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ABSTRACT Introduction and objectives: Geographical and organizational differences between different autonomous communities (AC) can generate differences in care for ST-segment elevation myocardial infarction (STEMI). A total of 17 heart attack code programs have been compared in terms of incidence rate, clinical characteristics, reperfusion therapy, delay to reperfusion, and 30-day mortality. Methods: National prospective observational study (83 centers included in 17 infarction networks). The recruitment period was 3 months (April 1 to June 30, 2019) with clinical follow-up at 30 days. Results: 4366 patients with STEMI were included. The incidence rate was variable between different AC (P < .0001), as was gender (P = .003) and the prevalence of cardiovascular risk factors (P < .0001). Reperfusion treatment was primary angioplasty (range 77.5%-97.8%), fibrinolysis (range 0%-12.9%) or no treatment (range 2.2%- 13.5%). The analysis of the delay to reperfusion showed significant differences (P < .001) for all the intervals analyzed. There were significant differences in 30-days mortality that disappeared after adjusting for clinical and healthcare network characteristics. Conclusions: Large differences in STEMI care have been detected between the different AC, in terms of incidence rate, clinical characteristics, reperfusion treatment, delay until reperfusion, and 30-day mortality. The differences in mortality disappeared after adjusting for the characteristics of the patient and the care network.

Objectives To estimate the readiness of Spanish National Health Service (NHS) hospitals to provide chimeric antigen receptor T cell (CAR-T), and to identify and quantify the different resources needed to provide CAR-T considering three scenarios defined by 10, 25 and 50 patients per centre per year.Design Targeted literature review and quantitative study using a questionnaire and telephone interviews. An algorithm was created to determine hospitals’ readiness based on their capacity and capability. All the requirements for quantification were assessed and validated by the steering committee, formed by members of the Spanish Group of Haematopoietic Transplantation and Cell Therapy. A weighting system (from 0 to 1) was established for capability quantification. For resources quantification, a scoring system was established, with 0 points representing the minimum and 3 points the maximum of additional resources that a hospital indicated necessary.Setting 40 Spanish hospital centres that perform allogeneic haematopoietic stem cell transplantation were invited to complete the questionnaire for capacity quantification, 28 of which provided valid responses. Nine hospitals participated in the interviews for resource quantification, eight of which had previously been designated by the Ministry of Health (MoH) to provide CAR-T.Outcome measure Current capacity of NHS Spanish sites to administer CAR-T under different theoretical scenarios with varying numbers of procedures, and the potential healthcare resources that would be needed to realise the theoretical capacity requirements.Results Four hospitals were optimally ready, 17 were somewhat ready and 7 were not ready. The actual extrapolated capacity of the currently designated MoH CAR-T sites would allow treatment of approximately 250 patients per year. Regarding healthcare resource needs, the numbers of haematologists, nurses and beds were the most important limiting factors, and those requiring further growth as patient numbers increased.Conclusions Increasing the number of CAR-T-qualified centres and/or increasing resources in the current designated sites are two potential strategies that should be considered to treat CAR-T-eligible patients in Spain.

ABSTRACT Hypertension is the most prevalent cardiovascular risk factor. Despite pharmacological treatment, a high percentage of patients do not achieve an adequate blood pressure control. Renal sympathetic denervation is a minimally invasive intervention for the management of hypertension involving the interruption of the renal artery sympathetic nervous system using a catheter-based approach. The early studies showed promising results, but the controversial results coming from the SYMPLICITY HTN-3 trial sent this technique into oblivion. Over the last 3 years, new clinical trials have appeared including new devices used in different populations, which definitively proves the effectiveness of renal sympathetic denervation. This joint position statement from the Spanish Society of Hypertension-Spanish League for Combating High Blood Pressure (SEH-LELHA), and the Interventional Cardiology Association of the Spanish Society of Cardiology (ACI-SEC) reviews the evidence available on the efficacy and safety profile of renal sympathetic denervation for the management of hypertension. Based on the results of clinical trials, recommendations have been established on what patients may be eligible for renal sympathetic denervation and under what circumstances.

