Risk and fate of residual interatrial shunting after transcatheter closure of patent foramen ovale: a long term follow up study

<p>Abstract</p> <p>Background</p> <p>Percutaneous transcatheter closure of patent foramen ovale (PFO) in cryptogenic stroke is an alternative to medical therapy. There is still debate on different outcome for each currently available device. The impact of residual shunting after PFO-clo- sure on recurrent arterial embolism is unknown.</p> <p>Aims</p> <p>(i) To evaluate the prevalence of residual interatrial shunting after device- closure of PFO, (ii) to identify risk factors predicting residual interatrial shunting after device implantation, and (iii) to investigate the outcome of patients after PFO-closure during long- term follow- up (FU).</p> <p>Methods and results</p> <p>Between 2000- 2005 PFO-closure was performed in 124 patients using four different devices: Amplatzer PFO-(n = 52), CardioSeal (n = 33), Helex (n = 23) and Premere (n = 16) occluder. All patients underwent serial contrast-enhanced transesophageal echocardiography (TEE) for 24 months after PFO- closure; clinical FU was at minimum 5 years up to 9.75 years (mean 6.67 ± 1.31 years). Overall-closure rate was 87% at 2 years, device-specific closure time curves differed significantly (p-logrank = 0.003). Independent risk factors for residual-shunting were implantation of a Helex occluder (hazard ratio [HR] 12.6, 95% confidence interval [CI] 2.6- 57.4, p = 0.002), PFO- canal- lengths (HR 1.2, 95%CI 1.1- 1.3, p = 0.004) and extend of atrial-septal-aneurysm (HR 1.1, 95%CI 0.9- 1.3; p = 0.05). 4 (3.2%) arterial embolic events occurred during a FU-period of 817.2 patient-years, actuarial annual thromboembolic-risk was 0.49%. All ischemic events were not related to residual PFO-shunting or device-related thrombus- formation.</p> <p>Conclusion</p> <p>Success rates of PFO- closure are mainly dependent on occluder-type, extend of concomitant atrial-septum-aneurysm and PFO-canal- length. Importantly, residual shunting after PFO-closure was not associated with recurrence of arterial embolism during long-term follow-up.</p

POLITICHE DI AMMISSIONE E GESTIONE DEI FLUSSI MIGRATORI DA LAVORO IN ITALIA DALLA TURCO-NAPOLITANO AD OGGI.

