LSD1 inhibition suppresses ASCL1 and de-represses YAP1 to drive potent activity against neuroendocrine prostate cancer.

Lysine-specific demethylase 1 (LSD1 or KDM1A ) has emerged as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Among mCRPC subtypes, neuroendocrine prostate cancer (NEPC) is an exceptionally aggressive variant driven by lineage plasticity, an adaptive resistance mechanism to androgen receptor axis-targeted therapies. Our study shows that LSD1 expression is elevated in NEPC and associated with unfavorable clinical outcomes. Using genetic approaches, we validated the on-target effects of LSD1 inhibition across various models. We investigated the therapeutic potential of bomedemstat, an orally bioavailable, irreversible LSD1 inhibitor with low nanomolar potency. Our findings demonstrate potent antitumor activity against CRPC models, including tumor regressions in NEPC patient-derived xenografts. Mechanistically, our study uncovers that LSD1 inhibition suppresses the neuronal transcriptional program by downregulating ASCL1 through disrupting LSD1:INSM1 interactions and de-repressing YAP1 silencing. Our data support the clinical development of LSD1 inhibitors for treating CRPC - especially the aggressive NE phenotype. Statement of Significance: Neuroendocrine prostate cancer presents a clinical challenge due to the lack of effective treatments. Our research demonstrates that bomedemstat, a potent and selective LSD1 inhibitor, effectively combats neuroendocrine prostate cancer by downregulating the ASCL1- dependent NE transcriptional program and re-expressing YAP1.

Identification of a Novel Substrate-Derived Spermine Oxidase Inhibitor.

Homeostasis of the biogenic polyamines spermine (Spm) and spermidine (Spd), present in µM-mM concentrations in all eukaryotic cells, is precisely regulated by coordinated activities of the enzymes of polyamine synthesis, degradation, and transport, in order to sustain normal cell growth and viability. Spermine oxidase (SMOX) is the key and most recently discovered enzyme of polyamine metabolism that plays an essential role in regulating polyamine homeostasis by catalyzing the back-conversion of Spm to Spd. The development of many types of epithelial cancer is associated with inflammation, and disease-related inflammatory stimuli induce SMOX. MDL72527 is widely used in vitro and in vivo as an irreversible inhibitor of SMOX, but it is also potent towards N1-acetylpolyamine oxidase. Although SMOX has high substrate specificity, Spm analogues have not been systematically studied as enzyme inhibitors. Here we demonstrate that 1,12-diamino-2,11-bis(methylidene)-4,9-diazadodecane (2,11-Met2-Spm) has, under standard assay conditions, an IC50 value of 169 µM towards SMOX and is an interesting instrument and lead compound for studying polyamine catabolism.

Reduction in polyamine catabolism leads to spermine-mediated airway epithelial injury and induces asthma features.

BACKGROUND: Airway epithelial injury is a crucial component of acute and severe asthma pathogenesis and a promising target for treatment of refractory asthma. However, the underlying mechanism of epithelial injury remains poorly explored. Although high levels of polyamines, mainly spermine, have been found in asthma and comorbidity, their role in airway epithelial injury and the cause of their altered levels in asthma have not been explored. METHODS: We measured key polyamine metabolic enzymes in lung samples from normal and asthmatic subjects and in mice with OVA-induced allergic airway inflammation (AAI). Polyamine metabolism was modulated using pharmacologic/genetic modulators. Epithelial stress and apoptosis were measured by TSLP levels and TUNEL assay, respectively. RESULTS: We found loss of the polyamine catabolic enzymes spermidine/spermine-N (1)-acetyltransferase-1 (SAT1) and spermine oxidase (SMOX) predominantly in bronchial epithelial cells (BECs) of human asthmatic lung samples and mice with AAI. In naïve mice, SAT1 or SMOX knockdown led to airway hyper-responsiveness, remodeling, and BEC apoptosis. Conversely, in mice with AAI, overexpression of either SAT1 or SMOX alleviated asthmatic features and reduced TSLP levels and BEC apoptosis. Similarly, while pharmacological induction of SAT1 and SMOX using the polyamine analogue bis(ethyl)norspermine (BENSPM) alleviated asthmatic features with reduced TSLP levels and BEC apoptosis, pharmacological inhibition of these enzymes using BERENIL or MDL72527, respectively, worsened them. Spermine accumulation in lungs correlated with BEC apoptosis, and spermine treatment caused apoptosis of human BEAS-2B cells in vitro. CONCLUSIONS: Spermine induces BEC injury. Induction of polyamine catabolism may represent a novel therapeutic approach for asthma via reversing BEC stress.

