Biomarkers in ocular chronic graft versus host disease: tear cytokine- and chemokine-based predictive model.

Producción CientíficaPurpose: To develop a tear molecule level-based predictive model based on a panel of tear cytokines and their correlation with clinical features in ocular chronic graft versus host disease (cGVHD). Methods: Twenty-two ocular cGVHD patients and 21 healthy subjects were evaluated in a controlled environmental research laboratory (CERLab). Clinical parameters were recorded, and tears were collected. Levels of 15 molecules (epidermal growth factor [EGF], IL receptor antagonist [IL-1Ra], IL-1β, IL-2, IL-6, IL-8/CXCL8, IL-10, IL-12p70, IL-17A, interferon inducible protein [IP]-10/CXCL10, IFN-γ, VEGF, TNF-α, eotaxin 1, and regulated on activation normal T cell expressed and secreted [RANTES]) were measured by multiplex-bead assay and correlated with clinical parameters. Logistic regression was used to develop a predictive model. Leave-one-out cross-validation was applied. Classification capacity was evaluated in a cohort of individuals with dry eye (DE) of other etiologies different from GVHD. Results: Epidermal growth factor and IP-10/CXCL10 levels were significantly decreased in ocular cGVHD, positively correlating with tear production and stability and negatively correlating with symptoms, hyperemia, and vital staining. Interleukin-1Ra, IL-8/CXCL8, and IL-10 were significantly increased in ocular cGVHD, and the first two correlated positively with symptoms, hyperemia, and ocular surface integrity while negatively correlating with tear production and stability. Predictive models were generated, and the best panel was based on IL-8/CXCL8 and IP-10/CXCL10 tear levels along with age and sex, with an area under the receiving operating curve of 0.9004, sensitivity of 86.36%, and specificity of 95.24%. Conclusions: A predictive model based on tear levels of IL-8/CXCL8 and IP-10/CXCL10 resulted in optimal sensitivity and specificity. These results add further knowledge to the search for potential biomarkers in this devastating ocular inflammatory disease.Ministry of Economy and Competitiveness, Madrid, Spain, SAF-2010 15631 (AES)

Age and sex-adjusted reference intervals in tear cytokine levels in healthy subjects

Producción CientíficaAlterations in tear cytokine levels have been associated with various ocular disorders as compared to those in healthy subjects. However, age and sex are not always considered in these comparisons. In this study we aimed to establish age and sex reference intervals (RIs) for tear cytokine levels in healthy people. Tear samples were taken from 75 males and 82 females, aged 18–88 years, and tear cytokine levels were determined. Age- and sex-adjusted RIs for epidermal growth factor (EGF), fractalkine, interleukin (IL)-1 receptor antagonist (RA), IL-7, IL-8, interferon inducible protein (IP)-10, monocyte chemotactic protein (MCP)-1, and vascular endothelial growth factor (VEGF) tear cytokine levels in a healthy sample were established using generalized additive for location, scale and shape (GAMLSS) models. RIs were tested in two external samples: a validation sample of 40 individuals with normal results at four Dry Eye Disease (DED) clinical diagnostic tests (OSDI, T-BUT, corneal staining and Schirmer test); and a utility sample of 13 severe DED cases. IL-1RA, IL-8, IP-10, and MCP-1 levels showed a positive association with age, while EGF was negatively correlated. IL-7 concentration increased up to 40 years and again after 70 years, observing a quasi-linear decrease between them. For VEGF, higher levels were observed in the middle-aged range. Regarding sex-influence, fractalkine tear levels were higher in men, whereas those of IL-7, IL-8, and IP-10 were higher in women. Using the estimated age- and sex-adjusted RIs, more than 92% of the validation sample was correctly classified, and 100% of the severe DED patients in the utility sample had concentrations outside the RIs in at least two of the cytokines evaluated

