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1.  Increased Frequency of α-Synuclein in the Substantia Nigra in HIV Infection 
Journal of neurovirology  2009;15(2):131-138.
The frequency of neurodegenerative markers among long surviving HIV infected individuals is unknown, therefore, the present study investigated the frequency of α-synuclein, β-amyloid and HIV-associated brain pathology in the brains of older HIV infected individuals. We examined the substantia nigra of 73 clinically well-characterized HIV infected individuals aged 50 to 76 years from the National NeuroAIDS Tissue Consortium. We also examined the frontal and temporal cortical regions of a subset of 36 individuals. The brain regions were examined for the presence of α-synuclein, β-amyloid and HIV-associated brain pathology. Neuritic α-synuclein expression was found in 16% (12/73) of the substantia nigra of the HIV+ cases and none of the older control cases (0/18). β-amyloid deposits were prevalent and found in nearly all of the HIV+ cases (35/36). Despite these increases of degenerative pathology, HIV-associated brain pathology was present in only 10% of cases. Among older HIV+ adults HIV-associated brain pathology does not appear elevated; however, the frequency of both α-synuclein and β-amyloid is higher than that found in older healthy persons. The increased prevalence of α-synuclein and β-amyloid in the brains of older HIV-infected individuals may predict an increased risk of developing neurodegenerative disease.
PMCID: PMC3979854  PMID: 19115126
HIV; Brain Pathology; Aging; Substantia Nigra; Cognition
2.  Protocol for a systematic review and economic evaluation of the clinical and cost-effectiveness of non-hospital-based non-invasive ventilation (NIV) in patients with stable end-stage COPD with hypercapnic respiratory failure 
Systematic Reviews  2014;3:32.
Chronic obstructive pulmonary disease (COPD) remains a significant public health burden. Non-invasive ventilation (NIV) is a method of supported breathing used as standard care for acutely unwell patients in hospital with COPD, but there is uncertainty around the potential benefits of using NIV in the treatment of stable patients in a non-hospital setting. This is a protocol for systematic reviews of the clinical and cost-effectiveness of NIV in this context, being undertaken in support of a model based economic evaluation.
Standard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction for both the clinical and economic systematic reviews. Bibliographic databases (for example MEDLINE, EMBASE) and ongoing trials registers will be searched from 1980 onwards. The search strategy will combine terms for the population with those for the intervention. Studies will be selected for review if the population includes adult patients with COPD and hypercapnic respiratory failure, however defined. Systematic reviews, randomised controlled trials and observational studies (with n >1) will be included, and quality assessment will be tailored to the different study designs. The primary outcome measures of interest are survival, quality of life, and healthcare utilisations (hospitalisation and Accident and Emergency attendances). Meta-analyses will be undertaken where clinical and methodological homogeneity exists, supported by predefined subgroup analyses where appropriate. A systematic review of the evidence on the cost-effectiveness of non-hospital NIV will be completed, and a model-based cost-utility analysis undertaken to determine the cost-effectiveness of non-hospital-based NIV compared with standard care.
These reviews will attempt to clarify the clinical effectiveness of non-hospital NIV in COPD patients as well as the cost-effectiveness. The findings may indicate whether NIV in a non-hospital setting should be considered more routinely in this patient group, and what the likely cost implications will be.
PROSPERO registration
PMCID: PMC3977879  PMID: 24669937
COPD; Non-hospital-based non-invasive ventilation; Hypercapnia; Clinical effectiveness; Cost-effectiveness; Systematic review; Meta-analysis
3.  Bile acids activate YAP to promote liver carcinogenesis 
Cell reports  2013;5(4):1060-1069.
Elevated bile acid levels increase hepatocellular carcinoma by unknown mechanisms. Here we show that mice with a severe defect in bile acid homeostasis due to loss of the nuclear receptors FXR and SHP have enlarged livers, progenitor cell proliferation, YAP (Yes Associated Protein) activation, and develop spontaneous liver tumorigenesis. This phenotype mirrors mice with loss of hippo kinases or overexpression of their downstream target YAP. Bile acids act as upstream regulators of YAP via a novel pathway dependent on induction of the scaffold protein Iqgap1. Patients with diverse biliary dysfunctions exhibit enhanced Iqgap1 and nuclear YAP expression. Our findings reveal an unexpected mechanism for bile acid regulation of liver growth and tumorigenesis via the Hippo pathway.
PMCID: PMC3961013  PMID: 24268772
4.  Temporal Association in Hospitalizations for Tuberculosis, Invasive Pneumococcal Disease and Influenza Virus Illness in South African Children 
PLoS ONE  2014;9(3):e91464.
The seasonal variability in hospitalization for tuberculosis may in part relate to super-imposed bacterial or predisposing respiratory viral infections. We aimed to study the temporal association between hospitalization for culture-confirmed pulmonary tuberculosis (PTB), invasive pneumococcal disease (IPD) and influenza virus epidemics in South African children.
