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1.  Are Current Law Enforcement Strategies Associated with a Lower Risk of Repeat Speeding Citations and Crash Involvement? A Longitudinal Study of Speeding Maryland Drivers 
Annals of epidemiology  2011;21(9):641-647.
To determine whether traffic court appearances and different court verdicts were associated with risk of subsequent speeding citations and crashes.
A cohort of 29,754 Maryland drivers ticketed for speeding who either went to court or paid fines by mail in May/June 2003 was followed for 3 years. Drivers appearing in court were categorized by verdicts: 1) not guilty, 2) suspension of prosecution/no prosecution (STET/NP), 3) case dismissed, 4) probation before judgment and fines (PBJ), or 5) fines and demerit points. Cox proportional hazard models were used to estimate adjusted hazard ratios (AHR).
Court appearances were associated with lower risk of subsequent speeding citations (AHR = 0.92; 95% CI: 0.88-0.96), but higher risk of crashes (AHR=1.25; 95% CI: 1.16-1.35). PBJ was associated with significantly lower repeat speeding tickets (AHR = 0.83; 95% CI = 0.75-0.91) and a non-significant decrease in crashes (AHR = 0.87; 95% CI 0.75-1.02). Both repeat speeding tickets and subsequent crashes were significantly lower in the STET/NP group.
PBJ and STET/NP may reduce speeding and crashes, but neither verdict eliminated excess crash risk among drivers who choose court appearances. Randomized controlled evaluations of speeding countermeasures are needed to inform traffic safety policies.
PMCID: PMC3915799  PMID: 21684176
traffic accidents; safety; risk factors; speeding; motor vehicle crashes; law enforcement
2.  Nonalcoholic fatty liver disease is associated with benign gastrointestinal disorders 
AIM: To explore associations between nonalcoholic fatty liver disease (NAFLD) and benign gastrointestinal and pancreato-biliary disorders.
METHODS: Patient demographics, diagnoses, and hospital outcomes from the 2010 Nationwide Inpatient Sample were analyzed. Chronic liver diseases were identified using International Classification of Diseases, the 9th Revision, Clinical Modification codes. Patients with NAFLD were compared to those with other chronic liver diseases for the endpoints of total hospital charges, disease severity, and hospital mortality. Multivariable stepwise logistic regression analyses to assess for the independent association of demographic, comorbidity, and diagnosis variables with the event of NAFLD (vs other chronic liver diseases) were also performed.
RESULTS: Of 7800441 discharge records, 32347 (0.4%) and 271049 (3.5%) included diagnoses of NAFLD and other chronic liver diseases, respectively. NAFLD patients were younger (average 52.3 years vs 55.3 years), more often female (58.8% vs 41.6%), less often black (9.6% vs 18.6%), and were from higher income areas (23.7% vs 17.7%) compared to counterparts with other chronic liver diseases (all P < 0.0001). Diabetes mellitus (43.4% vs 28.9%), hypertension (56.9% vs 47.6%), morbid obesity (36.9% vs 8.0%), dyslipidemia (37.9% vs 15.6%), and the metabolic syndrome (28.75% vs 8.8%) were all more common among NAFLD patients (all P < 0.0001). The average total hospital charge ($39607 vs $51665), disease severity scores, and intra-hospital mortality (0.9% vs 6.0%) were lower among NALFD patients compared to those with other chronic liver diseases (all P < 0.0001).Compared with other chronic liver diseases, NAFLD was significantly associated with diverticular disorders [OR = 4.26 (3.89-4.67)], inflammatory bowel diseases [OR = 3.64 (3.10-4.28)], gallstone related diseases [OR = 3.59 (3.40-3.79)], and benign pancreatitis [OR = 2.95 (2.79-3.12)] on multivariable logistic regression (all P < 0.0001) when the latter disorders were the principal diagnoses on hospital discharge. Similar relationships were observed when the latter disorders were associated diagnoses on hospital discharge.
CONCLUSION: NAFLD is associated with diverticular, inflammatory bowel, gallstone, and benign pancreatitis disorders. Compared with other liver diseases, patients with NAFLD have lower hospital charges and mortality.
PMCID: PMC3857453  PMID: 24363521
Nationwide inpatient sample; Nonalcoholic fatty liver disease; Chronic liver disease; Diverticular disease; Pancreatitis; Gallstones; Inflammatory bowel disease
3.  Associations differ by sex for catechol-O-methyltransferase genotypes and bladder cancer risk in South Egypt✰ 
Urologic oncology  2011;30(6):841-847.
To examine associations between urinary bladder cancer risk and polymorphisms of the gene encoding the catechol estrogen-metabolizing enzyme, catechol-O-methyltransferase (COMT), among Egyptian women and men.
Materials and methods
We used questionnaire and genotype data from a case-control study in Egypt. This analysis focused on South Egypt cases with confirmed urothelial (UC) or squamous cell (SCC) carcinoma of the bladder, and controls frequency-matched on sex, 5-year age-group, and residence governorate. Real-time PCR on blood specimen DNA was used to determine COMT genotypes encoding for Val/Val, Val/Met, and Met/Met, the enzyme forms associated with high, intermediate, or low activity, respectively.
