RESUMEN
Se describe el caso de un paciente de 70 años que consultó por cefalea súbita, tipo trueno, sin alteración del estado de consciencia, acompañada de dolor torácico de una hora de evolución y de baja intensidad. A su ingreso fue enfocado como cefalea en trueno, que es clasificada, en cuanto a la atención, como bandera roja. La medición de troponina fue negativa y una tomografía de cráneo fue leída como normal. Desde el ingreso presentaba signos vitales normales, cuando iba a ser dado de alta se torna hipotenso (completamente asintomático) y por su síntoma cardinal (cefalea), que se asoció a dolor torácico leve y no anginoso, se solicitó angiotomografía toracoabdominal, con la que se demostró aneurisma disecante de la aorta. Con la presentación de este caso, se busca resaltar la importancia en el servicio de urgencias de la asociación de la cefalea tipo trueno, con condiciones vasculares como la disección aórtica.
We describe the case of a 70-year-old patient, who seeks medical advice due to sudden, thunder headache, without alteration of the state of consciousness, accompanied by chest pain of 1 hour of evolution and of low intensity. Upon his admission, the patient was treated as a thunderclap headache, which is considered a red flag. His troponin was negative, and his head tomography was interpreted as normal. From admission he had normal vital signs, but when he was going to be discharged, he became hypotensive (completely asymptomatic) and due to his cardinal symptom (headache) that was asso-ciated with mild non-anginal chest pain, a thoracoabdominal angioCT was requested, with which dissecting aneurysm of the aorta was evidenced. With the presentation of this case, we seek to highlight the importance of the association of thunder-type headache with possible vascular conditions such as aortic dissection in the emergency department.
Descrevemos o caso de uma paciente de 70 anos que consultou por quadro de cefaleia súbita, tipo trovão, sem alteração do estado de consciência, acompanhada de dor torácica de uma hora de evolução e de baixa intensidade. Na admissão, foi tratado como cefaleia em trovoada, que é classificada, em termos de atenção, como bandeira vermelha. A me-dição da troponina foi negativa e uma tomografia de crânio foi lida como normal. Desde a admissão apresentava sinais vitais normais, quando ia receber alta ficou hipotenso (totalmente assintomático) e devido ao seu sintoma cardinal (cefaleia), que se associou a dores torácicas ligeiras e não anginosas, foi solicitada angiografia toracoabdominal, com cujo aneurisma dissecante da aorta foi demonstrado. Com a apresentação deste caso, o objetivo é destacar a importância no pronto-socorro da associação da cefaleia do tipo trovão com afecções vasculares como a dissecção da aorta.
Asunto(s)
Humanos , Disección Aórtica , Aorta , Dolor en el Pecho , Angiografía , CefaleaRESUMEN
Este trabalho teve como objetivo avaliar o efeito da substituição da farinha e do óleo de peixe pelo concentrado proteico de soja e óleo de soja, na sobrevivência, no crescimento e na composição corporal dos camarões (Litopenaeus vannamei) produzidos em sistema de bioflocos (BFT). Foram formuladas cinco dietas, isoproteicas e isoenergéticas, com diferentes níveis de substituição da farinha e do óleo de peixe por concentrado proteico de soja e óleo de soja, sendo os tratamentos designados como: 0% (sem substituição), 25%, 50%, 75% e 100%. As rações foram elaboradas para conter aproximadamente 35% de proteína e 8% de lipídios. O experimento foi conduzido durante 49 dias, com juvenis com peso inicial de 2,93±0,83g, em sistema de bioflocos (BFT). Não foram encontradas diferenças significativas entre os tratamentos até 75% de substituição para as variáveis de ganho de peso, conversão alimentar e sobrevivência. O tratamento de 100% de substituição apresentou menor taxa de crescimento específico. O presente resultado sugere que, nas dietas para camarões criados em sistema bioflocos, a farinha e o óleo de peixe possam ser substituídos em até 75% por concentrado proteico de soja e óleo de soja, sem prejudicar o desenvolvimento dos animais.(AU)
