Glutamate imbalance in key structure of the default mode network in adults with attention-deficit/hyperactivity disorder.

The default mode network (DMN) is atypically active in patients with ADHD, likely contributing to the inattention patterns observed in patients with the disorder. Nonetheless, magnetic resonance spectroscopy (MRS) studies have rarely targeted the posterior cingulate cortex, a key DMN region, and little is known about the biochemical setting within this network in patients with ADHD. We aimed to assess the differences in metabolite profiles of the posterior cingulate cortex-a key region of the DMN-between patients with ADHD and controls. Five brain metabolites-glutamate, inositol, N-acetyl aspartate, choline, and creatine-were measured through MRS in the posterior cingulate cortex of patients and controls in a 3.0 T scanner. Between-group comparison of neurometabolite concentrations in PCC was performed using multivariate analysis of covariance. A total of 88 patients and 44 controls were included in the analysis. Patients with ADHD showed lower levels of glutamate in the posterior cingulate cortex compared to controls (p = 0.003). Lower concentrations of glutamate in the posterior cingulate cortex suggest that a glutamatergic imbalance within the posterior cingulate cortex might play a role in the pathogenesis of ADHD. Further understanding of the causes and consequences of such glutamate decrease might help explain how some glutamate-related drug effects impact on ADHD symptomatology.

The symptomatology of Attention-Deficit/Hyperactivity Disorder and the genetic control of vitamin D levels.

OBJECTIVES: Vitamin D deficiency has been associated with psychiatric disorders and behavioral phenotypes such as Attention-Deficit/Hyperactivity Disorder (ADHD). Considering that vitamin D levels are polygenic, we aim to evaluate the overall effects of its genetic architecture on symptoms of inattention, hyperactivity, and impulsivity and on the serum levels of vitamin D in two independent samples of adults, as well as the specific effects of five relevant polymorphisms in vitamin D-related genes. METHODS: We evaluated 870 subjects from an ADHD sample (407 cases and 463 controls) and 319 subjects from an academic community (nutrigenetic sample). Vitamin D serum levels were obtained through Elisa test and genetic data by TaqMan™ allelic discrimination and Infinium PsychArray-24 BeadChip genotyping. Polygenic Scores (PGS) were calculated on PRSice2 based on the latest GWAS for Vitamin D and statistical analyses were conducted at Plink and SPSS software. RESULTS: Vitamin D PGSs were associated with inattention in the ADHD sample and with hyperactivity when inattention symptoms were included as covariates. In the nutrigenetic sample, CYP2R1 rs10741657 and DHCR7 rs12785878 were nominally associated with impulsivity and hyperactivity, respectively, and both with vitamin D levels. In the clinical sample, RXRG rs2134095 was associated with impulsivity. DISCUSSION: Our findings suggest a shared genetic architecture between vitamin D levels and ADHD symptoms, as evidenced by the associations observed with PGS and specific genes related to vitamin D levels. Interestingly, differential effects for vitamin D PGS were found in inattention and hyperactivity, which should be considered in further studies involving ADHD.

Renoprotective mechanisms of exercise training against acute and chronic renal diseases - A perspective based on experimental studies.

Regular exercise training can lead to several health benefits, reduce mortality risk, and increase life expectancy. On the other hand, a sedentary lifestyle is a known risk factor for chronic diseases and increased mortality. Acute kidney injury (AKI) and chronic kidney disease (CKD) represent a significant global health problem, affecting millions of people worldwide. The progression from AKI to CKD is well-recognized in the literature, and exercise training has emerged as a potential renoprotective strategy. Thus, this article aims to review the main molecular mechanisms underlying the renoprotective actions of exercise training in the context of AKI and CKD, focusing on its antioxidative, anti-inflammatory, anti-apoptotic, anti-fibrotic, and autophagy regulatory effects. For that, bibliographical research was carried out in Medline/PubMed and Scielo databases. Although the pathophysiological mechanisms involved in renal diseases are not fully understood, experimental studies demonstrate that oxidative stress, inflammation, apoptosis, and dysregulation of fibrotic and autophagic processes play central roles in the development of tissue damage. Increasing evidence has suggested that exercise can beneficially modulate these mechanisms, potentially becoming a safe and effective non-pharmacological strategy for kidney health protection and promotion. Thus, the evidence base discussed in this review suggests that an adequate training program emerges as a valuable tool for preserving renal function in experimental animals, mainly through the production of antioxidant enzymes, nitric oxide (NO), irisin, IL-10, and IL-11. Future research can continue to explore these mechanisms to develop specific guidelines for the prescription of exercise training in different populations of patients with kidney diseases.