Parámetros subjetivos de sueño y estado de ánimo disfórico

The objective of the present study is to analyse the relationship between several subjective parameters of sleep quantity and sleep quality and dysphoric mood in healthy subjects under normal conditions. The sample was composed of 257 university students. A questionnaire about sleep habits and the Beck Depression Inventory were carried out. There were significant differences in dysphoric mood according to habitual sleep duration but not to necessary sleep duration. The subjects who habitually sleep for less than 7 hours are those who present a worse dysphoric mood. There were differences in dysphoric mood dependent upon the existence or otherwise of an adjustment between habitual and necessary sleep hours. The subjects who habitually sleep less hours than they need are those who show more symptoms of dysphoric mood. On the other hand, it has been found that dysphoric mood is related to sleep latency, number of awakenings, sleep regularity and satisfaction with sleep quality. The data supports the importance of sleep and its relationship to measures of well-being in the non-clinical population. El objetivo del presente estudio es analizar la relación entre diversos parámetros subjetivos de cantidad y calidad de sueño y estado de ánimo disfórico en una muestra de sujetos sanos bajo condiciones normales. La muestra estaba compuesta por 257 estudiantes universitarios. Se administró un cuestionario sobre hábitos de sueño y el Inventario de Depresión de Beck. Se han encontrado diferencias significativas en estado de ánimo disfórico en función de las horas habituales de sueño pero no de las horas necesarias de sueño. Los sujetos que duermen habitualmente menos de 7 horas presentan un estado de ánimo más disfórico. También se han encontrado diferencias en estado de ánimo disfórico en función del ajuste o no entre horas habituales y horas necesarias de sueño. Los sujetos que duermen habitualmente menos horas de las que necesitan muestran más síntomas de disforia. Por otro lado, el estado de ánimo disfórico se relaciona con latencia de sueño, número de despertares nocturnos, regularidad del sueño y grado de satisfacción con la calidad de sueño. Los datos apoyan la importancia del sueño y su relación con medidas del bienestar psicológico en poblaciones no clínicas

Anti-Inflammatory (M2) Response Is Induced by a sp(2)-Iminosugar Glycolipid Sulfoxide in Diabetic Retinopathy

Diabetic retinopathy (DR) is one of the most common complications of Diabetes Mellitus (DM) and is directly associated with inflammatory processes. Currently, neuro-inflammation is considered an early event in DR and proceeds via microglia polarization. A hallmark of DR is the presence of retinal reactive gliosis. Here we report the beneficial effect of (S (S),1R)-1-docecylsulfiny-5N,6O-oxomethylidenenojirimycin ((Ss)-DS-ONJ), a member of the sp(2)-iminosugar glycolipid (sp(2)-IGL) family, by decreasing iNOS and inflammasome activation in Bv.2 microglial cells exposed to pro-inflammatory stimuli. Moreover, pretreatment with (Ss)-DS-ONJ increased Heme-oxygenase (HO)-1 as well as interleukin 10 (IL10) expression in LPS-stimulated microglial cells, thereby promoting M2 (anti-inflammatory) response by the induction of Arginase-1. The results strongly suggest that this is the likely molecular mechanism involved in the anti-inflammatory effects of (S (S))-DS-ONJ in microglia. (S (S))-DS-ONJ further reduced gliosis in retinal explants from type 1 diabetic BB rats, which is consistent with the enhanced M2 response. In conclusion, targeting microglia polarization dynamics in M2 status by compounds with anti-inflammatory activities offers promising therapeutic interventions at early stages of DR

La calidad de vida relacionada con la salud en fumadores que han recaído

Background: Previous studies have shown that smoking is associated with health-related quality of life (HRQoL) impairment. In order to evaluate HRQoL in a sample of Spanish relapsers, a cross-sectional study was conducted. Method: The sample was made up of 775 smokers who had relapsed after a period of abstinence. HRQoL was evaluated using the Euro-Qol questionnaire (EQ-5D); through the descriptive profi le, the EQ-5D index and the visual analogue scale (EQ-VAS). Results: Higher nicotine dependence was related to worse HRQL. According to the EQ-VAS, higher daily cigarette consumption and more years smoking were related to worse perceived health. In the EQ-5D those who had quit smoking in the previous year perceived worse health. Mobility and anxiety / depression are the dimensions affected by smoking. Those who are more nicotine dependent (OR = 2.29) and have been smoking for longer (OR = 4.12) are more likely to have mobility problems; and those who are nicotine dependent (OR = 1.85) and relapsed more than a year ago (OR = 0.63), are more likely to experience anxiety / depression. Conclusions: Nicotine dependence demonstrated a determining effect on HRQOL deterioration in smokers who have relapsedAntecedentes: estudios previos demuestran que fumar produce un deterioro de la calidad de vida relacionada con la salud (CVRS). Para evaluar la CVRS en fumadores españoles que han recaído se realizó un estudio transversal. Método: la muestra estaba formada por 775 fumadores que habían recaído tras un período de abstinencia. La CVRS se evaluó mediante el cuestionario Euro-Qol 5D (EQ-5D), utilizando el perfi l descriptivo, el índice EQ-5D y la escala visual-analógica (EQ-EVA). Resultados: a mayor dependencia de la nicotina peor CVRS. En la EQEVA, a mayor consumo diario de cigarrillos y más años consumiendo, peor estado de salud percibido. En el EQ-5D los que dejaron de fumar en el último año son los que perciben peor estado de salud. Movilidad y ansiedad/depresión son las dimensiones afectadas en esta muestra de fumadores que han recaído. Es más probable que tengan problemas en movilidad los que tienen dependencia (OR = 2,29) y llevan más años fumando (OR = 4,12), y es más probable que presenten ansiedad/depresión los dependientes (OR = 1,85) y los que recayeron hace más de un año (OR = 0,63). Conclusiones: la dependencia de la nicotina mostró un efecto determinante en el deterioro de la CVRS en fumadores que han recaídoThis research was supported by Spanish Ministerio de Economía y Competitividad (References: PSI2012-31196) and FEDER (European Regional Development Fund)S

