ABSTRACT
BACKGROUND: Gastrointestinal cancers represent one of the most prevalent diseases worldwide. Strikingly, the incidence of Early Onset Gastrointestinal Cancer (EOGIC) has been rising during the last decades and changes in lifestyle and environmental exposure seem to play a role. EOGIC has been defined as a different entity compared to on-average gastrointestinal cancer, with distinct clinical and molecular characteristics. Inherent to the particularities of younger age, there is an unmet need for a tailored approach for the management of these patients. The TEOGIC proposes a comprehensive study to characterize EOGIC patients in the northern of Spain. METHODS: Patients with histologically confirmed new diagnosis of colorectal, gastroesophageal and pancreatic adenocarcinoma will be considered for two cohorts: EOGIC (≤ 50 years old) and non-EOGIC (60-75 years old), with a ratio of 1:2. Two hundred and forty patients will be recruited in 4 Public Hospitals from northern Spain. After receiving unified informed consent, demographic and clinical data of the patients will be collected in a REDCap database. Lifestyle related data will be obtained in questionnaires assessing diet, physical activity and the general quality of life of the patients before diagnosis. Biological samples prior to any onco-specific treatment will be obtained for the analyses of circulating inflammatory proteins, gut microbiota, and the proteome of the tumor microenvironment. Histologic characteristics and routine biomarkers will be also collected. Thereafter, data will be integrated and analyzed to assess tumor specific, pan-tumor and sex-associated differential characteristics of EOGIC. DISCUSSION: The underlying risk factors and differential characteristics of EOGIC remain poorly studied, particularly in our geographical area. Although limited by the exploratory nature and the small sample size estimated to be recruited, TEOGIC represents the first attempt to comprehensively characterize these young patients, and thus attend to their special needs. Findings derived from this study could contribute to raise awareness and preventive behaviors in the population. In parallel, molecular studies could lead to the identification of potential novel non-invasive biomarkers and therapeutic targets that would help in the development of the tailored clinical management of these patients, focusing on screening programs for early diagnosis and precision medicine.
Subject(s)
Gastrointestinal Neoplasms , Humans , Spain/epidemiology , Middle Aged , Male , Female , Aged , Gastrointestinal Neoplasms/epidemiology , Gastrointestinal Neoplasms/diagnosis , Gastrointestinal Neoplasms/pathology , Gastrointestinal Neoplasms/therapy , Adult , Age of Onset , Life Style , Adenocarcinoma/epidemiology , Adenocarcinoma/diagnosis , Adenocarcinoma/pathology , Adenocarcinoma/therapy , Tumor Microenvironment , Quality of Life , Incidence , Biomarkers, Tumor , Esophageal Neoplasms/epidemiology , Esophageal Neoplasms/diagnosis , Esophageal Neoplasms/pathology , Esophageal Neoplasms/therapy , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/pathologyABSTRACT
This systematic review provides a comprehensive overview of the association between premorbid adjustment and social cognition in people with psychotic spectrum disorder. Obtaining evidence of this association will facilitate early detection and intervention before the onset of psychosis. Literature searches were conducted in Scopus, PubMed and PsycINFO. Studies were eligible if they included patients with a psychotic disorder or at a high-risk state; social cognition and premorbid adjustment were measured; and the relationship between premorbid adjustment and social cognition was analysed. The authors independently extracted data from all included articles, and discrepancies were resolved through discussion. Literature searches were conducted in Scopus, PubMed and PsycINFO. Studies were eligible if they included patients with a psychotic disorder or at a high-risk state; social cognition and premorbid adjustment were measured; and the relationship between premorbid adjustment and social cognition was analysed. The authors independently extracted data from all included articles, and discrepancies were resolved through discussion. Of 229 studies identified, 23 met the inclusion criteria. Different methods of assessment were used to measure premorbid adjustment, such as the Premorbid Adjustment Scale or premorbid IQ, among others. Social cognition was assessed as a global measure or by domains using different instruments. A total of 16 articles found a relationship between social cognition (or its domains) and premorbid adjustment: general social cognition (n = 3); Theory of Mind (n = 12); Emotional Recognition and Social Knowledge (n = 1). This review shows evidence of a significant relationship between social cognition and premorbid adjustment, specifically between Theory of Mind and premorbid adjustment. Social cognition deficits may already appear in phases prior to the onset of psychosis, so an early individualized intervention with stimulating experiences in people with poor premorbid adjustment can be relevant for prevention. We recommend some future directions, such as carrying out longitudinal studies with people at high-risk of psychosis, a meta-analysis study, broadening the concept of premorbid adjustment, and a consensual assessment of social cognition and premorbid adjustment variables. PROSPERO registration number: CRD42022333886.
