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AIM: The present study looked for variation in the miRNA-24 sequence, and evaluated the associations between the dihydrofolate reductase (DHFR) gene-829 C-T polymorphism and plasma DHFR concentrations with response to methotrexate (MTX) treatment in Mexican patients with rheumatoid arthritis (RA). METHODS: A total of 135 women with RA were classified as responders (disease activity score [DAS28] <3.2) or nonresponders to MTX (DAS28 > 3.2). We determined the genotype of the patients using the polymerase chain reaction-restriction fragment length polymorphism method. Plasma DHFR enzyme levels and mi-RNA24 sequences were assessed by enzyme-linked immunosorbent assay (ELISA) and Sanger sequencing, respectively. Allelic frequencies and the genotypic distribution of the polymorphism were analyzed by the chi-square test. RESULTS: The genotype frequencies of the DHFR -829C-T polymorphism among responders were 37.0% CC, 52.1% CT, and 10.9% TT and for nonresponders were 33.9% CC, 56.4% CT, and 9.7% TT. No significant differences in genotype frequencies were found between the groups (p = 0.88). The DHFR levels relative to genotype for responders were 6.8 ± 2.7, 6.1 ± 2.7, and 6.5 ± 1.5 ng/mL for CC, CT, and TT, respectively, and for nonresponders were 6.5 ± 2.0, 6.1 ± 3.1, and 7.4 ± 1.8 ng/mL for CC, CT, and TT, respectively. No significant differences were found between the two groups. Similarly, both groups showed no sequence variations in miRNA-24 gene. CONCLUSION: The -829C-T polymorphism of DHFR gene was not associated with response to MTX by RA patients, and no variations were found in the miRNA-24 sequence that might modify the response to treatment or DHFR enzyme levels in a Mexican population with RA.
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Artritis Reumatoide/genética , MicroARNs/genética , Tetrahidrofolato Deshidrogenasa/genética , Adulto , Anciano , Alelos , Biomarcadores Farmacológicos/sangre , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Metotrexato/farmacología , Metotrexato/uso terapéutico , México , MicroARNs/fisiología , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Tetrahidrofolato Deshidrogenasa/fisiologíaRESUMEN
Using biomarkers as a guide to tailor the duration of antibiotic treatment in respiratory infections is an attractive hypothesis assessed in several studies. Recent work aiming to summarize the evidence assessed the effect of a procalcitonin (PCT)-guided antibiotic treatment on outcomes in acute lower respiratory tract infections (LRTI), suggesting that significant reductions in antibiotic duration occur when using a PCT-guided algorithm. However, controversial evidence also suggested PCT-guided algorithms were associated with increased antibiotic duration and increased incidence of Clostridium difficile, without any impact on mortality, in real-world settings. So, although using PCT-guided antibiotic stewardship is promising, after more than a decade of randomized controlled trials on this topic the evidence in its favor is still less than compelling due to limitations in trial design, not taking into consideration fundamental aspects of PCT biology, and the absence of evidence-based antimicrobial duration in intervention and control groups. In this commentary we highlight some questions and limitations of primary PCT study data that might impact interpretation and clinical use of PCT at the bedside.
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Antibacterianos/administración & dosificación , Calcitonina/análisis , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Antibacterianos/uso terapéutico , Biomarcadores Farmacológicos/análisis , Biomarcadores Farmacológicos/sangre , Calcitonina/sangre , Humanos , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/mortalidad , Factores de TiempoRESUMEN
BACKGROUND: Classical homocystinuria (HCU) is a monogenic disease caused by the deficient activity of cystathionine ß-synthase (CßS). The objective of this study was to identify the CBS mutations in Brazilian patients with HCU. METHODS: gDNA samples were obtained for 35 patients (30 families) with biochemically confirmed diagnosis of HCU. All exons and exon-intron boundaries of CBS gene were sequenced. Gene expression analysis by qRT-PCR was performed in six patients. Novel missense point mutations were expressed in E. coli by site-directed mutagenesis. RESULTS: Parental consanguinity was reported in 16 families, and pyridoxine responsiveness in five (15%) patients. Among individuals from the same family, all presented the same phenotype. Both pathogenic mutations were identified in 29/30 patients. Twenty-one different mutations were detected in nine exons and three introns; being six common mutations. Most prevalent were p.Ile278Thr (18.2%), p.Trp323Ter (11.3%), p.Thr191Met (11.3%), and c.828+1G>A (11.3%). Eight novel mutations were found [c.2T>C, c.209+1delG, c.284T>C, c.329A>T, c.444delG, c.864_868delGAG c.989_991delAGG, and c.1223+5G>T]. Enzyme activity in E. coli-expressed mutations was 1.5% for c.329A>T and 17.5% for c.284T>C. qRT-PCR analysis revealed reduced gene expression in all evaluated genotypes: [c.209+1delG; c.572C>T]; [c.2T>C; c.828+1G>A]; [c.828+1G>A; c.1126G>A]; [c.833T>C; c.989_991delAGG]; [c.1058C>T; c.146C>T]; and [c.444delG; c.444delG]. The expected phenotype according to the genotype (pyridoxine responsiveness) matched in all cases. CONCLUSIONS: Most patients studied were pyridoxine nonresponsive and presented early manifestations, suggesting severe phenotypes. Many private mutations were observed, but the four most prevalent mutations together accounted for over 50% of mutated alleles. A good genotype-phenotype relationship was observed within families and for the four most common mutations.
