The association between white matter changes and development of malignant middle cerebral artery infarction: A case–control study

Disrupted blood–brain barrier (BBB) in patients with ischemic stroke plays a critical role in malignant middle cerebral artery infarction (MMI) development.Cerebral white matter changes (WMC), particularly in the deep subcortical area or in severe one, may be also underlain by disrupted BBB. It is unclear whether the presence of WMC with potential premorbid disruption of BBB makes patients susceptible to MMI. Therefore, this study aimed to clarify any putative relationship between the MMI and WMC in terms of their severity and locations.In this case–control study, patients with infarction in the middle cerebral artery territory were retrospectively reviewed. Brain magnetic resonance images were analyzed according to Fazekas scale, and identified WMC were divided into periventricular WMC (PV-WMC) and deep subcortical WMC (deep-WMC). Patients were scored as having WMC, PV-WMC, deep-WMC, severe PV-WMC, and severe deep-WMC according to the severity and locations. Patients were defined as having MMI if either a progressive conscious disturbance or signs of uncal herniation was recorded in combination with a midline shift >5 mm identified on the follow-up computed tomography.Among 297 patients admitted between July 2009 and February 2015, 92 patients were eligible for final analysis. Compared to patients without MMI, patients with MMI had a higher score of National Institutes of Health Stroke Scale, a larger infarct volume, and an increasingly greater proportion of severe PV-WMC, deep-WMC, and severe deep-WMC, respectively. After adjustment for sex, age, infarct volume, and history of hypertension, severe deep-WMC (odds ratio [OR] = 6.362, 95% confidence interval [CI] = 1.444–28.023, P = .0144) and severe PV-WMC (odds ratio = 5.608, 95% confidence interval = 1.107–28.399, P = .0372) were significantly associated with MMI development.MMI and WMC are significantly associated such that MMI development is more likely when PV-WMC or deep-WMC is more severe. We hypothesize that Fazekas scale-defined severe deep-WMC and PV-WMC may be considered as clinically approachable predictors of MMI development. These findings support that the WMC with potential premorbid disrupted BBB may make patients susceptible to MMI, and further prospective study should be conducted to clarify this hypothesis.     

云南恶性疟病例疟原虫Pfhrp2基因序列多态性分析董莹1|孙艾明1|2|陈梦妮1|徐艳春1|毛祥华1|邓艳1|杨恒林1*

目的 目的 分析云南省恶性疟病例疟原虫虫株的富组氨酸蛋白Ⅱ （Histidine?rich protein?2,HRPⅡ） 基因 （Pfhrp2） 序 列的多态性, 为研究疟原虫抗原基因缺失奠定基础。方法 方法 搜集2012年8月-2015年9月云南省恶性疟现症病例的滤纸 血样和相关信息, 用PCR技术扩增血样中恶性疟原虫Pfhrp2基因exon2区并测序, 测序成功序列与AY816237、 AY816240、 AY816301参比序列比对; 用Mega 5.04分析Pfhrp2基因exon2区序列多态性, 计算序列间保守位点、 遗传距离 等; 根据氨基酸序列间遗传距离绘制聚类树状图。结果 结果 共收集云南省15个州 （市） 的恶性疟现症病例血样218份, 病例 感染来源地包括云南本地、 非洲、 缅甸等流行区。其中155份Pfhrp2基因exon2区扩增阳性和测序成功, 编码氨基酸数在 115～298之间, 平均为239.7 aa, 非洲 （239.9 aa）、 缅甸 （239.5 aa）、 云南 （241.6 aa） 感染虫株的氨基酸残基均数差异无统计 学意义 （F = 0.025, P > 0.05）。所有氨基酸残基序列均以12型重复作为结尾, 以1型、 2型重复为起始, 比例各占98.1% （152/155） 和1.9% （3/155）, 2型重复次数最多, 为12.9次。155条Pfhrp2 基因exon2区DNA序列的同源位点为894 bp, 保 守位点占20.8% （186/894）, 变异位点占78.2% （699/894）, 非洲虫株序列间遗传距离为0.000～0.741, 缅甸为0.000～ 0.948, 云南为0.000～0.750。所有155条序列按氨基酸序列大小聚类成3个大类, 同一个层级的序列具有近似的序列长 度和氨基酸重复类型。结论 结论 云南省恶性疟现症病例所感染疟原虫的Pfhrp2基因exon2区存在高度多态性, 恶性疟原虫 株主要按Pfhrp2基因exon2区的氨基酸序列长度进行聚类。     

