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1.  Leprosy Drug Resistance Surveillance in Colombia: The Experience of a Sentinel Country 
PLoS Neglected Tropical Diseases  2016;10(10):e0005041.
An active search for Mycobacterium leprae drug resistance was carried out, 243 multibacillary patients from endemic regions of Colombia were included from 2004 to 2013 in a surveillance program. This program was a World Health Organization initiative for drug resistance surveillance in leprosy, where Colombia is a sentinel country. M. leprae DNA from slit skin smear and/or skin biopsy samples was amplified and sequenced to identify mutations in the drug resistance determining region (DRDR) in rpoB, folP1, gyrA, and gyrB, the genes responsible for rifampicin, dapsone and ofloxacin drug-resistance, respectively. Three isolates exhibited mutations in the DRDR rpoB gene (Asp441Tyr, Ser456Leu, Ser458Met), two in the DRDR folP1 gene (Thr53Ala, Pro55Leu), and one isolate exhibited mutations in both DRDR rpoB (Ser456Met) and DRDR folP1 (Pro55Leu), suggesting multidrug resistance. One isolate had a double mutation in folP1 (Thr53Ala and Thr88Pro). Also, we detected mutations outside of DRDR that required in vivo evaluation of their association or not with drug resistance: rpoB Arg505Trp, folP1 Asp91His, Arg94Trp, and Thr88Pro, and gyrA Ala107Leu. Seventy percent of M. leprae mutations were related to drug resistance and were isolated from relapsed patients; the likelihood of relapse was significantly associated with the presence of confirmed resistance mutations (OR range 20.1–88.7, p < 0.05). Five of these relapsed patients received dapsone monotherapy as a primary treatment. In summary, the current study calls attention to M. leprae resistance in Colombia, especially the significant association between confirmed resistance mutations and relapse in leprosy patients. A high frequency of DRDR mutations for rifampicin was seen in a region where dapsone monotherapy was used extensively.
Author Summary
Mycobacterium leprae drug resistance is cause of surveillance due to the increase of leprosy relapsed cases. World Health Organization initiative for drug resistance surveillance in leprosy included Colombia, a country considered in post-elimination stage, as a sentinel country. During 10 years (2004–20013) an active search for M. leprae drug resistance was carried out in volunteer patients (each of whom signed a consent form) recruited from a convenience sample of patients diagnosed with leprosy in fourteen departments of Colombia: Amazonas, Antioquia, Atlántico, Bolívar, Caquetá, Cesar, Cundinamarca, Chocó, Huila, Magdalena, Norte de Santander, Santander, Tolima, and Valle. 243 multibacillary patients in various stages of multi drug therapy (MDT) were enrolled with the aim to search for primary and secondary M. leprae drug resistance: 33 new patients before treatment, 136 currently undergoing MDT with not clinical improvement of lesions after three months or more of MDT, 36 post-MDT with positive bacillary index (BI) persistence, 4 non-adherent to MDT, and 34 relapsed cases. M. leprae DNA from patient´s samples was tested to identify mutations in the drug resistance determining region (DRDR) in rpoB, folP1, gyrA, and gyrB, the genes responsible for rifampicin, dapsone and ofloxacin drug-resistance, respectively. We obtained isolates that exhibited mutations in the DRDR, three in rpoB gene, two in folP1 gene, and one isolate exhibited mutations in both rpoB and folP1, suggesting multidrug resistance. One isolate had a double mutation in folP1. Also, we detected mutations outside of DRDR that required in vivo test validation. 70% of M. leprae confirmed resistance mutations were isolated from relapsed patients (OR range 20.1–88.7, p < 0.05). Five of these relapsed patients received dapsone monotherapy as a primary treatment. The current study calls attention to M. leprae resistance in Colombia, especially the significant association between confirmed resistance mutations and relapsed in leprosy patients.
PMCID: PMC5051701  PMID: 27706165
2.  Using Innovative Acoustic Analysis to Predict the Postoperative Outcomes of Unilateral Vocal Fold Paralysis 
BioMed Research International  2016;2016:7821415.
Objective. Autologous fat injection laryngoplasty is ineffective for some patients with iatrogenic vocal fold paralysis, and additional laryngeal framework surgery is often required. An acoustically measurable outcome predictor for lipoinjection laryngoplasty would assist phonosurgeons in formulating treatment strategies. Methods. Seventeen thyroid surgery patients with unilateral vocal fold paralysis participated in this study. All subjects underwent lipoinjection laryngoplasty to treat postsurgery vocal hoarseness. After treatment, patients were assigned to success and failure groups on the basis of voice improvement. Linear prediction analysis was used to construct a new voice quality indicator, the number of irregular peaks (NIrrP). It compared with the measures used in the Multi-Dimensional Voice Program (MDVP), such as jitter (frequency perturbation) and shimmer (perturbation of amplitude). Results. By comparing the [i] vowel produced by patients before the lipoinjection laryngoplasty (AUC = 0.98, 95% CI = 0.78–0.99), NIrrP was shown to be a more accurate predictor of long-term surgical outcomes than jitter (AUC = 0.73, 95% CI = 0.47–0.91) and shimmer (AUC = 0.63, 95% CI = 0.37–0.85), as identified by the receiver operating characteristic curve. Conclusions. NIrrP measured using the LP model could be a more accurate outcome predictor than the parameters used in the MDVP.
PMCID: PMC5050388  PMID: 27738634
3.  Intravenous Thrombolysis after Reversal of Dabigatran by Idarucizumab: A Case Report 
Case Reports in Neurology  2016;8(2):140-144.
