Hepatocyte-specific mitogen-activated protein kinase phosphatase 1 in sexual dimorphism and susceptibility to alcohol induced liver injury.

Background: It is well established that females are more susceptible to the toxic effects of alcohol, although the exact mechanisms are still poorly understood. Previous studies noted that alcohol reduces the expression of mitogen-activated protein kinase phosphatase 1 (MKP1), a negative regulator of mitogen-activated protein kinases (MAPK) in the liver. However, the role of hepatocyte- specific MKP1 in the pathogenesis of alcohol-associated liver disease (ALD) remains uncharacterized. This study aimed to evaluate the role of hepatocyte-specific MKP1 in the susceptibility and sexual dimorphism in alcohol-induced liver injury. Methods: C57Bl/6 mice were used in an intragastric ethanol feeding model of alcohol-associated steatohepatitis (ASH). Hepatocyte-specific Mkp1-/- knockout and (Mkp1+/+ "f/f" male and female mice were subjected to the NIAAA chronic plus binge model. Primary mouse hepatocytes were used for in vitro studies. Liver RNA sequencing was performed on an Illumina NextSeq 500. Liver injury was evaluated by plasma alanine transaminase (ALT), hepatic ER stress and inflammation markers. Statistical analysis was carried out using ANOVA and the unpaired Student's t-test. Results: ASH was associated with the severe injury accompanied by increased endoplasmic reticulum (ER) stress and significant downregulation of Dusp1 mRNA expression. In vitro, ethanol treatment resulted in a time-dependent decrease in Dusp1 mRNA and protein expression in primary hepatocytes in both males and females; however, this effect was significantly more pronounced in hepatocytes from females. In vivo, female mice developed more liver injury in a chronic plus binge model which was accompanied by a significant decrease in liver Dusp1 mRNA expression. In comparison, liver Dusp1 was not changed in male mice, while they developed milder injury to alcohol. Mkp1 deletion in hepatocytes led to increased alcohol induced liver injury, ER stress and inflammation in both sexes. Conclusion: Hepatocyte Mkp1 plays a significant role in alcohol induced liver injury. Alcohol downregulates Mkp1 expression in hepatocytes in a sex dependent manner and could play a role in sexual dimorphism in increased female susceptibility to alcohol.

Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies.

BACKGROUND: Cyclic nucleotides are second messengers, which play significant roles in numerous biological processes. Previous work has shown that cAMP and cGMP signaling regulates various pathways in liver cells, including Kupffer cells, hepatocytes, hepatic stellate cells, and cellular components of hepatic sinusoids. Importantly, it has been shown that cAMP levels and enzymes involved in cAMP homeostasis are affected by alcohol. Although the role of cyclic nucleotide signaling is strongly implicated in several pathological pathways in liver diseases, studies describing the changes in genes regulating cyclic nucleotide metabolism in ALD are lacking. METHODS: Male C57B/6 mice were used in an intragastric model of alcohol-associated steatohepatitis (ASH). Liver injury, inflammation, and fibrogenesis were evaluated by measuring plasma levels of injury markers, liver tissue cytokines, and gene expression analyses. Liver transcriptome analysis was performed to examine the effects of alcohol on regulators of cyclic AMP and GMP levels and signaling. cAMP and cGMP levels were measured in mouse livers as well as in livers from healthy human donors and patients with alcohol-associated hepatitis (AH). RESULTS: Our results show significant changes in several phosphodiesterases (PDEs) with specificity to degrade cAMP (Pde4a, Pde4d, and Pde8a) and cGMP (Pde5a, Pde6d, and Pde9a), as well as dual-specificity PDEs (Pde1a and Pde10a) in ASH mouse livers. Adenylyl cyclases (ACs) 7 and 9, which are responsible for cAMP generation, were also affected by alcohol. Importantly, adenosine receptor 1, which has been implicated in the pathogenesis of liver diseases, was significantly increased by alcohol. Adrenoceptors 1 and 3 (Adrb), which couple with stimulatory G protein to regulate cAMP and cGMP signaling, were significantly decreased. Additionally, beta arrestin 2, which interacts with cAMP-specific PDE4D to desensitize G-protein-coupled receptor to generate cAMP, was significantly increased by alcohol. Notably, we observed that cAMP levels are much higher than cGMP levels in the livers of humans and mice; however, alcohol affected them differently. Specifically, cGMP levels were higher in patients with AH and ASH mice livers compared with controls. As expected, these changes in liver cyclic nucleotide signaling were associated with increased inflammation, steatosis, apoptosis, and fibrogenesis. CONCLUSIONS: These data strongly implicate dysregulated cAMP and cGMP signaling in the pathogenesis of ASH. Future studies to identify changes in these regulators in a cell-specific manner could lead to the development of novel targeted therapies for ASH.

Increased expression of phosphodiesterase 4 in activated hepatic stellate cells promotes cytoskeleton remodeling and cell migration.

