OBJECTIVES::
Measurements of extravascular lung water (EVLW) correlate to the degree of pulmonary edema and have substantial prognostic information in critically ill patients. Prior studies using single indicator thermodilution have reported that 21% to 35% of patients with clinical acute respiratory distress syndrome (ARDS) have normal EVLW (<10 mL/kg). Given that lung size is independent of actual body weight, we sought to determine whether indexing EVLW to predicted or adjusted body weight affects the frequency of increased EVLW in patients with ARDS. DESIGN:: Prospective, observational cohort study. SETTING:: Medical and surgical intensive care units at two academic hospitals. PATIENTS:: Thirty patients within 72 hrs of meeting American-European Consensus Conference definition of ARDS and 14 severe sepsis patients without ARDS. INTERVENTIONS:: None. MEASUREMENT AND MAIN RESULTS:: EVLW was measured for 7 days by PiCCO transpulmonary thermodilution; 225 measurements of EVLW indexed to actual body weight (ActBW) were compared with EVLW indexed to predicted body weight (PBW) and adjusted body weight (AdjBW). Mean EVLW indexed to ActBW was 12.7 mg/kg for ARDS patients and 7.8 mg/kg for non-ARDS sepsis patients (p < .0001). In all patients, EVLW increased an average of 1.1 ± 2.1 mL/kg when indexed to AdjBW and 2.0 ± 4.1 mL/kg when indexed to PBW. Indexing EVLW to PBW or AdjBW increased the proportion of ARDS patients with elevated EVLW (each p < .05) without increasing the frequency of elevated EVLW in non-ARDS patients. EVLW indexed to PBW had a stronger correlation to Lung Injury Score (r = .39 vs. r = .17) and Pao2/Fio2 ratio (r = .25 vs. r = .10) than did EVLW indexed to ActBW. CONCLUSIONS:: Indexing EVLW to PBW or AdjBW reduces the number of ARDS patients with normal EVLW and correlates better to Lung Injury Score and oxygenation than using ActBW. Studies are needed to confirm the presumed superiority of this method for diagnosing ARDS and to determine the clinical treatment implications.
Despite using imaging studies, tissue sampling, and serologic tests about 5-10% of surgeries done for presumed pancreatic malignancies will have benign findings on final pathology. Endoscopic ultrasound (EUS) is used with increasing frequency to study pancreatic masses. The aim of this study is to examine the effect of EUS on prevalence of benign diseases undergoing Whipple over the last decade. Patients who underwent Whipple procedure for presumed malignancy at Emory University Hospital from 1998 to 2011 were selected. Demographic data, history of smoking and drinking, history of diabetes and pancreatitis, imaging data, pathology reports, and tumor markers were extracted. 878 patients were found. 95 (10.82%) patients had benign disease. Prevalence of benign finding had increased over the recent years despite using more EUS. Logistic regression models showed that abdominal pain (OR: 5.829, 95% CI 2.681-12.674, P ≤ 0.001) and alcohol abuse (OR: 3.221, CI 95%: 1.362-7.261, P: 0.002) were predictors of benign diseases. Jaundice (OR: 0.221, 95% CI: 0.084-0.58, P: 0.002), mass (OR: 0.145, 95% CI: 0.043-0.485, P: 0.008), and ductal dilation (OR: 0.297, 95% CI 0.134-0.657, P: 0.003) were associated with malignancy. Use of imaging studies, ERCP, and EUS has not decreased the percentage of benign findings after surgery for presumed pancreatic malignancy.
Behaviors associated with sickness (food consumption, weight maintenance, exploratory activity and grooming frequency) were examined on post-surgical days 1, 3, 5, 7 and 9 in male rats treated with progesterone (4. mg/kg) and/or vehicle. Rats with medial frontal cortex contusions showed reduced food consumption on days 1 and 3 (p< 0.01), reduced weight maintenance on days 1, 3, 5, 7 and 9 (p< 0.01), reduced grooming frequency on day 1 (p< .01), and reduced exploratory activity on day 1 (p< 0.01), after injury compared to sham rats. Contusion induced behaviors were not attenuated with 5 days of progesterone treatment (p> 0.05). Progesterone did reduce lesion size at 9 days after injury (p< 0.05). Our results suggest sickness behaviors occur after traumatic brain injury and that they might not respond to some neurosteroidal agents.
