High Glucose Promotes Inflammation and Weakens Placental Defenses against E. coli and S. agalactiae Infection: Protective Role of Insulin and Metformin.

Placentas from gestational diabetes mellitus (GDM) patients undergo significant metabolic and immunologic adaptations due to hyperglycemia, which results in an exacerbated synthesis of proinflammatory cytokines and an increased risk for infections. Insulin or metformin are clinically indicated for the treatment of GDM; however, there is limited information about the immunomodulatory activity of these drugs in the human placenta, especially in the context of maternal infections. Our objective was to study the role of insulin and metformin in the placental inflammatory response and innate defense against common etiopathological agents of pregnancy bacterial infections, such as E. coli and S. agalactiae, in a hyperglycemic environment. Term placental explants were cultivated with glucose (10 and 50 mM), insulin (50-500 nM) or metformin (125-500 µM) for 48 h, and then they were challenged with live bacteria (1 × 105 CFU/mL). We evaluated the inflammatory cytokine secretion, beta defensins production, bacterial count and bacterial tissue invasiveness after 4-8 h of infection. Our results showed that a GDM-associated hyperglycemic environment induced an inflammatory response and a decreased beta defensins synthesis unable to restrain bacterial infection. Notably, both insulin and metformin exerted anti-inflammatory effects under hyperglycemic infectious and non-infectious scenarios. Moreover, both drugs fortified placental barrier defenses, resulting in reduced E. coli counts, as well as decreased S. agalactiae and E. coli invasiveness of placental villous trees. Remarkably, the double challenge of high glucose and infection provoked a pathogen-specific attenuated placental inflammatory response in the hyperglycemic condition, mainly denoted by reduced TNF-α and IL-6 secretion after S. agalactiae infection and by IL-1ß after E. coli infection. Altogether, these results suggest that metabolically uncontrolled GDM mothers develop diverse immune placental alterations, which may help to explain their increased vulnerability to bacterial pathogens.

Incidencia de cáncer de mama a 5 años en mujeres con lesiones premalignas / Incidence of breast cancer at 5 years in women with premalignant lesions

Resumen OBJETIVO: Determinar la incidencia acumulada de cáncer de mama a cinco años de seguimiento en pacientes con lesiones preinvasoras o premalignas de la glándula mamaria en un centro de referencia y establecer los factores de riesgo asociados. MATERIALES Y MÉTODOS: Estudio de cohorte retrospectiva efectuado en pacientes atendidas en el Hospital Ángeles Lomas entre los años 2012 a 2016 con diagnóstico, durante su tamizaje mastográfico, de alguna lesión precursora o preinvasora de cáncer de mama. El seguimiento fue a cinco años para determinar la incidencia. Las variables categóricas se expresan en frecuencias y porcentajes. Se utilizó la prueba de χ2 para diferencia de proporciones entre grupos. RESULTADOS: Se obtuvieron 3360 pacientes que acudieron al servicio de Mastología durante el tiempo establecido. Se obtuvieron 245 pacientes con lesiones premalignas pero 30 de ellas no cumplieron con el seguimiento a cinco años y se perdieron en ese tiempo estipulado de vigilancia. Al final quedaron 215 pacientes que cumplieron todos los criterios de inclusión establecidos. La incidencia acumulada global de cáncer de mama invasivo fue que a 5 años el 14.9% de las pacientes con lesiones premalignas tendrá cáncer de mama. El carcinoma lobulillar in situ fue el de mayor incidencia o progresión de cáncer invasor, con un 32.1% a los cinco años, seguido de las lesiones mucocele-like, carcinoma ductal in situ y papiloma intraductal con un 23.1, 21.1 y 17.1%, respectivamente. CONCLUSIONES: El cáncer de mama sigue siendo un problema de salud pública en México y en todo el mundo. Si bien cada vez se dispone de más y mejores programas de tamizaje, ello ha traído consigo otras problemáticas, como las lesiones premalignas o de alto riesgo de carcinogénesis, que han aumentado su incidencia.

Abstract OBJECTIVE: To determine the cumulative incidence of breast cancer at five years of follow-up in patients with preinvasive or premalignant lesions of the mammary gland in a referral canter and to establish the associated risk factors. MATERIALS AND METHODS: Retrospective cohort study carried out in patients seen at Hospital Ángeles Lomas between 2012 and 2016 with a diagnosis, during their mastographic screening, of a precursor or pre-invasive lesion of breast cancer. Categorical variables are expressed in frequencies and percentages. The χ2 test was used for difference of proportions between groups. RESULTS: We obtained 3360 patients who attended the mastology service during the established time. We obtained 245 patients with premalignant lesions but 30 of them did not comply with the five-year follow-up and were lost within the stipulated surveillance period. This left 215 patients who met all the inclusion criteria. The overall cumulative incidence of invasive breast cancer was that at 5 years 14.9% of patients with premalignant lesions will have breast cancer. Lobular carcinoma in situ had the highest incidence or progression of invasive cancer, with 32.1% at 5 years, followed by mucocele-like lesions, ductal carcinoma in situ and intraductal papilloma with 23.1, 21.1 and 17.1%, respectively. CONCLUSIONS: Breast cancer remains a public health problem in Mexico and worldwide. Although more and better screening programmes are becoming available, this has brought with it other problems, such as premalignant or high-risk carcinogenic lesions, which have increased in incidence.