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Human cells encode up to 15 DNA polymerases with specialized functions in chromosomal DNA synthesis and damage repair. In contrast, complex DNA viruses, such as those of the herpesviridae family, encode a single B-family DNA polymerase. This disparity raises the possibility that DNA viruses may rely on host polymerases for synthesis through complex DNA geometries. We tested the importance of error-prone Y-family polymerases involved in translesion synthesis (TLS) to human cytomegalovirus (HCMV) infection. We find most Y-family polymerases involved in the nucleotide insertion and bypass of lesions restrict HCMV genome synthesis and replication. In contrast, other TLS polymerases, such as the polymerase ζ complex, which extends past lesions, was required for optimal genome synthesis and replication. Depletion of either the polζ complex or the suite of insertion polymerases demonstrate that TLS polymerases suppress the frequency of viral genome rearrangements, particularly at GC-rich sites and repeat sequences. Moreover, while distinct from HCMV, replication of the related herpes simplex virus type 1 is impacted by host TLS polymerases, suggesting a broader requirement for host polymerases for DNA virus replication. These findings reveal an unexpected role for host DNA polymerases in ensuring viral genome stability.

Condensin II subunits are known to be expressed and localized to interphase nuclei of eukaryotic cells. Although some studies have shown that condensin II likely exerts axial compaction forces, organizes chromosome territories, and has possible transcriptional modulatory functions, the full range of condensin II interphase activities are not known. In particular, it is not known if condensin II interphase activities are generally genome‐wide or if they have additional local activities unique to specific chromosomal structures such as telomeres. Here, we find that NCAPH2 interacts with TRF1 and these two proteins co‐localize at telomeres. Depletion of NCAPH2 leads to ATR‐dependent accumulation of 53BP1 and γH2AX DNA damage foci, including damage specific to telomeres. Furthermore, depletion of NCAPH2 results in a fragile telomere phenotype and apparent sister‐telomere fusions only days after NCAPH2 depletion. Taken together these observations suggest that NCAPH2 promotes telomere stability, possibly through a direct interaction with the TRF1 shelterin component, and prevents telomere dysfunction resulting from impaired DNA replication. Because proper telomere function is essential for chromosome integrity these observations reveal a previously unappreciated function for NCAPH2 in ensuring genome and telomere stability.

The role of aortic clamping techniques on the occurrence of neurological complications after right mini-thoracotomy mitral valve surgery is still debated. Brain injuries can occur also as silent cerebral micro-embolizations (SCM), which have been linked to significant deficits in physical and cognitive functions. Aims of this study are to evaluate the overall rate of SCM and to compare endoaortic clamp (EAC) with trans-thoracic clamp (TTC). Patients enrolled underwent a pre-operative, a post-operative, and a follow-up MRI. Forty-three patients were enrolled; EAC was adopted in 21 patients, TTC in 22 patients. Post-operative SCM were reported in 12 cases (27.9%). No differences between the 2 groups were highlighted (23.8% SCM in the EAC group versus 31.8% in the TTC). MRI analysis showed post-operative SCM in nearly 30% of selected patients after right mini-thoracotomy mitral valve surgery. Subgroup analysis on different types of aortic clamping showed comparable results. CLINICAL RELEVANCE: The rate of SCM reported in the present study on patients undergoing minimally invasive MVS and RAP is consistent with data in the literature on patients undergoing cardiac surgery through median sternotomy and antegrade arterial perfusion. Moreover, no differences were reported between EAC and TTC: both the aortic clamping techniques are safe, and the choice of the surgical setting to adopt can be really done according to the patient's characteristics.

