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1.  Spread of Artemisinin Resistance in Plasmodium falciparum Malaria 
The New England journal of medicine  2014;371(5):411-423.
Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies.
Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined.
The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand–Cambodia border. Slowly clearing in fections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the “propeller” region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days.
Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; number, NCT01350856.)
PMCID: PMC4143591  PMID: 25075834
2.  An anti-leishmanial thiadiazine agent induces multiple myeloma cell apoptosis by suppressing the nuclear factor kappaB signalling pathway 
Chen, G | Han, K | Xu, X | Du, X | Zhang, Z | Tang, J | Shi, M | Wang, M | Li, J | Cao, B | Mao, X
British Journal of Cancer  2013;110(1):63-70.
Nuclear factor κB (NFκB) has a critical role in the pathophysiology of multiple myeloma. Targeting NFκB is an important strategy for anti-myeloma drug discovery.
Luciferase assay was used to evaluate the effects of DETT on NFκB activity. Annexin V–PI double staining and immunoblotting were used to evaluate DETT-induced cell apoptosis and suppression of NFκB signalling. Anti-myeloma activity was studied in nude mice.
DETT downregulated IKKα, β, p65, and p50 expression and inhibited phosphorylation of p65 (Ser536) and IκBα. Simultaneously, DETT increased IκBα, an inhibitor of the p65/p50 heterodimer, even in the presence of stimulants lipopolysaccharide, tumour necrosis factor-α, or interleukin-6. DETT inhibited NFκB transcription activity and downregulated NFκB-targeted genes, including Bcl-2, Bcl-XL, and XIAP as measured by their protein expression. Deregulation of NFκB signalling by DETT resulted in MM cell apoptosis characterised by cleavage of caspase-3, caspase-8, and PARP. Notably, this apoptosis was partly blocked by the activation of NFκB signalling in the presence of TNFα and IL-6. Moreover, DETT delayed myeloma tumour growth in nude mice without overt toxicity.
DETT displays a promising potential for MM therapy as an inhibitor of the NFκB signalling pathway.
PMCID: PMC3887303  PMID: 24231956
3,5-diethyl-1,3,5-thiadiazinane-2-thione (DETT); NFκB; multiple myeloma; apoptosis
3.  Combined effects of magnetic interaction and domain wall pinning on the coercivity in a bulk Nd60Fe30Al10 ferromagnet 
Scientific Reports  2014;4:6805.
Understanding the coercivity mechanism has a substantial impact on developing novel permanent materials. However, the current coercivity mechanisms used widely in permanent alloys cannot explain well the amorphous phase produced hard magnetic behavior of Nd-based bulk amorphous alloys (BAAs). Here, we propose that the coercivity in as-cast Nd60Fe30Al10 alloy is from the combination of magnetic interaction and strong pinning of domain walls. Moreover, the role of domain wall pinning is less affected after crystallization, while the magnetic interaction is dependent on the annealing temperature. Our findings give further insight into the coercivity mechanism of Nd-based bulk ferromagnets and provide a new idea to design prospective permanent alloys with coercivity from the combination of magnetic interaction and pinning of domain walls.
PMCID: PMC4210938  PMID: 25348232
4.  Moisture Concentration Variation of Silages Produced on Commercial Farms in the South-Central USA 
Preservation of forage crops as silage offers opportunity to avoid the high risk of rain-damaged hay in the humid south-central USA. Recent developments with baled silage or baleage make silage a less expensive option than typical chopped silage. Silage has been important in the region primarily for dairy production, but baleage has become an option for the more extensive beef cattle industry in the region. Silage samples submitted to the Louisiana State University Agricultural Center Forage Quality Lab from 2006 through 2013 were assessed for dry matter (DM) and forage nutritive characteristics of chopped silage and baleage of the different forage types from commercial farms primarily in Louisiana and Mississippi. Of the 1,308 silage samples submitted, 1,065 were annual ryegrass (AR) with small grains (SG), the warm-season annual (WA) grasses, sorghums and pearl millet, and the warm-season perennial (WP) grasses, bermudagrass and bahiagrass, providing the remaining samples. Concentration of DM was used to indicate an effective ensiling opportunity, and AR silage was more frequently within the target DM range than was the WA forage group. The AR samples also indicated a high-quality forage with average crude protein (CP) of 130 g/kg and total digestible nutrient (TDN) near 600 g/kg. The cooler winter weather at harvest apparently complicated harvest of SG silage with chopped SG silage lower in both CP and TDN (104 and 553 g/kg, respectively) than either AR silage or baleage of SG (137 and 624 g/kg for CP and TDN, respectively). The hot, humid summer weather along with large stems and large forage quantities of the WA grasses and the inherently higher fiber concentration of WP grasses at harvest stage indicate that preservation of these forage types as silage will be challenging, although successful commercial silage samples of each forage type and preservation approach were included among samples of silages produced in the region.
