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1.  Uric acid suppresses 1 alpha hydroxylase in vitro and in vivo 
Metabolism: clinical and experimental  2013;63(1):10.1016/j.metabol.2013.09.018.
Objective
Patients with gout have lower calcitriol levels that improve when uric acid is lowered. The mechanism of these observations is unknown. We hypothesized that uric acid inhibits 1- αhydroxylase.
Materials and methods
In vivo, Sprague Dawley rats were randomized to control (n=5), allantoxanamide (n=8), febuxostat (n=5), or allantoxanamide+febuxostat (n=7). Vitamin D, PTH, and 1-αhydroxylase protein were evaluated. In order to directly evaluate the effect of uric acid on 1-αhydroxylase, we conducted a series of dose response and time course experiments in vitro. Nuclear factor κ-B (NFκB) was inhibited pharmacologically. Finally, to evaluate the potential implications of these findings in humans, the association between uric acid and PTH in humans was evaluated in a cross-sectional analysis of data from the NHANES (2003-2006); n= 9773.
Results
1,25(OH)2D and 1-αhydroxylase protein were reduced in hyperuricemic rats and improved with febuxostat treatment. Uric acid suppressed 1-αhydroxylase protein and mRNA expression in proximal tubular cells. This was prevented by NFκB inhibition. In humans, for every 1 mg/dL increase in uric acid, the adjusted odds ratio for an elevated PTH (>65 pg/mL) was 1.21 (95% C.I. 1.14, 1.28; P< 0.0001), 1.15 (95% C.I. 1.08, 1.22; P<0.0001), and 1.16 (95% C.I. 1.03, 1.31; P=0.02) for all subjects, subjects with estimated GFR ≥60, and subjects with estimated GFR <60 mL/min/1.73 m2 respectively.
Conclusion
Hyperuricemia suppresses 1-αhydroxylase leading to lower 1,25(OH)2D and higher PTH in rats. Our results suggest this is mediated by NFκB. The association between uric acid and PTH in NHANES suggests potential implications for human disease.
doi:10.1016/j.metabol.2013.09.018
PMCID: PMC3859721  PMID: 24269076
uric acid; parathyroid hormone; mineral and bone disorders
2.  High Fat and High Sucrose (Western) Diet Induce Steatohepatitis that is Dependent on Fructokinase 
Hepatology (Baltimore, Md.)  2013;58(5):1632-1643.
Fructose intake from added sugars has been implicated as a cause of nonalcoholic fatty liver disease. Here we tested the hypothesis that fructose may interact with high fat diet to induce fatty liver, and to determine if this was dependent on a key enzyme in fructose metabolism, fructokinase. Wild type or fructokinase knockout mice were fed a low fat (11%), high fat (36%) or high fat (36%) and high sucrose (30%) diet for 15 weeks. Both wild type and fructokinase knockout mice developed obesity with mild hepatic steatosis and no evidence for hepatic inflammation on a high fat diet compared to a low fat diet. In contrast, wild type mice fed a high fat and high sucrose diet developed more severe hepatic steatosis with low grade inflammation and fibrosis, as noted by increased CD68, TNF-alpha, MCP-1, alpha-smooth muscle actin, and collagen I and TIMP1 expression. These changes were prevented in the fructokinase knockout mice.
Conclusion
An additive effect of high fat and high sucrose diet on the development of hepatic steatosis exists. Further, the combination of sucrose with high fat diet may induce steatohepatitis. The protection in fructokinase knockout mice suggests a key role for fructose (from sucrose) in this development of steatohepatitis. These studies emphasize the important role of fructose in the development of fatty liver and nonalcoholic steatohepatitis (NASH).
doi:10.1002/hep.26594
PMCID: PMC3894259  PMID: 23813872
nonalcoholic fatty liver disease; hepatic steatosis; hepatic fibrosis; fructose and ketohexokinase
3.  Coexistence of two anatomical bronchial variances 
BMJ Case Reports  2012;2012:bcr0120125621.
doi:10.1136/bcr.01.2012.5621
PMCID: PMC3387433  PMID: 22729326
4.  Biological Activity of Celecoxib in the Bronchial Epithelium of Current and Former Smokers 
Purpose
Non-small-cell lung cancer (NSCLC) is the primary cause of cancer-related death in Western countries. One important approach taken to address this problem is the development of effective chemoprevention strategies. In this study, we examined whether the cyclooxygenase-2 (COX-2) inhibitor celecoxib, as evidenced by decreased cell proliferation, is biologically active in the bronchial epithelium of current and former smokers.