Activation and transdifferentiation of hepatic stellate cells (HSC) into migratory myofibroblasts is a key process in liver fibrogenesis. Cell migration requires an active remodeling of the cytoskeleton, which is a tightly regulated process coordinated by Rho-specific guanine nucleotide exchange factors (GEFs) and the Rho family of small GTPases. Rho-associated kinase (ROCK) promotes assembly of focal adhesions and actin stress fibers by regulating cytoskeleton organization. GEF exchange protein directly activated by cAMP 1 (EPAC1) has been implicated in modulating TGFß1 and Rho signaling; however, its role in HSC migration has never been examined. The aim of this study was to evaluate the role of cAMP-degrading phosphodiesterase 4 (PDE4) enzymes in regulating EPAC1 signaling, HSC migration, and fibrogenesis. We show that PDE4 protein expression is increased in activated HSCs expressing alpha smooth muscle actin and active myosin light chain (MLC) in fibrotic tissues of human nonalcoholic steatohepatitis cirrhosis livers and mouse livers exposed to carbon tetrachloride. In human livers, TGFß1 levels were highly correlated with PDE4 expression. TGFß1 treatment of LX2 HSCs decreased levels of cAMP and EPAC1 and increased PDE4D expression. PDE4 specific inhibitor, rolipram, and an EPAC-specific agonist decreased TGFß1-mediated cell migration in vitro. In vivo, targeted delivery of rolipram to the liver prevented fibrogenesis and collagen deposition and decreased the expression of several fibrosis-related genes, and HSC activation. Proteomic analysis of mouse liver tissues identified the regulation of actin cytoskeleton by the kinase effectors of Rho GTPases as a major pathway impacted by rolipram. Western blot analyses confirmed that PDE4 inhibition decreased active MLC and endothelin 1 levels, key proteins involved in cytoskeleton remodeling and contractility. The current study, for the first time, demonstrates that PDE4 enzymes are expressed in hepatic myofibroblasts and promote cytoskeleton remodeling and HSC migration. © 2023 The Pathological Society of Great Britain and Ireland.

Pedro Belou. Conferencia de 1936 sobre la hipoacusia laboral y el ruido urbano / Pedro Belou. Conference delivered in 1936 on occupational hearing loss and urban noise / Pedro Belou. Conferência de 1936 sobre perda auditiva ocupacional e ruído urbano

La problemática del ruido en las ciudades toma preponderancia internacional a finales del siglo XX, y pocas veces se comentan los esfuerzos pioneros realizados por especialistas que abogaron por un ambiente sonoro saludable. Éste es el caso de Pedro Belou, un médico otorrinolaringólogo nacido en Uruguay quien realizó toda su carrera profesional en Argentina, y que se destacó como científico de renombre mundial. A Belou podríamos ubicarlo como uno de los pioneros en el Río de la Plata en advertir acerca de las enfermedades que genera en las personas la exposición al ruido en las ciudades y en las industrias durante una conferencia que dio en Buenos Aires en 1936. En este artículo se rescatan los contenidos de su ponencia por la actualidad que tienen sus argumentos, y también para contribuir a su biografía, ya que esta conferencia no se menciona en ninguna de sus biografías.

Summary: City noise became a significant issue at the global level towards the end of the 20th Century, and discussions on pioneer efforts conducted by specialists who advocated for a healthy sound environment are rare. This is the case of Pedro Belou, a Uruguayan born otolaryngologist who developed his professional career in Argentina and was a renowned scientist worldwide. Belou could be regarded as one of the first physicians in the River Plate to warn us about diseases arising from noise exposure in cities and factories, during a conference he delivered in Buenos Aires in 1936. This article brings his presentation to you given the current relevance of his argument and to contribute to his biography, since this conference has not been mentioned in any of his previous biographies.

O problema do ruído nas cidades ganha preponderância internacional no final do século XX, porém raramente se discute o pioneirismo de especialistas que defendiam um ambiente sonoro saudável, como é o caso de Pedro Belou; otorrinolaringologista nascido no Uruguai, passou toda a sua carreira profissional na Argentina, destacando-se como um cientista de renome mundial. Poderíamos colocar Belou como um dos pioneiros no Río de la Plata em alertar, em uma conferência que deu em Buenos Aires em 1936, sobre as doenças que afetam as pessoas devido à exposição ao ruído nas cidades e nas indústrias. Neste artigo o conteúdo de sua apresentação é resgatado devido não somente pela atualidade de seus argumentos, como também para contribuir com sua biografia, já que esta conferência não é mencionada em nenhuma delas.

Novel Liposomal Rolipram Formulation for Clinical Application to Reduce Emesis.

Introduction: The phosphodiesterase 4 (PDE4) inhibitor, rolipram, has beneficial effects on tissue inflammation, injury and fibrosis, including in the liver. Since rolipram elicits significant CNS side-effects in humans (ie, nausea and emesis), our group developed a fusogenic lipid vesicle (FLV) drug delivery system that targets the liver to avoid adverse events. We evaluated whether this novel liposomal rolipram formulation reduces emesis. Methods: C57Bl/6J male mice were used to compare the effect of three doses of free and FLV-delivered (FLVs-Rol) rolipram in a behavioral correlate model of rolipram-induced emesis. Tissue rolipram and rolipram metabolite levels were measured using LC-MS/MS. The effect of FLVs-Rol on brain and liver PDE4 activities was evaluated. Results: Low and moderate doses of free rolipram significantly reduced anesthesia duration, while the same doses of FLVs-Rol had no effect. However, the onset and duration of adverse effects (shortening of anesthesia period) elicited by a high dose of rolipram was not ameliorated by FLVs-Rol. Post-mortem analysis of brain and liver tissues demonstrated that FLVs affected the rate of rolipram uptake by liver and brain. Lastly, administration of a moderate dose of FLVs-Rol attenuated endotoxin induced PDE4 activity in the liver with negligible effect on the brain. Discussion: The findings that the low and moderate doses of FLVs-Rol did not shorten the anesthesia duration time suggest that FLV delivery prevented critical levels of drug from crossing the blood-brain barrier (BBB) to elicit CNS side-effects. However, the inability of high dose FLVs-Rol to prevent CNS side-effects indicates that there was sufficient unencapsulated rolipram to cross the BBB and shorten anesthesia duration. Notably, a moderate dose of FLVs-Rol was able to decrease PDE4 activity in the liver without affecting the brain. Taken together, FLVs-Rol has a strong potential for clinical application for the treatment of liver disease without side effects.

Genome Sequences of 22 T1-like Bacteriophages That Infect Enterobacteriales.

