肠道微生物群与认知损害

随着全球老龄化加剧，罹患认知损害的人数不断增加，其给患者、患者家属和社会带来了沉重的负担，但有关病因尚未完全明确。越来越多的研究显示，肠道微生物群与认知损害的发生密切相关。肠道菌群通过肠―脑轴与中枢神经系统进行双向通讯交流，而肠道生态系统的紊乱可能导致认知损害的发生和进展。其机制可能包括神经炎症、屏障功能破坏、菌群代谢产物及饮食结构改变等，通过调整肠道菌群可以改善认知功能。基于二者的关联可为认知损害的防治提供新的临床思路。国际神经病学神经外科学杂志, 2023, 50(4): 90-94]     

Determination and modelling of stereoselective interactions of ligands with drug transporters: A key dimension in the understanding of drug disposition

1.?Stereochemistry is an important dimension in pharmacology and plays a role in every aspect of the pharmacological fate of chiral xenobiotics. This includes small molecule–drug transporter binding.

2.?This paper reviews the reported stereoselectivities of substrate and inhibitor interactions with P-glycoprotein and the organic cation transporter obtained using standard functional and binding studies, as well as data obtained from online cellular membrane affinity chromatography studies.

3.?The use of stereochemical data in quantitative structure–activity relationship (QSAR) and pharmacophore modelling is also addressed as is the effect of ignoring the fact that small molecule–drug transporter interactions take place in three-dimensional and asymmetric space.     

唑来膦酸对女性骨质疏松症的疗效及其对骨标志物的影响

目的探讨唑来膦酸注射液(密固达)对女性不同原因所致骨质疏松的临床疗效及其对骨代谢标志物的影响。方法回顾性分析2012年4月至2016年7月在长海医院风湿免疫科接受唑来膦酸治疗的119例女性骨质疏松症患者,根据病情分为原发性骨质疏松组和继发性骨质疏松组,其中原发性骨质疏松组66例,年龄52~87岁,平均69.8±9.6岁;继发性骨质疏松组53例,年龄51~82岁,平均66.1±8.4岁;原发性骨质疏松组患者发病年龄高于继发性骨质疏松组患者(P0.05),两组患者在陈旧性骨折史、血钙、血磷、BUN、Cr、骨代谢标志物、骨密度等方面差异均无统计学意义。所有患者均接受每年1次5mg唑来膦酸,联合骨化三醇0.25μg/日和600 mg碳酸钙D3片/日治疗1年。比较两组患者治疗前和治疗1年后腰椎和髋部骨密度及骨代谢相关指标,观察患者药物不良反应和新发骨折情况。结果与治疗前比较,原发性骨质疏松组患者治疗1年后腰椎和髋部骨密度值均明显增加(P0.05或0.01);骨代谢标志物P1NP、β-CTX、N-MID水平均明显下降(P0.01),25羟基维生素D水平明显升高(P0.01)。继发性骨质疏松组患者治疗1年后腰椎(L_2、L_3、L_4、L_(1-4))、髋部大粗隆和髋部平均骨密度值均明显增加(P0.05或0.01),骨代谢标志物P1NP、β-CTX、N-MID水平均明显下降(P0.01)。治疗1年后,继发性骨质疏松组患者N-MID明显低于原发性骨质疏松组(P0.01),两组间腰椎、髋部骨密度值及骨代谢标志物P1NP、β-CTX、25羟基维生素D、PTH水平无明显差异。两组患者治疗前后的血钙、血磷、BUN、Cr水平均无明显变化。治疗期间两组均无新发骨折。原发性骨质疏松组患者出现2例发热,继发性骨质疏松组3例发热,两组患者不良反应发生率无差异。结论唑来膦酸治疗不同原因导致的女性骨质疏松患者能够有效改善骨代谢标志物水平,降低骨吸收,显著提高腰椎、髋部的骨密度,降低骨折风险,不良反应少。     