PMCID: PMC4150176  PMID: 25178295
Baleage; Chopped Silage; Commercial Farm; Nutritive Value; Silage Moisture
5.  Feasibility of tailored treatment based on risk stratification in patients with early rheumatoid arthritis 
Personalized medicine is the holy grail of medicine. The EULAR recommendations for the management of rheumatoid arthritis (RA) support differential treatment between patients with baseline characteristics suggestive of a non-poor prognosis (non-PP) or poor prognosis (PP) (presence of autoantibodies, a high inflammatory activity and damage on radiographs). We aimed to determine which prognostic risk groups benefit more from initial monotherapy or initial combination therapy.
508 patients were randomized to initial monotherapy (iMono) or initial combination therapy (iCombo). Disease outcomes of iMono and iCombo were compared within non-PP or PP groups as determined on baseline characteristics
PP patients treated with iCombo after three months more often achieved ACR20 (70% vs 38%, P <0.001), ACR50 (48% vs 13%, P <0.001) and ACR70 response (24% vs 4%, P <0.001) than those treated with iMono, and had more improvement in HAQ (median decrease 0.75 vs 0.38, P <0.001). After 1 year, differences in ACR20 response and DAS-remission remained; PP patients treated with iCombo (vs iMono) had less radiographic progression (median 0.0 vs 1.5, P =0.001).
Non-PP patients treated with iCombo after three months more often achieved an ACR response (ACR20: 71% versus 44%, P <0.001; ACR50: 49% vs 13%, P <0.001; ACR70: 17% vs 3%, P =0.001) than with iMono, and functional ability showed greater improvement (median decrease in HAQ 0.63 vs 0.38, P <0.001). After 1 year, differences in ACR20 and ACR50 response remained; radiographic progression was comparable between the groups.
Non-PP and PP patients responded equally well to iCombo in terms of improvement of functional ability, with similar toxicity.
Since PP and non-PP patients benefit equally from iCombo through earlier clinical response and functional improvement than with iMono, we conclude that personalized medicine as suggested in the guidelines is not yet feasible. The choice of treatment strategy should depend more on rapid relief of symptoms than on prognostic factors.
Trial registration
Netherlands Trial Register NTR262 (registered 7 September 2005) and NTR265 (8 September 2005).
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0430-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4203912  PMID: 25253199
6.  Bale Location Effects on Nutritive Value and Fermentation Characteristics of Annual Ryegrass Bale Stored in In-line Wrapping Silage 
In southeastern regions of the US, herbage systems are primarily based on grazing or hay feeding with low nutritive value warm-season perennial grasses. Nutritious herbage such as annual ryegrass (Lolium multiflorum Lam.) may be more suitable for preserving as baleage for winter feeding even with more intensive production inputs. Emerging in-line wrapped baleage storage systems featuring rapid wrapping and low polyethylene film requirements need to be tested for consistency of storing nutritive value of a range of annual ryegrass herbage. A ryegrass storage trial was conducted with 24-h wilted ‘Marshall’ annual ryegrass harvested at booting, heading and anthesis stages using three replicated in-line wrapped tubes containing ten round bales per tube. After a six-month storage period, nutritive value changes and fermentation end products differed significantly by harvest stage but not by bale location. Although wilted annual ryegrass exhibited a restricted fermentation across harvest stages characterized by high pH and low fermentation end product concentrations, butyric acid concentrations were less than 1 g/kg dry matter, and lactic acid was the major organic acid in the bales. Mold coverage and bale aroma did not differ substantially with harvest stage or bale location. Booting and heading stage-harvested ryegrass baleage were superior in nutritive value to anthesis stage-harvested herbage. Based on the investigated nutritive value and fermentation characteristics, individual bale location within in-line tubes did not significantly affect preservation quality of ryegrass round bale silages.
PMCID: PMC4150194  PMID: 25178371
Round Bale Silage; Baleage; Annual Ryegrass; Lolium multiflorum; Harvest Maturity; In-line Wrap; Dry Matter Concentration
7.  Lack of toxicity in a patient with germline TP53 mutation treated with radiotherapy 
Current Oncology  2014;21(2):e349-e353.
Li–Fraumeni syndrome is an autosomal dominant disorder characterized by germline TP53 mutation and increased susceptibility to cancer. Despite certain in vitro findings and a theoretical rationale for patients with TP53 mutation to be more radiosensitive and more prone to developing radiotherapy (rt)–induced secondary malignancies, corresponding clinical data remain elusive. Here, we report the case of a woman with TP53 mutation who was treated with adjuvant pelvic rt for stage ib uterine leiomyosarcoma in 2000, with radioactive iodine for papillary thyroid cancer in 2001, and with palliative rt to the humerus in 2010 for metastatic uterine leiomyosarcoma. She has not developed any acute or late rt-related toxicity, nor any secondary malignancies, since her first rt treatment. The literature review describes the potential risks and benefits of using irradiation in patients with TP53 mutation.
