RESUMO
BACKGROUND: Prader-Willi syndrome (PWS), a genetically determined disorder, the most frequent cause of early onset obesity, is associated with physical and cognitive dysfunctions and behavioural disturbances; these disturbances are frequently treated with psychotropic medication. The aim of this cross-sectional study was to describe the characteristics of the first large national sample of persons with PWS in Spain and analyse the relationships of those characteristics with key demographic and clinical factors, particularly with obesity and the regular use of psychotropic medication. METHODS: Participants were recruited among all members of the Spanish Prader-Willi Association who agreed to take part in the study and fulfilled its inclusion criteria. Family and patient demographic features, family size and birth order, intelligence quotient (IQ), anthropometric measures, lifestyle habits, behavioural disturbances (with the Aberrant Behavior Checklist) and clinical data, as well as use of psychotropic drugs and their side effects (with the UKU scale), were collected in genetically confirmed cases of PWS. Bivariate and logistic regression analyses were used for determining the associations of demographic and clinical factors with both obesity and the regular use of psychotropic medication. RESULTS: The cohort included 177 participants (aged 6-48 years), that is, 90 (50.8%) males and 87 (49.2%) females. Behavioural disturbances were present in a range of 75% to 93% of participants; psychotropic medication was prescribed to 81 (45.8%) of them. Number of siblings showed a direct correlation with IQ, especially among males, and inappropriate speech was more intense in only-child females. Obesity was, in parallel, strongly associated with ascending age and with not being currently under growth hormone (GH) treatment. Participants taking any psychotropic medication were characterised by more frequent age ≥30 years, high level of hyperactivity and a psychiatric diagnosis. CONCLUSIONS: Characterisation of persons with PWS in Spain confirms their physical and behavioural phenotype and supports the long-term application of GH therapy and the rational use of psychotropic medication.
Assuntos
Síndrome de Prader-Willi , Masculino , Feminino , Humanos , Síndrome de Prader-Willi/complicações , Espanha , Estudos Transversais , Obesidade/complicações , Psicotrópicos/uso terapêuticoRESUMO
Functionalized ZnAl layered double hydroxide based photocatalyst was obtained by the addition of sodium dodecyl sulfate (SDS) during the synthesis by the coprecipitation method, and further calcination at 400 °C. Bare and modified materials were characterized by X-ray diffraction, nitrogen adsorption-desorption, IR, UV-Vis, EPR and XPS spectroscopies, SEM and HRTEM. The synthesized material was evaluated in the photodegradation of phenol in a 40 ppm aqueous solution (4.25 × 10-4 mol of phenol/L), under UV light irradiation. An increasing in the degradation of phenol from 62 to 95%, and from 62 to 82% in the mineralization of phenol was obtained using SDS functionalized ZnAl LDH, in comparison with the unmodified material. This increase could be attributed to the presence of sulfate radicals, confirmed by the EPR study.
Assuntos
Poluentes Químicos da Água , Purificação da Água , Adsorção , Hidróxidos , FotóliseRESUMO
Facioscapulohumeral muscular dystrophy (FSHD) is caused by the loss of repression at the D4Z4 locus leading to aberrant double homeobox 4 (DUX4) expression in skeletal muscle. Activation of this early embryonic transcription factor results in the expression of its target genes causing muscle fiber death. Although progress toward understanding the signals driving DUX4 expression has been made, the factors and pathways involved in the transcriptional activation of this gene remain largely unknown. Here, we describe the identification and characterization of p38α as a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent, and specific inhibitors of p38α/ß, we show a robust reduction of DUX4 expression, activity, and cell death across patient-derived FSHD1 and FSHD2 lines. RNA-seq profiling reveals that a small number of genes are differentially expressed upon p38α/ß inhibition, the vast majority of which are DUX4 target genes. Our results reveal a novel and apparently critical role for p38α in the aberrant activation of DUX4 in FSHD and support the potential of p38α/ß inhibitors as effective therapeutics to treat FSHD at its root cause. SIGNIFICANCE STATEMENT: Using patient-derived facioscapulohumeral muscular dystrophy (FSHD) myotubes, we characterize the pharmacological relationships between p38α/ß inhibition, double homeobox 4 (DUX4) expression, its downstream transcriptional program, and muscle cell death. p38α/ß inhibition results in potent and specific DUX4 downregulation across multiple genotypes without significant effects in the process of myogenesis in vitro. These findings highlight the potential of p38α/ß inhibitors for the treatment of FSHD, a condition that today has no approved therapies.