Patients and Methods
Current or former smokers with at least a 20 pack-year (pack-year = number of packs of cigarettes per day times number of years smoked) smoking history were randomized into one of four treatment arms (3-month intervals of celecoxib then placebo, celecoxib then celecoxib, placebo then celecoxib, or placebo then placebo) and underwent bronchoscopies with biopsies at baseline, 3 months, and 6 months. The 204 patients were primarily (79.4%) current smokers; 81 received either low-dose celecoxib or placebo and 123 received either high-dose celecoxib or placebo. Celecoxib was originally administered orally at 200 mg twice daily and the protocol subsequently increased the dose to 400 mg twice daily. The primary endpoint was change in Ki-67 labeling (from baseline to 3 months) in bronchial epithelium.
Results
No cardiac toxicities were observed in the participants. Although the effect of low-dose treatment was not significant, high-dose celecoxib decreased Ki-67 labeling by 3.85% in former smokers and by 1.10% in current smokers—a significantly greater reduction (P = 0.02) than that seen with placebo after adjusting for metaplasia and smoking status.
Conclusion
A 3–6-month celecoxib regimen proved safe to administer. Celecoxib 400 mg bid was biologically active in the bronchial epithelium of current and former smokers; additional studies on the efficacy of celecoxib in NSCLC chemoprevention may be warranted.
doi:10.1158/1940-6207.CAPR-09-0233
PMCID: PMC4028718  PMID: 20103722
5.  Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome 
Nature communications  2013;4:10.1038/ncomms3434.
Carbohydrates with high glycemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations glucose are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously-produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductase deficient mice were protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism whereby glucose promotes the development of metabolic syndrome.
doi:10.1038/ncomms3434
PMCID: PMC3833672  PMID: 24022321
6.  Diabetes Control Among Hispanics in the Action to Control Cardiovascular Risk in Diabetes Trial 
Journal of General Internal Medicine  2012;27(11):1499-1505.
ABSTRACT
BACKGROUND
Hispanics in the United States represent diverse racial, ethnic, and socioeconomic groups, and manifest heterogeneous cardiovascular risks including diabetes. It is not known if there are residual differences in the control of diabetes among Hispanic groups given uniform access to diabetes care.
OBJECTIVE
To evaluate glucose control differences among Mexicans, Puerto Ricans, and Dominicans receiving substantial diabetes care and support in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
DESIGN
Secondary analysis of data from a randomized trial comparing two treatment strategies: intensive, targeting glycated hemoglobin below 6.0 %, and standard, targeting glycated hemoglobin between 7.0 % and 7.9 %.
PARTICIPANTS
Seven hundred and sixteen Hispanic and 6066 non-Hispanic white participants were recruited from 77 clinical sites across the United States and Canada. There were 243 Mexicans, 199 Puerto Ricans, and 150 Dominicans; and 135 of these Hispanic groups were born in the United States.
MAIN MEASURE
Glycated hemoglobin
RESULTS
Compared to Puerto Ricans, Mexicans were more likely (HR = 1.38, CI:0.90–2.10) and Dominicans as likely (HR = 1.01, CI:0.66–1.54) to achieve glycated hemoglobin goal in the intensive arm. Participants born in the United States achieved glycated hemoglobin goal at a higher rate than those born elsewhere (HR = 1.57, CI:0.99–2.51 in the intensive arm, HR = 1.51, CI:0.95–2.43 in the standard arm). These differences were not statistically significant. In the intensive arm, Puerto Ricans (OR = 0.47, CI:0.31–0.71), and Dominicans (OR = 0.41, CI:0.26–0.66) were less likely than non-Hispanic whites to achieve glycated hemoglobin goal, whereas the difference between non-Hispanic whites and Mexicans was not statistically significant, (OR = 0.66, CI:0.43–1.02).
CONCLUSIONS
Hispanic groups, given access to comprehensive diabetes care, differed from each other non-significantly and had a variable divergence from non-Hispanic whites in achieving intensive glycated hemoglobin goal. These differences, if confirmed, could be due to such factors as variable acculturation and functional health literacy levels that were not measured in the ACCORD trial, but should be further explored in future studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-012-2131-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s11606-012-2131-4
PMCID: PMC3475813  PMID: 22744725
type 2 diabetes; hispanic; diabetes control; Action to Control Cardiovascular Risk in Diabetes (ACCORD); glycated hemoglobin
7.  An Integrated Model for Patient Care and Clinical Trials (IMPACT) to Support Clinical Research Visit Scheduling Workflow for Future Learning Health Systems 
Journal of biomedical informatics  2013;46(4):642-652.