Tosatto, Silvio/0000-0003-4525-7793; Zhang, Feng/0000-0003-3447-897X; Gonzalez, Jose Maria Fernandez/0000-0002-4806-5140; Devignes, Marie-Dominique/0000-0002-0399-8713; Wass, Mark/0000-0001-5428-6479; Falda, Marco/0000-0003-2642-519X; Thurlby, Natalie/0000-0002-1007-0286; Zosa, Elaine/0000-0003-2482-0663; Dessimoz, Christophe/0000-0002-2170-853X; Yunes, Jeffrey/0000-0003-1869-3231; Hamid, Md Nafiz/0000-0001-8681-6526; Hoehndorf, Robert/0000-0001-8149-5890; Dogan, Tunca/0000-0002-1298-9763; NOTARO, MARCO/0000-0003-4309-2200; Cozzetto, Domenico/0000-0001-6752-5432; Lewis, Kimberley/0000-0003-3010-8453; Roche, Daniel/0000-0002-9204-1840; Martin, Maria-Jesus/0000-0001-5454-2815; Tress, Michael/0000-0001-9046-6370; Tolvanen, Martti/0000-0003-3434-7646; Cheng, Jianlin/0000-0003-0305-2853; Rose, Peter/0000-0001-9981-9750; Renaux, Alexandre/0000-0002-4339-2791; Kacsoh, Balint/0000-0001-9171-0611; O'Donovan, Claire/0000-0001-8051-7429; Kulmanov, Maxat/0000-0003-1710-1820; Friedberg, Iddo/0000-0002-1789-8000; Zhou, Naihui/0000-0001-6268-6149, WOS: 000498615000001, PubMed ID: 31744546, Background The Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function. Results Here, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes. Specifically, we performed experimental whole-genome mutation screening in Candida albicans and Pseudomonas aureginosa genomes, which provided us with genome-wide experimental data for genes associated with biofilm formation and motility. We further performed targeted assays on selected genes in Drosophila melanogaster, which we suspected of being involved in long-term memory. Conclusion We conclude that while predictions of the molecular function and biological process annotations have slightly improved over time, those of the cellular component have not. Term-centric prediction of experimental annotations remains equally challenging; although the performance of the top methods is significantly better than the expectations set by baseline methods in C. albicans and D. melanogaster, it leaves considerable room and need for improvement. Finally, we report that the CAFA community now involves a broad range of participants with expertise in bioinformatics, biological experimentation, biocuration, and bio-ontologies, working together to improve functional annotation, computational function prediction, and our ability to manage big data in the era of large experimental screens., National Science FoundationNational Science Foundation (NSF) [DBI1564756, DBI-1458359, DBI-1458390, DMS1614777, CMMI1825941, NSF 1458390]; Gordon and Betty Moore FoundationGordon and Betty Moore Foundation [GBMF 4552]; National Institutes of Health NIGMSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [P20 GM113132]; Cystic Fibrosis Foundation [CFRDP STANTO19R0]; BBSRCBiotechnology and Biological Sciences Research Council (BBSRC) [BB/K004131/1, BB/F00964X/1, BB/M025047/1, BB/M015009/1]; Consejo Nacional de Ciencia y Tecnologia Paraguay (CONACyT)Consejo Nacional de Ciencia y Tecnologia (CONACyT) [14-INV-088, PINV15-315]; NSFNational Science Foundation (NSF) [1660648, DBI 1759934, IIS1763246, DBI-1458477, 0965768, DMR-1420073, DBI-1458443]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01GM093123, DP1MH110234, UL1 TR002319, U24 TR002306]; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy-EXC 2155 "RESIST"German Research Foundation (DFG) [39087428]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01GM123055, R01GM60595, R15GM120650, GM083107, GM116960, AI134678, NIH R35-GM128637, R00-GM097033]; ERCEuropean Research Council (ERC) [StG 757700]; Spanish Ministry of Science, Innovation and Universities [BFU2017-89833-P]; Severo Ochoa award; Centre of Excellence project "BioProspecting of Adriatic Sea"; Croatian Government; European Regional Development FundEuropean Union (EU) [KK.01.1.1.01.0002]; ATT Tieto kayttoon grant; Academy of FinlandAcademy of Finland; University of Turku; CSC-IT Center for Science Ltd.; University of Miami; National Cancer Institute of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [U01CA198942]; Helsinki Institute for Life Sciences; Academy of FinlandAcademy of Finland [292589]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [31671367, 31471245, 91631301, 61872094, 61572139]; National Key Research and Development Program of China [2016YFC1000505, 2017YFC0908402]; Italian Ministry of Education, University and Research (MIUR) PRIN 2017 projectMinistry of Education, Universities and Research (MIUR) [2017483NH8]; Shanghai Municipal Science and Technology Major Project [2017SHZDZX01, 2018SHZDZX01]; UK Biotechnology and Biological Sciences Research CouncilBiotechnology and Biological Sciences Research Council (BBSRC) [BB/N019431/1, BB/L020505/1, BB/L002817/1]; Elsevier; Extreme Science and Engineering Discovery Environment (XSEDE) award [MCB160101, MCB160124]; Ministry of Education, Science and Technological Development of the Republic of Serbia [173001]; Taiwan Ministry of Science and Technology [106-2221-E-004-011-MY2]; Montana State University; Bavarian Ministry for Education; Simons Foundation; NIH NINDSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [1R21NS103831-01]; University of Illinois at Chicago (UIC) Cancer Center award; UIC College of Liberal Arts and Sciences Faculty Award; UIC International Development Award; Yad Hanadiv [9660/2019]; National Institute of General Medical Science of the National Institute of Health [GM066099, GM079656]; Research Supporting Plan (PSR) of University of Milan [PSR2018-DIP-010-MFRAS]; Swiss National Science FoundationSwiss National Science Foundation (SNSF) [150654]; EMBL-European Bioinformatics Institute core funds; CAFA BBSRC [BB/N004876/1]; European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grantEuropean Union (EU) [778247]; COST ActionEuropean Cooperation in Science and Technology (COST) [BM1405]; NIH/NIGMSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R01 GM071749]; National Human Genome Research Institute of the National of Health [U41 HG007234]; INB Grant (ISCIII-SGEFI/ERDF) [PT17/0009/0001]; TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [EEEAG-116E930]; KanSil [2016K121540]; Universita degli Studi di Milano; 111 ProjectMinistry of Education, China - 111 Project [B18015]; key project of Shanghai Science Technology [16JC1420402]; ZJLab; project Ribes Network POR-FESR 3S4H [TOPP-ALFREVE18-01]; PRID/SID of University of Padova [TOPP-SID19-01]; NIGMSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R15GM120650]; King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research (OSR) [URF/1/3454-01-01, URF/1/3790-01-01]; "the Human Project from Mind, Brain and Learning" of the NCCU Higher Education Sprout Project by the Taiwan Ministry of Education; National Center for High-performance ComputingIstanbul Technical University, The work of IF was funded, in part, by the National Science Foundation award DBI-1458359. The work of CSG and AJL was funded, in part, by the National Science Foundation award DBI-1458390 and GBMF 4552 from the Gordon and Betty Moore Foundation. The work of DAH and KAL was funded, in part, by the National Science Foundation award DBI-1458390, National Institutes of Health NIGMS P20 GM113132, and the Cystic Fibrosis Foundation CFRDP STANTO19R0. The work of AP, HY, AR, and MT was funded by BBSRC grants BB/K004131/1, BB/F00964X/1 and BB/M025047/1, Consejo Nacional de Ciencia y Tecnologia Paraguay (CONACyT) grants 14-INV-088 and PINV15-315, and NSF Advances in BioInformatics grant 1660648. The work of JC was partially supported by an NIH grant (R01GM093123) and two NSF grants (DBI 1759934 and IIS1763246). ACM acknowledges the support by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy -EXC 2155 "RESIST" - Project ID 39087428. DK acknowledges the support from the National Institutes of Health (R01GM123055) and the National Science Foundation (DMS1614777, CMMI1825941). PB acknowledges the support from the National Institutes of Health (R01GM60595). GB and BZK acknowledge the support from the National Science Foundation (NSF 1458390) and NIH DP1MH110234. FS was funded by the ERC StG 757700 "HYPER-INSIGHT" and by the Spanish Ministry of Science, Innovation and Universities grant BFU2017-89833-P. FS further acknowledges the funding from the Severo Ochoa award to the IRB Barcelona. TS was funded by the Centre of Excellence project "BioProspecting of Adriatic Sea", co-financed by the Croatian Government and the European Regional Development Fund (KK.01.1.1.01.0002). The work of SK was funded by ATT Tieto kayttoon grant and Academy of Finland. JB and HM acknowledge the support of the University of Turku, the Academy of Finland and CSC -IT Center for Science Ltd. TB and SM were funded by the NIH awards UL1 TR002319 and U24 TR002306. The work of CZ and ZW was funded by the National Institutes of Health R15GM120650 to ZW and start-up funding from the University of Miami to ZW. The work of PWR was supported by the National Cancer Institute of the National Institutes of Health under Award Number U01CA198942. PR acknowledges NSF grant DBI-1458477. PT acknowledges the support from Helsinki Institute for Life Sciences. The work of AJM was funded by the Academy of Finland (No. 292589). The work of FZ and WT was funded by the National Natural Science Foundation of China (31671367, 31471245, 91631301) and the National Key Research and Development Program of China (2016YFC1000505, 2017YFC0908402]. CS acknowledges the support by the Italian Ministry of Education, University and Research (MIUR) PRIN 2017 project 2017483NH8. SZ is supported by the National Natural Science Foundation of China (No. 61872094 and No. 61572139) and Shanghai Municipal Science and Technology Major Project (No. 2017SHZDZX01). PLF and RLH were supported by the National Institutes of Health NIH R35-GM128637 and R00-GM097033. JG, DTJ, CW, DC, and RF were supported by the UK Biotechnology and Biological Sciences Research Council (BB/N019431/1, BB/L020505/1, and BB/L002817/1) and Elsevier. The work of YZ and CZ was funded in part by the National Institutes of Health award GM083107, GM116960, and AI134678; the National Science Foundation award DBI1564756; and the Extreme Science and Engineering Discovery Environment (XSEDE) award MCB160101 and MCB160124.; The work of BG, VP, RD, NS, and NV was funded by the Ministry of Education, Science and Technological Development of the Republic of Serbia, Project No. 173001. The work of YWL, WHL, and JMC was funded by the Taiwan Ministry of Science and Technology (106-2221-E-004-011-MY2). YWL, WHL, and JMC further acknowledge the support from "the Human Project from Mind, Brain and Learning" of the NCCU Higher Education Sprout Project by the Taiwan Ministry of Education and the National Center for High-performance Computing for computer time and facilities. The work of IK and AB was funded by Montana State University and NSF Advances in Biological Informatics program through grant number 0965768. BR, TG, and JR are supported by the Bavarian Ministry for Education through funding to the TUM. The work of RB, VG, MB, and DCEK was supported by the Simons Foundation, NIH NINDS grant number 1R21NS103831-01 and NSF award number DMR-1420073. CJJ acknowledges the funding from a University of Illinois at Chicago (UIC) Cancer Center award, a UIC College of Liberal Arts and Sciences Faculty Award, and a UIC International Development Award. The work of ML was funded by Yad Hanadiv (grant number 9660/2019). The work of OL and IN was funded by the National Institute of General Medical Science of the National Institute of Health through GM066099 and GM079656. Research Supporting Plan (PSR) of University of Milan number PSR2018-DIP-010-MFRAS. AWV acknowledges the funding from the BBSRC (CASE studentship BB/M015009/1). CD acknowledges the support from the Swiss National Science Foundation (150654). CO and MJM are supported by the EMBL-European Bioinformatics Institute core funds and the CAFA BBSRC BB/N004876/1. GG is supported by CAFA BBSRC BB/N004876/1. SCET acknowledges funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 778247 (IDPfun) and from COST Action BM1405 (NGP-net). SEB was supported by NIH/NIGMS grant R01 GM071749. The work of MLT, JMR, and JMF was supported by the National Human Genome Research Institute of the National of Health, grant numbers U41 HG007234. The work of JMF and JMR was also supported by INB Grant (PT17/0009/0001 - ISCIII-SGEFI/ERDF). VA acknowledges the funding from TUBITAK EEEAG-116E930. RCA acknowledges the funding from KanSil 2016K121540. GV acknowledges the funding from Universita degli Studi di Milano - Project "Discovering Patterns in Multi-Dimensional Data" and Project "Machine Learning and Big Data Analysis for Bioinformatics". SZ is supported by the National Natural Science Foundation of China (No. 61872094 and No. 61572139) and Shanghai Municipal Science and Technology Major Project (No. 2017SHZDZX01). RY and SY are supported by the 111 Project (NO. B18015), the key project of Shanghai Science & Technology (No. 16JC1420402), Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX01), and ZJLab. ST was supported by project Ribes Network POR-FESR 3S4H (No. TOPP-ALFREVE18-01) and PRID/SID of University of Padova (No. TOPP-SID19-01). CZ and ZW were supported by the NIGMS grant R15GM120650 to ZW and start-up funding from the University of Miami to ZW. The work of MK and RH was supported by the funding from King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research (OSR) under Award No. URF/1/3454-01-01 and URF/1/3790-01-01. The work of SDM is funded, in part, by NSF award DBI-1458443.

