Assessment of Susceptibility Risk Factors for ADHD in Imaging Genetic Studies.

OBJECTIVE: ADHD consists of a count of symptoms that often presents heterogeneity due to overdispersion and excess of zeros. Statistical inference is usually based on a dichotomous outcome that is underpowered. The main goal of this study was to determine a suited probability distribution to analyze ADHD symptoms in Imaging Genetic studies. METHOD: We used two independent population samples of children to evaluate the consistency of the standard probability distributions based on count data for describing ADHD symptoms. RESULTS: We showed that the zero-inflated negative binomial (ZINB) distribution provided the best power for modeling ADHD symptoms. ZINB reveals a genetic variant, rs273342 (Microtubule-Associated Protein [MAPRE2]), associated with ADHD ( p value = 2.73E-05). This variant was also associated with perivascular volumes (Virchow-Robin spaces; p values < 1E-03). No associations were found when using dichotomous definition. CONCLUSION: We suggest that an appropriate modeling of ADHD symptoms increases statistical power to establish significant risk factors.

Child t-shirt size data set from 3D body scanner anthropometric measurements and a questionnaire.

A dataset of a fit assessment study in children is presented. Anthropometric measurements of 113 children were obtained using a 3D body scanner. Children tested a t-shirt of different sizes and a different model for boys and girls, and their fit was assessed by an expert. This expert labeled the fit as 0 (correct), -1 (if the garment was small for that child), or 1 (if the garment was large for that child) in an ordered factor called Size-fit. Moreover, the fit was numerically assessed from 1 (very poor fit) to 10 (perfect fit) in a variable called Expert evaluation. This data set contains the differences between the reference mannequin of the evaluated size and the child׳s anthropometric measurements for 27 variables. Besides these variables, in the data set, we can also find the gender, the size evaluated, and the size recommended by the expert, including if an intermediate, but nonexistent size between two consecutive sizes would have been the right size. In total, there are 232 observations. The analysis of these data can be found in Pierola et al. (2016) [2].

Interaction between airborne copper exposure and ATP7B polymorphisms on inattentiveness in scholar children.

Recent research indicates that airborne copper exposure in scholar children negatively affects brain functioning. These effects are likely to be influenced by the efficiency of copper metabolism, which is partly regulated by the ATPase copper transporting beta (ATP7B) gene. We investigated whether indoor and outdoor airborne copper exposure is differentially associated with child inattentiveness depending on genetic variation within the ATP7B gene in 1645 scholar children from the BREATHE project. Outdoor (courtyard) and indoor (classroom) air pollution levels were measured during class hours in each school. Inattentiveness was assessed through a follow-up with four measurements via the Attentional Network Test (4475 observations). Linear mixed models considering repeated measures were conducted to assess genetic and exposure main and interaction effects. Two interactions were detected indicating that ATP7B-rs1061472 (P for interaction 0.016) and ATP7B-rs1801243 (P for interaction 0.003) polymorphisms modified the association between indoor copper exposure and inattentiveness. Stratified analysis by genotypes revealed that both outdoor and indoor copper exposure increased inattentiveness in rs1061472-CC and rs1801243-CC carriers. These findings suggest that the genetic background promotes the association between airborne copper exposure at school with inattentiveness in children.

Childhood abuse in the etiological continuum underlying psychosis from first-episode psychosis to psychotic experiences.

GOAL: The present study aimed to examine the prevalence of child abuse across the continuum of psychosis. PATIENTS AND METHODS: The sample consisted of 198 individuals divided in three groups: (1) 48 FEP patients, (2) 77 individuals scoring high in Community Assessment of Psychic Experiences (CAPE), classified as "High CAPE" group and (3) 73 individuals scoring low, classified as "Low CAPE" group. Childhood abuse was assessed using self-report instruments. Chi(2) tests and logistic regression models controlling by sex, age and cannabis were used to perform three comparisons: (i) FEP vs. Low CAPE; (ii) FEP vs. High CAPE and (iii) High CAPE vs. Low CAPE. RESULTS: The frequency of individuals exposed to childhood abuse for FEP, High CAPE and Low CAPE groups were 52.1%, 41.6% and 11%, respectively. FEP and High CAPE group presented significantly higher rates of childhood abuse compared to Low CAPE group, however, no significant differences were found between FEP and High CAPE groups regarding the frequency of childhood abuse. CONCLUSION: There is an increasing frequency of childhood abuse from low subclinical psychosis to FEP patients. However, childhood abuse is equally common in FEP and at risk individuals.