Subject(s)
Humans , Status Epilepticus , Epilepsy , Vitamin B 6 Deficiency , Parkinson Disease , Levodopa , CarbidopaABSTRACT
BACKGROUND: There are currently no drug therapies modifying the natural history of patients suffering Alzheimer's disease (AD). Most recent clinical trials in the field include only subjects in early stage of the disease, while patients with advanced AD are usually not represented. OBJECTIVES: To evaluate the feasibility, safety and efficacy of systemic infusions of adenosine triphosphate (ATP) in patients with moderate to severe AD, and to select the minimum effective dose of infusion. DESIGN: A phase IIb, randomized, double-blind, placebo-controlled clinical trial investigates. PARTICIPANTS: A total of 20 subjects with moderate or severe AD were included, 16 in the treatment group and 4 in the placebo group (4:1 randomization) at two dosage regimens, 6-hour or 24-hour infusions. RESULTS: The proof-of-concept study was successfully conducted, with no significant deviations from the study protocol and no serious adverse events reported. Regarding efficacy, only marginal differences were observed between ATP and placebo arms for H-MRS and MMSE variables. CONCLUSIONS: Our study demonstrates that the use of ATP infusion as therapy is feasible and safe. Larger studies are however needed to assess the efficacy of ATP in moderate to severe AD.
Subject(s)
Alzheimer Disease , Adenosine Triphosphate/therapeutic use , Alzheimer Disease/drug therapy , Double-Blind Method , Feasibility Studies , Humans , Infusions, IntravenousABSTRACT
TITLE: Síndrome de duplicación MECP2 familiar.
Subject(s)
Mental Retardation, X-Linked/genetics , Humans , Infant , Male , PedigreeABSTRACT
TITLE: Neurofibromatosis 1 y cavernomatosis multiple familiar en un lactante con sialorrea profusa episodica.
Subject(s)
Brain Neoplasms/complications , Hemangioma, Cavernous/complications , Neoplasms, Multiple Primary/complications , Neurofibromatosis 1/complications , Sialorrhea/complications , Brain Neoplasms/diagnosis , Hemangioma, Cavernous/diagnosis , Humans , Infant , Male , Neoplasms, Multiple Primary/diagnosis , Neurofibromatosis 1/diagnosis , Sialorrhea/diagnosisABSTRACT
Perfluorooctane sulfonate (PFOS) is an endocrine disruptor highly persistent, bioaccumulative and neurotoxic, whose presence has been detected in different compartments of the environment. The aim of this study was to investigate whether PFOS could alter the HPA axis activity by modifying the gene and protein expression of corticotropin-releasing factor 1 receptor (CRF1r) and glucocorticoid receptor (Gr). For that purpose, Sprague-Dawley adult male rats were orally treated by gavage with 0.5; 1.0; 3.0 and 6.0â¯mg of PFOS/kg/day for 28 consecutive days. After PFOS administration, gene and protein expression of CRF1r were analysed in the hypothalamus, hippocampus, pituitary and adrenal glands. Moreover, Gr gene and protein expression were measured in hypothalamus, pituitary gland, prefrontal cortex, amygdala and hippocampus. The reported results indicate that (1) PFOS could inhibit HPA axis activity by diminishing gene and protein expression of CRF1r in the pituitary gland; (2) PFOS inhibits Gr protein expression in both prefrontal cortex and amygdala, which could be related to the toxic effects of this contaminant in this neuroendocrine axis and finally, (3) PFOS-treated rats would try to maintain the physiological levels of corticosterone by reducing the protein expression of Gr in the pituitary gland.
