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We discovered a simple regime where a near-critical plasma irradiated by a laser of experimentally available intensity can self-organize to produce positrons and accelerate them to ultrarelativistic energies. The laser pulse piles up electrons at its leading edge, producing a strong longitudinal plasma electric field. The field creates a moving gamma-ray collider that generates positrons via the linear Breit-Wheeler process-annihilation of two gamma rays into an electron-positron pair. At the same time, the plasma field, rather than the laser, serves as an accelerator for the positrons. The discovery of positron acceleration was enabled by a first-of-its-kind kinetic simulation that generates pairs via photon-photon collisions. Using available laser intensities of 10^{22} W/cm^{2}, the discovered regime can generate a GeV positron beam with a divergence angle of around 10° and a total charge of 0.1 pC. The result paves the way to experimental observation of the linear Breit-Wheeler process and to applications requiring positron beams.
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High-power, short-pulse laser-driven fast electrons can rapidly heat and ionize a high-density target before it hydrodynamically expands. The transport of such electrons within a solid target has been studied using two-dimensional (2D) imaging of electron-induced Kα radiation. However, it is currently limited to no or picosecond scale temporal resolutions. Here, we demonstrate femtosecond time-resolved 2D imaging of fast electron transport in a solid copper foil using the SACLA x-ray free electron laser (XFEL). An unfocused collimated x-ray beam produced transmission images with sub-micron and â¼10 fs resolutions. The XFEL beam, tuned to its photon energy slightly above the Cu K-edge, enabled 2D imaging of transmission changes induced by electron isochoric heating. Time-resolved measurements obtained by varying the time delay between the x-ray probe and the optical laser show that the signature of the electron-heated region expands at â¼25% of the speed of light in a picosecond duration. Time-integrated Cu Kα images support the electron energy and propagation distance observed with the transmission imaging. The x-ray near-edge transmission imaging with a tunable XFEL beam could be broadly applicable for imaging isochorically heated targets by laser-driven relativistic electrons, energetic protons, or an intense x-ray beam.
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High energy density physics is the field of physics dedicated to the study of matter and plasmas in extreme conditions of temperature, densities and pressures. It encompasses multiple disciplines such as material science, planetary science, laboratory and astrophysical plasma science. For the latter, high energy density states can be accompanied by extreme radiation environments and super-strong magnetic fields. The creation of high energy density states in the laboratory consists in concentrating/depositing large amounts of energy in a reduced mass, typically solid material sample or dense plasma, over a time shorter than the typical timescales of heat conduction and hydrodynamic expansion. Laser-generated, high current-density ion beams constitute an important tool for the creation of high energy density states in the laboratory. Focusing plasma devices, such as cone-targets are necessary in order to focus and direct these intense beams towards the heating sample or dense plasma, while protecting the proton generation foil from the harsh environments typical of an integrated high-power laser experiment. A full understanding of the ion beam dynamics in focusing devices is therefore necessary in order to properly design and interpret the numerous experiments in the field. In this work, we report a detailed investigation of large-scale, kilojoule-class laser-generated ion beam dynamics in focusing devices and we demonstrate that high-brilliance ion beams compress magnetic fields to amplitudes exceeding tens of kilo-Tesla, which in turn play a dominant role in the focusing process, resulting either in a worsening or enhancement of focusing capabilities depending on the target geometry.
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Acceleration of particles from the interaction of ultraintense laser pulses up to 5×10^{21} W cm^{-2} with thin foils is investigated experimentally. The electron beam parameters varied with decreasing spot size, not just laser intensity, resulting in reduced temperatures and divergence. In particular, the temperature saturated due to insufficient acceleration length in the tightly focused spot. These dependencies affected the sheath-accelerated protons, which showed poorer spot-size scaling than widely used scaling laws. It is therefore shown that maximizing laser intensity by using very small foci has reducing returns for some applications.
