Combination therapy of cyclosporine with steroid inhibits γ-interferon and interleukin-1 gene expression at the level of mRNA synthesisin vivo

The present study examined the effect of cyclosporine (CsA) administered with steroidin vivo on the capacity of peripheral blood mononuclear cells (PBMC) from kidney transplant recipients to generate cytokines and their gene expression at the level of messenger RNA (mRNA). PBMC from CsA-prednisolone (Pred)-treated recipients displayed 66.9% inhibition (54.3±12.4 IU/ml;N=42;P<0.01) of -interferon (-IFN) production compared with normal individuals (134.6±18.6 IU/ml;N=23). Azathioprine (Az)-Pred-treated recipients displayed significantly less inhibition of -IFN generation (96.0±16.1 IU/ml;N=22;P<0.05) than CsA-treated patients. Macrophages (m) from CsA-Pred-treated recipients displayed 60.0% inhibition (5.1±0.7 U/ml;N=20;P<0.01) of interleukin-1 (IL-1) production compared with normal individuals (13.0±2.9 U/ml;N=21). These results were confirmed by the experiments using cDNA probe for -IFN or IL-1 (, ). High levels of -IFN mRNA in phytohemagglutinin (PHA)-stimulated PBMC or IL-1() mRNA in lipopolysaccharide (LPS)-stimulated m were present in normal individuals but not in CsA-treated recipients as judged by hybridization to a cloned human -IFN or IL-1() cDNA probe. These studies demonstrated that combination therapy of CsA with steroid inhibits both -IFN and IL-1 gene expression at the level of mRNA at physiological concentrations.     

Next-generation calcineurin inhibitors for ophthalmic indications

Calcineurin inhibitors (CNIs) are potent immunosuppressants that reversibly inhibit T-cell proliferation and prevent the release of pro-inflammatory cytokines by blocking the activity of calcineurin, a ubiquitous enzyme that is found in cell cytoplasm. CNIs can be highly effective in immune-mediated ophthalmic diseases such as uveitis, dry eye syndrome and inflammatory blepharitis, as well as for the prevention of rejection in corneal transplants. ISA-247/LX-211 is a novel CNI that is in Phase III clinical development for the treatment of various forms of non-infectious uveitis. ISA-247/LX-211 is a rationally designed analog of ciclosporin A that exhibits more predictable pharmacokinetic and pharmacodynamic properties and a 4-fold greater calcineurin inhibition than its parent compound, ciclosporin A. ISA-247/LX-211 has been observed to be effective, well-tolerated, and safe in early clinical trials, exhibiting a much wider therapeutic window compared with classic CNIs, such as ciclosporin A and tacrolimus. An alternative approach to widening the therapeutic window for the therapy of ophthalmic disorders lies in local delivery of CNIs through polymeric implants that release the drug over long periods of time. The silicone matrix episcleral implant LX-201 is in Phase III development at present for the prevention of rejection in high-risk cornea transplantation.     

鬼臼毒素纳米脂质载体通过线粒体途径诱导人阴道上皮细胞凋亡的机制研究

目的:研究鬼臼毒素纳米脂质载体(POD-NLC)对体外培养的永生化人阴道上皮细胞(VK2/E6E7细胞)线粒体途径相关凋亡基因表达的影响,探索POD-NLC诱导VK2/E6E7细胞凋亡的作用机制。方法:自制0.5%POD-NLC,用不同浓度的POD-NLC(0.25,1μg/mL)和空白NLC作用VK2/E6E7细胞24 h后,采用实时荧光定量核酸扩增法(Real-time Quantitative PCR,qPCR)检测bcl-2、bax、caspace-3、caspase-9等mRNA表达水平,Western Bolt检测bcl-2、bax蛋白的表达水平。结果:POD-NLC呈剂量依赖性的上调bax mRNA的表达水平(P值均<0.01),同时也增加caspase-3、caspase-9 mRNA的表达(P值均<0.05),并降低bcl-2 mRNA表达量(P值均<0.01);空白-NLC组对上述mRNA的影响均无统计学意义(P值均>0.05)。POD-NLC可剂量依赖性地上调bax蛋白表达量(P值均<0.01),同时下调bcl-2蛋白表达量(P值均<0.01),但各药物处理组之间差异无统计学意义(P值均>0.05)。结论:POD-NLC能通过线粒体途径诱导VK2/E6E7细胞发生凋亡。     

