Search

Background: Although minimally invasive distal pancreatectomy (MIDP) is considered a standard approach it still presents a non-negligible rate of conversion to open that is mainly related to some difficulty factors, as obesity. The aim of this study is to analyze the preoperative factors associated with conversion in obese patients with MIDP., Methods: In this multicenter study, all obese patients who underwent MIDP at 18 international expert centers were included. The preoperative factors associated with conversion to open surgery were analyzed., Results: Out of 436 patients, 91 (20.9%) underwent conversion to open, presenting higher blood loss, longer operative time and similar rate of major complications. Twenty (22%) patients received emergent conversion. At univariate analysis, the type of approach, radiological invasion of adjacent organs, preoperative enlarged lymphnodes and ASA ≥ III were significantly associated with conversion to open. At multivariate analysis, robotic approach showed a significantly lower conversion rate (14.6 % vs 27.3%, OR = 2.380, p = 0.001). ASA ≥ III (OR = 2.391, p = 0.002) and preoperative enlarged lymphnodes (OR = 3.836, p = 0.003) were also independently associated with conversion., Conclusion: Conversion rate is significantly lower in patients undergoing robotic approach. Radiological enlarged lymphnodes and ASA ≥ III are also associated with conversion to open. Conversion is associated with poorer perioperative outcomes, especially in case of intraoperative hemorrhage., (Copyright © 2024. Published by Elsevier Ltd.)

Background & Aims: Infections by multidrug-resistant bacteria (MDRB) are an increasing healthcare problem worldwide. This study analyzes the incidence, burden, and risk factors associated with MDRB infections after liver transplant(ation) (LT)., Methods: This retrospective, multicenter cohort study included adult patients who underwent LT between January 2017 and January 2020. Risk factors related to pre-LT disease, surgical procedure, and postoperative stay were analyzed. Multivariate logistic regression analysis was performed to identify independent predictors of MDRB infections within the first 90 days after LT., Results: We included 1,045 LT procedures (960 patients) performed at nine centers across Spain. The mean age of our cohort was 56.8 ± 9.3 years; 75.4% (n = 782) were male. Alcohol-related liver disease was the most prevalent underlying etiology (43.2.%, n = 451). Bacterial infections occurred in 432 patients (41.3%) who presented with a total of 679 episodes of infection (respiratory infections, 19.3%; urinary tract infections, 18.5%; bacteremia, 13.2% and cholangitis 11%, among others). MDRB were isolated in 227 LT cases (21.7%) (348 episodes). Enterococcus faecium (22.1%), Escherichia coli (18.4%), and Pseudomonas aeruginosa (15.2%) were the most frequently isolated microorganisms. In multivariate analysis, previous intensive care unit admission (0-3 months before LT), previous MDRB infections (0-3 months before LT), and an increasing number of packed red blood cell units transfused during surgery were identified as independent predictors of MDRB infections. Mortality at 30, 90, 180, and 365 days was significantly higher in patients with MDRB isolates., Conclusion: MDRB infections are highly prevalent after LT and have a significant impact on prognosis. Enterococcus faecium is the most frequently isolated multi-resistant microorganism. New pharmacological and surveillance strategies aimed at preventing MDRB infections after LT should be considered for patients with risk factors., Impact and Implications: Multidrug-resistant bacterial infections have a deep impact on morbidity and mortality after liver transplantation. Strategies aimed at improving prophylaxis, early identification, and empirical treatment are paramount. Our study unveiled the prevalence and main risk factors associated with these infections, and demonstrated that gram-positive bacteria, particularly Enterococcus faecium, are frequent in this clinical scenario. These findings provide valuable insights for the development of prophylactic and empirical antibiotic treatment protocols after liver transplantation., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Introduction: Volcanic eruptions emit gases and particulate matter into the atmosphere which, if inhaled, can have an impact on health. The eruption of the volcano situated in the Cumbre Vieja Nature Reserve (La Palma, Canary Islands, Spain) affords a unique opportunity to study the effect of such a phenomenon on health. The aim of the proposed study is to assess the short-, medium- and long-term respiratory health effects of exposure to volcanic emissions from the eruption in three different population groups., Methods: We propose to undertake a multidesign study: an ambispective cohort study to analyze the effect of the eruption on the general population, the highly exposed population, and the childhood population; and a pre-post quasi-experimental study on subjects with previously diagnosed respiratory diseases. The information will be collected using a personal interview, biologic specimens, air pollution data, data from medical records, respiratory tests and imaging tests. The study has an envisaged follow-up of five years, to run from the date of initial recruitment, with annual data-collection. This study has been approved by the Santa Cruz de Tenerife Provincial Research Ethics Committee (Canary Island Health Service) on March 10, 2022., Conclusions: This study will make it possible to advance our knowledge of the effect a volcano eruption has on population health, both short- and long-term, and to assess the potential respiratory injury attributable to volcanic eruptions. It may serve as a model for future studies of new volcanic eruptions in the coming years., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alberto Ruano-Ravina reports financial support was provided by Spanish Society of Pneumology and Thorax Surgery., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Minimally invasive methods, such as balloon kyphoplasty (BKP) and percutaneous sacroplasty (PS), which are now widely used for the surgical treatment of compression fractures, involve injection of a bolus of poly (methyl methacrylate) bone cement (hereafter, "bone cement") into the fractured tissue. Many of the common complications following these surgeries, such as cement leakage and adjacent-level fractures (in the case of BKP), have been postulated to be related to the quality of the cancellous bone-bone cement interface, which, in turn, is a function of its fracture resistance. It is common to use bovine cancellous bone or polyurethane foam (PF) as a substitute for human cancellous bone in biomechanical studies of these surgical methods. The literature is lacking in studies of determination of fracture properties of human cancellous bone-bone cement interface, bovine cancellous bone-bone cement interface, and PF-bone cement interface. In the present work, an integrated methodology (combination of wedge splitting test and Heaviside-based digital image correlation) was used to make these determinations as well as those for the bone cement, bones and the PF alone. The fracture properties determined were maximum fracture load (F max ), fracture toughness (K c ), and specific fracture energy (G f ). For example, G f values for human cancellous bone and human cancellous bone-bone interface were 0.48±0.14 N/mm and 0.38±0.05 N/mm, respectively, whereas in the case of bovine cancellous bone and bovine cancellous bone-bone cement interface, they were 1.08±0.11 N/mm and 0.22±0.05 N/mm, respectively, and for PF (Grades 12.5 and 15.0) and PF-bone cement interface, they were 0.81±0.12 and 0.55±0.06 N/mm, respectively. The same trends were seen in the F max and K c results. These results suggest that it may not be justified to use either bovine cancellous bone or either of the PF grades as a substitute for human cadaveric cancellous bone in biomechanical studies of BKP, PS, and similar surgical methods., (Copyright © 2021. Published by Elsevier Ltd.)

