MeDS

  • 文章类型: Case Reports
    最近,一种常染色体隐性遗传疾病,包括小头畸形三联症,婴儿癫痫性脑病,和永久性新生儿糖尿病综合征(MEDS,OMIM#614231)已成为一种新的区分综合征。八例其中七例来自阿拉伯国家,已报道与IER3IP1基因(立即早期反应-3相互作用蛋白-1)中的双等位基因变体相关。这里,我们描述了一个患有永久性新生儿糖尿病的突尼斯男孩,小头畸形,全身性癫痫发作和由小生殖器和单侧隐睾组成的低病毒外生殖器。染色体分析表明,所有中期的核型均为46,XY。外显子组测序鉴定了IER3IP1基因中的纯合错义变体(c.62T>G;p。Val21Gly),预测会改变疏水/跨膜内的蛋白质结构。先前在两个与MEDS相关的病例中报道了该变体。这是突尼斯报告的第一例MEDS病例。我们的报告着重于IER3IP1相关的表型谱,并假定生殖器异常是该综合征的一部分。因此,我们建议对该主题进行激素检测,以了解IER3IP1变异体对男性生殖器通路的影响.
    Recently, an autosomal recessive disorder including the triad of microcephaly, infantile epileptic encephalopathy, and permanent neonatal diabetes syndrome (MEDS, OMIM#614231) has emerged as a new distinguishing syndrome. Eight cases of whom seven from Arab countries, have been reported in association with biallelic variants in the IER3IP1 gene (Immediate early response-3 interacting protein-1). Here, we describe a Tunisian boy who presented with permanent neonatal diabetes, microcephaly, generalized seizures and hypovirilized external genitalia consisting of a small genitalia and unilateral cryptorchidism. Chromosomal analysis indicated a 46, XY karyotype in all metaphases. Exome sequencing identified a homozygous missense variant (c.62 T > G; p. Val21Gly) in the IER3IP1 gene, that is predicted to alter the protein structure within the hydrophobic/transmembrane. This variant was previously reported in two cases associated with MEDS. This is the first reported case of MEDS in Tunisia. Our report focuses on the IER3IP1 related phenotypic spectrum and assumes abnormal genitalia as part of the syndrome. Consequently, we recommend to perform hormonal testing on this topic to understand the effect of the IER3IP1 variant on the male genital pathway.
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  • 文章类型: Journal Article
    背景:神经管缺陷(NTDs)是人类最常见和最严重的先天性缺陷之一。他们的遗传病因很复杂,仍然知之甚少。介体复合体(MED)在动物模型的神经管发育中起着至关重要的作用。然而,尚未有研究检查其人类同源物在NTDs病因中的作用。
    方法:在本研究中,来自NTD的48对神经损伤部位和脐带组织以及21个病例-亲本三重奏参与筛选NTD相关的体细胞和种系从头变异。进行一系列功能细胞测定。我们使用CRISPR/Cas9技术产生了Med12p.Arg1784Cys敲入小鼠来验证人类发现。
    结果:一个体细胞变体,MED12p.Arg1782Cys,在NTD胎儿的病变部位组织中鉴定。该变体在同一病例的不同胚层的任何其他正常组织中都不存在。在21个案例父三重奏中,一个从头停止增益变体,MED13Lp.Arg1760*,已确定。细胞功能研究表明,MED12p.Arg1782Cys降低了MED12蛋白水平,并影响了MED12对经典WNT信号通路的调节。Med12p.Arg1784Cys敲入小鼠表现出脑外裂和脊柱裂。
    结论:这些发现提供了强有力的证据,证明MED基因的功能变异与某些NTDs的病因有关。我们证明了体细胞变异在NTDs发生中的潜在重要作用。我们的研究是第一个使用CRISPR/Cas9技术在小鼠中验证在人类中鉴定的NTD相关变体的研究。
    BACKGROUND: Neural tube defects (NTDs) are among the most common and severe congenital defects in humans. Their genetic etiology is complex and remains poorly understood. The Mediator complex (MED) plays a vital role in neural tube development in animal models. However, no studies have yet examined the role of its human homolog in the etiology of NTDs.
    METHODS: In this study, 48 pairs of neural lesion site and umbilical cord tissues from NTD and 21 case-parent trios were involved in screening for NTD-related somatic and germline de novo variants. A series of functional cell assays were performed. We generated a Med12 p.Arg1784Cys knock-in mouse using CRISPR/Cas9 technology to validate the human findings.
    RESULTS: One somatic variant, MED12 p.Arg1782Cys, was identified in the lesion site tissue from an NTD fetus. This variant was absent in any other normal tissue from different germ layers of the same case. In 21 case-parent trios, one de novo stop-gain variant, MED13L p.Arg1760∗, was identified. Cellular functional studies showed that MED12 p.Arg1782Cys decreased MED12 protein level and affected the regulation of MED12 on the canonical-WNT signaling pathway. The Med12 p.Arg1784Cys knock-in mouse exhibited exencephaly and spina bifida.
