The effect of enzyme replacement therapy on clinical outcomes in female patients with Fabry disease – A systematic literature review by a European panel of experts

BackgroundHeterozygous females with Fabry disease have a wide range of clinical phenotypes depending on the nature of their mutation and their X-chromosome inactivation pattern; it is therefore important to examine outcomes of enzyme replacement therapy (ERT) in the female patient population specifically. This paper presents the findings of a systematic literature review of treatment outcomes with ERT in adult female patients.MethodsA comprehensive systematic literature review was conducted through January 2017 to retrieve published papers with original data on ERT in the treatment of Fabry disease. The review included all original articles that presented ERT outcomes data on patients with Fabry disease, irrespective of the study type.ResultsClinical evidence for the efficacy of ERT in female patients was available from 67 publications including six clinical trial publications, and indicates significant reductions in plasma and urine globotriaosylceramide (GL-3) accumulation (in female patients with elevated pre-treatment levels) and improvements in cardiac parameters and quality of life (QoL). To date, data are insufficient to conclude on the effects of ERT on the nervous system, gastrointestinal manifestations, and pain in female patients with Fabry disease.ConclusionsThis review of available literature data demonstrates that ERT in adult female patients with Fabry disease has a beneficial effect on GL-3 levels and cardiac outcomes. The current evidence also suggests that ERT may improve QoL in this patient population, though further studies are needed to examine these results.     

基于网络药理学探究兰艾双香方治疗细菌感染的机制研究*

目的 旨在通过网络药理学的研究方法寻找兰艾双香方在治疗细菌感染方面存在的潜在的分子机制及相关分子通路,为进一步研究兰艾双香方提供理论依据。方法 通过中药数据分析平台（TCMSP）筛选兰艾双香方的活性成分及对应靶点,对兰艾双香方进行复方成分分析,利用Cytoscape软件构建兰艾双香方治疗细菌感染的“单味药-活性成分-作用靶点”网络,再通过Gene Cards,OMIM和DigSee 3个数据库整合细菌感染的相关靶点,将靶点数据导入jvenn平台做出韦恩图,导入String平台得到PPI,导入Metascape中对兰艾双香方治疗细菌感染的作用靶点进行GO功能富集分析和KEGG通路富集分析,根据KEGG富集得到的通路绘制相关气泡图,将KEGG分析得到的通路导入Cytoscape软件构建“靶点通路”网络。结果 ①筛选得到兰艾双香方共110个药效成分和1 788个作用靶点,关键靶点包括过氧化物酶体增殖物激活受体、血管内皮生长因子A、肿瘤坏死因子和表皮生长因子受体等;②细菌感染相关靶点1 442个;③蛋白互作核心网络共97个蛋白,分析得到4个蛋白模块;④获得2 401个GO生物过程,KEGG通路富集筛选得到324条相关信号通路,通路类型包括癌症的路径、糖尿病并发症中的AGE-RAGE信号通路、乙型肝炎、肿瘤坏死因子信号通路、小细胞肺癌、利什曼病、HIF-1信号通路、军团杆菌病等,这些通路均与细菌感染的发生发展相关;⑤结果证实,兰艾双香方可能通过调节细胞代谢、增殖与凋亡、脂代谢等多种途径达到治疗细菌感染的目的,该目的是多成分、多靶点和多通路相互作用的结果。结论 兰艾双香方在癌症、糖尿病和乙型肝炎疾病进展过程中并发细菌感染的治疗可能有更好的疗效。     

Changes in bone mass,biomechanical properties,and microarchitecture of calcium- and iron-deficient rats fed diets supplemented with inulin-type fructans

