The retinoid X receptor: a nuclear receptor that modulates the sleep-wake cycle in rats.

RATIONALE: The nuclear receptor retinoid X receptor (RXR) belongs to a nuclear receptor superfamily that modulates diverse functions via homodimerization with itself or several other nuclear receptors, including PPARα. While the activation of PPARα by natural or synthetic agonists regulates the sleep-wake cycle, the role of RXR in the sleep modulation is unknown. OBJECTIVES: We investigated the effects of bexarotene (Bexa, a RXR agonist) or UVI 3003 (UVI, a RXR antagonist) on sleep, sleep homeostasis, levels of neurochemical related to sleep modulation, and c-Fos and NeuN expression. METHODS: The sleep-wake cycle and sleep homeostasis were analyzed after application of Bexa or UVI. Moreover, we also evaluated whether Bexa or UVI could induce effects on dopamine, serotonin, norepinephrine epinephrine, adenosine, and acetylcholine contents, collected from either the nucleus accumbens or basal forebrain. In addition, c-Fos and NeuN expression in the hypothalamus was determined after Bexa or UVI treatments. RESULTS: Systemic application of Bexa (1 mM, i.p.) attenuated slow-wave sleep and rapid eye movement sleep. In addition, Bexa increased the levels of dopamine, serotonin, norepinephrine epinephrine, adenosine, and acetylcholine sampled from either the nucleus accumbens or basal forebrain. Moreover, Bexa blocked the sleep rebound period after total sleep deprivation, increased in the hypothalamus the expression of c-Fos, and decreased NeuN activity. Remarkably, UVI 3003 (1 mM, i.p.) induced opposite effects in sleep, sleep homeostasis, neurochemicals levels, and c-Fos and NeuN activity. CONCLUSIONS: The administration of RXR agonist or antagonist significantly impaired the sleep-wake cycle and exerted effects on the levels of neurochemicals related to sleep modulation. Moreover, Bexa or UVI administration significantly affected c-Fos and NeuN expression in the hypothalamus. Our findings highlight the neurobiological role of RXR on sleep modulation.

Sleep and Neurochemical Modulation by DZNep and GSK-J1: Potential Link With Histone Methylation Status.

Histone methylation/demethylation plays an important modulatory role in chromatin restructuring, RNA transcription and is essential for controlling a plethora of biological processes. Due to many human diseases have been related to histone methylation/demethylation, several compounds such as 3-deazaneplanocin A (DZNep) or 3-((6-(4,5-Dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid; N-[2-(2-pyridinyl)-6-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-4-pyrimidinyl]-ß-Alanine (GSK-J1), have been designed to inhibit histone methylase or suppress histone demethylase, respectively. In the present study, we investigated the effects on the sleep-wake cycle and sleep-related neurochemical levels after systemic injections of DZNep or GSK-J1 given during the light or dark phase in rats. DZNep dose-dependently (0.1, 1.0, or 10 mg/kg, i.p.) prolonged wakefulness (W) duration while decreased slow wave sleep (SWS) and rapid eye movement sleep (REMS) time spent during the lights-on period with no changes observed in dark phase. In opposite direction, GSK-J1 (0.1, 1.0, or 10 mg/kg, i.p.) injected at the beginning of the lights-on period induced no statistical changes in W, SWS, or REMS whereas if administered at darkness, we found a diminution in W and an enhancement in SWS and REMS. Finally, brain microdialysis experiments in freely moving animals were used to evaluate the effects of DZNep or GSK-J1 treatments on contents of sleep-related neurochemicals. The results showed that DZNep boosted extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, adenosine, and acetylcholine if injected at the beginning of the lights-on period whereas GSK-J1 exerted similar outcomes but when administered at darkness. In summary, DZNep and GSK-J1 may control the sleep-wake cycle and sleep-related neurochemicals through histone methylation/demethylation activity.

A genome-wide RNAi screen identifies the SMC5/6 complex as a non-redundant regulator of a Topo2a-dependent G2 arrest.

The Topo2a-dependent arrest is associated with faithful segregation of sister chromatids and has been identified as dysfunctional in numerous tumour cell lines. This genome-protecting pathway is poorly understood and its characterization is of significant interest, potentially offering interventional opportunities in relation to synthetic lethal behaviours in arrest-defective tumours. Using the catalytic Topo2a inhibitor ICRF193, we have performed a genome-wide siRNA screen in arrest-competent, non-transformed cells, to identify genes essential for this arrest mechanism. In addition, we have counter-screened several DNA-damaging agents and demonstrate that the Topo2a-dependent arrest is genetically distinct from DNA damage checkpoints. We identify the components of the SMC5/6 complex, including the activity of the E3 SUMO ligase NSE2, as non-redundant players that control the timing of the Topo2a-dependent arrest in G2. We have independently verified the NSE2 requirement in fibroblasts from patients with germline mutations that cause severely reduced levels of NSE2. Through imaging Topo2a-dependent G2 arrested cells, an increased interaction between Topo2a and NSE2 is observed at PML bodies, which are known SUMOylation hotspots. We demonstrate that Topo2a is SUMOylated in an ICRF193-dependent manner by NSE2 at a novel non-canonical site (K1520) and that K1520 sumoylation is required for chromosome segregation but not the G2 arrest.

