Factors affecting the therapeutic response of enalapril in treatment of post transplant erythrocytosis

Summary: Enalapril was used for post transplant erythrocytosis (PTE) in 19 stable male hypertensive renal allograft recipients. Post transplant erythrocytosis was defined as haematocrit (Hct) >0.45 for 3 consecutive months. Dosage of enalapril was adjusted according to the blood pressure of individual patients and varied from 2.5 mg to 20 mg per day in divided doses. Patients'serum creatinine level, blood pressure and haematocrit were monitored. Therapeutic response was expressed as percentage drop in Hct (Δ%Hct). Factors affecting Δ%Hct was then determined. After 32 weeks of treatment, haematocrit fell from 0.495 ± 0.021 to 0.396 ± 0.053, which represented a 19.9% drop (paired Student's t-test, P > 0.001). With multiple regression analysis, reciprocal of plasma creatinine (RCr) prior to enalapril therapy (B = 3.40 ± 0.72, P > 0.0005), dose of enalapril adjusted with bodyweight (B = - 0.058 ± 0.020, P > 0.02, and pre-treatment haematocrit level (B = - 1.90 ± 0.71, P > 0.02) were found to be independent factors affecting Δ%Hct. We concluded that the dosage of enalapril, renal allograft function and severity of erythrocytosis were the major factors affecting the therapeutic response of PTE by enalapril treatment.     

Endocytotic uptake of small unilamellar liposomes by human trophoblast cells in culture

We evaluated the mechanism of uptake of carboxyfluorescein-containing small unilamellar liposomes of different surface charge by trophoblast cells in culture. Carboxyfluorescein-encapsulated neutral liposomes were prepared by using equimolar concentrations of lecithin and cholesterol. Anionic and cationic liposomes were prepared by adding dicetylphosphate and stearylamine. Trophoblast cells from human term placenta were cultured and incubated on the first day at 37 degrees C with liposome-encapsulated carboxyfluorescein or 500 nM of free carboxyfluorescein. The mechanism of uptake was determined by pre- treating the cells with metabolic inhibitors: 2 mM of sodium azide and 25 mM of deoxyglucose for 30 min. The uptake of liposomes was also evaluated both qualitatively under fluorescent microscope and quantitatively by measuring carboxyfluorescein fluorometrically. The uptake of free carboxyfluorescein and cationic liposomes was comparable. The anionic liposomes were taken up by the trophoblast cells more avidly than the neutral (13.2 +/- 1.6 versus 9.5 +/- 1.4%; P <0.01), cationic (2.9 +/- 0.4%; P <0.001) and the free carboxyfluorescein (2.1 +/- 0.9%; P <0.01). When cells were pre-treated with metabolic inhibitors, the uptake of anionic (5.9 +/- 1.8%; P <0.001) and neutral liposomes (4.0 +/- 0.8%; P <0.01) was significantly reduced, whereas uptake of cationic and free carboxyfluorescein remained unaltered. This study indicates that small unilamellar liposomes are internalized by the trophoblast cells in culture by an energy-dependent pathway; most probably by endocytosis. The neutral and anionic liposomes are internalized more avidly than cationic liposomes.      

Spontaneous calcific cerebral embolus

Spontaneous calcific cerebral embolus is a rare complication of calcific vascular disease such as calcified aortic plaques, and calcific aortic and mitral stenosis. Fewer than 10 case reports are described in the literature. Cerebral ischaemic symptoms may provide the indication for surgical replacement, even in the absence of valvular insufficiency or stenotic symptoms. We report a case of stroke in a young man with a known bicuspid calcific aortic valve.     

自主运动对颈源性头痛复发的预防和治疗作用

目的:观察自主运动对颈源性头痛的影响。方法:选择本科2000-08/2005-08颈源性头痛患者,纳入标准:①按诊断标准确诊为颈源性头痛。②年龄19～68岁。③愿意接受自主运动训练。排除标准:①合并心脑血管、肝、肾、造血系统严重原发性疾病或精神病患者。②合并有脊柱炎症性疾病、椎旁肿瘤及结核疾病。③未按规定治疗或资料不全者。纳入152例患者,随机分为实验组、对照组,每组76例。实验组采用牵引、手法、中药内服外敷加每天2次自主运动训练。对照组为单纯牵引、手法、中药内服外敷。疗效评定标准:有效:症状和阳性体征改善,双侧上肢肌电图由明显神经损害好转为一般损害。结果:实验组总有效率97%,对照组有效率82%,差异有显著性意义(P<0.01)。结论:自主运动训练疗法指导患者进行康复训练,对颈源性头痛有预防和治疗作用。     