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Cistationina betasintasa/genética , Homocistinuria/genética , Piridoxina/genética , Adolescente , Adulto , Alelos , Secuencia de Bases/genética , Biomarcadores Farmacológicos/sangre , Brasil/epidemiología , Niño , Cistationina betasintasa/metabolismo , Exones/genética , Femenino , Expresión Génica/genética , Estudios de Asociación Genética/métodos , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Piridoxina/farmacologíaRESUMEN
Visceral leishmaniasis (VL) is a potentially fatal disease, in which the treatment based on chemotherapy is considered toxic. The cure of disease is associated with the life-long Th1-type immunity against the infection. The Th1-related cytokines production by peripheral blood mononuclear cells (PBMCs) seems to be crucial for host control of parasite load and clinical cure. In the current study, we used five proteins (IgE-dependent histamine-releasing factor [HRF], LiHyD, LiHyV, LiHyT and LiHyp6) recently shown to be antigenic and/or immunogenic in the canine VL, aiming to evaluate the antigen-specific antibody levels and cytokine production in PBMCs culture supernatants collected from VL patients before and after anti-VL treatment. In the results, when PBMCs were exposed to rHRF, rLiHyD and rLiHyT, higher IFN-γ and lower IL-10 levels were observed in all patients that were treated and clinically cured. Analysis of specific antibody subclasses was in line with in vitro cellular response, since a higher IgG2 production was found in the treated and cured patients, when compared to the IgG1 subclass levels. In addition, evaluating the diagnostic efficacy of the recombinant molecules, the rHRF, rLiHyD and rLiHyT proteins showed the best results in the serology assays to identify all VL patients, as well as these antigens were not recognized by antibodies in sera from non-infected subjects or those with leishmaniasis-related diseases. Our results corroborate the view that clinical cure of VL is associated with a sustained Th1-related response, and indicate the potential use of rHRF, rLiHyD and rLiHyT as immune biomarkers of VL treatment.
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Anticuerpos Antiprotozoarios/sangre , Biomarcadores Farmacológicos/sangre , Leishmania infantum/fisiología , Leishmaniasis Visceral/diagnóstico , Leucocitos Mononucleares/inmunología , Células TH1/inmunología , Adulto , Animales , Antígenos de Protozoos/genética , Antígenos de Protozoos/inmunología , Células Cultivadas , Progresión de la Enfermedad , Perros , Femenino , Humanos , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Leishmaniasis Visceral/terapia , Leucocitos Mononucleares/parasitología , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Adulto JovenRESUMEN
This study aimed to investigate the immunogenicity of a cancer vaccine consisting of the NeuGcGM3 ganglioside combined with the outer membrane protein complex of Neisseria meningitides to form very small size particles. The vaccine is administered together with Montanide ISA51, as adjuvant treatment for breast cancer patients. After surgical resection and standard first-line chemo/radiotherapy, breast cancer patients in stage II-III were enrolled in a phase III clinical trial and allocated into 2 strata, according to the number of positive lymph nodes [stratum I (0-3); stratum II (≥4)]. Subsequently, patients were randomly assigned to receive the vaccine or placebo. The treatment consisted of 5 vaccine doses (200 µg) every 2 weeks and thereafter monthly reimmunizations to complete 15 doses. The vaccine was well-tolerated and high titers of immunoglobulin M and immunoglobulin G anti-NeuGcGM3 antibodies were similarly detected in each stratum. Hyperimmune sera were able to specifically recognize and kill the NeuGcGM3-expressing L1210 tumor cell line, and these functional capacities were significantly associated with a better clinical outcome in patients of stratum II. Besides, postimmune sera had the capacity to revert in vitro the immunosuppression induced by NeuGcGM3, as measured by the prevention of CD4 downmodulation on human T lymphocytes. Vaccination had no impact on the frequency of regulatory T cells or circulating NK cells. This study demonstrated, for the first time, the immunogenicity of the NeuGcGM3/VSSP/Montanide ISA 51 vaccine in the adjuvant setting and describes the functionality of induced anti-NeuGcGM3 antibodies as potential surrogate biomarkers of clinical benefit.