ObjectiveTo assess the clinical outcome (death and/or Intensive Care Unit (ICU) admission) based on the time from hospital admission to the administration of anakinra and the possible usefulness of a "simplified" SCOPE score to stratify the risk of worse prognosis in our cohort of patients with moderate/severe SARS-CoV-2 pneumonia, both vaccinated and unvaccinated, that received anakinra and corticosteroids. In addition, the clinical, analytical, and imaging characteristics of patients at admission are described.MethodsRetrospective cohort study of 312 patients admitted to Hospital Clínico San Cecilio in Granada for moderate/severe pneumonia caused by SARS-CoV-2 that received anakinra and corticosteroids between March 2020 and January 2022. Clinical and analytical data were collected as well as the patient outcome at 30 and 60 days after admission. Three treatment groups were established according to the time from hospital admission to administration of anakinra: early (1st-2nd day), intermediate (3rd-5th day), and late (after the 5th day).ResultsThe median age was 67.4 years (IQR 22-97 years) and 204 (65.4%) were male. The most common comorbidity was hypertension (58%). The median time from the start of symptoms to anakinra administration was 6 days (IQR 5-10) and the SaFi (SaO2/FiO2) was 228 (IQR 71-471). The cure rate was higher in the early-onset anakinra group versus the late-onset group (73% vs 56.6%). The latter had a higher percentage of deaths (27.4%) and a greater number of patients remained hospitalized for a month (16%). On admission, the patients had elevated C-reactive protein (CRP), ferritin, and D-dimer values and decreased total lymphocytes. Analytical improvement was observed at both 72 hours and one month after treatment. 42 (13.5%) required ICU admission, and 23 (7.3%) orotracheal intubation. At 60 days, 221 (70.8%) were discharged, 87 (27.8%) had died and 4 (1.4%) remained hospitalized. The mean dose of anakinra was 1000 mg (100-2600 mg) with differences found between the dose administered and the clinical outcome. There were no differences in the primary outcome based on vaccination. A simplified SCOPE score at the start of anakinra administration was lower in patients with better clinical evolution.ConclusionsEarly treatment with anakinra and corticosteroids was associated with a better outcome regardless of vaccination status. A simplified SCOPE was found to be a good prognostic tool.

ABSTRACT Over the last two decades, several key advances have been made in the field of interventional cardiology including new techniques and treatments, organizational changes such as the management of acute myocardial infarction, and the arrival of satellite catheterization laboratories. All these advances require the updating of the requirements and equipment that are needed in an interventional cardiology unit. This consensus document by the Interventional Cardiology Association of the Spanish Society of Cardiology, the Ischemic Heart Disease and Acute Cardiac Care Association of the Spanish Society of Cardiology and the Spanish Association of Nursing in Cardiology which describes the recommendations that should be followed by percutaneous coronary intervention capable hospitals or centers intend to build interventional cardiology units. It also describes the requirements for provision, qualification of professionals, technological and material resource allocation, and aspects related to supervised catheterization laboratories and structural heart disease programs.

Abstract Alterations in brain cholesterol homeostasis in midlife are correlated with a higher risk of developing Alzheimer’s disease (AD). However, global cholesterol-lowering therapies have yielded mixed results when it comes to slowing down or preventing cognitive decline in AD. We used the transgenic mouse model Cyp27Tg, with systemically high levels of 27-hydroxycholesterol (27-OH) to examine long-term potentiation (LTP) in the hippocampal CA1 region, combined with dendritic spine reconstruction of CA1 pyramidal neurons to detect morphological and functional synaptic alterations induced by 27-OH high levels. Our results show that elevated 27-OH levels lead to enhanced LTP in the Schaffer collateral-CA1 synapses. This increase is correlated with abnormally large dendritic spines in the stratum radiatum. Using immunohistochemistry for synaptopodin (actin-binding protein involved in the recruitment of the spine apparatus), we found a significantly higher density of synaptopodin-positive puncta in CA1 in Cyp27Tg mice. We hypothesize that high 27-OH levels alter synaptic potentiation and could lead to dysfunction of fine-tuned processing of information in hippocampal circuits resulting in cognitive impairment. We suggest that these alterations could be detrimental for synaptic function and cognition later in life, representing a potential mechanism by which hypercholesterolemia could lead to alterations in memory function in neurodegenerative diseases.

