HIV-infection, atherosclerosis and the inflammatory pathway: candidate gene study in a Spanish HIV-infected population.

BACKGROUND: Higher prevalence of atherosclerosis and higher cardiovascular risk is observed in HIV-infected individuals. The biological mechanisms underlying these processes are unclear. Several studies have implicated genetic variants in the inflammatory genes in cardiovascular disease and in HIV natural course infection. METHODS & FINDINGS: In this study we have tested the possible association between genetic variants in several inflammatory genes and asymptomatic cardiovascular disease measured by carotid intima media thickness (cIMT) and atherosclerotic plaque presence as dependent variables in 213 HIV-infected individuals. A total of 101 genetic variants in 25 candidate genes have been genotyped. Results were analyzed using Plink and SPSS statistical packages. We have found several polymorphisms in the genes ALOX5 (rs2115819 p = 0.009), ALOX5AP (rs9578196 p = 0.007; rs4769873 p = 0.004 and rs9315051 p = 0.0004), CX3CL1 (rs4151117 p = 0.040 and rs614230 p = 0.015) and CCL5 (rs3817655 p = 0.018 and rs2107538 p = 0.018) associated with atherosclerotic plaque. cIMT mean has been associated with CRP (1130864 p = 0.0003 and rs1800947 p = 0.008), IL1RN (rs380092 p = 0.002) and ALOX5AP (rs3885907 p = 0.02) genetic variants. CONCLUSIONS: In this study we have found modest associations between genetic variants in several inflammatory genes and atherosclerotic plaque or cIMT. Nevertheless, our study adds evidence to the association between inflammatory pathway genetic variants and the atherosclerotic disease in HIV-infected individuals

Compared to conventional, ecological intensive management promotes beneficial proteolytic soil microbial communities for agro-ecosystem functioning under climate change-induced rain regimes

Projected climate change and rainfall variability will affect soil microbial communities, biogeochemical cycling and agriculture. Nitrogen (N) is the most limiting nutrient in agroecosystems and its cycling and availability is highly dependent on microbial driven processes. In agroecosystems, hydrolysis of organic nitrogen (N) is an important step in controlling soil N availability. We analyzed the effect of management (ecological intensive vs. conventional intensive) on N-cycling processes and involved microbial communities under climate change-induced rain regimes. Terrestrial model ecosystems originating from agroecosystems across Europe were subjected to four different rain regimes for 263 days. Using structural equation modelling we identified direct impacts of rain regimes on N-cycling processes, whereas N-related microbial communities were more resistant. In addition to rain regimes, management indirectly affected N-cycling processes via modifications of N-related microbial community composition. Ecological intensive management promoted a beneficial N-related microbial community composition involved in N-cycling processes under climate change-induced rain regimes. Exploratory analyses identified phosphorus-associated litter properties as possible drivers for the observed management effects on N-related microbial community composition. This work provides novel insights into mechanisms controlling agro-ecosystem functioning under climate change

Synaptic, axonal damage and inflammatory cerebrospinal fluid biomarkers in neurodegenerative dementias

INTRODUCTION: Synaptic damage, axonal neurodegeneration, and neuroinflammation are common features in Alzheimer's disease (AD), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD). METHODS: Unicentric cohort of 353 participants included healthy control (HC) subjects, AD continuum stages, genetic AD and FTD, and FTD and CJD. We measured cerebrospinal fluid neurofilament light (NF-L), neurogranin (Ng), 14-3-3, and YKL-40 proteins. RESULTS: Biomarkers showed differences in HC subjects versus AD, FTD, and CJD. Disease groups differed between them except AD versus FTD for YKL-40. Only NF-L differed between all stages within the AD continuum. AD and FTD symptomatic mutation carriers presented differences with respect to HC subjects. Applying the AT(N) system, 96% subjects were positive for neurodegeneration if 14-3-3 was used, 94% if NF-L was used, 62% if Ng was used, and 53% if YKL-40 was used. DISCUSSION: Biomarkers of synapse and neurodegeneration differentiate HC subjects from neurodegenerative dementias and between AD, FTD, and CJD. NF-L and 14-3-3 performed similar to total tau when AT(N) system was applied

Treatment of post-cholecystectomy biliary strictures with fully-covered self-expanding metal stents - results after 5 years of follow-up

