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BACKGROUND AND AIM: To evaluate the combined contribution of UCP3-55CT and PPAR?2 Pro12Ala polymorphisms as correlates of BMI, energy expenditure (REE) and substrate oxidation in people with type 2 diabetes. METHODS AND RESULTS: Two independent population with type 2 diabetes were studied: population A, n = 272; population B, n = 269. Based on both UCP3 and PPAR?2 genotypes three groups were created. Carriers of the PPAR?2 Pro12Ala in combination with the CC genotype of UCP3 (ProAla/CC, group 1); carriers of only one of these genotypes (either CC/ProPro or CT-TT/ProAla, group 2); people with neither variants (CT-TT/ProPro, group 3). In both populations BMI (kg/m(2)) was highest in group 1, intermediate in group 2 and lowest in group 3, independent of energy intake (i.e 35.3 ± 6.7 vs 33.4 ± 5.4 vs 31.8 ± 3, p < 0.02, population A; 32.4 ± 4.2 vs 31.7 ± 3.8 vs 30.1 ± 2.7; p < 0.03, population B). People with the ProAla/CC genotype (group 1) showed similar REE, but lower lipid oxidation (10.9 vs 13.9 g/kg fat free mass/day; p = 0.04) and higher carbohydrate oxidation (23.6 vs 15.6 g/kg fat free mass/day; p = 0.02) than carriers of other genotypes. CONCLUSIONS: The combination of UCP3-55 CC and PPAR?2 Pro12Ala genotypes is associated with significantly higher BMI than other PPAR?2-UCP3 genotype combinations, partly due to a reduced ability in lipids oxidation. The relative importance of these mechanism(s) may be different in non diabetic people. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Background: The role of polyphenol intake on cardiovascular risk factors is little explored, particularly in people with diabetes. Aim: To evaluate the association between the intake of total polyphenols and polyphenol classes with the major cardiovascular risk factors in a population with type 2 diabetes. Methods: Dietary habits were investigated in 2573 males and females participants of the TOSCA.IT study. The European Prospective Investigation on Cancer and Nutrition (EPIC) questionnaire was used to assess dietary habits. In all participants, among others, we assessed anthropometry, plasma lipids, blood pressure, C-reactive protein and HbA1c following a standard protocol. The USDA and Phenol-Explorer databases were used to estimate the polyphenol content of the habitual diet. Results: Average intake of polyphenols was 683.3 ± 5.8 mg/day. Flavonoids and phenolic acids were the predominant classes (47.5% and 47.4%, respectively). After adjusting for potential confounders, people with the highest intake of energy-adjusted polyphenols (upper tertile) had a more favorable cardiovascular risk factors profile as compared to people with the lowest intake (lower tertile) (BMI was 30.7 vs 29.9 kg/m2, HDL-cholesterol was 45.1 vs 46.9 mg/dl, LDL-cholesterol was 103.2 vs 102.1 mg/dl, triglycerides were 153.4 vs 148.0 mg/dl, systolic and diastolic blood pressure were respectively 135.3 vs 134.3 and 80.5 vs 79.6 mm/Hg, HbA1c was 7.70 vs 7.67%, and C-reactive Protein was 1.29 vs 1.25 mg/dl, p < .001 for all). The findings were very similar when the analysis was conducted separately for flavonoids or phenolic acids, the two main classes of polyphenols consumed in this population. Conclusions: Polyphenol intake is associated with a more favorable cardiovascular risk factors profile, independent of major confounders. These findings support the consumption of foods and beverages rich in different classes of polyphenols particularly in people with diabetes. Clinical trial: . http://www.clinicaltrials.gov; Study ID number: . NCT00700856. © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism.

Background The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes. Methods TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50–75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2–3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15–45 mg) or a sulfonylurea (5–15 mg glibenclamide, 2–6 mg glimepiride, or 30–120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856. Findings Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74–1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p

Background and purpose: Grey matter (GM) and white matter (WM) are both affected in multiple sclerosis (MS). WM is predominantly involved in inflammatory demyelination of relapsing–remitting MS (RRMS), whereas GM is predominantly involved in neurodegenerative processes of secondary progressive MS. Thus, we investigated the ratio between GM and WM volumes in predicting MS evolution. Methods: The present 10-year retrospective cohort study included 149 patients with newly-diagnosed RRMS, undergoing magnetic resonance imaging for segmentation and brain volumetry. The ratio between GM and normal-appearing WM (NAWM) volumes was calculated for each subject. Outcome measures of interest were Expanded Disability Status Scale (EDSS) progression, reaching EDSS 4.0 and conversion to secondary progressive (SP) MS. Results: During a period of 10.6 ± 2.4 years, a median 1.5 EDSS progression was observed (range 0–5.5), 54 subjects (36.2%) reached EDSS 4.0 and 30 subjects (20.1%) converted to SP. With ordinal logistic regression models, EDSS progression was associated with GM:NAWM ratio (coefficient, −2.918; 95% CI, −4.739–1.097). With Cox regression models, subjects with higher GM:NAWM ratio at diagnosis had a 90% lower rate of reaching EDSS 4.0 (hazard ratio, 0.111; 95% CI, 0.020–0.609) and of converting to secondary progressive MS (hazard ratio, 0.017; 95% CI, 0.001–0.203) compared with subjects with lower GM:NAWM ratio. Conclusions: The GM:NAWM ratio is a predictor of disability progression and of SP conversion in subjects with newly diagnosed RRMS, suggesting that GM and NAWM are variably affected in relation to disease evolution from the early phases of MS. © 2016 EAN

PURPOSE: Multiple sclerosis (MS) has been proposed as a possible differential diagnosis for Fabry disease (FD). The aim of this work was to evaluate the involvement of corpus callosum (CC) on MR images and its possible role as a radiological sign to differentiate between FD and MS. METHODS: In this multicentric study, we retrospectively evaluated the presence of white matter lesions (WMLs) on the FLAIR images of 104 patients with FD and 117 patients with MS. The incidence of CC-WML was assessed in the two groups and also in a subgroup of 37 FD patients showing neurological symptoms. RESULTS: WMLs were detected in 50 of 104 FD patients (48.1%) and in all MS patients. However, a lesion in the CC was detected in only 3 FD patients (2.9%) and in 106 MS patients (90.6%). In the FD subgroup with neurological symptoms, WMLs were present in 26 of 37 patients (70.3%), with two subjects (5.4%) showing a definite callosal lesion. CONCLUSION: FD patients have a very low incidence of CC involvement on conventional MR images compared to MS, independently from the clinical presentation and the overall degree of WM involvement. Evaluating the presence of CC lesions on brain MR scans can be used as a radiological sign for a differential diagnosis between MS and FD, rapidly addressing the physician toward a correct diagnosis and subsequent treatment options.

