Dietary intake of S-(α-carboxybutyl)-dl-homocysteine induces hyperhomocysteinemia in rats

Betaine homocysteine S-methyltransferase (BHMT) catalyzes the transfer of a methyl group from betaine to homocysteine (Hcy), forming dimethylglycine and methionine. We previously showed that inhibiting BHMT in mice by intraperitoneal injection of S-(α-carboxybutyl)-dl-homocysteine (CBHcy) results in hyperhomocysteinemia. In the present study, CBHcy was fed to rats to determine whether it could be absorbed and cause hyperhomocysteinemia as observed in the intraperitoneal administration of the compound in mice. We hypothesized that dietary administered CBHcy will be absorbed and will result in the inhibition of BHMT and cause hyperhomocysteinemia. Rats were meal-fed every 8 hours an l-amino acid–defined diet either containing or devoid of CBHcy (5 mg per meal) for 3 days. The treatment decreased liver BHMT activity by 90% and had no effect on methionine synthase, methylenetetrahydrofolate reductase, phosphatidylethanolamine N-methyltransferase, and CTP:phosphocholine cytidylyltransferase activities. In contrast, cystathionine β-synthase activity and immunodetectable protein decreased (56% and 26%, respectively) and glycine N-methyltransferase activity increased (52%) in CBHcy-treated rats. Liver S-adenosylmethionine levels decreased by 25% in CBHcy-treated rats, and S-adenosylhomocysteine levels did not change. Furthermore, plasma choline decreased (22%) and plasma betaine increased (15-fold) in CBHcy-treated rats. The treatment had no effect on global DNA and CpG island methylation, liver histology, and plasma markers of liver damage. We conclude that CBHcy-mediated BHMT inhibition causes an elevation in total plasma Hcy that is not normalized by the folate-dependent conversion of Hcy to methionine. Furthermore, metabolic changes caused by BHMT inhibition affect cystathionine β-synthase and glycine N-methyltransferase activities, which further deteriorate plasma Hcy levels.     

Blood blister-like aneurysms: Single center experience and systematic literature review

Blood blister-like aneurysms (BBAs) are a controversial entity. They arise from non-branching sites on the supraclinoid internal carotid artery (ICA) and are suspected to originate from a dissection. Our aim is to describe the BBA cases seen in our center and to present a systematic review of the literature on BBAs.     

Bilateral vertebral artery dissecting aneurysms presenting with subarachnoid hemorrhage treated by staged coil trapping and covered stents graft

The treatment of bilateral vertebral artery dissecting aneurysms (VADAs) presenting with subarachnoid hemorrhage (SAH) is still challenging. The authors report a rare case of bilateral VADA treated with coil trapping of ruptured VADA and covered stents implantation after multiple unsuccessful stent assisted coiling of the contralateral unruptured VADA. A 44-year-old woman was admitted to our hospital because of severe headache and sudden stuporous consciousness. Brain CT showed thick SAH and intraventricular hemorrhage. Cerebral angiography demonstrated bilateral VADA. Based on the SAH pattern and aneurysm configurations, the right VADA was considered ruptured. This was trapped with endovascular coils without difficulty. One month later, the contralateral unruptured VADA was protected using a stent-within-a-stent technique, but marked enlargement of the left VADA was detected by 8-months follow-up angiography. Subsequently two times coil packing for pseudosacs resulted in near complete occlusion of left VADA. However, it continued to grow. Covered stents graft below the posterior inferior cerebellar artery (PICA) origin and a coronary stent implantation across the origin of the PICA resulted in near complete obliteration of the VADA. Covered stent graft can be used as a last therapeutic option for the management of VADA, which requires absolute preservation of VA flow.     

