Population Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults and Adolescents Including Patients With Influenza

Baloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral replication by inhibiting cap-dependent endonuclease. Our aim is to characterize its pharmacokinetics and exposure-response relationships. Population pharmacokinetic analysis of the baloxavir acid was performed using 8310 plasma concentration data points from 1109 subjects. Exposure-response analyses were performed regarding the time to alleviation of symptoms and the reduction in the influenza virus titer. A 2-compartment model with first-order absorption and lag time well described the plasma concentration data for baloxavir acid, and body weight and race were found to be the most important factors influencing the clearance and distribution volume. A dose regimen based on the body weight (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg) could provide sufficient exposures for expecting efficacy irrespective of body weight or race; however, the exposures were dependent on the body weight and race. Exposure-response analyses suggested that the reduction in the influenza virus titer was greater in any exposure-based groups in baloxavir marboxil treatment than in the oseltamivir phosphate treatment and placebo groups. In conclusion, the population pharmacokinetic model and exposure-response relationships would be useful for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir acid.     

血清S100ββ变化与老年患者腹部手术后认知功能障碍的关系

目的观察老年患者腹部手术后S100ββ蛋白的变化以及术后认知功能障碍(POCD)的发生情况,并探讨二者的关系。方法26例65岁以上的老年患者ASAⅡ~Ⅲ级,行腹部手术。监测术前、术毕、术后6、24、48、72h血清S100ββ的变化,并评定术前及术后1周内的认知功能。结果老年患者血清S100ββ蛋白在术毕最高(P<0·01),术后6h和24h逐渐下降,但术后48h再次上升(P<0·01),术后72h回复至术前水平。26例老年患者腹部手术后1周内有7例发生POCD。POCD组与非POCD组相比,术毕及术后6h血清S100ββ蛋白水平明显增高(P<0·05)。结论老年患者腹部手术后POCD的发生与血清S100ββ蛋白的变化有密切关系。血清S100ββ蛋白可作为评估老年患者术后发生POCD的重要指标。     

Spindle-cell glioblastoma or gliosarcoma?

'Gliosarcomas' have long been considered to be mixed gliomas and sarcomas. The present study failed to define criteria which clearly delineate 'gliosarcomas' from glioblastoma multiforme and suggests that 'gliosarcomas' should be considered as spindle cell glioblastomas. A total of six cases originally diagnosed as 'gliosarcomas' were compared with four cases of glioblastoma multiforme. No clinical or prognostic features were defined which would clearly separate 'gliosarcomas' from glioblastoma multiforme. Macroscopically, biopsies from 'gliosarcomas' ranged from firm, apparently well-circumscribed tumours to poorly circumscribed lesions with a soft consistency resembling glioblastoma multiforme. Histology revealed a continuous spectrum in which 'gliosarcomas' with large reticulin-rich areas of spindle cells merged with typical glioblastomas containing only small islands of spindle cells and reticulin staining. Immunocytochemistry for glial fibrillary acidic protein (GFAP); S100 protein and alpha-smooth muscle actin (ASMA) showed that the majority of cells in reticulin-poor areas of 'gliosarcoma' and glioblastomas expressed S100 protein and GFAP; many expressed ASMA and some expressed both GFAP and ASMA. Spindle cells in reticulin-rich areas of 'gliosarcomas' and glioblastomas most frequently expressed ASMA but many cells also expressed S100 protein and GFAP; some cells expressed both GFAP and ASMA. The results of this study and a review of the literature suggests that there is a clinical, radiological and pathological continuum with glioblastoma and 'gliosarcoma' at different ends of the spectrum. It is suggested, therefore, that most, if not all, 'gliosarcomas' be redesignated as spindle cell glioblastomas and not be considered as a mixture of glioma and sarcoma.     

Immune reactivity towards insulin, its amyloid and protein S100B in blood sera of Parkinson's disease patients

Peripheral immune responses can be sensitive indicators of disease pathology. We evaluated the autoimmune reactions to endocrine (insulin) and astrocytical (S100B) biomarkers in the blood sera of 26 Parkinson's disease (PD) patients compared with controls by using ELISA. We found a statistically significant increase of the autoimmune responses to both antigens in PD patients compared with controls with a mean increase of 70% and 50% in the autoimmune reactions towards insulin and S100B, respectively. Heterogeneity of the immune responses observed in patients may reflect the modulating effect of multiple variables associated with neurodegeneration and also changes in the basic mechanisms of individual autoimmune reactivity. We did not detect any pronounced immune reactions towards insulin amyloid fibrils and oligomers in PD patients, indicating that an amyloid-specific conformational epitope is not involved in immune recognition of this amyloid type, while sequential epitope of native insulin is hidden within the amyloid structures. Immune reactions towards S100B and insulin may reflect the neurodegenerative brain damaging processes and impaired insulin homeostasis occurring in PD.     