PMCID: PMC3997467  PMID: 24764719
Radiation; oncology; Li–Fraumeni; toxicity; p53
8.  Epithelial–mesenchymal transition markers expressed in circulating tumor cells in hepatocellular carcinoma patients with different stages of disease 
Cell Death & Disease  2013;4(10):e831-.
The presence of circulating tumor cells (CTCs) in peripheral blood is associated with metastasis and prognosis in hepatocellular carcinoma (HCC) patients. The epithelial–mesenchymal transition (EMT) has a pivotal role in tumor invasion and dissemination. To identify more sensitive biomarkers for evaluating metastasis and prognosis, we investigated the expression of EMT markers, including vimentin, twist, ZEB1, ZEB2, snail, slug and E-cadherin in CTCs, primary HCC tumors and adjacent non-tumoral liver tissues. After isolating viable CTCs from the peripheral blood of HCC patients using asialoglycoprotein receptors (ASGPRs), the CTCs were identified with immunofluorescence staining. CTCs were detected in the peripheral blood obtained from 46 of 60 (76.7%) HCC patients. Triple-immunofluorescence staining showed that twist and vimentin expression could be detected in CTCs obtained from 39 (84.8%) and 37 (80.4%) of the 46 patients, respectively. The expression of both twist and vimentin in CTCs was significantly correlated with portal vein tumor thrombus. Coexpression of twist and vimentin in CTCs could be detected in 32 (69.6%) of the 46 patients and was highly correlated with portal vein tumor thrombus, TNM classification and tumor size. Quantitative fluorescence western blot analysis revealed that the expression levels of E-cadherin, vimentin and twist in HCC tumors were significantly associated with the positivity of isolated CTCs (P=0.013, P=0.012, P=0.009, respectively). However, there was no significant difference in ZEB1, ZEB2, snail and slug expression levels in CTCs, primary HCC tumors and adjacent non-tumoral liver tissues across samples with regard to the clinicopathological parameters. Our results demonstrate that the EMT has a role in promoting the blood-borne dissemination of primary HCC cells, and the twist and vimentin expression levels in CTCs could serve as promising biomarkers for evaluating metastasis and prognosis in HCC patients.
PMCID: PMC3824657  PMID: 24091674
circulating tumor cells; epithelial–mesenchymal transition; hepatocellular carcinoma; metastasis; biomarkers
9.  Poststroke depression and emotional incontinence 
Neurology  2012;78(15):1130-1137.
To investigate the characteristics and prevalence of poststroke depression (PSD) and poststroke emotional incontinence (PSEI) and the factors related to these conditions at admission and 3 months after stroke.
We evaluated 508 consecutive patients with acute ischemic stroke for PSD and PSEI at admission and 3 months later. PSD was evaluated using the Beck Depression Inventory, and PSEI was evaluated using Kim's criteria. Blood samples were collected and genotyped for the promoter region of the serotonin transporter protein (5-HTTLPR) and the number of tandem repeats within intron 2 (STin2 VNTR). Perceived social support (the ENRICHD Social Support Inventory) was also measured.
PSD and PSEI were present in 13.7% and 9.4% of patients, respectively, at admission and in 17.7% and 11.7%, respectively, at 3 months after stroke. Multivariate analyses showed that PSD at admission was associated with the NIH Stroke Scale score at admission (p < 0.001), whereas PSD at 3 months was associated with the presence of microbleeds (p < 0.01) and perceived low social support (p < 0.001). In contrast, only lesion location (p = 0.022) was associated with PSEI at admission, whereas modified Rankin Scale score (p = 0.019), STin2 VNTR (p = 0.040), and low social support (p = 0.042) were related to PSEI 3 months after stroke.
Diverse factors such as neurologic dysfunction, lesion location, microbleeds, genetic traits, and social support are differently related to acute and subacute emotional disturbances. Strategies to prevent or manage these problems should consider these differences.
PMCID: PMC3320054  PMID: 22459674
10.  Nuclear Factor κB is Required for Tumor Growth Inhibition Mediated by Enavatuzumab (PDL192), a Humanized Monoclonal Antibody to TweakR 
TweakR is a TNF receptor family member, whose natural ligand is the multifunctional cytokine TWEAK. The growth inhibitory activity observed following TweakR stimulation in certain cancer cell lines and the overexpression of TweakR in many solid tumor types led to the development of enavatuzumab (PDL192), a humanized IgG1 monoclonal antibody to TweakR. The purpose of this study was to determine the mechanism of action of enavatuzumab’s tumor growth inhibition and to provide insight into the biology behind TweakR as a cancer therapeutic target. A panel of 105 cancer lines was treated with enavatuzumab in vitro; and 29 cell lines of varying solid tumor backgrounds had >25% growth inhibition in response to the antibody. Treatment of sensitive cell lines with enavatuzumab resulted in the in vitro and in vivo (xenograft) activation of both classical (p50, p65) and non-classical (p52, RelB) NFκB pathways. Using NFκB DNA binding functional ELISAs and microarray analysis, we observed increased activation of NFκB subunits and NFκB-regulated genes in sensitive cells over that observed in resistant cell lines. Inhibiting NFκB subunits (p50, p65, RelB, p52) and upstream kinases (IKK1, IKK2) with siRNA and chemical inhibitors consistently blocked enavatuzumab’s activity. Furthermore, enavatuzumab treatment resulted in NFκB-dependent reduction in cell division as seen by the activation of the cell cycle inhibitor p21 both in vitro and in vivo. The finding that NFκB drives the growth inhibitory activity of enavatuzumab suggests that targeting TweakR with enavatuzumab may represent a novel cancer treatment strategy.