Erdheim-Chester disease (ECD) is a clonal hematopoietic disorder characterized by the accumulation of foamy histiocytes within organs (in particular, frequent retroperitoneal involvement) and a high frequency of BRAFV600E mutations. Although ECD is not commonly recognized to have overt peripheral blood (PB) or bone marrow (BM) disease, we recently identified that ECD patients have a high frequency of a concomitant myeloid malignancy. We thus conducted a systematic clinical and molecular analysis of the BM from 120 ECD patients. Surprisingly, 42.5% of ECD patients (51 of 120) had clonal hematopoiesis whereas 15.8% of patients (19 of 120) developed an overt hematologic malignancy (nearly all of which were a myeloid neoplasm). The most frequently mutated genes in BM were TET2, ASXL1, DNMT3A, and NRAS. ECD patients with clonal hematopoiesis were more likely to be older (P < .0001), have retroperitoneal involvement (P = .02), and harbor a BRAFV600E mutation (P = .049) than those without clonal hematopoiesis. The presence of the TET2 mutation was associated with a BRAFV600E mutation in tissue ECD lesions (P = .0006) and TET2-mutant ECD patients were more likely to have vascular involvement than TET2 wild-type ECD patients. Clonal hematopoiesis mutations in ECD were detected in cells derived from CD34+CD38- BM progenitors and PB monocytes but less frequently present in PB B and T lymphocytes. These data identify a heretofore unrecognized high frequency of clonal hematopoiesis in ECD patients, reaffirm the development of additional high risk of myeloid neoplasms in ECD, and provide evidence of a BM-based precursor cell of origin for many patients with ECD., (© 2021 by The American Society of Hematology.)

