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1.  The Effect of HIV-Hepatitis C Co-Infection on Bone Mineral Density and Fracture: A Meta-Analysis 
PLoS ONE  2014;9(7):e101493.
There is a variable body of evidence on adverse bone outcomes in HIV patients co-infected with hepatitis C virus (HCV). We examined the association of HIV/HCV co-infection on osteoporosis or osteopenia (reduced bone mineral density; BMD) and fracture.
Systematic review and random effects meta-analyses.
A systematic literature search was conducted for articles published in English up to 1 April 2013. All studies reporting either BMD (g/cm2, or as a T-score) or incident fractures in HIV/HCV co-infected patients compared to either HIV mono-infected or HIV/HCV uninfected/seronegative controls were included. Random effects meta-analyses estimated the pooled odds ratio (OR) and the relative risk (RR) and associated 95% confidence intervals (CI).
Thirteen eligible publications (BMD N = 6; Fracture = 7) of 2,064 identified were included with a total of 427,352 subjects. No publications reported data on HCV mono-infected controls. Meta-analysis of cross-sectional studies confirmed that low bone mineral density was increasingly prevalent among co-infected patients compared to HIV mono-infected controls (pooled OR 1.98, 95% CI 1.18, 3.31) but not those uninfected (pooled OR 1.47, 95% CI 0.78, 2.78). Significant association between co-infection and fracture was found compared to HIV mono-infected from cohort and case-control studies (pooled RR 1.57, 95% CI 1.33, 1.86) and compared to HIV/HCV uninfected from cohort (pooled RR 2.46, 95% CI 1.03, 3.88) and cross-sectional studies (pooled OR 2.30, 95% CI 2.09, 2.23).
The associations of co-infection with prevalent low BMD and risk of fracture are confirmed in this meta-analysis. Although the mechanisms of HIV/HCV co-infection’s effect on BMD and fracture are not well understood, there is evidence to suggest that adverse outcomes among HIV/HCV co-infected patients are substantial.
PMCID: PMC4102482  PMID: 25033046
2.  A Descriptive Model of Patient Readiness, Motivators, and Hepatitis C Treatment Uptake among Australian Prisoners 
PLoS ONE  2014;9(2):e87564.
Hepatitis C virus infection (HCV) has a significant global health burden with an estimated 2%–3% of the world's population infected, and more than 350,000 dying annually from HCV-related conditions including liver failure and liver cancer. Prisons potentially offer a relatively stable environment in which to commence treatment as they usually provide good access to health care providers, and are organised around routine and structure. Uptake of treatment of HCV, however, remains low in the community and in prisons. In this study, we explored factors affecting treatment uptake inside prisons and hypothesised that prisoners have unique issues influencing HCV treatment uptake as a consequence of their incarceration which are not experienced in other populations.
Method and Findings
We undertook a qualitative study exploring prisoners' accounts of why they refused, deferred, delayed or discontinued HCV treatment in prison. Between 2010 and 2013, 116 Australian inmates were interviewed from prisons in New South Wales, Queensland, and Western Australia. Prisoners experienced many factors similar to those which influence treatment uptake of those living with HCV infection in the community. Incarceration, however, provides different circumstances of how these factors are experienced which need to be better understood if the number of prisoners receiving treatment is to be increased. We developed a descriptive model of patient readiness and motivators for HCV treatment inside prisons and discussed how we can improve treatment uptake among prisoners.
This study identified a broad and unique range of challenges to treatment of HCV in prison. Some of these are likely to be diminished by improving treatment options and improved models of health care delivery. Other barriers relate to inmate understanding of their illness and stigmatisation by other inmates and custodial staff and generally appear less amenable to change although there is potential for peer-based education to address lack of knowledge and stigma.
PMCID: PMC3937313  PMID: 24586281
3.  Spending of HIV resources in Asia and Eastern Europe: systematic review reveals the need to shift funding allocations towards priority populations 
It is increasingly important to prioritize the most cost-effective HIV interventions. We sought to summarize the evidence on which types of interventions provide the best value for money in regions with concentrated HIV epidemics.
We conducted a systematic review of peer-reviewed and grey literature reporting measurements of cost-effectiveness or cost-benefit for HIV/AIDS interventions in Asia and Eastern Europe. We also collated HIV/AIDS spending assessment data from case-study countries in the region.
We identified 91 studies for inclusion, 47 of which were from peer-reviewed journals. Generally, in concentrated settings, prevention of mother-to-child transmission programmes and prevention programmes targeting people who inject drugs and sex workers had lower incremental cost-effectiveness ratios than programmes aimed at the general population. The few studies evaluating programmes targeting men who have sex with men indicate moderate cost-effectiveness. Collation of prevention programme spending data from 12 countries in the region (none of which had generalized epidemics) indicated that resources for the general population/non-targeted was greater than 30% for eight countries and greater than 50% for five countries.
There is a misalignment between national spending on HIV/AIDS responses and the most affected populations across the region. In concentrated epidemics, scarce funding should be directed more towards most-at-risk populations. Reaching consensus on general principles of cost-effectiveness of programmes by epidemic settings is difficult due to inconsistent evaluation approaches. Adopting a standard costing, impact evaluation, benefits calculation, analysis and reporting framework would enable cross comparisons and improve HIV resource prioritization and allocation.
