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ABSTRACT: Parathyroid hormone-related protein (PTHrP) is a polyhormone secretory protein that plays fundamental roles in the development and function of various tissues. Transforming growth factor (TGF)-β is an important tumor suppressor that induces cell cycle arrest and apoptosis. Increased PTHrP expression has been implicated in TGF-β-induced growth inhibition in human hepatocellular carcinoma cells. However, whether PTHrP is involved in TGF-β-induced apoptosis remains unknown. Using Hep3B and HuH-7, two human hepatocellular carcinoma cell lines, the current study examined the hypothesis that TGF-β-induced apoptosis is mediated by the induction of PTHrP expression. We found that (1) TGF-β induces PTHrP mRNA expression, protein expression and secretion in a time-dependent fashion; (2) knockdown of PTHrP gene expression or neutralization of secreted PTHrP isoforms blocks TGF-β-induced apoptosis; and (3) TGF-β-induced PTHrP expression is Smad3-dependent. Thus, we have identified PTHrP as a novel mediator for TGF-β-induced apoptosis in Hep3B cells. Our findings provide further insights into the mechanisms through which TGF-β conveys tumor suppression activity.
Regulatory Peptides 03/2013; · 2.11 Impact Factor
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ABSTRACT: BACKGROUND: Current guidelines recommend minimally invasive breast biopsy (MIBB) as the gold standard for the diagnosis of breast lesions. The purpose of this study was to describe geographic patterns and time trends in the use of MIBB in Texas. METHODS: We used 100% Texas Medicare claims data (2000-2008) to identify women older than 66 years of age who underwent breast biopsy. Biopsies were classified as open or MIBB. Time trends, racial/ethnic variation, and geographic variation in the use of biopsy techniques were examined. RESULTS: A total of 87,165 breast biopsies were performed on 75,518 breast masses in 67,582 women; 65.8% of the initial biopsies were MIBB. Radiologists performed 70.3% and surgeons performed 26.2% of MIBB. Surgeons performed 94.2% of open biopsies. Hispanic women were less likely to undergo MIBB (55.9%) compared with white (66.6%) and black (68.9%) women (p < 0.0001). Women undergoing MIBB were also more likely to live in metropolitan areas and have higher income and educational levels (p < 0.0001). The rate of MIBB increased from 44.4% in 2001 to 79.1% in 2008 (p < 0.0001). There are clear geographic patterns in MIBB use, with highest use near major cities. Although rates are increasing overall, rates of improvement in the use of MIBB vary considerably across geographic regions and remain persistently low in more rural areas. CONCLUSIONS: Despite an increase in the use of MIBB over time, MIBB use was consistently lower than recommended. We must identify specific barriers in rural areas to effectively change practice and achieve the statewide goal of 90% MIBB.
Journal of the American College of Surgeons 01/2013; · 4.55 Impact Factor
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Ji Tae Kim,
Jing Li,
Eun Ryoung Jang,
Pat Gulhati,
Piotr G Rychahou,
Dana L Napier,
Chi Wang,
Heidi L Weiss,
Eun Y Lee,
Lowell Anthony, Courtney M Townsend,
Chunming Liu,
B Mark Evers
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ABSTRACT: Carcinoid tumors are rare neuroendocrine tumors (NETs) that are increasing in incidence recently. Mutation and altered expression of Wnt/β-catenin signaling components have been described in many tumors but have not been well-studied in NETs. Here, we observed accumulation of β-catenin in the cytoplasm and/or nucleus in 25% of clinical NET tissues. By mutational analysis, the mutations of β-catenin (I35S) and APC (E1317Q, T1493T) were identified in NET cells and tissues. Expression of representative cytosolic and extracellular Wnt inhibitors was absent or markedly decreased inBON, NET cells; treatment with 5-aza-2'-deoxycytidine (5-aza-CdR) increased expression levels of the Wnt inhibitors. Methylation analyses demonstrated that CpG islands of SFRP-1 and Axin-2 were methylated, while the promoters of DKK-1, DKK-3 and WIF-1 were unmethylated. Especially, aberrant methylation of SFRP-1 was observed in most of clinical NET tissues. In addition, the repressions of these unmethylated genes are associated with histone H3 Lys9 di-methyl modification(H3K9me2) in BON cells. Together, treatment of 5-aza-CdR decreased the protein levels of H3K9me2 and G9a. A novel G9a inhibitor, UNC0638 suppressed BON cell proliferation through inhibition of H3K9me2 and Wnt/β-catenin pathway. Overexpression of the inhibitory genes, decreased TCF/LEF transcriptional activity and colony formation. In particular, restoration of SFRP-1 and WIF-1 resulted in suppression of anchorage-independent growth and inhibition of tumor growth in mice. Our findings suggest that aberrant Wnt/β-catenin signaling, through either mutations or epigenetic silencing of Wnt antagonists, contributes to the pathogenesis and growth of NETs and have important clinical implications for the prognosis and treatment of NETs.