We describe a 75-year-old female patient with nonvalvular atrial fibrillation who presented with acute ischemic stroke during treatment with dabigatran 2 × 110 mg per day. After informed consent, we reversed the anticoagulant effects of dabigatran using idarucizumab and applied an intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (off-label use). An intracerebral hemorrhage was excluded after systemic thrombolysis. Despite the IVT, the patient's clinical condition deteriorated and she developed an ischemic lesion in the right pons, the right thalamus and right cerebellum. To date, the literature lacks data concerning the thrombolytic treatment of acute ischemic stroke in patients after specific reversal of the non-vitamin K oral anticoagulant dabigatran using idarucizumab. Given the rapid and sustainable efficacy of idarucizumab, the reversal of dabigatran followed by thrombolysis seems to be safe, but further studies and register data are still needed to confirm our preliminary observation, especially to provide additional data concerning the risk-benefit evaluation.
PMCID: PMC4945814  PMID: 27482196
Atrial fibrillation; Embolic stroke; Non-vitamin K oral anticoagulants; Dabigatran; Idarucizumab; Intravenous thrombolysis
4.  The Alpha-1A Adrenergic Receptor in the Rabbit Heart 
PLoS ONE  2016;11(6):e0155238.
The alpha-1A-adrenergic receptor (AR) subtype is associated with cardioprotective signaling in the mouse and human heart. The rabbit is useful for cardiac disease modeling, but data on the alpha-1A in the rabbit heart are limited. Our objective was to test for expression and function of the alpha-1A in rabbit heart. By quantitative real-time reverse transcription PCR (qPCR) on mRNA from ventricular myocardium of adult male New Zealand White rabbits, the alpha-1B was 99% of total alpha-1-AR mRNA, with <1% alpha-1A and alpha-1D, whereas alpha-1A mRNA was over 50% of total in brain and liver. Saturation radioligand binding identified ~4 fmol total alpha-1-ARs per mg myocardial protein, with 17% alpha-1A by competition with the selective antagonist 5-methylurapidil. The alpha-1D was not detected by competition with BMY-7378, indicating that 83% of alpha-1-ARs were alpha-1B. In isolated left ventricle and right ventricle, the selective alpha-1A agonist A61603 stimulated a negative inotropic effect, versus a positive inotropic effect with the nonselective alpha-1-agonist phenylephrine and the beta-agonist isoproterenol. Blood pressure assay in conscious rabbits using an indwelling aortic telemeter showed that A61603 by bolus intravenous dosing increased mean arterial pressure by 20 mm Hg at 0.14 μg/kg, 10-fold lower than norepinephrine, and chronic A61603 infusion by iPRECIO programmable micro Infusion pump did not increase BP at 22 μg/kg/d. A myocardial slice model useful in human myocardium and an anthracycline cardiotoxicity model useful in mouse were both problematic in rabbit. We conclude that alpha-1A mRNA is very low in rabbit heart, but the receptor is present by binding and mediates a negative inotropic response. Expression and function of the alpha-1A in rabbit heart differ from mouse and human, but the vasopressor response is similar to mouse.
PMCID: PMC4892533  PMID: 27258143
5.  Improving Rates of Influenza Vaccination Through Electronic Health Record Portal Messages, Interactive Voice Recognition Calls and Patient-Enabled Electronic Health Record Updates: Protocol for a Randomized Controlled Trial 
JMIR Research Protocols  2016;5(2):e56.
Clinical decision support (CDS), including computerized reminders for providers and patients, can improve health outcomes. CDS promoting influenza vaccination, delivered directly to patients via an electronic health record (EHR) patient portal and interactive voice recognition (IVR) calls, offers an innovative approach to improving patient care.
To test the effectiveness of an EHR patient portal and IVR outreach to improve rates of influenza vaccination in a large multispecialty group practice in central Massachusetts.
We describe a nonblinded, randomized controlled trial of EHR patient portal messages and IVR calls designed to promote influenza vaccination. In our preparatory phase, we conducted qualitative interviews with patients, providers, and staff to inform development of EHR portal messages with embedded questionnaires and IVR call scripts. We also provided practice-wide education on influenza vaccines to all physicians and staff members, including information on existing vaccine-specific EHR CDS. Outreach will target adult patients who remain unvaccinated for more than 2 months after the start of the influenza season. Using computer-generated randomization and a factorial design, we will assign 20,000 patients who are active users of electronic patient portals to one of the 4 study arms: (1) receipt of a portal message promoting influenza vaccines and offering online appointment scheduling; (2) receipt of an IVR call with similar content but without appointment facilitation; (3) both (1) and (2); or (4) neither (1) nor (2) (usual care). We will randomize patients without electronic portals (10,000 patients) to (1) receipt of IVR call or (2) usual care. Both portal messages and IVR calls promote influenza vaccine completion. Our primary outcome is percentage of eligible patients with influenza vaccines administered at our group practice during the 2014-15 influenza season. Both outreach methods also solicit patient self-report on influenza vaccinations completed outside the clinic or on barriers to influenza vaccination. Self-reported data from both outreach modes will be uploaded into the EHR to increase accuracy of existing provider-directed EHR CDS (vaccine alerts).
With our proposed sample size and using a factorial design, power calculations using baseline vaccination rate estimates indicated that 4286 participants per arm would give 80% power to detect a 3% improvement in influenza vaccination rates between groups (α=.05; 2-sided). Intention-to-treat unadjusted chi-square analyses will be performed to assess the impact of portal messages, either alone or in combination with the IVR call, on influenza vaccination rates. The project was funded in January 2014. Patient enrollment for the project described here completed in December 2014. Data analysis is currently under way and first results are expected to be submitted for publication in 2016.