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Increasing the laser energy absorption into energetic particle beams represents a longstanding quest in intense laser-plasma physics. During the interaction with matter, part of the laser energy is converted into relativistic electron beams, which are the origin of secondary sources of energetic ions, γ-rays and neutrons. Here we experimentally demonstrate that using multiple coherent laser beamlets spatially and temporally overlapped, thus producing an interference pattern in the laser focus, significantly improves the laser energy conversion efficiency into hot electrons, compared to one beam with the same energy and nominal intensity as the four beamlets combined. Two-dimensional particle-in-cell simulations support the experimental results, suggesting that beamlet interference pattern induces a periodical shaping of the critical density, ultimately playing a key-role in enhancing the laser-to-electron energy conversion efficiency. This method is rather insensitive to laser pulse contrast and duration, making this approach robust and suitable to many existing facilities.
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Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10-9), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (Pbest=5.8 × 10-10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (Pbest=1.9 × 10-9), TRANK1 (Pbest=2.1 × 10-9) and ODZ4 (Pbest=3.3 × 10-9). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for 'within Japanese comparisons', Pbest~10-29, R2~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for 'trans-European-Japanese comparison,' Pbest~10-13, R2~0.27%). This 'trans population' effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD 'risk' effect are shared between Japanese and European populations.
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Transtorno Bipolar/genética , Adulto , Proteínas de Ciclo Celular/genética , Citocinas/genética , Dessaturase de Ácido Graxo Delta-5 , Ácidos Graxos Dessaturases/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Japão/epidemiologia , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Herança Multifatorial/genética , Fatores de Transcrição NFI/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Reticulon 4 receptor (RTN4R) plays an essential role in regulating axonal regeneration and plasticity in the central nervous system through the activation of rho kinase, and is located within chromosome 22q11.2, a region that is known to be a hotspot for schizophrenia (SCZ) and autism spectrum disorder (ASD). Recently, rare variants such as copy-number variants and single-nucleotide variants have been a focus of research because of their large effect size associated with increased susceptibility to SCZ and ASD and the possibility of elucidating the pathophysiology of mental disorder through functional analysis of the discovered rare variants. To discover rare variants with large effect size and to evaluate their role in the etiopathophysiology of SCZ and ASD, we sequenced the RTN4R coding exons with a sample comprising 370 SCZ and 192 ASD patients, and association analysis using a large number of unrelated individuals (1716 SCZ, 382 ASD and 4009 controls). Through this mutation screening, we discovered four rare (minor allele frequency <1%) missense mutations (R68H, D259N, R292H and V363M) of RTN4R. Among these discovered rare mutations, R292H was found to be significantly associated with SCZ (P=0.048). Furthermore, in vitro functional assays showed that the R292H mutation affected the formation of growth cones. This study strengthens the evidence for association between rare variants within RTN4R and SCZ, and may shed light on the molecular mechanisms underlying the neurodevelopmental disorder.
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Transtorno do Espectro Autista/genética , Receptor Nogo 1/genética , Esquizofrenia/genética , Adolescente , Adulto , Transtorno do Espectro Autista/fisiopatologia , Criança , Éxons , Feminino , Frequência do Gene , Cones de Crescimento/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/fisiopatologia , Adulto Jovem , Quinases Associadas a rho/metabolismoRESUMO
CX3CR1, a G protein-coupled receptor solely expressed by microglia in the brain, has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in transcriptomic and animal studies but not in genetic studies. To address the impacts of variants in CX3CR1 on neurodevelopmental disorders, we conducted coding exon-targeted resequencing of CX3CR1 in 370 Japanese SCZ and 192 ASD patients using next-generation sequencing technology, followed by a genetic association study in a sample comprising 7054 unrelated individuals (2653 SCZ, 574 ASD and 3827 controls). We then performed in silico three-dimensional (3D) structural modeling and in vivo disruption of Akt phosphorylation to determine the impact of the detected variant on CX3CR1-dependent signal transduction. We detected a statistically significant association between the variant Ala55Thr in CX3CR1 with SCZ and ASD phenotypes (odds ratio=8.3, P=0.020). A 3D structural model indicated that Ala55Thr could destabilize the conformation of the CX3CR1 helix 8 and affect its interaction with a heterotrimeric G protein. In vitro functional analysis showed that the CX3CR1-Ala55Thr mutation inhibited cell signaling induced by fractalkine, the ligand for CX3CR1. The combined data suggested that the variant Ala55Thr in CX3CR1 might result in the disruption of CX3CR1 signaling. Our results strengthen the association between microglia-specific genes and neurodevelopmental disorders.