We undertook a retrospective analysis which examined seasonal trends, from 2005 to 2008, for hospitalization for culture-confirmed PTB and IPD among children in relation to the influenza epidemics in Soweto, South Africa. Original time-series of the influenza virus epidemics and hospitalization rates for PTB and IPD were decomposed into three components: a trend cycle component, a seasonal component and an irregular component using the X-11 seasonal adjustment method. To compare the seasonality amongst the three series, the trend and irregular components were removed and only seasonal components examined.
Across the study period, the influenza virus epidemics peaked during May to July (winter) months, which was closely followed by an increase in the incidence of hospitalization for IPD (August to October) and PTB (August to November).
Within- and between-year temporal changes associated with childhood TB hospitalization may in part be driven by factors which influence temporal changes in pneumococcal disease, including potential variability in the severity of influenza virus epidemics in temperate climates. The dynamics of the interplay between the host and these infectious agents appears to be complex and multifactorial.
PMCID: PMC3950213  PMID: 24618667
5.  A Delayed and Rather Unusual Presentation of a Bladder Injury after Pelvic Trauma: 5 Years after a Road Traffic Accident 
Case Reports in Orthopedics  2014;2014:873079.
Associated injuries frequently occur in patients who sustain fractures of the pelvis. Specifically, high-energy trauma resulting in pelvic fractures places the bladder and urethra at risk for injury, often resulting in significant complications. Timely identification and management of genitourinary injuries minimize associated morbidity. Prompt injury identification depends upon a systematic evaluation with careful consideration of the mechanism of injury. Physical examination is pertinent as well as analysis of the urine and appropriate diagnostic imaging. Despite such increased vigilance genitourinary injuries get missed and delayed presentations in the order of a few weeks have been well documented. To our knowledge, this is the first report of its kind in the literature showing such a particularly delayed (5 years) and rather unusual presentation of a bladder injury after pelvic trauma.
PMCID: PMC3971558  PMID: 24716066
6.  Staples Equal Sutures for Skin Closure After Soft Tissue Tumor Resection 
Wound closure accounts for a relatively constant portion of the time required to complete a surgical case. Both longer closure times and wound infections contribute to higher medical costs and patient morbidity.
We therefore determined whether (1) biologic and treatment factors greater influenced wound healing than the choice of sutures or staples; and (2) different times to closure affected cost when sutures or staples are used in patients with musculoskeletal tumors.
We retrospectively reviewed 511 patients who had sarcoma resections of the buttock, thigh, and femur from 2003 to 2010; 376 had closure with sutures and 135 with staples. Data were abstracted on patient demographics, comorbidities, select procedural data, and wound complications. Wound complications were defined by hospitalization within 6 months postoperatively for a wound problem, irrigation and débridement, or infection treated with antibiotics. We determined the association between staples versus sutures and wound complications after controlling for confounding factors. The minimum followup was 2 weeks. A prospective, timed analysis of wounds closed with either sutures or staples was also performed.
We found an association between obesity and radiation and wound complications. Wounds were closed an average of 5.3 minutes faster with staples than with suture (0.29 minutes versus 5.6 minutes, respectively), saving a mean 2.1% of the total operating time although the total operating time was similar in the two groups.
We found no difference in wound complications after closure with sutures or staples, although obesity and radiation treatment appear to affect wound outcomes. Data suggest that time saved in the operating room by closing with staples compensates for added material costs and does not compromise wound care in patients with lower extremity sarcomas.
Level of Evidence
Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3563796  PMID: 22903280
7.  FXR inhibits gankyrin in mouse livers and prevents development of liver cancer 
Hepatology (Baltimore, Md.)  2013;57(3):1098-1106.
One of the early events in development of liver cancer is a neutralization of tumor suppressor proteins Rb, p53, HNF4α and C/EBPα. The elimination of these proteins is mediated by a small subunit of proteasome, gankyrin, which is activated by cancer. The aim of this study was to determine mechanisms which repress gankyrin in quiescent livers and mechanisms of activation of gankyrin in liver cancer. We found that farnesoid X receptor, FXR, inhibits expression of gankyrin in quiescent livers by silencing the gankyrin promoter through HDAC1-C/EBPβ complexes. C/EBPβ is a key transcription factor which delivers HDAC1 to gankyrin promoter and causes epigenetic silencing of the promoter. We show that down-regulation of C/EBPβ in mouse hepatoma cells and in mouse livers reduces C/EBPβ-HDAC1 complexes and activates the gankyrin promoter. Deletion of FXR signaling in mice leads to de-repression of the gankyrin promoter and to spontaneous development of liver cancer at 12 months of age. DEN-mediated liver cancer in WT mice also involves the reduction of FXR and activation of gankyrin. Examination of liver cancer in old mice and liver cancer in human patients revealed that FXR is reduced; while gankyrin is elevated during spontaneous development of liver cancer. Searching for animal models with altered levels of FXR, we found that long-lived Little mice have high levels of FXR and do not develop liver cancer with age and after DEN injections due to failure to activate gankyrin and eliminate Rb, p53, HNF4α and C/EBPα proteins.
FXR prevents liver cancer by inhibiting the gankyrin promoter via C/EBPβ-HDAC1 complexes leading to subsequent protection of tumor suppressor proteins from degradation.
