RESUMO
Ketamine is an NMDA (N-methyl-d-aspartate) glutamate receptor antagonist, which has a myriad of dose-dependent pharmacological and behavioral effects, including anesthetic, sedative, amnestic, analgesic, and anti-inflammatory properties. Intriguingly, ketamine at subanesthetic doses displays a relevant profile both in mimicking symptoms of schizophrenia and also as the first fast-acting treatment for depression. Here, we present an overview of the state-of-the-art knowledge about ketamine as an antidepressant as well as a pharmacological model of schizophrenia in animal models and human participants. Ketamine's dual effect appears to arise from its mechanism of action involving NMDA receptors, with both immediate and downstream consequences being triggered as a result. Finally, we discuss the feasibility of a unified approach linking the glutamatergic hypothesis of schizophrenia to the promising preclinical and clinical success of ketamine in the treatment of refractory depression.
Assuntos
Antidepressivos , Modelos Animais de Doenças , Ketamina , Receptores de N-Metil-D-Aspartato , Ketamina/farmacologia , Ketamina/uso terapêutico , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Humanos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Antagonistas de Aminoácidos Excitatórios/farmacologia , Esquizofrenia/tratamento farmacológico , Depressão/tratamento farmacológicoRESUMO
BACKGROUND: Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. PATIENTS AND METHODS: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. RESULTS: Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. CONCLUSION: The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.
Assuntos
Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Mutação , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos Retrospectivos , Acrilamidas/uso terapêutico , Acrilamidas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Receptores ErbB/genética , Compostos de Anilina/uso terapêutico , Compostos de Anilina/farmacologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Indóis , PirimidinasRESUMO
Porcine colostrum lipid classes and fatty acids (FA) were characterized in 6 pools (from 69 samples) from 3 sow breeds (Italian Large White, Italian Landrace, and Italian Duroc) and different parity orders (only Large White). Triacylglycerols (TAG; 94.44 expressed as g/100 g of fat) were the most abundant lipid class, followed by diacylglycerols (DAG; 3.36 g/100 g of fat), free fatty acids (FFA; 0.98 g/100 g of fat), and cholesterol (0.84 g/100 g of fat). The main FAs found in swine colostrum were palmitic (27.29%, expressed as g/100 g of total FA), oleic (28.81%), and linoleic (23.39%) acids. Both the breed of sow and parity order affected the FA and lipid composition. The results suggest that the FA composition of swine colostrum is similar to that of human colostrum and could represent a new source of nutrients for human infants, after further assessment of hygienic and quality aspects. The swine model could be an opportunity for a better understanding of colostrum effects on newborns.
Assuntos
Cruzamento , Colostro/química , Ácidos Graxos/análise , Lipídeos/análise , Paridade/fisiologia , Sus scrofa/fisiologia , Animais , Colesterol/análise , Diglicerídeos/análise , Ácidos Graxos não Esterificados/análise , Feminino , Humanos , Leite/química , Leite Humano/química , Especificidade da Espécie , TriglicerídeosRESUMO
BACKGROUND/OBJECTIVES: Epidemiological studies suggest a link between chromium (Cr) status and cardiovascular disease. Increased urinary excretion of Cr was reported in subjects with diabetes compared with non-diabetic controls and those with non-diabetic insulin resistance. Epigenetic alterations have been linked to the presence of Cr, and microRNA (miRNA) expression has been implicated in the pathogenesis of metabolic diseases and cardiovascular diseases (CVDs). We investigated the association between Cr excretion and miRNA expression in leukocytes from obese subjects. We also examined the relationship between altered miRNA expression and selected clinical parameters to further investigate mechanisms linking Cr to metabolic diseases and CVDs. SUBJECTS/METHODS: We analyzed urinary Cr in 90 Italian subjects using inductively coupled plasma-mass spectrometry. Peripheral blood miRNA levels were screened with TaqMan Low-Density Array Human MicroRNA A. Cr level-associated expression of miRNAs was detected with multivariate regression analyses, and the top 10 candidate miRNAs were selected for validation. We also used multivariate regression analyses to assess possible associations between validated miRNAs and glycated hemoglobin (A1c) and blood pressure (BP). The validated miRNAs were further investigated by functional analysis with Ingenuity Pathway Analysis software. RESULTS: Urinary Cr levels (mean: 0.35 µg/l; s.d.=0.24) ranged from 0.05 to 1.27 µg/l. In the screening phase, 43 miRNAs were negatively associated with Cr. Of the top 10 miRNAs selected for validation, nine (miR-451, miR-301, miR-15b, miR-21, miR-26a, miR-362-3p, miR-182, miR-183 and miR-486-3p) were downregulated in association with Cr (P-false discovery rate (FDR)<0.10). miR-451 expression was associated with A1c (ß=-0.06; P=0.0416), whereas miR-486-3p expression was associated both with diastolic (ß=2.1; P=0.004) and systolic BP (ß=3.3; P=0.003). CONCLUSIONS: These results indicate that miR-451 and miR-486-3p are involved in the link between Cr levels and metabolic diseases and CVDs.