The study sample, which included 255 women and 666 men, consisted of 394 cases with histologically confirmed UC (225) or SCC (n=169), and 527 controls. The odds of having either type of bladder cancer was lower among men with genotypes encoding Val/Met or Met/Met than among those with the genotype encoding Val/Val, even after adjustment for other factors, such as smoking and schistosomiasis history [adjusted odds ratio (AOR): 0.64; 95% confidence interval (CI): 0.43, 0.96]; however, the association was statistically significant for SCC (AOR 0.57; 95% CI: 0. 34, 0.96) but marginal for UC (AOR: 0.64; 95% CI: 0.39, 1.02). No significant associations were detected between bladder cancer risk and COMT genotypes among postmenopausal women.
These findings suggest that, even after controlling for established risk factors, the involvement of COMT genotypes in bladder cancer risk differs among men compared to women in South Egypt.
PMCID: PMC3146583  PMID: 21397529
Catechol-O-methyltransferase gene polymorphism; Urinary bladder cancer; Smoking; Schistosomiasis; Sex differences; Egypt
4.  Different Involvement of Promoter Methylation in the Expression of Organic Cation/Carnitine Transporter 2 (OCTN2) in Cancer Cell Lines 
PLoS ONE  2013;8(10):e76474.
Organic cation/carnitine transporter 2 (OCTN2) is responsible for the cellular uptake of the antineoplastic agent, oxaliplatin. Epigenetic modification is a possible mechanism of altered drug-transporter expression in cancers, leading to altered efficacy of chemotherapeutic drugs. However, the mechanisms governing OCTN2 regulation are not completely understood. In this study, the low levels of OCTN2 in HepG2 and LS174T cells were elevated by the demethylating reagent, decitabine (DCA). To further reveal the epigenetic mechanism of down-regulation of OCTN2, we found that Region-1 within the OCTN2 promoter (spanning −354 to +85) was a determinant of OCTN2 expression in a luciferase reporter assay. Moreover, methylation-specific PCR (MSP) and bisulfite genomic sequencing showed that the degree of individual methylated CpG sites within this region was inversely correlated with the levels of OCTN2 in different cancer cells. Application of DCA to HepG2 and LS174T cells reversed the hypermethylation status of the OCTN2 promoter and increased OCTN2 expression, enhancing cellular uptake of oxaliplatin. Thus, we identified that promoter methylation is responsible for epigenetic down-regulation of OCTN2 in HepG2 and LS174T cells. Given the essential role of OCTN2 in cancer cell uptake of chemotherapeutics, and thus treatment efficacy, pretreatment with a demethylating reagent is a possible strategy for optimizing pharmacotherapies against cancers.
PMCID: PMC3797819  PMID: 24146874
5.  Health-related quality of life and survival in Chinese patients with chronic liver disease 
To investigate the relationship between health-related quality of life (HRQOL) and survival in Chinese patients with chronic liver disease (CLD).
HRQOL was measured with the Chinese version of Short Form 36 (SF-36). SF-36 scores, demographic and clinical data were collected at baseline and after 18 months follow-up. Kaplan-Meier and Cox Proportional Hazard Regression survival analyses were used for interpretation of data. Surviving patients were censored in the analyses.
A total of 415 Chinese patients with CLD and 86 healthy controls were enrolled. During the follow-up period 50 patients died. SF-36 scores in healthy controls and surviving patients were higher compared with those in deceased patients. Scores of physical component summary (PCS) in healthy controls, surviving and deceased patients were 54.1 ± 5.2, 48.9 ± 7.7 and 33.5 ± 8.2 respectively (p < 0.001). Scores of mental component summary (MCS) in healthy controls, surviving and deceased patients were 56.6 ± 8.2, 53.0 ± 5.6 and 37.1 ± 12.1 (p < 0.001) respectively. Survival was significantly associated with PCS and MCS scores, and the presence of ascites.
HRQOL was associated with survival in patients with CLD. PCS and MCS scores were predictors of survival.
PMCID: PMC3734055  PMID: 23902894
Health-related quality of life; Chronic liver disease; SF-36; Survival
6.  Chronic kidney disease as an under-recognized threat to patient safety 
Chronic kidney disease (CKD) is common, but under-recognized, among patients in the health care system, where improving patient safety is a high priority. Poor disease recognition and several other features of CKD make it a high risk condition for adverse safety events. In this review, we will discuss the unique attributes of CKD, which make it a high risk condition for patient safety mishaps. We will point out that adverse safety events in this disease have the potential to contribute to disease progression; namely, accelerated loss of kidney function and an increased incidence of end-stage renal disease (ESRD). We will also propose a framework in which to consider patient safety in CKD, highlighting the need for disease-specific safety indicators that reflect unsafe practices in this disease. Finally, we will discuss the hypothesis that increased recognition of CKD will reduce disease-specific safety events, and in this way decrease the likelihood of adverse outcomes including an accelerated rate of kidney function loss and an increased incidence of ESRD.
PMCID: PMC3710448  PMID: 19246142
patient safety; chronic kidney disease; disease recognition; medical errors
7.  The influence of creatinine versus GFR on NSAID prescriptions in CKD 
American journal of nephrology  2012;36(1):19-26.
