Citations

Purpose. The goal of this study was to identify potential clinical predictors for the development of disseminated intravascular coagulation (DIC) in patients with septic shock. Material and Methods. We performed a retrospective analysis of a cohort of adult (>18 years of age) patients with septic shock admitted to a medical ICU in a tertiary care hospital from July 2005 until September 2007. A multivariate logistic regression model was used to determine the association of risk factors with overt DIC. Results. In this study, a total of 390 patients with septic shock were analyzed, of whom 66 (17%) developed overt DIC. Hospital mortality was significantly greater in patients who developed overt DIC (68% versus 38%, P<0.001). A delay in the timing of antibiotics was associated with an increased risk of the development of overt DIC (P<0.001). Patients on antiplatelet therapy prior to hospital admission and who that received adequate early goal-directed therapy (EGDT) were associated with a decreased risk of overt DIC (P<0.001). Conclusions. In our cohort of patients with septic shock, there was a risk reduction for overt DIC in patients on antiplatelet therapy and adequate EGDT, while there was an increased risk of DIC with antibiotic delay.

The availability of population-based epidemiological data on the incident risk of stroke is very scarce in Argentina and other Latin American countries. In response to the priorities established by the World Health Organization and the United Nations, PREVISTA was envisaged as a population-based program to determine the risk of first-ever and recurrent stroke and transient ischemic attack incidence and mortality in Tandil, Buenos Aires, Argentina. The study will be conducted according to Standardized Tools for Stroke Surveillance (STEPS Stroke) methodology and will enroll all new (incident) and recurrent consecutive cases of stroke and transient ischemic attack in the City of Tandil between May 1st, 2013 and April 30, 2015. The study will include patients with ischemic stroke, non-traumatic primary intracerebral hemorrhage, subarachnoid hemorrhage, and transient ischemic attack. To ensure the inclusion of every cerebrovascular event during an observation period of two years, we will instrument an ‘intensive screening program’, consisting of a comprehensive daily tracking of every potential event of stroke or transient ischemic attack using multiple overlapping sources. Mortality would be determined during follow-up for every enrolled patient. Also, fatal community events would be screened daily through revision of death certificates at funeral homes and local offices of vital statistics. All causes of death will be adjudicated by an ad-hoc committee. The close population of Tandil is representative of a large proportion of Latin-American countries with low- and middle-income economies. The findings and conclusions of PREVISTA may provide data that could support future health policy decision-making in the region.

Abstract Purpose: Here, we describe a novel interplay between NAD synthesis and degradation involved in pancreatic tumor growth. Experimental Design: We used human pancreatic cancer cells, both in vitro (cell culture experiments) and in vivo (xenograft experiments), to demonstrate the role of NAD synthesis and degradation in tumor cell metabolism and growth. Results: We demonstrated that pharmacologic and genetic targeting of Nampt, the key enzyme in the NAD salvage synthesis pathway, inhibits cell growth and survival of pancreatic cancer cells. These changes were accompanied by a reduction of NAD levels, glycolytic flux, lactate production, mitochondrial function, and levels of ATP. The massive reduction in overall metabolic activity induced by Nampt inhibition was accompanied by a dramatic decrease in pancreatic tumor growth. The results of the mechanistic experiments showed that neither the NAD-dependent enzymes PARP-1 nor SIRT1 play a significant role on the effect of Nampt inhibition on pancreatic cancer cells. However, we identified a role for the NAD degradation pathway mediated by the NADase CD38 on the sensitivity to Nampt inhibition. The responsiveness to Nampt inhibition is modulated by the expression of CD38; low levels of this enzyme decrease the sensitivity to Nampt inhibition. In contrast, its overexpression decreased cell growth in vitro and in vivo, and further increased the sensitivity to Nampt inhibition. Conclusions: Our study demonstrates that NAD metabolism is essential for pancreatic cancer cell survival and proliferation and that targeting NAD synthesis via the Nampt pathway could lead to novel therapeutic treatments for pancreatic cancer. Clin Cancer Res; 20(1); 120–30. ©2013 AACR.

The accuracy of continuous interstitial fluid (ISF) glucose sensing is an essential component of current and emerging open- and closed-loop systems for type 1 diabetes. An important determinant of sensor accuracy is the physiological time lag of glucose transport from the vascular to the interstitial space. We performed the first direct measurement of this phenomenon to our knowledge in eight healthy subjects under an overnight fasted condition. Microdialysis catheters were inserted into the abdominal subcutaneous space. After intravenous bolus administrations of glucose tracers, timed samples of plasma and ISF were collected sequentially and analyzed for tracer enrichments. After accounting for catheter dead space and assay noise, the mean time lag of tracer appearance in the interstitial space was 5.3–6.2 min. We conclude that in the overnight fasted state in healthy adults, the physiological delay of glucose transport from the vascular to the interstitial space is 5–6 min. Physiological delay between blood glucose and ISF glucose, therefore, should not be an obstacle to sensor accuracy in overnight or fasting-state closed-loop systems of insulin delivery or open-loop therapy assessment for type 1 diabetes.

Key PointsPhenotypic and genotypic profiling of MDM2 in DLBCL. MDM2 as a negative regulator of p53 tumor suppressor function.