PMCID: PMC3649861  PMID: 23172628
Cancer; liver; gankyrin; C/EBP; HDAC1
8.  Expansion of HAART Coverage Is Associated with Sustained Decreases in HIV/AIDS Morbidity, Mortality and HIV Transmission: The “HIV Treatment as Prevention” Experience in a Canadian Setting 
PLoS ONE  2014;9(2):e87872.
There has been renewed call for the global expansion of highly active antiretroviral therapy (HAART) under the framework of HIV treatment as prevention (TasP). However, population-level sustainability of this strategy has not been characterized.
We used population-level longitudinal data from province-wide registries including plasma viral load, CD4 count, drug resistance, HAART use, HIV diagnoses, AIDS incidence, and HIV-related mortality. We fitted two Poisson regression models over the study period, to relate estimated HIV incidence and the number of individuals on HAART and the percentage of virologically suppressed individuals.
HAART coverage, median pre-HAART CD4 count, and HAART adherence increased over time and were associated with increasing virological suppression and decreasing drug resistance. AIDS incidence decreased from 6.9 to 1.4 per 100,000 population (80% decrease, p = 0.0330) and HIV-related mortality decreased from 6.5 to 1.3 per 100,000 population (80% decrease, p = 0.0115). New HIV diagnoses declined from 702 to 238 cases (66% decrease; p = 0.0004) with a consequent estimated decline in HIV incident cases from 632 to 368 cases per year (42% decrease; p = 0.0003). Finally, our models suggested that for each increase of 100 individuals on HAART, the estimated HIV incidence decreased 1.2% and for every 1% increase in the number of individuals suppressed on HAART, the estimated HIV incidence also decreased by 1%.
Our results show that HAART expansion between 1996 and 2012 in BC was associated with a sustained and profound population-level decrease in morbidity, mortality and HIV transmission. Our findings support the long-term effectiveness and sustainability of HIV treatment as prevention within an adequately resourced environment with no financial barriers to diagnosis, medical care or antiretroviral drugs. The 2013 Consolidated World Health Organization Antiretroviral Therapy Guidelines offer a unique opportunity to further evaluate TasP in other settings, particularly within generalized epidemics, and resource-limited setting, as advocated by UNAIDS.
PMCID: PMC3922718  PMID: 24533061
9.  Substance Use is a Risk Factor for Neurocognitive Deficits and Neuropsychiatric Distress in Acute and Early HIV Infection 
Journal of neurovirology  2012;19(1):65-74.
The acute and early stages of HIV infection (AEH) are characterized by substantial viral replication, immune activation, and alterations in brain metabolism. However, little is known about the prevalence and predictors of neurocognitive deficits and neuropsychiatric disturbances during this period. The present study examined the impact of demographic, HIV disease, and substance use factors on HIV-associated neurocognitive impairment and self-reported neuropsychiatric distress among 46 antiretroviral-naïve adults with median duration of infection of 75 days, relative to sample a of 21 HIV seronegative (HIV-) adults with comparable demographics and risk factors. Participants were administered a brief neurocognitive battery that was adjusted for demographics and assessed executive functions, memory, psychomotor speed, and verbal fluency, as well as the Profile of Mood States (POMS), a self-report measure of neuropsychiatric distress. Odds ratios revealed that AEH participants were nearly four times more likely than their seronegative counterparts to experience neurocognitive impairment, particularly in the areas of learning and information processing speed. Similarly, AEH was associated with a nearly five-fold increase in the odds of neuropsychiatric distress, most notably in anxiety and depression. Within the AEH sample, HIV-associated neurocognitive impairment was associated with problematic methamphetamine use and higher plasma HIV RNA levels, whereas neuropsychiatric distress was solely associated with high-risk alcohol use. Extending prior neuroimaging findings, results from this study indicate that HIV-associated neurocognitive impairment and neuropsychiatric distress are highly prevalent during AEH and are associated with high-risk substance use.
PMCID: PMC3568179  PMID: 23250704
HIV; substance abuse; viral load; neuropsychiatry; AIDS dementia complex
10.  Prospective Memory and Antiretroviral Medication Non-Adherence in HIV: An Analysis of Ongoing Task Delay Length Using the Memory for Intentions Screening Test 
Using McDaniel & Einstein’s (2000) multi-process framework, the current study examined whether the length of prospective memory (PM) delay intervals as measured by the 2- and 15- minute subscales of the Memory for Intentions Screening Test (MIST) have differential predictive value for antiretroviral (ARV) adherence. Participants included 74 HIV-infected individuals whose ARV adherence was tracked with an electronic monitoring system. Participants were classified as “adherent” (n = 49) or “non-adherent” (n = 25) based on recorded pill bottle openings of ≥90% of prescribed doses over 30 days. An adherence group by MIST delay interval interaction was observed, such that non-adherent participants had worse performance on the 15-min, but not 2-min delay PM MIST subscales. The observed MIST 15- min delay effects were significantly more pronounced on time- versus event-cued PM trials. Long-delay time-based PM was predictive of non-adherence independent of demographics, mood state, self-reported adherence, and general cognitive functioning. Findings from this clinical study indicate that ARV non-adherence may be particularly associated with deficits in strategic cue monitoring over longer PM delays, which may inform interventions to improve adherence among persons living with HIV infection.
