A new measure of trip risk integrating minimum foot clearance and dynamic stability across the swing phase of gait

Minimum toe clearance (MTC) is thought to quantify the risk of the toe contacting the ground during the swing phase of gait and initiating a trip, but there are methodological issues with this measure and the risk of trip-related falls has been shown to also be associated with gait speed and dynamic stability. This paper proposes and evaluates a new measure, trip risk integral (TRI), that circumvents many issues with MTC as typically calculated at a single point by considering minimum foot clearance across the entire swing phase and taking into account dynamic stability to estimate risk of falling due to a trip rather than risk of the foot contacting the floor. Shoes and floor surfaces were digitized and MTC and TRI calculated for unimpaired younger (N = 14, age = 26 ± 5), unimpaired older (N = 14, age = 73 ± 7), and older adults who had recently fallen (N = 11, age = 72 ± 5) walking on surfaces with no obstacles, visible obstacles, and hidden obstacles at slow, preferred, and fast gait speeds. MTC and TRI had significant (F ≥ 5, p ≤ 0.005) but differing effects of gait speed and floor surface. As gait speed increased (which increases risk of trip-related falls) MTC indicated less and TRI greater risk, indicating that TRI better quantifies risk of falling due to a trip. While MTC and TRI did not differ by subject group, strong speed-related effects of TRI (F ≥ 8, p ≤ 0.0007) resulted in improved TRI for fallers due to their slower self-selected preferred gait. This demonstrates that slower gait is both an important covariate and potential intervention for trip-related falls.     

Glucagon increases insulin levels by stimulating insulin secretion without effect on insulin clearance in mice

Circulating insulin is dependent on a balance between insulin appearance through secretion and insulin clearance. However, to what extent changes in insulin clearance contribute to the increased insulin levels after glucagon administration is not known. This study therefore assessed and quantified any potential effect of glucagon on insulin kinetics in mice. Prehepatic insulin secretion in mice was first estimated following glucose (0.35 g/kg i.v.) and following glucose plus glucagon (10 μg/kg i.v.) using deconvolution of plasma C-peptide concentrations. Plasma concentrations of glucose, insulin, and glucagon were then measured simultaneously in individual mice following glucose alone or glucose plus glucagon (pre dose and at 1, 5, 10, 20 min post). Using the previously determined insulin secretion profiles and the insulin concentration-time measurements, a population modeling analysis was applied to estimate the one-compartment kinetics of insulin disposition with and without glucagon. Glucagon with glucose significantly enhanced prehepatic insulin secretion (Cmax and AUC_0-20) compared to that with glucose alone (p < 0.0001). From the modeling analysis, the population mean and between-animal SD of insulin clearance was 6.4 ± 0.34 mL/min for glucose alone and 5.8 ± 1.5 mL/min for glucagon plus glucose, with no significant effect of glucagon on mean insulin clearance. Therefore, we conclude that the enhancement of circulating insulin after glucagon administration is solely due to stimulated insulin secretion.     

Young microglia restore amyloid plaque clearance of aged microglia

Alzheimer′s disease (AD) is characterized by deposition of amyloid plaques, neurofibrillary tangles, and neuroinflammation. In order to study microglial contribution to amyloid plaque phagocytosis, we developed a novel ex vivo model by co‐culturing organotypic brain slices from up to 20‐month‐old, amyloid‐bearing AD mouse model (APPPS1) and young, neonatal wild‐type (WT) mice. Surprisingly, co‐culturing resulted in proliferation, recruitment, and clustering of old microglial cells around amyloid plaques and clearance of the plaque halo. Depletion of either old or young microglial cells prevented amyloid plaque clearance, indicating a synergistic effect of both populations. Exposing old microglial cells to conditioned media of young microglia or addition of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) was sufficient to induce microglial proliferation and reduce amyloid plaque size. Our data suggest that microglial dysfunction in AD may be reversible and their phagocytic ability can be modulated to limit amyloid accumulation. This novel ex vivo model provides a valuable system for identification, screening, and testing of compounds aimed to therapeutically reinforce microglial phagocytosis.     

