Exposure to endogenous and exogenous sex hormones and reproductive history influence prognosis in women with ALS.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a higher incidence in men suggesting an influence of sex steroids. Our objective was to investigate past exposure to endogenous and synthetic steroids in female ALS patients and controls. METHODS: We administered a questionnaire to 158 postmenopausal women (75 ALS patients and 83 controls). We calculated reproductive time span (RTS), lifetime endogenous estrogen (LEE) and progesterone exposures (LPE), oral contraceptive pill (OCP) use, and reproductive history. RESULTS: ALS patients showed shorter LEE and LPE, a lower proportion of breast cancer, and 11% showed no history of pregnancies vs. 4% of controls. Odds ratios (ORs) showed that <17 y of LEE and a delayed menarche (>13 y) constitute risk factors for ALS [OR = 2.1 (95% confidence interval {CI}, 1.08-4.2); and OR = 2.4 (95% CI, 1.1-5.1) respectively]. According to Cox survival analysis, for each year the LEE increased over 17 y, it was independently associated with longer survival [hazard ratio (HR) = 0.37 (95% CI, 0.16-0.85)] after adjusting for smoking, age and site of onset. Multivariate regression analysis demonstrated that for each month using OCP for longer than 40 mo increased the risk of ALS [adjusted OR = 4.1 (95% CI, 1.2-13.8)]. DISCUSSION: Thus, longer exposure to endogenous female sex steroids increased survival and reduced ALS susceptibility. In contrast, longer exposure to synthetic sex steroids showed a negative impact by reducing the production of endogenous female sex steroids or due to crossover with other steroid receptors. Given the neuroprotective effects of sex steroids, we suggest that abnormalities of neuroendocrine components may alter motor function in women with ALS.

Renin-angiotensin system blockade on angiotensin-converting enzyme 2 and TMPRSS2 in human type II pneumocytes.

AIMS: Angiotensin-converting enzyme (ACE) 2 is the receptor for severe acute respiratory syndrome coronavirus 2 which causes coronavirus disease 2019 (COVID-19). Viral cellular entry requires ACE2 and transmembrane protease serine 2 (TMPRSS2). ACE inhibitors (ACEIs) or angiotensin (Ang) receptor blockers (ARBs) influence ACE2 in animals, though evidence in human lungs is lacking. We investigated ACE2 and TMPRSS2 in type II pneumocytes, the key cells that maintain lung homeostasis, in lung parenchymal of ACEI/ARB-treated subjects compared to untreated control subjects. MAIN METHODS: Ang II and Ang-(1-7) levels and ACE2 and TMPRSS2 protein expression were measured by radioimmunoassay and immunohistochemistry, respectively. KEY FINDINGS: We found that the ratio Ang-(1-7)/Ang II, a surrogate marker of ACE2 activity, as well as the amount of ACE2-expressing type II pneumocytes were not different between ACEI/ARB-treated and untreated subjects. ACE2 protein content correlated positively with smoking habit and age. The percentage of TMPRSS2-expressing type II pneumocytes was higher in males than females and in subjects under 60 years of age but it was not different between ACEI/ARB-treated and untreated subjects. However, there was a positive association of TMPRSS2 protein content with age and smoking in ACEI/ARB-treated subjects, with high TMPRSS2 protein levels most evident in ACEI/ARB-treated older adults and smokers. SIGNIFICANCE: ACEI/ARB treatment influences human lung TMPRSS2 but not ACE2 protein content and this effect is dependent on age and smoking habit. This finding may help explain the increased susceptibility to COVID-19 seen in smokers and older patients with treated cardiovascular-related pathologies.

Difluprednate 0.05% twice a day vs prednisolone acetate 1% 4 times a day for cataract postsurgical inflammation treatment: noninferiority trial.

PURPOSE: To establish whether difluprednate 0.05% nanoemulsion (DIFL) twice a day is as effective as prednisolone acetate 1% + phenylephrine hydrochloride 0.12% suspension (PRED) 4 times a day for postsurgical inflammation treatment. SETTING: 4 private Argentine ophthalmological centers. DESIGN: Noninferiority, prospective, multicenter, double-blind, randomized, parallel-group, comparative trial. METHODS: A total of 259 patients who underwent phacoemulsification randomly received DIFL or PRED, starting the day before surgery and continuing for 28 days. The primary endpoint was central corneal thickness. Noninferior anti-inflammatory efficacy was considered if the difference of corneal thickness between baseline and day 4 did not differ beyond 17 µm between treatments. Secondary endpoints were cell and flare, corrected distance visual acuity (CDVA), endothelial cell count, optical coherence tomography (OCT) central macular thickness, and intraocular pressure. All outcomes were evaluated at baseline and day 1, 4, and 28 postoperatively. RESULTS: 225 patients finished the study. The difference in corneal thickness at baseline and day 4 did not differ beyond 17 µm between treatments (95% CI -2.78 µm to 14.84 µm), with no statistically significant difference ( P = .523). No statistically significant differences were found between groups in total anterior chamber clearance at any study timepoint ( P > .05). Moreover, no statistically significant differences were reported between treatments in CDVA ( P = .455), endothelial cell count ( P = .811), OCT central macular thickness ( P = .869), and intraocular pressure outcome ( P = .316). CONCLUSIONS: Difluprednate administered twice a day was at least as effective as prednisolone acetate administered 4 times a day for inflammatory treatment after cataract surgery.