PMCID: PMC3884146  PMID: 24409185
enavatuzumab; monoclonal antibody; TweakR; Fn14; NFκB; p21
11.  Self-reported post-exertional fatigue in Gulf War veterans: roles of autonomic testing 
To determine if objective evidence of autonomic dysfunction exists from a group of Gulf War veterans with self-reported post-exertional fatigue, we evaluated 16 Gulf War ill veterans and 12 Gulf War controls. Participants of the ill group had self- reported, unexplained chronic post-exertional fatigue and the illness symptoms had persisted for years until the current clinical study. The controls had no self-reported post-exertional fatigue either at the time of initial survey nor at the time of the current study. We intended to identify clinical autonomic disorders using autonomic and neurophysiologic testing in the clinical context. We compared the autonomic measures between the 2 groups on cardiovascular function at both baseline and head-up tilt, and sudomotor function. We identified 1 participant with orthostatic hypotension, 1 posture orthostatic tachycardia syndrome, 2 distal small fiber neuropathy, and 1 length dependent distal neuropathy affecting both large and small fiber in the ill group; whereas none of above definable diagnoses was noted in the controls. The ill group had a significantly higher baseline heart rate compared to controls. Compound autonomic scoring scale showed a significant higher score (95% CI of mean: 1.72–2.67) among ill group compared to controls (0.58–1.59). We conclude that objective autonomic testing is necessary for the evaluation of self-reported, unexplained post-exertional fatigue among some Gulf War veterans with multi-symptom illnesses. Our observation that ill veterans with self-reported post-exertional fatigue had objective autonomic measures that were worse than controls warrants validation in a larger clinical series.
PMCID: PMC3882719  PMID: 24431987
self-reported symptom; post-exertional fatigue; objective testing; autonomic; Gulf War veteran
12.  Effect of Lysine to Digestible Energy Ratio on Growth Performance and Carcass Characteristics in Finishing Pigs 
This experiment was performed to investigate the effects of lysine (Lys) to DE ratio on growth performance, and carcass characterics in finishing barrows. Ninety six cross-bred finishing barrows ((Landrace×Yorkshire) ×Duroc, average BW 58.25±0.48 kg) were assigned as a randomized complete block design by 2 energy levels and 4 Lys:DE ratios on the basis of BW to one of 8 treatments with 3 replications with 4 animals per pen. The levels of DE and Lys:DE ratio for each treatment were i) DE 3.35 Mcal/kg, 1.5 g Lys/Mcal DE, ii) DE 3.35 Mcal/kg, 1.8 g Lys/Mcal DE, iii) DE 3.35 Mcal/kg, 2.1 g Lys/Mcal DE, iv) DE 3.35 Mcal/kg, 2.4 g Lys/Mcal DE, v) DE 3.60 Mcal/kg, 1.5 g Lys/Mcal DE, vi) DE 3.60 Mcal/kg, 1.8 g Lys/Mcal DE, vii) DE 3.60 Mcal/kg, 2.1 g Lys/Mcal DE, viii) DE 3.60 Mcal/kg, 2.4 g Lys/Mcal DE. During finishing period from 58 kg to 103 kg of BW, increased energy density in the diet increased (p<0.05) ADG and gain:feed ratio, but did not influence ADFI. As Lys:DE ratio was increased, ADG, ADFI and gain:feed ratio were improved in finishing barrows (p<0.05). There were positive interactions (p<0.05) between carcass weight, grade, and backfat thickness and energy density and Lys level (p<0.05). In conclusion, data from our current study suggest that maximum yields including ADG, gain:feed ratio, carcass weight and grade can be achieved by administrating finishing pigs with an ideal Lys:DE ratio, Lys 2.1 g/DE Mcal.