Assuntos
Proteínas de Homeodomínio/metabolismo , Distrofia Muscular Facioescapuloumeral/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Morte Celular/fisiologia , Linhagem Celular , Regulação da Expressão Gênica/fisiologia , Humanos , Células Musculares/metabolismo , Músculo Esquelético/metabolismoRESUMO
Efficacy and toxicity of anthracycline treatment in acute myeloid leukemia (AML) is mediated by reactive oxygen species (ROS). NADPH oxidase is the major endogenous source of ROS and a key mediator of oxidative cardiac damage. The impact of NADPH oxidase polymorphisms (CYBA:rs4673, NCF4:rs1883112, RAC2:rs13058338) was evaluated in 225 adult de novo AML patients. Variant alleles of NCF4 and RAC2 were related to higher complete remission (P=0.035, P=0.016), and CYBA homozygous variant showed lower overall survival with recessive model (P=0.045). Anthracycline-induced cardiotoxicity was associated to NCF4 homozygous variant (P=0.012) and CYBA heterozygous genotype (P=0.027). Novel associations were found between variant allele of CYBA and lower lung and gastrointestinal toxicities, and a protective effect in nephrotoxicity and RAC2 homozygous variant. Moreover, RAC2 homozygous variant was related to delayed thrombocytopenia recovery. This study supports the interest of NADPH oxidase polymorphisms regarding efficacy and toxicity of AML induction therapy, in a coherent integrated manner.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia de Indução/métodos , Leucemia Mieloide Aguda/genética , NADPH Oxidases/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Indução de Remissão/métodos , Estudos Retrospectivos , Proteínas rac de Ligação ao GTP/genética , Proteína RAC2 de Ligação ao GTPRESUMO
It is well accepted that the presence of cytokines belonging to the Th1/Th17/Th22 axis of immuno-inflammatory response in the joint environment, such as IL-1ß, IL-17 and IL-22, respectively, are associated with pathogenesis of several synovial joint degenerative disorders. During temporomandibular joint osteoarthritis (TMJ-OA), IL-1ß and IL-17 have been implicated in the inflammation and resorption of sub-chondral bone; however, the role of Th22 response in the TMJ-OA pathophysiology has not been established. This study aimed to compare the expression of Th1/Th17/Th22-type cytokines, chemokines and chemokine receptors in synovial fluid samples obtained from TMJ-OA or disk displacement with reduction (DDWR) patients. In addition, it aimed to associate these levels with joint pain, imagenological signs of bone degeneration, RANKL production, osteoclastogenesis and osteoclast-induced bone resorption. Higher levels of IL-1ß, IL-17 and IL-22 were expressed in TMJ-OA compared with DDWR subjects, and these increased levels significantly correlated with RANKL expression, joint pain and articular bone degeneration. Higher levels of CCR5, CCR6 and CCR7, as well as their respective ligands CCL5 and CCL20, responsible for recruitment of IL-1ß, IL-17 and IL-22-producing cells, were over-expressed in TMJ-OA compared with DDWR subjects. Osteoclastogenesis and osteoclast-induced bone resorption were significantly greater in presence of synovial fluid from TMJ-OA compared with DDWR subjects. These data demonstrate that cytokines, CCLs and CCRs associated with the Th1/Th17/Th22 axis of immuno-inflammatory response are involved in TMJ-OA pathogenesis. These findings suggest that IL-22 is involved in the RANKL expression in TMJ-OA, which in turn induces differentiation of osteoclasts and subsequent resorption of sub-chondral bone.