P73 plays a role in erythroid differentiaion through GATA1 induction

The TP73 gene gives rise to transactivation domain-p73 isoforms (TAp73) as well as ΔNp73 variants with a truncated N terminus. Although TAp73α and -Β proteins are capable of inducing cell cycle arrest, apoptosis, and differentiation, ΔNp73 acts in many cell types as a dominant-negative repressor of p53 and TAp73. It has been proposed that p73 is involved in myeloid differentiation, and its altered expression is involved in leukemic degeneration. However, there is little evidence as to which p73 variants (TA or ΔN) are expressed during differentiation and whether specific p73 isoforms have the capacity to induce, or hinder, this differentiation in leukemia cells. In this study we identify GATA1 as a direct transcriptional target of TAp73α. Furthermore, TAp73α induces GATA1 activity, and it is required for erythroid differentiation. Additionally, we describe a functional cooperation between TAp73 and ΔNp73 in the context of erythroid differentiation in human myeloid cells, K562 and UT-7. Moreover, the impaired expression of GATA1 and other erythroid genes in the liver of p73KO embryos, together with the moderated anemia observed in p73KO young mice, suggests a physiological role for TP73 in erythropoiesis.Peer reviewe

p73 deficiency results in impaired self renewal and premature neuronal differentiation of mouse neural progenitors independently of p53

[EN] The question of how neural progenitor cells maintain its self-renewal throughout life is a fundamental problem in cell biology with implications in cancer, aging and neurodegenerative diseases. In this work, we have analyzed the p73 function in embryonic neural progenitor cell biology using the neurosphere (NS)-assay and showed that p73-loss has a significant role in the maintenance of neurosphere-forming cells in the embryonic brain. A comparative study of NS from Trp73-/-, p53KO, p53KO;Trp73-/- and their wild-type counterparts demonstrated that p73 deficiency results in two independent, but related, phenotypes: a smaller NS size (related to the proliferation and survival of the neural-progenitors) and a decreased capacity to form NS (self-renewal). The former seems to be the result of p53 compensatory activity, whereas the latter is p53 independent. We also demonstrate that p73 deficiency increases the population of neuronal progenitors ready to differentiate into neurons at the expense of depleting the pool of undifferentiated neurosphere-forming cells. Analysis of the neurogenic niches demonstrated that p73-loss depletes the number of neural-progenitor cells, rendering deficient niches in the adult mice. Altogether, our study identifies TP73 as a positive regulator of self-renewal with a role in the maintenance of the neurogenic capacity. Thus, proposing p73 as an important player in the development of neurodegenerative diseases and a potential therapeutic targetSILGC is beneficiary of a predoctoral fellowship from Consejo de Educación de la Junta de Castilla y León and RFA from Spanish Ministerio de Ciencia e Innovación. This work was supported by Grants SAF2009-07897 from Spanish Ministerio de Ciencia e Innovacion (to MCM), Grant from Cajas de Ahorro de Castilla y León (to MCM), and Grants LE030A07 (to MMM) and LE015A10-2 (to MCM) from the Junta de Castilla y Leó

Inflammation-related molecules in tears of patients with chronic ocular pain and dry eye disease