PMCID: PMC3936108  PMID: 24572053
HIV; cost-benefit analyses; programme evaluation; systematic review; concentrated epidemics; Asia; Eastern Europe; cost-effectiveness
4.  Artesunate/dihydroartemisinin pharmacokinetics in acute falciparum malaria in pregnancy: absorption, bioavailability, disposition and disease effects 
To determine if reported lower plasma concentrations of artemisinin derivatives for malaria in pregnancy result from reduced oral bioavailability, expanded volume of distribution or increased clearance.
In a sequentially assigned crossover treatment study, pregnant women with uncomplicated falciparum malaria received i.v. artesunate (i.v. ARS) (4 mg kg−1) on the first day and oral ARS (4 mg kg−1) on the second, or, oral on the first and i.v. on the second, in both groups followed by oral ARS (4 mg kg−1 day−1) for 5 days. Plasma concentrations of ARS and dihyroartemisinin (DHA) were measured by liquid chromatography-mass-spectrometry on days 0, 1, 2 and 6. Controls were the same women restudied when healthy (3 months post partum).
I.v. ARS administration resulted in similar ARS and DHA pharmacokinetics in pregnant women with malaria (n = 20) and in controls (n = 14). Oral administration resulted in higher total drug exposure in pregnancy [AUC (95% CI) in (ng ml−1 h)/(mg kg−1)] of 55.1 (30.1, 100.0) vs. 26.5 (12.2, 54.3) for ARS, P = 0.002 and 673 (386, 1130) vs. 523 (351, 724) for DHA, P = 0.007. The corresponding median absolute oral bioavailability (F%) was 21.7 (12.6, 75.1) vs. 9.9 (6.0, 36.81) for ARS (P = 0.046) and 77.0 (42.2, 129) vs. 72.7 (42.0, 87.7) for DHA, P = 0.033. Total DHA exposure was lower at day 6 in pregnant women with malaria (P < 0.001) compared with day 0 or 1, but not in the controls (P = 0.084).
This study demonstrates the effects of malaria on oral ARS drug disposition are greater than those of pregnancy. This probably results from a disease related reduction in first pass metabolism. The data are reassuring regarding current dosing recommendations.
PMCID: PMC3370352  PMID: 21950338
artesunate; dihyroartemisinin; malaria; pharmacokinetics; post partum; pregnancy
5.  Influence of Socioeconomic Status on Survival of Hepatocellular Carcinoma in the Ontario Population; A Population-Based Study, 1990–2009 
PLoS ONE  2012;7(7):e40917.
Research has shown that people from higher socioeconomic status (SES) have better hepatocellular carcinoma (HCC) survival outcomes, although no such research has been carried out in Canada. We aimed to assess if an association between SES and HCC survival existed in the Canadian context.
Methodology/Prinicpal Findings
We conducted a population-based cohort study linking HCC cases identified in the Ontario Cancer Registry between 1990 and 2009 to administrative and hospital data. Logistic regression and chi-squared tests were used to evaluate associations between SES (income quintile) and covariates. The Kaplan-Meier method was used to estimate survival. Sequential analysis of the proportional-hazards models were used to determine the association between SES and HCC survival controlling for potential prognostic covariates. During the period 1990–2009, 5,481 cases of HCC were identified. A significant association was found between SES and curative treatment (p = 0.0003), but no association was found between SES and non-curative treatment (p = 0.064), palliative treatment (p = 0.680), or ultrasound screening (p = 0.615). The median survival for the lowest SES was 8.5 months, compared to 8.8 months for the highest SES group. The age- and sex-adjusted proportional-hazards model showed statistically significant difference in HCC survival among the SES groups, with hazard ratio 0.905 (95% confidence intervals 0.821, 0.998) when comparing highest to lowest SES group. Further adjustments indicated that potentially curative treatment was the likely explanation for the association between SES and HCC survival.
Our findings suggest that a 10% HCC survival advantage exists for the higher SES groups. This association between SES and HCC survival is most likely a reflection of lack of access to care for low SES groups, revealing inequities in the Canadian healthcare system.
PMCID: PMC3396620  PMID: 22808283
6.  Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Falciparum Malaria▿† 
Antimicrobial Agents and Chemotherapy  2011;55(12):5500-5506.
Dihydroartemisinin-piperaquine is a fixed-dose artemisinin-based combination treatment. Some antimalarials have altered pharmacokinetics in pregnancy. Pregnant women in the 2nd or 3rd trimester and matched nonpregnant women with uncomplicated falciparum malaria were treated with a total of 6.4 mg/kg of body weight dihydroartemisinin and 51.2 mg/kg piperaquine once daily for 3 days. Venous blood samples were drawn at prespecified time points over 9 weeks. Plasma dihydroartemisinin and piperaquine concentrations were analyzed by liquid chromatography-mass spectrometry. Piperaquine and dihydroartemisinin pharmacokinetics were well described. There were no significant differences in total piperaquine exposure (P = 0.80) or drug exposure during the terminal elimination phase (72 h to infinity) (P = 0.64) between the two groups. The apparent volume of distribution of piperaquine was significantly smaller (602 liters/kg versus 877 liters/kg) in pregnant women than in nonpregnant women (P = 0.0057), and the terminal elimination half-life was significantly shorter (17.8 days versus 25.6 days; P = 0.0023). Dihydroartemisinin exposure after the first dose was significantly lower (844 h × ng/ml versus 1,220 h × ng/ml, P = 0.0021) in pregnant women, but there were no significant differences in total dihydroartemisinin exposure or maximum concentrations between the two groups. There were no significant differences in any pharmacokinetic parameters between the second and third trimester. These results obtained through noncompartmental analysis suggest that in the treatment of falciparum malaria, there are no clinically important differences in the pharmacokinetics of dihydroartemisinin or piperaquine between pregnant and nonpregnant women. However, a more detailed analysis using population pharmacokinetic modeling is needed to fully investigate the differences found for some of the pharmacokinetic parameters, such as the terminal half-life.