Communicating bad news in the context of COVID-19 / Comunicación de malas noticias en el contexto de la COVID-19

Abstract Communicating bad news is one of the most frequent activities in hospitals, for which some recommendations have been adapted to the needs within the coronavirus-2 disease (COVID-19) context. This document presents nine steps to deliver bad news (face to face or remotely) adapted to the COVID-19 context from two international protocols (SPIKES and GRIEV_ING). The importance of promoting physical and emotional self-care skills in health personnel is also described, as well as psychological first aid strategies to address the emotional response of the family member who receives the news. Finally, the limitations and advantages of the proposal should be considered.

Resumen La comunicación de malas noticias es una de las actividades más frecuentes en los hospitales dentro del contexto de la COVID-19. A pesar de su alta frecuencia, existen pocas recomendaciones adaptadas a las necesidades que el contexto de la COVID-19 demanda. Debido a lo anterior, en el presente escrito se presentan nueve pasos para dar malas noticias (cara a cara o por vía remota) de dos protocolos internacionales (SPIKES y GRIEV_ING) adaptados a las necesidades de transmisión de información de la COVID-19. Se describe también la importancia de promover habilidades de autocuidado físico y emocional en el personal de salud, así como estrategias de primeros auxilios psicológicos para el abordaje de la respuesta emocional del familiar que recibe la noticia. Finalmente, se deben considerar las limitaciones y ventajas de la propuesta.

Apoptotic regulator BCL-2 blockade as a potential therapy in classical Hodgkin Lymphoma.

The challenge in classical Hodgkin Lymphoma (cHL) management is the 30-40% of refractory/relapsed cases. AIMS: The aim of this work was to determine whether NIK and BCL-2 could be useful as prognosis biomarkers in cHL. In addition, we evaluated BCL-2 as a directed-therapy in cHL cell lines using venetoclax. MAIN METHODS: We evaluated NIK and BCL-2 expression in 112 untreated cHL patients' lymph-node biopsies by immunohistochemistry. cHL cell lines were treated with venetoclax alone or combined with vincristine or doxorubicin. Cell viability, metabolic activity and cell death were analyzed by trypan-blue exclusion method, MTS assay and FDA/IP staining respectively. KEY FINDINGS: No correlation between NIK or BCL-2 expression and the majority of the clinical parameters was found. Patients with ≥60% BCL-2+ HRS-cells had a shorter disease-free survival (DFS) and overall survival (OS) (p = 0.002, p = 0.02 respectively). A decision tree analysis, in a 30 patients subgroup, showed that patients with <60% NIK+ HRS-cells but with ≥60% BCL-2+ HRS-cells had a worse outcome in terms of DFS and OS. These parameters performed better as prognosis indicators as compared to the diagnosis bone marrow status. Human cHL cell lines U-H01, KM-H2, L1236, SUPHD1, L540 showed sensitivity to venetoclax. The co-treatment effect of venetoclax and vincristine or doxorubicin on cell viability was diverse depending on the cell line evaluated. SIGNIFICANCE: BCL-2 should be considered as a prognosis biomarker as well as a potential new therapeutic target in cHL. We report for the first time the cytotoxic effect of venetoclax in human cHL cell lines.

Impaired frequencies and function of platelets and tissue remodeling in chronic Chagas disease.

Chronic inflammation, as a consequence of the persistent infection with Trypanosoma cruzi, leads to continuous activation of the immune system in patients with chronic Chagas disease. We have previously shown that increased sera levels of soluble P-selectin are associated with the severity of the cardiomyopathy distinctive of chronic Chagas disease. In this study, we explored the expression of biomarkers of platelet and endothelial activation, tissue remodeling, and mediators of the coagulation cascade in patients at different clinical stages of chronic Chagas heart disease. The frequencies of activated platelets, measured by the expression of CD41a and CD62P were decreased in patients with chronic Chagas disease compared with those in uninfected subjects, with an inverse association with disease severity. Platelet activation in response to adenosine diphosphate was also decreased in T. cruzi-infected subjects. A major proportion of T. cruzi infected subjects showed increased serum levels of fibrinogen. Patients with severe cardiac dysfunction showed increased levels of endothelin-1 and normal values of procollagen I. In conclusion, chronic infection with T. cruzi induced hemostatic alterations, even in those patients who do not yet present cardiac symptoms.