Epigenetic silencing of miR-124 prevents spermine oxidase regulation: implications for Helicobacter pylori-induced gastric cancer.

Chronic inflammation contributes to the development of various forms of cancer. The polyamine catabolic enzyme spermine oxidase (SMOX) is induced in chronic inflammatory conditions, including Helicobacter pylori-associated gastritis, where its production of hydrogen peroxide contributes to DNA damage and subsequent tumorigenesis. MicroRNA expression levels are also altered in inflammatory conditions; specifically, the tumor suppressor miR-124 becomes silenced by DNA methylation. We sought to determine if this repression of miR-124 is associated with elevated SMOX activity and concluded that miR-124 is indeed a negative regulator of SMOX. In gastric adenocarcinoma cells harboring highly methylated and silenced mir-124 gene loci, 5-azacytidine treatment allowed miR-124 re-expression and decreased SMOX expression. Overexpression of an exogenous miR-124-3p mimic repressed SMOX mRNA and protein expression as well as H2O2 production by >50% within 24 h. Reporter assays indicated that direct interaction of miR-124 with the 3'-untranslated region of SMOX mRNA contributes to this negative regulation. Importantly, overexpression of miR-124 before infection with H. pylori prevented the induction of SMOX believed to contribute to inflammation-associated tumorigenesis. Compelling human in vivo data from H. pylori-positive gastritis tissues indicated that the mir-124 gene loci are more heavily methylated in a Colombian population characterized by elevated SMOX expression and a high risk for gastric cancer. Furthermore, the degree of mir-124 methylation significantly correlated with SMOX expression throughout the population. These results indicate a protective role for miR-124 through the inhibition of SMOX-mediated DNA damage in the etiology of H. pylori-associated gastric cancer.

Inhibitors of DNA Methylation, Histone Deacetylation, and Histone Demethylation: A Perfect Combination for Cancer Therapy.

Epigenetic silencing and inappropriate activation of gene expression are frequent events during the initiation and progression of cancer. These events involve a complex interplay between the hypermethylation of CpG dinucleotides within gene promoter and enhancer regions, the recruitment of transcriptional corepressors and the deacetylation and/or methylation of histone tails. These epigenetic regulators act in concert to block transcription or interfere with the maintenance of chromatin boundary regions. However, DNA/histone methylation and histone acetylation states are reversible, enzyme-mediated processes and as such, have emerged as promising targets for cancer therapy. This review will focus on the potential benefits and synergistic/additive effects of combining DNA-demethylating agents and histone deacetylase inhibitors or lysine-specific demethylase inhibitors together in epigenetic therapy for solid tumors and will highlight what is known regarding the mechanisms of action that contribute to the antitumor response.

Subpleural artifact in lung pulse evidenced by M-mode ultrasound in a patient with atelectasis / Artefacto subpleural en pulso pulmonar evidenciado mediante ultrasonidos en modo M en un paciente con atelectasia

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Continuous tissue glucose monitoring correlates with measurement of intermittent capillary glucose in patients with distributive shock / La monitorización continua de la glucosa de tejido se correlaciona con la medición de glucosa capilar intermitente en pacientes con shock distributivo

