Real-time pelvic ultrasonography as an adjunct to digital examination

The authors suggest that diagnostic accuracy could be improved in 1% of cases by combining real-time ultrasound with digital examination of the pelvis or rectum. Differences of opinion between clinician and ultrasonologist regarding a possible pelvic mass can easily be settled. This technique can also be used to displace loops of bowel, help characterize congenital anomalies, and aid in the training of medical students and residents in obstetrics and gynecology.     

重组pEGFP-N1-IGF-1体内转基因预处理对脊髓损伤后一氧化氮合酶活性的影响

目的:观察阳离子脂质体介导的重组pEGFP-N1-IGF-1体内转基因预处理对脊髓损伤后血清一氧化氮合酶及脊髓组织诱导型一氧化氮合酶影响,进一步探讨转基因治疗脊髓损伤的机制。方法:实验于2005-07/11在解放军第二军医大学动物实验中心完成。取54只雄性SD大鼠单纯随机分为3组:①生理盐水组(24只):采用脊髓内直接注射法,将2μL生理盐水 6μLTransfectamreagent共8μL注入T8～T10脊髓内,无下肢功能障碍者1周后按改良Nystr"m’s压迫法制作大鼠脊髓不完全损伤模型(压迫总质量35g,压迫时间5min)。②pEGFP-N1-IGF-1转基因组(24只):给药方法、部位、剂量以及造模方法与生理盐水组相同,但脊髓内注入6μLTransfectamreagent 2μg质粒pEGFP-N1-IGF-1。③正常组(6只):不损伤脊髓,不给药,作为正常对照。前2组损伤后1,4,8,24h、1,2周,取尾静脉血和损伤区域脊髓,测定血清一氧化氮合酶活性及局部脊髓组织诱导型一氧化氮合酶活性变化。结果:经补充后54只大鼠进入结果分析。①血清一氧化氮合酶活性:正常组为(305.4±52.0)μkat/L,其他2组在损伤后1～8h迅速升高,并于伤后24h达到高峰[pEGFP-N1-IGF-1转基因组:(522.6±60.3)μkat/L;生理盐水组:(757.0±83.7)μkat/L],其后逐渐降低,术后一两周仍维持在较高水平。pEGFP-N1-IGF-1转基因组各个时间点均低于生理盐水组(P<0.05,0.01)。②脊髓组织诱导型一氧化氮合酶活性:正常组为(72.5±17.3)μkat/g,其他2组在损伤后1～8h迅速升高,并于伤后24h达到高峰[pEGFP-N1-IGF-1转基因组:(140.2±24.2)μkat/g;生理盐水组:(207.2±36.8)μkat/g],其后逐渐降低,术后一两周仍维持在较高水平。pEGFP-N1-IGF-1转基因组各个时间点均低于生理盐水组(P<0.05,0.01)。结论:阳离子脂质体介导胰岛素样生长因子1基因转染预处理能够有效地下调大鼠一氧化氮合酶活性,特别是其可有效抑制诱导型一氧化氮合酶,从而减轻继发性损伤所致的神经组织的损害,侧面证明了胰岛素样生长因子1转基因治疗的可行性。     

Pre-clinical properties of the α4β2 nicotinic acetylcholine receptor partial agonists varenicline,cytisine and dianicline translate to clinical efficacy for nicotine dependence

Background and purpose:

Smoking cessation trials with three high-affinity partial agonists of α4β2 neuronal nicotinic acetylcholine receptors (nAChRs) have demonstrated differences in their clinical efficacy. This work examines the origin of the differences by taking into account brain exposure and pharmacological effects at human α4β2 nAChRs.

Experimental approach:

Rat plasma and brain pharmacokinetics were characterized and used to predict human steady-state plasma and brain concentrations following recommended doses of each of the three compounds. The pharmacological characterization included in vitro affinities at different nAChR subtypes, functional efficacies and potencies at the human α4β2 nAChR, as well as in vivo effects on rat mesolimbic dopamine turn-over.

Key results:

A comparison of predicted human brain concentrations following therapeutic doses demonstrated that varenicline and nicotine, but not dianicline and cytisine, can extensively desensitize and, to a lesser extent, activate α4β2 nAChRs. The limited clinical efficacy of dianicline may be accounted for by a combination of weak functional potency at α4β2 nAChRs and moderate brain penetration, while recommended doses of cytisine, despite its high in vitro potency, are predicted to result in brain concentrations that are insufficient to affect α4β2 nAChRs.

Conclusions and implications:

The data provide a plausible explanation for the higher abstinence rate in smoking cessation trials following treatment with varenicline than with the two other α4β2 nAChR partial agonists. In addition, this retrospective analysis demonstrates the usefulness of combining in vitro and in vivo parameters with estimated therapeutic human brain concentrations for translation to clinical efficacy.     

Tenofovir induced acute kidney injury in a patient with unilateral renal agenesis despite initially non-impaired renal function

Nephrotoxicity is observed in 1.6 % of patients treated with tenofovir disoproxil fumarat (Fux 2007).