BACKGROUND AND PURPOSE: The pulvinar sign refers to exclusive T1WI hyperintensity of the lateral pulvinar. Long considered a common sign of Fabry disease, the pulvinar sign has been reported in many pathologic conditions. The exact incidence of the pulvinar sign has never been tested in representative cohorts of patients with Fabry disease. The aim of this study was to assess the prevalence of the pulvinar sign in Fabry disease by analyzing T1WI in a large Fabry disease cohort, determining whether relaxometry changes could be detected in this region independent of the pulvinar sign positivity. MATERIALS AND METHODS: We retrospectively analyzed brain MR imaging of 133 patients with Fabry disease recruited through specialized care clinics. A subgroup of 26 patients underwent a scan including 2 FLASH sequences for relaxometry that were compared with MRI scans of 34 healthy controls. RESULTS: The pulvinar sign was detected in 4 of 133 patients with Fabry disease (3.0%). These 4 subjects were all adult men (4 of 53, 7.5% of the entire male population) with renal failure and under enzyme replacement therapy. When we tested for discrepancies between Fabry disease and healthy controls in quantitative susceptibility mapping and relaxometry maps, no significant difference emerged for any of the tested variables. CONCLUSIONS: The pulvinar sign has a significantly lower incidence in Fabry disease than previously described. This finding, coupled with a lack of significant differences in quantitative MR imaging, allows hypothesizing that selective involvement of the pulvinar is a rare neuroradiologic sign of Fabry disease.

In 2016, an update of the 2009 recommendations for the evaluation of left ventricular (LV) diastolic function (DF) was released by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. The aims of this study were to assess the concordance between the 2016 and 2009 recommendations and to test the impact of the consideration of "myocardial disease" recommended in the 2016 update on the evaluation of diastolic dysfunction (DD) and LV filling pressures in patients with normal and reduced LV ejection fractions referred to a general echocardiography laboratory.A total of 1,508 outpatients referred to an echocardiography laboratory during a predefined 5-month period were prospectively enrolled. All patients underwent targeted clinical history and Doppler echocardiographic examination. DD and LV filling pressures were assessed according to 2009 and 2016 recommendations. Concordance was calculated using the κ coefficient and overall proportion of agreement.Overall proportion of agreement between the two recommendations was 64.7% (κ = 0.43). Comparing the 2009 and 2016 recommendations, 47.5% and 36.1% patients, respectively, had DD (P .0001), and 22.7% and 12.6% had elevated LV filling pressures (P .0001). This difference remained significant in the setting of patients with normal LV ejection fractions (21.6% vs 10.7%, P .0001). In the application of the 2016 recommendations, whether or not the presence of "myocardial disease" was considered, the prevalence of indeterminate diastolic function was, respectively, 7.3% versus 13.7%, while patients in whom the DD grade could not be determined were 8.1% versus 14.4% (P .0001 for all).Considering the presence of myocardial disease when applying the 2016 recommendations resulted in a lower prevalence of inconclusive diagnosis.

Background and purpose Heterozygous mutations in the STUB1 gene have recently been associated with an autosomal dominant form of spinocerebellar ataxia (SCA) associated with cerebellar cognitive-affective syndrome (CCAS), named SCA48. Methods Molecular screening was performed in a cohort of 235 unrelated patients with adult-onset, autosomal dominant (17) or sporadic (218) cerebellar ataxia, negative for pathological trinucleotide expansions in the common SCAs, FRDA and FXTAS loci, by using targeted multigene panels or whole-exome sequencing. Bioinformatics analyses, detailed neurological phenotyping and family segregation studies corroborated the pathogenicity of the novel STUB1 mutations. Clinico-diagnostic findings were reviewed to define the phenotypic spectrum. Results Eight heterozygous STUB1 mutations were identified, six of which were novel in 11 patients from eight index families, giving an estimated overall frequency of 3.4% (8/235) for SCA48 in our study cohort, rising to 23.5% (4/17) when considering only familial cases. All our SCA48 patients had cerebellar ataxia and dysarthria associated with cerebellar atrophy on brain magnetic resonance imaging; of note, many cases were also associated with parkinsonism, chorea and dystonia. CCAS also occurred frequently, whereas definite signs of pyramidal tract dysfunction and peripheral nervous system involvement were absent. One SCA48 patient presented with hypogonadism, associated with other autoimmune endocrine dysfunctions. Conclusions Our results support SCA48 as a significant cause of adult-onset SCA. Besides CCAS, our SCA48 patients often showed movement disorders and other clinical manifestations previously described in SCAR16, linked to biallelic variants in the same gene, thus suggesting a continuous clinical spectrum and significant overlap amongst recessive and dominantly inherited mutations in STUB1.

Background Diagnostic imaging guidelines are increasingly embraced in oncologic imaging in order to improve examinations appropriateness and technical quality. The usefulness of guidelines employment in clinical practice is dramatically related to the quality of the guidelines themselves. However, an extreme variability in guidelines’ quality may occur. Following a European Network for the Assessment of Imaging in Medicine (EuroAIM) initiative, the aim of this study was to assess the quality of the available guidelines regarding head and neck cancer (HNC) imaging. Methods A literature search was conducted to identify imaging guidelines focused on HNC. Selected guidelines were evaluated by four independent appraisers using the Appraisal of Guidelines for Research & Evaluation version 2.0 (AGREE II) tool, which comprises 23 key items, rated on a 7‐point scale (1—strongly disagree to 7—strongly agree) and organized within six domains. For each domain, the intraclass correlation coefficient (ICC) was used to assess the agreement among appraisers’ scores. Results After literature search, three guidelines were selected and evaluated. One guideline scored “average” as overall quality, while the remaining two scored a “low” overall quality. The highest result (total score = 75.0% ± 19.3%) was obtained in domain 4 (Clarity of presentation) while the lowest (total score = 27.1% ± 4.2%) in domain 6 (Editorial independence). ICC analysis showed a very good agreement (range: 0.932‐0.961) among the four appraisers. Conclusions Our results showed a heterogeneous quality of existing guidelines in HNC imaging. Issues raised from this appraisal should be considered when developing future guidelines on HNC imaging.

Cognitive impairment is a frequent and meaningful symptom in multiple sclerosis (MS), caused by the accrual of brain structural damage only partially counteracted by effective functional reorganization. As both these aspects can be successfully investigated through the application of advanced neuroimaging, here, we offer an up-to-date overview of the latest findings on structural, functional and metabolic correlates of cognitive impairment in adults with MS, focusing on the mechanisms sustaining damage accrual and on the identification of useful imaging markers of cognitive decline.