蛛网膜下腔出血对ICP、rCBF及死亡率影响的实验研究

目的 :研究不同严重程度SAH对颅内压 (ICP) ,脑灌注压 (CPP) ,局部脑血流量 (rCBF)及死亡率的影响。方法 :建立一种新的大鼠颈总动脉 视交叉前池体外转流蛛网膜下腔可控制性出血动物模型 ,比较出血 3 0 ,60 ,90s及重复 3 0s 3次出血后上述指标的变化。结果 :SAH后ICP急剧上升至接近平均动脉压水平 ,当ICP超过 6kPa(80mmHg)即可引起部分动物呼吸抑制而死亡 ;60s和 90s出血组ICP水平相差未具显著性 ,提示在此期间内出血可能趋向停止 ;SAH后rCBF立即受到大幅抑制 ,其后恢复程度与SAH严重程度呈反比。结论 :SAH后ICP剧升引起呼吸功能衰竭是死亡的主要原因 ;SAH后普遍存在脑微循环障碍 ,故应及早开始脑缺血的治疗     

Moyamoya病的病理、CT与临床研究(附70例报告)

目的研究ｍｏｙａｍｏｙａ病的临床及病理特点。方法分析经脑血管造影（５５例）及剖检（１５例）证实的ｍｏｙａｍｏｙａ病的临床、ＣＴ及病理资料。结果７０例平均年龄２９．２５岁。出血组５５例，平均年龄３３．１３岁，以原发性脑室出血（２１例）、脑叶出血（１３例）及ＳＡＨ（９例）为多，出血原因为异网血管、动脉瘤破裂及梗塞性出血；缺血组１５例，平均年龄１８．４岁，８０％病灶多发，８６．７％为２次以上发病，８０％有两侧症状及体征。结论儿童及青壮年发生脑血管病，血压不高，反复出现脑梗塞或出现脑室出血、脑叶出血或ＳＡＨ等要考虑ｍｏｙａｍｏｙａ病的可能     

Gender differences in methionine accumulation and metabolism in freshly isolated mouse hepatocytes: Potential roles in toxicity

l-Methionine (Met) is hepatotoxic at high concentrations. Because Met toxicity in freshly isolated mouse hepatocytes is gender-dependent, the goal of this study was to assess the roles of Met accumulation and metabolism in the increased sensitivity of male hepatocytes to Met toxicity compared with female hepatocytes. Male hepatocytes incubated with Met (30 mM) at 37 °C exhibited higher levels of intracellular Met at 0.5, 1.0, and 1.5 h, respectively, compared to female hepatocytes. Conversely, female hepatocytes had higher levels of S-adenosyl-l-methionine compared to male hepatocytes. Female hepatocytes also exhibited higher l-methionine-l-sulfoxide levels relative to control hepatocytes, whereas the increases in l-methionine-d-sulfoxide (Met-d-O) levels were similar in hepatocytes of both genders. Addition of aminooxyacetic acid (AOAA), an inhibitor of Met transamination, significantly increased Met levels at 1.5 h and increased Met-d-O levels at 1.0 and 1.5 h only in Met-exposed male hepatocytes. No gender differences in cytosolic Met transamination activity by glutamine transaminase K were detected. However, female mouse liver cytosol exhibited higher methionine-dl-sulfoxide (MetO) reductase activity than male mouse liver cytosol at low (0.25 and 0.5 mM) MetO concentrations. Collectively, these results suggest that increased cellular Met accumulation, decreased Met transmethylation, and increased Met and MetO transamination in male mouse hepatocytes may be contributing to the higher sensitivity of the male mouse hepatocytes to Met toxicity in comparison with female mouse hepatocytes.     

Resveratrol supplementation worsen the dysregulation of genes involved in hepatic lipid homeostasis observed in hyperhomocysteinemic mice

Hyperhomocysteinemia is characterized by an increase of plasma homocysteine, a thiol-containing amino acid produced during methionine metabolism. Hyperhomocysteinemia has often been associated with coronary artery disease, vascular thrombosis and the development of premature atherosclerosis. We have recently demonstrated that the supplementation of catechin, a polyphenol found in the red wine, significantly reduced plasma homocysteine level in cystathionine beta synthase (CBS) deficient mice, a murine model of hyperhomocysteinemia. In the present study, we have investigated the influence of another well-studied polyphenol found in red wine, resveratrol, on hyperhomocysteinemia. After two months on high methionine diet, heterozygous Cbs deficient mice were administrated the resveratrol in drinking water (0.001%) for one month. High methionine diet significantly increased serum homocysteine levels, and decreased the serum activity of HDL-associated enzyme paraoxonase-1. Chronic administration of resveratrol significantly increased plasma homocysteine level, which was associated with a decreased serum paraoxonase-1 activity, in hyperhomocysteinemic mice. Then we looked at gene expression of several proteins involved in HDL stability and found a down-regulation of lecithin:cholesterol acyltransferase. In conclusion, we found a deleterious effect of resveratrol onto homocysteine and HDL metabolism in a murine model of hyperhomocysteinemia.     