Assuntos
Osteoartrite/imunologia , Osteoclastos/metabolismo , Ligante RANK/metabolismo , Líquido Sinovial/citologia , Linfócitos T Auxiliares-Indutores/metabolismo , Transtornos da Articulação Temporomandibular/imunologia , Articulação Temporomandibular/patologia , Adulto , Idoso , Reabsorção Óssea , Diferenciação Celular , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/fisiopatologia , Subpopulações de Linfócitos T , Transtornos da Articulação Temporomandibular/fisiopatologia , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: Two new T-helper (Th) phenotypes have been recently described and named Th9 and Th22 lymphocytes; however, their role in the pathogenesis of periodontitis remains unclear. This study was aimed to assess whether Th9 and Th22 lymphocytes, through interleukin (IL)-9 and IL-22 production, respectively, are associated with the severity of periodontitis and bone resorption. MATERIAL AND METHODS: Gingival crevicular fluid samples and biopsies were obtained from patients with moderate-to-advanced chronic periodontitis and gingivitis, and healthy controls. The levels for the Th9 and Th22-associated cytokines and master-switch transcription factors Spi-B and aryl hydrocarbon receptor (AhR) were quantified by enzyme-linked immunosorbent assay, real-time reverse-transcription quantitative polymerase chain reaction and flow cytometry. In addition, the osteoclast activity in response to tissue homogenates from periodontitis and healthy samples was analyzed quantifying the number of TRAP-positive cells and areas of bone resorption pits produced, in the presence or absence of recombinant human IL-22 and anti-IL-22 neutralization antibody. RESULTS: Higher levels of IL-22 and AhR were detected in patients with periodontitis compared with gingivitis and healthy individuals. In addition, higher levels of IL-9 and Spi-B were detected in gingivitis patients compared with periodontitis and healthy individuals. In patients with periodontitis, a significant positive correlation was detected between secreted levels of IL-22 and clinical attachment level of the sampled periodontal pockets. When osteoclasts were exposed to tissue homogenates obtained from patients with periodontitis, higher levels of resorptive activity were observed as compared with the same cells exposed to tissue homogenates obtained from healthy individuals, and this increment was dependent on the presence and neutralization of IL-22. CONCLUSION: Increased levels of IL-22 produced by Th22 lymphocytes are associated with the pathogenesis of periodontitis, in particular, with osteoclast resorptive activity and severity of disease.
Assuntos
Periodontite Crônica/imunologia , Citocinas/metabolismo , Líquido do Sulco Gengival/química , Interleucinas/metabolismo , Osteoclastos/imunologia , Osteoclastos/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Adulto , Periodontite Crônica/patologia , Citocinas/análise , Citocinas/genética , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/metabolismo , Feminino , Expressão Gênica , Gengivite/imunologia , Gengivite/patologia , Humanos , Interleucina-9/análise , Interleucina-9/metabolismo , Interleucinas/análise , Masculino , Perda da Inserção Periodontal , Bolsa Periodontal/imunologia , RNA/isolamento & purificação , RNA Ribossômico 18S/análise , Receptores de Hidrocarboneto Arílico/análise , Fatores de Transcrição/análise , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Interleucina 22RESUMO
Single nucleotide polymorphisms (SNPs) carried in calpain (CAPN1), calpastatin (CAST), and leptin (LEP) genes are associated with meat tenderness. Due to the economic importance of this meat quality attribute, the development of fast, reliable, and affordable methods to identify bovine carriers of favorable alleles is of great importance for genetic improvement. Currently, PCR-RFLP is accepted as the standard gold method for genotyping SNPs associated with meat tenderness. But these SNPs can be detected by other techniques as high-resolution melting (HRM) analysis - a post-PCR method - that offers several advantages and has great application potential in the meat industry. In this study, we standardized, validated, and compared the performance of PCR-HRM to that of PCR-RFLP in genotyping bovine SNPs associated with meat tenderness: CAPN4751, CAPN316, CAST2959, CAST282, LEPE2FB, and LEPE2JW. We analyzed genotypes of a total of 380 bovines, 110 Bos taurus and 270 Bos indicus. Results obtained with PCR-HRM were consistent with those found by PCR-RLFP. Furthermore, HRM was found to be highly sensitive, and our results confirmed the repeatability (intra-assay precision) and reproducibility (inter-assay precision) of this assay. An internal control for endonuclease activity was created using site-directed mutagenesis to generate an additional enzymatic restriction point useful to discriminate SNP alleles. Our results show that PCR-HRM is an efficient method that produces reliable and rapid results. However, should be had in account that the method of DNA extraction, the quality and quantity of DNA, analyst-related variations, and primer design may generate challenges for allele discrimination.
