Subclinical carotid atherosclerosis predicts all-cause mortality and cardiovascular events in obese patients with negative exercise echocardiography

BACKGROUND: Obesity is a major health problem due to its high prevalence. The relationship between obesity and cardiovascular disease is unclear. Some studies agree that certain conditions associated with obesity, such as physical inactivity or cardiovascular risk factors, are responsible for cardiovascular risk excess among obese people. Carotid intima-media thickness and carotid plaques (CP) have been associated with cardiovascular adverse events in healthy populations, and recent data suggest a higher prevalence of subclinical carotid atherosclerosis in obese and metabolically unhealthy patients. However, there are no studies correlating subclinical atherosclerosis and adverse events (AE) in obese subjects. AIM: To determine the association between carotid disease and AE in obese patients with negative exercise echocardiography (EE). METHODS: From January 1, 2006 to December 31, 2010, 2000 consecutive patients with a suspicion of coronary artery disease were submitted for EE and carotid ultrasonography. Exclusion criteria included previous vascular disease, left ventricular ejection fraction < 50%, positive EE, significant valvular heart disease and inferior to submaximal EE. An AE was defined as all-cause mortality, myocardial infarction and cerebrovascular accident. Subclinical atherosclerosis was defined as CP presence according to Manheim and the American Society of Echocardiography Consensus. RESULTS: Of the 652 patients who fulfilled the inclusion criteria, 226 (34.7%) had body mass indexes ≥ 30 kg/m2, and 76 of them (33.6%) had CP. During a mean follow-up time of 8.2 (2.1) years, 27 AE were found (11.9%). Mean event-free survival at 1, 5 and 10 years was 99.1% (0.6), 95.1% (1.4) and 86.5% (2.7), respectively. In univariate analysis, CP predicted AE [hazard ratio (HR) 2.52, 95% confidence interval (CI) 1.17-5.46; P = 0.019]. In multivariable analysis, the presence of CP remained a predictor of AE (HR 2.26, 95%CI 1.04-4.95, P = 0.041). Other predictors identified were glomerular filtration rate (HR 0.98, 95%CI 0.96-0.99; P = 0.023), peak metabolic equivalents (HR 0.83, 95%CI 0.70-0.99, P = 0.034) and moderate mitral regurgitation (HR 5.02, 95%CI 1.42-17.75, P = 0.012). CONCLUSION: Subclinical atherosclerosis defined by CP predicts AE in obese patients with negative EE. These patients could benefit from aggressive prevention measures

Persistence of wild rabbit (Oryctolagus cuniculus) latrines and its implication for monitoring programs

Counting latrines is a standard method to estimate European wild rabbits (Oryctolagus cuniculus) abundance. This method plays an important role in endangered predators’ conservation programs in the Iberian Peninsula, especially in potential reintroduction areas for the Iberian lynx (Lynx pardinus). However, since the last half-century, rabbit populations have declined dramatically within their native range, mainly due to the effect of two viral diseases, which have caused even local extinctions of natural populations. Hence, we raise the question regarding how reliable the method of counting latrines may be in ensuring the abundance of rabbit populations after an event of sudden decline or even local extinction. To answer this question, we carry out a simple experiment where we set ten lines with rabbit latrines with two different sizes each (small and large) and simulated low- and high-abundant rabbit population scenarios on five latrine lines each, respectively

Biomarkers of tumor-reactive CD4+ and CD8+ TILs associate with improved prognosis in endometrial cancer