An overview on neurobiology and therapeutics of attention-deficit/hyperactivity disorder.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent psychiatric condition characterized by developmentally inappropriate symptoms of inattention and/or hyperactivity/impulsivity, which leads to impairments in the social, academic, and professional contexts. ADHD diagnosis relies solely on clinical assessment based on symptom evaluation and is sometimes challenging due to the substantial heterogeneity of the disorder in terms of clinical and pathophysiological aspects. Despite the difficulties imposed by the high complexity of ADHD etiology, the growing body of research and technological advances provide good perspectives for understanding the neurobiology of the disorder. Such knowledge is essential to refining diagnosis and identifying new therapeutic options to optimize treatment outcomes and associated impairments, leading to improvements in all domains of patient care. This review is intended to be an updated outline that addresses the etiological and neurobiological aspects of ADHD and its treatment, considering the impact of the "omics" era on disentangling the multifactorial architecture of ADHD.

Refining patterns of MEF2C effects in white matter microstructure and psychiatric features.

Several GWAS reported Myocyte Enhancer Factor 2 C (MEF2C) gene associations with white matter microstructure and psychiatric disorders, and MEF2C involvement in pathways related to neuronal development suggests a common biological factor underlying these phenotypes. We aim to refine the MEF2C effects in the brain relying on an integrated analysis of white matter and psychiatric phenotypes in an extensively characterized sample. This study included 870 Brazilian adults (47% from an attention-deficit/hyperactivity disorder outpatient clinic) assessed through standardized psychiatric interviews, 139 of which underwent a magnetic resonance imaging scan. We evaluated variants in the MEF2C region using two approaches: 1) a gene-wide analysis, which uses the sum of polymorphism effects, and 2) SNP analyses, restricted to the independent variants within the gene. The outcomes included psychiatric phenotypes and fractional anisotropy for brain images. Results: The gene-wide analyses pointed to a nominal association between MEF2C and the Temporal Portion of the Superior Longitudinal Fasciculus (SLFTEMP). The SNP analysis identified four independent variants significantly associated with SLFTEMP and one (rs4218438) with Substance Use Disorder. Our findings showing specific associations of MEF2C variants with temporal-frontal circuitry components may help to elucidate how the MEF2C gene underlies a broad range of psychiatric phenotypes since these regions are relevant to executive and cognitive functions.

Dissecting the cross-trait effects of the FOXP2 GWAS hit on clinical and brain phenotypes in adults with ADHD.

The Forkhead box P2 (FOXP2) encodes for a transcription factor with a broad role in embryonic development. It is especially represented among GWAS hits for neurodevelopmental disorders and related traits, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, neuroticism, and risk-taking behaviors. While several functional studies are underway to understand the consequences of FOXP2 variation, this study aims to expand previous findings to clinically and genetically related phenotypes and neuroanatomical features among subjects with ADHD. The sample included 407 adults with ADHD and 463 controls. Genotyping was performed on the Infinium PsychArray-24 BeadChip, and the FOXP2 gene region was extracted. A gene-wide approach was adopted to evaluate the combined effects of FOXP2 variants (n = 311) on ADHD status, severity, comorbidities, and personality traits. Independent risk variants presenting potential functional effects were further tested for association with cortical surface areas in a subsample of cases (n = 87). The gene-wide analyses within the ADHD sample showed a significant association of the FOXP2 gene with harm avoidance (P = 0.001; PFDR = 0.015) and nominal associations with hyperactivity symptoms (P = 0.026; PFDR = 0.130) and antisocial personality disorder (P = 0.026; PFDR = 0.130). An insertion/deletion variant (rs79622555) located downstream of FOXP2 was associated with the three outcomes and nominally with the surface area of superior parietal and anterior cingulate cortices. Our results extend and refine previous GWAS findings pointing to a role of FOXP2 in several neurodevelopment-related phenotypes, mainly those involving underlying symptomatic domains of self-regulation and inhibitory control. Taken together, the available evidence may constitute promising insights into the puzzle of the FOXP2-related pathophysiology.

The course of attention-deficit/hyperactivity disorder through midlife.

