Vascular endothelial growth factor (VEGF), an angiogenic factor with neuroprotective effects: The VEGF was initially characterized by its vasculogenic and angiogenic activities and its capacity to promote vascular permeability (Yancopoulos et al., 2000). VEGF is also known as VEGF-A and is the prototype member of a related group of five trophic factors,VEGF-B, VEGF-C, VEGF-D and placental growth factor (PlGF; Lange et al., 2016). Interestingly, VEGF-B shares a high degree of homology with VEGF but, in contrast to VEGF, has low angiogenic activity and is not pro-in fl ammatory. VEGF-A binds to two tyrosine quinase receptors,named VEGFR-1 and VEGFR-2, and also to the coreceptor neuropilin-1.By contrast, VEGF-B only binds to the tyrosine kinase receptor VEGFR-1 and also to the coreceptor neuropilin-1 (Lange et al., 2016).

Nowadays, it is emerging that, in addition to its vascular actions, VEGF also has a signi fi cant impact on neurons by protecting them from trauma or disease. Thus, the administration of VEGF, both in vitro and in vivo through different delivery procedures, prevents or delays the death of neurons exposed to different types of insult (Lange et al., 2016). Since the knockout mice for VEGF is not viable, leading to embryonic lethality due to insufficient development of the vascular system, cardiovascular researchers designed a mutant mice with low levels of VEGF by deleting the hypoxia response element in the promoter region of the VEGF gene. Unexpectedly, these mutant mice developed an adult-onset muscle weakness accompanied by motoneuron degeneration that resembled the human disease amyotrophic lateral sclerosis (Oosthuyse et al., 2001). This work provided a novel insight to explain motoneuron degeneration in amyotrophic lateral sclerosis, since it established, for the fi rst time, a link between low levels of VEGF and motoneuron atrophy or death. Studies of cerebrospinal fl uid samples obtained from patients suffering amyotrophic lateral sclerosis, or post-mortem investigation of human spinal cord have also con fi rmed a correlation between low levels of VEGF and/or its receptors and amyotrophic lateral sclerosis (Sathasivam, 2008).

In this line, it was expected that the administration of VEGF in animal models of motoneuron degeneration might lead to neuroprotective effects.Several experiments indeed confirmed this possibility. When mice that overexpress VEGF (VEGF+/+) were crossed with the mutant mice G93A superoxide dismutase 1 (SOD1G93A), a classical model of amyotrophic lateral sclerosis, the double-transgenic mice showed delayed motoneuron loss and prolonged survival as compared to the SOD1G93A single-transgenic mice.Similar results were obtained when VEGF was injected intrathecally using an adeno-associated virus vector (Wang et al., 2016). Moreover, VEGF delivery with retrogradely transported lentivector to SOD1G93A mice also delayed the onset of the disease, slowed the progression of motoneuronal degeneration and increased life expectancy (Azzouz et al., 2004). Using a different model of motoneuron degeneration, it has also been shown that the chronic administration of VEGF in the spinal cord through a miniosmotic pump prevents the paralysis and motoneuronal death in rats exposed to excitotoxic motoneuron damage (Tovar-y-Romo et al., 2007). It is important to emphasize that VEGF can also exert neuroprotective roles in other neuronal types following different types of insult, such as ischemia,seizures, or neurological diseases (Lange et al., 2016).

足的纵弓和横弓出现塌陷或消失，或者比正常人低，就是扁平足。与其说扁平足是一种疾病倒不如说是一种状态。父母不必过度担心。大多数的扁平足并不会引起疼痛，更不会影响行走和体育活动。

VEGF neurophysiological effects on motoneurons: All these investigations have led to the statement that VEGF can be considered as a neurotrophic factor, especially for motoneurons, and have promising implications for the use of VEGF in the treatment of motoneuron disease.However, although it seems clear that VEGF can rescue vulnerable motoneurons from cell death, nothing is known about the physiological state in which these “rescued” motoneurons remain, for example, do they receive the same synaptic inputs or, on the contrary, do they lose afferent boutons as happens in severed motoneurons? Do these VEGF-treated motoneurons retain normal discharge characteristics or, rather, do they exhibit an altered firing? Damaged motoneurons not only need to be protected from cell death or atrophy, but should also maintain a normal synaptic complement and fi ring properties if VEGF treatment is expected to lead to functional recovery. We have pursued these questions recently (Calvo et al., 2018) in the chronic alert animal preparation, using the abducens motoneurons as the experimental model. It should be mentioned that although extraocular motoneurons, located in the abducens, trochlear and oculomotor nuclei,are more resistant to amyotrophic lateral sclerosis, they also exhibit some signs of degeneration and cell death at later stages of the disease.