PMCID: PMC3693472  PMID: 23095304
episodic memory; medication adherence; everyday functioning; neuropsychological assessment; executive functions; AIDS dementia complex
11.  Broad-Spectrum Biosensor Capable of Detecting and Identifying Diverse Bacterial and Candida Species in Blood 
Journal of Clinical Microbiology  2013;51(8):2670-2678.
We describe an assay which uses broad-spectrum, conserved-site PCR paired with mass spectrometry analysis of amplicons (PCR/electrospray ionization-mass spectrometry [ESI-MS]) to detect and identify diverse bacterial and Candida species in uncultured specimens. The performance of the assay was characterized using whole-blood samples spiked with low titers of 64 bacterial species and 6 Candida species representing the breadth of coverage of the assay. The assay had an average limit of detection of 100 CFU of bacteria or Candida per milliliter of blood, and all species tested yielded limits of detection between 20 and 500 CFU per milliliter. Over 99% of all detections yielded correct identifications, whether they were obtained at concentrations well above the limit of detection or at the lowest detectable concentrations. This study demonstrates the ability of broad-spectrum PCR/ESI-MS assays to detect and identify diverse organisms in complex natural matrices that contain high levels of background DNA.
PMCID: PMC3719611  PMID: 23761152
12.  Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons 
Neurology  2013;80(4):371-379.
To describe the prevalence of neurocognitive impairment (NCI) among early diagnosed and managed HIV-infected persons (HIV+) compared to HIV-negative controls.
We performed a cross-sectional study among 200 HIV+ and 50 matched HIV-uninfected (HIV−) military beneficiaries. HIV+ patients were categorized as earlier (<6 years of HIV, no AIDS-defining conditions, and CD4 nadir >200 cells/mm3) or later stage patients (n = 100 in each group); both groups were diagnosed early and had access to care. NCI was diagnosed using a comprehensive battery of standardized neuropsychological tests.
HIV+ patients had a median age of 36 years, 91% were seroconverters (median window of 1.2 years), had a median duration of HIV of 5 years, had a CD4 nadir of 319, had current CD4 of 546 cells/mm3, and 64% were on highly active antiretroviral therapy (initiated 1.3 years after diagnosis at a median CD4 of 333 cells/mm3). NCI was diagnosed among 38 (19%, 95% confidence interval 14%–25%) HIV+ patients, with a similar prevalence of NCI among earlier and later stage patients (18% vs 20%, p = 0.72). The prevalence of NCI among HIV+ patients was similar to HIV− patients.
HIV+ patients diagnosed and managed early during the course of HIV infection had a low prevalence of NCI, comparable to matched HIV-uninfected persons. Early recognition and management of HIV infection may be important in limiting neurocognitive impairment.
PMCID: PMC3589242  PMID: 23303852
13.  The Disruptive Effects of Pain on Complex Cognitive Performance and Executive Control 
PLoS ONE  2013;8(12):e83272.
Pain interferes and disrupts attention. What is less clear is how pain affects performance on complex tasks, and the strategies used to ensure optimal outcomes. The aim of the current study was to examine the effect of pain on higher-order executive control processes involved in managing complex tasks. Sixty-two adult volunteers (40 female) completed two computer-based tasks: a breakfast making task and a word generation puzzle. Both were complex, involving executive control functions, including goal-directed planning and switching. Half of those recruited performed the tasks under conditions of thermal heat pain, and half with no accompanying pain. Whilst pain did not affect central performance on either task, it did have indirect effects. For the breakfast task, pain resulted in a decreased ability to multitask, with performance decrements found on the secondary task. However, no effects of pain were found on the processes thought to underpin this task. For the word generation puzzle, pain did not affect task performance, but did alter subjective accounts of the processes used to complete the task; pain affected the perceived allocation of time to the task, as well as switching perceptions. Sex differences were also found. When studying higher-order cognitive processes, pain-related interference effects are varied, and may result in subtle or indirect changes in cognition.
PMCID: PMC3875458  PMID: 24386168
14.  WNT Signaling Pathway Gene Polymorphisms and Risk of Hepatic Fibrosis and Inflammation in HCV-Infected Patients 
PLoS ONE  2013;8(12):e84407.
Chronic hepatitis C infection is the leading cause of hepatocellular carcinoma (HCC), a highly lethal malignancy with rapidly increasing prevalence in the United States. Little is known about genetic variations and HCC risk. This study aimed to determine if genetic variation in Wnt signaling pathway genes are associated with advanced hepatic fibrosis and inflammation risk in a hepatitis C virus (HCV) infected population.
We performed a genetic association cross-sectional study evaluating single nucleotide polymorphisms (SNPs) in 58 candidate genes and risk of FibroSURE-Acti Test determined advanced fibrosis (F3/F4-F4 advanced cases vs. F0-F3 mild controls) and inflammation (A2/A3-A3 advanced cases vs. A0-A2 mild controls). We calculated odds ratios (ORs) and 95% confidence intervals (CIs) employing multivariate logistic regression. Haplotypes were inferred by the HAPLO.STAT program, interactions were evaluated using multifactor dimensionality reduction (MDR) analysis.