PMCID: PMC3232755  PMID: 21947392
7.  Health status utilities and the impact of pressure ulcers in long-term care residents in Ontario 
Quality of Life Research  2009;19(1):81-89.
To estimate health status utilities in long-term care (LTC) residents in Ontario, both with and without pressure ulcers (PUs), and to determine the impact of PU on health-related quality of life (HRQOL).
A retrospective population-based study was carried out using Minimum Data Set (MDS) health assessment data among all residents in 89 LTC homes in Ontario who had a full MDS assessment between May 2004 and November 2007. The Minimum Data Set-Health Status Index (MDS-HSI) was used to measure HRQOL. A stepwise regression was used to determine the impact of PU on MDS-HSI scores.
A total of 1,498 (9%) of 16,531 LTC residents had at least one stage II PU or higher. The mean ± SD MDS-HSI scores of LTC residents without PU and those with PU were 0.36 ± 0.17 and 0.26 ± 0.13, respectively (p < 0.001). Factors associated with lower MDS-HSI scores included: older age; being female; having a PU; recent hip fracture; multiple comorbid conditions; bedfast; incontinence; Changes in Health, End-stage disease and Symptoms and Signs; clinically important depression; treated with a turning/repositioning program; taking antipsychotic medications; and use of restraints.
LTC residents with PU had slightly though statistically significantly lower HRQOL than those without PU. Comorbidity contributed substantially to the low HRQOL in these populations. Community-weighted MDS-HSI utilities for LTC residents are useful for cost-effectiveness analyses and help guide health policy development.
PMCID: PMC2804787  PMID: 20033300
Health-related quality of life; Long-term care; Minimum Data Set; Health Status Index; Ontario/Canada; Utilities
8.  Health-state utilities in a prisoner population: a cross-sectional survey 
Health-state utilities for prisoners have not been described.
We used data from a 1996 cross-sectional survey of Australian prisoners (n = 734). Respondent-level SF-36 data was transformed into utility scores by both the SF-6D and Nichol's method. Socio-demographic and clinical predictors of SF-6D utility were assessed in univariate analyses and a multivariate general linear model.
The overall mean SF-6D utility was 0.725 (SD 0.119). When subdivided by various medical conditions, prisoner SF-6D utilities ranged from 0.620 for angina to 0.764 for those with none/mild depressive symptoms. Utilities derived by the Nichol's method were higher than SF-6D scores, often by more than 0.1. In multivariate analysis, significant independent predictors of worse utility included female gender, increasing age, increasing number of comorbidities and more severe depressive symptoms.
The utilities presented may prove useful for future economic and decision models evaluating prison-based health programs.
PMCID: PMC2741437  PMID: 19715571
9.  Biological and Molecular Characteristics of Mycobacterium tuberculosis Clinical Isolates with Low-Level Resistance to Isoniazid in Japan▿  
Journal of Clinical Microbiology  2008;46(7):2263-2268.
We reevaluated the BACTEC MGIT 960 antimicrobial susceptibility testing system (MGIT 960 AST) by using 1,112 isolates of Mycobacterium tuberculosis. When the results of MGIT 960 AST were compared with that of the proportion method using Ogawa medium (Ogawa PM), discrepant results were obtained for 30 strains with isoniazid, all resistant by MGIT 960 AST but susceptible by Ogawa PM. For 93% of the strains that produced discrepant results, the MIC was 0.4 or 0.8 μg/ml, showing resistance by the proportion method using Middlebrook agar plates. Furthermore, it was also established by analyses of the katG and inhA genes that strains resistant only by MGIT 960 AST have a low level of isoniazid (INH) resistance, indicating that MGIT 960 AST is a reliable method. Ninety-six strains were resistant to 0.1 μg/ml INH by MGIT 960 AST. When they were divided into three groups, Low-S (susceptible at 0.2 μg/ml), Low-R (resistant at 0.2 μg/ml), and High-R (resistant at 1.0 μg/ml), by Ogawa PM, 43.3% of the Low-S strains had mutations in the promoter region of inhA and no mutations were detected in katG codon 315, while 61.7% of the High-R strains had katG codon 315 mutations or a gross deletion of katG. These results suggest that mutations in inhA are associated with low-level resistance to INH and katG codon 315 mutations are associated with high-level resistance to INH. In addition, the analyses demonstrated some relationship of mutations in the inhA gene with ethionamide resistance for the Low-S strains, but not for the High-R strains.