Assuntos
Bovinos/genética , Técnicas de Genotipagem/métodos , Carne/normas , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Nucleotídeo Único , Animais , Proteínas de Ligação ao Cálcio/genética , Calpaína/genética , Técnicas de Genotipagem/normas , Leptina/genética , Reação em Cadeia da Polimerase/normasRESUMO
The polymorphism rs16754 of the WT1 gene has been described as a possible prognostic marker in different acute myeloid leukemia (AML) cohorts; however, it is not supported by all the studies. We performed the first meta-analysis evaluating the effect of this polymorphism upon the effectiveness of standard AML therapy. Fourteen cohort studies were included (3618 patients). Patients with the variant allele showed a significant higher overall survival (OS) at 5 years (OR:1.24, 95% CI: 1.06-1.45, P=0.007, with dominant model). WT1 did not influence complete remission, but a higher disease-free survival was observed with the variant allele. In the subgroup analysis, Caucasians, pediatric and patients treated with idarubicin and etoposide carrying the variant allele showed consistent results in OS, whereas patients with cytogenetically normal AML did not show differences. To verify the effect of this polymorphism upon other outcomes, studies in larger and multiracial populations are needed.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas WT1/genética , Antraciclinas/administração & dosagem , Estudos de Coortes , Citarabina/administração & dosagem , Etoposídeo/administração & dosagem , Estudos de Associação Genética , Humanos , Leucemia Mieloide Aguda/genética , Estudos Observacionais como Assunto , Polimorfismo de Nucleotídeo Único , Análise de SobrevidaRESUMO
Host-viral genetic interaction has a key role in hepatitis C infection (HCV) and maybe in the viral selection. In a preliminary GWAS analysis, we identified BTN3A2 rs9104 to be associated with HCV genotype 1. Therefore, our aim was to determine the influence of BTN family on the selection of HCV genotype. We performed a fine-mapping analysis of BTN gene region in a cohort of chronic HCV infection (N=841), validating significant results in another independent chronic HCV infection cohort (N=637), according to selection of viral genotype. BTN3A2 rs9104, BTN3A2 rs733528, BTN2A1 rs6929846, BTN2A1 rs7763910 and BTN3A3 rs13220495 were associated with viral genotype selection. Interestingly, BTN3A2 rs9104 GG genotype was closely related to genotype 1 infection (80.7% (394/488) compared with genotype 3 infection (53.5% (23/43); P=0.0001) in patients harboring IL28B-CT/TT genotype, although this effect was not observed in IL28B-CC genotype. Similarly, BTN3A3 rs13220495 CC genotype was linked to genotype 3 infection (100% (32/32)) compared to genotype 1 (87.3% (137/157); P=0.028) in patients harboring IL28B-CC genotype, but did not in IL28B-CT/TT genotype. Genetic variants in the butyrophilin family genes may alter susceptibility to infection, selecting HCV genotype and influencing disease progression. BTN3A2 rs9104 was strongly associated with genotype 1 infection and the haplotype BTN3A3 rs13220495 CC+IL28B genotype CC was universal in patients with hepatitis C genotype 3a.
