysical behavior. All mutants exhibited reduced enzymatic activity, namely from 38% to 69% of wild-type activity. Biophysical characterization was performed by size-exclusion chromatography, light scattering and circular dichroism. In the purified wild-type PAH, we identified the monomer in equilibrium with the dimer and tetramer. In most mutants, the equilibrium shifted toward the dimer and most tended to form aggregates. All PAH variants displayed different biophysical behaviors due to loss of secondary structure and thermal destabilization. Specifically, p.F382L was highly unstable at physiological temperature. Moreover, using confocal microscopy with the number and brightness technique, we studied the effect of BH4 addition directly in living human cells expressing wild-type PAH or p.A403V, a mild mutant associated with BH4 responsiveness in vivo. Our results demonstrate that BH4 addition promotes re-establishment of the oligomerization equilibrium, thus indicating that the dimer-to-tetramer shift in pA403V plays a key role in BH4 responsiveness. In conclusion, we show that the oligomerization process and conformational stability are altered by mutations that could affect the physiological behavior of the enzyme. This endorses the hypothesis that oligomerization and folding defects of PAH variants are the most common causes of HPAs, particularly as regards mild human phenotypes. [Copyright &y& Elsevier]