If successful, this study’s intervention may be adapted by other large health care organizations to increase vaccination rates among their eligible patients.
ClinicalTrial NCT02266277; (Archived by WebCite at
PMCID: PMC4875493  PMID: 27153752
electronic health records; influenza vaccines; clinical decision support; Internet; Telephone; Electronic Mail; Health Records, Personal; Medical Informatics Applications
6.  Using a Mobile App to Promote Smoking Cessation in Hospitalized Patients 
JMIR mHealth and uHealth  2016;4(2):e59.
The potential of interactive health education for preventive health applications has been widely demonstrated. However, use of mobile apps to promote smoking cessation in hospitalized patients has not been systematically assessed.
This study was conducted to assess the feasibility of using a mobile app for the hazards of smoking education delivered via touch screen tablets to hospitalized smokers.
Fifty-five consecutive hospitalized smokers were recruited. Patient sociodemographics and smoking history was collected at baseline. The impact of the mobile app was assessed by measuring cognitive and behavioral factors shown to promote smoking cessation before and after the mobile app use including hazards of smoking knowledge score (KS), smoking attitudes, and stages of change.
After the mobile app use, mean KS increased from 27(3) to 31(3) (P<0.0001). Proportion of patients who felt they “cannot quit smoking” reduced from 36% (20/55) to 18% (10/55) (P<0.03). Overall, 13% (7/55) of patients moved toward a more advanced stage of change with the proportion of patients in the preparation stage increased from 40% (22/55) to 51% (28/55). Multivariate regression analysis demonstrated that knowledge gains and mobile app acceptance did not depend on age, gender, race, computer skills, income, or education level. The main factors affecting knowledge gain were initial knowledge level (P<0.02), employment status (P<0.05), and high app acceptance (P<0.01). Knowledge gain was the main predictor of more favorable attitudes toward the mobile app (odds ratio (OR)=4.8; 95% confidence interval (CI) (1.1, 20.0)). Attitudinal surveys and qualitative interviews identified high acceptance of the mobile app by hospitalized smokers. Over 92% (51/55) of the study participants recommended the app for use by other hospitalized smokers and 98% (54/55) of the patients were willing to use such an app in the future.
Our results suggest that a mobile app promoting smoking cessation is well accepted by hospitalized smokers. The app can be used for interactive patient education and counseling during hospital stays. Development and evaluation of mobile apps engaging patients in their care during hospital stays is warranted.
PMCID: PMC4875494  PMID: 27154792
mobile apps; patient engagement; hospital; smoking cessation; health literacy
7.  Stress, depression and medication nonadherence in diabetes: test of the exacerbating and buffering effects of family support 
Journal of behavioral medicine  2014;38(2):363-371.
Stressors and depressive symptoms have been associated with medication nonadherence among adults with type 2 diabetes (T2DM). We tested whether these associations were exacerbated by obstructive family behaviors or buffered by supportive family behaviors in a sample of 192 adults with T2DM and low socioeconomic status using unadjusted and adjusted regression models. We found support for the exacerbating hypothesis. Stressors and nonadherence were only associated at higher levels of obstructive family behaviors (adjusted interaction OR=1.12, p=.002). Similarly, depressive symptoms and nonadherence were only associated at higher levels of obstructive family behaviors (adjusted interaction OR=3.31, p=.002). When participants reported few obstructive family behaviors, neither stressors nor depressive symptoms were associated with nonadherence. We did not find support for the buffering hypothesis; stressors and depressive symptoms were associated with nonadherence regardless of supportive family behaviors. Nonadherent patients experiencing stressors and/or major depressive symptoms may benefit from interventions that reduce obstructive family behaviors.
PMCID: PMC4355092  PMID: 25420694
Stress/stressors; depression; family support; social support; medication adherence; diabetes
8.  A Meta-Analysis of the Relationship between Social Constraints and Distress in Cancer Patients 
Journal of behavioral medicine  2014;38(2):294-305.
Social constraints on cancer-related disclosure have been associated with increased distress among cancer patients. The goals of this meta-analysis were: (1) to quantify the average strength of the relationships between social constraints and general and cancer-specific distress in cancer patients; and (2) to examine potential moderators of these relationships. A literature search was conducted using electronic databases, and 30 studies met inclusion criteria. Moderate, significant relationships were found between social constraints and both general distress (r=0.37; 95% CI: 0.31-0.43) and cancer-specific distress (r=0.37; 95% CI: 0.31-0.44). The relationship between social constraints and cancer-specific distress was stronger for studies of patients who, on average, had been diagnosed more recently. Relationships between social constraints and both general and cancer-specific distress did not vary by age or gender. Findings suggest that social constraints may be important to target in interventions to reduce distress in cancer patients, especially those who have been recently diagnosed.
PMCID: PMC4355094  PMID: 25262383
cancer; distress; social constraints; social support; meta-analysis
9.  Recommending Self-Paced Exercise among Overweight and Obese Adults: A Randomized Pilot Study 
National guidelines call for exercise of at least moderate intensity; however, recommending self-paced exercise may lead to better adherence, particularly among overweight and obese adults.
Test proof-of-concept for recommending self-paced exercise among overweight adults.