Carcinogenesis 01/2013; · 5.70 Impact Factor
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ABSTRACT: Routine preoperative laboratory testing for ambulatory surgery is not recommended.
Patients who underwent elective hernia repair (N = 73,596) were identified from the National Surgical Quality Improvement Program (NSQIP) database (2005-2010). Patterns of preoperative testing were examined. Multivariate analyses were used to identify factors associated with testing and postoperative complications.
A total of 46,977 (63.8%) patients underwent testing, with at least one abnormal test recorded in 61.6% of patients. In patients with no NSQIP comorbidities (N = 25,149) and no clear indication for testing, 54% received at least one test. In addition, 15.3% of tested patients underwent laboratory testing the day of the operation. In this group, surgery was done despite abnormal results in 61.6% of same day tests. In multivariate analyses, testing was associated with older age, ASA (American Society of Anesthesiologists) class >1, hypertension, ascites, bleeding disorders, systemic steroids, and laparoscopic procedures. Major complications (reintubation, pulmonary embolus, stroke, renal failure, coma, cardiac arrest, myocardial infarction, septic shock, bleeding, or death) occurred in 0.3% of patients. After adjusting for patient and procedure characteristics, neither testing nor abnormal results were associated with postoperative complications.
Preoperative testing is overused in patients undergoing low-risk, ambulatory surgery. Neither testing nor abnormal results were associated with postoperative outcomes. On the basis of high rates of testing in healthy patients, physician and/or facility preference and not only patient condition currently dictate use. Involvement from surgical societies is necessary to establish guidelines for preoperative testing.
Annals of surgery 08/2012; 256(3):518-28. · 7.90 Impact Factor
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Jing Li,
Jun Song,
Margaret G Cassidy,
Piotr Rychahou,
Marlene E Starr,
Jianyu Liu,
Xin Li,
Garretson Epperly,
Heidi L Weiss, Courtney M Townsend,
Tianyan Gao,
B Mark Evers
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ABSTRACT: Neurotensin (NT), an intestinal peptide secreted from N cells in the small bowel, regulates a variety of physiological functions of the gastrointestinal tract, including secretion, gut motility, and intestinal growth. The class IA phosphatidylinositol 3-kinase (PI3K) family, which comprised of p110 catalytic (α, β and δ) and p85 regulatory subunits, has been implicated in the regulation of hormone secretion from endocrine cells. However, the underlying mechanisms remain poorly understood. In particular, the role of PI3K in intestinal peptide secretion is not known. Here, we show that PI3K catalytic subunit, p110α, negatively regulates NT secretion in vitro and in vivo. We demonstrate that inhibition of p110α, but not p110β, induces NT release in BON, a human endocrine cell line, which expresses NT mRNA and produces NT peptide in a manner analogous to N cells, and QGP-1, a pancreatic endocrine cell line that produces NT peptide. In contrast, overexpression of p110α decreases NT secretion. Consistently, p110α-inhibition increases plasma NT levels in mice. To further delineate the mechanisms contributing to this effect, we demonstrate that inhibition of p110α increases NT granule trafficking by up-regulating α-tubulin acetylation; NT secretion is prevented by overexpression of HDAC6, an α-tubulin deacetylase. Moreover, ras-related protein Rab27A (a small G protein) and kinase D-interacting substrate of 220 kDa (Kidins220), which are associated with NT granules, play a negative and positive role, respectively, in p110α-inhibition-induced NT secretion. Our findings identify the critical role and novel mechanisms for the PI3K signaling pathway in the control of intestinal hormone granule transport and release.
