Induction of interleukin-1 and tumor necrosis factor by 12-O-tetradecanoylphorbol-13-acetate in phorbol ester-sensitive (SENCAR) and resistant (B6C3F1) mice

12-O-tetradecanoylphorbol-13-acetate (TPA), the most potentskin tumor promoter known, evokes significant inflammatory responsesin mouse skin after topical application. Infiltrating inflammatorycells have been hypothesized to contribute to genetic damagein epidermal cells through the generation of reactive oxygenintermediates (ROIs), thus facilitating the development of tumors.Interleukin-1 (IL-1) and tumor necrosis factor (TNF), smallmol. wt cytokines produced by macrophages (MPs), are known tohave important roles in the inflammatory process. Lipopolysaccharide(LPS)-triggered release of IL-1 and TNF was determined in culturesupernatants of splenic MPs from phorbol ester-sensitive (SENCAR)and resistant (B6C3F1) mice following topical application of8 µg of TPA twice in one week. The findings reported hereinindicated that topical application of TPA primed splenic MPsfrom both SENCAR and B6C3F1 mice in a quantitatively similarmanner for the production of IL-1 and TNF; in addition, therelease of IL-1 and TNF by splenic MPs from control (naive oracetone-dosed) SENCAR and B6C3F1 mice in response to LPS-triggeringin vitro was not significantly different. Therefore, the productionand release of these cytokines by activated MPs does not correlatewith the reported strain-dependent susceptibilities to TPA-inducedinflammation and/or tumor promotion.     

Efficacy of enteric-coated mycophenolate sodium in patients with resistant-type lupus nephritis: a prospective study

The role of mycophenolate mofetil (MMF) is still controversial in the treatment of cyclophosphamide-resistant proliferative lupus nephritis (PLN). Enteric-coated mycophenolate sodium (EC-MPS) has less gastrointestinal adverse effects than MMF and is, therefore, increasingly utilised in organ transplantation. The aim of this study was to compare the efficacy and safety of EC-MPS versus an extended-course of intravenous cyclophosphamide (ED-IVCY) in resistant-type PLN. Thirty-one, biopsy-proven PLN, patients who failed to respond to an induction of IVCY were enrolled in a prospective, open-labelled, historically controlled study. Patients received 6 month of EC-MPS (720 mg b.i.d.) treatment. The patients in the ED-IVCY group, collected from a database, received a repeated 6-month course of monthly IVCY 0.5-1 g/m(2) of body surface area. Both groups received 0.5-1 mg/kg/day of prednisolone. Primary outcomes were partial or complete responses. A repeated kidney biopsy was performed to evaluate the histological response. No serious adverse events or patient deaths were observed during the study. Both groups had comparable baseline characteristics. At 6 months, the EC-MPS group had a comparable response rate with the ED-IVCY group. There were significantly less adverse events in the EC-MPS group. Repeated biopsies showed significant improvement in the EC-MPS group. EC-MPS provides salutary efficacy and safety in the treatment of resistant-type PLN and can be a suitably alternative treatment to ED-IVCY.     

Silicon-coordinated nitrogen-doped graphene as a promising metal-free catalyst for N2O reduction by CO: a theoretical study

Metal-free catalysts for the transformation of N₂O and CO into green products under mild conditions have long been expected. The present work proposes using silicon-coordinated nitrogen-doped graphene (SiN₄G) as a catalyst for N₂O reduction and CO oxidation based on periodic DFT calculations. The reaction proceeds via two steps, which are N₂O reduction at the Si reaction center, producing Si–O*, which subsequently oxidizes CO to CO₂. The N₂O reduction occurs with an activation energy barrier of 0.34 eV, while the CO oxidation step requires an energy of 0.66 eV. The overall reaction is highly exothermic, with a reaction energy of −3.41 eV, mostly due to the N₂ generation step. Compared to other metal-free catalysts, SiN₄G shows the higher selectivity because it not only strongly prefers to adsorb N₂O over CO, but the produced N₂ and CO₂ are easily desorbed, which prevents the poisoning of the active catalytic sites. These results demonstrate that SiN₄G is a promising metal-free catalyst for N₂O reduction and CO oxidation under mild conditions, as the reaction is both thermodynamically and kinetically favorable.

Mechanistic insight into the N₂O reduction and CO oxidation on SiN₄G is reported in this theoretical study. The high reactive and selective SiN₄ center leads this metal-free catalyst as a promising catalyst for this reaction under mild conditions.     

High Prevalence of Obesity in Thai Renal Transplant Recipients: A Multicenter Study

Background

Obesity is a risk factor for cardiovascular disease and cardiovascular mortality in renal transplant recipients (RTRs). There are limited studies of prevalence and associated factors of obesity in Asian RTRs.