PMCID: PMC4093041  PMID: 25049520
Barrows; Backfat; Lysine:DE Ratio; Carcass Characteristics
13.  Estimation of Effective Population Size in the Sapsaree: A Korean Native Dog (Canis familiaris) 
Effective population size (Ne) is an important measure to understand population structure and genetic variability in animal species. The objective of this study was to estimate Ne in Sapsaree dogs using the information of rate of inbreeding and genomic data that were obtained from pedigree and the Illumina CanineSNP20 (20K) and CanineHD (170K) beadchips, respectively. Three SNP panels, i.e. Sap134 (20K), Sap60 (170K), and Sap183 (the combined panel from the 20K and 170K), were used to genotype 134, 60, and 183 animal samples, respectively. The Ne estimates based on inbreeding rate ranged from 16 to 51 about five to 13 generations ago. With the use of SNP genotypes, two methods were applied for Ne estimation, i.e. pair-wise r2 values using a simple expectation of distance and r2 values under a non-linear regression with respective distances assuming a finite population size. The average pair-wise Ne estimates across generations using the pairs of SNPs that were located within 5 Mb in the Sap134, Sap60, and Sap183 panels, were 1,486, 1,025 and 1,293, respectively. Under the non-linear regression method, the average Ne estimates were 1,601, 528, and 1,129 for the respective panels. Also, the point estimates of past Ne at 5, 20, and 50 generations ago ranged between 64 to 75, 245 to 286, and 573 to 646, respectively, indicating a significant Ne reduction in the last several generations. These results suggest a strong necessity for minimizing inbreeding through the application of genomic selection or other breeding strategies to increase Ne, so as to maintain genetic variation and to avoid future bottlenecks in the Sapsaree population.
PMCID: PMC4093000  PMID: 25049664
Effective Population Size; Inbreeding Rate; Linkage Disequilibrium; SNP; Sapsaree Dog
14.  Selected Health Conditions Among Overweight, Obese, and Non-Obese Veterans of the 1991 Gulf War: Results from a Survey Conducted in 2003–2005 
Several health conditions and concerns have been reported to be increased among Gulf War veterans including post-traumatic stress disorder (PTSD), chronic fatigue syndrome (CFS), CFS-like illness, and unexplained multi-symptom illness (MSI). As the cohort of Gulf War veterans advance in age, they are likely to be at risk of not only certain deployment-related health conditions but also chronic diseases associated with lifestyle factors.
To clarify relationships between PTSD, CFS-like illness, MSI, and obesity, we analyzed data from a cross-sectional survey of health information among population-based samples of 15,000 Gulf War veterans and 15,000 veterans who served during the same era. Data had been collected from 9,970 respondents in 2003–2005 via a structured questionnaire or telephone survey.
Based upon body mass index (BMI) estimated from self-reported information about height and weight, the percentages of Gulf War and Gulf Era veterans who were overweight (BMI 25 to ≤ 29.9), were 46.8% and 48.7%, respectively. The percentages who were obese (BMI ≥ 30) were 29.6% and 28.3%, respectively. Without adjustment for Gulf deployment status (Gulf War vs Gulf Era), age, sex, or other factors, PTSD, MSI, CFS-like illness, and other chronic health conditions were more common among obese veterans than those who were normal weight (BMI 18.5 to ≤ 24.9). In multivariate analyses, PTSD was positively associated with obesity after adjustment for age, sex, Gulf deployment status, rank, income, education, and current smoking. In the model for PTSD, the adjusted odds ratio for obesity was 1.5 (95% CI 1.2–1.8). No associations were observed between BMI categories and CFS-like illness or MSI in multivariate analysis.
Gulf War and Gulf Era veterans who were obese were more likely to have certain chronic health conditions including PTSD. Associations between Gulf status and CFS-like illness and MSI identified in the 2003–2005 follow-up survey were not accounted for by group differences in the prevalence of overweight or obesity.
PMCID: PMC3125597  PMID: 21731594
Body mass; chronic fatigue syndrome; obesity; post-traumatic stress disorder; survey; veterans
15.  Alcohol Use and Selected Health Conditions of 1991 Gulf War Veterans: Survey Results, 2003-2005 
Preventing Chronic Disease  2011;8(3):A52.
A sizable literature has analyzed the frequency of alcohol consumption and patterns of drinking among veterans. However, few studies have examined patterns of alcohol use in veterans of the first Gulf War or factors associated with problem drinking in this population. We examined the frequency and patterns of alcohol use in male and female veterans who served in the 1991 Gulf War or during the same era and the relationships between alcohol use and selected health conditions.
We analyzed data from a follow-up survey of health information among population-based samples of 15,000 Gulf War and 15,000 Gulf Era veterans. Data had been collected from 9,970 respondents during 2003 through 2005 via a structured questionnaire or telephone survey.
Posttraumatic stress disorder (PTSD), major depressive disorder (MDD), unexplained multisymptom illness (MSI), and chronic fatigue syndrome (CFS)–like illness were more frequent among veterans with problem drinking than those without problem drinking. Approximately 28% of Gulf War veterans with problem drinking had PTSD compared with 13% of Gulf War veterans without problem drinking. In multivariate analysis, problem drinking was positively associated with PTSD, MDD, unexplained MSI, and CFS–like illness after adjustment for age, sex, race/ethnicity, branch of service, rank, and Gulf status. Veterans who were problem drinkers were 2.7 times as likely to have PTSD as veterans who were not problem drinkers.
These findings indicate that access to evidence-based treatment programs and systems of care should be provided for veterans who abuse alcohol and who have PTSD and other war-related health conditions and illnesses.