Here, the full genome sequences of 22 T1-like bacteriophages isolated from wastewater are reported. Eight (BlueShadow, Brooksby, Devorator, ElisaCorrea, Reinasaurus, SorkZaugg, Supreme284, ZeroToHero) were isolated on Citrobacter, six on Klebsiella (Chell, FairDinkum, HazelMika, Opt-817, P528, PeteCarol), and eight on Escherichia (Fulano1, Mishu, Opt-719, PhleaSolo, Punny, Poky, Phunderstruck, Sadiya).

Phosphodiesterase 4 Inhibition as a Therapeutic Target for Alcoholic Liver Disease: From Bedside to Bench.

Alcoholic liver disease (ALD) is a major cause of liver-related mortality. There is still no US Food and Drug Administration-approved therapy for ALD, and therefore, identifying therapeutic targets is needed. Our previous work demonstrated that ethanol exposure leads to up-regulation of cAMP-degrading phosphodiesterase 4 (PDE4) expression, which compromises normal cAMP signaling in monocytes/macrophages and hepatocytes. This effect of ethanol on cAMP signaling contributes to dysregulated inflammatory response and altered lipid metabolism. It is unknown whether chronic alcohol consumption in humans alters hepatic PDE4 expression and cAMP signaling and whether inadequate cAMP signaling plays a pathogenic role in alcohol-induced liver injury. Our present work shows that expression of the PDE4 subfamily of enzymes is significantly up-regulated and cAMP levels are markedly decreased in hepatic tissues of patients with severe ALD. We also demonstrate the anti-inflammatory efficacy of roflumilast, a clinically available PDE4 inhibitor, on endotoxin-inducible proinflammatory cytokine production ex vivo in whole blood of patients with alcoholic hepatitis. Moreover, we demonstrate that ethanol-mediated changes in hepatic PDE4 and cAMP levels play a causal role in liver injury in in vivo and in vitro models of ALD. This study employs a drug delivery system that specifically delivers the PDE4 inhibitor rolipram to the liver to avoid central nervous system side effects associated with this drug. Our results show that PDE4 inhibition significantly attenuates ethanol-induced hepatic steatosis and injury through multiple mechanisms, including reduced oxidative and endoplasmic reticulum stress both in vivo and in vitro. Conclusion: Increased PDE4 plays a pathogenic role in the development of ALD; hence, directed interventions aimed at inhibiting PDE4 might be an effective treatment for ALD.

Síndrome de cimitarra, valoración con ecocardiografía transesofágica intraoperatoria. Informe de caso / Scimitar syndrome; intraoperative transesophageal echocardiography assessment. Case report

9-year-old patient diagnosed with scimitar syndrome through transthoracic echocardiogram and cardiac catheterization. Surgical correction is performed by anastomosing the collector of the pulmonary right vein to AI through the interatrial septum, tunneling it with a pericardic patch. The study findings and echocardiographic images of such surgical repair and the spectrum of pulsed Doppler differentiating between right and left pulmonary veins will be shown below. The connection through the septum was evidenced, simulating an interatrial communication. A difference was found among the measured points S, D, A and between the left and right pulmonary veins, without this resulting in a stenosis during the repair.

Paciente de 9 años de edad el cual es diagnosticado con síndrome de cimitarra a través de ecografía transtorácica y cateterismo cardiaco. Se realiza cirugía correctora la cual se anastomosa el colector de vena pulmonar derecha hacia AI a través del septum interauricular, tunelizándolo con parche pericárdico. A continuación se muestran los hallazgos e imágenes ecocardiográficas de tal reparación y el espectro doppler pulsado diferenciado entre las venas pulmonares derechas e izquierdas. Se pudo evidenciar la conexión a través del septum, simulando una comunicación interauricular. Se halló una diferencia entre los puntos medidos S, D, A entre las venas pulmonares izquierdas y derechas, sin que esto significara una estenosis en la reparación.

Ecocardiografía intraoperatoria: causa de la hipotensión post circulación extracorporea / Intraoperative echocardiography. cause of the hypotension post circulation extracorporea / Ecocardiografia intraoperatória. causa da hipotensão pós-circulação extracorporea

RESUMEN: En la práctica diaria uno de los eventos que más se presenta es la hipotensión luego de la salida de circulación extracorpórea (CEC). La posibilidad de contar con ecocardiografía a partir del 2015 en el nosocomio ha ayudado a orientar al anestesiólogo sobre el estado hemodinámico, sin embargo, no se ha podido esclarecer la causa de esta hipotensión utilizando esta herramienta. El objetivo de este estudio es hallar los parámetros ecocardiográficos que más se relacionan con la hipotensión refractaria luego de la salida de la (CEC). Se seleccionaron pacientes sometidos a cirugías de comunicación interauricular e interventricular monitorizados con ecocardiografía transesofágica. La muestra se estratificó en dos grupos, hipotensos (casos) y normotensos (controles) luego de la salida de CEC. Estudio observacional, de casos y controles, retrospectivo. En el análisis del total de pacientes se encontraron diferencias estadísticamente significativas (p<0.05) de los parámetros ecocardiográficos indicadores de hipovolemia entre los grupos. No hubo diferencias estadísticas (p=0.083) en los parámetros ecocardiográficos de contractilidad. Los resultados obtenidos demostraron que los parámetros ecográficos de hipovolemia fueron los que más se asociaron al momento de la hipotensión. Esto permite orientar al profesional a un uso racional de drogas inotrópicas y reposición de volumen.

SUMMARY: In daily practice, one of the most frequent events is hypotension after the of extracorporeal circulation (ECC). The possibility of having an echocardiography from 2015 has been a guiding means in the hemodynamic state, however, the cause of this hypotension has not been clarified. The aim of this study is to find the echocardiographic parameters that are most related to refractory hypotension after ECC. Patients undergoing atrial and interventricular communication surgeries monitored with transesophageal echocardiography were selected. The sample was stratified into two groups, hypotensive (cases) and normotensive (controls) after ECC. Observational, case-control study, retrospective. In the analysis of the total of the patients, were found statistically significant differences (p <0.05) in the echocardiographic parameters indicating hypovolemia between the groups. There were no differences in the statistics (p = 0.83) in the echocardiographic parameters of contractility. The results showed that the ultrasonographic parameters of hypovolemia were those associated with hypotension. This allows the professional to be guided to a rational use of inotropic drugs and volume replacement.

