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The left inferior frontal cortex, the caudate and the anterior cingulate have been proposed as the neural origin of language switching, but most of the studies were conducted in low proficient bilinguals. In the present study, we investigated brain areas involved in language switching in a sample of 19 early, high-proficient Spanish-Catalan bilinguals using a picture naming task that allowed contrasting switch and non-switch trials. Compared to the non-switching condition, language switching elicited greater activation in the head of the left caudate and the pre-SMA/ACC. When the direction of the switching was considered, the left caudate was more associated with forward switching and the pre-SMA/ACC with backward switching. The discussion is focused on the relevance of these brain structures in language control in early, high-proficient bilinguals, and the comparison with previous results in late bilinguals. (Contains 3 tables and 1 figure.)

COMT (Catechol-O methyltransferase) gene is one of the key players in synaptic plasticity and in learning and memory mechanisms. A single nucleotide polymorphism (rs4680; G to A) in the COMT coding region causes Val158Met aminoacid substitution in the corresponding protein, with Val allele exhibiting a 3- to 4-fold increase in enzyme activity compared to Met. With the purpose of examining the influence of COMT as a genetic risk factor for cognitive impairment, we analyzed a sample of 248 healthy subjects, 276 patients affected by Alzheimer's disease (AD), and 70 subjects with mild cognitive impairment (MCI), the latter condition possibly representing a prodrome for dementia. All subjects were analyzed for COMT rs4680 polymorphism and APOE genotype. Our study strengthens data showing that APOE ε4 allele is an independent risk factor for AD and also a risk factor for MCI. Neither COMT alleles nor genotypes proved to be independently associated with the risk of AD or MCI in our sample. However, we found an association between COMT GG genotype (Val/Val) and APOE ε4 carrier status and the risk of AD and MCI. In particular, when GG genotype is included into the multinomial analysis, the risk of AD and MCI due to APOE ε4 allele is increased of about 2-3 fold; moreover, the risk conferred by the combination of G and ε4 alleles is more pronounced in male patients. To our knowledge, this synergistic effect is here shown for the first time on a population sample representative of Caucasian patients. [ABSTRACT FROM AUTHOR]

As cells age, they lose their ability to properly fold proteins, maintain protein folding, and eliminate misfolded proteins, which leads to the accumulation of abnormal protein aggregates and loss of protein homeostasis (proteostasis). Loss of proteostasis can accelerate aging and the onset of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Mechanisms exist to prevent the detrimental effects of abnormal proteins that incorporate chaperones, autophagy, and the ubiquitin-proteasome system. These mechanisms are evolutionarily conserved across various species. Therefore, the effect of impaired proteostasis on aging has been studied using model organisms that are appropriate for aging studies. In this review, we focus on the relationship between proteostasis and aging, and factors that affect proteostasis in Drosophila. The manipulation of proteostasis can alter lifespan, modulate neurotoxicity, and delay the onset of neurodegeneration, indicating that proteostasis may be a novel pharmacological target for the development of treatments for various age-associated diseases.

