Glutamate infusion associated with reduced rises of p-Copeptin after coronary surgery: Substudy of GLUTAMICS II

Background

Glutamate plays a key role for post-ischaemic recovery of myocardial metabolism. According to post hoc analyses of the two GLUTAMICS trials, patients without diabetes benefit from glutamate with less myocardial dysfunction after coronary artery bypass surgery (CABG). Copeptin reflects activation of the Arginine Vasopressin system and is a reliable marker of heart failure but available studies in cardiac surgery are limited. We investigated whether glutamate infusion is associated with reduced postoperative rises of plasma Copeptin (p-Copeptin) after CABG.

Methods

A prespecified randomised double-blind substudy of GLUTAMICS II. Patients had left ventricular ejection fraction ≤0.30 or EuroSCORE II ≥3.0 and underwent CABG ± valve procedure. Intravenous infusion of 0.125 M L-glutamic acid or saline at 1.65 mL/kg/h was commenced 10–20 min before the release of the aortic cross-clamp and then continued for another 150 min P-Copeptin was measured preoperatively and postoperatively on day one (POD1) and day three. The primary endpoint was an increase in p-Copeptin from the preoperative level to POD1. Postoperative stroke ≤24 h and mortality ≤30 days were safety outcomes.

Results

We included 181 patients of whom 48% had diabetes. The incidence of postoperative mortality ≤30 days (0% vs. 2.1%; p = .50) and stroke ≤24 h (0% vs. 3.2%; p = .25) did not differ between the glutamate group and controls. P-Copeptin increased postoperatively with the highest values recorded on POD1 without significant inter-group differences. Among patients without diabetes, p-Copeptin did not differ preoperatively but postoperative rise from preoperative level to POD1 was significantly reduced in the glutamate group (73 ± 66 vs. 115 ± 102 pmol/L; p = .02). P-Copeptin was significantly lower in the Glutamate group on POD1 (p = .02) and POD 3 (p = .02).

Conclusions

Glutamate did not reduce rises of p-Copeptin significantly after moderate to high-risk CABG. However, glutamate was associated with reduced rises of p-Copeptin among patients without diabetes. These results agree with previous observations suggesting that glutamate mitigates myocardial dysfunction after CABG in patients without diabetes. Given the exploratory nature of these findings, they need to be confirmed in future studies.     

Ocular dysfunctions and toxicities induced by antiepileptic medications: Types,pathogenic mechanisms,and treatment strategies

Introduction: Ocular dysfunctions and toxicities induced by antiepileptic drugs (AEDs) are rarely reviewed and not frequently received attention by treating physicians compared to other adverse effects (e.g. endocrinologic, cognitive and metabolic). However, some are frequent and progressive even in therapeutic concentrations or result in permanent blindness. Although some adverse effects are non-specific, others are related to the specific pharmacodynamics of the drug.

Areas covered: This review was written after detailed search in PubMed, EMBASE, ISI web, SciELO, Scopus, and Cochrane Central Register databases (from 1970 to 2019). It summarized the reported ophthalmologic adverse effects of the currently available AEDs; their risks and possible pathogenic mechanisms. They include ocular motility dysfunctions, retinopathy, maculopathy, glaucoma, myopia, optic neuropathy, and impaired retinal vascular autoregulation. In general, ophthalmo-neuro- or retino-toxic adverse effects of AEDs are classified as type A (dose-dependent), type B (host-dependent or idiosyncratic) or type C which is due to the cumulative effect from long-term use.

Expert opinion: Ocular adverse effects of AEDs are rarely reviewed although some are frequent or may result in permanent blindness. Increasing knowledge of their incidence and improving understanding of their risks and pathogenic mechanisms are crucial for monitoring, prevention, and management of patients’ at risk.     

Paired associated magnetic stimulation promotes neural repair in the rat middle cerebral artery occlusion model of stroke

Paired associative stimulation has been used in stroke patients as an innovative recovery treatment. However, the mechanisms underlying the therapeutic effectiveness of paired associative stimulation on neurological function remain unclear. In this study, rats were randomly divided into middle cerebral occlusion model(MCAO) and paired associated magnetic stimulation(PAMS) groups. The MCAO rat model was produced by middle cerebral artery embolization. The PAMS group received PAMS on days 3 to 20 post MCAO. The MCAO group received sham stimulation, three times every week. Within 18 days after ischemia, rats were subjected to behavioral experiments—the foot-fault test, the balance beam walking test, and the ladder walking test. Balance ability was improved on days 15 and 17, and the footfault rate was less in their affected limb on day 15 in the PAMS group compared with the MCAO group. Western blot assay showed that the expression levels of brain derived neurotrophic factor, glutamate receptor 2/3, postsynaptic density protein 95 and synapsin-1 were significantly increased in the PAMS group compared with the MCAO group in the ipsilateral sensorimotor cortex on day 21. Resting-state functional magnetic resonance imaging revealed that regional brain activities in the sensorimotor cortex were increased in the ipsilateral hemisphere, but decreased in the contralateral hemisphere on day 20. By finite element simulation, the electric field distribution showed a higher intensity, of approximately 0.4 A/m~2, in the ischemic cortex compared with the contralateral cortex in the template. Together, our findings show that PAMS upregulates neuroplasticity-related proteins, increases regional brain activity, and promotes functional recovery in the affected sensorimotor cortex in the rat MCAO model. The experiments were approved by the Institutional Animal Care and Use Committee of Fudan University, China(approval No. 201802173 S) on March 3, 2018.     

