Atherogenesis and atherosclerosis in primary antiphospholipid syndrome

ABSTRACT: In the late seventies the term “Haematological Stress Syndrome” defined some haematological abnormalities appearing in the course of acute and chronic disorders, such as raised plasma levels of fibrinogen (FNG) and factor VIII, reduced fibrinolytic activity and hyperviscosity. In the early nineties the “Membrane stress syndrome hypothesis” proposed the unification of the concepts of haematological stress syndrome with those of oxidation, inflammation and immune activation to explain the pathogenesis of the antiphospholipid syndrome (APS) Antiphospholipid antibodies, coagulation, fibrinolysis and thrombosis. This chapter investigated the occurrence of the “Haematological Stress Syndrome” and thrombosis in 144 participants positive for aPL detected by clotting and immune tests. Among the clotting assays for the detection of lupus anticoagulant, dilute Russell's viper venom time better correlated with a history of venous thrombosis than activated partial thromboplastin time (p<0.0002 vs p<0.009) and was the only test correlated with a history of arterial thrombosis (p<0.01). By regression analysis, serum levels of IgG anticardiolipin antibodies (aCL) associated with the number of venous occlusions (p<0.001). With regards to FNG and von Willebrand factor (vWF), the former rose by 36% (95% CI; 21%, 53%) and the latter by 50% (95% CI; 29%, 75%) at the first venous occlusion and remained unchanged after subsequent occlusions. At variance FNG rose by 45% (95% CI; 31%, 60%) per arterial occlusion and vWF by 27% (95% CI; 10%, 47%) per arterial occlusion throughout. The coagulation/fibrinolytic balance was cross-sectionally evaluated on 18 thrombotic PAPS patients, 18 subjects with persistence of idiopathic aPL and in healthy controls. Markers of thrombin generation prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT) and of fibrin turnover D-Dimer (D-D) were higher in thrombotic (p=0.006)and non-thrombotic subjects (p=0.0001) than in controls as were those of D-D (p<0.0001 and p=0.003 respectively). TAT levels did not differ. Gender analysed data revealed blunted tPA release (hence a negative venous occlusion test) in thrombotic females but neither in thrombotic males (p=0.01) nor in asymptomatic subjects of either sex. Also, in both patient groups females had higher mean PAI than males (p<0.0002) and control females (p<0.02). The activity of factor XIII (FXIIIa) was evaluated was evaluated in 29 patients with PAPS, 14 persistent carriers of aPL without thrombosis, 24 thrombotic patients with inherited thrombophilia, 28 healthy controls and 32 patients with mitral and aortic valve prosthesis as controls for FXIII only. FXIIIa was highest in PAPS (p=0.001), particularly in patients with multiple (n=12) than single occlusion (p=0.02) and in correlation with PAI (p=0.003) and FNG (p=0.005). Moreover FXIIIa was strongly associated with IgG aCL and IgG anti-2GPI (p=0.005 for both) in the PAPS group and to a lesser degree in the aPL group (FXIIIa with IgG aCL, p=0.02, with IgG anti-2GPI, p=0.04). Altogether these results indicate: 1) a differential relationship of aPL, vWF and FNG with venous and arterial thrombosis; 2) heightened thrombin generation, accelerated fibrin turnover and fibrinolysis abnormalities also in asymptomatic carriers of aPLs; 3) enhanced FXIIIa that may contribute to atherothrombosis via increased fibrin/fibrinogen cross-linking. Lipid profile, lipid peroxidation and anti-lipoprotein antibodies in thrombotic primary antiphospholipid syndrome. Given the atherogenic lipid profile of SLE, the same possibility was explored in PAPS by comparing high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (CHO), apolipoprotein AI (ApoAI), apolipoprotein B (ApoB), triglycerides (TG), anti-lipoprotein antibodies, beta-2-glycoprotein I complexed to oxidized low-density lipoprotein (oxLDL-2GPI) and C-reactive protein (CRP) in 34 thrombotic PAPS patients compared to 36 thrombotic patients with inherited thrombophilia (IT), to 18 subjects persistently positive for antiphospholipid antibodies (aPL) with no underlying autoimmune or non-autoimmune disorders and to 28 healthy controls. Average concentrations of HDL (p<0.0001), LDL (p<0.0001), CHO (p=0.0002), ApoAI (p=0.002) were lower in PAPS whereas average TRY was higher (p=0.01) than other groups. Moreover PAPS showed higher IgG anti-HDL (p=0.01) and IgG anti-ApoAI (p<0.0001) as well as greater average oxLDL-2GPI (p=0.001) and CRP (p=0.003). Within PAPS, IgG anti-HDL correlated negatively to HDL (p=0.004) and was an independent predictor of oxLDL-2GPI (p=0.009). HDL and ApoAI correlated negatively with CRP (p=0.001 and p=0.007, respectively). IgG anti-HDL may hamper the antioxidant and anti-inflammatory effect of HDL favouring low-grade inflammation and enhanced oxidation in thrombotic PAPS. Indeed plasma 8-epi-prostaglandin F2α (a very specific marker of lipid peroxidation) was significantly higher in 10 patients with PAPS than 10 age and sex matched healthy subjects (p=0.0002) and strongly related to the titre of plasma IgG aCL (r=0.89, p=0.0004). Hence oxidative stress, a major player in atherogenesis, also characterises PAPS. Nitric oxide and nitrative stress in thrombotic primary antiphosholipid syndrome. Oxidative stress goes hand in hand with nitrative stress and to address the latter plasma nitrotyrosine (NT, marker of nitrative stress), nitrite (NO2-) and nitrate (NO3-) were measured in 46 thrombotic PAPS patients, 21 asymptomatic but persistent carriers of antiphospholipid antibodies (PCaPL), 38 patients with inherited thrombophilia (IT), 33 patients with systemic lupus erythematosus (SLE) and 29 healthy controls (CTR). Average crude NT was higher in PAPS and SLE (p=0.01) whereas average plasma NO2- was lower in PAPS and average NO3- highest in SLE (p<0.0001). In PAPS, IgG aCL titer and number of vascular occlusions negatively predicted NO2-, (p=0.03 and p=0.001, respectively) whereas arterial occlusions and smoking positively predicted NO3- (p=0.05 and p=0.005). Moreover CRP (an inflammatory marker) positively predicted NT (p=0.004). Nitric oxide metabolites relates to type and number of vascular occlusions and to aPL titers, whereas nitrative stress relates to low grade marker) positively predicted NT (p=0.004). Nitric oxide metabolites relates to type and number of vascular occlusions and to aPL titers, whereas nitrative stress relates to low grade inflammation and both phenomena may have implications for thrombosis and atherosclerosis in PAPS Inflammation and immune activation in thrombotic primary antiphospholipid syndrome. To investigate inflammation and immune activation in thrombotic PAPS high-sensitivity CRP (hs-CRP), serum amyloid A (SAA), oxLDL-2GPI, CRP bound to oxLDL-2GPI (CRP-oxLDL-2GPI) (as inflammatory markers) neopterin (NPT) and soluble CD14 (sCD14) (as immune activation markers) were measured by ELISA in 41 PAPS patients, in 44 patients with inherited thrombophilia (IT) and 39 controls (CTR). Compared to other groups, PAPS presented with higher plasma concentrations of inflammatory, hs-CRP (p=0.0004), SAA (p<0.01), CRP-oxLDL-2GPI (p=0.0004) and immune activation markers, NPT (p<0.0001) and sCD14 (p=0.007). By regression analysis SAA independently predicted thrombosis number (p=0.003) and NPT independently predicted thrombosis type (arterial, p=0.03) and number (p=0.04). These data confirm that low-grade inflammation and immune activation occur and relate to vascular features of PAPS. Antiphosholipid antibodies, haemostatic variables and atherosclerosis in thrombotic primary antiphospholipid syndrome To evaluate whether IgG aCL titre, haemostatic variables and the lipid profile bore any relationship to the intima media thickness (IMT) of carotid arteries high-resolution sonography was applied to the common carotid (CC), carotid bifurcation (CB) and internal carotid (IC) of 42 aPL subjects, 29 with primary thrombotic antiphospholipid syndrome and 13 with persistence of aPL in the absence of any underlying disorder. The following were measured: plasma FNG, vWF, PAI, homocysteine (HC), CHO, TG, HDL, LDL, platelet numbers and aCL of IgG and IgM isotype. By multiple regression analysis, IgG aCL titre independently predicted IMT at all carotid segments examined (p always <0.005). Plasma FNG and HC independently predicted IMT at the CB (p=0.001 and p<0.0001, respectively) and IC (p=0.03 and p<0.0001, respectively). These data strongly support an atherogenic role for IgG aCL in patients with aPL in addition to traditional risk factors. The atherosclerosis hypothesis was investigated in an age and sex-matched case-double-control study including 49 thrombotic PAPS patients (18 M, 31 F, mean age 37 ± 11), 49 thrombotic patients for IT and 49 healthy subjects. Average IMT was always greater in PAPS than control patients (CC: p=0.004, CB: p=0.013, IC: p=0.001). By dividing participants into age tertiles the IMT was greater in the second (CC: p=0.003, CB: p=0.023, IC: p=0.003) and third tertiles (CC: p=0.03, CB: p=0.004, IC: p=0.007). Conclusion: Coagulation activation, fibrinolysis depression, hightened fibrin turnover, oxidative and nitrative stress in parallel with low grade inflammation and immune activation characterise thrombotic PAPS: all these are early atherogenic processes and contribute to the demonstrated premature atherosclerosis that should be considered a clinical feature of PAPS.