BACKGROUND: Intermittent glycemic measurements in patients admitted to the intensive care unit (ICU) can result in episodes of severe hypoglycemia or in a poor control of glycemia range. We designed a study to assess accuracy and reliability of continuous monitoring of tissue glucose for patients with distributive shock. METHODS: Consecutive patients admitted to the ICU with a diagnosis of distributive shock and the need of insulin infusion for glycemic control were included in the study. These patients were implanted a Continuous Glucose Control Monitoring System (CGMS) with the sensor inserted subcutaneously into the abdominal wall. CGMS values were recorded every 5min. Capillary glucose (CG) was monitored for adjusting insulin perfusion according to the ICU protocol. Correlation between both methods was assessed. RESULTS: A total of 11,673 CGMS and 348 CG values were recorded. In five patients, CGMS failed to detect tissue glucose. A glucose value < 3.33 mmol/l (< 60 mg/dl) was observed in 3.6% of CGMS and in 0.29% CG values. 295 pairs of measurements were included in the statistical analysis for correlation assessment. The intraclass correlation coefficient was 0.706. The Pearson correlation coefficient was 0.71 (p < 0.0001, 95% CI 0.65-0.76). The mean of differences between both measurement methods was 0.22 mmol/l (3.98 mg/dl) (95% CI 0.66-7.31). CONCLUSIONS: When the Continuous Glucose Control Monitoring System (CGMS) is able to obtain data (75% of the patients), there is correlation between the values obtained by this method and capillary blood glucose in patients with distributive shock. CGMS can detect more episodes of glycemic excursions outside the normal range than intermittent capillary glucose monitoring. Variables that may impair glucose metabolism and peripheral soft tissues perfusion could impair CGMS measurements

ANTECEDENTES: la medición de glucemia intermitente pueden provocar episodios de hipoglucemia severa o un mal control glucémico en los pacientes ingresados en la Unidad de Cuidados Intensivos (UCI). Diseñamos un estudio para evaluar la exactitud y fiabilidad de la monitorización continua de glucosa tisular en pacientes con shock distributivo. MÉTODOS: Se incluyeron en el estudio todos los pacientes ingresados consecutivamente en la UCI con el diagnóstico de shock distributivo y la necesidad de insulina en perfusión para el control glucémico. A estos pacientes se les implantó un Sistema de Monitorización Continua de la Glucosa Tisular (CGMS) con un sensor insertado en tejido subcutáneo de la pared abdominal. CGMS valores se registraron cada cinco minutos. La glucosa capilar (GC) fue monitorizada para ajustar la perfusión de insulina de acuerdo con el protocolo de la UCI. Se evaluó la correlación entre ambos métodos. RESULTADOS: Se registraron un total de 11.673 valores de CGMS y 348 valores de CG. En cinco pacientes, la CGMS no pudo ser detectada. Un valor de glucosa < 3,33 mmol/l (< 60 mg/dl) se observó en 3,6% de los valores de CGMS y en el 0,29% de los valores de CG. 295 pares de mediciones se incluyeron en el análisis estadístico para la evaluación de la correlación. El coeficiente de correlación intraclase fue de 0,706. El coeficiente de correlación de Pearson fue de 0,71 (p < 0,0001; IC 95% 0,65-0,76). La media de las diferencias entre los dos métodos de medición fue de 0,22 mmol/l (3,98 mg/dl) (IC 95% 0,66 a 7,31). CONCLUSIONES: Cuando el sensor de medición de glucosa tisular continua es capaz de obtener datos (75% de los pacientes), existe correlación entre los valores obtenidos mediante este método y la glucemia capilar en los pacientes que presentan shock distributivo. CGMS puede detectar más episodios de excursiones glucémicas fuera del rango de normalidad que la monitorización intermitente de glucosa capilar. Variables que pueden perjudicar el metabolismo de la glucosa y la perfusión periférica de los tejidos blandos podrían afectar las mediciones CGMS

Continuous tissue glucose monitoring correlates with measurement of intermittent capillary glucose in patients with distributive shock.