PMCID: PMC3103557  PMID: 21477492
16.  Bioavailability and Population Pharmacokinetics of Voriconazole in Lung Transplant Recipients▿  
Antimicrobial Agents and Chemotherapy  2010;54(10):4424-4431.
This study was undertaken to characterize the pharmacokinetics and bioavailability of voriconazole in adult lung transplant patients during the early postoperative period, identify factors significantly associated with various pharmacokinetic parameters, and make recommendations for adequate dosing regimens. Thirteen lung transplant patients received two intravenous infusions (6 mg/kg, twice daily [b.i.d.]) immediately posttransplant followed by oral doses (200 mg, b.i.d.) for prophylaxis. Blood samples (9/interval) were collected during one intravenous and one oral dosing interval from each patient. Voriconazole plasma concentrations were measured by high-pressure liquid chromatography (HPLC). NONMEM was used to develop pharmacokinetic models, evaluate covariate relationships, and perform Monte Carlo simulations. There was a good correlation (R2 = 0.98) between the area under the concentration-time curve specific for the dose evaluated (AUC0-∞) and trough concentrations. A two-compartment model adequately described the data. Population estimates of bioavailability, clearance, Vc, and Vp were 45.9%, 3.45 liters/h, 54.7 liters, and 143 liters. Patients with cystic fibrosis (CF) exhibited a significantly lower bioavailability (23.7%, n = 3) than non-CF patients (63.3%, n = 10). Bioavailability increased with postoperative time and reached steady levels in about 1 week. Vp increased with body weight. Bioavailability of voriconazole is substantially lower in lung transplant patients than non-transplant subjects but significantly increases with postoperative time. CF patients exhibit significantly lower bioavailability and exposure of voriconazole and therefore need higher doses. Intravenous administration of voriconazole during the first postoperative day followed by oral doses of 200 mg or 400 mg appeared to be the optimal dosing regimen. However, voriconazole levels should be monitored, and the dose should be individualized based on trough concentrations as a good measure of drug exposure.
PMCID: PMC2944566  PMID: 20679503
19.  Patient preferences for treatment: report from a randomised comparison of treatment strategies in early rheumatoid arthritis (BeSt trial) 
Annals of the Rheumatic Diseases  2007;66(9):1227-1232.
To determine treatment preferences among patients with recent onset rheumatoid arthritis participating in a randomised controlled trial comparing four therapeutic strategies.
A questionnaire was sent to all 508 participants of the BeSt trial, treated for an average of 2.2 years with either sequential monotherapy (group 1), step‐up combination therapy (group 2), initial combination therapy with tapered high‐dose prednisone (group 3), or initial combination therapy with infliximab (group 4). Treatment adjustments were made every 3 months to achieve low disease activity (DAS ⩽2.4). The questionnaire explored patients' preferences or dislikes for the initial therapy.
In total, 440 patients (87%) completed the questionnaire. Despite virtually equal study outcomes at 2 years, more patients in group 4 reported much or very much improvement of general health: 50%, 56%, 46% and 74% in groups 1–4, respectively (overall, P<0.001). Almost half of the patients expressed no preference or aversion for a particular treatment group, 33% had hoped for assignment to group 4 and 38% had hoped against assignment to group 3. This negative perception was much less prominent in patients actually in group 3. Nevertheless, 50% of patients in group 3 disliked having to take prednisone, while only 8% in group 4 disliked going to the hospital for intravenous treatment.
Within the limitations of our retrospective study, patients clearly preferred initial combination therapy with infliximab and disliked taking prednisone. After actual exposure, this preference remained, but the perception of prednisone improved. Patient perceptions need to be addressed when administering treatment.
PMCID: PMC1955131  PMID: 17405834
20.  Voriconazole Pharmacokinetics in Liver Transplant Recipients▿  
The objective of this study was to evaluate the pharmacokinetics of voriconazole and the potential correlations between pharmacokinetic parameters and patient variables in liver transplant patients on a fixed-dose prophylactic regimen. Multiple blood samples were collected within one dosing interval from 15 patients who were initiated on a prophylactic regimen of voriconazole at 200 mg enterally (tablets) twice daily starting immediately posttransplant. Voriconazole plasma concentrations were measured using high-pressure liquid chromatography (HPLC). Noncompartmental pharmacokinetic analysis was performed to estimate pharmacokinetic parameters. The mean apparent systemic clearance over bioavailability (CL/F), apparent steady-state volume of distribution over bioavailability (Vss/F), and half-life (t1/2) were 5.8 ± 5.5 liters/h, 94.5 ± 54.9 liters, and 15.7 ± 7.0 h, respectively. There was a good correlation between the area under the concentration-time curve from 0 h to infinity (AUC0-∞) and trough voriconazole plasma concentrations. t1/2, maximum drug concentration in plasma (Cmax), trough level, AUC0-∞, area under the first moment of the concentration-time curve from 0 h to infinity (AUMC0-∞), and mean residence time from 0 h to infinity (MRT0-∞) were significantly correlated with postoperative time. t1/2, λ, AUC0-∞, and CL/F were significantly correlated with indices of liver function (aspartate transaminase [AST], total bilirubin, and international normalized ratio [INR]). The Cmax, last concentration in plasma at 12 h (Clast), AUMC0-∞, and MRT0-∞ were significantly lower in the presence of deficient CYP2C19*2 alleles. Donor characteristics had no significant correlation with any of the pharmacokinetic parameters estimated. A fixed dosing regimen of voriconazole results in a highly variable exposure of voriconazole in liver transplant patients. Given that trough voriconazole concentration is a good measure of drug exposure (AUC), the voriconazole dose can be individualized based on trough concentration measurements in liver transplant patients.