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Proteínas de la Membrana Bacteriana Externa/genética , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/inmunología , Gangliósido G(M3)/análogos & derivados , Neisseria meningitidis/genética , Adyuvantes Inmunológicos/administración & dosificación , Anticuerpos/sangre , Apoptosis , Biomarcadores Farmacológicos/sangre , Neoplasias de la Mama/inmunología , Vacunas contra el Cáncer/genética , Línea Celular Tumoral , Femenino , Gangliósido G(M3)/genética , Humanos , Inmunidad Humoral , Manitol/administración & dosificación , Manitol/análogos & derivados , Persona de Mediana Edad , Neisseria meningitidis/metabolismo , Estadificación de Neoplasias , Ácidos Oléicos/administración & dosificación , Resultado del TratamientoRESUMEN
In this study, strategies for serum biomarker assessment were developed for therapeutic monitoring of HCV patients. For this purpose, serum chemokine/cytokine levels were measured by cytometric-bead-array in HCV patients, categorized according to immunotherapy response as: non-responder/NR, relapser/REL and sustained-virologic-responder/SVR. The results demonstrated an overall increase of serum chemokine/cytokine levels in HCV patients. In general, therapeutic failure was associated with presence of a predominant baseline proinflammatory pattern with enhanced CCL5/RANTES, IFN-α, IFN-γ along with decreased IL-10 levels in NR and increased IL-6 and TNF in REL. SVR displayed lower baseline proinflammatory status with decreased CXCL8/IL-8, IL-12 and IL-17 levels. The inability to uphold IFN-α levels during immunotherapy was characteristic of NR. Serum chemokine/cytokine signatures further support the deleterious effect of proinflammatory baseline status and the critical role of increased/persistent IFN-α levels to guarantee the sustained virologic response. The prominent baseline proinflammatory milieu observed in NR and REL yielded a restricted biomarker network with small number of neighborhood connections, whereas SVR displayed a network with integrated cytokine connectivity. Noteworthy was that SVR presented a shift towards a proinflammatory pattern upon immunotherapy, assuming a pattern similar to that observed in NR and REL at baseline. Moreover, the immunotherapy guided REL towards a profile similar to SVR at baseline. Analysis of baseline-fold changes during treatment pointed out IFN-α and TNF as high-performance biomarkers to monitor immunotherapy outcome. This knowledge may contribute for novel insights into the treatment and control of the continuous public health threat posed by HCV infection worldwide.
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Antivirales/uso terapéutico , Quimiocinas/sangre , Citocinas/sangre , Monitoreo de Drogas/métodos , Hepatitis C Crónica/terapia , Adulto , Anciano , Biomarcadores Farmacológicos/sangre , Femenino , Hepatitis C Crónica/sangre , Humanos , Inmunoterapia , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Interleucina-12/sangre , Interleucina-17/sangre , Interleucina-8/sangre , Masculino , Persona de Mediana Edad , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Carga Viral/efectos de los fármacos , Adulto JovenRESUMEN
Objective. To evaluate the association of -174G/C IL-6 polymorphism with failure in therapeutic response to methotrexate (MTX) or leflunomide (LEF). This prospective, observational cohort included 96 Mexican-Mestizo patients with moderate or severe rheumatoid arthritis (RA), initiating MTX or LEF, genotyped for IL-6 -174G/C polymorphism by PCR-RFLP. Therapeutic response was strictly defined: only if patients achieved remission or low disease activity (DAS-28 < 3.2). Results. Patients with MTX or LEF had significant decrement in DAS-28 (p < 0.001); nevertheless, only 14% and 12.5% achieved DAS-28 < 3.2 at 3 and 6 months. After 6 months with any of these drugs the -174G/G genotype carriers (56%) had higher risk of therapeutic failure compared with GC (RR: 1.19, 95% CI: 1.07-1.56). By analyzing each drug separately, after 6 months with LEF, GG genotype confers higher risk of therapeutic failure than GC (RR = 1.56; 95% CI = 1.05-2.3; p = 0.003), or CC (RR = 1.83; 95% CI = 1.07-3.14; p = 0.001). This risk was also observed in the dominant model (RR = 1.33; 95% CI = 1.03-1.72; p = 0.02). Instead, in patients receiving MTX no genotype was predictor of therapeutic failure. We concluded that IL-6 -174G/G genotype confers higher risk of failure in therapeutic response to LEF in Mexicans and if confirmed in other populations this can be used as promissory genetic marker to differentiate risk of therapeutic failure to LEF.