BACKGROUND: Intermittent glycemic measurements in patients admitted to the intensive care unit (ICU) can result in episodes of severe hypoglycemia or in a poor control of glycemia range. We designed a study to assess accuracy and reliability of continuous monitoring of tissue glucose for patients with distributive shock. METHODS: Consecutive patients admitted to the ICU with a diagnosis of distributive shock and the need of insulin infusion for glycemic control were included in the study. These patients were implanted a Continuous Glucose Control Monitoring System (CGMS) with the sensor inserted subcutaneously into the abdominal wall. CGMS values were recorded every 5min. Capillary glucose (CG) was monitored for adjusting insulin perfusion according to the ICU protocol. Correlation between both methods was assessed. RESULTS: A total of 11,673 CGMS and 348 CG values were recorded. In five patients, CGMS failed to detect tissue glucose. A glucose value <3.33mmol/l (<60mg/dl) was observed in 3.6% of CGMS and in 0.29% CG values. 295 pairs of measurements were included in the statistical analysis for correlation assessment. The intraclass correlation coefficient was 0.706. The Pearson correlation coefficient was 0.71 (p<0.0001, 95% CI 0.65-0.76). The mean of differences between both measurement methods was 0.22mmol/l (3.98mg/dl) (95% CI 0.66-7.31). CONCLUSIONS: When the Continuous Glucose Control Monitoring System (CGMS) is able to obtain data (75% of the patients), there is correlation between the values obtained by this method and capillary blood glucose in patients with distributive shock. CGMS can detect more episodes of glycemic excursions outside the normal range than intermittent capillary glucose monitoring. Variables that may impair glucose metabolism and peripheral soft tissues perfusion could impair CGMS measurements.

Increased Helicobacter pylori-associated gastric cancer risk in the Andean region of Colombia is mediated by spermine oxidase.

Helicobacter pylori infection causes gastric cancer, the third leading cause of cancer death worldwide. More than half of the world's population is infected, making universal eradication impractical. Clinical trials suggest that antibiotic treatment only reduces gastric cancer risk in patients with non-atrophic gastritis (NAG), and is ineffective once preneoplastic lesions of multifocal atrophic gastritis (MAG) and intestinal metaplasia (IM) have occurred. Therefore, additional strategies for risk stratification and chemoprevention of gastric cancer are needed. We have implicated polyamines, generated by the rate-limiting enzyme ornithine decarboxylase (ODC), in gastric carcinogenesis. During H. pylori infection, the enzyme spermine oxidase (SMOX) is induced, which generates hydrogen peroxide from the catabolism of the polyamine spermine. Herein, we assessed the role of SMOX in the increased gastric cancer risk in Colombia associated with the Andean mountain region when compared with the low-risk region on the Pacific coast. When cocultured with gastric epithelial cells, clinical strains of H. pylori from the high-risk region induced more SMOX expression and oxidative DNA damage, and less apoptosis than low-risk strains. These findings were not attributable to differences in the cytotoxin-associated gene A oncoprotein. Gastric tissues from subjects from the high-risk region exhibited greater levels of SMOX and oxidative DNA damage by immunohistochemistry and flow cytometry, and this occurred in NAG, MAG and IM. In Mongolian gerbils, a prototype colonizing strain from the high-risk region induced more SMOX, DNA damage, dysplasia and adenocarcinoma than a colonizing strain from the low-risk region. Treatment of gerbils with either α-difluoromethylornithine, an inhibitor of ODC, or MDL 72527 (N(1),N(4)-Di(buta-2,3-dien-1-yl)butane-1,4-diamine dihydrochloride), an inhibitor of SMOX, reduced gastric dysplasia and carcinoma, as well as apoptosis-resistant cells with DNA damage. These data indicate that aberrant activation of polyamine-driven oxidative stress is a marker of gastric cancer risk and a target for chemoprevention.