L'obiettivo di questo elaborato è quello di analizzare gli strumenti di cui si è dotata l'Italia al fine di regolare i flussi immigratori da lavoro. Dall'analisi svolta emerge la difficoltà dei governi italiani ad abbandonare una gestione emergenziale e contingente del fenomeno in favore di una maggiore consapevolezza di fronte all'immigrazione, in generale, e quella economica in particolare, in quanto elemento strutturale del tessuto socio-economico italiano. Le difficoltà oggettive, incontrate nella stesura dell'elaborato, sono frutto della complessità del fenomeno di per sé di natura transnazionale e che coinvolge una moltitudine di soggetti, oltre a presentare molteplici aspetti, da quelli socio-economici a quelli prettamente politici, fortemente intrecciati tra loro. Data la complessità di questo versante della politica migratoria, ho scelto una chiave di lettura storica, in quanto permette di evidenziare il profondo legame tra la discussione politica, caratterizzata da una forte polarizzazione ideologica, e gli interventi attuati in questa materia. All'interno di questi equilibri s'inserisce, inoltre, il crescente ruolo dell'Unione Europea che chiede, nonostante le resistenze dei singoli Stati, di rinunciare a una porzione di sovranità col fine di creare una politica migratoria comune. Nel primo capitolo vengono analizzati l'origine del fenomeno e la nascita della politica migratoria in Italia. Con l'approvazione della legge Turco-Napolitano nel 1998, e il conseguente raggruppamento delle leggi all'interno del Testo Unico, l'Italia cerca di dotarsi di una legge organica in materia migratoria. Il sistema è incentrato sulla chiamata nominativa del lavoratore ancora all'estero, che avviene secondo i limiti numerici definiti dalla programmazione dei flussi ed attuati attraverso il cosiddetto decreto-flussi. Questo meccanismo dimostra, fin dalla nascita, notevoli inadeguatezze e carenze, per cui si deve ricorrere sistematicamente a strumenti di regolarizzazione ex post di una presenza irregolare che tende a riprodursi, anche a causa del lavoro sommerso che funge da potente fattore d'attrazione dei flussi, e tutto questo perché, sia i datori di lavoro che i lavoratori immigrati, non trovano conveniente utilizzare i canali d'ingresso regolari. Nel secondo capitolo il punto di partenza è rappresentato dalla riforma attuata dalla legge Bossi-Fini nel 2001. Tale legge è frutto della nuova maggioranza di centro-destra che fa dell'immigrazione un tema cruciale per raccogliere consensi, associandola a situazioni problematiche di sicurezza e ordine pubblico. La legge interviene in maniera sostanziale sui meccanismi di ammissione, inasprendo le condizioni di ingresso con l'introduzione del “contratto di soggiorno” (che subordina la presenza alla disponibilità di un'occupazione lavorativa) e precarizzando il soggiorno dei regolari, dimezzando la durata dei permessi. Ai fattori interni si aggiunge l'influenza dell'Unione Europea. L'allargamento verso i paesi dell'Est rappresenta l'apice delle carenze del meccanismo di ammissione: una larga parte degli ingressi si sottrae al potere regolatorio del sistema delle quote, dal momento che buona parte dei flussi si compone di soggetti che non necessitano più di alcun permesso di soggiorno. La medesima incapacità emerge anche con il presentarsi della crisi economica alla fine del 2008. Infatti, nonostante la drastica riduzione delle quote, i flussi, prevalentemente diretti al servizio alle famiglie, si mantengono elevati e subiscono una battuta d'arresto solo a partire dal 2011. Nel terzo capitolo vengono presi in considerazione i provvedimenti più recenti: l'Accordo d'Integrazione all'interno del Piano per l'Integrazione e la Carta Blu sono frutto del crescente ruolo dell'Unione Europea e dell'affermarsi del nuovo (e più impegnativo) concetto d'integrazione e, pertanto, rappresentano il tentativo dell'azione politica di adeguarsi ai principi della politica migratoria dell'Unione Europea. Tali provvedimenti, tuttavia, hanno suscitato perplessità e critiche, sia in termini ideologici che in termini di attuabilità concreta, data la mancata predisposizione di risorse aggiuntive necessarie. Il quadro che emerge è che l'Italia ha attratto ingenti flussi senza che a questi corrispondesse una crescita economica, e questo è frutto del potere d'attrazione costituito dai fattori socio-demografici, come la bassa natalità, l'invecchiamento della popolazione, l'evoluzione delle aspettative lavorative, soprattutto dei giovani. In conclusione i problemi rimangono aperti, anche se oggi meno visibili principalmente per due fattori. Il primo consiste nella mancanza di un dibattito politico e mediatico, nonché scientifico, causato dalla poca notiziabilità dell'immigrazione regolare, in favore degli aspetti più eclatanti e conflittuali. Il secondo invece è rappresentato dalla battuta d'arresto dei flussi di arrivo, che fa apparire il problema lontano. E così l'azione politica aspetta, finché non si presenterà la prossima emergenza

DNA Damage Responses in Human Induced Pluripotent Stem Cells and Embryonic Stem Cells

