Safety,tolerability, and pharmacokinetics of single and multiple topical ophthalmic administration of imatinib mesylate in healthy subjects

For the long‐term efficacy of dry eye disease treatment, relieving underlying inflammation is necessary. Imatinib mesylate is a novel ophthalmic formulation of imatinib mesylate, which is expected to alleviate inflammation by inhibiting the discoidin domain receptor 1 activity. This study aims to evaluate the safety and pharmacokinetics of imatinib mesylate in healthy subjects. A randomized, double‐blind, placebo‐controlled study was conducted. In a single ascending dose, 16 subjects received a single eye drop of imatinib mesylate 0.1%, 0.3%, or matching placebo. In the multiple ascending dose (MAD), subjects received multiple eye drops of imatinib mesylate 0.1%, 0.3%, or matching placebo once daily for 7 days. Safety and tolerability were assessed by ophthalmic examination, including the visual analog scale (VAS) to monitor the burning sensation in the eyes. A total of four treatment‐emergent adverse events (TEAEs) occurred during the study. All TEAEs were mildly severe with no serious cases. VAS results in the 0.1% MAD group exhibited highest score of two points, whereas it was less than one point in others. Insignificant difference between the imatinib mesylate and placebo groups in the VAS results was seen. After a single dose administration of imatinib mesylate 0.1%, all plasma concentrations were below the lower limit of quantification. The peak plasma concentrations of imatinib were less than 0.54 µg/L in all groups. In conclusion, a single and multiple topical ophthalmic administration of imatinib mesylate was well‐tolerated in healthy subjects. Because there was minimal systemic exposure to imatinib, the adverse effect in the body seems to be insignificant.     

来曲唑微刺激超排卵对卵泡液中IGF-I和IGFBP-1水平的影响

目的:探讨来曲唑(LE)微刺激超排卵对卵泡液中胰岛素样生长因子I(IGF-I)和胰岛素样生长因子结合蛋白1(IGFBP-1)水平的影响。方法:96例体外受精-胚胎移植(IVF-ET)患者分为两组,LE微刺激组(42例)采用LE微刺激超排卵,GnRH-a方案组(54例)采用GnRH-a方案超排卵做对照,酶联免疫吸附法(ELISA)检测取卵时平均直径16 mm以上卵泡的卵泡液中IGF-I、IGFBP-1水平。结果:⑴LE组超排卵天数、总促性腺激素(Gn)用量、hCG日血清E2水平、获卵数显著低于GnRH-a组,受精率、优质胚胎率、种植率、临床妊娠率两组相比均无显著性差异(P>0.05);⑵LE组卵泡液中IGF-I水平(197.2±35.6)ng/mL显著高于GnRH-a组水平(118.5±23.8)ng/mL(P<0.05),IGFBP-1水平(3 057.7±346.7)pg/mL显著低于GnRH-a组水平(7 093.9±435.3)pg/mL(P<0.05)。结论:LE微刺激超排卵可刺激卵泡液内IGF-I分泌,使卵巢对Gn敏感性增加,用较少的Gn达到同GnRH-a方案相似的超排卵效果。     

Chemoprevention of liver cancer by plant polyphenols

Primary liver cancer or hepatocellular carcinoma (HCC) is one of the most frequent tumors representing the fifth commonest malignancy worldwide and the third cause of mortality from cancer. Currently, the treatments for HCC are not so effective and new strategies are needed for its fight. Chemoprevention, the use of natural or synthetic chemical agents to reverse, suppress or prevent carcinogenesis is considered an important way for confronting HCC. Many of the chemopreventive agents are phytochemicals, namely non-nutritive plant chemicals with protective or disease preventive properties. In this review, we focus on plant polyphenols, one of the most important classes of phytochemicals, their chemopreventive properties against HCC and discuss the molecular mechanisms accounting for this activity.     