Unlabelled: High interindividual variability in postoperative opioid consumption is related to genetic and environmental factors. We tested the association between morphine consumption, postoperative pain, and single nucleotide polymorphisms (SNPs) within opioid receptor μ 1 (OPRM1), catechol-O-methyltransferase (COMT), uridine diphosphate glucose-glucuronosyltransferase-2B7, and estrogen receptor (ESR1) gene loci to elucidate genetic prediction of opioid consumption. We analyzed 20 SNPs in 201 unrelated Caucasian patients who underwent abdominal surgery and who were receiving postoperative patient-controlled analgesia-administered morphine. Morphine consumption and pain intensity were dependent variables; age and sex were covariates. A haplotype of 7 SNPs in OPRM1 showed significant additive effects on opioid consumption (P = .007); a linear regression model including age and 9 SNPs in ESR1, OPRM1, and COMT explained the highest proportion of variance of morphine consumption (10.7%; P = .001). The minimal model including 3 SNPs in ESR1, OPRM1, and COMT explained 5% of variance (P = .007). We found a significant interaction between rs4680 in COMT and rs4986936 in ESR1 (P = .007) on opioid consumption. SNPs rs677830 and rs540825 of OPRM1 and rs9340799 of ESR1 were nominally associated with pain Numeric Rating Scale scores. Combinations of genetic variants within OPRM1, COMT, and ESR1 better explain variability in morphine consumption than single genetic variants. Our results contribute to the development of genetic markers and statistical models for future diagnostic tools for opioid consumption/efficacy., Perspective: This article presents the efforts dedicated to detect correlations between the genetic polymorphisms and the clinical morphine effect self-administered by patients using a patient-controlled analgesia pump after major surgery. The clinical effect is expressed in terms of morphine consumption and pain scores. REGISTERED ON CLINICALTRIALS.GOV: NCT01233752., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Autoimmune rheumatic diseases in pregnancies are associated with increased adverse obstetric outcomes. We compared maternal soluble human leucocyte antigen-G (sHLA-G) blood levels in subjects with a rheumatic disease preexisting pregnancy and unaffected controls. Third-trimester blood maternal sHLA-G concentrations were significantly higher in subjects with rheumatic diseases than in controls (mean 93.1ng/ml [SD 42.1] vs 58.1ng/ml [SD 96.3], p=0.003). Cord blood sHLA-G concentrations were significantly higher in rheumatic disease than in those born to control mothers (median 41.2ng/ml [IQR: 3.3-44.0] vs 17.9ng/ml [IQR: 17.2-88.1], p=0.007). A strict positive correlation (r=0.88, p<0.001) was found between the maternal and fetal titers of ANA autoantibodies as well as between maternal and fetal sHLAG circulating levels (r=0.58 and r=0.67, respectively, for controls and cases, p<0.001). Maternal s-HLA-G blood concentrations were significantly higher in subjects with rheumatic disease DEL/DEL homozygous for a polymorphism of the 3' untranslated regulatory region of HLA-G (HLA-G 14bp) than in the corresponding healthy controls (mean values 141.5ng/ml [SD: 166] vs 54.2ng/ml [SD: 35], p=0.009). Increasing maternal and cord blood levels of s-HLA-G concentrations among pregnant subjects with rheumatic diseases compared with controls suggest that autoimmune diseases prompt a maternal and fetal immune response that favors pregnancy immune tolerance., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Problem: To target gestational diabetes mellitus (GDM) by means of temporal variation in pregnancy-associated plasma protein A (PAPP-A) and soluble human leukocyte antigen-G (sHLA-G)., Method of Study: Retrospective analysis of PAPP-A and sHLA-G blood levels in historical samples of 112 GDM and 112 controls, drawn at first trimester, and prospective study in 18 GDM and 105 controls collected in triplicate along the pregnancy. Six hundred and sixty-five samples were analyzed., Results: Gestational diabetes mellitus had significantly lower first-trimester PAPP-A concentrations than controls (2343±1519 versus 2996±1955 mU/mL, in retrospective brunch and 2490.57±1828.52 versus 3240.84±1930.69 mU/L in prospective one, P<0.001). First-trimester sHLA-G level was significantly lower in GDM than in controls (52.88±59.69 versus 66.81±50.14 ng/mL, P<0.001) and increased during gestation in diabetic women showing an opposite trend with respect to the controls., Conclusion: PAPP-A and sHLA-G are independent markers of GDM. Quantitative variations during pregnancy help to early unravel the onset of GDM., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To investigate interindividual variability in response to pain treatment, we characterized postoperative patients for morphine metabolism and for COMT, OPRM1 and UGT2B7 polymorphisms., Methods: A total of 109 patients treated with morphine were genotyped by DNA sequencing for 12 DNA polymorphisms of the COMT, OPRM1 and UGT2B7 genes. The plasma concentration of morphine and of M3G/M6G metabolites were evaluated by means of reversed phase high-performance liquid chromatography coupled with mass spectrometry., Results: An association between average morphine consumption during the first 24 postoperative hours by patient-controlled analgesia (PCA) and COMT haplotypes was found. Specifically, patients with the diplotype for average pain intensity (APS/APS) required the lowest morphine doses compared to the other subjects (p = 0.011). The APS haplotype contains an adenine corresponding to methionine, instead of valine, at position 158 of the COMT protein. Met/Met homozygous patients consumed significantly lower morphine doses than other subjects (p = 0.014); accordingly, Val158Met genotyping alone might be used in the clinical setting to predict PCA morphine need. Considering both COMT Val158Met and OPRM1 A118G polymorphisms, carriers of both the Met/Met and AA genotypes required less morphine than other subjects, although the difference was not significant. The analysis of UGT2B7 revealed the occurrence of two common haplotypes (G&#95;C&#95;C&#95;A&#95;C and A&#95;T&#95;T&#95;G&#95;T) that did not prove to be related with plasma morphine and M3G/M6G concentration., Conclusions: By considering COMT, OPRM1, and UGT2B7 genotypes, as well as pharmacokinetic results, only COMT polymorphisms appear to be predictive of morphine need in postoperative pain therapy.