Glutamate hypothesis in schizophrenia

Schizophrenia is a chronic and severe psychiatric disorder that has profound impact on an individual’s life and on society. Thus, developing more effective therapeutic interventions is essential. Over the past quarter‐century, an abundance of evidence from pharmacologic challenges, post‐mortem studies, brain imaging, and genetic studies supports the role of glutamatergic dysregulation in the pathophysiology of schizophrenia, and the results of recent randomized clinical trials based on this evidence have yielded promising results. In this article, we review the evidence that alterations in glutamatergic neurotransmission, especially focusing on the N‐methyl‐d ‐aspartate receptor (NMDAR) function, may be a critical causative feature of schizophrenia, how this contributes to pathologic circuit function in the brain, and how these insights are revealing whole new avenues for treatment development that could reduce treatment‐resistant symptoms, which account for persistent disability.     

The relationship between measurement of in vivo brain glutamate and markers of iron metabolism: A proton magnetic resonance spectroscopy study in healthy adults

Fundamental human studies which address associations between glutamate and iron metabolism are needed. Basic research reports associations between glutamate and iron metabolism. Human studies report sex differences in iron metabolism and glutamate concentrations, which suggest that these relationships may differ by sex. We hypothesised associations would be apparent between in vivo glutamate and peripheral markers of iron metabolism, and these associations would differ by sex. To test this, we recruited 40 healthy adults (20 men, 20 women) and measured (a) standard clinical biomarker concentrations for iron metabolism and (b) an in vivo proxy for glutamate concentration, glutamate with glutamine in relation to total creatine containing metabolites using proton magnetic resonance spectroscopy studies with a two‐dimensional chemical shift imaging slice, with voxels located in bilateral dorsolateral prefrontal cortices, anterior cingulate cortices and frontal white matter. Only the female group reported significant associations between peripheral markers of iron metabolism and Glx:tCr concentration: (a) right dorsolateral prefrontal cortex Glx:tCr associated positively with serum transferrin (r = .60, p = .006) and negatively with transferrin saturation (r = ?.62, p = .004) and (b) right frontal white matter Glx:tCr associated negatively with iron concentration (r = ?.59, p = .008) and transferrin saturation (r = ?.65, p = .002). Our results support associations between iron metabolism and our proxy for in vivo glutamate concentration (Glx:tCr). These associations were limited to women, suggesting a stronger regulatory control between iron and glutamate metabolism. These associations support additional fundamental research into the molecular mechanisms of this regulatory control.     

Hippocampal and prefrontal contributions to memory retrieval: Examination of immediate early gene,NMDA receptor and environmental interactions

Animals can use a range of strategies to recall important locations. These include simple stimulus–response strategies and more complex spatial (place) strategies, which are thought to have distinct neural substrates. The hippocampus—and NMDA receptor activation therein—is considered to be crucial for spatial, but not response strategies. The medial prefrontal cortex has also been implicated in memory retrieval; however, evidence concerning its specific role is equivocal. Both hippocampal and prefrontal regions have been associated with flexible behavioural responding (e.g. when task demands change). Here, we investigated the use of spatial and non‐spatial strategies in the Morris water maze and their associated brain areas in rats using immediate early gene (IEG) imaging of Zif268 and c‐Fos. Specifically, we charted the involvement of hippocampal and prefrontal subregions during retrieval of spatial and non‐spatial memories. Behavioural flexibility was also examined using intact and partial cue configurations during recall. Results indicated that regions of both the hippocampus (area CA3) and prefrontal cortex (anterior cingulate cortex) were preferentially engaged in spatial memory recall compared to response learning. In addition, both spatial and non‐spatial memories were dependent on NMDA receptor activation. MK801 impaired recall performance across all groups and reduced IEG activation across hippocampal and prefrontal regions. Finally, IEG results revealed divergent patterns of Zif268 and c‐Fos activity and support the suggestion that Zif268 plays a functional role in the recall of long‐term memories.     

