Hospital General De Segovia

BACKGROUND: Weaning patients from mechanical ventilation is an important problem in intensive care units. Weaning is usually conducted in an empirical manner, and a standardized approach has not been developed. METHODS: We carried out a prospective, randomized, multicenter study involving 546 patients who had received mechanical ventilation for a mean (+/- SD) of 7.5 +/- 6.1 days and who were considered by their physicians to be ready for weaning. One hundred thirty patients had respiratory distress during a two-hour trial of spontaneous breathing. These patients were randomly assigned to undergo one of four weaning techniques: intermittent mandatory ventilation, in which the ventilator rate was initially set at a mean (+/- SD) of 10.0 +/- 2.2 breaths per minute and then decreased, if possible, at least twice a day, usually by 2 to 4 breaths per minute (29 patients); pressure-support ventilation, in which pressure support was initially set at 18.0 +/- 6.1 cm of water and then reduced, if possible, by 2 to 4 cm of water at least twice a day (37 patients); intermittent trials of spontaneous breathing, conducted two or more times a day if possible (33 patients); or a once-daily trail of spontaneous breathing (31 patients). Standardized protocols were followed for each technique. RESULTS: The median duration of weaning was 5 days for intermittent mandatory ventilation (first quartile, 3 days; third quartile, 11 days), 4 days for pressure-support ventilation (2 and 12 days, respectively), 3 days for intermittent (multiple) trials of spontaneous breathing (2 and 6 days, respectively), and 3 days for a once-daily trial of spontaneous breathing (1 and 6 days, respectively). After adjustment for other covariates, the rate of successful weaning was higher with a once-daily trial of spontaneous breathing than with intermittent mandatory ventilation (rate ratio, 2.83; 95 percent confidence interval, 1.36 to 5.89; P < 0.006) or pressure-support ventilation (rate ratio, 2.05; 95 percent confidence interval, 1.04 to 4.04; P < 0.04). There was no significant difference in the rate of success between once-daily trials and multiple trials of spontaneous breathing. CONCLUSIONS: A once-daily trial of spontaneous breathing led to extubation about three times more quickly than intermittent mandatory ventilation and about twice as quickly as pressure-support ventilation. Multiple daily trials of spontaneous breathing were equally successful.

Adiponectin, also called GBP-28, apM1, AdipoQ and Acrp30, is a novel adipose tIssue-specific protein that has structural homology to collagen VIII and X and complement factor C1q, and that circulates in human plasma at high levels. It is one of the physiologically active polypeptides secreted by adipose tIssue, whose multiple functions have started to be understood in the last few Years.A reduction in adiponectin expression is associated with insulin resistance in some animal models. Administration of adiponectin has been accompanied by a reduction in plasma glucose and an increase in insulin sensitivity. In addition, thiazolidinediones, drugs that enhance insulin sensitivity through stimulation of the peroxisome proliferator-activated receptor-gamma, increase plasma adiponectin and mRNA levels in mice. On the other hand, this adipocyte protein seems to play a protective role in experimental models of vascular injury. In humans, adiponectin levels are inversely related to the degree of adiposity and positively associated with insulin sensitivity both in healthy subjects and in diabetic patients. Plasma adiponectin levels have been reported to be decreased in some insulin-resistant states, such as obesity and type 2 diabetes mellitus, and also in patients with coronary artery disease. On the contrary, chronic renal failure, type 1 diabetes and anorexia nervosa are associated with increased plasma adiponectin levels. Concentrations of plasma adiponectin have been shown to correlate negatively with glucose, insulin, triglyceride levels and body mass index, and positively with high-density lipoprotein-cholesterol levels and insulin-stimulated glucose disposal. Weight loss and therapy with thiazolidinediones increased endogenous adiponectin production in humans. Adiponectin increases insulin sensitivity by increasing tIssue fat oxidation, resulting in reduced circulating fatty acid levels and reduced intracellular triglyceride contents in liver and muscle. This protein also suppresses the expression of adhesion molecules in vascular endothelial cells and cytokine production from macrophages, thus inhibiting the inflammatory processes that occur during the early phases of atherosclerosis. In view of these data, it is possible that hypoadiponectinemia may play a role in the development of atherosclerotic vascular disease. In summary, the ability of adiponectin to increase insulin sensitivity in conjunction with its anti-inflammatory and anti-atherogenic properties have made this novel adipocytokine a promising therapeutic tool for the future, with potential applications in states associated with low plasma adiponectin levels.