Reappraisal of the Traditional Wenckebach Phenomenon with a Modified Ladder Diagram

Understanding of the traditional Wenckebach phenomenon is enhanced by using a modified ladder diagram where AV conduction in any cycle is represented by a slanted line in the AV bar together with similar AV conduction lines of all the preceding cycles. The diagram facilitates calculation of the duration of RR intervals (equal to the basic PP or sinus interval minus the PR or AV increment applied to this particular cycle) and the duration of the pause (equal to 2 × PP or sinus interval minus the sum of all the increments applied to the AV delay). The modified Wenckebach diagram should help students understand the mysterious clustering of QRS complexes or “paradoxical” increase of the ventricular rate that occurs during a Wenckebach sequence. Ann Noninvasive Electrocardiol 2012;17(1):3–7     

Exploring the intergenerational persistence of mental health: Evidence from three generations

This paper uses data from the 1970 British Cohort Study to quantify the intergenerational persistence of mental health, and the long-run economic costs associated with poor parental mental health. We find a strong and significant intergenerational correlation that is robust to different covariate sets, sample restrictions, model specifications and potential endogeneity. Importantly, the intergenerational persistence is economically relevant, with maternal mental health associated with lasting effects on the child's educational attainment, future household income and the probability of having criminal convictions. These results do not disappear after controlling for children's own childhood and adulthood mental health.     

Increasing organ donation via changes in the default choice or allocation rule

This research utilizes a laboratory experiment to evaluate the effectiveness of alternative public policies targeted at increasing the rate of deceased donor organ donation. The experiment includes treatments across different default choices and organ allocation rules inspired by the donor registration systems applied in different countries. Our results indicate that the opt-out with priority rule system generates the largest increase in organ donation relative to an opt-in only program. However, sizeable gains are achievable using either a priority rule or opt-out program separately, with the opt-out rule generating approximately 80% of the benefits achieved under a priority rule program.     

The political economy of the public–private mix in heath expenditure: An empirical review of thirteen OECD countries

This study investigates the factors that may have influenced the public–private mix of health expenditure in 13 OECD countries from 1981 to 2007. The degree to which health services are socialized is regarded as the product of a trade-off between the desire to redistribute income through the fiscal system and the losses some citizens will incur when the public health care system expands.     

The changing of the guards : Can family doctors contain worker absenteeism?

Using administrative data from Norway, we examine the extent to which family doctors influence their clients’ propensity to claim sick-pay. The analysis exploits exogenous switches of family doctors occurring when physicians quit, retire, or for other reasons sell their patient lists. We find that family doctors have significant influence on their clients’ absence behavior, particularly on absence duration. Their influence is stronger in geographical areas with weaker competition between physicians. We conclude that it is possible for family doctors to contain sick-pay expenditures to some extent, and that there is a considerable variation in the way they perform this task.     

Measurement Of Angiotensinogen In Human Serum By Fluorescence Polarization Immunoassay

Fluorescence polarization immunoassay (F.P.I.A.) has rarely been used to measure components of the renin system. Using an Abbott TDX polarimeter and fluorescein - labelled angiotensin I as a tracer we measured angiotensin I by F.P.I.A. Combining this procedure with a renin incubation step enabled measurement of angiotensinogen in human serum. Using sera from male patients and from pregnant females, a good correlation between radioimmunoassay (R.I.A.). and F.P.I.A. was found. Two procedures were developed; one involving taking samples from the renin incubation mixture, the other involving measurement of generated angiotensin I at intervals without interrupting the renin incubation procedure. F.P.I.A. is less expensive and somewhat simpler than R.I.A. but, with the instrument used, it     

Primary Aldosteronism: A New Understanding

Primary aldosteronism (PAL) may always have a genetic basis. This leads to either abnormally regulated, increased biosynthesis (Familial Hyperaldosteronism Type I, FHI) or to unrestrained hyperplasia and neoplasia, usually benign. The distinction between diffuse hyperplasia, nodular hyperplasia and adenoma may be relatively unimportant in functional and etiological terms. The genetic basis must be understood before diagnosis of disease (FHI) or of predispostion (all other PAL) can be made at birth and appropriate surveillance commenced. The natural history of PAL other than FHI is for a progressive increase in severity, with both adrenals eventually involved. Long-term follow-up of PAL is therefore mandatory, and postoperative assessment of residual non-suppressible aldosterone production by fludrocortisone suppression testing useful in defining biochemical cure or improvement, and the need for specific medical treatment.