Three-dimensional analysis of combination effect of ellagitannins and acyclovir on herpes simplex virus types 1 and 2

The effects of combinations of three nonahydroxyterphenoyl-bearing C-glucosidic ellagitannins (castalagin, vescalagin and grandinin) with acyclovir (ACV) on the replication of type-1 and type-2 herpes simplex viruses in MDBK cells were tested by the focus-forming units reduction test. Ellagitannins included in these combinations possess a high individual antiviral activity: selectivity index of castalagin and vescalagin versus HSV-1 was similar to that of ACV, and relatively lower against HSV-2. The three-dimensional analytical approach of Prichard and Shipman was used to evaluate the impact of drug-drug interactions. The combination effects of ellagitannins with acyclovir were markedly synergistic.     

Oxytocin protects against negative behavioral and autonomic consequences of long-term social isolation

Positive social interactions and social support may protect against various forms of mental and physical illness, although the mechanisms for these effects are not well identified. The socially monogamous prairie vole, which – like humans – forms social bonds and displays high levels of parasympathetic activity, has provided a useful model for investigating neurobiological systems that mediate the consequences of sociality. In the present study, adult female prairie voles were exposed to social isolation or continued pairing with a female sibling (control conditions) for 4 weeks. During weeks 3 and 4 of this period, animals were administered oxytocin (20 μg/50 μl, SC) or saline vehicle (50 μl, SC) daily for a total of 14 days. In Experiment 1, autonomic parameters were recorded during and following isolation or pairing. Isolation (vs. pairing) significantly increased basal heart rate (HR) and reduced HR variability and vagal regulation of the heart; these changes in isolated animals were prevented with oxytocin administration. In Experiment 2, behaviors relevant to depression [sucrose intake and swimming in the forced swim test (FST)] were measured as a function of isolation. Isolation reduced sucrose intake and increased immobility in the FST; these behaviors also were prevented by oxytocin. Administration of oxytocin did not significantly alter cardiac, autonomic or behavioral responses of paired animals. These findings support the hypothesis that oxytocinergic mechanisms can protect against behavioral and cardiac dysfunction in response to chronic social stressors, and can provide insight into social influences on behavior and autonomic function in humans.     

VLA‐4 blockade by natalizumab inhibits sickle reticulocyte and leucocyte adhesion during simulated blood flow

Very Late Antigen‐4 (VLA‐4, α4β1‐integrin, ITGA4) orchestrates cell‐cell and cell‐endothelium adhesion. Given the proposed role of VLA‐4 in sickle cell disease (SCD) pathophysiology, we evaluated the ability of the VLA‐4 blocking antibody natalizumab to inhibit SCD blood cell adhesion. Natalizumab recognized surface VLA‐4 on leucocytes and reticulocytes in whole blood from SCD subjects. SCD reticulocytes were positive for VLA‐4, while VLA‐4 staining of non‐SCD reticulocytes was undetectable. Titrations with natalizumab revealed the presence of saturable levels of VLA‐4 on both SCD reticulocytes and leucocytes similar to healthy subject leucocytes. Under physiological flow conditions, the adhesion of SCD whole blood cells and isolated SCD leucocytes to immobilized vascular cell adhesion molecule 1 (VCAM‐1) was blocked by natalizumab in a dose‐dependent manner, which correlated with cell surface receptor binding. Natalizumab also inhibited >50% of whole blood cell binding to TNF‐α activated human umbilical vein endothelial cell monolayers under physiological flow at clinically relevant concentrations (10 to 100 μg/ml). This indicates that VLA‐4 is the dominant receptor that drives SCD reticulocyte and mononuclear cell adhesion to VCAM‐1 and that the VLA‐4 adhesion to VCAM‐1 is a significant contributor to SCD blood cell adhesion to endothelium. Thus, VLA‐4 blockade may be beneficial in sickle cell disease.     

