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1.
Biochim Biophys Acta Mol Basis Dis ; 1865(10): 2657-2670, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31299217

RESUMO

Staphylococcus aureus is the most prominent cause of skin and soft tissue infections (SSTI) worldwide. Mortality associated with invasive SSTI is a major threat to public health considering the incidence of antibiotic resistant isolates in particular methicillin resistant S. aureus both in the hospital (HA-MRSA) and in the community (CA-MRSA). To overcome the increasing difficulties in the clinical management of SSTI due to MRSA, new prophylactic and therapeutic approaches are urgently needed and a preventive vaccine would be welcome. The rational design of an anti-S. aureus vaccine requires a deep knowledge of the role that the different bacterial virulence factors play according to the type of infection. In the present study, using a set of isogenic deficient mutants and their complemented strains we determined that the staphylococcal surface proteins SpA and Sbi play an important role in the induction of inflammatory cytokines and chemokines in the skin during SSTI. SpA and Sbi initiate signaling cascades that lead to the early recruitment of neutrophils, modulate their lifespan in the skin milieu and contribute to proper abscess formation and bacterial eradication. Moreover, the expression of SpA and Sbi appear critical for skin repair and wound healing. Thus, these results indicate that SpA and Sbi can promote immune responses in the skin that are beneficial for the host and therefore, should not be neutralized with vaccine formulations designed to prevent SSTI.

2.
Sci Rep ; 9(1): 10260, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311983

RESUMO

Cholesterol mediates its proliferative and metastatic effects via the metabolite 27-hydroxycholesterol (27-HC), at least in breast and endometrial cancer. We determined the serum lipoprotein profile, intratumoral cholesterol and 27-HC levels in a cohort of patients with well-differentiated papillary thyroid carcinoma (PTC; low/intermediate and high risk), advanced thyroid cancers (poorly differentiated, PDTC and anaplastic thyroid carcinoma, ATC) and benign thyroid tumors, as well as the expression of genes involved in cholesterol metabolism. We investigated the gene expression profile, cellular proliferation, and migration in Nthy-ori 3.1 and CAL-62 cell lines loaded with human low-density lipoprotein (LDL). Patients with more aggressive tumors (high-risk PTC and PDTC/ATC) showed a decrease in blood LDL cholesterol and apolipoprotein B. These changes were associated with an increase in the expression of the thyroid's LDL receptor, whereas 3-hydroxy-3-methylglutaryl-CoA reductase and 25-hydroxycholesterol 7-alpha-hydroxylase were downregulated, with an intratumoral increase of the 27-HC metabolite. Furthermore, LDL promoted proliferation in both the Nthy-ori 3.1 and CAL-62 thyroid cellular models, but only in ATC cells was its cellular migration increased significantly. We conclude that cholesterol and intratumoral accumulation of 27-HC promote the aggressive behavior process of PTC. Targeting cholesterol metabolism could be a new therapeutic strategy in thyroid tumors with poor prognosis.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30123776

RESUMO

Early research on sepsis has focused on the initial hyper-inflammatory, cytokine mediated phase of the disorder whereas the events that govern the concomitant and subsequent anti-inflammatory compensatory response are not completely understood. In this context, the putative participation of TNFR1-mediated signaling in the immunosuppressive phase of Staphylococcus aureus sepsis has not been elucidated. The aim of this study was to determine the role of TNFR1 in directing the immune dysfunction during S. aureus sepsis and the potential contribution of MDSC to this process. Using a model of sepsis of peritoneal origin and tnfr1-/- mice, we demonstrated that during staphylococcal sepsis CD4+ T cell anergy is significantly dependent on TNFR1 expression and that signaling through this receptor has an impact on bacterial clearance in the spleen. MDSC played a major role in the generation of anergic CD4+ T cells and their accumulation in the spleen during S. aureus sepsis correlated with IL-6 induction. Although TNFR1 signaling was not required for MDSC accumulation and expansion in the spleen, it determined the in vivo expression of Arginase 1 and iNOS, enzymes known to participate in the suppressive function of this population. Moreover, our data indicate that TNFR1-mediated IL-10 production may modulate MDSC function during staphylococcal sepsis. Taken together these results indicate that TNFR1 plays a critical role on T cell dysfunction during S. aureus sepsis by regulating immunomodulatory mediators in MDSC. The role of TNFR1-mediated signaling during the immunosuppressive phase of staphylococcal sepsis should be considered when designing novel alternative therapeutic approaches.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Imunossupressão , Células Supressoras Mieloides/imunologia , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Sepse/patologia , Transdução de Sinais , Infecções Estafilocócicas/patologia , Animais , Arginase/metabolismo , Interleucina-6/metabolismo , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/deficiência , Sepse/imunologia , Baço/patologia , Infecções Estafilocócicas/imunologia
4.
Diabetes Technol Ther ; 20(5): 380-385, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29620918