Fifty-nine healthy, low-active (exercise <60 min/week), overweight (Body Mass Index: 25.0-39.9) adults (18-65) received a six-month print-based exercise promotion program with the goal of walking 30-60 min/day. Participants were surreptitiously randomly assigned to receive a recommendation for either self-paced (n=30) or moderate (64-76% maximum heart rate; n=29) intensity exercise. All participants used electronic diaries and heart rate monitors to track exercise frequency, duration, and intensity.
The self-paced condition reported more min/week of walking (f2=0.17, p=.045) and a trend toward greater exercise-related energy expenditure/week (f2=0.12; p=0.243), corresponding to approximately 26 additional min/week and 83 additional kcals/week over six months.
Explicit recommendation for self-paced exercise may improve adherence to exercise programs among overweight and obese adults.
PMCID: PMC4355095  PMID: 25223963
10.  Performance Comparison of 1.5 T Endorectal Coil MRI with Non-Endorectal Coil 3.0 T MRI in Patients with Prostate Cancer 
Academic radiology  2015;22(4):467-474.
Rationale and Objectives
To compare prostate morphology, image quality, and diagnostic performance of 1.5 T endorectal coil MRI and 3.0 T non-endorectal coil MRI in patients with prostate cancer.
Materials and Methods
MR images obtained of 83 patients with prostate cancer using 1.5 T MRI systems with an endorectal coil were compared to images collected from 83 patients with a 3.0 T MRI system. Prostate diameters were measured and image quality was evaluated by one ABR-certified radiologist (Reader 1) and one ABR-certified diagnostic medical physicist (Reader 2). The likelihood of the peripheral zone cancer presence in each sextant and local extent were rated and compared with histopathologic findings.
Prostate anterior-posterior diameter measured by both readers was significantly shorter with 1.5 T endorectal MRI than with 3.0 T MRI. The overall image quality score difference was significant only for Reader 1. Both readers found that the two MRI systems provided similar diagnostic accuracy in cancer localization, extraprostatic extension, and seminal vesicle involvement.
Non-endorectal coil 3.0 T MRI provides prostate images that are natural in shape and that have comparable image quality to those obtained at 1.5 T with an endorectal coil, but not superior diagnostic performance. These findings suggest an opportunity exists for improving technical aspects of 3.0 T prostate MRI.
PMCID: PMC4355101  PMID: 25579637
prostate cancer; magnetic resonance imaging; image quality; endorectal coil; tumor localization; tumor staging
11.  Improvement of anticipatory postural adjustments for balance control: effect of a single training session 
Humans use anticipatory and compensatory postural strategies to maintain and restore balance when perturbed. Inefficient generation and utilization of anticipatory postural adjustments (APAs) is one of the reasons for postural instability. The aim of the study was to investigate the role of training in improvement of APAs and its effect on subsequent control of posture. Thirteen healthy young adults were exposed to predictable external perturbations before and after a single training session consisting of catches of a medicine ball thrown at the shoulder level. 3-D body kinematics, EMG activity of thirteen trunk and leg muscles, and ground reaction forces were recorded before and immediately after a single training session. Muscle onsets, EMG integrals, center of pressure (COP), and center of mass (COM) displacements were analyzed during the anticipatory and compensatory phases of postural control. The effect of a single training session was seen as significantly early muscle onsets and larger anticipatory COP displacements. As a result, significantly smaller peak COM displacements were observed after the perturbation indicating greater postural stability. The outcome of this study provides a background for examining the role of training in improvement of APAs and its effect on postural stability in individuals in need.
PMCID: PMC4355316  PMID: 25434280
balance control; anticipatory postural adjustments; training; ball catching; postural stability; rehabilitation
12.  Structure of Salmonella FlhE, conserved member of a flagellar Type III secretion operon 
Journal of molecular biology  2014;427(6 0 0):1254-1262.
The bacterial flagellum is assembled by a multicomponent transport apparatus categorized as a Type III secretion (T3S) system. The secretion of proteins that assemble into the flagellum is driven by the proton motive force. The periplasmic protein FlhE is a member of the flhBAE operon in the majority of bacteria where FlhE is found. FlhA and FlhB are established components of the flagellar T3S system. The absence of FlhE results in a proton leak through the flagellar system, inappropriate secretion patterns, and cell death, indicating that FlhE regulates an important aspect of proper flagellar biosynthesis. We isolated FlhE from the periplasm of Salmonella and solved its structure to 1.5 Å resolution. Possible roles of FlhE, including that of a chaperone, are discussed.
PMCID: PMC4355100  PMID: 25545591
Flagellar motility; proton motive force; proton leak
13.  The Prevalence of Hepatitis B Virus Among Municipal Solid Waste Workers: Necessity for Immunization of At-Risk Groups 
Hepatitis Monthly  2016;16(3):e30887.
Hepatitis B virus (HBV) is likely to be more prevalent in certain populations and occupational groups, such as municipal solid waste workers (MSWWs).
The current study aimed to estimate the prevalence of HBV and its risk factors among MSWWs compared to other municipal employees not exposed to waste.
Patients and Methods
The current cross-sectional study included 654 municipal employees in Zahedan (south-eastern Iran). A sample of blood was taken from each participant and tested for HBsAg through the enzyme-linked immunosorbent assay (ELISA). Demographic and other data on high risk behaviors were also collected through in-depth interviews. Data were analyzed using chi-square test and multiple regression analysis by STATA.
