Role of Soluble ST2 Biomarker in Predicting Recurrence of Atrial Fibrillation after Electrical Cardioversion or Pulmonary Vein Isolation.

This study aims to determine the predictive value of the soluble suppression of tumorigenicity 2 (sST2) biomarker in atrial fibrillation (AF) recurrence. This prospective, observational study included patients with AF referred for electrical cardioversion (ECV) or pulmonary vein isolation (PVI) procedures. Baseline characteristics were collected, and sST2 was determined at baseline and at 3 and 6 months of follow-up. sST2 was determined at baseline in a matched control group. Left atrial voltage mapping was performed in patients undergoing PVI. The sST2 maximal predictive capacity of AF recurrence was at the 3-month FU in the cohort of patients undergoing ECV with respect to 6-month AF recurrence with an AUC of 0.669, a cut-off point of 15,511 pg/mL, a sensitivity of 60.97%, and a specificity of 69.81%. The ROC curve of the sST2 biomarker at baseline and 3 months in the cohort of patients undergoing PVI showed AUCs of 0.539 and 0.490, respectively. The logistic regression model identified the rhythm (AF) and the sST2 biomarker at 3 months as independent factors for recurrence at 6 months in the ECV cohort. In the logistic regression model, sST2 was not an independent factor for recurrence at 6 months of follow-up in the PVI cohort. In patients who underwent ECV, sST2 values at 3 months may provide utility to predict AF recurrence at 6 months of follow-up. In patients who underwent PVI, sST2 had no value in predicting AF recurrence at 6 months of follow-up.

Revisión sistemática sobre la percepción del profesorado y alumnado de la materia de Educación Física como facilitadora de una escuela inclusiva / Systematic review on the perception of teachers and students of the subject of Physical Education as a promoter of an inclusive school

Actualmente la educación inclusiva es uno de los grandes retos en la comunidad educativa. El objetivo principal de esta investigación analizar las publicaciones que investigaron la percepción del alumnado y profesorado en la educación física sobre la escuela inclusiva en el contexto español. Se llevó a cabo una revisión sistemática, donde se empleó la declaración de PRISMA para analizar la inclusión percepción del profesorado y del alumnado en la Ed. Fís en la literatura científica española. Los resultados más relevantes muestran que las clases de Ed. Fís son un escenario idóneo para el desarrollo de la inclusión educativa, siendo esto percibido tanto por el profesorado como el alumnado, quienes además refuerzan que se adaptan de manera adecuada cuando se adaptan los contenidos en las clases. Por último, las investigaciones muestran que el docente tiene un papel fundamental en el desarrollo de las clases, debiendo ser capaz de integrar, siendo su formación en materia de inclusión un aspecto a mejorar. (AU)

Inclusive education is currently one of the major challenges in the education community. The main objective of this research was to analyse the importance of the subject of physical education (PE) within the current inclusive school through students and teachers. A systematic review was carried out, using the PRISMA statement to analyse teacher and student perceptions of inclusion in PE spanish literature. The most relevant results show that PE classes are an ideal setting for the development of inclusive education, being this perceived by both teachers and students, who also reinforce that they adapt appropriately when content is adapted in the classes. Finally, research shows that the teacher has a fundamental role in the development of classes, and must be able to integrate, with their training in inclusion being an aspect to be improved. (AU)

Identification of Asthma Phenotypes in the Spanish MEGA Cohort Study Using Cluster Analysis.

INTRODUCTION: The definition of asthma phenotypes has not been fully established, neither there are cluster studies showing homogeneous results to solidly establish clear phenotypes. The purpose of this study was to develop a classification algorithm based on unsupervised cluster analysis, identifying clusters that represent clinically relevant asthma phenotypes that may share asthma-related outcomes. METHODS: We performed a multicentre prospective cohort study, including adult patients with asthma (N=512) from the MEGA study (Mechanisms underlying the Genesis and evolution of Asthma). A standardised clinical history was completed for each patient. Cluster analysis was performed using the kernel k-groups algorithm. RESULTS: Four clusters were identified. Cluster 1 (31.5% of subjects) includes adult-onset atopic patients with better lung function, lower BMI, good asthma control, low ICS dose, and few exacerbations. Cluster 2 (23.6%) is made of adolescent-onset atopic asthma patients with normal lung function, but low adherence to treatment (59% well-controlled) and smokers (48%). Cluster 3 (17.1%) includes adult-onset patients, mostly severe non-atopic, with overweight, the worse lung function and asthma control, and receiving combination of treatments. Cluster 4 (26.7%) consists of the elderly-onset patients, mostly female, atopic (64%), with high BMI and normal lung function, prevalence of smokers and comorbidities. CONCLUSION: We defined four phenotypes of asthma using unsupervised cluster analysis. These clusters are clinically relevant and differ from each other as regards FEV1, age of onset, age, BMI, atopy, asthma severity, exacerbations, control, social class, smoking and nasal polyps.