Assuntos
Cromo/urina , Leucócitos/metabolismo , MicroRNAs/metabolismo , Obesidade/urina , Adulto , Idoso , Pressão Sanguínea/genética , Estudos de Casos e Controles , Regulação para Baixo , Feminino , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , MicroRNAs/análise , Pessoa de Meia-Idade , Análise Multivariada , Obesidade/sangue , Obesidade/genética , Análise de Regressão , Adulto JovemRESUMO
RATIONALE: Secondary ion mass spectrometry (SIMS) with polyatomic primary ions provides a successful tool for molecular depth profiling of polymer systems, relevant in many technological applications. Widespread C60 sources, however, cause in some polymers extensive damage with loss of molecular information along depth. We study a method, based on the use of a radical scavenger, for inhibiting ion-beam-induced reactions causing sample damage. METHODS: Layered polystyrene sulfonate and polyacrylic acid based polyelectrolyte films, behaving differently towards C60 beam-induced damage, were selected and prepared as model systems. They were depth profiled by means of time-of-flight (TOF)-SIMS in dual beam mode, using fullerene ions for sputtering. Nitric oxide was introduced into the analysis chamber as a radical scavenger. The effect of sample cooling combined with NO-dosing on the quality of depth profiles was explored. RESULTS: NO-dosing during C60-SIMS depth profiling of >1 micrometer-thick multilayered polyelectrolytes allows detection, along depth, of characteristic fragments from systems otherwise damaged by C60 bombardment, and increases sputtering yield by more than one order of magnitude. By contrast, NO has little influence on those layers that are well profiled with C60 alone. Such leveling effect, more pronounced at low temperature, leads to a dramatic improvement of profile quality, with a clear definition of interfaces. CONCLUSIONS: NO-dosing provides a tool for extending the applicability, in SIMS depth profiling, of the widely spread fullerene ion sources. In view of the acceptable erosion rates on inorganics, obtainable with C60, the method could be of relevance also in connection with the 3D-imaging of hybrid polymer/inorganic systems.
Assuntos
Resinas Acrílicas/análise , Fulerenos/química , Óxido Nítrico/química , Poliestirenos/análise , Espectrometria de Massa de Íon Secundário/métodos , Eletrólitos/análise , Íons/químicaRESUMO
The development of effective feeding strategies to reduce the detrimental effect of enterotoxigenic F4ac (ETEC) plays a crucial role in reducing the occurrence of therapeutic intervention with antibiotics in livestock. The ability of CNCM I-4407 (SCC), supplied in different patterns to counteract ETEC infection in weaned pigs, was evaluated. Fifty pigs weaned at 24 d were then divided into 5 groups: control (CO), CO + colistin (AB), CO + 5 × 10(10) cfu of SCC/ kg feed, from d 0 to 21 (PR), CO + 5 × 10(10) cfu of SCC/ kg feed from d 7 to 11 (CM), and CO + 1 shot of 2 × 10(11) cfu of SCC when the first diarrhea appeared (CU). On d 7 postweaning, all the pigs were orally challenged with 10(8) cfu of ETEC. Blood samples were taken from the pigs (d 7, 8, 12, and 21) while the fecal excretion of ETEC was assessed on d 7 and 10. Fecal consistency was scored from 12 h before infection to 144 h postinfection (p.i.). On d 21, the pigs were sacrificed. The in vitro adhesion test on the intestinal villi confirmed individual susceptibility to ETEC, excluding the presence of resistant pigs. Growth performance did not differ between the treatments. Mortality was reduced in the AB group (P< 0.01) and, marginally, in the PR group (P = 0.089) when compared to the CO group. The CO group had a higher fecal score than AB in the period of observation (from P = 0.01 to P< 0.001). Yeast administration reduced the fecal score when compared to the CO group 12 and 48 h p.i. (P = 0.04). Total IgA never differed among the treatments, but the ETEC-specific IgA concentration was lower in the AB group than in CO (P = 0.04) at d 12. Four days p.i., the pigs fed live yeast had reduced ETEC excretion compared with the CO pigs (P = 0.05). Blood concentrations of dodecenoyl-L-carnitine (P < 0.01), glutaryl-L-carnitine/hydroxyhex¬anoyl-L-carnitine, phosphatidylcholine diacyl and phosphatidylcholine diacyl (P = 0.01 and P< 0.01, respectively), and α-amino adipic acid (P < 0.01) were reduced in the AB group compared to the CO group; PR + CM reduced the concentration of sphingomyelin-ceramide (P = 0.02) and increased the concentration of decadienyl-L-carnitine (C10:2; P= 0.02) vs. CO. The CM group had an increased concentration of C10:2 (P < 0.01) compared to the PR group. In conclusion, the administration of live yeast, even in concomitance with ETEC infections, reduces pig illness and mortality. The strain of SCC tested did not show a therapeutic effect.