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Artritis Reumatoide/tratamiento farmacológico , Interleucina-6/genética , Isoxazoles/administración & dosificación , Metotrexato/administración & dosificación , Anciano , Artritis Reumatoide/genética , Artritis Reumatoide/patología , Biomarcadores Farmacológicos/sangre , Femenino , Marcadores Genéticos , Genotipo , Humanos , Interleucina-6/sangre , Isoxazoles/efectos adversos , Leflunamida , Masculino , Metotrexato/efectos adversos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Regiones Promotoras GenéticasRESUMEN
INTRODUÇÃO: A leishmaniose visceral (LV) é, principalmente, causada pelo protozoário Leishmania infantum nas Américas, podendo acometer o Homem e animais. Dentre estes, o cão é considerado o principal reservatório doméstico do parasito. O curso da LV canina (LVC) varia entre os animais, podendo alguns se mostrar resistentes à infecção, se mantendo subclínicos, e outros susceptíveis, que irão desenvolver sinais da doença. O estado de resistência ou susceptibilidade à LVC reflete na gravidade da infecção do animal, e não pode ser definido pelo quadro clínico apresentado ou por qualquer parâmetro isolado de resposta imune. OBJETIVO: Avaliar a carga parasitária como biomarcador parasitológico, as proteínas LJM11/LJM17 como biomarcadores de exposição à saliva do vetor, e identificar biomarcadores inflamatórios de gravidade da infecção por L. infantum em cães. Primeiramente, foi realizada a padronização de uma ferramenta diagnóstica de PCR quantitativa (qPCR), utilizando diferentes amostras biológicas (aspirado esplênico, linfonodos, pele, sangue, medula óssea e swab conjuntival) de cães sintomáticos provenientes da área endêmica de Jequié-BA. A avaliação da carga parasitária de L. infantum teve seu desempenho comparado com outras técnicas diagnósticas (cultura de aspirado esplênico, teste rápido e ELISA para LVC) empregando a análise de classe latente (ACL). Para essa análise, foi construída uma variável latente a ser empregada como padrão ouro para avaliação da acurácia desses métodos. Na avaliação inicia dos cães sintomáticos, a qPCR detectou DNA do parasita em 100%...
INTRODUCTION: In the Americas, visceral leishmaniasis (VL) is caused by the protozoan Leishmania infantum, which can affect humans and animals. Among these, dog is considered the main domestic reservoir of this parasite. Canine VL (CVL) clinical outcome varies among animals, some of which may be resistant to infection remaining subclinical, and others may be susceptible showing signs of the disease. The state of resistance or susceptibility to CVL reflects on the severity of infection in the animal and cannot be defined solely by the clinical condition presented or by any isolated parameter of the immune response. OBJECTIVE: Assess parasite load as parasitological biomarkers, LJM11/LJM17 proteins as sandfly saliva exposure biomarkers, and identify inflammatory biomarkers that indicates L. infantum infection severity in dogs. Firstly, we performed the standardization of a quantitative PCR diagnostic tool (qPCR) using different biological samples (splenic aspirate, lymph nodes, skin, blood, bone marrow and conjunctival swab) of symptomatic dogs from the endemic area of Jequié-BA. The evaluation of the parasitic load of L. infantum had its performance compared to other diagnostic techniques (splenic aspirate culture, rapid test and CVL ELISA) using latent class analysis (LCA). In this analysis, a latent variable was constructed to be used as a gold standard to evaluate the accuracy of these methods. In the initial evaluation of the symptomatic dogs, qPCR detected DNA from the parasite in 100%...
