Long‐term remission of bilateral Wilms tumors that developed from premature separation of chromatids/mosaic variegated aneuploidy syndrome due to bilateral nephrectomy and peritoneal dialysis

We report a 38‐month‐old Japanese male with premature chromatid separation/mosaic variegated aneuploidy syndrome bearing biallelic BUB1B germline mutations who suffered from bilateral Wilms tumor. After right nephrectomy, dactinomycin monotherapy was administered for the left Wilms tumor; however, severe adverse reaction prevented the patient from receiving further chemotherapy. Left nephrectomy was then performed without postoperative chemotherapy. The patient survived for 15 months after bilateral nephrectomy without peritoneal relapse, metastasis of Wilms tumor, or the occurrence of rhabdomyosarcoma and maintained a good quality of life while receiving peritoneal dialysis at home.     

动脉药盒植入系统治疗肝癌发生堵塞的预防与处理

目的探讨动脉药盒植入系统治疗肝癌发生堵塞的预防与处理方法。材料与方法107例晚期肝癌患者行介入手术经皮经股动脉或经皮经锁骨下动脉于肝固有动脉内植入动脉药盒系统107个,进行随访,主要对动脉药盒系统堵塞的发生情况进行观察并总结预防与处理方法。结果动脉药盒系统植入术后的发生堵塞有8个,发生率为7.48%（8/107）,经肝素生理盐水溶液冲洗动脉药盒系统或/和高浓度尿激酶溶液动脉药盒系统内推注（部分在胃肠X光机或DSA机下进行）后复通率为75.00%（6/8）。结论在胃肠X光机或DSA机下进行肝素生理盐水溶液冲洗动脉药盒系统或/和高浓度尿激酶溶液动脉药盒系统内推注是处理堵塞的有效办法。     

Pain in childbirth and postpartum recovery – The role of catastrophizing

This prospective study investigated how pain catastrophizing was related to labor pain intensity and physical recovery after childbirth. Eighty‐eight women giving birth for the first time completed the first questionnaire before delivery. Eighty‐two of those returned the second questionnaire after delivery. Participants were classified as catastrophizers (n=38) or non‐catastrophizers (n=44) based on their scores on the Pain Catastrophizing Scale. Comparison of the groups showed that catastrophizers anticipated and experienced more intense pain (p<.0125) and had poorer physical recovery (p<.0125), measured as the level of self‐reported functioning in activities of daily living, than non‐catastrophizers. These results extend the association between catastrophizing and pain, to pain and recovery in childbirth and provide support for the fear‐avoidance model. It is concluded that pain catastrophizing plays a role in the experience of pain in childbirth and postpartum recovery. Further research is needed to identify appropriate interventions for catastrophizing women during the latter part of pregnancy.     

A new proportion measure of the treatment effect captured by candidate surrogate endpoints

The use of surrogate endpoints is expected to play an important role in the development of new drugs, as they can be used to reduce the sample size and/or duration of randomized clinical trials. Biostatistical researchers and practitioners have proposed various surrogacy measures; however, (i) most of these surrogacy measures often fall outside the range [0,1] without any assumptions, (ii) these surrogacy measures do not provide a cut‐off value for judging a surrogacy level of candidate surrogate endpoints, and (iii) most surrogacy measures are highly variable; thus, the confidence intervals are often unacceptably wide. In order to solve problems (i) and (ii), we propose a new surrogacy measure, a proportion of the treatment effect captured by candidate surrogate endpoints (PCS), on the basis of the decomposition of the treatment effect into parts captured and non‐captured by the candidate surrogate endpoints. In order to solve problem (iii), we propose an estimation method based on the half‐range mode method with the bootstrap distribution of the estimated surrogacy measures. Finally, through numerical experiments and two empirical examples, we show that the PCS with the proposed estimation method overcomes these difficulties. The results of this paper contribute to the reliable evaluation of how much of the treatment effect is captured by candidate surrogate endpoints. Copyright © 2014 John Wiley & Sons, Ltd.     

Diffusion weighted imaging and neuropsychological correlates in adults with mild traumatic brain injury

Diffusion Tensor Imaging (DTI) is increasingly being used as a research tool in mild Traumatic Brain Injury (mTBI). This article reviews the concepts of diffusion tensor imaging, neuropsychological testing and results to date when applied to mTBI in adults. DTI is being used in conjunction with neuropsychological and electrophysiological measures to provide improved structural/functional correlations of mTBI. Future directions and applications of DTI in mTBI research are suggested.     

Metabolomics analysis reveals elevation of 3-indoxyl sulfate in plasma and brain during chemically-induced acute kidney injury in mice: investigation of nicotinic acid receptor agonists

An investigative renal toxicity study using metabolomics was conducted with a potent nicotinic acid receptor (NAR) agonist, SCH 900424. Liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques were used to identify small molecule biomarkers of acute kidney injury (AKI) that could aid in a better mechanistic understanding of SCH 900424-induced AKI in mice. The metabolomics study revealed 3-indoxyl sulfate (3IS) as a more sensitive marker of SCH 900424-induced renal toxicity than creatinine or urea. An LC-MS assay for quantitative determination of 3IS in mouse matrices was also developed. Following treatment with SCH 900424, 3IS levels were markedly increased in murine plasma and brain, thereby potentially contributing to renal- and central nervous system (CNS)-related rapid onset of toxicities. Furthermore, significant decrease in urinary excretion of 3IS in those animals due to compromised renal function may be associated with the elevation of 3IS in plasma and brain. These data suggest that 3IS has a potential to be a marker of renal and CNS toxicities during chemically-induced AKI in mice. In addition, based on the metabolomic analysis other statistically significant plasma markers including p-cresol-sulfate and tryptophan catabolites (kynurenate, kynurenine, 3-indole-lactate) might be of toxicological importance but have not been studied in detail. This comprehensive approach that includes untargeted metabolomic and targeted bioanalytical sample analyses could be used to investigate toxicity of other compounds that pose preclinical or clinical development challenges in a pharmaceutical discovery and development.     

High loading efficiency and sustained release of siRNA encapsulated in PLGA nanoparticles: Quality by design optimization and characterization

Poly(dl-lactide-co-glycolide acid) (PLGA) is an attractive polymer for delivery of biopharmaceuticals owing to its biocompatibility, biodegradability and outstanding controlled release characteristics. The purpose of this study was to understand and define optimal parameters for preparation of small interfering RNA (siRNA)-loaded PLGA nanoparticles by the double emulsion solvent evaporation method and characterize their properties. The experiments were performed according to a 2⁵⁻¹ fractional factorial design based on five independent variables: The volume ratio between the inner water phase and the oil phase, the PLGA concentration, the sonication time, the siRNA load and the amount of acetylated bovine serum albumin (Ac-BSA) in the inner water phase added to stabilize the primary emulsion. The effects on the siRNA encapsulation efficiency and the particle size were investigated. The most important factors for obtaining an encapsulation efficiency as high as 70% were the PLGA concentration and the volume ratio whereas the size was mainly affected by the PLGA concentration. The viscosity of the oil phase was increased at high PLGA concentration, which explains the improved encapsulation by stabilization of the primary emulsion and reduction of siRNA leakage to the outer water phase. Addition of Ac-BSA increased the encapsulation efficiency at low PLGA concentrations. The PLGA matrix protected siRNA against nuclease degradation, provided a burst release of surface-localized siRNA followed by a triphasic sustained release for two months. These results enable careful understanding and definition of optimal process parameters for preparation of PLGA nanoparticles encapsulating high amounts of siRNA with immediate and long-term sustained release properties.