Assuntos
Diarreia/veterinária , Suplementos Nutricionais , Escherichia coli/patogenicidade , Doenças dos Suínos/prevenção & controle , Suínos/microbiologia , Fermento Seco/farmacologia , Ração Animal/análise , Animais , Antibacterianos/uso terapêutico , Diarreia/microbiologia , Diarreia/prevenção & controle , Dieta/veterinária , Infecções por Escherichia coli/complicações , Infecções por Escherichia coli/prevenção & controle , Infecções por Escherichia coli/veterinária , Fezes , Nível de Saúde , Metaboloma/efeitos dos fármacos , Saccharomyces cerevisiae/fisiologia , Suínos/sangue , Doenças dos Suínos/microbiologia , Desmame , Fermento Seco/uso terapêuticoRESUMO
AIM: Controlling obesity and other comorbidities in the population is a challenge in modern society. High-intensity interval training (HIIT) combines short periods of high-intensity exercise with long recovery periods or a low-intensity exercise. The aim was to assess the impact of HIIT in the context of diet-induced obesity in the animal model. METHODS: C57BL/6 mice were fed one of the two diets: standard chow (Lean group - LE) or a high--fat diet (Obese group - OB). After twelve weeks, the animals were divided into non-trained groups (LE--NT and OB-NT) and trained groups (LE-T and OB--T), and began an exercise protocol. For biochemical analysis of inflammatory and lipid profile, we used a colorimetric enzymatic method and an automatic spectrophotometer. One-way ANOVA was used for statistical analysis of the experimental groups with Holm-Sidak pos hoc test. Two-way ANOVA analyzed the interactions between diet and HIIT protocol. RESULTS: HIIT leads to significant reductions in body mass, blood glucose, glucose tolerance and hepatic lipid profile in T-groups compared to NT-groups. HIIT was able to reduce plasma levels of inflammatory cytokines. Additionally, HIIT improves the insulin immunodensity in the islets, reduces the adiposity and the hepatic steatosis in the T-groups. HIIT improves beta--oxidation and peroxisome proliferator--activated receptor (PPAR)-alpha and reduces lipogenesis and PPAR--gamma levels in the liver. In skeletal muscle, HIIT improves PPAR--alpha and glucose transporter-4 and reduces PPAR--gamma levels. CONCLUSION: HIIT leads to attenuate the adverse effects caused by a chronic ingestion of a high-fat diet.
RESUMO
C57BL/6 mice develop signs and symptoms comparable, in part, to the human metabolic syndrome. The objective of the present study was to evaluate the effects of exercise training on carbohydrate metabolism, lipid profile, visceral adiposity, pancreatic islet alterations, and nonalcoholic fatty liver disease in C57BL/6 mice. Animals were fed one of two diets during an 8-week period: standard (SC, N = 12) or very high-fat (HF, N = 24) chow. An exercise training protocol (treadmill) was then established and mice were divided into SC and HF sedentary (SC-Sed, HF-Sed), exercised groups (SC-Ex, HF-Ex), or switched from HF to SC (HF/SC-Sed and HF/SC-Ex). HF/HF-Sed mice had the greatest body mass (65% more than SC/SC-Sed; P < 0.0001), and exercise reduced it by 23% (P < 0.0001). Hepatic enzymes ALP (+80%), ALT (+100%) and AST (+70%) were higher in HF/HF mice than in matched SC/SC. Plasma insulin was higher in both the HF/HF-Sed and HF/SC-Sed groups than in the matched exercised groups (+85%; P < 0.001). Pancreatic islets, adipocytes and liver structure were greatly affected by HF, ultimately resulting in islet beta-cell hypertrophy and severe liver steatosis. The HF group had larger islets than the SC/SC group (+220%; P < 0.0001), and exercise significantly reduced liver steatosis and islet size in HF. Exercise attenuated all the changes due to HF, and the effects were more pronounced in exercised mice switched from an HF to an SC diet. Exercise improved the lipid profile by reducing body weight gain, visceral adiposity, insulin resistance, islet alterations, and fatty liver, contributing to obesity and steatohepatitis control.