Optimización de la metodología de cultivo de condrocitos de discos procedentes de hernias discales y comprobación de la presencia del Toll-like receptor 4 (TLR 4) / Optimization of methods of chondrocyte cell culture from human disc hernia subjects and testing the presence of Toll-like receptor 4 (TLR 4)

Objetivo: Optimizar la técnica de cultivo de células del disco intervertebral en humanos y confirmar la expresión del Toll-like receptor 4 (TLR4 ). Material y método: Se cultivaron muestras de núcleo pulposo obtenidas durante la cirugía de hernia discal. Las células cultivadas de los nueve pacientes (todos con degeneración del disco moderada-grave en la escala de Pfirrmann) fueron observadas para determinar su capacidad de crecimiento. Las células cultivadas obtenidas se estudiaron con el fin de determinar su fenotipo mediante inmunotinción y rtPCR. La presencia de TLR4 fue comprobada por los mismos métodos. Resultados: Las células aisladas se sembraron a diferentes concentraciones. La concentración ideal se obtuvo para las condiciones óptimas del cultivo. Se confirmó que el fenotipo de las células fue condrocitario y se confirmó la presencia del receptor TLR4 en las células cultivadas. Conclusión: Se confirma la presencia tanto de ARNm como de la proteína del receptor TLR4 en los condrocitos del disco intervertebral. Este hallazgo allana el camino para la caracterización de las funciones de este receptor en los procesos inflamatorios de la hernia de disco (AU)

Objective: To optimize the technique of culturing human intervertebral disc cells, and to confirm the expression of toll-like receptor 4 (TLR4) in these cells. Material and method: Samples of nucleus pulposus obtained during disc hernia surgery were cultured. Cells from nine patients (all with moderate-severe disc degeneration scores, based on the Pfirmann scale) were followed up to determine their growing capacity. The obtained cultured cells were tested for the chondrocyte phenotype by immunostaining and rt-PCR and the presence of TLR4 was tested by the same methods. Results: The cells were isolated and seeded at different concentrations. The ideal concentration was obtained for optimal culture conditions. The cells were confirmed to have the chondrocyte phenotype and TLR4 was confirmed to be present in the cultured cells. Conclusion: This study confirms the presence of both mRNA and TLR4 protein in intervertebral disc chondrocytes. This paves the way for elucidating of the roles of this receptor in the inflammatory processes of disc hernia (AU)

Cortical thickness correlates of psychotic experiences: examining the effect of season of birth using a genetically informative design.

Season of birth has been shown to influence risk for several neuropsychiatric diseases. Furthermore, it has been suggested that season of birth modifies a number of brain morphological traits. Since cortical thickness alterations have been reported across some levels of the psychosis-spectrum, this study was aimed at i) assessing the scarcely explored relationship between cortical thickness and severity of subclinical psychotic experiences (PEs) in healthy subjects, and ii) evaluating the potential impact of season of birth in the preceding thickness-PEs relationship. As both PEs and brain cortical features are heritable, the current work used monozygotic twins to separately evaluate familial and unique environmental factors. High-resolution structural MRI scans of 48 twins (24 monozygotic pairs) were analyzed to estimate cortical thickness using FreeSurfer. They were then examined in relation to PEs, accounting for the effects of birth season; putative differential relationships between PEs and cortical thickness depending on season of birth were also tested. Current results support previous findings indicative of cortical thickening in healthy individuals with high psychometrically assessed psychosis scores, probably in line with theories of compensatory aspects of brain features in non-clinical populations. Additionally, they suggest distinct patterns of cortical thickness-PEs relationships depending on birth seasonality. Familial factors underlying the presence of PEs may drive these effects.