Fighting obesity: Non-pharmacological interventions.

The abnormal or excessive fat accumulation that impairs health is one of the criteria that fulfills obesity. According to epidemiological data, obesity has become a worldwide public health problem that in turn would trigger additional pathologies such as cardiorespiratory dysfunctions, cancer, gastrointestinal disturbances, depression, sleep disorders, just to mention a few. Then, the search for a therapeutical intervention aimed to prevent and manage obesity has been the focus of study during the last years. As one can assume, the increased prevalence of obesity has translated to search of efficient pharmaceuticals designed to manage this health issue. However, to further complicate the scenario, scientific literature has described that obesity is the result of interaction between multiple events. Therefore, pharmacological approaches have faced a serious challenge for develop the adequate treatment. Here, we argue that a wide range of non-pharmacological/invasive techniques can be used to manage obesity, such as diets, cognitive behavioral interventions, exercise and transcranial direct current stimulation. Combining these techniques may allow improving quality of life of obese patients.

CRISPR/Cas9, the Powerful New Genome-Editing Tool for Putative Therapeutics in Obesity.

The molecular technology known as clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) is revolutionizing the field of medical research and deepening our understanding of numerous biological processes. The attraction of CRISPR/Cas9 lies in its ability to efficiently edit DNA or modulate gene expression in living eukaryotic cells and organisms, a technology that was once considered either too expensive or scientifically risky. CRISPR/Cas9 has been successfully applied in agriculture to develop the next generation of disease-resistant plants. Now, the capability of gene editing has been translated to the biomedical area, focusing on the future of medicine faced with drug-resistant microbes by selectively targeting genes involved in antibiotic resistance, for example, or finding the ultimate strategy for cancer or HIV. In this regard, it was recently demonstrated that an injection of cancer-fighting CRISPR-modified white blood cells in a patient suffering from metastatic lung cancer could lead to promising results. Researchers and bioethicists are debating questions about the regulation of CRISPR/Cas9 that must be addressed. While legal challenges surround the use of this technique for genetically modifying cell lines in humans, we review the basic understanding of CRISPR/Cas9 and discuss how this technology could represent a candidate for treatment of non-communicable diseases in nutrition, such as obesity.

An Overview of the Clinical Uses, Pharmacology, and Safety of Modafinil.

Modafinil (MOD) is a wakefulness-inducing compound prescribed for treatment of excessive daytime sleepiness as a consequence of sleep disturbances such as shift work sleep disorder, obstructive sleep apnea, restless leg syndrome, or narcolepsy. While providing effective results in patients with sleepiness, MOD also produces positive outcomes in the management of fatigue associated with different conditions including depression, cancer, or tiredness in military personnel. Although there is clear evidence of the stimulant effects of MOD, current data also show that administration of this drug apparently induces positive neurobiological effects, such as improvement in memory. However, serious concerns have been raised since some reports have suggested MOD dependence. Taken together, these findings highlight the need to characterize the changes induced by MOD which have been observed in several neurobiological functions. Moreover, further work should follow up on the likely long-term effects of this drug if used for treatment of drowsiness and tiredness. Here, we review and summarize recent findings of the medical uses of MOD in the management of sleepiness and fatigue associated with depression or cancer as well as exhaustion in military personnel. We also discuss the available literature related with the cognitive enhancing properties of this stimulant, as well as what is known and unknown about MOD addiction.

The metabolic syndrome- associated small G protein ARL15 plays a role in adipocyte differentiation and adiponectin secretion.

Common genetic variants at the ARL15 locus are associated with plasma adiponectin, insulin and HDL cholesterol concentrations, obesity, and coronary atherosclerosis. The ARL15 gene encodes a small GTP-binding protein whose function is currently unknown. In this study adipocyte-autonomous roles for ARL15 were investigated using conditional knockdown of Arl15 in murine 3T3-L1 (pre)adipocytes. Arl15 knockdown in differentiated adipocytes impaired adiponectin secretion but not adipsin secretion or insulin action, while in preadipocytes it impaired adipogenesis. In differentiated adipocytes GFP-tagged ARL15 localized predominantly to the Golgi with lower levels detected at the plasma membrane and intracellular vesicles, suggesting involvement in intracellular trafficking. Sequencing of ARL15 in 375 severely insulin resistant patients identified four rare heterozygous variants, including an early nonsense mutation in a proband with femorogluteal lipodystrophy and non classical congenital adrenal hyperplasia, and an essential splice site mutation in a proband with partial lipodystrophy and a history of childhood yolk sac tumour. No nonsense or essential splice site mutations were found in 2,479 controls, while five such variants were found in the ExAC database. These findings provide evidence that ARL15 plays a role in adipocyte differentiation and adiponectin secretion, and raise the possibility that human ARL15 haploinsufficiency predisposes to lipodystrophy.

