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1.  HER2-associated radiation resistance of breast cancer stem cells isolated from HER2-negative breast cancer cells 
Purpose
To understand the role of HER2-associated signaling network in breast cancer stem cells (BCSCs); using radiation-resistant breast cancer cells and clinical recurrent breast cancers to evaluate HER2-targeted therapy as a tumor eliminating strategy for recurrent HER2−/low breast cancers.
Experimental Design
HER2-expressing BCSCs (HER2+/CD44+/CD24−/low) were isolated from radiation-treated breast cancer MCF7 cells and in vivo irradiated MCF7 xenograft tumors. Tumor aggressiveness and radiation resistance were analyzed by gap filling, Matrigel invasion, tumor-sphere formation, and clonogenic survival assays. The HER2/CD44 feature was analyzed in 40 primary and recurrent breast cancer specimens. Protein expression profiling in HER2+/CD44+/CD24−/low versus HER2−/CD44+/CD24−/low BCSCs was conducted with 2-D DIGE and HPLC-MS/MS analysis and HER2-mediated signaling network was generated by MetaCore™ program.
Results
Compared to HER2-negative BCSCs, HER2+/CD44+/CD24−/low cells showed elevated aldehyde dehydrogenase (ALDH) activity and aggressiveness tested by matrigel invasion, tumor sphere formation and in vivo tumorigenesis. The enhanced aggressive phenotype and radioresistance of the HER2+/CD44+/CD24−/low cells were markedly reduced by inhibition of HER2 via siRNA or Herceptin treatments. Clinical breast cancer specimens revealed that cells co-expressing HER2 and CD44 were more frequently detected in recurrent (84.6%) than primary tumors (57.1%). In addition, 2-D DIGE and HPLC-MS/MS of HER2+/CD44+/CD24−/low versus HER2−/CD44+/CD24−/low BCSCs reported a unique HER2-associated protein profile including effectors involved in tumor metastasis, apoptosis, mitochondrial function and DNA repair. A specific feature of HER2-STAT3 network was identified.
Conclusion
This study provides the evidence that HER2-mediated pro-survival signaling network is responsible for the aggressive phenotype of breast cancer stem cells that could be targeted to control the therapy-resistant HER2−/low breast cancer.
doi:10.1158/1078-0432.CCR-12-1436
PMCID: PMC3593096  PMID: 23091114
2.  Activity Scheduling as a Core Component of Effective Care Management for Late-Life Depression 
Objective
Activity scheduling is an established component of evidenced-based treatment for late-life depression in primary care. We examined participant records from the Improving Mood-Promoting Access to Collaborative Treatment (IMPACT) trial to identify activity scheduling strategies used in the context of successful depression care management (CM), associations of activity scheduling with self-reported activity engagement, and depression outcomes.
Methods
Observational mixed methods analysis of 4,335 CM session notes from 597 participants in the intervention arm of the IMPACT trial. Grounded theory was used to identify seventeen distinct activity categories from CM notes. Logistic regression was used to evaluate associations between activity scheduling, activity engagement, and depression outcomes at 12 months. All relevant institutional review boards approved the research protocol.
Results
Seventeen distinct activity categories were generated. The majority of patients worked on at least one social and one solitary activity during their course of treatment. Common activity categories included physical activity (32%), medication management (22%), active-non-physical (19%) and passive (14%) activities. We found significant, positive associations between activity scheduling, self reported engagement in activities at 12 months, and depression outcomes at 12 months.
Conclusion
Older primary care patients in CM for depression worked on a wide range of activities. Consistent with depression theory that has placed emphasis on social activities, our data indicates a benefit for intentional social engagement versus passive social and solitary activities. Care Managers should encourage patients to balance instrumental activities (e.g. attending to medical problems) with social activities targeting direct interpersonal engagement.
doi:10.1002/gps.3784
PMCID: PMC3429703  PMID: 22367982
Care Management; Depression; Geriatric; Behavioral Activation
3.  Differential modulation by vascular nitric oxide synthases of the ethanol-evoked hypotension and autonomic dysfunction in female rats 
Alcohol (Fayetteville, N.Y.)  2012;46(8):727-735.
We recently reported that chronic exposure to ethanol lowers blood pressure (BP) via altering cardiac contractility and autonomic control in female rats. In this investigation we conducted pharmacological and molecular studies to elucidate the role of constitutive and inducible nitric oxide synthase (NOS) in these hemodynamic effects of ethanol. Changes caused by selective inhibition of eNOS [N5-(1-iminoethyl)-L-ornithine; L-NIO], nNOS (Nω-propyl-L-arginine; NPLA), or iNOS (1400W) in BP, heart rate (HR), myocardial contractility index (dP/dtmax), and power spectral indices of hemodynamic variability were evaluated in telemetered female rats receiving ethanol (5%, w/v) or control liquid diet for 8 weeks. Ethanol increased plasma nitrite/nitrate (NOx) and enhanced the phosphorylation of eNOS and nNOS, but not iNOS, in the tail artery. Ethanol also reduced BP, +dP/dtmax, low-frequency bands of interbeat intervals (IBILF, 0.25–0.75 Hz) and IBILF/HF ratio while high-frequency bands (IBIHF, 0.75–3 Hz) were increased, suggesting parasympathetic overactivity. L-NIO (20 mg/kg i.p.) caused greater increases in BP in control than in ethanol-fed rats but elicited similar reductions in IBILF/HF and +dP/dtmax both groups. NPLA (1 mg/kg i.p.) caused minimal effects in control rats but exacerbated the reductions in BP, +dP/dtmax, and IBILF/HF in ethanol-fed rats. No hemodynamic modifications were caused by 1400W (5 mg/kg i.p.) in either rat group. Together, these findings suggest that nNOS acts tonically to offset the detrimental cardiovascular actions of ethanol in female rats, and the enhanced vascular NO bioavailability may explain the blunted L-NIO evoked pressor response in ethanol-fed rats.
doi:10.1016/j.alcohol.2012.09.001
PMCID: PMC3496835  PMID: 23046587
Ethanol; blood pressure; cardiac autonomic control; nitric oxide synthases; female rats
4.  Bullying and School Safety 
The Journal of pediatrics  2007;152(1):10.1016/j.jpeds.2007.05.045.