The BDNF-Val66Met polymorphism modulates parental rearing effects on adult psychiatric symptoms: a community twin-based study.

PURPOSE: To test whether firstly, different parental rearing components were associated with different dimensions of psychiatric symptoms in adulthood, secondly BDNF-Val66Met polymorphism moderated this association and thirdly, this association was due to genetic confounding. METHOD: Perceived parental rearing according to Parental Bonding Instrument (PBI), psychiatric symptoms evaluated with the Brief Symptom Inventory (BSI) and the BDNF-Val66Met polymorphism were analyzed in a sample of 232 adult twins from the general population. RESULTS: In the whole sample, paternal care was negatively associated with depression. Maternal overprotection was positively associated with paranoid ideation, obsession-compulsion and somatization. Gene-environment interaction effects were detected between the BDNF-Val66Met polymorphism and maternal care on phobic anxiety, paternal care on hostility, maternal overprotection on somatization and paternal overprotection also in somatization. In the subsample of MZ twins, intrapair differences in maternal care were associated with anxiety, paranoid ideation and somatization. CONCLUSIONS: Met carriers were, in general, more sensitive to the effects of parental rearing compared to Val/Val carriers in relation to anxiety and somatization. Contra-intuitively, our findings suggest that high rates of maternal care might be of risk for Met carriers regarding anxiety. Results from analyses controlling for genetic confounding were in line with this finding.

Psychosis-inducing effects of cannabis are related to both childhood abuse and COMT genotypes.

OBJECTIVE: To test whether the association between childhood abuse, cannabis use and psychotic experiences (PEs) was moderated by the COMT (catechol-O-methyltransferase) gene. METHOD: Psychotic experiences (PEs), childhood abuse, cannabis use and COMT Val158Met genotypes were assessed in 533 individuals from the general population. Data were analysed hierarchically by means of multiple linear regression models. RESULTS: Childhood abuse showed a significant main effect on both positive (ß = 0.09; SE = 0.04; P = 0.047) and negative PEs (ß = 0.11; SE = 0.05; P = 0.038). A significant three-way interaction effect was found among childhood abuse, cannabis use and the COMT gene on positive PEs (ß = -0.30; SE = 0.11; P = 0.006). This result suggests that COMT genotypes and cannabis use only influenced PE scores among individuals exposed to childhood abuse. Furthermore, exposure to childhood abuse and cannabis use increased PE scores in Val carriers. However, in individuals exposed to childhood abuse but who did not use cannabis, PEs increased as a function of the Met allele copies of the COMT gene. CONCLUSION: Cannabis use after exposure to childhood abuse may have opposite effects on the risk of PEs, depending on the COMT genotypes providing evidence for a qualitative interaction. Val carriers exposed to childhood abuse are vulnerable to the psychosis-inducing effects of cannabis.

Childhood adversity and psychosis: examining whether the association is due to genetic confounding using a monozygotic twin differences approach.

PURPOSE: To test whether the association between childhood adversity and positive and negative psychotic experiences is due to genetic confounding. METHOD: Childhood adversity and psychotic experiences were assessed in an ongoing sample of 226 twins from the general population. A monozygotic (MZ) twin differences approach was used to assess possible genetic confounding. RESULTS: In the whole sample, childhood adversity was significantly associated with positive (ß=45; SE=0.16; P=0.008) and negative psychotic experiences (ß=0.77; SE=0.18; P<0.01). Within-pair MZ twin differences in exposure to childhood adversity were significantly associated with differences in positive (ß=71; SE=0.29; P=0.016) and negative psychotic experiences (ß=98; SE=0.38; P=0.014) in a subsample of 85 MZ twin pairs. CONCLUSIONS: Individuals exposed to childhood adversity are more likely to report psychotic experiences. Furthermore, our findings indicate that this association is not due to genetic confounding.