一种西门子新型X线机的综合性能与安装

本文叙述西门子型号为Polydoros 80/100的新型X线主机,该主机采用微电脑控制技术、光纤维传输技术及中频技术,X射线剂量精度高,影像质量优良,故障率低,是一种技术较为成熟的X线主机,也是当今西门子公司产品的主流机种。该机的安装调试具有一定难度,本文同时针对这一问题进行讨论,并总结归纳出一套安装调试全过程。     

Anti-S-100 Serum blocks long-term potentiation in the hippocampal slice

S-100 is a calcium-binding, glial protein which has been shown to be involved in behavioral learning and memory tasks. Long-term potentiation (LTP) in the hippocampus is a long-lasting enhancement of synaptic efficacy evoked by repetitive afferent stimulation. When anti-S-100 serum is applied by pressure ejection onto the stratum radiatum of area CA1 of the hippocampal slice, the amplitude of the extracellularly recorded population spike is not affected. However, repetitive stimulation of the afferents during S-100 application failed to produce LTP. At a distant site in the same slice, LTP occurs normally. Preimmune normal rabbit serum had no effect on the development of LTP. It appears that S-100 protein is involved in the establishment of LTP.     

S100 protein-immunoreactive primary sensory neurons in the trigeminal and dorsal root ganglia of the rat

The cell body size (cross-sectional area) of S100-immunoreactive (-ir) primary neurons was measured in the trigeminal (TG) and lumbar dorsal root ganglia (DRG). About a half of neurons exhibited S100-immunoreactivity (-ir) in the DRG (44.0%) and TG (59.0%). DRG neurons with cell bodies >1200 μm² mostly exhibited S100-ir (96.5%), whereas S100-ir DRG neurons <600 μm² were rare (8.0%). 36.6% of DRG neurons in the cell size range 600–1200 μm² showed the ir. TG neurons >800 μm² mostly exhibited S100-ir (93.1%), whereas those <400 μm² were devoid of it (positive cells 10.5%). 58.3% of TG cells in the range 400–800 μm² contained S100-ir. Double-immunofluorescence method revealed the co-expression of S100 and other calcium-binding proteins. Parvalbumin-ir neurons mostly exhibited S100-ir in the DRG (97.4%) and TG (97.0%). The co-expression of S100 and calbindin D-28k was very rare in the DRG, because the DRG contained few calbindin D-28k-ir neurons. Unlike in the DRG, numerous neurons co-expressed S100- and calbindin D-28k-ir in the TG. Most calbindin D-28k-ir TG neurons were also immunoreactive for S100 (90.7%). Sub-populations of calretinin (CR)-ir neurons co-expressed S100-ir in both the DRG (68%) and TG (50.0%). Virtually all CR-ir neurons >1400 μm² co-expressed S100-ir in the DRG (100%) and TG (95.9%). CR-ir neurons <800 μm² were rarely exhibited S100-ir (DRG 18.0%, TG 21.9%). 71.3 and 60.5% of CR-ir neurons in the range 800–1400 μm² co-expressed S100-ir in the DRG and TG, respectively. The present study indicates that S100 is closely correlated to the primary neuronal cell size in the DRG and TG.     

全主动脉弓替换术中顺行性脑灌注时血流变化观察

目的　利用前瞻性随机对照方法比较全主动脉弓替换术中单侧顺行性脑灌注 (ASCP)和双侧ASCP时视网膜中央动脉、球后血管血流变化和血S1 0 0蛋白浓度变化。方法　 1 6例全主动脉弓替换术患者随机分为单侧AS CP和双侧ASCP组 ,每组各 8例。两组均行术前术后颅脑计算机体层摄影 (CT)。术中采用经眼球超声监测视网膜中央动脉及球后血管血流。术中术后动态测定血S1 0 0蛋白浓度。结果　两组各有 1例出现短暂性神经功能异常。ASCP过程中单侧组右侧视网膜中央动脉可探及血流 ,左侧视网膜中央动脉不可探及 ,双侧组两侧视网膜中央动脉均可探及血流。所有患者球后动脉均可探及血流。两组间各阶段血S1 0 0蛋白浓度无显著性差异 (P >0 .0 5 )。结论　在基底动脉环完整 ,存在有效侧支循环条件下 ,单侧灌注操作较为简便 ,双侧灌注在ASCP期间两侧脑灌注较为均衡 ,但两种灌注方法对S1 0 0蛋白浓度的影响无显著性差异。     

口腔黏膜下纤维性变S100蛋白表达

目的 :研究口腔黏膜下纤维性变中S10 0蛋白的表达水平及其与正常口腔黏膜上皮、异常增生上皮的比较。方法 :应用免疫组织化学 (SP)法 ,检测 10例口腔黏膜下纤维性变、10例上皮异常增生、8例正常口腔黏膜上皮S10 0蛋白表达水平 ,并作对比研究。结果 :S10 0蛋白在正常口腔黏膜上皮中无表达 ,口腔黏膜下纤维性变上皮中和异常增生上皮中S10 0的阳性表达率为 5 0 %,后两者的阳性表达率明显高于正常黏膜组上皮 (P <0 .0 5 ) ;口腔黏膜下纤维性变组与异常增生上皮组比较 ,差异无显著性 (P >0 .0 5 )。结论 :口腔黏膜下纤维性变发生发展与S10 0蛋白过表达密切相关 ,S10 0蛋白表达强度与异常增生上皮表达强度一致。