Non-steroidal anti-inflammatory drugs (NSAIDs), including cyclo-oxygenase-2 (COX-2) inhibitors, are generally contraindicated in chronic kidney disease (CKD). This investigation sought to identify the frequency of NSAID/COX2 prescription and determine the influence of serum Cr versus estimated GFR on this practice pattern.
An established Veterans Health Administration (VHA) CKD safety cohort (n = 70,154) was examined to determine the frequency of NSAID/COX2 in fiscal year 2005 (FY05) for up to 30 days preceding the index hospitalization and as many as 365 days during that year. Binomial regression was used to determine adjusted prevalence ratios for prescription of NSAID/COX2 with respect to continuous eGFR measurement and serum creatinine (Cr) categories. CKD was defined as eGFR < 60 ml/min/1.73m2.
15.4% of subjects had an NSAID/COX2 prescription during the observation period with the proportion prescribed these agents decreasing with declining renal function, but remained significant at any stage of CKD given the renal harm related to these medications. At specific GFR estimates, serum creatinine (Cr) remained a significant predictor of NSAID/COX prescription. At GFR set at 42 ml/min/1.73, the predicted proportion prescribed NSAID/COX2 was 0.29 (95% CI: 0.24,0.36); 0.23 (95% CI: 0.22,0.26); 0.20 (95%: 0.19,0,22); 0.12 (95% CI: 0.10,0.14) for Cr strata of ≤ 1.3 mg/dl, 1.4 – 1.6 mg/dl, 1.7 –2.1 mg/dl, ≥ 2.2 mg/dl, respectively (all p < 0.05).
A significant proportion of individuals with CKD continue to be prescribed NSAID/COX2 and serum Cr remains an influential guide to NSAID/COX2 prescription, even in GFR ranges where these agents are ill-advised.
PMCID: PMC3417055  PMID: 22699456
chronic kidney disease; safety; recognition; NSAIDs
8.  Association between Methicillin-Resistant Staphylococcus aureus Colonization and Infection May Not Differ by Age Group 
We assessed whether age modified the association between methicillin-resistant Staphylococcus aureus (MRSA) anterior nares colonization and subsequent infection. Among 7,405 patients (9,511 admissions), MRSA colonization was significantly associated with infection (adjusted odds ratio, 13.7 [95% confidence interval, 7.3–25.7]) but did not differ significantly by age group.
PMCID: PMC3677581  PMID: 23221199
9.  Prolonged Colonization with the Methicillin-Resistant Staphylococcus aureus Strain USA300 among Residents of Extended Care Facilities 
We performed a retrospective cohort study (n = 129) to assess whether residents of extended care facilities who were initially colonized or infected with the methicillin-resistant Staphylococcus aureus (MRSA) strain USA300 were less likely to have prolonged colonization than were residents colonized or infected with other MRSA strains. We found no difference in prolonged colonization (adjusted odds ratio, 1.1 [95% confidence interval, 0.5–2.4]).
PMCID: PMC3677585  PMID: 20569116
10.  Comparison of the Methicillin-Resistant Staphylococcus aureus Acquisition among Rehabilitation and Nursing Home Residents 
To assess risk factors for methicillin-resistant Staphylococcus aureus (MRSA) acquisition among extended care residents focusing on level of care (residential vs rehabilitation) and room placement with an MRSA-positive resident.
Prospective cohort study.
Extended care units at 2 healthcare systems in Maryland.
Four hundred forty-three residents with no history of MRSA and negative MRSA surveillance cultures of the anterior nares and areas of skin breakdown at enrollment.
Follow-up cultures were collected every 4 weeks and/or at discharge for a period of 12 weeks. Study data were collected by a research nurse from the medical staff and the electronic medical records. Cox proportional hazards modeling was used to calculate adjusted hazards ratios (aHRs) and 95% confidence intervals (CIs).
. Residents in rehabilitation care had 4-fold higher risk of MRSA acquisition compared with residents in residential care (hazard ratio [HR], 4. [95% CI, 2.2–8.8]). Being bedbound was significantly associated with MRSA acquisition in both populations (residential care, aHR, 4.3 [95% CI, 1.5–12.2]; rehabilitation care, aHR, 4.8 [95% CI, 1.2–18.7]). Having an MRSA-positive roommate was not significantly associated with acquisition in either population (residential care, aHR, 1.4 [95% CI, 0.5–3.9]; rehabilitation care, aHR, 0.5 [95% CI, 0.1–2.2]); based on concordant spa typing, only 2 of 8 residents who acquired MRSA and had room placement with an MRSA-positive resident acquired their MRSA isolate from their roommate.
Residents in rehabilitation care appear at higher risk and have different risk factors for MRSA acquisition compared to those in residential care.
PMCID: PMC3677603  PMID: 21460509
11.  Risk of Acquiring Extended-Spectrum β-Lactamase–Producing Klebsiella Species and Escherichia coli from Prior Room Occupants in the Intensive Care Unit 
To quantify the association between admission to an intensive care unit (ICU) room most recently occupied by a patient positive for extended-spectrum β-lactamase (EBSL)–producing gram-negative bacteria and acquisition of infection or colonization with that pathogen.
Retrospective cohort study.
The study included patients admitted to medical and surgical ICUs of an academic medical center between September 1, 2001, and June 30, 2009.