Assuntos
Hepatite C/genética , Glicoproteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Seleção Genética , Butirofilinas , Genótipo , Hepacivirus/genética , Hepatite C/virologia , Interações Hospedeiro-Patógeno/genética , Humanos , Família MultigênicaRESUMO
Oncolytic adenoviruses can promote immune responses against tumors by expressing and/or displaying tumor-associated antigens. However, the strong immunodominance of viral antigens mask responses against tumor epitopes. In addition, defects in major histocompatibility complex class I antigen presentation pathway such as the downregulation of the transporter-associated with antigen processing (TAP) are frequently associated with immune evasion of tumor cells. To promote the immunogenicity of exogenous epitopes in the context of an oncolytic adenovirus, we have taken advantage of the ER localization of the viral protein E3-19K. We have inserted tumor-associated epitopes after the N-terminal signal sequence for membrane insertion of this protein and flanked them with linkers cleavable by the protease furin to facilitate their TAP-independent presentation. This strategy allowed an enhanced presentation of the exogenous epitopes in TAP-deficient tumor cells in vitro and the generation of higher specific immune responses in vivo that were able to significantly control tumor growth.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas E3 de Adenovirus/genética , Adenovírus Humanos/genética , Epitopos/genética , Mutagênese Insercional , Neoplasias/terapia , Vírus Oncolíticos/genética , Adenovírus Humanos/metabolismo , Animais , Apresentação de Antígeno , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Camundongos Endogâmicos C57BLRESUMO
The ABCB1 gene encodes for P-glycoprotein (P-gp), an efflux pump for a variety of xenobiotics. The role of ABCB1 polymorphisms in acute myeloid leukemia (AML) outcomes of standard chemotherapy (cytarabine plus anthracyclines) remains controversial. A systematic search was made of studies evaluating the association between ABCB1 polymorphisms 1236C>T, 2677G>T/A and 3435C>T and effectiveness variables. We found seven cohort studies (1241 patients) showing a significantly higher overall survival (OS) among carriers of the variant allele of 1236C>T at year 4 (odds ratio (OR): 1.47, 95% confidence interval (CI): 1.07-2.01), 2677G>T/A at years 4-5 (OR: 1.37, 95% CI: 1.01-1.86) and 3435C>T at years 3 (OR: 1.41, 95% CI: 1.03-1.94) and 4-5 (OR: 1.42, 95% CI: 1.05-1.91). In the subgroup analysis according to ethnicity, Caucasians carrying variant allele showed consistent results in OS. ABCB1 influence upon complete remission could not be demonstrated. Future studies based on larger populations and multiethnic groups should help clarify the effect of P-gp polymorphisms upon other outcomes.
Assuntos
Antraciclinas/uso terapêutico , Citarabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Polimorfismo Genético/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Resultado do Tratamento , Adulto JovemRESUMO
The highly variable pharmacokinetics of tacrolimus can hamper the optimal management of kidney transplant patients. This variability has been attributed to the genetic polymorphism of CYP3A5 6986A>G, but the evidence is not clear. We conducted a meta-analysis of studies evaluating the effect of CYP3A5 polymorphism on kidney transplant recipients with tacrolimus plasma concentration divided by daily dose per body weight (C/D) and clinical outcomes. We searched in MEDLINE and EMBASE. We found evidence suggesting a significantly lower C/D among CYP3A5*1 allele carriers compared with carriers of the CYP3A5*3/*3 genotype at weeks 1 and 2, and months 1, 3, 6 and 12. We demonstrated that the expresser genotype might have higher risk of acute rejection and chronic nephrotoxicity. In conclusion, CYP3A5 6986A>G polymorphism can affect tacrolimus pharmacokinetics and the incidence of acute rejection and chronic nephrotoxicity on kidney transplant recipients. Patients at high risk of developing tacrolimus-related complications could be detected even before their kidney transplant.
Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/uso terapêutico , Transplante de Rim , Tacrolimo/uso terapêutico , Transplantados , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/prevenção & controle , Humanos , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Estudos Observacionais como Assunto/métodosRESUMO
BACKGROUND: To evaluate the immunological situation against hepatitis B virus (HBV) of a cohort of dentistry students, to analyze the behavior of the levels of hepatitis B surface antigen (anti-HBs) after the administration of one or three vaccine doses, and to determine the influence of age and sex on the immune response. MATERIAL AND METHODS: This retrospective cohort study included students attending the School of Dentistry of the institution where the study was performed from 2005 to 2012 who had completed the public health vaccination calendar for HBV at the age of 12-13. Data on age, sex, basal anti-HBs levels, post-vaccination anti-HBs results and final anti-HBs levels were collected. Comparisons of the basal and final levels, as well as associations regarding age and sex, were performed by means of the Student t and Chi-square tests. RESULTS: Of the 359 students, 97 (27.02%) had basal antibody concentrations <10 mIU/ml, whereas in 262 the levels of anti-HBs were ≥10 mIU/ml (72.98%). Of the 288 participating students who completed the School's protocol for immunization, 287 (99.65%) attained a level of protection ≥10 mIU/ml. Globally, there were statistically significant differences between the basal antibody levels and those achieved after administration of the vaccine and booster, but no association with age or sex was observed. CONCLUSIONS: About 70% of dental students vaccinated as pre-adolescents had serologic evidence of protection against HBV. Administering a booster is associated with the presence of an excellent immune memory. There is clearly a need to reinforce control of the antibody levels in groups at risk, such as Dentistry students.