Background Cognitive impairment occurs in multiple sclerosis (MS) and undergoes a progressive worsening over disease course. However, clinicians still struggle to predict the course of cognitive function. To evaluate baseline clinical and imaging predictors of cognitive abilities worsening over time, we performed a latent trajectory analysis for cognitive performances in MS patients, up to 15 years from disease onset. Methods We collected age, sex, education, dominant and non-dominant 9-hole peg test (9HP) and timed 25-foot walk (T25-FW) as well as MRI measures (grey matter volume and lesion load) within 6 months from disease diagnosis for relapsing–remitting MS (RR-MS) patients. At diagnosis and over the follow-up, we also assessed cognitive status through the symbol digit modalities test (SDMT). Cognitive impairment was defined by applying age-, gender- and education-adjusted normative values. Group-based trajectory analysis was performed to determine trajectories, and the predictive value of clinical and imaging variables at baseline was assessed through multinomial logistic regression. Results We included 148 RR-MS (98 females and 50 males). Over 11 ± 4 year follow-up, 51.4% remained cognitively stable whereas 48.6% cognitively worsened. Cognitively worsening patients had a higher T25FW time (p = 0.004) and a reduced hippocampal volume at baseline (p = 0.04). Conclusion Physical disability as well as hippocampal atrophy might depict patients at risk of cognitive worsening over the disease course. Therefore, using such predictors, clinicians may select patients to carefully evaluate for cognitive impairment as to eventually introduce cognitive rehabilitation treatments.

The bidirectional microbiota&ndash, gut&ndash, brain axis has raised increasing interest over the past years in the context of health and disease, but there is a lack of information on molecular mechanisms underlying this connection. We hypothesized that change in microbiota composition may affect brain epigenetics leading to long-lasting effects on specific brain gene regulation. To test this hypothesis, we used Zebrafish (Danio Rerio) as a model system. As previously shown, treatment with high doses of probiotics can modulate behavior in Zebrafish, causing significant changes in the expression of some brain-relevant genes, such as BDNF and Tph1A. Using an ultra-deep targeted analysis, we investigated the methylation state of the BDNF and Tph1A promoter region in the brain and gut of probiotic-treated and untreated Zebrafishes. Thanks to the high resolution power of our analysis, we evaluated cell-to-cell methylation differences. At this resolution level, we found slight DNA methylation changes in probiotic-treated samples, likely related to a subgroup of brain and gut cells, and that specific DNA methylation signatures significantly correlated with specific behavioral scores.

Central nervous system involvement has been described in peripheral neuropathies, including different forms of Charcot-Marie-Tooth (CMT) disease. The aimof our study was to systematically investigate possible brain structural modifications in CMT1A patients, using volumetric MRI, and diffusion tensor imaging (DTI). In this prospective cross-sectional study, from May 2017 to May 2019, we acquired 3T MRI brain scans of genetically confirmed CMT1A patients and age- and sex-comparable healthy controls. Patients also underwent clinical and electrophysiological examinations assessing motor and sensory domains. Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) analyses were performed using a non-parametric approach based on permutations, including age and sex (and total intracranial volume for VBM) as nuisance covariates. When between-group differences emerged at VBM or TBSS analyses, the first eigenvariate was extracted from the cluster and its age- and sex-adjusted standardized residuals tested for correlation with clinical and electrophysiological variables. Twenty CMT1A patients (34.5 +/- 11.1 years; M/F:11/9) were enrolled, along with 20 healthy controls (30.1 +/- 10.2 years; M/F:11/9). The VBM analysis revealed clusters of significantly increased GM volume in CMT1A patients compared to healthy controls, encompassing the bilateral cerebellar lobules III-VI and the left hippocampus (all ps = 0.04), with no differences in terms of DTI metrics at the TBSS analysis. A negative correlation (r = -0.502, p = 0.03) emerged between ulnar compound motor action potential and the z-scores corresponding to the right cerebellar cluster of augmented GM volume. Our data show evidence of structural reorganization in the brain of CMT1A patients, possibly reflecting neural plasticity mechanisms in response to peripheral nerve pathology and modulating the effect of axonal degeneration on functional impairment.

Background: We evaluate whether the Pro12Ala polymorphism of peroxisome proliferator-activated receptor γ2 (PPARγ2) has a role in the progression of diabetes by modulating the occurrence of treatment failure to glucose-lowering drugs. Methods: We studied 215 patients with type 2 diabetes participating in the Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents Intervention Trial study. All participants were insufficiently controlled (glycated haemoglobin [HbA1c] 7.0%-9.0%) with metformin 2 g/day and were randomly allocated to add-on pioglitazone or a sulfonylurea. Treatment failure was defined as HbA1c ≥8% on two consecutive visits, 3 months apart. Results: Carriers or non-carriers of the polymorphism had similar age, body mass index, and diabetes duration. Ala carriers had lower fasting plasma insulin, better insulin sensitivity (Homeostasis Model Assessment [HOMA]2-%S), and worse beta cell secretion (HOMA2-%B) than non-carriers. During 24 months of follow-up, 32.5% among the Ala carriers and 8.6% among non-carriers (P < 0.001) developed treatment failure with a cumulative incidence of 18.6 vs 4.6/100 person-years. Those patients who developed treatment failure were older, had a younger age at diabetes diagnosis (48 ± 10 vs 52 ± 7 years; P = 0.032), higher HbA1c (8.1 ± 0.5 vs 7.7 ± 0.5%; P < 0.001), and lower HOMA2-%B (30 ± 12 vs 46 ± 29; P = 0.015) at study entry, as compared to those who did not develop treatment failure. At multivariate analysis, the Pro12Ala polymorphism was significantly associated with treatment failure (hazard ratio [HR] 4.45; 95% confidence interval [CI] 1.79-11.1; P < 0.001); HbA1c at study entry was the other independent predictor of failure in this study population. Conclusion: The Pro12Ala polymorphism is associated with a greater insulin sensitivity, reduced beta cell function and a substantially increased risk of treatment failure.

Introduction In recent years, cerebellar abnormalities have gained increasing attention as possible physiopathological substratum of idiopathic cervical dystonia (ICD), but a consistent pattern of cerebellar structural modifications has not yet been established. We systematically investigated the presence of volumetric alterations of cerebellar gray (GM) and white matter (WM) in ICD patients, as well as their clinical relevance. Methods In this two-centers prospective cross-sectional study, from May 2013 to December 2017, 27 patients with ICD and 27 age- and sex-comparable healthy controls underwent brain MRI including 3D T1-weighted sequences for volumetric analyses. Between-group differences in terms of gray matter and cerebellar peduncles volumes were investigated using both region of interest (ROI)-based and voxel-based approaches using the SUIT tool (SPM12), and significant volumetric changes were correlated with clinical impairment (as measured with the Tsui score) and presence of tremor. Results ICD patients showed significant volumetric reduction of cerebellar GM in the anterior lobe and lobule VI, resulting from both ROI-based (p ≤ 0.009) and voxel-based (p ≤ 0.04) analyses, while small clusters of reduced WM volume were found in the right cerebellum and left midbrain (p = 0.04), along with reduced volume of the bilateral superior (p = 0.04) and middle (p = 0.03) cerebellar peduncles. Furthermore, higher middle cerebellar peduncles volume was associated with the presence of tremor (p = 0.04). Conclusion Our data show evidence of a specific pattern of cerebellar structural abnormalities in ICD patients, with volume loss mainly involving cortical GM regions related to the somatotopic representation of the affected body parts and, to a lesser extent, cerebellar peduncles.

