NOV/CCN3 attenuates inflammatory pain through regulation of matrix metalloproteinases-2 and -9

<p>Abstract</p> <p>Background</p> <p>Sustained neuroinflammation strongly contributes to the pathogenesis of pain. The clinical challenge of chronic pain relief led to the identification of molecules such as cytokines, chemokines and more recently matrix metalloproteinases (MMPs) as putative therapeutic targets. Evidence points to a founder member of the matricial CCN family, NOV/CCN3, as a modulator of these inflammatory mediators. We thus investigated the possible involvement of NOV in a preclinical model of persistent inflammatory pain.</p> <p>Methods</p> <p>We used the complete Freund's adjuvant (CFA)-induced model of persistent inflammatory pain and cultured primary sensory neurons for <it>in vitro </it>experiments. The mRNA expression of NOV and pro-inflammatory factors were measured with real-time quantitative PCR, CCL2 protein expression was assessed using ELISA, MMP-2 and -9 activities using zymography. The effect of drugs on tactile allodynia was evaluated by the von Frey test.</p> <p>Results</p> <p>NOV was expressed in neurons of both dorsal root ganglia (DRG) and dorsal horn of the spinal cord (DHSC). After intraplantar CFA injection, NOV levels were transiently and persistently down-regulated in the DRG and DHSC, respectively, occurring at the maintenance phase of pain (15 days). NOV-reduced expression was restored after treatment of CFA rats with dexamethasone. <it>In vitro</it>, results based on cultured DRG neurons showed that siRNA-mediated inhibition of NOV enhanced IL-1β- and TNF-α-induced MMP-2, MMP-9 and CCL2 expression whereas NOV addition inhibited TNF-α-induced MMP-9 expression through β₁integrin engagement. <it>In vivo</it>, the intrathecal delivery of MMP-9 inhibitor attenuated mechanical allodynia of CFA rats. Importantly, intrathecal administration of NOV siRNA specifically led to an up-regulation of MMP-9 in the DRG and MMP-2 in the DHSC concomitant with increased mechanical allodynia. Finally, NOV intrathecal treatment specifically abolished the induction of MMP-9 in the DRG and, MMP-9 and MMP-2 in the DHSC of CFA rats. This inhibitory effect on MMP is associated with reduced mechanical allodynia.</p> <p>Conclusions</p> <p>This study identifies NOV as a new actor against inflammatory pain through regulation of MMPs thus uncovering NOV as an attractive candidate for therapeutic improvement in pain relief.</p

Morfología Fluvial.-Drainage system inversion in the Guadalentin Depression during the Late Pleistocene – Holocene (Murcia, Spain)

RESUMEN Este artículo expone los resultados de los estudios realizados en el sector central de la Depresión del Guadalentín (Murcia) respecto a la acumulación anórmala (mas de 17 m) de los depósitos pleistocenos y holocenos aguas arriba del umbral tectónico de Romeral (Librilla). Dataciones 14C, restos y yacimientos arqueológicos, junto con su análysis estratigráfico muestran que las tres secuencias detríticas holocenas que constituyen el relleno de la Depresión, se encuentran superpuestas y progradan sobre los travertinos del Pleistoceno superior aguas arriba de la confluencia del río Guadalentín con la Rambla de Librilla. Entre el Librilla y el umbral de Romeral, solo parecen los depósitos holocenos a lo largo de la margen izquierda (15-17m). Por el contrario, la margen derecha muestra levantamiento significativa de los travertinos pleistocenos hasta la zona del umbral de Romeral, donde aflora el sustrato neógeno. En este escenario, no solo las fluctuaciones climáticas (cambio de régimen de precipitaciones) han jugado un papel importante, sino que fue más determinante la actividad de la falla ciega de Romeral entre 6340±60 BP y 3885±60 BP provocando cambios de nivel de base intracuencales que aceleraron el proceso de erosión remontante e inversión del drenaje en el interior de la Depresión, facilitando el tránsito entre las condiciones endorreicas a las exorreicas, ya durante el Holoceno reciente

Mammography Utilization: Patient Characteristics and Breast Cancer Stage at Diagnosis

OBJECTIVE. Missed mammograms represent missed opportunities for earlier breast cancer diagnosis. The purposes of this study were to identify patient characteristics associated with missed mammograms and to examine the association between missed mammograms and breast cancer stage at diagnosis. MATERIALS AND METHODS. Mammography frequency and cancer stage were retrospectively examined in 1368 cases of primary breast cancer diagnosed at our clinic from 2002 to 2008. RESULTS. Regardless of age (median, 62.7 years), 1428 women who underwent mammography were more likely to have early-stage (stage 0-II) breast cancer at diagnosis than were those who did not undergo mammography (p < 0.001). Similarly, the number of mammographic examinations in the 5 years before diagnosis was inversely related to stage: 57.3% (94/164) of late-stage cancers were diagnosed in women missing their last five annual mammograms. In a multivariate analysis, family history of breast cancer was most predictive of undergoing mammography (odds ratio, 3.492; 95% CI, 2.616-4.662; p < 0.0001) followed by number of medical encounters (odds ratio, 1.022; 95% CI, 1.017-1.027; p < 0.0001). Time to travel to the nearest mammography center was also predictive of missing mammograms: Each additional minute of travel time decreased the odds of undergoing at least one mammographic examination in the 5 years before cancer diagnosis (odds ratio, 0.990; 95% CI, 0.986-0.993; p < 0.0001). CONCLUSION. Missing a mammogram, even in the year before a breast cancer diagnosis, increases the chance of a cancer diagnosis at a later stage. Interventions to encourage use of mammography may be of particular benefit to women most likely to miss mammograms, including those with no family history of breast cancer, fewer encounters with the health care system, and greater travel distance to the mammography center