Allogeneic B cell immunomodulatory therapy in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease. Immune system dysregulation plays an essential role in ALS onset and progression. Our preclinical studies have shown that the administration of exogenous allogeneic B cells improves outcomes in murine models of skin and brain injury through a process termed pligodraxis, in which B cells adopt an immunoregulatory and neuroprotective phenotype in an injured environment. Here, we investigated the effects of B-cell therapy in the SOD1G93A mouse preclinical model of ALS and in a person living with ALS. Purified splenic mature naïve B cells from haploidentical donor mice were administered intravenously in SOD1G93A mice for a total of 10 weekly doses. For the clinical study in a person with advanced ALS, IgA gammopathy of unclear significance, and B lymphopenia, CD19+ B cells were positively selected from a healthy haploidentical donor and infused intravenously twice, at a 60-day interval. Repeated intravenous B-cell administration was safe and significantly delayed disease onset, extended survival, reduced cellular apoptosis, and decreased astrogliosis in SOD1G93A mice. Repeated B-cell infusion in a person with ALS was safe and did not appear to generate a clinically evident inflammatory response. An improvement of 5 points on the ALSFRS-R scale was observed after the first infusion. Levels of inflammatory markers showed persistent reduction post-infusion. This represents a first demonstration of the efficacy of haploidentical B-cell infusion in the SOD1G93A mouse and the safety and feasibility of using purified haploidentical B lymphocytes as a cell-based therapeutic strategy for a person with ALS.

Metacarpal fractures.

Metacarpal fractures are common and can be functionally disabling. The majority are managed non-operatively. When surgical intervention is indicated, various methods of fixation are available with the utility of each being based on injury pattern, patient function and surgeon preference. Early mobilization, especially in case of open reduction and internal fixation, is a critical component of treatment to prevent stiffness and restore function. When possible, a fixation construct that can withstand the applied forces of early postoperative motion is chosen. We provide an updated description for diagnosis, treatment options and operative fixation for metacarpal fractures.

Cultivated autologous limbal epithelial cell (CALEC) transplantation: Development of manufacturing process and clinical evaluation of feasibility and safety.

To treat unilateral limbal stem cell (LSC) deficiency, we developed cultivated autologous limbal epithelial cells (CALEC) using an innovative xenobiotic-free, serum-free, antibiotic-free, two-step manufacturing process for LSC isolation and expansion onto human amniotic membrane with rigorous quality control in a good manufacturing practices facility. Limbal biopsies were used to generate CALEC constructs, and final grafts were evaluated by noninvasive scanning microscopy and tested for viability and sterility. Cultivated cells maintained epithelial cell phenotype with colony-forming and proliferative capacities. Analysis of LSC biomarkers showed preservation of "stemness." After preclinical development, a phase 1 clinical trial enrolled five patients with unilateral LSC deficiency. Four of these patients received CALEC transplants, establishing preliminary feasibility. Clinical case histories are reported, with no primary safety events. On the basis of these results, a second recruitment phase of the trial was opened to provide longer term safety and efficacy data on more patients.

Validation of TMMS-24 in Three Spanish-Speaking Countries: Argentina, Ecuador, and Spain.

Emotional intelligence (EI) is a fundamental skill related to different aspects of human life, such as psychological well-being or mood states. The present study has a triple objective: first, to explore the psychometric properties of the TMMS-24 in three Spanish-speaking countries (Argentina, Ecuador, and Spain); second, to examine the relation of EI with mood and avoidance of responsibility; and finally, to analyse the influence of sex, age and national differences on EI. The relevance of this study is given by the need for tools to assess EI in different cultures. A sample of 1048 adults (Mage = 21.11 years, SD = 5.84; 52.3% male) was selected by convenience sampling. The psychometric properties of the TMMS-24 were adequate, and the Spanish sample showed lower levels of EI than the Argentinian and Ecuadorian ones. EI was associated with mood and the avoidance of responsibility, with higher levels in women in all cases. Regarding the national and sex-specific differences, the Spanish sample showed significant differences in attention and repair, with men exhibiting higher scores in attention and women having higher scores in repair. In the Argentinean sample, no significant differences were found, and in the Ecuadorian one, women presented higher scores in attention than men. The TMMS-24 can be considered a useful, practical tool to assess EI in adults in different cultures and with different languages.

Cross-cultural validation of the Mood Questionnaire in three Spanish-speaking countries Argentina, Ecuador, and Spain.

This study validates the Mood Questionnaire for adults in three Spanish-speaking countries: Argentina, Ecuador, and Spain. It then analyzes the influence of gender and cultural differences on mood, and whether there is a relationship between mood, emotional intelligence, and the Avoidance of Responsibility. A convenience sample of 1048 adults, with a middle-class socioeconomic background, was selected from three Spanish-speaking countries (Spain, Argentina, and Ecuador). The psychometric properties of the Mood Questionnaire are adequate, which is particularly interesting given the need for transcultural tools to evaluate moods. Moreover, the mood was associated with avoidance of responsibility and emotional intelligence. In addition, differences in mood were observed according to country and gender. These findings are interesting because the Spanish version of the Mood Questionnaire has been validated for children but not for adults, and it compares three Spanish-speaking countries. The use of this diagnostic tool with Spanish adults can be justified according to these results.