The objective of this work was to evaluate the effect of the substitution of fishmeal and fish oil with soy protein concentrate and soybean oil on survival, growth and body composition of shrimp (Litopenaeus vannamei) produced in biofloc system (BFT). Five diets were formulated to be isoproteic and isoenergetic with different levels of substitution of fishmeal and fish oil with soy protein concentrate and soybean oil. The treatments were named as: 0% (without substitution), 25%, 50%, 75% and 100%. The diets were formulated to contain approximately 35% protein and 8% lipids. The experiment was conducted for 49 days, with juveniles with initial weight of (2.93±0.83g) in a biofloc system (BFT). No significant differences were found between treatments up to 75% of substitution for the variables of weight gain, feed conversion ratio, and survival. The 100% substitution treatment showed a lower specific growth rate. The present study suggests fish meal and fish oil can be substituted in up to 75% for soy protein concentrate and soybean oil, without harming the development of the shrimps when reared in biofloc system.(AU)
Asunto(s)
Animales , Mariscos , Aceite de Soja , Penaeidae , Alimentos de Soja , Dieta/veterinaria , Productos Pesqueros , Alimentación Animal/análisisRESUMEN
BACKGROUND: The multicenter randomized controlled COBALT trial demonstrated that ultrasound-guided breast-conserving surgery (USS) results in a significant reduction of margin involvement (3.1% vs. 13%) and excision volumes compared to palpation-guided surgery (PGS). The aim of the present study was to determine long term oncological and patient-reported outcomes including quality of life (QoL), together with their progress over time. METHODS: 134 patients with T1-T2 breast cancer were randomized to USS (N = 65) or PGS (N = 69). Cosmetic outcomes were assessed with the Breast Cancer Conservative Treatment cosmetic results (BCCT.core) software, panel-evaluation and patient self-evaluation on a 4-point Likert-scale. QoL was measured using the EORTC QLQ-C30/-BR23 questionnaire. RESULTS: No locoregional recurrences were reported after mean follow-up of 41 months. Seven patients (5%) developed distant metastatic disease (USS 6.3%, PGS 4.4%, p = 0.466), of whom six died of disease (95.5% overall survival). USS achieved better cosmetic outcomes compared to PGS, with poor outcomes of 11% and 21% respectively, a result mainly attributable to mastectomies due to involved margins following PGS. There was no difference after 1 and 3 years in cosmetic outcome. Dissatisfied patients included those with larger excision volumes, additional local therapies and worse QoL. Patients with poor/fair cosmetic outcomes scored significantly lower on aspects of QoL, including breast-symptoms, body image and sexual enjoyment. CONCLUSION: By significantly reducing positive margin status and lowering resection volumes, USS improves the rate of good cosmetic outcomes and increases patient-satisfaction. Considering the large impact of cosmetic outcome on QoL, USS has great potential to improve QoL following breast-conserving therapy.
Asunto(s)
Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/cirugía , Carcinoma Lobular/cirugía , Mastectomía Segmentaria/métodos , Satisfacción del Paciente , Cirugía Asistida por Computador/métodos , Adulto , Anciano , Axila , Imagen Corporal , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/diagnóstico por imagen , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/diagnóstico por imagen , Carcinoma Lobular/patología , Estética , Femenino , Humanos , Escisión del Ganglio Linfático , Márgenes de Escisión , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Estadificación de Neoplasias , Medición de Resultados Informados por el Paciente , Calidad de Vida , Salud Reproductiva , Encuestas y Cuestionarios , Resultado del Tratamiento , Ultrasonografía MamariaAsunto(s)
Cisteína Endopeptidasas/genética , Diabetes Mellitus Tipo 1/enzimología , Células Secretoras de Insulina/fisiología , Péptidos y Proteínas de Señalización Intracelular/genética , Animales , Apoptosis , Cisteína Endopeptidasas/metabolismo , Citocinas/fisiología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones Noqueados , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfaRESUMEN
Diets rich in saturated fats may contribute to the loss of pancreatic ß-cells in type 2 diabetes. JunB, a member of the activating protein 1 (AP-1) transcription factor family, promotes ß-cell survival and mediates part of the beneficial effects of GLP-1 agonists. In this study we interrogated the molecular mechanisms involved in JunB-mediated ß-cell protection from lipotoxicity. The saturated fatty acid palmitate decreased JunB expression, and this loss may contribute to ß-cell apoptosis, as overexpression of JunB protected cells from lipotoxicity. Array analysis of JunB-deficient ß-cells identified a gene expression signature of a downregulated endoplasmic reticulum (ER) stress response and inhibited AKT signaling. JunB stimulates XBP1 expression via the transcription factor c/EBPδ during ER stress, and forced expression of XBP1s rescued the viability of JunB-deficient cells, constituting an important antiapoptotic mechanism. JunB silencing inhibited AKT activation and activated the proapoptotic Bcl-2 protein BAD via its dephosphorylation. BAD knockdown reversed lipotoxic ß-cell death potentiated by JunB siRNA. Interestingly, XBP1s links JunB and AKT signaling as XBP1 knockdown also reduced AKT phosphorylation. GLP-1 agonists induced cAMP-dependent AKT phosphorylation leading to ß-cell protection against palmitate-induced apoptosis. JunB and XBP1 knockdown or IRE1 inhibition decreased AKT activation by cAMP, leading to ß-cell apoptosis. In conclusion, JunB modulates the ß-cell ER stress response and AKT signaling via the induction of XBP1s. The activation of the JunB gene network and the crosstalk between the ER stress and AKT pathway constitute a crucial defense mechanism by which GLP-1 agonists protect against lipotoxic ß-cell death. These findings elucidate novel ß-cell-protective signal transduction in type 2 diabetes.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Células Secretoras de Insulina/metabolismo , Factores de Transcripción/metabolismo , Animales , Proteínas de Unión al ADN/genética , Diabetes Mellitus Tipo 2/enzimología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Células Secretoras de Insulina/enzimología , Masculino , Persona de Mediana Edad , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Factores de Transcripción del Factor Regulador X , Transducción de Señal , Factores de Transcripción/genética , Proteína 1 de Unión a la X-BoxRESUMEN
A acne é uma doença de pele extremamente comum. Sua patogênese é multifatorial, incluindo hiperqueratinização folicular, hiperplasia sebácea, hipercolonização bacteriana. A Propionibacterium acnes possui um papel relevante na resposta inflamatória da patogênese da acne. Os antibióticos representam uma das classes de medicamentos utilizadas no tratamento da acne. No entanto, as reações adversas causadas por esses fármacos tornam o tratamento desagradável, além de casos relatados de resistência bacteriana. Por esse motivo, o uso de produtos naturais tem sido destaque na área de dermatologia. O presente trabalho visou avaliar "in vitro" os possíveis efeitos antimicrobianos do óleo essencial de Rosmarinus officinalis e da tintura de própolis sobre cepa de Propionibacterium acnes (ATCC 1969). O óleo essencial foi extraído pela técnica de hidrodestilação e obteve-se a tintura de própolis por maceração. O ensaio antimicrobiano foi realizado pela técnica da diluição em tubos. O óleo foi testado em diferentes concentrações, variando de 16% a 0,0625% e a tintura de 10% a 0,072312%. Pode-se verificar que o óleo essencial de Rosmarinus officinalis L. não apresentou atividade antibacteriana contra a cepa de Propionibacterium acnes. A tintura de própolis teve ação em várias concentrações, sendo a concentração inibitória mínima de 0,625%.
Acne is an extremely common skin disease. The pathogenesis of acne is multifactorial, including follicular hyperkeratinization, sebaceous hyperplasia and hypercolonization of bacteria. The Propionibacterium acnes has an important role in the inflammatory response of the pathogenesis of acne. Antibiotics are one of the drugs used in the treatment of acne. However, the adverse reactions caused by these drugs turn the treatment unpleasant, besides the existence of cases of bacterial resistance. For this reason, the use of natural products has been prominent in the dermatology area. This work intended to perform an in vitro evaluation of the possible antimicrobial effects of the essential oil of Rosmarinus officinalis and propolis tincture on the Propionibacterium acnes (ATCC 1969) strain. The essential oil was extracted by hydrodistillation, and the propolis tincture was obtained by maceration. The antimicrobial test was conducted by the tube dilution technique. The oil was tested in different concentrations varying between 16% and 0.0625%, and the tincture, between 10% and 0.072312%. We verified that the essential oil of Rosmarinus officinalis has no effects against the Propionibacterium acnes strain. The propolis tincture showed some action in several concentrations, being the minimal inhibitory concentration: 0.625%.