RESUMO: Na prática diária, um dos eventos mais frequentes é a hipotensão após a saída da circulação extracorpórea (CEC). A possibilidade de ter ecocardiografia a partir de 2015 no hospital ajudou a orientar o anestesista sobre o estado hemodinâmico, no entanto, não foi capaz de esclarecer a causa desta hipotensão usando esta ferramenta. O objetivo deste estudo é encontrar os parâmetros ecocardiográficos mais relacionados à hipotensão refratária após a saída da artéria coronária (CEC). Pacientes submetidos a cirurgias de comunicação atrial e interventricular monitoradas por ecocardiograma transesofágico foram selecionados. A amostra foi estratificada em dois grupos, hipotensivos (casos) e normotensos (controles) após a saída do CEC. Estudo observacional, caso-controle, retrospectivo. Na análise do número total de pacientes, foram encontradas diferenças estatisticamente significantes (p <0,05) nos parâmetros ecocardiográficos indicativos de hipovolemia entre os grupos. Não houve diferenças estatísticas (p = 0,083) nos parâmetros ecocardiográficos de contratilidade. Os resultados obtidos mostraram que os parâmetros ultrassonográficos da hipovolemia foram os mais associados no momento da hipotensão. Isso permite que o profissional seja orientado para o uso racional de drogas inotrópicas e reposição de volume.

Primeros implantes de la válvula sin sutura Perceval S® en Argentina / First Perceval S™ Sutureless Aortic Valve Prosthesis Implantations in Argentina

RESUMEN El reemplazo valvular aórtico con prótesis sin sutura es una alternativa innovadora para el tratamiento de la estenosis aórtica en los ancianos y en los pacientes de alto riesgo. Aunque la experiencia mundial con estas prótesis lleva ya varios años, solo recientemente comenzó a comercializarse en Argentina el modelo Perceval S®. Se trata de una prótesis autoexpandible sin sutura hecha de pericardio bovino y montada en un stent de nitinol. En este estudio se presentan los primeros tres casos de reemplazo valvular aórtico con la bioprótesis Perceval realizados en Argentina. La técnica sin sutura es una alternativa prometedora para el reemplazo valvular aórtico quirúrgico con una bioprótesis, y, posiblemente, pueda competir con la terapéutica intravascular en los pacientes de alto riesgo.

ABSTRACT Aortic valve replacement with sutureless prostheses is an innovative alternative for the treatment of aortic stenosis in the el-derly and in high-risk patients. Although the world experience with these prostheses has been going on for several years, only recently, the Perceval S™ model, consisting of a self-expanding sutureless prosthesis made of bovine pericardium and mounted on a nitinol stent, has begun to be commercialized in Argentina. In this study, we present the first three cases of aortic valve replacement with Perceval bioprostheses performed in Argentina. The sutureless technique is a promising alternative for surgi-cal aortic valve replacement with a bioprosthesis, and may possibly compete with intravascular therapy in high-risk patients.

Portomesenteric Vein Thrombosis After Laparoscopic Sleeve Gastrectomy: Incidence, Analysis and Follow-Up in 1236 Consecutive Cases.

BACKGROUND: Portomesenteric vein thrombosis (PMVT) is a rare but severe complication after laparoscopic bariatric surgery, with potentially serious consequences. We aimed to describe the incidence, clinical features, management, outcome, and midterm follow-up in patients with PMVT after laparoscopic sleeve gastrectomy (LSG). METHODS: This retrospective and descriptive study included patients who underwent LSG between November 2009 and July 2015 and developed PMVT. The following data were analyzed: age, gender, body mass index (BMI), thrombosis risk factors, surgical technique, thromboembolic prophylaxis, primary surgery outcomes, clinical features, treatment, thrombophilia testing results, and follow-up findings, including imaging and endoscopic findings. RESULTS: A total of 1236 patients underwent LSG, and 5 (0.4 %) developed PMVT. The mean age was 34.4 years, and 3 patients were women. The mean BMI was 38.5 kg/m2. Two patients had received hormonal contraceptive treatment. Four patients had a history of smoking. All of the patients received anticoagulant treatment, and none required surgery. The mean hospitalization duration was 7.6 days. Two patients showed complete recanalization. One patient showed portal cavernomatosis on delayed images. Two patients had a positive thrombophilia test. No portal hypertension endoscopic findings were observed. CONCLUSIONS: PMVT is a rare complication, for which smoking was identified as a predominant risk factor. Early diagnosis and prompt anticoagulant therapy could lead to a dramatic decrease in the incidence of intestinal infarction, mortality, and extrahepatic portal hypertension in the near future. However, careful follow-up is necessary to evaluate the impact of PMVT on long-term patient outcomes.

Task and error analysis balancing benefits over business of electronic medical records.

Task and error analysis research was performed to identify: a) the process for healthcare organisations in managing healthcare for patients with mental illness or substance abuse; b) how the process can be enhanced and; c) if electronic medical records (EMRs) have a role in this process from a business and safety perspective. The research question is if EMRs have a role in enhancing the healthcare for patients with mental illness or substance abuse. A discussion on the business of EMRs is addressed to understand the balancing act between the safety and business aspects of an EMR.

