Glucocorticoid receptor knockdown decreases the antioxidant protection of B16 melanoma cells: an endocrine system-related mechanism that compromises metastatic cell resistance to vascular endothelium-induced tumor cytotoxicity.

We previously reported an interorgan system in which stress-related hormones (corticosterone and noradrenaline), interleukin-6, and glutathione (GSH) coordinately regulate metastatic growth of highly aggressive B16-F10 melanoma cells. Corticosterone, at levels measured in tumor-bearing mice, also induces apoptotic cell death in metastatic cells with low GSH content. In the present study we explored the potential role of glucocorticoids in the regulation of metastatic cell death/survival during the early stages of organ invasion. Glucocorticoid receptor (GCR) knockdown decreased the expression and activity of γ-glutamylcysteine synthetase (γ-GCS), the rate-limiting step in GSH synthesis, in metastatic cells in vivo independent of the tumor location (liver, lung, or subcutaneous). The decrease in γ-GCS activity was associated with lower intracellular GSH levels. Nrf2- and p53-dependent down-regulation of γ-GCS was associated with a decrease in the activities of superoxide dismutase 1 and 2, catalase, glutathione peroxidase, and glutathione reductase, but not of the O2--generating NADPH oxidase. The GCR knockdown-induced decrease in antioxidant protection caused a drastic decrease in the survival of metastatic cells during their interaction with endothelial cells, both in vitro and in vivo; only 10% of cancer cells attached to the endothelium survived compared to 90% survival observed in the controls. This very low rate of metastatic cell survival was partially increased (up to 52%) in vivo by inoculating B16-F10 cells preloaded with GSH ester, which enters the cell and delivers free GSH. Taken together, our results indicate that glucocorticoid signaling influences the survival of metastatic cells during their interaction with the vascular endothelium.

Evolución temporal de la afectación renal en una serie necrópsica de pacientes VIH de las eras pre y TARGA / Temporal evolution of renal involvement in a necropsy study of HIV patients from the pre and HAART eras

Fundamento: El objetivo del estudio es analizar la evolución de las lesiones anatomopatológicas renales en VIH que hubiesen recibido o no medicación antirretroviral de alta actividad (TARGA).Sujetos y métodos: Se revisaron las historias clínicas de 100 pacientes fallecidos entre 1984 y 2006, con registros clínico-analíticos y muestras anatomopatológicas. Sesenta y uno habían fallecido antes de 1997 (grupo I) y 39 pacientes después, de los cuales24 no habían recibido TARGA (grupo II) y 15 sí (grupo III). Las muestras renales se tiñeron con hematoxilina-eosina, PAS, tricrómico de Masson y plata-meteramina. Se registraron para todos los pacientes los diagnósticos anatomopatológicos finales, así como las lesiones a cada uno de los tres niveles: glomérulo, túbulo e intersticio. Se definió NAVIH como la presencia de glomerulosclerosis segmentaria y focal, con colapso glomerular y lesiones microquísticas túbulo-intersticiales. Resultados: Las principales causas de muerte fueron infecciones (68%) o tumores (14%), y el resto (18%) fueron otras causas, especialmente hepatopatías. Un42% de los individuos presentaban insuficiencia renal en el momento del fallecimiento. En los tres grupos de estudio predominaban las lesiones tubulares, seguidas de las lesiones intersticiales y de las glomerulares. Cuando se compararon aquellos sujetos en tratamiento con TARGA con aquellos sin tratamiento, encontramos un porcentaje significativamente mayor de lesiones en el intersticio en el grupo con TARGA. En este grupo hubo también más casos de necrosis tubular aguda NTA, si bien estas diferencias no fueron estadísticamente significativas. Conclusiones: Las lesiones renales son frecuentes en pacientes afectados de VIH en el momento de la muerte, independientemente del período de estudio considerado y del tratamiento recibido (AU)