To assess prognostic factors for a second clinical attack and a first disability worsening event in pediatric clinically isolated syndrome (pCIS) suggestive of Multiple Sclerosis (MS) patients. Objective: To assess prognostic factors for a second clinical attack and a first disability-worsening event in pediatric clinically isolated syndrome (pCIS) suggestive of multiple sclerosis (MS) patients. Methods: A cohort of 770 pCIS patients was followed up for at least 10 years. Cox proportional hazard models and Recursive Partitioning and Amalgamation (RECPAM) tree-regression were used to analyze data. Results: In pCIS, female sex and a multifocal onset were risk factors for a second clinical attack (hazard ratio [HR], 95% confidence interval [CI] = 1.28, 1.06–1.55; 1.42, 1.10–1.84, respectively), whereas disease-modifying drug (DMD) exposure reduced this risk (HR, 95% CI = 0.75, 0.60–0.95). After pediatric onset MS (POMS) diagnosis, age at onset younger than 15 years and DMD exposure decreased the risk of a first Expanded Disability Status Scale (EDSS)-worsening event (HR, 95% CI = 0.59, 0.42–0.83; 0.75, 0.71–0.80, respectively), whereas the occurrence of relapse increased this risk (HR, 95% CI = 5.08, 3.46–7.46). An exploratory RECPAM analysis highlighted a significantly higher incidence of a first EDSS-worsening event in patients with multifocal or isolated spinal cord or optic neuritis involvement at onset in comparison to those with an isolated supratentorial or brainstem syndrome. A Cox regression model including RECPAM classes confirmed DMD exposure as the most protective factor against EDSS-worsening events and relapses as the most important risk factor for attaining EDSS worsening. Interpretation: This work represents a step forward in identifying predictors of unfavorable course in pCIS and POMS and supports a protective effect of early DMD treatment in preventing MS development and disability accumulation in this population. Ann Neurol 2017;81:729–739.

The acute distal intracranial occlusion of the internal carotid artery (ICA) is a very complex heterogeneous pathology, characterized by various patterns. Aim of this work is to identify the different types and propose a classification. Among the patients admitted for stroke in the anterior circulation from august 2014 to October 2017, 46 (25%) presented with intracranial distal carotid artery occlusion. The mean age of the patients was 71 (SD 13.7), 65,2% female. The protocol included general and specific neurological examinations, CT, CT-Angiography with multiphase CTA, followed by Angiography. The occlusion was treated by aspiration device alone or associated with stent-retriever. NIHSS at the admission, at discharge and modified ranking Scale (mRS) at four months were examined. The occlusions presented with various patterns. Depending on its site (located at the distal ICA bifurcation or more proximal at the level of the ophthalmic segment of ICA, with or without extent to ICA bifurcation) taking also into account the various involvement of the cerebral vessels and anatomic variations of Circle of Willis, three groups of occlusion types could be identified (T1, T2 and T3). The collateral circulation, and the possibilities of the endovascular revascularization important for the final outcome, were clearly connected with the type of occlusion. NIHSS at admission was 19.1 (Range from 8 to 30, SD 4.4). Good outcome defined as mRS 0-2 at for months was obtained in 17 patients (37%). The proposed classification reproduces more precisely the complexity and heterogeneity of this pathology, being useful in the diagnosis and treatment of these patients.

The packaging and organization of the genome within the eukaryotic interphase nucleus directly influence how the genes are expressed. An underappreciated aspect of genome structure is that it is highly dynamic and that the physical positioning of a gene can impart control over its transcriptional status. In this review, we assess the current knowledge of how gene positioning at different levels of genome organization can directly influence gene expression during interphase. The levels of organization discussed include chromatin looping, topologically associated domains, chromosome territories, and nuclear compartments. We discuss specific studies demonstrating that gene positioning is a dynamic and highly regulated feature of the eukaryotic genome that allows for the essential spatiotemporal regulation of genes.

Mutations in COL4A1, encoding one of the six collagen type IV proteins, cover a wide spectrum of autosomal dominant overlapping phenotypes including porencephaly, small-vessel disease and hemorrhagic stroke, leukoencephalopathy, hereditary angiopathy with nephropathy, aneurysms and muscle cramp (HANAC) syndrome, and Walker-Warburg syndrome. Over 50 mutations are known, mainly being missense changes. Intra- and inter-familial variability has been reported. We studied two Italian families in which the proband had a clinical diagnosis of COL4A1-related disorder. We found two novel mutations (c.1249G>C; p.Gly417Arg and c.2662G>C; p.Gly888Arg). Both involved highly conserved amino acids and were predicted as being deleterious by bioinformatics tools. The c.1249G>C (p.Gly417Arg) segregated in four subjects with variable neurological phenotypes, namely leukoencephalopathy with muscle symptoms, brain small-vessel disease, and mild infantile encephalopathy. A fourth case was a carrier of the mutation without any neurological symptoms and an MRI with a specific white matter anomaly. The c.2662G>C (p.Gly888Arg) mutation was de novo in the proband. After a temporary motor impairment at age 14, the subject complained of mild imbalance at age 30, during the third trimester of her twin pregnancy, when an anomaly of the left brain hemisphere was documented in one fetus. Both her male dizygotic twins presented a severe motor delay, early convulsions, and leukoencephalopathy, and were carriers of the mutation. In summary, we confirm that high intra-familial variability of COL4A1 mutations with very mild phenotypes, the apparent incomplete penetrance, and de novo changes may become a "dilemma" for clinicians and genetic counselors.