Ocular adnexal aterio-venous malformations (AVMs) are rare congenital disabling anomalies, which may enlarge causing disfiguring deformity and rarely severe hemorrhage. These lesions are generally treated by preliminary endovascular embolization to shrink the arterio-venous malformation, followed by surgical gross total resection. The authors report a case of eyelid arterio-venous malformation in a 12-year-old girl, which progressively increased in size in few months. The patient complained mild itching, blurring of the vision, and mild tenderness. Magnetic resonance imaging showed an expansive mass with multiple arterial vessels at the left superior eyelid and left forehead. The diagnosis of arterio-venous malformation was then confirmed by digital subtraction angiography. Primary surgical excision was excluded because of the high risk of intrasurgical bleeding. Embolization through superselective cannulation of the left external carotid feeder vessels was performed resulting in flow exclusion up to the 80% of the nidus. Subsequent surgical resection was not recommended due to clinical evidence of keloid-prone skin.

PurposeMoyamoya syndrome (MMS) is a rare intracranial arterial vasculopathy which can occur in neurofibromatosis type 1 (NF1) disease, representing a cause of cerebrovascular reserve (CVR) impairment, possibly leading to ischemic stroke. Here, we evaluated noninvasive imaging techniques used to assess CVR in MMS patients, describing clinical and imaging findings in patients affected by MMS-NF1.MethodsFollowing strict inclusion and exclusion criteria, in this retrospective observational study, we evaluated imaging data of nine consecutive MMS-NF1 patients (M/F = 5/4, mean age: 12.6 ± 4.0). Subjects underwent a multimodal evaluation of cerebral vascular status, including intracranial arterial MR Angiography (MRA), MRI perfusion with dynamic susceptibility contrast (DSC) technique, and 99mTc-hexamethylpropyleneamine oxime (HMPAO) SPECT.ResultsIn 8 out 9 patients (88.8%, 6/8 symptomatic), time-to-peak maps were correlated with the involved cerebral hemisphere, while in 6 out 9 patients (66.6%, 5/6 symptomatic), mean transit time (MTT) maps showed correspondence with the affected cerebrovascular territories. Cerebral blood flow (CBF) calculated using DSC perfusion failed to detect the hypoperfused regions instead identified by SPECT-CBF in all patients, while MTT maps overlapped with SPECT-CBF data in all cases and time-to-peak maps in 60.0%.ConclusionsAlthough SPECT imaging still represents the gold standard for CBF assessment, our results suggest that data obtained using DSC perfusion technique, and in particular MTT maps, might be a very useful and noninvasive tool for evaluating hemodynamic status in MMS-NF1 patients.

DNA methylation is a heritable epigenetic mark that plays a key role in regulating gene expression. Mathematical modeling has been extensively applied to unravel the regulatory mechanisms of this process. In this study, we aimed to investigate DNA methylation by performing a high-depth analysis of particular loci, and by subsequent modeling of the experimental results. In particular, we performed an in-deep DNA methylation profiling of two genomic loci surrounding the transcription start site of the D-Aspartate Oxidase and the D-Serine Oxidase genes in different samples (n = 51). We found evidence of cell-to-cell differences in DNA methylation status. However, these cell differences were maintained between different individuals, which indeed showed very similar DNA methylation profiles. Therefore, we hypothesized that the observed pattern of DNA methylation was the result of a dynamic balance between DNA methylation and demethylation, and that this balance was identical between individuals. We hence developed a simple mathematical model to test this hypothesis. Our model reliably captured the characteristics of the experimental data, suggesting that DNA methylation and demethylation work together in determining the methylation state of a locus. Furthermore, our model suggested that the methylation status of neighboring cytosines plays an important role in this balance.

We explored the relationship between cultural and social participation, physical activity, and well-being in a group of residents of the metropolitan area of Naples, Italy and the role that resilience plays in this relationship. Naples offers a remarkable urban environment with the potentially beneficial psychological effects of outstanding natural beauty, and one of the world’s most impressive repositories of tangible and intangible cultural heritage. However, Naples was also, and still is, heavily affected by the 2008 economic crisis, in addition to preexisting social and economic issues. The major finding of this study is that, despite this highly contrasting urban environment, the combination of physical activity and engagement in social and cultural activities has a positive effect on subjective (self-reported) psychological well-being (SPWB) in a group of residents, and that resilience mediates this relationship.

Background/Aim: To investigate whether a radiomic machine learning (ML) approach employing texture-analysis (TA) features extracted from primary tumor lesions (PTLs) is able to predict tumor grade (TG) and nodal status (NS) in patients with oropharyngeal (OP) and oral cavity (OC) squamous-cell carcinoma (SCC). Patients and Methods: Contrast-enhanced CT images of 40 patients with OP and OC SCC were post-processed to extract TA features from PTLs. A feature selection method and different ML algorithms were applied to find the most accurate subset of features to predict TG and NS. Results: For the prediction of TG, the best accuracy (92.9%) was achieved by Naïve Bayes (NB), bagging of NB and K Nearest Neighbor (KNN). For the prediction of NS, J48, NB, bagging of NB and boosting of J48 overcame the accuracy of 90%. Conclusion: A radiomic ML approach applied to PTLs is able to predict TG and NS in patients with OC and OP SCC.

Background: Recent studies have suggested the presence of a significant atrophy affecting the cerebellar cortex in Friedreich ataxia (FRDA) patients, an area of the brain long considered to be relatively spared by neurodegenerative phenomena. Cognitive deficits, which occur in FRDA patients, have been associated with cerebellar volume loss in other conditions. The aim of this study was to investigate the correlation between cerebellar volume and cognition in FRDA. Methods: Nineteen FRDA patients and 20 healthy controls (HC) were included in this study and evaluated via a neuropsychological examination. Cerebellar global and lobular volumes were computed using the Spatially Unbiased Infratentorial Toolbox (SUIT). Furthermore, a cerebellar voxel-based morphometry (VBM) analysis was also carried out. Correlations between MRI metrics and clinical data were tested via partial correlation analysis. Results: FRDA patients showed a significant reduction of the total cerebellar volume (p = 0.004), significantly affecting the Lobule IX (p = 0.001). At the VBM analysis, we found a cluster of significant reduced GM density encompassing the entire lobule IX (p = 0.003). When correlations were probed, we found a direct correlation between Lobule IX volume and impaired visuo-spatial functions (r = 0.58, p = 0.02), with a similar correlation that was found between the same altered function and results obtained at the VBM (r = 0.52; p = 0.03). Conclusions: With two different image analysis techniques, we confirmed the presence of cerebellar volume loss in FRDA, mainly affecting the posterior lobe. In particular, Lobule IX atrophy correlated with worse visuo-spatial abilities, further expanding our knowledge about the physiopathology of cognitive impairment in FRDA.