We describe a clinical research visit scheduling system that can potentially coordinate clinical research visits with patient care visits and increase efficiency at clinical sites where clinical and research activities occur simultaneously. Participatory Design methods were applied to support requirements engineering and to create this software called Integrated Model for Patient Care and Clinical Trials (IMPACT). Using a multi-user constraint satisfaction and resource optimization algorithm, IMPACT automatically synthesizes temporal availability of various research resources and recommends the optimal dates and times for pending research visits. We conducted scenario-based evaluations with 10 clinical research coordinators (CRCs) from diverse clinical research settings to assess the usefulness, feasibility, and user acceptance of IMPACT. We obtained qualitative feedback using semi-structured interviews with the CRCs. Most CRCs acknowledged the usefulness of IMPACT features. Support for collaboration within research teams and interoperability with electronic health records and clinical trial management systems were highly requested features. Overall, IMPACT received satisfactory user acceptance and proves to be potentially useful for a variety of clinical research settings. Our future work includes comparing the effectiveness of IMPACT with that of existing scheduling solutions on the market and conducting field tests to formally assess user adoption.
doi:10.1016/j.jbi.2013.05.001
PMCID: PMC3716847  PMID: 23684593
workflow; software; personnel staffing and scheduling; health resources; clinical research informatics; learning health systems
8.  Counteracting Roles of AMP Deaminase and AMP Kinase in the Development of Fatty Liver 
PLoS ONE  2012;7(11):e48801.
Fatty liver (hepatic steatosis) is associated with nucleotide turnover, loss of ATP and generation of adenosine monophosphate (AMP). It is well known that in fatty liver, activity of the AMP-activated kinase (AMPK) is reduced and that its stimulation can prevent hepatic steatosis by both enhancing fat oxidation and reducing lipogenesis. Here we show that another AMP dependent enzyme, AMPD2, has opposing effects on fatty acid oxidation when compared to AMPK. In human hepatocytres, AMPD2 activation –either by overexpression or by lowering intracellular phosphate levels with fructose- is associated with a significant reduction in AMPK activity. Likewise, silencing of AMPK spontaneously increases AMPD activity, demonstrating that these enzymes counter-regulate each other. Furthermore, we show that a downstream product of AMP metabolism through AMPD2, uric acid, can inhibit AMPK activity in human hepatocytes. Finally, we show that fructose-induced fat accumulation in hepatocytes is due to a dominant stimulation of AMPD2 despite stimulating AMPK. In this regard, AMPD2-deficient hepatocytes demonstrate a further activation of AMPK after fructose exposure in association with increased fatty acid oxidation, and conversely silencing AMPK enhances AMPD-dependent fat accumulation. In vivo, we show that sucrose fed rats also develop fatty liver that is blocked by metformin in association with both a reduction in AMPD activity and an increase in AMPK activity. In summary, AMPD and AMPK are both important in hepatic fat accumulation and counter-regulate each other. We present the novel finding that uric acid inhibits AMPK kinase activity in fructose-fed hepatocytes thus providing new insights into the pathogenesis of fatty liver.
doi:10.1371/journal.pone.0048801
PMCID: PMC3494720  PMID: 23152807
9.  Uric Acid Stimulates Fructokinase and Accelerates Fructose Metabolism in the Development of Fatty Liver 
PLoS ONE  2012;7(10):e47948.
Excessive dietary fructose intake may have an important role in the current epidemics of fatty liver, obesity and diabetes as its intake parallels the development of these syndromes and because it can induce features of metabolic syndrome. The effects of fructose to induce fatty liver, hypertriglyceridemia and insulin resistance, however, vary dramatically among individuals. The first step in fructose metabolism is mediated by fructokinase (KHK), which phosphorylates fructose to fructose-1-phosphate; intracellular uric acid is also generated as a consequence of the transient ATP depletion that occurs during this reaction. Here we show in human hepatocytes that uric acid up-regulates KHK expression thus leading to the amplification of the lipogenic effects of fructose. Inhibition of uric acid production markedly blocked fructose-induced triglyceride accumulation in hepatocytes in vitro and in vivo. The mechanism whereby uric acid stimulates KHK expression involves the activation of the transcription factor ChREBP, which, in turn, results in the transcriptional activation of KHK by binding to a specific sequence within its promoter. Since subjects sensitive to fructose often develop phenotypes associated with hyperuricemia, uric acid may be an underlying factor in sensitizing hepatocytes to fructose metabolism during the development of fatty liver.
doi:10.1371/journal.pone.0047948
PMCID: PMC3480441  PMID: 23112875
10.  Sucrose induces Fatty Liver and Pancreatic Inflammation in Male Breeder Rats Independent of Excess Energy Intake 
Aims
Fructose induces metabolic syndrome in rats but studies have been criticized for using high concentrations of fructose that are not physiologic, for using only pure fructose, and for not controlling for energy intake. We tested the hypothesis that a 40% sucrose diet (containing 20% fructose) might induce features of metabolic syndrome in male breeder rats independent of excess energy intake.