Perianal surveillance cultures were obtained at admission to the ICU, weekly, and at discharge from the ICU. Patients were included if they had culture results that were negative for ESBL-producing gram-negative bacteria at ICU admission and had an ICU length of stay longer than 48 hours. Pulsed-field gel electrophoresis (PFGE) was performed on ESBL-positive isolates from patients who acquired the same bacterial species (eg, Klebsiella species or Escherichia coli) as the previous room occupant.
Among 9,371 eligible admissions (7,651 unique patients), 267 (3%) involved patients who acquired an ESBL-producing pathogen in the ICU; of these patients, 32 (12%) were hospitalized in a room in which the prior occupant had been positive for ESBL. Logistic regression results suggested that the prior occupant's ESBL status was not significantly associated with acquisition of an ESBL-producing pathogen (adjusted odds ratio, 1.39 [95% confidence interval, 0.94–2.08]) after adjusting for colonization pressure and antibiotic exposure in the ICU. PFGE results suggested that 6 (18%) of 32 patients acquired a bacterial strain that was the same as or closely related to the strain obtained from the prior occupant.
These data suggest that environmental contamination may not play a substantial role in the transmission of ESBL-producing pathogens among ICU patients. Intensifying environmental decontamination may be less effective than other interventions in preventing transmission of ESBL-producing pathogens.
PMCID: PMC3660030  PMID: 23571360
12.  Association of Serial Measures of Cardiac Troponin T Using a Sensitive Assay With Incident Heart Failure and Cardiovascular Mortality in Older Adults 
Older adults comprise the majority of new-onset heart failure (HF) diagnoses, but traditional risk-factor prediction models have limited accuracy in this population to identify those at highest risk for hospitalization or death.
To determine if cardiac troponin T (cTnT) measured by a highly sensitive assay would be detectable in the majority of community-dwelling older adults, and if serial measures were associated with risk of HF hospitalization and cardiovascular death.
Design, Setting, and Participants
A longitudinal nationwide cohort study (Cardiovascular Health Study) of 4221 community-dwelling adults aged 65 years or older without prior HF who had cTnT measured using a highly sensitive assay at baseline (1989–1990) and repeated after 2 to 3 years (n = 2918).
Main Outcome Measures
New-onset HF and cardiovascular death were examined through June 2008 with respect to cTnT concentrations, accounting for clinical risk predictors.
Cardiac troponin T was detectable (≥3.00 pg/mL) in 2794 participants (66.2%). During a median follow-up of 11.8 years, 1279 participants experienced new-onset HF and 1103 cardiovascular deaths occurred, with a greater risk of both end points associated with higher cTnT concentrations. Among those participants with the highest cTnT concentrations (>12.94 pg/mL), there was an incidence rate per 100 person-years of 6.4 (95% confidence interval [CI], 5.8–7.2; adjusted hazard ratio [aHR], 2.48; 95% CI, 2.04–3.00) for HF and an incidence rate of 4.8 (95% CI, 4.3–5.4; aHR, 2.91; 95% CI, 2.37–3.58) for cardiovascular death compared with participants with undetectable cTnT levels (incidence rate, 1.6; 95% CI, 1.4–1.8 and 1.1; 95% CI, 0.9–1.2 for HF and cardiovascular death, respectively). Among individuals with initially detectable cTnT, a subsequent increase of more than 50% (n = 393, 22%) was associated with a greater risk for HF (aHR, 1.61; 95% CI, 1.32–1.97) and cardiovascular death (aHR, 1.65; 95% CI, 1.35–2.03) and a decrease of more than 50% (n = 247, 14%) was associated with a lower risk for HF (aHR, 0.73; 95% CI, 0.54–0.97) and cardiovascular death (aHR, 0.71; 95% CI, 0.52–0.97) compared with participants with 50% or less change. Addition of baseline cTnT measurements to clinical risk factors was associated with only modest improvement in discrimination, with change in C statistic of 0.015 for HF and 0.013 for cardiovascular death.
In this cohort of older adults without known HF, baseline cTnT levels and changes in cTnT levels measured with a highly sensitive assay were significantly associated with incident HF and cardiovascular death.
PMCID: PMC3559101  PMID: 21078811
13.  The frequency of hyperkalemia and its significance in chronic kidney disease 
Archives of internal medicine  2009;169(12):1156-1162.
Hyperkalemia is a potential threat to patient safety in chronic kidney disease (CKD). This study determined the incidence of hyperkalemia in CKD and whether it is associated with excess mortality.
This retrospective analysis of a national cohort comprised of 2,103,422 records from 245,808 veterans with at least one hospitalization and at least one inpatient or outpatient serum potassium record during fiscal year 2005. CKD and treatment with ACE-I and/or ARBs (RAAS blockers) were the key predictors of hyperkalemia. Death within one day of a hyperkalemic event was the principal outcome.