Stereoselective and regiospecific hydroxylation of ketamine and norketamine

The objective was to determine the cytochrome P450s (CYPs) responsible for the stereoselective and regiospecific hydroxylation of ketamine [(R,S)-Ket] to diastereomeric hydroxyketamines, (2S,6S;2R,6R)-HK (5a) and (2S,6R;2R,6S)-HK (5b) and norketamine [(R,S)-norKet] to hydroxynorketamines, (2S,6S;2R,6R)-HNK (4a), (2S,6R;2R,6S)-HNK (4b), (2S,5S;2R,5R)-HNK (4c), (2S,4S;2R,4R)-HNK (4d), (2S,4R;2R,4S)-HNK (4e), (2S,5R;2R,5S)-HNK (4f). The enantiomers of Ket and norKet were incubated with characterized human liver microsomes (HLMs) and expressed CYPs. Metabolites were identified and quantified using LC/MS/MS and apparent kinetic constants estimated using single-site Michaelis-Menten, Hill or substrate inhibition equation. 5a was predominantly formed from (S)-Ket by CYP2A6 and N-demethylated to 4a by CYP2B6. 5b was formed from (R)- and (S)-Ket by CYP3A4/3A5 and N-demethylated to 4b by multiple enzymes. norKet incubation produced 4a, 4c and 4f and minor amounts of 4d and 4e. CYP2A6 and CYP2B6 were the major enzymes responsible for the formation of 4a, 4d and 4f, and CYP3A4/3A5 for the formation of 4e. The 4b metabolite was not detected in the norKet incubates. 5a and 4b were detected in plasma samples from patients receiving (R,S)-Ket, indicating that 5a and 5b are significant Ket metabolites. Large variations in HNK concentrations were observed suggesting that pharmacogenetics and/or metabolic drug interactions may play a role in therapeutic response.     

Renal failure in pediatric Castleman disease: Four French cases with thrombotic microangiopathy

Pediatric Castleman disease (CD) is an uncommon and poorly understood disorder of the lymph nodes. Renal failure has not been described in pediatric multicentric CD (MCD). We report four cases, who presented with polyadenopathy, organomegaly, edema and fluid accumulations, high blood pressure, and acute renal failure. In all cases, renal biopsy confirmed diffuse thrombotic microangiopathy. Definitive diagnosis of MCD was made by a biopsy of an affected lymph node located by computer tomography before initiation of corticosteroid therapy. Treatment of CD with corticosteroid therapy and rituximab was rapidly effective without relapse to date.     

Resveratrol supplementation confers neuroprotection in cortical brain tissue of nonhuman primates fed a high-fat/sucrose diet

Previous studies have shown positive effects of long-term resveratrol (RSV) supplementation in preventing pancreatic beta cell dysfunction, arterial stiffening and metabolic decline induced by high-fat/high-sugar (HFS) diet in nonhuman primates. Here, the analysis was extended to examine whether RSV may reduce dietary stress toxicity in the cerebral cortex of the same cohort of treated animals. Middle-aged male rhesus monkeys were fed for 2 years with HFS alone or combined with RSV, after which whole-genome microarray analysis of cerebral cortex tissue was carried out along with ELISA, immunofluorescence, and biochemical analyses to examine markers of vascular health and inflammation in the cerebral cortices. A number of genes and pathways that were differentially modulated in these dietary interventions indicated an exacerbation of neuroinflammation (e.g., oxidative stress markers, apoptosis, NF-κB activation) in HFS-fed animals and protection by RSV treatment. The decreased expression of mitochondrial aldehyde dehydrogenase 2, dysregulation in endothelial nitric oxide synthase, and reduced capillary density induced by HFS stress were rescued by RSV supplementation. Our results suggest that long-term RSV treatment confers neuroprotection against cerebral vascular dysfunction during nutrient stress.     