Heme Oxygenase 1 Impairs Glucocorticoid Receptor Activity in Prostate Cancer.

Glucocorticoids are used during prostate cancer (PCa) treatment. However, they may also have the potential to drive castration resistant prostate cancer (CRPC) growth via the glucocorticoid receptor (GR). Given the association between inflammation and PCa, and the anti-inflammatory role of heme oxygenase 1 (HO-1), we aimed at identifying the molecular processes governed by the interaction between HO-1 and GR. PCa-derived cell lines were treated with Hemin, Dexamethasone (Dex), or both. We studied GR gene expression by RTqPCR, protein expression by Western Blot, transcriptional activity using reporter assays, and nuclear translocation by confocal microscopy. We also evaluated the expression of HO-1, FKBP51, and FKBP52 by Western Blot. Hemin pre-treatment reduced Dex-induced GR activity in PC3 cells. Protein levels of FKBP51, a cytoplasmic GR-binding immunophilin, were significantly increased in Hemin+Dex treated cells, possibly accounting for lower GR activity. We also evaluated these treatments in vivo using PC3 tumors growing as xenografts. We found non-significant differences in tumor growth among treatments. Immunohistochemistry analyses revealed strong nuclear GR staining in almost all groups. We did not observe HO-1 staining in tumor cells, but high HO-1 reactivity was detected in tumor infiltrating macrophages. Our results suggest an association and crossed modulation between HO-1 and GR pathways.

Heme Oxygenase-1 Has an Antitumor Role in Breast Cancer.

Aims: Heme oxygenase-1 (HO-1) is an enzyme involved in cellular responses to oxidative stress and has also been shown to regulate processes related to cancer progression. In this regard, HO-1 has been shown to display a dual effect with either antitumor or protumor activity, which is also true for breast cancer (BC). In this work, we address this discrepancy regarding the role of HO-1 in BC. Results: HO-1 was detected in human BC tissues, and its protein levels correlated with reduced tumor size and longer overall survival time of patients, thus suggesting the clinical importance of HO-1 in this type of cancer. Contrariwise, nuclear localization of HO-1 correlated with higher tumor grade suggesting that the effect of HO-1 is dependent on its cellular localization. In vivo experiments showed that both pharmacological activation and genetic overexpression of HO-1 reduce the tumor burden in two different animal models of BC. Furthermore, the pharmacological and genetic activation of HO-1 in several BC cell lines reduce the cellular viability by inducing apoptosis and cell cycle arrest and decrease the cellular migration and invasion rates by modulating pathways involved in the epithelial-mesenchymal transition. Furthermore, HO-1 activation impaired in vivo the metastatic dissemination. Innovation and Conclusion: By using various BC cell lines and animal models as well as human tumor samples, we demonstrated that total HO-1 displays antitumor activities in BC. Furthermore, our study suggests that HO-1 subcellular localization may explain the differential effects observed for the protein in different tumor types.

Validación de inmunoensayos en fase sólida / Validation of solid phase immunoassays / Validação de imunoensaios em fase solida

La determinación del nivel de anticuerpos por medio de ensayos ELISA exige construir una curva de calibración según el modelo logístico de 4 parámetros (4PL); no obstante, es común que el bioquímico realice estimaciones y ajuste los datos de calibración con modelos alternativos. Se buscó determinar para un ensayo ELISA semicuantitativo el modelo que mejor ajusta los datos de calibración y cuál de los modelos alternativos explorados genera menor error relativo porcentual (ERP) al predecir las concentraciones de los calibradores. Para esto se empleó un ELISA indirecto y se ajustaron las densidades ópticas (DO) de los calibradores según los modelos i) exponencial ii) Boltzmann iii) Boltzmann semi log iv) Deming v) regresión lineal vi) 4PL vii) cuadrático. Se encontró que el mejor ajuste lo proveen los modelos v) (R2=0,9914), i) (R2=0,9652) y iii) (R2=0,9650). Sin embargo, los modelos i) y iii) tienen mejor desempeño en el procedimiento de ajuste inverso: el ERP se mantuvo ≤20% en el rango cubierto por los 6 calibradores (0-100 UI/mL). Los modelos lineales iv) y v) presentaron ERP elevados en el rango testeado. En resumen, el ajuste exponencial i) y el ajuste de Boltzmann iii), combinan valores de R2 y ERP comparables al modelo 4PL, por lo cual es inapropiado cualquier tipo de ajuste lineal.