Methods
Male Sprague-Dawley breeder rats were pair fed 40% sucrose or isocaloric starch diet for 4 months and evaluated for metabolic syndrome and diabetes. In vitro studies were performed in rat insulinoma cells (RIN-m5F) exposed to uric acid and markers of inflammation were assessed.
Results
Rats fed a 40% sucrose diet developed accelerated features of metabolic syndrome with upregulation of fructose-dependent transporter Glut 5 and fructokinase. Fatty liver and low grade pancreatic inflammation also occurred. Uric acid was found to stimulate inflammatory mediators and oxidative stress in islet cells in vitro.
Conclusions
Sucrose, at concentrations ingested by a subset of Americans, can accelerate metabolic syndrome, fatty liver and type 2 diabetes in male breeder rats, and the effects are independent of excess energy intake.
doi:10.1016/j.metabol.2011.01.008
PMCID: PMC3137694  PMID: 21489572
Sucrose; Fructose; Insulin Resistance; Uric acid; Nonalcoholic Fatty Liver Disease
11.  Obesity is an independent risk factor for pre-transplant portal vein thrombosis in liver recipients 
BMC Gastroenterology  2012;12:114.
Background
Portal vein thrombosis is a frequent complication in end-stage cirrhosis with a considerable peri-operative risk for liver transplant candidates. We aimed to characterize the pre-transplant portal vein thrombosis in a cohort of liver transplant recipients, and to identify independent risk factors for this complication.
Methods
380 consecutive primary orthotopic liver transplants were performed in the Digestive Surgery Department of “12 de Octubre” Hospital (Madrid, Spain), between January 2001 and December 2006. The main risk factors considered were smoking, obesity, metabolic disorders, previous immobility, surgery or trauma, nephrotic syndrome, associated tumor, inflammatory disease, neoplasm myeloprolipherative. Furthermore we have reported genetic thrombophilia results for 271 recipients.
Results
Sixty-two (16.3%) patients developed pre-transplant portal vein thrombosis and its presence had no impact in the overall survival of liver recipients. Obesity was the only independent risk factor for pre-transplant portal vein thrombosis.
Conclusion
We recommend close control of cardiovascular factors in patients with liver cirrhosis in order to avoid associated thrombosis.
doi:10.1186/1471-230X-12-114
PMCID: PMC3502589  PMID: 22909075
Thrombophilia; Portal vein thrombosis; Liver transplant recipient
12.  Implementation of a Critical Pathway for Complicated Gallstone Disease: Translation of Population-based Data into Clinical Practice 
BACKGROUND
Evidence-based guidelines recommend cholecystectomy during initial hospitalization for complicated gallstone disease. Previous studies as well as quality initiative data from our institution demonstrated that only 40–75% of patients underwent cholecystectomy on index admission.
STUDY DESIGN
In January 2009, we implemented a critical pathway to improve cholecystectomy rates for all patients emergently admitted for acute cholecystitis, mild gallstone pancreatitis, or common bile duct stones. We compared cholecystectomy rates during initial hospitalization, time to cholecystectomy, length of initial stay (LOS), and readmission rates in pre-pathway (1/05–2/08) and post-pathway patients (1/09–5/10).
RESULTS
Demographic and clinical characteristics were similar between pre-pathway (n=455) and post-pathway patients (n=112). Cholecystectomy rates during initial hospitalization increased from 48% to 78% after pathway implementation (P<0.0001). There were no differences in operative mortality or operative complications between the two groups. For patients undergoing cholecystectomy on initial hospitalization, the mean LOS decreased after pathway implementation (7.1 days to 4.5 days; P<0.0001), primarily due to a decrease in the time from admission to cholecystectomy (4.1 days to 2.1 days; P<0.0001). 33% of pre-pathway and 10% of post-pathway patients required readmission for gallstone-related problems or operative complications (P<0.0001), and each readmission generated an average of $19,000 in additional charges.