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Transtorno do Espectro Autista/genética , Receptor 1 de Quimiocina CX3C/genética , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Criança , Simulação por Computador , Éxons , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
Using one of the world most powerful laser facility, we demonstrate for the first time that high-contrast multi-picosecond pulses are advantageous for proton acceleration. By extending the pulse duration from 1.5 to 6 ps with fixed laser intensity of 1018 W cm-2, the maximum proton energy is improved more than twice (from 13 to 33 MeV). At the same time, laser-energy conversion efficiency into the MeV protons is enhanced with an order of magnitude, achieving 5% for protons above 6 MeV with the 6 ps pulse duration. The proton energies observed are discussed using a plasma expansion model newly developed that takes the electron temperature evolution beyond the ponderomotive energy in the over picoseconds interaction into account. The present results are quite encouraging for realizing ion-driven fast ignition and novel ion beamlines.
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Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10-9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.
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Esquizofrenia/genética , Adulto , Estudos de Casos e Controles , Hibridização Genômica Comparativa/métodos , Variações do Número de Cópias de DNA/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Japão , Masculino , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Many schizophrenia susceptibility loci have been identified through genome-wide association studies (GWASs) in European populations. However, until recently, schizophrenia GWASs in non-European populations were limited to small sample sizes and have yielded few loci associated with schizophrenia. To identify genetic risk variations for schizophrenia in the Han Chinese population, we performed a two-stage GWAS of schizophrenia comprising 4384 cases and 5770 controls, followed by independent replications of 13 single-nucleotide polymorphisms in an additional 4339 schizophrenia cases and 7043 controls of Han Chinese ancestry. Furthermore, we conducted additional analyses based on the results in the discovery stage. The combined analysis confirmed evidence of genome-wide significant associations in the Han Chinese population for three loci, at 2p16.1 (rs1051061, in an exon of VRK2, P=1.14 × 10-12, odds ratio (OR)=1.17), 6p22.1 (rs115070292 in an intron of GABBR1, P=4.96 × 10-10, OR=0.77) and 10q24.32 (rs10883795 in an intron of AS3MT, P=7.94 × 10-10, OR=0.87; rs10883765 at an intron of ARL3, P=3.06 × 10-9, OR=0.87). The polygenic risk score based on Psychiatric Genomics Consortium schizophrenia GWAS data modestly predicted case-control status in the Chinese population (Nagelkerke R2: 1.7% ~5.7%). Our pathway analysis suggested that neurological biological pathways such as GABAergic signaling, dopaminergic signaling, cell adhesion molecules and myelination pathways are involved in schizophrenia. These findings provide new insights into the pathogenesis of schizophrenia in the Han Chinese population. Further studies are needed to establish the biological context and potential clinical utility of these findings.