The reinforcement sensitivity theory (RST) relates individual differences in reward sensitivity to the activation of the behavioral approach system (BAS). Dopamine-related brain structures have been repeatedly associated with reward processing, but also with cognitive processes such as task switching. In the present study, we examined the association between reward sensitivity and the event-related fMRI BOLD response with set switching in 31 males. As expected, the right inferior frontal cortex (rIFG) and the striatum (i.e. the left putamen) were involved in set-switching activity for the overall sample. Interindividual differences in Gray's reward sensitivity were related to stronger activity in the rIFG and the ventral striatum. Thus, trait reward sensitivity contributed to the modulation of brain responsiveness in set-switching tasks. Having considered previous research, we propose that higher BAS activity is associated with a stronger reward to process a better implementation of goal-directed tasks and the diminished processing of secondary cues.

Unlabelled: Human herpesvirus type 6-(HHV-6) has been associated with morbidity after liver transplantation., Objective: The aim of this study was to determine the HHV-6 seroprevalence among donor-recipient pairs, analyze the incidence of early active infection, its clinical manifestation, interaction with CMV, and the related morbidity in the first year after kidney transplantation., Methods: 46 donor-recipient pairs had IgG evaluated by ELISA before transplantation: HHV-6(Pambio - USA) and CMV-(Roche - USA). A frozen whole blood sample collected weekly (from the 1st to the 6th week) was retrospectively tested for HHV-6 viral load (VL) determination by real time quantitative PCR (qPCR, Nanogen - Italy). Patients were preemptively surveyed for CMV by pp65 antigenemia (Ag, APAAP, immunohistochemistry, Biotest - Germany) from the 4th to the 12th week after transplantation. Active infection was defined as qPCR-HHV6+ (viral-load/mL-VL) and Ag+ (+cells/100.000 granulocytes), for HHV-6 and CMV, respectively. DCMV was defined as simultaneous positive antigenemia and suggestive signs/symptoms. Concerning +qPCR-HHV6, associated factors, clinical manifestation, interaction with CMV and morbidity were searched., Results: Pre-transplant HHV-6 seroprevalence was significantly higher among kidney recipients compared to their donors (82.6x54.8%; p = 0.005 [3.9 (1.4-10.4)]). Active infection by this virus occurred in 26.1% (12/46), with no association with previous IgG (p = 0.412). Median VL was 125 copies/mL (53-11.264), and the median Ag was 21 +cells (2-740). There was no association between HHV-6 and CMV activation after transplantation (p = 0.441), neither concerning DCMV (p = 0.596). Median highest Ag+ and days of ganciclovir treatment were similar between qPCR-HHV6 + or - (p = 0.206 and p = 0.124, respectively). qPCR-HHV6+ was associated with higher incidence of bacterial (p = 0.009) and fungal (p = 0.001) infections, and higher number (p = 0.001) of hospital admission and longer duration of hospitalization over the first 6 and 12 months post-transplantation (p = 0.033 and p = 0.001)., Conclusion: Latent HHV-6 infection is more common among recipients than donors before transplantation. Early active infection by this pathogen after transplantation does not increase DCMV incidence or severity during the first 3 months of follow-up. However, early HHV-6 replication is associated with other infections and hospitalizations in the first year.