Subject(s)
Alkanesulfonic Acids/toxicity , Endocrine Disruptors/toxicity , Fluorocarbons/toxicity , Hypothalamo-Hypophyseal System/drug effects , Pituitary-Adrenal System/drug effects , Receptors, Corticotropin-Releasing Hormone/drug effects , Receptors, Glucocorticoid/drug effects , Adrenocorticotropic Hormone/blood , Animals , Corticosterone/blood , Corticotropin-Releasing Hormone/blood , Dose-Response Relationship, Drug , Down-Regulation , Hypothalamo-Hypophyseal System/metabolism , Hypothalamo-Hypophyseal System/physiopathology , Male , Pituitary-Adrenal System/metabolism , Pituitary-Adrenal System/physiopathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats, Sprague-Dawley , Receptors, Corticotropin-Releasing Hormone/genetics , Receptors, Corticotropin-Releasing Hormone/metabolism , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Signal Transduction/drug effects , Time FactorsABSTRACT
INTRODUCTION: The high prevalence of attention deficit hyperactivity disorder (ADHD), with at least one pupil per classroom, poses a challenge for all the professionals in contact with them, especially for teachers. AIM: To examine how much primary school teachers know about ADHD in three areas (general information, symptoms and diagnosis, and treatment). SUBJECTS AND METHODS: 125 primary school teachers from different communities answered the Knowledge of Attention Deficit Hyperactivity Disorder Scale (KADDS). RESULTS: The teachers answered fewer than half the items correctly, the symptoms and diagnosis subscale being the one where they were seen to be most knowledgeable. Teachers who had had children with ADHD in class displayed greater knowledge in the areas of general information and treatment, but less on the symptoms and diagnosis subscale. 32.8% of the teachers reported feeling somewhat or totally unable to teach children with ADHD in an effective way and recommend special education as a better educational style. Teachers with specific training in ADHD obtained better scores than those who had not received such instruction. CONCLUSION: Teachers with training in ADHD are more knowledgeable and more confident about their abilities when it comes to teaching children with ADHD.
TITLE: Estudio de los conocimientos de los maestros de educacion primaria sobre el trastorno por deficit de atencion/hiperactividad.Introduccion. La alta prevalencia del trastorno por deficit de atencion/hiperactividad (TDAH), con al menos un alumno por aula, supone un reto para todos los profesionales que estan en contacto con ellos, en especial para los maestros. Objetivo. Examinar los conocimientos de los maestros de educacion primaria sobre el TDAH en tres areas (informacion general, sintomas y diagnostico, y tratamiento). Sujetos y metodos. Un total de 125 maestros de educacion primaria de varias comunidades cumplimentaron la Knowledge of Attention Deficit Hyperactivity Disorder Scale (KADDS). Resultados. Los maestros contestaron de forma correcta a menos de la mitad de los items, y la subescala de sintomas y diagnostico es donde mas conocimientos demostraron. Los maestros que habian tenido niños con TDAH en clase mostraron mas conocimientos en las areas de informacion general y tratamiento, pero no en la subescala de sintomas y diagnostico. Un 32,8% de los maestros describe sentirse poco o nada capaz de enseñar eficazmente a niños con TDAH y recomienda la educacion especial como mejor estilo educativo. Los maestros con formacion especifica en TDAH obtuvieron mejores resultados en la KADDS en comparacion con los maestros sin formacion. Conclusion. Los maestros formados en TDAH demuestran un mayor grado de conocimiento y aumenta su confianza para llevar a cabo la labor educativa de los niños con TDAH.