Asunto(s)
Propionibacterium acnes/clasificación , Aceites Volátiles/farmacología , Rosmarinus/clasificación , Própolis/farmacología , Acné Vulgar/tratamiento farmacológico , Componentes Aéreos de las PlantasRESUMEN
Cell-to-cell communication mediated by gap junctions made of Connexin36 (Cx36) contributes to pancreatic ß-cell function. We have recently demonstrated that Cx36 also supports ß-cell survival by a still unclear mechanism. Using specific Cx36 siRNAs or adenoviral vectors, we now show that Cx36 downregulation promotes apoptosis in INS-1E cells exposed to the pro-inflammatory cytokines (IL-1ß, TNF-α and IFN-γ) involved at the onset of type 1 diabetes, whereas Cx36 overexpression protects against this effect. Cx36 overexpression also protects INS-1E cells against endoplasmic reticulum (ER) stress-mediated apoptosis, and alleviates the cytokine-induced production of reactive oxygen species, the depletion of the ER Ca(2+) stores, the CHOP overexpression and the degradation of the anti-apoptotic protein Bcl-2 and Mcl-1. We further show that cytokines activate the AMP-dependent protein kinase (AMPK) in a NO-dependent and ER-stress-dependent manner and that AMPK inhibits Cx36 expression. Altogether, the data suggest that Cx36 is involved in Ca(2+) homeostasis within the ER and that Cx36 expression is downregulated following ER stress and subsequent AMPK activation. As a result, cytokine-induced Cx36 downregulation elicits a positive feedback loop that amplifies ER stress and AMPK activation, leading to further Cx36 downregulation. The data reveal that Cx36 plays a central role in the oxidative stress and ER stress induced by cytokines and the subsequent regulation of AMPK activity, which in turn controls Cx36 expression and mitochondria-dependent apoptosis of insulin-producing cells.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Conexinas/metabolismo , Citocinas/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Calcio/metabolismo , Caspasa 3/metabolismo , Supervivencia Celular/efectos de los fármacos , Conexinas/genética , AMP Cíclico/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Retroalimentación Fisiológica/efectos de los fármacos , Humanos , Insulina/biosíntesis , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Interleucina-1beta/farmacología , Metformina/farmacología , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Modelos Biológicos , Ratas , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Elementos de Respuesta/genética , Transcripción Genética/efectos de los fármacos , Proteína delta-6 de Union ComunicanteRESUMEN
Ultrasound-guided surgery (USS) has recently been proven to result in a significant reduction of tumour-involved surgical margins, for patients with palpable invasive breast cancer. The objective of this economic evaluation alongside a randomised trial was to evaluate the costs and benefits of USS compared to palpation-guided surgery (PGS). The hospital perspective was used. On the cost side of the analysis, resource use related to baseline treatment was taken into account and on the benefit side, resource use related to additional treatments was included. On the cost side, the difference in costs per patient was 193 (95% CI 153-233) with higher costs in the USS group. On the benefit side, the difference in costs per patient was -349 (95% CI -591 to -103) with higher costs in the PGS group. This resulted in a cost decrease of -154 (95% CI -388 to 81) in the USS group compared to the PGS group. Intra-operative use of a US system during BCS reduces the rate of tumour-involved margins and thereby the costs of additional treatments.
Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/cirugía , Mastectomía Segmentaria/economía , Ultrasonografía Intervencional/economía , Análisis Costo-Beneficio , Femenino , Humanos , Mastectomía Segmentaria/métodos , Persona de Mediana Edad , Neoplasia Residual , Países BajosRESUMEN
AIM: The Enhanced Recovery After Surgery (ERAS) programme is a multimodal approach to improve peri-operative care in colon surgery. The aim of this study was to report on the adherence to and outcomes of ERAS in the first years after implementation. METHOD: Data of patients undergoing elective colon resections for malignancy in 2006 until 2010 were compared with patients receiving conventional care in 2005. Retrospective analysis was performed including length of stay (LOS), protocol adherence and complications. The predictive values of ERAS items and baseline characteristics on LOS and complications were analysed using univariate and multivariate analysis. RESULTS: Length of stay (LOS) was significantly shorter in 2006 and 2007 (P ≤ 0.009 and P ≤ 0.004) but not in 2008 and 2009. The mean adherence rate to the ERAS items was 84.1% in 2006 and 2007 and 72.4% in 2008 and 2009 (P < 0.001). In 2005, 2008 and 2009 LOS was significantly shorter for laparoscopically operated patients than for patients with open resections (P < 0.002, P < 0.001 and P < 0.004 respectively). Multivariate analysis showed that age, laparoscopic surgery, removal of nasogastric tube before extubation, mobilization within 24 h after surgery, starting nonsteroidal anti-inflammatory drugs at day 1 and removal of thoracic epidural analgesia at day 2 were independent predictors of LOS. CONCLUSION: Strict adherence to the ERAS protocol was associated with reduced LOS and improved outcome in elective colon surgery for malignancy. These benefits were lost when protocol adherence was lower. Embedding the ERAS protocol into an organization and repetitive education are vital to sustain its beneficial effects on LOS and outcome.