Purpose: A new form of autosomal dominant hereditary spinocerebellar ataxia (SCA) has been recently described (SCA48), and here we investigate its conventional MRI findings to identify the presence of a possible imaging feature of this condition. Methods: In this retrospective observational study, we evaluated conventional MRI scans from 10 SCA48 patients (M/F = 5/5; 44.7 ± 7.8 years). For all subjects, atrophy of both supratentorial and infratentorial compartments were recorded, as well as the presence of possible T2-weighted imaging (T2WI) signal alterations. Results: In SCA48 patients, no meaningful supratentorial changes were found, both in terms of volume loss or MRI signal changes. Atrophy of the cerebellum was present in all cases, involving both the vermis and the hemispheres, but particularly affecting the postero-lateral portions of the cerebellar hemispheres. In all patients, with the exception of only one subject (90.0% of the cases), a T2WI hyperintensity of both dentate nuclei was found. The association of such signal alteration with the pattern of cerebellar atrophy resembled the appearance of a crab (“crab sign”). Conclusion: Our findings suggest that SCA48 patients are characterized by cerebellar atrophy, mainly involving the postero-lateral hemisphere areas, along with a T2WI hyperintensity of dentate nuclei. We propose that the association of such signal change, along with the atrophy of the lateral portion of the cerebellar hemispheres, resembled the appearance of a crab, and therefore, we propose the “crab sign” as a neuroradiological sign present in SCA48 patients.

Purpose Fabry Disease (FD) has been frequently proposed as possible underestimated differential diagnosis of Multiple Sclerosis (MS), but no study has been performed to test prevalence of GLA gene mutations in a population fulfilling diagnostic criteria of MS. Aim of this study is to determine the prevalence of GLA gene mutations in a large and representative population diagnosed with MS, simultaneously providing a critical revision of current literature reports of coexistence or misdiagnosis between these two conditions. Methods In this mono-centric cross-sectional study, 927 patients fulfilling McDonald diagnostic criteria and encompassing all MS phenotypes were enrolled. Patients underwent evaluation of α-GalA activity and genotyping. Both genetic variants annotated as pathogenic and GVUS were considered. Estimated alleles frequencies were then compared to the ones reported in the gnomAD database. Results GLA gene variants were found in seven individuals. Five patients carried variants previously described having controversial impact on FD phenotype, and the analysis of exome database revealed that they are not rare among healthy individuals. One patient showed a new variant never described before, and another one carried a late-onset FD cardiac variant. Conclusions The overall prevalence of GLA gene variants in MS patients is comparable to the one estimated in healthy population. This result is further supported by critical revision of current literature evidences of misdiagnosis between MS and FD, arguing in favour of independence between these disorders.

We describe an Italian family with adult‐onset pure hereditary spastic paraplegia due to biallelic variants in POLR3A gene [c.1909 + 22G > A and c.3839dupT (p.M1280fs*20]. MRI showed a mild hyperintensity of superior cerebellar peduncles and cervical spinal cord atrophy. The neurophysiological metrics about intracortical excitability showed higher values of motor thresholds and a significant reduction of short interval intracortical inhibition (SICI) in the patient with a more severe phenotype. Our multimodal evaluation further expands the wide phenotypic spectrum associated with mutations in the POLR3A gene. An extensive genotype–phenotype correlation study is necessary to explain the role of the many new mutations on the function of protein.

Fabry disease (FD) is a rare X-linked disorder characterised by abnormal progressive lysosomal deposition of globotriaosylceramide in a large variety of cell types. The central nervous system (CNS) is often involved in FD, with a wide spectrum of manifestations ranging from mild symptoms to more severe courses related to acute cerebrovascular events. In this review we present the current knowledge on brain imaging for this condition, with a comprehensive and critical description of its most common neuroradiological imaging findings. Moreover, we report results from studies that investigated brain physiopathology underlying this disorder by using advanced imaging techniques, suggesting possible future directions to further explore CNS involvement in FD patients. • Conventional neuroradiological findings in FD are aspecific. • White matter hyperintensities represent the more consistent brain imaging feature of FD • Abnormalities of the vasculature wall of posterior circulation are also consistent features. • The pulvinar sign is not reliable as a finding pathognomonic for FD. • Advanced imaging techniques have increased our knowledge about brain involvement in FD.

(1) Although guidelines about the use of MRI sequences for Multiple Sclerosis (MS) diagnosis and follow-up are available, variability in acquisition protocols is not uncommon in everyday clinical practice. The aim of this study was to evaluate the real-world application of MS imaging guidelines in different settings to clarify the level of adherence to these guidelines. (2) Via an on-line anonymous survey, neuroradiologists (NR) were asked about MRI protocols and parameters routinely acquired when MS patients are evaluated in their center, both at diagnosis and follow-up. Furthermore, data about report content and personal opinions about emerging neuroimaging markers were also retrieved. (3) A total of 46 participants were included, mostly working in a hospital or university hospital (80.4%) and with more than 10 years of experience (47.9%). We found a relatively good adherence to the suggested MRI protocols regarding the use of T2-weighted sequences, although almost 10% of the participants routinely acquired 2D sequences with a slice thickness superior to 3 mm. On the other hand, a wider degree of heterogeneity was found regarding gadolinium administration, almost routinely performed at follow-up examination (87.0% of cases) in contrast with the current guidelines, as well as a low use of a standardized reporting system (17.4% of cases). (4) Although the MS community is getting closer to a standardization of MRI protocols, there is still a relatively wide heterogeneity among NR, with particular reference to contrast administration, which must be overcome to guarantee an adequate quality of patients’ care in MS.

Background Programmed epigenetic modifications occurring at early postnatal brain developmental stages may have a long-lasting impact on brain function and complex behavior throughout life. Notably, it is now emerging that several genes that undergo perinatal changes in DNA methylation are associated with neuropsychiatric disorders. In this context, we envisaged that epigenetic modifications during the perinatal period may potentially drive essential changes in the genes regulating brain levels of critical neuromodulators such as d-serine and d-aspartate. Dysfunction of this fine regulation may contribute to the genesis of schizophrenia or other mental disorders, in which altered levels of d-amino acids are found. We recently demonstrated that Ddo, the d-aspartate degradation gene, is actively demethylated to ultimately reduce d-aspartate levels. However, the role of epigenetics as a mechanism driving the regulation of appropriate d-ser levels during brain development has been poorly investigated to date. Methods We performed comprehensive ultradeep DNA methylation and hydroxymethylation profiling along with mRNA expression and HPLC-based d-amino acids level analyses of genes controlling the mammalian brain levels of d-serine and d-aspartate. DNA methylation changes occurring in specific cerebellar cell types were also investigated. We conducted high coverage targeted bisulfite sequencing by next-generation sequencing and single-molecule bioinformatic analysis. Results We report consistent spatiotemporal modifications occurring at the Dao gene during neonatal development in a specific brain region (the cerebellum) and within specific cell types (astrocytes) for the first time. Dynamic demethylation at two specific CpG sites located just downstream of the transcription start site was sufficient to strongly activate the Dao gene, ultimately promoting the complete physiological degradation of cerebellar d-serine a few days after mouse birth. High amount of 5′-hydroxymethylcytosine, exclusively detected at relevant CpG sites, strongly evoked the occurrence of an active demethylation process. Conclusion The present investigation demonstrates that robust and selective demethylation of two CpG sites is associated with postnatal activation of the Dao gene and consequent removal of d-serine within the mouse cerebellum. A single-molecule methylation approach applied at the Dao locus promises to identify different cell-type compositions and functions in different brain areas and developmental stages.

