Sustained meningeal lymphatic vessel atrophy or expansion does not alter Alzheimer's disease-related amyloid pathology.

Discovery of meningeal lymphatic vessels (LVs) in the dura mater, also known as dural LVs (dLVs) that depend on vascular endothelial growth factor C expression, has raised interest in their possible involvement in Alzheimer's disease (AD). Here we find that in the APdE9 and 5xFAD mouse models of AD, dural amyloid-ß (Aß) is confined to blood vessels and dLV morphology or function is not altered. The induction of sustained dLV atrophy or hyperplasia in the AD mice by blocking or overexpressing vascular endothelial growth factor C, impaired or improved, respectively, macromolecular cerebrospinal fluid (CSF) drainage to cervical lymph nodes. Yet, sustained manipulation of dLVs did not significantly alter the overall brain Aß plaque load. Moreover, dLV atrophy did not alter the behavioral phenotypes of the AD mice, but it improved CSF-to-blood drainage. Our results indicate that sustained dLV manipulation does not affect Aß deposition in the brain and that compensatory mechanisms promote CSF clearance.

ciRS-7 and miR-7 regulate ischemia-induced neuronal death via glutamatergic signaling.

Brain functionality relies on finely tuned regulation of gene expression by networks of non-coding RNAs (ncRNAs) such as the one composed by the circular RNA ciRS-7 (also known as CDR1as), the microRNA miR-7, and the long ncRNA Cyrano. We describe ischemia-induced alterations in the ncRNA network both in vitro and in vivo and in transgenic mice lacking ciRS-7 or miR-7. Our data show that cortical neurons downregulate ciRS-7 and Cyrano and upregulate miR-7 expression during ischemia. Mice lacking ciRS-7 exhibit reduced lesion size and motor impairment, while the absence of miR-7 alone results in increased ischemia-induced neuronal death. Moreover, miR-7 levels in pyramidal excitatory neurons regulate neurite morphology and glutamatergic signaling, suggesting a potential molecular link to the in vivo phenotype. Our data reveal the role of ciRS-7 and miR-7 in modulating ischemic stroke outcome, shedding light on the pathophysiological function of intracellular ncRNA networks in the brain.

Control of protein synthesis through mRNA pseudouridylation by dyskerin.

Posttranscriptional modifications of mRNA have emerged as regulators of gene expression. Although pseudouridylation is the most abundant, its biological role remains poorly understood. Here, we demonstrate that the pseudouridine synthase dyskerin associates with RNA polymerase II, binds to thousands of mRNAs, and is responsible for their pseudouridylation, an action that occurs in chromatin and does not appear to require a guide RNA with full complementarity. In cells lacking dyskerin, mRNA pseudouridylation is reduced, while at the same time, de novo protein synthesis is enhanced, indicating that this modification interferes with translation. Accordingly, mRNAs with fewer pseudouridines due to knockdown of dyskerin are translated more efficiently. Moreover, mRNA pseudouridylation is severely reduced in patients with dyskeratosis congenita caused by inherited mutations in the gene encoding dyskerin (i.e., DKC1). Our findings demonstrate that pseudouridylation by dyskerin modulates mRNA translatability, with important implications for both normal development and disease.

Neutralization of the Positive Charges on Histone Tails by RNA Promotes an Open Chromatin Structure.

RNA associates extensively with chromatin and can influence its structure; however, the potential role of the negative charges of RNA on chromatin structure remains unknown. Here, we demonstrate that RNA prevents precipitation of histones and can attenuate electrostatic interactions between histones and DNA, thereby loosening up the chromatin structure. This effect is independent of the sequence of RNA but dependent on its single-stranded nature, length, concentration, and negative charge. Opening and closure of chromatin by RNA occurs rapidly (within minutes) and passively (in permeabilized cells), in agreement with electrostatics. Accordingly, chromatin compaction following removal of RNA can be prevented by high ionic strength or neutralization of the positively charged histone tails by hyperacetylation. Finally, LINE1 repeat RNAs bind histone H2B and can decondense chromatin. We propose that RNA regulates chromatin opening and closure by neutralizing the positively charged tails of histones, reducing their electrostatic interactions with DNA.

Point-of-care-based protocol with first-line therapy with coagulation factor concentrates is associated with decrease allogenic blood transfusion and costs in cardiovascular surgery: an Italian single-center experience.