CONCLUSIONS
Implementation of a multidisciplinary critical pathway improved cholecystectomy rates on initial hospitalization and lowered costs by shortening length of stay and markedly decreasing readmission rates for gallstone-related problems. Broader implementation of similar pathways offers the potential to translate evidence-based guidelines into clinical practice and minimize the cost of medical care.
doi:10.1016/j.jamcollsurg.2010.12.047
PMCID: PMC3350377  PMID: 21398156
acute cholecystitis; gallstone pancreatitis; common bile duct stones; cholecystectomy; critical pathway; clinical pathway
13.  Effects of 2-Bromoethanamine on TonEBP Expression and Its Possible Role in Induction of Renal Papillary Necrosis in Mice 
Toxicological Sciences  2010;118(2):510-520.
Chronic analgesic abuse has been shown to induce severe renal injury characterized by renal papillary necrosis (RPN), an injury detectable at late stage. While direct toxicity of the drug may exist, the molecular mechanisms underlying analgesics induction of RPN remain unknown. A major limitation to study the pathogenesis of RPN is the required chronic exposure before detection of injury. Here, we employed 2-bromoethanamine (BEA) to simulate rapid papillary toxicity using inner medullary collecting duct (IMCD3) cells. Although exposure to 10μM BEA had no effect on cellular viability under isotonic conditions, a 50% loss in cell viability was observed in the first 24 h when cells were subjected to sublethal hypertonic stress and nearly complete cell death after 48 h suggesting that BEA exerts cytotoxicity only under hypertonic conditions. Because TonEBP is a transcription factor critical for cell survival during hypertonic conditions, we undertook experiments to examine the effect of BEA on TonEBP expression and activity. Exposure of cells to 10μM BEA resulted in a substantial reduction in TonEBP protein expression after 24 h. In addition, TonEBP was not translocated to the nucleus in BEA-treated IMCD3 cells under acute hypertonic stress for transcription of target genes essential for osmolyte accumulation. Finally, we found a substantial decrease in TonEBP expression in medullary kidney tissues of mice injected with a single ip dose of BEA. Our data suggest that TonEBP is a potential target for BEA leading to the process of papillary necrosis in the settings of hypertonic stress.
doi:10.1093/toxsci/kfq261
PMCID: PMC2984534  PMID: 20823374
Renal papillary necrosis; 2-bromoetanamine; TonEBP; Hypertonic stress
14.  Recipient and donor thrombophilia and the risk of portal venous thrombosis and hepatic artery thrombosis in liver recipients 
BMC Gastroenterology  2011;11:130.
Background
Vascular complications, such as HAT, are an important cause of graft loss and recipient mortality. We aimed to characterize post-transplant thrombotic events in a cohort of liver transplant recipients, and identify independent risk factors for these complications.
Methods
We conducted a thrombophilic study of 293 orthotopic liver transplants performed in the Digestive Surgery Department of the 12 de Octubre Hospital (Madrid, Spain) between January 2001 and December 2006.
Results
The most frequent post-transplant thrombotic events were HAT (9%) and PVT (1.7%). The one variable associated with post-transplant thrombotic event was a high fibrinogen level in the global cohort of liver transplantation. But toxicity as event post-OLT has been associated with post-transplant thrombotic event in the retrospective group and high fibrinogen level and low protein C levels were associated post-transplant thrombotic event in the prospective group. Liver disease relapse (HR 6.609, p < 0.001), high levels of FVIII (HR 1.008, p = 0.019)) and low levels of antithrombin (HR 0.946, p < 0.001) were associated with poor overall survival (OS).
In conclusion, high fibrinogen and decreased protein C levels were associated with allograft thrombosis. Further studies are required in order to assess the clinical relevance of these parameters in prospective studies and to study the effect of anticoagulation prophylaxis in this group of risk.
doi:10.1186/1471-230X-11-130
PMCID: PMC3287260  PMID: 22123067
15.  Hepatitis B and Hepatitis C Infection Biomarkers and TP53 Mutations in Hepatocellular Carcinomas from Colombia 
Hepatocellular Carcinoma (HCC) is a leading cause of cancer-related death worldwide. Globally, the most important HCC risk factors are Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV), chronic alcoholism, and dietary exposure to aflatoxins. We have described the epidemiological pattern of 202 HCC samples obtained from Colombian patients. Additionally we investigated HBV/HCV infections and TP53 mutations in 49 of these HCC cases. HBV biomarkers were detected in 58.1% of the cases; HBV genotypes F and D were characterized in three of the samples. The HCV biomarker was detected in 37% of the samples while HBV/HCV coinfection was found in 19.2%. Among TP53 mutations, 10.5% occur at the common aflatoxin mutation hotspot, codon 249. No data regarding chronic alcoholism was available from the cases. In conclusion, in this first study of HCC and biomarkers in a Colombian population, the main HCC risk factor was HBV infection.
doi:10.1155/2011/582945
PMCID: PMC3207138  PMID: 22114738
16.  Genetically Abnormal Circulating Cells in Lung Cancer Patients: An Antigen Independent Fluorescence in-situ Hybridization Based Case-Control Study 
Purpose
We performed a study to determine if a fluorescence in-situ hybridization (FISH)-based assay using isolated peripheral blood mononuclear cells (PBMCs) with DNA probes targeting specific sites on chromosomes known to have abnormalities in Non Small Cell Lung Cancer (NSCLC) cases could detect circulating genetically abnormal cells (CACs).