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Humanos , Biomarcadores Farmacológicos/análisis , Biomarcadores Farmacológicos/sangre , Biomarcadores Farmacológicos/orina , Reacción en Cadena de la Polimerasa/estadística & datos numéricos , Reacción en Cadena de la Polimerasa/métodosRESUMEN
The present study aimed to explore the changes in serum endostatin and fibroblast growth factor 19 (FGF-19) in acute myeloid leukemia patients, and to determine their effects on chemotherapeutic sensitivity. Sixty acute myeloid leukemia patients and 30 healthy controls were included in the study. Patient serum endostatin and FGF-19 levels were measured on admission, and then, standard chemotherapy was administered. The patients were divided into 2 groups according to chemotherapeutic effects: 21 patients in the chemotherapeutic sensitivity group (complete remission + partial remission) and 39 in the chemotherapeutic resistance group (no remission + degradation). A receiver operating characteristic (ROC) curve was used to analyze the relationship of serum endostatin and FGF-19 levels with chemotherapeutic sensitivity in acute myeloid leukemia patients. The levels of serum endostatin and FGF-19 in acute myeloid leukemia patients before chemotherapy were significantly higher than those in the control group. Moreover, these levels significantly decreased after chemotherapy (P < 0.01). The levels of serum endostatin and FGF-19 in the chemotherapeutic sensitivity group were lower than those in the chemotherapeutic resistance group, both before and after chemotherapy (P < 0.05 and P < 0.01, respectively). ROC curve analysis showed that the predictive values of endostatin and FGF-19 were good, and there was no significant difference between these results. In conclusion, serum endostatin and FGF-19 can be used as predictors of chemotherapeutic sensitivity for acute myeloid leukemia patients, and may be important for determining prognosis.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Endostatinas/sangre , Factores de Crecimiento de Fibroblastos/sangre , Leucemia Mieloide Aguda/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores Farmacológicos/sangre , Estudios de Casos y Controles , Citarabina/uso terapéutico , Daunorrubicina/uso terapéutico , Resistencia a Antineoplásicos/genética , Endostatinas/genética , Femenino , Factores de Crecimiento de Fibroblastos/genética , Expresión Génica , Harringtoninas/uso terapéutico , Homoharringtonina , Humanos , Idarrubicina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Pronóstico , Curva ROC , Inducción de Remisión , Resultado del TratamientoRESUMEN
The aim of this study was to characterize and validate the population pharmacokinetics of gentamicin in infants and to determine the influences of clinically relevant covariates to explain the inter- and intraindividual variabilities associated with this drug. Infants receiving intravenous gentamicin and with routine therapeutic drug monitoring were consecutively enrolled in the study. Plasma concentration and time data were retrospectively collected from 208 infants (1 to 24 months old) of the Hospital Universitario Severo Ochoa (Spain), of whom 44% were males (mean age [± standard deviation], 5.8 ± 4.8 months; mean body weight, 6.4 ± 2.2 kg). Data analysis was performed with NONMEM 7.2. One- and two-compartment open models were analyzed to estimate the gentamicin population parameters and the influences of several covariates. External validation was carried out in another population of 55 infants. The behavior of gentamicin in infants exhibits two-compartment pharmacokinetics, with total body weight being the covariate that mainly influences central volume (Vc) and clearance (CL); this parameter was also related to creatinine clearance. Both parameters are age related and different from those reported for neonatal populations. On the basis of clinical presentation and diagnosis, a once-daily dosage regimen of 7 mg/kg of body weight every 24 h is proposed for intravenous gentamicin, followed by therapeutic drug monitoring in order to avoid toxicity and ensure efficacy with minimal blood sampling. Gentamicin pharmacokinetics and disposition were accurately characterized in this pediatric population (infants), with the parameters obtained being different from those reported for neonates and children. These differences should be considered in the dosing and therapeutic monitoring of this antibiotic.
