基于CSA-PLS算法的养殖水体水质快速高光谱预测反演模型研究

养殖水体水质的优劣直接影响养殖对象的成长,准确、快速、全面地掌控养殖水环境的水质参数变化情况具有重要意义。传统的水质指标监测方法都通过人工采样的方式,不仅耗费时间长,且只能体现局部水体情况。针对这些问题,提出了一种乌鸦搜索算法(CSA)结合偏最小二乘回归(PLSR)的高光谱特征波段筛选方法,快速构建回归模型,实现光谱数据的精准预测反演。以连片的养殖小区为研究对象,采集养殖水体样本并拍摄同时期的高光谱影像数据。首先对提取的采样点光谱数据利用多种数据变换方法分别预处理;其次利用这些数据,对水质指标总氮(TN)、氨氮(NH_(4)^(+)-N)、总磷(TP)和化学需氧量(COD)分别构建全波段的SVR和AdaBoost回归模型,同时与提出的CSA-PLS自动筛选波段方法和传统的连续投影算法(SPA)筛选波段后构建的模型进行比较分析;最后根据决定系数(R^(2))和均方根误差(REMS)选出适合各水质指标的最优模型。从实验结果可以看出,所提波段筛选方法的AdaBoost模型预测结果优于SVR和传统SPA方法提取特征波段后构建的模型,与全波段最优模型相比,在评价指标R^(2)和RMSE上TN提升了18.32%和10.73%;NH_(4)^(+)-N提升了17.42%和11.19%;COD提升了2.15%和2.54%。结果表明,基于CSA-PLS算法的光谱波段自动筛选方法结合AdaBoost构建的预测反演模型是有效、可行的,具有较高的精准度,为实现养殖水环境实时准确的预警调控提供了一种新的数据预测模型。

环孢霉素A(Cyclosporin A,CsA)对穿透性异种角膜移植的影响——免疫学检测与形态学观察

以鸡→兔穿透性角膜移植为实验模型,运用ELISA 技术和微量全血~3H—TdR 掺入法、光镜和扫描电镜进行检测和观察。结果:术后3～4周血清中抗角膜抗体水平和外周血淋巴细胞转化程度达峰值,而CsA 治疗组与对照组比,上述二项免疫指标水平都有明显下降。组织病理学检查:在对照组的移植片内出现明显的炎性细胞浸润和新生血管,而CsA 治疗组,异种植片基本正常,没有出现炎性细胞浸润和新生血管。

Cyclosporine玻璃体腔内注射对异种视网膜色素上皮移植的排异抑制作用

目的 观察兔眼视网膜下腔植入人胚眼视网膜色素上皮 (retinal pigm ent epithe-lium,RPE)后不同时期的眼底和组织学改变。研究环胞菌素 A (Cyclosporines,Cs A )玻璃体腔内注射能否抑制人胚眼 RPE在兔眼视网膜下腔中诱导的异种移植排异反应。方法 人胚眼色素上皮片和浓缩色素上皮细胞悬液植入 36只兔眼的视网膜下腔 ,其中 16眼为对照组 ,用于观察排异的自然转规。分别于 7d(8眼 )和 30 d(8眼 )后获取组织标本。另 2 0眼为实验组。RPE移植后 ,每周一次玻璃体腔内注射 Cs A1mg(12眼 )或 Cs A0 .1mg(8眼 )。视网膜和视神经的毒性反应使用 ERG进行检查。结果 人胚眼 RPE片和浓缩的 RPE细胞均能在视网膜下腔短期存活。移植的 RPE与视细胞结合良好并显示吞噬功能。排异反应发生时间约在术后 10～ 30 d。对照组中 7d的排异发生率为 0 /8;30 d排异发生率为 7/8。排异发生后荧光造影中移植区为高荧光区 ,组织切片中显示有大量的组织细胞积聚。 Cs A1mg组 30 d排异发生率为 0 /12 ,0 .1mg组为 5 /8。ERG波幅的下降与 Cs A剂量和注射次数呈正相关。结论 异种 RPE视网膜下腔移植在无免疫抑制剂的条件下 ,只能短期存活。Cs A玻璃体腔中注射能抑制异种 RPE移植的排异反应但易引起明显的视网膜毒性反应。