Determination of the levels of specific antibodies by semiquantitative ELISAs requires the construction of a 4 parameter logistic regression (4PL) calibration curve. However, alternative models are often employed to adjust and estimate calibration data. The aims of this work were to determine the model that best adjusts calibration data, and which alternative model generates a lower relative percentage error (RPE) in the prediction of calibrator concentrations. An IgA anti-gliadin ELISA was used. The optical density values (OD) of calibrators were adjusted with the following mathematical models: i) Exponential, ii) Boltzmann, iii) Boltzmann semilog, iv) Deming, v) Linear regression, vi) 4PL, and vii) Quadratic. Results indicated that the best adjustment is given by models v) (R2=0.9914), i) (R2=0.9652) and iii) (R2=0.9650). However, models i) and iii) performed better in the reciprocal adjustment procedure: RPE values were ≤20% for all the calibrator levels analyzed (0-100 IU/mL). The linear models iv) and v) had high RPE values. To sum up, the exponential (i) and Boltzmann (iii) adjustments present R2 and RPE values similar to those of the 4PL, the use of any linear adjustment being inappropriate.

A determinação do nível de anticorpos por meio de ELISA requer a construção de uma curva de calibração de acordo com o modelo logístico de 4 parâmetros (4PL); no entanto, é comum o bioquímico fazer estimativas e ajustar os dados de calibração com modelos alternativos. Procurou-se determinar para um ensaio ELISA de modelo semiquantitativo o modelo que melhor se ajusta os dados de calibração e qual dos modelos alternativos explorados gera menor erro relativo percentual (ERP) ao prever as concentrações dos calibradores. Para isso, um ELISA indireto foi utilizado e se ajustaram as densidades ópticas (DO) dos calibradores segundo os modelos i) exponencial ii) Boltzmann iii) Boltzmann semi log iv) Deming v) regressão lineal iv) 4PL vii) quadrático. Verificou-se que o melhor ajuste é fornecido pelos modelos v) (R2= 0,9914), vi) (R2= 0,9652) e iii) (R2= 0,9650). No entanto, os modelos i) e iii) têm melhor desempenho no procedimento de ajuste inverso: o ERP permaneceu ≤20% na faixa coberta pelos 6 calibradores (0-100 UI/mL). Os modelos lineares iv) e v) apresentaram alto ERP na faixa testada. Em resumo, o ajuste exponencial i) e o ajuste de Boltzmann iii) combinam valores de R2 e ERP comparáveis ao modelo de 4PL, sendo inadequado qualquer tipo de ajuste linear.

Improving risk stratification of patients with childhood acute lymphoblastic leukemia: Glutathione-S-Transferases polymorphisms are associated with increased risk of relapse.

The inclusion of genotype at Acute Lymphoblastic Leukemia (ALL) diagnosis as a genetic predictor of disease outcome is under constant study. However, results are inconclusive and seem to be population specific. We analyzed the predictive value of germline polymorphisms for childhood ALL relapse and survival. We retrospectively recruited 140 Argentine patients with de novo ALL. Genotypes were analyzed using PCR-RFLP (GSTP1 c.313A > G, MDR1 c.3435T > C, and MTHFR c.665C > T) and multiplex PCR (GSTT1 null, GSTM1 null). Patients with the GSTP1 c.313GG genotype had an increased risk for relapse in univariate (OR = 2.65, 95% CI = 1.03-6.82, p = 0.04) and multivariate (OR = 3.22, 95% CI = 1.17-8.83, p = 0.02) models. The combined genotype slightly increased risk for relapse in the univariate (OR = 2.82, 95% CI = 1.09-7.32, p = 0.03) and multivariate (OR = 2.98, 95% CI = 1.14-7.79, p = 0.03) models for patients with 2/3-risk-genotypes (GSTT1 null, GSTM1 null, GSTP1 c.313GG). The Recurrence-Free Survival (RFS) was shorter for GSTP1 c.313GG (p = 0.025) and 2/3-risk-genotypes (p = 0.021). GST polymorphisms increased the risk of relapse and RFS of patients with childhood ALL. The inclusion of these genetic markers in ALL treatment protocols might improve risk stratification and reduce the number of relapses and deaths.

Glycosylation-dependent binding of galectin-8 to activated leukocyte cell adhesion molecule (ALCAM/CD166) promotes its surface segregation on breast cancer cells.