Subject(s)
Attention Deficit Disorder with Hyperactivity/psychology , Health Knowledge, Attitudes, Practice , School Teachers/psychology , Attitude to Health , Child , Education, Special , Humans , Interpersonal Relations , Schools , Surveys and Questionnaires , Symptom Assessment , Teaching/psychologyABSTRACT
Introduction: Differences in response to fluoxetine (FLX) may be influenced by certain genes that are involved in FLX transportation (ABCB1). We examined remission and recovery from the index episode in a cohort of patients treated with FLX, and also investigated associations between genetic variants in ABCB1 and remission, recovery, and suicide risk. Methods: This was a naturalistic 1-year follow-up study of 46 adolescents diagnosed with major depressive disorder (MDD). At 12 months they underwent a diagnostic interview with the K-SADS-PL. Results: It was found that remission was around 69.5% and recovery 56.5%. Remission and recovery were associated with lower scores on the CDI at baseline, with fewer readmissions and suicide attempts, and with lower scores on the CGI and higher scores on the GAF scale. No relationship was found between ABCB1 and remission or recovery. However, a significant association was observed between the G2677T ABCB1 polymorphism and suicide attempts. Conclusion: Other factors such as stressful events, family support, and other genetic factors are likely to be involved in MDD outcome.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/genetics , Fluoxetine/therapeutic use , Polymorphism, Single Nucleotide/genetics , Selective Serotonin Reuptake Inhibitors/therapeutic use , Adolescent , Depressive Disorder, Major/psychology , Female , Follow-Up Studies , Genotype , Humans , Male , Pharmacogenetics , Psychiatric Status Rating Scales , Recurrence , Retrospective Studies , Suicide, Attempted/psychology , Treatment OutcomeABSTRACT
This study investigated whether the risk of presenting antipsychotic (AP)-induced extrapyramidal symptoms (EPS) could be related to single-nucleotide polymorphisms (SNPs) in a naturalistic cohort of first episode psychosis (FEP) patients. Two hundred and two SNPs in 31 candidate genes (involved in dopamine, serotonin and glutamate pathways) were analyzed in the present study. One hundred and thirteen FEP patients (43 presenting EPS and 70 non-presenting EPS) treated with high-potency AP (amisulpride, paliperidone, risperidone and ziprasidone) were included in the analysis. The statistical analysis was adjusted by age, gender, AP dosage, AP combinations and concomitant treatments as covariates. Four SNPs in different genes (DRD2, SLC18A2, HTR2A and GRIK3) contributed significantly to the risk of EPS after correction for multiple testing (P<1 × 10(-4)). These findings support the involvement of dopamine, serotonin and glutamate pathways in AP-induced EPS.
Subject(s)
Antipsychotic Agents/adverse effects , Basal Ganglia Diseases/chemically induced , Dopamine/metabolism , Glutamic Acid/metabolism , Pharmacogenomic Variants , Polymorphism, Single Nucleotide , Psychotic Disorders/drug therapy , Serotonin/metabolism , Adolescent , Adult , Basal Ganglia Diseases/genetics , Basal Ganglia Diseases/metabolism , Basal Ganglia Diseases/physiopathology , Case-Control Studies , Child , Female , Follow-Up Studies , Genetic Association Studies , Genetic Predisposition to Disease , Haplotypes , Humans , Longitudinal Studies , Male , Pharmacogenetics , Phenotype , Prospective Studies , Psychotic Disorders/diagnosis , Psychotic Disorders/physiopathology , Receptor, Serotonin, 5-HT2A/genetics , Receptors, Dopamine D2/genetics , Receptors, Kainic Acid/genetics , Risk Assessment , Risk Factors , Spain , Treatment Outcome , Vesicular Monoamine Transport Proteins/genetics , Young Adult , GluK3 Kainate ReceptorABSTRACT
This study was undertaken to evaluate the possible role of several reproductive hormone receptors on the disruption of the hypothalamic-pituitary-testis (HPT) axis activity induced by perfluorooctane sulfonate (PFOS). The studied receptors are the gonadotropin-releasing hormone receptor (GnRHr), luteinizing hormone receptor (LHr), follicle-stimulating hormone receptor (FSHr), and the androgen receptor (Ar). Adult male rats were orally treated with 1.0; 3.0 and 6.0 mg of PFOS kg(-1) d(-1) for 28 days. In general terms, PFOS can modify the relative gene and protein expressions of these receptors in several tissues of the reproductive axis. At the testicular level, apart from the expected inhibition of both gene and protein expressions of FSHr and Ar, PFOS also stimulates the GnRHr protein and the LHr gene expression. The receptors of the main hormones involved in the HPT axis may have an important role in the disruption exerted by PFOS on this axis.
