藏药七十味珍珠丸对阿尔茨海默病小鼠模型脑组织Aβ表达的影响

目的 观察藏药七十味珍珠丸(ratanasampil,RNSP)对阿尔茨海默病(AD)转基因鼠脑组织β-淀粉样蛋白(Aβ1-40和Aβ1-42)生成和改善认知功能的作用.方法 利用Y-迷宫明暗分辨学习和旷场实验来观察23只13～14月龄雌性阿尔茨海默病转基因鼠(Tg2576)和同龄雌性BL6×SJL非转基因鼠(NTg)的学习记忆功能和焦虑水平.治疗组选取6只Tg2576鼠和5只NTg鼠给予七十味珍珠丸用针管灌胃1 μl(0.14 mg/d),每天1次,连续用药8周;对照组选取7只Tg2576鼠和5只NTg鼠用蒸馏水和芝麻油各0.5 μl混匀后用针管灌胃1 μl,每天1次,连续用药8周.用蛋白印迹法和酶标免疫吸附测试法联合测定鼠脑组织β淀粉样蛋白(Aβ1-40和Aβ1-42)以及人鼠嵌合型跨膜蛋白淀粉样前体蛋白(β-amyloid precursor protein,APP)的蛋白含量,采用免疫组织化学法观察Aβ在鼠脑海马和大脑皮质的表达.结果 通过Y-迷宫明暗分辨学习测试,Tg2576鼠治疗组达标所需要的训练时间(34.23±9.65)s,比Tg2576鼠对照组(52.35±12.50)s显著降低;t=5.871,P＜0.01.与Tg2576鼠对照组比较,旷场实验测定结果显示Tg2576鼠治疗组在中央格停留时间明显减低[(4.70±3.56)s和(12.91±9.02)s;t=3.465,P＜0.01],跨格次数和站立次数增加[(85.33±17.64)次和(56.25±13.86)次;(57.67±17.08)次和(20.63±17.39)次;t=8.200,3.093,P＜0.01,P＜0.05],粪便排泄次数也明显减少[(1.17±0.56)次和(3.38±0.86)次;t=2.231,P＜0.05].两对照组比较,Tg2576鼠达标所需要的训练时间延长[(52.35±12.25)s和(37.03±8.98)s;t=3.131,P＜0.05],在中央格停留时间NTg较长,跨格次数和站立次数减少[(12.91±9.02)s和(5.24±5.88)s;(56.25±13.86)次和(82.75±22.54)次;(20.63±17.39)次和(53.50±13.94)次;P均＜0.05].上述训练项目NTg鼠在治疗组和对照组之间差异均无统计学意义.蛋白印迹法和酶标免疫吸附测试法联合结果显示Tg2576治疗组的脑组织内Aβ1-40和Aβ1-42含量均较对照组显著减低;通过RNSP治疗8周后Aβ42/Aβ40比率低于对照组(P＜0.05);但对Tg2576脑APP的表达未能减低.RNSP能够明显减少大脑皮质和海马周围老年淀粉样斑块的数目和面积.结论 藏药七十味珍珠丸可能通过减少Tg2576转基因鼠脑内Aβ1-40和Aβ1-42水平抑制老年斑的形成来改善转基因鼠学习空间记忆和探索运动能力,减少焦虑行为的发生.     

Imaging of amyloid beta in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism

BACKGROUND: Amyloid-beta (Abeta) plaque formation is a hallmark of Alzheimer's disease (AD) and precedes the onset of dementia. Abeta imaging should allow earlier diagnosis, but clinical application is hindered by the short decay half-life of current Abeta-specific ligands. (18)F-BAY94-9172 is an Abeta ligand that, due to the half-life of (18)F, is suitable for clinical use. We thus studied the effectiveness of this ligand in identifying patients with AD. METHODS: 15 patients with mild AD, 15 healthy elderly controls, and five individuals with frontotemporal lobar degeneration (FTLD) were studied. (18)F-BAY94-9172 binding was quantified by use of the standardised uptake value ratio (SUVR), which was calculated for the neocortex by use of the cerebellum as reference region. SUVR images were visually rated as normal or AD. FINDINGS: (18)F-BAY94-9172 binding matched the reported post-mortem distribution of Abeta plaques. All AD patients showed widespread neocortical binding, which was greater in the precuneus/posterior cingulate and frontal cortex than in the lateral temporal and parietal cortex. There was relative sparing of sensorimotor, occipital, and medial temporal cortex. Healthy controls and FTLD patients showed only white-matter binding, although three controls and one FTLD patient had mild uptake in frontal and precuneus cortex. At 90-120 min after injection, higher neocortical SUVR was observed in AD patients (2.0 [SD 0.3]) than in healthy controls (1.3 [SD 0.2]; p<0.0001) or FTLD patients (1.2 [SD 0.2]; p=0.009). Visual interpretation was 100% sensitive and 90% specific for detection of AD. INTERPRETATION: (18)F-BAY94-9172 PET discriminates between AD and FTLD or healthy controls and might facilitate integration of Abeta imaging into clinical practice.     