Molecular Endocrinology 06/2012; 26(8):1380-93. · 4.54 Impact Factor
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ABSTRACT: The role of intraoperative cholangiography (IOC) in prevention of common bile duct (CBD) injuries and the management of CBD stones is controversial, and current variation in use of IOC has not been well described.
Multilevel hierarchical models using data from the Texas Hospital Inpatient Discharge Public Use data files (2001 to 2008) were used to evaluate the percentage of variance in the use of IOC that was attributable to patient, surgeon, and hospital factors.
A total of 176,981 cholecystectomies were performed in 212 hospitals in Texas. There was wide variation in IOC use, ranging from 2.4% to 98.4% of cases among surgeons and 3.7% to 94.8% of cases among hospitals, even after adjusting for case mix differences. The percentage of variance in IOC use attributable to the surgeon was 20.7% and an additional 25.7% was attributable to the hospital. IOC use was associated with increased age, gallstone pancreatitis or CBD stones, Hispanic race, decreased illness severity, insurance, and later year of cholecystectomy. ERCP (24.0% vs 14.9%, p < 0.0001) and CBD exploration (1.63% vs 0.42%, p < 0.0001) were more commonly performed in patients undergoing IOC.
Uncertainty regarding the benefit of IOC leads to wide variation in use across surgeons and hospitals. The surgeon and hospital are more important determinants of IOC use than measured patient characteristics. Our study highlights the need for further evaluation of comparative effectiveness of IOC in the prevention of CBD injuries and retained stones, taking into account patient risk factors, surgeon skill, cost, and availability of local expertise.
Journal of the American College of Surgeons 02/2012; 214(4):668-79; discussion 679-81. · 4.55 Impact Factor
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Xiyun Deng,
Yanna Cao,
Yan Liu,
Fazhi Li,
Kamalanathan Sambandam,
Srinivasan Rajaraman,
Archibald S Perkins,
Alan P Fields,
Mark R Hellmich, Courtney M Townsend,
E Aubrey Thompson,
Tien C Ko
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ABSTRACT: Human colorectal cancer (CRC) cells are resistant to the anti-proliferative effect of transforming growth factor-β (TGF-β), suggesting that disruption of TGF-β signaling plays an important role in colorectal carcinogenesis. Ecotropic virus integration site-1 (Evi-1) oncoprotein represses TGF-β signaling by interacting with Smads, but its role in CRC has not been established. The purpose of this study is to determine whether Evi-1 plays role(s) in CRCs and to characterize Evi-1 transcript(s) in CRCs. Evi-1 was overexpressed in 53% of human CRC samples, 100% of colon adenoma samples, and 100% of human colon cancer cell lines tested. Using 5' RACE, we cloned a novel Evi-1 transcript (Evi-1e) from a human CRC tissue and found that this novel transcript was expressed at a higher level in CRC tissues than in normal tissues and was the major Evi-1 transcript in CRCs. Transient Evi-1 transfection inhibited TGF-β-induced transcriptional activity and reversed the growth inhibitory effect of TGF-β in MC-26 mouse colon cancer cells. In conclusion, we have identified overexpression of Evi-1 oncoprotein as a novel mechanism by which a subset of human CRCs may escape TGF-β regulation. We have also identified a novel Evi-1 transcript, Evi-1e, as the major Evi-1 transcript expressed in human CRCs. © 2011 Wiley Periodicals, Inc.