BACKGROUND: Endoscopic treatment of post-cholecystectomy biliary strictures (PCBS) with multiple plastic biliary stents placed sequentially is a minimally invasive alternative to surgery but requires multiple interventions. Temporary placement of a single fully-covered self-expanding metal stent (FCSEMS) may offer safe and effective treatment with fewer re-interventions. Long-term effectiveness of treatment with FCSEMS to obtain PCBS resolution has not yet been studied. METHODS: In this prospective multi-national study in patients with symptomatic benign biliary strictures (N = 187) due to various etiologies received a FCSEMS with scheduled removal at 6-12 months and were followed for 5 years. We report here long-term outcomes of the subgroup of patients with PCBS (N = 18). Kaplan Meier analyses assessed long-term freedom from re-stenting. Adverse events were documented. RESULTS: Endoscopic removal of the FCSEMS was achieved in 83.3% (15/18) of patients after median indwell of 10.9 (range 0.9-13.8) months. In the remaining 3 patients (16.7%), the FCSEMS spontaneously migrated and passed without complications. At the end of FCSEMS indwell, 72% (13/18) of patients had stricture resolution. At 5 years after FCSEMS removal, 84.6% (95% CI 65.0-100.0%) of patients who had stricture resolution at FCSEMS removal remained stent-free. In addition, at 75 months after FCSEMS placement, the probability of remaining stent-free was 61.1% (95% CI 38.6-83.6%) for all patients. Stent or removal related serious adverse events occurred in 38.9% (7/18) all resolved without sequalae. CONCLUSIONS: In patients with symptomatic PCBS, temporary placement of a single FCSEMS intended for 10-12 months indwell is associated with long-term stricture resolution up to 5 years. Temporary placement of a single FCSEMS may be considered for patients with PCBS not involving the main hepatic confluence. TRIAL REGISTRATION NUMBERS: NCT01014390; CTRI/2012/12/003166; Registered 17 November 2009

APP-derived peptides reflect neurodegeneration in frontotemporal dementia

Altres ajuts: The Catalan frontotemporal initiative (CATFI) is funded by the Health Department of the Government of Catalonia (grant PERIS SLT002/16/00408 to Alberto Lleó and Raquel Sánchez-Valle). This work was also supported by research grants from the CIBERNED Program (Program 1, Alzheimer Disease to Alberto Lleó and SIGNAL study, file://www.signalstudy.es), partly funded by Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, "Una manera de hacer Europa." This work has also been supported by a "Marató TV3" grant (20141210 to Juan Fortea, 044412 to Rafael Blesa, 20143710 to Ricard Rojas-García and 20143810 to Raquel Sánchez-Valle) and Fundación BBVA (grant to A. Lleó) and a grant from the Fundació Bancaria La Caixa to Rafael Blesa. Ignacio Illán-Gala and Sergi Borrego-Écija are supported by the Rio Hortega grant from "Acción estratégica en Salud 2013-2016" and the European Social Fund. Ignacio Illán-Gala is supported by the Global Brain Health Institute (Atlantic Fellow for Equity in Brain Health). We acknowledge all the participants in this study and all the collaborators of the SPIN cohort. We also acknowledge Soraya Torres and Laia Muñoz for technical assistance. We thank EUROIMMUN for providing Aβ1-38 and Aβ1-40 ELISA assays for this study.Objective: We aimed to investigate the relationship between cerebrospinal fluid levels (CSF) of amyloid precursor protein (APP)-derived peptides related to the amyloidogenic pathway, cortical thickness, neuropsychological performance, and cortical gene expression profiles in frontotemporal lobar degeneration (FTLD)-related syndromes, Alzheimer's disease (AD), and healthy controls. Methods: We included 214 participants with CSF available recruited at two centers: 93 with FTLD-related syndromes, 57 patients with AD, and 64 healthy controls. CSF levels of amyloid β (Aβ)1-42, Aβ1-40, Aβ1-38, and soluble β fragment of APP (sAPPβ) were centrally analyzed. We compared CSF levels of APP-derived peptides between groups and, we studied the correlation between CSF biomarkers, cortical thickness, and domain-specific cognitive composites in each group. Then, we explored the relationship between cortical thickness, CSF levels of APP-derived peptides, and regional gene expression profile using a brain-wide regional gene expression data in combination with gene set enrichment analysis. Results: The CSF levels of Aβ1-40, Aβ1-38, and sAPPβ were lower in the FTLD-related syndromes group than in the AD and healthy controls group. CSF levels of all APP-derived peptides showed a positive correlation with cortical thickness and the executive cognitive composite in the FTLD-related syndromes group but not in the healthy control or AD groups. In the cortical regions where we observed a significant association between cortical thickness and CSF levels of APP-derived peptides, we found a reduced expression of genes related to synaptic function. Interpretation: APP-derived peptides in CSF may reflect FTLD-related neurodegeneration. This observation has important implications as Aβ1-42 levels are considered an indirect biomarker of cerebral amyloidosis

