Subclinical Depressive Symptoms and Continued Cannabis Use: Predictors of Negative Outcomes in First Episode Psychosis

Background Although depressive symptoms in first episode psychosis have been associated with cannabis abuse, their influence on the long-term functional course of FEP patients who abuse cannabis is unknown. The aims of the study were to examine the influence of subclinical depressive symptoms on the long-term outcome in first episode-psychosis patients who were cannabis users and to assess the influence of these subclinical depressive symptoms on the ability to quit cannabis use. Methods 64 FEP patients who were cannabis users at baseline were followed-up for 5 years. Two groups were defined: (a) patients with subclinical depressive symptoms at least once during follow-up (DPG), and (b) patients without subclinical depressive symptoms during follow-up (NDPG). Psychotic symptoms were measured using the Positive and Negative Syndrome Scale (PANSS), depressive symptoms using the Hamilton Depression Rating Scale (HDRS)-17, and psychosocial functioning was assessed using the Global Assessment of Functioning (GAF). A linear mixed-effects model was used to analyze the combined influence of cannabis use and subclinical depressive symptomatology on the clinical outcome. Results Subclinical depressive symptoms were associated with continued abuse of cannabis during follow-up (beta=4.45; 95% confidence interval [CI]: 1.78 to 11.17; P=.001) and with worse functioning (beta=-5.50; 95% CI: -9.02 to -0.33; P=.009). Conclusions Subclinical depressive symptoms and continued cannabis abuse during follow-up could be predictors of negative outcomes in FEP patients.

Effects of Spring Temperatures on the Strength of Selection on Timing of Reproduction in a Long-Distance Migratory Bird

Climate change has differentially affected the timing of seasonal events for interacting trophic levels, and this has often led to increased selection on seasonal timing. Yet, the environmental variables driving this selection have rarely been identified, limiting our ability to predict future ecological impacts of climate change. Using a dataset spanning 31 years from a natural population of pied flycatchers (Ficedula hypoleuca), we show that directional selection on timing of reproduction intensified in the first two decades (1980-2000) but weakened during the last decade (2001-2010). Against expectation, this pattern could not be explained by the temporal variation in the phenological mismatch with food abundance. We therefore explored an alternative hypothesis that selection on timing was affected by conditions individuals experience when arriving in spring at the breeding grounds: arriving early in cold conditions may reduce survival. First, we show that in female recruits, spring arrival date in the first breeding year correlates positively with hatch date; hence, early-hatched individuals experience colder conditions at arrival than late-hatched individuals. Second, we show that when temperatures at arrival in the recruitment year were high, early-hatched young had a higher recruitment probability than when temperatures were low. We interpret this as a potential cost of arriving early in colder years, and climate warming may have reduced this cost. We thus show that higher temperatures in the arrival year of recruits were associated with stronger selection for early reproduction in the years these birds were born. As arrival temperatures in the beginning of the study increased, but recently declined again, directional selection on timing of reproduction showed a nonlinear change. We demonstrate that environmental conditions with a lag of up to two years can alter selection on phenological traits in natural populations, something that has important implications for our understanding of how climate can alter patterns of selection in natural populations.

Patterns of Impact Resulting from a 'Sit Less, Move More' Web-Based Program in Sedentary Office Employees

Purpose Encouraging office workers to 'sit less and move more' encompasses two public health priorities. However, there is little evidence on the effectiveness of workplace interventions for reducing sitting, even less about the longer term effects of such interventions and still less on dual-focused interventions. This study assessed the short and mid-term impacts of a workplace web-based intervention (Walk@WorkSpain, W@WS; 2010-11) on self-reported sitting time, step counts and physical risk factors (waist circumference, BMI, blood pressure) for chronic disease. Methods Employees at six Spanish university campuses (n=264; 42 +/- 10 years; 171 female) were randomly assigned by worksite and campus to an Intervention (used W@WS; n=129; 87 female) or a Comparison group (maintained normal behavior; n=135; 84 female). This phased, 19-week program aimed to decrease occupational sitting time through increased incidental movement and short walks. A linear mixed model assessed changes in outcome measures between the baseline, ramping (8 weeks), maintenance (11 weeks) and follow-up (two months) phases for Intervention versus Comparison groups. Results A significant 2 (group) x 2 (program phases) interaction was found for self-reported occupational sitting (F[3]=7.97, p=0.046), daily step counts (F[3]=15.68, p=0.0013) and waist circumference (F[3]=11.67, p=0.0086). The Intervention group decreased minutes of daily occupational sitting while also increasing step counts from baseline (446 +/- 126; 8,862 +/- 2,475) through ramping (+425 +/- 120; 9,345 +/- 2,435), maintenance (+422 +/- 123; 9,638 +/- 3,131) and follow-up (+414 +/- 129; 9,786 +/- 3,205). In the Comparison group, compared to baseline (404 +/- 106), sitting time remained unchanged through ramping and maintenance, but decreased at follow-up (-388 +/- 120), while step counts diminished across all phases. The Intervention group significantly reduced waist circumference by 2.1cms from baseline to follow-up while the Comparison group reduced waist circumference by 1.3cms over the same period. Conclusions W@WSis a feasible and effective evidence-based intervention that can be successfully deployed with sedentary employees to elicit sustained changes on "sitting less and moving more".