Background Non-motor symptoms (NMS) in Parkinson's disease (PD) are common, increase the patients' disability and have a significantly negative impact on their quality of life. Essential tremor (ET) is also affected by non-motor symptoms and often enters into the differential diagnosis with PD. Brain scintigraphy with [123I]β-CIT SPECT is a technique used to facilitate differential diagnosis between PD and ET. Methods We evaluated both motor impairment (MDS-UPDRS-III) and non-motor symptoms (NMSQuest) in patients who underwent a [123I]β-CIT SPECT examination for diagnostic purposes. Both the clinical and the scintigraphic data obtained from the selected PD (n = 31) and ET (n = 22) patients were compared. Results We did not detect a significant difference in the total number of NMS reported by either PD (10.4 ± 4.9) or ET patients (8.41 ± 3.3). PD patients reported more drooling (29%), hyposmia (32.2%), hallucinations (19.3%), difficulty in concentrating (51.6%), orthostatic dizziness (67.7%), falling (19.3%), vivid dreams (32.2%), REM sleep behavior disorder (58%), and diplopia (22.5%) compared with ET patients. PD patients who complained of drooling, orthostatic dizziness, and diplopia had greater denervation of the caudata than did the PD patients who did not report the same symptoms. The differences observed were not associated with differences in age, sex, UPDRS-III score, and the presence/absence of tremor. Conclusions The declaration of non-motor symptoms is influenced by subjective factors that are widely suggestible. When analyzed early and before receiving a definitive diagnosis, PD patients complain of specific symptoms that seem to depend on different pathogenetic mechanisms.

Many potentially modifiable risk factors for MS are investigated. It is not known, however, if these factors also apply to MS-related cognitive impairment (CI), a frequent consequence of MS.The aim of our study was to assess risk factors for CI in MS patients, focusing on environmental exposures, lifestyle and comorbidities.We included MS patients referring to MS Centers in Florence and Barletta between 2014 and 2017. Neuropsychological performance was assessed through the Rao's battery and Stroop test, cognitive reserve (premorbid intelligence quotient-IQ) was evaluated using the National Adult Reading Test (NART). Potential risk factors were investigated through a semi-structured questionnaire.150 patients were included. CI was detected in 45 (30%) subjects and was associated with older age (p0.005), older age at MS onset (p = 0.016), higher EDSS score (p0.005), progressive disease course (p = 0.048) and lower premorbid IQ score (p0.005). As for risk factors, CI was related with lower physical activity in childhood-adolescence (p0.005). In women, hormonal therapy resulted to be protective against CI (p = 0.041). However, in the multivariable analysis, the only significant predictors of CI were older age (p0.05; OR 1.06, 95% CI 1.02-1.10) and lower premorbid IQ (p0.05; OR 0.93, 95% CI: 0.88-0.98). Removing IQ from the model, CI was associated with higher EDSS (p = 0.030; OR 1.25, 95% CI 1.02-1.53) and, marginally, previous physical activity (p = 0.066; OR 0.49, 95% CI: 0.23-1.05).Our findings suggest that physical activity in childhood-adolescence could be a contributor to cognitive reserve building, thus representing a potential protective factors for MS-related CI susceptible to preventive strategies.

none 34 no studio multicentrico The comparative effectiveness of fingolimod versus interferon beta/glatiramer acetate was assessed in a multicentre, observational, prospectively acquired cohort study including 613 patients with relapsing multiple sclerosis discontinuing natalizumab in the Italian iMedWeb registry. First, after natalizumab suspension, the relapse risk during the untreated wash-out period and during the course of switch therapies was estimated through Poisson regression analyses in separated models. During the wash-out period an increased risk of relapses was found in patients with a higher number of relapses before natalizumab treatment (incidence rate ratio = 1.31, P = 0.0014) and in patients discontinuing natalizumab due to lack of efficacy (incidence rate ratio = 2.33, P = 0.0288), patient's choice (incidence rate ratio = 2.18, P = 0.0064) and adverse events (incidence rate ratio = 2.09, P = 0.0084). The strongest independent factors influencing the relapse risk after the start of switch therapies were a wash-out duration longer than 3 months (incidence rate ratio = 1.78, P < 0.0001), the number of relapses experienced during and before natalizumab treatment (incidence rate ratio = 1.61, P < 0.0001; incidence rate ratio = 1.13, P = 0.0118, respectively) and the presence of comorbidities (incidence rate ratio = 1.4, P = 0.0097). Switching to fingolimod was associated with a 64% reduction of the adjusted-risk for relapse in comparison with switching to interferon beta/glatiramer acetate (incidence rate ratio = 0.36, P < 0.0001). Secondly, patients who switched to fingolimod or to interferon beta/glatiramer acetate were propensity score-matched on a 1-to-1 basis at the switching date. In the propensity score-matched sample a Poisson model showed a significant lower incidence of relapses in patients treated with fingolimod in comparison with those treated with interferon beta/glatiramer acetate (incidence rate ratio = 0.52, P = 0.0003) during a 12-month follow-up. The cumulative probability of a first relapse after the treatment switch was significantly lower in patients receiving fingolimod than in those receiving interferon beta/glatiramer acetate (P = 0.028). The robustness of this result was also confirmed by sensitivity analyses in subgroups with different wash-out durations (less or more than 3 months). Time to 3-month confirmed disability progression was not significantly different between the two groups (Hazard ratio = 0.58; P = 0.1931). Our results indicate a superiority of fingolimod in comparison to interferon beta/glatiramer acetate in controlling disease reactivation after natalizumab discontinuation in the real life setting. none Iaffaldano, Pietro; Lucisano, Giuseppe; Pozzilli, Carlo; Brescia Morra, Vincenzo; Ghezzi, Angelo; Millefiorini, Enrico; Patti, Francesco; Lugaresi, Alessandra; Zimatore, Giovanni Bosco; Marrosu, Maria Giovanna; Amato, Maria Pia; Bertolotto, Antonio; Bergamaschi, Roberto; Granella, Franco; Coniglio, Gabriella; Tedeschi, Gioacchino; Sola, Patrizia; Lus, Giacomo; Ferrò, Maria Teresa; Iuliano, Gerardo; Corea, Francesco; Protti, Alessandra; Cavalla, Paola; Guareschi, Angelica; Rodegher, Mariaemma; Paolicelli, Damiano; Tortorella, Carla; Lepore, Vito; Prosperini, Luca; Saccà, Francesco; Baroncini, Damiano; Comi, Giancarlo; Trojano, Maria; Italian iMed-Web database Iaffaldano, Pietro; Lucisano, Giuseppe; Pozzilli, Carlo; Brescia Morra, Vincenzo; Ghezzi, Angelo; Millefiorini, Enrico; Patti, Francesco; Lugaresi, Alessandra; Zimatore, Giovanni Bosco; Marrosu, Maria Giovanna; Amato, Maria Pia; Bertolotto, Antonio; Bergamaschi, Roberto; Granella, Franco; Coniglio, Gabriella; Tedeschi, Gioacchino; Sola, Patrizia; Lus, Giacomo; Ferrò, Maria Teresa; Iuliano, Gerardo; Corea, Francesco; Protti, Alessandra; Cavalla, Paola; Guareschi, Angelica; Rodegher, Mariaemma; Paolicelli, Damiano; Tortorella, Carla; Lepore, Vito; Prosperini, Luca; Saccà, Francesco; Baroncini, Damiano; Comi, Giancarlo; Trojano, Maria; Italian iMed-Web database

Condensin complexes exist across all domains of life and are central to the structure and organization of chromatin. As architectural proteins, condensins control chromatin compaction during interphase and mitosis. Condensin activity has been well studied in mitosis but have recently emerged as important regulators of genome organization and gene expression during interphase. Here, we focus our discussion on recent findings on the molecular mechanism and how condensins are used to shape chromosomes during interphase. These findings suggest condensin activity during interphase is required for proper chromosome organization. J. Cell. Physiol. 232: 1617-1625, 2017. © 2016 Wiley Periodicals, Inc.