Antibodies against 4 Atypical Post-Translational Protein Modifications in Patients with Rheumatoid Arthritis.

Patients with rheumatoid arthritis (RA) show autoantibodies against post-translational protein modifications (PTMs), such as anti-citrullinated protein antibodies. However, the range of recognized PTMs is unknown. Here, we addressed four PTMs: chlorination, non-enzymatic glycation, nitration, and homocysteinylation, identified as targets of atypical RA autoantibodies in studies whose protocols we have followed. The modified antigens included collagen type II, an extract of synovial proteins and a selection of peptides. We interpreted the results according to the optical density (OD) obtained in an enzyme-linked immunosorbent assay ( ELISA) with the modified antigen and the corrected OD obtained after subtracting the reactivity against the unmodified antigen. The results showed evidence of specific antibodies against glycated collagen type II, as the corrected ODs were higher in the 182 patients with RA than in the 164 healthy controls (p = 0.0003). However, the relevance of these antibodies was doubtful because the magnitude of the specific signal was small (median OD = 0.072 vs. 0.027, respectively). There were no specific antibodies against any of the other three PTMs. Therefore, our results showed that the four PTMs are not inducing a significant autoantibody response in patients with RA. These results indicated that the repertoire of PTM autoantigens in RA is restricted.

Serum levels of inflammatory mediators as prognostic biomarker in silica exposed workers.

Silicosis is a diffuse interstitial lung disease caused by sustained inhalation of silica and silicates. Several cytokines are activated by their inhalation and can mediate the process of pulmonary fibrosis. The identification of biomarkers could allow an early diagnosis before the development of radiological alterations and help monitor the evolution of patients. The objetive of this study was to determine the clinical significance of specific biomarkers, to estimate their association with the development, severity and/or progression of silicosis, and identify determinants of this evolution. We conducted a prospective observational study in patients attending the pulmonology clinic from 2009 to 2018. Serum levels of the following inflammatory mediators were assessed: interleukin-6 (IL-6), interleukin 2 receptor subunit alpha (IL2R) interleukin 1 beta (IL1B), interleukin-8 (IL-8), tumour necrosis factor-alpha (TNF-α), transforming growth factor-beta1 (TGF-ß1), alpha-1 antitrypsin (AAT), C-reactive protein (CRP), lactate dehydrogenase (LDH) and ferritin in subjects exposed to silica, with and without silicosis. Association between those inflammatory mediators with lung function measurements and radiological severity of disease and their impact on prognosis were analysed. 337 exposed to silica (278 with silicosis) and 30 subjects in the control group were included. IL-8, α1AT, ferritin, CRP and LDH levels were higher in silicosis than in those exposed to silica without silicosis. IL-8, LDH and AAT levels were associated with progression of silicosis and IL-6, IL-8, LDH, AAT, ferritin, and CRP with vital status. The results of the ROC analysis indicated the potential of IL-8 as a biomarker in the presence of silicosis and for the prediction of mortality.

Increased Serum Levels of sCD14 and sCD163 Indicate a Preponderant Role for Monocytes in COVID-19 Immunopathology.

Background: Emerging evidence indicates a potential role for monocytes in COVID-19 immunopathology. We investigated two soluble markers of monocyte activation, sCD14 and sCD163, in COVID-19 patients, with the aim of characterizing their potential role in monocyte-macrophage disease immunopathology. To the best of our knowledge, this is the first study of its kind. Methods: Fifty-nine SARS-Cov-2 positive hospitalized patients, classified according to ICU or non-ICU admission requirement, were prospectively recruited and analyzed by ELISA for levels of sCD14 and sCD163, along with other laboratory parameters, and compared to a healthy control group. Results: sCD14 and sCD163 levels were significantly higher among COVID-19 patients, independently of ICU admission requirement, compared to the control group. We found a significant correlation between sCD14 levels and other inflammatory markers, particularly Interleukin-6, in the non-ICU patients group. sCD163 showed a moderate positive correlation with the time lapsed from admission to sampling, independently of severity group. Treatment with corticoids showed an interference with sCD14 levels, whereas hydroxychloroquine and tocilizumab did not. Conclusions: Monocyte-macrophage activation markers are increased and correlate with other inflammatory markers in SARS-Cov-2 infection, in association to hospital admission. These data suggest a preponderant role for monocyte-macrophage activation in the development of immunopathology of COVID-19 patients.