Objective
To identify an association between involvement in bullying and problems in school.
Study design
This was a cross-sectional study of 5391 students in grades 7, 9, and 11 in an urban public school district. The main outcome measure was involvement in bullying. Secondary outcomes included attendance, grade point average, psychosocial distress, and perceived acceptability of carrying guns to school.
Results
Of the 5391 children surveyed, 26% were involved in bullying either as victim, bully, or both (bully-victim). All 3 groups were significantly more likely than bystanders to feel unsafe at school and sad most days. Victims and bully-victims were more likely to say they are “no good.” Victims were more likely to feel that they “do not belong” in their school. The odds of being a victim (vs a bystander) were 10% lower for every 1 point increase in grade point average. Bully-victims were more likely to say that it is “not wrong” to take a gun to school.
Conclusions
Associations between involvement in bullying and academic achievement, psychological distress, and the belief that it is not wrong to take a gun to school reinforce the notion that school environment is interrelated with mental health and school success.
doi:10.1016/j.jpeds.2007.05.045
PMCID: PMC3839286  PMID: 18154913
5.  Manganese superoxide dismutase interacts with a large scale of cellular and mitochondrial proteins in low dose radiation-induced adaptive radioprotection 
Free radical biology & medicine  2012;53(10):1838-1847.
Cellular adaptive response to certain low level genotoxic stresses including the exposure to low dose ionizing radiation (LDIR) shows promise as a tool to enhance radioprotection in normal cells but not in tumor cells. Manganese superoxide dismutase (MnSOD), a fundamental mitochondrial antioxidant in mammalian cells plays a key role in LDIR-induced adaptive response. In this study, we aim to elucidate the signaling network associated with the MnSOD-induced radiation protection. A MnSOD-interacting protein profile was established in LDIR-treated human skin cells. Human skin keratinocytes (HK18) were irradiated with a single dose LDIR (10 cGy x-ray) and the cell lysates were immunoprecipitated using α-MnSOD and applied to two different gel-based proteomics followed by mass spectrometry for protein identification. Analysis of the profiles of MnSOD interacting partners before and after LDIR detected different patterns of MnSOD protein-protein interactions in response to LDIR. Interestingly, many of the MnSOD interacting proteins are known to have functions related to mitochondrial regulations on cell metabolism, apoptosis and DNA repair. These results provide the evidence indicating that in addition to the enzymatic action detoxifying superoxide, the antioxidant MnSOD may function as a signaling regulator in stress induced adaptive protection through cell survival pathways.
doi:10.1016/j.freeradbiomed.2012.08.589
PMCID: PMC3494792  PMID: 23000060
MnSOD; protein interaction; low dose radiation; adaptive response; human keratinocytes
6.  Long-term Cost Effects of Collaborative Care for Late-life Depression 
Objective
To determine the long-term effects on total healthcare costs of the Improving Mood: Promoting Access to Collaborative Treatment (IMPACT) program for late-life depression compared with usual care.
Study Design
Randomized controlled trial with enrollment from July 1999 through August 2001. The IMPACT trial, conducted in primary care practices in 8 delivery organizations across the United States, enrolled 1801 depressed primary care patients 60 years or older. Data are from the 2 IMPACT sites for which 4-year cost data were available. Trial enrollment across these 2 health maintenance organizations was 551 patients.
Methods
Participants were randomly assigned to the IMPACT intervention (n = 279) or to usual primary care (n = 272). Intervention patients had access to a depression care manager who provided education, behavioral activation, support of antidepressant medication management prescribed by their regular primary care provider, and problem-solving treatment in primary care for up to 12 months. Care managers were supervised by a psychiatrist and a primary care provider. The main outcome measures were healthcare costs during 4 years.
Results
IMPACT participants had lower mean total healthcare costs ($29 422; 95% confidence interval, $26 479-$32 365) than usual care patients ($32 785; 95% confidence interval, $27 648-$37 921) during 4 years. Results of a bootstrap analysis suggested an 87% probability that the IMPACT program was associated with lower healthcare costs than usual care.
Conclusion
Compared with usual primary care, the IMPACT program is associated with a high probability of lower total healthcare costs during a 4-year period.
PMCID: PMC3810022  PMID: 18269305
7.  Age and Sex Trends in Long-term Opioid Use in Two Large American Health Systems Between 2000 and 2005 
Pain medicine (Malden, Mass.)  2009;11(2):248-256.
Objective
To estimate recent age- and sex-specific changes in long-term opioid prescription among patients with chronic pain in two large American Health Systems.
Design
Analysis of administrative pharmacy data to calculate changes in prevalence of long-term opioid prescription (90 days or more during a calendar year) from 2000 to 2005, within groups based on sex and age (18–44, 45–64, and 65 years and older). Separate analyses were conducted for patients with and without a diagnosis of a mood disorder or anxiety disorder. Changes in mean dose between 2000 and 2005 were estimated, as were changes in the rate of prescription for different opioid types (short-acting, long-acting, and non-Schedule 2).