基于信息敏感性与CSA-BP神经网络的“智慧工地系统”实施风险评价研究

为提高“智慧工地系统”在实施过程中的安全性,减少其因应用不当等原因造成的损失。参考WSR方法论与信息敏感性理论建立“智慧工地系统”实施风险评价指标体系。引入CSA-BP神经网络算法,该方法通过乌鸦搜索算法(CSA)弥补BP神经网络易陷入局部最优及收敛速度慢等缺陷,建立了实施风险评价模型。将该模型应用到广西某码头油库项目进行实例验证,评价结果与实际情况相符,表明其可行性较高,具有实际应用价值。根据模型评价结果有针对性地提出建议及措施,为“智慧工地系统”的推广与实施过程提供理论依据。

茶树CsAS1和CsAS2基因的克隆及功能分析

叶片是植物进行光合作用等代谢过程的重要场所,所以对其形态建成及发育过程的研究非常重要.AS蛋白能够参与叶片极性建立的调控,但关于茶树AS蛋白的研究还较少.本研究从“福鼎大白茶”茶树中克隆获得了2个AS蛋白基因:CsAS1和CsAS2,编码蛋白长度分别为344 aa和229 aa,理论等电点分别为10.04和7.36,分别分布在第4和10号染色体上,均定位于细胞核;系统进化树和保守结构域分析表明,CsAS1和CsAS2蛋白间氨基酸序列和空间结构高度保守,且分别与葡萄和水稻的AS蛋白亲缘最近;CsAS1和CsAS2在茶树中的表达模式分析显示,CsAS1基因在茶树芽中的表达量最高,CsAS2基因在茶树根中的表达量最高,且CsAS1和CsAS2基因在茶树一芽二叶中的表达量均受到外源IAA和GA 3的诱导表达;启动子元件和转录组数据分析结果显示,CsAS1和CsAS2基因启动子序列中均含有多个非生物逆境胁迫响应的元件,且受到不同逆境胁迫的抑制或诱导表达.综上所述,CsAS1和CsAS2基因可参与茶树叶片的形态建成及非生物逆境胁迫的响应过程,可为进一步研究CsAS1和CsAS2基因在茶树叶片极性建立及叶片发育过程中的功能提供理论参考.

CSA模式视角下乡村六次产业融合发展的可行性探析——基于辽宁省部分农场与乡村的调查

CSA模式以其临近消费市场的地理位置、生态化有机种植与产销高度融合等条件在诸多发达国家得到成功验证。我国可借鉴其成功经验,在我国乡村振兴战略背景下,通过CSA模式视角重新审视乡村自身条件与环境,进而找到以农业为基础的六次产业融合与长远可持续发展的路径。

Cyclosporine A stimulated hair growth from mouse vibrissae follicles in an organ culture model

Hypertrichosis is one of the most common side effects of systemic cyclosporine A therapy.It has been previously shown that cyclosporine A induces anagen and inhibits catagen development in mice.In the present study,to explore the mechanisms of cyclosporine A,we investigated the effects of cyclosporine A on hair shaft elongation,hair follicle cell proliferation,apoptosis,and mRNA expression of selected growth factors using an organ culture model of mouse vibrissae.In this model,cyclosporine A stimulated hair growth of normal mouse vibrissae follicles by inhibiting catagen-like development and promoting matrix cell proliferation.In addition,cyclosporine A caused an increase in the expression of vascular endothelial growth factor（VEGF）,hepatocyte growth factor（HGF）,and nerve growth factor（NGF）,and inhibited follistatin expression.Our findings provide an explanation for the clinically observed effects of cyclosporine A on hair growth.The mouse vibrissae organ culture offers an attractive model for identifying factors involved in the modulation of hair growth.