ABSTRACT Introduction and objectives: The COVID-19 epidemic and the declaration of the state of alarm have led to a decrease in healthcare activity in interventional cardiology units. The objective of this study is to quantify these changes in activity, with special interest in the treatment of patients with ST-segment elevation myocardial infarction (STEMI). Methods: A telematic survey of 81 centers involved in STEMI networks in the 17 autonomous communities of Spain. Information was collected on diagnostic activity, percutaneous coronary intervention (PCI), structural interventions, and PCI in STEMI on changes in the organization of STEMI networks, and on the prevalence of COVID-19 among interventional cardiologists. Data was compared for the week of February 24 through March 1 (before the outbreak) and for the week of March 16 through March 22 (during the outbreak). Results: Response has been obtained from 73 centers (90%). A very significant decrease in the number of diagnostic procedures (─56%), PCI (─48%), structural interventions (─81%) and PCI in STEMI (─40%) has been observed. A slight increase in the use of pharmacological thrombolysis has been reported, although primary angioplasty remains the leading reperfusion strategy. Up to 5% of interventional cardiologists (17) had COVID-19. Conclusions: An important reduction in the activity in interventional cardiology has been observed during the COVID-19 epidemic. Likewise, a great decrease has been detected in the number of patients treated in the STEMI networks, with the risk of increased morbidity and mortality that this represents. Scientific societies and health authorities have to promote that patients presenting STEMI compatible symptoms proceed with no delay to access the health system to receive reperfusion treatment in an appropriate way.

ABSTRACT Introduction and objectives: ST-segment elevation myocardial infarction (STEMI) regional networks pose great organizational differences that may compromise their results. The Working Group on Hemodynamics and Interventional Cardiology has carried out a survey among its members on the level of satisfaction and the state of primary angioplasty programs in Spain. Methods: On-line, open and anonymous survey, among the Hemodynamics and Interventional Cardiology Working Group members conducted between May 22 and June 5, 2018 on the necessities of the aforementioned programs and the degree of satisfaction of the professionals involved. Results: Answers were obtained from 172 professionals with representation from 75 centers and 17 autonomous communities. The number of angioplasties performed in the STEMI setting per year and per center was 259 ± 110. The degree of satisfaction of the professionals with the application of the Infarction Code and the degree of personal satisfaction scored 7.2 ± 2.2 and 7.2 ± 2.4 points out of 10, respectively, although with significant regional differences. The main areas of concern detected were logistics issues, insufficient paycheck compensations and lack of rest. The 55% were inclined to leave their on-call duties when possible. Conclusions: The survey has revealed a high degree of satisfaction by the professionals involved in STEMI treatment, although with notable differences among different autonomous communities and has allowed detecting logistical, structural and paycheck disturbances that can put primary angioplasty programs in situations of vulnerability.

Introduction and objectivesPatients with type 2 diabetes (T2D) and stable coronary artery disease (CAD) previously revascularized with percutaneous coronary intervention (PCI) are at high risk of recurrent ischemic events. We aimed to provide real-world insights into the clinical characteristics and management of this clinical population, excluding patients with a history of myocardial infarction (MI) or stroke, using Natural Language Processing (NLP) technology.MethodsThis is a multicenter, retrospective study based on the secondary use of 2014-2018 real-world data captured in the Electronic Health Records (EHRs) of 1,579 patients (0.72% of the T2D population analyzed; n = 217,632 patients) from 12 representative hospitals in Spain. To access the unstructured clinical information in EHRs, we used the EHRead® technology, based on NLP and machine learning. Major adverse cardiovascular events (MACE) were considered: MI, ischemic stroke, urgent coronary revascularization, and hospitalization due to unstable angina. The association between MACE rates and the variables included in this study was evaluated following univariate and multivariate approaches.ResultsMost patients were male (72.13%), with a mean age of 70.5±10 years. Regarding T2D, most patients were non-insulin-dependent T2D (61.75%) with high prevalence of comorbidities. The median (Q1-Q3) duration of follow-up was 1.2 (0.3-4.5) years. Overall, 35.66% of patients suffered from at least one MACE during follow up. Using a Cox Proportional Hazards regression model analysis, several independent factors were associated with MACE during follow up: CAD duration (p < 0.001), COPD/Asthma (p = 0.021), heart valve disease (p = 0.031), multivessel disease (p = 0.005), insulin treatment (p < 0.001), statins treatment (p < 0.001), and clopidogrel treatment (p = 0.039).ConclusionsOur results showed high rates of MACE in a large real-world series of PCI-revascularized patients with T2D and CAD with no history of MI or stroke. These data represent a potential opportunity to improve the clinical management of these patients.