Background: Following the EuroAIM initiative to assess the quality of medical imaging guidelines by using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, we aimed to evaluate the quality of the current imaging guidelines in patients with gliomas. Methods: A literature search was conducted to identify eligible imaging guidelines considered in the management of adult patients with gliomas. The selected guidelines were evaluated using the AGREE II instrument by four independent appraisers. The agreement among the four appraisers was estimated using the intraclass correlation coefficient (ICC) analysis. Results: Seven guidelines were selected for the appraisal. Six out of the seven guidelines showed an average level of quality with only one showing a low quality. The highest scores were found in Domain 1 “Scope and purpose” (mean score = 81.2%) and Domain 4 “Clarity of presentation” (mean score = 77.6%). The remaining domains showed a low level of quality and, in particular, Domain 5 “Applicability” was the most critical with a mean score of 41.7%, mainly related to a minor attention to barriers and facilitators as well as costs and resources implications of applying the guidelines. The ICC analysis showed a very good agreement among the four appraisers with ICC values ranging from 0.907 to 0.993. Conclusions: The available guidelines on glioma imaging emerged as of average quality according to the AGREE II tool analysis. Based on these results, further efforts should be made in order to involve different professional bodies and stakeholders and increase patient and public involvement in any future guideline drafting as well as to improve the applicability of these guidelines into the clinical practice.

Introduction Spinocerebellar ataxia 48 has recently been described as an adult onset ataxia associated with a cerebellar cognitive affective syndrome, caused by a heterozygous mutation in the STUB1 gene. Methods We characterized the clinical and neuroimaging phenotype of eight patients from two autosomal dominant ataxia multigenerational Italian families, in whom we conducted whole exome sequencing, targeted multigene sequencing, and Sanger sequencing studies. Results We describe a complex syndrome characterized by ataxia and cognitive-psychiatric disorder in all cases, variably associated with chorea, parkinsonism, dystonia, urinary symptoms, and epilepsy. MRI showed a significant cerebellar atrophy, coupled to a T2-weighted hyperintensity affecting the dentate nuclei and extending to the middle cerebellar peduncles, whereas FDG-PET studies revealed glucose hypometabolism in cerebellum, striatum, and cerebral cortex. We identified two different novel STUB1 mutations segregating in the two families. One of the two mutations, p.(Gly33Ser), occurs in the TRP domain, whereas p.(Pro228Ser) is located in the ubiquitin ligase region. Discussion We emphasize the similarity of the described clinical picture with that of SCAR16, an autosomal recessive ataxia caused by biallelic mutations in the same gene, and of spinocerebellar ataxia type 17, which is considered the main Huntington's disease-like syndrome. The pathogenesis of the disease and the relationship between SCA48 and SCAR16 remain to be clarified.

Background/Aim: Prostate multiparametric magnetic resonance imaging (mpMRI) is the reference imaging modality for extraprostatic extension of disease (EPE) assessment. We aimed to compare the diagnostic accuracy of different abbreviated MRI protocols to the standard prostate mpMRI in the identification of EPE of PCa. Patients and Methods: Fifty patients were retrospectively enrolled. Dual-pulse (dpMRI) and biparametric (bpMRI) abbreviated protocols were obtained from mpMRI. The performance of two experienced radiologists and two radiology residents was correlated with a reference standard and compared. Inter and intra-reader agreements were evaluated. Results: All protocols were strongly correlated to the reference standard (p≤0.001). A significant difference was found between dpMRI and mpMRI (p=0.009), no differences emerged between bpMRI and mpMRI (p=0.27). All readers showed moderate agreement (ĸ=0.47, ĸ=0.50 and ĸ=0.53 for dpMRI, bpMRI and mpMRI, respectively). Intra-reader agreement was good (all ĸ values ≥0.70). Conclusion: Only bpMRI showed similar diagnostic performance to mpMRI, thus appearing as a feasible alternative to the standard protocol for EPE detection.

Background Fabry's disease (FD) is a rare, multi-organ lysosomal disease, caused by the deficiency of the enzyme α-galactosidase A, and is difficult to diagnose. Although parapelvic cysts (PC) were previously associated with FD, their prevalence and significance are unclear. Methods The present study aimed to: (i) evaluate, by renal ultrasound, the real prevalence of PC and of their determinants in a multicentre, nationwide cohort of FD patients (n = 173, Study 1) and (ii) ascertain whether a greater accuracy of PC detection improved their identification, in FD patients from a single centre (n = 67, Study 2). In both studies, for each FD patient, an age- and renal function-matched subject was selected for comparison (1:1). Results In Study 1, PC were detected in 28.9% of FD subjects and in only 1.1% of control subjects (P

Purpose: Bi-parametric prostate MR (bp-MR) is a valuable tool for detection and characterization of prostate cancer (PCa). Recent studies suggested that PSA-density (PSA-D) in combination with multi-parametric prostate MR as well as bp-MR may achieve a higher diagnostic accuracy than either alone. We aimed to evaluate the diagnostic performance of bp-MR, PSA-D and their combination in biopsy-naïve patients. Methods and materials: We retrospectively analyzed 334 consecutive patients who underwent prostate MR on a 3T scanner. Only patients (n = 114) who underwent TRUS-biopsy within 30 days following MR with no previous prostate biopsies were considered. Our protocol included T2-weighted and DWI sequences. A Likert score based on PI-RADS v2 was used for bp-MR evaluation. Lesions were graded histopathologically using the ISUP score. We assessed three scenarios: detection of lesions independently of ISUP score (ISUP ≥ 1), detection of both intermediate and clinically significant lesions (ISUP ≥ 2) and detection of clinically significant lesions alone (ISUP ≥ 3). Predictive value of bp-MR and PSA-D was evaluated by ROC curves and logistic regression analysis. A p value < 0.05 was considered statistically significant. Results: In all evaluated scenarios, bp-MR showed a significantly higher predictive power (AUC = 0.87-0.95) compared to the performance of PSA-D (AUC = 0.73–0.79), while their combination (AUC = 0.91-0.95) showed no statistically significant improvement compared to bp-MR alone. Conclusion: Our results confirm that bp-MR is a powerful tool in detection of clinically significant PCa. Contrary to findings in the recent literature, PSA-D does not appear to significantly improve its diagnostic performance.