Computed Tomographic Angiography for the Evaluation of Aneurysmal Subarachnoid Hemorrhage

Objectives: Computed tomography (CT) followed by lumbar puncture (LP) is currently the criterion standard for diagnosing subarachnoid hemorrhage (SAH) in the emergency department (ED); however, this is based on studies involving a limited number of patients. The authors sought to assess the ability of CT angiography (CTA), a new diagnostic modality, in conjunction with CT/LP to detect SAH. Methods: Consecutive patients presenting to the ED with symptoms concerning for SAH were approached. All patients had an intravenous catheter placed and underwent a noncontrast head CT followed by CTA. Patients whose CT did not reveal evidence of SAH or other pathology underwent LP in the ED. CTAs were read within 24 hours by a neuroradiologist blinded to the patient's history. Results: A total of 131 patients were approached, 116 were enrolled, and 106 completed the study. In six of 116 patients (5.1%), aneurysm was found on CTA with normal CT and positive findings on LP; three had a positive CTA with normal CT and LP findings (one of which had a negative cerebral angiogram), and there was one false‐positive CTA. Follow‐up of all 131 patients showed no previously undiagnosed intracranial pathology. In this patient population, 4.3% (5/116) were ultimately found to have an SAH and/or aneurysm. Conclusions: In this pilot study, CTA was found to be useful in the detection of cerebral aneurysms and may be useful in the diagnosis of aneurysmal SAH. A larger multicenter study would be useful to confirm these results.     

Cilostazol attenuates cerebral vasospasm after experimental subarachnoid hemorrhage

Abstract

Background and purpose: Cerebral vasospasm is a major cause of morbidity and mortality in patients with subarachnoid hemorrhage (SAH). Cilostazol, a selective inhibitor of phosphodiesterase 3, is a peripheral vasodilator, an anti-inflammatory, and causes antiplatelet aggregation. We investigated these effects on cerebral vasospasm after rat SAH.

Methods: Thirty-eight Sprague–Dawley rats were randomly divided into three groups: SAH + normal feed (SAH group; n=14), SAH + feed containing 0·1% cilostazol (cilostazol group; n=12) and sham-operated rats (sham group; n=12). The basilar arteries (BA) of all groups were analysed by measuring wall thickness, internal luminal perimeter and cross-sectional area on day 7. Immunohistochemical study with RM-4, an anti-rat macrophage/dendritic cells monoclonal antibody and ultrastructural study with transmission electron microscopy were performed.

Results: Although most animals in the SAH group presented with typical vasospasm, the means of inner perimeter and cross-section area of the BA in the cilostazol group were significantly greater than the SAH group (836 ± 134 μm versus 771 ± 125 μm and 39177 ± 15405 μm² versus 33098 ± 13871 μm², respectively). Wall thickness of the BA in the cilostazol group demonstrated significant decrease, compared with the SAH group (17·4 ± 2·3 versus 21·0 ± 2·7 μm). In immunohistological study, SAH induced an obvious increase in mean perivascular RM-4-positive cell count, whereas cilostazol significantly reduced it by 59%. Ultrastructural study depicted cilostazol markedly attenuating structural deterioration of the vascular wall due to SAH.

Conclusions: This work demonstrates that cilostazol attenuates cerebral vasospasm after SAH in rat, possibly in part due to the anti-inflammatory effect.     

蛛网膜下腔出血伴急性脑积水60例临床分析

目的探讨蛛网膜下腔出血（SAH）伴急性脑积水的临床特点及影响预后的相关因素。方法回顾分析60例SAH伴急性脑积水患者的临床资料。结果本组60例SAH伴急性脑积水患者治愈35例,占58．3％;死亡25例,病死率为41．6％,其中血糖升高者病亡率为62．5％,发病有意识障碍者死亡率为60．0％。结论SAH伴急性脑积水的症状体征难以与SAH鉴别,动态CT或MRI检查可确诊,有意识障碍、反应性血糖升高者死亡率显著增加,脑室积血、脑血管痉挛及血压升高的发生率显著增加,是影响预后的重要因素。而SAH伴急性脑积水是导致蛛网膜下腔出血早期死亡的重要因素,动态观察、早期诊治十分重要。