Validación prospectiva y multicéntrica del ArgenSCORE en la cirugía de reemplazo valvular aórtico.: Comparación con el EuroSCORE I y el EuroSCORE II / Prospective and Multicentric Validation of the ArgenSCORE in Aortic Valve Replacement Surgery.: Comparison with the EuroSCORE I and the EuroSCORE II

Introducción En pacientes con estenosis aórtica e indicación de reemplazo valvular resulta imprescindible una estratificación correcta del riesgo operatorio para ofrecer la mejor opción posible en cada caso. Los modelos de riesgo preoperatorio han recobrado un papel protagónico en la evaluación de estos pacientes. Objetivos Validar el ArgenSCORE en forma prospectiva y multicéntrica en pacientes con reemplazo valvular aórtico y comparar su rendimiento con el EuroSCORE I y el EuroSCORE II. Material y métodos Se incluyeron 250 pacientes consecutivos con reemplazo valvular aórtico en cuatro centros de Buenos Aires desde febrero de 2008 hasta diciembre de 2012. Se comparó el rendimiento del ArgenSCORE, del EuroSCORE I y del EuroSCORE II mediante la evaluación de la discrimi­nación a través del cálculo del área bajo la curva ROC y del poder de calibración comparando la relación entre mortalidad observada y mortalidad predicha. Resultados La edad media de la población de validación (n = 250) fue de 68,62 ± 13,3 años y la mortalidad global fue del 3,6%. El ArgenSCORE mostró buen poder de discriminación (curva ROC 0,82) y buena capacidad para asignar riesgo (relación mortalidad observada 3,6% vs. mortalidad predicha 3,39%; p = 0,471). El EuroSCORE I mostró bajo poder de discriminación (curva ROC 0,62) y además sobrevaloró el riesgo estimado (relación mortalidad observada 3,6% vs. mortalidad predicha 5,58%; p < 0,0001). El EuroSCORE II mostró una aceptable capacidad de discriminación (curva ROC 0,76), aunque menor que la del ArgenSCORE, pero evidenció una subvaloración significativa del riesgo estimado (relación mortalidad observada 3,6% vs. mortalidad predicha 1,64%; p < 0,0001). Conclusiones El ArgenSCORE demostró que posee un rendimiento excelente en pacientes con reemplazo valvular aórtico. Este modelo local mostró buen poder de discriminación y mejor calibración en comparación con los modelos europeos, ya que el riesgo estimado fue sobrevalorado por el EuroSCORE I y subvalorado por el EuroSCORE II.

Introduction In patients with aortic stenosis and planned aortic valve replacement, an accurate stratification of surgical risk is mandatory to offer the best individual option. Preoperative risk scores have recovered a leading role in the assessment of these patients. Objectives The aim of this study was to perform a prospective, multicentric validation of the ArgenSCORE and compare its performance with the EuroSCORE I and the EuroSCORE II. Methods A total of 250 adult patients undergoing aortic valve replacement at four centers of the City of Buenos Aires were included in the study from February 2008 to December 2012. The ArgenSCORE was compared with the EuroSCORE I and the EuroSCORE II, evaluating model discrimination with the area under the ROC curve and calibration comparing the relation between observed mortality and predicted mortality. Results The mean age of the validation population (n = 250) was 68.62 ± 13.3 years and overall mortality of 3.6%. The ArgenSCORE showed good discrimination power (area under the ROC curve of 0.82) and a good predictive capacity to allocate risk (relation between observed mortality: 3.6% vs. predicted mortality: 3.39%; p = 0.471). The EuroSCORE I showed poor discrimination power (area under the ROC curve of 0.62) and risk overestimation (relation between observed mortality: 3.6% vs. predicted mortality: 5.58%; p < 0.0001). The EuroSCORE II showed an acceptable discrimination power (area under the ROC curve of 0.76), though lower than that of the ArgenSCORE, but a significant underestimation of predicted risk (relation between observed mortality: 3.6% vs. predicted mortality: 1.64%; p < 0.0001). Conclusions The ArgenSCORE evidenced adequate ability to predict mortality in patients undergoing AVR surgery. This local model demonstrated good discrimination power and better calibration compared to the European models, as the EuroSCORE I overestimated and the EuroSCORE II underestimated predicted risk.

Primer puntaje de riesgo latinoamericano en cirugía cardíaca (ArgenSCORE): validación externa y temporal a 10 años de su desarrollo / External and Temporal Validation 10 Years after the Development of the First Latin- American Risk Stratification Score for Cardiac Surgery (ArgenSCORE) / External and Temporal Validation 10 Years after the Development of the First Latin-American Risk Stratification Score for Cardiac Surgery (ArgenSCORE)

Introducción En las últimas décadas se han aplicado diversos modelos de riesgo para predecir mortalidad en cirugía cardíaca, pero ninguno de estos sistemas de evaluación fue desarrollado en poblaciones de América Latina. Estos modelos presentan un rendimiento menor cuando son aplicados en poblaciones diferentes de aquellas en las que fueron desarrollados. Objetivos Validar un modelo de riesgo local de mortalidad intrahospitalaria en cirugía cardíaca [Argentinean System for Cardiac Operative Risk Evaluation (ArgenSCORE)] en forma externa y temporal y compararlo con el EuroSCORE. Material y métodos Se incluyeron 5.268 pacientes adultos, consecutivos, intervenidos quirúrgicamente desde junio de 1994 hasta diciembre de 2009. El modelo fue desarrollado mediante regresión logística en 2.903 pacientes intervenidos en un centro desde junio de 1994 hasta diciembre de 1999. Se realizó validación interna prospectiva desde enero de 2000 hasta junio de 2001 en 708 pacientes. Desde febrero de 2000 hasta diciembre de 2009 se validó en forma externa y temporal el modelo recalibrado evaluando su discriminación y calibración en pacientes operados en cuatro centros diferentes del de su desarrollo y se comparó su rendimiento con el EuroSCORE. Resultados La población de validación externa incluyó 1.657 pacientes, con una edad media de 62,8 ± 13,3 años y una mortalidad global del 4,58%. El ArgenSCORE mostró un buen poder de discriminación (curva ROC: 0,80) y buena capacidad para asignar riesgo en todos los pacientes (relación mortalidad observada: 4,58% vs. mortalidad predicha: 4,54%; p = 0,842). El EuroSCORE mostró un buen poder discriminativo (curva ROC: 0,79), pero sobrevaloró el riesgo estimado (relación mortalidad observada: 4,58% vs. mortalidad predicha: 5,23%; p < 0,0001). Conclusiones El ArgenSCORE mostró una capacidad adecuada para predecir mortalidad intrahospitalaria en cirugía cardíaca a 10 años de su desarrollo. Su aplicación en poblaciones con características geográficas similares a las de aquellas donde fue desarrollado muestra un rendimiento mejor en comparación con un puntaje internacional ya consolidado y de uso global.