Resultados de una encuesta sobre la práctica clínica habitual en el empleo de albúmina en UCI / Results of a survey on albumin use in clinical practice in intensive care units

INTRODUCCIÓN: Las soluciones de albúmina humana se emplean en diversas enfermedades, aunque su indicación no es clara en todas. Presentan un coste elevado y su beneficio no se encuentra plenamente establecido. Resulta interesante conocer cuál es la presencia de las soluciones de albúmina en la práctica clínica diaria de los intensivistas. OBJETIVO: Documentar prácticas clínicas habituales y describir la variabilidad de las mismas en cuanto al empleo de soluciones de albúmina en enfermos críticos. DISEÑO: Encuesta enviada mediante correo electrónico a unidades de cuidados intensivos (UCI) españolas y sudamericanas. Periodo: Planificación y realización durante el año 2012. Ámbito: UCI españolas y sudamericanas. MÉTODOS: Cuestionario de 35 preguntas. RESULTADOS: Se han analizado 57 encuestas. El empleo de las soluciones de albúmina fue esporádico o no se empleaba en el paciente crítico (96,5%). La excepción fueron los pacientes hepatópatas (un 87,7% de los encuestados la administraba). Un elevado porcentaje declaró conocer la evidencia científica disponible sobre el empleo de albúmina en pacientes hepatópatas (82,5%) y no hepatópatas (77,2%). El 5,3% de los encuestados prefería basarse en su experiencia para establecer las indicaciones del empleo de albúmina. CONCLUSIONES: El empleo de soluciones de albúmina no es frecuente en las UCI, salvo en pacientes hepatópatas. Los profesionales del enfermo crítico manifiestan tener un amplio conocimiento de la evidencia científica. Las opiniones emitidas, acerca del empleo de albúmina, son acordes con las recomendaciones establecidas, sobre todo, en pacientes hepatópatas. La experiencia profesional prevalece en escasas ocasiones sobre las recomendaciones publicadas

BACKGROUND: Human albumin solutions are used in a number of disorders, though their indications are not clear in all circumstances. These solutions are costly, and their benefit has not been established in all settings. It is therefore interesting to assess the presence of albumin solutions in the daily clinical practice of critical care professionals. OBJECTIVES: To report the standard clinical practices and to describe the variability of albumin solutions use in critically ill patients. DESIGN: A survey sent by e-mail to Spanish and South American Intensive Care Units (ICUs) Period: Planning and execution during the year 2012. METHODS: A questionnaire comprising 35 questions. RESULTS: Fifty-seven surveys were analyzed. The use of albumin solutions was sporadic or negligible in critically ill patients (96.5%). The exceptions were patients with liver disease (87.7% of the responders administered albumin to these patients). A high percentage of professionals claimed to know the available scientific evidence on the use of albumin in patients with liver disease (82.5%) and in patients without liver disease (77.2%). Only 5.3% of the responders preferred to rely on their own experience to establish the indications of albumin use. CONCLUSIONS: The use of albumin solutions is infrequent in ICUs, except in patients with liver disease. Evidence-based knowledge on albumin use is declared to be extensive in ICUs. As a rule, opinions on the use of albumin solutions are based on the scientific recommendations, especially in patients with liver disease. Professional experience rarely prevails over the published clinical guidelines

Results of a survey on albumin use in clinical practice in intensive care units.

BACKGROUND: Human albumin solutions are used in a number of disorders, though their indications are not clear in all circumstances. These solutions are costly, and their benefit has not been established in all settings. It is therefore interesting to assess the presence of albumin solutions in the daily clinical practice of critical care professionals. OBJECTIVES: To report the standard clinical practices and to describe the variability of albumin solutions use in critically ill patients. DESIGN: A survey sent by e-mail to Spanish and South American Intensive Care Units (ICUs) PERIOD: Planning and execution during the year 2012. METHODS: A questionnaire comprising 35 questions. RESULTS: Fifty-seven surveys were analyzed. The use of albumin solutions was sporadic or negligible in critically ill patients (96.5%). The exceptions were patients with liver disease (87.7% of the responders administered albumin to these patients). A high percentage of professionals claimed to know the available scientific evidence on the use of albumin in patients with liver disease (82.5%) and in patients without liver disease (77.2%). Only 5.3% of the responders preferred to rely on their own experience to establish the indications of albumin use. CONCLUSIONS: The use of albumin solutions is infrequent in ICUs, except in patients with liver disease. Evidence-based knowledge on albumin use is declared to be extensive in ICUs. As a rule, opinions on the use of albumin solutions are based on the scientific recommendations, especially in patients with liver disease. Professional experience rarely prevails over the published clinical guidelines.