Assuntos
Gorduras na Dieta/administração & dosagem , Fígado Gorduroso/prevenção & controle , Resistência à Insulina/fisiologia , Gordura Intra-Abdominal/metabolismo , Lipídeos/sangue , Condicionamento Físico Animal , Animais , Fígado Gorduroso/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de RiscoRESUMO
C57BL/6 mice develop signs and symptoms comparable, in part, to the human metabolic syndrome. The objective of the present study was to evaluate the effects of exercise training on carbohydrate metabolism, lipid profile, visceral adiposity, pancreatic islet alterations, and nonalcoholic fatty liver disease in C57BL/6 mice. Animals were fed one of two diets during an 8-week period: standard (SC, N = 12) or very high-fat (HF, N = 24) chow. An exercise training protocol (treadmill) was then established and mice were divided into SC and HF sedentary (SC-Sed, HF-Sed), exercised groups (SC-Ex, HF-Ex), or switched from HF to SC (HF/SC-Sed and HF/SC-Ex). HF/HF-Sed mice had the greatest body mass (65 percent more than SC/SC-Sed; P < 0.0001), and exercise reduced it by 23 percent (P < 0.0001). Hepatic enzymes ALP (+80 percent), ALT (+100 percent) and AST (+70 percent) were higher in HF/HF mice than in matched SC/SC. Plasma insulin was higher in both the HF/HF-Sed and HF/SC-Sed groups than in the matched exercised groups (+85 percent; P < 0.001). Pancreatic islets, adipocytes and liver structure were greatly affected by HF, ultimately resulting in islet â-cell hypertrophy and severe liver steatosis. The HF group had larger islets than the SC/SC group (+220 percent; P < 0.0001), and exercise significantly reduced liver steatosis and islet size in HF. Exercise attenuated all the changes due to HF, and the effects were more pronounced in exercised mice switched from an HF to an SC diet. Exercise improved the lipid profile by reducing body weight gain, visceral adiposity, insulin resistance, islet alterations, and fatty liver, contributing to obesity and steatohepatitis control.
Assuntos
Animais , Masculino , Camundongos , Gorduras na Dieta/administração & dosagem , Fígado Gorduroso/prevenção & controle , Resistência à Insulina/fisiologia , Gordura Intra-Abdominal/metabolismo , Lipídeos/sangue , Condicionamento Físico Animal , Fígado Gorduroso/metabolismo , Ilhotas Pancreáticas/metabolismo , Fatores de RiscoRESUMO
BACKGROUND: Cystic fibrosis is the most common lethal recessive disorder among Caucasians. Over 1500 mutations have been identified in cystic fibrosis transmembrane conductance regulator disease-gene so far. A large variability of the clinical phenotype has been observed both in cystic fibrosis patients bearing the same genotype, and in affected sibpairs. Thus, genes inherited independently from cystic fibrosis transmembrane conductance regulator could modulate the clinical expression of cystic fibrosis. METHODS: We analysed some putative modifier genes of liver cystic fibrosis phenotype (serpin 1, hemochromatosis, transferrin receptor 2, ferroportin 1, mannose binding lectin and adenosine triphospate-binding cassette subfamily B member 4) in 108 unrelated cystic fibrosis patients with and without liver involvement. RESULTS: HYPD mannose binding lectin haplotype was significantly (p<0.05) more frequent in cystic fibrosis patients with liver disease versus those without liver disease. This haplotype already related to a more severe pulmonary cystic fibrosis phenotype, is associated to a reduced MBL immunological activity. The c.834-66G>T variant of adenosine triphospate-binding cassette subfamily B member 4 gene was significantly (p<0.05) less frequent in cystic fibrosis patients with liver disease as compared to those with no liver disease. CONCLUSIONS: The HYPD mannose binding lectin haplotype may predispose a subgroup of cystic fibrosis patients to a more severe liver involvement impairing the local defence mechanisms whereas the c.834-66G>T adenosine triphospate-binding cassette subfamily B member 4 variant may enhance the activity of the protein and thus exert a protective effect toward liver disease.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Fibrose Cística/genética , Hepatopatias/genética , Lectina de Ligação a Manose/genética , Adolescente , Adulto , Fibrose Cística/complicações , Feminino , Haplótipos , Humanos , Hepatopatias/complicações , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