Subject(s)
Alkanesulfonic Acids/pharmacology , Fluorocarbons/pharmacology , Gene Expression Regulation/drug effects , Receptors, Androgen/metabolism , Receptors, FSH/metabolism , Receptors, LHRH/metabolism , Receptors, LH/metabolism , Alkanesulfonic Acids/chemistry , Animals , Blotting, Western , Fluorocarbons/chemistry , Follicle Stimulating Hormone/metabolism , Gonadotropin-Releasing Hormone/metabolism , Luteinizing Hormone/metabolism , Male , Polymerase Chain Reaction , Rats , Rats, Sprague-Dawley , Receptors, Androgen/genetics , Receptors, FSH/genetics , Receptors, LH/genetics , Receptors, LHRH/genetics , Reproduction/drug effects , Testis/drug effects , Testis/metabolismABSTRACT
Perfluorooctane sulfonate (PFOS) is the most representative of a rising class of persistent organic pollutants perfluorochemicals. In the present study, its neurotoxicity was examined using adult male rats orally treated with 0.5; 1.0; 3.0 and 6.0 mg of PFOS/kg/day for 28 days. At the end of the treatment, the dopamine concentration and its metabolism expressed like the ratio 3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine and homovanillic acid (HVA)/dopamine were measured in the amygdala, prefrontal cortex and hippocampus. Gene and protein expression of the dopamine receptors D1 and D2 were also determined in these limbic areas. The obtained results suggest that: (1) PFOS can alter the dopamine system by modifying its neuronal activity and/or its D1 and D2 receptors in the studied brain regions; (2) the dopamine concentration and metabolism seem to be more sensitive against PFOS toxicity in the hippocampus than in the other analyzed brain areas; (3) the inhibited gene and protein expression of the D1 receptors induced by PFOS in the amygdala could be related to several changes in the HPA axis activity, and lastly; (4) the observed alterations on the dopamine system induced by PFOS could be a possible neurotoxicity mechanism of PFOS, leading to many neurological diseases.
Subject(s)
Alkanesulfonic Acids/toxicity , Amygdala/drug effects , Fluorocarbons/toxicity , Hippocampus/drug effects , Prefrontal Cortex/drug effects , 3,4-Dihydroxyphenylacetic Acid/metabolism , Amygdala/metabolism , Animals , Dose-Response Relationship, Drug , Hippocampus/metabolism , Homovanillic Acid/metabolism , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/metabolism , Male , Prefrontal Cortex/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolismABSTRACT
To identify potential candidate genes for future pharmacogenetic studies of antipsychotic (AP)-induced extrapyramidal symptoms (EPS), we used gene expression arrays to analyze changes induced by risperidone in mice strains with different susceptibility to EPS. We proposed a systems biology analytical approach that combined the identification of gene co-expression modules related to AP treatment, the construction of protein-protein interaction networks with genes included in identified modules and finally, gene set enrichment analysis of constructed networks. In response to risperidone, mice strain with susceptibility to develop EPS showed downregulation of genes involved in the mammalian target of rapamycin (mTOR) pathway and biological processes related to this pathway. Moreover, we also showed differences in the phosphorylation pattern of the ribosomal protein S6 (rpS6), which is a major downstream effector of mTOR. The present study provides new evidence of the involvement of the mTOR pathway in AP-induced EPS and offers new and valuable markers for pharmacogenetic studies.
Subject(s)
Antipsychotic Agents , Basal Ganglia Diseases/genetics , Gene Expression Profiling , Gene Regulatory Networks , Risperidone , TOR Serine-Threonine Kinases/genetics , Animals , Basal Ganglia Diseases/chemically induced , Basal Ganglia Diseases/enzymology , Basal Ganglia Diseases/physiopathology , Behavior, Animal , Blotting, Western , Disease Models, Animal , Gene Expression Profiling/methods , Genetic Predisposition to Disease , Male , Mice , Mice, Inbred DBA , Motor Activity , Phosphorylation , Protein Interaction Mapping , Ribosomal Protein S6/metabolism , Signal Transduction , Systems Biology , TOR Serine-Threonine Kinases/metabolismABSTRACT
El presente documento expone un resumen de la actual sistemática de trabajo de las Unidades dc Neuropediatría y Metabolismo del Hospital Universitario Miguel Servet de Zaragoza. Se dispone de herramientas de trabajo de enorme utilidad: bases de datos de neuropediatría y metabolismo, protocolos, hojas de información y consentimientos informados. A partir de dichas herramientas, se expone la actividad de las Unidades asistenciales, docentes y de investigación, incluida la actividad generada por el cribado neonatal ampliado (AU)