Flow cytometry has become a highly valuable method to monitor minimal residual disease (MRD) and evaluate the depth of complete response (CR) in bone marrow (BM) of multiple myeloma (MM) after therapy. However, current flow-MRD has lower sensitivity than molecular methods and lacks standardization. Here we report on a novel next generation flow (NGF) approach for highly sensitive and standardized MRD detection in MM. An optimized 2-tube 8-color antibody panel was constructed in five cycles of design-evaluation-redesign. In addition, a bulk-lysis procedure was established for acquisition of ⩾107 cells/sample, and novel software tools were constructed for automatic plasma cell gating. Multicenter evaluation of 110 follow-up BM from MM patients in very good partial response (VGPR) or CR showed a higher sensitivity for NGF-MRD vs conventional 8-color flow-MRD -MRD-positive rate of 47 vs 34% (P=0.003)-. Thus, 25% of patients classified as MRD-negative by conventional 8-color flow were MRD-positive by NGF, translating into a significantly longer progression-free survival for MRD-negative vs MRD-positive CR patients by NGF (75% progression-free survival not reached vs 7 months; P=0.02). This study establishes EuroFlow-based NGF as a highly sensitive, fully standardized approach for MRD detection in MM which overcomes the major limitations of conventional flow-MRD methods and is ready for implementation in routine diagnostics.

Monoclonal gammopathy of uncertain significance (MGUS) and smoldering multiple myeloma (SMM) are plasma cell disorders with a risk of progression of approximately 1% and 10% per year, respectively. We have previously shown that the proportion of bone marrow (BM) aberrant plasma cells (aPCs) within the BMPC compartment (aPC/BMPC) as assessed by flow cytometry (FC) contributes to differential diagnosis between MGUS and multiple myloma (MM). The goal of the present study was to investigate this parameter as a marker for risk of progression in MGUS (n = 407) and SMM (n = 93). Patients with a marked predominance of aPCs/BMPC (> or = 95%) at diagnosis displayed a significantly higher risk of progression both in MGUS and SMM (P< .001). Multivariate analysis for progression-free survival (PFS) selected the percentage aPC/BMPC (> or = 95%) as the most important independent variable, together with DNA aneuploidy and immunoparesis, for MGUS and SMM, respectively. Using these independent variables, we have identified 3 risk categories in MGUS (PFS at 5 years of 2%, 10%, and 46%, respectively; P< .001) and SMM patients (PFS at 5 years of 4%, 46%, and 72%, respectively; P < .001). Our results show that multiparameter FC evaluation of BMPC at diagnosis is a valuable tool that could help to individualize the follow-up strategy for MGUS and SMM patients.

INTRODUCTION: Sepsis is a leading cause of admission to non-cardiological intensive care units (ICUs) and the second leading cause of death among ICU patients. We present the first extensive dataset on the epidemiology of severe sepsis treated in ICUs in Spain. METHODS: We conducted a prospective, observational, multicentre cohort study, carried out over two 3-month periods in 2002. Our aims were to determine the incidence of severe sepsis among adults in ICUs in a specific area in Spain, to determine the early (48 h) ICU and hospital mortality rates, as well as factors associated with the risk of death. RESULTS: A total of 4,317 patients were admitted and 2,619 patients were eligible for the study; 311 (11.9%) of these presented at least 1 episode of severe sepsis, and 324 (12.4%) episodes of severe sepsis were recorded. The estimated accumulated incidence for the population was 25 cases of severe sepsis attended in ICUs per 100,000 inhabitants per year. The mean logistic organ dysfunction system (LODS) upon admission was 6.3; the mean sepsis-related organ failure assessment (SOFA) score on the first day was 9.6. Two or more organ failures were present at diagnosis in 78.1% of the patients. A microbiological diagnosis of the infection was reached in 209 episodes of sepsis (64.5%) and the most common clinical diagnosis was pneumonia (42.8%). A total of 169 patients (54.3%) died in hospital, 150 (48.2%) of these in the ICU. The mortality in the first 48 h was 14.8%. Factors associated with early death were haematological failure and liver failure at diagnosis, acquisition of the infection prior to ICU admission, and total LODS score on admission. Factors associated with death in the hospital were age, chronic alcohol abuse, increased McCabe score, higher LODS on admission, DeltaSOFA 3-1 (defined as the difference in the total SOFA scores on day 3 and on day 1), and the difference of the area under the curve of the SOFA score throughout the first 15 days. CONCLUSIONS: We found a high incidence of severe sepsis attended in the ICU and high ICU and hospital mortality rates. The high prevalence of multiple organ failure at diagnosis and the high mortality in the first 48 h suggests delays in diagnosis, in initial resuscitation, and/or in initiating appropriate antibiotic treatment.