Asunto(s)
Colectomía/rehabilitación , Neoplasias del Colon/cirugía , Tiempo de Internación , Cooperación del Paciente , Cuidados Posoperatorios/métodos , Recuperación de la Función/fisiología , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Colectomía/efectos adversos , Neoplasias del Colon/rehabilitación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Programas y Proyectos de Salud , Análisis de Regresión , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Protein synthesis is increased by several-fold in stimulated pancreatic beta cells. Synthesis and folding of (pro)insulin takes place in the endoplasmic reticulum (ER), and beta cells trigger the unfolded protein response (UPR) to upgrade the functional capacity of the ER. Prolonged or excessive UPR activation contributes to beta cell dysfunction and death in type 2 diabetes, but there is another side of the UPR that may be of particular relevance for autoimmune type 1 diabetes, namely, the cross-talk between the UPR and innate immunity/inflammation. Recent evidence, discussed in this review, indicates that both saturated fats and inflammatory mediators such as cytokines trigger the UPR in pancreatic beta cells. The UPR potentiates activation of nuclear factor κB, a key regulator of inflammation. Two branches of the UPR, namely IRE1/XBP1s and PERK/ATF4/CHOP, mediate the UPR-induced sensitisation of pancreatic beta cells to the proinflammatory effects of cytokines. This can contribute to the upregulation of local inflammatory mechanisms and the aggravation of insulitis. The dialogue between the UPR and inflammation may provide an explanation for the parallel increase in the prevalence of childhood obesity and type 1 diabetes.
Asunto(s)
Estrés del Retículo Endoplásmico/fisiología , Islotes Pancreáticos/metabolismo , Respuesta de Proteína Desplegada/fisiología , Animales , Estrés del Retículo Endoplásmico/genética , Humanos , Transducción de Señal/genética , Transducción de Señal/fisiología , Respuesta de Proteína Desplegada/genéticaRESUMEN
Induction of the C/EBP homologous protein (CHOP) is considered a key event for endoplasmic reticulum (ER) stress-mediated apoptosis. Type 1 diabetes (T1D) is characterized by an autoimmune destruction of the pancreatic ß-cells. Pro-inflammatory cytokines are early mediators of ß-cell death in T1D. Cytokines induce ER stress and CHOP overexpression in ß-cells, but the role for CHOP overexpression in cytokine-induced ß-cell apoptosis remains controversial. We presently observed that CHOP knockdown (KD) prevents cytokine-mediated degradation of the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1), thereby decreasing the cleavage of executioner caspases 9 and 3, and apoptosis. Nuclear factor-κB (NF-κB) is a crucial transcription factor regulating ß-cell apoptosis and inflammation. CHOP KD resulted in reduced cytokine-induced NF-κB activity and expression of key NF-κB target genes involved in apoptosis and inflammation, including iNOS, FAS, IRF-7, IL-15, CCL5 and CXCL10. This was due to decreased IκB degradation and p65 translocation to the nucleus. The present data suggest that CHOP has a dual role in promoting ß-cell death: (1) CHOP directly contributes to cytokine-induced ß-cell apoptosis by promoting cytokine-induced mitochondrial pathways of apoptosis; and (2) by supporting the NF-κB activation and subsequent cytokine/chemokine expression, CHOP may contribute to apoptosis and the chemo attraction of mononuclear cells to the islets during insulitis.
Asunto(s)
Apoptosis/efectos de los fármacos , Citocinas/farmacología , Células Secretoras de Insulina/metabolismo , Factor de Transcripción CHOP/metabolismo , Animales , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Línea Celular , Núcleo Celular/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Estrés del Retículo Endoplásmico , Quinasa I-kappa B/metabolismo , Células Secretoras de Insulina/citología , Interferón gamma/farmacología , Interleucina-1beta/farmacología , Mitocondrias/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Factor de Transcripción CHOP/antagonistas & inhibidores , Factor de Transcripción CHOP/genética , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Type 1 diabetes is a chronic autoimmune disease involving the progressive loss of beta cell mass. Cytokines released by immune cells are early contributors to beta cell apoptosis. Thus, an understanding of the signal transduction mechanisms induced by cytokines in beta cells is necessary for the rational design of novel therapies to prevent or to cure this disease. Cytokine-mediated beta cell apoptosis is a complex phenomenon that includes activation of the transcription factors signal transducer and activator of transcription 1 and nuclear factor κB (NFκB), c-Jun N-terminal kinase, endoplasmic reticulum (ER) stress and the intrinsic mitochondrial apoptotic pathway. NFκB has both a pro-inflammatory and a pro-apoptotic role in beta cells. One of the mechanisms by which NFκB contributes to beta cell apoptosis is via activation of ER stress. The role for ER stress in beta cell apoptosis is not completely clarified but involves production of C/EBP homologous protein and activation of the intrinsic mitochondrial apoptotic pathway. In this issue of Diabetologia, Roggli et al (DOI 10.1007/s00125-011-2399-7) report on a new player in this elaborate response, the RNA-binding protein ARE/poly(U)-binding factor 1. This commentary discusses these findings and their relevance to the field.