Striatal dopamine transporter (DAT) uptake assessment through I 123 -Ioflupane Single-Pphoton Emission Computed Tomography (SPECT) provides valuable information about the dopaminergic denervation occurring in Parkinson's disease (PD). However, little is known about the clinical or biological relevance of extrastriatal DAT uptake in PD. Here, from the Parkinson's Progression Markers Initiative, we studied 623 participants (431 PD and 192 healthy controls) with available SPECT data. Even though striatal denervation was undoubtedly the imaging hallmark of PD, extrastriatal DAT uptake was also reduced in patients with PD. Topographically, widespread frontal but also temporal and posterior cortical regions showed lower DAT uptake in PD patients with respect to healthy controls. Importantly, a longitudinal voxelwise analysis confirmed an active one-year loss of extrastriatal DAT uptake within the PD group. Extrastriatal DAT uptake also correlated with the severity of motor symptoms, cognitive performance, and cerebrospinal fluid α-synuclein levels. In addition, we found an association between the Catechol-O-methyltransferase val 158 met genotype and extrastriatal DAT uptake. These results highlight the clinical and biological relevance of extrastriatal SPECT-DAT uptake in PD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In recent years quantum dots (QDs) have risen as useful luminescent nanoparticles with multiple applications ranging from laser, image displays and biomedical applications. Here we review and discuss the studies of these nanoparticles in patient derived cellular samples or tissues, including cellular models from iPSCs from patients, biopsied and post-mortem tissue. QD-based multiplexed imaging has been proved to overcome most of the major drawbacks of conventional techniques, exhibiting higher sensitivity, reliability, accuracy and simultaneous labeling of key biomarkers. In this sense, QDs are very promising tools to be further used in clinical applications including diagnosis and therapy approaches. Analyzing the possibilities of these materials in these biological samples gives an overview of the future applications of the nanoparticles in models closer to patients and their specific disease., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: A variety of techniques have been described for the construction of the HJ (hepaticojejunostomy). Due to its technical challenges, HJ is rarely performed in a pure laparoscopic setting. In stark contrast, the increasing availability of the robotic platform has sparked new interest in pursuing this procedure in a minimally invasive fashion. The aim of our study was to describe our surgical technique and to identify risk factors for anastomotic leak and stenosis following robotic surgery., Methods: We performed a retrospective analysis of a prospectively collected database, including all consecutive HJ carried out for different indications over a 10 year period., Results: One hundred fifty-two patients undergoing robotic HJ performed by the same surgeon were analyzed. Bile leak occurred in 2.6% of the patients. Stricture rate was 3.3%. The median follow up was 25.5 months. There was no mortality related to anastomotic complications. On univariate analysis, patient's age less than 65 years was the only risk factor for anastomotic stricture. On multivariate analysis, no predictor factors for leak or stenosis were identified., Conclusion: HJs carried out in a robotic fashion allow highly satisfactory results. No independent risk factors for bile leak of stenosis were identified on multivariate analysis., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Epigenetic changes during B-cell differentiation generate distinct DNA methylation signatures specific for B-cell subsets, including memory B cells (MBCs) and plasma cells (PCs). Waldenström macroglobulinemia (WM) is a B-cell malignancy uniquely comprising a mixture of lymphocytic and plasmacytic phenotypes. Here, we integrated genome-wide DNA methylation, transcriptome, mutation, and phenotypic features of tumor cells from 35 MYD88-mutated WM patients in relation to normal plasma and B-cell subsets. Patients naturally segregate into 2 groups according to DNA methylation patterns, related to normal MBC and PC profiles, and reminiscent of other memory and PC-derived malignancies. Concurrent analysis of DNA methylation changes in normal and WM development captured tumor-specific events, highlighting a selective reprogramming of enhancer regions in MBC-like WM and repressed and heterochromatic regions in PC-like WM. MBC-like WM hypomethylation was enriched in motifs belonging to PU.1, TCF3, and OCT2 transcription factors and involved elevated MYD88/TLR pathway activity. PC-like WM displayed marked global hypomethylation and selective overexpression of histone genes. Finally, WM subtypes exhibited differential genetic, phenotypic, and clinical features. MBC-like WM harbored significantly more clonal CXCR4 mutations (P = .015), deletion 13q (P = .006), splenomegaly (P = .02), and thrombocytopenia (P = .004), whereas PC-like WM harbored more deletion 6q (P = .012), gain 6p (P = .033), had increased frequencies of IGHV3 genes (P = .002), CD38 expression (P = 4.1e-5), and plasmacytic differentiation features (P = .008). Together, our findings illustrate a novel approach to subclassify WM patients using DNA methylation and reveal divergent molecular signatures among WM patients., (© 2020 by The American Society of Hematology.)

Background: Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome., Methods: We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid β peptides 1-42 and 1-40 and their ratio (Aβ 1-42/1-40 ), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with 18 F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate., Findings: Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aβ 1-42/1-40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. 18 F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5-54·1), and Alzheimer's disease dementia at 53·7 years (49·5-57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90-100% in the seventh decade of life., Interpretation: Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments., Funding: Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The fracture mechanics (FM) parameters of cancellous bone tissues are very important from a clinical point of view especially for the bone cement augmentation. From the literature review, one can observe that the experimental determination of fracture mechanic parameters of cancellous bone are still lacking. This can be due to the conditions associated with the unstable crack propagation in the cancellous bone and lack of tools to extract and measure the parameters (like crack opening displacement (COD) and crack length) in the course of fracture tests, which are necessary to evaluate the fracture properties. To address above mentioned, a platform was developed integrating an optical measurement technique like digital image correlation (DIC) with classical wedge splitting test (WST) method to extract precise and real crack tip positions, crack opening displacement (COD) at each load step. These indeed used for the evaluation of the fracture mechanic properties (fracture toughness, specific fracture energy (G f )) of the cancellous bone. Two approaches were used to evaluate the fracture mechanic properties of the bone. The first method is based on the global approach, which was widely used in the literature and the second method is based on the local approach. In this local approach, the local fracture energy (G i ) during the course of the test was evaluated, which give access to local fracture mechanics. The results evaluated by both the methods were in good accordance and compared with available literature. In addition, an attempt made to retrieve the real crack tip position at each load step during the test., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Patients with Philadelphia-negative myeloproliferative neoplasm (MPN) are prone to the development of second cancers, but the factors associated with these events have been poorly explored. In an international nested case-control study, we recruited 647 patients with carcinoma, nonmelanoma skin cancer, hematological second cancer, and melanoma diagnosed concurrently or after MPN diagnosis. Up to 3 control patients without a history of cancer and matched with each case for center, sex, age at MPN diagnosis, date of diagnosis, and MPN disease duration were included (n = 1234). Cases were comparable to controls for MPN type, driver mutations and cardiovascular risk factors. The frequency of thrombosis preceding MPN was similar for cases and controls (P = .462). Thrombotic events after MPN and before second cancer were higher in cases than in controls (11.6% vs 8.1%; P = .013), because of a higher proportion of arterial thromboses (6.2% vs 3.7%; P = .015). After adjustment for confounders, the occurrence of arterial thrombosis remained independently associated with the risk of carcinoma (odds ratio, 1.97; 95% confidence interval, 1.14-3.41), suggesting that MPN patients experiencing arterial events after MPN diagnosis deserve careful clinical surveillance for early detection of carcinoma. This study was registered at www.clinicaltrials.gov as NCT03745378., (© 2020 by The American Society of Hematology.)