Postprandial glycemic response in a non-diabetic adult population: the effect of nutrients is different between men and women.

BACKGROUND: There is a growing interest in the pathopysiological consequences of postprandial hyperglycemia. It is well known that in diabetic patients 2 h plasma glucose is a better risk predictor for coronary heart disease than fasting plasma glucose. Data on the glycemic response in healthy people are scarce. OBJECTIVE: To evaluate the effect of macronutrients (carbohydrates, fats, and proteins) and fiber on postprandial glycemic response in an observational study of a non-diabetic adult population. DESIGN: Cross-sectional study. 150 non-diabetic adults performed continuous glucose monitoring for 6 days. During this period they recorded food and beverage intake. The participants were instructed not to make changes in their usual diet and physical exercise.Variables analyzed included clinical parameters (age, sex, body weight, height, body mass index, blood pressure, and waist measurement), meal composition (calories, carbohydrates, fats, proteins, and fiber) and glycemic postprandial responses separated by sexes.The study period was defined from the start of dinner to 6 h later. RESULTS: A total of 148 (51% women) subjects completed all study procedures. Dinner intake was higher in males than in females (824 vs 531 kcal). Macronutrient distribution was similar in both sexes. No significant differences were found in fiber intake between men and women (5.5 g vs 4.5 g).In both sexes, the higher intake of carbohydrates corresponded to a significantly higher glycemic response (p = 0.0001 in women, p = 0.022 in men). Moreover, in women, as fat intake was higher, a flattening of the postprandial glycemic curve was observed (p = 0.003). With respect to fiber, a significantly lower glycemic response was observed in the group of women whose fiber intake at dinner was higher (p = 0.034). CONCLUSIONS: Continuous glucose monitoring provides important information about glucose levels after meals. In this study, the postprandial glycemic response in women was different from that of men, and carbohydrates were the main determinant of elevated postprandial glucose levels.

Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegaly.

BACKGROUND: Acromegaly is produced by excess growth hormone secreted by a pituitary adenoma of somatotroph cells (ACRO). First-line therapy, surgery and adjuvant therapy with somatostatin analogs, fails in 25% of patients. There is no predictive factor of resistance to therapy. New therapies are investigated using few dispersed tumor cells in acute primary cultures in standard conditions where the cells do not grow, or using rat pituitary cell lines that do not maintain the full somatotroph phenotype. The RET/PIT1/p14ARF/p53 pathway regulates apoptosis in normal pituitary somatotrophs whereas the RET/GDNF pathway regulates survival, controlling PIT1 levels and blocking p14ARF (ARF) and p53 expression. METHODS: We investigated these two RET pathways in a prospective series of 32 ACRO and 63 non-functioning pituitary adenomas (NFPA), studying quantitative RNA and protein gene expression for molecular-clinical correlations and how the RET pathway might be implicated in therapeutic success. Clinical data was collected during post-surgical follow-up. We also established new'humanized' pituitary cultures, allowing 20 repeated passages and maintaining the pituitary secretory phenotype, and tested five multikinase inhibitors (TKI: Vandetanib, Lenvatinib, Sunitinib, Cabozantinib and Sorafenib) potentially able to act on the GDNF-induced RET dimerization/survival pathway. Antibody arrays investigated intracellular molecular pathways. FINDINGS: In ACRO, there was specific enrichment of all genes in both RET pathways, especially GDNF. ARF and GFRA4 gene expression were found to be opposing predictors of response to first-line therapy. ARF cut-off levels, calculated categorizing by GNAS mutation, were predictive of good response (above) or resistance (below) to therapy months later. Sorafenib, through AMPK, blocked the GDNF/AKT survival action without altering the RET apoptotic pathway. INTERPRETATION: Tumor ARF mRNA expression measured at the time of the surgery is a prognosis factor in acromegaly. The RET inhibitor, Sorafenib, is proposed as a potential treatment for resistant ACRO. FUND: This project was supported by national grants from Agencia Estatal de Investigación (AEI) and Instituto Investigación Carlos III, with participation of European FEDER funds, to IB (PI150056) and CVA (BFU2016-76973-R). It was also supported initially by a grant from the Investigator Initiated Research (IIR) Program (WI177773) and by a non-restricted Research Grant from Pfizer Foundation to IB. Some of the pituitary acromegaly samples were collected in the framework of the Spanish National Registry of Acromegaly (REMAH), partially supported by an unrestricted grant from Novartis to the Spanish Endocrine Association (SEEN). CVA is also supported from a grant of Medical Research Council UK MR/M018539/1.