Adherence levels in Africa have been found to be better than those in the US. However around one out of four ART users fail to achieve optimal adherence, risking drug resistance and negative treatment outcomes. A high demand for 2nd line treatments (currently ten times more expensive than 1st line ART) undermines the sustainability of African ART programs. There is an urgent need to identify context-specific constraints to adherence and implement interventions to address them. We used rapid appraisals (involving mainly qualitative methods) to find out why and when people do not adhere to ART in Uganda, Tanzania and Botswana. Multidisciplinary teams of researchers and local health professionals conducted the studies, involving a total of 54 semi-structured interviews with health workers, 73 semi-structured interviews with ARTusers and other key informants, 34 focus group discussions, and 218 exit interviews with ART users. All the facilities studied in Botswana, Tanzania and Uganda provide ARVs free of charge, but ART users report other related costs (e.g. transport expenditures, registration and user fees at the private health facilities, and lost wages due to long waiting times) as main obstacles to optimal adherence. Side effects and hunger in the initial treatment phase are an added concern. We further found that ART users find it hard to take their drugs when they are among people to whom they have not disclosed their HIV status, such as co-workers and friends. The research teams recommend that (i) health care workers inform patients better about adverse effects; (ii) ART programmes provide transport and food support to patients who are too poor to pay; (iii) recurrent costs to users be reduced by providing three-months, rather than the one-month refills once optimal adherence levels have been achieved; and (iv) pharmacists play an important role in this follow-up care.

Minimal residual disease (MRD) assessment is standard in many hematologic malignancies but is considered investigational in multiple myeloma (MM). We report a prospective analysis of the prognostic importance of MRD detection by multiparameter flow cytometry (MFC) in 295 newly diagnosed MM patients uniformly treated in the GEM2000 protocol VBMCP/VBAD induction plus autologous stem cell transplantation [ASCT]). MRD status by MFC was determined at day 100 after ASCT. Progression-free survival (PFS; median 71 vs 37 months, P < .001) and overall survival (OS; median not reached vs 89 months, P = .002) were longer in patients who were MRD negative versus MRD positive at day 100 after ASCT. Similar prognostic differentiation was seen in 147 patients who achieved immunofixation-negative complete response after ASCT. Moreover, MRD(-) immunofixation-negative (IFx(-)) patients and MRD(-) IFx(+) patients had significantly longer PFS than MRD(+) IFx(-) patients. Multivariate analysis identified MRD status by MFC at day 100 after ASCT as the most important independent prognostic factor for PFS (HR = 3.64, P = .002) and OS (HR = 2.02, P = .02). Our findings demonstrate the clinical importance of MRD evaluation by MFC, and illustrate the need for further refinement of MM re-sponse criteria. This trial is registered at http://clinicaltrials.gov under identifier NCT00560053.

Early response to therapy is one of the most important prognostic factors in acute leukemia. It is hypothesized that early immunophenotypical evaluation may help identify patients at high risk for relapse from those who may remain in complete remission (CR). Using multiparametric flow cytometry, the level of minimal residual disease (MRD) was evaluated in the first bone marrow (BM) in morphologic CR obtained after induction treatment from 126 patients with acute myeloid leukemia (AML) who displayed aberrant phenotypes at diagnosis. Based on MRD level, 4 different risk categories were identified: 8 patients were at very low risk (fewer than 10(-4) cells), and none have relapsed thus far; 37 were at low risk (10(-4) to 10(-3) cells); and 64 were at intermediate risk (fewer than 10(-3) to 10(-2) cells), with 3-year cumulative relapse rates of 14% and 50%, respectively. The remaining 17 patients were in the high-risk group (more than 10(-2) residual aberrant cells) and had a 3-year relapse rate of 84% (P =.0001). MRD level not only influences relapse-free survival but also overall survival (P =.003). The adverse prognostic impact was also observed when M3 and non-M3 patients with AML were separately analyzed, and was associated with adverse cytogenetic subtypes, 2 or more cycles to achieve CR, and high white blood cell counts. Multivariate analysis showed that MRD level was the most powerful independent prognostic factor, followed by cytogenetics and number of cycles to achieve CR. In conclusion, immunophenotypical investigation of MRD in the first BM in mCR obtained after AML induction therapy provides important information for risk assessment in patients with AML.