Assuntos
Antígenos de Superfície da Hepatite B/sangue , Vacinas contra Hepatite B , Hepatite B/prevenção & controle , Estudantes de Odontologia , Estudos de Coortes , Feminino , Humanos , Masculino , Estudos Retrospectivos , Espanha , Universidades , Adulto JovemRESUMO
INTRODUCTION: Malnutrition, growth retardation and opportunistic infections outlast the metabolic, immune and gastrointestinal disorders produced by HIV. Zinc deficiency has been associated with deteriorating nutritional status, growth failure, and risk of infection. The aim of this study is to determine the association between zinc levels in peripheral blood mononuclear cells (PBMC) and the nutritional status of HIV-infected and uninfected children exposed to the virus. PATIENTS AND METHODS: An analytical, observational, cross-sectional study was conducted on 17 infected and 17 exposed children, aged 2-10 years. Anthropometric measurements, clinical and nutritional history, 24h recall, measurement of physical activity, and zinc in PBMC by flow cytometry analysis were recorded. RESULTS: Height according to age, energy consumption and adequacy of energy, protein and dietary zinc were significantly higher in children exposed to the virus compared to those infected with HIV (P <.05). No significant differences were found in BMI, levels of zinc in monocytes, CD4 + and CD4- lymphocytes between the two study groups (P >.05). However, the median levels of zinc in monocytes of infected patients was higher (218.6) compared to the control group (217.0). No association was found between zinc intake and levels of intracellular zinc. CONCLUSIONS: The deterioration of nutritional status and growth retardation in children were associated with HIV, but not with the levels of intracellular zinc. The dietary intake of this nutrient was not associated with levels of zinc in monocytes or CD4 + and CD4- lymphocytes.
Assuntos
Infecções por HIV/complicações , Leucócitos Mononucleares/metabolismo , Estado Nutricional , Zinco/metabolismo , Linfócitos T CD4-Positivos , Criança , Pré-Escolar , Estudos Transversais , Citometria de Fluxo , Humanos , Linfócitos/metabolismo , Monócitos/metabolismo , Zinco/administração & dosagemRESUMO
Endovenously administered oncolytic viruses extravasate and penetrate poorly into tumors. iRGD is a cyclic peptide that enhances tumor penetration when conjugated or coadministered with different types of molecules such as drugs, nanoparticles or phages. iRGD-mediated tumor penetration occurs in three steps: binding to αv-integrins on tumor vasculature or tumor cells, exposure by proteolysis of a C-terminal motif that binds to neuropilin-1 (NRP-1) and cell internalization. We have genetically inserted the iRGD peptide in the fiber C terminus of ICOVIR15K, an oncolytic tumor-retargeted adenovirus to increase its tumor penetration. In vitro, NRP-1 interaction improved binding and internalization of the virus in different cancer cells overexpressing integrins and NRP-1. However, such NRP-1-mediated internalization did not affect transduction or cytotoxicity. In vivo, iRGD did not change the normal organ transduction pattern, with liver and spleen as main targeted organs. In tumors, however, iRGD enhanced transduction and early adenovirus dissemination through the tumor mass leading to an improved antitumor efficacy.