Role of N-Arachidonoyl-Serotonin (AA-5-HT) in Sleep-Wake Cycle Architecture, Sleep Homeostasis, and Neurotransmitters Regulation.

The endocannabinoid system comprises several molecular entities such as endogenous ligands [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)], receptors (CB1 and CB2), enzymes such as [fatty acid amide hydrolase (FAHH) and monoacylglycerol lipase (MAGL)], as well as the anandamide membrane transporter. Although the role of this complex neurobiological system in the sleep-wake cycle modulation has been studied, the contribution of the blocker of FAAH/transient receptor potential cation channel subfamily V member 1 (TRPV1), N-arachidonoyl-serotonin (AA-5-HT) in sleep has not been investigated. Thus, in the present study, varying doses of AA-5-HT (5, 10, or 20 mg/Kg, i.p.) injected at the beginning of the lights-on period of rats, caused no statistical changes in sleep patterns. However, similar pharmacological treatment given to animals at the beginning of the dark period decreased wakefulness (W) and increased slow wave sleep (SWS) as well as rapid eye movement sleep (REMS). Power spectra analysis of states of vigilance showed that injection of AA-5-HT during the lights-off period diminished alpha spectrum across alertness in a dose-dependent fashion. In opposition, delta power spectra was enhanced as well as theta spectrum, during SWS and REMS, respectively. Moreover, the highest dose of AA-5-HT decreased wake-related contents of neurotransmitters such as dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT) whereas the levels of adenosine (AD) were enhanced. In addition, the sleep-inducing properties of AA-5-HT were confirmed since this compound blocked the increase in W caused by stimulants such as cannabidiol (CBD) or modafinil (MOD) during the lights-on period. Additionally, administration of AA-5-HT also prevented the enhancement in contents of DA, NE, EP, 5-HT and AD after CBD of MOD injection. Lastly, the role of AA-5-HT in sleep homeostasis was tested in animals that received either CBD or MOD after total sleep deprivation (TSD). The injection of CBD or MOD increased alertness during sleep rebound period after TSD. However, AA-5-HT blocked this effect by allowing animals to display an enhancement in sleep across sleep rebound period. Overall, our findings provide evidence that AA-5-HT is an important modulator of sleep, sleep homeostasis and neurotransmitter contents.

Hypoinsulinaemic, hypoketotic hypoglycaemia due to mosaic genetic activation of PI3-kinase.

OBJECTIVE: Genetic activation of the insulin signal-transducing kinase AKT2 causes syndromic hypoketotic hypoglycaemia without elevated insulin. Mosaic activating mutations in class 1A phospatidylinositol-3-kinase (PI3K), upstream from AKT2 in insulin signalling, are known to cause segmental overgrowth, but the metabolic consequences have not been systematically reported. We assess the metabolic phenotype of 22 patients with mosaic activating mutations affecting PI3K, thereby providing new insight into the metabolic function of this complex node in insulin signal transduction. METHODS: Three patients with megalencephaly, diffuse asymmetric overgrowth, hypoketotic, hypoinsulinaemic hypoglycaemia and no AKT2 mutation underwent further genetic, clinical and metabolic investigation. Signalling in dermal fibroblasts from one patient and efficacy of the mTOR inhibitor Sirolimus on pathway activation were examined. Finally, the metabolic profile of a cohort of 19 further patients with mosaic activating mutations in PI3K was assessed. RESULTS: In the first three patients, mosaic mutations in PIK3CA (p.Gly118Asp or p.Glu726Lys) or PIK3R2 (p.Gly373Arg) were found. In different tissue samples available from one patient, the PIK3CA p.Glu726Lys mutation was present at burdens from 24% to 42%, with the highest level in the liver. Dermal fibroblasts showed increased basal AKT phosphorylation which was potently suppressed by Sirolimus. Nineteen further patients with mosaic mutations in PIK3CA had neither clinical nor biochemical evidence of hypoglycaemia. CONCLUSIONS: Mosaic mutations activating class 1A PI3K cause severe non-ketotic hypoglycaemia in a subset of patients, with the metabolic phenotype presumably related to the extent of mosaicism within the liver. mTOR or PI3K inhibitors offer the prospect for future therapy.

Constitutive Activation of AKT2 in Humans Leads to Hypoglycemia Without Fatty Liver or Metabolic Dyslipidemia.