ABSTRACT Primary percutaneous coronary intervention (pPCI) is the best modality of reperfusion in ST segment elevation in acute myocardial infarction (STEMI). Its application requires networked assistance systems whose implementation requires significant organizational and logistical changes. In comparison with other scenarios of urgent action, a series of aspects are specific to the pPCI programs. They require immediate, clearly pre-established strategies, carried out by highly skilled professionals who attend to a high volume of highly complex patients. The lack of homogeneity in the creation and development of reperfusion programs in Spain has led to great differences in their implementation. If the pPCI programs are not carried out under adequate conditions, their sustainability can be complex. The present document, agreed between different scientific societies, aims to analyze the current situation in Spain of the network care programs for STEMI, identify their limitations and deficiencies, assess their vulnerability and establish a series of recommendations to ensure their sustainability.

Introduction: Spinal cord injury (SCI) is a devastating event with physical, psychological and socioeconomic implications. Morphophysiological changes are observed in the tissue close to the injury, which allow determining the functional recovery of the medullary segment and the effector organs that depend on the injured axonal tracts. Objective: To describe the most relevant sequential biochemical events of glial cells response after SCI. Materials and methods: A search of scientific publications released in the past 18 years was carried out in PubMed and Science Direct databases, with the terms spinal cord injury (SCI), SCI pathophysiology, SCI inflammation, microglia in SCI, glial scar and chondroitin sulfate proteoglycans (CSPG). Results: The pathophysiological processes resulting from SCI are determinant for the neurological recovery of patients. Activation of glial cells plays an important role in promoting bioactive molecules and the formation of physical barriers that inhibit neural regeneration. Conclusion: Knowledge of neurobiological changes after SCI allows a greater understanding of the pathophysiology and favors the search for new therapeutic alternatives that limit the progression of the primary injury and minimize secondary damage, responsible for neurological dysfunction.

Sixty-four year-old male patient with ST-segment elevation acute myocardial infarction due to occlusion of his anterior descending artery who received one 3 × 18 mm direct bioresorbable vascular scaffold (BVS) (figure 1A-C). Then he received acetylsalicylic acid and atorvastatin. Fifty-two months later he experienced an anterior reinfarction due to the occlusion of the same segment of the anterior descending artery. Thrombo-aspiration with flow recovery (figure 1D-E) was conducted and the optical coherence tomography showed strut remnants almost indistinguishable in the BVS segment. Thrombosis was attributed to a tear in the neoatherosclerotic lipid plaque (figura 1H-I, video of the supplementary data). Figures figura 1G-L show the BVS markers (pound sign) and the presence of the aforementioned torn lipid plaque (asterisk and arrow, respectively). One drug-eluting metallic stent was implanted inside the stent (figura 1F). Figure 1. The primary goal of BVSs is to eliminate the risk of very late thrombosis once the device is gone. In several series of very late thromboses in drug-eluting metallic stents, one of the main causes seen in the optical coherence tomography is the tear of the neoatherosclerotic lipid-laden plaque (26% to 31%). Therefore, we should expect a significant drop in...