不明原因不孕夫妇行IVF-ET时机的探讨

目的 :探讨对不明原因不孕妇女进行辅助生殖技术的最佳时机及方法。方法 :将 2 5 6例不明原因的不孕妇女分成 A、 B、C3组 ,A组为经历 1～ 3个 COH/ IUI周期的妇女 2 5 6人 ,共 475周期。B组为经历第 4、第 5、第6 COH/ IUI周期的妇女 41人 ,共 74周期。C组为经历前 3个 COH/ IUI周期失败后 ,进行 IVF和 ICSI治疗 1周期的5 9人。结果 :A组 75人获得妊娠 ,平均每周期妊娠率为 15 .8%,累积妊娠率为 2 9.2 %。B组 4人获得妊娠 ,平均每周期的妊娠率为 5 .4%,累积妊娠率为 38.9%,与 A组相比妊娠率明显降低 ,有统计学上的差异 ( P<0 .0 5 ) ,进一步增加的妊娠率为 9.7%。C组 2 2人获得妊娠 ,妊娠率为 37.2 %,明显高于 B组 ,有统计学上的差异 ( P<0 .0 1)。结论 :对于原因不明的妇女首先应进行 COH/ IUI周期治疗 ,当 3周期 COH/ IU I失败后 ,应进行 IVF和 ICSI治疗。     

Percutaneous transcystic balloon dilation for common bile duct stone removal in high-surgical-risk patients with acute cholecystitis and co-existing choledocholithiasis

Background

Percutaneous procedures to treat common bile duct (CBD) stones typically require access via intrahepatic bile ducts. This study aimed to describe the outcomes of a percutaneous transcystic approach that expelled the CBD stones into the duodenum after percutaneous transcystic balloon dilation of the ampulla (PTCBDA) for high-risk patients who present with acute cholecystitis and CBD stones.

Circumsporozoite protein gene diversity among temperate and tropical Plasmodium vivax isolates from Iran

To date, there is no information on the genetic diversity of the circumsporozoite protein (CSP), a leading vaccine candidate, in Plasmodium vivax populations circulating in Iran. The gene for this protein, Pvcsp, was amplified from 374 P. vivax isolates collected in the temperate northern, and in the tropical southern endemic areas. PCR-RFLP analysis of the repeated central region revealed that the parasites collected in the northern area were almost exclusively of the VK210 type. Parasites collected in the south-eastern areas were of both VK210 and VK247 types. We detected VK210 parasite in 70.5% of the samples, VK247 parasites in 17.5% and mixed type infections in 12% of the isolates. Sequence analysis of 137 isolates obtained from both areas identified a total of 25 distinct genotypes. The degree of genetic diversity was generally higher for the tropical (21 genotypes) than the temperate (7 genotypes) P. vivax populations, a difference possibly reflecting the high cross-border exchanges between Afghanistan and Pakistan and southern Iran. Interestingly, all but two VK210 type isolates sequenced harboured a 36-bp post-repeat insert previously only observed in North Korea and China. This large-scale survey of parasite diversity in the Eastern Mediterranean Region provides a set of baseline data suitable for future molecular epidemiological studies of P. vivax.     

Can hepatokines be regarded as novel non-invasive serum biomarkers of intrahepatic lipid content in obese children?

PurposeHepatokines are proteins produced by the liver and involved in regulating glucose and lipid metabolism. However, their role as the biomarkers of intrahepatic lipid content is not clear. The aim of the study was to evaluate the serum concentration of selected hepatokines: fibroblast growth factor-21 (FGF-21), selenoprotein P (SELENOP) and sex hormone-binding globulin (SHBG) in obese children.Patients and methodsThe cross-sectional study included 86 obese children with suspected liver disease. Nonalcoholic fatty liver disease (NAFLD) was diagnosed in children with liver steatosis in ultrasound with elevated alanine aminotransferase (ALT) serum activity and excluded other liver diseases. The total intrahepatic lipid content (TILC) was assessed by magnetic resonance proton spectroscopy (¹H-MRS).ResultsThe concentration of FGF-21 and SELENOP was significantly higher and SHBG significantly lower in children with NAFLD compared to controls. Only FGF-21 level was significantly higher in NAFLD children than in obese patients without NAFLD. The significant positive correlation of FGF-21 with ALT, gamma glutamyltransferase (GGT), triglycerides, homeostatic model assessment–insulin resistance (HOMA-IR), the degree of liver steatosis in ultrasound and TILC in ¹H-MRS were found. The ability of serum FGF-21 to diagnose severe liver steatosis was significant.ConclusionsFGF-21 can be considered as a suitable biomarker in predicting TILC and fatty liver in obese children.