Recent advances in the molecular biology of metazoan polyamine transport.

Very limited molecular knowledge exists about the identity and protein components of the ubiquitous polyamine transporters found in animal cells. However, a number of reports have been published over the last 5 years on potential candidates for metazoan polyamine permeases. We review the available evidence on these putative polyamine permeases, as well as establish a useful "identikit picture" of the general polyamine transport system, based on its properties as found in a wide spectrum of mammalian cells. Any molecular candidate encoding a putative "general" polyamine permease should fit that provided portrait. The current models proposed for the mechanism of polyamine internalization in mammalian cells are also briefly reviewed.

[Recidivant laryngeal leishmaniasis: an unusual case in an immunocompetent patient treated with corticosteroids]. / Leishmaniosis laríngea recidivante: un caso inusual en un paciente inmunocompetente tratado con corticoides.

Leishmaniosis is a chronic parasitic disease, which in Argentina is mainly caused by protozoa belonging to the Leishmania (Viannia) braziliensis complex, leading to cutaneous and mucosal pathologies. We report a rare case of laryngeal leishmaniosis in a 29 year-old man from Jujuy province, Argentina, who had been misdiagnosed with other pathologies, carrying this infectious disease for about 20 years. During 2008, the patient was admitted with complaints of progressive hoarseness of the voice and dyspnea. He also reported having received tuberculostatics, antifungal and corticosteroids treatments since 2002. Different biopsies and direct laryngoscopic exams revealed inespecific granulomatous larynx, TBC-related laryngitis, laryngitis related to Histoplasma infection, extra-nodal Natural Killer-cell lymphoma. Finally, the patient was evaluated at the University Hospital and the final diagnosis was: granulomatous larynx, intra and extra-cytoplasmic Leishmania spp amastigotes, negative for TBC and Histoplasma cultures, and chronic laryngitis related to Leishmania infection, according to the laryngeal endoscopy, microbiological and histopathological exams, respectively. The patient received pentavalent antimonial treatment and his condition improved after 2 months of follow-up. Primary laryngeal leishmaniosis is rare and this localization does not belong to the most prevalent mucosal leishmaniosis. However, this parasitic disease warrants special concern, especially in patients who received prolonged corticosteroid treatments, in order to avoid a misdiagnosis of this disease.

Posición inusual de cables de marcapasos a través de vena cava superior izquierda / Unusual position of a pacemaker cable

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[Absence of benefit with triple antiaggregation in acute non persistent ST segment elevation myocardial infarction in patients not subjected to early interventionism]. / Ausencia de beneficio con triple antiagregación en el síndrome coronario agudo sin elevación persistente del segmento ST, en pacientes no sometidos a intervencionismo precoz.