The retinoblastoma tumor suppressor protein (RB) is inactivated in a majority of cancers. RB restricts cell proliferation by inhibiting the E2F family of transcription factors. The current model for RB/E2F function describes its role in regulating transcription at gene promoters. Whether the RB or E2F proteins might play a role in gene expression beyond transcription initiation is not well known. This review describes evidence that points to a novel role for the RB/E2F network in the regulation of RNA processing, and we propose a model as a framework for future research. The elucidation of a novel role of RB in RNA processing will have a profound impact on our understanding of the role of this tumor suppressor family in cell and developmental biology.

Expression of intracellular heat shock protein 27 (Hsp27) rises in the brain of animal models of cerebral ischemia and stroke. Hsp27 is also released into the circulation and the aim of the present study was to investigated if serum Hsp27 (sHsp27) levels are altered in patients with acute ischemic stroke. sHsp27 was measured in 15 patients with acute ischemic stroke and in 14 control subjects comparable for age, sex, and cardiovascular risk factors. In patients, measurements were performed at admission and 1, 2, and 30 days thereafter. At admission, mean sHsp27 values were threefold higher in patients than in controls. In patients, sHsp27 values dropped after 24 h, rose again at 48 h, and markedly declined at 30 days, indicating the presence of a temporal trend of sHsp27 values following acute ischemic stroke.

We previously identified a Drosophila maternal effect-lethal mutant named ‘no poles’ (nopo). Embryos from nopo females undergo mitotic arrest with barrel-shaped, acentrosomal spindles during the rapid cycles of syncytial embryogenesis because of activation of a Chk2-mediated DNA checkpoint. NOPO is the Drosophila homolog of human TNF receptor associated factor (TRAF)-interacting protein (TRIP), which has been implicated in TNF signaling. NOPO and TRIP contain RING domains closely resembling those of known E3 ubiquitin ligases. We herein sought to elucidate the mechanism by which TRIP/NOPO promotes genomic stability by performing a yeast two-hybrid screen to identify potential substrates/interactors. We identified members of the Y-family of DNA polymerases that facilitate replicative bypass of damaged DNA (translesion synthesis) as TRIP interactors. We show that TRIP and NOPO co-immunoprecipitate with human and Drosophila Polη, respectively, from cultured cells. We generated a null mutation in Drosophila Polη (dPolη) and found that dPolη-derived embryos have increased sensitivity to ultraviolet irradiation and exhibit nopo-like mitotic spindle defects. dPolη and nopo interact genetically in that overexpression of dPolη in hypomorphic nopo-derived embryos suppresses nopo phenotypes. We observed enhanced ubiquitylation of Polη by TRIP and NOPO E3 ligases in human cells and Drosophila embryos, respectively, and show that TRIP promotes hPolη localization to nuclear foci in human cells. We present a model in which TRIP/NOPO ubiquitylates Polη to positively regulate its activity in translesion synthesis.

Lipoprotein(a) [Lp(a)] is a plasma lipoprotein that consists of a low-density lipoprotein (LDL)-like particle containing APO B-100 and apolipoprotein(a), linked by a disulphide bridge. There is evidence that higher serum level of Lp(a) is a predictor of various vascular diseases, such as myocardial infarction, coronary stenosis, re-occlusion of aortocoronary bypass vein grafts, peripheral atherosclerosis and cerebral infarction [1-4]. We describe a young man with a cryptogenic stroke with very high serum level of Lp(a) as the only vascular risk factor.

Background. We reviewed our experience with left internal mammary artery (LIMA)-to-left anterior descending artery (LAD) anastomosis on a beating heart through a left anterior small thoracotomy. Methods. This procedure was performed in 343 of 358 scheduled patients; in 15 (4.2%) the LAD was not suitable or was too small. The chest was opened in the fourth (127, 37.0%) or fifth (197, 57.4%) intercostal space, or both (19, 5.6%); the length of the harvested LIMA was 4–15 cm. The LAD was occluded by means of two 4-0 Prolene (Ethicon, Somerville, NJ) sutures, both snared on a small piece of silicone tubing. The anastomosis was performed with two 8-0 Prolene sutures. In the early postoperative period all patients underwent angiography or a doppler flow assessment of the LIMA or both. Results. In 310 patients the LIMA was connected directly to the LAD; to elongate the LIMA, in 30 patients an inferior epigastric artery and in 3 patients a saphenous vein was used. In 2 patients the diagonal branch was also grafted using an inferior epigastric artery from the LIMA. Three patients (0.9%) died during the first 30 days after the operation, and 4 other patients (1.2%) died after the first month. Twenty-five patients (7.3%) were reoperated on because of anastomotic or conduit failure, 18 (5.2%) early and 7 (2.1%) late; one additional patient had a late percutaneous transluminal coronary angioplasty for anastomotic stenosis. At a mean of 9.5 ± 5.7 months of follow-up, 336 patients (98.0%) were alive, asymptomatic with or without medical treatment, and without cardiac events. Comment. Left internal mammary artery-to-LAD anastomosis performed on a beating heart through a left anterior small thoracotomy is a procedure that can be performed with low risk and acceptable midterm results in selected patients.

Background: Intermittent antegrade warm blood cardioplegia (IAWBC) is a well established technique of myocardial protection for coronary artery surgery, with metabolic and experimental basis. Methods: To evaluate its effectiveness in aortic valve replacement (AVR), we compared 171 consecutive patients who underwent first AVR using IAWBC (group A) with the last 100 consecutive patients who underwent first AVR using intermittent antegrade cold blood cardioplegia (IACBC) (group B). The endpoints considered were myocardial protection related (recovery of spontaneous rhythm, need for mechanical support, incidence of low-output syndrome, perioperative Q wave myocardial infarct, CK-MB levels, ventricular arryhthmias and lidocaine infusion requirement, cardiac-related deaths, and death for any cause) and temperature perfusion related (bleeding, awaking time, time to extubation, and cerebrovascular accidents). Results: Mortality was similar in both groups, but no patient in group A died for cardiac-related cause (0 vs 4, p < 0.01). More patients in group A recovered a spontaneous rhythm (144 vs 47, p < 0.0001). Incidence of low-output syndrome was higher in group B (16 vs 3, p < 0.0005), as well as ventricular arryhthmias incidence and need for lidocaine infusion (respectively 15 vs 2, p < 0.0001, and 10 vs 1, p < 0.0005). Awaking time was shorter in warm patients (2.5 ± 2.5 hours vs 4.4 ± 3.7 hours, p < 0.0005), as the extubation time (9.4 ± 7.7 hours vs 13.5 ± 11.7 hours, p < 0.0005) and bleeding (803 ± 714 mL/24 hours vs 1051 ± 1375 mL/24 hours, p < 0.05). As a consequence, the intensive care unit and the postoperative hospital stays were shorter in group A (32 ± 27 hours vs 48 ± 20 hours, p < 0.0005, and 7.2 ± 3.1 days vs 11.3 ± 5.4 days, p < 0.0001, respectively). Conclusions: IAWBC provides lower cardiac-related mortality and morbidity in patients who undergo AVR in comparison with IACBC.

Infection in patients supported with left ventricular assist devices (LVAD) is common and it can limit widespread implantation of mechanical assistance as destination therapy (DT). The infection-resistance power delivery system could improve longevity and quality of life. The Jarvik 2000 (Jarvik Heart, New York, NY, USA) driveline design showed a prolonged infection-free survival and a better quality of life compared to those patients supported with traditional LVAD with an abdominal cable. We report a singular driveline complication in a 71-year-old patient supported with a Jarvik 2000. A new retroauricular pedestal was successfully repositioned after the detachement of the first one.