Skin lesions simulating blue toe syndrome caused by prolonged contact with a millipede

Venomous animals are those that, by means of a hunting and defense mechanism, are able to inject their prey with a toxic substance produced in their bodies, directly from specialized glands (e.g., tooth, sting, spur) through which the poison passes. Millipedes are poisonous animals; they can be harmful to humans, and their effects usually manifest as erythematous, purpuric, and cyanotic lesions; local pain; and paresthesia. Here, we report a case of skin contact with a millipede for 6h resulting in skin lesions similar to blue toe syndrome.

Clinical decisions in breast cancer, a heterogenous disease

RESUMO: Introdução: Tratamento do carcinoma da mama Este trabalho inicia-se com a história do tratamento do carcinoma da mama, desde os primeiros documentos que descrevem doentes com carcinoma da mama até 1950. Desde 1950 até 2000 o diagnóstico, risco e as modalidades terapêuticas usadas no tratamento das doentes são mais detalhadas com ênfase nas terapêuticas locais, regionais e sistémicas. Parte 1:Quem tratar com terapêutica sistémica adjuvante Capítulo 1: A classificação TNM não está morta no carcinoma da mama Tem sido dito que a classificação TNM não é adequada para usar como ferramenta de prognóstico e decisão terapêutica no carcinoma da mama, especialmente em doentes com carcinoma detectado através de rastreio, que tem geralmente menores dimensões. A razão desta classificação não ser adequada prendese com o facto de não estarem incluidos parâmetros biológicos na classificação TNM atual. Pusemos a hipótese de que numa população com alta percentagem de carcinoma da mama não detectado em exames de rastreio, com uma mediana de idade baixa e com alta percentagem de estadios II e III, o estadiamento clássico, pela classificação TNM, é mais descriminatório que as características biológicas na determinação do prognóstico. Para isto analisámos uma população de doentes com carcinoma da mama tratados consecutivamente na mesma instituição, durante 10 anos. Caracterizámos os fatores de prognóstico do estadiamento clássico incluídos na classificação TNM e as variantes biológicas, presentemente não incluídas na classificação TNM. Quantificámos a capacidade de cada um dos factores de prognóstico para para prever a sobrevivência. A população é de 1699 doentes com carcinoma da mama que foram tratádos com terapêutica sistémica adjuvante. Individualmente, cada um dos fatores de prognostico, clássicos ou biológicos, diferem significativamente entre doentes que sobrevivem e que não sobrevivem. Explicitamente, como previsto, doentes com tumores maiores, envolvimento dos gânglios axilares, estadios TNM mais avançados, que não expressam recetor de esrogéneo, com amplificação do gene Her2, triplos negativos ou de menor diferenciação têm menor sobrevida. Na análise multivariada, só os fatores de prognostico da classificação TNM, o grau histológico e a amplificação do gene Her2, esta última com menos significância estatistica são preditores independentes de sobrevivência. Capítulo 2: Em busca de novos factores de prognostico: Poder preditivo e mecanismo das alterações de centrossomas em carcinoma da mama Compilámos inúmeros grupos de experiências de genómica feitas em tumores primários de doentes com carcinoma da mama para as quais existe informação prognóstica. Estas experiências são feitas com o objectivo de descobrir novos factores de prognóstico. Reanalisámos os dados, repetindo a mesma pergunta: Quais são os genes com expressão diferencial estatisticamente significativa entre doentes que recaíram e doentes que não recaíram. Identificámos 65 genes nestas condições e o MKI67, o gene que codifica a proteina Ki67, estava nesse grupo. Identificámos vários genes que se sabe estarem envolvidos no processo de agregação de centrossomas. O gene que considerámos mais promissor foi a kinesina KiFC1, que já tinha sido identificada como regulador da agregação de centrossomas. Anomalias cetrossomais numéricas e estruturais têm sido observadas em neoplasias. Há dados correlacionando anolmalias centrossomais estruturais e e numéricas com o grau de malignidade e os eventos precoces da carcinogénese. Mas estas anomalias centrossomais têm um peso para a célula que deve adapatar-se ou entrará em apoptose. Os nossos resultados sugerem que existe um mecanismo adaptativo, a agregação de centrossomas, com impacto prognóstico negativo. O nosso objetivo foi quantificar o valor prognóstico das anomalias centrossomais no carcinoma da mama. Para isto usámos material de doentes dos quais sabemos a história natural. Avaliámos os genes de agregação de centrossomas, KIFC1 e TACC3, nas amostras tumorais arquivadas em parafina: primeiro com PCR (polymerase chain reaction) quantitativa e depois com imunohistoquímica (IHQ). Apenas a proteína KIFC1 foi discriminatória em IHQ, não se tendo conseguido otimizar o anticorpo da TACC3. Os níveis proteicos de KIFC1 correlacionam-se com mau prognóstico. Nas doentes que recaíram observámos, no tumor primário, maior abundância desta proteína com localização nuclear. Em seguida, demonstrámos que a agregação de centrossomas é um fenómeno que ocorre in vivo. Identificámos centrossomas agregados em amostras de tumores primários de doentes que recaíram. Tecnicamente usámos microscopia de fluorescência e IHQ contra proteínas centrossomais que avaliámos nos tumores primários arquivados em blocos de parafina. Observámos agregação de centrossomas num pequeno número de doentes que recaíram, não validámos, ainda, este fenótipo celular em larga escala. Parte 2: Como tratar com terapêutica sistémica os vários subtipos de carcinoma da mama Capítulo 3: Quantas doenças estão englobadas na definição carcinoma da mama triplo negativo? (revisão) O carcinoma da mama triplo negativo é um tumor que não expressa três proteínas: recetor de estrogénio, recetor de progesterona e o recetor do fator de crescimento epidermico tipo 2 (Her2). As doentes com estes tumores não são ainda tratadas com terapêutica dirigida, possivelmente porque esta definição negativa não tem ajudado. Sabemos apenas as alterações genéticas que estes tumores não têm, não as que eles têm. Talvez por esta razão, estes tumores são o subtipo mais agressivo de carcinoma da mama. No entanto, na prática clínica observamos que estas doentes não têm sempre mau prognóstico, além de que dados de histopatologia e epidemiologia sugerem que esta definição negativa não está a capturar um único subtipo de carcinoma da mama, mas vários. Avaliámos criticamente esta evidência, clínica, histopatológica, epidemiológica e molecular. Há evidência de heterogeneidade, mas não é claro quantos subtipos estão englobados nesta definição de carcinoma da mama triplo negativo. A resposta a esta pergunta, e a identificação do fundamento molecular desta heterogeneidade vai ajudar a melhor definir o prognóstico e eventualmente a definir novos alvos terapêuticos nesta população difícil. Capítulo 4: Terapêuica sistémica em carcinoma da mama triplo negativo (revisão) A quimioterapia é a única terapêutica sistémica disponível para as doentes com carcinoma da mama triplo negativo, ao contrário dos outros dois subtipo de carcinoma da mama que têm com a terapêutica antiestrogénica e anti Her2, importantes benefícios. Apesar de terem surgido várias opções terapêuticas para estes doentes nennhuma terapêutica dirigida foi validada pelos ensaios clínicos conduzidos, possivelmente porque a