Patients
Enrollees in HealthCore (N = 2,716,163 in 2000) and Arkansas Medicaid (N = 115,914 in 2000).
Results
Within each of the age and sex groups, less than 10% of patients with a chronic pain diagnosis in HealthCore, and less than 33% in Arkansas Medicaid, received long-term opioid prescriptions. All age, sex, and anxiety/depression groups showed similar and statistically significant increases in long-term opioid prescription between 2000 and 2005 (35–50% increase). Per-patient daily doses did not increase.
Conclusions
No one group showed especially large increases in long-term opioid prescriptions between 2000 and 2005. These results argue against a recent epidemic of opioid prescribing. These trends may result from increased attention to pain in clinical settings, policy or economic changes, or provider and patient openness to opioid therapy. The risks and benefits to patients of these changes are not yet established.
doi:10.1111/j.1526-4637.2009.00740.x
PMCID: PMC3773537  PMID: 20002323
Opioids; Prescriptions; Chronic Pain; Disparities—Gender; Aged; Mood; Anxiety
8.  Emergency Department Visits Among Recipients of Chronic Opioid Therapy 
Archives of internal medicine  2010;170(16):1425-1432.
Background
There has been an increase in over dose deaths and emergency department visits (EDVs) involving use of prescription opioids, but the association between opioid prescribing and adverse outcomes is unclear.
Methods
Data were obtained from administrative claim records from Arkansas Medicaid and HealthCore commercially insured enrollees, 18 years and older, who used prescription opioids for at least 90 continuous days within a 6-month period between 2000 and 2005 and had no cancer diagnoses. Regression analysis was used to examine risk factors for EDVs and alcohol- or drug-related encounters (ADEs) in the 12 months following 90 days or more of prescribed opioids.
Results
Headache, back pain, and preexisting substance use disorders were significantly associated with EDVs and ADEs. Mental health disorders were associated with EDVs in HealthCore enrollees and with ADEs in both samples. Opioid dose per day was not consistently associated with EDVs but doubled the risk of ADEs at morphine-equivalent doses over 120 mg/d. Use of short-acting Drug Enforcement Agency Schedule II opioids was associated with EDVs compared with use of non–Schedule II opioids alone (relative risk range, 1.09–1.74). Use of Schedule II long-acting opioids was strongly associated with ADEs (relative risk range, 1.64–4.00).
Conclusions
Use of Schedule II opioids, headache, back pain, and substance use disorders are associated with EDVs and ADEs among adults prescribed opioids for 90 days or more. It may be possible to increase the safety of chronic opioid therapy by minimizing the prescription of Schedule II opioids in these higher-risk recipients.
doi:10.1001/archinternmed.2010.273
PMCID: PMC3715046  PMID: 20837827
9.  Adaptive Modulation of Adult Brain Gray and White Matter to High Altitude: Structural MRI Studies 
PLoS ONE  2013;8(7):e68621.
The aim of this study was to investigate brain structural alterations in adult immigrants who adapted to high altitude (HA). Voxel-based morphometry analysis of gray matter (GM) volumes, surface-based analysis of cortical thickness, and Tract-Based Spatial Statistics analysis of white matter fractional anisotropy (FA) based on MRI images were conducted on 16 adults (20–22 years) who immigrated to the Qinghai-Tibet Plateau (2300–4400 m) for 2 years. They had no chronic mountain sickness. Control group consisted of 16 matched sea level subjects. A battery of neuropsychological tests was also conducted. HA immigrants showed significantly decreased GM volumes in the right postcentral gyrus and right superior frontal gyrus, and increased GM volumes in the right middle frontal gyrus, right parahippocampal gyrus, right inferior and middle temporal gyri, bilateral inferior ventral pons, and right cerebellum crus1. While there was some divergence in the left hemisphere, surface-based patterns of GM changes in the right hemisphere resembled those seen for VBM analysis. FA changes were observed in multiple WM tracts. HA immigrants showed significant impairment in pulmonary function, increase in reaction time, and deficit in mental rotation. Parahippocampal and middle frontal GM volumes correlated with vital capacity. Superior frontal GM volume correlated with mental rotation and postcentral GM correlated with reaction time. Paracentral lobule and frontal FA correlated with mental rotation reaction time. There might be structural modifications occurred in the adult immigrants during adaptation to HA. The changes in GM may be related to impaired respiratory function and psychological deficits.
doi:10.1371/journal.pone.0068621
PMCID: PMC3712920  PMID: 23874692
10.  Structural Modulation of Brain Development by Oxygen: Evidence on Adolescents Migrating from High Altitude to Sea Level Environment 
PLoS ONE  2013;8(7):e67803.
The present study aimed to investigate structural modulation of brain by high level of oxygen during its peak period of development. Voxel-based morphometry analysis of gray matter (GM) and white matter (WM) volumes and Tract-Based Spatial Statistics analysis of WM fractional anisotropy (FA) and mean diffusion (MD) based on MRI images were carried out on 21 Tibetan adolencents (15–18 years), who were born and raised in Qinghai-Tibetan Plateau (2900–4700 m) and have lived at sea level (SL) in the last 4 years. The control group consisted of matched Tibetan adolescents born and raised at high altitude all the time. SL immigrants had increased GM volume in the left insula, left inferior parietal gyrus, and right superior parietal gyrus and decreased GM in the left precentral cortex and multiple sites in cerebellar cortex (left lobule 8, bilateral lobule 6 and crus 1/2). Decreased WM volume was found in the right superior frontal gyrus in SL immigrants. SL immigrants had higher FA and lower MD at multiple sites of WM tracts. Moreover, we detected changes in ventilation and circulation. GM volume in cerebellum lobule 8 positively correlated with diastolic pressure, while GM volume in insula positively correlated vital capacity and hypoxic ventilatory response. Our finding indicate that the structural modulations of GM by high level of oxygen during its peak period of development are related to respiratory and circulatory regulations, while the modulation in WM mainly exhibits an enhancement in myelin maturation.
doi:10.1371/journal.pone.0067803
PMCID: PMC3706444  PMID: 23874449
11.  Malignant meningioma of the cerebellopontine angle in a 2-year-old girl: a case report and literature review 
Chinese Journal of Cancer  2013;32(7):415-417.