Experimental Design
We evaluated 59 NSCLC cases with stage I through IV disease and 24 controls. PBMCs and matched tumors were hybridized with 2 two-color (3p22.1/CEP3 and 10q22.3 [SP-A]/CEP10) and 2 four-color (CEP3, CEP7, CEP17, and 9p21.3 [URO]) and (EGFR, c-MYC, 6p11-q11, and 5p15.2 [LAV]) FISH probes. Percentages of cytogenetically abnormal cells (CACs) in peripheral blood and in matched tumor specimens were quantified using an automated fluorescent scanner. Numbers of CACs were calculated based on the percentage of CACs (defined as PBMCs with genetic abnormalities) per mL of blood and expressed per microliter of blood.
Results
Patients with NSCLC had significantly higher numbers of CACs than did controls. Mean number of CACs ranged from 7.23±1.32/μl for deletions of 10q22.3/CEP10 to 45.52±7.49/μl for deletions of 3p22.1/CEP3. Numbers of CACs with deletions of 3p22.1, 10q22.3, and 9p21.3, and gains of URO, increased significantly from early to advanced stage of disease.
Conclusions
We have developed a sensitive and quantitative antigen-independent FISH-based test for detecting CACs in peripheral blood of patients with NSCLC which showed a significant correlation with the presence of cancer. If this pilot study can be validated in a larger study, CACs may have a role in the management of patients with NSCLC.
doi:10.1158/1078-0432.CCR-09-3358
PMCID: PMC2949278  PMID: 20651054
17.  Using quantitative breath sound measurements to predict lung function following resection 
Background
Predicting postoperative lung function is important for estimating the risk of complications and long-term disability after pulmonary resection. We investigated the capability of vibration response imaging (VRI) as an alternative to lung scintigraphy for prediction of postoperative lung function in patients with intrathoracic malignancies.
Methods
Eighty-five patients with intrathoracic malignancies, considered candidates for lung resection, were prospectively studied. The projected postoperative (ppo) lung function was calculated using: perfusion scintigraphy, ventilation scintigraphy, and VRI. Two sets of assessments made: one for lobectomy and one for pneumonectomy. Clinical concordance was defined as both methods agreeing that either a patient was or was not a surgical candidate based on a ppoFEV1% and ppoDLCO% > 40%.
Results
Limits of agreement between scintigraphy and VRI for ppo following lobectomy were -16.47% to 15.08% (mean difference = -0.70%;95%CI = -2.51% to 1.12%) and for pneumonectomy were -23.79% to 19.04% (mean difference = -2.38%;95%CI = -4.69% to -0.07%). Clinical concordance between VRI and scintigraphy was 73% for pneumonectomy and 98% for lobectomy. For patients who had surgery and postoperative lung function testing (n = 31), ppoFEV1% using scintigraphic methods correlated with measured postoperative values better than projections using VRI, (adjusted R2 = 0.32 scintigraphy; 0.20 VRI), however the difference between methods failed to reach statistical significance. Limits of agreement between measured FEV1% postoperatively and ppoFEV1% based on perfusion scintigraphy were -16.86% to 23.73% (mean difference = 3.44%;95%CI = -0.29% to 7.16%); based on VRI were -19.56% to 28.99% (mean difference = 4.72%;95%CI = 0.27% to 9.17%).
Conclusions
Further investigation of VRI as an alternative to lung scintigraphy for prediction of postoperative lung function is warranted.
doi:10.1186/1749-8090-5-81
PMCID: PMC2964689  PMID: 20939900
18.  Does pleural fluid appearance really matter? The relationship between fluid appearance and cytology, cell counts, and chemical laboratory measurements in pleural effusions of patients with cancer 
Background
Previous reports have suggested that the appearance of pleural effusions (i.e., the presence or absence of blood) might help to establish the etiology of the effusions. This study explores the relationship between pleural fluid appearance and the results of chemical and cytological analyses in a group of patients with recurrent symptomatic pleural effusions and a diagnosis of cancer.