Relative Clinical Outcomes Comparing Manual and Robotic-Assisted Total Knee Arthroplasty at Minimum 1-Year Follow-up

Background: Total knee arthroplasty (TKA) demonstrates excellent durability using jig-based manual techniques (manual TKA [mTKA]), but significant rates of dissatisfaction remain. Modifications of mTKA techniques and TKA implant designs to improve outcomes have had minimal success. Studies comparing relative outcomes of mTKA and robotic-assisted TKA (raTKA) are limited. Purpose: This study sought to compare outcomes of mTKA and raTKA in patients at a single institution. Methods: We retrospectively reviewed all primary TKAs performed by 1 surgeon from 2015 to 2017. In all, 139 consecutive mTKAs (2015–2016) and 148 consecutive raTKAs (2016–2017) were included. No cases were excluded. Patient demographics, complications, readmission rates, and clinical and patient-reported outcomes were compared at a minimum of 1-year follow-up. A post hoc student t test and Pearson χ² test were used for continuous and categorical data. Results: We found that mTKA patients compared with raTKA patients required significantly longer length of stay (LOS) (1.73 vs 1.18 days, respectively), greater morphine milligram equivalents consumption (89.6 vs 65.2, respectively), and increased physical therapy (PT) visits (13.0 vs 11.0, respectively) with increased 30-day readmission rates (4.3 vs 0.7%, respectively) that approached significance. Knee Injury and Osteoarthritis Outcome Score for Joint Replacement and the University of California at Los Angeles activity score did not differ significantly comparing raTKA with mTKA patients at 1 year. There were no differences in complication rates. Conclusion: Significant early clinical benefits were noted with raTKA, including lower opioid requirements, shorter LOS, and fewer PT visits when compared with mTKA. A reduction in 30-day readmission rates was noted with raTKA that was not significant. Excellent clinical results with similar patient-reported outcomes were noted in both groups at 1-year follow-up. Further prospective investigations at longer follow-up intervals comparing these techniques are warranted.     

盐酸关附甲素注射液治疗室性心律失常的多中心随机双盲试验

目的 评价国家一类新药盐酸关附甲素注射液（GFA）治疗室性心律失常的疗效和安全性.方法 随机双盲多中心阳性药对照试验,由全国8家临床药理基地完成.入选不伴严重器质性心脏病的频发室性早搏（室早）患者,室早平均每小时≥150次（用Holter评价）,伴或不伴短阵室性心动过速.采用1∶1随机对照使用GFA或盐酸普罗帕酮.采用静脉负荷加维持量的方法维持6 h.用药前一天和用药日均进行24 h Holter及心电监测进行疗效评价.监测生命体征、心电图及观察不良事件.结果 共入选201例患者,用药前两组在病史、体检、实验室检查、室早数量、短阵室性心动过速数量差异均无统计学意义.GFA组与盐酸普罗帕酮组室早减少百分数和总有效率差异无统计学意义.室早减少百分数分层分析,GFA有优于盐酸普罗帕酮的趋势,达到统计学差异临界值（P=0.0609）.GFA抑制室早的程度以及控制室早的作用出现时间与盐酸普罗帕酮差异无统计学意义.GFA静脉应用耐受性较好,发生不良事件的严重程度明显轻于盐酸普罗帕酮,差异有统计学意义.结论 GFA控制室性心律失常安全有效,其疗效相当于盐酸普罗帕酮,发生的不良事件较盐酸普罗帕酮为轻,今后应对其抗心律失常作用进行进一步的研究.     

Cat allergen level: its determinants and relationship to specific IgE to cat across European centers

BACKGROUND: Cat allergen level in settled house dust and its determinants in Europe are unknown. OBJECTIVE: The aim of this study is to quantify the level of cat allergens in mattress dust, to study its determinants, and to analyze the relationship with cat specific IgE on community level across European centers. METHODS: Trained field workers collected dust from approximately 3000 mattresses during home visits in 22 European Community Respiratory Health Survey II centers. Sieved dust extracts were assayed for cat allergen using a mAb ELISA assay. RESULTS: The overall geometric mean cat allergen was 0.94 microg/g, ranging from 0.12 microg/g in Huelva, Spain, to 3.76 microg/g in Antwerp, Belgium. Current cat owners' homes showed substantially higher levels than past cat owners' and never cat owners' homes (geometric mean and 95% CI, 61.4 microg/g [48.4-77.9] vs 1.37 microg/g [0.97-1.9] vs 0.29 microg/g [0.27-0.31]). Community prevalence of cat ownership was moderately correlated with cat allergen levels in noncat owners (r(s) = 0.50), but not for past or current cat owners. The multilevel model identified community prevalence of cat keeping as the only statistically significant determinant of mattress cat allergen levels for noncat owners. However, averaged cat allergen levels per center were not related to community prevalence of detectable specific IgE to cat. CONCLUSION: Not having a cat in the home is associated with substantially lower Fel d 1 concentration, but does not protect against high Fel d 1 exposure in communities where cat ownership is common. CLINICAL IMPLICATIONS: People (including patients with cat allergy) who do not own cats may be exposed to high levels of cat allergen in their home, particularly if they live in communities with high levels of cat ownership.