Context: The activating p.Glu17Lys mutation in AKT2, a kinase mediating many of insulin's metabolic actions, causes hypoinsulinemic hypoglycemia and left-sided hemihypertrophy. The wider metabolic profile and longer-term natural history of the condition has not yet been reported. Objective: To characterize the metabolic and cellular consequences of the AKT2 p.Glu17Lys mutation in two previously reported males at the age of 17 years. Design and Intervention: Body composition analysis using dual-energy X-ray absorptiometry, overnight profiling of plasma glucose, insulin, and fatty acids, oral glucose tolerance testing, and magnetic resonance spectroscopy to determine hepatic triglyceride content was undertaken. Hepatic de novo lipogenesis was quantified using deuterium incorporation into palmitate. Signaling in dermal fibroblasts was studied ex vivo. Results: Both patients had 37% adiposity. One developed hypoglycemia after 2 hours of overnight fasting with concomitant suppression of plasma fatty acids and ketones, whereas the other maintained euglycemia with an increase in free fatty acids. Blood glucose excursions after oral glucose were normal in both patients, albeit with low plasma insulin concentrations. In both patients, plasma triglyceride concentration, hepatic triglyceride content, and fasting hepatic de novo lipogenesis were normal. Dermal fibroblasts of one proband showed low-level constitutive phosphorylation of AKT and some downstream substrates, but no increased cell proliferation rate. Conclusions: The p.Glu17Lys mutation of AKT2 confers low-level constitutive activity upon the kinase and produces hypoglycemia with suppressed fatty acid release from adipose tissue, but not fatty liver, hypertriglyceridemia, or elevated hepatic de novo lipogenesis. Hypoglycemia may spontaneously remit.

Association between depression severity and executive functioning in late-life depression: a systematic review / Associação entre a severidade dos sintomas depressivos e o funcionamento executivo de idosos com depressão: uma revisão sistemática

OBJECTIVE: Late-life depression is an under-diagnosed and under-treated disease that reduces the well-being of older adults. Executive dysfunction is another critical impairment in elderly depressed individuals which further disrupts their everyday functioning. This systematic review aims to analyze the association between executive function and depression severity in elderly individuals diagnosed with major depressive disorder. METHOD: The studies were retrieved from MEDLINE/PubMed, ISI Web of Knowledge and PsychInfo, after a search strategy combining the terms "depression", "executive function", "neuropsychological assessment", "elderly" and "late life". Study selection, data collection and quality ratings was performed by two independent raters. RESULTS: A total of 1,130 articles were found but only 8 studies met the defined eligibility criteria and evaluated the association between depression severity and executive functioning. Six out of 8 studies found an association between depression severity and executive function, with correlations ranging from small to large (r= -0.15 to -0.53). The included reports had several methodological limitations such as selective data reporting, non-comprehensive executive function assessment and not controlling potential biases. CONCLUSION: Depression severity may be more strongly correlated with a specific set of executive abilities although it also seems to be a broad-based association with executive functioning as a whole. Future high-quality prospective studies are recommended in order to understand the causal relationship between depression severity and executive functioning taking into account possible mediators such as age-related or neurodegenerative cognitive impairment, educational level and other clinic characteristics (e.g. age of onset, medication).

OBJETIVO: A depressão de início tardio é uma doença subdiagnosticada e subtratada que reduz o bem-estar da pessoa idosa. A disfunção executiva é outra alteração crítica em idosos deprimidos, perturbando ainda mais o seu funcionamento diário. Esta revisão sistemática tem como objetivo analisar a associação entre o funcionamento executivo e a severidade dos sintomas depressivos em idosos diagnosticados com transtorno depressivo major. MÉTODOS: Foi realizada uma busca nas bases de dados MEDLINE/PubMed, ISI Web of Knowledge e PsychInfo utilizando os termos "depression", "executive function", "neuropsychological assessment", "elderly" e "late life". A seleção, classificação dos estudos e coleta de dados foram realizadas por dois avaliadores independentes. RESULTADOS: Foram encontrados 1130 artigos, mas apenas 8 estudos preencheram os critérios de elegebilidade. Três avaliaram a associação entre a severidade dos sintomas e o funcionamento executivo. Seis dos 8 estudos encontraram uma associação entre a severidade dos sintomas e o funcionamento executivo, com correlações de diversas magnitudes (r= -0,15 a -0,53). Os artigos incluídos apresentaram várias limitações metodológicas, tais como descrição seletiva de dados, avaliação não compreensiva do funcionamento executivo e falha no controlo de possíveis vieses. CONCLUSÃO: A severidade dos sintomas depressivos pode ser fortemente correlacionada com um conjunto específico de habilidades executivas, embora pareça também existir uma associação mais ampla com o funcionamento executivo como um todo. Recomenda-se a realização de estudos prospetivos com o fim de compreender a relação causal entre a severidade dos sintomas depressivos e o funcionamento executivo, tendo em conta possíveis mediadores tais como défices cognitivos associados ao envelhecimento ou outros processos neuro-degenerativos, nível de escolaridade e outras características clínicas (idade de início da doença, medicação).

Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis.