Feeding mineral-deficient diets enhances absorptive efficiency as an attempt of the body to compensate for the lack of an essential nutrient. Under certain circumstances, it does not succeed; and nutritional deficiency is produced. Our hypothesis was that inulin-type fructans (ITF), which are known to affect mineral absorption, could increase Ca and Fe bioavailability in Ca- and Fe-deficient rats. Male Wistar rats (n = 48, 4 weeks old) were assigned to 1 of 8 groups derived from 2 × 2 × 2 factorial design with 2 levels of added Fe (0 and 35 mg/kg), Ca (0 and 5 g/kg), and ITF (0 and 100 g/kg) for 33 days. The Fe status (hemoglobin, serum Fe, total Fe-binding capacity, transferrin saturation, liver minerals) was evaluated. Tibia minerals (Ca, Mg, and Zn), bone strength, and histomorphometry were determined. In nondeficient rats, ITF supplementation did not affect Fe status or organ minerals, with the exception of tibia Mg. Moreover, ITF improved bone resilience and led to a reduction in eroded surface per body surface and number of osteoclasts per area. In Ca-deficient rats, ITF increased liver (Fe and Zn) and tibia (Zn) mineral levels but impaired tibia Mg, yield load, and resilience. In conclusion, ITF worsened the tibia Mg levels and elastic properties when supplemented in Ca-deficient diets. In contrast, although bone Ca was not affected in nondeficient rats under the present experimental conditions, bone quality improved, as demonstrated by a moderate reduction in femur osteoclast resorption and significant increases in tibia Mg content and elasticity.     

大鼠蛛网膜下腔出血致多器官功能障碍综合征延髓内脏带FOS蛋白的表达及迷走神经的作用研究

目的 观察大鼠蛛网膜下腔出血(SAH)致多器官功能障碍综合征(MODS)并/不并迷走神经切断时延髓内脏带(MVZ)FOS蛋白的表达规律,探讨MVZ和迷走神经在SAH致MODS中的可能调控机制.方法 Willis环注血法建立SAH致MODS模型,膈下迷走神经切断法阻断迷走神经,免疫组织化学法检测MVZ内FOS蛋白的表达.结果 (1)SAH组和SAH+SDV组MVZ内FOS阳性表达明显高于正常对照组、假手术组、SDV组(P<0.01).但SAH+SDV组明显少于SAH组(P<0.01),两组FOS蛋白表达均在24h达峰.(2)SAH组和SAH+SDV组各时相点各脏器存在不同程度的炎性损害,以24～36h病理改变最显著,与FOS蛋白的表达峰值一致,而且SAH+SDV组的炎性损害较SAH组更明显、持久.结论 (1)SAH后各周围脏器的炎性改变与MVZ内FOS蛋白的表达规律相一致,提示MVZ参与了SAH后周围脏器功能的调控,是SAH致MODS的直接调控中枢之一;(2)膈下迷走神经切断增加了SAH后MODS的发生率,增强了SAH所致的周围脏器的炎性损害,提示迷走神经在SAH致MODS时对周围脏器具有潜在的保护作用.

Abstract：

Objective To investigate FOS protein expression in the medullary visceral zone( MVZ) of the rats following subarachnoid hemorrhage ( SAH) complicated with multiple organ dysfunction syndrome ( MODS ) which complicated or uncomplicated by vagotomy,and to discuss the possible pathogenesis of MVZ and vagus nerve in the rats following SAH complicated with MODS. Methods SAH was induced in rats by injecting arterial blood through the circle of willis. The vagus never was blocked in rats from subdlaphragamatic vagotomy. The area density of positive staining expressing FOS protein were analyzed for the relative content of immunohistochemistry. Results (1) In the MVZ, the expression in FOS protein in SAH and SAH + SDV groups were all obviously more than control group, sham-operative group and SDV group ( P < 0. 01). But the expression in SAH + SDV group were fewer and sparser than SAH group( P < 0. 01) . FOS protein expressed in SAH and SAH + SDV groups showed time progress and reached peak at 24h after SAH. (2) After SAH there are various inflammatory lesions on the organ tissue at every time point in SAH group and SAH + SDV group. The organ has significantly pathological changes at 24 ～ 36h point which is at equal pace the regularity of the expression of FOS protein. But the inflammatory lesions in SAH + SDV group was more serious and persistent than that in SAH group. Conclusions ( 1) There was the consistency between FOS protein expression and histological changes of each organ after SAH. It cued that MVZ may be one of the direct regulative centre after SAH by MODS. ( 2 ) Subdlaphragamatic vagotomy can add the incidences of MODS after SAH and can aggravate the imflamming lesions of peri-organs. Vagus never can protect peri-organs potatially when SAH complicated by MODS.     