The course of ADHD from childhood up to young adulthood has been characterized in several studies. However, little is known about the course of symptoms into middle age and beyond. This study aims to evaluate predictors of ADHD trajectories in midlife based on three assessments. The follow-up sample comprised 323 adults with ADHD, evaluated at baseline and seven and thirteen years later, from the average ages of 34 up to 47 years old. ADHD status at reassessments was used to characterize trajectories. Demographics, ADHD features, comorbidities, and polygenic scores for ADHD and genetically correlated psychiatric disorders were evaluated to predict ADHD trajectories. Study retention rate was 67% at T2 (n = 216) and 62% at T3 (n = 199). Data from patients evaluated three times showed that 68.8% coursed stable, 25.5% unstable, and 5.7% remission trajectory of ADHD. Women, individuals with more severe syndromes, higher frequency of comorbidities at reassessments, and genetic liability to depression present a higher probability of a stable trajectory. Our findings shed light on midlife ADHD trajectories and their gender, genomic and clinical correlates.

Emerging findings of glutamate-glutamine imbalance in the medial prefrontal cortex in attention deficit/hyperactivity disorder: systematic review and meta-analysis of spectroscopy studies.

One of the main challenges in investigating the neurobiology of ADHD is our limited capacity to study its neurochemistry in vivo. Magnetic resonance spectroscopy (MRS) estimates metabolite concentrations within the brain, but approaches and findings have been heterogeneous. To assess differences in brain metabolites between patients with ADHD and healthy controls, we searched 12 databases screening for MRS studies. Studies were divided into 'children and adolescents' and 'adults' and meta-analyses were performed for each brain region with more than five studies. The quality of studies was assessed by the Newcastle-Ottawa Scale. Thirty-three studies met our eligibility criteria, including 874 patients with ADHD. Primary analyses revealed that the right medial frontal area of children with ADHD presented higher concentrations of a composite of glutamate and glutamine (p = 0.02, SMD = 0.53). Glutamate might be implicated in pruning and neurodegenerative processes as an excitotoxin, while glutamine excess might signal a glutamate depletion that could hinder neurotrophic activity. Both neuro metabolites could be implicated in the differential cortical thinning observed in patients with ADHD across all ages. Notably, more homogeneous designs and reporting guidelines are the key factors to determine how suitable MRS is for research and, perhaps, for clinical psychiatry. Results of this meta-analysis provided an overall map of the brain regions evaluated so far, addressed the role of glutamatergic metabolites in the pathophysiology of ADHD, and pointed to new perspectives for consistent use of the tool in the field.

Caffeine-related genes influence anxiety disorders in children and adults with ADHD.

Attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders (AD) frequently co-occur, increasing morbidity and challenging treatment. Caffeine is a central nervous system stimulant and acts in the brain through adenosine receptors, influencing attention, alertness, and anxiety. In the present study, we performed a gene-set analysis to verify if genes related to caffeine response are associated with anxiety disorders in 240 children and 406 adults with ADHD. We demonstrated an association between the gene-set with AD in children (P = 0.0054) and with the number of anxiety disorders in adults (P = 0.0197). In order to test if this effect is a result of anxiety in general or is related to AD comorbid with ADHD, we evaluated the association between caffeine gene-set with AD in an adult control sample. The gene-set was neither associated with the AD presence (P = 0.3008) nor with the number of AD (P = 0.5594) in this control sample. We also test this gene set with ADHD (n = 55,374) and AD (n = 18,186) GWAS summary statistics, and we did not observe significant results with ADHD (P = 0.5587) or AD (P = 0.3930). These findings suggest the caffeine-related genes play a role in the etiology of an anxiety disorder phenotype present in children and adults with ADHD.

The neuroendocrine modulation of global DNA methylation in neuropsychiatric disorders.

There is an increasing body of knowledge on the influence of differential DNA methylation of specific genomic regions in psychiatric disorders. However, fewer studies have addressed global DNA methylation (GMe) levels. GMe is an estimative of biological functioning that is regulated by pervasive mechanisms able to capture the big picture of metabolic and environmental influences upon gene expression. In the present perspective article, we highlighted evidence for the relationships between cortisol and sex hormones and GMe in psychiatric disorders. We argue that the far-reaching effects of cortisol and sexual hormones on GMe may lie on the pathways linking stress and mental health. Further research on these endocrine-epigenetic links may help to explain the role of environmental stress as well as sex differences in the prevalence of psychiatric disorders.