Of the 66,529 hyperkalemic events (3.2% of records), more occurred inpatient (34937 (52.7%)) versus outpatient (31322 (47.3%)). The adjusted rate of hyperkalemia was higher in patients with CKD than without CKD among individuals treated with RAAS blockers (7.67 vs. 2.30 per 100 patient months, p<0.0001) and those without RAAS blocker treatment (8.22 vs. 1.77 per 100 patient months, p<0.0001). The adjusted odds (OR) of death with a moderate (K+≥ 5.5 and < 6.0mg/dl) and severe (K+≥ 6.0 mg/dl) hyperkalemic event was highest with no CKD (OR: 10.32, 31.64, respectively), versus Stage 3 (5.35, 19.52), Stage 4 (OR: 5.73, 11.56), or Stage 5 CKD (OR: 2.31, 8.02) with all p<0.0001 versus normokalemia and no CKD.
The risk of hyperkalemia is increased with CKD, and its occurrence increases the odds of mortality within one day of the event. These findings underscore the importance of this metabolic disturbance as a threat to patient safety in CKD.
PMCID: PMC3544306  PMID: 19546417
chronic kidney disease; hyperkalemia; patient safety
14.  Left ventricular ejection fraction assessment in older adults: An adjunct to natriuretic peptide testing to identify risk of new onset heart failure and cardiovascular death? 
Determine whether assessment of left ventricular ejection fraction (LVEF) enhances prediction of new onset heart failure (HF) and cardiovascular mortality over and above N-terminal pro–B-type natriuretic peptide (NT-proBNP) level in older adults.
Elevated NT-proBNP levels are common in older adults and associated with increased risk of HF.
NT-proBNP and LVEF were measured in 4,137 older adults free of HF. Repeat measures of NT-proBNP were performed 2–3 years later and echocardiography was repeated 5 years later (n=2,375) with a median follow-up of 10.7 years. The addition of an abnormal (<55%) LVEF (n=317 [7.7%]) to initially elevated or rising NT-proBNP levels was evaluated to determine risk of HF or cardiovascular mortality. Change in NT-proBNP levels were also assessed for estimating the risk of conversion from a normal to abnormal LVEF.
For participants with a low baseline NT-proBNP level (<190 pg/mL) (n=2,918), addition of an abnormal LVEF didn’t improve the estimation of risk of HF and identified a moderate increase in adjusted risk for cardiovascular mortality (HR 1.69; 95%CI: 1.22 to 2.31). Among those whose NT-proBNP subsequently increased ≥ 25% to ≥190 pg/mL, an abnormal LVEF was likewise associated with an increased risk of cardiovascular mortality but not HF. Participants with an initially high NT-proBNP (≥190 pg/mL) were at greater risk overall for both outcomes, and those with an abnormal LVEF were at the highest risk. However, an abnormal LVEF did not improve model classification or risk stratification for either endpoint when added to demographic factors and change in NT-proBNP. An initially elevated NT-proBNP or rising level was associated with an increased risk of developing an abnormal LVEF.
Assessment of LVEF in HF free older adults based on NT-proBNP levels should be considered on an individual basis, as such assessments do not routinely improve prognostication.
PMCID: PMC3540778  PMID: 21939835
Elderly; heart failure; echocardiography; natriuretic peptides; outcomes
15.  A study of mifepristone/IFN-γ-induced apoptosis of human cholangiocarcinoma cell line FRH-0201 in vitro 
OncoTargets and therapy  2012;5:335-342.
To investigate the effects of mifepristone, a progesterone receptor (PR) antagonist, through the proliferation of human cholangiocarcinoma cell line FRH-0201 in vitro and the possible mechanisms involved.
A two-step addition of poly-HRP anti-mouse immunoglobulin G detection system was used to detect the expression of PR in FRH-0201 cells. After treatments with various concentrations of mifepristone (10, 20, 40, 80, 160, and 320 μmol/L) at various time intervals (24, 48, and 72 hours), the rate of cell inhibition, the rate of cell apoptosis, and the expression of bax/bcl-2/Fas were analyzed with tetrazolium blue (MTT) assay, flow cytometry, reverse transcription polymerase chain reaction and Western blotting. The effect of mifepristone and mifepristone combined with interferon (IFN)-γ-inducing apoptosis on the cells was observed.
Mifepristone remarkably inhibited the proliferation of FRH-0201 cells, which was revealed by MTT assay in a dose- and time-dependent manner. The inhibitory rate gradually increased following the increase of the dosage of mifepristone from a low dosage (10 μmol/L) to a high dosage (320 μmol/L) at different time intervals. Flow cytometry analysis showed mifepristone increased the rate of the FRH-0201 cell-line apoptosis. Notably, the rate of apoptosis increased markedly when the cells were pretreated with IFN-γ and then treated with mifepristone. In addition, mifepristone obviously upregulated bax and Fas expression and downregulated bcl-2 expression.
Mifepristone effectively inhibited the growth of PR-positive human cholangiocarcinoma cell line FRH-0201 in vitro through multiple mechanisms. Mifepristone combined with IFN-γ might therefore induce the apoptosis of the cell line, which is possibly a beneficial clinical scheme for patients suffering from cholangiocarcinoma.
PMCID: PMC3497892  PMID: 23180967
cholangiocarcinoma; apoptosis; mifepristone; progesterone; IFN-γ
16.  Estrogen exposure and bladder cancer risk in Egyptian women 
Maturitas  2010;67(4):353-357.
To examine associations between reproductive history and urinary bladder cancer in Egyptian women.