Locust bean gum safety in neonates and young infants: An integrated review of the toxicological database and clinical evidence

Locust bean gum (LBG) is a galactomannan polysaccharide used as thickener in infant formulas with the therapeutic aim to treat uncomplicated gastroesophageal reflux (GER). Since its use in young infants below 12 weeks of age is not explicitly covered by the current scientific concept of the derivation of health based guidance values, the present integrated safety review aimed to compile all the relevant preclinical toxicological studies and to combine them with substantial evidence gathered from the clinical paediatric use as part of the weight of evidence supporting the safety in young infants below 12 weeks of age. LBG was demonstrated to have very low toxicity in preclinical studies mainly resulting from its indigestible nature leading to negligible systemic bioavailability and only possibly influencing tolerance. A standard therapeutic level of 0.5 g/100 mL in thickened infant formula is shown to confer a sufficiently protective Margin of Safety. LBG was not associated with any adverse toxic or nutritional effects in healthy term infants, while there are limited case-reports of possible adverse effects in preterms receiving the thickener inappropriately. Altogether, it can be concluded that LBG is safe for its intended therapeutic use in term-born infants to treat uncomplicated regurgitation from birth onwards.     

FOS蛋白在胶质瘤中的表达及其对胶质瘤细胞生长的影响

目的 探讨FOS蛋白在胶质瘤中的表达及其对胶质瘤细胞生长的影响.方法 用免疫组化染色法检测FOS蛋白在各级别胶质瘤组织中的表达水平.应用RNA干扰技术降低FOS表达后,应用四甲基偶氮唑盐微量酶反应比色法和流式细胞技术检测胶质瘤细胞的增殖和周期的改变;应用Transwell实验检测胶质瘤细胞侵袭能力的改变;采用Western印迹法检测FOS下游功能蛋白的变化.结果 胶质瘤组织中FOS的表达随着级别的增高而增高;抑制FOS的表达后,U87和U251细胞生长受抑制,细胞生长阻滞在G1期且细胞侵袭能力下降,下游的功能蛋白CyclinD1和MMP9表达水平降低.结论 FOS在胶质瘤中高表达;抑制其表达可以下调功能蛋白CyclinD1和MMP9的表达,进而调控细胞的生长和侵袭能力.     

甜味觉对大鼠杏仁中央核神经肽Y及FOS表达的影响

[目的]观察刺激SD大鼠甜味觉后杏仁中央核内神经肽Y（NPY）及FOS表达情况。[方法]选取成年健康SD大鼠16只,随机分为两组,给实验组大鼠摄入15 mL蔗糖溶液,给对照组SD大鼠摄入15 mL蒸馏水,2h后应用免疫组织化学方法观察杏仁中央核内NPY及FOS表达。[结果]与对照组相比,实验组大鼠蔗糖甜味觉刺激后引起杏仁中央核内NPY及FOS表达显著增多。[结论]甜味觉食物的促食欲作用可能与其激活了杏仁中央核内的NPY能神经元使NPY表达上调有关。     

异丙酚诱导大鼠中枢FOS核蛋白表达的研究

目的　通过检测异丙酚静脉全麻诱导大鼠中枢FOS核蛋白的表达 ,明确静脉全身麻醉的中枢作用位点。方法　 2 1只Wistar大鼠随机分成 3组 :对照组 (C组 )腹腔注入生理盐水 2ml,异丙酚组 (P组 )腹腔注入异丙酚 10 0mg kg ,异丙酚作用后断尾刺激组 (S组 )。 1h后应用FOS蛋白免疫组织化学法 (ABC法 ) ,检测FOS免疫反应 (FOS IR ,immunityreactionofFOS)阳性神经元在大脑的分布。结果　C组可见部分散在FOS IR阳性神经元分布 ,P组FOS IR阳性神经元数比C组明显增多 (P <0 .0 1) ,并呈核特异性分布 ,S组在杏仁基底外侧核、丘脑室旁核、外侧缰核及海马回嗅觉小岛等核团发现FOS IR阳性神经元较P组分布增多 (P <0 .0 1)。结论　异丙酚在大鼠中枢神经系统有与其静脉麻醉作用相关的神经核团。