Convergence of ion channel genome content in early animal evolution

Multicellularity has evolved multiple times, but animals are the only multicellular lineage with nervous systems. This fact implies that the origin of nervous systems was an unlikely event, yet recent comparisons among extant taxa suggest that animal nervous systems may have evolved multiple times independently. Here, we use ancestral gene content reconstruction to track the timing of gene family expansions for the major families of ion-channel proteins that drive nervous system function. We find that animals with nervous systems have broadly similar complements of ion-channel types but that these complements likely evolved independently. We also find that ion-channel gene family evolution has included large loss events, two of which were immediately followed by rounds of duplication. Ctenophores, cnidarians, and bilaterians underwent independent bouts of gene expansion in channel families involved in synaptic transmission and action potential shaping. We suggest that expansions of these family types may represent a genomic signature of expanding nervous system complexity. Ancestral nodes in which nervous systems are currently hypothesized to have originated did not experience large expansions, making it difficult to distinguish among competing hypotheses of nervous system origins and suggesting that the origin of nerves was not attended by an immediate burst of complexity. Rather, the evolution of nervous system complexity appears to resemble a slow fuse in stem animals followed by many independent bouts of gene gain and loss.Animal nervous systems are complex cellular networks that encode internal states and behavioral output. They achieve this complexity primarily in two ways. First, nervous systems encode information in a wiring scheme whose connections differ in strength and sign (excitatory or inhibitory). The strengths can often change in an activity-dependent fashion (1). Second, nervous systems have a dynamic neural code made up of all-or-none action potentials and subtler graded potentials (2). The shape, timing, and duration of evoked electrical potentials vary greatly among—and even within—neurons and can also be activity-dependent. These two types of complex signaling, respectively, among and within cells are the fundamental work of nervous systems (1), and they are made possible by the great variety of ion channel proteins expressed in neurons.Recent studies have found that most ion channels and proteins involved in the formation of synapses are ancient, having originated long before the advent of nervous systems or even of animal multicellularity (3–7). However, the nature of the first animals and of the cells from which nervous systems evolved are not well understood, although many theories exist (8–11), and little is known about the genomic events that facilitated the rise of complex nervous systems. New information about animal phylogeny has demanded a return to these old questions concerning the nature of the first animals and the evolutionary history of nervous systems (12–15).This new information concerns the placement of the ctenophores, or comb jellies. Recent studies place ctenophores as the sister group to all other metazoans, a surprising finding given that ctenophores are complex predators with fairly sophisticated nervous systems (15). In contrast, sponges, which traditionally were considered to be the sister group of the remaining animals (16), and placozoans do not have nervous systems (but see refs. 17 and 18). Recent genomic analyses have found that ctenophores are lacking many nervous system and muscle-associated genes, suggesting independent origins of these structures in ctenophores (15, 19, 20). Conversely, the genomic presence and expression of certain developmental genes involved in nervous system differentiation (13, 14) and genes expressed in the synapse (13, 21) indicate deep similarities between ctenophore nervous systems and others. These findings have revived the debate about whether animal nervous systems have one or more origins. Although it is clear that there has been some degree of homoplasy and/or secondary simplifications or losses, the nature and timing of these events remains debatable (refs. 14, 20, and 21 are excellent reviews on this subject).Many studies have addressed the origin of animal nervous systems by using comparative physiological, developmental, or morphological evidence (22–24). We used a different technique: ancestral gene content reconstruction. This approach has been used to explore the origin of multicellularity (25), the evolution of prokaryotic metabolism (26), and the expansion of G-protein–coupled receptors in animals (27). Gene duplication has long been known to be a major source of novelty and complexity (28), and many of the families we analyzed play few known roles outside of nervous systems. We therefore hypothesized that the elaboration of nervous systems coincided with an expansion of the ion-channel families that are expressed there. We used two methods (27, 29) to reconstruct the ancestral copy number for a variety of ion channel families and tracked the evolution of gene duplications across the animal and fungal tree. The evolution of some of these families have been studied by other groups (15, 27, 30–32), but here we combine current methods of ancestral genome content reconstruction with dense sampling of early branching species and gene families to search for patterns of gene duplication that might illuminate the early history of nervous systems.     

石榴皮鞣质对肾小球硬化大鼠内源性物质代谢的影响及代谢通路分析

目的利用高效液相色谱串联质谱(HPLC-MS)的尿液代谢组学研究方法,考察石榴皮鞣质对肾小球硬化大鼠内源性物质代谢的影响,寻找潜在的生物标志物并分析其代谢途径,为研究石榴皮鞣质对肾小球硬化大鼠的改善作用及其机制提供理论依据。方法将48只SD大鼠随机分为假手术组,模型组,贝那普利组,石榴皮鞣质高、中、低剂量组,采用单侧肾切除结合2次尾iv盐酸多柔比星的方法制备肾小球硬化大鼠模型,ig给药8周,每周收集大鼠24 h尿液,用HPLC-MS对其检测分析;采用主成分分析(PCA)、偏最小二乘法判别分析(PLS-DA)及正交偏最小二乘法判别分析(OPLS-DA)等方法对各组大鼠尿液代谢物进行聚类分析,筛选出潜在的生物标志物并构建相应的代谢通路。结果代谢组学分析发现给药后第8周各组大鼠尿液有明显的聚类现象,通过对重要变量的分析鉴定,筛选出10个潜在的生物标志物;涉及的代谢通路包括色氨酸、丙氨酸、天冬氨酸和谷氨酸等多种氨基酸的代谢通路。结论石榴皮鞣质干预下的肾小球硬化大鼠内源性代谢物聚类性趋近正常水平,为进一步阐明石榴皮鞣质对肾小球硬化大鼠的作用机制提供依据。