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Antibacterianos/farmacocinética , Biomarcadores Farmacológicos/sangre , Monitoreo de Drogas , Gentamicinas/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Peso Corporal , Preescolar , Creatinina/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Gentamicinas/administración & dosificación , Gentamicinas/sangre , Humanos , Lactante , Recién Nacido , Masculino , Estudios RetrospectivosRESUMEN
Lambda interferon IL-28A/B and IL-29 serum levels have been associated with the course of hepatitis C virus (HCV) infection. However, there is not information about these cytokine in patients with antiviral therapy. We investigated IL-28A/B and IL-29 serum levels in 45 samples from patients chronically infected with HCV genotype 1, and undergoing therapy with PEG-IFN/RBV, at baseline and after 12 weeks of therapy, comparing those that developed a sustained virologic response (SVR) with null responders (NR). IL-28B polymorphisms (rs12979860, rs12980275, and rs8099917) were also considered. We found that, IL-28A/B and IL-29 levels were not significantly different between SVR and NR patients at baseline or after 12 weeks of therapy. TT rs8099917 genotype carriers had significantly higher IL29 levels at baseline (60.5 vs 19.5 pg/mL; p=0.045) and after 12 weeks of therapy (35 vs 16.5 pg/mL; p=0.023) than non-TT carriers. In conclusion, there were no differences in IL-28A/B or IL-29 levels according to response to therapy, suggesting that these cytokines do not play an important role in viral elimination during treatment, at least not during the first 12 weeks of therapy. Genotypes associated with high IL-28B levels may be related to a mechanism of protection against infection but are not involved in the response to antiviral therapy.
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Hepacivirus/inmunología , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/terapia , Inmunoterapia/métodos , Adulto , Biomarcadores Farmacológicos/sangre , Progresión de la Enfermedad , Femenino , Genotipo , Hepatitis C Crónica/inmunología , Humanos , Inmunidad/efectos de los fármacos , Inmunidad/genética , Interferón-alfa/administración & dosificación , Interferones , Interleucinas/sangre , Interleucinas/genética , Masculino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Polimorfismo de Nucleótido Simple , Proteínas Recombinantes/administración & dosificación , Estudios Retrospectivos , Ribavirina/administración & dosificación , Carga Viral/efectos de los fármacosRESUMEN
Five patients with active disseminated vitiligo were given 1g of a chimeric (murine/human) monoclonal antibody to CD20 in a single intravenous infusion and followed-up for 6 months. Three of the patients showed an overt clinical and histological improvement of the disease, one presented slight improvement and the remaining patient showed no changes. Improvement was neither associated with changes in laboratory parameters nor to a specific human leucocyte antigen D-related (HLA-DR) phenotype. We believe that these preliminary results are encouraging, and further clinical trials should be undertaken. An important aim should be the finding of a marker with a good response to this therapeutic approach.
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Anticuerpos Monoclonales/uso terapéutico , Antígenos CD20/inmunología , Vitíligo/terapia , Animales , Anticuerpos Monoclonales/administración & dosificación , Biomarcadores Farmacológicos/sangre , Progresión de la Enfermedad , Estudios de Seguimiento , Antígenos HLA-DR/metabolismo , Humanos , Infusiones Intravenosas , Ratones , Proyectos Piloto , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/uso terapéutico , Balance Th1 - Th2 , Resultado del TratamientoRESUMEN
La infección persistente por ciertos tipos de alto riesgo oncogénico de virus papiloma humano (VPHAR) es el principal factor de riesgo para el desarrollo de cáncer de cuello uterino y sus lesiones precursoras. Los VPHAR inducen alteraciones moleculares durante todo el proceso de carcinogénesis cervical, que provocan la acumulación de errores genéticos, con la consecuente inestabilidad genética y transformación maligna. Estas alteraciones son producidas por la acción directa de las oncoproteínas virales E6 y E7 sobre las principales proteínas celulares supresoras de tumor, p53 y pRb, respectivamente, y pueden ser monitoreadas durante el surgimiento de la lesión neoplásica, mediante el uso de biomarcadores. En este artículo se revisan las últimas tendencias sobre el uso del estudio inmunocitoquímico, como una prueba complementaria a la citología y a la detección y tipificación de VPHAR en la evaluación de la expresión de biomarcadores como la proteína inhibidora de la proliferación celular p16INK4a, marcador único o combinada con otros biomarcadores, que puedan contribuir eficazmente en la detección de las pacientes con mayor riesgo a desarrollar neoplasia del cuello uterino asociada a la infección por VPHAR, durante la pesquisa de cáncer de cuello uterino de rutina y en el manejo clínico adecuado y oportuno.
Persistent infection with certain types of high oncogenic risk human papillomavirus (HR-HPV) is the main risk factor for developing cervical cancer and its precursor lesions. HR-HPV induces molecular changes during cervical carcinogenesis, causing the accumulation of genetic anomalies, with subsequent genetic instability and malignant transformation. These alterations are produced by the direct action of the E6 and E7 viral oncoproteins on principal tumor cell suppressor proteins, p53 and pRb, respectively, and can be monitored during growth of the neoplastic lesion using biomarkers. In this paper we review the latest trends on the use of immunocytochemistry as a complementary test to cytology and HR-HPV detection and typing in evaluating expression of biomarkers such as the p16INK4a cell proliferation inhibitor protein, as a single marker or combined with other biomarkers, which can contribute effectively to the detection of patients with increased risk of developing cervical neoplasia associated with HR-HPV infection during routine screening for cervical cancer and in appropriate clinical management.