RESUMO

An ongoing clinical trial is testing the efficacy of web telematic support in a structured program for obesity treatment and diabetes prevention. Participants were recruited from two tertiary-care hospitals and randomized to receive either a telematic intervention (TI) supported by PREDIRCAM2 web platform or a non-telematic intervention (NTI). All receive 1-year follow-up. Both interventions consist of tailored dietary and exercise prescriptions, based on a Mediterranean dietary pattern and general WHO exercise recommendations for adults. At 6 months, both groups have received 7 contacts, 3 exclusively telematic for the TI group. This is a preliminary result intention-to-treat analysis. One hundred eighty-three participants were recruited, with a mean body mass index of 34.75 ± 2.75 kg/m2. General dropout rate at 6 months was 26.8%. Weight changes were statistically significant at months 3 and 6 compared to baseline, -2.915 ± 0.24 kg, -3.29 ± 0.36 kg, respectively (P < 0.001), but not statistically significant between the 3- and 6-month time points -0.37 ± 0.21 kg (P = 0.24). Mean group differences showed that the TI group lost 1.61 ± 1.88 kg more than the NTI group (P = 0.39). Waist, waist/hip ratio, resting heart rate, blood pressure, HbA1c, and low-density lipoprotein cholesterol also showed statistically significant changes at 6 months, with no significant differences between groups. Weight loss in the TI group shows similar results as the usual care NTI group for weight loss and control of obesity comorbidities. At completion of the clinical trial, these results will be reevaluated to assess the potential role of web support in weight-loss maintenance and its cost-effectiveness.


Assuntos
Dieta Mediterrânea , Exercício , Estilo de Vida Saudável , Obesidade/prevenção & controle , Perda de Peso , Adulto , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
5.
Artigo em Inglês | MEDLINE | ID: mdl-29456969

RESUMO

Selection pressures exerted on Staphylococcus aureus by host factors may lead to the emergence of mutants better adapted to the evolving conditions at the infection site. This study was aimed at identifying the changes that occur in S. aureus exposed to the host defense mechanisms during chronic osteomyelitis and evaluating whether these changes affect the virulence of the organism. Genome assessment of two S. aureus isolates collected 13 months apart (HU-85a and HU-85c) from a host with chronic osteomyelitis was made by whole genome sequencing. Agr functionality was assessed by qRT-PCR. Isolates were tested in a rat model of osteomyelitis and the bacterial load (CFU/tibia) and the morphometric osteomyelitic index (OI) were determined. The ability of the isolates to trigger the release of proinflammatory cytokines was determined on macrophages in culture. Persistence of S. aureus within the host resulted in an agrC frameshift mutation that likely led to the observed phenotype. The capacity to cause bone tissue damage and trigger proinflammatory cytokines by macrophages of the agr-deficient, unencapsulated derivative (HU-85c) was decreased when compared with those of the isogenic CP8-capsulated parental strain (HU-85a). By comparison, no significant differences were found in the bacterial load or the OI from rats challenged with isogenic Reynolds strains [CP5, CP8, and non-typeable (NT)], indicating that lack of CP expression alone was not likely responsible for the reduced capacity to cause tissue damage in HU-85c compared with HU-85a. The production of biofilm was significantly increased in the isogenic derivative HU-85c. Lack of agr-dependent factors makes S. aureus less virulent during chronic osteomyelitis and alteration of the agr functionality seems to permit better adaptation of S. aureus to the chronically infected host.


Assuntos
Adaptação Biológica/genética , Proteínas de Bactérias/genética , Interações Hospedeiro-Patógeno , Mutação , Osteomielite/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologia , Transativadores/genética , Animais , Carga Bacteriana , Biofilmes , Doença Crônica , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Ratos , Adulto Jovem
6.
Immunology ; 154(3): 510-521, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29377107

RESUMO

Ultraviolet radiation (UVr) promotes several well-known molecular changes, which may ultimately impact on health. Some of these effects are detrimental, like inflammation, carcinogenesis and immunosuppression. On the other hand, UVr also promotes vitamin D synthesis and other beneficial effects. We recently demonstrated that exposure to very low doses of UVr on four consecutive days [repetitive low UVd (rlUVd)] does not promote an inflammatory state, nor the recruitment of neutrophils or lymphocytes, as the exposure to a single high UV dose (shUVd) does. Moreover, rlUVd reinforce the epithelium by increasing antimicrobial peptides transcription and epidermal thickness. The aim of this study was to evaluate the adaptive immune response after shUVd and rlUVd, determining T-cell and B-cell responses. Finally, we challenged animals exposed to both irradiation procedures with Staphylococcus aureus to study the overall effects of both innate and adaptive immunity during a cutaneous infection. We observed, as expected, a marked suppression of T-cell and B-cell responses after exposure to an shUVd but a novel and significant increase in both specific responses after exposure to rlUVd. However, the control of the cutaneous S. aureus infection was defective in this last group, suggesting that responses against pathogens cannot be ruled out from isolated stimuli.


