Effectiveness of a multifaceted prevention programme for melioidosis in diabetics (PREMEL): A stepped-wedge cluster-randomised controlled trial

BackgroundMelioidosis, an often-fatal infectious disease caused by the environmental Gram-negative bacillus Burkholderia pseudomallei, is endemic in tropical countries. Diabetes mellitus and environmental exposure are important risk factors for melioidosis acquisition. We aim to evaluate the effectiveness of a multifaceted prevention programme for melioidosis in diabetics in northeast Thailand.Methodology/Principal findingsFrom April 2014 to December 2018, we conducted a stepped-wedge cluster-randomized controlled behaviour change trial in 116 primary care units (PCUs) in Ubon Ratchathani province, northeast Thailand. The intervention was a behavioural support group session to help diabetic patients adopt recommended behaviours, including wearing rubber boots and drinking boiled water. We randomly allocated the PCUs to receive the intervention starting in March 2016, 2017 and 2018. All diabetic patients were contacted by phone yearly, and the final follow-up was December 2018. Two primary outcomes were hospital admissions involving infectious diseases and culture-confirmed melioidosis. Of 9,056 diabetics enrolled, 6,544 (72%) received a behavioural support group session. During 38,457 person-years of follow-up, we observed 2,195 (24%) patients having 3,335 hospital admissions involved infectious diseases, 80 (0.8%) melioidosis, and 485 (5%) deaths. In the intention-to-treat analysis, implementation of the intervention was not associated with primary outcomes. In the per-protocol analysis, patients who received a behavioural support group session had lower incidence rates of hospital admissions involving infectious diseases (incidence rate ratio [IRR] 0.89; 95%CI 0.80–0.99, p = 0.03) and of all-cause mortality (IRR 0.54; 95%CI 0.43–0.68, p<0.001). However, the incidence rate of culture-confirmed melioidosis was not significantly lower (IRR 0.96, 95%CI 0.46–1.99, p = 0.66).Conclusions/SignificanceClear benefits of this multifaceted prevention programme for melioidosis were not observed. More compelling invitations for the intervention, modification of or addition to the behaviour change techniques used, and more frequent intervention may be needed.Trial registrationThis trial is registered with ClinicalTrials.gov, number {"type":"clinical-trial","attrs":{"text":"NCT02089152","term_id":"NCT02089152"}}NCT02089152.     

An ONIOM investigation on anion recognition of alkali–metal complexes with diurea calix[4]arene receptor

The ONIOM(B3LYP/6-31G(d):AM1) optimized structures of complexes of diurea calix[4]arene receptor (L) with alkali metals Li(+), Na(+) and K(+) and their complexes with halide ions F(-), Cl(-), Br(-), oxygen-containing anions HCO(3)(-), HSO(4)(-) and CH(3)COO(-) ions were obtained. Binding energies and thermodynamic properties of complex receptors LiL(+), NaL(+) and KL(+) with these anions were determined. The binding stabilities according to binding energies of LiL(+), NaL(+) and KL(+) associated with anions computed either at the ZPVE-corrected ONIOM(B3LYP/6-31G(d):AM1) or BSSE-corrected B3LYP/6-31 + G(d,p)//ONIOM(B3LYP/6-31G(d):AM1) are in the same order: F(-) > CH(3)COO(-) ≈ HCO(3)(-) > Br(-) ≈ HSO(4)(-) ≈ Cl(-). All the receptors LiL(+), NaL(+) and KL(+) were found to be selective toward fluoride ion.     

The role of short-chain dehydrogenase/oxidoreductase, induced by salt stress, on host interaction of B. pseudomallei

Background

Burkholderia pseudomallei is the causative agent of melioidosis, a frequently occurring disease in northeastern Thailand, where soil and water high in salt content are common. Using microarray analysis, we previously showed that B. pseudomallei up-regulated a short-chain dehydrogenase/oxidoreductase (SDO) under salt stress. However, the importance of SDO in B. pseudomallei infection is unknown. This study aimed to explore the function of B. pseudomallei SDO, and to investigate its role in interactions between B. pseudomallei and host cells.

Results

Bioinformatics analysis of B. pseudomallei SDO structure, based on homology modeling, revealed a NAD⁺ cofactor domain and a catalytic triad containing Ser149, Tyr162, and Lys166. This is similar to Bacillus megaterium glucose 1-dehydrogenase. To investigate the role of this protein, we constructed a B. pseudomallei SDO defective mutant, measured glucose dehydrogenase (GDH) activity, and tested the interactions with host cells. The B. pseudomallei K96243 wild type exhibited potent GDH activity under condition containing 300 mM NaCl, while the mutant showed activity levels 15 times lower. Both invasion into the A549 cell line and early intracellular survival within the J774A.1 macrophage cell were impaired in the mutant. Complementation of SDO was able to restore the mutant ability to produce GDH activity, invade epithelial cells, and survive in macrophages.

Conclusions

Our data suggest that induced SDO activity during salt stress may facilitate B. pseudomallei invasion and affect initiation of successful intracellular infection. Identifying the role of B. pseudomallei SDO provides a better understanding of the association between bacterial adaptation and pathogenesis in melioidosis.     

Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T cells

The glucocorticoid-induced TNF receptor (GITR), which is a member of the TNF receptor family, is expressed preferentially at high levels on CD25+CD4+ regulatory T cells and plays a key role in the peripheral tolerance that is mediated by these cells. GITR is also expressed on conventional CD4+ and CD8+ T cells, and its expression is enhanced rapidly after activation. In this report we show that the GITR provides a potent costimulatory signal to both CD25+ and CD25- CD4+ T cells. GITR-mediated stimulation induced by anti-GITR mAb DTA-1 or GITR ligand transfectants efficiently augmented the proliferation of both CD25-CD4+ and CD25+CD4+ T cells under the limited dose of anti-CD3 stimulation. The augmentation of T cell activation was further confirmed by the enhanced cell cycle progression; early induction of the activation Ags, CD69 and CD25; cytokine production, such as IL-2, IFN-gamma, IL-4, and IL-10; anti-CD3-induced redirected cytotoxicity; and intracellular signaling, assessed by translocation of NF-kappaB components. GITR costimulation showed a potent ability to produce high amounts of IL-10, which resulted in counter-regulation of the enhanced proliferative responses. Our results highlight evidence that GITR acts as a potent and unique costimulator for an early CD4+ T cell activation.     

Responses of Growing Japanese Quails that Received Selenium from Selenium Enriched Kale Sprout (Brassica oleracea var. alboglabra L.)

The objectives of this study were to determine the effect of selenium (Se) from Se-enriched kale sprout (Brassica oleracea var. alboglabra L.) on the performance and Se concentrations in tissues of growing Japanese quails. Two hundred quails were divided into five treatments. Each treatment consisted of four replicates and each replicate contained ten quails in a completely randomize design. The experiment was conducted for 5?weeks. The treatments were T1, control diet; T2, control diet plus 0.2?mg Se/kg from sodium selenite; T3, T4, and T5, control diet plus 0.2, 0.5, and 1.0?mg Se/kg from Se-enriched kale sprout. The results revealed that Se supplementation had no impact on feed intake, performance, and carcass characteristics of quails (p?>?0.05). However, Se supplementation from both sodium selenite and Se-enriched kale sprout increased (p?相似文献   

Increased urinary 1,N6-ethenodeoxyadenosine and 3,N4-ethenodeoxycytidine excretion in thalassemia patients: markers for lipid peroxidation-induced DNA damage

Thalassemic diseases including homozygous beta-thalassemia and beta-thalassemia/Hb E (beta-Thal/Hb E) are prevalent in Southeast Asia. Iron overload is a common complication in beta-thalassemia patients which induces intracellular oxidative stress and lipid peroxidation (LPO). LPO end products generate miscoding etheno adducts in DNA which after their repair are excreted in urine. We investigated whether urinary levels of 1,N6-ethenodeoxyadenosine (epsilondA) and 3,N4-ethenodeoxycytidine (epsilondC) can serve as putative cancer risk markers in beta-Thal/Hb E patients. epsilondA and epsilondC levels were assayed in collected urine samples by immunoprecipitation-HPLC-fluorescence and 32P-postlabeling TLC, respectively. Mean epsilondA (fmol/micromol creatinine) levels in urine of beta-Thal/Hb E patients ranged from 4.8 to 120.4 (33.8+/-3.9; n=37) and were 8.7 times higher compared to asymptomatic controls (1.4-13.8; 3.9+/-0.8; n=20). The respective epsilondC levels ranged from 0.15 to 32.5 (5.2+/-1.3; n=37) and were increased some 13 times over controls (0.04-1.2; 0.4+/-0.7; n=20). epsilondC levels were correlated positively with NTBI (r=0.517; P=0.002), whereas epsilondA showed only a trend (r=0.257; P=0.124). We conclude that the strongly increased urinary excretion of etheno adducts indicates elevated LPO-induced DNA damage in internal organs such as the liver. These highly promutagenic lesions may contribute to the increased risk of thalassemia patients to develop hepatocellular carcinoma.     

Elevated F2-isoprostanes in thalassemic patients

This study was aimed at investigating oxidative stress in thalassemic patients by measurement of the oxidative damage biomarker, F₂-isoprostanes (F₂-IsoPs), using gas chromatography-mass spectrometry. The results showed that the mean value of urinary F₂-IsoPs, normalized with creatinine, in the thalassemic group was significantly higher than that from healthy subjects (3.38 ± 2.15 ng/mg creatinine vs 0.86 ± 0.55 ng/mg creatinine, respectively), and the mean value of plasma total F₂-IsoPs in the thalassemic group was also significantly higher than that from healthy subjects (0.39 ± 0.15 ng/ml vs 0.18 ± 0.03 ng/ml, respectively). Serum ferritin, erythrocyte superoxide dismutase (SOD), glutathione peroxidase, glutathione, and TBARS levels after treatment of erythrocytes with H₂O₂ were also investigated, and serum ferritin and erythrocyte SOD levels were significantly higher in thalassemic patients. Our findings are consistent with oxidative stress in thalassemia patients.