Assuntos
Terapia Genética/métodos , Oligopeptídeos/uso terapêutico , Terapia Viral Oncolítica/métodos , Motivos de Aminoácidos , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Feminino , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Neuropilina-1/metabolismo , Internalização do Vírus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The aim of this study was to evaluate whether continuous sexual behavior could attenuate the effects of chronic stress on spermatogenesis, sexual glands, plasma testosterone and corticosterone in sexually experienced male rats. Rats were exposed to stress by immersion in cold water (ICW) daily for 20 or 50 consecutive days. Plasma testosterone and corticosterone, masculine sexual behavior, as well as the number of offspring, the epithelial area of seminiferous, prostatic and seminal glands were assessed. In stressed males, body and testicular weights decreased, male sexual behavior was disrupted, and adrenal weights increased. In males stressed for 50 days, prostate and seminal glands had lower weights compared with controls. Prostate and seminal epithelial areas also decreased in these males. Seminiferous tubules in testes from rats stressed for 20 or 50 days showed several degenerative signs, such as vacuoles in the basal epithelium, with picnotic indicia; moderate to severe exfoliation of degenerative germinal cells in the tubule lumen was also observed. In males stressed for 50 days a significant decrease in seminiferous epithelial area was observed from stages I-VIII, regardless of copulation. The litters from females that copulated with males stressed for 50 days decreased significantly. Chronic stress caused increase in plasma levels of corticosterone, which were higher in males stressed for 20 days than in males stressed for 50 days. Testosterone decreased in stressed males and it was lower in males stressed for 50 days. In stressed males allowed to copulate, body and testicular weights were similar to controls. Adrenal, seminal glands, and prostate weights, as well as epithelial areas of males stressed for 50 days allowed to copulate were also similar to controls. Corticosterone was lower than in males stressed for 50 days, but still higher than in controls. Testosterone in males stressed for 50 days and allowed to copulate was higher than in stressed males not allowed to copulate and control males without copulation, but still lower than in control copulating males. These results show that chronic stress causes germ cell loss in testes and a decrease in prostate and seminal epithelium, possibly as a result of testosterone decrease, affecting fertility. Continuous copulation can attenuate the effects of stress on testosterone levels and on the epithelial area in male sexual glands, but not on the seminiferous epithelium after 50 days of stress.
Assuntos
Glândulas Suprarrenais/patologia , Próstata/patologia , Glândulas Seminais/patologia , Comportamento Sexual Animal/fisiologia , Estresse Psicológico/fisiopatologia , Testículo/patologia , Testosterona/sangue , Animais , Peso Corporal , Doença Crônica , Copulação/fisiologia , Corticosterona/sangue , Feminino , Masculino , Tamanho do Órgão , Ratos , Ratos Wistar , Espermatogênese/fisiologia , Estresse Psicológico/sangue , Estresse Psicológico/patologiaRESUMO
OBJECTIVE: To identify risk factors associated with suicide of patients with schizophrenia and provide clinical recommendations, which integrate research findings into a consensus based on clinical experience and evidence. METHOD: A task force formed of experts and clinicians iteratively developed consensus through serial revisions using the Delphi method. Initial survey items were based on systematic literature review published up to June 2013. RESULTS: Various risk factors were reported to be implicated in suicide in schizophrenia. Our findings indicate that suicide risk in schizophrenia is mainly related to affective symptoms, history of a suicide attempt and number of psychiatric admissions. Other risk factors identified are given by younger age, closeness to illness onset, older age at illness onset, male sex, substance abuse and period during or following psychiatric discharge. Integrating the evidence and the experience of the task force members, a consensus was reached on 14 clinical recommendations. CONCLUSION: Identification of risk factors for suicide in individuals diagnosed with schizophrenia is imperative to improve clinical management and develop strategies to reduce the incidence of suicide in this population. This study provides the critical overview of available data and clinical recommendations on recognition and management of the above-mentioned risk factors.