BACKGROUND: We previously demonstrated that the activated leukocyte cell adhesion molecule (ALCAM/CD166) can interact with galectin-8 (Gal-8) in endothelial cells. ALCAM is a member of the immunoglobulin superfamily that promotes homophilic and heterophilic cell-cell interactions. Gal-8 is a "tandem-repeat"-type galectin, known as a matricellular protein involved in cell adhesion. Here, we analyzed the physical interaction between both molecules in breast cancer cells and the functional relevance of this phenomenon. METHODS: We performed binding assays by surface plasmon resonance to study the interaction between Gal-8 and the recombinant glycosylated ALCAM ectodomain or endogenous ALCAM from MDA-MB-231 breast cancer cells. We also analyzed the binding of ALCAM-silenced or control breast cancer cells to immobilized Gal-8 by SPR. In internalization assays, we evaluated the influence of Gal-8 on ALCAM surface localization. RESULTS: We showed that recombinant glycosylated ALCAM and endogenous ALCAM from breast carcinoma cells physically interacted with Gal-8 in a glycosylation-dependent fashion displaying a differential behavior compared to non-glycosylated ALCAM. Moreover, ALCAM-silenced breast cancer cells exhibited reduced binding to Gal-8 relative to control cells. Importantly, exogenously added Gal-8 provoked ALCAM segregation, probably trapping this adhesion molecule at the surface of breast cancer cells. CONCLUSIONS: Our data indicate that Gal-8 interacts with ALCAM at the surface of breast cancer cells through glycosylation-dependent mechanisms. GENERAL SIGNIFICANCE: A novel heterophilic interaction between ALCAM and Gal-8 is demonstrated here, suggesting its physiologic relevance in the biology of breast cancer cells.

La hipertensión no controlada se asocia con hipotensión posprandial / Uncontrolled Hypertension is Associated with Postprandial Hypotension

Introducción: En un estudio previo que incorporó mediciones posalmuerzo al esquema convencional de monitoreo domiciliario de la presión arterial hemos detectado hipotensión posprandial en alrededor de la cuarta parte de nuestros pacientes hipertensos. Objetivos: Comparar el cambio posprandial de la presión arterial sistólica, y la correspondiente respuesta cronotrópica, en relación con el control de la hipertensión. Material y métodos: Se evaluaron prospectivamente con monitoreo domiciliario de la presión arterial 140 pacientes hipertensos tratados, mayores de 40 años. El control de la hipertensión se basó en el promedio de la presión arterial matinal y la vespertina, tomando como valor de corte 135/85 mm Hg. Se consideró hipotensión posprandial cuando la presión arterial sistólica disminuyó 20 mm Hg o más respecto del valor preprandial en al menos uno de tres almuerzos. Resultados: Se detectó hipotensión posprandial en el 13,2% (n = 10) de los hipertensos controlados y en el 42,2% (n = 27) de los no controlados (p < 0,001). Después de los almuerzos, la presión arterial sistólica disminuyó en promedio 9,5 ± 10,5 mm Hg (6,4% ± 7,8%) en los hipertensos no controlados y 3,2 ± 7,8 mm Hg (2,6% ± 6,5%) en los controlados (p < 0,001), sin diferencia significativa en la respuesta cronotrópica. Al estratificar a los pacientes por el control de la hipertensión se observó una correlación inversa entre la respuesta posprandial de la frecuencia cardíaca y de la presión arterial sistólica en los controlados (r = -0,24; p = 0,035), sin relación significativa en los no controlados. En el análisis de regresión lineal múltiple, la falta de control de la hipertensión (beta = -0,26; p = 0,002) y el sexo femenino (beta = 0,22; p < 0,001) fueron predictores significativos de la caída posprandial en la presión arterial sistólica, sin influencia significativa de la edad o del número de fármacos antihipertensivos. Conclusión: La falta de control de la hipertensión se asoció con una respuesta circulatoria posprandial anormal que favorece la hipotensión.

Background: In a previous study that incorporated post-lunch measurements to the conventional scheme of home-based blood pressure monitoring, we detected postprandial hypotension in about a quarter of hypertensive patients. Objectives: The aim of this study was to compare the postprandial change of systolic blood pressure, and the corresponding chronotropic response, associated to the control of hypertension. Methods: We prospectively evaluated 140 treated hypertensive patients, aged over 40 years, with home-based blood pressure monitoring. The control of hypertension was based on the average morning and evening blood pressure, considering 135/85 mmHg as cutoff value. Postprandial hypotension was defined as a drop in systolic blood pressure equal to or greater than 20 mmHg with respect to the preprandial value in at least one of three lunches. Results: Postprandial hypotension was found in 13.2% (n=10) of patients with controlled hypertension and in 42.2% (n=27) with uncontrolled hypertension (p<0.001). After lunch, the average decrease of systolic blood pressure was 9.5±10.5 mmHg (6.4%±7.8%) in patients with uncontrolled hypertension and 3.2±7.8 mmHg (2.6%±6.5%) in those with controlled hypertension (p<0.001), with no significant difference in the chronotropic response. After stratifying the patients by hypertension control, the postprandial response of heart rate and systolic blood pressure showed a significant inverse correlation in controlled hypertensive patients (r=-0.24; p=0.035), and a not significant correlation in uncontrolled patients. On the multiple linear regression analysis, lack of blood pressure control (beta=0.26, p=0.002) and female gender (beta=0.22; p<0.001) were significant predictors of a postprandial drop in systolic blood pressure, without a significant influence of age or number of antihypertensive drugs. Conclusion: Lack of blood pressure control was associated with an abnormal postprandial circulatory response that predisposes to hypotension.