biologia deste carcinoma ainda não foi elucidada. Muitos ensaios demonstram que os tumores triplos negativos beneficiam com quimioterapia e que as mais altas taxas de resposta patológica completa à terapêutica neoadjuvante são observadas precisamente nestes tumors. A resposta patológica completa correlaciona-se com a sobrevivência. Estamos a estudar regimes adjuvantes específicos para doentes com estes tumors, mas, neste momento, regimes de terceira geração com taxanos e antraciclinas são os mais promissores. O papel de subgrupos de fármacos específicos, como os sais de platina, mantémse mal definido. Quanto às antraciclinas e taxanos, estes grupos não mostraram beneficio específico em carcinoma da mama triplo negativo quando comparado com os outros subtipos. Os próprios carcinomas da mama triplos negativos são heterogéneos e carcinomas da mama basais triplos negativos com elevada taxa de proliferação e carcinomas da mama triplos negativos surgidos em doentes com mutação germinal BRCA1 poderão ser mais sensíveis a sais de platino e menos sensíveis a taxanos. Como a definição molecular ainda não foi explicada a busca de terapêutica dirigida vai continuar. Capítulo 5: Ensaio randomizado de fase II do anticorpo monoclonal contra o recetor do fator de crescimento epidérmico tipo 1 combinado com cisplatino versus cisplatino em monoterapia em doentes com carcinoma da mama triplo negativo metastizado O recetor do fator de crescimento epidérmico tipo 1 está sobre expresso nos tumores das doentes com carcinoma da mama triplo negativo metastizado, um subtipo agressivo de carcinoma da mama. Este ensaio investigou a combinação de cetuximab e cisplatino versus cisplatino isolado em doentes deste tipo. Doentes em primeira ou segunda linha de terapêutica para doença metastizada foram randomizadas, num sistema de 2 para 1, para receber até 6 ciclos da combinação de cisplatino e cetuximab ou cisplatino isolado. Às doentes randomizadas para o braço de monoterapia podiamos, após progressão, acrescentar cetuximab ou tratá-las com cetuximab isolado. O objetivo primário foi a taxa de resposta global. Os objetivos secundários foram a sobrevivência livre de doença, a sobrevivência global e o perfil de segurança dos fármacos. A população em análise foram 115 doentes tratadas com a combinação e 58 doentes tratadas com cisplatino em monoterapia, 31 destas em quem se documentou progressão passaram a ser tratadas com um regime que incluía cetuximab, isolado ou em combinação. A taxa de resposta global foi de 20% no braço da combinaçao e de 10% no braço da monoterapia (odds ratio, 2.13). A sobrevivência livre de doença foi de 3.7 meses no braço da combinação e de 1.5 meses no braço em monoterapia (hazard ratio, 0.67). A sobrevivência global foi de 12.9 meses no braço da combinação versus 9.4 meses no braço de cisplatino. Conclui-se que, apesar de não ter sido alcançado o objectivo primário, acrescentar cetuximab, duplica a resposta e prolonga tanto a sobrevivência livre de doença como a sobrevivência global. Capítulo 6: Bloquear a angiogénese para tratar o carcinoma da mama (revisão) A angiogénese é uma característica que define a neoplasia, porque tumores com mais de 1mm precisam de formar novos vasos para poderem crescer. Desde que se descobriram as moléculas que orquestram esta transformação, que se têm procurado desenvolver e testar fármacos que interfiram com este processo. No carcinoma da mama o bevacizumab foi o primeiro fármaco aprovado pela FDA em primeira linha para tratar doença metastática. Depois foram estudados um grupo de inibidores de tirosina cinase associados aos recetores transmembranares envolvidos na angiogénese como o VEGFR, PDGFR, KIT, RET, BRAF e Flt3: sunitinib, sorafenib, pazopanib e axitinib Neste capítulo, analisaram-se e resumiram-se os dados dos ensaios clínicos das drogas anti-angiogénicas no tratamaneto do carcinoma da mama. Os ensaios de fase III do bevacizumab em carcinoma da mama mostraram uma redução na progressão de doença de 22 a 52% e aumento da sobrevivência livre de doença de 1.2 a 5.5 meses mas nunca foi demonstrado prolongamento de sobrevivência. Os ensaios de fase III em carcinoma da mama adjuvante com bevacizumab são dois e foram ambos negativos. O ensaio de fase III com o inibidor da tirosina cinase, sunitinib foi negativo, enquanto que os ensaios de fase II com os inibidores da tirosina cinase sorafenib e pazopanib melhoraram alguns indicadores de resposta e sobrevivência. A endostatina foi testada no contexto neoadjuvante com antraciclinas e melhorou a taxa de resposta, mas, mais ensaios são necessários para estabelecer este fármaco. A maioria dos ensaios clínicos dos agentes antiangiogénicos em carcinoma da mama reportaram aumento da taxa de resposta e de sobrevivência livre de doença mas nunca aumento da sobrevivência global quando comparado com quimioterapia isolada o que levou ao cepticismo a que assistimos atualmente em relação ao bloqueio da angiogénese. Ensaios clínicos selecionados em doentes específicas com objetivos translacionais relacionados com material biológico colhido, preferefencialmente em diferentes intervalos da terapêutica, serão cruciais para o bloqueio da angiogénese sobreviver como estratégia terapêutica em carcinoma da mama. Capítulo 7: A resposta à hipoxia medeia a resistência primária ao sunitinib em carcinoma da mama localmente avançado O sunitinib é um fármaco antiangiogénico que nunca foi avaliado isolado em doentes com carcinoma da mama não tratadas. O nosso objetivo foi caracaterizar a atividade do sunitinib isolado e em combinação com o docetaxel em carcinoma da mama não tratado, localmente avançado ou operável, mas de dimensão superior a 2 cm, para compreender os mecanismos de resposta. Doze doentes foram tratadas com duas semanas iniciais de sunitinib seguido de quatro ciclos de combinação de sunitinib e docetaxel. A resposta, a reistência e a toxicidade foram avaliadas de acordo com parametros clínicos, ressonância magnética nuclear, tomografia de emissão de positrões, histopatologia e perfis de expressão genómica. Detetámos resistência primária ao sunitinib na janela inicial de duas semanas, evidenciada em quatro doentes que não responderam. À data da cirurgia, cinco doentes tinham tumor viável na mama e axila, quatro tinahm tumor viável na mama e três foram retiradas do ensaio. Não houve respostas patológicas completas. A comparação dos perfis de expressão genómica entre os respondedores e os não respondedores, aos quinze dias iniciais, permitiu-nos identificar sobre expressão de VEGF e outras vias angiogénicas nos não respondedores. Especificamente, em tumores resistentes ao sunitinib isolado detectámos uma resposta transcricional à hipoxia caracterizada por sobre expressão de vários dos genes alvo do HIF1α. Neste ensaio de sunitinib isolado em doentes não tratadas com carcinoma da mama localmente avançado, encontrámos evidência molecular de resistência primária ao sunitinib possivelmente mediada por sobre expressão de genes que respondem à hipoxia. Parte 3: Quando parar a terapêutica sistémica às doentes com carcinoma da mama Capítulo 8: Agressividade terapêutica ns últimos três meses de vida num estudo retrospetivo dum centro único Incluímos todos os adultos que morreram com tumores sólidos na instituição em 2003 e foram tratados com quimioterapia para tratar neoplaias metastizadas. Colhemos dados detalhados relacionados com quimioterapia e toxicidade nos últimos três meses de vida a partir do processo clínico. Trezentas e dezanove doentes foram incluídos, a mediana de idade foi 61 anos. A mediana de sobrevivência de doença metastática foi de 11 meses. 