Meningioma is a common intracranial tumor in adults. Pediatric cases account for approximately 1.5% of all intracranial meningiomas, and very few cases show malignant histological features. Primary pediatric malignant meningioma in the cerebellopontine angle is extremely uncommon. Herein, we report a 2-year-old girl with malignant meningioma in the cerebellopontine angle. The clinical features, diagnosis, and treatment protocol are discussed.
doi:10.5732/cjc.012.10211
PMCID: PMC3845606  PMID: 23470145
Malignant meningioma; the cerebellopontine angle; pediatric; craniotomy
12.  A framework for scalable parameter estimation of gene circuit models using structural information 
Bioinformatics  2013;29(13):i98-i107.
Motivation: Systematic and scalable parameter estimation is a key to construct complex gene regulatory models and to ultimately facilitate an integrative systems biology approach to quantitatively understand the molecular mechanisms underpinning gene regulation.
Results: Here, we report a novel framework for efficient and scalable parameter estimation that focuses specifically on modeling of gene circuits. Exploiting the structure commonly found in gene circuit models, this framework decomposes a system of coupled rate equations into individual ones and efficiently integrates them separately to reconstruct the mean time evolution of the gene products. The accuracy of the parameter estimates is refined by iteratively increasing the accuracy of numerical integration using the model structure. As a case study, we applied our framework to four gene circuit models with complex dynamics based on three synthetic datasets and one time series microarray data set. We compared our framework to three state-of-the-art parameter estimation methods and found that our approach consistently generated higher quality parameter solutions efficiently. Although many general-purpose parameter estimation methods have been applied for modeling of gene circuits, our results suggest that the use of more tailored approaches to use domain-specific information may be a key to reverse engineering of complex biological systems.
Availability: http://sfb.kaust.edu.sa/Pages/Software.aspx
Contact: xin.gao@kaust.edu.sa
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt232
PMCID: PMC3694671  PMID: 23813015
13.  Decrease expression of microRNA-20a promotes cancer cell proliferation and predicts poor survival of hepatocellular carcinoma 
Background
Growing evidences indicate microRNAs play important roles in cancer development, progression, metastasis and may constitute robust biomarkers for cancer prognosis. The aim of this study was to identify the clinical and functional association of microRNA-20a (miR-20a) in hepatocellular carcinoma (HCC).
Methods
MiR-20a was detected using Taqman real-time polymerase chain reaction. Kaplan-Meier and Cox proportional regression analyses were utilized to determine the association of miR-20a with survival of patients. The potential functions of miR-20a on proliferation were evaluated by proliferation and flow cytometry analysis. The direct target gene of miR-20a was also identified by luciferase reporter assays.
Results
MiR-20a was lower in primary HCC than normal liver, and were further decreased in those with post-liver transplantation (LT) HCC recurrence compared with those with non-recurrence (p = 0.001). Patients with lower miR-20a expression had significantly poorer recurrence-free survival (RFS, Log rank p < 0.001) and overall survival (OS, Log rank p < 0.001). Multivariate analysis revealed that lower miR-20a was an independent predictor of poor prognosis. MiR-20a restoration could suppress HepG2 and SMMC-7721 cells proliferation and induce cell cycle G1 arrest and apoptosis. Subsequent investigations revealed that miR-20a directly targeted myeloid cell leukemia sequence 1 (Mcl-1) and reduced the endogenous protein level of Mcl-1 in HCC cells.
Conclusions
MiR-20a is decreased in HCCs and correlates with HCC recurrence and prognosis. Down-regulation of miR-20a increases the proliferation abilities of HCC cells. Our findings suggest miR-20a may represent a novel potential therapeutic target and biomarker for survival of HCC patients.
doi:10.1186/1756-9966-32-21
PMCID: PMC3699415  PMID: 23594563
MicroRNA-20a; Hepatocellular Carcinoma; Recurrence; Prognosis; Liver transplantation
14.  Cross-sectional study of sociodemographic patterning of risk factors for cardiovascular disease in three isolated-based subgroups of the Uyghur population in Xinjiang, China 
BMJ Open  2013;3(3):e002279.
Objective
To explore the sociodemographic patterning of risk factors for cardiovascular disease (CVD) in three isolated-based subgroups of the Uyghur population in Xinjiang, China.
Design
A cross-sectional study. Between 2005 and 2008, a non-probability sampling design method was used to select three specific groups of the Uyghur rural populations based on their potential socioeconomic status (ie, isolated, semi-isolated and open-environment status).
Setting
Three communities (named Desert, Turpan and Yuli Rob) in Southern Xinjiang autonomous region, China.
Participants
1656 people were included in this study. The inclusion criteria were that all participants were 18 years or older, they were descendants of at least three generations living in the same region, and there was no history of intermarriage.
Main outcome measures
The prevalence of CVD risk factors (ie, tobacco use, alcohol use, obesity, dyslipidemia, hypertension, diabetes, etc) was assessed.