Epidermoid cysts are rare, slow-growing, benign, developmental cysts that are derived from abnormally situated ectodermal tissue. Epidermoid cysts may grow anywhere on the body and about 7% of them are located in the head and neck. In literature, very few epidermoid cysts have been reported in the temporal region. Histopathologically, they are lined with plain stratified keratin-producing squamous epithelium, although in some cases part of the lining is made up of mucous secreting and ciliated epithelium. This may suggest an endodermal rather than an ectodermal origin. We present and discuss the management of a patient presenting a posttraumatic epidermoid cyst of the temporal region.

Synovial chondromatosis (SC) of the temporomandibular joint (TMJ) is an uncommon disease, which is characterized by chondrometaplasia of the synovial membrane. It is characterized by cartilaginous metaplasia of the mesenchymal remnants of the synovial tissue of the joints. Loose bodies can be found within the joint space. The cause of SC in the TMJ remains unclear. The nonspecific signs of SC often lead to a delay in diagnosis or a misdiagnosis. Removal of the loose bodies and of the synovial membrane involved is sufficient to control the disease in most cases. We present and discuss the diagnosis and surgical management of a new case of unilateral SC of the TMJ.

Gardner syndrome (GS) is a rare autosomal-dominant genetic disorder characterized by multiple colorectal adenomatous polyps and extraintestinal lesions, such as multiple osteomas, dental abnormalities, polyps of the stomach and small bowel, and mesenchymal tumors of the skin and soft tissues. Although most cases show familial clustering, about 30% of cases occur because of a new dominant mutation. 1-4

Purpose Achieving functional and anatomic restoration is remarkably difficult in patients with symphyseal mandibular fractures associated with bicondylar fractures. Our objective was to evaluate the functional and esthetic outcomes of a group of patients who underwent surgery using rigid fixation. Patients and Methods In our study, 25 patients with symphyseal mandibular fractures associated with bicondylar fractures surgically treated from 1998 to 2008 at the Division of Maxillofacial Surgery of the University of Turin were retrospectively analyzed. The standardized evaluation consisted of an evaluation of occlusion, assessment of mandibular motion, and esthetic evaluation of facial width. Results The patients showed good mandibular motion and good occlusion. After esthetic evaluation of the facial width of the 25 patients, 23 patients were rated as “excellent” or “good.” Conclusion Successful treatment of multiple mandibular fractures may be achieved by different techniques. The key point is the re-establishment of the transversal bigonial dimension by a correct reconstruction of the mandibular arch.

Cervical artery dissection is an important cause of stroke in young patients and accounts of 10%–20% of stroke or TIA in patients aged less than 50 years. Basilar artery occlusion (BAO) is an infrequent cause of acute stroke, which invariably leads to death or long-term disability if not recanalized. We describe three patients with BAO caused by vertebral dissection, successfully treated with intra-arterial thrombolysis. The lysis of the occluding embolus was obtained by injection of the thrombolytic drug directly or near the thrombus without haemor-rhagic complications. Our cases confirm the safety and efficacy of intra-arterial thrombolysis in patients with BAO due to a vertebral artery dissection.

Acute hepatitis C virus infection becomes chronic in 50-80% of patients; in recent years a number of studies on acute hepatitis C have shown that interferon treatment can solve more than 80% of cases. In this study we evaluated all cases of acute hepatitis C referred to our unit from 1998 to 2005 to study the epidemiological and clinical features and the efficacy of interferon therapy during the course of the disease. Forty-three patients (28 males, 15 females) were monitored: 22 were drug-addicts, 6 patients referred from recent surgery, in 3 cases a percutaneous exposure was described, 2 patients had had a colonoscopy, 4 were partners of subjects with chronic hepatitis C and in the remaining cases the transmission route was uncertain. All subjects were symptomatic, jaundice was evident in 20 out of 43 patients and in all cases hepatic protein synthesis was unaltered. Of the 21 patients who consented to interferon therapy, in 19 cases a sustained virological response was achieved while in 2 cases the follow-up period was too short for evaluation. Four of the 22 non-treated patients had a spontaneous resolution of the infection, in 13 cases the infection became chronic, and in 4 cases the follow-up was too short for an analysis. In our study all patients were young, in 58% of subjects a parenteral exposure was described and most patients were drug-addicts. All the treated patients obtained a sustained response, while in the majority of non-treated cases the infection became chronic.

Moya-Moya is a rare cerebrovascular occlusive disease characterized by bilateral stenosis or occlusion at the terminal portion of the internal carotid artery and abnormal vascular network at the base of the brain, named "moya-moya". In children, Moya-Moya disease usually presents with ischemic cerebrovascular events, mainly TIA or lacunar stroke, leading to mental deterioration. In adults, especially in females, it presents with intracranial haemorrhages. We describe the case of an adult patient with an atherosclerotic Moya-Moya disease which presented with a cerebral borderzone infarction.

The aim of this study was to evaluate the risk of recurrent ischaemic cerebrovascular events (stroke or transient ischaemic attack (TIA)) in patients with patent foramen ovale (PFO) or atrial septal aneurysm (ASA) treated with different therapeutic regimens. We enrolled 86 patients aged 18-60 years with an unexplained ischaemic stroke or TIA referred to our inpatient department in the period May 1994-December 1999. Follow-up lasted until April 2003. Patients were excluded if the stroke or TIA was related to large-artery atherosclerosis, small artery occlusion, major cardiac sources of embolism or other uncommon causes. During a follow-up (mean+/-SD) of 64.1+/-28.8 months (range 8.1-105.6) a recurrent ischaemic cerebrovascular event occurred in 11/86 patients (12.8%) (5 TIA and 6 strokes). Eight events (4 TIA, 4 strokes) occurred in the 59 patients with PFO alone, three (1 TIA, 2 strokes) in the 21 with PFO plus ASA and none in the 6 patients with ASA alone. In the overall population the cumulative risk of recurrent stroke/TIA was 1.2% at 2 years, 5.5% at 4 years, 7.6% at 6 years and 23.6% at 8 years, and was similar in patients with PFO alone vs. patients with PFO plus ASA (9.0% vs. 6.1% at 6 years, 26.0% vs. 23.1% at 8 years; p0.05). Nine cerebral ischaemic events (4 TIA, 5 strokes) occurred in the 48 patients treated with antiplatelet drugs (7 in patients with PFO, 2 in patients with PFO plus ASA), and two (1 TIA, 1 stroke) in the 17 patients treated with oral anticoagulants (1 with PFO, 1 with PFO plus ASA). No events occurred in patients submitted to transcatheteral closure.

Background: Studies have indicated that apolipoprotein E (ApoE)-ε4 is a risk factor for ischemic cerebrovascular diseases (ICVD), but the existence of this association is still controversial. The aims of this study were: (1) to compare ApoE genotype and allele frequencies in Italian cases with ICVD and in healthy control subjects and (2) to compare ApoE allele frequencies among ischemic stroke subtypes. Methods: A hospital-based cohort of 302 Italian subjects with ICVD and 228 healthy subjects have been recruited to investigate the role of ApoE polymorphisms as risk factors for ICVD. TOAST criteria were employed to stratify ICVD cases by subtypes. Results: No significant differences in ApoE genotype and allele frequencies were found between cases and control subjects. The frequency of ApoE-ε4 was lower in cases than in control subjects (6% vs. 10.1%), although not significantly. No differences in ApoE genotype and allele frequencies were evident among ICVD subtypes. However, out of 36 ApoE-ε4 alleles 23 (3.7%) were found in subjects with ICVD related to primary degenerative arterial disease related to large vessel disease and small vessel disease, and 13 (2.1%) in remaining subjects. Using logistic regression analysis we assessed whether ApoE-ε4 allele was independently associated with risk of ICVD related to a primary degenerative arterial disease compared to other ICVD subtypes. While classical risk factors were significantly associated with higher risk for ICVD due to large vessel disease and small vessel disease than other ICVD subtypes, the role of ApoE-ε4 allele was not significant (OR 1.25, 95% CI 0.57–2.74). Conclusion: Our study shows similar ApoE-ε4 genotype and allele frequencies in patients with ICVD and in control subjects. No differences were found among different ICVD subtypes either.

