Role of MicroRNA Modulation in the Interferon-α/Ribavirin Suppression of HIV-1 In Vivo.

BACKGROUND Interferon-α (IFN-α) treatment suppresses HIV-1 viremia and reduces the size of the HIV-1 latent reservoir. Therefore, investigation of the molecular and immunologic effects of IFN-α may provide insights that contribute to the development of novel prophylactic, therapeutic and curative strategies for HIV-1 infection. In this study, we hypothesized that microRNAs (miRNAs) contribute to the IFN-α-mediated suppression of HIV-1. To inform the development of novel miRNA-based antiretroviral strategies, we investigated the effects of exogenous IFN-α treatment on global miRNA expression profile, HIV-1 viremia, and potential regulatory networks between miRNAs and cell-intrinsic anti-HIV-1 host factors in vivo. METHODS Global miRNA expression was examined in longitudinal PBMC samples obtained from seven HIV/HCV-coinfected, antiretroviral therapy-naïve individuals before, during, and after pegylated interferon-α/ribavirin therapy (IFN-α/RBV). We implemented novel hybrid computational-empirical approaches to characterize regulatory networks between miRNAs and anti-HIV-1 host restriction factors. RESULTS miR-422a was the only miRNA significantly modulated by IFN-α/RBV in vivo (p<0.0001, paired t test; FDR<0.037). Our interactome mapping revealed extensive regulatory involvement of miR-422a in p53-dependent apoptotic and pyroptotic pathways. Based on sequence homology and inverse expression relationships, 29 unique miRNAs may regulate anti-HIV-1 restriction factor expression in vivo. CONCLUSIONS The specific reduction of miR-422a is associated with exogenous IFN-α treatment, and likely contributes to the IFN-α suppression of HIV-1 through the enhancement of anti-HIV-1 restriction factor expression and regulation of genes involved in programmed cell death. Moreover, our regulatory network analysis presents additional candidate miRNAs that may be targeted to enhance anti-HIV-1 restriction factor expression in vivo.

Drug-eluting stents compared to bare-metal stents improve short-term survival in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: a nationwide prospective analysis of the AMIS Plus registry

BACKGROUND Recently, it has been suggested that the type of stent used in primary percutaneous coronary interventions (pPCI) might impact upon the outcomes of patients with acute myocardial infarction (AMI). Indeed, drug-eluting stents (DES) reduce neointimal hyperplasia compared to bare-metal stents (BMS). Moreover, the later generation DES, due to its biocompatible polymer coatings and stent design, allows for greater deliverability, improved endothelial healing and therefore less restenosis and thrombus generation. However, data on the safety and performance of DES in large cohorts of AMI is still limited. AIM To compare the early outcome of DES vs. BMS in AMI patients. METHODS This was a prospective, multicentre analysis containing patients from 64 hospitals in Switzerland with AMI undergoing pPCI between 2005 and 2013. The primary endpoint was in-hospital all-cause death, whereas the secondary endpoint included a composite measure of major adverse cardiac and cerebrovascular events (MACCE) of death, reinfarction, and cerebrovascular event. RESULTS Of 20,464 patients with a primary diagnosis of AMI and enrolled to the AMIS Plus registry, 15,026 were referred for pPCI and 13,442 received stent implantation. 10,094 patients were implanted with DES and 2,260 with BMS. The overall in-hospital mortality was significantly lower in patients with DES compared to those with BMS implantation (2.6% vs. 7.1%,p < 0.001). The overall in-hospital MACCE after DES was similarly lower compared to BMS (3.5% vs. 7.6%, p < 0.001). After adjusting for all confounding covariables, DES remained an independent predictor for lower in-hospital mortality (OR 0.51,95% CI 0.40-0.67, p < 0.001). Since groups differed as regards to baseline characteristics and pharmacological treatment, we performed a propensity score matching (PSM) to limit potential biases. Even after the PSM, DES implantation remained independently associated with a reduced risk of in-hospital mortality (adjusted OR 0.54, 95% CI 0.39-0.76, p < 0.001). CONCLUSIONS In unselected patients from a nationwide, real-world cohort, we found DES, compared to BMS, was associated with lower in-hospital mortality and MACCE. The identification of optimal treatment strategies of patients with AMI needs further randomised evaluation; however, our findings suggest a potential benefit with DES.