Molecular Carcinogenesis 12/2011; · 3.16 Impact Factor
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ABSTRACT: The recommended therapy for mild gallstone pancreatitis is cholecystectomy on initial hospitalization.
Using a 5% national Medicare sample (1996-2005), we evaluated adherence to current recommendations for gallstone pancreatitis (cholecystectomy rates on initial hospitalization and the use of endoscopic retrograde cholangiopancreatography [ERCP]/sphincterotomy). We evaluated predictors of cholecystectomy, gallstone-related readmissions, and 2-year mortality.
Adherence to current guidelines was low. Only 57% of 8,452 Medicare beneficiaries presenting to an acute care hospital with a first episode of mild gallstone pancreatitis underwent cholecystectomy on initial hospitalization. Of the patients who did not undergo cholecystectomy, 55% were never evaluated by a surgeon. Likewise, only 28% of patients who did not undergo cholecystectomy had a sphincterotomy. The 2-year readmission rates were higher among patients who did not undergo cholecystectomy (44% vs 4%; P < .0001), and 33% of these patients required cholecystectomy after discharge. In the no cholecystectomy group, ERCP prevented readmissions (hazard ratio, 0.53; 95% confidence interval, 0.47-0.61) and when readmissions occurred they were less likely to be for gallstone pancreatitis in patients who had an ERCP (27.8% vs 53.2%; P < .0001). On multivariate analysis, patients who were older, black, admitted to a nonsurgical service, lived in certain US regions, and had specific comorbidities were less likely to undergo cholecystectomy.
Adherence to current recommendations for the management of mild gallstone pancreatitis is low in older patients. Our data suggest that >40% of patients who did not undergo cholecystectomy would have benefited from early definitive therapy. Implementation of policies to increase adherence to guidelines would prevent gallstone-related morbidity and mortality in older patients.
Surgery 09/2011; 150(3):515-25. · 3.10 Impact Factor
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ABSTRACT: When compared with ultrasound, CT scans are more expensive, have substantial radiation exposure and lower sensitivity, specificity, positive, and negative predictive values for patients with gallstone disease.
We reviewed data on patients emergently admitted with complicated gallstone disease between January 2005 and May 2010. Use of CT and ultrasound imaging on admission was described. Multivariate logistic regression was used to evaluate factors predicting receipt of CT.
Five hundred and sixty-two consecutive patients presented emergently with complicated gallstone disease. Mean age was 45 years. Seventy-two percent of patients were female, 46% were white, and 41% were Hispanic. Seventy-two percent of patients had an ultrasound during the initial evaluation and 41% had a CT. Both studies were performed in 25% of patients (n = 141), 16% (n = 93) had CT only, and 47% (n = 259) had ultrasound only. CT was performed first in 67% of those who underwent both studies. Evening imaging (7 PM-7 AM, odds ratio [OR] = 4.44; 95% CI, 2.88-6.85), increased age (OR = 1.14 per 5-year increase; 95% CI, 1.07-1.21), leukocytosis (OR = 1.67; 95% CI, 1.10-2.53), and hyperamylasemia (OR = 2.02; 95% CI, 1.16-3.51) predicted use of CT.
Our study demonstrates the overuse of CT in evaluation of complicated gallstone disease. Evening imaging was the biggest predictor of CT use, suggesting that CT is performed not to clarify the diagnosis, but rather a surrogate for the indicated study. Surgeons and emergency physicians should be trained to perform right upper quadrant ultrasound to avoid unnecessary studies in the appropriate clinical setting.