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Humanos , Adulto , Femenino , Adulto Joven , Biomarcadores Farmacológicos/análisis , Biomarcadores Farmacológicos/sangre , Células Epiteliales/química , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/etiología , Neoplasias del Cuello Uterino/patología , Papiloma/etiología , Papiloma/química , Papiloma/sangre , Análisis Químico de la Sangre , Hematología , Inmunohistoquímica , Oncología MédicaRESUMEN
BACKGROUND: Polymorphisms in the oestrogen receptor 1 (ESR1) and oestrogen receptor 2 (ESR2) genes are associated with intermediate or endpoint markers of cardiovascular disease and with the efficacy of postmenopausal hormone therapy (HT). Contradictory findings have been described in the past and the role of these genetics variants remains unclear. METHODS: A cross-sectional study was carried out with 266 postmenopausal women, of whom 115 received oral HT (HT+) and 151 did not receive any HT (HT-). We analysed three single-nucleotide polymorphisms (SNPs) in ESR1 (rs1801132, rs7757956 and rs2813544) and two in ESR2 (rs3020450 and rs7154455) and derived haplotypes with three additional polymorphisms that had been previously investigated by our group (ESR1 rs2234693 and ESR2 rs1256049 and rs4986938). RESULTS: The ESR1 rs2813544 polymorphism was associated with low-density lipoprotein cholesterol (LDL-C) in HT+ postmenopausal women (p = 0.044; pC = 0.388), while one ESR2 gene haplotype was associated with total cholesterol (T-chol) (p = 0.015; pC = 0.090) and LDL-C in HT+ postmenopausal women (p = 0.021; pC = 0.126). CONCLUSION: Our findings suggest that, in HT+ postmenopausal women, the rs2813544 polymorphism may influence LDL-C levels and, as previously described, ESR2 rs1256049 is associated with T-chol and LDL-C. No previous study has investigated the association of this SNP set with lipoprotein levels in women while taking into account the hormonal status of the patients.
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Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Terapia de Reemplazo de Estrógeno/efectos adversos , Hiperlipidemias/inducido químicamente , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Biomarcadores Farmacológicos/sangre , Brasil/epidemiología , Enfermedades Cardiovasculares/epidemiología , Colesterol/sangre , LDL-Colesterol/sangre , Estudios Transversales , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Estrógenos/efectos adversos , Femenino , Estudios de Asociación Genética , Humanos , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Persona de Mediana Edad , Posmenopausia , Reproducibilidad de los Resultados , Factores de RiesgoRESUMEN
BACKGROUND: Hepatic lipase (HL), an enzyme present in the hepatic sinusoids, is responsible for the lipolysis of lipoproteins. Human HL contains four polymorphic sites: G-250A, T-710C, A-763G, and C-514T single-nucleotide polymorphism (SNPs). The last polymorphism is the focus of the current study. The genotypes associated with the C-514T polymorphism are CC (normal homozygous - W), CT (heterozygous - H), and TT (minor-allele homozygous - M). HL activity is significantly impaired in individuals of the TT and CT genotypes. A total of 58 post-menopausal women were studied. The subjects were hysterectomized women receiving hormone replacement therapy consisting of 0.625 mg of conjugated equine estrogen once a day. The inclusion criteria were menopause of up to three years and normal blood tests, radiographs, cervical-vaginal cytology, and densitometry. DNA was extracted from the buccal and blood cells of all 58 patients using a commercially available kit (GFX® - Amersham-Pharmacia, USA). RESULTS: Statistically significant reductions in triglycerides (t = 2.16; n = 58; p = 0.03) but not in total cholesterol (t = 0.14; n = 58; p = 0.89) were found after treatment. This group of good responders were carriers of the T allele; the CT and TT genotypes were present significantly more frequently than in the group of non-responders (p = 0.02 or p = 0.07, respectively). However, no significant difference in HDL-C (t = 0.94; n = 58; p = 0.35) or LDL-C (t = -0.83; n = 58; p = 0.41) was found in these patients. CONCLUSIONS: The variation in lipid profile associated with the C-514T polymorphism is significant, and the T allele is associated with the best response to ERT.