价值共创如何影响CSA的质量安全治理能力?——基于共生理论的案例研究

价值共创的核心是在遭遇空间中实现各方的价值创造,以满足主体的利益诉求和价值诉求。价值共创将社区支持农业(CSA)的模式优势转换为治理效能,能够有效促使CSA质量安全治理能力的积淀、形成与提升。研究采用单案例研究方法,基于共生理论,从共生主体、共生关系和共生效益三重视角分析价值共创影响CSA质量安全治理能力的内在逻辑,并构建相应的理论模型。研究发现:在CSA模式发展前期,价值共创通过聚合共生主体,积淀CSA质量安全治理能力;在CSA模式发展中期,价值共创通过构建共生关系,形成CSA质量安全治理能力;在CSA模式发展后期,价值共创通过输出共生效益,提升CSA质量安全治理能力。

Comparative analysis of different cyclosporine A doses on protection after myocardial ischemia/reperfusion injury in rat

Objective:To investigate the protective effect of different cyclosporin A(CsA)doses on myocardial ischemia/reperfusion injury in rat models.Methods:A rat model of myocardial ischemia/reperfusion injury was established in vivo and the rats were randomly divided into four groups:placebo(PBS;T1),low-dose(CsA dose:1.0 mg/kg:T2),medium-dose(CsA dose:2.5 mg/kg:T3),and high-dose(CsA dose:5.0 mg/kg;T4)groups.Heart function indexes were monitored at different time points,the extent of myocardial infarction was assessed by Evans Blue-TTC staining,and creatine kinase MB mass and cardiac troponin 1 values were measured by biochemical assays.Results:Compared with the T1 and T2 groups,both the creatine kinase MB mass and cardiac troponin 1 were significantly lower in the T3 and T4 groups(P<0.05).The mean arterial pressure(MAP)and left ventricular systolic pressure(LVSP)decreased sequentially in each group,with the extending reperfusion time.Significant decreases in LVSP and MAP were observed in the T3 and T4 groups as compared to the T1 and T2 group(P<0.05)and the T2 group showed a significantly lower LVSP and MAP decline than the T1 group(P<0.05).Compared with the Tl group,the rats from the T2.T3,and T4 groups suffered from a significantly lower extent of myocardial infarction(P<0.05).Also,the a animals in the T3 and T4 groups had a significantly smaller extent of myocardial infarction than those in the T2 group(P<0.05).Conclusions:Various CsA doses exert different degrees of protection against ischemia/reperfusion injury,and this protective effect peaks at approximately 2.5 mg/kg in rat models.

Treatment of ocular rosacea: comparative study of topical cyclosporine and oral doxycycline

AIM: To compare the effectiveness of topical cyclosporine A emulsion with that of oral doxycycline for rosacea associated ocular changes and dry eye complaints.METHODS: One hundred and ten patients with rosacea were screened. Thirty-eight patients having rosacea associated eyelid and ocular surface changes and dry eye complaints were included in the study. Patients were randomly divided into two groups: nineteen patients were given topical cyclosporine twice daily and nineteen patients were given oral doxycycline 100 mg twice daily for the first month and once daily for the following two months. Symptom and sign scores, ocular surface disease index questionnarie and tear function tests were evaluated at baseline and monthly for 3mo. Three months after results were compared with that of baseline.RESULTS: Mean values of symptom, eyelid sign and corneal/conjunctival sign scores of each treatment group at baseline and 3mo after treatments were compared and both drugs were found to be effective on rosacea associated ocular changes(P 【0.001). Cyclosporine was more effective in symptomatic relief and in the treatment of eyelid signs(P =0.01). There was statistically significant increase in the mean Schirmer score with anesthesia and tear break up time scores in the cyclosporine treatment group compared to the doxycycline treatment group(P 【0.05).CONCLUSION: Cyclosporine as a topical drug can be used in the treatment of rosacea associated ocular complications because it is more effective than doxycycline. In addition ocular rosacea as a chronic disease requires long term treatment and doxycycline has various side effects limiting its long term usage.

Effect of topical 0.05% cyclosporine A on the tear protein lacritin in a rat model of dry eye