Contribution of CSF biomarkers to early-onset Alzheimer's disease and frontotemporal dementia neuroimaging signatures

Prior studies have described distinct patterns of brain gray matter and white matter alterations in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), as well as differences in their cerebrospinal fluid (CSF) biomarkers profiles. We aim to investigate the relationship between early‐onset AD (EOAD) and FTLD structural alterations and CSF biomarker levels. We included 138 subjects (64 EOAD, 26 FTLD, and 48 controls), all of them with a 3T MRI brain scan and CSF biomarkers available (the 42 amino acid‐long form of the amyloid‐beta protein [Aβ42], total‐tau protein [T‐tau], neurofilament light chain [NfL], neurogranin [Ng], and 14‐3‐3 levels). We used FreeSurfer and FSL to obtain cortical thickness (CTh) and fraction anisotropy (FA) maps. We studied group differences in CTh and FA and described the “AD signature” and “FTLD signature.” We tested multiple regression models to find which CSF‐biomarkers better explained each disease neuroimaging signature. CTh and FA maps corresponding to the AD and FTLD signatures were in accordance with previous literature. Multiple regression analyses showed that the biomarkers that better explained CTh values within the AD signature were Aβ and 14‐3‐3; whereas NfL and 14‐3‐3 levels explained CTh values within the FTLD signature. Similarly, NfL levels explained FA values in the FTLD signature. Ng levels were not predictive in any of the models. Biochemical markers contribute differently to structural (CTh and FA) changes typical of AD and FTLD

Cerebral Amyloid Angiopathy in Down Syndrome and Sporadic and Autosomal-Dominant Alzheimer\u27s Disease

Introduction—We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer\u27s disease (AD) (early-onset AD [EOAD]). Methods—Neuroimaging features of CAA, APOE, and cerebrospinal fluid-Aβ40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68). Results—CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE-ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (p = .06) but not with DS or ADAD. There were no differences in Aβ040 levels between groups or between subjects with and without CAA. Discussion—CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid-Aβ40 levels are not a useful biomarker for CAA in AD

Receptor Sorting within Endosomal Trafficking Pathway Is Facilitated by Dynamic Actin Filaments

Early endosomes (EEs) are known to be a sorting station for internalized molecules destined for degradation, recycling, or other intracellular organelles. Segregation is an essential step in such sorting, but the molecular mechanism of this process remains to be elucidated. Here, we show that actin is required for efficient recycling and endosomal maturation by producing a motile force. Perturbation of actin dynamics by drugs induced a few enlarged EEs containing several degradative vacuoles and also interfered with their transporting ability. Actin repolymerization induced by washout of the drug caused the vacuoles to dissociate and individually translocate toward the perinuclear region. We further elucidated that cortactin, an actin-nucleating factor, was required for transporting contents from within EEs. Actin filaments regulated by cortactin may provide a motile force for efficient sorting within early endosomes. These data suggest that actin filaments coordinate with microtubules to mediate segregation in EEs

Objective Evaluation of Multiple Sclerosis Lesion Segmentation using a Data Management and Processing Infrastructure

We present a study of multiple sclerosis segmentation algorithms conducted at the international MICCAI 2016 challenge. This challenge was operated using a new open-science computing infrastructure. This allowed for the automatic and independent evaluation of a large range of algorithms in a fair and completely automatic manner. This computing infrastructure was used to evaluate thirteen methods of MS lesions segmentation, exploring a broad range of state-of-theart algorithms, against a high-quality database of 53 MS cases coming from four centers following a common definition of the acquisition protocol. Each case was annotated manually by an unprecedented number of seven different experts. Results of the challenge highlighted that automatic algorithms, including the recent machine learning methods (random forests, deep learning, …), are still trailing human expertise on both detection and delineation criteria. In addition, we demonstrate that computing a statistically robust consensus of the algorithms performs closer to human expertise on one score (segmentation) although still trailing on detection scores