Neuroprotective effects of erythropoietin on neurodegenerative and ischemic brain diseases: the role of erythropoietin receptor

Erythropoietin (Epo) is a fundamental hormone in the regulation of hematopoiesis, and other secondary roles mediated by the binding of the hormone to its specific receptor (EpoR), which leads to an activation of key signaling pathways that induce an increase in cell differentiation, apoptosis control and neuroprotection. It has been suggested that their function depends on final conformation of glycosylations, related with affinity to the receptor and its half-life. The presence of EpoR has been reported in different tissues including central nervous system, where it has been demonstrated to exert a neuroprotective function against oxidative stress conditions, such as ischemic injury and neurodegenerative diseases. There is also evidence of an increase in EpoR expression in brain cell lysates of Alzheimer's patients with respect to healthy patients. These results are related with extensivein vitro experimental data of neuroprotection obtained from cell lines, primary cell cultures and hippocampal slices. Additionally, this data is correlated with in vivoexperiments (water maze test) in mouse models of Alzheimer's disease where Epo treatment improved cognitive function. These stud-ies support the idea that receptor activation induces a neuroprotective effect in neurodegenerative disorders including dementias, and especially Alzheimer's disease. Taken together, available evidence suggests that Epo appears to be a central element for EpoR activation and neuroprotective properties in the central nervous system. In this review, we will describe the mechanisms associated with neuroprotection and its relation with the activation of EpoR in order with identify new targets to develop pharmacological strategies.     

Elevated neurofilament levels in neurological diseases

Neurofilaments, a major cytoskeletal constituent of neuronal cells, can be released into the cerebrospinal fluid during several neurodegenerative diseases. By means of a new sensitive ELISA capable of measuring 60 ng/l of neurofilament light, significant elevations were observed for different neurological disorders. Cerebral infarction presented levels of 19800+/-9100 ng/l, amyothropic lateral sclerosis 3600+/-1200 ng/l, 'relapsing-remitting' MS 2500+/-1500 ng/l, extrapyramidal symptoms 1100+/-300 ng/l, late onset AD 300+/-100 ng/l and vascular dementia 1400+/-800 ng/l. In patients with no signs of neurological diseases the upper normal level and cut-off values was determined to be below 100 ng/l. NF-L determinations will be a valuable complement in identifying neuronal degradation and can be used clinically for diagnostic and monitoring purposes.     

Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain

Using immunohistochemistry, expression of erythropoietin (EPO), a hypoxia-inducible neuroprotective factor, and its receptor (EPOR) were investigated in human brain tissue after ischemia/hypoxia. Autopsy brains of neuropathologically normal subjects were compared to those with ischemic infarcts or hypoxic damage. In normal brain, weak EPO/EPOR immunoreactivity was mainly neuronal. In fresh infarcts, EPO immunoreactivity appeared in vascular endothelium, EPOR in microvessels and neuronal fibers. In older infarcts reactive astrocytes exhibited EPO/EPOR immunoreactivity. Acute hypoxic brain damage was associated with vascular EPO expression, older hypoxic damage with EPO/EPOR immunoreactivity in reactive astrocytes. The pronounced up-regulation of EPO/EPOR in human ischemic/hypoxic brains underlines their role as an endogenous neuroprotective system and suggests a novel therapeutic potential in cerebrovascular disease for EPO, a clinically well-characterized and safe compound.     

106例缺血性脑血管病患者全脑血管造影分析

目的分析缺血性脑血管病患者颅内外动脉狭窄的分布。方法对我院实施DSA检查的106例缺血性脑血管病的结果进行分析,均经头颅CT排除脑出血,TCD及颈动脉彩超检查后怀疑有动脉狭窄的缺血性脑血管病。所有患者均实施选择性全脑血管造影术,椎动脉和颈动脉均有正侧位血管造影像;根据患者的DSA检查结果,分析动脉狭窄的部位、受累血管数目及血管狭窄形态;重度狭窄的病例予以支架治疗和球囊成型术。结果血管造影结果提示89.6%患者有不同程度的血管狭窄或闭塞,其中75.5%为前循环受累,37.7%为后循环受累。前循环受累血管中以颈内动脉(56.6%)和大脑中动脉(26.4%)受累最常见,后循环受累血管中以椎动脉(33.0%)最多见。支架治疗和球囊成型术临床疗效显著。结论缺血性脑血管病造影显示大部分患者有肯定的脑血管狭窄和闭塞。脑梗死患者血管病变以颈内动脉病变为主,椎基底动脉供血不足亦以颈内动脉病变多见,支架治疗和球囊成型可作为重度狭窄的治疗方法。     