Mindfulness in the Maintenance of Cognitive Capacities in Alzheimer's Disease: A Randomized Clinical Trial.

BACKGROUND: The Canary Islands longitudinal study on non-pharmacological treatments showed the overall effectiveness of mindfulness in Alzheimer's disease (AD). However, no specific data on the maintenance of cognitive capacities were presented. OBJECTIVE: To determine whether the practice of mindfulness modifies the course of cognitive impairment in AD. DESIGN: Longitudinal, non-inferiority and equivalence, randomized clinical trial, repeated-measures design, with three experimental groups and one control group. PARTICIPANTS: Patients with AD who voluntarily attended the Lidia García Foundation (n = 502). Only those who were treated with donepezil and MMSE ≥18 were included (n = 120). INTERVENTION: Over a two-year period, each group carried out three weekly sessions of stimulation based on mindfulness, cognitive stimulation therapy, and progressive muscle relaxation. MEASURES: Cognitive assessment CAMDEX-R (MMSE and CAMCOG). STATISTICAL ANALYSIS: Repeated-measures ANOVA (p <  0.05) and the effect size Cohen's d were performed. RESULTS: The mindfulness group showed significant scores compared with the control and muscle relaxation groups (p <  0.05), while mindfulness and cognitive stimulation therapy were equivalent (p≥0.05). Group cognitive stimulation evolved better than the control (p <  0.05) group but not better than the muscle relaxation group (p≥0.05). The effect size compared over two years was large for the mindfulness group (p≥0.80), moderate for the relaxation group (p≥0.50), and low for the cognitive stimulation group (p≥0.20). CONCLUSION: The practice of mindfulness maintained cognitive function over a period of two years. This longitudinal study suggests that mindfulness can be used as a non-pharmacological treatment to slow cognitive impairment in AD.

Neuroprotective effects of dexmedetomidine conditioning strategies: Evidences from an in vitro model of cerebral ischemia.

AIMS: Dexmedetomidine is a selective agonist of α2-adrenergic receptors with clinical anesthetic and analgesic properties that has also shown neuroprotective effects on several models of brain injury. Because perioperative stroke and brain damage are frequent causes of death in critical care units, we aimed to investigate neuroprotective properties of dexmedetomidine using an in vitro model of cerebral ischemia. MAIN METHODS: Primary mixed rat brain cortical cultures were subjected to oxygen and glucose deprivation and treated with different doses of dexmedetomidine in order to analyze three conditioning strategies: preconditioning, intraconditioning and postconditioning. KEY FINDINGS: All dexmedetomidine pre-, intra- and postconditioning treatments showed neuroprotective effects reducing brain cell necrosis, although only preconditioning showed antiapoptotic effects. Dexmedetomidine treatments also reduced IL-6 and TNF-α levels, especially in the preconditioning groups. Oxidative stress was attenuated with all dexmedetomidine preconditioning treatments, but only with the higher dose in the intraconditioning group, and no effects were observed in the postconditioning. All conditioning strategies increased BDNF levels. SIGNIFICANCE: Dexmedetomidine-mediated neuroprotective effects in an in vitro model of cerebral ischemia involve the attenuation of inflammation and oxidative stress and the increment of BDNF expression.

High incidence of hypoglycemia in stable insulin-treated type 2 diabetes mellitus: continuous glucose monitoring vs. self-monitored blood glucose. Observational prospective study.

OBJECTIVES: Hypoglycemia is a limiting factor in the achievement of strict glycemic control. The primary objective of this 9-week study was to determine the frequency of hypoglycemia in patients with stable insulin-treated type 2 diabetes mellitus by comparing self-monitored blood glucose (SMBG) measurement with continuous glucose monitoring (CGM). METHODS: This was an observational prospective study. Included in the study were 63 stable, insulin-treated patients with type 2 diabetes. They were instructed to record 2 daily capillary blood glucose readings, pre- and/or postprandial, in a sequential way during 8 consecutive weeks. A CGM system was worn during an additional week. We evaluated the frequency of hypoglycemia using the 8-week SMBG profile and the 1 CGM week. RESULTS: SMBG revealed that 50% of the patients had experienced hypoglycemia. CGM found hypoglycemia in 59% of patients. Significantly higher percentages of hyperglycemic and hypoglycemic episodes were detected by CGM than by capillary blood glucose measurements (61.1% vs. 50.8%; p=0.047) and (3.8% vs. 1.7%; p=0.016); 33% of patients experienced nocturnal hypoglycemia, and 19% of patients who had no data concerning hypoglycemia recorded in the capillary blood glucose diary had experienced hypoglycemia as measured by CGM, and the hypoglycemia occurred mainly during the nocturnal period. CONCLUSIONS: In stable well-controlled, insulin-treated patients with type 2 diabetes, CGM showed higher numbers of hypoglycemic events than did SMBG, especially at night. CGM is a useful tool that provides clinically valuable information about glucose control in these patients.