Journal of the American College of Surgeons 08/2011; 213(4):524-30. · 4.55 Impact Factor
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ABSTRACT: The mammalian target of rapamycin (mTOR) signaling exists in two complexes: mTORC1 and mTORC2. Neurotensin (NT), an intestinal hormone secreted by enteroendocrine (N) cells in the small bowel, has important physiological effects in the gastrointestinal tract. The human endocrine cell line BON abundantly expresses the NT gene and synthesizes and secretes NT in a manner analogous to that of N cells. Here, we demonstrate that the inhibition of mTORC1 by rapamycin (mTORC1 inhibitor), torin1 (both mTORC1 and mTORC2 inhibitor) or short hairpin RNA-mediated knockdown of mTOR, regulatory associated protein of mTOR (RAPTOR), and p70 S6 kinase (p70S6K) increased basal NT release via upregulating NT gene expression in BON cells. c-Jun activity was increased by rapamycin or torin1 or p70S6K knockdown. c-Jun overexpression dramatically increased NT promoter activity, which was blocked by PD98059, an mitogen-activated protein kinase kinase (MEK) inhibitor. Furthermore, overexpression of MEK1 or extracellular signal-regulated kinase 1 (ERK1) increased c-Jun expression and NT promoter activity. More importantly, PD98059 blocked rapamycin- or torin1-enhanced NT secretion. Consistently, rapamycin and torin1 also increased NT gene expression in Hep3B cells, a human hepatoma cell line that, similar to BON, expresses high levels of NT. Phosphorylation of c-Jun and ERK1/2 was also increased by rapamycin and torin1 in Hep3B cells. Finally, we showed activation of mTOR in BON cells treated with amino acids, high glucose, or serum and, concurrently, the attenuation of ERK1/2 and c-Jun phosphorylation and NT secretion. Together, mTORC1, as a nutrient sensor, negatively regulates NT secretion via the MEK/ERK/c-Jun signaling pathway. Our results identify a physiological link between mTORC1 and MEK/ERK signaling in controlling intestinal hormone gene expression and secretion.
AJP Cell Physiology 04/2011; 301(1):C213-26. · 3.54 Impact Factor
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ABSTRACT: Carcinoid tumors are associated with the carcinoid syndrome, a set of symptoms resulting from the peptide and amine products, including serotonin, secreted from the cancer cells. The purpose of this study was to investigate the relationship between the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) inhibitor PTEN (phosphatase and tensin homolog deleted on chromosome ten) and serotonin synthesis and secretion in the carcinoid cancer cell line BON.
PTEN was inhibited by pharmacological and molecular approaches, and the resultant secretion of serotonin and expression of tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme in serotonin synthesis, was assessed.
Inhibition of PTEN in vitro, with concomitant increased Akt signaling, resulted in decreased secretion of serotonin, as well as decreased serotonin synthesis, as confirmed by reduced expression of TPH1. Inhibition of PTEN in BON cells in an animal model resulted in decreased serum serotonin.
By inhibiting signaling through Akt, PTEN indirectly promotes serotonin synthesis and secretion.
Anticancer research 04/2011; 31(4):1153-60. · 1.73 Impact Factor
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ABSTRACT: Carcinoid tumors are slow growing and highly vascular neuroendocrine neoplasms that are increasing in incidence. Previously, we showed that carcinoid tumors express vascular endothelial growth factor receptor 2 (VEGFR-2) in the epithelial compartment of carcinoid tumor sections; yet, its role is not completely understood. The purpose of our study was to: (i) assess the expression of VEGFR-2 in the novel human carcinoid cell line BON, (ii) to determine the role of PI3K/Akt signaling on VEGFR-2 expression and (iii) to assess the effect of VEGFR-2 on BON cell invasion, migration and proliferation. We found that, although VEGFR-2 is expressed in BON cells, reduction in VEGFR-2 expression actually enhanced proliferation, invasion, and migration of the BON cell line. Also, expression of VEGFR-2 was inversely related to PI3K signaling. Carcinoid liver metastases in mice demonstrated decreased VEGFR-2 expression. Furthermore, the expression of a truncated, soluble form of VEGFR-2 (sVEGFR-2), a protein demonstrated to inhibit cell growth, was detected in BON cells. The presence of VEGFR-2 in the epithelial component of carcinoid tumors and in the BON cell line suggests an alternate role for VEGFR-2, in addition to its well-defined role in angiogenesis. The expression of sVEGFR-2 may explain the inverse relationship between VEGFR-2 expression and PI3K/Akt signaling and the inhibitory effect VEGFR-2 has on BON cell proliferation, migration and invasion.