Various vascular syndromes have been described in patients with midbrain infarction.1,2 The clinical picture is dominated by third-nerve palsy, conjugate or disconjugate gaze impairment, contralateral motor and sensory deficit and homolateral or contralateral limb ataxia. We describe a patient with a pontomesencephalic tegmental infarction with hearing loss and hypogeusia as dominant features. A 52-year-old man had dizziness and loss of taste while eating dinner. The next morning upon awakening, he developed sensory changes of the left half of his face, clumsiness of the right arm and leg, and sensation of bilateral ear wadding. At admission, neurologic examination revealed right limb ataxia, decreased pinprick and touch sensation over the left half of his face, and bilateral hypoacusia, more marked on the left side. There was a marked diminution of taste on the left side of the tongue. His taste was examined by application of 0.5 M NaCl, 10% glucose, 0.2 M acetic acid, and 0.02 M quinine. The rest of the neurologic examination was normal. Limb ataxia and left face hypoesthesia gradually disappeared, and 10 days later only left tongue hypogeusia …

A wide spectrum of sensory syndromes with different topographic patterns have been described in patients with cerebral infarction.1–4 The sensory abnormalities may be limited to small areas, mimicking a radicular or trunk distribution, mainly for lesions in sensory cortex and thalamus. A 31-year-old man suddenly had a right arm pain, numbness, and burning sensation on his right forearm and hand, predominant on the ulnar side. He also reported an expressive aphasia that resolved in a few minutes. There was no history of previous strokes. Two hours later, at admission, neurologic examination revealed a full sensory loss for pinprick and temperature modalities restricted to the V digit, the lateral side of the IV digit, the lateral palm, and the dorsal area of his right hand (figure, A and B). Lemniscal sensory modalities were normal. The hypoesthesia strictly coincided with the sensory distribution of the ulnar nerve. Moreover, the patient had a fastidious hyperalgesia for brush, touch, and pinprick stimuli. There was no evidence of motor impairment; specifically, the ulnar-dependent movements were normal. The rest of the …

The aim of this study was to compare the effect of intermittent antegrade warm blood cardioplegia and intermittent antegrade cold blood cardioplegia on myocardial metabolism and free radical generation of the ischemic-reperfused human myocardium. Thirty patients undergoing mitral valve procedures were randomly allocated to two groups: group 1 (15 patients) received warm blood cardioplegia and group 2 (15 patients), cold blood cardioplegia. Myocardial metabolism was assessed before aortic clamping, 1 minute after crossclamp removal, and after 20 minutes of reperfusion, by collecting blood simultaneously from the radial artery and coronary sinus. All samples were analyzed for lactate, creatine kinase, reduced and oxidized glutathione, ascorbic acid, fluorescent products of lipid peroxidation, and leukocyte activation (elastase). In all patients, early reperfusion was associated with significant coronary sinus lactate release. In group 2, but not in group 1, significant coronary sinus release of reduced and oxidized glutathione, fluorescent products of lipid peroxidation, and creatine kinase was also found; moreover, arterial-coronary sinus difference of ascorbic acid content was increased only in group 2, suggesting a transmyocardial consumption of this antioxidant vitamin. After 20 minutes of reperfusion, coronary sinus lactate release was no longer present in group 1, whereas significant production was still evident in group 2. In this group, significant coronary sinus release of fluorescent products of lipoperoxidation and reduced and oxidized glutathione was also observed at this time. No significant release of elastase from the coronary sinus was noted in the two groups throughout the study. The left ventricular stroke work index measured at the end of the study indicated a better functional recovery in group 1 than in group 2. In conclusion, intermittent antegrade warm blood cardioplegia protects the myocardium from ischemia-reperfusion injury better than intermittent antegrade cold blood cardioplegia; this phenomenon may be partly due to the decreased tissue oxidant burden mediated by intermittent warm blood cardioplegia. (J THORAC CARDIOVASC SURG 1995;109:787-95)

Intermittent antegrade warm blood cardioplegia has been used routinely at our institution over the last 3 years. We report here a comparison between the first 250 consecutive patients undergoing elective coronary artery bypass grafting in which intermittent antegrade warm blood cardioplegia was used (group A) and the last 250 consecutive patients who received intermittent antegrade cold blood cardioplegia, during bypass grafting (group B). There were no differences in sex, age, number of grafts, and functional status between the two groups; left ventricular ejection fraction was lower in group A. The overall mortality rate in group A was 0.8% versus 3.6% in group B (p0.05). There was no in-hospital mortality among high-risk patients (ejection fractionor = 0.35) in group A (0/53) versus two deaths in group B (2/28) (p0.05). No patient in group A needed circulatory assistance; 4 patients in group B received intraaortic balloon pumping. Only 1 patient in group A required inotropic support versus 20 patients in group B (p0.0005), and 5 patients in group A received lidocaine hydrochloride for ventricular arrhythmias versus 18 in group B (p0.01). The rates of myocardial infarction and stroke were not different between the two groups. The peak concentration of the myocardial-specific isoenzyme of creatine kinase were higher in group B in absolute value (51 +/- 30 IU/L) than in Group A (38 +/- 38 IU/L) (p0.0005) and in percent of total creatine kinase (8.2% +/- 4.1% versus 6.2% +/- 2.9%, respectively).

Optimal dual antiplatelet therapy (DAPT) duration for patients undergoing percutaneous coronary intervention (PCI) for coronary bifurcations is an unmet issue. The BIFURCAT registry was obtained by merging two registries on coronary bifurcations. Three groups were compared in a two-by-two fashion: short-term DAPT (≤ 6 months), intermediate-term DAPT (6-12 months) and extended DAPT (>12 months). Major adverse cardiac events (MACE) (a composite of all-cause death, myocardial infarction (MI), target-lesion revascularization and stent thrombosis) were the primary endpoint. Single components of MACE were the secondary endpoints. Events were appraised according to the clinical presentation: chronic coronary syndrome (CCS) versus acute coronary syndrome (ACS). 5537 patients (3231 ACS, 2306 CCS) were included. After a median follow-up of 2.1 years (IQR 0.9-2.2), extended DAPT was associated with a lower incidence of MACE compared with intermediate-term DAPT (2.8% versus 3.4%, adjusted HR 0.23 [0.1-0.54], p

International audience; Background: The PARIS risk score (PARIS-rs) and percutaneous coronary intervention complexity (PCI-c) predict clinical and procedural residual ischemic risk following PCI. Their accuracy in patients undergoing unprotected left main (ULM) or bifurcation PCI has not been assessed.Methods: The predictive performances of the PARIS-rs (categorized as low, intermediate, and high) and PCI-c (according to guideline-endorsed criteria) were evaluated in 3,002 patients undergoing ULM/bifurcation PCI with very thin strut stents.Results: After 16 (12-22) months, increasing PARIS-rs (8.8% vs. 14.1% vs. 27.4%, p < .001) and PCI-c (15.2% vs. 11%, p = .025) were associated with higher rates of major adverse cardiac events ([MACE], a composite of death, myocardial infarction [MI], and target vessel revascularization), driven by MI/death for PARIS-rs and target lesion revascularization/stent thrombosis for PCI-c (area under the curves for MACE: PARIS-rs 0.60 vs. PCI-c 0.52, p-for-difference < .001). PCI-c accuracy for MACE was higher in low-clinical-risk patients; while PARIS-rs was more accurate in low-procedural-risk patients. ≥12-month dual antiplatelet therapy (DAPT) was associated with a lower MACE rate in high PARIS-rs patients, (adjusted-hazard ratio 0.42 [95% CI: 0.22-0.83], p = .012), with no benefit in low to intermediate PARIS-rs patients. No incremental benefit with longer DAPT was observed in complex PCI.Conclusions: In the setting of ULM/bifurcation PCI, the residual ischemic risk is better predicted by a clinical risk estimator than by PCI complexity, which rather appears to reflect stent/procedure-related events. Careful procedural risk estimation is warranted in patients at low clinical risk, where PCI complexity may substantially contribute to the overall residual ischemic risk.