A multidimensional approach to the generation of helmets' design criteria: a preliminar study.

The design and development process of helmets incorporates systematically design criteria related to safety to accomplish European and local standards for the commercialization. However, there are few studies focused on user's comfort and adaptation. Present study tackles a multidimensional approach to gain better understanding of the interaction between helmet and user to generate design criteria for the internal helmet surface. Morphological characteristics of the target population, pressure distribution over head and subjective perception of fitting and discomfort are the factors considered to establish the criteria that assure a proper fit. Ten men corresponding to helmet size M and usual drivers of motorbike wore two helmet models in three sizes (S, M and L). The head shape of participants was acquired using the head scanner of I-Ware laboratory and an instrumented pad was used to measure pressure in five head regions. After wearing the helmet, users filled in a perception questionnaire about fitting, comfort and usability considering the five regions. Users' fitting perception provided the relation between pressure levels and the comfort felt in the five regions. This study constitutes a first approach to a new methodology to generate criteria to improve the design of helmets under a multidimensional approach.

A study of the viability of obtaining a generic animation of the foot while walking for the virtual testing of footwear using dorsal pressures.

Establishing the appropriate pressure exerted by the shoe upper over the foot surface is fundamental for the design of specific footwear, although measuring the dorsal pressures can also provide important additional information. In previous works, a virtual simulator to perform studies of comfort and functionality in CAD footwear design was presented. This paper describes the procedure carried out to obtain the foot animations used in this simulator. The virtual feet used in the simulator are feet without a standard form scanned in a static way. Their movements are rebuilt from the register of movements of several foot anatomical points during a complete step. The dorsal pressures exerted by some shoe uppers on these anatomical points were measured for several subjects and used to establish the viability of the use of these animations in a virtual simulator for footwear.

Estudio epidemiológico en voley y fútbol playa / Epidemiology of beach volleyball and beach soccer

Los deportes practicados en la arena están experimentando en la actualidad un gran auge, sin embargo y pese a su enorme difusión, la literatura epidemiológica en estos deportes es escasa. El propósito de este trabajo es presentar un estudio epidemiológico de vóley-playa y fútbol playa en el contexto español para conocer sus necesidades y contribuir a mejorar la vida deportiva de sus jugadores. Para ello, se realizó una encuesta a 89 sujetos, 54 jugadores de vóley-playa y 35 jugadores de fútbol playa, en la cual se recogían los aspectos epidemiológicos, así como las molestias y la sensación de disconfort. Los resultados del estudio muestran que las lesiones más habituales en vóley-playa son las de tipo tendinoso o ligamentoso (36%). Siendo las lesiones dermatológicas en fútbol playa las que presentan mayor incidencia (36%). Por zonas corporales, el pie y el tobillo son, en ambos deportes, las partes que sufren un mayor índice de lesión, la mayoría dermatológicas. La falta de protección de los pies y la ausencia de criterios para caracterizar la arena pueden ser dos razones de todo lo anterior. Teniendo en cuenta los resultados obtenidos se puede concluir que una buena protección para los pies así como el estudio de la arena son aspectos fundamentales para prevenir y minimizar las lesiones en estos deportes (AU)

In the last years beach sports are becoming more popular, although not many epidemiological studies can be found in the scientific literature. The aim of this paper consists of an epidemiological study focused in Spanish beach volley and beach soccer players, in order to analyze the player’s needs and improve several aspects of those sports. 89 subjects took part in the survey, 54 beach volley players and 35 beach soccer players. Epidemiological and personal data were gathered. Tendon and ligament injuries (36%) are the most common in beach volley. In beach soccer dermatological are the most common injuries (36%). In both sports foot and ankle are the anatomical zones that suffer the higher injury rate; it must be highlighted that the majority are of dermatological nature. The lack of foot protection and the lack of knowledge to characterize the sand are possible reasons for it. To conclude, a good sport gear to protect foot and ankle and a deep study of the sport surface (sand) is deemed necessary to prevent and reduce injury rate in both sports (AU)

p27kip protein levels and E2F activity are targets of Cot kinase during G1 phase progression in T cells.