Shared genetic background between children and adults with attention deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

Association between cognitive performance and SYT1-rs2251214 among women with cocaine use disorder.

The SNP rs2251214 of the SYT1 gene was recently associated with externalizing phenotypes, including ADHD and cocaine use disorder (CUD). Here, we investigated whether SYT1-rs2251214 could also be implicated with cognitive performance variations among women with CUD. Results showed that G homozygous (n = 146) have lower cognitive performance in the Stroop, Trail Making and Matrix Reasoning tests compared with A-allele carriers (n = 64), suggesting that rs2251214 may influence the severity of cognitive impairments in CUD.

Integrative genomic analysis of methylphenidate response in attention-deficit/hyperactivity disorder.

Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder (ADHD). However, a considerable interindividual variability exists in clinical outcome. Thus, we performed a genome-wide association study of MPH efficacy in 173 ADHD paediatric patients. Although no variant reached genome-wide significance, the set of genes containing single-nucleotide polymorphisms (SNPs) nominally associated with MPH response (P < 0.05) was significantly enriched for candidates previously studied in ADHD or treatment outcome. We prioritised the nominally significant SNPs by functional annotation and expression quantitative trait loci (eQTL) analysis in human brain, and we identified 33 SNPs tagging cis-eQTL in 32 different loci (referred to as eSNPs and eGenes, respectively). Pathway enrichment analyses revealed an over-representation of genes involved in nervous system development and function among the eGenes. Categories related to neurological diseases, psychological disorders and behaviour were also significantly enriched. We subsequently meta-analysed the association with clinical outcome for the 33 eSNPs across the discovery sample and an independent cohort of 189 ADHD adult patients (target sample) and we detected 15 suggestive signals. Following this comprehensive strategy, our results provide a better understanding of the molecular mechanisms implicated in MPH treatment effects and suggest promising candidates that may encourage future studies.

Intraurethral injection with LPS: an effective experimental model of prostatic inflammation.

OBJECTIVE: Chronic inflammation has been recognized as having a prominent role pathogenesis of benign prostatic hyperplasia (BPH) and cancer. It is believed that chronic inflammation induces prostatic fibromuscular growth. This correlation has been clearly illustrated by both in vivo and in vitro studies; however, current experimental models of BPH require complex surgery or hormonal treatment. Therefore, the aim of the present study was to propose a new murine model of BPH/prostatitis induced by intraurethral injection of LPS. METHODS: Male Swiss and C57Bl/6 mice were then sacrificed 3, 7, 10, and 14 days after intraurethral injection of LPS. The prostates were quickly dissected and fixed for morphological and immunohistochemical analyses. RESULTS: The results showed that LPS played an important role in the cell proliferation of the prostate. Histological and ultrastructural analysis showed epithelial hyperplasia, clear stromal cells, little inflammatory infiltration, and heavy bleeding. Treatment with LPS also promoted the increase of growth factor (FGF-7 and TGF-ß), α-actin, and proinflammatory cytokines (IL-1, IL-6, IL-17), both in the stroma and epithelium. CONCLUSION: According to the present findings, it can be concluded that the intraurethral administration of LPS promotes tissue remodeling, as well as stimulating the pattern of pro-inflammatory cytokines, and therefore, constitutes an effective experimental model of BPH/inflammation.

Replicated association of Synaptotagmin (SYT1) with ADHD and its broader influence in externalizing behaviors.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder, affecting both children and adults. The Soluble N-ethylmaleimide sensitive factor Attachment REceptors (SNARE) complex has been implicated in ADHD pathophysiology since it is a key component of neurotransmitter release events and neurodevelopment processes, and SNPs in this complex have been associated with ADHD. Here we aim to analyze the effects of SNARE complex variants on ADHD susceptibility and its clinical heterogeneity in affected adults. We tested the association between ADHD and polymorphisms on the SNARE genes STX1A (rs2228607), SYT1 (rs1880867 and rs2251214), VAMP2 (26bp Ins/Del) and SNAP25 (rs6108461 and rs8636) on a sample comprised of 548 adults with ADHD and 644 non-affected controls. Regarding clinical heterogeneity, we further investigated the effects of associated SNPs on age at onset of impairment due to ADHD and on relevant externalizing behaviors (i.e. school suspensions/expulsions and problems with law/authority) and comorbidities (i.e. Substance Use Disorder, Oppositional Defiant Disorder, Conduct Disorder and Antisocial Personality Disorder). We replicated a previously reported association between SYT1-rs2251214 and ADHD in adulthood. This SNP was also associated with age at onset of impairment due to ADHD symptoms and with a range of externalizing phenotypes. These findings involving SYT1 suggest that variation in neurotransmitter exocytosis mechanisms may represent an underlying genetic factor shared by a spectrum of externalizing behaviors and disorders, including - but not restricted to - ADHD.