Background-In a previous study, we found that a biomarker risk score (BRS) comprised of C-reactive protein, fibrin-degradation products, and heat shock protein-70 predicts risk of myocardial infarction and death in coronary artery disease patients. We sought to: (1) validate the BRS in the independent BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) cohort, (2) investigate whether 1 year of intensive medical therapy is associated with improved BRS, and (3) elucidate whether an altered BRS parallels altered risk. Methods and Results-Two thousand thirty-two subjects with coronary artery disease were followed for 5.3±1.1 years for cardiovascular events. Biomarkers were measured at baseline and retested in 1304 subjects at 1 year. BRS was determined as the biomarker number above previously defined cut-off values (C-reactive protein > 3 mg/L, heat shock protein-70 > 0.313 ng/mL, and fibrin-degradation products > 1 lg/mL). After adjustment for covariates, those with a BRS of 3 had a 4-fold increased risk of allcause death and a 6.8-fold increased risk of cardiac death compared with those with a BRS of 0 (95% CI, 2.9-16.0; P < 0.0001). All individual biomarkers decreased by 1 year, with ≈80% of patients decreasing their BRS. BRS recalibrated at 1 year also predicted risk. Those with 1-year BRS of 2 to 3 had a 4-year mortality rate of 21.1% versus 7.4% for those with BRS of 0 to 1 (P < 0.0001). Conclusions-Our results validate the ability of the BRS to identify coronary artery disease patients at very high near-term risk of myocardial infarction/death. After 1 year of intensive medical therapy, the BRS decreased significantly, and the reclassified BRS continued to track with risk. Our results suggest that repeated BRS measurements might be used to assess risk and recalibrate therapy.
Murine gammaherpesvirus 68 (γHV68) infection of mice provides a tractable small-animal model system for assessing the requirements for the establishment and maintenance of gammaherpesvirus latency within the lymphoid compartment. The M2 gene product of γHV68 is a latency-associated antigen with no discernible homology to any known proteins. Here we focus on the requirement for the M2 gene in splenic B-cell latency. Our analyses showed the following. (i) Low-dose (100 PFU) inoculation administered via the intranasal route resulted in a failure to establish splenic B-cell latency at day 16 postinfection. (ii) Increasing the inoculation dose to 4 × 10 5 PFU administered via the intranasal route partially restored the establishment of B-cell latency at day 16, but no virus reactivation was detected upon explant into tissue cultures. (iii) Although previous data failed to detect a phenotype of the M2 mutant upon high-dose intraperitoneal inoculation, decreasing the inoculation dose to 100 PFU administered intraperitoneally revealed a splenic B-cell latency phenotype at day 16 that was very similar to the phenotype observed upon high-dose intranasal inoculation. (iv) After low-dose intraperitoneal inoculation, fractionated B-cell populations showed that the M2 mutant virus was able to establish latency in surface immunoglobulin B-negative (sIgD - ) B cells; by 6 months postinfection, equivalent frequencies of M2 mutant and marker rescue viral genome-positive sIgD - B cells were detected. (v) Like the marker rescue virus, the M2 mutant virus also established latency in splenic naive B cells upon low-dose intraperitoneal inoculation, but there was a significant lag in the decay of this latently infected reservoir compared to that seen with the marker rescue virus. (vi) After low-dose intranasal inoculation, by day 42 postinfection, latency was observed in the spleen, although at a frequency significantly lower than that in the marker rescue virus-infected mice; by 3 months postinfection, nearly equivalent levels of viral genome-positive cells were observed in the spleens of marker rescue virus- and M2 mutant virus-infected mice, and these cells were exclusively sIgD - B cells. Taken together, these data convincingly demonstrate a role for the M2 gene product in reactivation from splenic B cells and also suggest that disruption of the M2 gene leads to dose- and route-specific defects in the efficient establishment of splenic B-cell latency.
