注射用重组人血清白蛋白-人粒细胞集落刺激因子(Ⅰ)融合蛋白在健康受试者的耐受性研究

目的评价重组(酵母分泌型)人血清白蛋白-人粒细胞集落刺激因子(Ⅰ)融合蛋白在健康受试者的耐受性和安全性。方法将26例健康受试者(男女各半)按先后顺序入组,进行4个剂量组试验(150,300,500,650μg·kg^-1),每组分别入组4,6,8,8例。根据体重计算给药剂量,受试者于给药当天上臂三角肌部位皮下注射给药1次。用药后观察药物不良事件(AE),定时进行实验室检查、心电图检查。结果共25例受试者发生AE,共145例次。150,300,500及650μg·kg^-1剂量组的AE分别为13,11,56和65例次。其中134例次考虑与研究药物相关。常见的AE有骨痛、单核细胞计数升高、血碱性磷酸酶升高、头痛、高尿酸血症、血乳酸脱氢酶升高、脾肿大、肌肉疲劳。研究中未出现AE导致的用药暂停、受试者退出或试验提前中止。未发生严重不良事件(SAE)。未发生剂量限制性毒性。结论注射用重组(酵母分泌型)人血清白蛋白-人粒细胞集落刺激因子(Ⅰ)融合蛋白在中国健康受试者中单次给药150,650μg·kg^-1剂量范围内有较好的安全性,本临床试验未探索到健康人群的最大耐受剂量。     

Calcium-Sensing Receptors of Human Astrocyte-Neuron Teams: Amyloid-β-Driven Mediators and Therapeutic Targets of Alzheimer’s Disease

It is generally assumed that the neuropathology of sporadic (late-onset or nonfamilial) Alzheimer’s disease (AD) is driven by the overproduction and spreading of first Amyloid-β_x-42 (Aβ₄₂) and later hyperphosphorylated (hp)-Tau oligomeric “infectious seeds”. Hitherto, only neurons were held to make and spread both oligomer types; astrocytes would just remove debris. However, we have recently shown that exogenous fibrillar or soluble Aβ peptides specifically bind and activate the Ca²⁺-sensing receptors (CaSRs) of untransformed human cortical adult astrocytes and postnatal neurons cultured in vitro driving them to produce, accrue, and secrete surplus endogenous Aβ₄₂. While the Aβ-exposed neurons start dying, astrocytes survive and keep oversecreting Aβ₄₂, nitric oxide (NO), and vascular endothelial growth factor (VEGF)-A. Thus astrocytes help neurons’ demise. Moreover, we have found that a highly selective allosteric CaSR agonist (“calcimimetic”), NPS R-568, mimics the just mentioned neurotoxic actions triggered by Aβ●CaSR signaling. Contrariwise, and most important, NPS 2143, a highly selective allosteric CaSR antagonist (“calcilytic”), fully suppresses all the Aβ●CaSR signaling-driven noxious actions. Altogether our findings suggest that the progression of AD neuropathology is promoted by unceasingly repeating cycles of accruing exogenous Aβ₄₂ oligomers interacting with the CaSRs of swelling numbers of astrocyte-neuron teams thereby recruiting them to overrelease additional Aβ₄₂ oligomers, VEGF-A, and NO. Calcilytics would beneficially break such Aβ/CaSR-driven vicious cycles and hence halt or at least slow the otherwise unstoppable spreading of AD neuropathology     

Correction of pelvic obliquity in neuromuscular spinal deformities using the “T construct”: results and complications in a prospective series of 60 patients

Background

We present the results of a prospective series of 60 patients treated for neuromuscular spinal deformities with an original spinopelvic construct using two sacral screws and two iliac screws. Clinical and radiological results obtained with this new surgical technique were studied and discussed according to the epidemiological data and relevant literature.

Methods

From January 2008 to June 2010, the clinical data of every patient who underwent spinopelvic fixation for treatment of a neuromuscular spinal deformity were recorded prospectively.

Results

Sixty patients were operated on during the study period. Spinal correction and fusion was performed by posterior approach. In six patients with a residual spinopelvic imbalance more than 15° on lateral preoperative bending films, an anterior release of the thoracolumbar junction was performed on the same day, before posterior correction. Preoperative pelvic obliquity (PO) ranged from 4° to 44° (mean 21.6°). Postoperative pelvic obliquity ranged from 0° to 14 (mean 4.6°). No significant loss of correction was noted at the last follow-up. One patient died 3 months after the initial procedure due to respiratory compromise. 11 patients had early postoperative infections of the posterior approach.

Conclusions

Despite a high rate of infectious complications, optimal correction of pelvic obliquity requires extension of spinal instrumentation to the pelvis. Spinopelvic fixation remains a difficult challenge in neurological patients with hypotrophy. We think that pelvic fixation with the “T construct” did provide effective and improved spinal stabilization in these patients, while reducing the need for a postoperative cast or brace. As a result, patients had a favourable postoperative course with early mobilization and return to a comfortable sitting position.     

Enhancing patient research partner engagement: Research in psoriatic arthritis

The perspective from individuals with psoriatic arthritis (PsA) can be beneficial to PsA research, increasing the likelihood that the results are meaningful and relevant to PsA patients. While there has been an advancement of patient research partner (PRP) involvement in PsA research over time, the effort is still in its infancy. Measures to ensure PRP engagement (PRPE) occurs and its impact evaluated need to be implemented routinely to increase PRPE in PsA research.     