Background The clinical impact of stent strut thickness in coronary bifurcation lesions in small vessels has not been assessed in a real-world population. Methods and results All 506 patients enrolled in the RAIN study, undergoing PCI in a vessel with a diameter 2.5 mm or less were retrospectively evaluated and divided into two groups according to stent strut thickness: 74 μm (n = 206) versus 81 μm (n = 300); 87.1% of the lesions involved bifurcations. TLF [defined as a composite of myocardial infarction (MI) and target lesion revascularization (TLR)] was the primary endpoint, with MACE (a composite of death, MI and TLR), its components and stent thrombosis the secondary endpoint. After 16 (14-18) months, a lower incidence of TLF (4.3 vs. 9.8%, P = 0.026) and ST (1.0 vs. 3.0%, P = 0.042) was seen in the 74 μm group, whereas MACE occurred in 60 of 506 patients, with no statistical difference between the two groups (9.7 vs. 13.3%, P = 0.070). At multivariate analysis, chronic renal failure increased the risk of TLF while thinner strut was an independent protective factor (hazard ratio 0.51, CI 0.17-0.85, P = 0.005). Conclusion In this real-world population, patients being treated for small vessels lesions with thinner strut stents had lower rates of TLF, MI and ST.

Background There are limited data regarding the impact of bioresorbable polymer drug eluting stent (BP-DES) compared to durable polymer drug eluting stent (DP-DES) in patients treated with percutaneous coronary intervention using ultrathin stents in left main or bifurcations. Methods In the RAIN registry (ClinicalTrials NCT03544294, june 2018 retrospectively registered) patients with a ULM or bifurcation stenosis treated with PCI using ultrathin stents (struts thinner than 81 μm) were enrolled. The primary endpoint was the rate of target lesion revascularization (TLR); major adverse cardiovascular events (MACE, a composite of all-cause death, myocardial infarction, TLR and stent thrombosis) and its components, along with target vessel revascularization (TVR) were the secondary ones. A propensity score with matching analysis to compare patients treated with BP-DES versus DP-DES was also assessed. Results From 3001 enrolled patients, after propensity score analysis 1400 patients (700 for each group) were selected. Among them, 352 had ULM disease and 1048 had non-LM bifurcations. At 16 months (12–22), rates of TLR (3.7% vs 2.9%, p = 0.22) and MACE were similar (12.3% vs. 11.6%, p = 0.74) as well as for the other endpoints. Sensitivity analysis of outcomes after a two-stents strategy, showed better outcome in term of MACE (20.4% vs 10%, p = 0.03) and TVR (12% vs 4.6%, p = 0.05) and a trend towards lower TLR in patients treated with BP-DES. Conclusion In patients with bifurcations or ULM treated with ultrathin stents BP-DES seems to perform similarly to DP-DES: the trends toward improved clinical outcomes in patients treated with the BP-DES might potentially be of value for speculating the stent choice in selected high-risk subgroups of patients at increased risk of ischemic events. Trial registration ClinicalTrials.gov Identifier: NCT03544294. Retrospectively registered June 1, 2018.

International audience; Objectives: To evaluate the independent clinical impact of stent structural features in a large cohort of patients undergoing unprotected left main (ULM) or coronary bifurcation percutaneous coronary intervention (PCI) with a range of very thin strut stents.Background: Clinical impact of structural features of contemporary stents remains to be defined.Methods: All consecutive patients enrolled in the veRy thin stents for patients with left mAIn or bifurcatioN in real life (RAIN) registry were included. The following stent structural features were studied: antiproliferative drugs (everolimus vs. sirolimus vs. zotarolimus), strut material (platinum-chromium vs. cobalt-chromium), polymer (bioresorbable vs. durable), number of crowns (

International audience; Hepatitis C virus (HCV) infection is associated with tremendous morbidity and mortality due to liver complications. HCV infection is also associated with many extrahepatic manifestations including cardiovascular diseases, glucose metabolism impairment, cryoglobulinemia vasculitis, B cell non-Hodgkin lymphoma and chronic kidney disease (CKD). Many studies have shown a strong association between HCV and CKD, by reporting (i) an increased prevalence of HCV infection in patients on haemodialysis, (ii) an increased incidence of CKD and proteinuria in HCV-infected patients, and (iii) the development of membranoproliferative glomerulonephritis secondary to HCV-induced cryoglobulinemia vasculitis. HCV seropositivity is found to be associated with an increased relative risk for all-cause and cardiovascular mortality in the dialysis population. HCV seropositivity is linked to lower patient and graft survival after kidney transplantation. Such poor HCV-associated prognosis should have encouraged clinicians to treat HCV in CKD patients. However, due to frequent side effects and the poor efficacy of interferon-based treatments, very few HCV dialysis patients have received HCV medications until now. The emergence of new direct acting, interferon-free antiviral treatment, leading to HCV cure in most cases with a satisfactory safety profile, will shortly modify the management of HCV infection in CKD patients. In patients with a glomerular filtration rate (GFR) >30 ml/min, the choice of DAA is not restricted. In those with a GFR 15 ml/min, only paritaprevir/ritonavir/ombitasvir/dasabuvir or a grazoprevir plus elbasvir regimen are approved. In patients with end stage renal disease (GFR

Background: Recently, a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) has been developed as an international and standardized brief cognitive test, which is easily performed in everyday clinical practice for neuropsychological assessment in multiple sclerosis (MS). However, we need to gather more information about this tool compared to other neuropsychological batteries. The aim of our study is to compare the performance of BICAMS and Brief Repeatable Battery (BRB) in MS subjects. Methods: Tests of the BRB and BICAMS were administered to MS patients recruited from 11 Italian MS centres. Cognitive impairment (CI) was defined as the failure on at least two tests (scores below the fifth percentile) on the BRB and as the failure on at least one test of the BICAMS. The agreement between the performances on the two batteries was assessed through Cohen's K statistic. Finally we calculated the effects sizes for each test of the two batteries using Cohen's d. Results: The two batteries were administered to 192 MS patients (142 women, 50 men; mean age 41.4 ± 10.8 years, mean education 12.3 ± 3.5 years). Mean scores of patients were lower compared to those of healthy subjects in all the cognitive measures examined. Forty-six MS patients were identified as impaired and 48 as unimpaired on both of the batteries, when the Symbol Digit Modalities Test (SDMT) was included in the analysis. Cohen's K statistic was 0.46 which corresponds to a moderate accord. If the SDMT was excluded from the BRB, 37 MS patients were identified as impaired and 57 as unimpaired on both of the batteries. Cohen's K statistic was 0.3 which corresponds to a poor accord. The SDMT, the Paced Auditory Serial Addition Test (PASAT) 3 and 2 yielded higher d values (SDMT 0.83, PASAT 3 0.65, PASAT 2 0.84). Conclusions: This study confirms the feasibility of BICAMS in everyday clinical practice for the identification of CI and highlights the good psychometric properties of the SDMT.