Inhibition of p300 suppresses growth of breast cancer. Role of p300 subcellular localization.

There is evidence that p300, a transcriptional co-factor and a lysine acetyl-transferase, could play a role both as an oncoprotein and as a tumor suppressor, although little is known regarding its role in breast cancer (BC). First we investigated the role p300 has on BC by performing pharmacological inhibition of p300 acetyl-transferase function and analyzing the effects on cell count, migration and invasion in LM3 murine breast cancer cell line and on tumor progression in a syngeneic murine model. We subsequently studied p300 protein expression in human BC biopsies and evaluated its correlation with clinical and histopathological parameters of the patients. We observed that inhibition of p300 induced apoptosis and reduced migration and invasion in cultured LM3 cells. Furthermore, a significant reduction in tumor burden, number of lung metastases and number of tumors invading the abdominal cavity was observed in a syngeneic tumor model of LM3 following treatment with the p300 inhibitor. This reduction in tumor burden was accompanied by a decrease in the mitotic index and Ki-67 levels and an increase in Bax expression. Moreover, the analysis of p300 expression in human BC samples showed that p300 immunoreactivity is significantly higher in the cancerous tissues than in the non-malignant mammary tissues and in the histologically normal adjacent tissues. Interestingly, p300 was observed in the cytoplasm, and the rate of cytoplasmic p300 was higher in BC than in non-tumor tissues. Importantly, we found that cytoplasmic localization of p300 is associated with a longer overall survival time of the patients. In conclusion, we demonstrated that inhibition of the acetylase function of p300 reduces both cell count and invasion in LM3 cells, and decreases tumor progression in the animal model. In addition, we show that the presence of p300 in the cytoplasm correlates with increased survival of patients suggesting that its nuclear localization is necessary for the pro-tumoral effects.

Clinical relevance of galectin-1 expression in non-small cell lung cancer patients.

BACKGROUND: Identification of biomarkers in lung cancer, a leading cause of cancer-related mortality, has a meaningful clinical relevance in the quest of novel prognostic factors and therapeutic targets. The glycan-binding protein galectin-1 (Gal-1) modulates tumor progression by mediating cell-cell and cell-extracellular matrix interactions, as well as angiogenesis and tumor immune-escape. Previous works reported the expression of Gal-1 in lung cancer, although its clinical significance remains uncertain. OBJECTIVE: To assess the clinicopathologic relevance and prognostic value of Gal-1 expression in a cohort of 103 Stage I-III non-small cell lung cancer (NSCLC) patients. METHODS: Gal-1 expression was determined by immunohistochemistry in tumor tissue samples. The percentage of immunoreactive tumor cells and stroma, as well as the presence of blood vessels with positively stained endothelium in the tumor and surrounding normal tissue, were recorded. Results were correlated with the clinicopathologic factors of the patients (Spearman's rank correlation coefficient, chi-square test) and overall survival by univariate (Kaplan Meier) and multivariate analyses (Cox regression hazard model). RESULTS: We did not observe significant associations between Gal-1 expression and relevant clinicopathologic features at diagnosis of NSCLC. However, Kaplan Meier analysis revealed a significant association between Gal-1 expression and overall survival, when Gal-1 expression was analyzed on tumor cells alone ("tumor cell percentage") or when an integrated score accounting for tumor cell as well as stromal expression of Gal-1 ("total score") was assessed. Patients showing high Gal-1 expression evidenced a poorer clinical outcome. Furthermore, "total score" remained significantly associated with survival by multivariate Cox regression analysis in the whole cohort of patients, even when controlling for the classical predictors and prognostic factors of NSCLC. CONCLUSION: We conclude that Gal-1 expression may be a useful biomarker for better prediction of the clinical outcome and management of NSCLC patients.

Cambios en la hemodinamia cerebral en consumidores crónicos de paco y cocaína: estudio de casos y controles / [Changes in cerebral hemodynamics in chronic users of \"PACO\" and cocaine: case-control study].