Current animal models of hemophilia: the state of the art

Hemophilia is the most well-known hereditary bleeding disorder, with an incidence of one in every 5000 to 30,000 males worldwide. The disease is treated by infusion of protein products on demand and as prophylaxis. Although these therapies have been very successful, some challenging and unresolved tasks remain, such as reducing bleeding rates, presence of target joints and/or established joint damage, eliminating the development of inhibitors, and increasing the success rate of immune-tolerance induction (ITI). Many preclinical trials are carried out on animal models for hemophilia generated by the hemophilia research community, which in turn enable prospective clinical trials aiming to tackle these challenges. Suitable animal models are needed for greater advances in treating hemophilia, such as the development of better models for evaluation of the efficacy and safety of long-acting products, more powerful gene therapy vectors than are currently available, and successful ITI strategies. Mice, dogs, and pigs are the most commonly used animal models for hemophilia. With the advent of the nuclease method for genome editing, namely the CRISPR/Cas9 system, it is now possible to create animal models for hemophilia other than mice in a short period of time. This review presents currently available animal models for hemophilia, and discusses the importance of animal models for the development of better treatment options for hemophilia.     

Multidetector CT Characteristics of Fumarate Hydratase-Deficient Renal Cell Carcinoma and Papillary Type II Renal Cell Carcinoma

ObjectiveTo investigate the multidetector computed tomography (MDCT) features of fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) with germline or somatic mutations, and compare them with those of papillary type II RCC (pRCC type II).Materials and MethodsA total of 24 patients (mean ± standard deviation, 40.4 ± 14.7 years) with pathologically confirmed FH-deficient RCC (15 with germline and 9 with somatic mutations) and 54 patients (58.6 ± 12.6 years) with pRCC type II were enrolled. The MDCT features were retrospectively reviewed and compared between the two entities and mutation subgroups, and were correlated with the clinicopathological findings.ResultsAll the lesions were unilateral and single. Compared with pRCC type II, FH-deficient RCC was more prevalent among younger patients (40.4 ± 14.7 vs. 58.6 ± 12.6, p < 0.001) and tended to be larger (8.1 ± 4.1 vs. 5.4 ± 3.2, p = 0.002). Cystic solid patterns were more common in FH-deficient RCC (20/24 vs. 16/54, p < 0.001), with 16 of the 20 (80.0%) cystic solid tumors having showed typical polycystic and thin smooth walls and/or septa, with an eccentric solid component. Lymph node (16/24 vs. 16/54, p = 0.003) and distant (11/24 vs. 3/54, p < 0.001) metastases were more frequent in FH-deficient RCC. FH-deficient RCC and pRCC type II showed similar attenuation in the unenhanced phase. The attenuation in the corticomedullary phase (CMP) (76.3% ± 25.0% vs. 60.2 ± 23.6, p = 0.008) and nephrographic phase (NP) (87.7 ± 20.5, vs. 71.2 ± 23.9, p = 0.004), absolute enhancement in CMP (39.0 ± 24.8 vs. 27.1 ± 22.7, p = 0.001) and NP (50.5 ± 20.5 vs. 38.2 ± 21.9, p = 0.001), and relative enhancement ratio to the renal cortex in CMP (0.35 ± 0.26 vs. 0.24 ± 0.19, p = 0.001) and NP (0.43 ± 0.24 vs. 0.29 ± 0.19, p < 0.001) were significantly higher in FH-deficient RCC. No significant difference was found between the FH germline and somatic mutation subgroups in any of the parameters.ConclusionThe MDCT features of FH-deficient RCC were different from those of pRCC type II, whereas there was no statistical difference between the germline and somatic mutation subgroups. A kidney mass with a cystic solid pattern and metastatic tendency, especially in young patients, should be considered for FH-deficient RCC.     