We used questionnaire data from an ongoing, multicenter case-control study in Egypt. Controls were matched on age and residence area. This analysis focused on female cases with confirmed urothelial (UC) and squamous cell (SCC) carcinoma of the bladder.
We recruited 779 women (540 controls, 239 cases; >98.0% nonsmokers). Younger age at menopause (<45 y) and older age at first pregnancy (>18 y) were factors significantly associated with increased risk of bladder cancer, even after adjusting for schistosomiasis history and other covariates in the multivariable logistic model; adjusted odds ratio and 95% confidence intervals were 1.98 (1.41, 2.77) and 6.26 (3.46, 11.34), respectively. On the other hand, multiple pregnancies or use of oral contraceptives were associated with decreased odds of having bladder cancer. Similar associations were observed with UC and SCC when analyzed separately; however, the magnitude of association with SCC was lower than with UC.
Our data suggest that early estrogen exposure, or the relative lack of it, plays a role in urinary bladder carcinoma development among Egyptian women.
PMCID: PMC3433170  PMID: 20813471
estrogen; bladder cancer; Egypt; epidemiology; risk factors
17.  Systematic Review of Measurement and Adjustment for Colonization Pressure in Studies of Methicillin-Resistant Staphylococcus aureus, Vancomycin-Resistant Enterococci, and Clostridium difficile Acquisition 
Colonization pressure is an important infection control metric. The aim of this study was to describe the definition and measurement of and adjustment for colonization pressure in nosocomial-acquisition risk factor studies of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and Clostridium difficile.
We performed a computerized search of studies of nosocomial MRSA, VRE, and C. difficile acquisition published before July 1, 2009, through MEDLINE. Studies were included if a study outcome was MRSA, VRE, or C. difficile acquisition; the authors identified risk factors associated with MRSA, VRE, or C. difficile acquisition; and the study measured colonization pressure.
The initial MEDLINE search yielded 505 articles. Sixty-six of these were identified as studies of nosocomial MRSA, VRE, or C. difficile acquisition; of these, 18 (27%) measured colonization pressure and were included in the final review. The definition of colonization pressure varied considerably between studies: the proportion of MRSA- or VRE-positive patients (5 studies), the proportion of MRSA- or VRE-positive patient-days (6 studies), or the total or mean number of MRSA-, VRE-, or C. difficile–positive patients or patient-days (7 studies) in the unit over periods of varying length. In 10 of 13 studies, colonization pressure was independently associated with MRSA, VRE, or C. difficile acquisition.
There is a need for a simple and consistent method to quantify colonization pressure in both research and routine clinical care to accurately assess the effect of colonization pressure on cross-transmission of antibiotic-resistant bacteria.
PMCID: PMC3383663  PMID: 21515979
18.  A mouse model for interstitial cystitis/painful bladder syndrome based on APF inhibition of bladder epithelial repair: a pilot study 
BMC Urology  2012;12:17.
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic bladder disorder with bladder epithelial thinning or ulceration, pain, urinary frequency and urgency. There is no reliably effective therapy for IC/PBS, and no generally accepted animal model for the disorder in which potential therapies can be tested. Bladder epithelial cells from IC/PBS patients make a small glycopeptide antiproliferative factor or "APF" that inhibits proliferation, decreases tight junction protein expression, increases paracellular permeability, and induces changes in gene expression of bladder epithelial cells in vitro that mimic abnormalities in IC/PBS patient biopsy specimens in vivo. We therefore determined the ability of a synthetic APF derivative to inhibit bladder epithelial repair in mice.
The bladder epithelium of female CBA/J mice was stripped by transurethral infusion of 3% acetic acid, and mice were subsequently treated daily with one of three intravesical treatments [synthetic as-APF, inactive unglycosylated control peptide, or phosphate buffered saline carrier (PBS)] for 1–21 days. Fixed bladder sections were either stained with haematoxylin and eosin for determination of epithelial area by image analysis, or incubated with anti-uroplakin III (UPIII) or anti-zonula occludens type 1 (ZO-1) antibodies for immunofluorescence microscopy. Epithelial measurement data were analyzed by a two-way analysis of variance (ANOVA); post hoc comparisons of multiple groups were carried out using the Tukey-Kramer method.
Bladder epithelial repair was significantly attenuated in as-APF-treated mice as compared to control mice on days 3–21 (p < 0.05); the mean epithelial/total area over all measured days was also significantly lower in as-APF-treated mice vs. mice in either control group by post hoc analysis (p < 0.0001 for both comparisons). UPIII and ZO-1 expression was also decreased in as-APF-treated mice as compared to mice in either control group by day 7 (UPIII) or day 14 (ZO-1).
This model demonstrates in vivo effects of as-APF which abrogates bladder epithelial repair and expression of UPIII and ZO-1 in CBA/J mice following transurethral acetic acid infusion. As bladder epithelial thinning, decreased UPIII expression, and decreased ZO-1 expression are histopathologic features of IC/PBS patient biopsies, this model may be useful for studying the pathophysiology of IC/PBS and the effect of potential therapies.
PMCID: PMC3459789  PMID: 22682521
Interstitial cystitis; Painful bladder syndrome; Mouse model
19.  Patient Understanding of Diabetes Self-Management: Participatory Decision-Making in Diabetes Care 
Our aim was to determine whether patient participation in decision-making about diabetes care is associated with understanding of diabetes self-management and subsequent self-care practices. We also identified issues that would impact messaging for use in mobile diabetes communication.
