美国国立神经疾病和卒中研究所-加拿大卒中网血管性认知障碍统一标准

背景和目的：1／3的个体会罹患卒中和（或）痴呆,而且,除卒中或痴呆外,2倍于此数的人会出现认知障碍。常用的卒中量表并不能评价认知功能,而痴呆的诊断标准则集中在认知障碍的晚期阶段,且在很大程度上偏向Alzheimer病（AD）的诊断。尚缺乏普遍公认的标准用于识别和描述存在认知障碍的个体,尤其是在早期阶段,而且特别是与血管因素有关的认知障碍或血管性认知障碍。方法：美国国立神经疾病和卒中研究所（MINDS）与加拿大卒中网（CSN）召集临床诊断、流行病学、神经心理学、脑影像学、神经病理学、试验模型、生物标记物、遗传学和临床试验方面的研究人员,为血管性认知障碍的描述和研究推荐一些最低限度的常用的临床和研究标准。结果：将这些讨论的结果发表于此。结论：一个统一标准的制定代表着使用、确认和改进过程中的第一步。使用相同的标准将有助于在认知障碍的早期阶段识别患者,使不同的研究具有可比性,并且通过整合知识来加速研究进展的步伐。     

Multitarget microangiopathy in a young healthy man with COVID-19 disease: A case report

A 41-year-old man presented to the emergency department complaining of decrease of vision in his left eye. Initial examination was consistent with retrobulbar optic neuritis, and an intravenous drip of methylprednisolone was started. On the third day, the fundus examination revealed the appearance of multiple Purtscher-like cotton-wool spots in the posterior pole and nasally to the optic disc, slight retinal whitening around the fovea, and cherry-red spot. The patient reported flu-like symptoms, and he tested positive at PCR (polymerase chain reaction) test for 2019-nCoV (2019 novel coronavirus) infection. Assuming possible 2019-nCoV-related vascular damage, we prescribed low-molecular-weight heparin. The lesions were regressing at follow-up, and we registered a complete visual recovery.     

Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-beta

Increasing evidence indicates that cerebrovascular dysfunction plays a pathogenic role in Alzheimer's dementia (AD). Amyloid-β (Aβ), a peptide central to the pathogenesis of AD, has profound vascular effects mediated, for the most part, by reactive oxygen species produced by the enzyme NADPH oxidase. The mechanisms linking Aβ to NADPH oxidase-dependent vascular oxidative stress have not been identified, however. We report that the scavenger receptor CD36, a membrane glycoprotein that binds Aβ, is essential for the vascular oxidative stress and neurovascular dysfunction induced by Aβ1-40. Thus, topical application of Aβ1-40 onto the somatosensory cortex attenuates the increase in cerebral blood flow elicited by neural activity or by endothelium-dependent vasodilators in WT mice but not in CD36-null mice (CD36(0/0)). The cerebrovascular effects of infusion of Aβ1-40 into cerebral arteries are not observed in mice pretreated with CD36 blocking antibodies or in CD36(0/0) mice. Furthermore, CD36 deficiency prevents the neurovascular dysfunction observed in transgenic mice overexpressing the Swedish mutation of the amyloid precursor protein Tg2576 despite elevated levels of brain Aβ1-40. CD36 is also required for the vascular oxidative stress induced by exogenous Aβ1-40 or observed in Tg2576 mice. These observations establish CD36 as a key link between Aβ1-40 and the NADPH oxidase-dependent vascular oxidative stress underlying the neurovascular dysfunction and suggest that CD36 is a potential therapeutical target to counteract the cerebrovascular dysfunction associated with Aβ.     

Cisplatin-induced kidney injury in the rat: l-carnitine modulates the relationship between MMP-9 and TIMP-3

Renal interstitial fibrosis is a major complication of cisplatin treatment, due to the increased accumulation of extracellular matrix (ECM) proteins whose remodeling is important for the development of normal tissues; indeed, its malfunction might play a role in the etiology of various diseases.Biopharmacological evaluations suggest that l-carnitine can prevent cardiac metabolic damage caused by doxorubicin, as well as can inhibit cisplatin-induced injury in the kidney and in the small intestine, without any interference with the drug's antitumoral properties. Since the glomerular basement membrane and the mesangial matrix constitute the ECM of the renal glomerulus, we examined the localization and expression of MMP-9 and TIMP-3 in normal rat kidney and the changes in their expression over a period of time by treatment with cisplatin, with and without l-carnitine. MMP-9 immunoreaction in cisplatin-treated rat kidney tissue suggests an involution of the basal membrane, an alteration of ECM components and low glomerular function, due to the increased thickness of the mesangium. Our results suggest that the matrix remodeling by MMP-9 and TIMP-3, in the later stages, can play an important role in the development of glomerular sclerosis and interstitial fibrosis after cisplatin treatment. It can also be postulated that l-carnitine protects from cisplatin injury, by modulating the relationship between MMP-9 and TIMP-3.     

ER stress in the brain subfornical organ mediates angiotensin-dependent hypertension

Although endoplasmic reticulum (ER) stress is a pathologic mechanism in a variety of chronic diseases, it is unclear what role it plays in chronic hypertension (HTN). Dysregulation of brain mechanisms controlling arterial pressure is strongly implicated in HTN, particularly in models involving angiotensin II (Ang II). We tested the hypothesis that ER stress in the brain is causally linked to Ang II–dependent HTN. Chronic systemic infusion of low-dose Ang II in C57BL/6 mice induced slowly developing HTN, which was abolished by co-infusion of the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) into the lateral cerebroventricle. Investigations of the brain regions involved revealed robust increases in ER stress biomarkers and profound ER morphological abnormalities in the circumventricular subfornical organ (SFO), a region outside the blood-brain barrier and replete with Ang II receptors. Ang II–induced HTN could be prevented in this model by selective genetic supplementation of the ER chaperone 78-kDa glucose-regulated protein (GRP78) in the SFO. These data demonstrate that Ang II–dependent HTN is mediated by ER stress in the brain, particularly the SFO. To our knowledge, this is the first report that ER stress, notably brain ER stress, plays a key role in chronic HTN. Taken together, these findings may have broad implications for the pathophysiology of this disease.