SNARE complex in developmental psychiatry: neurotransmitter exocytosis and beyond.

Multiple biological processes throughout development require intracellular vesicular trafficking, where the SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors) complex plays a major role. The core proteins forming the SNARE complex are SNAP-25 (synaptosomal-associated protein 25), VAMP (vesicle-associated membrane protein) and Syntaxins, besides its regulatory proteins, such as Synaptotagmin. Genes encoding these proteins (SNAP25, VAMP1, VAMP2, STX1A, SYT1 and SYT2) have been studied in relation to psychiatric disorders susceptibility. Here, we review physiological aspects of SNARE complex and genetic association results reported for attention deficit hyperactivity disorder, both in children and adults, autism spectrum disorders, major depressive disorder, bipolar disorder and schizophrenia. Moreover, we included findings from expression, pharmacogenetics and animal model studies regarding these clinical phenotypes. The overall scenario depicted here suggests that the SNARE complex may exert distinct roles throughout development, with age-specific effects of genetic variants in psychiatric disorders. Such perspective should be considered in future studies regarding SNARE complex genes.

Padrão de exposição radiológica em profissionais da saúde durante procedimentos cardiológicos invasivos / Pattern of radiation exposure in healthcare professionals during coronary angiography

Introdução: Procedimentos cardiológicos invasivos expõem Médicos e enfermeiros/técnicos de enfermagem aos riscos da radiação ionizante. O objetivo deste estudo foi determinar os padrões de exposição radiológica em profissionais da saúde durante procedimentos cardiológicos. Métodos: Estudo prospectivo incluindo pacientes submetidos a procedimento cardiológico invasivo entre dezembro de 2011 e agosto de 2012 em equipamento com detectores do tipo plano. Características clínicas, angiográficas e de exposição à radiação foram registradas em banco de dados específico. Os padrões de exposição à radiação foram determinados em pacientes submetidos ao cateterismo cardíaco diagnóstico. Correlação entre dose do médico operador e enfermeiro/técnico de enfermagem também foi efetuada. Resultados: Amostra incluiu 119 pacientes submetidos ao cateterismo. A dose de kerma no ar e o produto dose-área médio de radiação recebida pelos pacientes foram de 549 ± 220 mGy e 29.054 ± 14.696 mGy.cm2, respectivamente. Médicos e enfermeiros/técnicos de enfermagem foram expostos à dose efetiva média por exame de 0,47 ± 0,16 e 0,28 ± 0,13 mSv, respectivamente. A correlação entre dose efetiva dos Médicos e enfermeiro/técnicos de enfermagem foi de 0,54 ( p < 0,001). Conclusões: Médicos e enfermeiros/técnicos de enfermagem são expostos a doses pequenas de radiação ionizante durante cateterismo cardíaco diagnóstico. Enfermeiros/técnicos de enfermagem são expostos a cerca de 60% da dose do médico operador...

Background: Invasive cardiologic procedures expose physicians and nurses/technicians to the risks of ionizing radiation. The aim of this study was to determine the exposure patterns in healthcare professionals during cardiologic procedures. Methods: Prospective study including patients undergoing invasive cardiologic procedures between December 2011 and August 2012 using flat-panel detector fluoroscopy. Clinical, angiographic and radiation exposure characteristics were recorded in a dedicated database. Patterns of radiation exposure were determined in patients undergoing diagnostic cardiac catheterization. The correlation between surgeon and nurse/technician dose was also evaluated. Results: The sample included 119 patients undergoing catheterization. The patient mean air kerma dose and dose-area product was 549 ± 220 mGy and 29,054 ± 14,696 mGy.cm2, respectively. Physicians and nurses/technicians were exposed to a mean effective dose of 0.47 ± 0.16 and 0.28 ± 0.13 mSv per exam, respectively. The correlation between physicians and nurses/technicians effective dose was 0.54 (p < 0.001). Conclusions: Physicians and nurses/technicians are exposed to low ionizing radiation doses during diagnostic cardiac catheterization. Nurses/technicians are exposed to approximately 60% of the operating physician's dose...