Estimulación basada en mindfulness en la enfermedad de Alzheimer avanzada: ensayo clínico piloto comparativo de equivalencia / Mindfulness-based stimulation in advanced Alzheimer's disease: a comparative, non-inferiority, clinical pilot study

Introducción. Se llevó a cabo un estudio longitudinal para analizar la viabilidad, la seguridad y los efectos de la práctica de mindfulness, relajación y estimulación cognitiva en la evolución clínica de la enfermedad de Alzheimer (EA) con el objetivo de analizar la equivalencia de estos tratamientos. Material y métodos. En el estudio participaron 168 personas con EA probable en tratamiento con donepezilo. En este artículo se muestra a los 21 participantes en estadio grave que completaron el seguimiento de 24 meses. Se agrupó a los sujetos en 3 grupos experimentales (estimulación cognitiva, relajación y mindfulness) y uno control. Cada grupo desarrolló 3 sesiones semanales con medidas semestrales de seguimiento (cognición: CAMCOG y MMSE; funcionalidad: RDRS-2; psicopatología: NPI). Se realizaron análisis no paramétricos. Resultados. Las puntuaciones de la función cognitiva y la funcionalidad indicaron que no existían diferencias significativas entre los diferentes grupos. No obstante, los grupos de mindfulness y estimulación cognitiva no perdieron puntuación en la capacidad cognitiva en el análisis intragrupo. En el NPI se produjeron diferencias entre el grupo de mindfulness y el control al final del estudio (p < 0,017). Conclusión. Los datos muestran que el tratamiento de donepezilo con mindfulness o estimulación cognitiva presenta una mejor evolución clínica que el tratamiento farmacológico solo o combinado con relajación. Estos datos indican que se debe seguir trabajando en nuevas alternativas terapéuticas para la EA avanzada y que los tratamientos no farmacológicos deben ser recomendados en la práctica clínica para el control evolutivo de la enfermedad a largo plazo. Ensayos con un mayor número de participantes son necesarios para confirmar los resultados informados en este estudio (AU)

Introduction. A longitudinal study was conducted in order to analyze the feasibility, safety, and effects of the practice of mindfulness, relaxation and cognitive stimulation on the evolution of Alzheimer's disease, with the aim of testing the equivalence of these interventions. Material and methods. There were a total of 168 participants with probable Alzheimer's disease (AD) treated with donepezil. In the present article, the 21 participants with advanced AD who completed a follow-up period of 24 months are presented. The participants were grouped into three experimental groups (mindfulness, relaxation, and cognitive stimulation) and one control group. Each group carried out three weekly sessions with bi-annual follow-up measurements (cognition: CAMCOG and MMSE; functionality: RDRS; psychopathology: NPI). Non-parametric analyses were performed. Results. The cognitive function and functionality scores showed no significant differences between the groups. However, the scores in cognitive function of the mindfulness group and the cognitive stimulation group did not decrease in an intra-group analysis. In NPI, there were significant differences between the mindfulness group and the control group by the end of the study (P<.017). Conclusion. The data showed that the treatment with donepezil in combination with mindfulness or cognitive stimulation presented a better clinical evolution than the pharmacological treatment alone or combined with relaxation. These data suggest that these therapeutic alternatives should be investigated further, and that the non-pharmacological treatments should be recommended in clinical practice in order to control the evolution of AD in the long term. In order to confirm these findings, a larger study is necessary (AU)

[Mindfulness-based stimulation in advanced Alzheimer's disease: A comparative, non-inferiority, clinical pilot study]. / Estimulación basada en mindfulness en la enfermedad de Alzheimer avanzada: ensayo clínico piloto comparativo de equivalencia.