Background: High ferritin concentration is associated with hypertriglyceridemia, although it is not elucidated if iron overload has a causal role., Objective: To evaluate the efficacy of repeated phlebotomies in patients with iron overload and hypertriglyceridemia., Methods: Twelve weeks, 1:1 randomized, parallel-groups trial conducted at a University Hospital Lipid Clinic, including 86 subjects aged 18-70 years with serum ferritin >300 ng/mL in men or >200 ng/mL in women and triglycerides >200 mg/dL. Participants underwent: (1) three phlebotomies (every 3 weeks) and lipid-lowering dietary counseling or (2) lipid-lowering dietary counseling. The main outcome measured was the mean difference in percent change in triglyceride concentration between groups after the intervention. The mean differences in percent change of other clinical and biochemical variables (including cytokines and proinflammatory markers) after the intervention were also evaluated., Results: Subjects who received phlebotomies showed a significant improvement in iron metabolism. The mean percent change in triglycerides between groups was -4.68 [-20.8, 11.4]%, P = .721. Retinol-binding protein 4 decreased by 9.98 ± 21.7% after phlebotomies, with a mean percent change between groups of -14.2 [-25.8, -2.73]%, P = .017, and correlated to gamma glutamyl transferase, alanine aminotransferase and aspartate aminotransferase change. Subjects with a large reduction in hepcidin showed a large improvement in liver enzymes and proinflammatory markers., Conclusions: A lipid-lowering diet plus a substantial reduction in iron deposits with repeated phlebotomies in subjects with hyperferritinemia and hypertriglyceridemia did not reduce triglyceride concentration in comparison with a lipid-lowering diet. Iron depletion for lipid management in these patients is not supported., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Intensive groundwater uptake is a process at the intersection of the anthroposphere, hydrosphere, and lithosphere. In this study, groundwater uptake on a peninsula where only one aquifer system - the Cambrian-Vendian (CmV) - is available for drinking water uptake is observed for a period of four years for relevant radionuclides and chemical parameters (Cl, Mn, Fe, δ 18 O). Intensive groundwater uptake from the CmV aquifer system may lead to water inflow either from the sea, through ancient buried valleys or from the under-laying crystalline basement rock which is rich in natural radionuclides. Changes in the geochemical conditions in the aquifer may in turn bring about desorption of Ra from sediment surface. Knowing the hydrogeological background of the wells helps to predict possible changes in water quality which in turn are important for sustainable groundwater management and optimization of water treatment processes. Changes in Cl and Ra concentrations are critical parameters to monitor for sustainable management of the CmV groundwater. Radionuclide activity concentrations in groundwater are often considered rather stable, minimum monitoring frequency of the total indicative dose from drinking water is set at once every ten years. The present study demonstrates that this is not sufficient for ensuring stable drinking water quality in case of aquifer systems as sensitive as the CmV aquifer system. Changes in Cl concentrations can be used as a tool to predict Ra activity concentrations and distribute the production between different wells opening to the same aquifer system., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: This study sought to evaluate the prognostic effect of carbohydrate antigen-125 (CA125)-guided therapy (CA125 strategy) versus standard of care (SOC) after a hospitalization for acute heart failure (AHF)., Background: CA125 has emerged as a surrogate of fluid overload and inflammatory status in AHF. After an episode of AHF admission, elevated values of this marker at baseline as well as its longitudinal profile relate to adverse outcomes, making it a potential tool for treatment guiding., Methods: In a prospective multicenter randomized trial, 380 patients discharged for AHF and high CA125 were randomly assigned to the CA125 strategy (n = 187) or SOC (n = 193). The aim in the CA125 strategy was to reduce CA125 to ≤35 U/ml by up or down diuretic dose, enforcing the use of statins, and tightening patient monitoring. The primary endpoint was 1-year composite of death or AHF readmission. Treatment strategies were compared as a time to first event and longitudinally., Results: Patients allocated to the CA125 strategy were more frequently visited, and treated with ambulatory intravenous loop diuretics and statins. Likewise, doses of oral loop diuretics and aldosterone receptor blockers were more frequently modified. The CA125 strategy resulted in a significant reduction of the primary endpoint, whether evaluated as time to first event (66 events vs. 84 events; p = 0.017) or as recurrent events (85 events vs. 165 events; incidence rate ratio: 0.49; 95% confidence interval: 0.28 to 0.82; p = 0.008). The effect was driven by significantly reducing rehospitalizations but not mortality., Conclusions: The CA125 strategy was superior to the SOC in terms of reducing the risk of the composite of 1-year death or AHF readmission. This effect was mainly driven by significantly reducing the rate of rehospitalizations. (Carbohydrate Antigen-125-guided Therapy in Heart Failure [CHANCE-HF]; NCT02008110)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The family of Ten-Eleven Translocation (TET) proteins is implicated in the process of active DNA demethylation and thus in epigenetic regulation. TET 1, 2 and 3 proteins are oxygenases that can hydroxylate 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) and further oxidize 5-hmC into 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC). The base excision repair (BER) pathway removes the resulting 5-fC and 5-caC bases paired with a guanine and replaces them with regular cytosine. The question arises whether active modification of 5-mC residues and their subsequent elimination could affect the genomic DNA stability. Here, we generated two inducible cell lines (Ba/F3-EPOR, and UT7) overexpressing wild-type or catalytically inactive human TET2 proteins. Wild-type TET2 induction resulted in an increased level of 5-hmC and a cell cycle defect in S phase associated with higher level of phosphorylated P53, chromosomal and centrosomal abnormalities. Furthermore, in a thymine-DNA glycosylase (Tdg) deficient context, the TET2-mediated increase of 5-hmC induces mutagenesis characterized by GC>AT transitions in CpG context suggesting a mutagenic potential of 5-hmC metabolites. Altogether, these data suggest that TET2 activity and the levels of 5-hmC and its derivatives should be tightly controlled to avoid genetic and chromosomal instabilities. Moreover, TET2-mediated active demethylation might be a very dangerous process if used to entirely demethylate the genome and might rather be used only at specific loci., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Anti-TNF treatment is effective for Crohn's disease (CD); however, some patients did not achieve remission with these drugs., Aims: To evaluate the short-term effectiveness of a second anti-TNF in CD patients who did not achieve remission with the first one and to assess its durability., Methods: Patients who did not achieve remission with their first anti-TNF were included. The short-term response of the second anti-TNF was assessed, the long-term response was evaluated in patients who achieved remission (Kaplan-Meier). Cox-regression was performed to identify predictors of loss of efficacy., Results: In all, 118 CD patients received a second anti-TNF after primary failure of the first. The first anti-TNF was discontinued because of non-response in 54% of patients and partial response in 46%. Fifty-one percent of patients achieved remission in the short-term. The probability of remission was lower in patients for whom the drug indication was perianal disease (OR=0.3, 95% CI=0.1-0.7, P=0.005). The dose was increased in 33% of patients, and 37% achieved/regained remission. The probability of maintaining remission was 76%, 68% and 64% at 12, 18 and 24 months, respectively., Conclusions: Approximately half of the patients achieved remission with a second anti-TNF after primary failure of the first, this strategy was less effective in patients with perianal disease., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Identifying feasible therapeutic interventions is crucial for ameliorating the intellectual disability and other afflictions of fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism. Hippocampal glycogen synthase kinase-3 (GSK3) is hyperactive in the mouse model of FXS (FX mice), and hyperactive GSK3 promotes locomotor hyperactivity and audiogenic seizure susceptibility in FX mice, raising the possibility that specific GSK3 inhibitors may improve cognitive processes., Methods: We tested if specific GSK3 inhibitors improve deficits in N-methyl-D-aspartate receptor-dependent long-term potentiation at medial perforant path synapses onto dentate granule cells and dentate gyrus-dependent cognitive behavioral tasks., Results: GSK3 inhibitors completely rescued deficits in long-term potentiation at medial perforant path-dentate granule cells synapses in FX mice. Furthermore, synaptosomes from the dentate gyrus of FX mice displayed decreased inhibitory serine-phosphorylation of GSK3β compared with wild-type littermates. The potential therapeutic utility of GSK3 inhibitors was further tested on dentate gyrus-dependent cognitive behaviors. In vivo administration of GSK3 inhibitors completely reversed impairments in several cognitive tasks in FX mice, including novel object detection, coordinate and categorical spatial processing, and temporal ordering for visual objects., Conclusions: These findings establish that synaptic plasticity and cognitive deficits in FX mice can be improved by intervention with inhibitors of GSK3, which may prove therapeutically beneficial in FXS., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Invasive pneumococcal disease (IPD) is a serious problem in some risk groups: patients with stage 4 and 5 chronic kidney disease, stage 3 CKD undergoing immunosuppressive treatment, nephrotic syndrome or diabetes. These individuals are more susceptible to infections and more prone to suffering more severe and worsening symptoms. Vaccination is one of the strategies for preventing IPD, although vaccination coverage in this group at present is lower than desired. Currently, there are two vaccinations for adults. The polysaccharide vaccine (PPSV23), used for decades in patients over the age of 2, includes most serotypes (23), but it does not generate immune memory, causing the immune tolerance phenomenon and it does not act on nasopharyngeal colonisation. The conjugate vaccine (VNC13) can be used from infancy until adulthood (advice in patients over 18 years old received approval from the European Medicines Agency in July 2013) and generates a more powerful immune response than PPSV23 against the majority of the 13 serotypes that it includes. The 16 scientific societies most directly associated with the groups at risk of IPD have discussed and drafted a series of vaccination recommendations based on scientific evidence related to pneumococcal vaccination in adults with underlying conditions and pathologies, which are the subject of the document &ldquo;, Consensus: Pneumococcal vaccination in adults with underlying pathology&rdquo;. This text sets out the vaccination recommendations for the chronic kidney disease population.