BACKGROUND: Transfusion in patients having cardiac surgery has been associated with increased morbidity, mortality, and costs. This analysis assessed the impact of a rotational thromboelastometry (ROTEM®)- and functional platelet assessment (Multiplate®)-based protocol for bleeding management on perioperative outcomes and costs in patients undergoing cardiac surgery. METHODS: This retrospective analysis of the records of all patients who underwent cardiac surgery at the Hesperia Hospital, Modena, Italy, from December 2012 to December 2013 compared outcomes and costs of bleeding management for the two 6-month periods before/after introduction of the ROTEM- and Multiplate-based protocol. Descriptive and correlation analysis were performed as appropriate. Propensity score matching and its correlation analysis were performed. RESULTS: Data from 768 consecutive patients (mean age ~69 years, ~66% male) were included; 50.7% and 49.3% of patients had surgery before and after protocol introduction, respectively. Significantly fewer patients required transfusions of packed red blood cells after the protocol introduction over the 24 hours postsurgery (100 vs. 197 patients; P<0.001) and during ICU stay (134 vs. 221 patients; P<0.001). A significantly greater proportion of patients treated after protocol introduction received prothrombin complex concentrate (31 vs. 16; P<0.05) and fibrinogen concentrate (36 vs. 13; P<0.001). A significantly greater proportion of patients treated after protocol introduction had an ICU stay duration <48 hours (81.5% vs. 71.5%; P<0.001). ROTEM-based bleeding management was associated with a saving of €128,676.23 for the 379 patients undergoing surgery post-protocol introduction (€339.52 per patient). CONCLUSIONS: ROTEM-guided bleeding management in patients undergoing cardiac surgery was cost-effective and associated with an increase of administration of coagulation factor concentrates and a decrease of ICU length of stay.

Benefits and medium-term outcome of the Sorin Pericarbon Freedom stentless aortic prosthesis in cases of acute bacterial endocarditis.

OBJECTIVES: The aim of this study is to evaluate the ease of use and the advantages of Sorin Pericarbon Freedom (SPF) stentless valve in cases of acute bacterial endocarditis and to check the intermediate-term results after the implant of SPF with respect to resistance to infection, valve deterioration and durability. METHODS: Between June 2003 and February 2015, 26 patients with active aortic valve bacterial endocarditis underwent aortic valve replacement with SPF pericardial stentless aortic prosthesis. The mean age was 57 ± 18 years; 73% of the patients were in preoperative NYHA class III and VI. Mean Logistic EuroSCORE was 14.2 ± 12.7. Endocarditis occurred in 18 patients with native valves, and in 9 patients with prosthetic valves (4 mechanical aortic valve prostheses; 5 aortic bioprostheses). Aortic root abscesses were observed in 16 cases (61.5%). Surgery was emergent in 3 cases (11.5%). Redo surgery was performed in 9 cases (35%). Cumulative follow-up was 126.8 patient-years (mean 4.9 ± 3.3 years). RESULTS: Operative hospital mortality was 0% for all patients. Residual mean prosthetic gradient at discharge was 9.4 ± 3.6 mmHg. Neither residual aortic incompetence nor residual abscess cavity was observed at discharge. Mean ejection fraction at discharge was 54 ± 8% (Min; Max: 35%; 65%). A total of 4 patients died at follow-up, all for non-cardiac causes. One patient was lost to follow-up. Two patients (8%) underwent non-valve-related reoperation with 0% mortality. Residual mean gradient at follow-up was 7.2 ± 2.1 mmHg. Three patients (17%) presented with mild/moderate aortic incompetence and 89% of patients were in NYHA Class I-II at follow-up. At 9 years, actuarial freedom from valve-related reoperation and from structural valve deterioration was 100%. CONCLUSIONS: The SPF aortic prosthesis is a true pericardial stentless prosthesis suitable for the treatment of acute bacterial endocarditis. Intermediate-time results in terms of freedom from reoperation, structural valve deterioration and resistance to infections are satisfactory. Haemodynamic performances are excellent since a complete exclusion of aortic root abscesses is achieved without any reduction of the aortic annular diameter, usually due to marsupialization or patch closure of the infected cavities.

Effectiveness of sepsis bundle application in cirrhotic patients with septic shock: a single-center experience.

PURPOSE: To evaluate the effect of adherence to evidence-based guidelines of the Surviving Sepsis Campaign (SSC) on the outcome of cirrhotic patients with septic shock admitted to the intensive care unit. METHODS: This prospective observational cohort study included 38 patients with documented liver cirrhosis and septic shock admitted to a multidisciplinary intensive care unit at a University Hospital from January 2005 to June 2009. In each patient, the compliance to 4 resuscitation (ie, 6-hour bundle) and to 3 management (i.e. 24-hour bundle) interventions recommended by the SSC guidelines and the 30-day mortality were measured. RESULTS: The 6-hour, 24-hour, and all bundles were completed in 50 %, 52%, and 39% of the patients, respectively. The characteristics at admission and the 30-day mortality of patients with all-bundle compliance (n = 15; mortality 86.6%) were similar to those of patients without bundle compliance (n = 23; mortality 78.2%), except for central venous O2 saturation. Unadjusted and adjusted regression analysis showed that none of the single sepsis interventions and bundles were independently associated with 30-day mortality. CONCLUSIONS: In our observational study, the adherence to the interventions recommended by the SSC evidence-based guidelines did not provide an improvement in the survival rate of cirrhotic patients with septic shock.