We aimed to analyze the natural course of subclinical hypothyroidism, quantify the incidence rate of overt hypothyroidism, and evaluate the risk factors for the development of definitive thyroid failure in elderly patients. One hundred seven patients (93 women and 14 men) over age 55 yr with subclinical hypothyroidism and no previous history of thyroid disease were prospectively studied. Subjects were followed up for 6 -72 months (mean, 31.7 months) with repeated determinations of TSH and free T 4 . Twenty-eight patients (26.8%) developed overt hypothyroidism, and 40 (37.4%) showed normalization of their TSH values. The incidence rate of overt hypothyroidism was 9.91 cases per 100 patient-years in the whole population, and 1.76, 19.67, and 73.47 cases per 100 patient-years in subjects with initial TSH values between 5.0 -9.9, 10.0 -14.9, and 15.0 -19.9 mU/liter, respectively. Kaplan-Meier analysis showed that the development of definitive thyroid hypofunction was significantly related to the presence of symptoms of hypothyroidism, goiter, positive thyroid antibodies (P < 0.05), and mainly low normal free T 4 (P < 0.01) and high TSH (P < 0.0001) concentrations at baseline. A stepwise multivariate Cox regression analysis showed that the only significant factor for progression to overt hypothyroidism was serum TSH concentration (P < 0.0001). In conclusion, TSH concentration is the most powerful predictor for the outcome of spontaneous subclinical hypothyroidism in patients over age 55 yr. Subjects with mildly elevated TSH have a low incidence rate of overt hypothyroidism. We recommend follow-up with clinical and biochemical monitoring in these patients. (J Clin Endocrinol Metab 89: 4890 -4897, 2004) One hundred seven patients (93 women and 14 men) with spontaneous subclinical hypothyroidism were studied. All patients were older than 55 yr at the start of the study (mean age, 62.2 7.6 yr; range, 55-83 yr), and there were no significant differences between women and men in age (61.9 7.4 vs. 64.4 8.3 yr, respectively), body mass index (27.4 4.3 vs. 26.6 3.0 kg/m 2 , respectively), and serum concentrations of TSH (median, 8.40; interquartile range, 6.69 -12.53 mU/liter vs. median, 8.15; interquartile range, 6.55-11.36 mU/liter) and free T 4 (FT 4 ; 1.04 0.20 vs. 1.00 0.17 ng/dl; 13.4 2.6 vs. 12.9 2.2 pmol/liter). All patients were ambulatory and were studied as outpatients during visits to an endocrinology clinic. Our aim was to evaluate a cohort of patients that was Abbreviations: FT 4 , Free T 4 ; TPOAb, thyroid peroxidase antibody.