PMCID: PMC2446907  PMID: 18508939
10.  The Effect of Hepatitis C Virus Infection on Health-Related Quality of Life in Prisoners 
Journal of Urban Health   2006;83(2):275-288.
Hepatitis C virus (HCV) infection in prisoners represents an important public health problem. However, there is very little information about HCV-related health-related quality of life (HRQOL). We examined the effect of HCV antibody positivity, HCV viremia, and being a prisoner on prisoners'' HRQOL. Population-based health surveys incorporating HCV screening were conducted among prisoners at New South Wales (NSW), Australia, correctional centers in 1996 and 2001. HCV antibody and HCV RNA status were determined from venous blood sampling. HRQOL and mood status were assessed using the Short Form-36 (SF-36) Health Survey and Beck Depression Inventory (BDI). Comparison of HRQOL scores between HCV antibody negative, HCV antibody positive/non-viremic, and HCV antibody positive/viremic and assessment of temporal change in HRQOL between 1996 and 2001 within groups were made using ANCOVA adjusting for confounders. Factors associated with HRQOL were determined in linear regression models. Analyses between HCV antibody negative (n = 423), HCV positive/non-viremic (n = 89), and HCV positive/viremic (n = 178) prisoners found no measurable effect of HCV on HRQOL, including that attributable to HCV viremia. Compared to uninfected Australian population norms, prisoners had lower HRQOL irrespective of HCV status. The prevalence of ‘moderate’ to ‘severe’ depressive symptoms was greater in the HCV antibody positive/viremic group than the HCV antibody positive/non-viremic group or the HCV antibody negative group. Selected demographic factors (age), co-morbidity, severity of depressive symptoms and medical care utilization influenced HRQOL. There was evidence to support the effect of knowledge of HCV status on HRQOL. In conclusion, our findings contrast with previous studies in non-prisoner groups in which HCV infection appears to decrease overall HRQOL. Non-HCV factors may override HCV-specific HRQOL impairment in this population. Targeted management strategies are required to improve HRQOL of prisoners.
PMCID: PMC2527173  PMID: 16736376
Australia; HCV; Prisoner; Quality of life; SF-36
11.  Artesunate/dihydroartemisinin pharmacokinetics in acute falciparum malaria in pregnancy: absorption, bioavailability, disposition and disease effects 
To determine if reported lower plasma concentrations of artemisinin derivatives for malaria in pregnancy result from reduced oral bioavailability, expanded volume of distribution or increased clearance.
In a sequentially assigned crossover treatment study, pregnant women with uncomplicated falciparum malaria received i.v. artesunate (i.v. ARS) (4 mg kg−1) on the first day and oral ARS (4 mg kg−1) on the second, or, oral on the first and i.v. on the second, in both groups followed by oral ARS (4 mg kg−1 day−1) for 5 days. Plasma concentrations of ARS and dihyroartemisinin (DHA) were measured by liquid chromatography-mass-spectrometry on days 0, 1, 2 and 6. Controls were the same women restudied when healthy (3 months post partum).
I.v. ARS administration resulted in similar ARS and DHA pharmacokinetics in pregnant women with malaria (n = 20) and in controls (n = 14). Oral administration resulted in higher total drug exposure in pregnancy [AUC (95% CI) in (ng ml−1 h)/(mg kg−1)] of 55.1 (30.1, 100.0) vs. 26.5 (12.2, 54.3) for ARS, P = 0.002 and 673 (386, 1130) vs. 523 (351, 724) for DHA, P = 0.007. The corresponding median absolute oral bioavailability (F%) was 21.7 (12.6, 75.1) vs. 9.9 (6.0, 36.81) for ARS (P = 0.046) and 77.0 (42.2, 129) vs. 72.7 (42.0, 87.7) for DHA, P = 0.033. Total DHA exposure was lower at day 6 in pregnant women with malaria (P < 0.001) compared with day 0 or 1, but not in the controls (P = 0.084).
This study demonstrates the effects of malaria on oral ARS drug disposition are greater than those of pregnancy. This probably results from a disease related reduction in first pass metabolism. The data are reassuring regarding current dosing recommendations.
PMCID: PMC3370352  PMID: 21950338
artesunate; dihyroartemisinin; malaria; pharmacokinetics; post partum; pregnancy
12.  Interdisciplinary communication of infectious disease research – translating complex epidemiological findings into understandable messages for village chicken farmers in Myanmar 
SpringerPlus  2014;3:726.
Improvement in animal disease control and prevention is dependent on several factors including farmers’ uptake of new technologies and skills, particularly in developing countries. Extension is the means by which information about these technologies and skills is delivered to farmers, in order that they can use this knowledge to improve farming practices and their quality of life. This implies a shift from traditional methods to new science-based methods of production. However, in many developing countries farmers are illiterate and unable to understand written outcomes of scientific research. This paper summarizes approaches to communicate epidemiological findings and reports on experiences obtained from a research project in Myanmar, where results from epidemiological field investigations and intervention studies were ‘translated’ in an understandable manner to village communities. Rural chicken farmers were the central focus of this extension work and simple and sustainable methods to improve the health and production of scavenging chicken flocks were promoted. Unique extension materials transformed scientific outputs published in international journals into clear pictographic messages comprehendible by villagers, while maintaining country-specific, traditional, religious and public perspectives. Benefits, difficulties and pitfalls in using extension methods to communicate advice on preventive veterinary medicine measures in different cross-cultural settings are discussed and guidelines on how to distribute epidemiological research results to illiterate farmers are provided.