Lettres de quelques Juifs portugais, allemands et polonais, à M. de Voltaire : avec un petit comm., extrait d'un plus grand, à l'usage de ceux qui lisent ses oeuvres ; suivies des mémoires sur la feritilité de la Judée

par [Antoine] Guénée. Revue et augm. de plusieurs notes nouv. par [Léon M.] Desdouits

IPRG/LugÜ plus Verweise: Internationales Privat- und Verfahrensrecht

Diese Textausgabe enthält die in der Schweiz geltenden Rechtsquellen zum internationalen Privat- und Verfahrensrecht und bietet sowohl Studierenden als auch in der Praxis Wirkenden ein benutzerfreundliches Nachschlagewerk. Die Sammlung erfasst nebst dem aktuellen Gesetzestext des Internationalen Privatrechts (IPRG; Stand: 1. März 2015) auch das Lugano-Übereinkommen (LugÜ). Weitere für die Schweiz relevante Staatsverträge sind vollständig oder auszugsweise abgedruckt. Eine übersichtliche, nach Sachgebieten gegliederte Zusammenstellung ermöglicht das rasche Auffinden der insgesamt knapp 60 Gesetze und Konventionen. Die Textausgabe enthält viele wertvolle Querverweise, welche dem Benutzer die rasche Erschliessung der Zusammenhänge ermöglichen. Neu ist das Werk mit Randregistern und Inhaltsübersicht auf der Innenklappe versehen, was das Arbeiten besonders effizient macht.

ZPO/StPO plus Verweise: Schweizerisches Prozessrecht inklusive SchKG und Verwaltungsverfahrensrecht des Bundes

Diese Textausgabe enthält mit der ZPO und der StPO zwei unentbehrliche Gesetze für Zivil- und Strafprozesse. Dank dem Einbezug des Verwaltungsverfahrensrechts des Bundes und des SchKG – neu auch mit weiteren massgebenden Erlassen zu Schuldbetreibung und Konkurs – deckt das Werk alle relevanten Bereiche des schweizerischen Prozessrechts ab. Alle in diesen handlichen Band aufgenommenen 23 Erlasse sind auf dem aktuellsten Stand der Gesetzgebung (Stichtag 1. Januar 2015). Diese für Studium und Beruf bestens geeignete Textausgabe ist mit vielen Querverweisen sowie Hinweisen auf die neuste Rechtsprechung des obersten Gerichts versehen, was eine rasche und umfassende Erschliessung der komplexen Materie ermöglicht. Neu ist das Werk mit Randregistern und Inhaltsübersicht auf der Innenklappe versehen, was das Arbeiten besonders effizient macht.

Lettres de quelques Juifs portugais, allemands et polonais, à M. de Voltaire : avec un petit comm., extrait d'un plus grand

[Antoine Guénée] Revue et augm. de plusieurs notes nouv. par [Léon M.] Desdouits

Essai sur l'histoire des Israélites de Tunisie depuis les temps les plus reculés jusqu'à l'établissement du protectorat de la France en Tunisie

par D. Cazès

Catalogue d'une collection Anconienne dont la plus grande partie dérive de la bibliothèque appartenant aux célèbres C. J. D. Azulai et son fils Rafael

mise en vente par Samuel Schönblum

Novel mitochondrial tRNA(Ile) m.4282A>G gene mutation leads to chronic progressive external ophthalmoplegia plus phenotype

BACKGROUND/AIM To investigate the underlying pathomechanism in a 33-year-old female Caucasian patient presenting with chronic progressive external ophthalmoplegia (CPEO) plus symptoms. METHODS Histochemical analysis of skeletal muscle and biochemical measurements of individual oxidative phosphorylation (OXPHOS) complexes. Genetic analysis of mitochondrial DNA in various tissues with subsequent investigation of single muscle fibres for correlation of mutational load. RESULTS The patient's skeletal muscle showed 20% of cytochrome c oxidase-negative fibres and 8% ragged-red fibres. Genetic analysis of the mitochondrial DNA revealed a novel point mutation in the mitochondrial tRNA(Ile) (MTTI) gene at position m.4282G>A. The heteroplasmy was determined in blood, buccal cells and muscle by restriction fragment length polymorphism (RFLP) combined with a last fluorescent cycle. The total mutational load was 38% in skeletal muscle, but was not detectable in blood or buccal cells of the patient. The phenotype segregated with the mutational load as determined by analysis of single cytochrome c oxidase-negative/positive fibres by laser capture microdissection and subsequent LFC-RFLP. CONCLUSIONS We describe a novel MTTI transition mutation at nucleotide position m.4282G>A associated with a CPEO plus phenotype. The novel variant at position m.4282G>A disrupts the middle bond of the D-stem of the tRNA(Ile) and is highly conserved. The conservation and phenotype-genotype segregation strongly suggest pathogenicity and is in good agreement with the MTTI gene being frequently associated with CPEO. This novel variant broadens the spectrum of MTTI mutations causing CPEO.