Aims The cost-effectiveness of screening for silent coronary heart disease (CHD) in type 2 diabetes (DM2) is still debated. Methods We applied a diagnostic algorithm for silent CHD detection, in a cohort of 102 asymptomatic DM2 subjects (57 ± 7 years), attending 5 Italian outpatient clinics, to verify its predictive value. The risk of silent CHD was calculated considering classical risk factors, and presence of microangiopathy/macroangiopathy. Patients were divided in 3 groups, i.e. group 1: normal ECG and low silent CHD risk; group 2: abnormal ECG, irrespective of silent CHD risk; group 3: high silent CHD risk, irrespective of ECG. To group 2 and 3, a functional test was recommended and performed in 78% of patients. Results Silent CHD prevalence was similar in group 2 and 3 (25 vs. 17% respectively; p = 0.495). However, evaluating the entire cohort, a significant higher prevalence of silent CHD was observed in subjects with abnormal vs. normal ECG (23 vs. 4%; P = 0.004), but not in subjects with high vs. low pre-test silent CHD risk (14 vs. 9%; p = 0.472). Conclusions An abnormal ECG was a strong, independent predictor of silent CHD (OR 8.9; CI 1.27–62.5; p = 0.028) in DM2. Therefore, a functional stress testing should be considered in DM2 patients with ECG abnormalities.

Irritable bowel syndrome (IBS) is characterized by visceral hypersensitivity likely related to altered processing of sensory stimuli along the brain-gut axis. Previous neuroimaging studies demonstrated structural and functional alteration of several brain areas involved in bodily representation, e.g. the insula, in patients with IBS. By means of resting-state functional magnetic resonance imaging (rs-fMRI) we searched for alteration of functional connectivity within the network involved in self-bodily consciousness. We found significant inverse correlation between hypochondriasis assessed through a clinical questionnaire and connectivity between posterior cingulate cortex and left supramarginal gyrus, extending into the adjacent superior temporal gyrus. Moreover, we observed a significant and positive correlation between a clinical questionnaire assessing interoception and connectivity between left anterior ventral insula and two clusters located in supramarginal gyrus bilaterally. Our findings highlight an “abnormal network synchrony” reflecting functional alteration, in the absence of structural and micro-structural changes, which might represent a possible therapeutic target for Irritable Bowel Syndrome.

We thank Sechi et al. for the comments on our article.1 We agree that investigating the relationship between functional changes and disease course is a core issue for defining the role of functional imaging in both pathophysiology and clinical studies in Fabry disease (FD). The findings of Ortu et al.2 help define the role of the functional connectivity (FC) alterations in patients. Indeed, in their study,2 motor cortex hyperexcitability partly subsided when enzyme replacement therapy was started (although the small number of patients and the incomplete reversal of transcranial magnetic stimulation findings, possibly related to insufficient follow-up, does not allow for firm conclusions due to its complete reversibility). On the contrary, we found that resting-state–fMRI alterations were present in successfully treated patients, mitigating against the hypothesis that these changes may reflect reversible FD features.1 While our view is that “a direct relationship between motor cortex hyperexcitability…and present FC changes remains speculative,”1 longitudinal studies with suitable sample sizes assessing both FC and motor cortex excitability are needed. Only this approach will demonstrate if FC changes are related to a residual, nonreversible hyperexcitability, or if different neural circuit alterations are probed by the 2 techniques.

Objective To investigate global and lobular cerebellar volumetries in patients with progressive multiple sclerosis (MS), testing the contribution of cerebellar lobular atrophy to both motor and cognitive performances. Methods Eighty-two patients with progressive MS and 46 healthy controls (HC) were enrolled in this cross-sectional study. Clinical evaluation included motor and cognitive testing: Expanded Disability Status Scale, cerebellar Functional System score, Timed 25-Foot Walk Test, 9-Hole Peg Test (9-HPT), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test–Revised (BVMT) and California Verbal Learning Test II (CVLT). Cerebellar volumes were automatically obtained using the Spatially Unbiased Infratentorial Toolbox. A hierarchical multiple linear regression analysis was performed to assess the relationship between MRI variables of supratentorial and cerebellar damage (grey matter fraction, T2 lesion volume, metrics of cerebellar atrophy and cerebellar lesion volume) and motor/cognitive scores. Results Patients with MS exhibited lower cerebellar volumes compared with HC. Regression analysis showed that cerebellar metrics accounted for extra variance in both motor and cognitive performances, with cerebellar lesion volume, cerebellar Lobules VI, Crus I and VIIIa atrophy being independent predictors of 9-HPT, SDMT, BVMT and CVLT performances. Conclusions Atrophy of specific cerebellar lobules explains different aspects of motor and cognitive disability in patients with progressive MS. Investigation of cerebellar involvement provides further insight into the pathophysiological basis of clinical disability in progressive MS.

Gadolinium-based contrast agents (GBCA), widely used in Magnetic Resonance Imaging (MRI) for almost 30 years, were recently shown to be deposited in the brain and to induce persistent T1 shortening in deep gray matter structures in subjects with normal renal function. The aim of the present study is to summarize the evidence derived from the rapidly growing scientific literature on Gadolinium retention in the brain and in the rest of the body. To this end, the original articles that described imaging and pathology findings in humans and animals exposed to GBCA were reviewed. The main aspects that emerged were the different effects of linear and macrocyclic GBCA on brain MRI appearance, the evidence of Gadolinium tissue retention in multiple organs, and the debated issue of the possible clinical consequences. Although no adverse health effects have been documented so far, updated information about GBCA build-up in the body is necessary for health professionals, also in view of the increasing concern in the general population. To date, our knowledge about the mechanisms of Gadolinium tissue deposition and, above all, its long-term consequences is still largely incomplete. However, while official guidelines are eagerly awaited, some advices may already be given, to help our radiological daily practice.

Objectives To prospectively determine the diagnostic accuracy of a biparametric 3T magnetic resonance imaging protocol (BP-MRI) for prostatic cancer detection, compared to a multiparametric MRI protocol (MP-MRI), in a biopsy naive patient population. Methods Eighty-two untreated patients (mean age 65 ± 7.6 years) with clinical suspicion of prostate cancer and/or altered prostate-specific antigen (PSA) levels underwent a MP-MRI, including T2-weighted imaging, diffusion-weighted imaging (with the correspondent apparent diffusion coefficient maps) and dynamic contrast enhanced sequence, followed by prostate biopsy. Two radiologists reviewed both the BP-MRI and the MP-MRI protocols to establish a radiological diagnosis. Receiver operating characteristics curves were obtained to determine the diagnostic performance of the two protocols. Results The mean PSA level was 8.8 ± 8.1 ng/ml. A total of 34 prostatic tumors were identified, with a Gleason score that ranged from 3 + 3 to 5 + 4. Of these 34 tumors, 29 were located within the peripheral zone and 5 in the transitional zone. BP-MRI and MP-MRI showed a similar performance in terms of overall diagnostic accuracy, with an area under the curve of 0.91 and 0.93, respectively (p = n.s.). Conclusions BP-MRI prostate protocol is feasible for prostatic cancer detection compared to a standard MP-MRI protocol, requiring a shorter acquisition and interpretation time, with comparable diagnostic accuracy to the conventional protocol, without the administration of gadolinium-based contrast agent.