Genetic Variants in MiRNA Processing Genes and Pre-MiRNAs Are Associated with the Risk of Chronic Lymphocytic Leukemia

Genome wide association studies (GWAS) have identified several low-penetrance susceptibility alleles in chronic lymphocytic leukemia (CLL). Nevertheless, these studies scarcely study regions that are implicated in non-coding molecules such as microRNAs (miRNAs). Abnormalities in miRNAs, as altered expression patterns and mutations, have been described in CLL, suggesting their implication in the development of the disease. Genetic variations in miRNAs can affect levels of miRNA expression if present in pre-miRNAs and in miRNA biogenesis genes or alter miRNA function if present in both target mRNA and miRNA sequences. Therefore, the present study aimed to evaluate whether polymorphisms in pre-miRNAs, and/or miRNA processing genes contribute to predisposition for CLL. A total of 91 SNPs in 107 CLL patients and 350 cancer-free controls were successfully analyzed using TaqMan Open Array technology. We found nine statistically significant associations with CLL risk after FDR correction, seven in miRNA processing genes (rs3805500 and rs6877842 in DROSHA, rs1057035 in DICER1, rs17676986 in SND1, rs9611280 in TNRC6B, rs784567 in TRBP and rs11866002 in CNOT1) and two in pre-miRNAs (rs11614913 in miR196a2 and rs2114358 in miR1206). These findings suggest that polymorphisms in genes involved in miRNAs biogenesis pathway as well as in pre-miRNAs contribute to the risk of CLL. Large-scale studies are needed to validate the current findings.

Dipeptidyl-Peptidase IV Activity Is Correlated with Colorectal Cancer Prognosis

Background Dipeptidyl-peptidase IV (EC 3.4.14.5) (DPPIV) is a serine peptidase involved in cell differentiation, adhesion, immune modulation and apoptosis, functions that control neoplastic transformation. Previous studies have demonstrated altered expression and activity of tissue and circulating DPPIV in several cancers and proposed its potential usefulness for early diagnosis in colorectal cancer (CRC). Methods and principal findings The activity and mRNA and protein expression of DPPIV was prospectively analyzed in adenocarcinomas, adenomas, uninvolved colorectal mucosa and plasma from 116 CRC patients by fluorimetric, quantitative RT-PCR and immunohistochemical methods. Results were correlated with the most important classic pathological data related to aggressiveness and with 5-year survival rates. Results showed that: 1) mRNA levels and activity of DPPIV increased in colorectal neoplasms (Kruskal-Wallis test, p<0.01); 2) Both adenomas and CRCs displayed positive cytoplasmic immunostaining with luminal membrane reinforcement; 3) Plasmatic DPPIV activity was lower in CRC patients than in healthy subjects (Mann-U test, p<0.01); 4) Plasmatic DPPIV activity was associated with worse overall and disease-free survivals (log-rank p<0.01, Cox analysis p<0.01). Conclusion/significance 1) Up-regulation of DPPIV in colorectal tumors suggests a role for this enzyme in the neoplastic transformation of colorectal tissues. This finding opens the possibility for new therapeutic targets in these patients. 2) Plasmatic DPPIV is an independent prognostic factor in survival of CRC patients. The determination of DPPIV activity levels in the plasma may be a safe, minimally invasive and inexpensive way to define the aggressiveness of CRC in daily practice.

What Can the Brain Teach Us about Winemaking? An fMRI Study of Alcohol Level Preferences

Over the last few decades, wine makers have been producing wines with a higher alcohol content, assuming that they are more appreciated by consumers. To test this hypothesis, we used functional magnetic imaging to compare reactions of human subjects to different types of wine, focusing on brain regions critical for flavor processing and food reward. Participants were presented with carefully matched pairs of high- and low- alcohol content red wines, without informing them of any of the wine attributes. Contrary to expectation, significantly greater activation was found for low- alcohol than for high- alcohol content wines in brain regions that are sensitive to taste intensity, including the insula as well as the cerebellum. Wines were closely matched for all physical attributes except for alcohol content, thus we interpret the preferential response to the low- alcohol content wines as arising from top-down modulation due to the low alcohol content wines inducing greater attentional exploration of aromas and flavours. The findings raise intriguing possibilities for objectively testing hypotheses regarding methods of producing a highly complex product such as wine.