A novel biomarker for retinal degeneration: vitreous body neurofilament proteins

Retinal degeneration leads to release of cell-type specific proteins into the adjacent compartment. Here we investigated whether the neurofilament heavy chain protein (NfH) could be measured from the vitreous body and anterior chamber fluid. This prospective study included 85 patients who underwent vitrectomy (44 retinal detachment, 12 macular hole, 15 epiretinal gliosis, 8 organ donors) or trabelectomy (six glaucoma). The cut-off level was calculated from the organ donors. An established enzyme-linked immunosorbent assay (ELISA, SMI35) was used for quantification of NfH (190–210 kDa). Measurable levels of NfH were detected from the vitreous body homogenate, but not from the anterior chamber fluid. The cut-off level was 0.29 ng/mL. A significant proportion of patients suffering from retinal detachment (43.2%, mean 0.74 ng/mL) had vitreous body NfH levels above cut-off when compared to organ donors (0%, 0.12 ng/mL, p = 0.02), epiretinal sclerosis (1.6%, 0.05 ng/mL, p = 0.01), macular hole (0%, 0.04 ng/mL, p = 0.004). Following retinal detachment, vitreous NfH-SMI35 levels correlated with time from onset (R = ?0.3, p < 0.05), persisting for up to 2 years. This study shows that NfH can be quantified from the human vitreous body and may be a useful novel biomarker for retinal degeneration. The method can be applied for investigating the dynamics of retinal degeneration and the response to neuroprotective strategies in a broad range of retinal diseases in either clinical or experimental research.     

氨甲酰促红细胞生成素对缺血性脑损伤的保护作用

目的 探讨氨甲酰促红细胞生成素(CEPO)对缺血性脑损伤的保护作用及机制,并与促红细胞生成素(EPO)进行比较.方法 用腔内线栓法制造小鼠脑缺血再灌注动物模型;用蛋白免疫印迹法分析内皮型一氧化氮合酶(eNOS)和活化型caspase-3的变化;用免疫组织化学方法观察诱导型一氧化氮合酶(iNOS)的改变;用TUNEL法观察凋亡细胞.结果 脑缺血后大脑皮质eNOS、iNOS和活化型caspase-3表达显著上升;CEPO和EPO对eNOS表达无明显影响,但使活化型caspase-3表达从95.4%±16.7%明显下降至43.5%±13.1%(t=5.99,P<0.01),使缺血皮质iNOS表达从(3.1±1.9)细胞数/矩形区域下降至(0.7±0.2)细胞数/矩形区域(t=3.08,P<0.05);EPO使缺血皮质细胞凋亡数从对照组的(94.2±15.2)TUNEL(+)细胞数/矩形区域降至(40.5±9.8)TUNEL(+)细胞数/矩形区域(t=7.27,P<0.01),CEPO的抗细胞凋亡作用与EPO相同.结论 CEPO具有与EPO相同的抗细胞凋亡作用,它们通过减少活化型caspase-3和iNOS的表达而发挥神经保护作用.     

Posterior vitreous detachment and retinal tear after repetitive transcranial magnetic stimulation

This case report describes a 60-year-old woman who experienced a posterior vitreous detachment (PVD) and retinal tear after her 11th session of 1 Hz repetitive transcranial magnetic stimulation (rTMS) for the treatment of major depression. Although we cannot conclude that rTMS caused her PVD and retinal tear, the temporal association is strong, and we hypothesize a possible pathophysiology of the event. As part of the routine clinical monitoring of rTMS side effects, we encourage attention toward ophthalmologic symptoms, especially in older patients.     

Elevated levels of anti-Chlamydia pneumoniae IgA and IgG antibodies in young adults with ischemic stroke

INTRODUCTION: Data on the role of Chlamydia pneumoniae in patients with ischemic stroke are inconsistent. We investigated the presence of anti-C. pneumoniae antibodies in young adults with ischemic stroke. METHODS: 94 patients (<55 years) with ischemic stroke and 103 controls were enrolled. Indices of anti-C. pneumoniae IgA and IgG were assessed with an ELISA. We determined OR and 95% CI for the IgA and IgG seropositivity in stroke cases. RESULTS: Mean IgA and IgG indices were higher in stroke patients vs controls (IgA: 1.40 vs 0.56; P < 0.001; IgG: 0.85 vs. 0.78; P < 0.003). The IgA seropositivity was associated with stroke risk (11.92; 5.94-23.92; P < 0.001) as well as IgG seropositivity was (2.31; 1.15-4.61; P < 0.016). Seropositivity assessed with combined IgA and IgG indices was associated with increased stroke risk (OR 9.35; 95% CI 4.78-18.29; P < 0.0001). After controlling for age and sex, the IgA seropositivity yielded a significantly adjusted OR for stroke (8.95; 4.44-18.07; P < 0.002), while IgG seropositivity did not (0.85; 0.53-1.63). CONCLUSIONS: We find an increased risk of stroke in young patients seropositive to C. pneumoniae in the IgA antibody class. Further studies to explore this finding are warranted.     