Among 425 chronically HCV-infected male veterans, 155 (37%) had advanced fibrosis and 180 (42%) had advanced inflammation. Of 3016 SNPs evaluated, eight were significantly associated with fibrosis risk (e.g., SFRP2 rs11937424: OR = 2.19, 95% CI 1.48-3.23, P = 0.00004), and seven were significantly associated with inflammation risk (e.g., SFRP1 rs16890282: OR = 2.15, 95% CI 1.39-3.16, P = 0.0004). MDR analysis identified overweight/obese, SOST rs1405952, SFRP2 rs11937424, and FZD4 rs11234870 as the best interaction model for predicting risk of fibrosis; whereas race/ethnicity, FZD1 rs1346665, and TBX3 rs1520177 as the best interaction model for predicting risk of inflammation.
Polymorphisms in several genes involved in the Wnt signaling pathway were associated with hepatic fibrosis or inflammation risk in HCV-infected males. Additional studies in other multi-ethnic HCV cohorts are needed to validate our findings in males and to assess if similar associations exist in chronically HCV-infected females.
PMCID: PMC3875538  PMID: 24386373
15.  Morphological Characterization of Mycobacterium tuberculosis in a MODS Culture for an Automatic Diagnostics through Pattern Recognition 
PLoS ONE  2013;8(12):e82809.
Tuberculosis control efforts are hampered by a mismatch in diagnostic technology: modern optimal diagnostic tests are least available in poor areas where they are needed most. Lack of adequate early diagnostics and MDR detection is a critical problem in control efforts.
The Microscopic Observation Drug Susceptibility (MODS) assay uses visual recognition of cording patterns from Mycobacterium tuberculosis (MTB) to diagnose tuberculosis infection and drug susceptibility directly from a sputum sample in 7–10 days with a low cost.
An important limitation that laboratories in the developing world face in MODS implementation is the presence of permanent technical staff with expertise in reading MODS.
We developed a pattern recognition algorithm to automatically interpret MODS results from digital images. The algorithm using image processing, feature extraction and pattern recognition determined geometrical and illumination features used in an object-model and a photo-model to classify TB-positive images. 765 MODS digital photos were processed. The single-object model identified MTB (96.9% sensitivity and 96.3% specificity) and was able to discriminate non-tuberculous mycobacteria with a high specificity (97.1% M. avium, 99.1% M. chelonae, and 93.8% M. kansasii). The photo model identified TB-positive samples with 99.1% sensitivity and 99.7% specificity.
This algorithm is a valuable tool that will enable automatic remote diagnosis using Internet or cellphone telephony. The use of this algorithm and its further implementation in a telediagnostics platform will contribute to both faster TB detection and MDR TB determination leading to an earlier initiation of appropriate treatment.
PMCID: PMC3865090  PMID: 24358227
16.  Breast cancer in lesbians and bisexual women: systematic review of incidence, prevalence and risk studies 
BMC Public Health  2013;13:1127.
The UK Parliamentary Enquiry and USA Institute of Medicine state that lesbians may be at a higher risk of breast cancer but there is insufficient information. Lesbians and bisexual (LB) women have behavioural risk-factors at higher rates compared to heterosexuals such as increased alcohol intake and higher stress levels. Conversely, breast cancer rates are higher in more affluent women yet income levels in LB women are relatively low. This systematic review investigated all evidence on whether there is, or likely to be, higher rates of breast cancer in LB women.
Cochrane library (CDSR, CENTRAL, HTA, DARE, NHSEED), MEDLINE, EMBASE, PsychINFO, CAB abstracts, Web of Science (SCI, SSCI), SIGLE and Social Care Online databases were searched to October 2013. Unpublished research and specific lesbian, gay and bisexual websites were checked, as were citation lists of relevant papers. Included were studies in LB populations reporting breast cancer incidence or prevalence rates, risk model results or risk-factor estimates. Inclusions, data-extraction and quality assessment were by two reviewers with disagreements resolved by discussion.
Searches found 198 references. No incidence rates were found. Nine studies gave prevalence estimates - two showed higher, four showed no differences, one showed mixed results depending on definitions, one had no comparison group and one gave no sample size. All studies were small with poor methodological and/or reporting quality. One incidence modelling study suggested a higher rate.
Four risk modelling studies were found, one Rosner-Colditz and three Gail models. Three suggested higher and one lower rate in LB compared to heterosexual women. Six risk-factor estimates suggested higher risk and one no difference between LB and heterosexual women.
The only realistic way to establish rates in LB women would be to collect sexual orientation within routine statistics, including cancer registry data, or from large cohort studies.
PMCID: PMC3890640  PMID: 24313963
Breast cancer; Incidence; Prevalence; Risk; Sexual orientation; Lesbian; Systematic review
17.  Liver X Receptor β and Peroxisome Proliferator-Activated Receptor δ regulate cholesterol transport in cholangiocytes 
Hepatology (Baltimore, Md.)  2012;56(6):2288-2296.