Results
Compared with the Desert and Turpan communities, Yuli Rob had the highest levels of obesity, dyslipidemia and hypertension, and the Desert had the lowest levels of CVD risk factors. Age standardisation slightly altered the estimates, though the patterns remained unchanged. Some unique characteristics were also found. For example, the Desert group displayed significantly lower high-density lipoprotein cholesterol (HDLC) level compared with Yuli Rob and Turpan groups. The mean values were 0.63, 1.06 and 1.45 mmol/l for men and 0.64, 1.22 and 1.51 mmol/l for women (p<0.0001). The HDLC levels in the Desert group increased with increase in body mass index and fasting glucose levels, which was inconsistent with previous studies.
Conclusions
Identifying the unique CVD risk factors of the ethnic-specific populations is very important in development of tailored strategies for the prevention of CVD.
doi:10.1136/bmjopen-2012-002279
PMCID: PMC3612766  PMID: 23503578
HEALTH PROMOTION; HEALTH STATUS; ENVIRONMENTAL HEALTH
15.  Hypoxia Promotes Dopaminergic Differentiation of Mesenchymal Stem Cells and Shows Benefits for Transplantation in a Rat Model of Parkinson’s Disease 
PLoS ONE  2013;8(1):e54296.
Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into dopaminergic (DAergic) neurons, which is one of the major cell types damaged in Parkinson’s disease (PD). For this reason, MSCs are considered a potential cell source for PD therapy. It has been proved that hypoxia is involved in the proliferation and differentiation of stem cells. In this study, we investigated the effect of hypoxia on MSC proliferation and DAergic neuronal differentiation. Our results demonstrate that 3% O2 treatment can enhance rat MSC proliferation by upregulation of phosphorylated p38 MAPK and subsequent nuclear translocation of hypoxia inducible factor (HIF)-1α. During neural differentiation, 3% O2 treatment increases the expression of HIF-1α, phosphorylated ERK and p38 MAPK. These changes are followed by promotion of neurosphere formation and further DAergic neuronal differentiation. Furthermore, we explored the physiological function of hypoxia-induced DAergic neurons from human fetal MSCs by transplanting them into parkinsonian rats. Grafts induced with hypoxia display more survival of DAergic neurons and greater amelioration of behavioral impairments. Altogether, these results suggest that hypoxia can promote MSC proliferation and DAergic neuronal differentiation, and benefit for intrastriatal transplantation. Therefore, this study may provide new perspectives in application of MSCs to clinical PD therapy.
doi:10.1371/journal.pone.0054296
PMCID: PMC3546985  PMID: 23342124
16.  Long-Term Chronic Opioid Therapy Discontinuation Rates from the TROUP Study 
Journal of General Internal Medicine  2011;26(12):1450-1457.
ABSTRACT
OBJECTIVE
To report chronic opioid therapy discontinuation rates after five years and identify factors associated with discontinuation.
METHODS
Medical and pharmacy claims records from January 2000 through December 2005 from a national private health network (HealthCore), and Arkansas (AR) Medicaid were used to identify ambulatory adult enrollees who had 90 days of opioids supplied. Recipients were followed until they discontinued opioid prescription fills or disenrolled. Kaplan Meier survival models and Cox proportional hazards models were estimated to identify factors associated with time until opioid discontinuation.
RESULTS
There were 23,419 and 6,848 chronic opioid recipients followed for a mean of 1.9 and 2.3 years in the HealthCore and AR Medicaid samples. Over a maximum follow up of 4.8 years, 67.0% of HealthCore and 64.9% AR Medicaid recipients remained on opioids. Recipients on high daily opioid dose (greater than 120 milligrams morphine equivalent (MED)) were less likely to discontinue than recipients taking lower doses: HealthCore hazard ratio (HR) = 0.66 (95%CI: 0.57–0.76), AR Medicaid HR = 0.66 (95%CI: 0.50–0.82). Recipients with possible opioid misuse were also less likely to discontinue: HealthCore HR = 0.83 (95%CI: 0.78–0.89), AR Medicaid HR = 0.78 (95%CI: 0.67–0.90).
CONCLUSIONS
Over half of persons receiving 90 days of continuous opioid therapy remain on opioids years later. Factors most strongly associated with continuation were intermittent prior opioid exposure, daily opioid dose ≥ 120 mg MED, and possible opioid misuse. Since high dose and opioid misuse have been shown to increase the risk of adverse outcomes special caution is warranted when prescribing more than 90 days of opioid therapy in these patients.
doi:10.1007/s11606-011-1771-0
PMCID: PMC3235603  PMID: 21751058
opioids; opioid misuse; persistence; discontinuation
17.  Trends in the Prescription of Opioids for Adolescents with Non-cancer Pain 
General hospital psychiatry  2011;33(5):423-428.
Objectives
Opioids are among the most commonly abused drugs among adolescents and the prescription of these drugs has increased over the last decade. The goal of the current study is to examine trends and factors associated with prescription opioid use among adolescents with common non-cancer pain (NCP) conditions, sampled from two contrasting populations.
Methods
We conducted a secondary data analysis examining time trends from 2001 to 2005 in opioid use in two dissimilar populations: a national, commercially-insured population and a state Medicaid plan. We examined trends in mean dose prescribed, mean number of prescriptions, and types of medications given, as well as clinical and demographic features of adolescents receiving opioids.