Elevated blood urea nitrogen/creatinine ratio is associated with poor outcome in patients with ischemic stroke

Objective

Dehydration may impair cerebral oxygen delivery and worsen clinical outcome in patients with acute ischemic stroke (AIS). We evaluated if elevated blood urea nitrogen to creatinine ratio (BUN/Cr) as a marker of dehydration was associated with poor clinical outcome in emergency department (ED) patients presenting with AIS.

Methods

We conducted a prospective cohort study using a stroke registry enrolling all ED patients with AIS from 10/2007 through 6/2009. Poor clinical outcome was defined as death, placement in a nursing home for purposes other than rehabilitation, or hospice within 30 days of ED presentation. A BUN/Cr ratio of ≥15 was considered elevated. (IQR). Logistic regression was performed adjusted for age >64 years, NIHSS >8, diabetes, prior CVA, and coma at presentation reporting odds ratios with 95% confidence intervals.

Results

324 patients had a final diagnosis of AIS. 163 (50%) were female, 19 (6%) died, 44 (14%) received t-PA, and 89 (27%) had a poor clinical outcome. The median NIHSS, BUN and Cr were 4 (IQR 1–9), 14 mg/dL (IQR 11–21), and 1.02 mg/dL (IQR 0.87–1.27) respectively. The median BUN/Cr was 13.9 (IQR 10.6–18.5). The variables associated with a poor clinical outcome were: high NIHSS OR 6.5 (3.6–11.8), age >64 years OR 2.7 (1.5–5.0), and BUN/Cr ratio of ≥15 OR 2.2 (1.2–4.0).

Conclusion

An elevated BUN/Cr ratio in patients with AIS is associated with poor outcome at 30 days. Further study is needed to see if acutely addressing hydration status in ED patients with AIS can alter outcome.     

Emerging roles of circular RNAs in retinal diseases

Retinal disorders are a group of ocular diseases whose onset is associated with a number of aberrant molecular and cellular processes or physical damages that affect retinal structure and function resulting in neural and vascular degeneration in the retina. Current research has primarily focused on delaying retinal disease with minimal success in preventing or reversing neuronal degeneration. In this review, we explore a relatively new field of research involving circular RNAs, whose potential r...     

缺血性脊髓血管病60例临床分析

目的深入探讨缺血性脊髓血管病的病因、临床表现、影像学改变、诊断及治疗。方法对1993年2月~2003年10月我院收治的60例缺血性脊髓血管病患者的临床资料进行回顾性分析。结果该病41岁~70岁为高发年龄段,病因及危险因素主要为高血压病。最常见的首发症状为根痛,占63.33%。典型的体征为四肢瘫或截瘫,分离性感觉障碍,直肠、膀胱括约肌功能障碍。MRI在24h后显影较好,典型表现为脊髓增粗并伴有髓内长T1长T2异常信号。本组痊愈6例,好转45例(肌力增加II级以上),无改善8例,死亡1例。结论有心血管系统高危因素的老年人突然出现根痛、四肢瘫或截瘫、分离性感觉障碍、膀胱直肠括约肌功能障碍等症状应高度怀疑缺血性脊髓血管病,MRI在24h后显影较好,一般采用内科保守治疗。     

Elevated gamma‐glutamyl transferase levels are associated with stroke recurrence after acute ischemic stroke or transient ischemic attack