Nuclear receptors (NRs) play crucial roles in regulation of hepatic cholesterol synthesis, metabolism and conversion to bile acids, but their actions in cholangiocytes have not been examined. In this study, we investigated the roles of NRs in cholangiocyte physiology and cholesterol metabolism and flux. We examined the expression of NRs and other genes involved in cholesterol homeostasis in freshly isolated and cultured rodent cholangiocytes and found that these cells express a specific subset of NRs which includes Liver X Receptor β (LXRβ) and Peroxisome Proliferator-Activated Receptor δ (PPARδ). Activation of LXRβ and/or PPARδ in cholangiocytes induces ATP-binding cassette cholesterol transporter A1 (ABCA1) and increases cholesterol export at the basolateral compartment in polarized cultured cholangiocytes. In addition, PPARδ induces Niemann Pick C1 Like L1 (NPC1L1), which imports cholesterol into cholangiocytes and is expressed on the apical cholangiocyte membrane, via specific interaction with a PPRE within the NPC1L1 promoter. Based on these studies, we propose that (i) LXRβ and PPARδ coordinate NPC1L1/ABCA1 dependent vectorial cholesterol flux from bile through cholangiocytes and (ii) manipulation of these processes may influence bile composition with important applications in cholestatic liver disease and gallstone disease, serious health concerns for humans.
PMCID: PMC3469731  PMID: 22729460
Cholangiocyte; LXRβ; PPARδ; ABCA1; NPC1L1
18.  Methamphetamine use and neuropsychiatric factors are associated with antiretroviral nonadherence 
AIDS care  2012;24(12):1504-1513.
The present study assesses the impact of methamphetamine (METH) on antiretroviral (ART) adherence among HIV+ persons, as well as examines the contribution of neurocognitive impairment and other neuropsychiatric factors (i.e., major depressive disorder (MDD), Antisocial Personality Disorder (ASPD), and Attention Deficit Disorder (ADHD)) for ART nonadherence. We examined HIV+ persons with DSM-IV-diagnosed lifetime history of METH abuse/dependence (HIV+/METH+; n = 67) as compared to HIV+ participants with no history of METH abuse/dependence (HIV+/METH−; n = 50). Ancillary analyses compared these groups with a small group of HIV+/METH+ persons with current METH abuse/dependence (HIV+/CU METH+; n = 8). Nonadherence was defined as self-report of any skipped ART dose in the last four days. Neurocognitive functioning was assessed with a comprehensive battery, covering seven neuropsychological domains. Lifetime METH diagnosis was associated with higher rates of detectable levels of plasma and CSF HIV RNA. When combing groups (i.e., METH+ and METH− participants), univariate analyses indicated co-occurring ADHD, ASPD, and MDD predicted ART nonadherence (p’s<0.10; not lifetime METH status or neurocognitive impairment). A significant multivariable model including these variables indicated that only MDD uniquely predicted ART nonadherence after controlling for the other variables (p<0.05). Ancillary analyses indicated that current METH users (use within 30 days) were significantly less adherent (50% prevalence of nonadherence) than lifetime METH+ users and HIV+/METH-participants, and that neurocognitive impairment was associated with nonadherence (p’s<0.05). METH use disorders are associated with worse HIV disease outcomes and ART medication nonadherence. Interventions often target substance use behaviors alone to enhance antiretroviral treatment outcomes; however, in addition to targeting substance use behaviors, interventions to improve ART adherence may also need to address coexisting neuropsychiatric factors and cognitive impairment to improve ART medication taking.
PMCID: PMC3466384  PMID: 22530794
HIV/AIDS; Cognition; Medication Adherence; Antiretroviral; Methamphetamine
19.  Bmal1 and β-Cell Clock Are Required for Adaptation to Circadian Disruption, and Their Loss of Function Leads to Oxidative Stress-Induced β-Cell Failure in Mice 
Molecular and Cellular Biology  2013;33(11):2327-2338.
Circadian disruption has deleterious effects on metabolism. Global deletion of Bmal1, a core clock gene, results in β-cell dysfunction and diabetes. However, it is unknown if this is due to loss of cell-autonomous function of Bmal1 in β cells. To address this, we generated mice with β-cell clock disruption by deleting Bmal1 in β cells (β-Bmal1−/−). β-Bmal1−/− mice develop diabetes due to loss of glucose-stimulated insulin secretion (GSIS). This loss of GSIS is due to the accumulation of reactive oxygen species (ROS) and consequent mitochondrial uncoupling, as it is fully rescued by scavenging of the ROS or by inhibition of uncoupling protein 2. The expression of the master antioxidant regulatory factor Nrf2 (nuclear factor erythroid 2-related factor 2) and its targets, Sesn2, Prdx3, Gclc, and Gclm, was decreased in β-Bmal1−/− islets, which may contribute to the observed increase in ROS accumulation. In addition, by chromatin immunoprecipitation experiments, we show that Nrf2 is a direct transcriptional target of Bmal1. Interestingly, simulation of shift work-induced circadian misalignment in mice recapitulates many of the defects seen in Bmal1-deficient islets. Thus, the cell-autonomous function of Bmal1 is required for normal β-cell function by mitigating oxidative stress and serves to preserve β-cell function in the face of circadian misalignment.
PMCID: PMC3648066  PMID: 23547261
20.  Cerebral β-amyloid deposition predicts HIV-associated neurocognitive disorders in APOE ε4 carriers 
AIDS (London, England)  2012;26(18):2327-2335.