Interpretation and relevance of basic RGB colors in Digital Image-Based Colorimetry have been treated in this paper. The studies were carried out using the chromogenic model formed by the reaction between Ca(II) ions and glyoxal bis(2-hydroxyanil). It produced orange-red colored solutions in alkaline media. Individual basic color data (RGB) and also the total intensity of colors, I(tot), were the original variables treated by Factorial Analysis. Te evaluation evidenced that the highest variance of the system and the highest analytical sensitivity were associated to the G color. However, after the study by Fourier transform the basic R color was recognized as an important feature in the information. It was manifested as an intrinsic characteristic that appeared differentiated in terms of low frequency in Fourier transform. The Principal Components Analysis study showed that the variance of the system could be mostly retained in the first principal component, but was dependent on all basic colors. The colored complex was also applied and validated as a Digital Image Colorimetric method for the determination of Ca(II) ions. RGB intensities were linearly correlated with Ca(II) in the range 0.2-2.0 mg L(-1). In the best conditions, using green color, a simple and reliable method for Ca determination could be developed. Its detection limit was established (criterion 3s) as 0.07 mg L(-1). And the reproducibility was lower than 6%, for 1.0 mg L(-1) Ca. Other chromatic parameters were evaluated as dependent calibration variables. Their representativeness, variance and sensitivity were discussed in order to select the best analytical variable. The potentiality of the procedure as a field and ready-to-use method, susceptible to be applied 'in situ' with a minimum of experimental needs, was probed. Applications of the analysis of Ca in different real water samples were carried out. Water of the city net, mineral bottled, and natural-river were analyzed and results were compared and evaluated statistically. The validity was assessed by the alternative techniques of flame atomic absorption spectroscopy and titrimetry. Differences were appreciated but they were consistent with the applied methods., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A cohort of MDS patients was examined for mutations affecting 4 splice genes (SF3B1, SRSF2, ZRSR2, and U2AF35) and evaluated in the context of clinical and molecular markers. Splice gene mutations were detected in 95 of 221 patients. These mutations were mutually exclusive and less likely to occur in patients with complex cytogenetics or TP53 mutations. SF3B1(mut) patients presented with lower hemoglobin levels, increased WBC and platelet counts, and were more likely to have DNMT3A mutations. SRSF2(mut) patients clustered in RAEB-1 and RAEB-2 subtypes and exhibited pronounced thrombocytopenias. ZRSR2(mut) patients clustered in International Prognostic Scoring System intermediate-1 and intermediate-2 risk groups, had higher percentages of bone marrow blasts, and more often displayed isolated neutropenias. SRSF2 and ZRSR2 mutations were more common in TET2(mut) patients. U2AF35(mut) patients had an increased prevalence of chromosome 20 deletions and ASXL1 mutations. Multivariate analysis revealed an inferior overall survival and a higher AML transformation rate for the genotype ZRSR2(mut)/TET2(wt) (overall survival: hazard ratio = 3.3; 95% CI, 1.4-7.7; P = .006; AML transformation: hazard ratio = 3.6; 95% CI, 2-4.2; P = .026). Our results demonstrate that splice gene mutations are among the most frequent molecular aberrations in myelodysplastic syndrome, define distinct clinical phenotypes, and show preferential associations with mutations targeting transcriptional regulation.

