A novel age-related venous amyloidosis derived from EGF-containing fibulin-like extracellular matrix protein 1

Most intractable tissue-degenerative disorders share a common pathogenic condition, so-called proteinopathy. Amyloid-related disorders are the most common proteinopathies and are characterized by amyloid fibril deposits in the brain or other organs. Aging is generally associated with the development of these amyloid-related disorders, but we still do not fully understand how functional proteins become pathogenic amyloid deposits during the human aging process. We identified a novel amyloidogenic protein, named epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1), in massive venous amyloid deposits in specimens that we obtained from an autopsied patient who died of gastrointestinal bleeding. Our postmortem analyses of additional patients indicate that EFEMP1 amyloid deposits frequently developed in systemic venous walls of elderly people. EFEMP1 was highly expressed in veins, and aging enhanced venous EFEMP1 expression. In addition, biochemical analyses indicated that these venous amyloid deposits consisted of C-terminal regions of EFEMP1. In vitro studies showed that C-terminal regions formed amyloid fibrils, which inhibited venous tube formation and cell viability. EFEMP1 thus caused a novel age-related venous amyloid-related disorder frequently found in the elderly population. Understanding EFEMP1 amyloid formation provides new insights into amyloid-related disorders occurring during the aging process. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Assessment of cartilage repair after chondrocyte transplantation with a fibrin-hyaluronan matrix--correlation of morphological MRI, biochemical T2 mapping and clinical outcome

Objective

To evaluate change over time of clinical scores, morphological MRI of cartilage appearance and quantitative T2 values after implantation with BioCart™II, a second generation matrix-assisted implantation system.

Methods

Thirty-one patients were recruited 6–49 months post surgery for cartilage defect in the femoral condyle. Subjects underwent MRI (morphological and T2-mapping sequences) and completed the International Knee Documentation Committee (IKDC) questionnaire. MRI scans were scored using the MR Observation of Cartilage Repair Tissue (MOCART) system and cartilage T2-mapping values were registered.Analysis included correlation of IKDC scores, MOCART and T2 evaluation with each other, with implant age and with previous surgical intervention history.

Results

IKDC score significantly correlated with MOCART score (r = −0.39, p = 0.031), inversely correlated with previous interventions (r = −0.39, p = 0.034) and was significantly higher in patients with longer follow-up time (p = 0.0028).MOCART score was slight, but not significantly higher in patients with longer term implants (p = 0.199).T2 values were significantly lower in patients with longer duration implants (p < 0.001). This trend was repeated in patients with previous interventions, although to a lesser extent.

Conclusions

Significant improvement with time from BioCart™II implantation can be expected by IKDC scoring and MRI T2-mapping values. Patients with previous knee operations can also benefit from this procedure.     

Effect of apolipoprotein E (apoE) phenotype on the apoE content of CSF-HDL in children

BACKGROUND: The majority of the lipoprotein in cerebrospinal fluid (CSF) is apolipoprotein E (apoE)-containing HDL. Since neuronal cells express lipoprotein receptors which recognize apoE, apoE in CSF-HDL is believed to be important for the development of central nervous system (CNS) in children. In adults, the apoE phenotype affects the plasma apoE concentration and the epsilon 4 allele is a risk factor for Alzheimer's disease. Due to the requirement for CNS development, we examined whether the apoE phenotype affects the composition and concentration of CSF-HDL in children. METHODS: We determined the apoE phenotype in 107 neurologically normal subjects, including 67 children (<20 years), by isoelectronic focusing. We also measured apoE, total cholesterol (TC), and phospholipid (PL) concentrations in the CSF. RESULTS: The respective frequencies of apoE4/3, E3/3 and E3/2 were 16.4%, 77.6%, and 6.0%. The allele frequencies of epsilon 4, epsilon 3, and epsilon 2 were 0.082, 0.888, and 0.030, respectively. There were no significant differences in the CSF-apoE, TC, or PL concentrations or the apoE/PL ratio among the apoE phenotypes. However, the CSF-apoE/PL ratio was significantly higher in children than in adults. CONCLUSION: The apoE phenotype does not affect the composition or concentration of CSF-HDL in children. We speculate that an apoE4 carrier is prevented in childhood from the impaired development of central nervous system by CSF-HDL enriched with apoE.     