BACKGROUND: A new automated immunoassay low-mid volume (< or = 250 immunoassays/day) chemiluminescent analyzer, Abbott Architect i1000sR, was evaluated by seven laboratories around the world (4 in Europe, one each in Canada, Japan, and the U.S.A.) to demonstrate equivalent performance for key operating characteristics (e.g., precision, turn around time, limit of detection, functional sensitivity, and linearity). METHODS: The laboratories followed standard protocols to assess precision, limit of detection (LoD), functional sensitivity, assay linearity, method comparison, and sample carryover. Turn around time for three stat assays (beta-hCG, BNP, and CK-MB) and the time required to complete workloads of 50 and 100 tests with a mixture of 75% routine tests and 25% stat tests was also evaluated. RESULTS: Total precision was typically < 5% CV for nine immunoassays. Analytical performance met design goals and demonstrated equivalency to package insert data for assays on market and in use for an existing high volume immunoassay system. Stat turn around times were consistent with the fixed analytical time of 15.6 minutes and met the expectations of the laboratories. Measured test throughput ranged from 47 - 54 tests per hour and demonstrated that the analyzer was fit for the intended purpose of supporting a laboratory that performs < or = 250 immunoassays per day. CONCLUSIONS: A multisite, international analyzer familiarization study is a practical means of confirming that a new instrument meets both a manufacturer's design specifications and users' real world expectations and provides a pragmatic test for the system. The experience of investigators at seven sites around the world indicates that a new fully automated chemiluminescent system is suitable for use.
Assuntos
Imunoensaio/instrumentação , Medições Luminescentes/instrumentação , Gonadotropina Coriônica Humana Subunidade beta/sangue , Creatina Quinase Forma MB/sangue , Estradiol/sangue , Humanos , Imunoensaio/métodos , Medições Luminescentes/métodos , Peptídeo Natriurético Encefálico/sangue , Curva ROC , Reprodutibilidade dos TestesRESUMO
Human cytomegalovirus (CMV) infection is common in most people but nearly asymptomatic in immunocompetent individuals. After primary infection the virus persists throughout life in a latent form in a variety of tissues, particularly in precursor cells of the monocytic lineage. CMV reinfection and occurrence of disease are associated with immunosuppressive conditions. Solid organ and bone marrow transplant patients are at high risk for CMV disease as they undergo immunosuppression. Antiviral treatment is effective in controlling viremia, but 10-15 percent of infected patients can experience CMV disease by the time the drug is withdrawn. In addition, long-term antiviral treatment leads to bone marrow ablation and renal toxicity. Furthermore, control of chronic CMV infection in transplant recipients appears to be dependent on the proper recovery of cellular immunity. Recent advances in the characterization of T-cell functions and identification of distinct functional signatures of T-cell viral responses have opened new perspectives for monitoring transplant individuals at risk of developing CMV disease.
Assuntos
Humanos , Transplante de Medula Óssea/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Hospedeiro Imunocomprometido/imunologia , Linfócitos T/imunologia , Antivirais/uso terapêutico , Doença Crônica , Citocinas/análise , Infecções por Citomegalovirus/tratamento farmacológico , Citomegalovirus/fisiologia , Citometria de Fluxo , Imunidade Celular , Memória Imunológica , Fatores de Risco , Replicação Viral , Ativação Viral/imunologiaRESUMO
Human cytomegalovirus (CMV) infection is common in most people but nearly asymptomatic in immunocompetent individuals. After primary infection the virus persists throughout life in a latent form in a variety of tissues, particularly in precursor cells of the monocytic lineage. CMV reinfection and occurrence of disease are associated with immunosuppressive conditions. Solid organ and bone marrow transplant patients are at high risk for CMV disease as they undergo immunosuppression. Antiviral treatment is effective in controlling viremia, but 10-15% of infected patients can experience CMV disease by the time the drug is withdrawn. In addition, long-term antiviral treatment leads to bone marrow ablation and renal toxicity. Furthermore, control of chronic CMV infection in transplant recipients appears to be dependent on the proper recovery of cellular immunity. Recent advances in the characterization of T-cell functions and identification of distinct functional signatures of T-cell viral responses have opened new perspectives for monitoring transplant individuals at risk of developing CMV disease.