Pseudohypoparathyroidism Type Ib Associated with Novel Duplications in the GNAS Locus

Context Pseudohypoparathyroidism type 1b (PHP-Ib) is characterized by renal resistance to PTH (and, sometimes, a mild resistance to TSH) and absence of any features of Albright's hereditary osteodystrophy. Patients with PHP-Ib suffer of defects in the methylation pattern of the complex GNAS locus. PHP-Ib can be either sporadic or inherited in an autosomal dominant pattern. Whereas familial PHP-Ib is well characterized at the molecular level, the genetic cause of sporadic PHP-Ib cases remains elusive, although some molecular mechanisms have been associated with this subtype. Objective The aim of the study was to investigate the molecular and imprinting defects in the GNAS locus in two unrelated patients with PHP-Ib. Design We have analyzed the GNAS locus by direct sequencing, Methylation-Specific Multiplex Ligation-dependent Probe Amplification, microsatellites, Quantitative Multiplex PCR of Short Fluorescent fragments and array-Comparative Genomic Hybridization studies in order to characterize two unrelated families with clinical features of PHP-Ib. Results We identified two duplications in the GNAS region in two patients with PHP-Ib: one of them, comprising similar to 320 kb, occurred 'de novo' in the patient, whereas the other one, of similar to 179 kb in length, was inherited from the maternal allele. In both cases, no other known genetic cause was observed. Conclusion In this article, we describe the to-our-knowledge biggest duplications reported so far in the GNAS region. Both are associated to PHP-Ib, one of them occurring 'de novo' and the other one being maternally inherited.

"Heroes" and "Villains" of World History across Cultures

Emergent properties of global political culture were examined using data from the World History Survey (WHS) involving 6,902 university students in 37 countries evaluating 40 figures from world history. Multidimensional scaling and factor analysis techniques found only limited forms of universality in evaluations across Western, Catholic/Orthodox, Muslim, and Asian country clusters. The highest consensus across cultures involved scientific innovators, with Einstein having the most positive evaluation overall. Peaceful humanitarians like Mother Theresa and Gandhi followed. There was much less cross-cultural consistency in the evaluation of negative figures, led by Hitler, Osama bin Laden, and Saddam Hussein. After more traditional empirical methods (e.g., factor analysis) failed to identify meaningful cross-cultural patterns, Latent Profile Analysis (LPA) was used to identify four global representational profiles: Secular and Religious Idealists were overwhelmingly prevalent in Christian countries, and Political Realists were common in Muslim and Asian countries. We discuss possible consequences and interpretations of these different representational profiles.

Long-Term Burden and Respiratory Effects of Respiratory Syncytial Virus Hospitalization in Preterm Infants — The SPRING Study

The health status of premature infants born 32(1)-35(0) weeks' gestational age (wGA) hospitalized for RSV infection in the first year of life (cases; n = 125) was compared to that of premature infants not hospitalized for RSV (controls; n = 362) through 6 years. The primary endpoints were the percentage of children with wheezing between 2-6 years and lung function at 6 years of age. Secondary endpoints included quality of life, healthcare resource use, and allergic sensitization. A significantly higher proportion of cases than controls experienced recurrent wheezing through 6 years of age (46.7% vs. 27.4%; p = 0.001). The vast majority of lung function tests appeared normal at 6 years of age in both cohorts. In children with pulmonary function in the lower limit of normality (FEV1 Z-score [-2; -1]), wheezing was increased, particularly for cases vs. controls (72.7% vs. 18.9%, p = 0.002). Multivariate analysis revealed the most important factor for wheezing was RSV hospitalization. Quality of life on the respiratory subscale of the TAPQOL was significantly lower (p = 0.001) and healthcare resource utilization was significantly higher (p<0.001) in cases than controls. This study confirms RSV disease is associated with wheezing in 32-35 wGA infants through 6 years of age.