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Metiltransferases/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de GABA-B/genética , Esquizofrenia/genética , Povo Asiático/genética , Estudos de Casos e Controles , China , Etnicidade/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Metiltransferases/metabolismo , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de GABA-B/metabolismo , Fatores de RiscoRESUMO
INTRODUCTION: No meta-analysis has evaluated azapirones (serotonin1A receptor partial agonists) as anxiolytics for attention deficit hyperactivity disorder (ADHD). METHODS: Randomized controlled trials (RCTs) and single-arm trials published before October 27, 2015 were retrieved from major healthcare databases and clinical trial registries. Relative risk and 95% confidence intervals were calculated. RESULTS: 5 RCTs (n=429) and 3 single-arm studies (n=70) were identified. 3 RCTs compared buspirone vs. methylphenidate in children/adolescents, one buspirone patches vs. placebo patches in children/adolescents, and one atomoxetine plus buspirone vs. atomoxetine vs. placebo in adults. The single-arm studies were buspirone trails in children/adolescents. All-cause discontinuation rates and adverse events did not differ between pooled buspirone and methylphenidate groups. No other meta-analyses of buspirone efficacy and safety vs. comparators were conducted due to insufficient data. 2 RCTs found no significant differences in parent and teacher ADHD-Rating Scale total scores between buspirone and methylphenidate, while one reported that methylphenidate improved parent and teacher ADHD-RS total scores vs. buspirone. DISCUSSION: It remains unclear whether buspirone use has benefit for ADHD patients and therefore further evidence is needed for better clinical use of buspirone in patients with ADHD.
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Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Buspirona/uso terapêutico , Agonistas do Receptor de Serotonina/uso terapêutico , Buspirona/química , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Typical abused drug-induced behavioral changes are ordinarily mediated by the mesolimbic dopaminergic system and even the phenotypes of behavior are different from each other. However, the mechanisms that underlie the behavioral changes induced by these abused drugs have not yet been elucidated. The present study was designed to investigate the mechanisms that underlie how abused drugs induce distinct behavioral changes using neurochemical as well as behavioral techniques in rats. Methamphetamine (2mg/kg) more potently increased dopamine release from the striatum more than that from the nucleus accumbens. In contrast, the administration of morphine (10mg/kg) produced a significant increase in the release of dopamine from the nucleus accumbens, but not the striatum, which is accompanied by a decrease in the release of GABA in the ventral tegmental area. These findings indicate that morphine and methamphetamine differentially regulate dopaminergic systems to produce behavioral changes, even though both drugs have abuse potential through activation of the mesolimbic dopaminergic system.
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Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Dopaminérgicos/farmacologia , Dopamina/metabolismo , Metanfetamina/farmacologia , Morfina/farmacologia , Animais , Cateteres de Demora , Masculino , Microdiálise , Movimento/efeitos dos fármacos , Movimento/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
Despite improvements in surgical techniques, perioperative management, and multidisciplinary therapy, treatment outcomes of patients with esophageal squamous cell carcinoma (ESCC) remain poor. Therefore, development of novel molecular biomarkers, which either predict patient survival or become therapeutic targets, is urgently required. In the present study, to facilitate early detection of ESCC and predict its clinical course, we investigated the relationship of the serum level of melanoma-associated antigen (MAGE)-D4 to patients' clinicopathological characteristics. Using quantitative real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assays, we determined the levels of MAGE-D4 mRNA and protein in cell lysates and conditioned medium of cultures, respectively, of nine ESCC cell lines. Further, we determined MAGE-D4 levels in serum samples collected from 44 patients with ESCC who underwent radical esophagectomy without neoadjuvant therapy as well as from 40 healthy volunteers. Samples of conditioned medium and cell lysates contained comparable levels of MAGE-D4 that correlated closely with the levels of MAGE-D4 mRNA. Preoperative MAGE-D4 levels in the sera of 44 patients with ESCC, which varied from 0 to 2,354 pg/mL (314 ± 505 pg/mL, mean ± standard deviation), were significantly higher compared with those of healthy volunteers. By setting the cutoff at the highest value for healthy volunteers (50 pg/mL), the MAGE-D4-positive group of patients was more likely to have shorter disease-specific and disease-free survival compared with those of the MAGE-D4-negative group, although the differences were not statistically significant. Our results indicate that the elevation of preoperative serum MAGE-D4 levels in some patients with ESCC was possibly caused by excess production of MAGE-D4 by tumor cells followed by its release into the circulation. Clinical implications of serum MAGE-D4 levels should be validated in a large population of patients with ESCC.