Assuntos
Imunidade Adaptativa/efeitos da radiação , Exposição à Radiação , Raios Ultravioleta , Animais , Formação de Anticorpos/imunologia , Formação de Anticorpos/efeitos da radiação , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/efeitos da radiação , Biomarcadores , Citocinas/metabolismo , Dermatite/imunologia , Dermatite/metabolismo , Dermatite/microbiologia , Dermatite/prevenção & controle , Modelos Animais de Doenças , Imunização , Imunofenotipagem , Masculino , Camundongos , Doses de Radiação , Infecções Cutâneas Estafilocócicas/imunologia , Infecções Cutâneas Estafilocócicas/microbiologia , Infecções Cutâneas Estafilocócicas/prevenção & controle , Staphylococcus aureus/imunologia , Staphylococcus aureus/efeitos da radiação , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/efeitos da radiação , Toxoide Tetânico/administração & dosagem , Toxoide Tetânico/imunologia
7.
Diabetes Technol Ther ; 19(11): 633-640, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29091477

RESUMO

BACKGROUND: Blood glucose meters are reliable devices for data collection, providing electronic logs of historical data easier to interpret than handwritten logbooks. Automated tools to analyze these data are necessary to facilitate glucose pattern detection and support treatment adjustment. These tools emerge in a broad variety in a more or less nonevaluated manner. The aim of this study was to compare eDetecta, a new automated pattern detection tool, to nonautomated pattern analysis in terms of time investment, data interpretation, and clinical utility, with the overarching goal to identify early in development and implementation of tool areas of improvement and potential safety risks. METHODS: Multicenter web-based evaluation in which 37 endocrinologists were asked to assess glycemic patterns of 4 real reports (2 continuous subcutaneous insulin infusion [CSII] and 2 multiple daily injection [MDI]). Endocrinologist and eDetecta analyses were compared on time spent to analyze each report and agreement on the presence or absence of defined patterns. RESULTS: eDetecta module markedly reduced the time taken to analyze each case on the basis of the emminens eConecta reports (CSII: 18 min; MDI: 12.5), compared to the automatic eDetecta analysis. Agreement between endocrinologists and eDetecta varied depending on the patterns, with high level of agreement in patterns of glycemic variability. Further analysis of low level of agreement led to identifying areas where algorithms used could be improved to optimize trend pattern identification. CONCLUSION: eDetecta was a useful tool for glycemic pattern detection, helping clinicians to reduce time required to review emminens eConecta glycemic reports. No safety risks were identified during the study.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 1/sangue , Automonitorização da Glicemia , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Sistemas de Infusão de Insulina
8.
Cir. Esp. (Ed. impr.) ; 94(7): 392-398, ago. 2016. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-155423

RESUMO

Introducción: El objetivo de este estudio fue evaluar las estrategias terapéuticas utilizadas y la eficacia de un programa de tratamiento de la hiperglucemia supervisado por Endocrinología. Métodos: Estudio retrospectivo de todos los pacientes con diabetes tipo II ingresados en Cirugía Vascular en un periodo de 12 meses. Registramos las características clínicas y los datos relacionados con el tratamiento de la hiperglucemia durante la hospitalización, al alta y a los 2-6 meses postalta. El control glucémico se evaluó mediante los perfiles glucémicos y la HbA1c al ingreso y a los 2-6 meses postalta. Resultados: Se incluyeron 140 hospitalizaciones de 123 pacientes. El protocolo para la selección de la pauta de insulina se aplicó en el 96,4% de los pacientes (22,8% correctora; el 23,6% basal-correctora y 50% basal-bolo-correctora [BBC]). Los pacientes con BBC tenían HbA1c inicial (7,7±1,5% frente a 6,7±0,8%; p<0,001) y glucemia media el día del ingreso más elevadas (184,4±59,2 frente a 140,5±31,4mg/dl; p<0,001). La glucemia media se redujo en la mitad (162,1±41,8mg/dl) y en las últimas 24 h del ingreso (160,8±43,3mg/dl) en los pacientes con BBC (p=0,007), pero no se modificó en el resto. En el 22,1% de los pacientes en los que se realizaron modificaciones del tratamiento previo al alta, la HbA1c se redujo de 8,2±1,6 a 6,8±1,6%, a los 2-6 meses postalta (p=0,019). Conclusiones: La aplicación por personal experto del protocolo de tratamiento de la hiperglucemia en el hospital permite identificar el tratamiento adecuado y mejorar el control glucémico durante la hospitalización y al alta, confirmando su eficacia en condiciones de práctica clínica (AU)


