Is dose modification or discontinuation of nilotinib necessary in nilotinib-induced hyperbilirubinemia?

Nilotinib is a specific breakpoint cluster region-Abelson leukemia virus-tyrosine kinase inhibitor that is used as an effective first- or second-line treatment in imatinib-resistant chronic myelogenous leukemia (CML) patients. Hepatotoxicity due to nilotinib is a commonly reported side effect; however, abnormal liver function test (LFT) results have been reported in asymptomatic cases. When alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are more than five-fold the upper limit of the normal (ULN) or when the serum total bilirubin level is more than three-fold the ULN, dose modification or discontinuation of nilotinib is recommended, resulting in decreased levels of hematological indicators in certain patients with CML. Nilotinib-induced hyperbilirubinemia typically manifests as indirect bilirubinemia without elevated ALT or AST levels. Such abnormal liver functioning is thus not attributed to the presence of a true histologic lesion of the liver. The underlying mechanism may be related to the inhibition of uridine diphosphate glucuronosyltransferase activity. Therefore, nilotinib dose adjustment is not recommended for this type of hyperbilirubinemia, and in the absence of elevated liver enzyme levels or presence of abnormal LFT findings, physicians should consider maintaining nilotinib dose intensity without modifications.     

Recipient hypertonic saline infusion prevents cardiac allograft dysfunction

Objective

Hypertonic saline (HTS) has potent immune and vascular effects. We assessed recipient pretreatment with HTS on allograft function in a porcine model of heart transplantation and hypothesized that HTS infusion would limit endothelial and left ventricular (LV) dysfunction following transplantation.

Clinical equivalence assessment of T2 synthesized pediatric brain magnetic resonance imaging

Background and purposeAutomated synthetic magnetic resonance imaging (MRI) provides qualitative, weighted image contrasts as well as quantitative information from one scan and is well-suited for various applications such as analysis of white matter disorders. However, the synthesized contrasts have been poorly evaluated in pediatric applications. The purpose of this study was to compare the image quality of synthetic T2 to conventional turbo spin-echo (TSE) T2 in pediatric brain MRI.Materials and methodsThis was a mono-center prospective study. Synthetic and conventional MRI acquisitions at 1.5 Tesla were performed for each patient during the same session using a prototype accelerated T2 mapping sequence package (TA_synthetic = 3:07 min, TA_conventional = 2:33 min). Image sets were blindly and randomly analyzed by pediatric neuroradiologists. Global image quality, morphologic legibility of standard structures and artifacts were assessed using a 4-point Likert scale. Inter-observer kappa agreements were calculated. The capability of the synthesized contrasts and conventional TSE T2 to discern normal and pathologic cases was evaluated.ResultsSixty patients were included. The overall diagnostic quality of the synthesized contrasts was non-inferior to conventional imaging scale (P = 0.06). There was no significant difference in the legibility of normal and pathological anatomic structures of synthetized and conventional TSE T2 (all P > 0.05) as well as for artifacts except for phase encoding (P = 0.008). Inter-observer agreement was good to almost perfect (kappa between 0.66 and 1).ConclusionsT2 synthesized contrasts, which also provides quantitative T2 information that could be useful, could be suggested as an equivalent technique in pediatric neuro-imaging, compared to conventional TSE T2.     

Intra-seasonal variation of injury patterns among German Bundesliga soccer players