Background: Despite the growing interest in immunotherapeutic interventions for endometrial cancer (EC), the prevalence, phenotype, specificity and prognostic value of tumor infiltrating lymphocytes (TILs) in this tumor type remains unclear. Methods: To better understand the role of TILs in EC, we analyzed the phenotypic traits of CD8+ and CD4+ EC-resident T cells from 47 primary tumors by high-dimensional flow cytometry. In addition, CD8+ and CD4+ TIL subpopulations were isolated based on the differential expression of programmed cell death protein-1 (PD-1) (negative, dim and high) and CD39 (positive or negative) by fluorescence activated cell sorting (FACS), expanded in vitro, and screened for autologous tumor recognition. We further investigated whether phenotypic markers preferentially expressed on CD8+ and CD4+ tumor-reactive TIL subsets were associated with the four distinct molecular subtypes of EC, tumor mutational burden and patient survival. Results: We found that CD8+TILs expressing high levels of PD-1 (PD-1hi) co-expressed CD39, TIM-3, HLA-DR and CXCL13, as compared with TILs lacking or displaying intermediate levels of PD-1 expression (PD-1- and PD-1dim, respectively). Autologous tumor reactivity of sorted and in vitro expanded CD8+ TILs demonstrated that the CD8+PD-1dimCD39+ and PD-1hiCD39+ T cell subsets both contained tumor-reactive TILs and that a higher level of PD-1 expression was associated with increased CD39 and a superior frequency of tumor reactivity. With respect to CD4+ T conventional (Tconv) TILs, co-expression of inhibitory and activation markers was more apparent on PD-1hi compared with PD-1- or PD-1dim T cells, and in fact, it was the CD4+PD-1hi subpopulation that accumulated the antitumor T cells irrespective of CD39 expression. Most importantly, detection of CD8+PD-1hiCD39+ and CD4+PD-1hi tumor-reactive T-cell subsets, but also markers specifically expressed by these subpopulations of TILs, that is, PD-1hi, CD39, CXCL13 and CD103 by CD8+ TILs and PD-1hi and CXCL13 by CD4+ Tconv TILs, correlated with prolonged survival of patients with EC. Conclusions: Our results demonstrate that EC are frequently infiltrated by tumor-reactive TILs, and that expression of PD-1hi and CD39 or PD-1hi can be used to select and expand CD8+ and CD4+ tumor-reactive TILs, respectively. In addition, biomarkers preferentially expressed on tumor-reactive TILs, rather than the frequency of CD3+, CD8+ and CD4+ lymphocytes, hold prognostic value suggesting their protective role in antitumor immunity

Decreasing the Expression of GABAA[alfa]5 Subunit-Containing Receptors Partially Improves Cognitive, Electrophysiological, and Morphological Hippocampal Defects in the Ts65Dn Model of Down Syndrome

Trisomy 21 or Down syndrome (DS) is the most common cause of intellectual disability of a genetic origin. The Ts65Dn (TS) mouse, which is the most commonly used and best-characterized mouse model of DS, displays many of the cognitive, neuromorphological, and biochemical anomalies that are found in the human condition. One of the mechanisms that have been proposed to be responsible for the cognitive deficits in this mouse model is impaired GABAmediated inhibition. Because of the well-known modulatory role of GABAA ?5 subunit-containing receptors in cognitive processes, these receptors are considered to be potential targets for improving the intellectual disability in DS. The chronic administration of GABAA ?5-negative allosteric modulators has been shown to be procognitive without anxiogenic or proconvulsant side effects. In the present study, we use a genetic approach to evaluate the contribution of GABAA ?5 subunit-containing receptors to the cognitive, electrophysiological, and neuromorphological deficits in TS mice.We show that reducing the expression of GABAA ?5 receptors by deleting one or two copies of the Gabra5 gene in TS mice partially ameliorated the cognitive impairments, improved longterm potentiation, enhanced neural differentiation and maturation, and normalized the density of the GABAergic synapse markers. Reducing the gene dosage of Gabra5 in TS mice did not induce motor alterations and anxiety or affect the viability of the mice. Our results provide further evidence of the role of GABAA ?5 receptor-mediated inhibition in cognitive impairment in the TS mouse model of DS.This work was supported by the Jérôme Lejeune Foundation, Fundación Tatiana Pérez de Guzmán el Bueno and the Spanish Ministry of Economy and Competitiveness (PSI2016-76194-R/ AEI/FEDER/UE

P2P4L2L (Peer to Peer for Learning to Learn)

Projecte: 2016PID-UB / 024Memòria del projecte P2P4L2L (Peer to Peer for Learning to Learn) 2016PID-UB / 024 llevado a cabo entre 2016 i 2018 sobre el disseny i desenvolupament de pràctiques d'avaluació entre iguals per desenvolupar la competència d'aprendre a aprendre.Memoria del proyecto P2P4L2L (Peer to Peer for Learning to Learn) 2016PID-UB / 024 implementado entre 2016 y 2018 sobre el diseño y desarrollo de prácticas de evaluación entre iguales para desarrollar la competencia de aprender a aprender.PMI

The Antimicrobial Activity of Curcumin and Xanthohumol on Bacterial Biofilms Developed over Dental Implant Surfaces