This document represents a summary of how the Neutopediatric and Metabolic Units work at the University Hospital Miguel Servet in Zaragoza. The extremely useful tools available today are Neuropediatric and Metabolic Data Bases, clinical protocols, parents and professionals information sheets and informed consent forms. Health-care, educational and research activity, including amplified neonatal screening, are drawn from these tools (AU)
Subject(s)
Humans , Male , Female , Child , Pediatrics/education , Pediatrics/methods , Metabolism/genetics , Infant Care/organization & administration , Teaching/classification , Teaching/organization & administration , Clinical Protocols/classification , Parental Consent/ethics , Primary Health Care , Pediatrics/classification , Pediatrics , Metabolism/physiology , Infant Care/history , Teaching/history , Teaching , Statistical Databases , Clinical Protocols/standards , Parental Consent/history , Primary Health Care/methodsABSTRACT
Cultured fibroblasts from first-episode schizophrenia patients (FES) have shown increased susceptibility to apoptosis, which may be related to glutamate dysfunction and progressive neuroanatomical changes. Here we determine whether apoptotic markers obtained from cultured fibroblasts in FES and controls correlate with changes in brain glutamate and N-acetylaspartate (NAA) and regional brain volumes. Eleven antipsychotic-naive FES and seven age- and gender-matched controls underwent 3-Tesla magnetic resonance imaging scanning. Glutamate plus glutamine (Glx) and NAA levels were measured in the anterior cingulate (AC) and the left thalamus (LT). Hallmarks of apoptotic susceptibility (caspase-3-baseline activity, phosphatidylserine externalization and chromatin condensation) were measured in fibroblast cultures obtained from skin biopsies after inducing apoptosis with staurosporine (STS) at doses of 0.25 and 0.5 µM. Apoptotic biomarkers were correlated to brain metabolites and regional brain volume. FES and controls showed a negative correlation in the AC between Glx levels and percentages of cells with condensed chromatin (CC) after both apoptosis inductions (STS 0.5 µM: r = -0.90; P = 0.001; STS 0.25 µM: r = -0.73; P = 0.003), and between NAA and cells with CC (STS 0.5 µM induction r = -0.76; P = 0.002; STS 0.25 µM r = -0.62; P = 0.01). In addition, we found a negative correlation between percentages of cells with CC and regional brain volume in the right supratemporal cortex and post-central region (STS 0.25 and 0.5 µM; P < 0.05 family-wise error corrected (FWEc)). We reveal for the first time that peripheral markers of apoptotic susceptibility may correlate with brain metabolites, Glx and NAA, and regional brain volume in FES and controls, which is consistent with the neuroprogressive theories around the onset of the schizophrenia illness.
Subject(s)
Apoptosis , Brain/metabolism , Brain/pathology , Fibroblasts/pathology , Schizophrenia/metabolism , Schizophrenia/pathology , Adult , Caspase 3/metabolism , Cell Culture Techniques , Female , Glutamic Acid/metabolism , Glutamine/metabolism , Humans , Magnetic Resonance Imaging , Male , Organ Size , Young AdultABSTRACT
Perfluorooctane sulfonate (PFOS) is a fluorinated organic compound. This chemical is neurotoxic and can alter the pituitary secretion. This is an initial study aimed at knowing the toxic effects of high doses of PFOS on prolactin secretion and the possible mechanisms involved in these alterations. For that, adult male rats were orally treated with 3.0 and 6.0 mg of PFOS/kg body weight (b.w.)/day for 28 days. At the end of the treatment, the serum levels of prolactin and estradiol as well as the concentration of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and gamma-aminobutyric acid (GABA) were quantified in the anterior and in the mediobasal hypothalamus. PFOS, at the administered doses, reduced prolactin and estradiol secretion, increased the concentration of dopamine and GABA in the anterior hypothalamus, and decreased the ratios DOPAC/dopamine and HVA/dopamine in this same hypothalamic area. The outcomes reported in this study suggest that (1) high doses of PFOS inhibit prolactin secretion in adult male rats; (2) only the periventricular-hypophysial dopaminergic (PHDA) neurons seem to be involved in this inhibitory effect but not the tuberoinfundibular dopaminergic (TIDA) and the tuberohypophysial dopaminergic (THDA) systems; (3) GABAergic cells from the paraventricular and supraoptic nuclei could be partially responsible for the PFOS action on prolactin secretion; and finally (4) estradiol might take part in the inhibition exerted by elevated concentration of PFOS on prolactin release.