云南省疟疾病例地理聚集特征分析

目的了解云南省疟疾病例的地理分布特征,为疟疾消除工作提供借鉴。方法收集2012-2015年云南省疟疾病例资料,建立数据库并分析病例聚集情况。结果 2012-2015年云南省共计报告疟疾病例2 586例,其中本地感染274例,占10.60%,境外输入2 311例,占89.37%,外省输入1例,占0.03%;按照来源地与病例所在地分别统计境外输入病例数与本地病例数,算术均数分别为96.29和10.96,标准差分别为421.18和19.12,均数差异无统计学意义(Z=-0.326,P0.10)。境外输入区域与本地感染区域的聚集性均可以群集数5来初分,均具备地理聚集的特点。境外输入病例与本地病例的赫尔芬达尔-赫希曼指数分别为8 121和1 598。结论云南省境外感染病例与本地感染病例分布差异不显著,防治工作需要并重进行;境外输入病例的不均匀度比本地感染病例高,但在防治上均可以划分为5个重点集群。     

云南省输入性疟疾病例时间分布特征分析

目的研究云南省输入性疟疾病例的时间分布特征,掌握输入性疟疾的流行动态。方法收集疟疾个案调查表和流行病学资料,剔除本地感染病例,整理归纳并进行统计分析。结果云南省输入性疟疾病例具有季节周期性(Q=26.574,P0.05)和趋势性(Q=35.487,P0.05),输入高峰为5月,低谷为2月,输入病例数差异有统计学意义(Z=-2.619,P0.05)。简单季节性模型为最佳分析预测模型(R~2=0.677,BIC=4.867),残差序列为白噪声(Q=14.226,P0.05)。运用模型对2016年1月、2月、3月的输入性疟疾病例数进行预测,预测值(95%CI)分别为29(7~50)、22(0~44)和31(8~54),实际发病数为29、24和38例,均在预测值的95%CI内。结论云南省输入性疟疾病例具有季节性和趋势性特征,所构建模型对近期病例有较好的预测效果。     

SOX9 was involved in TKIs resistance in renal cell carcinoma via Raf/MEK/ERK signaling pathway

Renal cell carcinoma (RCC) is common genitourinary malignancy in human, 30-40% of patients with RCC would be diagnosed with metastatic RCC (mRCC). Even in the era of targeted therapy, patients with mRCC would inevitably progress due to drug resistance. Herein, exploration of the mechanisms of resistance is noteworthy to study. In the present study, we firstly reported the expression profile of SOX9 in renal carcinoma cells and tissues, and found that its expression was significantly associated with Fuhrman grading. Dual luciferase analysis confirmed that Raf/MEK/ERK pathway could directly be regulated by SOX9, and sequential experiments demonstrated that, renal carcinoma cells could sensitize to Sorafenib/Sunitinib through Raf/MEK/ERK signaling pathway inhibition regulated by SOX9 down-regulation. In a small cases with mRCC treated with Sorafenib/Sunitinib (n=38), comparative analysis showed that patients with SOX9 (-) had much better therapeutic response to TKIs than those with SOX9 (+) (PD: 9.1% vs. 56.2%, P=0.002, DCR: 90.9% vs. 43.8%, P=0.002). Based on these findings, we concluded that, SOX9 was firstly described to be highly expressed in renal cell carcinoma, and its expression was involved in TKIs drug resistance through activation of Raf/MEK/ERK pathway. In vitro, patients with SOX9 (-) was related to better response to TKIs treatment than thoses with SOX9 (+). SOX9 could be expected to be a promising biomarker predicting TKIs response and even expected to be another novel target in the treatment of mRCC.     