Asunto(s)
Ribonucleoproteína Heterogénea-Nuclear Grupo D/metabolismo , Islotes Pancreáticos/metabolismo , Isoformas de Proteínas/metabolismo , Ribonucleoproteína Nuclear Heterogénea D0 , HumanosRESUMEN
AIMS/HYPOTHESIS: Endoplasmic reticulum (ER) stress has been implicated in the development of type 2 diabetes, via effects on obesity, insulin resistance and pancreatic beta cell health. C/EBP homologous protein (CHOP) is induced by ER stress and has a central role in apoptotic execution pathways triggered by ER stress. The aim of this study was to characterise the role of CHOP in obesity and insulin resistance. METHODS: Metabolic studies were performed in Chop ( -/- ) and wild-type C57Bl/6 mice, and included euglycaemic-hyperinsulinaemic clamps and indirect calorimetry. The inflammatory state of liver and adipose tissue was determined by quantitative RT-PCR, immunohistology and macrophage cultures. Viability and absence of ER stress in islets of Langerhans was determined by electron microscopy, islet culture and quantitative RT-PCR. RESULTS: Systemic deletion of Chop induced abdominal obesity and hepatic steatosis. Despite marked obesity, Chop ( -/- ) mice had preserved normal glucose tolerance and insulin sensitivity. This discrepancy was accompanied by lower levels of pro-inflammatory cytokines and less infiltration of immune cells into fat and liver. CONCLUSIONS/INTERPRETATION: These observations suggest that insulin resistance is not induced by fat accumulation per se, but rather by the inflammation induced by ectopic fat. CHOP may play a key role in the crosstalk between excessive fat deposition and induction of inflammation-mediated insulin resistance.
Asunto(s)
Hígado Graso/metabolismo , Inflamación/metabolismo , Resistencia a la Insulina/fisiología , Obesidad/metabolismo , Factor de Transcripción CHOP/metabolismo , Tejido Adiposo/metabolismo , Animales , Hígado Graso/genética , Intolerancia a la Glucosa/genética , Intolerancia a la Glucosa/metabolismo , Inflamación/genética , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Hígado/metabolismo , Ratones , Ratones Noqueados , Obesidad/genética , Factor de Transcripción CHOP/genéticaRESUMEN
AIMS: To evaluate if intra-operative guidance with ultrasonography (US) could improve surgical accuracy of palpable breast cancer excision, and to evaluate the performance of surgeons during training for US-guided excision. MATERIALS AND METHODS: Thirty female patients undergoing breast-conserving surgery for palpable T1-T2 invasive breast cancer were recruited. Three individual breast surgeons, assisted by US, targeted and excised the tumours. The main objective was to obtain adequate resection margins with optimal resection volumes. The specimen volume, tumour diameter and histological margin status were recorded. The specimen volume was divided by the optimal resection volume, defined as the spherical tumour volume plus a 1.0-cm margin. The resulting calculated resection ratio (CRR) indicated the amount of excess tissue resected. RESULTS: All tumours were correctly identified during surgery, 29 of 30 tumours (96.7%) were removed with adequately negative margins, and one tumour was removed with focally positive margins. The median CRR was 1.0 (range, 0.4-2.8), implying optimal excision volume. For all breast surgeons, CRR improved during the training period. By the 8th procedure, all surgeons showed proficiency in performing intra-operative breast US. CONCLUSION: Surgeons can easily learn the skills needed to perform intra-operative US for palpable breast tumour excision. The technique is non-invasive, simple, safe and effective for obtaining adequate resection margins. Within the first two cases, resections reached optimal volumes, thereby, presumably resulting in improved cosmetic outcomes. In a multicentre, randomised, clinical trial, intra-operative US guidance for palpable breast tumours will be evaluated for oncological and cosmetic outcomes.
Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/cirugía , Curva de Aprendizaje , Mastectomía Segmentaria/educación , Mastectomía Segmentaria/métodos , Ultrasonografía Mamaria , Adulto , Neoplasias de la Mama/patología , Carcinoma Adenoescamoso/diagnóstico por imagen , Carcinoma Adenoescamoso/cirugía , Carcinoma Ductal de Mama/diagnóstico por imagen , Carcinoma Ductal de Mama/cirugía , Carcinoma Intraductal no Infiltrante/diagnóstico por imagen , Carcinoma Intraductal no Infiltrante/cirugía , Carcinoma Papilar/diagnóstico por imagen , Carcinoma Papilar/cirugía , Estudios de Factibilidad , Femenino , Humanos , Periodo Intraoperatorio , Masculino , Persona de Mediana Edad , Proyectos de InvestigaciónRESUMEN
Pancreatic ß-cell apoptosis is a key feature of diabetes mellitus and the mitochondrial pathway of apoptosis is a major mediator of ß-cell death. We presently evaluated the role of the myeloid cell leukemia sequence 1 (Mcl-1), an antiapoptotic protein of the Bcl-2 family, in ß-cells following exposure to well-defined ß-cell death effectors, for example, pro-inflammatory cytokines, palmitate and chemical endoplasmic reticulum (ER) stressors. All cytotoxic stresses rapidly and preferentially decreased Mcl-1 protein expression as compared with the late effect observed on the other antiapoptotic proteins, Bcl-2 and Bcl-xL. This was due to ER stress-mediated inhibition of translation through eIF2α phosphorylation for palmitate and ER stressors and through the combined action of translation inhibition and JNK activation for cytokines. Knocking down Mcl-1 using small interference RNAs increased apoptosis and caspase-3 cleavage induced by cytokines, palmitate or thapsigargin, whereas Mcl-1 overexpression partly prevented Bax translocation to the mitochondria, cytochrome c release, caspase-3 cleavage and apoptosis induced by the ß-cell death effectors. Altogether, our data suggest that Mcl-1 downregulation is a crucial event leading to ß-cell apoptosis and provide new insights into the mechanisms linking ER stress and the mitochondrial intrinsic pathway of apoptosis. Mcl-1 is therefore an attractive target for the design of new strategies in the treatment of diabetes.
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Apoptosis , Citocinas/farmacología , Células Secretoras de Insulina/metabolismo , Palmitatos/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Animales , Caspasa 3/metabolismo , Línea Celular Tumoral , Citocromos c/metabolismo , Regulación hacia Abajo , Retículo Endoplásmico/metabolismo , Células Secretoras de Insulina/citología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas Proto-Oncogénicas c-bcl-2/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Ratas , Tapsigargina/farmacología , Proteína X Asociada a bcl-2/metabolismo , Proteína bcl-X/metabolismoRESUMEN
Multiple system atrophy (MSA) is a Parkinson's Disease (PD)-like α-synucleinopathy clinically characterized by dysautonomia, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. We aimed to determine whether the clinical presentation of MSA as well as diagnostic and therapeutic strategies differ across Europe and Israel. In 19 European MSA Study Group centres all consecutive patients with a clinical diagnosis of MSA were recruited from 2001 to 2005. A standardized minimal data set was obtained from all patients. Four-hundred thirty-seven MSA patients from 19 centres in 10 countries were included. Mean age at onset was 57.8 years; mean disease duration at inclusion was 5.8 years. According to the consensus criteria 68% were classified as parkinsonian type (MSA-P) and 32% as cerebellar type (MSA-C) (probable MSA: 72%, possible MSA: 28%). Symptomatic dysautonomia was present in almost all patients, and urinary dysfunction (83%) more common than symptomatic orthostatic hypotension (75%). Cerebellar ataxia was present in 64%, and parkinsonism in 87%, of all cases. No significant differences in the clinical presentation were observed between the participating countries. In contrast, diagnostic work up and therapeutic strategies were heterogeneous. Less than a third of patients with documented orthostatic hypotension or neurogenic bladder disturbance were receiving treatment. This largest clinical series of MSA patients reported so far shows that the disease presents uniformly across Europe. The observed differences in diagnostic and therapeutic management including lack of therapy for dysautonomia emphasize the need for future guidelines in these areas.
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Atrofia de Múltiples Sistemas/diagnóstico , Atrofia de Múltiples Sistemas/terapia , Sistema de Registros , Edad de Inicio , Antiparkinsonianos/uso terapéutico , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/fisiopatología , Europa (Continente) , Femenino , Humanos , Hipotensión Ortostática/diagnóstico , Hipotensión Ortostática/fisiopatología , Levodopa/uso terapéutico , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/fisiopatología , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/fisiopatología , Síndrome de Shy-Drager/diagnóstico , Síndrome de Shy-Drager/fisiopatologíaRESUMEN
OBJECTIVE: We report a case of anterior spinal artery syndrome, an extremely rare complication, following head and neck surgery. METHOD: A case report and literature review concerning anterior spinal artery syndrome is presented. RESULTS: A 64-year-old man developed an anterior spinal artery infarction following total laryngectomy and bilateral neck dissections for post-radiotherapy glottic carcinoma. Anterior spinal artery infarction is a rare syndrome. It typically presents with weakness, loss of pain and temperature sensation below the level of the injury, with relative sparing of position and vibratory sensation. Recovery is variable. CONCLUSION: To the best of our knowledge, this is the first case report in the English language literature of anterior spinal artery syndrome following a head and neck procedure. This case report highlights a rare complication, and also the susceptibility of head and neck surgery patients to different complications. In head and neck cancer patients suffering anterior spinal artery syndrome following primary surgical treatment, we recommend that the management of this complication should be as aggressive as that of the primary cancer.