OBJECTIVE: To assess the efficacy and safety of a treatment with clopidogrel when associated or not to the treatment with tirofiban and aspirin for high-risk non-ST segment elevation myocardial infarction (non-STEMI), without early angioplasty. SETTING: Intensive Care and Coronary Unit (ICCU), in a center with no Hemodynamic Laboratory. DESIGN: Non randomized clinical trial. PARTICIPANTS: One hundred and twenty-three patients admitted with the diagnosis of high-risk non-STEMI, defined as patients with chest pain and one of the following: ST segment depression or transient elevation or an elevation in cardiac troponin I (TropIc). INTERVENTIONS: We included patients admitted in a 24-month period. During the first 12-month period, the patients received tirofiban and clopidogrel (group A). In the second one, clopidogrel was not administered (group B). Urgent cardiac catheterism was requested if recurrent ischemic chest pain with ST segment changes, left ventricular failure or hemodynamic instability were present. PRIMARY VARIABLES: A composite of recurrent ischemic chest pain with ST segment changes or death during ICCU admission was evaluated as an efficacy variable. A variable of safety was defined as the occurrence of intracranial or gastrointestinal bleeding, or any hemorrhagic event accompanied by a drop of at least 3 g/dl of hemoglobin. The rate of urgent cardiac catheterisms was recorded. RESULTS: Neither the rate of the efficacy variable (19.6 % in group A and 19.4% in group B; p = 0.97), nor the rate of the safety variable (3.5% and 2.9% of patients in groups A and B, p = 1) showed statistically significant difference. There was no statistically significant difference in the rate of urgent cardiac catheterism (19.6% in group A and 13.4% in group B; p = 0.35). CONCLUSIONS: In the early course of high-risk non-STEMI with a conservative management strategy, the addition of clopidogrel to tirofiban does not change the rate of ischemic events, death, need of urgent catheterism or hemorrhagic events.

Ausencia de beneficio con triple antiagregación en el síndrome coronario agudo sin elevación persistente del segmento ST, en pacientes no sometidos a intervencionismo precoz / Absence of benefit with tripleantiaggregation in acute non persistent ST segment elevation myocardial infarction in patients not subjected to early interventionism

Objetivo. Valorar la eficacia y seguridad del tratamiento con clopidogrel cuando se asocia o no al tratamiento con tirofibán más ácido acetilsalicílico (AAS) en el síndrome coronario agudo sin elevación persistente del segmento ST (SCASEST) de alto riesgo, sin intervencionismo precoz. Ámbito. Unidad de Cuidados Intensivos (UCI), en centro sin laboratorio de hemodinámica. Diseño. Ensayo clínico sin asignación aleatoria. Pacientes. Ciento veintitrés pacientes con SCASEST de alto riesgo, definido como dolor torácico y uno de los siguientes: descenso del segmento ST o ascenso transitorio o aumento de troponina I cardíaca (TropIc). Intervenciones. Estudio desarrollado durante veinticuatro meses. Los primeros doce meses el tratamiento incluía tirofibán y clopidogrel (grupo A); en los siguientes doce meses, el clopidogrel no se administraba (grupo B). El cateterismo cardíaco urgente se solicitó si aparecía dolor torácico recurrente con cambios en el segmento ST, fallo ventricular izquierdo o inestabilidad hemodinámica. Variables principales. Se evaluó una variable de eficacia, formada por la combinación de la aparición de dolor torácico con cambios en el segmento ST o muerte durante la estancia en la UCI, y una variable de seguridad, definida por la existencia de hemorragias intracraneales, digestivas o aquellas asociadas a una disminución de hemoglobina de al menos 3 g/dl. Se registró la frecuencia de realización de cateterismo urgente. Resultados. No hubo diferencias estadísticas significativas en la frecuencia de la variable de eficacia (19,6% en el grupo A y 19,4% en el grupo B; p = 0,97), ni en la de seguridad (3,5 y 2,9% en los grupos A y B respectivamente; p = 1). Tampoco existió diferencia estadística significativa en la realización de cateterismo urgente (19,6% en el grupo A y 13,4% en el grupo B; p = 0,35). Conclusiones. En el curso inicial del SCASEST de alto riesgo con una estrategia de tratamiento conservadora, la adición de clopidogrel al tirofibán no modifica la aparición de eventos isquémicos, muerte o necesidad de cateterismo urgente, ni se asocia a un incremento de complicaciones hemorrágicas