BACKGROUND: Induced pluripotent stem (iPS) cells have the capability to undergo self-renewal and differentiation into all somatic cell types. Since they can be produced through somatic cell reprogramming, which uses a defined set of transcription factors, iPS cells represent important sources of patient-specific cells for clinical applications. However, before these cells can be used in therapeutic designs, it is essential to understand their genetic stability.\ud \ud METHODOLOGY/PRINCIPAL FINDINGS: Here, we describe DNA damage responses in human iPS cells. We observe hypersensitivity to DNA damaging agents resulting in rapid induction of apoptosis after γ-irradiation. Expression of pluripotency factors does not appear to be diminished after irradiation in iPS cells. Following irradiation, iPS cells activate checkpoint signaling, evidenced by phosphorylation of ATM, NBS1, CHEK2, and TP53, localization of ATM to the double strand breaks (DSB), and localization of TP53 to the nucleus of NANOG-positive cells. We demonstrate that iPS cells temporary arrest cell cycle progression in the G(2) phase of the cell cycle, displaying a lack of the G(1)/S cell cycle arrest similar to human embryonic stem (ES) cells. Furthermore, both cell types remove DSB within six hours of γ-irradiation, form RAD51 foci and exhibit sister chromatid exchanges suggesting homologous recombination repair. Finally, we report elevated expression of genes involved in DNA damage signaling, checkpoint function, and repair of various types of DNA lesions in ES and iPS cells relative to their differentiated counterparts.\ud \ud CONCLUSIONS/SIGNIFICANCE: High degrees of similarity in DNA damage responses between ES and iPS cells were found. Even though reprogramming did not alter checkpoint signaling following DNA damage, dramatic changes in cell cycle structure, including a high percentage of cells in the S phase, increased radiosensitivity and loss of DNA damage-induced G(1)/S cell cycle arrest, were observed in stem cells generated by induced pluripotency.\ud \u

DNA Repair in Human Pluripotent Stem Cells Is Distinct from That in Non-Pluripotent Human Cells

The potential for human disease treatment using human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells (iPSCs), also carries the risk of added genomic instability. Genomic instability is most often linked to DNA repair deficiencies, which indicates that screening/characterization of possible repair deficiencies in pluripotent human stem cells should be a necessary step prior to their clinical and research use. In this study, a comparison of DNA repair pathways in pluripotent cells, as compared to those in non-pluripotent cells, demonstrated that DNA repair capacities of pluripotent cell lines were more heterogeneous than those of differentiated lines examined and were generally greater. Although pluripotent cells had high DNA repair capacities for nucleotide excision repair, we show that ultraviolet radiation at low fluxes induced an apoptotic response in these cells, while differentiated cells lacked response to this stimulus, and note that pluripotent cells had a similar apoptotic response to alkylating agent damage. This sensitivity of pluripotent cells to damage is notable since viable pluripotent cells exhibit less ultraviolet light-induced DNA damage than do differentiated cells that receive the same flux. In addition, the importance of screening pluripotent cells for DNA repair defects was highlighted by an iPSC line that demonstrated a normal spectral karyotype, but showed both microsatellite instability and reduced DNA repair capacities in three out of four DNA repair pathways examined. Together, these results demonstrate a need to evaluate DNA repair capacities in pluripotent cell lines, in order to characterize their genomic stability, prior to their pre-clinical and clinical use

Radiation-Induced Bystander Effects in Cultured Human Stem Cells

The radiation-induced "bystander effect" (RIBE) was shown to occur in a number of experimental systems both in vitro and in vivo as a result of exposure to ionizing radiation (IR). RIBE manifests itself by intercellular communication from irradiated cells to non-irradiated cells which may cause DNA damage and eventual death in these bystander cells. It is known that human stem cells (hSC) are ultimately involved in numerous crucial biological processes such as embryologic development; maintenance of normal homeostasis; aging; and aging-related pathologies such as cancerogenesis and other diseases. However, very little is known about radiation-induced bystander effect in hSC. To mechanistically interrogate RIBE responses and to gain novel insights into RIBE specifically in hSC compartment, both medium transfer and cell co-culture bystander protocols were employed.Human bone-marrow mesenchymal stem cells (hMSC) and embryonic stem cells (hESC) were irradiated with doses 0.2 Gy, 2 Gy and 10 Gy of X-rays, allowed to recover either for 1 hr or 24 hr. Then conditioned medium was collected and transferred to non-irradiated hSC for time course studies. In addition, irradiated hMSC were labeled with a vital CMRA dye and co-cultured with non-irradiated bystander hMSC. The medium transfer data showed no evidence for RIBE either in hMSC and hESC by the criteria of induction of DNA damage and for apoptotic cell death compared to non-irradiated cells (p>0.05). A lack of robust RIBE was also demonstrated in hMSC co-cultured with irradiated cells (p>0.05).These data indicate that hSC might not be susceptible to damaging effects of RIBE signaling compared to differentiated adult human somatic cells as shown previously. This finding could have profound implications in a field of radiation biology/oncology, in evaluating radiation risk of IR exposures, and for the safety and efficacy of hSC regenerative-based therapies