DNA methylation is often analyzed by reporting the average methylation degree of each cytosine. In this study, we used a single molecule methylation analysis in order to look at the methylation conformation of individual molecules. Using D-aspartate oxidase as a model gene, we performed an in-depth methylation analysis through the developmental stages of three different mouse tissues (brain, lung, and gut), where this gene undergoes opposite methylation destiny. This approach allowed us to track both methylation and demethylation processes at high resolution. The complexity of these dynamics was markedly simplified by introducing the concept of methylation classes (MCs), defined as the number of methylated cytosines per molecule, irrespective of their position. The MC concept smooths the stochasticity of the system, allowing a more deterministic description. In this framework, we also propose a mathematical model based on the Markov chain. This model aims to identify the transition probability of a molecule from one MC to another during methylation and demethylation processes. The results of our model suggest that: 1) both processes are ruled by a dominant class of phenomena, namely, the gain or loss of one methyl group at a time; and 2) the probability of a single CpG site becoming methylated or demethylated depends on the methylation status of the whole molecule at that time.

Introduction To evaluate if advanced neuroimaging research is mainly conducted by imaging specialists, we investigated the number of first authorships by radiologists and nonradiologist scientists in articles published in the field of advanced neuroimaging in the past 10 years. Methods Articles in the field of advanced neuroimaging identified in this retrospective bibliometric analysis were divided in four groups, depending on the imaging technique used. For all included studies, educational background of the first authors was recorded (based on available online curriculum vitae) and classified in subgroups, depending on their specialty. Finally, journal impact factors were recorded and comparatively assessed among subgroups as a metric of research quality. Results A total number of 3831 articles were included in the study. Radiologists accounted as first authors for only 12.8 % of these publications, while 56.9 % of first authors were researchers without a medical degree. Mean impact factor (IF) of journals with non-MD researchers as first authors was significantly higher than the MD subgroup (p < 10−20), while mean IF of journals with radiologists as first authors was significantly lower than articles authored by other MD specialists (p < 10−11). Conclusions The majority of the studies in the field of advanced neuroimaging in the last decade is conducted by professional figures other than radiologists, who account for lessthan the 13 % of the publications. Furthermore, the mean IF value of radiologists-authored articles was the lowest among all subgroups. These results, taken together, should question the radiology community about its future role in the development of advanced neuroimaging.

We performed ultra-deep methylation analysis at single molecule level of the promoter region of developmentally regulated D-Aspartate oxidase (Ddo), as a model gene, during brain development and embryonic stem cell neural differentiation. Single molecule methylation analysis enabled us to establish the effective epiallele composition within mixed or pure brain cell populations. In this framework, an epiallele is defined as a specific combination of methylated CpG within Ddo locus and can represent the epigenetic haplotype revealing a cell-to-cell methylation heterogeneity. Using this approach, we found a high degree of polymorphism of methylated alleles (epipolymorphism) evolving in a remarkably conserved fashion during brain development. The different sets of epialleles mark stage, brain areas, and cell type and unravel the possible role of specific CpGs in favoring or inhibiting local methylation. Undifferentiated embryonic stem cells showed non-organized distribution of epialleles that apparently originated by stochastic methylation events on individual CpGs. Upon neural differentiation, despite detecting no changes in average methylation, we observed that the epiallele distribution was profoundly different, gradually shifting toward organized patterns specific to the glial or neuronal cell types. Our findings provide a deep view of gene methylation heterogeneity in brain cell populations promising to furnish innovative ways to unravel mechanisms underlying methylation patterns generation and alteration in brain diseases. We performed ultra-deep methylation analysis at single molecule level of the promoter region of developmentally regulated D-Aspartate oxidase (Ddo), as a model gene, during brain development and embryonic stem cell neural differentiation. Single molecule methylation analysis enabled us to establish the effective epiallele composition within mixed or pure brain cell populations. In this framework, an epiallele is defined as a specific combination of methylated CpG within Ddo locus and can represent the epigenetic haplotype revealing a cell-to-cell methylation heterogeneity. Using this approach, we found a high degree of polymorphism of methylated alleles (epipolymorphism) evolving in a remarkably conserved fashion during brain development. The different sets of epialleles mark stage, brain areas, and cell type and unravel the possible role of specific CpGs in favoring or inhibiting local methylation. Undifferentiated embryonic stem cells showed non-organized distribution of epialleles that apparently originated by stochastic methylation events on individual CpGs. Upon neural differentiation, despite detecting no changes in average methylation, we observed that the epiallele distribution was profoundly different, gradually shifting toward organized patterns specific to the glial or neuronal cell types. Our findings provide a deep view of gene methylation heterogeneity in brain cell populations promising to furnish innovative ways to unravel mechanisms underlying methylation patterns generation and alteration in brain diseases.

Purpose: Proper evaluation of polyphenols intake at the population level is a necessary step in order to establish possible associations with health outcomes. Available data are limited, and so far no study has been performed in people with diabetes. The aim of this work was to document the intake of polyphenols and their major food sources in a cohort of people with type 2 diabetes and in socio-demographic subgroups. Methods: We studied 2573 men and women aged 50–75 years. Among others, anthropometry was measured by standard protocol and dietary habits were investigated by food frequency questionnaire (EPIC). The intake of polyphenols was evaluated using US Department of Agriculture and Phenol-Explorer databases. Results: The mean total polyphenol intake was 683.3 ± 5.8 mg/day. Non-alcoholic beverages represented the main food source of dietary polyphenols and provided 35.5% of total polyphenol intake, followed by fruits (23.0%), alcoholic beverages (14.0%), vegetables (12.4%), cereal products and tubers (4.6%), legumes (3.7%) and oils (2.1%); chocolate, cakes and nuts are negligible sources of polyphenols in this cohort. The two most important polyphenol classes contributing to the total intake were flavonoids (47.5%) and phenolic acids (47.4%). Polyphenol intake increased with age and education level and decreased with BMI; furthermore, in the northern regions of Italy, the polyphenol intake was slightly, but significantly higher than in the central or southern regions. Conclusions: The study documents for the first time the intake of polyphenols and their main food sources in people with diabetes using validated and complete databases of the polyphenol content of food. Compared with published data, collected in people without diabetes, these results suggest a lower intake and a different pattern of intake in people with diabetes. © 2016 Springer-Verlag Berlin Heidelberg