Results
In 2005, 21% of adolescents with common NCP conditions in HealthCore and 40.2% of adolescents with NCP in Arkansas Medicaid had received prescription opioids. The majority of opioid prescriptions in both 2001 and 2005 were for DEA Schedule II and III short acting opioids. In both samples, rates of prescription were higher for adolescents with comorbid mental health diagnoses compared to those without and for adolescents with multiple pain conditions compared to a single pain condition.
Discussion
Prescription of opioids among adolescents with NCP is common and the prescription rate is higher among adolescents with multiple pain conditions and comorbid mental health disorders. Further research is necessary to determine risk factors for abuse and misuse of opioids in adolescents to help develop guidelines for use in this age group.
doi:10.1016/j.genhosppsych.2011.04.009
PMCID: PMC3175336  PMID: 21749839
Pain; Adolescents; Opioids
18.  The relationship between attention deficit hyperactivity disorder and premature infants in Taiwanese: a case control study 
BMC Psychiatry  2012;12:85.
Background
Preterm survivors from the neonatal intensive care unit (NICU) are considered to be at risk for some neurobehavioral disorders such as attention-deficit/hyperactivity disorder (ADHD). The current study aimed to explore the relationship between ADHD and premature infants in Taiwan.
Methods
A total of 195 children (157 males and 38 females) diagnosed with ADHD based on DSM-IV and aged between 6 to 12 years and a control group of 212 (164 males, 48 females) age- and sex-matched healthy children were enrolled. The ADHD-Rating scale and CGI severity were performed by child psychiatrists. Demographic data of the children, including birth history, perinatal neurological and respiratory problems were collected to facilitate the investigation of whether a correlation exists between ADHD and prematurity.
Results
The ADHD group had a significantly higher rate of prematurity and significantly higher rate of low birth body weight (defined as <2500 g) than the control group (both P = 0.003). Pearson correlation showed a significantly negative correlation between gestational age and ADHD-RS score, inattentive score, hyperactivity and CGI-S score (P = 0.004, 0.013, 0.015 and 0.002, respectively). However, only a CGI-S score (P = 0.018) showed a significantly correlation between low birth weight and ADHD.
Conclusions
Premature infants have significantly more severe symptoms of ADHD at school age and they were highly correlated. Further study is necessary to determine the main effect and pathogenesis of moderate as well as extreme preterm birth on the development of ADHD.
doi:10.1186/1471-244X-12-85
PMCID: PMC3411486  PMID: 22824325
Premature infant; Attention-deficit/hyperactivity disorder; Behavioral disorder; DSM-IV; Gestational age
19.  SECOM: A Novel Hash Seed and Community Detection Based-Approach for Genome-Scale Protein Domain Identification 
PLoS ONE  2012;7(6):e39475.
With rapid advances in the development of DNA sequencing technologies, a plethora of high-throughput genome and proteome data from a diverse spectrum of organisms have been generated. The functional annotation and evolutionary history of proteins are usually inferred from domains predicted from the genome sequences. Traditional database-based domain prediction methods cannot identify novel domains, however, and alignment-based methods, which look for recurring segments in the proteome, are computationally demanding. Here, we propose a novel genome-wide domain prediction method, SECOM. Instead of conducting all-against-all sequence alignment, SECOM first indexes all the proteins in the genome by using a hash seed function. Local similarity can thus be detected and encoded into a graph structure, in which each node represents a protein sequence and each edge weight represents the shared hash seeds between the two nodes. SECOM then formulates the domain prediction problem as an overlapping community-finding problem in this graph. A backward graph percolation algorithm that efficiently identifies the domains is proposed. We tested SECOM on five recently sequenced genomes of aquatic animals. Our tests demonstrated that SECOM was able to identify most of the known domains identified by InterProScan. When compared with the alignment-based method, SECOM showed higher sensitivity in detecting putative novel domains, while it was also three orders of magnitude faster. For example, SECOM was able to predict a novel sponge-specific domain in nucleoside-triphosphatase (NTPases). Furthermore, SECOM discovered two novel domains, likely of bacterial origin, that are taxonomically restricted to sea anemone and hydra. SECOM is an open-source program and available at http://sfb.kaust.edu.sa/Pages/Software.aspx.
doi:10.1371/journal.pone.0039475
PMCID: PMC3386278  PMID: 22761802
20.  Over-expression of BMPR-IB reduces the malignancy of glioblastoma cells by upregulation of p21 and p27Kip1 
Background
In our previous study, we detected decreased expression of phospho-Smad1/5/8 and its upstream signaling molecule, bone morphogenetic protein receptor IB subunit (BMPR-IB), in certain glioblastoma tissues, unlike normal brain tissues. In order to clarify the functional roles and mechanism of BMPR-IB in the development of glioblastoma, we studied the effects of BMPR-IB overexpression on glioblastoma cell lines in vitro and in vivo.
Methods
We selected glioblastoma cell lines U251, U87, SF763, which have different expression of BMPR-IB to be the research subjects. Colony formation analysis and FACS were used to detect the effects of BMPR-IB on the growth and proliferation of glioblastoma cells in vivo. Immunofluresence was used to detect the differentiation changes after BMPR-IB overexpression or knocking-down. Then we used subcutaneous and intracranial tumor models to study the effect of BMPR-IB on the growth and differentiation of glioblastoma cells in vivo. The genetic alterations involved in this process were examined by real-time PCR and western blot analysis.ed.