Highly potent and selective NaV1.7 inhibitors for use as intravenous agents and chemical probes

The discovery and selection of a highly potent and selective Na_V1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed. A proposed protein–ligand binding mode for this compound is also provided to rationalise the high levels of potency and selectivity over inhibition of related sodium channels. To further support the proposed binding mode, potent conjugates are described which illustrate the potential for development of chemical probes to enable further target evaluation.     

舒普深联合左氧氟沙星治疗哮喘并发肺部感染的疗效分析

目的:研究舒普深联合左氧氟沙星治疗哮喘并发肺部感染的临床疗效。方法:选取2012年6月到2016年6月来我院治疗的哮喘合并肺部感染患者80例,按照患者入院时间将患者随机分为观察组(n=40)和对照组(n=40)。对照组采用舒普深治疗,观察组采用舒普深和左氧氟沙星联合治疗,两组患者均治疗2周,观察比较两组患者的治疗疗效、病原菌清除率以及肺功能的恢复情况。结果:观察组患者的总效率、病原菌清除率均较对照组总有效率显著提高,差异具有统计学意义(P0.05)。与治疗前相比,两组患者治疗后的肺功能指标均显著提高,且观察组患者的肺功能指标较治疗组改善更显著。结论:舒普深联合左氧氟沙星治疗哮喘并发肺部感染临床疗效显著,可显著改善患者肺功能。     

局部亚低温联合血肿清除术治疗外伤性脑内血肿的临床疗效观察

目的:探讨局部亚低温联合血肿清除术治疗外伤性脑内血肿患者的临床疗效。方法:选择我院收治的外伤性脑内血肿患者89例,均给予血肿清除术治疗,其中47例接受血肿清除术联合局部亚低温治疗,评价和比较两组治疗后的临床疗效,术前及术后1天、1周、2周的美国国立卫生研究院卒中量表(NIHSS)评分和血肿体积。结果:治疗组有效率为93.6%,明显高于对照组(P0.05);治疗组术后1天、1周、2周的NIHSS评分明显高于对照组(P0.05),血肿大小明显小于对照组(P0.05)。结论:局部亚低温联合血肿清除术治疗外伤性脑内血肿能有效减轻患者脑部损害,提高患者神经功能。     

前列地尔联合尿毒清颗粒对慢性肾衰竭患者血清甲状旁腺激素、同型半胱氨酸水平及临床疗效的影响

目的:探究前列地尔联合尿毒清颗粒对慢性肾衰竭患者血清甲状旁腺激素、同型半胱氨酸及临床疗效的影响。方法:收集我院收治的慢性肾衰竭患者74例,根据随机对照表分为对照组和试验组,每组37例。对照组予以前列地尔注射液治疗,试验组在对照组基础上予以尿毒清颗粒治疗。观察并比较两组患者临床疗效,治疗前后血清肌酐(SCr)、尿素氮(BUN)、血尿酸(UA)、内生肌酐清除率(Ccr)、超敏C反应蛋白(hs-CRP)、同型半胱氨酸(Hcy)、甲状旁腺素(PTH)、β2微球蛋白(β2-MG)水平以及不良反应的发生情况。结果:与对照组相比,试验组治疗后临床总有效率较高(P0.05)。两组治疗后血清肌酐、尿素氮、血尿酸水平下降(P0.05),内生肌酐清除率水平升高(P0.05);与对照组相比,试验组血清肌酐、尿素氮、血尿酸水平较低(P0.05),内生肌酐清除率水平较高(P0.05)。两组治疗后超敏C反应蛋白、同型半胱氨酸、甲状旁腺素以及β2微球蛋白水平降低(P0.05);与对照组相比,试验组超敏C反应蛋白、同型半胱氨酸、甲状旁腺素以及β2微球蛋白水平较低(P0.05)。两组不良反应发生情况相比差异无统计学意义(P0.05)。结论:前列地尔联合尿毒清颗粒对慢性肾衰竭患者的临床疗效显著,安全性较高,可能与其下调血清甲状旁腺激素以、同型半胱氨酸及β2微球蛋白水平有关。     