Internal carotid artery occlusion related to poorly controlled rheumatoid arthritis presenting with continuous hand shaking: A case report and literature review

Rationale:Limb-shaking syndrome is a special manifestation of transient ischemic attack, resulting from internal carotid artery (ICA) occlusion. Extra-articular manifestations of rheumatoid arthritis (RA) are likely to occur in patients with severe or active RA. RA may accelerate atherosclerotic processes through inflammation. Here, we present a case of ICA occlusion related to poorly controlled RA that presented with continuous hand shaking.Patient concerns:A 73-year-old man with a history of poorly controlled RA developed total occlusion of the right ICA in recent 4 months. He presented with 2 days of continuous and rhythmic left-hand shaking before admission.Diagnosis:The patient was suspected to have transient ischemic attack resulting from ICA occlusion.Interventions:Antiplatelets and antiepileptic drugs were used for continuous nonepileptic focal myoclonus. A disease-modifying antirheumatic drug-based regimen for RA was developed to prevent further atherosclerosis.Outcomes:Following the initial intervention, continuous hand shaking subsided on hospital day 7. Prednisolone was titrated as an active RA control. At the 6-month follow-up visit, neither painful wrist swelling nor recurrent shaking of the hand was noted.Lessons:Continuous hand shaking (nonepileptic focal myoclonus) can be the initial presentation of ICA occlusion in patients with poorly controlled RA. Every patient with RA should be treated aggressively with anti-rheumatic agents since RA is an independent risk factor for stroke. Additionally, every patient with RA should be surveyed for ICA stenosis, especially in those with poor control.     

Repositioning antipsychotic chlorpromazine for treating colorectal cancer by inhibiting sirtuin 1

Investigating existing drugs for repositioning can enable overcoming bottlenecks in the drug development process. Here, we investigated the effect and molecular mechanism of the antipsychotic drug chlorpromazine (CPZ) and identified its potential for treating colorectal cancer (CRC). Human CRC cell lines harboring different p53 statuses were used to investigate the inhibitory mechanism of CPZ. CPZ effectively inhibited tumor growth and induced apoptosis in CRC cells in a p53-dependent manner. Activation of c-jun N-terminal kinase (JNK) was crucial for CPZ-induced p53 expression and the subsequent induction of tumor apoptosis. Induction of p53 acetylation at lysine382 was involved in CPZ-mediated tumor apoptosis, and this induction was attenuated by sirtuin 1 (SIRT1), a class III histone deacetylase. By contrast, knocking down SIRT1 sensitized tumor cells to CPZ treatment. Moreover, CPZ induced the degradation of SIRT1 protein participating downstream of JNK, and JNK suppression abrogated CPZ-mediated SIRT1 downregulation. Clinical analysis revealed a significant association between high SIRT1 expression and poor outcome in CRC patients. These data suggest that SIRT1 is an attractive therapeutic target for CRC and that CPZ is a potential repositioned drug for treating CRC.     

Posterior reversible encephalopathy syndrome (PRES) in a patient with moyamoya disease: A case report

Introduction:Moyamoya disease (MMD) and posterior reversible encephalopathy syndrome (PRES) share similar pathophysiological characteristics of endothelial dysfunction and impaired cerebral autoregulation. However, there have never been any published studies to demonstrate the relationship between these 2 rare diseases.Patient concerns:A 26-year-old Asian man presented with a throbbing headache, blurred vision, and extremely high blood pressure. We initially suspected acute cerebral infarction based on the cerebral computed tomography, underlying MMD, and prior ischemic stroke. However, the neurological symptoms deteriorated progressively.Diagnosis:Cerebral magnetic resonance imaging indicated the presence of vasogenic edema rather than cerebral infarction.Interventions and outcomes:An appropriate blood pressure management prevents the patient from disastrous outcomes successfully. Cerebral magnetic resonance imaging at 2 months post treatment disclosed the complete resolution of cerebral edema. The patient''s recovery from clinical symptoms and the neuroimaging changes supported the PRES diagnosis.Conclusion:This report suggests that patients with MMD may be susceptible to PRES. It highlights the importance of considering PRES as a differential diagnosis while providing care to MMD patients with concurrent acute neurological symptoms and a prompt intervention contributes to a favorable clinical prognosis.