Methods
Medical records were reviewed from all 390 patients who were diagnosed with cancer, who underwent thoracentesis before placement of an intrapleural catheter (IPC) between April 2000 and January 2006. Adequate information for data analysis was available in 365 patients. The appearance of their pleural fluid was obtained from procedure notes dictated by the pulmonologists who had performed the thoracenteses. The patients were separated into 2 groups based on fluid appearance: non-bloody and bloody. Group differences in cytology interpretation were compared by using the chi square test. Cellular counts, chemical laboratory results, and survival after index procedure were compared by using the student's t test.
Results
Pleural fluid cytology was positive on 82.5% of the non-bloody effusions and on 82.4% of the bloody ones. The number of red blood cells (220.5 × 103/μL vs. 12.3 × 103/μL) and LDH values (1914 IU/dl vs. 863 IU/dl) were statistically higher in bloody pleural effusions.
Conclusion
The presence or absence of blood in pleural effusions cannot predict their etiology in patients with cancer and recurrent symptomatic pleural effusions.
doi:10.1186/1749-8090-5-63
PMCID: PMC2933602  PMID: 20718978
19.  Diagnosis of invasive aspergillus tracheobronchitis facilitated by endobronchial ultrasound-guided transbronchial needle aspiration: a case report 
Introduction
Invasive pulmonary aspergillosis is the most common form of infection by Aspergillus species among immunocompromised patients. Although this infection frequently involves the lung parenchyma, it is unusual to find it limited to the tracheobronchial tree, a condition known as invasive aspergillus tracheobronchitis.
Case presentation
A 65 year-old Hispanic man from Bolivia with a history of chronic lymphocytic leukemia developed cough and malaise eight months after having an allogenic stem cell transplant. A computed tomography of the chest revealed an area of diffuse soft tissue thickening around the left main stem bronchus, which was intensely fluorodeoxyglucose-avid on positron emission tomography scanning. An initial bronchoscopic exam revealed circumferential narrowing of the entire left main stem bronchus with necrotic and friable material on the medial wall. Neither aspirates from this necrotic area nor bronchial washing were diagnostic. A second bronchoscopy with endobronchial ultrasound evidenced a soft tissue thickening on the medial aspect of the left main stem bronchus underlying the area of necrosis visible endoluminally. Endobronchial ultrasound-guided transbronchial needle aspiration performed in this area revealed multiple fungal elements suggestive of Aspergillus species.
Conclusion
We describe the first case of invasive aspergillus tracheobronchitis in which the diagnosis was facilitated by the use of endobronchial ultrasound guided trans-bronchial needle aspiration. To the best of our knowledge, we are also presenting the first positron emission tomography scan images of this condition in the literature. We cautiously suggest that endobronchial ultrasound imaging may be a useful tool to evaluate the degree of invasion and the involvement of vascular structures in these patients prior to bronchoscopic manipulation of the affected areas in an effort to avoid potentially fatal hemorrhage.
doi:10.1186/1752-1947-3-9290
PMCID: PMC2783092  PMID: 19946509
20.  Clinical implications of granulomatous inflammation detected by endobronchial ultrasound transbronchial needle aspiration in patients with suspected cancer recurrence in the mediastinum 
Background
Granulomatous inflammation has been previously reported in association with cancer. Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is a new minimally invasive test for investigating mediastinal lymphadenopathy. The identification of granulomatous inflammation by EBUS-TBNA and the clinical implications of such detection in a series of patients with previously treated cancer and new mediastinal lymphadenopathy has not previously been performed.
Methods
All 153 consecutive patients undergoing EBUS-TBNA in an academic cancer institution for suspected cancer in the mediastinum (mediastinal lymphadenopathy by CT imaging) were reviewed. Patients with non-caseating granuloma identified by EBUS-TBNA were included.
Results
EBUS-TBNA identified non-caseating granuloma in 17/153 (11%) patients. A subset of 8/153 (5.2%) had sarcoid like lymphadenopathy mimicking cancer recurrence (5/5 PET positive). Another 8/153 (5.2%) patients with new mediastinal lymphadenopathy and no prior history of cancer had a clinical syndrome consistent with sarcoidosis. One other patient with a history of breast cancer was diagnosed with non-tuberculous mycobacteria infection. No patient required mediastinoscopy and there were no complications.
Conclusion
In an academic cancer institute, at least 5% of patients undergoing EBUS-TBNA have sarcoid-like lymphadenopathy mimicking cancer recurrence. Further studies to define the precise etiology, natural history and prognosis of this phenomenon are warranted.
doi:10.1186/1749-8090-3-8
PMCID: PMC2291049  PMID: 18298864
21.  Treatment of bronchial airway obstruction using a rotating tip microdebrider: a case report 
Background
Central airway obstruction is a common complication of lung cancer. The microdebrider is a new device available for treatment of central airway obstruction.