66% (211) dos doentes foram tratados com QT nos últimos 3 meses de vida, 37% foram tratados com QT no úlimo mês de vida e 21% nas últimas duas semanas. Nos doentes que foram tratados com QT nos últimos três meses de vida, 50% começaram um novo regime terapêutico neste período e 14% começaram um novo regime no último mês. Identificámos como determinantes de tratamento com QT no fim de vida a idade jovem, o carcinoma da mama, do ovário e do pâncreas. Concluímos que administrámos QT no fim de vida frequentemente e iniciámos novos regimes terapêuticos no último mês de vida em 14% dos casos. Precisamos de aprofundar este trabalho para compreender se esta atitude agressiva resulta em melhor paliação de sintomas e qualidade de vida no fim de vida dos doentes com neoplasias disseminadas. Capítulo 9: O tratamento do carcinoma da mama no fim de vida está a mudar? Quisémos caracterizar a modificação da tendência no uso de QT e de estratégias paliativas no fim de vida das doentes com carcinoma da mama em diferentes instituições e em intervalos de tempo diferentes. Para isto selecionámos doentes que morreram de carcinoma da mama durante 6 anos, entre 2007 e 2012, num hospital geral e comparámos com as doentes que morreram de carcinoma da mama em 2003 num centro oncológico. Avaliámos um total de 232 doentes. O grupo mais recente tem 114 doentes e o grupo anterior tem 118 doentes. Usámos estatística descritiva para caracterizar QT no fim de vida e o uso de estratégias paliativas. Ambas as coortes são comparáveis em termos das características do carcinoma da mama. Observámos aumento do uso de estatégias paliativas: consulta da dor, consulta de cuidados paliativos e radioterapia paliativa no cuidado das doentes com carcinoma da mama metastizado. Evidenciámos aumento do número de mortes em serviços de cuidados paliativos. No entanto, a QT paliativa continua a ser prolongada até aos últimos meses de vida, embora tenhamos mostrado uma diminuição desta prática. Outros indicadores de agressividade como a admissão hospitalar também mostraram diminuição. Confirmámos a nossa hipótese de que há maior integração da medicina paliativa multidisciplinar e menos agressividade na terapêutica sistémica das doentes com carcinoma da mama nos últimos meses de vida. Chapter 10: Porque é que os nossos doentes são tratados com quimioterapia até ao fim da vida? (editorial) Este capítulo começa por dar o exmeplo duma jovem de 22 anos que viveu três meses após começar QT paliatva. Este caso epitomiza a futilidade terapêutica e é usado como ponto de partida para explorar as razões pelas quais administramos QT no fim de vida aos doentes quando é inútil, tóxica, logisticamente complexa e cara. Será que estamos a prescrever QT até tarde demais? Os oncologistas fazem previsões excessivamente otimistas e têm uma atitude pró terapêutica excessiva e são criticados por outros intervenientes nas instituições de saúde por isto. Crescentemente doentes, familiares, associações de doentes, definidores de políticas de saúde, jornalistas e a sociedade em geral afloram este tema mas tornam-se inconsistentes quando se trata dum doente próximo em que se modifica o discurso para que se façam terapêuticas sitémicas agressivas. Há uma crescente cultura de preservação da qualidade de vida, paliação, abordagem sintomática, referenciação a unidades de cuidados paliativos e outros temas do fim de vida dos doentes oncológicos terminais. Infelizmente, este tema tem ganhado momentum não porque os oncologistas estejam a refletir criticamente sobre a sua prática, mas porque os custos dos cuidados de saúde são crescentes e incomportáveis. Seja qual fôr o motivo, as razões que levam os oncologistas a administrar QT no fim de vida devem ser criticamente elucidadas. Mas há poucos dados para nos guiar nesta fase delicada da vida dos doentes e os que existem são por vezes irreconciliáveis, é uma revisão destes dados que foi feita neste capítulo. Conclusão: A abordagem do carcinoma da mama no futuro? Na conclusão, tenta-se olhar para o futuro e prever como será a tomada a cargo dum doente com carcioma da mama amanhã. Faz-se uma avaliação das várias àreas desde prevenção, rastreio, suscetibilidade genética e comportamental e terapêutica. Na terapêutica separa-se a terapêutica locoregional, sistémica adjuvante e da doença metastizada. Nos três últimos parágrafos a história duma mulher com um carcinoma localmente avançado que sobre expressa o recetor Her2, serve como ilustração de como devemos estar preparados para incorporar evolução, heterogeneidade e dinamismo no cuidado de doentes com carcinoma da mama. -------------------------------------------------------------------------------------------------- ABSTRACT: Introduction: Breast cancer care in the past This work starts with an overview of the treatment of breast cancer (BC). From the first reports of patients ill with BC until 1950. From 1950 until 2000, there is a more detailed account on how BC patients were treated with emphasis on the different modalities, local, regional and systemic treatments and their evolution. Part 1: Who to treat with adjuvant systemic therapy? Chapter 1: TNM is not dead in breast cancer It has been said that the current TNM staging system might not be suitable for predicting breast cancer (BC) outcomes and for making therapeutic decisions, especially for patients with screen detected BC which is smaller. The reason for this is also due to the non inclusion of tumor biology parameters in the current TNM system. We hypothesize that in a population where there is still a large abundance of non screen detected BC, with a low median age of incidence and abundance of high TNM staged lesions, biology is still second to classical staging in predicting prognosis. We analyzed a population of consecutive BC patients from a single institution during ten years. We characterized current established prognostic factors, classical staging variables included in the current TNM staging system and biological variables, currently not included in the TNM system. We quantified the capacity of individual prognostic factors to predict survival. We analyzed a population of 1699 consecutive BC patients. We found that individually both the TNM system prognostic factors and the biological prognostic factors are differing among BC survivors and dead patients in a statistically significant distribution. Explicitly, patients with larger tumors, positive nodes, higher stage lesions, ER negative, HER2 positive, TN or lower differentiation tumors show decreased survival. In the multivariate analysis we can conclude that in a population such as ours classical TNM staging variables, irrespective of tumor biological features, are still the most powerful outcome predictors. Chapter 2: Defining breast cancer prognosis: The predictive power and mechanism of centrosome alterations in breast cancer We performed a systematic analysis of the literature and compiled an extensive data set of gene expression data originated in primary tumours of BC patients with prognostic information. We analysed this data seeking for genes consistently up or down regulated in poor prognosis BC, i.e. that relapsed after initial treatment. In the course this bioinformatics analysis our lab identified 65 genes statistically significant across multiple datasets that can discriminate