Oncogenic pathways underlying in the development of myelodysplastic syndromes (MDS) remain poorly characterized, but mutations of the ten-eleven translocation 2 (TET2) gene are frequently observed. In the present work, we evaluated the prognostic impact of TET2 mutations in MDS. Frameshift, nonsense, missense mutations, or defects in gene structure were identified in 22 (22.9%) of 96 patients (95% confidence interval [CI], 14.5-31.3 patients). Mutated and unmutated patients did not significantly differ in initial clinical or hematologic parameters. The 5-year OS was 76.9% (95% CI, 49.2%-91.3%) in mutated versus 18.3% (95% CI, 4.2%-41.1%) in unmutated patients (P = .005). The 3-year leukemia-free survival was 89.3% (95% CI, 63.1%-97.0%) in mutated versus 63.7% (95% CI, 48.2%-75.4%) in unmutated patients (P = .035). In univariate analysis (Cox proportional hazard model), the absence of TET2 mutation was associated with a 4.1-fold (95% CI, 1.4-12.0-fold) increased risk of death (P = .009). In multivariate analysis adjusted for age, International Prognostic Scoring System, and transfusion requirement, the presence of TET2 mutation remained an independent factor of favorable prognosis (hazard ratio, 5.2; 95% CI, 1.6-16.3; P = .005). These results indicate that TET2 mutations observed in approximately 20% of patients, irrespective of the World Health Organization or French-American-British subtype, represent a molecular marker for good prognosis in MDS.

Background: The overall situation in Guatemala, Central America, regarding programs caring for women's reproductive health has been lagging behind for some decades. Since the year 2000, 56% of Guatemalan families have lived below the poverty line. Guatemala has one of the highest fertility rates (lifetime births per woman) in Latin America and the Caribbean countries, comparable to those observed in less developed countries in Africa. Considering the lack of sex education, poor access to effective contraceptive methods and issues of unwanted pregnancy, Guatemalan women engage in illegal and unsafe abortions, which often causes harm and sometimes death. A key strategy designed to improve women's health is through free and informed access to contraceptive methods that are effective and accepted by Guatemalan women., Study Design: From July 1, 2003, to December 31, 2006, specially hired trained facilitators visited 22 public hospitals for 1 week to train corresponding physician staff in postabortion counseling, enabling them to assist patients to select and use an effective contraceptive method. To monitor the progress achieved, the trained facilitators returned 4 weeks later. The main purpose of the training was to focus in strengthening the understanding and technical capacity of the hospital staff to implement postabortion contraceptive counseling and to enable women to obtain an effective contraceptive method prior to hospital discharge., Results: Out of 22 hospitals, 21 managed to improve their record for counseling patients admitted for postabortion complications, from 31% to 96%. Furthermore, the percentage of women being discharged from the hospital with an effective contraceptive method rose from 20% to 64% from 2003 to 2006., Conclusion: The successful results obtained during this study to meet postabortion demands by Guatemalan women point out to the urgent need for the government to expand this initiative within the national health system, including health centers nationwide. This is one of the worldwide recommendations previously made by the World Health Organization.