INTRODUCTION: A longitudinal study was conducted in order to analyze the feasibility, safety, and effects of the practice of mindfulness, relaxation and cognitive stimulation on the evolution of Alzheimer's disease, with the aim of testing the equivalence of these interventions. MATERIAL AND METHODS: There were a total of 168 participants with probable Alzheimer's disease (AD) treated with donepezil. In the present article, the 21 participants with advanced AD who completed a follow-up period of 24 months are presented. The participants were grouped into three experimental groups (mindfulness, relaxation, and cognitive stimulation) and one control group. Each group carried out three weekly sessions with bi-annual follow-up measurements (cognition: CAMCOG and MMSE; functionality: RDRS; psychopathology: NPI). Non-parametric analyses were performed. RESULTS: The cognitive function and functionality scores showed no significant differences between the groups. However, the scores in cognitive function of the mindfulness group and the cognitive stimulation group did not decrease in an intra-group analysis. In NPI, there were significant differences between the mindfulness group and the control group by the end of the study (P<.017). CONCLUSION: The data showed that the treatment with donepezil in combination with mindfulness or cognitive stimulation presented a better clinical evolution than the pharmacological treatment alone or combined with relaxation. These data suggest that these therapeutic alternatives should be investigated further, and that the non-pharmacological treatments should be recommended in clinical practice in order to control the evolution of AD in the long term. In order to confirm these findings, a larger study is necessary.

Utilidad de los marcadores de remodelado óseo en la detección de enfermedad mineral ósea en pacientes con fenilcetonuria / Utility of bone turnover markers in metabolic bone disease detection in patients with phenylketonuria

Fundamento y objetivo: La enfermedad mineral ósea (EMO) es más frecuente en pacientes con fenilcetonuria. Los objetivos del estudio son conocer la utilidad de los marcadores de remodelado óseo para identificar a pacientes con fenilcetonuria con EMO y conocer las alteraciones del remodelado óseo subyacentes. Pacientes y método: Estudio observacional transversal de 43 pacientes con fenilcetonuria > 7 años (extremos 7,1-41 años). Se realizó encuesta nutricional, densitometría, determinación de fosfatasa alcalina ósea (FAO), procollagen type 1 N-terminal propeptide (PNP-1, «propéptido aminoterminal del procolágeno tipo 1»), beta-crosslaps y relación calcio/creatinina en orina. Se estratificó a los pacientes por edad y tipo de tratamiento. Resultados: El 20,9% de los pacientes presentaron marcadores de remodelado óseo patológicos; el 90% de ellos eran adultos. La FAO estaba disminuida en el 70% de ellos, y el beta-crosslaps en el 42,8%. Los valores de FAO fueron patológicos con más frecuencia en diagnosticados de fenilcetonuria tardíamente (41,7 frente a 10,7%; p < 0,05) y en pacientes con EMO (60 frente a 14,3%; p < 0,05). Los valores de PNP-1 y calcio/creatinina fueron similares entre todos los pacientes con fenilcetonuria independientemente de presentar EMO, diagnóstico tardío o tratamiento con tetrahidrobiopterina. Los pacientes con disminución de FAO y beta-crosslaps recibieron menor ingesta de proteínas naturales: FAO (media [DE] de 0,21 [0,13] frente a 0,65 [0,65] g/kg; p < 0,05); beta-crosslaps (media de 0,29 [0,23] frente a 0,65 [0,66] g/kg; p < 0,05). Ninguno de los tratados con tetrahidrobiopterina presentó valores alterados de marcadores óseos. Conclusiones: Los pacientes adultos fenilcetonúricos con menor ingesta de proteínas naturales tienden a presentar valores disminuidos de FAO, marcador que puede resultar útil para identificar a los pacientes con riesgo de presentar EMO (AU)

Background and objective: Mineral bone disease is more common in phenylketonuric patients. The objectives of this study were to determine the usefulness of biochemical bone markers to identify phenylketonuric patients with mineral bone disease (MBD) and know the underlying bone remodeling alterations. Patients and method: Cross-sectional study of 43 phenylketonuric patients > 7 years (range: 7.1-41 years). A nutritional survey was performed and bone alkaline phosphatase (BAP), procollagen type 1 N-terminal propeptide (PNP-1), beta-crosslaps and ratio calcium/creatinine in urine were determined. Results: A percentage of 20.9 of patients had pathological biochemical bone markers, 90% of them being adults. BAP was decreased in 70% of them and beta-crosslaps in 42.8%. BAP values were more often pathological in phenylketonuric patients with a late diagnosis (41.7 vs. 10.7%; P < .05) and in patients with MBD (60 vs. 14.3%; P < .05). PNP-1 values and calcium/creatinine were similar among all phenylketonuric patients regardless of presenting MBD, late diagnosis or tetrahydrobipterin treatment (enzyme cofactor). Patients with decreased BAP and beta-crosslaps had lower natural protein intake: BAP (0.21 ± 0.13 vs. 0.65 ± 0.65 g/kg; P < .05); beta-crosslaps (0.29 ± 0.23 vs. 0.65 ± 0.66 g/kg; P < .05). None of the tetrahydrobiopterin treated patients showed altered values of BAP, PNP-1 or calcium/creatinine. Conclusions: Adult phenylketonuric patients with lower natural protein intake tend to have lower values of BAP, which is a marker that may be useful to identify patients at risk for MBD (AU)

[Utility of bone turnover markers in metabolic bone disease detection in patients with phenylketonuria]. / Utilidad de los marcadores de remodelado óseo en la detección de enfermedad mineral ósea en pacientes con fenilcetonuria.