体外培养人脐静脉内皮细胞在高糖状态下黏附分子表达及粒细胞黏附的性能：α-亚麻酸干预与影响

目的:观察α-亚麻酸对高糖作用下体外培养的人脐静脉内皮细胞分泌细胞间黏附分子1、血管细胞黏附分子1及中性粒细胞与人脐静脉内皮细胞黏附的影响。探讨α-亚麻酸在糖尿病血管合并症防治中的可能作用。方法:实验于2005-10/2006-09在解放军第四军医大学西京医院心血管内科实验室完成。①实验材料:α-亚麻酸由解放军第四军医大学药物研究所自花椒籽中提成,含量>91.6%;婴儿脐带(由解放军第四军医大学西京医院妇产科提供,家属知情同意,经医院伦理委员会批准)。②实验过程及分组:采用体外培养的第2～4代人脐静脉内皮细胞,分为正常对照组、高糖组及高糖组 α-亚麻酸(α-亚麻酸浓度分别为10,50,100和200μmol/L)组。各组细胞于不同培养环境中培养48h后收集标本。③实验评估:用酶联免疫吸附试验检测细胞培养上清中细胞间黏附分子1和血管细胞黏附分子1含量,计数法观察粒细胞与内皮细胞的黏附率。结果:高糖组内皮细胞分泌细胞间黏附分子1、血管细胞黏附分子1的量和粒细胞与人脐静脉内皮细胞黏附率较正常对照组增高。经较低浓度(10,50,100μmol/L)α-亚麻酸预处理18h后,细胞上清夜中细胞间黏附分子1、血管细胞黏附分子1的含量及粒细胞-内皮细胞黏附率较高糖组降低(P<0.05),尤以50μmol/L时为显著;以高浓度(200μmol/L)α-亚麻酸预处理,上清液中细胞间黏附分子1、血管细胞黏附分子1的含量和粒细胞黏附率较高糖组进一步增多。结论:高糖环境下,低浓度α-亚麻酸可抑制内皮细胞的炎性反应,发挥血管内皮保护作用;而高浓度的α-亚麻酸进一步加剧炎性反应,加重高糖对内皮细胞的损伤。     

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

Inflammation-related changes in the concentrations of kynurenine pathway metabolites occur in depression secondary to medical conditions but are not firmly established in primary mood disorders. Reductions in hippocampal and amygdalar volume that putatively reflect dendritic atrophy are widely reported in major depressive disorder (MDD). Here we tested whether the relative serum concentrations of putatively neuroprotective (kynurenic acid (KA)) and neurotoxic (3-hydroxykynurenine (3HK) and quinolinic acid (QA)) kynurenine pathway metabolites were altered in primary MDD and whether these metabolites were associated with hippocampal and amygdalar volume. A total of 29 moderately to severely depressed unmedicated subjects who met DSM-IV criteria for MDD and 20 healthy controls (HCs) completed a structural MRI scan and provided blood sample for kynurenine metabolite analysis, performed using high-performance liquid chromatography with tandem mass spectrometry. Cytokine concentrations were measured with ELISA and gray matter volumes were measured with the automated segmentation software, FreeSurfer. An a priori defined variable of interest, the KA/QA ratio, a putative neuroprotective index, trended lower in the MDD versus the HC group and correlated negatively with anhedonia but positively with the total hippocampal and amygdala volume in the MDD subjects. The post hoc data reduction methods yielded three principal components. Component 1 (interleukin-1 receptor antagonist, QA, and kynurenine) was significantly elevated in MDD participants versus the HCs, whereas component 2 (KA, tryptophan, and kynurenine) was positively correlated with hippocampal and amygdala volume within the MDD group. Our results raise the possibility that an immune-related imbalance in the relative metabolism of KA and QA predisposes to depression-associated dendritic atrophy and anhedonia.     

Hematologic engraftment and immune reconstitution posttransplantation with anti-B1 purged autologous bone marrow

Hematologic engraftment and immune reconstitution were examined in patients who received cyclophosphamide and total body irradiation therapy followed by infusion of autologous bone marrow purged with anti- B1 monoclonal antibody (MoAb) and complement as therapy for non- Hodgkin's lymphoma. Hematologic engraftment was prompt with return of greater than or equal to 0.5 X 10(3)/microL granulocytes and greater than or equal to 2 X 10(4)/microL platelets at a median of 26 and 29 days posttransplant, respectively. Immunologic reconstitution, in contrast, was prolonged. Normal numbers of circulating B cells were consistently noted by five months posttransplant, whereas return of normal immunoglobulin levels in some patients did not occur for one year. Normal numbers of T cells were evident within the first month posttransplant, but a reversed T4:T8 ratio persisted in some patients up to three years. In vitro responses of either B cells to triggers of activation or of T cells to mitogens and antigens were not normal for at least three months posttransplant. Natural killer (NK) cells predominated early after transplant and may demonstrate cytotoxicity against tumor cells. Our studies demonstrate that transplantation with anti-B1 purged autologous bone marrow results in complete hematologic and delayed immunologic engraftment. No significant acute or chronic clinical toxicities have been observed.     

Loss of Function Variants in Human PNPLA8 Encoding Calcium‐Independent Phospholipase A2γ Recapitulate the Mitochondriopathy of the Homologous Null Mouse

Mitochondriopathies are a group of clinically heterogeneous genetic diseases caused by defects in mitochondrial metabolism, bioenergetic efficiency, and/or signaling functions. The large majority of proteins involved in mitochondrial function are encoded by nuclear genes, with many yet to be associated with human disease. We performed exome sequencing on a young girl with a suspected mitochondrial myopathy that manifested as progressive muscle weakness, hypotonia, seizures, poor weight gain, and lactic acidosis. She was compound heterozygous for two frameshift mutations, p.Asn112HisfsX29 and p.Leu659AlafsX4, in the PNPLA8 gene, which encodes mitochondrial calcium‐independent phospholipase A₂γ (iPLA₂γ). Western blot analysis of affected muscle displayed the absence of PNPLA8 protein. iPLA₂s are critical mediators of a variety of cellular processes including growth, metabolism, and lipid second messenger generation, exerting their functions through catalyzing the cleavage of the acyl groups in glycerophospholipids. The clinical presentation, muscle histology and the mitochondrial ultrastructural abnormalities of this proband are highly reminiscent of Pnpla8 null mice. Although other iPLA₂‐related diseases have been identified, namely, infantile neuroaxonal dystrophy and neutral lipid storage disease with myopathy, this is the first report of PNPLA8‐related disease in a human. We suggest PNPLA8 join the increasing list of human genes involved in lipid metabolism associated with neuromuscular diseases due to mitochondrial dysfunction.