Quantification of IgG monoclonal antibody clearance in tissues

Monoclonal antibodies are an important therapeutic entity, and knowledge of antibody pharmacokinetics has steadily increased over the years. Despite this effort, little is known about the extent of IgG antibody degradation in different tissues of the body. While studies have been published identifying sites of degradation with the use of residualizing and non-residualizing radiolabels, quantitative tissue clearances have not yet been derived. Here, we show that in physiologically-based pharmacokinetic (PBPK) models we can combine mouse data of Indium-111 and Iodine-125 labeled antibodies with prior physiologic knowledge to determine tissue-specific intrinsic clearances. Unspecific total tissue clearance (mL/day) in the mouse was estimated to be: liver = 4.75; brain = 0.02; gut = 0.40; heart = 0.07; kidney = 0.97; lung = 0.20; muscle = 3.02; skin = 3.89; spleen = 0.45; rest of body = 2.16. The highest catabolic activity (per g tissue) was in spleen for an FcRn wild-type antibody, but shifts to the liver for an antibody with reduced FcRn affinity. In the model developed, this shift can be explained by the liver having a greater FcRn-mediated protection capacity than the spleen. The quantification of tissue intrinsic clearances and FcRn salvage capacity increases our understanding of quantitative processes that drive the therapeutic responses of antibodies. This knowledge is critical, for instance to estimate the non-specific cellular uptake and degradation of antibodies used for targeted delivery of payloads.     

Ecosystem Processes Performed by Unionid Mussels in Stream Mesocosms: Species Roles and Effects of Abundance

Unionid mussels are a guild of freshwater, sedentary filter-feeders experiencing a global decline in both species richness and abundance. To predict how these losses may impact stream ecosystems we need to quantify the effects of both overall mussel biomass and individual species on ecosystem processes. In this study we begin addressing these fundamental questions by comparing rates of ecosystem processes for two common mussel species, Amblema plicata and Actinonaias ligamentina, across a range of abundance levels and at two trophic states (low and high productivity) in stream mesocosms. At both low and high productivity, community respiration, water column ammonia, nitrate, and phosphorus concentrations, and algal clearance rates were all linearly related to overall mussel biomass. After removing the effects of biomass with ANCOVA, we found few differences between species. In a separate series of experiments, nutrient excretion (phosphorus, ammonia, and molar N:P) and biodeposition rates were only marginally different between species. For the species studied here, functional effects of unionids in streams were similar between species and linearly related to biomass, indicating the potential for strong effects when overall mussel biomass is high and hydrologic residence times are long.     

Selective grazing by adults and larvae of the zebra mussel (Dreissena polymorpha): application of flow cytometry to natural seston

1. Selective grazing of adults and larvae of the zebra mussel (Dreissena polymorpha) on phytoplankton and detritus from both laboratory cultures and natural seston was quantified using flow cytometry. 2. Mean clearance rate of adult zebra mussels was higher on a mixture of the green alga Scenedesmus and the cyanobacterium Microcystis than when Scenedesmus was offered as single food, suggesting selective feeding by the mussels. 3. Feeding on lake seston both adults and larvae showed a higher clearance rate on phytoplankton than on detritus particles, suggesting that zebra mussels select for phytoplankton. Furthermore, it was noted that adults preferred seston particles in the 0–1 and 30–100 μm size ranges. 4. In our study, zebra mussels did not discriminate against cyanobacteria, and our results indicate that they may even ingest them preferentially.     

Natriuretic Peptide Clearance Receptor Alleles and Susceptibility to Abdominal Adiposity

Objective: To test the association of the C(?55)A polymorphism of the natriuretic peptide clearance receptor (NPRC) with blood pressure (BP), overweight/obesity, and body fat distribution in a large male adult population. Research Methods and Procedures: The study population was from a cross‐sectional and follow‐up study of 787 untreated male participants in the 1994 to 1995 follow‐up examination of the Olivetti Heart Study in Naples (356 of whom were examined previously in 1975). BP and anthropometric measures were taken, and biochemical assays were performed. The NPRC gene polymorphism C(?55)A was evaluated by polymerase chain reaction and HgaI digestion. Results: In the whole study population, there was no difference in BP, BMI, and biochemical tests among genotypes. Considering an A(?55) recessive model of inheritance, the AA subjects had lower BMI and waist circumference and lower prevalence of overweight, obesity, and abdominal adiposity as compared with the CC+CA subjects. On reviewing the characteristics of the subgroup previously examined in 1975, the AA subjects had already lower BMI, and their 20‐year rate of overweight and obesity was lower than the CC+CA subjects; no difference was observed in the rate of hypertension. Discussion: Male subjects carrying the A(?55)A NPRC genotype had a significantly lower prevalence of overweight, obesity, and abdominal adiposity. They also had a lower 20‐year rate of overweight compared with CC+CA individuals. These findings from a large unselected and untreated male population are in keeping with the recent evidence of a powerful lipolytic and lipomobilizing activity of natriuretic peptides.     