BACKGROUND AND OBJECTIVE: Mineral bone disease is more common in phenylketonuric patients. The objectives of this study were to determine the usefulness of biochemical bone markers to identify phenylketonuric patients with mineral bone disease (MBD) and know the underlying bone remodeling alterations. PATIENTS AND METHOD: Cross-sectional study of 43 phenylketonuric patients>7 years (range: 7.1-41 years). A nutritional survey was performed and bone alkaline phosphatase (BAP), procollagen type 1 N-terminal propeptide (PNP-1), beta-crosslaps and ratio calcium/creatinine in urine were determined. RESULTS: A percentage of 20.9 of patients had pathological biochemical bone markers, 90% of them being adults. BAP was decreased in 70% of them and beta-crosslaps in 42.8%. BAP values were more often pathological in phenylketonuric patients with a late diagnosis (41.7 vs. 10.7%; P<.05) and in patients with MBD (60 vs. 14.3%; P<.05). PNP-1 values and calcium/creatinine were similar among all phenylketonuric patients regardless of presenting MBD, late diagnosis or tetrahydrobipterin treatment (enzyme cofactor). Patients with decreased BAP and beta-crosslaps had lower natural protein intake: BAP (0.21 ± 0.13 vs. 0.65 ± 0.65 g/kg; P<.05); beta-crosslaps (0.29 ± 0.23 vs. 0.65 ± 0.66 g/kg; P<.05). None of the tetrahydrobiopterin treated patients showed altered values of BAP, PNP-1 or calcium/creatinine. CONCLUSIONS: Adult phenylketonuric patients with lower natural protein intake tend to have lower values of BAP, which is a marker that may be useful to identify patients at risk for MBD.

Humanized medium (h7H) allows long-term primary follicular thyroid cultures from human normal thyroid, benign neoplasm, and cancer.

CONTEXT: Mechanisms of thyroid physiology and cancer are principally studied in follicular cell lines. However, human thyroid cancer lines were found to be heavily contaminated by other sources, and only one supposedly normal-thyroid cell line, immortalized with SV40 antigen, is available. In primary culture, human follicular cultures lose their phenotype after passage. We hypothesized that the loss of the thyroid phenotype could be related to culture conditions in which human cells are grown in medium optimized for rodent culture, including hormones with marked differences in its affinity for the relevant rodent/human receptor. OBJECTIVE: The objective of the study was to define conditions that allow the proliferation of primary human follicular thyrocytes for many passages without losing phenotype. METHODS: Concentrations of hormones, transferrin, iodine, oligoelements, antioxidants, metabolites, and ethanol were adjusted within normal homeostatic human serum ranges. Single cultures were identified by short tandem repeats. Human-rodent interspecies contamination was assessed. RESULTS: We defined an humanized 7 homeostatic additives medium enabling growth of human thyroid cultures for more than 20 passages maintaining thyrocyte phenotype. Thyrocytes proliferated and were grouped as follicle-like structures; expressed Na+/I- symporter, pendrin, cytokeratins, thyroglobulin, and thyroperoxidase showed iodine-uptake and secreted thyroglobulin and free T3. Using these conditions, we generated a bank of thyroid tumors in culture from normal thyroids, Grave's hyperplasias, benign neoplasms (goiter, adenomas), and carcinomas. CONCLUSIONS: Using appropriate culture conditions is essential for phenotype maintenance in human thyrocytes. The bank of thyroid tumors in culture generated under humanized humanized 7 homeostatic additives culture conditions will provide a much-needed tool to compare similarly growing cells from normal vs pathological origins and thus to elucidate the molecular basis of thyroid disease.

Evolution of subclinical hypothyroidism in children treated with antiepileptic drugs.

The concentration levels of serum free thyroxine, serum free triiodothyronine, and thyroid-stimulating hormone were measured in 20 children receiving carbamazepine, 32 children receiving valproic acid, and 5 children receiving phenobarbital at the following times: (1) during chronic treatment, and (2) 3 months after the end of treatment with antiepileptic drugs. Patients during chronic treatment revealed significant changes in serum thyroid hormones, especially the children treated with carbamazepine and valproic acid. A number of children receiving long-term therapy with the two last antiepileptic drugs had varying grades of subclinical hypothyroidism. Three months after the end of treatment, a complete return to normal of all parameters was observed. These data demonstrate that the changes induced by these drugs are transient and reversible.