Background: The aim of this study was to evaluate the strategy and efficacy of a hyperglycemia treatment program supervised by Endocrinology. Methods: All patients with type 2 diabetes hospitalized at the vascular surgery department over a 12 month period were retrospectively reviewed. Clinical characteristics and hyperglycemia treatment during hospitalization, at discharge and 2-6 month after discharge were collected. Glycemic control was assessed using capillary blood glucose profiles and HbA1c at admission and 2-6 months post-discharge. Results: A total of 140 hospitalizations of 123 patients were included. The protocol to choose the insulin regimen was applied in 96.4% of patients (22.8% correction dose, 23.6% basal-correction dose and 50% basal-bolus-correction dose [BBC]). Patients with BBC had higher HbA1c (7.7±1.5% vs. 6.7 ±0.8%; P<.001) and mean glycemia on the first day of hospitalization (184.4±59.2 vs. 140.5±31.4mg/dl; P<.001). Mean blood glucose was reduced to 162.1±41.8mg/dl in the middle and 160.8±43.3mg/dl in the last 24h of hospitalization in patients with BBC (P=.007), but did not change in the remaining patients. In 22.1% patients with treatment changes performed at discharge, HbA1c decreased from 8.2±1.6 to 6.8±1.6% at 2–6 months post-discharge (P=.019). Conclusions: The hyperglycemia treatment protocol applied by an endocrinologist in the hospital, allows the identification of the appropriate therapy and the improvement of the glycemic control during hospitalization and discharge, supporting its efficacy in clinical practice (AU)


Assuntos
Humanos , Masculino , Feminino , Hiperglicemia/tratamento farmacológico , Hiperglicemia/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Alta do Paciente/normas , Insulina/uso terapêutico , Glicemia/análise , Endocrinologia/organização & administração , Endocrinologia/normas , Resultado do Tratamento , Avaliação de Eficácia-Efetividade de Intervenções , Estudos Retrospectivos , Análise Estatística , Tempo de Internação/tendências
9.
J Innate Immun ; 8(3): 284-98, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26967533

RESUMO

Interleukin 1 (IL-1) ß is a critical cytokine that orchestrates host defenses against Staphylococcus aureus and is crucial for the eradication of bacteria. The production and action of IL-1ß are regulated by multiple control pathways. Among them, IL-1RII (the type II IL-1 receptor) acts as a decoy receptor and has been shown to regulate the biological effects of IL-1ß. High levels of soluble IL-1RII are present in septic patients; however, the stimuli that regulate the expression and release of IL-1RII in pathological conditions are incompletely elucidated. In the present study, we demonstrated the ability of S. aureus and protein A to induce IL-1RII shedding in myeloid cells. The positive modulation of IL-1RII expression and cleavage was associated with the failure to detect IL-1ß in response to S. aureus both in vitro and in vivo, suggesting that the soluble form of the receptor could be masking the availability of IL-1ß. The absence of detectable IL-1ß was associated with low levels of inflammatory cytokines and chemokines known to be regulated by IL-1ß and with increased bacterial persistence. Modulation of decoy receptors during systemic S. aureus infection is proposed as a new strategy used by this bacterium to evade the immune response.


Assuntos
Interleucina-1beta/imunologia , Monócitos/imunologia , Neutrófilos/imunologia , Receptores Tipo II de Interleucina-1/metabolismo , Sepse/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Animais , Linhagem Celular , Regulação da Expressão Gênica , Humanos , Evasão da Resposta Imune , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/microbiologia , Neutrófilos/microbiologia , Proteólise , Receptores Tipo II de Interleucina-1/genética , Proteína Estafilocócica A/imunologia
10.
Diabetes Technol Ther ; 18(5): 282-7, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26886163

RESUMO

OBJECTIVE: This study was designed to assess the impact of the use of an automated bolus advisor (ABA) on glycemic control, quality of life, and satisfaction in adult patients with type 1 diabetes mellitus treated with multiple daily injections of insulin. MATERIALS AND METHODS: A crossover, prospective, randomized, controlled, multicenter study of 36 weeks duration was conducted. Patients were randomized to start in either control phase (CP) using a traditional blood glucose meter to calculate insulin doses (Accu-Chek(®) Aviva Nano; Roche Diagnostics, Indianapolis, IN) or intervention phase (IP) using an ABA meter (Accu-Chek Aviva Expert; Roche Diagnostics) and switched to the other phase after a washout period. Each phase was 12 weeks in duration. RESULTS: Significant glycated hemoglobin (HbA1c) reduction was observed in both phases (CP, initial HbA1c of 8.05 ± 0.7%, final HbA1c of 7.59 ± 0.7% [P < 0.001]; IP, initial HbA1c of 8.13 ± 1%, final HbA1c of 7.61 ± 0.8% [P < 0.001]). Although the trend was to a higher HbA1c reduction in IP, no statistically significant differences were observed between phases (CP, HbA1c -0.39%; IP, HbA1c -0.52% [P = 0.8]). During IP, the number of daily glucose measurements was greater (4.28 ± 1.2 vs. 4.01 ± 1.1 [P < 0.006]), the rate of postprandial hypoglycemia was lower, and an improvement in quality of life and higher satisfaction were observed. CONCLUSIONS: In this first crossover study comparing the use of an ABA with the standard usual care, the use of an ABA was effective and well accepted. Furthermore, reduction in hypoglycemic events, improvement in adherence and quality of life, and higher treatment satisfaction were observed.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Adulto , Estudos Cross-Over , Feminino , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
11.
Cir Esp ; 94(7): 392-8, 2016.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-25882331