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Antígenos de Neoplasias/sangue , Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/sangue , Neoplasias Esofágicas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/cirurgia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Intervalo Livre de Doença , Ensaio de Imunoadsorção Enzimática , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago , Esofagectomia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/sangue , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Historically, total pharyngolaryngectomy with total esophagectomy has been the standard radical surgical treatment for synchronous cancer of the thoracoabdominal esophagus and pharyngolaryngeal region, and for cancer of the cervical esophagus that has invaded as far as the thoracic esophagus. Although definitive chemoradiotherapy that enables preservation of the larynx has often been the first choice of treatment for cancers involving the cervical esophagus, total pharyngolaryngectomy with total esophagectomy is required as a salvage therapy for cases involving failure of complete remission or locoregional recurrence after chemoradiotherapy. However, salvage esophageal surgery after definitive high-dose chemoradiotherapy is generally associated with high morbidity and mortality. The aim of this study was to examine the short-term outcome of salvage total pharyngolaryngectomy with total esophagectomy. From 2001 to 2014, nine patients underwent salvage total pharyngolaryngectomy with total esophagectomy at the Department of Gastroenterological Surgery, Nagoya University. The mortality and morbidity rates were high at 22% and 89%, respectively. Four patients (44%) developed tracheal necrosis, which in two patients eventually led to lethal hemorrhage. Salvage total pharyngolaryngectomy with total esophagectomy is an uncommon and highly demanding surgical procedure that should be carefully planned and conducted in selected centers of excellence. Measures must be taken to preserve the tracheal blood supply, thus avoiding fatal complications.
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Carcinoma de Células Escamosas/terapia , Neoplasias Esofágicas/terapia , Esofagectomia , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias Laríngeas/terapia , Laringectomia , Neoplasias Primárias Múltiplas/terapia , Neoplasias Faríngeas/terapia , Faringectomia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Cisplatino/administração & dosagem , Carcinoma de Células Escamosas do Esôfago , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estudos Retrospectivos , Terapia de Salvação , Carcinoma de Células Escamosas de Cabeça e Pescoço , Resultado do TratamentoRESUMO
Piccolo (PCLO) inhibits methamphetamine-induced neuropharmacological effects via modulation of dopamine (DA) uptake and regulation of the transport of synaptic vesicles in neuronal cells. Clinical studies have recently suggested that the single nucleotide polymorphism (SNP) rs13438494 in the intron 24 of the PCLO gene is associated with psychiatric disorder, in the meta-analysis of GWAS. Therefore, in this study, we attempted to evaluate the possible role of the PCLO SNP in the mechanisms of uptake of monoamines. To characterize rs13438494 in the PCLO gene, we constructed plasmids carrying either the C or A allele of the SNP and transiently transfected them into SH-SY5Y cells to analyze genetic effects on the splicing of PCLO mRNA. The C and A allele constructs produced different composition of the transcripts, indicating that the intronic SNP does affect the splicing pattern. We also transfected DA and serotonin (5-hydroxytryptamine; 5- HT) transporters into cells and analyzed their uptakes to elucidate the association to psychiatric disorders. In the cells transfected with the C allele, both the DA and 5-HT uptake were enhanced compared to the A allele. We also conducted a clinical study, in order to clarify the genetic associations. PCLO rs13438494 exhibits a relationship with the symptoms of drug dependence or related parameters, such as the age of first exposure to methamphetamine, eating disorders, tobacco dependence and fentanyl requirement. Our findings suggest that rs13438494 is associated with drug abuse and contributes to the pathogenesis of psychiatric disorders via modulation of neurotransmitter turnover.