Gasto público y salud en el mundo, 1990-2012 / A Public expenditure and world's health, 1990-2012

Introducción: La evidencia empírica dispar relacionada con el efecto del gasto público en materia sanitaria puede deberse a las importantes variaciones metodológicas de los estudios y a las diferencias significativas en la forma en que el gasto público influye dependiendo del nivel de desarrollo de los países. Objetivo: Determinar la relación entre el gasto público total del Gobierno general y la mortalidad infantil y la esperanza de vida. Métodos: Investigación realizada en una muestra de 78 países segmentada por niveles de renta, desde 1990 hasta 2012. Se constituyeron cinco submuestras de países divididos por su nivel de renta mediante un procedimiento de agrupación no jerárquico de k-medias. Se verificó la procedencia de la segmentación mediante el test de Chow. Para cada una de las submuestras construidas, se estimó el modelo correspondiente por mínimos cuadrados generales lineales y un test de cointegración. Resultados: En las submuestras superiores en nivel de renta, la salud se relacionó significativa y consistentemente con el gasto público. Sin embargo, en los países de renta inferior-baja, el coeficiente del gasto presentó un signo contrario al esperado. Conclusiones: Se demuestra un impacto positivo y de largo plazo entre el gasto público y la situación sanitaria. Sin embargo, para los países de menor renta, este parece haber superado su punto óptimo, lo que indicaría su ineficiencia en términos sanitarios. Se conjetura que lo anterior se debe a la baja capacidad institucional de estos países, lo que impide que un mayor gasto obtenga mejores resultados sanitarios(AU)

Introduction: The disparate empirical evidence related with the effect of public expenditure on health may be due to the significant methodological variations of the studies, as well as the significant differences in the way in which public expenditure influences depending on the level of development of the countries. Objective: To determine the relation among the total public expenditure of the General Government, and infant mortality and life expectancy. Methods: Research project carried out with a sample of 78 countries segmented by income levels from 1990 to 2012. By means of a non - hierarchical grouping of k - media, five sub-samples of countries were formed and divided by their income level. The origin of the segmentation was verified by means of the Chow test. Linear GLS and a cointegration test were applied on each subsample. Results: In the upper subsamples at the income level, health was significantly and consistently related to public expenditure. However, in the lower-low income countries, the expenditure coefficient showed a sign opposite to that expected. Conclusions: There is evidence of a positive and long-term impact among public expenditure and the health situation. However, for lower income countries, this seems to have surpassed its optimum point, which would indicate its inefficiency in sanitary terms. It is conjectured that this is due to the low institutional capacity of these countries, which hampers that greater expenditure obtains better sanitary results(AU)

Gasto público y salud en el mundo, 1990-2012 / A Public expenditure and world's health, 1990-2012

Introducción: La evidencia empírica dispar relacionada con el efecto del gasto público en materia sanitaria puede deberse a las importantes variaciones metodológicas de los estudios y a las diferencias significativas en la forma en que el gasto público influye dependiendo del nivel de desarrollo de los países. Objetivo: Determinar la relación entre el gasto público total del Gobierno general y la mortalidad infantil y la esperanza de vida. Métodos: Investigación realizada en una muestra de 78 países segmentada por niveles de renta, desde 1990 hasta 2012. Se constituyeron cinco submuestras de países divididos por su nivel de renta mediante un procedimiento de agrupación no jerárquico de k-medias. Se verificó la procedencia de la segmentación mediante el test de Chow. Para cada una de las submuestras construidas, se estimó el modelo correspondiente por mínimos cuadrados generales lineales y un test de cointegración. Resultados: En las submuestras superiores en nivel de renta, la salud se relacionó significativa y consistentemente con el gasto público. Sin embargo, en los países de renta inferior-baja, el coeficiente del gasto presentó un signo contrario al esperado. Conclusiones: Se demuestra un impacto positivo y de largo plazo entre el gasto público y la situación sanitaria. Sin embargo, para los países de menor renta, este parece haber superado su punto óptimo, lo que indicaría su ineficiencia en términos sanitarios. Se conjetura que lo anterior se debe a la baja capacidad institucional de estos países, lo que impide que un mayor gasto obtenga mejores resultados sanitarios(AU)

Introduction: The disparate empirical evidence related with the effect of public expenditure on health may be due to the significant methodological variations of the studies, as well as the significant differences in the way in which public expenditure influences depending on the level of development of the countries. Objective: To determine the relation among the total public expenditure of the General Government, and infant mortality and life expectancy. Methods: Research project carried out with a sample of 78 countries segmented by income levels from 1990 to 2012. By means of a non - hierarchical grouping of k - media, five sub-samples of countries were formed and divided by their income level. The origin of the segmentation was verified by means of the Chow test. Linear GLS and a cointegration test were applied on each subsample. Results: In the upper subsamples at the income level, health was significantly and consistently related to public expenditure. However, in the lower-low income countries, the expenditure coefficient showed a sign opposite to that expected. Conclusions: There is evidence of a positive and long-term impact among public expenditure and the health situation. However, for lower income countries, this seems to have surpassed its optimum point, which would indicate its inefficiency in sanitary terms. It is conjectured that this is due to the low institutional capacity of these countries, which hampers that greater expenditure obtains better sanitary results(AU)

Ranolazine for stable angina pectoris.