A high complete remission rate is currently achieved in patients with acute myeloid leukemia (AML). However, many patients eventually relapse due to the persistence of low numbers of residual leukemic cells that are undetectable by conventional cytomorphologic criteria (minimal residual disease [MRD]). Using immunophenotypic multiparametric flow cytometry, we have investigated in sequential studies (diagnosis and follow-up) the impact of MRD detection on the outcome of 53 AML patients that had achieved morphologic remission with standard AML protocols and displayed at diagnosis an aberrant phenotype. Patients were studied at diagnosis with a panel of 35 monoclonal antibodies in triple staining combinations for detection of aberrant or uncommon phenotypic features. According to these features, a patient's probe was custom-built at diagnosis for the identification of possible residual leukemic cells during follow-up. The level of MRD at the end of induction and intensification therapy correlated with the number of relapses and relapse-free survival (RFS). Thus, patients with more than 5 x 10(-3) residual cells (5 residual cells among 1,000 normal bone marrow [BM] cells) identified as leukemic by immunophenotyping in the first remission BM showed a significant higher rate of relapse (67% v 20% for patients with less than 5 x 10(-3) residual cells; P = .002) and a lower median RFS (17 months v not reached; P = .01). At the end of intensification, with a cut-off value of 2 x 10(-3) leukemic cells, AML patients also separated into two distinct groups with relapse rates of 69% versus 32% (P = .02), respectively, and median RFS of 16 months versus not reached (P = .04). In addition, overall survival was also significantly related to the level of residual cells in the marrow obtained at the end of induction and particularly after intensification therapy (P = .008). Furthermore, we have explored whether residual disease was related with the functional expression of multidrug resistance (MDR-1) at diagnosis as assessed by the rhodamine123 assay. Patients with > or =5 x 10(-3) residual leukemic cells at the end of induction therapy had a significantly higher rhodamine-123 efflux (mean, 56% +/- 24%) than those with less than 5 x 10(-3) residual cells (mean, 32% +/- 31%; P = .04). Finally, multivariate analysis showed that the number of residual cells at the end of induction or intensification therapy was the most important prognostic factor for prediction of RFS. Overall, our results show that immunophenotypical investigation of MRD strongly predicts outcome in patients with AML and that the number of residual leukemic cells correlates with multidrug resistance.

OBJECTIVE: To investigate the efficacy and safety of liraglutide added to capped insulin doses in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: A 26-week, placebo-controlled, double-blind, parallel-group trial enrolling 835 subjects randomized 3:1 receiving once-daily subcutaneous liraglutide (1.8, 1.2, and 0.6 mg) or placebo added to an individually capped total daily dose of insulin. RESULTS: Mean baseline glycated hemoglobin (HbA1c) (8.1% [65.0 mmol/mol]) was significantly decreased with liraglutide versus placebo at week 26 (1.8 mg: -0.33% [3.6 mmol/mol]; 1.2 mg: -0.22% [2.4 mmol/mol]; 0.6 mg: -0.23% [2.5 mmol/mol]; placebo: 0.01% [0.1 mmol/mol]). Liraglutide significantly reduced mean body weight (-5.1, -4.0, and -2.5 kg for 1.8, 1.2, and 0.6 mg, respectively) versus placebo (-0.2 kg). Significant reductions in daily insulin dose and increases in quality of life were seen with liraglutide versus placebo. There were higher rates of symptomatic hypoglycemia (21.3 vs. 16.6 events/patient/year; P = 0.03) with liraglutide 1.2 mg vs. placebo and of hyperglycemia with ketosis >1.5 mmol/L with liraglutide 1.8 mg vs. placebo (0.5 vs. 0.1 events/patient/year; P = 0.01). CONCLUSIONS: In a broad population of subjects with long-standing type 1 diabetes, liraglutide added to capped insulin reduced HbA1c, body weight, and insulin requirements but with higher rates of hypoglycemia for liraglutide 1.2 mg and hyperglycemia with ketosis for liraglutide 1.8 mg.

Parkinson's disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson's disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson's disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson's disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson's disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson's disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson's disease drug development.

Abstract Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).