A Kinome RNAi Screen Identified AMPK as Promoting Poxvirus Entry through the Control of Actin Dynamics

Poxviruses include medically important human pathogens, yet little is known about the specific cellular factors essential for their replication. To identify genes essential for poxvirus infection, we used high-throughput RNA interference to screen the Drosophila kinome for factors required for vaccinia infection. We identified seven genes including the three subunits of AMPK as promoting vaccinia infection. AMPK not only facilitated infection in insect cells, but also in mammalian cells. Moreover, we found that AMPK is required for macropinocytosis, a major endocytic entry pathway for vaccinia. Furthermore, we show that AMPK contributes to other virus-independent actin-dependent processes including lamellipodia formation and wound healing, independent of the known AMPK activators LKB1 and CaMKK. Therefore, AMPK plays a highly conserved role in poxvirus infection and actin dynamics independent of its role as an energy regulator

Comparison of Human Primary with Human iPS Cell-Derived Dopaminergic Neuron Grafts in the Rat Model for Parkinson's Disease

Neuronal degeneration within the substantia nigra and the loss of the dopaminergic nigro-striatal pathway are the major hallmarks of Parkinson’s disease (PD). Grafts of foetal ventral mesencephalic (VM) dopaminergic (DA) neurons into the striatum have been shown to be able to restore striatal dopamine levels and to improve overall PD symptoms. However, human foetus-derived cell grafts are not feasible for clinical application. Autologous induced pluripotent stem cell (iPS cell)-derived DA neurons are emerging as an unprecedented alternative. In this review, we summarize and compare the efficacy of human iPS cell-derived DA neuron grafts to restore normal behaviour in a rat model for PD with that of human foetal primary DA neurons. The differences we observed in the efficacy to restore normal function between the 2 types of DA neuron grafts could be ascribed to intrinsic properties of the iPS cell-derived DA neurons that critically affected survival and proper neurite extension in the striatum after implantation

2015/16 seasonal vaccine effectiveness against hospitalisation with influenza a(H1N1)pdm09 and B among elderly people in Europe: Results from the I-MOVE+ project

We conducted a multicentre test-negative caseâ\u80\u93control study in 27 hospitals of 11 European countries to measure 2015/16 influenza vaccine effectiveness (IVE) against hospitalised influenza A(H1N1)pdm09 and B among people aged â\u89¥ 65 years. Patients swabbed within 7 days after onset of symptoms compatible with severe acute respiratory infection were included. Information on demographics, vaccination and underlying conditions was collected. Using logistic regression, we measured IVE adjusted for potential confounders. We included 355 influenza A(H1N1)pdm09 cases, 110 influenza B cases, and 1,274 controls. Adjusted IVE against influenza A(H1N1)pdm09 was 42% (95% confidence interval (CI): 22 to 57). It was 59% (95% CI: 23 to 78), 48% (95% CI: 5 to 71), 43% (95% CI: 8 to 65) and 39% (95% CI: 7 to 60) in patients with diabetes mellitus, cancer, lung and heart disease, respectively. Adjusted IVE against influenza B was 52% (95% CI: 24 to 70). It was 62% (95% CI: 5 to 85), 60% (95% CI: 18 to 80) and 36% (95% CI: -23 to 67) in patients with diabetes mellitus, lung and heart disease, respectively. 2015/16 IVE estimates against hospitalised influenza in elderly people was moderate against influenza A(H1N1)pdm09 and B, including among those with diabetes mellitus, cancer, lung or heart diseases