De Arcano Kethib et Keri Libri Duo Pro vindicanda S. Codicis Hebraei Integritate, et firmanda Locorum plus octingentorum explicatione

a Matthaeo Hillero, Logices, Metaphysices & Linguarum Orientalium in Academia Tubingensi Professore Publico

Le plus ancien manuscrit Hébreu

par Ph. Berger et M. Schwab

Interferon-free treatment of chronic hepatitis C with faldaprevir, deleobuvir and ribavirin: SOUND-C3, a Phase 2b study.

BACKGROUND & AIMS The safety and efficacy of the interferon-free combination of faldaprevir (NS3/A4 protease inhibitor), deleobuvir (BI 207127, non-nucleoside polymerase inhibitor), and ribavirin in treatment-naïve patients chronically infected with HCV genotype-1 was explored. METHODS SOUND-C3 was a multicenter, open-label Phase 2b study. Treatment-naïve patients chronically infected with HCV genotype-1a (IL28B CC genotype only; n = 12) and genotype-1b (n = 20) were assigned to 16 weeks of treatment with faldaprevir 120 mg once daily, deleobuvir 600 mg twice daily, and weight-based ribavirin. Patients with compensated liver disease, including cirrhosis, were eligible for inclusion in this study. The primary endpoint was sustained virological response 12 weeks after completion of therapy. RESULTS Sustained virological response rates 12 weeks after completion of therapy were 17% and 95% in patients infected with HCV genotype-1a and genotype-1b respectively. All four patients with cirrhosis achieved sustained virological response 12 weeks after completion of therapy. The most frequently reported adverse events of at least moderate intensity were anaemia (16%), nausea, vomiting and fatigue (9% each). Three (9%) patients discontinued because of adverse events. CONCLUSIONS The interferon-free regimen of faldaprevir, deleobuvir and ribavirin was efficacious in patients infected with genotype-1b and generally well tolerated.

Survival after somatostatin based radiopeptide therapy with (90)Y-DOTATOC vs. (90)Y-DOTATOC plus (177)Lu-DOTATOC in metastasized gastrinoma.

We aimed to explore the effects of (90)Y-DOTATOC and (90)Y-DOTATOC plus (177)Lu-DOTATOC on survival of patients with metastasized gastrinoma. Patients with progressive metastasized gastrinoma were treated with repeated cycles of (90)Y-DOTATOC or with cycles alternating between (90)Y-DOTATOC and (177)Lu-DOTATOC until tumor progression or permanent toxicity. Multivariable Cox regression analyses were used to study predictors of survival. A total of 36 patients were enrolled; 30 patients received (90)Y-DOTATOC (median activity per patient 11.8GBq; range: 6.1-62.2GBq) and 6 patients received (90)Y-DOTATOC plus (177)Lu-DOTATOC (median activity per patient: 14.8GBq; range: 7.4-14.8GBq). Response was found in 26 patients (72.2%), including morphological (n=12, 33.3%), biochemical (n=14, 38.9%) and/or clinical response (n=6, 16.2%). A total of 21 patients (58.3%) experienced hematotoxicity grade 1/2, while 1 patient (2.8%) experienced hematotoxicity grade 3; no grade 4 hematotoxicity occurred. Furthermore, 2 patients (5.6%) developed grade 4 renal toxicity; no grade 5 renal toxicity occurred. Responders had a significantly longer median survival from time of enrollment than non-responders (45.1 months, range: 37.1-53.1 months vs. 12.6 months, range: 11.0-14.2, hazard ratio: 0.12 (0.027-0.52), p=0.005). Additionally, there was a trend towards longer median survival with (90)Y-DOTATOC plus (177)Lu-DOTATOC as compared to (90)Y-DOTATOC alone (60.2 months, range: 19.8-100.6 months vs. 27.0 months, range: 4.0-50.0, hazard ratio: 0.21 (0.01-3.98), p=0.16). Response to (90)Y-DOTATOC and (90)Y-DOTATOC plus (177)Lu-DOTATOC therapy is associated with a longer survival in patients with metastasized gastrinoma. Both treatment regimens are promising tools for management of progressive gastrinoma.

Recueil de chants religieux et populaires des Israélites : des temps les plus reculés jusq'à nos jours

partitions transcrites pour piano ou orgue harmonium ... par S. Naumbourg

Zemirot Yiśraʼel : contenant les hymnes, les psaumes et la liturgie complète de la Synagogue des temps le plus reculés jusqu'à nos jours ; avec accomp. d'orgue ou piano ad libitum

par S. Naumbourg