RESUMO

BACKGROUND: The aim of this study was to evaluate the strategy and efficacy of a hyperglycemia treatment program supervised by Endocrinology. METHODS: All patients with type 2 diabetes hospitalized at the vascular surgery department over a 12 month period were retrospectively reviewed. Clinical characteristics and hyperglycemia treatment during hospitalization, at discharge and 2-6 month after discharge were collected. Glycemic control was assessed using capillary blood glucose profiles and HbA1c at admission and 2-6 months post-discharge. RESULTS: A total of 140 hospitalizations of 123 patients were included. The protocol to choose the insulin regimen was applied in 96.4% of patients (22.8% correction dose, 23.6% basal-correction dose and 50% basal-bolus-correction dose [BBC]). Patients with BBC had higher HbA1c (7.7±1.5% vs. 6.7 ±0.8%; P<.001) and mean glycemia on the first day of hospitalization (184.4±59.2 vs. 140.5±31.4mg/dl; P<.001). Mean blood glucose was reduced to 162.1±41.8mg/dl in the middle and 160.8±43.3mg/dl in the last 24h of hospitalization in patients with BBC (P=.007), but did not change in the remaining patients. In 22.1% patients with treatment changes performed at discharge, HbA1c decreased from 8.2±1.6 to 6.8±1.6% at 2-6 months post-discharge (P=.019). CONCLUSIONS: The hyperglycemia treatment protocol applied by an endocrinologist in the hospital, allows the identification of the appropriate therapy and the improvement of the glycemic control during hospitalization and discharge, supporting its efficacy in clinical practice.


Assuntos
Hiperglicemia/terapia , Idoso , Protocolos Clínicos , Diabetes Mellitus Tipo 2/complicações , Endocrinologia , Feminino , Departamentos Hospitalares , Hospitalização , Humanos , Hiperglicemia/etiologia , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares
12.
PLoS One ; 10(6): e0131879, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26126119

RESUMO

Staphylococcus aureus is an important human pathogen that causes infections that may present high morbidity and mortality. Among its many virulence factors protein A (SpA) and Staphylococcal binding immunoglobulin protein (Sbi) bind the Fc portion of IgG interfering with opsonophagocytosis. We have previously demonstrated that SpA interacts with the TNF-α receptor (TNFR) 1 through each of the five IgG binding domains and induces the production of pro-inflammatory cytokines and chemokines. The IgG binding domains of Sbi are homologous to those of SpA, which allow us to hypothesize that Sbi might also have a role in the inflammatory response induced by S. aureus. We demonstrate that Sbi is a novel factor that participates in the induction of the inflammatory response during staphylococcal infections via TNFR1 and EGFR mediated signaling as well as downstream MAPKs. The expression of Sbi significantly contributed to IL-6 production and modulated CXCL-1 expression as well as neutrophil recruitment to the site of infection, thus demonstrating for the first time its relevance as a pro-inflammatory staphylococcal antigen in an in vivo model.


Assuntos
Proteínas de Bactérias/imunologia , Proteínas de Transporte/imunologia , Inflamação/imunologia , Infecções Estafilocócicas/imunologia , Proteína Estafilocócica A/imunologia , Staphylococcus aureus/imunologia , Animais , Sítios de Ligação de Anticorpos/imunologia , Quimiocina CXCL1/biossíntese , Receptores ErbB/imunologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Feminino , Flavonoides/farmacologia , Imidazóis/farmacologia , Imunoglobulina G/imunologia , Inflamação/microbiologia , Interleucina-6/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infiltração de Neutrófilos/imunologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Quinazolinas/farmacologia , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Transdução de Sinais/imunologia , Tirfostinas/farmacologia , Fatores de Virulência/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
13.
Endocrinol. nutr. (Ed. impr.) ; 62(6): 264-1269, jun.-jul. 2015. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-140169

RESUMO

Introducción: Recientemente, se ha constituido en Cataluña el Consorcio para el Estudio de Cáncer de Tiroides (CECaT). Se trata de una plataforma que reúne 20 hospitales y un instituto de investigación de la comunidad. Una de sus iniciativas ha sido la realización de un estudio retrospectivo de las características de pacientes tratados de cáncer diferenciado de tiroides (CDT). Material y métodos: Se incluyeron 1.855 pacientes de 11 hospitales tratados en el periodo (1998-2012). Resultados: Del total, 1.470 (79,2%) eran mujeres. La edad media al diagnóstico fue de 47,7 (15,7) años, siendo significativamente mayor en los varones que en las mujeres, 49,3 (15) versus 47,3 (15,8); p = 0,02. El 88,9% eran carcinomas papilares. El tamaño del tumor fue de 21,5 (16) mm, siendo significativamente menor en las mujeres que en los hombres, 20,1 (14,5) mm y 26,6 (20,3) mm, respectivamente (p < 0,001). Tras un seguimiento de 5,5 (3,8) años, se disponía de la situación final en 1.355 pacientes. De ellos, 1.065 (78,6%) se encontraban libres de enfermedad, 239 (17,6%) mantenían enfermedad activa y 51 (3,8%) habían fallecido. El riesgo de no estar libre de enfermedad se relacionaba de forma significativa con: mayor edad al diagnóstico, sexo masculino, mayor tamaño del tumor, metástasis linfáticas iniciales, ausencia de signos de tiroiditis en el resto de la glándula, y presencia de invasión vascular y/o extraglandular del tumor. Conclusiones: Los resultados muestran que las características del CDT de la cohorte son similares a las descritas en otros ámbitos geográficos (AU)