Generation of CD1+RelB+ dendritic cells and tartrate-resistant acid phosphatase-positive osteoclast-like multinucleated giant cells from human monocytes

We previously showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) stimulate the differentiation of human monocytes into two phenotypically distinct types of macrophages. However, in vivo, not only CSF but also many other cytokines are produced under various conditions. Those cytokines may modulate the differentiation of monocytes by CSFs. In the present study, we showed that CD14+ adherent human monocytes can differentiate into CD1+relB+ dendritic cells (DC) by the combination of GM-CSF plus interleukin-4 (IL-4) and that they differentiate into tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like multinucleated giant cells (MGC) by the combination of M-CSF plus IL-4. However, the monocyte-derived DC were not terminally differentiated cells; they could still convert to macrophages in response to M-CSF. Tumor necrosis factor-alpha (TNF-alpha) stimulated the terminal differentiation of the DC by downregulating the expression of the M-CSF receptor, cfms mRNA, and aborting the potential to convert to macrophages. In contrast to IL-4, interferon-gamma (IFN-gamma) had no demonstrable effect on the differentiation of monocytes. Rather, IFN- gamma antagonized the effect of IL-4 and suppressed the DC and MGC formation induced by GM-CSF + IL-4 and M-CSF + IL-4, respectively. Taken together, these results provide a new aspect to our knowledge of monocyte differentiation and provide evidence that human monocytes are flexible in their differentiation potential and are precursors not only of macrophages but also of CD1+relB+DC and TRAP-positive MGC. Such a diverse pathway of monocyte differentiation may constitute one of the basic mechanisms of immune regulation.     

Factor VIII-von Willebrand factor requires calcium for facilitation of platelet adherence

The role of divalent cations in platelet adherence to deendothelialized human arteries in flowing blood was investigated in an annular perfusion chamber. Spreading of platelets on the subendothelium was impaired below 30 microM of free Ca2+ ions (Ca2+). When Ca2+ was replaced by Mg2+, adherence was unchanged in perfusates without exogenous factor VIII-von Willebrand factor (FVIII-vWF), but the ability of FVIII-vWF to support platelet adherence was lost. Binding of FVIII-vWF to the vessel wall was independent of divalent cations, but bound FVIII-vWF was only able to mediate adherence after exposure to Ca2+. Pretreatment of FVIII-vWF with the calcium chelator EGTA (10 mM) resulted in loss of the ability to facilitate platelet adherence, while the ristocetin cofactor activity remained intact. Full restoration of the ability to mediate platelet adherence could only be obtained by prolonged dialysis against Ca2+ in the millimolar range. These data indicate that divalent cations have at least two separate roles to play in supporting platelet adherence: (1) platelet spreading on the subendothelium requires Ca2+ or Mg2+; (2) FVIII-vWF should be exposed to Ca2+ to obtain its optimal biologic activity in supporting platelet adherence.     

Effects of positive and negative pressure ventilation on cerebral blood volume of newborn infants

The effects of intermittent positive airway and continuous negative extrathoracic pressure ventilation on cerebral blood volume in preterm infants were studied using near infrared spectroscopy. In 12 infants continuous negative extrathoracic pressure caused a median decrease in cerebral blood volume of 0.14ml/100ml brain (95% confidence intervals (CI) 0.035–0.280) compared with no respiratory support. Oxygenated and deoxygenated haemoglobin also decreased, implying increased venous drainage as the main effect. In 17 infants intermittent positive pressure ventilation also caused a median reduction in cerebral blood volume of 0.06 ml/100 ml brain (95% CI 0.010–0.115) compared with endotracheal positive airway pressure. Deoxygenated haemoglobin increased by 0.07 ml/100 ml brain (95% CI 0.010–0.100) while oxygenated haemoglobin decreased by O.lOml/lOOml brain (95% CI 0.005–0.175). The increase in deoxygenated haemoglobin implies decreased venous drainage and the decrease in oxygenated haemoglobin implies that other factors may also be significant. Heart rate, blood pressure and oxygen saturation were monitored continuously and remained stable.     

Exceptional sensitivity of testicular germ cell tumour cell lines to the new anti-cancer agent, temozolomide.

Metastatic testicular germ cell tumours are cured in approximately 85% of patients using cisplatin-based combination chemotherapy. Patients who fail to respond have a poor prognosis, and there is a need for more effective treatments for cisplatin-resistant disease. In this study, it is shown that two of four cell lines derived from human non-seminomatous testicular germ cell tumours are exceptionally sensitive to temozolomide, a new imidazotetrazine which can cross the blood-brain barrier in mice. In addition, three pairs of cisplatin-resistant sublines show little cross-resistance to temozolomide. These data suggest that temozolomide might have activity against non-seminomatous testicular germ cell tumours which have relapsed following cisplatin-containing chemotherapy, and could have a role in the treatment of patients with metastatic lesions in the brain.     

The selenium status of children with phenylketonuria: results of selenium supplementation

The selenium status of children with phenylketonuria on a synthetic low phenylalanine diet was assessed. Correlation between blood selenium and red cell glutathione peroxidase was unsatisfactory (r = 0.65) due to the poor discrimination of red cell glutathione peroxidase with a low selenium diet. No symptoms of deficiency were observed. Supplementation with 50 micrograms per week of selenium as brewers yeast tablets over a period of 6 months significantly increased the blood selenium of the phenylketonuric children. Plasma Vitamin E levels were within normal limits. The supplementation effectively doubled their selenium intake to 15-17 micrograms per day, which is probably sufficient for this group with an adequate Vitamin E status, though considerably lower than the recommended minimum intake of 50 micrograms per day.