The endocannabinoid system comprises receptors (CB1 and CB2 cannabinoid receptors), enzymes (Fatty Acid Amide Hydrolase [FAAH], which synthesizes the endocannabinoid anandamide), as well as the anandamide membrane transporter (AMT). Importantly, previous experiments have demonstrated that the endocannabinoid system modulates multiple neurobiological functions, including sleep. For instance, SR141716A (the CB1 cannabinoid receptor antagonist) as well as URB597 (the FAAH inhibitor) increase waking in rats whereas VDM-11 (the blocker of the AMT) enhances sleep in rodents. However, no further evidence is available regarding the neurobiological role of the endocannabinoid system in the homeostatic control of sleep. Therefore, the aim of the current experiment was to test if SR141716A, URB597 or VDM-11 would modulate the sleep rebound after sleep deprivation. Thus, these compounds were systemically injected (5, 10, 20mg/kg; ip; separately each one) into rats after prolonged waking. We found that SR141716A and URB597 blocked in dose-dependent fashion the sleep rebound whereas animals treated with VDM-11 displayed sleep rebound during the recovery period. Complementary, injection after sleep deprivation of either SR141716A or URB597 enhanced dose-dependently the extracellular levels of dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT), as well as adenosine (AD) while VDM-11 caused a decline in contents of these molecules. These findings suggest that SR141716A or URB597 behave as a potent stimulants since they suppressed the sleep recovery period after prolonged waking. It can be concluded that elements of the endocannabinoid system, such as the CB1 cannabinoid receptor, FAAH and AMT, modulate the sleep homeostasis after prolonged waking.

Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations.

Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome.

Cognitive-behavioral therapy for schizophrenia: an overview on efficacy, recent trends and neurobiological findings / Terapia cognitivo-comportamental para esquizofrenia: uma revisão sobre eficácia, avanços recentes e achados neurobiológicos

OBJECTIVE: Cognitive Behavioral Therapy (CBT) has been recommended by several international guidelines as the gold-standard treatment to address the needs of patients with schizophrenia. This review provides an overview on recent advances regarding CBT for schizophrenia. METHODS: An electronic search was performed on PubMed/MEDLINE, Web of Science and Cochrane Database, using the key-words: "schizophrenia", "psychosis", "cognitive-behavioral therapy", "CBT" and "psychotherapy". RESULTS: Numerous systematic reviews support the immediate and long-term efficacy of Cognitive Behavioral Therapy to reduce positive and negative symptoms in patients with schizophrenia. In the last decade, CBT for schizophrenia has been applied to clinical high-risk subjects and delivered using innovative approaches (low intensity, web-based and self-guided). Brain regions and networks which support high-level cognitive functions have been associated with CBT responsiveness. There is preliminary evidence indicating that CBT induces a prefrontal dependent increase in the top-down modulation of social threat activation. CONCLUSION: In the last decade, CBT for schizophrenia has explored new treatment outcomes, targeted acute and pre-clinical populations and provided alternative methods to reach more patients and reduce intervention costs. The patients' neurocognitive profile seems to play a critical role in treatment response and combining CBT with cognitive remediation may allow to enhance therapeutic effects. Although CBT for schizophrenia is widely established as a gold-standard practice, future studies using innovative CBT protocols, exploring brain-related predictors and treatment outcomes may allow this intervention to be more effective, personalized and to reach a wider number of patients.

INTRODUÇÃO: A terapia cognitivo-comportamental (TCC) tem sido recomendada em diversas guidelines internacionais como a intervenção psicoterapêutica padrão de ouro para pacientes com esquizofrenia. Esta revisão tem como objetivo fornecer uma visão global sobre os avanços recentes da TCC na esquizofrenia. MÉTODOS: Para esta revisão narrativa foi realizada uma busca eletrônica na PubMed/MEDLINE, Web of Science e Cochrane Database utilizando as palavras-chave: "schizophrenia", "psychosis", "cognitive-behavioral therapy", "CBT" e "psychotherapy". RESULTADOS: Várias revisões sistemáticas suportam a eficácia da TCC na redução a curto e longo prazo dos sintomas positivos e negativos da esquizofrenia. Na última década, a TCC tem sido aplicada a indivíduos com alto risco de psicose, sendo também exploradas abordagens inovadoras na sua utilização (curta duração, web-based, autogestão). Redes neurais responsáveis por funções cognitivas de nível superior têm sido associadas a respostas positivas após TCC para esquizofrenia. Existe ainda evidência preliminar que a TCC promove a ativação de zonas pré-frontais responsáveis pela modulação top-down face a ameaças sociais. CONCLUSÃO: Na última década, a TCC para esquizofrenia tem explorado novos desfechos, intervindo em populações agudas e pré-clínicas e utilizado métodos alternativos para alcançar mais pacientes e reduzir custos O perfil neurocognitivo dos pacientes aparenta ter um papel crítico na resposta ao tratamento, pelo que combinar a TCC com reabilitação cognitiva poderá potenciar os seus efeitos terapêuticos. Apesar da TCC ser uma prática recomendada para a esquizofrenia, estudos futuros usando protocolos inovadores e explorando preditores e desfechos relacionados com o cérebro poderão possibilitar que esta intervenção seja mais eficaz, personalizável e alcance o máximo número de pacientes possível.