Subject(s)
Alkanesulfonic Acids/toxicity , Endocrine Disruptors/toxicity , Environmental Pollutants/toxicity , Fluorocarbons/toxicity , Hypothalamus, Anterior/drug effects , Hypothalamus, Middle/drug effects , Pituitary Gland, Anterior/drug effects , Prolactin/antagonists & inhibitors , Alkanesulfonic Acids/administration & dosage , Animals , Dopamine/chemistry , Dopamine/metabolism , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Dose-Response Relationship, Drug , Endocrine Disruptors/administration & dosage , Environmental Pollutants/administration & dosage , Estradiol/blood , Estradiol/metabolism , Fluorocarbons/administration & dosage , GABAergic Neurons/drug effects , GABAergic Neurons/metabolism , Hypothalamus, Anterior/metabolism , Hypothalamus, Middle/metabolism , Male , Paraventricular Hypothalamic Nucleus/drug effects , Paraventricular Hypothalamic Nucleus/metabolism , Pituitary Gland, Anterior/metabolism , Prolactin/blood , Prolactin/metabolism , Random Allocation , Rats, Sprague-Dawley , Supraoptic Nucleus/drug effects , Supraoptic Nucleus/metabolism , Toxicity Tests, Subacute , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/metabolismABSTRACT
To identify the candidate genes for pharmacogenetic studies of antipsychotic (AP)-induced extrapyramidal symptoms (EPS), we propose a systems biology analytical approach, based on protein-protein interaction network construction and functional annotation analysis, of changes in gene expression (Human Genome U219 Array Plate) induced by treatment with risperidone or paliperidone in peripheral blood. 12 AP-naïve patients with first-episode psychosis participated in the present study. Our analysis revealed that, in response to AP treatment, constructed networks were enriched for different biological processes in patients without EPS (ubiquitination, protein folding and adenosine triphosphate (ATP) metabolism) compared with those presenting EPS (insulin receptor signaling, lipid modification, regulation of autophagy and immune response). Moreover, the observed differences also involved specific pathways, such as anaphase promoting complex /cdc20, prefoldin/CCT/triC and ATP synthesis in no-EPS patients, and mammalian target of rapamycin and NF-κB kinases in patients with EPS. Our results showing different patterns of gene expression in EPS patients, offer new and valuable markers for pharmacogenetic studies.
Subject(s)
Antipsychotic Agents/adverse effects , Basal Ganglia Diseases/genetics , Protein Interaction Maps/genetics , Psychotic Disorders/genetics , Risperidone/adverse effects , Adult , Animals , Antipsychotic Agents/administration & dosage , Basal Ganglia Diseases/chemically induced , Basal Ganglia Diseases/pathology , Dose-Response Relationship, Drug , Female , Gene Expression Regulation/genetics , Humans , Male , NF-kappa B/genetics , NF-kappa B/metabolism , Pharmacogenetics , Psychotic Disorders/drug therapy , Psychotic Disorders/pathology , Risperidone/administration & dosage , Signal Transduction/genetics , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolismABSTRACT
Perfluorooctane sulfonate (PFOS) is an endocrine disruptor, whose exposure can induce several alterations on the reproductive axis activity in males during adulthood. This study was undertaken to evaluate the possible role of serotonin and neuropeptide Y (NPY) on the disruption of the hypothalamic-pituitary-testicular (HPT) axis induced by PFOS in adult male rats. For that, adult male rats were orally treated with 0.5; 1.0; 3.0 and 6.0mg of PFOS/kg/day for 28 days. After PFOS exposure, serotonin concentration increased in the anterior and mediobasal hypothalamus as well as in the median eminence. The metabolism of this amine (expressed as the ratio 5-hydroxyindolacetic acid (5-HIAA)/serotonin) was diminished except in the anterior hypothalamus, with the doses of 3.0 and 6.0mg/kg/day, being this dose 0.5mg/kg/day in the median eminence. In general terms, PFOS-treated rats presented a decrease of the hypothalamic concentration of the gonadotropin releasing hormone (GnRH) and NPY. A diminution of the serum levels of the luteinizing hormone (LH), testosterone and estradiol were also shown. These results suggest that both serotonin and NPY could be involved in the inhibition induced by PFOS on the reproductive axis activity in adult male rats.