Research Design and Methods:
A cross-sectional observational study was conducted with type 2 diabetes patients (n = 81) receiving their care at the University of Maryland Joslin Diabetes Center. A convenience sample of patients were eligible to participate if they were aged 25–85 years, had type 2 diabetes, spoke English, and visited their physician diabetes manager within the past 6 months. In-person patient interviews were conducted at the time of clinic visits to assess patient understanding of diabetes management, self-care practices, and perceptions of participation in decision-making about diabetes care.
African Americans reported fewer opportunities to participate in decision-making than Caucasians, after controlling for education [mean difference (MD) = -2.4, p = .02]. This association became insignificant after controlling for patient–physician race concordance (MD = -1.5, p = .21). Patient understanding of self-care was predicted by having greater than high school education (MD = 3.6, p = .001) and having physicians who involved them in decision-making about their care. For each unit increase in understanding of diabetes self-care, the mean patient self-care practice score increased by 0.16 (p = .003), after adjustment for patient race and education.
Patient participation in decision-making is associated with better understanding of care. Participation in decision-making plays a key role in patient understanding of diabetes self-management and subsequent self-care practices. Patients with limited education need specific instruction in foot care, food choices, and monitoring hemoglobin A1c.
PMCID: PMC3192639  PMID: 21722588
literacy; mobile; participatory; self-care
20.  Bacillus anthracis-derived edema toxin (ET) counter-regulates movement of neutrophils and macromolecules through the endothelial paracellular pathway 
BMC Microbiology  2012;12:2.
A common finding amongst patients with inhalational anthrax is a paucity of polymorphonuclear leukocytes (PMNs) in infected tissues in the face of abundant circulating PMNs. A major virulence determinant of anthrax is edema toxin (ET), which is formed by the combination of two proteins produced by the organism, edema factor (EF), which is an adenyl cyclase, and protective antigen (PA). Since cAMP, a product of adenyl cyclase, is known to enhance endothelial barrier integrity, we asked whether ET might decrease extravasation of PMNs into tissues through closure of the paracellular pathway through which PMNs traverse.
Pretreatment of human microvascular endothelial cell(EC)s of the lung (HMVEC-L) with ET decreased interleukin (IL)-8-driven transendothelial migration (TEM) of PMNs with a maximal reduction of nearly 60%. This effect required the presence of both EF and PA. Conversely, ET did not diminish PMN chemotaxis in an EC-free system. Pretreatment of subconfluent HMVEC-Ls decreased transendothelial 14 C-albumin flux by ~ 50% compared to medium controls. Coadministration of ET with either tumor necrosis factor-α or bacterial lipopolysaccharide, each at 100 ng/mL, attenuated the increase of transendothelial 14 C-albumin flux caused by either agent alone. The inhibitory effect of ET on TEM paralleled increases in protein kinase A (PKA) activity, but could not be blocked by inhibition of PKA with either H-89 or KT-5720. Finally, we were unable to replicate the ET effect with either forskolin or 3-isobutyl-1-methylxanthine, two agents known to increase cAMP.
We conclude that ET decreases IL-8-driven TEM of PMNs across HMVEC-L monolayers independent of cAMP/PKA activity.
PMCID: PMC3277462  PMID: 22230035
21.  Differential Macrophage Polarization Promotes Tissue Remodeling and Repair in a Model of Ischemic Retinopathy 
Scientific Reports  2011;1:76.
Diabetic retinopathy is the leading cause of visual loss in individuals under the age of 55. Umbilical cord blood (UCB)–derived myeloid progenitor cells have been shown to decrease neuronal damage associated with ischemia in the central nervous system. In this study we show that UCB-derived CD14+ progenitor cells provide rescue effects in a mouse model of ischemic retinopathy by promoting physiological angiogenesis and reducing associated inflammation. We use confocal microscopy to trace the fate of injected human UCB-derived CD14+ cells and PCR with species-specific probes to investigate their gene expression profile before and after injection. Metabolomic analysis measures changes induced by CD14+ cells. Our results demonstrate that human cells differentiate in vivo into M2 macrophages and induce the polarization of resident M2 macrophages. This leads to stabilization of the ischemia-injured retinal vasculature by modulating the inflammatory response, reducing oxidative stress and apoptosis and promoting tissue repair.
PMCID: PMC3216563  PMID: 22355595
22.  Diagnosis of lung cancer in individuals with solitary pulmonary nodules by plasma microRNA biomarkers 
BMC Cancer  2011;11:374.
Making a definitive preoperative diagnosis of solitary pulmonary nodules (SPNs) found by CT has been a clinical challenge. We previously demonstrated that microRNAs (miRNAs) could be used as biomarkers for lung cancer diagnosis. Here we investigate whether plasma microRNAs are useful in identifying lung cancer among individuals with CT-detected SPNs.
By using quantitative reverse transcriptase PCR analysis, we first determine plasma expressions of five miRNAs in a training set of 32 patients with malignant SPNs, 33 subjects with benign SPNs, and 29 healthy smokers to define a panel of miRNAs that has high diagnostic efficiency for lung cancer. We then validate the miRNA panel in a testing set of 76 patients with malignant SPNs and 80 patients with benign SPNs.