The overall prevalence of HBV among municipal employees was 3.06% (95% CI: 1.70 - 4.30); however, it varied among the different employee subgroups as follows: 6.20% (95% CI: 2.70 - 9.70) in MSWWs, 3.3% (95% CI: 0.08 - 5.80) in drivers and 1% among staff who were not exposed to waste. Multiple regression analysis showed that exposure to waste [OR = 9.36; 95% CI = 2.01 - 43.7], lack of vaccination against HBV [OR = 3.83; 95% CI = 1.86 - 25.2], jaundice [OR = 6.91; 95% CI = 1.51 - 31.5], history of endoscopy [OR = 2.86; 95% CI = 1.08 - 7.62], and high risk behaviors [OR = 4.80; 95% CI = 1.96 - 27.2] were independently associated with HBV.
Greater encouragement for immunization against HBV as well as better education on HBV transmission routes and work safety precautions should be implemented to reduce the prevalence of HBV in MSWWs.
PMCID: PMC4875503  PMID: 27226797
Hepatitis B; Municipality; Zahedan
14.  Relative Importance of Hepatitis B and C Viruses in Hepatocellular Carcinoma in EMRO Countries and the Middle East: A Systematic Review 
Hepatitis Monthly  2016;16(3):e35106.
Hepatocellular carcinoma (HCC) is the second most common cancer-related death worldwide. Although many factors including dietary aflatoxin B1 (AFB1) and alcoholic and non-alcoholic fatty liver diseases can lead to HCC, globally most HCC cases are due to hepatitis B virus (HBV) and hepatitis C virus (HCV). Considering the importance of these viral factors in most HCC cases and relative lack of literature from eastern Mediterranean region office of world health organization (EMRO) countries and the Middle East, we decided to perform this systematic review to find distribution of viral etiology of HCC in these regions.
Evidence Acquisition
In this systemic review, we included all studies from 1 January 1989 to 1 September 2015 with at least 20 samples that measured HBV surface antigen (HBsAg) and antibodies to HCV (anti-HCV). The authors searched MEDLINE, Embase, Popline, Web of Science and WHO indexed databases. We searched the following MeSH terms; hepatocellular carcinoma, hepatitis B virus and hepatitis C virus or hepacvirus. Only studies using second- and third-generation HCV assays were included. Only articles studying HCC patients from EMRO countries and the Middle East were analyzed. Duplicate results that reported the same cases more than once were found and omitted. Studies in English and Farsi were reviewed. If the study was eligible, we recorded the following data; the first author, publication year and journal, study population and number and percentage of patients with different serologic statuses.
We found 44 studies from 12 countries in EMRO and the Middle East. HCC cases from Iran, Lebanon, Turkey and Yemen were mainly due to HBV, while those of North African nations (Egypt, Tunisia, Morocco, Algeria and Somalia) in addition to Saudi Arabia and Pakistan were mostly HCV related. Sudan showed a high seronegativity and HBV infection in its HCC cases. Unfortunately, some countries from EMRO and the Middle East did not have eligible studies.
HBV and HCV are important culprits of HCC in EMRO countries and the Middle East and different nations need different strategies to tackle them accordingly. Countries with high rates of HBV such as Turkey should continue their HBV vaccination and also increase sanitation. Nations with high HCV rates such as Egypt should maintain their blood product monitoring in addition to increased sanitation, especially regarding injection drug users (IDU).
PMCID: PMC4875504  PMID: 27226803
Carcinoma; Hepatocellular; Hepatitis B Virus; Hepatitis C Virus; Review
15.  Transplantation of Epigenetically Modified Adult Cardiac c-Kit+ Cells Retards Remodeling and Improves Cardiac Function in Ischemic Heart Failure Model 
Stem Cells Translational Medicine  2015;4(9):1086-1096.
The cardiogenic potential of cardiac c-Kit+ cells through class I histone deacetylase (HDAC) inhibition was augmented and their therapeutic potency in the chronic heart failure (CHF) animal model evaluated. The low cell engraftment suggests that paracrine effects might account for the beneficial effects of c-Kit+ cells in CHF. Selective inhibition of class I HDACs induced expression of cardiac markers in c-Kit+ cells and partially augmented their efficacy for CHF repair.
Cardiac c-Kit+ cells have a modest cardiogenic potential that could limit their efficacy in heart disease treatment. The present study was designed to augment the cardiogenic potential of cardiac c-Kit+ cells through class I histone deacetylase (HDAC) inhibition and evaluate their therapeutic potency in the chronic heart failure (CHF) animal model. Myocardial infarction (MI) was created by coronary artery occlusion in rats. c-Kit+ cells were treated with mocetinostat (MOCE), a specific class I HDAC inhibitor. At 3 weeks after MI, CHF animals were retrogradely infused with untreated (control) or MOCE-treated c-Kit+ cells (MOCE/c-Kit+ cells) and evaluated at 3 weeks after cell infusion. We found that class I HDAC inhibition in c-Kit+ cells elevated the level of acetylated histone H3 (AcH3) and increased AcH3 levels in the promoter regions of pluripotent and cardiac-specific genes. Epigenetic changes were accompanied by increased expression of cardiac-specific markers. Transplantation of CHF rats with either control or MOCE/c-Kit+ cells resulted in an improvement in cardiac function, retardation of CHF remodeling made evident by increased vascularization and scar size, and cardiomyocyte hypertrophy reduction. Compared with CHF infused with control cells, infusion of MOCE/c-Kit+ cells resulted in a further reduction in left ventricle end-diastolic pressure and total collagen and an increase in interleukin-6 expression. The low engraftment of infused cells suggests that paracrine effects might account for the beneficial effects of c-Kit+ cells in CHF. In conclusion, selective inhibition of class I HDACs induced expression of cardiac markers in c-Kit+ cells and partially augmented the efficacy of these cells for CHF repair.