Evolution of serum lipids and lipoprotein (a) levels in epileptic children treated with carbamazepine, valproic acid, and phenobarbital.

The concentration levels of serum lipids and lipoprotein (a) were measured in 20 children receiving carbamazepine, 25 children receiving valproic acid, and 5 children receiving phenobarbital at the following times: (1) during chronic treatment while eating a normal diet, (2) during chronic treatment while eating a low-fat diet (children treated with carbamazepine and phenobarbital with high levels of total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), and (3) 3 months after the end of treatment with antiepileptic drugs. Patients during chronic treatment and eating a normal diet revealed significant changes in lipids, but when we reevaluated the groups of children treated with carbamazepine and phenobarbital when they were eating a low-fat diet and reevaluated the three groups of children 3 months after the end of treatment, a complete return to normal of all parameters was observed. These data demonstrate that the changes induced by these drugs are transient, reversible, and influenced by a low-fat diet. (J Child Neurol 2006;21:48-53).

Levels of pentosidine in the vitreous of eyes with proliferative diabetic retinopathy, proliferative vitreoretinopathy and retinal detachment.

BACKGROUND: Advanced glycosylation end products (AGEs) are thought to play an important role in the pathophysiology of diabetes. Particularly, these products have been implicated in the pathogenesis of proliferative diabetic retinopathy. The majority of these products are formed from a vast range of precursor molecules, the variable chemical nature of which contributes to AGE heterogeneity. There is a growing population of structurally defined AGE adducts such as pyrraline, pentosidine, CML and crossline that have been found to be elevated in diabetic tissues. In the present study, the levels of the glycoxidation product pentosidine were determined in vitreous samples obtained during vitrectomy from eyes with proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR), and retinal detachment (RD). Samples from cadaveric control eyes were also included in the study. The levels of pentosidine were compared among the groups. METHODS: Seventy-three vitreous samples were collected from eyes undergoing vitrectomy for PDR (n=33), PVR (n=28) and RD (n=12). Eighteen samples from cadaveric control eyes were also included in the study. A modified Bradford's method was used to assay protein content, and vitreous levels of pentosidine were determined by high-performance liquid chromatography after acid hydrolysis and pretreatment with SP-Sephadex. Statistical analyses were performed using a two-sided Mann-Whitney U test. RESULTS: The levels of pentosidine [median (interquartile range)] were 0.92 (0.55-1.26) pmol/mg of protein in the PDR cases, 1.12 (0.46-1.80) pmol/mg of protein in PVR, and 1.02 (0.24-1.44) pmol/mg of protein in RD. In the cadaveric control eyes pentosidine levels were 0.97 (0.68-1.30) pmol/mg of protein. The pentosidine levels of the four groups did not differ significantly. CONCLUSIONS: The levels of the glycoxidation product pentosidine (expressed as pmol/mg of protein) in the vitreous of eyes with PDR do not differ significantly from those in the vitreous of eyes with PVR, RD or cadaveric control eyes. Although these results do not refute the findings of previous studies that evaluated globally total AGE levels and the existence of diabetic vitreopathy, further investigation is needed to fully understand their relevance in this multifactorial disorder.

Neuron-specific enolase, nucleotides, nucleosides, purine bases, oxypurines and uric acid concentrations in cerebrospinal fluid of children with meningitis.

To determine the effects of meningitis on cerebral energy metabolism, cerebrospinal fluid concentrations of adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine and urate were determined by high-performance liquid chromatography, and neuron-specific enolase by an enzyme immunoassay method, in 100 children with meningitis (45 bacterial, 46 viral and nine tuberculous), aged between 1 month and 13 years, and in 160 age-matched controls. Compared with controls, patients with bacterial meningitis showed high concentrations of hypoxanthine, xanthine and urate; patients with viral meningitis showed high concentrations of inosine, guanosine, xanthine, urate and neuron-specific enolase; and patients with tuberculous meningitis showed very high concentrations of inosine, xanthine and urate. Xanthine and urate concentrations were significantly higher in patients with tuberculous meningitis than in patients with viral or bacterial meningitis. These results suggest that in the acute stage of bacterial, viral and tuberculous meningitis, neuronal energy metabolism may be altered. The measurement of cerebrospinal xanthine and uric acid concentrations may be useful for the early diagnosis of a tuberculous origin.