Background During the last decades, several risk assessment models have been applied to predict the risk of mortality after cardiac surgery; however, none of them have been developed in Latin American populations. These models have inferior performance when applied to patient groups other than the ones on whom they were developed. Objectives To perform external and temporal validation of a local risk score for cardiac surgery [Argentinean System for Cardiac Operative Risk Evaluation (ArgenSCORE)] and compare it to the EuroSCORE. Material and Methods A total of 5268 consecutive adult patients undergoing cardiac surgery were included from June 1994 to December 2009. The risk model was developed through logistic regression on the data of 2903 patients who underwent cardiac surgery between June 1994 and December 1999 at a center. Prospective internal validation was performed on 708 patients between January 2000 and June 2001. External and temporal validation of the recalibrated model were performed between February 2000 and December 2009, evaluating model discrimination and calibration in patients operated on at four centers different from the one where the score had been originally developed. The method was also compared to the EuroSCORE. Results The external validation was performed on 1657 patients, mean age was 62.8±13.3 years and global mortality was 4.58%. The ArgenSCORE showed both good discriminatory power with an area under the ROC curve of 0.80 and predictive capacity for risk assessment in all patients (observed mortality 4.58% vs. expected mortality 4.54%; p=0.842). The EuroSCORE showed good discriminatory power (area under the ROC curve of 0.79) but overestimated the risk (observed mortality 4.58% vs. expected mortality 5.23%; p <0.0001). Conclusions The ArgenSCORE showed an adequate capacity to predict in-hospital mortality in cardiac surgery 10 years after being developed. The score can be applied to populations with similar geographic characteristics, showing a better performance compared to an established international risk stratification model.

Cystathionine beta synthase gene dose dependent vascular remodeling in murine model of hyperhomocysteinemia.

Although children born with severe homocystinurea (i.e. cystathionine beta synthase homozygote knockout, CBS-/-) develop deleterious vascular complications with structural malformation and do not live past teenage, the heterozygote (CBS-/+) lives with apparently normal phenotype. Interestingly, this differential role of CBS expression in vascular remodeling is unclear. Peroxisome proliferator activated receptor gamma (PPARγ) is nuclear transcription factor that mitigates vascular complications. The hypothesis was that homocysteine (Hcy) decreased thioredoxin (Trx), peroxiredoxin (Prx), increased NADPH oxidase (NOX1), mitochondrial nitric oxide synthase (mtNOS) activity and reactive oxygen species (ROS) in mitochondria in a CBS gene dose-dependent manner. ROS transduced matrix metalloproteinase (MMP) activation causing thickening (fibrosis) of the basement membrane, rendering ineffective endothelial nitric oxide synthase (eNOS) and promoted endothelial-smooth muscle disconnection/uncoupling by antagonizing PPARγ. Wild type (WT-CBS+/+), CBS-/+ and CBS -/- mice were treated with or without ciglitazone (CZ, a PPARγ agonist) in food at birth. Aortic nuclear PPARγ expression was measured by EMSA. Aortic mtNOS activity and ROS production was measured using NO- and H(2)O(2)-electrodes, respectively. Aorta was analyzed for Trx, Prx, by Western blot, and PCR. MMP activity was by in situ zymography. Aortic function was measured in tissue myobath. The results suggested 90% morbidity in CBS-/- allele at 12 wks. However, treatment with the PPARγ agonist, CZ significantly reduced the morbidity to 20%. In addition, CZ restored the PPARγ activity in CBS-/+ and -/- mice to normal levels. The oxidative stress was alleviated by CZ treatment. In situ labeling with mito-tracker suggests co-localization of ROS with mitochondrial mitophagy. The mtNOS activity was increased in HHcy compared to WT. The data support the notion that Hcy decreases redoxins, increases mtNOS activity and ROS/oxidase in mitochondrial mitophagy in a gene dose-dependent manner of CBS. ROS transduces MMP activation, rendering ineffective eNOS and promotes endothelial-smooth muscle disconnection/uncoupling by antagonizing PPARγ. We suggest that the children born with severe ho-mocystineurea may do better if treated with PPARγ agonist.

Informe final de medición de metas sobre Desafíos de Toronto 2005. Guatemala / Final report measuring goals on Toronto Challenges 2005. Guatemala

El presente documento muestra los resultados de los 5 desafíos y las 20 metas del Informe final de medición de metas sobre el desafío de Toronto.