Results and conclusion
Forced BMPR-IB expression in malignant human glioma cells, which exhibit lower expression of BMPR-IB, induced the phosphorylation and nuclear localization of smad1/5/8 and arrested the cell cycle in G1. Additionally, BMPR-IB overexpression could suppress anchorage-independent growth and promote differentiation of theses glioblastoma cells. Furthermore, overexpression of BMPR-IB inhibited the growth of subcutaneous and intracranial tumor xenografts and prolonged the survival of mice injected intracranially with BMPR-IB-overexpressing glioblastoma cells. Conversely, inhibition of BMPR-IB caused SF763 malignant glioma cells, a line known to exhibit high BMPR-IB expression that does not form tumors when used for xenografts, to show increased growth and regain tumorigenicity in a nude mouse model system, ultimately shortening the survival of these mice. We also observed significant accumulation of p21 and p27kip1 proteins in response to BMPR-IB overexpression. Our study suggests that overexpression of BMPR-IB may arrest and induce the differentiation of glioblastoma cells due to upregulation of p21 and p27kip1 in vitro and that in vivo and decreased expression of BMPR-IB in human glioblastoma cells contributes to glioma tumorigenicity. BMPR-IB could represent a new potential therapeutic target for malignant human gliomas.
doi:10.1186/1756-9966-31-52
PMCID: PMC3408360  PMID: 22650359
1. BMPR-IB; 2. Glioblastoma; 3. Growth inhibition; 4. Differentiation
21.  Grey and white matter abnormalities in chronic obstructive pulmonary disease: a case–control study 
BMJ Open  2012;2(2):e000844.
Objectives
The irreversible airflow limitation characterised by chronic obstructive pulmonary disease (COPD) causes a decrease in the oxygen supply to the brain. The aim of the present study was to investigate brain structural damage in COPD.
Design
Retrospective case–control study. Patients with COPD and healthy volunteers were recruited. The two groups were matched in age, gender and educational background.
Setting
A hospital and a number of communities: they are all located in southern Fujian province, China.
Participants
25 stable patients and 25 controls were enrolled from December 2009 to May 2011.
Methods
Using voxel-based morphometry and tract-based spatial statistics based on MRI to analyse grey matter (GM) density and white matter fractional anisotropy (FA), respectively, and a battery of neuropsychological tests were performed.
Results
Patients with COPD (vs controls) showed decreased GM density in the limbic and paralimbic structures, including right gyrus rectus, left precentral gyrus, bilateral anterior and middle cingulate gyri, bilateral superior temporal gyri, bilateral anterior insula extending to Rolandic operculum, bilateral thalamus/pulvinars and left caudate nucleus. Patients with COPD (vs controls) had decreased FA values in the bilateral superior corona radiata, bilateral superior and inferior longitudinal fasciculus, bilateral optic radiation, bilateral lingual gyri, left parahippocampal gyrus and fornix. Lower FA values in these regions were associated with increased radial diffusivity and no changes of longitudinal diffusivity. Patients with COPD had poor performances in the Mini-Mental State Examination, figure memory and visual reproduction. GM density in some decreased regions in COPD had positive correlations with arterial blood Po2, negative correlations with disease duration and also positive correlations with visual tasks.
Conclusion
The authors demonstrated that COPD exhibited loss of regional GM accompanied by impairment of white matter microstructural integrity, which was associated with disease severity and may underlie the pathophysiological and psychological changes of COPD.
Article summary
Article focus
Decreased oxygen supply to brain may cause neuronal damage in COPD. However, the damage remains largely uninvestigated.
Key messages
We found that COPD extends to the brain, with the loss of regional cortical grey matter accompanied by impairment in the white matter microstructural integrity.
Our findings would be help for clinical therapy of COPD.
Strengths and limitations of this study
Multiple analyses were used based on MR images. The statistic power for FA analysis was weak.
doi:10.1136/bmjopen-2012-000844
PMCID: PMC3341600  PMID: 22535793
22.  The protective role of 5-hydroxymethyl-2-furfural (5-HMF) against acute hypobaric hypoxia 
Cell Stress & Chaperones  2011;16(5):529-537.
Our previous study showed that pretreatment with 5-hydroxymethyl-2-furfural (5-HMF) led to protection against hypoxic injury via a p-ERK-mediated pathway in vitro. Whether the protection of 5-HMF against hypoxia is effective in vivo is unknown. The present study is aimed to verify the role of 5-HMF in acute hypobaric hypoxia using Kunming mice as an in vivo model and further investigate the underlying mechanisms. Mice pretreated with or without 5-HMF for 1 h were exposed to acute hypobaric hypoxic condition for 6 h and then the survival time, the survival rate, the permeability of blood–brain barrier (BBB), the histological analysis in hippocampus and cortex, and the phosphorylation level of mitogen-activated protein kinases (ERK, JNK, and p38) were investigated. The results showed that 5-HMF significantly increased the survival time and the survival rate of mice. Accordingly, pretreatment with 5-HMF markedly attenuated acute hypobaric hypoxia-induced permeability of BBB (P < 0.01). In addition, the cellular damage extent of the hippocampus and the cortex induced by hypoxia for 6 h was also attenuated by pretreatment with 5-HMF, especially in the hippocampus CA1 region. Furthermore, the activation of ERK rather than JNK and p38 was involved in the protection of 5-HMF against acute hypobaric hypoxia. In summary, 5-HMF enhanced the survival capability of mice and decreased acute hypoxic damage to the brain, which may be associated with the effects on BBB and p-ERK.
Electronic supplementary material
The online version of this article (doi:10.1007/s12192-011-0264-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s12192-011-0264-8
PMCID: PMC3156263  PMID: 21494793
5-HMF; Hypobaric hypoxia; Brain injury; BBB
23.  Upregulation of cardiac NOS due to endotoxemia and vagal overactivity contribute to the hypotensive effect of chronic ethanol in female rats 
European journal of pharmacology  2010;650(1):317-323.