Polypharmacy is common among older adults. However, little is known about the composition of polypharmacy: which are the most frequently used drugs, and how much do these drugs contribute to the overall prevalence of polypharmacy.A total of 822,619 Swedes aged ≥75 years was identified from the Total Population Register. Through record-linkage with the Swedish Prescribed Drug Register and the Social Services Register we could analyze concurrent drug use in the entire population (both individuals living in the community and institution) on the 31 December 2013.The prevalence of polypharmacy (≥5 drugs) was 45%. The most frequently used drugs were cardiovascular drugs, analgesics, and psychotropics. By excluding the ten most frequently used drug classes or compounds, the prevalence of polypharmacy was reduced by 69% and 51% respectively. The majority of the users of either one of the 10 most frequently used drugs concurrently used at least 4 other drug classes (66%-85%).Almost half of the individuals aged ≥75 years are exposed to polypharmacy in Sweden. A handful of drugs make a large contribution to the overall prevalence of polypharmacy and the majority of drugs prescribed to persons aged ≥75 years are used in combination with other drugs. This highlights the high use of drugs, and the need to consider other concurrent drug treatments when prescribing for older adults.

BACKGROUND:Use of everolimus-eluting stents (EES) has proven to be clinically effective and safe in patients with ST-segment elevation myocardial infarction but it remains unclear whether it is cost-effective compared to bare-metal stents (BMS) in the long-term. We sought to assess the cost-effectiveness of EES versus BMS based on the 5-year results of the EXAMINATION trial, from a Spanish health service perspective. METHODS:Decision analysis of the use of EES versus BMS was based on the patient-level clinical outcome data of the EXAMINATION trial. The analysis adopted a lifelong time horizon, assuming that long-term survival was independent of the initial treatment strategy after the end of follow-up. Life-expectancy, health-state utility scores and unit costs were extracted from published literature and publicly available sources. Non-parametric bootstrapping was combined with probabilistic sensitivity analysis to co-assess the impact of patient-level variation and parameter uncertainty. The main outcomes were total costs and quality-adjusted life-years. The incremental cost-effectiveness ratio was expressed as cost per quality-adjusted life-years gained. Costs and effects were discounted at 3%. RESULTS:The model predicted an average survival time in patients receiving EES and BMS of 10.52 and 10.38 undiscounted years, respectively. Over the life-long time horizon, the EES strategy was €430 more costly than BMS (€8,305 vs. €7,874), but went along with incremental gains of 0.10 quality-adjusted life-years. This resulted in an average incremental cost-effectiveness ratio over all simulations of €3,948 per quality-adjusted life-years gained and was below a willingness-to-pay threshold of €25,000 per quality-adjusted life-years gained in 86.9% of simulation runs. CONCLUSIONS:Despite higher total costs relative to BMS, EES appeared to be a cost-effective therapy for ST-segment elevation myocardial infarction patients due to their incremental effectiveness. Predicted incremental cost-effectiveness ratios were below generally acceptable threshold values.

Pancreatic ductal adenocarcinoma is an aggressive form of pancreatic cancer and the fourth leading cause of cancer-related death. When possible, curative approaches are based on surgical resection, though not every patient is a candidate for surgery. There are clinical guidelines for the management of these patients that offer different treatment options depending on the clinical and pathologic characteristics. However, the survival rates seen in this kind of patients are still low. The CDSE1 gene is located upstream of NRAS and encodes an RNA-binding protein termed UNR. The aim of this study was to analyze UNR expression and its correlation with outcome in patients with resectable pancreatic ductal adenocarcinoma (PDAC). For this, samples from resectable PDAC patients who underwent duodenopancreatectomy were used to evaluate UNR protein expression by immunohistochemistry using a tissue microarray. Here, we observed that low UNR expression was significantly associated with shorter progression-free survival after surgery (P = 0.010). Moreover, this prognostic marker remained significant after Cox proportional hazards model (P = 0.036). We further studied the role of CDSE1 expression in patient's prognosis using data from public repositories (GEO and TGCA), confirming our results. Interestingly, CDSE1 expression correlated with that of genes characteristic of an immunogenic molecular subtype of pancreatic cancer. Based on these findings, UNR may be considered a potential prognostic biomarker for resectable PDAC and may serve to guide subsequent adjuvant treatment decisions.