Objective. To assess the efficacy and safety of a treatment with clopidogrel when associated or not to the treatment with tirofiban and aspirin for high-risk non-ST segment elevation myocardial infarction (non-STEMI), without early angioplasty. Setting. Intensive Care and Coronary Unit (ICCU), in a center with no Hemodynamic Laboratory. Design. Non randomized clinical trial. Participants. One hundred and twenty-three patients admitted with the diagnosis of high-risk non-STEMI, defined as patients with chest pain and one of the following: ST segment depression or transient elevation or an elevation in cardiac troponin I (TropIc). Interventions. We included patients admitted in a 24-month period. During the first 12-month period, the patients received tirofiban and clopidogrel (group A). In the second one, clopidogrel was not administered (group B). Urgent cardiac catheterism was requested if recurrent ischemic chest pain with ST segment changes, left ventricular failure or hemodynamic instability were present. Primary variables. A composite of recurrent ischemic chest pain with ST segment changes or death during ICCU admission was evaluated as an efficacy variable. A variable of safety was defined as the occurrence of intracranial or gastrointestinal bleeding, or any hemorrhagic event accompanied by a drop of at least 3 g/dl of hemoglobin. The rate of urgent cardiac catheterisms was recorded. Results. Neither the rate of the efficacy variable (19.6 % in group A and 19.4% in group B; p = 0.97), nor the rate of the safety variable (3.5% and 2.9% of patients in groups A and B, p = 1) showed statistically significant difference. There was no statistically significant difference in the rate of urgent cardiac catheterism (19.6% in group A and 13.4% in group B; p = 0.35). Conclusions. In the early course of high-risk non-STEMI with a conservative management strategy, the addition of clopidogrel to tirofiban does not change the rate of ischemic events, death, need of urgent catheterism or hemorrhagic events

Spermine and spermidine mediate protection against oxidative damage caused by hydrogen peroxide.

The polyamines spermidine and spermine have been hypothesized to possess different functions in the protection of DNA from reactive oxygen species. The growth and survival of mouse fibroblasts unable to synthesize spermine were compared to their normal counterparts in their native and polyamine-depleted states in response to oxidative stress. The results of these studies suggest that when present at normal or supraphysiological concentrations, either spermidine or spermine can protect cells from reactive oxygen species. However, when polyamine pools are pharmacologically manipulated to produce cells with low levels of predominately spermine or spermidine, spermine appears to be more effective. Importantly, when cells are depleted of both glutathione and endogenous polyamines, they exhibit increased sensitivity to hydrogen peroxide as compared to glutathione depletion alone, suggesting that polyamines not only play a role in protecting cells from oxidative stress but this role is distinct from that played by glutathione.

Inflammation and polyamine catabolism: the good, the bad and the ugly.

The induction of polyamine catabolism by specific anti-tumour polyamine analogues has increased interest in the roles polyamine catabolism play in cell growth, death and response to various anti-tumour agents. The relatively recent finding of an inducible mammalian spermine oxidase (SMO/PAOh1), in addition to the two-step spermidine/spermine N(1)-acetyltransferanse (SSAT)/N(1)-acetylpolyamine oxidase (APAO) catabolic pathway, underscores the complexities of the regulation of polyamine catabolism by various stimuli. Furthermore, recent data indicate that infectious agents and mediators of inflammation can also up-regulate polyamine catabolism. Induction of SSAT by these agents can reduce intracellular polyamine concentrations and cell growth rate, thus providing a beneficial mechanism by which cells may adapt to inflammatory stress. However, increased polyamine catabolism can also result in substantial increases in intracellular reactive oxygen species (ROS) through the production of H(2)O(2) as a by-product of either APAO or SMO/PAOh1 activity. This increased generation of ROS can have different results, depending on the mechanism of induction and cell types involved. Targeted killing of tumour cells by agents that stimulate SSAT/APAO and/or SMO/PAOh1 is obviously a 'good' effect. However, induction of SMO/PAOh1 by inflammation or infectious agents has the potential to produce sufficient ROS in normal, non-tumour cells to lead to DNA damage, mutation and, potentially, carcinogenic transformation ('bad'). The variation in the induction of these polyamine catabolic enzymes, as well as the level and timing of this induction will dictate the cellular outcome in the presence of both desirable and undesirable effects ('ugly'). Here we discuss the relative role of each of the steps in polyamine catabolism in response to inflammatory stress.