Proteomic Analysis of the Ubiquitin Landscape in the Drosophila Embryonic Nervous System and the Adult Photoreceptor Cells

Background Ubiquitination is known to regulate physiological neuronal functions as well as to be involved in a number of neuronal diseases. Several ubiquitin proteomic approaches have been developed during the last decade but, as they have been mostly applied to non-neuronal cell culture, very little is yet known about neuronal ubiquitination pathways in vivo. Methodology/Principal Findings Using an in vivo biotinylation strategy we have isolated and identified the ubiquitinated proteome in neurons both for the developing embryonic brain and for the adult eye of Drosophila melanogaster. Bioinformatic comparison of both datasets indicates a significant difference on the ubiquitin substrates, which logically correlates with the processes that are most active at each of the developmental stages. Detection within the isolated material of two ubiquitin E3 ligases, Parkin and Ube3a, indicates their ubiquitinating activity on the studied tissues. Further identification of the proteins that do accumulate upon interference with the proteasomal degradative pathway provides an indication of the proteins that are targeted for clearance in neurons. Last, we report the proof-of-principle validation of two lysine residues required for nSyb ubiquitination. Conclusions/Significance These data cast light on the differential and common ubiquitination pathways between the embryonic and adult neurons, and hence will contribute to the understanding of the mechanisms by which neuronal function is regulated. The in vivo biotinylation methodology described here complements other approaches for ubiquitome study and offers unique advantages, and is poised to provide further insight into disease mechanisms related to the ubiquitin proteasome system.

Pretreatment with Resveratrol Prevents Neuronal Injury and Cognitive Deficits Induced by Perinatal Hypoxia-Ischemia in Rats

Despite advances in neonatal care, hypoxic-ischemic brain injury is still a serious clinical problem, which is responsible for many cases of perinatal mortality, cerebral palsy, motor impairment and cognitive deficits. Resveratrol, a natural polyphenol with important anti-oxidant and anti-inflammatory properties, is present in grapevines, peanuts and pomegranates. The aim of the present work was to evaluate the possible neuroprotective effect of resveratrol when administered before or immediately after a hypoxic-ischemic brain event in neonatal rats by analyzing brain damage, the mitochondrial status and long-term cognitive impairment. Our results indicate that pretreatment with resveratrol protects against brain damage, reducing infarct volume, preserving myelination and minimizing the astroglial reactive response. Moreover its neuroprotective effect was found to be long lasting, as behavioral outcomes were significantly improved at adulthood. We speculate that one of the mechanisms for this neuroprotection may be related to the maintenance of the mitochondrial inner membrane integrity and potential, and to the reduction of reactive oxygen species. Curiously, none of these protective features was observed when resveratrol was administered immediately after hypoxia-ischemia.

Pharmacological Blockade of Cannabinoid CB1 Receptors in Diet-Induced Obesity Regulates Mitochondrial Dihydrolipoamide Dehydrogenase in Muscle

Cannabinoid CB1 receptors peripherally modulate energy metabolism. Here, we investigated the role of CB1 receptors in the expression of glucose/pyruvate/tricarboxylic acid (TCA) metabolism in rat abdominal muscle. Dihydrolipoamide dehydrogenase (DLD), a flavoprotein component (E3) of alpha-ketoacid dehydrogenase complexes with diaphorase activity in mitochondria, was specifically analyzed. After assessing the effectiveness of the CB1 receptor antagonist AM251 (3 mg kg(-1), 14 days) on food intake and body weight, we could identified seven key enzymes from either glycolytic pathway or TCA cycle-regulated by both diet and CB1 receptor activity-through comprehensive proteomic approaches involving two-dimensional electrophoresis and MALDI-TOF/LC-ESI trap mass spectrometry. These enzymes were glucose 6-phosphate isomerase (GPI), triosephosphate isomerase (TPI), enolase (Eno3), lactate dehydrogenase (LDHa), glyoxalase-1 (Glo1) and the mitochondrial DLD, whose expressions were modified by AM251 in hypercaloric diet-induced obesity. Specifically, AM251 blocked high-carbohydrate diet (HCD)-induced expression of GPI, TPI, Eno3 and LDHa, suggesting a down-regulation of glucose/pyruvate/lactate pathways under glucose availability. AM251 reversed the HCD-inhibited expression of Glo1 and DLD in the muscle, and the DLD and CB1 receptor expression in the mitochondrial fraction. Interestingly, we identified the presence of CB1 receptors at the membrane of striate muscle mitochondria. DLD over-expression was confirmed in muscle of CB1-/- mice. AM251 increased the pyruvate dehydrogenase and glutathione reductase activity in C2C12 myotubes, and the diaphorase/oxidative activity in the mitochondria fraction. These results indicated an up-regulation of methylglyoxal and TCA cycle activity. Findings suggest that CB1 receptors in muscle modulate glucose/pyruvate/lactate pathways and mitochondrial oxidative activity by targeting DLD.