Asociación de valores de proteína C reactiva preoperatoria con complicaciones en el posoperatorio de cirugía cardiovascular / Association between Preoperative C-Reactive Protein Levéis with Postoperative Complications of Cardiovascular Surgery

Introducción El síndrome de respuesta inflamatoria sistémica es una complicación frecuente en el posoperatorio de cirugía cardíaca, que puede evolucionar con shock vasopléjico y los casos más graves pueden derivar en falla de uno o más órganos. Se describieron predictores en el preoperatorio y el perioperatorio asociados con esta complicación; sin embargo, un estado de inflamación subclínico en la etapa preoperatoria, no detectado por estudios de rutina, podría relacionarse con la respuesta inflamatoria desencadenada en el posoperatorio. Niveles elevados de proteína C reactiva (PCR), un parámetro de inflamación en diferentes escenarios clínicos y que se asocia con el pronóstico de diversas patologías cardiovasculares, podrían predecir el síndrome. Objetivo Evaluar la contribución de la elevación de los niveles preoperatorios de proteína C reactiva para predecir el síndrome de respuesta inflamatoria sistémica y sus complicaciones posoperatorias en cirugía cardíaca. Material y métodos Se incluyeron 169 pacientes consecutivos, prospectivos (77,3% hombres, edad 61,1 ± 15,9, Euroscore 9,46 [DE 12,7]) sometidos a cirugía cardíaca entre abril de 2007 y diciembre de 2008. Se determinó el nivel de PCR en todos los pacientes. El punto final combinado incluyó síndrome de respuesta inflamatoria sistémica y su asociación con fibrilación auricular, insuficiencia renal, shock o muerte. Resultados Ochenta y siete pacientes (54%) desarrollaron el síndrome de respuesta inflamatoria sistémica y 50 pacientes (31%) presentaron el punto final combinado. La mortalidad intrahospitalaria fue del 5,6% (9 pacientes). Ajustados por variables preoperatorias e intraoperatorias, los niveles preoperatorios de PCR ≥ 2 mg/dl se asociaron independientemente con el punto final combinado (OR 2,95, IC 95% 1,20-7,23; p < 0,018), con la evolución con síndrome de respuesta inflamatoria sistémica (SRIS) (OR 2,46, IC 95% 1,17-5,15; p < 0,000), SRIS combinado con insuficiencia renal (OR 5,10, IC 95% 1,48-17,58; p < 0,010), SRIS combinado con shock (OR 6,50, IC 95% 1,59-27,34; p < 0,005), SRIS combinado con fibrilación auricular (OR 3,51, IC 95% 1,14-10,79; p < 0,028), insuficiencia renal (OR 2,91, IC 95% 1,19-7,12; p < 0,019) y shock (OR 4,13, IC 95% 1,25-13,60; p < 0,020). Conclusiones Los niveles preoperatorios de PCR ≥ 2,0 mg/dl pueden predecir el síndrome de respuesta inflamatoria sistémica y el síndrome de respuesta inflamatoria sistémica con insuficiencia renal, fibrilación auricular, shock y muerte en el posoperatorio de cirugía cardíaca.

Background Systemic inflammatory response syndrome is a frequent postoperative complication of cardiovascular surgery that can develop vasoplegic shock and organ or multiorgan dysfunction in tlie most severe cases. Preoperative and postoperative predictors associated with this complication have been described; however, a subclinical preoperative inflammatory state, not detected by routine tests, might be related to the postoperative inflammatory response. Elevated C-reactive protein (CRP) levéis, a parameter of inflammation in different clinical scenarios that is associated with the prognosis of diverse cardiovascular diseases, might predict the syndrome. Objective To evalúate the valué of elevated C-reactive protein to predict systemic inflammatory response syndrome and its postoperative complications after cardiovascular surgery. Material and Methods A total of 169 consecutive patients (77.3% were men, age 61.1±15.9, Euroscore 9.46 [SD 12.7]) undergoing cardiovascular surgery were prospectively included between April 2007 and December 2008. CRP levéis were determined in all patients. The combined endpoint included the incidence of systemic inflammatory response syndrome and its association with atrial fibrillation, kidney failure, shock or death. Results Eighty seven patients (54%) developed systemic inflammatory response syndrome and 50 patients (31%) presented the combined endpoint. In-hospital mortality was 5.6% (9 patients). The preoperative levéis of CRP >2 mg/dl adjusted for preoperative and postoperative variables were independently associated with the combined endpoint (OR 2.95, 95% CI 1.20-7.23; p<0.018), with the development of systemic inflammatory response syndrome (SIRS) (OR 2.46, 95% CI 1.17-5.15; p<0.000), and with the combination of SIRS and kidney failure (OR 5.10, 95% CI 1.48-17.58; p<0.010), SIRS and shock (OR 6.50, 95% CI 1.59-27.34; p<0.005), and SIRS and atrial fibrillation (OR 3.51, 95% CI 1.14-10.79; p<0.028), kidney failure (OR 2.91, 95% CI 1.19-7.12; p<0.019) and shock (OR 4.13, 95% CI 1.25-13.60; p < 0.020). Conclusions Preoperative levéis of CRP >2.0 mg/dl may predict the systemic inflammatory response syndrome and the systemic inflammatory response syndrome with kidney failure, atrial fibrillation, shock and death in the postoperative period of cardiovascular surgery.

Asistencia circulatoria temporaria como puente al retrasplante / Temporary Circulatory Support as a Bridge to Retransplantation

A pesar de las mejoras significativas en los criterios de selección de los receptores de trasplante cardíaco, la mejor preservación de los órganos, las nuevas terapéuticas inmunosupresoras y los avances en el cuidado postrasplante, los pacientes que recibieron un trasplante cardíaco continúan con una tasa alta de falla temprana y tardía del injerto. Se han propuesto múltiples intervenciones terapéuticas para estos casos; sin embargo, los dispositivos de asistencia ventricular y el retrasplante cardíaco permanecen como el tratamiento definitivo para este subgrupo de pacientes. En esta presentación se describe un caso de shock cardiogénico refractario posinfarto agudo de miocardio en un paciente con trasplante cardíaco previo, que fue tratado en forma consecutiva con balón de contrapulsación intraaórtico, cirugía de revascularización miocárdica y, finalmente, por continuar en shock cardiogénico refractario con falla multiorgánica, recibió asistencia circulatoria con Levitronix® CentriMag® como puente al retrasplante. Luego de 21 días en asistencia ventricular y mejoría franca de la falla multiorgánica, se realizó el trasplante ortotópico.