AIM: To observe the effect of topical 0.05% cyclosporine A(CsA) on the ocular surface and tear protein lacritin in a botulinum B-induced dry eye rat model. METHODS: A total of 36 female SD rats were randomly divided into 3 groups, botulinum B was injected into the right lacrimal gland of all rats. Group A and group B were treated with 0.05% CsA and 0.1% sodium hyaluronate, respectively, 3 times daily. The control group was not treated. Basal tear flow, corneal epithelial defects, and lacritin levels were measured. RESULTS: Tear secretion in all rats was reduced on day 3 and was even lower on day 7 postoperation(P<0.05). Tear secretion in group A increased by day 14 and was at the preoperative level on day 42. Tear secretion in group B and control rats was lower on days 14 and 42 compared with preoperative level(P<0.05). Corneal fluorescein staining in group A was higher on day 3, peaked on day 7, and then decreased gradually from day 7 until day 14, returning to normal by day 42 post-procedure. However, in group B, corneal fluorescein staining had improved, but was not fully recovered by day 42. Corneal fluorescein staining was more intense than before the operation and then in the control group at all time points. Tear protein lacritin levels reached the lowest levels on day 7 in all groups. In group A, tear protein lacritin levels began to increase on day 14 and were normal on day 42. In group B, tear protein lacritin levels began to increase on day 14, but had not completely recovered on day 42. In the control group, tear protein lacritin levels remained low post-procedure. CONCLUSION: CsA 0.05% prompts tear protein lacritin expression in a rat model of dry eye and improves the signs and symptoms of dry eye disease.

Azathioprine is essential following cyclosporine for patients with steroid-refractory ulcerative colitis

AIM: To evaluate long-term prognosis following cyclosporine treatment by examining the rate of surgery avoidance among cyclosporine responders.METHODS: We retrospectively reviewed clinical records for 29 patients diagnosed with severe steroid-refractory ulcerative colitis in our hospital from August 1997 to August 2008 and treated with cyclosporine by continuous intravenous infusion.All patients were treated with intravenous corticosteroids for more than 5 d prior to cyclosporine therapy.Administration was continued for up to 21 d under serum monitoring to maintain cyclosporine levels between 400 and 600 ng/mL.Clinical activity was assessed before and after cyclosporine therapy using the clinical activity index score,with a reduction of ≥ 5 considered to indicate a response.Among responders,we defined cases not requiring surgery for more than 5 years as exhibiting long-term efficacy of cyclosporine.Factors considered to be possibly predictive of long-term efficacy of cyclosporine were sex,age,disease duration,clinical activity index score,C-reactive protein level,hemoglobin level,disease extent,endoscopic findings,and clinical course.RESULTS: Cyclosporine was not discontinued due to side effects in any patient.Nineteen(65.5%) of 29 patients were considered responders.A statistically significant(P = 0.004) inverseas sociation wa s observed between an endoscopic finding of "mucosal bleeding" and responsive cases.Fifteen(9 males,6 females) of these 19 patients were followed for 5 years or more,of whom 9(60%) exhibited long-termefficacy of cyclosporine.Of the 10 non-responders,9(90%) underwent surgery within 6 mo of cyclosporine therapy.None of the following factors had a significant impact on the long-term efficacy of cyclosporine: sex,age,duration of disease,clinical activity index score,C-reactive protein level,hemoglobin level,extent of disease,endoscopic findings,or clinical course.In contrast,a significant association was observed for maintenance therapy with azathioprine after cyclosporine therapy(P = 0.0014).CONCLUSION: Maintenance therapy with azathioprine might improve the long-term efficacy of continuously infused cyclosporine for severe steroid-refractory ulcerative colitis patients.

Effect of topical 0.05% cyclosporine A on corneal endothelium in patients with dry eye disease

· AIM: To determine the effect of topical 0.05% cyclosporine A (CsA) on corneal endothelium in patients with dry eye disease. · METHODS: Observational, prospective, case series study. Fifty-five eyes of 29 consecutive patients (9 males and 20 females; median age: 66.8 years, interquartile range: 61 -73.2 years) with moderate -severe dry eye disease were evaluated. All patients were treated with topical 0.05% CsA ophthalmic emulsion twice a day in addition to lubricant eyedrops 5 times a day. The follow- up period was 12 months. Before treatment and at 3 and 12 months post -treatment central corneal specular microscopy was performed. The endothelial cell density (ECD), coefficient of variation of cell size (CoV), and percentage of hexagonal cells (Hex %) were analyzed. ·RESULTS: The median ECDs pre-treatment and at 3 and 12 months post-treatment were 2 352.5/mm 2 (inter- quartile range, 2 178 -2548.5), 2 364/mm 2 (interquartile range, 2 174.25 -2 657.5), and 2 366 cells/mm 2 (inter - quartile range, 2 174.75-2 539.75), respectively (P=0.927, one way ANOVA). The median CoVs pre-treatment and at 3 and 12 months post -treatment were 34.5 (interquartile range, 30 -37), 35 (interquartile range, 30 -38), and 34 (interquartile range, 30.75-38.25), respectively (P=0.7193, one way ANOVA). The median Hex % values pre - treatment and at 3 and 12 months post -treatment were 53 (interquartile range, 47 -58), 54 (interquartile range, 45.75 -59), and 50.5 (interquartile range, 45.75 -58), respectively (P=0.824, one way ANOVA). · CONCLUSION: Treatment of patients with dry eye disease for 12 months with topical 0.05% CsA does not seem to cause substantial changes on corneal endothelium.