OBJECTIVE: To assess if there are changes in brain hemodynamics evaluated by means of transcranial doppler’s flow velocity, pulsatile index and cerebral perfusion pressure, between cocaine chronic abusers and healthy volunteers. METHOD: Prospective, case and control, observational study. Sex, age, user history, vital signs and transcranial doppler findings.Statistical analysis was performed by means of normality test, Wilcoxon’s test for non parametric samples and T Student test. RESULTS: Fifty-three abusers and 35 healthy volunteers were studied. Statistical differences were found for a diminish in age(p=0.008) and cerebral perfusion pressure in all cerebral arteries (p

Alteraciones hidroelectrolíticas en pacientes tratados con diuréticos / Electrolytes disturbances in patients treated with diuretics

a) Introducción y objetivos: Los diuréticos son fármacos que han demostrado su utilidad en el trtamiento de la hipertensión arterial. Los objetivos de este estudio fueron analizar la prevalencia de las alteraciones hidroelectrolíticas en pacientes ambulatorios tratados con diuréticos y su asociación con el tipo de diuréticos utilizados. b) Métodos: Se evaluaron en forma prospectiva 93 pacientes adultos mayores de 31 años. La edad promedio fue de 66.3 años. La tensión arterial media fue de 127/76 mmHg. Se analizaron los siguientes parámetros: sodio, potasio, cloro, magnesio, bicarbonato, urea plasmática, creatinina sérica, calcio, fosforo y ácido úrico en sangre. c) Resultados: De los 93 pacientes, el 96 por ciento recibían diuréticos por hipertensión arterial. De ellos 64 por ciento recibían tiazidas, 11 por ciento indapamida, 6 por ciento furosemida, 5 por ciento clortalidona y 4 por ciento la combinación de tiazidas y amiloride. la alteración más frecuente encontrada fue la hiperazoemia en 28 por ciento, hiponatremia en 8.6 por ciento, hipokalemia en 4.3 por ciento de los casos. No presentaron hiponatremia ni hipokalemia ninguno de los pacientes tratados con indapamida. Los valores de cloro se encontraron por debajo de su valor normal en 11 por ciento, no observándose cambios significativos en los valores de calcio, fosforo, magnesio y ácido úrico. Once pacientes presentaron valores elevados de bicarbonato. d) Conclusiones: La alteración hidroelectrolítica más frecuentemente encontrada en nuestra población fue la hiperazoemia seguida de hiponatremia, siendo infrecuente la hipokalemia. Los diuréticos constituyen importantes herramientas terapéuticas en el manejo de la hipertensión arterial. Su utilización es segura y efectiva como monoterapia en pacientes con hipertensión arterial.

a) Background and Objectives: Diretics have demonstrated their utility for the management of hypertension. The goals of this study were to analyze the prevalence of electrolytes disturbances in ambulatory patients treated with diretics and the type of diuretics used. b) Methods: We prospectively evaluated 93 adults patients older than 31 years old. their mean age was 66.3 years and mean arterial blood pressure was 127/76 mmHg. The varialbes evaluated were: sodium, potassium, chlorine, magnesium, bicarbonte, blood urea nitrogen (BUN) serum cretinine, calcium, phosphorus and uric acid. c) Results: Ninety six percent of the patients received diuretics for the management of hypertension. Sixty four percent of the patients were treated with hydrochlorothiazide, 11 percent indapamide, 6 percent furosemide, 5 percent clortalidone and 4 percent the combination of thiazide with amiloride. The most common abnormality was increased blood urea nitrogen (BUN) seen in 28 percent of the patients, hyponatremia in 8.6 percent and hypokalemia in 4.3 percent. The majority of our patients were treated with thiazides. No patients treated with indapamide had hypnatremia or hypokalemia. The chlorine value was below the normal range in 11 percent of our patients. We haven't seen significant changes in serum calcium, phosphorus, and magnesium. Bicarbonate was elevated in 11 of 30 patients. d) Conclusions: In summary, the most common abnormality ound in our population was the increased BUN. Hyponatremia was mild and hypokalemia was exceptinal. Diuretics are important therapeutic tools for tretment of hypertension. The use of these drugs are safe and effective for the treatment of patients with hypertension.

Associated expressions of FGFR-2 and FGFR-3: from mouse mammary gland physiology to human breast cancer.

Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors which have been implicated in breast cancer. The aim of this study was to evaluate FGFR-1, -2, -3, and -4 protein expressions in normal murine mammary gland development, and in murine and human breast carcinomas. Using immunohistochemistry and Western blot, we report a hormonal regulation of FGFR during postnatal mammary gland development. Progestin treatment of adult virgin mammary glands resulted in changes in localization of FGFR-3 from the cytoplasm to the nucleus, while treatment with 17-ß-estradiol induced changes in the expressions and/or localizations of FGFR-2 and -3. In murine mammary carcinomas showing different degrees of hormone dependence, we found progestin-induced increased expressions, mainly of FGFR-2 and -3. These receptors were constitutively activated in hormone-independent variants. We studied three luminal human breast cancer cell lines growing as xenografts, which particularly expressed FGFR-2 and -3, suggesting a correlation between hormonal status and FGFR expression. Most importantly, in breast cancer samples from 58 patients, we found a strong association (P < 0.01; Spearman correlation) between FGFR-2 and -3 expressions and a weaker correlation of each receptor with estrogen receptor expression. FGFR-4 correlated with c-erbB2 over expression. We conclude that FGFR-2 and -3 may be mechanistically linked and can be potential targets for treatment of estrogen receptor-positive breast cancer patients.