PMCID: PMC4320238
Communication; Extension; Disease control; Myanmar; Village chicken; Newcastle disease
13.  S1P Control of Endothelial Integrity 
Sphingosine 1-phosphate (S1P), a lipid mediator produced by sphingolipid metabolism, promotes endothelial cell spreading, vascular maturation/stabilization, and barrier function. S1P is present at high concentrations in the circulatory system, whereas in tissues its levels are low. This so-called vascular S1P gradient is essential for S1P to regulate much physiological and pathophysiological progress such as the modulation of vascular permeability. Cellular sources of S1P in blood has only recently begun to be identified. In this review, we summarize the current understanding of S1P in regulating vascular integrity. In particular, we discuss the recent discovery of the endothelium-protective functions of HDL-bound S1P which is chaperoned by apolipoprotein M.
PMCID: PMC4240614  PMID: 24728594
14.  Comparison of keratometric and pachymetric parameters with Scheimpflug imaging in normal and keratoconic Asian eyes 
To evaluate the keratometric and pachymetric parameters of keratoconic corneas of Asian eyes with the Scheimpflug imaging camera.
Patients and methods
This is a cross-sectional study of 22 eyes with Amsler-Krumeich stage 1 keratoconus and 48 eyes from normal subjects conducted in a tertiary eye hospital. A rotating Scheimpflug imaging system, the Pentacam, was used to evaluate all eyes for tomographic parameters, as well as pachymetric progression indices (PPI) and Ambrósio relational thickness (ART).
All PPI and ART parameter values were significantly different between study and control groups. Cornea minimum radius of curvature, absolute distance from corneal apex to thinnest location, as well as the distance from corneal apex to thinnest location in Y-axis also demonstrated statistically significant differences. The mean ART values for keratoconus eyes were 241 μm (ART-maximum) and 352 μm (ART-average), falling within previously reported best cutoff values for detecting keratoconus. On receiver operating characteristics curve analysis, the area under the curve values were highest for PPI and ART parameters.
There are significant differences in tomographic parameters between stage 1 keratoconic and normal Asian eyes. Pachymetric indices such as the PPI and the ART index can serve as additional tools in differentiating keratoconic from normal eyes. The findings validate the usefulness of the ART in identifying keratoconic eyes in Asians.
PMCID: PMC4235509  PMID: 25419113
keratoconus; pentacam; corneal tomography; Ambrósio relational thickness
15.  Genetic Deletion of Microsomal Prostaglandin E Synthase-1 Suppresses Mouse Mammary Tumor Growth and Angiogenesis 
Prostaglandins & other lipid mediators  2013;0:10.1016/j.prostaglandins.2013.04.002.
The cyclooxygenase/prostaglandin (COX/PG) signaling pathway is of central importance in inflammation and neoplasia. COX inhibitors are widely used for analgesia and also have demonstrated activity for cancer prophylaxis. However, cardiovascular toxicity associated with this drug class diminishes their clinical utility and motivates the development of safer approaches both for pain relief and cancer prevention. The terminal synthase microsomal PGE synthase-1 (mPGES-1) has attracted considerable attention as a potential target. Overexpression of mPGES-1 has been observed in both colorectal and breast cancers, and gene knockout and overexpression approaches have established a role for mPGES-1 in gastrointestinal carcinogenesis. Here we evaluate the contribution of mPGES-1 to mammary tumorigenesis using a gene knockout approach. Mice deficient in mPGES-1 were crossed with a strain in which breast cancer is driven by overexpression of human epidermal growth factor receptor 2 (HER2/neu). Loss of mPGES-1 was associated with a substantial reduction in intramammary PGE2 levels, aromatase activity, and angiogenesis in mammary glands from HER2/neu transgenic mice. Consistent with these findings, we observed a significant reduction in multiplicity of tumors ≥1mm in diameter, suggesting that mPGES-1 contributes to mammary tumor growth. Our data identify mPGES-1 as a potential anti-breast cancer target.
PMCID: PMC3830707  PMID: 23624019
Mouse; mPGES-1; breast cancer; aromatase; angiogenesis; PGE2
16.  Knock Out of S1P3 Receptor Signaling Attenuates Inflammation and Fibrosis in Bleomycin-Induced Lung Injury Mice Model 
PLoS ONE  2014;9(9):e106792.