The effects of diltiazem in renal transplantation patients treated with cyclosporine A

Objective： To investigate the effects of diltiazem and cyclosporine A （CsA） combination therapy on protecting the kidney, promoting graft functioning and improving post-transplanted kidney recovery. Methods： The blood con- centrations of CsA, the condition of the post-transplant kidney, the rate of acute rejection （AR）, as well as hepatic and renal toxicity in 636 cases of renal transplant recipients were determined after being treated by CsA, with or without diltiazem. Results： Compared with the control group which received CsA, mycophenolate mofetil （MMF） and prednisolone （Pred） but lacked diltiazem, the group receiving these agents together with diltiazem required reduced dosage of CsA （P 〈 0.01）, while blood concentrations of CsA were significantly increased （P 〈 0.01）; the recovery time of graft function was reduced from （6.2± 1.5） d to （3.9± 1.4） d （P 〈 0.01）, and the rate of AR was decreased from 13.2% to 7.9% （P 〈 0.01）. Conclusion： In renal transplantation patients treated with CsA and diltiazem, blood concentrations of CsA were increased while the dosage was decreased. This efficient combination therapy reduced patients economic burden, at the same time retained kidney function, promoted graft function recovery and decreased hepatic and renal toxicity and the rate of AR.

Inhibitory effect of cyclosporine A on hepatitis B virus replication in vitro and its possible mechanisms

BACKGROUND: Hepatitis B related end-stage liver disease is recently acknowledged as one of the main indications for orthotopic liver transplantation (OLT). However, the high recurrence rate of hepatitis B virus infection following transplantation is regarded as a major factor affecting the long-term survival of transplant recipients especially in Chi- na. Cyclosporine A (CsA), which is routinely used to pre- vent the allograft rejection, is reported to have the inhibito- ry activity on hepatitis B virus (HBV) replication in vitro. In this paper, we review the inhibitory effect and its possi- ble mechanisms of CsA on HBV replication in vitro. DATA RESOURCES: An English-language literature search was conducted using MEDLINE (1990-2004) on cyclospo- rine A, hepatitis B virus, mitochondria, calcium and other related reports and review articles. RESULTS: Hepatitis B x protein (HBx) is essential to HBV replication. The cytosolic calcium signaling mediated by mitochondria and the Src kinase pathway were involved during HBx activation of HBV replication. CsA inhibits the HBV replication in vitro by its binding to mitochondrial cy- clophilin D, then blocking the mitochondria-mediated cy- tosolic calcium signaling. The derivates of CsA also have the HBV replication inhibitory effect in vitro. CONCLUSIONS; By interacting with mitochondria, pre- venting the release of intramitochondrial calcium, and then blocking the cytosolic calcium signaling, CsA inhibits the HBV replication in vitro. The derivates of CsA also have this activity.