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Transtornos Relacionados ao Uso de Anfetaminas/genética , Anorexia/genética , Proteínas do Citoesqueleto/genética , Dopamina/metabolismo , Neuropeptídeos/genética , Serotonina/metabolismo , Idade de Início , Analgésicos Opioides/uso terapêutico , Fentanila/uso terapêutico , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células HEK293 , Humanos , Íntrons , Cirurgia Ortognática , Polimorfismo de Nucleotídeo ÚnicoRESUMO
INTRODUCTION: No comprehensive meta-analysis has been performed concerning the efficacy and tolerability of adjunctive therapy with histamine-2 receptor antagonists (H2R-ANTs) in schizophrenia patients who were treated with antipsychotics. METHODS: Risk ratios, standardized mean differences (SMD), and 95% confidence intervals were calculated. RESULTS: We included 8 double-blinded, randomized placebo-controlled trials (RCTs) (n=418) that met the inclusion criteria (famotidine: N=3, n=74; nizatidine: N=4, n=292; ranitidine: N=1, n=52). Pooled H2R-ANTs were not different from placebo with regard to reduction in overall symptoms and body weight. However, pooled H2R-ANTs resulted in lower body mass index (BMI) than placebo (SMD=-0.68). Moreover, nizatidine was associated with an increase in plasma leptin levels (SMD=-1.14). There were no significant differences in the discontinuation rates due to all-cause, side effects, and inefficacy between pooled H2R-ANTs and placebo. However, nizatidine produced more depression and dry mouth than placebo. DISCUSSION: H2R-ANT adjunctive therapy did not improve overall symptoms. To clarify the opposite results between body weight and BMI, future research should investigate long-term efficacy and generate more safety data by using larger samples.
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Antipsicóticos/uso terapêutico , Antagonistas dos Receptores Histamínicos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Esquizofrenia/tratamento farmacológico , Peso Corporal/efeitos dos fármacos , Método Duplo-Cego , Feminino , Humanos , Masculino , Estudos Retrospectivos , Sensibilidade e Especificidade , Resultado do TratamentoRESUMO
The superior frontal gyrus (SFG), an area of the brain frequently found to have reduced gray matter in patients with schizophrenia, is involved in self-awareness and emotion, which are impaired in schizophrenia. However, no genome-wide association studies of SFG volume have investigated in patients with schizophrenia. To identify single-nucleotide polymorphisms (SNPs) associated with SFG volumes, we demonstrated a genome-wide association study (GWAS) of gray matter volumes in the right or left SFG of 158 patients with schizophrenia and 378 healthy subjects. We attempted to bioinformatically ascertain the potential effects of the top hit polymorphism on the expression levels of genes at the genome-wide region. We found associations between five variants on 1p36.12 and the right SFG volume at a widely used benchmark for genome-wide significance (P<5.0 × 10(-8)). The strongest association was observed at rs4654899, an intronic SNP in the eukaryotic translation initiation factor 4 gamma, 3 (EIF4G3) gene on 1p36.12 (P=7.5 × 10(-9)). No SNP with genome-wide significance was found in the volume of the left SFG (P>5.0 × 10(-8)); however, the rs4654899 polymorphism was identified as the locus with the second strongest association with the volume of the left SFG (P=1.5 × 10(-6)). In silico analyses revealed a proxy SNP of rs4654899 had effect on gene expression of two genes, HP1BP3 lying 3' to EIF4G3 (P=7.8 × 10(-6)) and CAPN14 at 2p (P=6.3 × 10(-6)), which are expressed in moderate-to-high levels throughout the adult human SFG. These results contribute to understand genetic architecture of a brain structure possibly linked to the pathophysiology of schizophrenia.
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Lobo Frontal/patologia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Substância Cinzenta/patologia , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Esquizofrenia/patologia , Adulto , Mapeamento Encefálico/métodos , Biologia Computacional/métodos , Feminino , Expressão Gênica/genética , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.
Assuntos
Cognição , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Testes Neuropsicológicos , Polimorfismo de Nucleotídeo Único , Risco , Esquizofrenia/epidemiologia , Adulto JovemRESUMO
Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. Although opioid sensitivity is well known to vary widely among individual subjects, several candidate genetic polymorphisms reported so far are not sufficient for fully understanding the wide range of interindividual differences in human opioid sensitivity. By conducting a multistage genome-wide association study (GWAS) in healthy subjects, we found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3-2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate single-nucleotide polymorphism (SNP), rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence' score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. These results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. Our findings provide valuable information for the personalized treatment of pain and drug dependence.