Despite the significant advances in recipient selection criteria for cardiac transplantation, organ preservation techniques, novel immunosuppressive agents, and care following transplantation, early and late graft failures are still high in heart transplant recipients. Several therapeutic interventions have been described for these cases; however, the use of ventricular assist devices and cardiac retransplantation still remain as the definite treatment for this subgroup of patients. We describe a case of refractory cardiogenic shock due to acute myocardial infarction in a patient with a history of heart transplantation that was consecutively treated with intraaortic balloon pump and myocardial revascularization surgery. Despite therapy, the patient remained in refractory cardiogenic shock with múltiple organ failure and received Levitronix® CentriMag® as a bridge to retransplantation. After 21 days under circulatory support, múltiple organ failure reverted and the patient underwent orthotopic heart transplantation.

The first Latin-American risk stratification system for cardiac surgery: can be used as a graphic pocket-card score.

This study aims to develop the first Latin-American risk model that can be used as a simple, pocket-card graphic score at bedside. The risk model was developed on 2903 patients who underwent cardiac surgery at the Spanish Hospital of Buenos Aires, Argentina, between June 1994 and December 1999. Internal validation was performed on 708 patients between January 2000 and June 2001 at the same center. External validation was performed on 1087 patients between February 2000 and January 2007 at three other centers in Argentina. In the development dataset the area under receiver operating characteristics (ROC) curve was 0.73 and the Hosmer-Lemeshow (HL) test was P=0.88. In the internal validation ROC curve was 0.77. In the external validation ROC curve was 0.81, but imperfect calibration was detected because the observed in-hospital mortality (3.96%) was significantly lower than the development dataset (8.20%) (P<0.0001). Recalibration was done in 2007, showing excellent level of agreement between the observed and predicted mortality rates on all patients (P=0.92). This is the first risk model for cardiac surgery developed in a population of Latin-America with both internal and external validation. A simple graphic pocket-card score allows an easy bedside application with acceptable statistic precision.

Cirugía en la disección aórtica aguda tipo A: resultados hospitalarios y seguimiento alejado / Surgical Treatment of Acute Type A Aortic Dissection: In-Hospital Outcomes and Long-Term Follow-Up

Introducción La disección aguda de la aorta tipo A (DAA-A) es una emergencia que requiere cirugía inmediata, debido al mal pronóstico de su evolución natural. A pesar del avance en las técnicas quirúrgicas, el procedimiento aún tiene una morbimortalidad elevada. Objetivos Analizar la morbimortalidad hospitalaria y la sobrevida alejada de una serie consecutiva de pacientes operados por DAA-A. Material y métodos Se incluyeron 63 pacientes consecutivos (el 71,4% eran hombres) en cuatro centros asistenciales de Buenos Aires desde julio de 1994 a mayo de 2007. El seguimiento se realizó en el 89% de los pacientes. La edad promedio fue de 63 ± 11,3 años. En 15 pacientes, el reemplazo se extendió hasta el hemiarco y en 5 se reemplazó el arco completo. La válvula aórtica se reemplazó en 12 pacientes. Resultados Durante la estadía hospitalaria fallecieron 19 pacientes (30,1%): un caso durante la cirugía, 7 por complicaciones isquémicas o falla multiorgánica, 3 por complicaciones neurológicas, 5 por complicaciones cardíacas, 1 por hemorragia digestiva y 2 pacientes a consecuencia de múltiples complicaciones. Durante el seguimiento fallecieron 12 pacientes (32,4%): 8 casos de causa cardiovascular y 4 de causa no cardíaca. El análisis multivariado detectó que las variables asociadas con mayor mortalidad hospitalaria fueron el bajo volumen minuto y el tiempo de circulación extracorpórea (CEC) prolongado, en tanto que las asociadas con mayor mortalidad alejada fueron la edad > 70 años y un tiempo menor de CEC. La sobrevida a 1, 3, 5 y 10 años fue del 89%, 79,5%, 73% y 58%, respectivamente. Conclusiones Los resultados del tratamiento quirúrgico de la DAA-A en nuestro medio pueden asimilarse a los obtenidos en series internacionales, lo que a su vez confirma la elevada morbimortalidad hospitalaria y alejada de esta entidad.

Background Acute type A aortic dissection (AAD-A) is an extremely severe condition that requires emergency surgery. In spite of advances in surgical techniques, the procedure still carries great morbidity and mortality rates. Objectives To analyze in-hospital morbidity and mortality and longterm survival of a consecutive series of patients undergoing surgery for AAD-A. Material and Methods We included 63 consecutive patients (71% were men) in four health care centers in Buenos Aires from July 1994 to May 2007. Eighty nine percent of patients completed follow-up. Mean age was 63±11.3 years. Aortic hemiarch was replaced in 15 patients and 5 patients received complete aortic replacement. Aortic valve replacement was performed in 12 patients. Results During hospitalization 19 patients (30.1%) died: one death occurred at the operation room, 7 patients died due to ischemic complications or multi organ failure, 3 patients died of neurological complications, 5 of cardiac complications, 1 of gastrointestinal bleeding and 2 deaths were a consequence of multiple complications. Twelve patients (32.4%) died during follow-up (8 cardiac deaths and 4 non cardiac deaths). Multivariate analysis detected that low cardiac output and cardiac bypass pump (CBP) duration were associated with greater in-hospital mortality rates, while age >70 years and lower CBP duration correlated with greater long-term mortality. Survival rates at 1, 3, 5 and 10 years were 89%, 79,5%, 73% and 58%, respectively. Conclusions Surgical results of AAD-A in our environment are similar to those published in international series, confirming high in-hospital and long-term morbidity and mortality rates associated with this condition.