The apolipoprotein E (APOE) ε4 allele enhances cerebral accumulation of β-amyloid (Aβ) and is a major risk factor for sporadic Alzheimer’s disease (AD). We hypothesized that HIV-associated neurocognitive disorders (HAND) would be associated with the APOE ε4 genotype and cerebral Aβ deposition.
Clinico-pathological study of HIV-infected adults from four prospective cohorts in the U.S. National NeuroAIDS Tissue Consortium.
We used multivariable logistic regressions to model outcomes (Aβ plaques [immunohistochemistry] and HAND [standard criteria]) on predictors (APOE ε4 [allelic discrimination assay], older age [≥ 50 years], Aβ plaques, and their two-way interactions) and co-morbid factors.
Isocortical Aβ deposits generally occurred as diffuse plaques and mild to moderate amyloid angiopathy. Isocortical phospho-Tau-immunoreactive neurofibrillary lesions were sparse. The APOE ε4 and older age were independently associated with the presence of Aβ plaques (adjusted odds ratio [OR] 10.16 and 5.77 [95% confidence interval (CI) 2.89–35.76 and 1.91–17.48], P=0.0003 and 0.0019, respectively, n=96). The probability of HAND was increased in the presence of Aβ plaques among APOE ε4 carriers (adjusted OR 30.00 [95% CI 1.41–638.63], P=0.029, n=15), but not in non-ε4 carriers (n=57).
The APOE ε4 and older age increased the likelihood of cerebral Aβ plaque deposition in HIV-infected adults. Generally Aβ plaques in HIV brains were immunohistologically different from those in symptomatic AD brains. Nonetheless, Aβ plaques were associated with HAND among APOE ε4 carriers. The detection of APOE ε4 genotype and cerebral Aβ deposition biomarkers may be useful in identifying living HAND subjects who could benefit from Aβ-targeted therapies.
PMCID: PMC3576852  PMID: 23018443
Apolipoprotein E; β-amyloid; HIV dementia; neurofibrillary pathology; phospho-Tau
21.  HIV-infected individuals with co-occurring bipolar disorder evidence poor antiretroviral and psychiatric medication adherence 
AIDS and behavior  2012;16(8):2257-2266.
The contribution of bipolar disorder (BD), a prevalent serious mental illness characterized by impulsivity and mood instability, to antiretroviral (ART) and psychiatric medication adherence among HIV-infected (HIV+) individuals is unknown. We examined medication adherence among 44 HIV+/BD+ persons as compared to 33 demographically- and medically-comparable HIV+/BD− persons. Classification of adherent (≥90%) or non-adherent (<90%) based on proportion of correctly taken doses over 30 days was determined using electronic medication monitoring devices. HIV+/BD+ persons were significantly less likely to be ART adherent (47.7%) as compared to HIV+/BD− (90.9%) persons. Within the HIV+/BD+ group, mean psychiatric medication adherence was significantly worse than ART medication adherence, although there was a significant correlation between ART and psychiatric adherence levels. Importantly, 30-day ART adherence was associated with plasma virologic response among HIV+/BD+ individuals. Given the high overlap of HIV and BD, and the observed medication adherence difficulties for these persons, specialized adherence improvement interventions are needed.
PMCID: PMC3351543  PMID: 22041931
Medication Adherence; HIV/AIDS; Bipolar Disorder
22.  Orphan Receptor Small Heterodimer Partner Suppresses Tumorigenesis by Modulating Cyclin D1 Expression and Cellular Proliferation 
Hepatology (Baltimore, Md.)  2008;48(1):289-298.
The small heterodimer partner (SHP; NROB2), a member of the nuclear receptor superfamily, contributes to the biological regulation of several major functions of the liver. However, the role of SHP in cellular proliferation and tumorigenesis has not been investigated before. Here we report that SHP negatively regulates tumorigenesis both in vivo and in vitro. SHP−/− mice aged 12 to 15 months old developed spontaneous hepatocellular carcinoma, which was found to be strongly associated with enhanced hepatocyte proliferation and increased cyclin D1 expression. In contrast, overexpressing SHP in hepatocytes of SHP-transgenic mice reversed this effect. Embryonic fibroblasts lacking SHP showed enhanced proliferation and produced increased cyclin D1 messenger RNA and protein, and SHP was shown to be a direct negative regulator of cyclin D1 gene transcription. The immortal SHP−/− fibroblasts displayed characteristics of malignant transformed cells and formed tumors in nude mice.
These results provide first evidence that SHP plays tumor suppressor function by negatively regulating cellular growth.
PMCID: PMC3800167  PMID: 18537191
23.  Protocol for a systematic review of prognostic models for the recurrence of venous thromboembolism (VTE) following treatment for a first unprovoked VTE 
Systematic Reviews  2013;2:91.