Selecting an ideal antithrombotic therapy for elderly patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) can be challenging since they have a higher thromboembolic and bleeding risk than younger patients. The current study aimed to assess the efficacy and safety of triple therapy (TT: oral anticoagulation plus dual antiplatelet therapy: aspirin plus clopidogrel) in patients ≥75 years of age with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI).A prospective multicenter study was conducted from 2003 to 2012 at 6 Spanish teaching hospitals. A cohort study of consecutive patients with AF undergoing PCI and treated with TT or dual antiplatelet therapy (DAPT) was analyzed. All outcomes were evaluated at 1-year of follow-up.Five hundred and eighty-five patients, 289 (49%) of whom were ≥75 years of age (79.6±3.4 years; 33% women) were identified. TT was prescribed in 55.9% of patients at discharge who had a higher thromboembolic risk (CHA2DS2VASc score: 4.23±1.51 vs 3.76±1.40, p = 0.007 and a higher bleeding risk (HAS-BLED ≥3: 88.6% vs 79.2%, p = 0.02) than those on DAPT. Therefore, patients on TT had a lower rate of thromboembolism than those on DAPT (0.6% vs 6.9%, p = 0.004; HR 0.08, 95% CI: 0.01-0.70, p = 0.004). Major bleeding events occurred more frequently in patients on TT than in those on DAPT (11.7% vs 2.4%, p = 0.002; HR 5.2, 95% CI: 1.53-17.57, p = 0.008). The overall mortality rate was similar in both treatment groups (11.9% vs 13.9%, p = 0.38); however, after adjustment for confounding variables, TT was associated with a reduced mortality rate (HR 0.33, 95% CI: 0.12-0.86, p = 0.02).In elderly patients with AF undergoing PCI, the use of TT compared to DAPT was associated with reduced thromboembolism and mortality rates, although a higher rate of major bleeding.

El adenocarcinoma gástrico (CG) en niños es una neoplasia muy rara y agresiva, la incidencia de CG y la infección por H. pylori en el sur occidente colombiano es importante y es un problema de salud pública, con este reporte se pretende dar a conocer los signos y síntomas, características anatomopatológico macroscópico, diagnostico microscópico y la virulencia del H pylori de un paciente de 12 años con cáncer gástrico en la ciudad de Popayán.

Gluten content from barley, rye, wheat and in certain oat varieties, must be avoid in individuals with celiac disease. In most of the Western countries, the level of gluten content in food to be considered as gluten-free products is below 20 parts per million measured by ELISA based on specific anti-gluten peptide antibody. However, in beverages or food suffering complex hydrolytic processes as beers, the relative proportion of reactive peptides for celiac patients and the analytical techniques may differ, because of the diversity of the resulting peptide populations after fermentations. A beer below 20 parts per million of gluten but yet detectable levels of gluten peptides by anti-gliadin 33-mer antibodies (G12 and A1) was analyzed. We identified and characterized the relevant peptides for either antibody recognition or immunoactivity in celiac patients. The beer was fractionated by HPLC. The relative reactivity of the different HPLC fractions to the G12/A1 antibodies correlated to the reactivity of peripheral blood mononuclear cells isolated from 14 celiac individuals. Peptides from representative fractions classified according to the relative reactivity to G12/A1 antibodies were identified by mass spectrometry. The beer peptides containing sequences with similarity to those of previously described G12 and A1 epitopes were synthesized and confirmed significant reactivity for the antibodies. The most reactive peptides for G12/A1 also confirmed the highest immunogenicity by peripheral blood mononuclear cell activation and interferon γ production from celiac patients. We concluded that preparative HPLC combined with anti-gliadin 33-mer G12/A1 antibodies were very sensitive and specific methods to analyze the relevant immunogenic peptides in hydrolyzed gluten.