Previous studies in our research group have also supplied axotomized abducens motoneurons with different neurotrophic factors, i.e., nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophic-3 (NT-3). Interestingly, neither of these factors yielded a complete recovery in fi ring and synaptic inputs after lesion. Thus, BDNF recovered only the tonic component of the discharge, whereas NT-3 recovered only the phasic fi ring (Davis-López de Carrizosa et al., 2009). These fi ndings indicate that these two factors produced only a partial recovery.NGF administration yielded very peculiar results in axotomized abducens motoneurons, yielding to high eye position and velocity sensitivities and an irregular firing rate (Davis-López de Carrizosa et al., 2010) (Figure 1). Although the administration of neurotrophins (NGF, BDNF or NT-3)or other neurotrophic factors stimulates motoneuron survival in amyotrophic lateral sclerosis mouse models, the loss of these factors does not cause adult-onset motoneuron degeneration resembling the disease, so that muscle paralysis and motoneuron degeneration are not induced in mice lacking these factors (Lange et al., 2016). In contrast, VEGF de fi cit leads to the development of amyotrophic lateral sclerosis-like motoneuron degeneration and paralysis. Altogether, these fi ndings strongly suggest that VEGF might be the crucial neurotrophic factor for the maintenance of a normal physiology in motoneurons.

Abducens motoneurons innervate the extraocular lateral rectus muscle.Their discharge correlates with eye movements in the horizontal plane.These motoneurons show a typical tonic-phasic fi ring pattern, thus having eye position and eye velocity sensitivities. Following axotomy, the discharge of abducens motoneurons shows several alterations such as an overall reduction in fi ring rate and a signi fi cant reduction in eye position and velocity sensitivities. Moreover, axotomy is followed by the withdrawal of synaptic boutons and a reduction in the efficacy of synaptically-driven signals (Davis-López de Carrizosa et al., 2009, 2010). Our recent study(Calvo et al., 2018) indicates that VEGF administration at the time of axotomy completely prevents the lesion-induced alterations in the discharge pattern as well as the synaptic stripping. If VEGF is administered after a delayed period of axotomy, this factor is able to recover the physiological activity of abducens motoneurons (both the tonic and the phasic components) and their synaptic inputs. To the best of our knowledge, this is the fi rst study demonstrating that a single neurotrophic factor is able to recover lesion-induced alterations in the discharge pattern and synaptic complement of motoneurons from a multidisciplinary approach that includes physiological and morphological experiments.

orcid: 0000-0002-6213-7454 (Angel M. Pastor)

Figure 1 Schematic diagram comparing the results obtained after different neurotrophic factor administration on axotomized abducens motoneurons.

In each panel, from top to bottom: experimental situation, eye position,and associated firing rate.(A) Control motoneurons show a typical tonic-phasic discharge proportional to eye position and velocity.(B) Axotomy decreases the discharge, affecting both the tonic and the phasic components. (C) Brain-derived neurotrophic factor(BDNF) administration recovers essentially the tonic fi ring. (D) Neurotrophic-3(NT-3) treatment restores basically the phasic activity. (E) Nerve growth factor(NGF) increases both the tonic and the phasic components as well as discharge variability over control values. (F) Vascular endothelial growth factor (VEGF) treatment completely recovers the fi ring pattern of axotomized motoneurons to control values.