between relapsed and non-relapsed BC patients. Among the identified genes, we have detected genes such as MKI67, a marker of mitotic activity which is routinely used in the clinic. Unexpectedly, we also discovered several genes found to be involved in centrosome clustering, The most prominent of these is the kinesin KIFC1, also called HSET, and previously identified as regulator of centrosome clustering. Centrosome abnormalities (numerical, structural) have been observed in cancer. Indeed, compelling data has shown that cells from many cancers have multiple and abnormal centrosomes, that are either correlated with tumour malignancy or considered an early tumorigenesis event. However, extra centrosomes come at a cost and cells must be able to handle such abnormalities or otherwise die. Thus our results suggested a new mechanism of breast cancer progression with negative prognostic value. We aimed at quantifying the predictive power of centrosome clustering in BC clinical setting and at detecting this process in BC patient material. We validated the centrosome clustering genes KIFC1 and TACC3 in formalin fixed paraffin embedded (FFPE) BC patient material, using quantitative real-time PCR (RT-qPCR) technology. Our results indicate that the tested KIFC1 has a clear IHC signal (1) and that the protein expression patterns and levels correlate with prognosis, with relapsing patients having increased expression and nuclear localisation of this kinesin (2). Next we were able to show that centrosome clustering does occur in vivo. We identified centrosome amplification and clustering in breast cancer samples, and we established a fluorescence microscopy-based IHC approach by staining FFPE samples with centrosomal markers. Using this approach we have observed centrosome amplification and clustering in a small set of poor prognosis samples. By expanding the number of samples in which we have characterised the number of centrosomes, we were able to confirm our preliminary observation that centrosomes are clustered in relapsed BC. Part 2: How to treat breast cancer subtypes? Chapter 3: How many diseases is triple negative breast cancer? (review) Triple negative breast cancer is a subtype of breast cancer that does not express the estrogen receptor, the progesterone receptor and the epidermal growth factor receptor type 2 (Her2). These tumors are not yet treated with targeted therapies probably because no positive markers have been described to reliably classify them - they are described for what they are not. Perhaps for this reason, they are among the most aggressive of breast carcinomas, albeit with very heterogenous clinical behavior. The clinical observation that these patients do not carry a uniformly dismal prognosis, coupled with data coming from pathology and epidemiology, suggests that this negative definition is not capturing a single clinical entity, but several. We critically evaluate this evidence in this paper, reviewing clinical and epidemiological data, as well as molecular data. There is evidence for heterogeneity, but it is not clear how many diseases are grouped into triple negative breast cancer. Answering this question, and identifying the molecular basis of heterogeneity will help define prognosis and, eventually, the identification of new targeted therapies. Chapter 4: Systemic treatment for triple negative breast cancer (review) Chemotherapy remains the backbone of treatment for triple negative breast cancer (TNBC). Despite the appearance of new targeted and biologic agents there has been no targeted therapy validated for TNBC, possibly because the biology of TNBC has not been conclusively elucidated. Many studies have shown that TNBC derive significant benefit of chemotherapy in the neoadjuvant, adjuvant and metastatic treatment, possibly more benefit than other BC subtypes. Neoadjuvant chemotherapy studies have repeatedly shown higher response rates in TNBC than non-TNBC. Pathologic complete response has been shown to predict improved long term outcomes in BC. Although specific adjuvant regimens for TNBC are under study, third generation chemotherapy regimens utilizing dose dense or metronomic polychemotherapy are among the most effective tools presently available. The role of specific chemotherapy agents, namely platinum salts, in the treatment of TNBC remains undefined. Taxanes and anthracyclines are active in TNBC and remain important agents, but have not shown specific benefit over non-TNBC. TNBC is itself a heterogeneous group in which subgroups like basal like BC defined by higher proliferation and including those TNBC arising in BRCA1 mutation carriers may be more sensitive to platinum agents and relatively less sensitive to taxanes. The molecular characterization of TNBC is lacking and therefore the search for targeted therapy is still ongoing. Chapter 5: Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer Epidermal growth factor receptor is overexpressed in metastatic triple-negative breast cancers, an aggressive subtype of breast cancer. Our randomized phase II study investigated cisplatin with or without cetuximab in this setting. Patients who had received no more than one previous chemotherapy regimen were randomly assigned on a 2:1 schedule to receive no more than six cycles of cisplatin plus cetuximab or cisplatin alone. Patients receiving cisplatin alone could switch to cisplatin plus cetuximab or cetuximab alone on disease progression. The primary end point was overall response rate (ORR). Secondary end points studied included progressionfree survival (PFS), overall survival (OS), and safety profiles. The full analysis set comprised 115 patients receiving cisplatin plus cetuximab and 58 receiving cisplatin alone; 31 patients whose disease progressed on cisplatin alone switched to cetuximab-containing therapy. The ORR was 20% with cisplatin plus cetuximab and 10% with cisplatin alone (odds ratio, 2.13). Cisplatin plus cetuximab resulted in longer PFS compared with cisplatin alone (median, 3.7 v 1.5 months; hazard ratio, 0.67. Corresponding median OS was 12.9 versus 9.4 months. While the primary study end point was not met, adding cetuximab to cisplatin doubled the ORR and appeared to prolong PFS and OS, warranting further investigation in mTNBC. Chapter 6: Blocking angiogenesis to treat breast cancer (review) Angiogenesis is a hallmark of cancer because tumors larger than 1mm need new vessels to sustain their growth. Since the discovery of the molecular players of this process and some inhibitors, that angiogenesis became a promising therapeutic target. Bevacizumab was the first molecular-targeted antiangiogenic therapy approved by the FDA and is used as first-line therapy in metastatic breast cancer. A second class of approved inhibitors (sunitinib, sorafenib, pazopanib and axitinib) include oral small-molecule tyrosine kinase inhibitors that target vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and other kinases including KIT, Ret, BRAF and Flt-3, but none of these have gained approval to treat breast cancer. This review analyzes and summarizes data from clinical trials of anti-angiogenic agents in the treatment of BC. Phase III trials of bevacizumab in advanced BC have demonstrated a reduction in disease progression (22–52%), increased response rates and improvements in progression-free survival of 1.2 to 5.5 months, but no improvements in OS. Bevacizumab phase III trials in early BC have both been negative. Bevacizumab combined