We studied whether celiac disease (CD) patients produce antibodies against a novel gliadin peptide specifically generated in the duodenum of CD patients by a previously described pattern of CD-specific duodenal proteases. Fingerprinting and ion-trap mass spectrometry of CD-specific duodenal gliadin-degrading protease pattern revealed a new 8-mer gliadin-derived peptide. An ELISA against synthetic deamidated 8-mer peptides (DGP 8-mer) was used to study the presence of IgA anti-DGP 8-mer antibodies in plasma samples from 81 children (31 active CD patients (aCD), 17 CD patients on a gluten-free diet (GFD), 10 healthy controls (C) and 23 patients with other gastrointestinal pathology (GP)) and 101 adults (16 aCD, 12 GFD, 27 C and 46 GP-patients). Deamidation of the 8-mer peptide significantly increased the reactivity of the IgA antibodies from CD patients against the peptide. Significant IgA anti-DGP 8-mer antibodies levels were detected in 93.5% of aCD-, 11.8% of GFD- and 4.3% of GP-patients in children. In adults, antibodies were detected in 81.3% of aCD-patients and 8.3% of GFD-patients while were absent in 100% of C- and GP-patients. Duodenal CD-specific gliadin degrading proteases release an 8-mer gliadin peptide that once deamidated is an antigen for specific IgA antibodies in CD patients which may provide a new accurate diagnostic tool in CD.

We previously described a heterozygous mouse model overexpressing human HA-tagged 24S-hydroxylase (CYP46A1) utilizing a ubiquitous expression vector. In this study, we generated homozygotes of these mice with circulating levels of 24OH 30-60% higher than the heterozygotes. Female homozygous CYP46A1 transgenic mice, aged 15 months, showed an improvement in spatial memory in the Morris water maze test as compared to the wild type mice. The levels of N-Methyl-D-Aspartate receptor 1, phosphorylated-N-Methyl-D-Aspartate receptor 2A, postsynaptic density 95, synapsin-1 and synapthophysin were significantly increased in the hippocampus of the CYP46A1 transgenic mice as compared to the controls. The levels of lanosterol in the brain of the CYP46A1 transgenic mice were significantly increased, consistent with a higher synthesis of cholesterol. Our results are discussed in relation to the hypothesis that the flux in the mevalonate pathway in the brain is of importance in cognitive functions.

A strict gluten-free diet (GFD) is the only currently available therapeutic treatment for patients with celiac disease (CD). Traditionally, treatment with a GFD has excluded wheat, barley and rye, while the presence of oats is a subject of debate. The most-recent research indicates that some cultivars of oats can be a safe part of a GFD. In order to elucidate the toxicity of the prolamins from oat varieties with low, medium, and high CD toxicity, the avenin genes of these varieties were cloned and sequenced, and their expression quantified throughout the grain development. At the protein level, we have accomplished an exhaustive characterization and quantification of avenins by RP-HPLC and an analysis of immunogenicity of peptides present in prolamins of different oat cultivars. Avenin sequences were classified into three different groups, which have homology with S-rich prolamins of Triticeae. Avenin proteins presented a lower proline content than that of wheat gliadin; this may contribute to the low toxicity shown by oat avenins. The expression of avenin genes throughout the development stages has shown a pattern similar to that of prolamins of wheat and barley. RP-HPLC chromatograms showed protein peaks in the alcohol-soluble and reduced-soluble fractions. Therefore, oat grains had both monomeric and polymeric avenins, termed in this paper gliadin- and glutenin-like avenins. We found a direct correlation between the immunogenicity of the different oat varieties and the presence of the specific peptides with a higher/lower potential immunotoxicity. The specific peptides from the oat variety with the highest toxicity have shown a higher potential immunotoxicity. These results suggest that there is wide range of variation of potential immunotoxicity of oat cultivars that could be due to differences in the degree of immunogenicity in their sequences.