In search for natural products with antimicrobial properties for use in the prevention and treatment of peri-implantitis, the purpose of this investigation was to evaluate the antimicrobial activity of curcumin and xanthohumol, using an in vitro multi-species dynamic biofilm model including Streptococcus oralis, Actinomyces naeslundii, Veillonella parvula, Fusobacterium nucleatum, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. The antimicrobial activities of curcumin (5 mM) and xanthohumol (100 μM) extracts, and the respective controls, were evaluated with 72-h biofilms formed over dental implants by their submersion for 60 seconds. The evaluation was assessed by quantitative polymerase chain reaction (qPCR), confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). For the data analysis, comparisons were tested applying ANOVA tests with post-hoc Bonferroni corrections to evaluate the antimicrobial activity of both extracts. With qPCR, statistically significant reductions in bacterial counts were observed for curcumin and xanthohumol, when compared to the negative control. The results with CLSM and SEM were consistent with those reported with qPCR. It was concluded that both curcumin and xanthohumol have demonstrated antimicrobial activity against the six bacterial species included in the dynamic in vitro biofilm model used

Post-mortem neuropathologic examination of a 5-case series of CAR T-cell treated patients

Introduction: Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy for the treatment of refractory hematopoietic malignancies. Adverse events are common, and neurotoxicity is one of the most important. However, the physiopathology is unknown and neuropathologic information is scarce.Materials and methods: Post-mortem examination of 6 brains from patients that underwent CAR T-cell therapy from 2017 to 2022. In all cases, polymerase chain reaction (PCR) in paraffin blocks for the detection of CAR T cells was performed.Results: Two patients died of hematologic progression, while the others died of cytokine release syndrome, lung infection, encephalomyelitis, and acute liver failure. Two out of 6 presented neurological symptoms, one with extracranial malignancy progression and the other with encephalomyelitis. The neuropathology of the latter showed severe perivascular and interstitial lymphocytic infiltration, predominantly CD8+, together with a diffuse interstitial histiocytic infiltration, affecting mainly the spinal cord, midbrain, and hippocampus, and a diffuse gliosis of basal ganglia, hippocampus, and brainstem. Microbiological studies were negative for neurotropic viruses, and PCR failed to detect CAR T -cells. Another case without detectable neurological signs showed cortical and subcortical gliosis due to acute hypoxic-ischemic damage. The remaining 4 cases only showed a mild patchy gliosis and microglial activation, and CAR T cells were detected by PCR only in one of them.Conclusions: In this series of patients that died after CAR T-cell therapy, we predominantly found non-specific or minimal neuropathological changes. CAR T-cell related toxicity may not be the only cause of neurological symptoms, and the autopsy could detect additional pathological findings

Expanding the clinical and genetic spectra of primary immunodeficiency-related disorders with clinical exome sequencing: expected and unexpected findings

Inmunodeficiencias primarias; Secuenciación de próxima generación; Secuenciación clínica del exomaImmunodeficiències primàries; Seqüenciació de propera generació; Seqüenciació clínica d’exomesPrimary immunodeficiencies; Next generation sequencing; Clinical exome sequencingPrimary immunodeficiencies (PIDs) refer to a clinically, immunologically, and genetically heterogeneous group of over 350 disorders affecting development or function of the immune system. The increasing use of next-generation sequencing (NGS) technology has greatly facilitated identification of genetic defects in PID patients in daily clinical practice. Several NGS approaches are available, from the unbiased whole exome sequencing (WES) to specific gene panels. Here, we report on a 3-year experience with clinical exome sequencing (CES) for genetic diagnosis of PIDs. We used the TruSight One sequencing panel, which includes 4,813 disease-associated genes, in 61 unrelated patients (pediatric and adults). The analysis was done in 2 steps: first, we focused on a virtual PID panel and then, we expanded the analysis to the remaining genes. A molecular diagnosis was achieved in 19 (31%) patients: 12 (20%) with mutations in genes included in the virtual PID panel and 7 (11%) with mutations in other genes. These latter cases provided interesting and somewhat unexpected findings that expand the clinical and genetic spectra of PID-related disorders, and are useful to consider in the differential diagnosis. We also discuss 5 patients (8%) with incomplete genotypes or variants of uncertain significance. Finally, we address the limitations of CES exemplified by 7 patients (11%) with negative results on CES who were later diagnosed by other approaches (more specific PID panels, WES, and comparative genomic hybridization array). In summary, the genetic diagnosis rate using CES was 31% (including a description of 12 novel mutations), which rose to 42% after including diagnoses achieved by later use of other techniques. The description of patients with mutations in genes not included in the PID classification illustrates the heterogeneity and complexity of PID-related disorders.This study was funded by Instituto de Salud Carlos III, grants PI14/00405 and PI17/00660, cofinanced by the European Regional Development Fund (ERDF)