ABSTRACT The purpose of this study was to examine the hypothesis that helping preschoolers learn words through categorization may enhance their ability to retain words and their conceptual properties, acting as a bootstrap for self‐learning. We examined this hypothesis by investigating the effects of the World of Words instructional program, a supplemental intervention for children in preschool designed to teach word knowledge and conceptual development through taxonomic categorization and embedded multimedia. Participants in the study included 3‐ and 4‐year‐old children from 28 Head Start classrooms in 12 schools, randomly assigned to treatment and control groups. Children were assessed on word knowledge, expressive language, conceptual knowledge, and categories and properties of concepts in a yearlong intervention. Results indicated that children receiving the WOW treatment consistently outperformed their control counterparts; further, treatment children were able to use categories to identify the meaning of novel words. Gains in word and categorical knowledge were sustained six months later for those children who remained in Head Start. These results suggest that a program targeted to learning words within taxonomic categories may act as a bootstrap for self‐learning and inference generation. كان الغرض من هذه الدراسة هو فحص فرضية أن مساعدة الأطفال في الروضة تعلم كلمات عن طريق التصنيف بإمكانه أن يعزز من قدراتهم على تذكر الكلمات وخصائصها المفاهيمية، بوصفها محفزا للتعلم. قمنا بفحص هذه الفرضية وذلك بالتحقيق في أثر البرنامج التعليمي "عالم المفردات" (WOW) الذي يعتبر تدخلا تكميليا لأطفال الروضة ومصمما من أجل تعليم معرفة الكلمات والتطور المفاهيمي، من خلال النظام التصنيفي ووسائل الإعلام. تضمنت الدراسة مشاركين تتراوح أعمارهم بين 3 و4 سنوات ينتمون إلى 28 روضة أطفال، التي تنتمي إلى 12 مدرسة, خضعت عشوائيا للبحث ومراقبة المجموعات. جرى تقييم الأطفال على معرفة الكلمات واللغة التعبيرية والمعرفة المفاهيمية وأصناف وخصائص المفاهيم في تدخل لمدة سنة كاملة. أظهرت النتائج أن الأطفال الذين خضعوا للبرنامج التعليمي "عالم المفردات" (WOW) قد تفوقوا بصورة مستمرة على نظرائهم الذين خضعوا للمراقبة. علاوة على ذلك, فإن أطفال البحث قد تمكنوا من استخدام الأصناف والتعرف على معنى الكلمات الجديدة. استمر اكتساب الكلمات والمعرفة التصنيفية بعد 6 أشهر بالنسبة للأطفال الذين بقوا في روضة الأطفال. توحي هذه النتائج إلى أنه يمكن لبرنامج يهدف إلى تعلم الكلمات أن يعمل كمحفز للتعلم الذاتي، وتوليد الاستنتاجات. 本研究旨在考查一个假设：帮助学龄前儿童通过分类来学习单词，可提高他们记忆单词及其概念属性的能力，从而发展他们的自主学习能力。作者通过调查「单词世界」(WOW)教学计划的影响来考查这个假设。该教学计划是一个学龄前儿童补充干预计划，旨在透过使用分类学的分类方法及嵌入式多媒体，教授单词知识和发展单词概念。研究参与者是来自12所学校中的28个「启蒙计划」学前儿童班里的3‐4岁儿童，他们被随机分配到干预组和对照组。在一年的干预中，儿童接受单词知识、表达语言、概念知识、类别和概念属性的评估。结果显示，「单词世界」(WOW)干预组的表现一致地优于对照组；此外，干预组儿童可以使用类别来确定新词的词义。仍然留在「启蒙计划」班里的儿童，其单词和类别知识的改进保持稳定至干预后6个月。这些研究结果显示，针对透过分类学的分类方法来学习单词的教学计划，可引导儿童凭自己的力量学习自学和产生推断。 Cette étude avait pour but d'examiner l'hypothíse qu'aider des enfants d'âge préscolaire à apprendre des mots en les catégorisant pourrait favoriser leur capacité à retenir les mots et leurs propriétés, agissant alors comme une amorce d'auto‐apprentissage. Nous avons examiné cette hypothíse en analysant les effets du matériel d'enseignement le Monde des Mots (MDM), un supplément pédagogique destiné aux enfants d'âge préscolaire conçu pour la connaissance des mots et le développement des concepts à l'aide d'une catégorisation taxinomique avec multimédia impliqué. Ont participé à l'étude des enfants de 3 et 4 ans provenant de 28 classes Head Start issus de 12 écoles assignées au hasard au groupe de traitement et au groupe contrôle. Les enfants ont été évalués sur leur connaissance des mots, l'expression orale, les connaissances conceptuelles, les catégories et les propriétés des concepts tout au long de l'année de l'intervention. Les résultats ont montré que les enfants du groupe de traitement MDM ont de maniíre systématique dépassé leur contrepartie du groupe contrôle; en outre, les enfants soumis au traitement ont été en mesure de se servir des catégories pour trouver le sens des mots nouveaux. Les bénéfices dans la connaissance des mots et les connaissances catégorielles sont demeurés six mois plus tard chez les enfants restés dans Head Start. Ces résultats suggírent qu'un programme visant l'apprentissage de mots au sein de catégories taxonomiques peut agir comme une amorce pour l'auto‐apprentissage et la production d'inférences. Проверялась гипотеза о том, что категоризация лексики при обучении дошкольников новым словам может существенно увеличить способность к запоминанию слов и их концептуальных свойств и стимулировать малышей к самообучению. Для расширения их словарного запаса и умения работать с концептами авторы исследовали учебный модуль “Мир слов” (WOW), разработанный в качестве дополнительного вмешательства для дошкольников, которые обучаются по программе Head Start. WOW знакомит детей с таксономической классификацией посредством мультимедийных средств. Трех‐ и четырехлетние дети из 28‐и дошкольных групп в 12‐и школах были случайным образом включены либо в экспериментальную, либо в контрольную группу. На протяжении годичного обучения оценивалось знание слов, выразительность речи, знание концептов, их свойств и категорий, к которым они могут быть причислены. Дети, обучавшиеся по программе WOW, стабильно показывали более высокие результаты, чем их ровесники из контрольных групп. Помимо прочего, эти дети способны использовать категоризацию для определения значений новых слов. Через полгода после окончания обучения эти дети продолжали опережать сверстников по знанию слов и умению категоризировать. Это свидетельствует о том, что программа, предлагающая изучение слов в рамках таксономических категорий, может помочь вырастить поколение, которое будет способно к самообучению и к самостоятельным выводам. La meta de este estudio fue el de investigar la hipótesis que ayudar a los preescolares a aprender palabras por medio de la categorización mejoraría su capacidad de retener palabras y sus propiedades conceptuales, sirviendo de arranque para el auto aprendizaje. Investigamos esta hipótesis estudiando los efectos del programa de enseñanza World of Words (Mundo de palabras; WOW por sus siglas en inglés), una intervención adicional para niños preescolares diseñada para el aprendizaje de palabras y el desarrollo conceptual por medio de la categorización taxonómica y el uso de diversos medios. En este estudio participaron niños de 3 y 4 años de 20 aulas de Head Start en 12 escuelas escogidas al azar en cuanto a grupos de tratamiento y de control. En un año completo de intervención, se evaluaron los estudiantes en cuanto a su conocimiento de palabras, su lenguaje expresivo, su conocimiento conceptual, y las categorías y propiedades de los conceptos. Los resultados mostraron que los niños del grupo de WOW sistemáticamente superaban a los niños del grupo de control; además, los niños del grupo de tratamiento podían usar categorías para encontrar el significado de palabras nuevas. Los adelantos en el conocimiento de palabras y categorías todavía existían 6 meses más tarde para los niños que seguían con Head Start. Estos resultados sugieren que un programa dedicado al aprendizaje de palabras dentro de categorías taxonómicas puede ayudar al autoaprendizaje y la producción de inferencias.