Organizational Dimensions of Relationship-centered Care

Four domains of relationship have been highlighted as the cornerstones of relationship-centered health care. Of these, clinician-patient relationships have been most thoroughly studied, with a rich empirical literature illuminating significant linkages between clinician-patient relationship quality and a wide range of outcomes. This paper explores the realm of clinician-colleague relationships, which we define to include the full array of relationships among clinicians, staff, and administrators in health care organizations. Building on a stream of relevant theories and empirical literature that have emerged over the past decade, we synthesize available evidence on the role of organizational culture and relationships in shaping outcomes, and posit a model of relationship-centered organizations. We conclude that turning attention to relationship-centered theory and practice in health care holds promise for advancing care to a new level, with breakthroughs in quality of care, quality of life for those who provide it, and organizational performance.     

《中国儿童发育量表》修订及效度研究

目的 研究“儿心量表”修订后《中国儿童发育量表》的结构效度及校标效度,为制定全国常模以及诊断性发育量表提供可行性依据。方法 在北京市地区抽样人群中,用《中国儿童发育量表》初始修订表进行测试;运用项目分析、探索性因素分析、验证性因素分析及结构方程模型分析方法确定量表的结构及结构效度;以Gesell发展量表为外在校标进行相关分析。结果 共测试0~84月龄儿童2 779名,男童1 468名,女童1 311名。男:女比为1.1∶1,按项目实际受试人次计,共测试77 329人次。具有鉴别力的(CR值,P<0.05)项目占99.2%(259/261)。将量表每3个月的项目为一个整体(子集)进行因素分析, 9个子集的KMO值分别为0.938、0.954、0.933、0.932、0.940、0.942、0.948、0.976、0.956;旋转后提取因子特征值大于1的累积方差贡献率分别为66.9%、 55.2%、57.6%、59.4%、50.5%、59.7%、61.0%、59.7%、59.2%。量表的5个维度与提取因子载荷匹配基本吻合。通过对以因素分析的9个子集进行强制性验证性因素分析,5个维度构想与实际数据的拟合度良好。考虑发展量表特点及验证性因素分析样本量要求,再将前后连续、相邻月龄项目进行组合即1月龄与2月龄,2月龄与3月龄之后以此类推,再进行验证分析,分析参数CFI及NNFI均大于0.9,RMSEA在0.08以下占79.2%(19/24),最大为0.98,仍提示五维度的构想合理。与Gesell量表的关系(Pearson)系数为0.637。结论 修订后《中国儿童发育量表》结构效度较高,测验项目鉴别力强,五维度的量表结构合理,符合诊断性发育评估量表参数,可作为制定全国常模的基础量表。     

Reduced variability in tacrolimus pharmacokinetics following intramuscular injection compared to oral administration in cynomolgus monkeys: Investigating optimal dosing regimens

Tacrolimus is one of the most commonly used immunosuppressive agents in animal models of transplantation. However, in these models, oral administration is often problematic due to the lowered compliance associated with highly invasive surgery and due to malabsorption in the intestinal tract. Therefore, we carried out a study to determine the pharmacokinetics of tacrolimus after intramuscular (IM) injection and to determine the optimal IM dosing regimens in primate models. Six male cynomolgus monkeys (Macaca fascicularis) were used in the study. Doses of 0.1 mg/kg and 5 mg were administered via IM injection and oral administration, respectively, once to determine single-dose pharmacokinetics and once daily for 5 days to determine multiple-dose pharmacokinetics. According to pharmacokinetic model estimates, the inter- and intra-individual variabilities in bioavailability following IM injection were remarkably reduced compared with those following oral administration. Monte Carlo simulations revealed that C_peak, C_trough and AUC would also have less variability following IM injection compared with oral administration. In this study, we found that the pharmacokinetic characteristics of tacrolimus were more constant following IM injection compared with oral administration. These results suggest that IM injection can be an alternative route of administration fin non-human primate model studies.     

Interdisciplinary Team Communication Among Forensic Nurses and Rape Victim Advocates

Victim advocates and forensic nurses provide integrated care to address the complex legal, medical, and mental health needs of rape survivors. Research suggests that conflict exists between nurses and advocates, but it remains unknown how their communication patterns contribute to or resolve these conflicts. Utilizing a qualitative case study approach, the current study interviewed 24 nurses and advocates from a Midwest organization to better understand team communication patterns when addressing conflicts. The findings suggest that most nurses communicate concerns directly while advocates avoid direct communication. Factors that influenced direct and indirect communication and their implications for practice will be discussed.     

Pharmacokinetic and pharmacodynamic study of a clinically effective anti-CD2 monoclonal antibody

The humanized IgG1κ monoclonal antibody siplizumab and its rat parent monoclonal IgG2b antibody BTI-322 are directed against the CD2 antigen. Siplizumab is species-specific, reacting with human and chimpanzee cells but not with cells from any other species, including other non-human primates. Because siplizumab treatment has recently shown great potential in clinical transplantation, we now present the results of our previous pharmacokinetic, pharmacodynamic and safety studies of both antibodies. Fourteen chimpanzees received 1-3 doses of 0.143 to 5.0 mg/kg iv The effects were followed with flow cytometry on peripheral lymphocytes and staining of lymph nodes. Side effects were recorded. Serum antibody concentrations were followed. Across the doses, a rapid, transient depletion of CD2, CD3, CD4 and CD8 lymphocytes and NK cells was observed for both antibodies. Immune reconstitution was more rapid for BTI-322 compared to siplizumab. Paracortical lymph node T cell depletion was moderate, estimated at 45% with doses of >0.6 mg/kg. Restoration of lymph node architecture was seen after two weeks to two months for all animals. All four subjects receiving BTI-322 experienced AEs on the first dosing day, while the eight subjects dosed with siplizumab experienced few mild, transient AEs. Infusion with siplizumab and BTI-322 resulted in rapid depletion of CD2⁺ cells in circulation and tissue. Siplizumab had a longer t_1/2 and fewer AEs compared to BTI-322.