Effects of dual-task interventions on gait performance of patients with Parkinson's Disease: A systematic review / Efeito da dupla tarefa na marcha em pacientes com doença de parkinson: uma revisão sistemática

OBJECTIVE: Parkinson's disease is characterized by motor and non-motor symptoms that impair patients' gait performance, especially while performing dual/concurrent tasks. These deficits impair patients' daily function, because dual-tasking is a crucial ability in terms of everyday living. The aim of this study was to systematically review the effects of dual task interventions on gait performance of patients with Parkinson's disease. METHOD: Studies were retrieved from MEDLINE/PubMed, LILACS and SciELO. We used the PICOS strategy to determine eligibility criteria. The search strategy included an advanced search on the included databases, using the following search query: "Parkinson's Disease" AND "Double Task" OR "Concurrent Tasks" OR "Gait" AND "Walk". Study selection was carried out by two independent researchers and a third one was called when consensus was needed. RESULTS: A total of 188 articles were identified: 169 articles from Medline/PubMed, 10 articles in SciELO, 8 articles in LILACS and 1 item from manual searches. A total of 56 articles were analyzed regarding the eligibility and exclusion criteria based on full text. A final total of 7 studies were included in the systematic review. CONCLUSION: The different types of dual-task interventions reported (dance, sound stimuli, visual and somatosensory) were associated to improvements in several gait performance indicators of Parkinson's disease patients, including gait speed, stride time and length, cadence and step length. External stimuli seem to play a critical role on specific training effects on dual-task gait performance.

OBJETIVO: A Doença de Parkinson é caracterizada por sintomas motores e não motores que prejudicam a marcha, especialmente durante a realização de tarefas duplas/simultâneas. Estes déficits afetam o funcionamento diário do paciente já que a realização de tarefas duplas é uma habilidade crucial para a vida normal.O objetivo deste estudo foi realizar uma Revisão Sistemática sobre os efeitos das tarefas duplas sobre a marcha em pacientes com Doença de Parkinson. MÉTODOS: Os estudos foram recuperados do MEDLINE/PubMed, SciELO e Lilacs. Adotamos a estratégia PICOS para determinar os critérios de elegibilidade. A estratégia de busca foi realizada utilizando uma pesquisa avançada MEDLINE/PubMed, SciELO e Lilacs com os seguintes termos adotados "Doença de Parkinson", "Dupla Tarefa", "Tarefas Concorrentes", "Marcha" e "Caminhada". Operadores booleanos AND e OR foram utilizados para combinação dos termos. A seleção dos estudos foi realizada por dois pesquisadores independentes que, em caso de desacordo, procuraram um consenso sobre a seleção. RESULTADOS: Foram identificados um total de 188 artigos:169 artigos do PubMed/Medline, 10 artigos no SciELO, 8 artigos no LILACS e 1 artigo em buscas manuais. Após uma seleção inicial, 56 artigos foram analisados pelos critérios de elegibilidade e os critérios de exclusão, sendo que um total de sete estudos foi incluído na revisão sistemática. CONCLUSÃO: De acordo com os estudos analisados nesta revisão, os diferentes tipos de intervenção incluídos (dança, estímulos sonoros, visuais e somato-sensoriais) permitem melhorias em vários indicadores de marcha tais como a velocidade, tempo da passada, cadência e comprimento do passo. A utilização de estímulos externos aparentam desempenhar um papel crítico nos efeitos espeíficos do treinamento na marcha em condições de dupla-tarefa.

Aerobic exercise reduces anxiety symptoms and improves fitness in patients with panic disorder / Exercícios aeróbicos reduziram os sintomas de ansiedade e melhoraram o desempenho cardiorrespiratório em portadores de transtorno de pânico

OBJECTIVE: To investigate the effects of a regularly repeated aerobic exercise series on anxiety and maximum oxygen consumption (VO2max) in Panic Disorder patients. METHODS: Ten previously sedentary female subjects diagnosed with Panic Disorder performed 36 sessions of aerobic exercise (at 70 to 75% of VO2max), 3 times per week during 12 weeks. A cardiopulmonary evaluation (ergospirometry test) was used to set the intensity of training as well as to establish baseline and post-training VO2max parameters. The assessment of anxiety symptoms was performed at baseline, at the end of the 6th and 12th weeks, using the Trait Anxiety Inventory (STAI-T) and State Anxiety Inventory (STAI-S), and the Subjective Units of Distress Scale (SUDS) questionnaires. One-way ANOVA for repeated measurements (at 3 moments: Baseline, 6th week (mid-training) and 12th week (post-training) was used to compare the evolution of the questionnaires; the Bonferroni post hoc test was applied to identify differences between moments. A dependent t-test was performed for measures of VO2max. RESULTS: Compared to baseline, (a) STAI-T showed significant anxiety reductions at mid- and post-training moments; (b) STAI-S and SUDS recorded anxiety reductions only at Post-training; (c) VO2max showed a significant improvement at Post-training. CONCLUSION: This protocol promoted beneficial effects on cardiorespiratory fitness and anxiety levels of Panic Disorder patients.