PMCID: PMC2812143  PMID: 19933807
21.  Has the practice of radiation oncology for locally advanced and metastatic non-small-cell lung cancer changed in Canada? 
Current Oncology  2010;17(1):33-40.
Previous surveys have revealed wide variations in the management by radiation oncologists of non-small-cell lung cancer (nsclc) in Canada. The aim of the present study was to determine the current patterns of practice for locally advanced and metastatic nsclc among Canadian radiation oncologists.
Materials and Methods
An online survey was distributed electronically to all members of the Canadian Association of Radiation Oncologists. Those who treat lung cancer were invited to participate. The survey consisted of three scenarios focusing on areas of nsclc treatment in which the radiotherapy (rt) regimen that provides the best therapeutic ratio is unclear.
Replies from 41 respondents were analyzed. For an asymptomatic patient with stage iiib nsclc unsuitable for radical treatment, 22% recommended immediate rt, and 78% recommended rt only if the patient were to become symptomatic. Those who believed that immediate rt prolongs survival were more likely to recommend it (p = 0.028). For a patient with a bulky stage iiib tumour and good performance status, 39% recommended palliative treatment, and 61% recommended radical treatment (84% concurrent vs. 16% sequential chemoradiation at 60–66 Gy in 30–33 fractions). Those who believed that chemoradiation has a greater impact on survival were more likely to recommend it (p < 0.001). For a symptomatic patient with stage iv nsclc, 54% recommended external-beam rt (ebrt) alone, 41% recommended other modalities (brachytherapy, endobronchial therapy, or chemotherapy) with or without ebrt, and 5% recommended best supportive care. A majority (76%) prescribed 20 Gy in 5 fractions for ebrt.
Compared with previous surveys, more radiation oncologists now offer radical treatment for locally advanced nsclc. Management of nsclc in Canada may be evidence-based, but perception by radiation oncologists of the treatment’s impact on survival also influences treatment decisions.
PMCID: PMC2826774  PMID: 20179801
Non-small-cell lung cancer; palliation; radiation; survey
22.  The tuning fork test—a useful tool for improving specificity in “Ottawa positive” patients after ankle inversion injury 
Emergency Medicine Journal : EMJ  2006;23(10):788-790.
The Ottawa ankle rules are a clinical instrument calibrated towards a high sensitivity in order not to miss any fractures of the ankle or mid‐foot. This is at the cost of a mean specificity of around only 32%. The aim of this study was to determine the suitability of tuning fork testing in combination with existing Ottawa guidance for increasing the specificity in detecting fractures of the lateral malleolus. A prospective pilot study was carried out, in which a single trained investigator examined all patients with already “Ottawa positive” findings for possible lateral malleolus injury by applying a tuning fork (C° 128 Hz). The tuning fork test findings were compared with formal reports of plain ankle radiographs using simple cross‐table analysis. The observed prevalence of ankle fractures was 5 of 49 (10%). Sensitivity and specificity were calculated as 100% and 61%, respectively, for tuning fork testing on the tip of the lateral malleolus (TLM), and as 100% and 95%, respectively, for testing on the distal fibula shaft (DFS). The associated positive and negative likelihood ratios were 2.59 and 0 (TLM), and 22 and 0 (DFS), respectively. The data were significant, with p = 0.014 (TLM) and p<0.001 (DFS). This study suggests that additional tuning fork testing of “Ottawa positive” patients may lead to a marked reduction in ankle radiographs, with consequently reduced radiation exposure and journey time. This may be particularly relevant in situations where radiological facilities are not readily available (expedition medicine) or where access to these has to be prioritised (major incidents, natural catastrophes).
PMCID: PMC2579601  PMID: 16988308
23.  Methotrexate, vinblastine, doxorubicin and cisplatin combination regimen as salvage chemotherapy for patients with advanced or metastatic transitional cell carcinoma after failure of gemcitabine and cisplatin chemotherapy 
British Journal of Cancer  2007;98(1):86-90.