The study has shown that selective class 1 histone deacetylase inhibition is sufficient to redirect c-Kit+ cells toward a cardiac fate. Epigenetically modified c-Kit+ cells improved contractile function and retarded remodeling of the congestive heart failure heart. This study provides new insights into the efficacy of cardiac c-Kit+ cells in the ischemic heart failure model.
PMCID: PMC4542868  PMID: 26240433
Stem cell transplantation; Epigenetic process; Myocardial infarct; Congestive heart failure
16.  Concise Review: Emerging Role of CD44 in Cancer Stem Cells: A Promising Biomarker and Therapeutic Target 
Stem Cells Translational Medicine  2015;4(9):1033-1043.
This study summarizes the current findings concerning the critical role of CD44/CD44v in regulation of cancer stemness and the research status of CD44/CD44v as biomarkers and therapeutic targets in cancer. This study also discusses the current challenges and future directions that may lead to best use of CD44/CD44v for clinical applications.
The reception and integration of the plethora of signals a cell receives from its microenvironment determines the cell’s fate. CD44 functions as a receptor for hyaluronan and many other extracellular matrix components, as well as a cofactor for growth factors and cytokines, and thus, CD44 is a signaling platform that integrates cellular microenvironmental cues with growth factor and cytokine signals and transduces signals to membrane-associated cytoskeletal proteins or to the nucleus to regulate a variety of gene expression levels related to cell-matrix adhesion, cell migration, proliferation, differentiation, and survival. Accumulating evidence indicates that CD44, especially CD44v isoforms, are cancer stem cell (CSC) markers and critical players in regulating the properties of CSCs, including self-renewal, tumor initiation, metastasis, and chemoradioresistance. Furthermore, there is ample evidence that CD44, especially CD44v isoforms, are valuable prognostic markers in various types of tumors. Therefore, therapies that target CD44 may destroy the CSC population, and this holds great promise for the cure of life-threatening cancers. However, many challenges remain to determining how best to use CD44 as a biomarker and therapeutic target. Here we summarize the current findings concerning the critical role of CD44/CD44v in the regulation of cancer stemness and the research status of CD44/CD44v as biomarkers and therapeutic targets in cancer. We also discuss the current challenges and future directions that may lead to the best use of CD44/CD44v for clinical applications.
Mounting evidence indicates that cancer stem cells (CSCs) are mainly responsible for cancer aggressiveness, drug resistance, and tumor relapse. CD44, especially CD44v isoforms, have been identified as CSC surface markers for isolating and enriching CSCs in different types of cancers. The current findings concerning the critical role of CD44/CD44v in regulation of cancer stemness and the research status of CD44/CD44v as biomarkers and therapeutic targets in cancer are summarized. The current challenges and future directions that may lead to best use of CD44/CD44v for clinical applications are also discussed.
PMCID: PMC4542874  PMID: 26136504
CD44; Cancer stem cell; Biomarker; Therapeutic target; Splicing variants; Tumor microenvironment
17.  Retrospective Ratings of Emotions: the Effects of Age, Daily Tiredness, and Personality 
Frontiers in Psychology  2016;6:2020.
Remembering the emotions we have experienced in the past is the core of one's unique life-experience. However, there are many factors, both at the state and trait level that can affect the way past feelings are seen. The main aim of the current study was to examine the impact of individual differences on systematic biases in retrospective ratings compared to the momentary experience of basic emotions such as sadness, fear, happiness, and anger. To this end, an experience sampling study across 2 weeks was conducted using a younger and an older age-group; the experience of momentary emotions was assessed on 7 randomly determined occasions per day, the retrospective ratings being collected at the end of each day about that day, as well as at the end of the study about the previous 2 weeks. The results indicated that age and daily tiredness have significant effects on retrospective emotion ratings over a 1-day period (state level), enhancing the retrospective ratings of negative emotions and decreasing the ratings of felt happiness. Whereas personality traits influence the more long-term emotion experience (trait level), with all Big Five personality traits having selective impact on retrospective emotion ratings of fear, sadness, happiness, and anger. Findings provide further evidence about the systematic biases in retrospective emotion ratings, suggesting that, although retrospective ratings are based on momentary experience, daily tiredness and personality traits systematically influence the way in which past feelings are seen.
PMCID: PMC4707248  PMID: 26793142
retrospective ratings; emotional memory; age; daily tiredness; personality
18.  Efficient gene delivery to human umbilical cord mesenchymal stem cells by cationized Porphyra yezoensis polysaccharide nanoparticles 
This study centered on an innovative application of Porphyra yezoensis polysaccharide (PPS) with cationic modification as a safe and efficient nonviral gene vector to deliver a plasmid encoding human Wnt3a (pWnt3a) into human umbilical cord mesenchymal stem cells (HUMSCs). After modification with branched low-molecular-weight (1,200 Da) polyethylenimine, the cationized PPS (CPPS) was combined with pWnt3a to form spherical nanoscale particles (CPPS-pWnt3a nanoparticles). Particle size and distribution indicated that the CPPS-pWnt3a nanoparticles at a CPPS:pWnt3a weight ratio of 40:1 might be a potential candidate for DNA plasmid transfection. A cytotoxicity assay demonstrated that the nanoparticles prepared at a CPPS:pWnt3a weight ratio of 40:1 were nontoxic to HUMSCs compared to those of Lipofectamine 2000 and polyethylenimine (25 kDa). These nanoparticles were further transfected to HUMSCs. Western blotting demonstrated that the nanoparticles (CPPS:pWnt3a weight ratio 40:1) had the greatest transfection efficiency in HUMSCs, which was significantly higher than that of Lipofectamine 2000; however, when the CPPS:pWnt3a weight ratio was increased to 80:1, the nanoparticle-treated group showed no obvious improvement in translation efficiency over Lipofectamine 2000. Therefore, CPPS, a novel cationic polysaccharide derived from P. yezoensis, could be developed into a safe, efficient, nonviral gene vector in a gene-delivery system.