Cot/Tpl-2 kinase, homologous to members of mitogen-activated protein kinase kinase kinase, was initially discovered by its capacity to promote cell transformation. Cot/Tpl-2 mRNA levels are increased during G(0) to G(1) phase progression in T lymphocytes, suggesting a role for this kinase later on in the cell cycle. The IL-2-dependent CTLL-2 cells were used to investigate the role of Cot kinase in G(1) to S phase transition. Transient expression of Cot kinase in CTLL-2 cells increases DNA synthesis triggered by IL-2 and the transient expression of a dominant negative form of Cot kinase in CTLL-2 markedly reduces the DNA synthesis triggered by this cytokine. Cell cycle analysis of synchronized CTLL-2 stabling overexpressing Cot kinase indicates that this kinase contributes to the passage to S and G(2)-M phases of the cell cycle. Cot kinase reduces the levels of the cyclin kinase inhibitor p27(kip), whereas bcl-x(L) expression is unaffected. Cot kinase also increases E2F transcriptional activity in a phosphatidylinositol 3 kinase-independent way and acts in synergy with this kinase. These data give evidence, for the first time, of the regulation of different G(1) progression events by Cot kinase.

Cot kinase induces cyclooxygenase-2 expression in T cells through activation of the nuclear factor of activated T cells.

Cyclooxygenase-2 (COX-2) is induced in human T lymphocytes upon T cell receptor triggering. Here we report that Cot kinase, a mitogen-activated protein kinase kinase kinase involved in T cell activation, up-regulates COX-2 gene expression in Jurkat T cells. Induction of COX-2 promoter activity by Cot kinase occurred mainly through activation of the nuclear factor of activated T cells (NFAT). Mutation of the distal (-105/-97) and proximal (-76/-61) NFAT response elements in the COX-2 promoter abolished the activation induced by Cot kinase. Even more, coexpression of a dominant negative version of NFAT inhibited Cot kinase-mediated COX-2 promoter activation, whereas cotransfection of a constitutively active version of the calcium-dependent phosphatase calcineurin synergizes with Cot kinase in the up-regulation of COX-2 promoter-driven transcription. Strikingly, Cot kinase increased transactivation mediated by a GAL4-NFAT fusion protein containing the N-terminal transactivation domain of NFATp. In contrast to phorbol ester plus calcium ionophore A23187, Cot kinase increases both COX-2 promoter activity and NFAT-mediated transactivation in a cyclosporin A-independent manner. These data indicate that Cot kinase up-regulates COX-2 promoter-driven transcription through the NFAT response elements, being the Cot kinase-induced NFAT-dependent transactivation presumably implicated in this up-regulation.

COT kinase proto-oncogene expression in T cells: implication of the JNK/SAPK signal transduction pathway in COT promoter activation.

COT/Tpl-2 proto-oncogene encodes a serine/threonine kinase implicated in cellular activation. In this study we have identified the human COT gene promoter region and three different human COT transcripts. These transcripts, with the same initiation site, display heterogeneity in their 5' untranslated regions and in their subcellular localization. Activation of Jurkat T cells with either calcium ionophore or alphaCD3 and a phorbol ester increases the levels of the different COT transcripts. Analysis of the 5' flanking region of the human COT gene reveals a unique transcription initiation site and a TATA element 20 nucleotides upstream. Transient expression of COT promoter constructs containing a reporter gene indicates that the transcriptional activity of the 5' flanking region of the COT gene is regulated by T cell-activating signals. Cotransfection of a dominant negative version of SEK-2 abolishes the inducible transcriptional activity of COT promoter, indicating that the inducible expression of the COT gene by T cell activating signals is mediated by the JNK/SAPK signal transduction pathway. All these data indicate stringent regulation of COT kinase proto-oncogene expression.

Regulation of cyclooxygenase activity by metamizol.