It has been hypothesized that VEGF can mediate its trophic actions by two possible mechanisms: i) acting as an angiogenic factor, VEGF can increase the supply of oxygen and nutrients to lesioned motoneurons, and ii)as a direct neurotrophic factor for motoneurons (Oosthuyse et al., 2001; Azzouz et al., 2004). It has been demonstrated that VEGF only induces angiogenic response in the central nervous system after the administration of extremely large doses. Thus, a dose-dependent study in ischemic rat brain has shown that low (2 μg/7 days) and intermediate (8 μg/7 days) doses of VEGF are not followed by angiogenesis, whereas a high dose (60 μg/7 days) does induce a powerful angiogenic response (Manoonkitiwongsa et al., 2004).Most of the authors who have applied VEGF exogenously to damaged neurons have used doses close to the low one (2 μg/7 days; (Tovar-y-Romo et al., 2007; Lange et al., 2016; Calvo et al., 2018) and have found neuroprotective effects. Altogether, it can be concluded that the neurotrophic and synaptotrophic effects of VEGF are due to a direct action on neurons.

VEGF-B is neuroprotective and non-angiogenic: There is less information regarding the effects of VEGF-B on damaged neurons as compared to VEGF-A. However, recent evidence points to a direct neuroprotective role of VEGF-B in degenerating motoneurons, with the advantage, in relation to VEGF, of not producing vascular side effects, such as inflammation and tissue edema (Poesen et al., 2008). We have also checked the effects of VEGF-B administration to axotomized abducens motoneurons using the same experimental approach as described above. We found that VEGF-B treatment also prevented axotomy-induced alterations (Calvo et al., 2018).This fi nding is of great clinical relevance because the angiogenic and permeability-promoting activity of VEGF precludes unrestricted delivery at high doses. In contrast, VEGF-B does not induce any vascular side effects, and exerts similar neurotrophic effects with a greater safety, therefore, providing an attractive alternative to VEGF for the treatment of motoneuron diseases.

b、退出保护装置中控制回路断线告警H92保护定值。需出新定值单，将 H92 控制回路断线告警由ON改为OFF。此时控制回路断线由位置接点的硬接点信号W135上送后台，保护装置逻辑不再判控制回路断线。

VEGF neurophysiological actions mediated through its receptors:VEGF binds to two tyrosine kinase receptors, VEGFR-1 and VEGFR-2.Both receptors are present in abducens motoneurons. We found that the selective blockage of VEGFR-2 with the inhibitor SU 1498 prevented the full recovery of abducens motoneuron discharge after axotomy during spontaneous, but not during vestibularly-induced, eye movements (Calvo et al., 2018). These data are in congruence with previous fi ndings indicating that both the vascular and neural effects induced by VEGF are mediated mainly through VEGFR-2 (Lange et al., 2016). On the other hand,VEGF-B only binds to VEGFR-1 and we found that VEGFR-1 prevented abducens motoneurons to enter into an axotomy-like mode of discharge maintaining fi ring characteristics similar to control during both spontaneous and vestibularly-induced eye movements (Calvo et al., 2018). Since spontaneous and vestibular driven-signals arise from different sources of afferent to abducens motoneurons, our data suggest that signaling through VEGFR-1 or VEGFR-2 could mediate synaptotrophic actions preferentially on different synaptic inputs. VEGF and VEGF-B can also bind to another membrane protein named neuropilin-1. A widely accepted mechanism of action of neuropilin-1 is the formation of VEGF-dependent complexes of VEGFR-1 or VEGFR-2 with neuropilin-1. Through these complexes,neuropilin-1 would act as a co-receptor of VEGFR-1 or VEGFR-2, enhancing the signaling activity and biological function of VEGF. However, other studies suggest the possibility that neuropilin-1 can signal independently of VEGFR-1 or VEGFR-2 acting as a receptor by itself (Lange et al., 2016).Abducens motoneurons express neuropilin-1 so it would be interesting to analyze the possible physiological role of neuropilin-1 in our model.

doi: 10.4103/1673-5374.235024

Accepted: 2018-05-24

＊Correspondence to: Angel M. Pastor, Ph.D., ampastor@us.es.

Paula M. Calvo, Angel M. Pastor＊, Rosa R. de la Cruz

Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain

This work was supported by Ministerio de Economía y Competitividad-FEDER (Grant reference: BFU2015-64515-P) in Spain. PMC was a scholar of MEC (BES-2016-077912) in Spain.