AimsGamma‐glutamyl transferase (GGT) is considered a marker of oxidative stress in vivo. In this study, we aimed to examine the association of serum GGT levels with 3‐month and 1‐year stroke recurrence in patients with acute ischemic stroke or transient ischemic attack (TIA).MethodsWe conducted a large and multicenter cohort study. Participants with ischemic stroke or TIA who had a baseline GGT measurement were enrolled in the China National Stroke Registry‐3 study from August 2015 to March 2018. They were divided into four groups according to sex‐specific quartiles of GGT levels. The effect of GGT on stroke recurrence and other vascular events was examined during the 1‐year follow‐up period. Multivariate Cox regression models were performed to evaluate the association. Discrimination tests were used to examine the degree to which incorporating GGT into the conventional model predicted stroke adverse outcomes.ResultsA total of 12,504 patients were enrolled. At both the 3‐month and 1‐year follow‐ups, patients in the highest quartile group of GGT levels exhibited a higher risk of stroke recurrence [HR 1.32 (95% CI 1.07–1.63), HR 1.34 (95% CI 1.13–1.60)], ischemic stroke [HR 1.37 (95% CI 1.10–1.71), HR 1.37 (95% CI 1.14–1.64)], and combined vascular events [HR 1.34 (95% CI 1.09–1.65), HR 1.34 (95% CI 1.13–1.59)] than those in the lowest quartile group. Moreover, the Kaplan–Meier curves revealed that the incidence rates of stroke adverse outcomes were quite different in the four groups. The highest quartile group showed the highest cumulative incidence, while the lowest quartile group showed the lowest cumulative incidence. After applying discrimination tests, adding GGT into the conventional model resulted in slight improvements in predicting stroke adverse outcomes (NRI: 10%–14%).ConclusionThis study demonstrated that elevated GGT levels were positively associated with an increased risk of stroke adverse outcomes, namely, recurrence, ischemic stroke, and combined vascular events.     

缺血性脑血管病患者ACE基因缺失多态性分析

目的研究血管紧张素转换酶（ＡＣＥ）基因插入／缺失多态性与ＩＣＶＤ的关系。方法应用聚合酶链式反应（ＰＣＲ）技术，对８８例缺血性脑血管病（ＩＣＶＤ）组患者和８２例对照组人群分别检测其基因频率和基因型频率。结果ＤＩ等位基因频率之比脑血管病组为０．５９０．４１，对照组为０．４２０．５８（Ｐ＜０．０５）；ＤＤ基因型在ＩＣＶＤ组更多见（３１／８８例），对照组１５／８２例（Ｐ＜０．０５）；ＤＤ基因型对各种类型ＩＣＶＤ的相对危险性为２．４３，进一步分析表明，其危险性增高主要是由腔隙性梗塞和脑栓塞所致。结论ＡＣＥ基因缺失多态性与ＩＣＶＤ的发生显著相关，ＡＣＥ基因的缺失多态性对腔隙性梗塞和脑栓塞均可能是独立的危险因素。     

缺血性脑血管病的影像学诊断

脑血管疾病是目前世界范围内病残率和病死率最高的疾病之一,我国脑血管疾病的发病率呈逐年上升趋势,发病年龄也趋于年轻化,其所造成的社会经济负担(包括医院、医师、药剂、康复治疗、间     

Elevated lipid peroxide levels in platelets of chronic ischemic heart disease patients

A significantly higher platelet malondialdehyde-like material (MDA--LM) content after physical and N-ethylmaleimide (NEM) stimulation is found in chronic ischemic heart disease (CHD) patients when compared to the control group. In subjects under aspirin treatment "in vivo" (1 gr/day) no difference is found between CHD and control group. It is suggested that the enhanced amount of lipid peroxides in CHD platelets is produced by a cyclooxygenase-dependent mechanism. This enhanced platelet lipid peroxide production in CHD may be another platelet-dependent risk factor for atherosclerosis in these patients.     

Elevated troponin and ECG alterations in acute ischemic stroke and subarachnoid hemorrhage

Vascular diseases are the most common cause of death and disability in industrialised countries. Ischaemic heart disease and cerebrovascular disease frequently coexist in one patient. Therefore it is not surprising that raised troponin levels and ECG changes are detected comparatively often in acute stroke; however these changes do not always indicate myocardial infarction. Clinical and experimental data suggest that some kind of neurologically mediated myocardial injury exists--especially in subarachnoid hemorrhage--but not as a manifestation of concomitant ischaemic heart disease. This review summarises the frequency and possible pathophysiological mechanisms. In any case, raised troponin levels and ECG changes after acute stroke are of negative prognostic value, and a cardiological diagnostic work-up should be done.     

Elevated intracranial pressure associated with idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome.

The idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome typically occurs in young patients and may produce multiple retinal macroaneurysms, neuroretinitis, and peripheral capillary nonperfusion. Optic disc edema has been described, but elevated intracranial pressure has not been previously documented. We report a case of a 12-year-old girl who presented with bilateral disc swelling and peripapillary hemorrhage. Brain magnetic resonance imaging (MRI) was normal, but lumbar puncture yielded an opening pressure of 360 mm H2O with normal constituents. Fluorescein angiography delineated saccular aneurysms of the retinal arteriolar vasculature, and IRVAN syndrome was diagnosed. MR venography disclosed poor filling of both transverse venous sinuses. Acetazolamide treatment of 14 months did not alter the fundus findings. IRVAN syndrome may present initially with optic nerve swelling and elevated intracranial pressure with subsequent development of the characteristic retinal vascular abnormalities.