The ability of metamizol to inhibit cyclooxygenase-1 and cyclooxygenase-2 activities has been evaluated using different cyclooxygenase sources. Metamizol inhibited purified cyclooxygenase-1 and cyclooxygenase-2 with an IC50 of about 150 microg/ml. A similar IC50 value for cyclooxygenase-2 was obtained in lipopolysaccharide-activated broken murine macrophages. Consistent with these findings, molecular models of the complexes between cyclooxygenase-1 or cyclooxygenase-2 with 4-methylaminoantipyrine, the major active derivative of metamizol, suggested a common binding mode to both isoforms. In intact cells, however, the inhibition profiles were markedly different. The IC50 values of metamizol for cyclooxygenase-1 in intact bovine aortic endothelial cells (BAEC) cells and human platelets were 1730 +/- 150 microg/ml and 486 +/- 56 microg/ml, respectively. Inhibition of cyclooxygenase-2 activity in murine macrophages and primary human leukocytes activated by lipopolysaccharide yielded IC50 values of 12 +/- 1.8 microg/ml and 21 +/- 2.9 microg/ml, respectively. These data indicate that the IC50 values obtained with purified enzymes or disrupted cells cannot always be extrapolated to the cyclooxygenase inhibitory activity of nonsteroidal antiinflammatory drugs (NSAIDs) in intact cells. The data presented here also indicate that cyclooxygenase-2 inhibition could play an important role in the pharmacological effects of metamizol.

Cot kinase activates tumor necrosis factor-alpha gene expression in a cyclosporin A-resistant manner.

Cot kinase is a protein serine/threonine kinase, classified as a mitogen-activated protein kinase kinase kinase, implicated in T lymphocyte activation. Here we show that an increase in Cot kinase expression promotes tumor necrosis factor-alpha (TNF-alpha) production in Jurkat T cells stimulated by soluble anti-CD3 or by low concentrations of phorbol 12,13-dibutyrate (PDBu) and calcium ionophore. Overexpression of Cot kinase in Jurkat cells activates TNF-alpha gene expression. Cot kinase promotes TNF-alpha promoter activation to a similar extent as calcium ionophore and PDBu or soluble anti-CD28 and PDBu. Neither phorbol esters nor calcium ionophore can replace Cot kinase on TNF-alpha promoter-driven transcription. Expression of a dominant negative form of Cot kinase inhibits TNF-alpha promoter activation induced by stimulation with either calcium ionophore and PDBu, soluble anti-CD28 and PDBu, or soluble anti-CD3 and PDBu. TNF-alpha promoter-driven transcription by Cot kinase is partially mediated by MAPK/ERK kinase and is cyclosporin A-resistant. Cot kinase increases at least the AP-1 and AP-2 response elements. These data indicate that Cot kinase plays a critical role in TNF-alpha production.

Cot kinase regulation of IL-2 production in Jurkat T cells.

tpl-2 is a rat gene that encodes a serine/threonine protein kinase that can act as a novel mitogen-activated protein (MAP) kinase kinase kinase. Tpl-2 is activated in Moloney murine leukemia virus-induced rat T lymphomas, due to a truncation in the C-terminal region of the protein. cot is a very closely related gene, if not the human homologue. The truncated form of Cot has been shown to have a higher transforming activity than the nontruncated form. In this paper we show that an increase in truncated Cot kinase expression correlates with an increase in IL-2 production in anti-CD3-treated Jurkat cells. Truncated Cot expression also cooperates with PHA or phorbol 12,13-dibutyrate (PDBu) and calcium ionophore for IL-2 production in Jurkat cells. Both the truncated and nontruncated Cot forms increased IL-2 transcription because they enhanced transcription of a reporter gene linked to the IL-2 promoter. The expression of a dominant negative form of Cot inhibits transcription directed by the IL-2 promoter in Jurkat cells stimulated by PDBu and ionophore. These data suggest a role of Tpl-2/Cot kinase in IL-2 production during T lymphocyte activation and could also explain its role in Moloney murine leukemia virus-induced lymphomagenesis.