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cellular processes, including proliferation, migration, and angiogenesis, through interaction with a family of five G protein–coupled receptors (S1P1–5). Some reports have implicated S1P as an important inflammatory mediator of the pathogenesis of airway inflammation, but the role of S1P3 in the pathogenesis of lung diseases is not completely understood. We used S1P3-deficient (knockout (KO)) mice to clarify the role of S1P3 receptor signaling in the pathogenesis of pulmonary inflammation and fibrosis using a bleomycin-induced model of lung injury. On the seventh day after bleomycin administration, S1P3 KO mice exhibited significantly less body weight loss and pulmonary inflammation than wild-type (WT) mice. On the 28th day, there was less pulmonary fibrosis in S1P3 KO mice than in WT mice. S1P3 KO mice demonstrated a 56% reduction in total cell count in bronchoalveolar lavage fluid (BALF) collected on the seventh day compared with WT mice; however, the differential white blood cell profiles were similar. BALF analysis on the seventh day showed that connective tissue growth factor (CTGF) levels were significantly decreased in S1P3 KO mice compared with WT mice, although no differences were observed in monocyte chemotactic protein-1 (MCP-1) or transforming growth factor β1 (TGF-β1) levels. Finally, S1P levels in BALF collected on the 7th day after treatment were not significantly different between WT and S1P3 KO mice. Our results indicate that S1P3 receptor signaling plays an important role in pulmonary inflammation and fibrosis and that this signaling occurs via CTGF expression. This suggests that this pathway might be a therapeutic target for pulmonary fibrosis.
PMCID: PMC4157792  PMID: 25198418
17.  FTY720 Inhibits Tumor Growth and Enhances the Tumor-Suppressive Effect of Topotecan in Neuroblastoma by Interfering With the Sphingolipid Signaling Pathway 
Pediatric blood & cancer  2013;60(9):10.1002/pbc.24564.
Neuroblastoma (NB) is the most common extra-cranial solid tumor in childhood. Poor outcomes for children with advanced disease underscore the need for novel therapeutic strategies. FTY720, an immunomodulating drug approved for multiple sclerosis, has been investigated in oncology with promising preclinical activities. To date, its effect in NB has not been explored. Herein we describe our preclinical experience with FTY720, alone or in combination with topotecan, and its putative mechanism of action in NB.
MTT assay was performed to assess the effect of FTY720 on cell viability. A NB xenograft model was employed to assess the efficacy of FTY720 on tumor growth. Quantitative real-time PCR and Western blot were employed to determine changes of mRNA and protein expression, respectively. Liquid chromatography/tandem mass spectrometry was used to measure sphingolipid levels.
FTY720, but not FTY720-P induced NB cell death. FTY720 inhibited the growth of NB xenografts and enhanced the tumor-suppressive effect of topotecan both in vitro and in vivo. FTY720 significantly inhibited sphingosine kinase 2 (SphK2) mRNA and protein expression in NB cells. Pro-apoptotic sphingosine levels were increased in NB cells and NB xenografts treated with FTY720. FTY720-induced cell death was caspase-independent and involved the dephosphorylation of Akt and BAD at Ser136.
Our data demonstrate that FTY720 has potent preclinical anti-cancer activity in NB. Its unique death signaling mechanism, interference with the sphingolipid pathway, acts cooperatively with that of topotecan, suggesting that FTY720 related molecules may be useful in NB treatment.
PMCID: PMC3751174  PMID: 23704073
apoptosis; FTY720; neuroblastoma; sphingosine; sphingosine kinase 2
18.  Sphingosine-1-phosphate/sphingosine-1-phosphate receptor 2 signaling induces COX-2 expression in Wilms tumor 
The Journal of urology  2009;181(3):1347-1352.
Cyclooxygenase-2 (COX-2) has been reported to be ubiquitously expressed in Wilms tumor, the most common malignant renal tumor in children. However, the regulation mechanism of COX-2 expression remains unexplored.
Materials and Methods
Quantitative real-time PCR and western blot analysis were performed to detect COX-2 mRNA and protein expression in WiT49 cells upon the stimulation by sphingosine-1-phosphate (S1P) as well as S1P2 and COX-2 mRNA expression in 10 fresh frozen Wilms tumor tissues and their matched normal tissues. Overexpression, blockade and downregulation of S1P2 were performed using adenoviral transduction, S1P2 antagonist JTE-013 and siRNA transfection, respectively. The level of prostaglandin E2 (PGE2) in WiT49 cells was determined by gas chromatography/mass spectrometry.
S1P induced COX-2 mRNA and protein expression in WiT49 cells in a concentration-dependent manner. Overexpression of S1P2 in WiT49 cells led to a significant increase in COX-2 mRNA and protein expression as well as subsequent PGE2 synthesis. In addition, pretreatment of those cells overexpressing S1P2 with S1P2 selective antagonist JTE-013 completely blocked S1P-induced COX-2 protein expression. In accordance with these results, silencing of S1P2 in WiT49 cells downregulated S1P-induced COX-2 expression. Further research on 10 Wilms tumor specimens found that S1P2 mRNA was greatly increased in Wilms tumor.
S1P induced COX-2 expression in Wilms tumor, and this effect was mediated by S1P2. This finding extends the biological function of S1P2 and provides the biochemical basis for the development of inhibitors targeting S1P/COX-2 signaling pathway.
PMCID: PMC4132875  PMID: 19157443
COX-2; sphingosine 1-phosphate; sphingosine 1-phosphate receptor 2; WiT49; Wilms tumor
19.  Defective sphingosine-1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation 
Nature immunology  2013;14(11):1166-1172.