基于Morisky量表调查某院校学员浅部真菌病用药依从性

目的 了解某部队院校学员浅部真菌病用药依从性。方法 将8条目Morisky用药依从性量表修改为7条目量表,调查患病学员用药依从性,对修改版Morisky量表进行信度和效度分析。结果 回收243份问卷,其中有效问卷242份,结果显示90.08%的学员采用局部用药治疗,8.68%的学员采用局部用药和全身用药联合治疗;抗真菌药物用药依从性高、中、低的患病学员比例分别为9.09%、23.97%、66.94%;修改版Morisky用药依从性量表信度分析,内部一致性系数（Cronbach’s α）为0.781,调整后Cronbach’s α系数为0.790,信度较好;效度分析KMO值0.798,Bartlett’s球形检验值440.866,P=0.000,效度较好;探索性因子分析提取1个因子,量表因子载荷值均大于0.5,量表条目聚合度较好。结论 修改版Morisky用药依从性量表信度和效度较好,可以推广应用。院校学员浅部真菌病用药依从性水平较低,需采取有效措施,帮助学员加强日常用药管理,改善用药依从性。     

早产儿肺脏的超声特征及超声评分

目的 观察早产儿肺脏的超声表现和超声评分。方法 选取无心肺疾病及低蛋白血症的早产儿37例（早产儿组）及足月儿33例（足月儿组）,并根据患儿年龄将每组分为<1周、1~4周、>4周3个亚组。对所有患儿行双肺超声检查并予以评分,观察早产儿肺脏超声表现,比较早产儿与足月儿及不同年龄间的超声评分差异。结果 早产儿肺脏超声主要表现为弥漫分布密集B线,伴或不伴"瀑布征",提示肺泡内积液。早产儿及足月儿肺部超声评分结果分别为（15.24±2.76）分和（12.21±3.62）分,差异有统计学意义（t=3.962,P<0.001）;年龄<1周的早产儿与足月儿超声评分差异无统计学意义（t=-0.669,P=0.513）,年龄为1~4周及>4周的早产儿与足月儿超声评分差异均有统计学意义（P均<0.05）。早产儿3个亚组间肺超声评分差异无统计学意义（F=0.960,P=0.393）;足月儿3个亚组间肺超声评分差异有统计学意义（F=4.277,P=0.023）。早产儿肺超声评分与胎龄呈负相关（r=-0.352,P=0.033）,其线性回归关方程为Y=33.805-0.548X。结论 早产儿肺脏超声主要表现为弥漫分布密集B线,伴或不伴"瀑布征",提示肺泡内积液,胎龄越小越显著。     

Immobilized P2X2 purinergic receptor stationary phase for chromatographic determination of pharmacological properties and drug screening

The purinergic receptor signaling system plays an important role in communication between cells in the nervous system and opens new opportunities for screening of potential drugs. Our objective was to explore the pharmacological properties and establish a new methodology for ligand screening for the P2X2 receptor, which has been developed by the combinatorial library approach Systematic Evolution of Ligands by Exponential enrichment (SELEX). To this end, membranes of 1321N1 cells stably transfected with rat P2X2 receptors were resuspended in 2% cholate detergent and subsequently coupled onto an immobilized artificial membrane (IAM). The IAM-cholate-P2X2 mixture was then dialyzed, centrifuged and packed into a FPLC column. Equilibrium binding to the receptor and competition between ATP and the purinergic antagonists suramin and 2'3'-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate (TNP-ATP) were analyzed by a chromatographic assay using 32P alpha ATP as a radioligand. Our data indicate that suramin does not compete with ATP for the ligand binding site and TNP-ATP is a competitive antagonist, confirming previous studies [C.A. Trujillo, A.A. Nery, A.H. Martins, P. Majumder, F.A. Gonzalez, H. Ulrich, Biochemistry 45 (2006) 224-233]. In addition, we demonstrate that this assay can be used in in vitro selection procedures for RNA aptamers binding to P2X2 receptors. The results demonstrate that the receptor can be immobilized in a stable format and reused over an extended period of time, facilitating the exploration of ligand-receptor interactions and screening of combinatorial pools for possible ligands.