In a functional MRI (fMRI) study, we have investigated the grammatical categories of object noun, event noun and verb in order to assess the cortical regions of activation supporting their processing. Twelve Italian healthy participants performed a lexical decision task. They had to decide whether a string was an Italian word or not. Words could be objects like medaglia (medal), or events like the noun pianto (cry); or the verb dormire (to sleep). Noun and verb comparison shows differences in regions of activation in the left Inferior Frontal cortex and in the extent of the same areas. We have found specific areas of activation for object noun, and similarities in the pattern of activation for event noun and verb. The activations induced by pseudowords highly resembled the areas activated by the corresponding word category. The implications of the results are discussed in light of the recent debate on the role of grammatical category in the brain.

Cytochromes P450 are members of a superfamily of hemoproteins that catalyze a variety of oxidative reactions in the metabolism of endogenous and exogenous hydrophobic substrates. Fifty-eight cytochrome P450 (CYP) isoenzymes belonging to 18 families have been identified in human cells; the corresponding genes are highly polymorphic, and genetic variability underlies interindividual differences in drug response. The polymorphisms of CYP2D6 significantly affect the pharmacokinetics of about 50% of the drugs in clinical use, which are CYP2D6 substrates. The number of functional CYP2D6 alleles per genome determines the existence of four different phenotypes, i.e. poor, intermediate, extensive, and ultrarapid metabolizers. CYP2D6 genetic variants include copy number variations, single nucleotide substitutions, frameshift and insertion/deletion mutations. This review reports some of the different methodological approaches used to screen for CYP2D6 variants and focuses on methods that have improved variation detection, from conventional techniques to more recent microarray technology and high throughput DNA sequencing. In addition, this review reports some results on clinical relevance of CYP2D6 polymorphisms and provides examples of variability in drug response associated with interindividual phenotypic differences.

The aim of this study is to investigate the consequences of using different gradient schemes, number of repeated measurements and voxel size on the fractional anisotropy (FA) value in a diffusion tensor imaging (DTI) sequence on the cervical tract of the spinal cord. Twenty healthy volunteers underwent a total of 86 DTI axial acquisitions performed by using different voxel size and number of diffusion gradient directions (NDGDs). Three different diffusion gradient schemes were applied, named 6, 15 and 32 according to the NDGD. Furthermore, some acquisitions were repeated to investigate the effects of image averaging on FA value. Our results indicate that the FA value in the cervical spinal cord decreases when increasing the NDGD for a fixed spatial resolution, or when identical acquisitions are repeated, thus, increasing the acquisition time. This effect is observed in all subjects without exceptions, and the differences result statistically significant: the average FA obtained from 6, 15 and 32 NDGD is 0.84 (range, 0.82-0.87), 0.75 (range, 0.68-0.80) and 0.70 (range, 0.65-0.77), respectively, for isotropic 8 mm(3) voxel size. When varying the spatial resolution in a volume range of 2 to 8 mm(3) for a fixed NDGD (6 or 15), the differences in FA values are smaller albeit still statistically significant: the smaller the voxel, the larger the FA. No significant dependence of the FA value from the spatial resolution is observed in the 32 NDGD acquisitions in the studied volume range. In conclusion, our results indicate that the value of the FA in the cervical tract of the spinal cord vary with regularity in intrasubject acquisitions when modifying the NDGD and when repeated acquisitions are used; these observations confirm that the signal-to-noise ratio introduces a systematic error in FA measurements that does not allow simple comparison of quantitative results obtained from separated studies.

The Symbol Digit Modalities Test is an easy test used to assess cognitive impairment in a wide range of neurological diseases, like multiple sclerosis. We adapted the oral version of this cognitive task making it suitable for functional Magnetic Resonance Imaging studies. Symbol Digit Modalities Test performance was associated with increased brain activity in frontal and parietal areas involved in selective attention and working memory functions. These may provide the basis for future studies assessing potential abnormal cortical activations in multiple sclerosis patients and other clinical populations.