In the training set, miR-21 and miR-210 display higher plasma expression levels, whereas miR-486-5p has lower expression level in patients with malignant SPNs, as compared to subjects with benign SPNs and healthy controls (all P ≤ 0.001). A logistic regression model with the best prediction was built on the basis of miR-21, miR-210, and miR-486-5p. The three miRNAs used in combination produced the area under receiver operating characteristic curve at 0.86 in distinguishing lung tumors from benign SPNs with 75.00% sensitivity and 84.95% specificity. Validation of the miRNA panel in the testing set confirms their diagnostic value that yields significant improvement over any single one.
The plasma miRNAs provide potential circulating biomarkers for noninvasively diagnosing lung cancer among individuals with SPNs, and could be further evaluated in clinical trials.
PMCID: PMC3175224  PMID: 21864403
23.  Increased Circulating Level of the Survival Factor GP88 (Progranulin) in the Serum of Breast Cancer Patients When Compared to Healthy Subjects 
GP88 (PC-Cell Derived Growth Factor, progranulin) is a glycoprotein overexpressed in breast tumors and involved in their proliferation and survival. Since GP88 is secreted, an exploratory study was established to compare serum GP88 level between breast cancer patients (BC) and healthy volunteers (HV).
An IRB approved prospective study enrolled 189 stage 1–4 BC patients and 18 HV. GP88 serum concentration was determined by immunoassay.
Serum GP88 level was 28.7 + 5.8 ng/ml in HV and increased to 40.7 + 16.0 ng/ml (P = 0.007) for stage 1–3 and 45.3 + 23.3 ng/ml (P = 0.0007) for stage 4 BC patients. There was no correlation between the GP88 level and BC characteristics such as age, race, tumor grade, ER, PR and HER-2 expression.
These data suggest that serial testing of serum GP88 levels may have value as a circulating biomarker for detection, monitoring and follow up of BC.
PMCID: PMC3140268  PMID: 21792312
progranulin; GP88; breast cancer; biomarker
24.  Gender, Alcohol Consumption Patterns, and Engagement in Sexually Intimate Behaviors Among Adolescents and Young Adults in Nha Trang, Viet Nam 
Youth & society  2011;43(1):118-141.
A randomly selected cross-sectional survey was conducted with 880 youth (16 to 24 years) in Nha Trang City to assess relationships between alcohol consumption and sexual behaviors. A timeline followback method was employed. Chi-square, generalized logit modeling and logistic regression analyses were performed. Of the sample, 78.2% male and 56.1% female respondents ever consumed alcohol. Males reporting sexual behaviors (vaginal, anal, oral sex) had a significantly higher calculated peak BAC of 0.151 compared to 0.082 for males reporting no sexual intimacy (p < .0001). Females reporting sexual behaviors had a peak BAC of 0.072 compared to 0.027 for those reporting no sexual intimacy (p = .016). Fifty percent of (33/66) males and 30.4% (7/23) females report event specific drinking and engagement in sexual behaviors. Males reporting 11+ drinks in 30 days had more sexual partners than those reporting 1 to 10 drinks (p = .037). Data suggest different physical and psychosocial mediators between alcohol consumption and sexual behaviors by gender.
PMCID: PMC3045200  PMID: 21373363
adolescent; alcohol use; sexual behaviors
25.  Altered miRNA Expression in Sputum for Diagnosis of Non-small Cell Lung Cancer 
Analysis of molecular genetic markers in biological fluids has been proposed as a useful tool for cancer diagnosis. MicroRNAs (miRNAs) are small regulatory RNAs that are frequently dysregulated in lung cancer and have shown promise as tissue-based markers for its prognostication. The aim of this study was to determine whether aberrant miRNA expression can be used as a marker in sputum specimen for the diagnosis of non-small cell lung cancer (NSCLC). Experimental Design: Expressions of mature miRNAs, mir-21 and mir-155, were examined by real-time reverse transcription polymerase chain reaction (RT-PCR) and normalized to that of control miRNA, U6B, in sputum of 23 patients with NSCLC and 17 cancer-free subjects. The data was compared with conventional sputum cytology for the diagnosis of lung cancer. All endogenous miRNAs were present in sputum in a remarkably stable form and sensitively and specifically detected by real-time RT-PCR. Mir-21 expression in the sputum specimens was significantly higher in cancer patients (76.32 ± 9.79) than cancer-free individuals (62.24±3.82) (p<0.0001). Furthermore, overexpression of mir-21 showed highly discriminative receiver-operator characteristic (ROC) curve profile, clearly distinguishing cancer patients from cancer-free subjects with areas under the ROC curve at 0.902 ± 0.054. Detection of mir-21 expression produced 69.66% sensitivity and 100.00% specificity in diagnosis of lung cancer, as compared with 47.82% sensitivity and 100.00% specificity by sputum cytology. The measurement of altered miRNA expression in sputum could be a useful noninvasive approach for the diagnosis of lung cancer.
PMCID: PMC2846426  PMID: 19446359
MicroRNA; sputum; lung cancer; real-time RT-PCR; diagnosis

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