Methods

A cross-sectional study was conducted from July to December 2012 in 4 kidney transplant centers in Bangkok, Thailand. Obesity was diagnosed based on the International Obesity Taskforce-proposed classification. At risk of obesity, obese I, and obese II were defined as having a body mass index (BMI) of 23–24.9 kg/m², 25–29.9 kg/m², and ≥30 kg/m², respectively.

Results

Of 263 recipients studied, 50 (19.0%), 70 (26.6%), and 17 (6.5%) were at risk of obesity, obese I, and obese II, respectively. The prevalence of obesity was 12.6% in the 1st year, was 28.6% in the first 3 years, and rose to 39.7% after 3 years after transplantation. Age (odds ratio [OR], 1.04; 95% CI, 1.01–1.07), systolic blood pressure ≥130/85 mm Hg (OR, 2.82; 95% CI, 1.51–5.26), number of antihypertensive medications (OR, 1.99; 95% CI, 1.42–2.79), fasting plasma glucose (OR, 1.03; 95% CI, 1.01–1.04,) and high-density lipoprotein (HDL) cholesterol (OR, 0.96; 95% CI, 0.94–0.98) were associated with obesity. Compared with 100 RTRs with normal BMI, obese patients tended to have higher prevalence of chronic kidney disease (OR, 1.59; 95% CI, 0.89–2.83).

Conclusions

The study demonstrates the high prevalence of obesity in Thai RTRs especially after 3 years after transplantation. Obesity is more prevalent with advanced age and variable components of metabolic syndrome in the RTR population. Obese RTRs had significantly higher blood pressure and required more antihypertensive medication when compared with RTRs with normal BMI.     

Effect of arginine hydrochloride and hydroxypropyl cellulose as stabilizers on the physical stability of high drug loading nanosuspensions of a poorly soluble compound

The objective of the present study is to formulate Naproxen nanosuspensions at high drug concentrations of up to 300 mg/ml using ball milling and is to investigate the additive effect between hydroxypropyl cellulose (HPC) and arginine hydrochloride as stabilizers. The nanosuspensions were obtained at different arginine hydrochloride/polymer weight ratios. Stability of Naproxen suspensions at 100 and 300 mg/ml was determined over a period of 14 days by measuring the particle size. The control, which contained only drug and buffers without the stabilizers agglomerated immediately after preparation. The study of the effect of arginine hydrochloride as a primary stabilizer indicated that arginine hydrochloride levels of up to 0.8% (w/v) were not able to help reduce particle size below one micron, and were also not able to provide stabilization to the suspensions on storage. Therefore, HPC was also added to the system to increase suspensions stability, presumably by a steric repulsion mechanism. When the Naproxen concentration was increased to 300 mg/ml, 1% (w/v) HPC was not able to provide good stabilization and it was found that arginine hydrochloride increased the stabilization efficiency of 1% (w/v) HPC by preventing flocculation. When HPC level was increased to 4% (w/v), HPC was high enough to sufficiently stabilize the nanosuspensions for 2 weeks and thereby could maintain the mean size diameter of the suspensions without the presence of arginine hydrochloride. Furthermore, stable nanosuspensions were successfully lyophilized without the use of additional cryoprotectants.     

Influence of ABCC2 and ABCC4 Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

Tenofovir (TFV) is eliminated by renal excretion, which is mediated through multidrug-resistant protein 2 (MRP2) and MRP4, encoded by ABCC2 and ABCC4, respectively. Genetic polymorphisms of these transporters may affect the plasma concentrations of tenofovir. Therefore, the aim of this study was to investigate the influence of genetic and nongenetic factors on tenofovir plasma concentrations. A cross-sectional study was performed in Thai HIV-infected patients aged ≥18 years who had been receiving tenofovir disoproxil fumarate at 300 mg once daily for at least 6 months. A middose tenofovir plasma concentration was obtained. Multivariate analysis was performed to investigate whether there was an association between tenofovir plasma concentrations and demographic data, including age, sex, body weight, estimated glomerular filtration rate (eGFR), hepatitis B virus coinfection, hepatitis C virus coinfection, duration of tenofovir treatment, concomitant use of ritonavir-boosted protease inhibitors, and polymorphisms of ABCC2 and ABCC4. A total of 150 Thai HIV-infected patients were included. The mean age of the patients was 43.9 ± 7.2 years. The mean tenofovir plasma concentration was 100.3 ± 52.7 ng/ml. In multivariate analysis, a low body weight, a low eGFR, the concomitant use of ritonavir-boosted protease inhibitors, and the ABCC4 4131T → G variation (genotype TG or GG) were independently associated with higher tenofovir plasma concentrations. After adjusting for weight, eGFR, and the concomitant use of ritonavir-boosted protease inhibitors, a 30% increase in the mean tenofovir plasma concentration was observed in patients having the ABCC4 4131 TG or GG genotype. Both genetic and nongenetic factors affect tenofovir plasma concentrations. These factors should be considered when adjusting tenofovir dosage regimens to ensure the efficacy and safety of a drug. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01138241","term_id":"NCT01138241"}}NCT01138241.)