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Sustitución de Aminoácidos , Terapia de Reemplazo de Estrógeno , Lipasa/genética , Polimorfismo de Nucleótido Simple , Análisis de Varianza , Biomarcadores Farmacológicos/sangre , Colesterol/sangre , Estrógenos Conjugados (USP)/uso terapéutico , Femenino , Estudios de Asociación Genética , Marcadores Genéticos , Haplotipos , Humanos , Histerectomía , Lipoproteínas/sangre , Persona de Mediana Edad , Posmenopausia , Resultado del Tratamiento , Triglicéridos/sangreRESUMEN
PURPOSE: The antihypertensive effects of angiotensin-converting enzyme inhibitors (ACEi) are explained, at least in part, by enhanced bradykinin-dependent nitric oxide (NO) formation and decreased angiotensin II-induced oxidative stress and vasoconstriction. We examined for the first time whether treatment with enalapril increases the plasma levels of markers of NO formation and decreases oxidative stress in mild to moderate hypertensive patients. METHODS: Eighteen untreated hypertensive patients were treated with enalapril 10 mg/day (n=10) or 20 mg/day (n=8) for 60 days. Eighteen normotensive healthy controls were followed for the same period. Venous blood samples were collected at baseline and after 30/60 days of treatment with enalapril. Plasma NOx (nitrites + nitrates) concentrations were determined by using the Griess reaction. Plasma nitrite and whole blood nitrite concentrations were determined by using an ozone-based chemiluminescence assay. Plasma thiobarbituric acid-reactive species (TBARS) and 8-isoprostane concentrations were determined by a fluorimetric method and by ELISA, respectively. RESULTS: Treatment with enalapril decreased blood pressure in hypertensive patients. However, we found no significant changes in plasma NOx, nitrite, whole blood nitrite, and in the levels of markers of oxidative stress in both normotensive controls and hypertensive patients treated with enalapril. CONCLUSIONS: Our data show that enalapril 10-20 mg/day does not affect the concentrations of relevant markers of NO formation or markers of oxidative stress in mild to moderately hypertensive subjects, despite satisfactory blood pressure control. Our findings do not rule out the possibility that ACEi may produce such effects in more severely hypertensive patients treated with higher doses of ACEi.
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Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Enalapril/farmacología , Enalapril/uso terapéutico , Hipertensión/tratamiento farmacológico , Óxido Nítrico/metabolismo , Adulto , Biomarcadores Farmacológicos/sangre , Presión Sanguínea/efectos de los fármacos , Dinoprost/análogos & derivados , Dinoprost/sangre , Humanos , Hipertensión/diagnóstico , Persona de Mediana Edad , Nitratos/sangre , Nitritos/sangre , Estrés Oxidativo/efectos de los fármacos , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
INTRODUCTION: It has been reported in some series that gsp+ somatotropinomas are more sensitive to somatostatin analogues (SA) and dopamine's actions which may be related to their somatostatin receptor (SSTR) and dopamine receptor (DR) profile. No previous studies have been undertaken to evaluate the SSTR and DR profile related with the gsp status in somatotropinomas. OBJECTIVES: To determine if (1) gsp status is correlated with response to octreotide LAR (LAR) and tumor expression patterns of SSTR1-5 and DR1-5 and (2) cAMP level can directly modulate SSTR and DR mRNA levels. METHODS: Response to SA was evaluated by GH and IGF-I percent reduction after 3 and 6 months of treatment with LAR. Conventional PCR and sequencing were used to identify gsp+ tumors. Quantitative real-time PCR was used to determine SSTR and DR tumor expression. Primary pituitary cell cultures of primates were used to study whether SSTR and DR expression is regulated by forskolin. RESULTS: The response to LAR did not significantly differ between patients with gsp+ and gsp- tumors; however, gsp+ tumors expressed higher levels of SSTR1, SSTR2, DR2 and a lower level of SSTR3. Forskolin increased SSTR1, SSTR2, DR1 and DR2 expression in cell cultures. CONCLUSION: Elevated SSTR1, SSTR2, and DR2 tumor expression may help improve responsiveness to SA and DA therapy; however, this study may not have been appropriately powered to observe significant effects in the clinical response. Elevated cAMP levels could be directly responsible for the upregulation in SSTR1, SSTR2 and DR2 mRNA levels observed in gsp+ patients.