with chemotherapy is associated with more adverse events. Phase III trials of the tyrosine kinase inhibitor sunitinib were negative, while randomized phase II trials of sorafenib and pazopanib have improved some outcomes. Endostatin has been tested in neoadjuvant clinical trials in combination with anthracyclinebased chemotherapy in treatment-naive patients and has increased the clinical response rate, but more trials are needed to establish this drug. Most trials of anti-angiogenic agents in BC have reported improved RR and PFS but no increase in OS compared to chemotherapy alone, leading to skepticism towards blocking angiogenesis. Selected trials in selected BC populations with translational endpoints related to harvested tumor tissue and other biological material samples, preferentially at several timepoints, will be crucial if antiangiogenesis is to survive as a strategy to treat BC. Chapter 7: Does hypoxic response mediate primary resistance to sunitinib in untreated locally advanced breast cancer? The antiangiogenic drug sunitinib has never been evaluated as single agent in untreated BC patients. We aimed to characterize the activity of sunitinib, alone and with docetaxel, in untreated locally advanced or operable BC, and, to uncover the mechanisms of response. Twelve patients were treated with an upfront window of sunitinib followed by four cycles of sunitinib plus docetaxel. Response, resistance and toxicity were evaluated according to standard clinical parameters, magnetic resonance imaging, positron emission tomography, pathology characterization and gene expression profiling. We detected primary resistance to sunitinib upfront window in untreated BC, as evidenced by four non-responding patients. At surgery, five patients had viable disease in the breast and axilla, four had viable tumor cells in the breast alone and three were taken off study due to unacceptable toxicity and thus not evaluated. Early functional imaging was useful in predicting response. There were no pathologic complete responses (pCR). Comparison of gene expression profiling tumor data between early responders and non-responders allowed us to identify upregulation of VEGF and angiogenic pathways in non responders. Specifically, in tumors resistant to the single-agent sunitinib we detected a transcriptional response to hypoxia characterized by over-expression of several HIF1α target genes. In this report of single-agent sunitinib treatment of untreated localized BC patients, we found molecular evidence of primary resistance to sunitinib likely mediated by up-regulation of hypoxia responsive genes. Part 3: When to stop systemic treatment of breast cancer patients? Chapter 8: The aggressiveness of cancer care in the last three months of life: a retrospective single centre analysis. All adult patients with solid tumors who died in our hospital in 2003 and received chemotherapy for advanced cancer, were included. Detailed data concerning chemotherapy and toxicity, in the last three months of life, were collected from patientsʼ clinical charts. A total of 319 patients were included. Median age was 61 years. Median time from diagnosis of metastatic disease to death was 11 months. The proportion of patients who received chemotherapy in the last three months of life was 66% (n=211), in the last month 37% and in the last two weeks 21%. Among patients who received chemotherapy in the last three months of life, 50% started a new chemotherapy regimen in this period and 14% in the last month. There was an increased probability of receiving chemotherapy in the last three months of life in younger patients and in patients with breast, ovarian and pancreatic carcinomas. There was a large proportion of patients who received chemotherapy in the last three months of life, including initiation of a new regimen within the last 30 days. Thus, further study is needed to evaluate if such aggressive attitude results in better palliation of symptoms at the end of life. Chapter 9: Is breast cancer treatment in the end of life changing? We aimed to characterize the shifting trends in use of anti-cancer chemotherapy and palliative care approaches in the end of life of BC patients in different institutions and times. For this, we selected women that died of BC during six years, from 2007 to 2012, and were treated in a central acute care general hospital and compared it with the BC patients that died in 2003 and were treated in a large cancer center. We analyzed a total of 232 patients: the more recent group has 114 women and the older cohort has 118. We used descriptive statistics to characterize CT in the EoL and use of palliative care resources. Both populations were similar in terms of BC characteristics. We observed more palliative care resources, pain clinic, palliative care teams and palliative radiotherapy, involved in the care of MBC patients and a shift towards more deaths at hospices. Systemic anti cancer treatments continue to be prolonged until very late in patients’ lives, notwithstanding, we could show a decrease in the use of such treatments. Other indicators of aggressiveness, namely hospital admissions, also show a decrease. We confirmed our hypothesis that there is more integration of multidisciplinary palliative care and less aggressiveness in the treatment of metastatic cancer patients, specifically, use of palliative anti-cancer treatment and hospital admissions. Nonetheless, we use systemic therapy until too late with underutilization of palliative medicine. Chapter 10: Why do our patients get chemotherapy until the end of life? (editorial) The editorial starts with a clinical case of a 21 year old patient that lives three months after starting palliative chemotherapy for the first time, a case that illustrates therapeutic futility at the end of life. Why are we not ceasing chemotherapy when it is useless, toxic, logistically complex and expensive? Are we prescribing chemotherapy until too late in solid tumor patientsʼ lives? Medical oncologists have overly optimistic predictions and, excessive, treatment-prone attitude and they are criticized by other health care providers for this. Increasingly, patients, their families, advocacy groups, policy makers, journalists and society at large dwell on this topic, which is a perplexing conundrum, because sometimes they are the ones demanding not to stop aggressive systemic anticancer treatments, when it comes to their loved ones. There is a growing culture of awareness toward preserving quality of life, palliative care, symptom-directed care, hospice referral and end of life issues regarding terminal cancer patients. Sadly, this issue is gaining momentum, not because oncologists are questioning their practice but because health care costs are soaring. Whatever the motive, the reasons for administering chemotherapy at the end of life should be known. There are few and conflicting scientific data to guide treatments in this delicate setting and we review this evidence in this paper. Conclusion: What is the future of breast cancer care? This work ends with a view into the future of BC care. Looking into the different areas from prevention, screening, hereditary BC, local, regional and systemic treatments of adjuvant and metastatic patients. The last three paragraphs are a final comment where the story of a patient with Her2 positive locally advanced breast cancer is used as paradigm of evolution, heterogeneity and dynamism in the management of BC.