OBJETIVO: O objetivo deste estudo foi investigar os efeitos do exercício aeróbio praticado regularmente sobre a ansiedade e o VO2max em pacientes com transtorno de pânico. MÉTODO: Dez mulheres sedentárias diagnosticadas com transtorno de pânico (TP) realizaram 36 sessões de exercícios aeróbico contínuo (70 a 75% VO2max) em esteira, 3x por semana, durante 12 semanas. Uma avaliação cardiopulmonar (teste ergo-espirométrico) definiu a intensidade do treinamento, bem como estabeleceu valores de VO2max pré e pós-treinamento. A avaliação dos sintomas de ansiedade nos três momentos (controle, 6° e 12° semana), foi realizada utilizando os questionários IDATE-T (Inventário do Traço de Ansiedade), IDATE-S (Inventário do Estado de Ansiedade) e SUDS (Unidades Subjetivas da Escala de Aflição). O teste ANOVA One-way para medidas repetidas (momentos) foi usado para comparar os questionários. O teste Bonferroni post-hoc foi aplicado para identificar as diferenças entre os momentos. As medidas de VO2max foram analisadas através de um teste de "t" dependente. RESULTADOS: Os resultados mostraram redução do IDATE-T na 6° e 12° semanas de exercício; no entanto, o IDATE-S e o SUDS monstraram uma redução apenas na 12° semana. O VO2max apresentou melhora significativa após 12 semanas de intervenção em relação à linha de base. CONCLUSÃO: Conclui-se que o protocolo adotado foi capaz de promover efeitos benéficos sobre a aptidão cardiorrespiratória e sobre os níveis de ansiedade dos pacientes com transtorno de pânico.

Room temperature aqueous self-assembly of poly(ethylene glycol)-poly(4-vinyl pyridine) block copolymers: From spherical to worm-like micelles.

The solution self-assembly and the formation, at room temperature, of a wide range of nanostructures based on monomethyl ether poly(ethylene glycol)-b-poly(4-vinyl pyridine) (mPEG-b-P4VP) block copolymer is reported. Copolymers with different compositions and molecular weights were synthesized through Atom Transfer Radical Polymerization (ATRP) method. The solution self-assembly of the block copolymers was studied by transmission electron microscopy (TEM) for different solution pHs. It was found that the formation of non-spherical nanostructures, such as rod- and worm-like micelles can be easily achieved, at room temperature, by simply varying the molecular weight of the different segments as well as the mPEG to P4VP ratio in the block copolymer structure. Because P4VP segments are known to form strong complexes with metals, the nanostructures prepared in this manuscript can find innovative applications in the biomedical field and be used as nano-templates for inorganic materials.

Working memory dysfunction in insomniac adults: a systematic metanalytical review / Disfunção da memória de trabalho em adultos insones: uma revisão sistemática

BACKGROUND: Insomnia is the most commonly occurring sleep disorder: recent reports estimate that 25-30% of adults in the general population occasional instances of experience insomnia, while 10% suffer from disturbances severe enough to meet diagnostic criteria for insomnia. Little is known about the mechanisms, causes, clinical course, and consequences of this condition. Over 30 studies have been published on the matter but only a small proportion has found differences in the working memory of individuals with vs. without insomnia. OBJECTIVE: To summarize evidence regarding the differences in working memory performance between insomniac vs. normal adult sleepers. METHODS: The survey was conducted using an advanced search in the ISI Web of Science and MEDLINE/PubMed with the terms "sleep", "insomnia" and "working memory" as major descriptors; these were crossed with the following keywords: "psychological tests", "neuropsychology" and "performance". RESULTS: A total of 112 articles were identified in the search conducted in PubMed and Web of Science. After the screening, 102 articles unrelated to the proposed theme were excluded. Thus, 10 articles were analyzed by the eligibility and exclusion criteria, and included in this systematic review. CONCLUSION: The information resulting from the analysis of the reviewed articles suggests that mild, but not definitive deficits in cognitive performance might be masked by insignificant disparities in studies comparing insomniac individuals with normal sleepers. This shortcoming can be circumvented by larger and better-characterized samples, together with optimized methodological control of factors which might otherwise result in confounding variations among participants.

INTRODUÇÃO: A insônia é o distúrbio do sono mais comum: relatórios recentes estimam que 25-30% dos adultos sofrem episódios de insônia, enquanto 10% sofrem de distúrbio do sono suficientemente grave para cumprir os critérios de diagnóstico para insônia. Além disso, pouco se sabe sobre os mecanismos, causas, evolução clínica, e consequências desta doença crónica altamente prevalente. Mais de 30 estudos foram publicados sobre o assunto, mas apenas uma pequena proporção encontrou diferenças entre os indivíduos com e sem insônia, por exemplo, na memória de trabalho. OBJETIVO: Examinar as evidências sobre as diferenças entre adultos insones e normais no desempenho da memória de trabalho. MÉTODOS: A pesquisa foi realizada usando uma pesquisa avançada no ISI Web of Science e MEDLINE/PubMed com os termos "sleep", "insônia" e "memória de trabalho" como os principais descritores, que foram cruzados com as seguintes palavras-chave: "testes psicológicos", "neuropsicologia" e "performance". RESULTADOS: Um total de 132 artigos foram identificados na pesquisa realizada no PubMed e Web of Science; 20 duplicações foram excluídas. Após a triagem, 102 artigos foram excluídos, que não estavam relacionadas com o tema proposto. Assim, 10 artigos foram selecionados por critérios de elegibilidade e de exclusão, e incluídos na revisão sistemática. CONCLUSÃO: As descobertas relatadas em nosso estudo sugerem que os deficits leves mas não permanentes de desempenho cognitivo podem ser mascarados por disparidades insignificantes em estudos que comparam indivíduos com insônia com pessoas com sono normal. Tal deficiência pode ser contornada pela análise de amostras maiores e mais bem caracterizadas, em conjunto com o controle metodológico otimizado de fatores que potencialmente podem incorrer em variações entre os participantes.