Oncogenic activation of tyrosine kinase signaling pathway is recurrent in human leukemia. To gain insight into the oncogenic process leading to acute megakaryoblastic leukemia (AMKL), we performed sequence analyses of a subset of oncogenes known to be activated in human myeloid and myeloproliferative disorders. In a series of human AMKL samples from both Down syndrome and non-Down syndrome patients, mutations were identified within KIT, FLT3, JAK2, JAK3, and MPL genes, with a higher frequency in DS than in non-DS patients. The novel mutations were analyzed using BaF3 cells, showing that JAK3 mutations were activating mutations. Finally, we report a novel constitutively active MPL mutant, MPLT487A, observed in a non-Down syndrome childhood AMKL that induces a myeloproliferative disease in mouse bone marrow transplantation assay.

The sympathetic nervous system has great influence on cardiovascular physiology, and the importance of cardiac innervation abnormalities in the physiopathology of various cardiac diseases has been emphasized. Cardiac neurotransmission imaging with single-photon emission computed tomography (SPECT) allows in vivo assessment of the myocardial nervous system. At present, the most commonly used SPECT tracer to assess cardiac neurotransmission is metaiodobenzylguanidine labelled with iodine-123 ((123)I-MIBG). In patients with heart transplantation, ischemic heart disease, dysautonomias and drug-induced cardiotoxicity, assessment of neuronal function can help characterise the disease and improve the prognostic stratification. Cardiac (123)I-MIBG scintigraphy allows autonomic neuropathy to be detected in the early stages of diabetes mellitus. In patients with heart failure, the assessment of cardiac sympathetic activity has important prognostic implications. Future directions in cardiac sympathetic neurotransmission include the development of new tracers, targeting of second-messenger molecules and early assessment of cardiac neurotransmission in genetically predisposed subjects for prevention of heart failure.

The t(5;14)(q35;q32) chromosomal translocation is specifically observed in up to 20% of childhood T-cell acute lymphoblastic leukemia (T-ALL). It affects the BCL11B/CTIP2 locus on chromosome 14 and the RANBP17-TLX3/HOX11L2 region on chromosome 5. It leads to ectopic activation of TLX3/HOX11L2. To investigate the reasons of the association between t(5;14) and T-ALL, we isolated the translocation breakpoints in 8 t(5;14) patients. Sequence analyses did not involve recombinase activity in the genesis of the translocation. We used DNAse1 hypersensitive experiments to locate transcriptional regulatory elements downstream of BCL11B. By transient transfection experiments, 2 of the 6 regions demonstrated cis-activation properties in T cells and were also effective on the TLX3 promoter. Our data indicate that the basis of the specific association between t(5;14) and T-ALL lies on the juxtaposition of TLX3 to long-range cis-activating regions active during T-cell differentiation.

Subtle variation in the expression or function of a small group of transcription factors can drive leukemogenesis. The CEBPA protein is known to regulate the balance between cell proliferation and differentiation during early hematopoietic development and myeloid differentiation. In human myeloid leukemia, CEBPA is frequently inactivated by mutation and indirect and posttranslational mechanisms, in keeping with tumor suppressor properties. We report that CEBPA is activated by juxtaposition to the immunoglobulin gene enhancer upon its rearrangement with the immunoglobulin heavy-chain locus in precursor B-cell acute lymphoblastic leukemia harboring t(14;19)(q32;q13). Overexpression of apparently normal CEBPA RNA or protein was observed in 6 patients. These data indicate that CEBPA may exhibit oncogenic as well as tumor suppressor properties in human leukemogenesis.

Vegetable oil with elevated saturated fatty acid content may be useful for producing solid fat without hydrogenation or transesterification. Under the nutritional point of view stearic acid is preferred to other saturated fatty acids because of its neutral effect on serum cholesterol lipoproteins. Selection of a very high stearic acid sunflower (Helianthus annuus L.) line (CAS-14), with up to a 37.3% of stearic acid in the seed oil, and the relationship between the expression of this character and the growth temperature are presented. The mutant was selected from the M(2) progeny of 3000 mutagenized seeds (4 mM sodium azide mutagenesis treatment) by analysing the fatty acid composition of half-seed by gas liquid chromatography. In order to genetically fix the mutant character, plants were grown at high day/night temperatures during seed formation. We found that temperatures higher than 30/20 degrees C are required for good expression of the phenotype, the maximum stearic acid content being obtained at 39/24 degrees C. This behaviour is totally opposed to that observed in normal and previously isolated high-stearic acid sunflower lines that contain more stearic acid at low temperature. Thus, a new type of temperature regulation on the stearate desaturation must occur. This line is the sunflower mutant with the highest stearic acid content reported so far.