PMCID: PMC4655959  PMID: 26604758
Porphyra yezoensis; nanoparticle; nonviral vector; human umbilical cord mesenchymal stem cells; Wnt3a
19.  Impact of lymphovascular invasion on recurrence and progression rates in patients with pT1 urothelial carcinoma of bladder after transurethral resection 
OncoTargets and therapy  2015;8:3401-3406.
To evaluate the clinical significance of lymphovascular invasion (LVI) on recurrence and progression rates in patients with pT1 urothelial carcinoma of bladder after transurethral resection.
This retrospective study was performed with 155 patients with newly diagnosed pT1 urothelial carcinoma of bladder who were treated with transurethral resection of bladder tumor at our institution from January 2006 to January 2010. The presence or absence of LVI was examined by pathologists. Chi-square test was performed to identify the correlations between LVI and other clinical and pathological features. Kaplan–Meier method was used to estimate the recurrence-free survival (RFS) and progression-free survival curves and difference was determined by the log-rank test. Univariate and multivariate analyses were performed to determine the predictive factors through a Cox proportional hazards analysis model.
LVI was detected in a total of 34 patients (21.9%). While LVI was associated with high-grade tumors (P<0.001) and intravesical therapy (P=0.009). Correlations with age (P=0.227), sex (P=0.376), tumor size (P=0.969), tumor multiplicity (P=0.196), carcinoma in situ (P=0.321), and smoking (P=0.438) were not statistically significant. There was a statistically significant tendency toward higher recurrence rate and shorter RFS time in LVI-positive patients. However, no statistically significant differences were observed in progression rate between the two groups. Moreover, multivariate Cox proportional hazards analysis revealed that LVI, tumor size, and smoking were independent prognostic predictors of recurrence. The hazard ratios (95% confidence interval) were 2.042 (1.113–3.746, P=0.021), 1.817 (1.014–3.256, P=0.045), and 2.079 (1.172–3.687, P=0.012), respectively.
The presence of LVI in transurethral resection of bladder tumor specimens is significantly associated with higher recurrence rate and shorter RFS time in patients with newly diagnosed T1 urothelial carcinoma of the bladder. It is an independent prognostic predictor for disease recurrence. Thus, patients with LVI should be followed up closely.
PMCID: PMC4655960  PMID: 26604797
bladder urothelial carcinoma; TURBT; lymphovascular invasion; recurrence; progression
20.  Experience with combination of nimotuzumab and intensity-modulated radiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma 
OncoTargets and therapy  2015;8:3383-3390.
To evaluate the efficacy and safety of using nimotuzumab in combination with intensity-modulated radiotherapy (IMRT) in the primary treatment of locoregionally advanced nasopharyngeal carcinoma.
Between December 2009 and December 2013, 38 newly diagnosed patients with stage III–IV nasopharyngeal carcinoma were treated with IMRT and nimotuzumab concomitantly. The distribution of disease was stage III in 20 (52.6%), stage IV A in 9 (23.7%), and stage IV B in 9 (23.7%). All the patients received at least two cycles of cisplatin-based neoadjuvant chemotherapy followed by nimotuzumab 200 mg/week concurrently with IMRT. Acute and late radiation-related toxicities were graded according to the Acute and Late Radiation Morbidity Scoring Criteria of Radiation Therapy Oncology Group.
With a median follow-up of 39.7 months (range, 13.3–66.5 months), the estimated 3-year local recurrence-free survival, regional recurrence-free survival, distant metastasis-free survival, progression failure-free survival, and overall survival rates were 92.8%, 92.9%, 89.5%, 78.7%, and 87.5%, respectively. The median cycle for nimotuzumab addition was 6 weeks. Grade 3 radiation-induced mucositis accounted for 36.8% of treated people. No skin rash and infusion reaction were observed, distinctly from what is reported in cetuximab-treated patients.
Nimotuzumab plus IMRT showed promising outcomes in terms of locoregional control and survival, without increasing the incidence of radiation-related toxicities for patients.
PMCID: PMC4655961  PMID: 26604795
nasopharyngeal carcinoma; intensity-modulated radiotherapy; nimotuzumab
21.  Combination of PEI-Mn0.5Zn0.5Fe2O4 nanoparticles and pHsp 70-HSV-TK/GCV with magnet-induced heating for treatment of hepatoma 
To explore a new combination of thermal treatment and gene therapy for hepatoma, a heat-inducible herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy system was developed in which thermal energy generated by Mn0.5Zn0.5Fe2O4 nanoparticles (MZF-NPs) under an alternating magnetic field was used to activate gene expression.
First, a recombinant eukaryotic plasmid, pHsp 70-HSV-TK, was constructed as a target gene for therapy. This recombinant plasmid was used to transfect SMMC-7721 hepatoma cells and the gene expression was evaluated. Magnet-induced heating was then applied to cells to assess the antihepatoma effects of the polyethylenimine (PEI)-MZF-NPs/pHsp 70-HSV-TK/GCV complex, in vitro and in vivo.