Venous thromboembolism (VTE) is a chronic disease, with fatal recurrences occurring in 5% to 9% of patients, yet it is also one of the best examples of preventable disease. Prognostic models that utilise multiple prognostic factors (demographic, clinical and laboratory patient characteristics) in combination to predict individual outcome risk may allow the identification of patients who would benefit from long-term anticoagulation therapy, and conversely those that would benefit from stopping such therapy due to a low risk of recurrence. The study will systematically review the evidence on potential prognostic models for the recurrence of VTE or adverse outcomes following the cessation of therapy, and synthesise and summarise each model’s prognostic value. The review has been registered with PROSPERO (CRD42013003494).
Articles will be sought from the Cochrane library (CENTRAL, CDSR, DARE, HTA databases), MEDLINE and EMBASE. Trial registers will be searched for ongoing studies, and conference abstracts will be sought. Reference lists and subject experts will be utilised. No restrictions on language of publications will be applied. Studies of any design will be included if they examine, in patients ceasing therapy after at least three months’ treatment with an oral anticoagulant therapy, whether more than one factor in combination is associated with the risk of VTE recurrence or another adverse outcome. Study quality will be assessed using appropriate guidelines for prognostic models. Prognostic models will be summarised qualitatively and, if tested in multiple validation studies, their predictive performance will be summarised using a random-effects meta-analysis model to account for any between-study heterogeneity.
The results of the review will identify prognostic models for the risk of VTE recurrence or adverse outcome following cessation of therapy for a first unprovoked VTE. These will be informative for clinicians currently treating patients for a first unprovoked VTE and considering whether to stop treatment or not for particular individuals. The conclusions of the review will also inform the potential development of new prognostic models and clinical prediction rules to identify those at high or low risk of VTE recurrence or adverse outcome following a first unprovoked VTE.
PMCID: PMC3852155  PMID: 24089702
Meta-analysis; Prediction; Prognosis; Pulmonary embolism; Recurrence; Risk factors; Thromboembolism; Venous thrombosis
24.  Neonatal activation of the nuclear receptor CAR results in epigenetic memory and permanent change of drug metabolism in mouse liver 
Hepatology (Baltimore, Md.)  2012;56(4):1499-1508.
Aberrant epigenetic alterations during development may result in long-term epigenetic memory and have a permanent effect on the health of subjects. Constitutive androstane receptor (CAR; NR1I3) is a central regulator of drug/xenobiotic metabolism. Here, we report that transient neonatal activation of CAR results in epigenetic memory and a permanent change of liver drug metabolism. CAR activation by neonatal exposure to a CAR-specific ligand, 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) led to persistently induced expression of the CAR target genes Cyp2B10 and Cyp2C37 throughout the life of exposed mice. These mice showed a permanent reduction in sensitivity to zoxazolamine treatment as adults. Compared with control groups, the induction of Cyp2B10 and Cyp2C37 in hepatocytes isolated from these mice was more sensitive to low concentrations of the CAR agonist TCPOBOP. Accordingly, neonatal activation of CAR led to a permanent increase of histone 3 lysine 4 (H3K4) mono-, di- and trimethylation and decrease of H3K9 trimethylation within the Cyp2B10 locus. Transcriptional coactivator ASC-2 and histone demethylase JMJD2d participated in this CAR-dependent epigenetic switch.
Neonatal activation of CAR results in epigenetic memory and a permanent change of liver drug metabolism.
PMCID: PMC3407349  PMID: 22488010
CAR; nuclear receptor; epigenetic memory; drug metabolism; histone methylation
25.  Metabolism and Toxicity of Thioacetamide and Thioacetamide S-Oxide in Rat Hepatocytes 
Chemical research in toxicology  2012;25(9):1955-1963.
The hepatotoxicity of thioacetamide (TA) has been known since 1948. In rats, single doses cause centrilobular necrosis accompanied by increases in plasma transaminases and bilirubin. To elicit these effects TA requires oxidative bioactivation leading first to its S-oxide (TASO) and then to its chemically reactive S,S-dioxide (TASO2) which ultimately modifies amine-lipids and proteins. To generate a suite of liver proteins adducted by TA metabolites for proteomic analysis, and to reduce the need for both animals and labeled compounds, we treated isolated hepatocytes directly with TA. Surprisingly, TA was not toxic at concentrations up to 50 mM for 40 hr. On the other hand, TASO was highly toxic to isolated hepatocytes as indicated by LDH release, cellular morphology and vital staining with Hoechst 33342/propidium iodide. TASO toxicity was partially blocked by the CYP2E1 inhibitors diallyl sulfide and 4-methylpyrazole, and was strongly inhibited by TA. Significantly, we found that hepatocytes produce TA from TASO relatively efficiently by back-reduction. The covalent binding of [14C]-TASO is inhibited by unlabeled TA which acts as a “cold-trap” for [14C]-TA and prevents its re-oxidation to [14C]-TASO. This in turn increases the net consumption of [14C]-TASO despite the fact that its oxidation to TASO2 is inhibited. The potent inhibition of TASO oxidation by TA, coupled with the back-reduction of TASO and its futile redox cycling with TA may help explain phenomena previously interpreted as “saturation toxicokinetics” in the in vivo metabolism and toxicity of TA and TASO. The improved understanding of the metabolism and covalent binding of TA and TASO facilitates the use of hepatocytes to prepare protein adducts for target protein identification.
PMCID: PMC3444651  PMID: 22867114

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