We previously reported that chronic ethanol lowers blood pressure in female rats. In this study, hemodynamic, biochemical, and immunoblot analyses were performed to investigate: (i) the roles of cardiac contractility and autonomic activity in the hypotensive action of ethanol, and (ii) whether endotoxemia-induced upregulation of cardiac and/or vascular nitric oxide synthase (NOS) isoforms underlies the hypotensive and cardiac effects of ethanol. Telemetric monitoring of blood pressure, heart rate, and myocardial contractility (dP/dtmax) was performed in female rats receiving liquid diet with or without ethanol (5% w/v, 13 weeks). Autonomic control was assessed by frequency domain analysis of interbeat intervals (IBI) and systolic blood pressure (SBP). Compared with pair-fed controls, ethanol caused sustained reductions in blood pressure, heart rate, and +dP/dtmax. Ethanol feeding increased the spectral power of high-frequency band (IBIHF, 0.75–3 Hz) and decreased the low-frequency band (IBILF, 0.25–0.75 Hz) and IBILF/HF ratio, suggesting increased cardiac parasympathetic dominance. In contrast, vascular tone was not affected by ethanol because SBP spectral bands and plasma norepinephrine remained unchanged. Myocardial expressions of eNOS and its upstream regulators, phosphatidylinositol 3-kinase(PI3K) and Akt, and plasma endotoxin and nitrite/nitrate were increased by ethanol. Myocardial iNOS was also increased by ethanol whereas nNOS remained unchanged and aortic levels of all NOS isoforms were not altered by ethanol. These findings suggest that facilitation of myocardial PI3K/Akt/eNOS and iNOS pathways, due possibly to ethanol-induced endotoxemia and/or increased cardiac parasympathetic dominance, might constitute a cellular mechanism for the reduced myocardial contractility and hypotension caused by ethanol in female rats.
doi:10.1016/j.ejphar.2010.10.032
PMCID: PMC3026607  PMID: 20970417
Ethanol; blood pressure; myocardial contractility; female rats; nitric oxide synthase; hemodynamic variability
24.  Risks for Opioid Abuse and Dependence Among Recipients of Chronic Opioid Therapy: Results from the TROUP Study 
Drug and alcohol dependence  2010;112(1-2):90-98.
Objective
To estimate the prevalence of and risk factors for opioid abuse/dependence in long-term users of opioids for chronic pain, including risk factors for opioid abuse/dependence that can potentially be modified to decrease the likelihood of opioid abuse/dependence, and non-modifiable risk factors for opioid abuse/dependence that may be useful for risk stratification when considering prescribing opioids.
Methods
We used claims data from two disparate populations, one national, commercially insured population (HealthCore) and one state-based, publicly insured (Arkansas Medicaid). Among users of chronic opioid therapy, we regressed claims-based diagnoses of opioid abuse/dependence on patient characteristics, including physical health, mental health and substance abuse diagnoses, sociodemographic factors, and pharmacological risk factors.
Results
Among users of chronic opioid therapy, 3% of both the HealthCore and Arkansas Medicaid samples had a claims-based opioid abuse/dependence diagnosis. There was a strong inverse relationship between age and a diagnosis of opioid abuse/dependence. Mental health and substance use disorders were associated with an increased risk of opioid abuse/dependence. Effects of substance use disorders were especially strong, although mental health disorders were more common. Concerning opioid exposure; lower days supply, lower average doses, and use of Schedule III-IV opioids only, were all associated with lower likelihood of a diagnosis of opioid abuse/dependence.
Conclusion
Opioid abuse and dependence are diagnosed in a small minority of patients receiving chronic opioid therapy, but this may underestimate actual misuse. Characteristics of the patients and of the opioid therapy itself are associated with the risk of abuse and dependence.
doi:10.1016/j.drugalcdep.2010.05.017
PMCID: PMC2967631  PMID: 20634006
pain; opioids; abuse; dependence
25.  The protective role of 5-HMF against hypoxic injury 
Cell Stress & Chaperones  2010;16(3):267-273.
In an attempt to find new types of anti-hypoxic agents from herbs, we identified 5-hydroxymethyl-2-furfural (5-HMF) as a natural agent that fulfills the criterion. 5-HMF, the final product of carbohydrate metabolism, has favorable biological effects such as anti-oxidant activity and inhibiting sickling of red blood cells. The role of 5-HMF in hypoxia, however, is not yet. Our pilot results showed that pretreatment with 5-HMF markedly increased both the survival time and the survival rate of mice under hypoxic stress. The present study was aimed to further investigate the protective role of 5-HMF and the underlying mechanisms in hypoxic injury using ECV304 cells as an in vitro model. ECV304 cells pretreated with or without 5-HMF for 1 h were exposed to hypoxic condition (0.3% O2) for 24 h and then cell apoptosis, necrosis, the changes of mitochondrial membrane potential (MMP) and the expressions of phosphorylation- extracellular signal-regulated kinase (p-ERK) were investigated. Pretreatment with 5-HMF markedly attenuated hypoxia-induced cell necrosis and apoptosis at late stage (p < 0.01). Furthermore, pretreatment with 5-HMF rescued both the decline of the MMP and the increase of p-ERK protein under hypoxia. In a word, these results indicated that 5-HMF had protective effects against hypoxic injury in ECV304 cells, and its effects on MMP and p-ERK may be involved in the mechanism.
doi:10.1007/s12192-010-0238-2
PMCID: PMC3077221  PMID: 21057989
5-HMF; Hypoxic injury; ECV304 cells; MMP

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