International Journal of Cancer 03/2011; 128(5):1045-56. · 5.44 Impact Factor
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ABSTRACT: To evaluate time trends in surgical resection rates and operative mortality in older adults diagnosed with locoregional pancreatic cancer and to determine the effect of age on surgical resection rates and 2-year survival after surgical resection.
Retrospective cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) and linked Medicare claims database (1992-2005).
Secondary data analysis of population-based tumor registry and linked claims data.
Medicare beneficiaries aged 66 and older diagnosed with locoregional pancreatic cancer (N=9,553), followed from date of diagnosis to time of death or censorship.
Percentage of participants undergoing surgical resection, 30-day operative mortality after resection, and 2-year survival according to age group.
Surgical resection rates increased significantly, from 20% in 1992 to 29% in 2005, whereas 30-day operative mortality rates decreased from 9% to 5%. After controlling for multiple factors, participants were less likely to be resected with older age. Resection was associated with lower hazard of death, regardless of age, with hazard ratios of 0.46, 0.51, 0.47, 0.43, and 0.35 for resected participants younger than 70, 70 to 74, 75 to 79, 80 to 84, and 85 and older respectively compared with unresected participants younger than 70 (P<.001).
With older age, fewer people with pancreatic cancer undergo surgical resection, even after controlling for comorbidity and other factors. This study demonstrated increased resection rates over time in all age groups, along with lower surgical mortality rates. Despite previous reports of greater morbidity and mortality after pancreatic resection in older adults, the benefit of resection does not diminish with older age in selected people.
Journal of the American Geriatrics Society 03/2011; 59(4):647-54. · 3.74 Impact Factor
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ABSTRACT: Dietary fiber intake links to decreased risk of colorectal cancers. The underlying mechanisms remain unclear. Recently, we found that butyrate, a short-chain fatty acid produced in gut by bacterial fermentation of dietary fiber, enhances TGF-β signaling in rat intestinal epithelial cells (RIE-1). Furthermore, TGF-β represses inhibitors of differentiation (Ids), leading to apoptosis. We hypothesized that dietary fiber enhances TGF-β's growth inhibitory effects on gut epithelium via inhibition of Id2. In this study, Balb/c and DBA/2N mice were fed with a regular rodent chow or supplemented with a dietary fiber (20% pectin) and Smad3 level in gut epithelium was measured. In vitro, RIE-1 cells were treated with butyrate and TGF-β(1), and cell functions were evaluated. Furthermore, the role of Ids in butyrate- and TGF-β-induced growth inhibition was investigated. We found that pectin feeding increased Smad3 protein levels in the jejunum (1.47 ± 0.26-fold, P = 0.045, in Balb/c mice; 1.49 ± 0.19-fold, P = 0.016, in DBA/2N mice), and phospho-Smad3 levels (1.92 ± 0.27-fold, P = 0.009, in Balb/c mice; 1.83 ± 0.28-fold, P = 0.022, in DBA/2N mice). Butyrate or TGF-β alone inhibited cell growth and induced cell cycle arrest. The combined treatment of butyrate and TGF-β synergistically induced cell cycle arrest and apoptosis in RIE-1 cells and repressed Id2 and Id3 levels. Furthermore, knockdown of Id2 gene expression by use of small interfering RNA caused cell cycle arrest and apoptosis. We conclude that dietary fiber pectin enhanced Smad3 expression and activation in the gut. Butyrate and TGF-β induced cell cycle arrest and apoptosis, which may be mediated by repression of Id2. Our results implicate a novel mechanism of dietary fiber in reducing the risk of colorectal cancer development.
AJP Gastrointestinal and Liver Physiology 03/2011; 301(1):G156-64. · 3.43 Impact Factor
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ABSTRACT: Evidence-based guidelines recommend cholecystectomy during initial hospitalization for complicated gallstone disease. Previous studies and quality initiative data from our institution demonstrated that only 40% to 75% of patients underwent cholecystectomy on index admission.