Background: The aim of the present study is to analyze the impact of high activity antiretroviral therapy (HAART)in the renal lesions observed in autopsies of HIV patients. Subjets and methods: Clinical records and renal pathologic samples from 100 HIV patients, dead from 1984 to 2006,were reviewed, 61 before 1997 (group I) and 39 after. Among them, 24 did not receive HAART (group II) and 15did (group III). Clinical and analytical data premortem were obtained. Renal samples were stained with hematoxilin eosin, PAS, Masson thricromic and silver-meteramine. Final pathologic diagnosis was recorded along with the finding sat glomerular, tubular and interstitial levels. HIVAN was defined by the presence of focal or segmental glomerulosclerosis with glomerular collapse and tubule-interstitial microcystic lesions. Results: The main causes of dead were infections 68%, tumors 14%, and others 18%, especially liver diseases. Renal failure was present in 42% at the time of the dead. A predominance of tubular lesions exists in the three study groups. The main diagnosis were acute tubular necrosis (ATN) and septic nephritis. Four cases of HIVAN were found. In subjects under HAART more interstitial lesions have been observed. There were also more cases of acute tubular necrosis but these differences were not statiscally significant. Conclusions: Renal lesions were frequent in HIV patients independent of the presence or the absence of HAART (AU)

[Temporal evolution of renal involvement in a necropsy study of HIV patients from the pre and HAART eras]. / Evolución temporal de la afectación renal en una serie necrópsica de pacientes VIH de las eras pre y TARGA.

BACKGROUND: The aim of the present study is to analyze the impact of high activity antiretroviral therapy (HAART) on renal lesions observed in autopsies of HIV patients. SUBJECTS AND METHODS: Clinical records and renal pathologic samples from 100 HIV patients, who had died between 1984 and 2006, were reviewed, 61 before 1997 (group I) and 39 after. 24 of them had not received HAART (group II) and 15 had (group III). Premortem clinical and analytical data were obtained. Renal samples were stained with hematoxilin-eosin, PAS, Masson trichrome and silver-methenamine. The final pathologic diagnosis was recorded along with the findings at glomerular, tubular and interstitial levels. HIVAN was defined as the presence of focal or segmental glomerulosclerosis with glomerular collapse and microcystic tubulo -interstitial lesions. RESULTS: The main causes of death were infections 68%, tumours 14%, and others 18%, especially liver diseases. Renal failure was present in 42% at the time of death. A predominance of tubular lesions exists in the three study groups, followed by interstitial lesions and glomerular lesions. The main diagnoses were acute tubular necrosis (ATN) and septic nephritis. Four cases of HIVAN were found. When the subjects who received HAART treatment were compared with those who did not, a significantly higher percentage of interstitial lesions in the group with HAART was observed. There were also more cases of acute tubular necrosis but these differences were not statistically significant. CONCLUSIONS: Renal lesions were frequent in HIV patients independent of the presence or absence of HAART.

[Infection in diabetes: the relation to the degree of metabolic control and protein malnutrition]. / Infección en la diabetes: relación con el grado de control metabólico y la malnutrición proteica.

Sixty-one diabetic patients, followed for two years, were divided in two groups for evaluation. One group consisted of the patients who had a bacterial or fungal infection, and the other those in whom no infection had been recorded. The association of the infection with the degree of metabolic control and with the presence or absence of protein malnutrition were assessed. The group of patients with infection was positively correlated with malnutrition and poor metabolic control. In the group with infections, the prevalence of protein malnutrition was 77% while in the patients without infection it was 36%. 11% of patients with sugar blood level lower than 140 mg/dl (7.7 mmol/l) had infections, whereas 79% of those with sugar blood levels higher than 200 mg/dl (11.1 mmol/l) had infections. We emphasize the relevance of hyperglycemia and protein malnutrition as predisposing factors of infection in diabetes and the need to assess the nutritional status in those patients.

[Pleural tuberculosis: yield of thoracoscopy]. / Tuberculosis pleural: rentabilidad de la toracoscopia.

34 tuberculosis with pleural affectation were diagnosed after examining 292 pleural effusions. 19 cases studied were diagnosed by pleuroscopy. The mean age of patients was 38 years old. The cytology, being mainly limphocytes, cultures and bacyloscopy, were all negative. The cultures of the biopsies was positive in 36.7% of the cases. The pathology report was positive in 88% of them. There was macroscopic suspicion of the disease in 73.6% with good macro-microscopic correlation this being the reason of the early treatment applied. We concluded that pleuroscopy is a good technique to diagnose pleural tuberculosis, reducing the hospital admission time.