Asunto(s)
Síndrome de la Arteria Espinal Anterior/etiología , Neoplasias Laríngeas/cirugía , Laringectomía/efectos adversos , Hemorragia Posoperatoria/complicaciones , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Disección del Cuello/efectos adversos , Paraparesia/etiología , Hemorragia Posoperatoria/cirugía , ReoperaciónRESUMEN
AIMS/HYPOTHESIS: Pro-inflammatory cytokines involved in the pathogenesis of type 1 diabetes deplete endoplasmic reticulum (ER) Ca2+ stores, leading to ER-stress and beta cell apoptosis. However, the cytokine-induced ER-stress response in beta cells is atypical and characterised by induction of the pro-apoptotic PKR-like ER kinase (PERK)-C/EBP homologous protein (CHOP) branch of the unfolded protein response, but defective X-box binding protein 1 (XBP1) splicing and activating transcription factor 6 activation. The purpose of this study was to overexpress spliced/active Xbp1 (XBP1s) to increase beta cell resistance to cytokine-induced ER-stress and apoptosis. METHODS: Xbp1s was overexpressed using adenoviruses and knocked down using small interference RNA in rat islet cells. In selected experiments, Xbp1 was also knocked down in FACS-purified rat beta cells and rat fibroblasts. Expression and production of XBP1s and key downstream genes and proteins was measured and beta cell function and viability were evaluated. RESULTS: Adenoviral-mediated overproduction of Xbp1s resulted in increased XBP1 activity and induction of several XBP1s target genes. Surprisingly, XBP1s overexpression impaired glucose-stimulated insulin secretion and increased beta cell apoptosis, whereas it protected fibroblasts against cell death induced by ER-stress. mRNA expression of Pdx1 and Mafa was inhibited in cells overproducing XBP1s, leading to decreased insulin expression. XBP1s knockdown partially restored cytokine/ER-stress-driven insulin and Pdx1 inhibition but had no effect on cytokine-induced ER-stress and apoptosis. CONCLUSIONS/INTERPRETATION: XBP1 has a distinct inhibitory role in beta cell as compared with other cell types. Prolonged XBP1s production hampers beta cell function via inhibition of insulin, Pdx1 and Mafa expression, eventually leading to beta cell apoptosis.
Asunto(s)
Apoptosis/fisiología , Proteínas de Unión al ADN/metabolismo , Retículo Endoplásmico/metabolismo , Células Secretoras de Insulina/metabolismo , Factores de Transcripción/metabolismo , Análisis de Varianza , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Recuento de Células , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Proteínas de Unión al ADN/genética , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/genética , Técnica del Anticuerpo Fluorescente , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Indoles/farmacología , Insulina/genética , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/efectos de los fármacos , Interferón gamma/farmacología , Interleucina-8/farmacología , Factores de Transcripción Maf/genética , Factores de Transcripción Maf/metabolismo , Masculino , Interferencia de ARN , ARN Interferente Pequeño , Ratas , Ratas Wistar , Factores de Transcripción del Factor Regulador X , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transactivadores/genética , Transactivadores/metabolismo , Factores de Transcripción/genética , Transfección , Proteína 1 de Unión a la X-BoxRESUMEN
Chronic inflammation and pro-inflammatory cytokines are important mediators of pancreatic beta-cell destruction in type 1 diabetes (T1D). We presently show that the cytokines IL-1beta+IFN-gamma and different ER stressors activate the Bcl-2 homology 3 (BH3)-only member death protein 5 (DP5)/harakiri (Hrk) resulting in beta-cell apoptosis. Chemical ER stress-induced DP5 upregulation is JNK/c-Jun-dependent. DP5 activation by cytokines also involves JNK/c-Jun phosphorylation and is antagonized by JunB. Interestingly, cytokine-inducted DP5 expression precedes ER stress: mitochondrial release of cytochrome c and ER stress are actually a consequence of enhanced DP5 activation by cytokine-mediated nitric oxide formation. Our findings show that DP5 is central for beta-cell apoptosis after different stimuli, and that it can act up- and downstream of ER stress. These observations contribute to solve two important questions, namely the mechanism by which IL-1beta+IFN-gamma induce beta-cell death and the nature of the downstream signals by which ER stress 'convinces' beta-cells to trigger apoptosis.