A novel class of conserved transcription factors has been identified from the molecular cloning of AF10, the gene involved in the t(10;11)(p12;q23) translocation of acute myeloid leukemias. AF10 encodes a 109-kD protein of 1,027 amino acids and contains an N-terminal zinc finger region and a C-terminal leucine zipper. These structures have been found to be conserved in sequence and position in three other proteins, AF17, BR140, and a previously unrecognized Caenorhabditis elegans gene, provisionally named CEZF. The overall structure, level of sequence conservation, and expression pattern suggest that these genes encode a new class of transcription factors, some of which are targets for chromosomal translocation in acute leukemia.

We have recently shown that permeabilization of the inner mitochondrial membrane by calcium plus prooxidants is associated with oxidation of protein thiols forming cross-linked protein aggregates [Fagian, M. M., Pereira da Silva, L., Martins, I. S. and Vercesi, A. E. (1990) J. Biol. Chem. 265, 19955-19960]. In this study we show that mitochondria could regenerate and sustain a membrane potential (delta psi) comparable to the control experiment after the protein aggregates were cleaved by dithiothreitol. The addition of ethylene glycol bis(beta-aminoethyl ether) N,N'-tetraacetic acid, which removes Ca2+ but does not eliminate the protein aggregates, caused an incomplete and nonsustainable recovery of delta psi. Exogenous catalase prevented the disruption of membrane potential and decreased the production of membrane protein aggregates when mitochondria were incubated in the presence of Ca2+ alone or Ca2+ plus a prooxidant. This strongly indicates that H2O2 and possibly other H2O2-derived reactive oxygen species are involved in the mechanism of membrane protein aggregates production that may result in the process of membrane pore formation.

We investigated the clinical, electrocardiographic and hemodynamic features and the prognostic implications of early spontaneous angina in 31 consecutive patients after acute myocardial infarction. Re-elevation of ST segments in the area of infarction occurred during angina and during reinfarction in all but one patient. Depression of ST segments, when present during pain, involved the same leads as in the acute infarction. Blood pressure and double product tended to increase during pain in 23 patients. The magnitude of this change, however, often varied from crisis to crisis and there were no increases in these parameters in one or more attacks in 15 patients. Sublingual nitroglycerin, 1.0 mg, failed to relieve one or all anginal episodes in 17 of the 28 patients in whom it was given. In-hospital mortality rate was 10% (3/31) and always followed reinfarction. In-hospital reinfarction rate was 16% (5/31) and followed a larger number of anginal crises (7.2 +/- 1.3 vs 3.0 +/- 2.1, P less than 0.001) and a higher incidence of transient hypotensive episodes than in the rest of patients (3/5 vs 3/26). Three additional patients died after discharge. Of the remaining 25 patients and during a follow-up of 26 months (16-34) only one developed reinfarction. Early resting angina after a transmural infarction is almost invariably associated with ECG evidence of ischemia in the leads overlying the infarcted zone. The inconsistent changes in blood pressure and heart rate during pain render these hemodynamic changes an unlikely cause of this form of angina. While postinfarction angina did not carry a grave short- or long-term prognosis, patients with recurrent crises demonstrated as high a risk of reinfarction and death as those with spontaneous hypotension.

This communication describes experiments showing that safranine, at the concentrations usually employed as a probe of mitochondrial membrane potential, causes significant undesirable side effects on Ca2+ transport by liver mitochondria. The major observations are: (i) safranine potentiates the spontaneous Ca2+ release from liver mitochondria induced by phosphate or acetoacetate. This is paralelled by potentiation of the release of state-4 respiration and of the rate of mitochondrial swelling, indicating a generalized effect of the dye on the mitochondrial membrane; (ii) the efflux of mitochondrial Ca2+ stimulated by hydroperoxide is irreversible in the presence of safranine even if membrane stabilizers such as Mg2+ and ATP are present. It is concluded that the use of safranine to monitor the changes in membrane potential during Ca2+ transport by mitochondria should be avoided or special care be taken.

A healthy 18-year-old man was admitted to our unit two hours after a suicidal ingestion of 2 gm of verapamil. There was mild hypotension, depression of the sinus node, atrioventricular dissociation, changes of repolarization, and first-degree intranodal atrioventricular block (the His bundle electrogram revealed an atrio-His [A-H] interval of 155 msec). Twenty-four hours after ingestion, the patient was well, and the electrocardiogram was completely normal. This case gave us a good opporturnity to study the electrocardiologic effects of a huge oral dose of verapamil on a healthy young heart.

PSL(p55) is a nuclear 55kD antigen present in various mammalian cell systems, which has been first identified by use of human autoimmune antibodies (Barque et al. 1983, EMBO J. 2, 743). It has been shown to be associated with interphase chromatine and to be synthesized in during the S phase of the cell cycle. In this work, we have analysed the status of PSL in promyelocytic HL-60 human cells in exponential or stationary growth, or undergoing granulocytic differentiation in presence of Retinoic acid. By use of 2-dimensional electrophoresis, PSL was found to be composed of two acidic proteins designated p55A and p55B. Unexpectedly, estimated 10-20 fold higher amounts of each species were found in cells treated for 5 days with 10(-6)M Retinoic acid, than in asynchronously growing cells or resting cells. Moreover, the p55A protein was phosphorylated during the process. On the basis of these results, PSL appears to be involved in some steps of the granulocytic differentiation process.