Producción CientíficaThe purpose of this study was to analyze inflammation- and pain-related molecules in tears of patients suffering from chronic ocular pain associated with dry eye (DE) and/or a previous corneal refractive surgery (RS). Based on history, symptomatology, and clinical signs, the subjects (n = 180, 51.0 ± 14.7 years, 118 females, 62 males) in this cross-sectional study were assigned to one of five groups: DE and chronic ocular pain after RS (P/DE-RS, n = 52); asymptomatic subjects, i.e., without DE and chronic ocular pain, after RS (A-RS, n = 30); DE and chronic ocular pain without previous RS (P/DE-nonRS, n = 31); DE, no pain, and no previous RS (DE-nonRS, n = 35); and asymptomatic subjects with no previous RS (controls, n = 32). The tear concentrations of 20 cytokines and substance P (SP) were analyzed by immunobead-based assay and enzyme-linked immunosorbent assay, respectively. We found that tear levels of interleukin (IL)-10 and SP were increased in the RS groups. There were significant differences in IL-8/CXCL8 among the five groups. Nerve growth factor (NGF) tear levels were significantly higher in P/DE-RS than in DE-nonRS and controls. IL-9 had the highest percentage of detection in the P/DE-RS and P/DE-nonRS groups, while macrophage inflammatory protein (MIP)-1α, IL-2, and interferon (IFN)-γ were higher in the P/DE-RS, A-RS, and P/DE-nonRS groups. IL-17A was detected only in the A-RS group. Moderate correlations were observed in the A-RS, P/DE-nonRS, DE-nonRS and controls groups. A positive correlation was obtained between growth related oncogene concentration and tear break-up time (rho = 0.550; p = 0.012), while negative correlation was found between monocyte chemoattractant protein-3/CCL7 and conjunctival staining (rho = −0.560; p = 0.001), both in the A-RS group. IL-10 correlated positively with ocular pain intensity (rho = 0.513; p = 0.003) in the P/DE-nonRS group. Regulated on Activation Normal T Cell Expressed and Secreted/CCL5 correlated negatively with conjunctival staining (rho = −0.545; p = 0.001) in the DE-nonRS group. SP correlated negatively with corneal staining (rho = −0.559; p = 0.001) in the controls. In conclusion, chronic ocular pain was associated with higher IL-9 tear levels. IL-10, SP, MIP-1α/CCL3, IL-2, and IFN-γ were associated with previous RS. Higher levels of IL-8/CXCL8, MIP-1α/CCL3, IL-2, and IFN-γ were associated with DE-related inflammation, while NGF levels were related to chronic ocular pain and DE in RS patients. These findings suggest that improved knowledge of tear cytokines and neuromodulators will lead to a more nuanced understanding of how these molecules can serve as biomarkers of chronic ocular pain, leading to better therapeutic and disease management decisions.Ministerio de Ciencia, Innovación y Universidades (grants SAF-2016-77080-P, FPU17/02715 and FPU15/01443

Leveraging electronic healthcare record standards and semantic web technologies for the identification of patient cohorts

Introduction The secondary use of Electronic Healthcare Records (EHRs) often requires the identification of patient cohorts. In this context, an important problem is the heterogeneity of clinical data sources, which can be overcome with the combined use of standardized information models, Virtual Health Records, and semantic technologies, since each of them contributes to solving aspects related to the semantic interoperability of EHR data. Our main objective is to develop methods allowing for a direct use of EHR data for the identification of patient cohorts leveraging current EHR standards and semantic web technologies. Materials and Methods We propose to take advantage of the best features of working with EHR standards and ontologies. Our proposal is based on our previous results and experience working with both technological infrastructures. Our main principle is to perform each activity at the abstraction level with the most appropriate technology available. This means that part of the processing will be performed using archetypes (i.e., data level) and the rest using ontologies (i.e., knowledge level). Our approach will start working with EHR data in proprietary format, which will be first normalized and elaborated using EHR standards and then transformed into a semantic representation, which will be exploited by automated reasoning. Results We have applied our approach to protocols for colorectal cancer screening. The results comprise the archetypes, ontologies and datasets developed for the standardization and semantic analysis of EHR data. Anonymized real data has been used and the patients have been successfully classified by the risk of developing colorectal cancer. Conclusion This work provides new insights in how archetypes and ontologies can be effectively combined for EHR-driven phenotyping. 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