Introduction: The consortium for the study of thyroid cancer (CECaT), including 20 hospitals and one research institute, was recently created in Catalonia (Spain). One of the first initiatives of the group was to perform a descriptive analysis of the characteristics of patients with differentiated thyroid carcinoma (DTC). Patients and methods: The cohort included 1,855 patients from 11 hospitals treated over a period of 15 years (1998-2012). Results: In this series, 1.470 (79.2%) patients were women. Mean age was 47.7 (15.7) years old. Age was significantly higher in male than in female patients, 49.3 (15) versus 47.3 (15.8); p = 0.02. Papillary thyroid carcinoma accounted for 88.9% of cases. Mean tumor size was 21.5 (16) mm, and was significantly lower in females than in males, 20.1 (14.5) mm and 26.6 (20.3) mm respectively (p < 0.001). After a follow-up period of 5.5 (3.7) years, information was available for 1,355 patient, of whom 1065 (78.6%) were free of disease, 239 (17.6%) had no tumor persistence, and 51 (3.8) % had died. The risk of persistent or recurrent disease was significantly associated to older age at diagnosis, male gender, larger tumor size, lymph node metastases at surgery, no signs of thyroiditis in the remaining thyroid tissue, and presence of vascular and/or extraglandular invasion. Conclusions: Patient characteristics analyzed are similar to those reported in other parts of the world (AU)


Assuntos
Adulto , Feminino , Humanos , Masculino , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia , Carcinoma Papilar/patologia , Metástase Linfática/patologia , Tireoidite/patologia
14.
Endocrinol Nutr ; 62(6): 264-9, 2015.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-25979187

RESUMO

INTRODUCTION: The consortium for the study of thyroid cancer (CECaT), including 20 hospitals and one research institute, was recently created in Catalonia (Spain). One of the first initiatives of the group was to perform a descriptive analysis of the characteristics of patients with differentiated thyroid carcinoma (DTC). PATIENTS AND METHODS: The cohort included 1,855 patients from 11 hospitals treated over a period of 15 years (1998-2012). RESULTS: In this series, 1.470 (79.2%) patients were women. Mean age was 47.7 (15.7) years old. Age was significantly higher in male than in female patients, 49.3 (15) versus 47.3 (15.8); p=0.02. Papillary thyroid carcinoma accounted for 88.9% of cases. Mean tumor size was 21.5 (16) mm, and was significantly lower in females than in males, 20.1 (14.5) mm and 26.6 (20.3) mm respectively (p<0.001). After a follow-up period of 5.5 (3.7) years, information was available for 1,355 patient, of whom 1065 (78.6%) were free of disease, 239 (17.6%) had no tumor persistence, and 51 (3.8) % had died. The risk of persistent or recurrent disease was significantly associated to older age at diagnosis, male gender, larger tumor size, lymph node metastases at surgery, no signs of thyroiditis in the remaining thyroid tissue, and presence of vascular and/or extraglandular invasion. CONCLUSIONS: Patient characteristics analyzed are similar to those reported in other parts of the world.


Assuntos
Neoplasias da Glândula Tireoide , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Espanha , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/cirurgia , Fatores de Tempo
15.
Biochim Biophys Acta ; 1852(5): 893-904, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25557389

RESUMO

Trypanosoma cruzi, the etiological agent of Chagas' disease, induces a persistent inflammatory response. Macrophages are a first line cell phenotype involved in the clearance of infection. Upon parasite uptake, these cells increase inflammatory mediators like NO, TNF-α, IL-1ß and IL-6, leading to parasite killing. Although desired, inflammatory response perpetuation and exacerbation may lead to tissue damage. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent nuclear transcription factors that, besides regulating lipid and carbohydrate metabolism, have a significant anti-inflammatory effect. This is mediated through the interaction of the receptors with their ligands. PPARγ, one of the PPAR isoforms, has been implicated in macrophage polarization from M1, the classically activated phenotype, to M2, the alternatively activated phenotype, in different models of metabolic disorders and infection. In this study, we show for the first time that, besides PPARγ, PPARα is also involved in the in vitro polarization of macrophages isolated from T. cruzi-infected mice. Polarization was evidenced by a decrease in the expression of NOS2 and proinflammatory cytokines and the increase in M2 markers like Arginase I, Ym1, mannose receptor and TGF-ß. Besides, macrophage phagocytic activity was significantly enhanced, leading to increased parasite load. We suggest that modulation of the inflammatory response by both PPARs might be due, at least in part, to a change in the profile of inflammatory macrophages. The potential use of PPAR agonists as modulators of overt inflammatory response during the course of Chagas' disease deserves further investigation.