Chronic effects of aerobic exercise on panic disorder: a systematic review of randomized and non-randomized trials / Efeitos crônicos do exercício aeróbio sobre o transtorno do pânico: uma revisão sistemática de ensaios clínicos randomizados e não-randomizados

BACKGROUND: In general, most studies have supported an association between the acute effects of exercise and a reduced state anxiety, but failed to completely explain the relationship between the chronic effect of exercise and anxiety traits. OBJECTIVE: The aim of this study was to systematically review the literature regarding the chronic effect of exercise on symptoms associated with panic disorder. METHODS: The studies were retrieved from a MEDLINE/PubMed, ISI Web of Knowledge and SciELO. We adopted PICOS’s strategy recommended to determine the eligibility criteria. The survey was conducted using an advanced search in the ISI Web of Science and MEDLINE / PubMed with MeSH terms and Entry Terms for the keywords “Panic Disorder” basis and “Exercise”. Boolean operators “AND” and “OR” were used separately or in combination. Two independent researchers performed the selection of studies; in case of disagreement they sought a consensus on the selection. RESULTS: A total of 265 articles were identified: 199 articles from PubMed/Medline, 63 articles from ISI Web of Science and 3 articles by manual searches. Thus, 31 articles were analyzed by the eligibility criteria and the exclusion criteria, a total of five studies included in the systematic review. CONCLUSION: The regular practice of aerobic exercise seems to be an appropriate intervention to promote improvements in the severity of anxiety symptoms in PD patients.

INTRODUÇÃO: Em geral, grande parte dos estudos indicam a existência de uma associação entre os efeitos agudos do exercício aeróbio e um estado de ansiedade reduzida; no entanto, estes estudos não conseguem elucidar completamente a relação entre o efeito crônico do exercício aeróbio e traços de ansiedade. OBJETIVO: O objetivo deste estudo foi revisar sistematicamente a literatura sobre o efeito crônico do exercício sobre sintomas associados com transtorno do pânico. MÉTODOS: Os estudos foram recuperados de: MEDLINE/PubMed, ISI Web of Knowledge e SciELO. Adotamos a estratégia PICOS para determinar os critérios de elegibilidade. A estratégia de busca foi realizada utilizando uma pesquisa avançada no ISI Web of Science, MEDLINE/PubMed e SciELO com os seguintes termos: “Transtorno de Pânico” e “Exercício”. Operadores booleanos AND e OR foram utilizados para combinação dos termos. A seleção dos estudos foi realizada por dois pesquisadores independentes que, em caso de desacordo, procuraram um consenso sobre a seleção. RESULTADOS: Foram identificados um total de 265 artigos: 199 artigos do PubMed/Medline, 63 artigos do ISI Web of Science e 3 artigos através de pesquisas manuais. Assim, 31 artigos foram analisados pelos critérios de elegibilidade e os critérios de exclusão, sendo que um total de cinco estudos foram incluídos na revisão sistemática. CONCLUSÃO: A prática regular de exercício aeróbio parece ser uma intervenção apropriada para promover a melhoria da gravidade dos sintomas de ansiedade em pacientes com transtorno de pânico.

Physical activity interventions in schools for improving lifestyle in European countries.

BACKGROUND: In the last decades, children's and adolescents' obesity and overweight have increased in European Countries. Unhealthy eating habits and sedentary lifestyle have been recognized to determine such an epidemic. Schools represent an ideal setting to modify harmful behaviors, and physical activity could be regarded as a potential way to avoid the metabolic risks related to obesity. Methods : A systematic review of the literature was carried out to summarize the evidence of school-based interventions aimed to promote, enhance and implement physical activity in European schools. Only randomized controlled trials were included, carried out in Europe from January 2000 to April 2014, universally delivered and targeting pupils aged between 3 and 18 years old. Results : Forty-seven studies were retrieved based either on multicomponent interventions or solely physical activity programs. Most aimed to prevent obesity and cardiovascular risks among youths. While few studies showed a decrease in BMI, positive results were achieved on other outcomes, such as metabolic parameters and physical fitness. Conclusion : Physical activity in schools should be regarded as a simple, non-expensive and enjoyable way to reach all the children and adolescents with adequate doses of moderate to vigorous physical activity.