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, and readmission rates in prepathway (January 2005 to February 2008) and postpathway patients (January 2009 to May 2010).
Demographic and clinical characteristics were similar between prepathway (n = 455) and postpathway 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 2 groups. For patients undergoing cholecystectomy on initial hospitalization, the mean length of stay 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). Thirty-three percent of prepathway and 10% of postpathway 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.
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.
Journal of the American College of Surgeons 03/2011; 212(5):835-43. · 4.55 Impact Factor
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ABSTRACT: Expression of the gene encoding neurotensin/neuromedin N (NT/N) is mostly limited to the brain and specialized enteroendocrine N cells in the distal small intestine. We have identified key regulatory elements in the promoter region that are involved in human NT/N (hNT/N) gene expression in the novel human endocrine cell line, BON, which resembles intestinal N cells in several important aspects including NT/N precursor protein processing, ratios of different NT/N mRNA isoforms, and high levels of constitutive expression of the NT/N gene. In this study, we demonstrated multiple cis-regulatory elements including a proximal region containing a cAMP-responsive element (CRE)/AP-1-like element that binds both the AP-1 and CRE-binding protein (CREB)/ATF proteins (c-Jun, ATF-1, ATF-2, JunD, and CREB). Similar to the rat NT/N gene, this region is critical for constitutive hNT/N gene expression. Moreover, we identified a novel region that binds the orphan hormone receptor, NR2F2. We have demonstrated that the C terminus of NR2F2 strongly represses hNT/N transcription, whereas an N-terminal domain antagonizes this repressive effect. Regulation of NT/N expression by NR2F2 may have important consequences for lipid metabolism. We speculate that a complex interplay between the proximal CRE/AP-1-like motif and NR2F2 binding region exists to regulate hNT/N expression, which is critical for the high level of constitutive expression of NT/N in enteroendocrine cells. Finally, the BON cell line provides a unique model to characterize the factors regulating expression of the hNT/N gene and to better understand the mechanisms responsible for terminal differentiation of the N cell lineage in the gut.
Journal of Biological Chemistry 10/2010; 286(1):542-54. · 4.77 Impact Factor
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ABSTRACT: Cholecystectomy during initial hospitalization is the current recommended therapy for acute cholecystitis. The rate of cholecystectomy and subsequent health care trajectory in elderly patients with acute cholecystitis has not been evaluated.
We used 5% national Medicare sample claims data from 1996 to 2005 to identify a cohort of patients aged 66 years and older, requiring urgent or emergent admission for acute cholecystitis. We evaluated cholecystectomy rates on initial hospitalization, factors independently predicting receipt of cholecystectomy, factors predicting further gallstone-related complications, and 2-year survival in the cholecystectomy and no cholecystectomy groups in univariate and multivariate models.
There were 29,818 Medicare beneficiaries who were urgently or emergently admitted for acute cholecystitis from 1996 to 2005. Mean age was 77.7 +/- 7.3 years, 89% of patients were white, and 58% were female. Twenty-five percent of patients did not undergo cholecystectomy during the index admission. Lack of definitive therapy was associated with a 27% subsequent cholecystectomy rate and a 38% gallstone-related readmission rate in the 2 years after discharge; the readmission rate was only 4% in patients undergoing cholecystectomy (p < 0.0001). No cholecystectomy on initial hospitalization was associated with worse 2-year survival (hazard ratio 1.56, 95% CI 1.47 to 1.65) even after controlling for patient demographics and comorbidities. Readmissions led to an additional $7,000 in Medicare payments per readmission.
Our study demonstrated that 25% of cholecystectomies on Medicare beneficiaries were not performed on initial hospitalization, leading to readmissions in 38% of surviving patients. For patients requiring readmission, the percentage of open procedures was increased, and the additional Medicare payment was $7,000 per re-admission. Cholecystectomy for acute cholecystitis in elderly patients should be performed during initial hospitalization to prevent recurrent episodes of cholecystitis, multiple readmissions, higher readmission rates, and increased costs.