Assuntos
Doença de Chagas/metabolismo , Macrófagos/metabolismo , PPAR alfa/metabolismo , PPAR gama/metabolismo , Animais , Arginase/genética , Arginase/metabolismo , Western Blotting , Células Cultivadas , Doença de Chagas/genética , Doença de Chagas/parasitologia , Citocinas/genética , Citocinas/metabolismo , Interações Hospedeiro-Patógeno , Mediadores da Inflamação/metabolismo , Lectinas/genética , Lectinas/metabolismo , Ligantes , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/classificação , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Microscopia de Fluorescência , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , PPAR alfa/genética , PPAR gama/genética , Fagocitose/efeitos dos fármacos , Prostaglandina D2/análogos & derivados , Prostaglandina D2/farmacologia , Pirimidinas/farmacologia , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Trypanosoma cruzi/fisiologia , beta-N-Acetil-Hexosaminidases/genética , beta-N-Acetil-Hexosaminidases/metabolismo
16.
Mol Cell Endocrinol ; 404: 37-45, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25617717

RESUMO

We investigated the role of VDAC2 in human epithelial thyroid tumours using proteomic 2D-DIGE analysis and qRT-PCR. We found a significant up-regulation of VDAC2 in thyroid tumours and in thyroid tumour cell lines (TPC-1 and CAL-62). We did not detect overexpression of VDAC2 in a normal thyroid cell line (Nthy-ori 3-1). Silico analysis revealed that two proteins, BAK1 and BAX, had a strong relationship with VDAC2. BAK1 gene expression showed down-regulation in thyroid tumours (follicular and papillary tumours) and in TPC-1 and CAL-62 cell lines. Transient knockdown of VDAC2 in TPC-1 and CAL-62 promoted upregulation of the BAK1 gene and protein expression, and increased susceptibility to sorafenib treatment. Overexpression of the BAK1 gene in CAL-62 showed lower sorafenib sensitivity than VDAC2 knockdown cells. We propose the VDAC2 gene as a novel therapeutic target in these tumours.


Assuntos
Neoplasias Epiteliais e Glandulares/metabolismo , Proteômica/métodos , Neoplasias da Glândula Tireoide/metabolismo , Eletroforese em Gel Diferencial Bidimensional/métodos , Canal de Ânion 2 Dependente de Voltagem/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/patologia , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Sorafenibe , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia , Regulação para Cima , Canal de Ânion 2 Dependente de Voltagem/genética , Adulto Jovem , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
17.
J Diabetes Sci Technol ; 9(3): 588-92, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25519294

RESUMO

BACKGROUND: The carbohydrate-to-insulin ratio (CIR) is initially calculated from the total daily insulin dose (TDID). However, CIR likely presents variations owing to different population characteristics and intraday variations not being taken into account by most formulas. No information is available concerning the Mediterranean population. We investigated the CIR used by patients with type 1 diabetes (T1DM) using continuous subcutaneous insulin infusion (CSII) therapy in a Mediterranean area, to identify possible intraday variations and establish an adequate formula to calculate CIR. METHODS: Data from 170 T1DM patients from Barcelona were obtained retrospectively from the Spanish National Registry of CSII Therapy (SNR-CSII). Theoretical CIR was calculated using the formula: 500 divided by TDID. This theoretical CIR was compared to the real CIR. RESULTS: The real CIR was also compared between main meals. Patients with HbA1c < 7% (n = 44) were considered a reference group for accurate bolus calculation and were analyzed as a subgroup. The real CIR used was 11.5 g/UI for breakfast, 12 g/UI for lunch, and 13.3 g/UI for dinner. CIR obtained by the 500/TDID formula for all meals was 15.5 g/UI. We obtained similar results for the group with HbA1c < 7%. The real CIR differed significantly from the theoretical CIR values and between breakfast and the other main meals (P < .005). CONCLUSIONS: CIR in our population was significantly lower for breakfast than for other meals. CIR using the 500/TDID formula underestimated prandial insulin requirements. A calculation of 350/TDID for breakfast and 400/TDID for lunch and dinner would be more appropriate for this population.