Sphingosine-1-phosphate (S1P) signaling regulates lymphocyte egress from lymphoid organs into systemic circulation. Sphingosine phosphate receptor 1 (S1P1) agonist, FTY-720 (Gilenya™) arrests immune trafficking and prevents multiple sclerosis (MS) relapses. However, alternative mechanisms of S1P-S1P1 signaling have been reported. Phosphoproteomic analysis of MS brain lesions revealed S1P1 phosphorylation on S351, a residue crucial for receptor internalization. Mutant mice harboring a S1pr1 gene encoding phosphorylation-deficient receptors [S1P1(S5A)] developed severe experimental autoimmune encephalomyelitis (EAE) due to T helper (TH) 17-mediated autoimmunity in the peripheral immune and nervous system. S1P1 directly activated Janus-like kinase–signal transducer and activator of transcription 3 (JAK-STAT3) pathway via interleukin 6 (IL-6). Impaired S1P1 phosphorylation enhances TH17 polarization and exacerbates autoimmune neuroinflammation. These mechanisms may be pathogenic in MS.
PMCID: PMC4014310  PMID: 24076635
20.  Increased Prevalence of Sleep-Disordered Breathing in Adults 
American Journal of Epidemiology  2013;177(9):1006-1014.
Sleep-disordered breathing is a common disorder with a range of harmful sequelae. Obesity is a strong causal factor for sleep-disordered breathing, and because of the ongoing obesity epidemic, previous estimates of sleep-disordered breathing prevalence require updating. We estimated the prevalence of sleep-disordered breathing in the United States for the periods of 1988–1994 and 2007–2010 using data from the Wisconsin Sleep Cohort Study, an ongoing community-based study that was established in 1988 with participants randomly selected from an employed population of Wisconsin adults. A total of 1,520 participants who were 30–70 years of age had baseline polysomnography studies to assess the presence of sleep-disordered breathing. Participants were invited for repeat studies at 4-year intervals. The prevalence of sleep-disordered breathing was modeled as a function of age, sex, and body mass index, and estimates were extrapolated to US body mass index distributions estimated using data from the National Health and Nutrition Examination Survey. The current prevalence estimates of moderate to severe sleep-disordered breathing (apnea-hypopnea index, measured as events/hour, ≥15) are 10% (95% confidence interval (CI): 7, 12) among 30–49-year-old men; 17% (95% CI: 15, 21) among 50–70-year-old men; 3% (95% CI: 2, 4) among 30–49-year-old women; and 9% (95% CI: 7, 11) among 50–70 year-old women. These estimated prevalence rates represent substantial increases over the last 2 decades (relative increases of between 14% and 55% depending on the subgroup).
PMCID: PMC3639722  PMID: 23589584
adult; middle age; obesity; sleep
21.  Sphingosine 1-phosphate (S1P)/S1P receptor 1 signaling regulates receptor activator of NF-κB ligand (RANKL) expression in rheumatoid arthritis 
Biochemical and biophysical research communications  2012;419(2):10.1016/j.bbrc.2012.01.103.
Sphingosine 1-phosphate (S1P)/S1P receptor 1 (S1P1) signaling plays an important role in synovial cell proliferation and inflammatory gene expression by rheumatoid arthritis (RA) synoviocytes. The purpose of this study is to clarify the role of S1P/S1P1 signaling in the expression of receptor activator of NF-κB ligand (RANKL) in RA synoviocytes and CD4+ T cells. We demonstrated MH7A cells, a human RA synovial cell line, and CD4+ T cells expressed S1P1 and RANKL. Surprisingly, S1P increased RANKL expression in MH7A cells and CD4+ T cells in a dose-dependent manner. Moreover, S1P enhanced RANKL expression induced by stimulation with TNF-α in MH7A cells and CD4+ T cells. These effects of S1P in MH7A cells were inhibited by pretreatment with PTX, a specific Gi/Go inhibitor. These findings suggest that S1P/S1P1 signaling may play an important role in RANKL expression by MH7A cells and CD4+ T cells. S1P/S1P1 signaling of RA synoviocytes is closely connected with synovial hyperplasia, inflammation, and RANKL-induced osteoclastogenesis in RA. Thus, regulation of S1P/S1P1 signaling may become a novel therapeutic target for RA.
PMCID: PMC3857967  PMID: 22326262
Sphingosine 1-phosphate; RANKL; Rheumatoid arthritis
22.  Community-centred eco-bio-social approach to control dengue vectors: an intervention study from Myanmar 
Pathogens and Global Health  2012;106(8):461-468.
To build up and analyse the feasibility, process, and effectiveness of a partnership-driven ecosystem management intervention in reducing dengue vector breeding and constructing sustainable partnerships among multiple stakeholders.
A community-based intervention study was conducted from May 2009 to January 2010 in Yangon city. Six high-risk and six low-risk clusters were randomized and allocated as intervention and routine service areas, respectively. For each cluster, 100 households were covered. Bi-monthly entomological evaluations (i.e. larval and pupal surveys) and household acceptability surveys at the end of 6-month intervention period were conducted, supplemented by qualitative evaluations.
Intervention description
The strategies included eco-friendly multi-stakeholder partner groups (Thingaha) and ward-based volunteers, informed decision-making of householders, followed by integrated vector management approach.