Application of sustained delivery microsphere of cyclosporine A for preventing posterior capsular opacification in rabbits

AIM:To explore the inhibitory effect of a sustained cyclosporin A (CsA) delivery microsphere (CsA-MS) on posterior capsular opacification (PCO) in rabbit eyes after cataract extraction. ·METHODS:Twenty New Zealand white rabbits accepted cataract extraction plus intraocular lens implantation and their left eyes were intraoperatively injected CsA-MS prepared using polymer polylactioglycolic acid (PLGA) as a carrier and their right eyes were injected with empty MS. The changes in cornea, anterior chamber reaction, intraocular pressure, PCO and CsA concentration in aqueous humor were examined postoperatively and all the eyes were enucleated 3 months after surgery for histopathological and morphological examination with light microscopy and electron microscopy. · RESULTS:Conjunctival hyperemia, corneal edema, intraocular pressure and anterior chamber response of experimental and control eyes were similar, while PCO in CsA MS injected eyes was greatly improved compared with that in control eyes. Posterior capsules in CsA-MS injected eyes were smooth and lens epithelial cells (LEC) did not proliferate significantly (P 】0.05), while LEC in posterior capsule of control eyes had different degrees of proliferation and cortical regeneration. LEC in CsA-MS injected eyes were not functionally active and underwent apoptosis, whereas LEC in control eyes were functionally active (F-test, P =0.025). In addition, the cornealultrastructure showed no differences between CsA-MS and MS injected eyes. CONCLUSION:CsA-MS has high bioavailability in rabbit eyes and could inhibit postoperative PCO occurrence and development during the study period, suggesting that CsA-MS may be a promising, effective and safe administration route to prevent PCO in clinic.

The clinical value of enzyme-multiplied immunoassay technique monitoring the plasma concentrations of cyclosporine A after renal transplantation

The feasibility and the clinical value of the enzyme-multiplied immunoassay technique （EMIT） monitoring of blood concentrations of cyclosporine A （CsA） in patients treated with CsA were investigated after kidney transplantation. The validation method was performed to the EMIT determination of CsA blood concentration, the CsA whole blood trough concentrations （Co） of patients in different time periods after renal transplantation were monitored, and combined with the clinical complications, the statistical results were analyzed and compared. EMIT was precise, accurate and stable, also with a high quality control. The mean postoperative blood concentration of CsA was as follows： 〈1 month, （281.4± 57.9）ng/mL; 2 - 3 months, （264.5 ± 41.2） ng/mL; 4 - 5 months, （236.4 ± 38.9） ng/mL; 6 - 12 months, （206.5± 32.6）ng/mL; 〉12 months, （185.6± 28.1）ng/mL. The toxic reaction rate of CsA blood concentration within the recommended therapeutic concentration was 14.1%, significantly lower than that of the none-recommended dose group （37.2%） （P〈0.05）; the transplantation rejection rate was 4.4%, significantly lower than that of the none- recommended dose group （22.5%） （P〈0.05）. Using EMIT to monitor the blood concentration of CsA as the routine laboratory method is feasible, and is able to reduce the CsA toxicity and rejection significantly, leading to achieving the desired therapeutic effect.

Clinical efficacy of combined topical 0.05%cyclosporine A and 0.1%sodium hyaluronate in the dry eyes with meibomian gland dysfunction

AIM： To investigate the efficacy of combined topical 0.05% cyclosporine A（CsA; Restasis~？, Allergan pharmaceuticals, USA） and 0.1% sodium hyaluronate treatment in dry eyes with meibomian gland dysfunction（MGD）.METHODS： In a retrospective analysis, 53 patients（106 eyes） with MGD were enrolled and performed lid warm massage for 10 min daily and be instilled preservative free sodium hyaluronate 0.1% eye drops 4 times daily. Patients were divided into subjects treated with topical 0.05% CsA and preservative free sodium hyaluronate vehicle（experimental group, n=74 eyes） and subjects treated with the preservative free sodium hyaluronate vehicle（control group, n=32 eyes）. They were evaluated at baseline and 1, 2, and 3 mo for subjective symptoms and objective signs including tear film break-up time（t BUT）, Schirmer test, corneal staining（CS） score, lid margin telangiectasia（LMT）, meibomian gland secretion（MGS）, and conjunctival injection（CI）.RESULTS： In the short-term treatment, the experimental group showed a statistically significant improvement in the ocular surface disease index（OSDI; P〈0.001）, tBUT（P=0.004）, Schirmer test score（P=0.008） and LMT（P=0.021） by repeated measure ANOVA. Additionally, mean changes from baseline in OSDI（P〈0.001）, tBUT（P=0.001）, Schirmer test score（P=0.029）, CS score（P=0.047）, LMT（P=0.002）, CI（P=0.030） were improved better in the experimental group than in the control group at 3 mo. However, there was no significant difference between the two groups in MGS（P=0.67）.CONCLUSION： In dry eyes with MGD, 0.05% CsA improves the tear film stability as well as subjective ocular discomfort, and is effective in controlling lid margin inflammation.