Ductular reaction promotes intrahepatic angiogenesis through Slit2-Roundabout 1 signaling

Background and aims: Ductular reaction (DR) expands in chronic liver diseases and correlates with disease severity. Besides its potential role in liver regeneration, DR plays a role in the wound-healing response of the liver, promoting periductular fibrosis and inflammatory cell recruitment. However, there is no information regarding its role in intrahepatic angiogenesis. In the current study we investigated the potential contribution of DR cells to hepatic vascular remodeling during chronic liver disease. Approach and results: In mouse models of liver injury, DR cells express genes involved in angiogenesis. Among angiogenesis-related genes, the expression of Slit2 and its receptor Roundabout 1 (Robo1) was localized in DR cells and neoangiogenic vessels, respectively. The angiogenic role of the Slit2-Robo1 pathway in chronic liver disease was confirmed in ROBO1/2-/+ mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which displayed reduced intrahepatic neovascular density compared to wild-type mice. However, ROBO1/2 deficiency did not affect angiogenesis in partial hepatectomy. In patients with advanced alcohol-associated disease, angiogenesis was associated with DR, and up-regulation of SLIT2-ROBO1 correlated with DR and disease severity. In vitro, human liver-derived organoids produced SLIT2 and induced tube formation of endothelial cells. Conclusions: Overall, our data indicate that DR expansion promotes angiogenesis through the Slit2-Robo1 pathway and recognize DR cells as key players in the liver wound-healing response.Supported by grants from Fondo de Investigación Sanitaria Carlos III (FIS), cofinanced by Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, “Una manera de hacer Europa” (FIS PI20/00765, PI17/00673, to P.S.-B; FIS 18-PI18/00862, to I.G and M.C); from the National Institute on Alcohol Abuse and Alcoholism (1U01AA026972-01 and AGAUR 2017-SGR-01456, to P.S.-B.); and from the European Foundation for Alcohol Research (EA1653, to P.S.-B.). M.C. is funded by the Ramon y Cajal program from the Ministerio de Ciencia e Innovación RYC2019-026662-I. P.G. is funded by the Agencia de Gestió d'Ajuts Universitaris i de Recerca 2014 SGR 708, Centro de Investigaciónen Red Enfermedades Hepáticas y Digestivas (CIBERehd), and Institució Catalana de Recerca i Estudis Avançats. S.A. received a grant from the Ministerio de Educación, Cultura y Deporte (FPU17/04992). B.A.-B. is funded by the Instituto de Salud Carlos III (FI16/00203

Factors Associated With Short-Term Eradication of Rectal Colonization by KPC-2 Producing Klebsiella pneumoniae in an Outbreak Setting

Background: KPC-producing Klebsiella pneumoniae (KPCKP) is a threat for patients admitted to healthcare institutions. Objectives: To assess the efficacy of several decolonization strategies for KPCKP rectal carriage. Methods: Observational study performed in a 750-bed university center from July to October 2018 on the efficacy of a 10-day non-absorbable oral antibiotic (NAA) regimen (colistin 10 mg/ml, amikacin 8 mg/ml, and nystatin 30 mg/ml, 10 ml/6 h) vs. the same regimen followed by a probiotic (Vivomixx®) for 20 days in adult patients with KPCKP rectal colonization acquired during an outbreak. Results: Seventy-three patients colonized by KPCKP were included, of which 21 (29%) did not receive any treatment and 52 (71.2%) received NAA either alone (n = 26, 35.6%) or followed by a probiotic (n = 26, 35.6%). Eradication was observed in 56 (76.7%) patients and the only variable significantly associated with it was not receiving systemic antibiotics after diagnosis of rectal carriage [22/24 (91.6%) vs. 34/49 (69.3%), p = 0.04]. Eradication in patients receiving NAA plus probiotic was numerically but not significantly higher than that of controls [23/26 (88.4%) vs. 15/21 (71.4%), p = 0.14] and of those receiving only NAA (OR = 3.4, 95% CI = 0.78-14.7, p = 0.09). Conclusion: In an outbreak setting, rectal carriage of KPCKP persisted after a mean of 36 days in about one quarter of patients. The only factor associated with eradication was not receiving systemic antibiotic after diagnosis. A 10-day course of NAA had no impact on eradication. Probiotics after NAA may increase the decolonization rate, hence deserving further study