Assuntos
Sintomas Afetivos/epidemiologia , Hospitalização/estatística & dados numéricos , Esquizofrenia/epidemiologia , Psicologia do Esquizofrênico , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Tentativa de Suicídio/estatística & dados numéricos , Suicídio/estatística & dados numéricos , Comitês Consultivos , Sintomas Afetivos/psicologia , Fatores Etários , Técnica Delphi , Feminino , Humanos , Masculino , Guias de Prática Clínica como Assunto , Medição de Risco , Fatores de Risco , Fatores Sexuais , Transtornos Relacionados ao Uso de Substâncias/psicologia , Suicídio/psicologiaRESUMO
INTRODUCTION: Evidence suggests that human toxocariasis (HT) could stimulate the onset of allergic diseases such as asthma. More specifically, in subjects having a hypothetical 'atopic genotype', HT could boost preexistent allergy symptoms. We tested the latter hypothesis in Cuba, a country where both asthma and HT are prevalent. MATERIAL AND METHODS: In a group of Cuban school-aged children (n = 958), we investigated the association of Toxocara seropositivity and atopic status with asthma. Toxocara seropositivity was diagnosed with ELISA and atopy by allergen skin prick test. Both physician-diagnosed asthma and current wheeze, as determined by International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, were considered. Associations were assessed using multivariable logistic regression analyses, with either 'physician-diagnosed asthma' or 'current wheeze' as outcome variable. RESULTS: 40.1% of the children were Toxocara seropositive. Prevalences were 21.7% for current wheeze and 32.7% for physician-diagnosed asthma. The odds of having asthma were almost two times higher in atopic children, but only reached borderline significance (OR=1.90, CI 95%: 0.95-3.80 for physician-diagnosed asthma and OR=1.94, CI 95%: 0.98-3.85 for current wheeze). Toxocara seropositivity and physician-diagnosed asthma were associated (OR=1.51, CI 95%: 1.01-2.26). Moreover, in children without antibodies to Toxocara, being atopic was significantly associated with having physician-diagnosed asthma (OR=2.53, CI 95%: 1.63-3.90), while this association was not present in Toxocara positives (OR=1.38, CI 95%: 0.82-2.37). CONCLUSION: Our data confirm previous observations of higher Toxocara seropositivity rates in asthmatic children. Toxocara seropositivity appeared to abrogate the apparent association between atopy and asthma in Cuban children. Although this observation was limited to physician-diagnosed asthma, it challenges the hypothesis that HT stimulates the onset of allergic diseases such as asthma in atopic individuals.
Assuntos
Anticorpos Anti-Helmínticos/sangue , Asma/imunologia , Hipersensibilidade Imediata/imunologia , Toxocara/imunologia , Toxocaríase/imunologia , Adolescente , Fatores Etários , Alérgenos/imunologia , Animais , Criança , Cuba , Ensaio de Imunoadsorção Enzimática , Humanos , Prevalência , Fatores de Risco , Testes Cutâneos , Inquéritos e Questionários , Toxocara/isolamento & purificaçãoRESUMO
Hybrid speciation represents a relatively rapid form of diversification. Early models of homoploid hybrid speciation suggested that reproductive isolation between the hybrid species and progenitors primarily resulted from karyotypic differences between the species. However, genic incompatibilities and ecological divergence may also be responsible for isolation. Iris nelsonii is an example of a homoploid hybrid species that is likely isolated from its progenitors primarily by strong prezygotic isolation, including habitat divergence, floral isolation and post-pollination prezygotic barriers. Here, we used linkage mapping and quantitative trait locus (QTL) mapping approaches to investigate genomic collinearity and the genetic architecture of floral differences between I. nelsonii and one of its progenitor species I. hexagona. The linkage map produced from this cross is highly collinear with another linkage map produced between I. fulva and I. brevicaulis (the two other species shown to have contributed to the genomic makeup of I. nelsonii), suggesting that karyotypic differences do not contribute substantially to isolation in this homoploid hybrid species. Similar to other studies of the genetic architecture of floral characteristics, at least one QTL was found that explained >20% variance in each color trait, while minor QTLs were detected for each morphological trait. These QTLs will serve as hypotheses for regions under selection by pollinators.
Assuntos
Flores/genética , Ligação Genética , Gênero Iris/genética , Ecossistema , Flores/anatomia & histologia , Genoma de Planta , Locos de Características Quantitativas , Isolamento ReprodutivoRESUMO
The inevitable structural disorder associated with the fluctuation of the applied external electric field, laser intensity, and bidimensional density in the low dimensional quantum system can affect noticeably optical absorption properties and the related phenomena. In this work, we study the effect of structural disorder on the optical absorption properties in delta-doped quantum wells (DDQWs). Starting from effective mass approximation and the Thomas-Fermi approach as well as using the matrix density, the electronic structure and the optical absorption coefficients of DDQWs are determined. It is found that the optical absorption properties depend on the strength and the type of structural disorder. Particularly, the bidimensional density disorder suppresses strongly the optical properties. Whilst, the disordered external applied electric field fluctuates moderately in the properties. In contrast, the disordered laser holds absorption properties unalterable. So, our results specify that to have and preserve good optical absorption properties in DDQWs, requires precise control of the bidimensional. Besides, the finding may improve the understanding of the impact of the disorder on the optoelectronic properties based on DDQWs.