Assuntos
Transplante de Medula Óssea/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Hospedeiro Imunocomprometido/imunologia , Linfócitos T/imunologia , Antivirais/uso terapêutico , Doença Crônica , Citocinas/análise , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/tratamento farmacológico , Citometria de Fluxo , Humanos , Imunidade Celular , Memória Imunológica , Fatores de Risco , Ativação Viral/imunologia , Replicação ViralRESUMO
The use of the hallucinogenic brew ayahuasca, obtained from infusing the shredded stalk of the malpighiaceous plant Banisteriopsis caapi with the leaves of other plants such as Psychotria viridis, is growing in urban centers of Europe, South and North America in the last several decades. Despite this diffusion, little is known about its effects on emotional states. The present study investigated the effects of ayahuasca on psychometric measures of anxiety, panic-like and hopelessness in members of the Santo Daime, an ayahuasca-using religion. Standard questionnaires were used to evaluate state-anxiety (STAI-state), trait-anxiety (STAI-trait), panic-like (ASI-R) and hopelessness (BHS) in participants that ingested ayahuasca for at least 10 consecutive years. The study was done in the Santo Daime church, where the questionnaires were administered 1h after the ingestion of the brew, in a double-blind, placebo-controlled procedure. While under the acute effects of ayahuasca, participants scored lower on the scales for panic and hopelessness related states. Ayahuasca ingestion did not modify state- or trait-anxiety. The results are discussed in terms of the possible use of ayahuasca in alleviating signs of hopelessness and panic-like related symptoms.
Assuntos
Ansiedade/tratamento farmacológico , Banisteriopsis/química , Transtorno Depressivo/tratamento farmacológico , Pânico/efeitos dos fármacos , Extratos Vegetais/farmacologia , Adulto , Ansiedade/psicologia , Bebidas , Brasil , Transtorno Depressivo/psicologia , Método Duplo-Cego , Feminino , Frutas/química , Harmalina/administração & dosagem , Harmalina/química , Harmalina/farmacologia , Harmina/administração & dosagem , Harmina/análogos & derivados , Harmina/química , Harmina/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , N,N-Dimetiltriptamina/administração & dosagem , N,N-Dimetiltriptamina/química , N,N-Dimetiltriptamina/farmacologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Folhas de Planta/química , Psicometria/métodos , Religião , Inquéritos e Questionários , Resultado do TratamentoRESUMO
The effect of the non-selective 5-HT2C receptor agonist trifluoromethyl-phenylpiperazine (TFMPP, 0.75, 1.5 and 3.0 microg) and the preferential 5-HT2C agonist 6-chloro-2(1-piperazinyl)pyrazine (MK-212, 0.1, 0.3 and 1.0 microg) microinjected into the ventral or dorsal hippocampus was investigated in anxiety measures of rats exposed to the elevated plus-maze test. Ventral hippocampal (VH) microinjections of the 0.75 or 1.5 microg doses of TFMPP reduced open-arm exploration without affecting the number of closed-arm entries, indicating a selective anxiogenic profile. The highest dose (3.0 microg) reduced open- and closed-arm entries, suggesting interference in locomotor activity. The 0.1 microg dose of MK-212 also caused a selective anxiogenic effect when microinjected into the ventral hippocampus, without disturbing locomotor activity. Microinjections of the two higher doses of MK-212 (0.3 or 1.0 microg) into the ventral hippocampus led to a decrease of exploration in both arms of the maze. In contrast to the anxiogenic effect observed in the VH, neither TFMPP nor MK-212 significantly changed anxiety measures when microinjected into the dorsal hippocampus. These results suggest that activation of 5-HT2C postsynaptic receptors located in the ventral, but not in the dorsal, hippocampus play an important role in anxiety triggered by the elevated plus-maze test.