Assuntos
Diabetes Mellitus Tipo 1/sangue , Carboidratos da Dieta/análise , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Insulina/uso terapêutico , Adulto , Idoso , Algoritmos , Feminino , Hemoglobina A Glicada/análise , Humanos , Sistemas de Infusão de Insulina , Masculino , Região do Mediterrâneo , Pessoa de Meia-Idade , Sistema de Registros , Reprodutibilidade dos Testes , Estudos Retrospectivos , Espanha
18.
Hormones (Athens) ; 13(1): 74-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24722129

RESUMO

OBJECTIVE: The aim of the study was to describe the clinical, biochemical, and genetic features of a sample of Mediterranean patients with RTH (resistance to thyroid hormone) due to mutations in TRß (thyroid hormone receptor beta) referred to our institution during the last 15 years. DESIGN: 166 blood samples were received for RTH genetic testing between January 1997 and December 2011. Genetic testing was performed by PCR amplification followed by sequencing of exons 7, 8, 9, and 10. Clinical and biochemical features were obtained from available information sent by referring hospitals. RESULTS: Mutations were identified in 50 patients (29 probands and 21 relatives). 64% were women, and mean ± stdev age at diagnosis among probands was 33.2 ± 20.5 years. The following clinical features were recorded: goiter in 50%, hyperkinetic behavior in 32%, and tachycardia in 29%. Up to 19% of the probands had undergone some type of thyroidal ablative therapy before diagnosis. As for biochemical features, mean ± stdev TSH was 10.2 ± 21.4 mUI/L, and mean ± stdev fT4 was 35.5 ± 10.8 pmol/L. We found four new mutations: p.Phe451Leu, p.Pro452Arg, p.Glu457Gly, and p.Phe459Leu. CONCLUSIONS: The clinical and biochemical characteristics of our samples of Mediterranean populations with RTH were similar to those described in the published literature. Interestingly, in our populations we have identified four novel mutations in the TRß gene.


Assuntos
Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Bócio/genética , Grécia , Humanos , Hipercinese/genética , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Espanha , Taquicardia/genética , Adulto Jovem
19.
Methods Mol Biol ; 1062: 165-73, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24057365

RESUMO

Transient assays provide a convenient alternative to stable transformation. Compared to the generation of stably transformed plants, agroinfiltration is more rapid, and samples can be analyzed a few days after inoculation. Nevertheless, at difference of tobacco and other plant species, Arabidopsis thaliana remains recalcitrant to routine transient assays. In this chapter, we describe a transient expression assay using simple infiltration of intact Arabidopsis leaves with Agrobacterium tumefaciens carrying a plasmid expressing a reporter fluorescent protein. In this protocol, Agrobacterium aggressiveness was increased by a prolonged treatment in an induction medium deficient in nutrients and containing acetosyringone. Besides, Arabidopsis plants were cultivated in intermediate photoperiod (12 h light-12 h dark) to promote leaf growth.


Assuntos
Agrobacterium tumefaciens/genética , Arabidopsis/genética , Engenharia Genética/métodos , Folhas de Planta/genética , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Técnicas de Cultura , Eletroporação , Técnicas de Transferência de Genes , Proteínas Luminescentes/biossíntese , Proteínas Luminescentes/genética , Microscopia Confocal , Microscopia de Fluorescência , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/metabolismo , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/crescimento & desenvolvimento , Plantas Geneticamente Modificadas/metabolismo , Transformação Genética
20.
Clin Endocrinol (Oxf) ; 80(2): 301-6, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23826916

RESUMO

INTRODUCTION: Thyroglobulin (Tg), the most common marker to determine remission of differentiated thyroid carcinoma (DTC), can take 18 months or longer to be undetectable. We hypothesized that Tg stimulated after surgery and immediately before radioiodine treatment (baseline-stimulated Tg) could be a good predictor of remission at 18-24 months. The aim of this study was to evaluate the role of baseline-stimulated Tg as early prognostic marker of DTC. PATIENTS AND METHODS: Retrospective study of 133 patients with DTC from 1998 to 2010 (age at diagnosis 47·4 ± 16·8, follow-up 5·09 ± 3·2 years). Initial subset analysis was performed after excluding patients with positive TgAb, who were later included in the second. Baseline-stimulated Tg was divided into tertiles. Multivariate logistic regression analysis included baseline Tg and other known prognostic markers and receiver operating characteristic (ROC) curve to identify the best cut-off level of baseline Tg were performed. RESULTS: Baseline-stimulated Tg in the highest tertile was the only predictive variable of persistence of disease at 18-24 months in the initial analysis (OR 45·3, P < 0·01). In the second analysis, the predictive variables were baseline-stimulated Tg (OR 39·6, P < 0·001), presence of TgAb (OR 23·4, P < 0·005) and uptake outside of the thyroid bed post-treatment whole body scan (WBS; OR 5·3, P < 0·05) were predictive of persistence of disease. The ROC curve showed that baseline-stimulated Tg below 8·55 µg/l identified 95% of disease-free patients at 18-24 months after initial treatment. CONCLUSIONS: Baseline-stimulated Tg is a good predictor of remission of disease at 18-24 months after initial treatment and could be a useful marker to stratify risk immediately after surgery.


Assuntos
Biomarcadores Tumorais/análise , Tireoglobulina/análise , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/terapia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Indução de Remissão , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/diagnóstico , Fatores de Tempo , Resultado do Tratamento
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