The results showed that cells were successfully transfected with pHsp 70-HSV-TK and that expression levels of HSV-TK remained stable. Both in vitro and in vivo results indicated that the combination of gene therapy and heat treatment resulted in better therapeutic effects than heating-alone group. The rates of apoptosis and necrosis in the combined treatment group were 49.0% and 7.21%, respectively. The rate of inhibition of cell proliferation in the combined treatment group was significantly higher (87.5%) than that in the heating-alone group (65.8%; P<0.01). The tumor volume and mass inhibition rates of the combined treatment group were 91.3% and 87.91%, respectively, and were significantly higher than the corresponding rates of the heating-alone group (70.41% and 57.14%; P<0.01). The expression levels of Stat3 and Bcl-xL messenger RNA and p-Stat3 and Bcl-xL protein in the combined treatment group were significantly lower than those in the other groups (P<0.01). The expression levels of Bax messenger RNA and protein in the recombinant plasmid group were significantly higher than those in the other groups (P<0.01).
It can therefore be concluded that the combined application of heat treatment and gene therapy has a synergistic and complementary effect and that PEI-MZF-NPs can simultaneously act both as a nonviral gene vector and a magnet-induced source of heat, thereby representing a viable approach for the treatment of cancer.
PMCID: PMC4655962  PMID: 26604760
Mn0.5Zn0.5Fe2O4 nanoparticles; heat-inducible gene expression; hyperthermia; gene therapy; HSV-TK/GCV; SMMC-7721 hepatoma cells
22.  Role of surface charge in determining the biological effects of CdSe/ZnS quantum dots 
The growing potential of quantum dots (QDs) in biomedical applications has provoked the urgent need to thoroughly address their interaction with biological systems. However, only limited studies have been performed to explore the effects of surface charge on the biological behaviors of QDs. In the present study, three commercially available QDs with different surface coatings were used to systematically evaluate the effects of surface charge on the cellular uptake, cytotoxicity, and in vivo biodistribution of QDs. Our results demonstrated that charged QDs entered both cancer cells and macrophages more efficiently than neutral ones, while negative QDs internalized mostly. Upon entry into cells, QDs were localized in different subcellular compartments (eg, cytoplasm and lysosomes) depending on the surface charge. Interestingly, inconsistent with the result of internalization, positive QDs but not negative QDs exhibited severe cytotoxicity, which was likely due to their disruption of cell membrane integrity, and production of reactive oxygen species. Biodistribution studies demonstrated that negative and neutral QDs preferentially distributed in the liver and the spleen, whereas positive QDs mainly deposited in the kidney with obvious uptake in the brain. In general, surface charge plays crucial roles in determining the biological interactions of QDs.
PMCID: PMC4655958  PMID: 26604757
cellular uptake; uptake pathways; intracellular distribution; reactive oxygen species; cytotoxicity; biodistribution
23.  Postoperative Bone Graft Displacement: An Unusual Sign of Infection Following Posterior Spinal Fusion 
Radiology Case Reports  2015;1(1):21-23.
We describe a case of a spinal fusion site infection, which was first suggested on plain radiographs due to interval displacement and partial dissolution of the bone graft material. These radiographic findings occurred 4 weeks before the infection became clinically evident. Cultures taken during eventual surgical debridement grew Aspergillus fumigatus. This case emphasizes the importance of noting changes in bone graft material in addition to the routine evaluation of alignment and hardware in patients who have undergone posterior spinal fusion.
PMCID: PMC4891402  PMID: 27298675
CT, computed tomography; MRI, magnetic resonance imaging
24.  A Novel Endogenous Betaretrovirus in the Common Vampire Bat (Desmodus rotundus) Suggests Multiple Independent Infection and Cross-Species Transmission Events 
Journal of Virology  2015;89(9):5180-5184.
The Desmodus rotundus endogenous betaretrovirus (DrERV) is fixed in the vampire bat D. rotundus population and in other phyllostomid bats but is not present in all species from this family. DrERV is not phylogenetically related to Old World bat betaretroviruses but to betaretroviruses from rodents and New World primates, suggesting recent cross-species transmission. A recent integration age estimation of the provirus in some taxa indicates that an exogenous counterpart might have been in recent circulation.
PMCID: PMC4403488  PMID: 25717107
25.  Ocular and Histologic Findings in a Series of Children with Infantile Pompe Disease Treated with Enzyme Replacement Therapy 
To report the ophthalmologic and histologic findings in a series of children with infantile Pompe disease treated with enzyme replacement therapy (ERT).
We reviewed the records of children with infantile Pompe disease treated with ERT who had at least one complete ophthalmic examination and the ocular histopathology of children with infantile Pompe disease who were treated with ERT. We reviewed the patient’s clinical history, including external ocular examination, ocular alignment and motility, dilated fundus examination, and cycloplegic refraction. A literature review was performed for ophthalmologic findings in infantile Pompe disease using PubMed.
We included the clinical findings of 13 children and reviewed the ocular histopathology of three children with infantile Pompe disease who were treated with ERT. Forty-six percent (6/13) had bilateral ptosis, 23% (3/13) strabismus, 62% myopia (8/13), and 69% (9/13) astigmatism. On histologic examination, there was vacuolar myopathy affecting the extraocular muscles, ciliary body, and iris smooth muscle and glycogen accumulation in corneal endothelial, lens epithelium, and retinal ganglion cells, and within lysosomes of scleral fibroblasts.
It is important that ophthalmic providers are aware of the high prevalence of myopia, astigmatism, and ptosis in children with infantile Pompe disease treated with ERT, as they are potentially amblyogenic, but treatable factors.
PMCID: PMC4413912  PMID: 25139343

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