Assuntos
Nível de Alerta/efeitos dos fármacos , Medo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Piperazinas/farmacologia , Pirazinas/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Animais , Mapeamento Encefálico , Relação Dose-Resposta a Droga , Masculino , Microinjeções , Ratos , Ratos WistarRESUMO
Deep layers of the superior colliculus (DLSC), the dorsal and ventral periaqueductal gray matter (PAG), and inferior colliculus (IC) are midbrain structures involved in the generation of defensive behavior. beta-Endorphin and Leu-enkephalin are some neurotransmitters that may modulate such behavior in mammals. Light microscopy immunocytochemistry with streptavidin method was used for the localization of the putative cells of defensive behavior with antibodies for endogenous opioids in rat brainstem. Midbrain structures showed positive neurons to beta-endorphin and Leu-enkephalin in similar distributions in the experimental animals, but we also noted the presence of varicose fibers positive to endogenous opioids in the PAG. Neuroanatomical techniques showed varicose fibers from the central nucleus of the inferior colliculus to ventral aspects of the PAG, at more caudal levels. Naloxonazine and nor-binaltorphimine, competitive antagonists that block mu(1)- and kappa-opioid receptors, were then used in the present work to investigate the involvement of opioid peptide neural system in the control of the fear-induced reactions evoked by electrical stimulation of the neural substrates of the inferior colliculus. The fear-like responses were measured by electrical stimulation of the central nucleus of the inferior colliculus, eliciting the escape behavior, which is characterized by vigorous running and jumping. Central administration of opioid antagonists (2.5 microg/0.2 microl and 5.0 microg/0.2 microl) was performed in non-anesthetized animals (Rattus norvegicus), and the behavioral manifestations of fear were registered after 10 min, 2 h, and 24 h of the pretreatment. Naloxonazine caused an increase of the defensive threshold, as compared to control, suggesting an antiaversive effect of the antagonism on mu(1)-opioid receptor. This finding was corroborated with central administration of nor-binaltorphimine, which also induced a decrease of the fear-like responses evoked by electrical stimulation of the inferior colliculus, since the threshold of the escape behavior was increased 2 and 24 h after the blockade of kappa-opioid receptor. These results indicate that endogenous opioids may be involved in the modulation of fear in the central nucleus of the inferior colliculus. Although the acute treatment (after 10 min) of both naloxonazine and nor-binaltorphimine causes nonspecific effect on opioid receptors, we must consider the involvement of mu(1)- and kappa-opioid receptors in the antiaversive influence of the opioidergic interneurons in the dorsal mesencephalon, at caudal level, after chronic (2-24 h) treatment of these opioid antagonists. The neuroanatomical study of the connections between the central nucleus of the inferior colliculus and the periaqueductal gray matter showed neuronal fibers with varicosities and with terminal bottons, both in the pericentral nucleus of the inferior colliculus and in ventral and dorsal parts of caudal aspects of the periaqueductal gray matter.
Assuntos
Biotina/análogos & derivados , Reação de Fuga/fisiologia , Colículos Inferiores/fisiologia , Naloxona/análogos & derivados , Naltrexona/análogos & derivados , Vias Neurais/fisiologia , Peptídeos Opioides/metabolismo , Substância Cinzenta Periaquedutal/fisiologia , Animais , Biotina/farmacologia , Dextranos/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Reação de Fuga/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/fisiologia , Colículos Inferiores/efeitos dos fármacos , Masculino , Naloxona/farmacologia , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Vias Neurais/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Terminações Pré-Sinápticas/ultraestrutura , Ratos , Ratos Wistar , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/metabolismoRESUMO
Mesenteric cysts are rare lesions, with 1 case per 100,000 hospital admission reported. They have to be differentiated from ovarian cysts, gastrointestinal duplications and desmoid cysts. The symptoms are variable, ranging from asymptomatic cases with incidental discovery to chronic abdominal discomfort and acute abdomen. They are usually correlated to the location and the size of the lesion. Abdominal ultrasonography and computed tomography may lead to a correct diagnosis, which is regularly made at the time of abdominal exploration. Surgery is the treatment of choice, consisting with the removal of the cyst, eventually associated with bowel resection. It has to be radical in order to prevent the recurrence of the disease. A case of mesenteric cyst in a sixty-nine-years-old woman hospitalized for chronic abdominal pain is reported. In this case the cyst has been enucleated from the mesentery with open surgery without the need for bowel resection.