蝮蛇三龙丹胶囊对大鼠实验性脑血肿的影响

目的探讨蝮蛇三龙丹胶囊对大鼠实验性脑血肿的影响。方法采用大鼠自体血液颅内注入造成大鼠脑血肿模型,观察蝮蛇三龙丹胶囊的作用。结果蝮蛇三龙丹胶囊（０．２ｇ／ｋｇ、０．４ｇ／ｋｇ）可明显降低脑指数、脑组织含水量（Ｐ＜０．０１）及Ｃａ２＋离子含量（Ｐ＜０．０１）,对Ｎａ＋、Ｋ＋离子含量无明显影响（Ｐ＜０．０５）。结论蝮蛇三龙丹胶囊对实验性脑血肿诱发脑水肿有一定防治作用,且对小鼠出、凝血时间无影响,亦未见对大鼠实验性脑血肿发生再出血。本实验为蛇毒制剂治疗高血压性脑出血提供可靠依据。关键词蝮蛇三龙丹胶囊脑血肿脑水肿     

丙泊酚靶控输注联合右美托咪定对颅脑外伤颅内血肿清除术患者血清炎症因子和脑损伤指标的影响

摘要 目的：观察丙泊酚靶控输注联合右美托咪定对颅脑外伤颅内血肿清除术患者血清炎症因子和脑损伤指标的影响。方法：选择2016年3月~2021年5月期间联勤保障部队第901医院麻醉科收治的颅脑外伤颅内血肿清除术患者115例。采用随机数字表法将患者分为对照组和实验组,例数分别为57例和58例。对照组患者接受丙泊酚靶控输注,实验组患者接受丙泊酚靶控输注联合右美托咪定。对比两组苏醒质量（苏醒时间、听指令睁眼时间、滞留苏醒室时间）、血流动力学指标[心率（HR）、收缩压（SBP）、舒张压（DBP）]、炎症因子[白介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）、白介素-6（IL-6）]、脑损伤指标[神经元特异性烯醇化酶（NSE）、S100β、脑源性神经营养因子（BDNF）]情况,同时观察两组围术期不良反应情况。结果：实验组的苏醒时间、听指令睁眼时间、滞留苏醒室时间短于对照组（P<0.05）。实验组气管插管时（T1）~拔管后（T4）时间点HR、SBP、DBP低于对照组（P<0.05）。实验组术后48hIL-1β、TNF-α、IL-6低于对照组（P<0.05）。实验组术后48hNSE、S100β低于对照组,BDNF高于对照组（P<0.05）。两组不良反应发生率组间对比未见差异（P>0.05）。结论：丙泊酚靶控输注联合右美托咪定应用于颅脑外伤颅内血肿清除术患者,可维持机体血流动力学稳定,减轻炎症反应和脑损伤,促进术后苏醒,且不良反应发生率无明显增加。     

Ⅰ型干扰素受体启动子多态性与慢性乙型肝炎易感性的相关性研究

目的 研究Ⅰ型干扰素受体启动子(IFNAR1)的基因多态性在不同个体间的差异,以及它们与慢性乙型肝炎病毒(HBV)感染之间的相关性。方法 对320例慢性乙型肝炎患者、148例自发康复者、148例健康对照和114例正常高加索人的IFNAR1进行基因分型,分析基因的多态性与慢性HBV感染的易感性之间的相关性;构建IFNAR1启动子-荧光素酶报告基因载体,比较不同IFNAR1启动子变异体的转录活性。结果 在-568,-408,-77和-3位点发现基因多态性,其中-568和-77位点,以及-408和-3位点之间存在等位基因连锁。相关性分析结果表明,-568G、-408C和单体型-568G/-408C/-3C/-77(M)与病毒清除有关,-568C、-408T和单体型-568C/-408T/-3T/-77(L)与HBV感染的慢性化有关。启动子-荧光素酶报告基因载体的检测显示,-408和(或)-3位点的多态性可影响调节IFNAR1启动子的转录水平,而-568位点的多态性总体上对转录活性无明显的影响。-77(9)在高加索人中明显多见,携带这一基因型启动子的转录活性明显高于其他基因型启动子的转录活性。结论 IFNAR1的基因多态性与慢性HBV感染的易感性有相关性。     

Treatment of Combined Injuries of the Axillary and Suprascapular Nerves with Scapulothoracic Dissociation

A 20-year-old man suffered the combined axillary and suprascapular nerve palsies associated with scapulothoracic dissociation by motorcycle accident. The dislocated shoulder girdle was reduced and stabilized with osteosynthesis of the fractured clavicle and reattachment of the trapezius avulsed from the scapular spine for removal of continuous traction force to these damaged nerves. Because of no evidence of recovery on manual muscle test and electromyogram, exploration for these nerves was administered 6 weeks after injury. Although neurolysis of both nerves revealed neural continuity, excessive tension still existed on the suprascapular nerve. It was thought that previous operation in which the shoulder girdle had been reduced and stabilized as much as possible could not achieve complete anatomical reduction of the scapula. As an additional treatment, medial walls of the suprascapular and spinoglenoid notches were shaven to relax the suprascapular nerve. After a year, complete recovery of both the axillary and suprascapular nerve was identified. Although scapulothoracic dissociation is commonly recognized as massive injury of the shoulder girdle with poor prognosis because of existence of accompanied severe neurovascular injuries, there are more than a few cases in which partial damage on the infraclavicular brachial plexus is only accompanied. In case of them, there is the possibility of lesions in continuity of the nerves in which good prognosis might be expected with surgical intervention including early reduction of the shoulder girdle for removal of excessive tension to the damaged nerve.