传统开颅手术、显微镜下微创手术治疗基底节区高血压脑出血的临床疗效分析

目的:观察和比较传统开颅手术、显微镜下微创手术治疗基底节区高血压脑出血的临床疗效及安全性。方法:选择2011年10月至2016年1月在我院进行手术治疗的基底节区高血压脑出血患者320例,根据手术方式分为两组,每组160例患者。A组患者接受传统开颅血肿清除术,B组患者接受显微镜下小骨窗血肿清除术,比较两组患者的手术情况、临床疗效、术后生活质量的变化和不良反应的发生情况。结果:B组患者手术时间、ICU时间以及住院时间均较A组显著缩短(P0.05),术中失血量、CSS评分以及术后24 h的血肿量显著低于A组(P0.05),术后1个月临床总有效率显著高于A组(P0.05)。随访6个月期间,B组生活质量显著优于A组(P0.05),术后肺部感染、再次出血的发生率均显著低于A组(P0.05)。结论:显微镜下行小骨窗血肿清除术治疗基底节区高血压脑出血的临床疗效显著优于传统开颅血肿清除术,且创伤较小,可有效缩短手术时间,提高手术安全性。     

Development of adsorptive hybrid filters to enable two-step purification of biologics

Recent progress in mammalian cell culture process has resulted in significantly increased product titers, but also a substantial increase in process- and product-related impurities. Due to the diverse physicochemical properties of these impurities, there is constant need for new technologies that offer higher productivity and improved economics without sacrificing the process robustness required to meet final drug substance specifications. Here, we examined the use of new synthetic adsorptive hybrid filters (AHF) modified with the high binding capacity of quaternary amine (Emphaze? AEX) and salt-tolerant biomimetic (Emphaze? ST-AEX) ligands for clearance of process-related impurities like host cell protein (HCP), residual DNA, and virus. The potential to remove soluble aggregates was also examined. Our aim was to develop a mechanistic understanding of the interactions governing adsorptive removal of impurities during filtration by evaluating the effect of various filter types, feed streams, and process conditions on impurity removal. The ionic capacity of these filters was measured and correlated with their ability to remove impurities for multiple molecules. The ionic capacity of AHF significantly exceeded that of traditional adsorptive depth filters (ADF) by 40% for the Emphaze? AEX and by 700% for the Emphaze? ST-AEX, providing substantially higher reduction of soluble anionic impurities, including DNA, HCPs and model virus. Nevertheless, we determined that ADF with filter aid provided additional hydrophobic functionality that resulted in removal of higher molecular weight species than AHF. Implementing AHF demonstrated improved process-related impurity removal and viral clearance after Protein A chromatography and enabled a two-step purification process. The consequences of enhanced process performance are far reaching because it allows the downstream polishing train to be restructured and simplified, and chromatographic purity standards to be met with a reduced number of chromatographic steps.     

Characterizing the impact of pressure on virus filtration processes and establishing design spaces to ensure effective parvovirus removal

Virus filtration provides robust removal of potential viral contaminants and is a critical step during the manufacture of biotherapeutic products. However, recent studies have shown that small virus removal can be impacted by low operating pressure and depressurization. To better understand the impact of these conditions and to define robust virus filtration design spaces, we conducted multivariate analyses to evaluate parvovirus removal over wide ranges of operating pressure, solution pH, and conductivity for three mAb products on Planova? BioEX and 20N filters. Pressure ranges from 0.69 to 3.43 bar (10.0–49.7 psi) for Planova BioEX filters and from 0.50 to 1.10 bar (7.3 to 16.0 psi) for Planova 20N filters were identified as ranges over which effective removal of parvovirus is achieved for different products over wide ranges of pH and conductivity. Viral clearance at operating pressure below the robust pressure range suggests that effective parvovirus removal can be achieved at low pressure but that Minute virus of mice (MVM) logarithmic reduction value (LRV) results may be impacted by product and solution conditions. These results establish robust design spaces for Planova BioEX and 20N filters where high parvovirus clearance can be expected for most antibody products and provide further understanding of viral clearance mechanisms. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1294–1302, 2017