Tacrolimus confers lower acute rejection rates and better renal allograft survival compared to cyclosporine

AIM To compare the impact of tacrolimus(FK) and cyclosporine(CYA) on acute rejection and graft survival and to assess the predominant causes of graft loss between patients receiving these two calcineurin inhibitors(CNIs).METHODS Retrospective review of 1835 patients who received a kidney transplant(KTX) between 1999-2012. Patients were grouped based on initial CNI utilized: 1195 in FK group, 640 in CYA group. Data on baseline characteristics, clinical outcomes, and causes of graft loss in both groups were analyzed. RESULTS Cumulative acute rejection rates were 14% in the FK vs 24% in the CYA group. Despite more marginal donor characteristics in the FK group, these patients had better graft survival rates compared to the CYA group. Three and five year graft survival rates were 88% and 84% respectively in the FK group compared to 79% and 70% respectively in the CYA group(P < 0.001). After multivariate analysis, which controlled for confounders, FK use was a strong predictor for lower acute rejectionrates [odds ratio(OR) 0.60, 95%CI: 0.45-0.79] and better renal allograft survival(OR 0.740, 95%CI: 0.58-0.94). Death with a functioning graft was the most common cause of graft loss in both groups. Common causes of death included cardiovascular disease, infections, and malignancies. Chronic allograft nephropathy was also found to be an important cause of graft loss, being more prevalent in the CYA group. CONCLUSION The use of FK-based maintenance immunosuppression therapy is associated with a significantly lower rate of acute rejection and better graft survival compared to CYA-based regimen. Individualizing immunosuppression through risk-stratified CNI choice may lead to improved outcomes across all spectra of KTX patients.

Combining cytochrome P-450 3A4 modulators and cyclosporine or everolimus in transplantation is successful

AIM: To describe the long term follow-up of kidney allograft recipients receiving ketoconazole with calcineurin inhibitors(CNI) alone or combined with everolimus. METHODS: This is an open-label, prospective observational clinical trial in low immunologic risk patients who, after signing an Institutional Review Board approved consent form, were included in one of two groups. The first one(n = 59) received everolimus(target blood level, 3-8 ng/m L) and the other(n = 114) azathioprine 2 mg/kg per day or mycophenolate mofetyl(MMF) 2 g/d. Both groups also received tapering steroids, the cytochrome P-450 3A4(CYP3A4) modulator, ketoconazole 50-100 mg/d, and cyclosporine with C0 targets in the everolimus group of 200-250 ng/mL in 1 mo, 100-125 ng/m L in 2 mo, and 50-65 ng/m L thereafter, and in the azathioprine or MMF group of 250-300 ng/mL in 1 mo, 200-250 ng/mL in 2 mo, 180-200 ng/m L until 3-6 mo, and 100-125 ng/mL thereafter. Clinical visits were performed monthly the first year and quarterly thereafter by treating physicians and all data was extracted by the investigators.RESULTS: The clinical characteristics of these two cohorts were similar. During the follow up(66 + 31 mo), both groups showed comparable clinical courses, but the biopsy proven acute rejection rate during the full follow-up period seemed to be lower in the everolimus group(20% vs 36%; P = 0.04). The everolimus group did not show a higher surgical complication rate thanthe other group. By the end of the follow-up period, the everolimus group tended to show a higher glomerular filtration rate. Nevertheless, we found no evidence of a consistent negative slope of the temporal allograft function estimated by the modification of the diet in renal disease formula in any of both groups. At 6 years of follow-up, the uncensored and death-censored graft survivals were 91% and 93%, and 91% and 83% in the everolimus plus cyclosporine, and cyclosporine alone groups, respectively. The addition of ketoconazole saved 80% of cyclosporine and 56% of everolimus doses. CONCLUSION: Combining CYP3A4 modulators with CNI or mammalian target of rapamycin inhibitor, in low immunological risk kidney transplant recipients is feasible, effective, safe and affordable even in the long term.