Number of Players and Relative Pitch Area per Player: Comparing Their Influence on Heart Rate and Physical Demands in Under-12 and Under-13 Football Players

The aim of the present study is to analyse the influence of different large-sided games (LSGs) on the physical and physiological variables in under-12s (U12) and -13s (U13) soccer players. The effects of the combination of different number of players per team, 7, 9, and 11 (P7, P9, and P11, respectively) with three relative pitch areas, 100, 200, and 300 m(2) (A100, A200, and A300, respectively), were analysed in this study. The variables analysed were: 1) global indicator such as total distance (TD); work:rest ratio (W:R); player-load (PL) and maximal speed (V-max); 2) heart rate (HR) mean and time spent in different intensity zones of HR (<75%, 75-84%, 84-90% and >90%), and; 3) five absolute (<8, 8-13, 13-16 and >16 Km h(-1)) and three relative speed categories (<40%, 40-60% and >60% V-max). The results support the theory that a change in format (player number and pitch dimensions) affects no similarly in the two players categories. Although it can seem that U13 players are more demanded in this kind of LSG, when the work load is assessed from a relative point of view, great pitch dimensions and/or high number of player per team are involved in the training task to the U12 players. The results of this study could alert to the coaches to avoid some types of LSGs for the U12 players such as:P11 played in A100, A200 or A300, P9 played in A200 or A300 and P7 played in A300 due to that U13>U12 in several physical and physiological variables (W:R, time spent in 84-90% HRmax, distance in 8-13 and 13-16 Km h(-1) and time spent in 40-60% V-max). These results may help youth soccer coaches to plan the progressive introduction of LSGs so that task demands are adapted to the physiological and physical development of participants.

LDLR and PCSK9 Are Associated with the Presence of Antiphospholipid Antibodies and the Development of Thrombosis in aPLA Carriers

Introduction The identification of the genetic risk factors that could discriminate non-thrombotic from thrombotic antiphospholipid antibodies (aPLA) carriers will improve prognosis of these patients. Several human studies have shown the presence of aPLAs associated with atherosclerotic plaque, which is a known risk factor for thrombosis. Hence, in order to determine the implication of atherosclerosis in the risk of developing thrombosis in aPLA positive patients, we performed a genetic association study with 3 candidate genes, APOH, LDLR and PCSK9. Material & Methods For genetic association study we analyzed 190 aPLA carriers -100 with non-thrombotic events and 90 with thrombotic events-and 557 healthy controls. Analyses were performed by chi(2) test and were corrected by false discovery rate. To evaluate the functional implication of the newly established susceptibility loci, we performed expression analyses in 86 aPLA carrier individuals (43 with thrombotic manifestations and 43 without it) and in 45 healthy controls. Results Our results revealed significant associations after correction in SNPs located in LDLR gene with aPLA carriers and thrombotic aPLA carriers, when compared with healthy controls. The most significant association in LDLR gene was found between SNP rs129083082 and aPLA carriers in recessive model (adjusted P-value = 2.55 x 10(-3); OR = 2.18; 95% CI = 1.49-3.21). Furthermore, our work detected significant allelic association after correction between thrombotic aPLA carriers and healthy controls in SNP rs562556 located in PCSK9 gene (adjusted P-value = 1.03 x 10(-2); OR = 1.60; 95% CI = 1.24-2.06). Expression level study showed significantly decreased expression level of LDLR gene in aPLA carriers (P-value < 0.0001; 95% CI 0.16-2.10; SE 0.38-1.27) in comparison to the control group. Discussion Our work has identified LDLR gene as a new susceptibility gene associated with the development of thrombosis in aPLA carriers, describing for the first time the deregulation of LDLR expression in individuals with aPLAs. Besides, thrombotic aPLA carriers also showed significant association with PCSK9 gene, a regulator of LDLR plasma levels. These results highlight the importance of atherosclerotic processes in the development of thrombosis in patients with aPLA.

Long-Term Epidemiology of Streptococcus pneumoniae Serogroup 6 in a Region of Southern Europe with Special Reference to Serotype 6E

Streptococcus pneumoniae serotype 6E has recently been described, but its long-term epidemiology is not well known. From 1981-2013, 704 serogroup 6 clinical isolates were obtained in Gipuzkoa, Basque Country, Spain. All invasive and one in four non-invasive isolates were included. Overall, 75, 97, 51 and 45 serotypes 6A, 6B, 6C and 6E isolates, respectively, were detected. No serotype 6D isolates were identified. The prevalence of serotypes 6E and 6B, but not that of serotypes 6A and 6C, declined after the introduction of pneumococcal conjugate vaccines. Serotype 6E isolates showed the highest resistance rate. Most serotype 6E isolates were ST90.