Assuntos
Cisto Mesentérico , Idoso , Feminino , Seguimentos , Humanos , Cisto Mesentérico/diagnóstico , Cisto Mesentérico/diagnóstico por imagem , Cisto Mesentérico/cirurgia , Radiografia Abdominal , Fatores de Tempo , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND AND OBJECTIVES: Low count of total and T helper lymphocytes predicts a poor prognosis in cancer patients and surgical trauma can worsen cancer-related immunodeficiency. Aim of this phase IB study is to verify toxicity and biological effects of interleukin-2 (IL-2) at 9 million IU/day subcutaneously (sc.) administered one, two or three preoperative days in patients with gastric cancer undergoing radical surgery. METHODS: Absolute value of total and T-helper (CD4) lymphocytes were measured at baseline and at 7th, 14th, and 50th postoperative days in 12 gastric cancer patients, who preoperatively received IL-2 at 9 million IU/day sc. as follows: group A (4 pts) 1-day; group B (4 pts) 2-days; group C (4 pts) 3-days administration. T and total lymphocytes count were recorded and retrospectively analyzed in a historical control-group of 22 consecutive patients, age and stage-matched. RESULTS: Toxicity consisted of fever grade I. In group A (1 day) T helper lymphocytes count decreased at 7th and at 14th postoperative day; in group B (2 days) and group C (3 days) no decrease of neither total nor T helper lymphocyte count occurred postoperatively, whereas in the historical group these parameters decreased significantly postoperatively and recovered only at 50th day. CONCLUSIONS: Two- and three-day schedules of sc. IL-2 preoperative administration at 9 million IU/daily prevented postoperative lymphocytopenia, whereas one-day administration did not. Since the IL-2 dose was so tolerable, that it could be given safely as outpatient, based on the previous results on survival observed in colorectal cancer patients with 3-days schedule we suggest that a 3-day schedule of Interleukin-2 as outpatient preoperative treatment seems advisable for further studies in gastric cancer patients.
Assuntos
Adenocarcinoma/cirurgia , Síndromes de Imunodeficiência/prevenção & controle , Interleucina-2/administração & dosagem , Cuidados Pré-Operatórios , Neoplasias Gástricas/cirurgia , Adenocarcinoma/complicações , Adulto , Idoso , Contagem de Linfócito CD4 , Esquema de Medicação , Feminino , Gastrectomia , Humanos , Síndromes de Imunodeficiência/etiologia , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/complicações , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
BACKGROUND: Gallbladder cancer (GC) is reported in 1.5-3% of cholecystectomies. Since the introduction of laparoscopic surgery, cholecystectomies have increased and occult GC may therefore be more frequent. METHODS: Here we conduct a retrospective study on a series of 1200 LC performed between January 1991 and December 1998 at our Institution, to determine whether there was an increase in GC. We also evaluated the risk factors for this outcome and the possibilities of treatment, in case of unsuspected GC discovered after LC at histological examination. Seven cases of GC undiagnosed before surgery (0.6% of the study population) were submitted to LC (against 0.3% GC discovered after open surgery). The clinical course depended on the histopathologic stage of the cancer. RESULTS: After a median follow-up of 18 months (range 12-48), 2 pT1 patients were alive and well, 2 pT2 patients were alive and disease free (in 1 case after a surgical removal of a trocar site metastasis appeared 6 months after LC). The other 3 patients died, 2 (1 pT2 and 1 pT3) after an additional resection of the liver bed with lymph node dissection, due to peritoneal dissemination of the disease. In 2 cases we found a gallbladder polyp pre and intraoperatively, which proved to be a carcinoma. CONCLUSIONS: Undiagnosed GC is on the increase with the introduction of LC. Polypoid lesions of the gallbladder, age > 70 years: a long history of stones and a thickened gallbladder wall all represent significant risk factors. If one or more is present, examination of the gallbladder and a frozen section are recommended.
Assuntos
Adenocarcinoma/cirurgia , Colecistectomia Laparoscópica , Neoplasias da Vesícula Biliar/cirurgia , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Colecistite/diagnóstico , Colecistite/cirurgia , Colelitíase/diagnóstico , Colelitíase/cirurgia , Diagnóstico Diferencial , Feminino , Seguimentos , Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores de TempoRESUMO
To obtain different cell populations at specific cell cycle stages, we used a cell culture synchronization protocol. Effects of five different cell cycle inhibitors acting throughout the cell cycle were examined by DNA flow cytometric analysis of a synchrony/release lymphoma cell line (CEM). The screening synchronized protocol showed that staurosporine, mimosine and aphidicolin are reversible G1 phase inhibitors that act at different times. Staurosporine acted in early G1, exhibited the strongest cytotoxic effect, and induced apoptosis. Mimosine and aphidicolin acted in late G1 and at the G1/S boundary, respectively. Hydroxyurea arrested CEM cells in early S phase, but later than the aphidicolin arrest point. Nocodazole synchronized CEM cells in M phase. All the inhibitors examined in this study can be used to synchronize cells at different phases of the cell cycle and were reversible with little toxicity except for staurosporine which is highly toxic. Because the regulatory mechanism of the cell cycle is disrupted by their effects on protein synthesis, however, these drugs must be used with caution.