ObjectiveHigh fluctuations in injury-risk during the playing season in soccer have been reported. As seasons are structured in periods with homogenous loads and intensities, we investigated injury-risk over season periods, contrarily to previous studies adopting a month-based approach.DesignCohort study; Level of evidence, 2.MethodsIncidence-rate ratios (IRRs) for match and training injuries were compared across six consecutive seasons of German Bundesliga, divided into six periods each: Pre-season (PS), winter-break (WB), quarter 1–4: (Q1–Q4).ResultsSignificant variations in injury-risk were observed for match and training injuries. IRRs in matches was 1.30 (95% CI: 1.11–1.53) times higher in Q3 and 1.53 (95% CI: 1.31–1.78) higher in Q4 compared to Q1. For training injuries, IRR peaked in Q1 and Q3 followed by a marked decrease in each subsequent quarter. Compared to Q4, IRR was 1.62 (95% CI: 1.40–1.86) times higher during Q3 and 1.78 (95% CI: 1.53–2.07) times higher in Q1. IRR was significantly higher in the competitive season compared to pre-season across match (IRR: 2.00, 95% CI: 1.30–3.00) and training (IRR: 1.27, 95% CI: 1.11–1.43) injuries.ConclusionsThe increased match IRRs later during the season indicate that, in practice, coaches should consider putting even more emphasis on recovery in the last part of the season. Moreover, training injuries seem to indicate a carry-over effect. Further studies need to investigate how training during preparatory phases can be implemented in a way that prevents injuries during the competitive season.     

Voluntary ambulation using voluntary upper limb muscle activity and Hybrid Assistive Limb® (HAL®) in a patient with complete paraplegia due to chronic spinal cord injury: A case report

Context: We sought to describe our experience with the Hybrid Assistive Limb® (HAL®) for active knee extension and voluntary ambulation with remaining muscle activity in a patient with complete paraplegia after spinal cord injury.

Findings: A 30-year-old man with complete paraplegia used the HAL® for 1 month (10 sessions) using his remaining muscle activity, including hip flexor and upper limb activity. Electromyography was used to evaluate muscle activity of the gluteus maximus, tensor fascia lata, quadriceps femoris, and hamstring muscles in synchronization with the Vicon motion capture system. A HAL® session included a knee extension session with the hip flexor and voluntary gait with upper limb activity. After using the HAL® for one month, the patient’s manual muscle hip flexor scores improved from 1/5 to 2/5 for the right and from 2/5 to 3/5 for the left knee, and from 0/5 to 1/5 for the extension of both knees.

Conclusion/clinical relevance: Knee extension sessions with HAL®, and hip flexor and upper-limb-triggered HAL® ambulation seem a safe and feasible option in a patient with complete paraplegia due to spinal cord injury.     

全国著名骨伤专家梁铁民教授学术思想和正骨经验

总结了全国著名骨伤专家梁铁民教授的学术思想和正骨经验,简述了梁老生平。梁老学术思想表现在突出整体观念,主张辨证施术;注重调理气血,强调药物接续;重视望问切触量法五诊结合等三个方面。对于梁老正骨经验先进行了综合论述,进一步佐证其学术思想;后分别从小儿桡骨头半脱位、颈椎错位、胸腰椎小关节错位、肋骨骨折等梁老研究较深入和比较擅长的几个方面进行了阐述。特别是颈椎错位这种高难度高风险的手法操作,体现出梁老高超的手法技艺。     

Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling

This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.     

Outcome of isolated posterior cruciate ligament reconstruction at mean 6.3-year follow up: a consecutive case series

Objectives: There is a paucity of reporting on surgical outcomes of isolated posterior cruciate ligament reconstruction (PCLR). We hypothesize that isolated PCL injuries failing nonoperative treatment achieve good outcomes and are able to return to sport following PCLR.

Methods: A retrospective analysis was performed to identify patients with isolated PCL injuries that underwent reconstruction between 2001 and 2014. Patients with multi-ligamentous injury or another concomitant knee pathology were excluded. Medical records were reviewed for demographic, clinical and operative data. Patients were contacted for administration of a telephone-based questionnaire which included the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation form, Lysholm-Tegner scales, Marx activity scale (MAS), return to sport status, and patient satisfaction instruments.

Results: A total of 15 isolated PCL reconstructions in 14 patients with a mean age of 27.5 years (range 17–43) met the study inclusion criteria; mean follow up was 6.3 years (range 1.4–15.2). Pre-operatively, the primary complaint was knee instability in all patients; on physical examination, lack of a firm end point during posterior drawer testing was found in 93% (14/15) of the knees. In total, 12 of 15 knees underwent transtibial, single-bundle PCLR and three of 15 underwent tibial inlay, double bundle PCLR. Graft types included: quadriceps autograft (7/15), Achilles allograft (6/15), and hamstring autograft (2/15). There were no graft failures in our patient cohort. At most recent follow up the mean scores respectively on the IKDC form, Lysholm-Tegner scales and MAS were (standard deviation): 77.3 (16.5), 83.1 (17.9), 6.13 (2.6), and 7.1 (6.0). All fourteen patients were athletes prior to their injury and 79% (11/14) returned to sport and overall patient satisfaction was 9.2/10.