Journal of the American College of Surgeons 05/2010; 210(5):668-77, 677-9. · 4.55 Impact Factor
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ABSTRACT: Previous studies have demonstrated that black patients with pancreatic cancer are less likely to undergo resection and have worse overall survival compared with white patients. The objective of this study was to determine whether these disparities occur at the point of surgical evaluation or after evaluation has taken place.
The authors used the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data (1992-2002) to compare black patients and white patients with locoregional pancreatic cancer in univariate models. Logistic regression was used to determine the effect of race on surgical evaluation and on surgical resection after evaluation. Cox proportional hazards models were used to identify which factors influenced 2-year survival.
Nine percent of 3777 patients were black. Blacks were substantially less likely than whites to undergo evaluation by a surgeon (odds ratio, 0.57; 95% confidence interval, 0.42-0.77) when the model was adjusted for demographics, tumor characteristics, surgical evaluation, socioeconomic status, and year of diagnosis. Patients who were younger and who had fewer comorbidities, abdominal imaging, and a primary care physician were more likely to undergo surgical evaluation. Once they were seen by a surgeon, blacks still were less likely than whites to undergo resection (odds ratio, 0.64; 95% confidence interval, 0.49-0.84). Although black patients had decreased survival in an unadjusted model, race no longer was significant after accounting for resection.
Twenty-nine percent of black patients with potentially resectable pancreatic cancers never received surgical evaluation. Without surgical evaluation, patients cannot make an informed decision and will not be offered resection. Attaining higher rates of surgical evaluation in black patients would be the first step to eliminating the observed disparity in the resection rate.
Cancer 02/2010; 116(4):930-9. · 4.77 Impact Factor
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ABSTRACT: To improve safety in the operating theater, a company of aviation pilots was employed to guide implementation of preprocedural briefings. A 5-point Likert scale survey that assessed the attitudes of operating room personnel toward patient safety was distributed before and 6 months following implementation of the briefings. Using Mann-Whitney analysis, the survey showed a significant (P < .05) improvement in 2 questions (of 13) involving reporting error and 2 questions (of 11) involving patient safety climate. When analyzed by occupation, there were no significant changes for faculty physicians; for resident physicians, there was a significant improvement in 1 question (of 13) regarding error reporting. For nurses, there were significant improvements in 3 questions (of 4) involving teamwork, 1 question (of 13) involving reporting error, and 3 questions (of 11) regarding patient safety climate. These results suggest that aviation-based crew resource management initiatives lead to an improved perception of patient safety, which was largely demonstrated by nursing personnel.
American Journal of Medical Quality 12/2009; 25(1):60-3. · 1.64 Impact Factor
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ABSTRACT: Mammalian intestinal epithelium undergoes continuous cell turn over, with cell proliferation in the crypts and apoptosis in the villus. Both transforming growth factor (TGF)-beta and gastrin-releasing peptide (GRP) are involved in the regulation of intestinal epithelial cells for division, differentiation, adhesion, migration and death. Previously, we have shown that TGF-beta and bombesin (BBS) synergistically induce cyclooxygenase-2 (COX-2) expression and subsequent prostaglandin E(2) (PGE2) production through p38(MAPK) in rat intestinal epithelial cell line stably transfected with GRP receptor (RIE/GRPR), suggesting the interaction between TGF-beta signaling pathway and GRPR. The current study examined the biological responses of RIE/GRPR cells to TGF-beta and BBS. Treatment with TGF-beta1 (40 pM) and BBS (100 nM) together synergistically inhibited RIE/GRPR growth and induced apoptosis. Pretreatment with SB203580 (10 microM), a specific inhibitor of p38(MAPK), partially blocked the synergistic effect of TGF-beta and BBS on apoptosis. In conclusion, BBS enhanced TGF-beta growth inhibitory effect through apoptosis induction, which is at least partially mediated by p38(MAPK).
Regulatory Peptides 08/2009; 158(1-3):26-31. · 2.11 Impact Factor