Hemostasis in patients with severe von Willebrand disease improves after normal platelet transfusion and normalizes with further correction of the plasma defect

BACKGROUND: A defective hemostatic effect of plasma concentrate infusion in patients with severe von Willebrand disease (vWD) has been ascribed to the absence of platelet von Willebrand factor (vWF) STUDY DESIGN AND METHODS: The role of platelet vWF in hemostasis of severe vWD was investigated. A plateletpheresis unit (4-5 × 10(11) platelets) from a normal compatible donor was transfused before any cryoprecipitate infusion to three type 3 vWD patients and to one patient with severe type 1 vWD with low levels of platelet vWF who required replacement therapy for bleeding episodes. Autologous platelets were transfused to one of the patients with type 3 vWD. RESULTS: Partial corrections of bleeding times (14-17 min vs. baseline>30 min) were observed in all patients after the transfusion of normal platelets. During cryoprecipitate infusion, bleeding times were normalized (<6 min), and bleeding episodes stopped when plasma levels of vWF activity ranged from 14 to 18 U per dL. Platelet interactions with the subendothelium increased in parallel with the correction of bleeding times. These results indicate that if approximately 20 percent of the total number of platelets have normal vWF antigen and if plasma vWF levels are at least 14 U per dL, then bleeding times will normalize and mucosal hemorrhages will stop. Transfusion of autologous platelets in one patient with type 3 vWD did not modify bleeding times or platelet adhesion on the subendothelium. CONCLUSION: The hemostatic effect of normal platelets in type 3 vWD seems to be related to the platelet vWF in the transfused platelets.     

Inhibition of human lymphocyte reactivity by plasma fibronectin in vitro

The effect of purified human plasma fibronectin (FN) on the reactivity of human lymphocyte-rich mononuclear cells to mitogens and allogeneic cell interactions was studied. Concentrations of FN from 25 to 100 micrograms per 250 microL of culture consistently depressed phytohemagglutinin (PHA) responses. To exert an inhibitory effect, FN must be present within 20 hours after the addition of PHA to cells, and, therefore, it appears to interfere with early events in the transformation process. Increasing the concentration of PHA failed to reduce the inhibitory effect of FN, which suggests that the depressed response was not the result of FN-PHA complex formation, which would reduce the amount of mitogen available for stimulation. This possibility was supported by the finding that FN also inhibited the mixed lymphocyte response (MLR), in a reaction that was not dependent on the activity of soluble antigen or mitogen. In contrast, the stimulation of lymphocytes to undergo transformation that is induced by the nonlectin mitogen, sodium periodate, was unaffected by FN. Periodate-treated cells are, however, already stimulated to undergo transformation, prior to their exposure to FN. FN did not interfere with the activity of interleukin-2, nor did it indirectly regulate lymphocyte responses by modifying the production and/or effect of humoral regulatory factors released from the adherent accessory cells (macrophages). These studies show that FN is a potent immunosuppressive agent in vitro.     

多孔髓芯减压联合干细胞移植治疗股骨头坏死的早期随访结果

目的:探讨多孔髓芯减压联合自体骨髓干细胞移植治疗股骨头坏死的疗效及临床分析。方法:选择2003-02/2006-12在南京医科大学附属南京第一医院骨关节中心采用多孔髓芯减压联合干细胞移植治疗的股骨头坏死患者22例,共28髋,年龄17～48岁,根据世界骨循环研究学会(ARCO)的国际骨坏死分期标准:Ⅰ期13髋,Ⅱ期11髋,Ⅲ期4髋。长期使用激素史9例,长期酗酒史6例,外伤史5例,原因不明者2例。纳入标准:有髋关节疼痛,功能受限;经髋关节X射线片及MRI检查确诊;ARCO分期Ⅰ～Ⅲ期;患者知情同意并签署知情同意书。排除标准:其他髋关节疾病。自患者髂前上棘处行骨髓穿刺分离与培养骨髓间充质干细胞。取患肢大粗隆下大腿外侧纵向直切口约3.0cm,钝性分离至股骨,在C形臂机引导下自股骨头中心钻入3枚直径4.0mm斯氏针,选位置较好的斯氏针,将直径约8.0mm特制套管在斯氏针的引导下钻至股骨头关节软骨面下1.0～2.0mm,不穿破关节面。将一长注射器针头置入股骨头坏死中心,立即行X射线正侧位摄片,确保针头位于股骨头内,从针头向股骨头内加压注入自体骨髓间充质干细胞悬液1.5～2.0mL。术后12个月随访,每3个月1次,随访时门诊复查,拍正、侧位和蛙式位X射线片,行MRI检查,观察病情变化。使用髋关节Harris评分进行疗效评价,>90分为优,75～90分为良,60～74分为可,<60分评定为差。若Harris评分提高,X射线骨形态变化改善及MRI股骨头坏死区体积变小可认为联合治疗有效。结果:①22例患者均完成随访,进入结果分析。②随访3个月时X射线及MRI检查:2例(2髋)激素引起的Ⅲ期患者股骨头发生进一步变形及塌陷,其余患者在随访期间未出现严重并发症,不良反应及病情恶化。股骨头坏死体积由术前31.07%减小到17.46%。激素组治疗前后股骨头坏死体积差值小于外伤、酗酒组,就本随访资料而言激素组疗效不如外伤及酗酒组。③随访12个月Harris评分:由术前54.3上升到84.6,有较明显提高,其中优7髋(25.0%),良15髋(53.6%),可4髋(14.3%),差2髋(0.07%)。结论:多孔髓芯减压联合干细胞移植是治疗股骨头坏死的一种新手段,尤其适合于年青、ARCO-Ⅰ或Ⅱ期、非激素导致的股骨头坏死治疗。