Conclusions: Isolated PCLR provides good outcomes at mean medium-term follow up with restoration of function, high rate of return to sport and overall patient satisfaction.     

N-乙酰-5-羟色胺对视网膜缺血-再灌注损伤大鼠视网膜 Fas、FasL 蛋白表达的影响

目的　探讨N-乙酰-5-羟色胺（N-acetylserotonin，NAS）对视网膜缺血-再灌注损伤（retina ischemia-reperfusion injury，RIRI）大鼠视网膜Fas、FasL蛋白表达的影响。方法　取健康成年Sprague Dawley大鼠54只，将大鼠随机分为正常组（6只）、RIRI组（24只）与NAS组（24只）；采用高眼压法建立大鼠RIRI模型，依据造模后不同时间点将RIRI组与NAS组大鼠又分为6 h、12 h、24 h及72 h四个亚组。NAS组于造模前30 min腹腔注射NAS（5 mg·kg^-1），RIRI组腹腔注射等剂量的生理盐水。通过HE染色在光学显微镜下观察各组大鼠视网膜形态学变化，并记录各组大鼠视网膜厚度及视网膜神经节细胞数，采用免疫组织化学染色法检测NAS对RIRI大鼠视网膜Fas、FasL蛋白表达的影响。结果　HE染色显示，正常组大鼠视网膜各层细胞分界清晰，形态正常，神经细胞排列整齐；RIRI组大鼠再灌注后6 h视网膜各层出现水肿，以神经节细胞层及内核层较显著，神经节细胞数较正常组减少；随后视网膜水肿进一步加重，神经节细胞继续减少；NAS组大鼠在再灌注后6 h、12 h、24 h 视网膜水肿程度较 RIRI组轻，NAS组在再灌注后72 h视网膜厚度较 RIRI组厚，NAS组各时间点神经节细胞数均较 RIRI组多，差异均有统计学意义（均为P＜0.05）。免疫组织化学染色显示，正常组几乎未见 Fas⁺细胞。再灌注后6 h，RIRI组视网膜神经节细胞及内核层开始出现少量 Fas⁺细胞；再灌注后12 h，RIRI组视网膜 Fas⁺细胞表达逐渐增多；再灌注后24 h视网膜Fas⁺细胞数达到高峰，棕色阳性染色细胞分布在视网膜神经节细胞层、内丛状层、内核层及神经纤维层；再灌注后 72 h 视网膜 Fas⁺细胞较再灌注后 24 h 减少。NAS组在再灌注后6 h、12 h、24 h、72 h 视网膜 Fas⁺细胞数均较 RIRI组各时间点减少，再灌注后24 h，Fas⁺细胞数达较高水平，随后下降，差异均有统计学意义（均为P＜0.05）。正常组视网膜可见 FasL 全层低表达。RIRI组再灌注后 6 h，视网膜神经节细胞层和神经纤维层存在少量 FasL⁺细胞；再灌注后12 h FasL蛋白表达逐渐增多；再灌注后24 h FasL⁺细胞数达高峰，可见深棕色的细胞膜及细胞质染色细胞分布在视网膜神经节细胞层、内丛状层、内核层及神经纤维层；再灌注后72 h FasL蛋白的阳性表达逐渐减少。NAS组再灌注后6 h、12 h、24 h、72 h 视网膜FasL⁺细胞数均少于 RIRI组各时间点阳性细胞数，差异均有统计学意义（均为P＜0.05）。结论　NAS可通过抑制RIRI大鼠视网膜细胞Fas、FasL蛋白的表达，减轻缺血再灌注对大鼠视网膜细胞造成的损伤。