Estrogen receptor ß and epidermal growth factor receptor as early-stage prognostic biomarkers of non-small cell lung cancer.

As 20% of stage I NSCLC patients develop recurrent and often incurable cancer, the identification of prognostic markers has a meaningful clinical application. The biological significance of steroid hormone and EGF receptors, able to regulate key physiological functions, remains elusive in NSCLC. Our aim was to investigate the prognostic input of estrogen receptors (ERα, ERß), progesterone receptors (PR) and EGFR in tumors from 58 stage I NSCLC patients. Antigen expression was analyzed by immunohistochemistry. Prognostic evaluation was performed with the multivariate Cox model. We found that about 70 and 40% of samples expressed ERα or ERß at cytoplasmic or nuclear level, respectively. Besides, only 12.1% of samples weakly expressed nuclear PR and 62.7% showed membrane EGFR staining. Correlation studies indicated an inverse association between EGFR expression and smoking status (p<0.01). Multivariate studies showed that the lack of nuclear ERß or the loss of EGFR expression were independent prognosis markers associated with shorter overall survival. We also found that patients whose tumors were negative for these two biomarkers presented the worst outcome. In conclusion, our findings could be useful for selecting stage I NSCLC patients with poor prognosis to apply an earlier treatment that impacts on survival.

Déficit de Vitamina D en mujeres adultas de la Ciudad de Buenos Aires / Vitamin D deficit in adult women living in Buenos Aires City

El déficit de vitamina D se asocia con importante morbilidad. El objetivo de este estudio fue investigar la frecuencia de este déficit en una población de mujeres adultas y su asociación con distintas variables. Se evaluaron 224 mujeres mayores de 30 años atendidas en tres consultorios de clínica médica de la Ciudad de Buenos Aires entre octubre de 2006 y marzo de 2008. El nivel de 25 OH vitamina D, por radioinmunoanálisis, se clasificó como suficiente (> 30 ng/ml), déficit leve (entre 20 y 30 ng/ml) y déficit grave (< 20 ng/ml). La edad media fue de 58.3 ± 12.9 años; 77% eran posmenopáusicas. Presentaron déficit leve de vitamina D el 29.9% y déficit grave el 26.8%. El déficit grave se asoció con mayor edad promedio (62 años vs. 56 años, p = 0.003), con falta de exposición al sol (25.8 ng/ml vs. 31.7 ng/ml, p < 0.005), con mayor peso promedio (70 kg vs. 61 kg, p < 0.05), con inactividad física (27.8 ng/ml vs. 31.04 ng/ml, p = 0.0007) y con menor calcemia (9.26 mg/dl vs. 9.51 mg/dl, p < 0.01). No se asoció con tabaquismo ni con los valores de fósforo, creatinina ni TSH plasmáticas. El déficit de vitamina D es frecuente, en especial en mujeres añosas, sedentarias, poco expuestas al sol, obesas y con bajos niveles de calcio.

Vitamin D deficiency is a common cause of morbidity. We prospectively studied 224 consecutive female patients in order to evaluate the prevalence of vitamin D deficiency and to assess the utility of various clinical and biochemical markers in predicting the deficiency. All of them were outpatients, 30 years old or older, and were evaluated from October 2006 through March 2008. Levels of 25 OH vitamin D > 30 ng/ml were considered sufficient. Mild deficiency was considered between 20 and 30 ng/ml and severe deficiency < 20 ng/ml. The mean age was 58 ± 12.9 years; 77% were menopausal. Twenty nine percent of the patients had mild deficit and 26.8% had severe deficit of the vitamin. Severe deficit was associated with increasing age (62 vs. 56 years, p = 0.003), absence of sun exposure (25.82 ng/ml vs. 31.7 ng/ml, p < 0.005), obesity (70 vs. 61 kg, p < 0.05), absence of physical activity (27.8 ng/ml vs. 31.04 ng/ml, p = 0.0007) and slightly low levels of serum calcium (9.26 mg/dl vs. 9.51 mg/dl, p 0.01). We did not find any association between smokers and non-smokers patients, levels of serum phosphorus, creatinine and TSH. Vitamin D deficiency is a common disorder. It correlates with older age, absence of physical activity, sun exposure, obesity and slightly low levels of serum calcium. Improving diagnosis of this condition may enable us to improve the management of this disease.