BackgroundInflammation may lead to tissue injury. We have studied the modulation of inflammatory milieu-induced tissue injury, as exemplified by the mesothelium. Peritoneal dialysis is complicated by peritonitis episodes that cause loss of mesothelium. Proinflammatory cytokines are increased in the peritoneal cavity during peritonitis episodes. However there is scarce information on the modulation of cell death by combinations of cytokines and on the therapeutic targets to prevent desmesothelization.MethodologyHuman mesothelial cells were cultured from effluents of stable peritoneal dialysis patients and from omentum of non-dialysis patients. Mesothelial cell death was studied in mice with S. aureus peritonitis and in mice injected with tumor necrosis factor alpha and interferon gamma. Tumor necrosis factor alpha and interferon gamma alone do not induce apoptosis in cultured mesothelial cells. By contrast, the cytokine combination increased the rate of apoptosis 2 to 3-fold over control. Cell death was associated with the activation of caspases and a pancaspase inhibitor prevented apoptosis. Specific caspase-8 and caspase-3 inhibitors were similarly effective. Co-incubation with both cytokines also impaired mesothelial wound healing in an in vitro model. However, inhibition of caspases did not improve wound healing and even impaired the long-term recovery from injury. By contrast, a polymeric nanoconjugate Apaf-1 inhibitor protected from apoptosis and allowed wound healing and long-term recovery. The Apaf-1 inhibitor also protected mesothelial cells from inflammation-induced injury in vivo in mice.ConclusionCooperation between tumor necrosis factor alpha and interferon gamma contributes to mesothelial injury and impairs the regenerative capacity of the monolayer. Caspase inhibition attenuates mesothelial cell apoptosis but does not facilitate regeneration. A drug targeting Apaf-1 allows protection from apoptosis as well as regeneration in the course of inflammation-induced tissue injury.

PTEN-induced novel kinase 1 (PINK1) mutations are associated with autosomal recessive parkinsonism. Previous studies have shown that PINK1 influences both mitochondrial function and morphology although it is not clearly established which of these are primary events and which are secondary. Here, we describe a novel mechanism linking mitochondrial dysfunction and alterations in mitochondrial morphology related to PINK1. Cell lines were generated by stably transducing human dopaminergic M17 cells with lentiviral constructs that increased or knocked down PINK1. As in previous studies, PINK1 deficient cells have lower mitochondrial membrane potential and are more sensitive to the toxic effects of mitochondrial complex I inhibitors. We also show that wild-type PINK1, but not recessive mutant or kinase dead versions, protects against rotenone-induced mitochondrial fragmentation whereas PINK1 deficient cells show lower mitochondrial connectivity. Expression of dynamin-related protein 1 (Drp1) exaggerates PINK1 deficiency phenotypes and Drp1 RNAi rescues them. We also show that Drp1 is dephosphorylated in PINK1 deficient cells due to activation of the calcium-dependent phosphatase calcineurin. Accordingly, the calcineurin inhibitor FK506 blocks both Drp1 dephosphorylation and loss of mitochondrial integrity in PINK1 deficient cells but does not fully rescue mitochondrial membrane potential. We propose that alterations in mitochondrial connectivity in this system are secondary to functional effects on mitochondrial membrane potential.

Background and aimsCeliac disease is a permanent intolerance to gluten prolamins from wheat, barley, rye and, in some patients, oats. Partially digested gluten peptides produced in the digestive tract cause inflammation of the small intestine. High throughput, immune-based assays using monoclonal antibodies specific for these immunotoxic peptides would facilitate their detection in food and enable monitoring of their enzymatic detoxification. Two monoclonal antibodies, G12 and A1, were developed against a highly immunotoxic 33-mer peptide. The potential of each antibody for quantifying food toxicity for celiac patients was studied.MethodsEpitope preferences of G12 and A1 antibodies were determined by ELISA with gluten-derived peptide variants of recombinant, synthetic or enzymatic origin.ResultsThe recognition sequences of G12 and A1 antibodies were hexameric and heptameric epitopes, respectively. Although G12 affinity for the 33-mer was superior to A1, the sensitivity for gluten detection was higher for A1. This observation correlated to the higher number of A1 epitopes found in prolamins than G12 epitopes. Activation of T cell from gluten digested by glutenases decreased equivalently to the detection of intact peptides by A1 antibody. Peptide recognition of A1 included gliadin peptides involved in the both the adaptive and innate immunological response in celiac disease.ConclusionsThe sensitivity and epitope preferences of the A1 antibody resulted to be useful to detect gluten relevant peptides to infer the potential toxicity of food for celiac patients as well as to monitor peptide modifications by transglutaminase 2 or glutenases.

Se define como modelo al animal producido y mantenido bajo condiciones controladas de bioterio, que posee claros antecedentes genéticos y microbiológicos comprobables, del cual pueden obtenerse respuestas fragmentarias de significado bológico fiable y reproducible.