Summary Background Limited published evidence shows oral desensitization to be a potential intervention option for cow's milk protein (CMPs) allergy. Objective The aim of this study was to evaluate the safety and efficacy of oral desensitization in 2‐year‐old children with cow's milk allergy, as a treatment alternative to elimination diet. Methods A total of 60 children aged 24–36 months with IgE‐mediated allergy to CMPs were included in this multi‐center study and were randomized into two groups. Thirty children (group A: treatment group) began oral desensitization immediately, whereas the remaining 30 (group B: control group) were kept on a milk‐free diet and followed‐up for 1 year. Results After 1‐year follow‐up period, 90% of the children in group A had become completely tolerant vs. 23% of the children in group B. In group A, cow's milk skin reactivity and serum‐specific IgE to milk and casein decreased significantly from the initial assessment, whereas group B showed no significant change after 1 year of follow‐up. Twenty‐four patients (80%) developed some reaction during the treatment period: 14 children developed moderate reaction (47%) and 10 mild reaction (33%). The most common manifestations were urticaria‐angioedema, followed by cough. Conclusions and Clinical Relevance In this study, oral desensitization was found to be effective in a significant percentage of 2‐year‐old children with cow's milk allergy. Oral desensitization appears to be efficacious as an alternative to elimination diet in the treatment of 2‐year‐old children with cow's milk allergy. The side‐effect profile appears acceptable but requires further study. Cite this as : A. Martorell, B. De la Hoz, M. D. Ibáñez, J. Bone, M. S. Terrados, A. Michavila, A. M. Plaza, E. Alonso, J. Garde, S. Nevot, L. Echeverria, C. Santana, J. C. Cerdá, C. Escudero, I. Guallar, M. Piquer, L. Zapatero, L. Ferré, T. Bracamonte, A. Muriel, M. I. Martínez and R. Félix, Clinical &amp; Experimental Allergy , 2011 (41) 1297–1304.