Case Description
We report a case a 59-yr-old male with T3N2M1 non-small cell lung cancer with malignant distal left mainstem obstruction treated successfully with a novel elongated rotating tip microdebrider via rigid bronchoscopy with sufficient length to reach distal bronchial lesions.
Discussion and Conclusion
The microdebrider is an excellent addition to the spectrum of interventions available for the management of central airway obstruction with advantages including accuracy and immediate removal of debris without a need for separate suctioning or limitation in oxygenation.
doi:10.1186/1749-8090-2-16
PMCID: PMC1847429  PMID: 17386099
22.  An unusual cause of alveolar hemorrhage post hematopoietic stem cell transplantation: A case report 
BMC Cancer  2006;6:87.
Background
Hematopoietic stem cell transplantation is being increasingly used in cancer therapy. Diffuse alveolar hemorrhage, an early complication of stem cell transplant, results from bacterial, viral and fungal infections, coagulopathy, and engraftment syndrome, or can be idiopathic. Diffuse alveolar hemorrhage associated with Strongyloides stercoralis hyperinfection in stem cell transplant patients has been rarely reported.
Case presentation
We describe an unusual cause of alveolar hemorrhage post hematopoietic stem cell transplant due to Strongyloides hyperinfection. Therapy with parenteral ivermectin and thiabendazole was initiated but the patient deteriorated and died of respiratory failure and septic shock.
Conclusion
Strongyloides stercoralis hyperinfection is an unusual cause of alveolar hemorrhage early after hematopoietic stem cell transplant with very high mortality.
doi:10.1186/1471-2407-6-87
PMCID: PMC1479356  PMID: 16603072
23.  Vesicular Stomatitis Virus Glycoprotein Is a Determinant of Pathogenesis in Swine, a Natural Host 
Journal of Virology  2003;77(14):8039-8047.
There are two major serotypes of vesicular stomatitis virus (VSV), Indiana (VSIV) and New Jersey (VSNJV). We recovered recombinant VSIVs from engineered cDNAs that contained either (i) one copy of the VSIV G gene (VSIV-GI); (ii) two copies of the G gene, one from each serotype (VSIV-GNJGI); or (iii) a single copy of the GNJ gene instead of the GI gene (VSIV-GNJ). The recombinant viruses expressed the appropriate glycoproteins, incorporated them into virions, and were neutralized by antibodies specific for VSIV (VSIV-GI), VSNJV (VSIV-GNJ), or both (VSIV-GNJGI), according to the glycoprotein(s) they expressed. All recombinant viruses grew to similar titers in cell culture. In mice, VSIV-GNJ and VSIV-GNJGI were attenuated. However, in swine, a natural host for VSV, the GNJ glycoprotein-containing viruses caused more severe lesions and replicated to higher titers than the parental virus, VSIV-GI. These observations implicate the glycoprotein as a determinant of VSV virulence in a natural host and emphasize the differences in VSV pathogenesis between mice and swine.
doi:10.1128/JVI.77.14.8039-8047.2003
PMCID: PMC161932  PMID: 12829843
24.  Fructokinase activity mediates dehydration-induced renal injury 
Kidney International  2013;86(2):294-302.
The epidemic of chronic kidney disease in Nicaragua (Mesoamerican nephropathy) has been linked with recurrent dehydration. Here we tested whether recurrent dehydration may cause renal injury by activation of the polyol pathway, resulting in the generation of endogenous fructose in the kidney that might subsequently induce renal injury via metabolism by fructokinase. Wild-type and fructokinase-deficient mice were subjected to recurrent heat-induced dehydration. One group of each genotype was provided water throughout the day and the other group was hydrated at night, after the dehydration. Both groups received the same total hydration in 24 h. Wild-type mice that received delayed hydration developed renal injury, with elevated serum creatinine, increased urinary NGAL, proximal tubular injury, and renal inflammation and fibrosis. This was associated with activation of the polyol pathway, with increased renal cortical sorbitol and fructose levels. Fructokinase-knockout mice with delayed hydration were protected from renal injury. Thus, recurrent dehydration can induce renal injury via a fructokinase-dependent mechanism, likely from the generation of endogenous fructose via the polyol pathway. Access to sufficient water during the dehydration period can protect mice from developing renal injury. These studies provide a potential mechanism for Mesoamerican nephropathy.
doi:10.1038/ki.2013.492
PMCID: PMC4120672  PMID: 24336030
aldose reductase; fructokinase; fructose; hydration; Mesoamerican nephropathy

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