Cell cycle progression and DNA synthesis are essential steps in cancer cell growth. Thymidylate synthase (TS) is a therapeutic target for 5FU. We tested the hypothesis that HSP90 transcriptional and functional inhibition can inhibit cell cycle progression, downregulate TS levels and sensitize colorectal cancer (CRC) cell lines to the effects of 5FU. Treatment with ganetespib (50nM) for 24 hours inhibited cyclin D1 and pRb at the transcriptional and translational levels and induced p21, leading to G0/G1 cell cycle arrest in both CRC cell lines (HCT-116 and HT-29). This was associated with downregulation of E2F1 and its target gene TS. In addition, ganetespib inhibited PI3K/Akt and ERK signalling pathways. Similar effects were observed with HSP90 knockdown in both cell lines. Ganetespib sensitized CRC cell lines to the effects of oxaliplatin and 5FU. Similar effects were also observed in tumors from animals treated with ganetespib, oxaliplatin and 5FU. In this study, we present in vitro and animal data supporting that the targeting of HSP90 decreases CRC cell survival and proliferation. Ganetespib sensitizes CRC cell lines to the effects of 5FUbased chemotherapy. Combining HSP90 inhibitors with chemotherapy is a rational approach for future drug development in CRC.
BACKGROUND: We hypothesized that nebivolol, a β-blocker with nitric oxide-mediated activity, compared with atenolol, a β-blocker without such activity, would decrease oxidative stress and improve the effects of endothelial dysfunction and wall shear stress (WSS), thereby reducing atherosclerosis progression and vulnerability in patients with nonobstructive coronary artery disease.
METHODS AND RESULTS: In this pilot double-blinded randomized controlled trial, 24 patients treated for 1 year with nebivolol 10 mg versus atenolol 100 mg plus standard medical therapy underwent baseline and follow-up coronary angiography with assessments of inflammatory and oxidative stress biomarkers, microvascular function, endothelial function, and virtual histology intravascular ultrasound. WSS was calculated from computational fluid dynamics. Virtual histology intravascular ultrasound segments were assessed for vessel volumetrics and remodeling. There was a trend toward more low-WSS segments in the nebivolol cohort (P=0.06). Low-WSS regions were associated with greater plaque progression (P<0.0001) and constrictive remodeling (P=0.04); conversely, high-WSS segments demonstrated plaque regression and excessive expansive remodeling. Nebivolol patients had decreased lumen and vessel areas along with increased plaque area, resulting in more constrictive remodeling (P=0.002). There were no significant differences in biomarker levels, microvascular function, endothelial function, or number of thin-capped fibroatheromas per vessel. Importantly, after adjusting for β-blocker, low-WSS segments remained significantly associated with lumen loss and plaque progression.
CONCLUSION: Nebivolol, compared with atenolol, was associated with greater plaque progression and constrictive remodeling, likely driven by more low-WSS segments in the nebivolol arm. Both β-blockers had similar effects on oxidative stress, microvascular function, and endothelial function.
In many observational longitudinal studies, the outcome of interest presents a skewed distribution, is subject to censoring due to detection limit or other reasons, and is observed at irregular times that may follow a outcome-dependent pattern. In this work, we consider quantile regression modeling of such longitudinal data, because quantile regression is generally robust in handling skewed and censored outcomes and is flexible to accommodate dynamic covariate-outcome relationships. Specifically, we study a longitudinal quantile regression model that specifies covariate effects on the marginal quantiles of the longitudinal outcome. Such a model is easy to interpret and can accommodate dynamic outcome profile changes over time. We propose estimation and inference procedures that can appropriately account for censoring and irregular outcome-dependent follow-up. Our proposals can be readily implemented based on existing software for quantile regression. We establish the asymptotic properties of the proposed estimator, including uniform consistency and weak convergence. Extensive simulations suggest good finite-sample performance of the new method. We also present an analysis of data from a long-term study of a population exposed to polybrominated biphenyls (PBB), which uncovers an inhomogeneous PBB elimination pattern that would not be detected by traditional longitudinal data analysis.
by
Daniel E. Forman;
Michael W. Rich;
Karen P. Alexander;
Susan Zieman;
Mathew S. Maurer;
Samer S. Najjar;
Joseph C. Cleveland;
Harlan M. Krumholz;
Nanette Wenger