Redefining the MED13L syndrome

Congenital cardiac and neurodevelopmental deficits have been recently linked to the mediator complex subunit 13-like protein MED13L, a subunit of the CDK8-associated mediator complex that functions in transcriptional regulation through DNA-binding transcription factors and RNA polymerase II. Heterozygous MED13L variants cause transposition of the great arteries and intellectual disability (ID). Here, we report eight patients with predominantly novel MED13L variants who lack such complex congenital heart malformations. Rather, they depict a syndromic form of ID characterized by facial dysmorphism, ID, speech impairment, motor developmental delay with muscular hypotonia and behavioral difficulties. We thereby define a novel syndrome and significantly broaden the clinical spectrum associated with MED13L variants. A prominent feature of the MED13L neurocognitive presentation is profound language impairment, often in combination with articulatory deficits.

Chest pain in the emergency room. Importance of a systematic approach

OBJECTIVE: To evaluate the efficiency of a systematic diagnostic approach in patients with chest pain in the emergency room in relation to the diagnosis of acute coronary syndrome (ACS) and the rate of hospitalization in high-cost units. METHODS: One thousand and three consecutive patients with chest pain were screened according to a pre-established process of diagnostic investigation based on the pre-test probability of ACS determinate by chest pain type and ECG changes. RESULTS: Of the 1003 patients, 224 were immediately discharged home because of no suspicion of ACS (route 5) and 119 were immediately transferred to the coronary care united because of ST elevation or left bundle-branch block (LBBB) (route 1) (74% of these had a final diagnosis of acute myocardial infarction [AMI]). Of the 660 patients that remained in the emergency room under observation, 77 (12%) had AMI without ST segment elevation and 202 (31%) had unstable angina (UA). In route 2 (high probability of ACS) 17% of patients had AMI and 43% had UA, whereas in route 3 (low probability) 2% had AMI and 7 % had UA. The admission ECG has been confirmed as a poor sensitivity test for the diagnosis of AMI ( 49%), with a positive predictive value considered only satisfactory (79%). CONCLUSION: A systematic diagnostic strategy, as used in this study, is essential in managing patients with chest pain in the emergency room in order to obtain high diagnostic accuracy, lower cost, and optimization of the use of coronary care unit beds.

Efficacy of a diagnostic strategy for patients with chest pain and no ST-segment elevation in the emergency room

PURPOSE: To evaluate the efficacy of a systematic model of care for patients with chest pain and no ST segment elevation in the emergency room. METHODS: From 1003 patients submitted to an algorithm diagnostic investigation by probability of acute ischemic syndrome. We analyzed 600 ones with no elevation of ST segment, then enrolled to diagnostic routes of median (route 2) and low probability (route 3) to ischemic syndrome. RESULTS: In route 2 we found 17% acute myocardial infarction and 43% unstable angina, whereas in route 3 the rates were 2% and 7%, respectively. Patients with normal/non--specific ECG had 6% probability of AMI whereas in those with negative first CKMB it was 7%; the association of the 2 data only reduced it to 4%. In patients in route 2 the diagnosis of AMI could only be ruled out with serial CKMB measurement up to 9 hours, while in route 3 it could be done in up to 3 hours. Thus, sensitivity and negative predictive value of admission CKMB for AMI were 52% and 93%, respectively. About one-half of patients with unstable angina did not disclose objective ischemic changes on admission. CONCLUSION: The use of a systematic model of care in patients with chest pain offers the opportunity of hindering inappropriate release of patients with ACI and reduces unnecessary admissions. However some patients even with normal ECG should not be released based on a negative first CKMB. Serial measurement of CKMB up to 9 hours is necessary in patients with medium probability of AMI.

Chest Pain Units: A Modern Way of Managing Patients with Chest Pain in the Emergency Department

It is estimated that 5 to 8 million individuals with chest pain or other symptoms suggestive of myocardial ischemia are seen each year in emergency departments (ED) in the United States 1,2, which corresponds to 5 to 10% of all visits 3,4. Most of these patients are hospitalized for evaluation of possible acute coronary syndrome (ACS). This generates an estimated cost of 3 - 6 thousand dollars per patient 5,6. From this evaluation process, about 1.2 million patients receive the diagnosis of acute myocardial infarction (AMI), and just about the same number have unstable angina. Therefore, about one half to two thirds of these patients with chest pain do not have a cardiac cause for their symptoms 2,3. Thus, the emergency physician is faced with the difficult challenge of identifying those with ACS - a life-threatening disease - to treat them properly, and to discharge the others to suitable outpatient investigation and management.

Do Diabetic Patients with Acute Coronary Syndromes Have a Higher Threshold for Ischemic Pain?

Background: Data from over 4 decades have reported a higher incidence of silent infarction among patients with diabetes mellitus (DM), but recent publications have shown conflicting results regarding the correlation between DM and presence of pain in patients with acute coronary syndromes (ACS). Objective: Our primary objective was to analyze the association between DM and precordial pain at hospital arrival. Secondary analyses evaluated the association between hyperglycemia and precordial pain at presentation, and the subgroup of patients presenting within 6 hours of symptom onset. Methods: We analyzed a prospectively designed registry of 3,544 patients with ACS admitted to a Coronary Care Unit of a tertiary hospital. We developed multivariable models to adjust for potential confounders. Results: Patients with precordial pain were less likely to have DM (30.3%) than those without pain (34.0%; unadjusted p = 0.029), but this difference was not significant after multivariable adjustment, for the global population (p = 0.84), and for subset of patients that presented within 6 hours from symptom onset (p = 0.51). In contrast, precordial pain was more likely among patients with hyperglycemia (41.2% vs 37.0% without hyperglycemia, p = 0.035) in the overall population and also among those who presented within 6 hours (41.6% vs. 32.3%, p = 0.001). Adjusted models showed an independent association between hyperglycemia and pain at presentation, especially among patients who presented within 6 hours (OR = 1.41, p = 0.008). Conclusion: In this non-selected ACS population, there was no correlation between DM and hospital presentation without precordial pain. Moreover, hyperglycemia correlated significantly with pain at presentation, especially in the population that arrived within 6 hours from symptom onset.