Multiple myeloma remains largely incurable. However, a few patients experience more than 10 years of relapse-free survival and can be considered as operationally cured. Interestingly, long-term disease control in multiple myeloma is not restricted to patients with a complete response, since some patients revert to having a profile of monoclonal gammopathy of undetermined significance. We compared the distribution of multiple compartments of lymphocytes and dendritic cells in the bone marrow and peripheral blood of multiple myeloma patients with long-term disease control (n=28), patients with newly diagnosed monoclonal gammopathy of undetermined significance (n=23), patients with symptomatic multiple myeloma (n=23), and age-matched healthy adults (n=10). Similarly to the patients with monoclonal gammopathy of undetermined significance and symptomatic multiple myeloma, patients with long-term disease control showed an expansion of cytotoxic CD8(+) T cells and natural killer cells. However, the numbers of bone marrow T-regulatory cells were lower in patients with long-term disease control than in those with symptomatic multiple myeloma. It is noteworthy that B cells were depleted in patients with monoclonal gammopathy of undetermined significance and in those with symptomatic multiple myeloma, but recovered in both the bone marrow and peripheral blood of patients with long-term disease control, due to an increase in normal bone marrow B-cell precursors and plasma cells, as well as pre-germinal center peripheral blood B cells. The number of bone marrow dendritic cells and tissue macrophages differed significantly between patients with long-term disease control and those with symptomatic multiple myeloma, with a trend to cell count recovering in the former group of patients towards levels similar to those found in healthy adults. In summary, our results indicate that multiple myeloma patients with long-term disease control have a constellation of unique immune changes favoring both immune cytotoxicity and recovery of B-cell production and homing, suggesting improved immune surveillance.

In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30-1.70; P = 5.9x10(-9)). Functional assays of rs1867277 (NM_004473.3:c.-283G>A) within the FOXE1 5' UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/alphaCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.

UNLABELLED: The incidence and prevalence of patients on renal replacement therapy (RRT) who receive a renal transplant are continuously increasing in Spain. At the moment, they are the main group of end-stage renal disease (ESRD) patients in our region (60% of total RRT patients). The aim of the present study was to assess the health related quality of life (HRQOL) of kidney transplanted patients of our region, and to identify socio-demographic and clinical variables that influence it. The intention was also to compare the HRQOL of these patients with that of chronic haemodialysis (HD) patients and of the general population. METHODS: Two hundred and ten kidney transplanted patients and 170 HD patients were evaluated using the Karnofsky performance scale (KPS), sickness impact profile (SIP), and SF-36 Health Survey (SF-36). Socio-demographic and clinical data, including a comorbidity index (CI), were also collected. To compare our patients with the general population we used SF-36 mean scores from an aleatory sample taken from our region. RESULTS: Transplant patients had lower mean scores on SIP dimensions and higher scores on SF-36 dimensions than chronic HD patients. In transplant patients, we found significant differences on SIP and SF-36 scores in gender, educational level, haematocrite and haemoglobin, CI, time since transplantation, and KPS. CONCLUSIONS: The HRQOL of transplant patients is clearly better than that of chronic HD patients and similar to that of the general population. Differences in the HRQOL within transplant patients did not appear to be as a result of patient's age, but rather it would appear to be a consequence of gender, analytic figures, CI, KPS score, time with transplant, and educational level.

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson's disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial function-associated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD.

Multiparametric immunophenotyping can be a sensitive method for analyzing the plasma cell (PC) compartment in patients with multiple myeloma because it discriminates between myelomatous and normal PCs. Using this approach, we compared the efficacy of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) with that of conventional chemotherapy. We found that ASCT provided a significantly greater reduction in the level of residual tumor PCs and with better recovery of normal PCs. This profile of coexistence of normal PCs and myelomatous PCs resembled that observed in monoclonal gammopathy of undetermined significance. We also found that treatment-induced changes in the PC compartment correlated with disease outcome. Thus, patients in whom at least 30% of gated PCs had a normal phenotype after treatment had a significantly longer progression-free survival (60 +/- 6 months versus 34 +/- 12 months; P =.02).