We investigated the safety and efficacy of a methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) combination regimen as second-line chemotherapy for patients with advanced or metastatic transitional cell carcinoma who failed first-line gemcitabine and cisplatin (GC) chemotherapy. Thirty patients who had progressed or relapsed after GC chemotherapy as first-line treatment were enrolled in this study. The major toxicities were neutropaenia and thrombocytopaenia. A grade 3 or 4 neutropaenia occurred in 19 (63.3%) and a grade 3 or 4 thrombocytopaenia developed in nine patients (30.0%). There were no life-threatening complications during the study. The overall response was 30%. A complete response was achieved in two patients (6.7%) and a partial response in seven (23.3%). The overall disease control rate was 50%. Seven out of 16 patients who had responded previously to GC responded to M-VAC, while 2 out of 14 who had not responded to GC responded to M-VAC. The median response duration was 3.9 months and the median progression-free survival was 5.3 months. The median overall survival was 10.9 months. M-VAC showed encouraging efficacy and reversible toxicities in patients who had progressed after GC chemotherapy and, especially, M-VAC appears to be a reasonable option as a sequential treatment regimen in patients who responded previously to GC chemotherapy.
PMCID: PMC2359702  PMID: 18087289
transitional cell carcinoma; chemotherapy; cisplatin; metastasis
24.  Oxidation of Flame Retardant Tetrabromobisphenol A by Singlet Oxygen 
Wide use of flame retardants can pose an environmental hazard and it is of interest to investigate how they may degrade. We report here that 3,3′,5,5′-tetrabromobisphenol A (TBBPA) is subject to photosensitized oxidation involving singlet molecular oxygen (1O2). By using visible light and Rose Bengal or Methylene Blue as 1O2 photosensitizers, we have found that TBBPA is a 1O2 quencher. The quenching rate constant, kq, depends on TBBPA ionization (pK=7.4). In acetonitrile, where TBBPA is undissociated, the kq value is 6.1×105 M-1s-1 for a TBBPA monomer and decreasing to kq=2.9×104M-1s-1 for TBBPA dimers/aggregates. TBBPA dissociates in aqueous solutions, and its kq value is 1.44×109 M-1s-1 in alkaline solution, decreasing to kq=3.9×108 M-1s-1 at pH 7.2. The strong 1O2 quenching by TBBPA anion initiates an efficient oxidation of TBBPA, which results in oxygen consumption in aqueous micellar (e.g. Triton-X 100) solutions containing photosensitizer. This oxygen consumption is mediated by transient radical species, which we detected by using EPR spectroscopy. We observed two major radicals and one minor radical generated from TBBPA by reaction with 1O2 at pH 10. One was identified as the 2,6-dibromo-p-benzosemiquinone radical (a2H = 2.36 G, g = 2.0056). A second radical (aH = 2.10 G, g = 2.0055) could not be identified but was probably a 2,6-dibromo-p-benzosemiquinone radical containing an EPR silent substituent in the 3-position. Spin trapping with 5,5,-dimethyl-1-pyrroline N-oxide (DPMO) showed that other minor radicals (hydroxyl, carbon centered) are also generated during the reaction of TBBPA with 1O2. The photosensitized production of radicals and oxygen consumption were completely inhibited by the azide anion, an efficient physical 1O2 quencher. Because TBBPA is a stable compound that at neutral pH does not absorb much of the atmosphere-filtered solar radiation, its photosensitized oxidation by 1O2 may be the key reaction initiating/mediating TBBPA degradation in the natural environment.
PMCID: PMC2376276  PMID: 18350892
25.  Healthcare utilization and mortality among veterans of the Gulf War 
The authors conducted an extensive search for published works concerning healthcare utilization and mortality among Gulf War veterans of the Coalition forces who served during the1990–1991 Gulf War. Reports concerning the health experience of US, UK, Canadian, Saudi and Australian veterans were reviewed. This report summarizes 15 years of observations and research in four categories: Gulf War veteran healthcare registry studies, hospitalization studies, outpatient studies and mortality studies. A total of 149 728 (19.8%) of 756 373 US, UK, Canadian and Australian Gulf War veterans received health registry evaluations revealing a vast number of symptoms and clinical conditions but no suggestion that a new unique illness was associated with service during the Gulf War. Additionally, no Gulf War exposure was uniquely implicated as a cause for post-war morbidity. Numerous large, controlled studies of US Gulf War veterans' hospitalizations, often involving more than a million veterans, have been conducted. They revealed an increased post-war risk for mental health diagnoses, multi-symptom conditions and musculoskeletal disorders. Again, these data failed to demonstrate that Gulf War veterans suffered from a unique Gulf War-related illness. The sparsely available ambulatory care reports documented that respiratory and gastrointestinal complaints were quite common during deployment. Using perhaps the most reliable data, controlled mortality studies have revealed that Gulf War veterans were at increased risk of injuries, especially those due to vehicular accidents. In general, healthcare utilization data are now exhausted. These findings have now been incorporated into preventive measures in support of current military forces. With a few diagnostic exceptions such as amyotrophic lateral sclerosis, mental disorders and cancer, it now seems time to cease examining Gulf War veteran morbidity and to direct future research efforts to preventing illness among current and future military personnel.
PMCID: PMC1569626  PMID: 16687261
Persian Gulf Syndrome; Gulf War Syndrome; veterans

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