BNP was Associated with Ischemic Myocardial Scintigraphy and Death in Patients at Chest Pain Unit

Background:Recent studies have suggested that B-type Natriuretic Peptide (BNP) is an important predictor of ischemia and death in patients with suspected acute coronary syndrome. Increased levels of BNP are seen after episodes of myocardial ischemia and may be related to future adverse events.Objectives:To determine the prognostic value of BNP for major cardiac events and to evaluate its association with ischemic myocardial perfusion scintigraphy (MPS).Methods:This study included retrospectively 125 patients admitted to the chest pain unit between 2002 and 2006, who had their BNP levels measured on admission and underwent CPM for risk stratification. BNP values were compared with the results of the MPS. The chi-square test was used for qualitative variables and the Student t test, for quantitative variables. Survival curves were adjusted using the Kaplan-Meier method and analyzed by using Cox regression. The significance level was 5%.Results:The mean age was 63.9 ± 13.8 years, and the male sex represented 51.2% of the sample. Ischemia was found in 44% of the MPS. The mean BNP level was higher in patients with ischemia compared to patients with non-ischemic MPS (188.3 ± 208.7 versus 131.8 ± 88.6; p = 0.003). A BNP level greater than 80 pg/mL was the strongest predictor of ischemia on MPS (sensitivity = 60%, specificity = 70%, accuracy = 66%, PPV = 61%, NPV = 70%), and could predict medium-term mortality (RR = 7.29, 95% CI: 0.90-58.6; p = 0.045) independently of the presence of ischemia.Conclusions:BNP levels are associated with ischemic MPS findings and adverse prognosis in patients presenting with acute chest pain to the emergency room, thus, providing important prognostic information for an unfavorable clinical outcome.

Post-Hospital Syndrome: A New Challenge in Cardiovascular Practice

AbstractThe image of the hospital representing the modern medicine and its diagnostic and therapeutic advances becomes more evident in the face of an aging population and patients with multiple comorbidities requiring highly complex care. However, recent studies have shown a growing number of hospital readmissions within 30 days after discharge. The post-hospital syndrome is a new clinical entity associated with multiple vulnerabilities that contribute to hospital readmissions. During hospitalization, the patient is exposed to different stressors of physical, environmental, and psychosocial natures that trigger pathophysiological and multisystemic responses and increase the risk of complications after hospital discharge. Patients with a cardiac disease have high rates of readmission within 30 days. Therefore, it is important for cardiologists to recognize the post-hospital syndrome since it may impact their daily practice. This review aims at discussing the current scientific evidence regarding predictors and stressors involved in the post-hospital syndrome and the measures that are currently being taken to minimize their effects.

Proteomic and Metabolomic Analyses of Mitochondrial Complex I-deficient Mouse Model Generated by Spontaneous B2 Short Interspersed Nuclear Element (SINE) Insertion into NADH Dehydrogenase (Ubiquinone) Fe-S Protein 4 (Ndufs4) Gene.

Eukaryotic cells generate energy in the form of ATP, through a network of mitochondrial complexes and electron carriers known as the oxidative phosphorylation system. In mammals, mitochondrial complex I (CI) is the largest component of this system, comprising 45 different subunits encoded by mitochondrial and nuclear DNA. Humans diagnosed with mutations in the gene NDUFS4, encoding a nuclear DNA-encoded subunit of CI (NADH dehydrogenase ubiquinone Fe-S protein 4), typically suffer from Leigh syndrome, a neurodegenerative disease with onset in infancy or early childhood. Mitochondria from NDUFS4 patients usually lack detectable NDUFS4 protein and show a CI stability/assembly defect. Here, we describe a recessive mouse phenotype caused by the insertion of a transposable element into Ndufs4, identified by a novel combined linkage and expression analysis. Designated Ndufs4(fky), the mutation leads to aberrant transcript splicing and absence of NDUFS4 protein in all tissues tested of homozygous mice. Physical and behavioral symptoms displayed by Ndufs4(fky/fky) mice include temporary fur loss, growth retardation, unsteady gait, and abnormal body posture when suspended by the tail. Analysis of CI in Ndufs4(fky/fky) mice using blue native PAGE revealed the presence of a faster migrating crippled complex. This crippled CI was shown to lack subunits of the "N assembly module", which contains the NADH binding site, but contained two assembly factors not present in intact CI. Metabolomic analysis of the blood by tandem mass spectrometry showed increased hydroxyacylcarnitine species, implying that the CI defect leads to an imbalanced NADH/NAD(+) ratio that inhibits mitochondrial fatty acid β-oxidation.

Methicillin-susceptible Staphylococcus aureus clonal complex 398: high prevalence and geographical heterogeneity in bone and joint infection and nasal carriage.

The prevalence of clonal complex (CC) 398 methicillin-susceptible Staphylococcus aureus (MSSA) was unexpectedly high among bone and joint infections (BJIs) and nasal-colonizing isolates in France, with surprising geographical heterogeneity. With none of the major, most-known staphylococcal virulence genes, MSSA CC398 BJI was associated with lower biological inflammatory syndrome and lower treatment failure rates.

Complex landslide behaviour and structural controlled by the structures: A 3D conceptual model example of Åknes rockslide, Norway

Åknes is an active complex large rockslide of approximately 30?40 Mm3 located within the Proterozoic gneisses of western Norway. The observed surface displacements indicate that this rockslide is divided into several blocks moving in different directions at velocities of between 3 and 10 cm year?1. Because of regional safety issues and economic interests this rockslide has been extensively monitored since 2004. The understanding of the deformation mechanism is crucial for the implementation of a viable monitoring system. Detailed field investigations and the analysis of a digital elevation model (DEM) indicate that the movements and the block geometry are controlled by the main schistosity (S1) in gneisses, folds, joints and regional faults. Such complex slope deformations use pre-existing structures, but also result in new failure surfaces and deformation zones, like preferential rupture in fold-hinge zones. Our interpretation provides a consistent conceptual three-dimensional (3D) model for the movements measured by various methods that is crucial for numerical stability modelling. In addition, this reinterpretation of the morphology confirms that in the past several rockslides occurred from the Åknes slope. They may be related to scars propagating along the vertical foliation in folds hinges. Finally, a model of the evolution of the Åknes slope is presented.