Pupae per person index (PPI) decreased at the last evaluation by 5.7% (0.35–0.33) in high-risk clusters. But in low-risk clusters, PPI remarkably decreased by 63.6% (0.33–0.12). In routine service area, PPI also decreased due to availability of Temephos after Cyclone Nargis. As for total number of pupae in all containers, when compared to evaluation 1, there was a reduction of 18.6% in evaluation 2 and 44.1% in evaluation 3 in intervention area. However, in routine service area, more reduction was observed. All intervention tools were found as acceptable, being feasible to implement by multi-stakeholder partner groups.
The efficacy of community-controlled partnership-driven interventions was found to be superior to the vertical approach in terms of sustainability and community empowerment.
PMCID: PMC3541898  PMID: 23318238
Partnership-driven ecosystem management intervention; Dengue vector breeding; Informed decision-making; Integrated vector management; Community empowerment
23.  Sphingolipid signaling in metabolic disorders 
Cell metabolism  2012;16(4):420-434.
Sphingolipids, ubiquitous membrane lipids in eukaryotes, carry out a myriad of critical cellular functions. The past two decades have seen significant advances in sphingolipid research and in 2010, a first sphingolipid receptor modulator was employed as a human therapeutic. Further, cellular signaling mechanisms regulated by sphingolipids are being recognized as critical players in metabolic diseases. This review focuses on recent advances in cellular and physiological mechanisms of sphingolipid regulation and how sphingolipid signaling influences metabolic diseases. Progress in this area may contribute to new understanding and therapeutic options in complex diseases such as atherosclerosis, diabetes, metabolic syndromes and cancer.
PMCID: PMC3466368  PMID: 22982021
24.  De novo ocular hypertension after Descemet stripping endothelial keratoplasty: comparative 3-year incidence, risk factors, and outcomes 
To compare the 3-year incidence of de novo ocular hypertension (OHT) after Descemet stripping automated endothelial keratoplasty (DSAEK) and penetrating keratoplasty (PK). For DSAEK, to evaluate predictors for OHT and 2-year outcomes after OHT development.
This was a review of the prospective Singapore Corneal Transplant Study at a single tertiary referral center. Consecutive DSAEKs and PKs for Fuchs’ endothelial dystrophy (FED) and pseudophakic bullous keratopathy (PBK) in eyes without pre-existing glaucoma were analyzed. OHT incidence after DSAEK and PK were compared using Kaplan–Meier survival analysis, and OHT risk factors identified using Cox proportional regression. OHT was defined: intraocular pressure (IOP) ≥ 24 mmHg or ≥ 10 mmHg from baseline. Secondary outcomes 2 years after OHT development in DSAEK were rates of glaucoma medical therapy failure, IOP success, graft failure and rejection, and best-spectacle corrected visual acuity (BSCVA).
There were 108 (96.4%) DSAEKs and 216 (96%) PKs. The 1-, 2- and 3-year de novo OHT incidence was not significantly different between DSAEK (36.1%, 47.2%, 47.2%, respectively) and PK (35.7%, 44.9%, 45.8%, respectively; P = 0.914). OHT incidence did not differ in subgroup analyses of multiple clinical variables (P > 0.1). OHT predictors after DSAEK were: fellow eye glaucoma (hazard ratio [HR] 3.20, P = 0.004), age <60 years (HR 2.41, P = 0.016), concurrent goniosynechiolysis (HR 3.29, P = 0.021), post-graft complications or procedures (HR 2.85, P = 0.006). Two years after OHT onset, 29.7% of DSAEKs failed glaucoma medical therapy requiring trabeculectomy. Complete and qualified IOP success was achieved in 23.5% and 76.5%, respectively. Graft failure developed in 9.8% and graft rejection in 5.9%. At 6 months, 1, and 2 years from OHT onset, 86.3%, 88.3%, and 92.1% achieved BSCVA 20/40, respectively.
DSAEK and PK have comparable OHT risks. A significant 30% of DSAEK eyes with OHT require filtration surgery. Effective IOP control and good graft and visual outcomes are achieved with treatment.
PMCID: PMC3788681  PMID: 24092962
DSAEK; glaucoma; ocular hypertension; risk factors
25.  Flow-regulated endothelial S1P receptor-1 signaling sustains vascular development 
Developmental cell  2012;23(3):600-610.
During angiogenesis, nascent vascular sprouts fuse to form vascular networks enabling efficient circulation. Mechanisms that stabilize the vascular plexus are not well understood. Sphingosine 1-phosphate (S1P) is a blood-borne lipid mediator implicated in the regulation of vascular and immune systems. Here we describe a mechanism by which the G protein-coupled S1P receptor-1 (S1P1) stabilizes the primary vascular network. A gradient of S1P1 expression from the mature regions of the vascular network to the growing vascular front was observed. In the absence of endothelial S1P1, adherens junctions are destabilized, barrier function is breached, and flow is perturbed resulting in abnormal vascular hypersprouting. Interestingly, S1P1 responds to S1P as well as laminar shear stress to transduce flow-mediated signaling in endothelial cells both in vitro and in vivo. These data demonstrate that blood flow and circulating S1P activate endothelial S1P1 to stabilize blood vessels in development and homeostasis.
PMCID: PMC3443394  PMID: 22975328

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