BACKGROUND: Stable angina pectoris is a chronic medical condition with significant impact on mortality and quality of life; it can be macrovascular or microvascular in origin. Ranolazine is a second-line anti-anginal drug approved for use in people with stable angina. However, the effects of ranolazine for people with angina are considered to be modest, with uncertain clinical relevance. OBJECTIVES: To assess the effects of ranolazine on cardiovascular and non-cardiovascular mortality, all-cause mortality, quality of life, acute myocardial infarction incidence, angina episodes frequency and adverse events incidence in stable angina patients, used either as monotherapy or as add-on therapy, and compared to placebo or any other anti-anginal agent. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and the Conference Proceedings Citation Index - Science in February 2016, as well as regional databases and trials registers. We also screened reference lists. SELECTION CRITERIA: Randomised controlled trials (RCTs) which directly compared the effects of ranolazine versus placebo or other anti-anginals in people with stable angina pectoris were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, extracted data and assessed risk of bias. Estimates of treatment effects were calculated using risk ratios (RR), mean differences (MD) and standardised mean differences (SMD) with 95% confidence intervals (CI) using a fixed-effect model. Where we found statistically significant heterogeneity (Chi² P < 0.10), we used a random-effects model for pooling estimates. Meta-analysis was not performed where we found considerable heterogeneity (I² ≥ 75%). We used GRADE criteria to assess evidence quality and the GRADE profiler (GRADEpro GDT) to import data from Review Manager 5.3 to create 'Summary of findings' tables. MAIN RESULTS: We included 17 RCTs (9975 participants, mean age 63.3 years). We found very limited (or no) data to inform most planned comparisons. Summary data were used to inform comparison of ranolazine versus placebo. Overall, risk of bias was assessed as unclear.For add-on ranolazine compared to placebo, no data were available to estimate cardiovascular and non-cardiovascular mortality. We found uncertainty about the effect of ranolazine on: all-cause mortality (1000 mg twice daily, RR 0.83, 95% CI 0.26 to 2.71; 3 studies, 2053 participants; low quality evidence); quality of life (any dose, SMD 0.25, 95% CI -0.01 to 0.52; 4 studies, 1563 participants; I² = 73%; moderate quality evidence); and incidence of non-fatal acute myocardial infarction (AMI) (1000mg twice daily, RR 0.40, 95% CI 0.08 to 2.07; 2 studies, 1509 participants; low quality evidence). Add-on ranolazine 1000 mg twice daily reduced the fervour of angina episodes (MD -0.66, 95% CI -0.97 to -0.35; 3 studies, 2004 participants; I² = 39%; moderate quality evidence) but increased the risk of non-serious adverse events (RR 1.22, 95% CI 1.06 to 1.40; 3 studies, 2053 participants; moderate quality evidence).For ranolazine as monotherapy compared to placebo, we found uncertain effect on cardiovascular mortality (1000 mg twice daily, RR 1.03, 95% CI 0.56 to 1.88; 1 study, 2604 participants; low quality evidence). No data were available to estimate non-cardiovascular mortality. We also found an uncertain effect on all-cause mortality for ranolazine (1000 mg twice daily, RR 1.00, 95% CI 0.81 to 1.25; 3 studies, 6249 participants; low quality evidence), quality of life (1000 mg twice daily, MD 0.28, 95% CI -1.57 to 2.13; 3 studies, 2254 participants; moderate quality evidence), non-fatal AMI incidence (any dose, RR 0.88, 95% CI 0.69 to 1.12; 3 studies, 2983 participants; I² = 50%; low quality evidence), and frequency of angina episodes (any dose, MD 0.08, 95% CI -0.85 to 1.01; 2 studies, 402 participants; low quality evidence). We found an increased risk for non-serious adverse events associated with ranolazine (any dose, RR 1.50, 95% CI 1.12 to 2.00; 3 studies, 947 participants; very low quality evidence). AUTHORS' CONCLUSIONS: We found very low quality evidence showing that people with stable angina who received ranolazine as monotherapy had increased risk of presenting non-serious adverse events compared to those given placebo. We found low quality evidence indicating that people with stable angina who received ranolazine showed uncertain effect on the risk of cardiovascular death (for ranolazine given as monotherapy), all-cause death and non-fatal AMI, and the frequency of angina episodes (for ranolazine given as monotherapy) compared to those given placebo. Moderate quality evidence indicated that people with stable angina who received ranolazine showed uncertain effect on quality of life compared with people who received placebo. Moderate quality evidence also indicated that people with stable angina who received ranolazine as add-on therapy had fewer angina episodes but increased risk of presenting non-serious adverse events compared to those given placebo.