Diethylcarbamazine inhibits NF-κB activation in acute lung injury induced by carrageenan in mice.

Diethylcarbamazine citrate (DEC) is widely used to treat lymphatic filariasis and Tropical Pulmonary Eosinophilia. A number of studies have reported a possible role in the host immune system, but exactly how DEC exerts this effect is still unknown. The present study reports the effects of DEC pretreatment on NF-κB regulation using the pleurisy model induced by carrageenan. Swiss male mice (Mus musculus) were divided into four experimental groups: control (SAL); carrageenan (CAR); diethylcarbamazine (DEC) and curcumin (CUR). The animals were pretreated with DEC (50mg/kg, v.o), CUR (50mg/kg, i.p) or distilled water for three consecutive days before pleurisy. One way analysis of variance (ANOVA) was performed by Tukey post-hoc test, and values were considered statistically significant when p<0.05. DEC pretreatment reduced tissue damage and the production of inflammatory markers, such as NO, iNOS, PGE2, COX-2, and PARP induced by carrageenan. Similarly, a known inhibitor of NF-κB pathway (curcumin) was also able to reduce these parameters. Like curcumin, DEC prevents NF-κB activation by reducing NF-κB p65 phosphorylation and IκBα degradation. DEC prevented NF-κB activation via p38 MAPK, but did not interfere in the ERK pathway in this experimental model. However, further studies should be developed to confirm this hypothesis. These findings suggest that DEC could be a promising drug for inflammatory disorders, especially in pulmonary diseases such as Acute Lung Inflammation, due its high anti-inflammatory potential which prevents NF-κB activation.

Should we keep on? Looking into pharmacogenomics of ADHD in adulthood from a different perspective.

A considerable proportion of adults with attention-deficit/hyperactivity disorder (ADHD) do not respond to the treatment with methylphenidate. This scenario could be due to inherited interindividual differences that may alter pharmacologic treatment response. In this sense, in 2012 we conducted a systematic search on PUBMED-indexed literature for articles containing information about pharmacogenomics of ADHD in adults. Five studies were found on methylphenidate pharmacogenomics and the only significant association was reported by one particular study. However, this single association with the SLC6A3 gene was not replicated in two subsequent reports. In the present review, although we could not find additional pharmacogenomics studies, we discuss these up-to-date findings and suggest new approaches for this field. Additionally, using systeomic-oriented databases, we provide a broad picture of new possible candidate genes as well as potential gene-gene interactions to be investigated in pharmacogenomics of persistent ADHD.

Inhibition of NF-κB activation by diethylcarbamazine prevents alcohol-induced liver injury in C57BL/6 mice.

Induction of NF-κB-mediated gene expression has been identified in the pathogenesis of alcoholic liver disease (ALD). Diethylcarbamazine (DEC) is a piperazine derivative drug with anti-inflammatory properties. The present study was designed to evaluate the effect of DEC on NF-κB pathways in mice undergoing alcoholism induced hepatic inflammation. Forty male C57BL/6 mice were divided equally into four groups: control group (C); DEC-treated group, which received 50mg/kg (DEC50); alcoholic group (EtOH), submitted to chronic alcohol consumption and the alcohol-DEC treated group (EtOH50), submitted to chronic alcoholism consumption plus DEC treatment. Histological analysis of the alcoholic group showed evident hepatocellular damage which was reduced in EtOH50 group. Immunohistochemistry and western blot results showed elevated expression of inflammatory markers such as MDA, TNF-α, IL-1ß, COX-2 and iNOS in hepatocytes of EtOH group. However, low immunopositivity for these markers was detected following DEC treatment. In the EtOH group the activation of NF-κB was observed by an increase in the expression of both NF-κB and pNF-κB in hepatocytes. This expression was significantly reduced in livers of EtOH50 group. Protein expression of Iκßα was measured to determine whether activation of NF-κB might be the result of Iκßα degradation. It was observed that expression of this protein was low in EtOH group, while animals treated with DEC had a high expression of Iκßα. The results of the present study indicate that DEC alleviates alcoholic liver injury, in part by the inhibiting activation of NF-κB and by suppressing the induction of NF-κB-dependent genes.