我向公司请了几天假，说是家里有事，再加上年假，大概有10天的时间，够我出去走一走了。其实是想躲避林全，希望在黄玲回来之前，可以平安无事。我已经打定主意，等她回来，我会告诉她这个男人的真实面目，让她离开他。

Conclusions and future perspectives: The trophic theory of neural connections postulates that neurons are strictly dependent on neurotrophic factors, mainly arising from target tissue, for both survival and the maintenance of a normal functional state. After the discovery of the fi rst neurotrophic factor, NGF, it was soon established that this molecule was crucial for postganglionic sympathetic neurons to survive and to exhibit a proper structure/function. In contrast, for decades, neuroscientists have been looking for a speci fi c neurotrophic factor that could be crucial for motoneurons. However, the list of trophic molecules with bene fi cial effects on motoneurons is extensive, and there is still no consensus about any particular factor as being the main neurotrophic molecule for this neuronal type.We hypothesize that VEGF might be that molecule acting as an essential neurotrophic factor for motoneurons. According to our data, it is the only neurotrophic factor among all those tested in our experimental model able to prevent and recover completely the firing alterations and synaptic loss induced by axotomy in motoneurons (Davis-López de Carrizosa et al., 2009, 2010; Calvo et al., 2018). Moreover, data obtained by other authors (Oosthuyse et al., 2001; Azzouz et al., 2004; Tovar-y-Romo et al.,2007; Lange et al., 2016; Wang et al., 2016) indicate that VEGF is the only neurotrophic factor studied to date whose de fi cit is followed by motoneuron degeneration while its administration is able to rescue degenerating motoneurons from cell death. If our hypothesis is correct, then it would be expected that the blockage of VEGF in control intact animals should lead to motoneuron alterations in synaptic inputs and firing pattern similar to those found after axotomy. VEGF blockage could be performed either by using virus vectors carrying the sequence of the RNA interference for inhibiting VEGF gene expression, or pharmacologically following the administration of VEGF neutralizing antibodies. This prospect would reveal the likely signi fi cant role played by VEGF in motoneuron physiology and provide valuable information regarding the potential use of VEGF as a therapeutic agent for the treatment of damaged or diseased motoneurons.

无钾处理区枣树叶缘焦枯，叶子皱缩，叶缘和叶尖失绿，呈棕黄色或棕褐色干枯，发病症状从枝梢中部叶片开始，随病势发展向上、下扩展。钾在树体内以无机酸盐、有机酸盐、钾离子等形式存在，在光合作用中占重要地位，对碳水化合物的运转、储存，特别是淀粉的形成有重要作用；对蛋白质的合成也有一定促进作用；钾还可作为某些酶和辅酶的活化剂。本试验钾肥50%作基肥施入，剩余50%于盛花期追施。

Copyright transfer agreement: The Copyright License Agreement has been signed by all authors before publication.

Plagiarism check: Checked twice by iThenticate.

Peer review: Externally peer reviewed.

由图8可以看出，随着砾石含量的增加，试样的沉降量在减小，当砾石含量在40%～50%附近时，变形幅度逐渐减小，变形开始趋于稳定。由图9可以看出，随着砾石含量的增加，试样的渗透系数在0～15%的砾石含量阶段减小，15%以后随着砾石含量的增加，试样的渗透系数开始逐渐减小，砾石含量大于45%后，渗透系数的变化显著增大，这与文献[28]中所说内容相符合，在一定范围内，随着砾石含量的增加，砾石起到了骨架作用，变形减小，但当砾石含量达到一定程度时，骨架作用增强，细粒含量减小，不能完全填充骨架内的孔隙，渗透系数随之减小。

Open access statement: This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License,which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

为了保证监管制度实施的有效性,必须确保具备可行的执行方案,在建立监管制度的同时要保证各项措施真正得以执行。具体来说,可以在产科组建一支护理质量监控小组,依据岗位职责内容、具体指标、各项工作标准,对产科护理工作实施、开展质量定期进行考核评估,将考评结果纳入到医护人员职称晋升、评优评先、奖金发放的评价中[2]。除此之外,小组还应该进行不定期抽查,及时发现存在的不足,重点控制容易出现护理差错、容易产生医疗纠纷的环节。建立关于产科护理质量的长效监管机制,对各项护理工作制度进行逐渐的完善,做好基础护理的质前控制、终末控制,以及期间各个环节的控制,改善抽查考核方法,最大程度减少疏漏,实现护理质量的提升。

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