    CONCLUSIONS: These findings provide strong evidence that functional variants of MED genes are associated with the etiology of some NTDs. We demonstrated a potentially important role for somatic variants in the occurrence of NTDs. Our study is the first study in which an NTD-related variant identified in humans was validated in mice using CRISPR/Cas9 technology.
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  • 文章类型: Letter
    暂无摘要。
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  • 文章类型: Journal Article
    OBJECTIVE: Scoring systems have been used to risk stratify in intensive care units (ICU), but not routinely used in emergency departments. The aim of this study was to determine accuracy for predicting mortality in emergency medicine with Sequential Organ Failure Assessment (SOFA), Mortality in ED Sepsis (MEDS) score and Simplified Acute Physiology Score (SAPSII).
    METHODS: This is a prospective observational study. Patients presenting with evidence of sepsis were all included. SAPSII, MEDS, and SOFA scores were calculated. Analysis compared areas under the receiver operator characteristic (ROC) curves for 28-day mortality.
    RESULTS: Two hundred patients were included; consisting of 31 (14.3%) septic shock. 138 (69%) severe sepsis and 31 (15.5%) infection without organ dysfunction. 53 (26.5%) patients died within 28 days. Area under the ROC curve for mortality was 0.76 for MEDS (0.69-0.82), 0.70 for SAPSII (0.62-0.78); and 1.68 for SOFA (0.60-0.76) scores. Pair wise comparison of AUC between MEDS, SAPSII, SOFA and Lactate were not significant.
    CONCLUSIONS: According to our results; SOFA, SAPSII and MEDS were not sufficient to predict mortality. Also this result, MEDS was better than other scoring system.
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  • 文章类型: Journal Article
    BACKGROUND: Soluble thrombomodulin (sTM) is a sensitive marker of endothelial damage. In this study we investigated the role of sTM in the evaluation of the severity and prognosis of septic patients in the emergency department (ED).
    METHODS: A prospective, observational cohort study was performed in the ED of an urban, university hospital. Patients who had suspected infection with two or more criteria of systemic inflammatory response syndrome were consecutively enrolled. sTM, D-Dimer and procalcitonin levels were measured on enrollment, and the Mortality in Emergency Department Sepsis (MEDS) score was calculated. A 30-day follow-up was performed for all patients.
    RESULTS: A total of 372 patients with sepsis, 210 patients with severe sepsis and 98 patients with septic shock were enrolled in this study. According to the disease severity, patients were divided into sepsis subgroup and severe sepsis subgroup (including septic shock). In addition, patients were divided into survivors subgroup and non-survivors subgroup according to the 30-day mortality. Plasma sTM levels in patients with severe sepsis were higher than those with sepsis (P<0.001). Compared with survivors, non-survivors has higher plasma sTM levels (P<0.001). Multivariate logistic regression analysis showed that sTM was an independent predictor of severe sepsis (odds ratio 1.11) and 30-day mortality (odds ratio 1.059). Receiver operating characteristic curve analysis showed that sTM was a useful parameter in prediction of severe sepsis (0.859) and 30-day mortality (0.78). Compared with the MEDS score alone, combination of sTM and the MEDS score can improve the accuracy in prediction of severe sepsis and 30-day mortality.
    CONCLUSIONS: sTM is a valuable biomarker in the risk stratification and prognosis evaluation of ED sepsis. Furthermore, sTM can enhance the ability of the MEDS score in prediction of severe sepsis and 30-day mortality.
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  • 文章类型: Journal Article
    OBJECTIVE: The Geriatric Nutritional Risk Index (GNRI) is a screening tool for nutrition-related risk that correlates with mortality rate in hospitalized older patients and is simple, objective, and readily available to clinicians. In this study, we aimed to validate the performance of the GNRI in predicting short-term hospital mortality in older patients with sepsis.
    METHODS: This observational study enrolled 401 older patients presenting with infection and systemic inflammatory response syndrome in an emergency department. Demographic, physiological, and laboratory data were collected. The GNRI score was categorized into five classes. The primary outcome was 28-day hospital mortality. Univariate and multivariate analyses were performed to identify clinical predictors of outcome. A logistic regression model was used.
    RESULTS: 51 patients (12.7%) died in the hospital within 28 days. Co-morbid metastatic cancer, heart rate, respiratory rate, temperature, serum creatinine, total lymphocyte count, and GNRI (<87) were independently related to the outcome in the multivariable logistic regression analysis.
    CONCLUSIONS: The GNRI is a prognostic factor for short-term hospital mortality in older patients with sepsis. A GNRI below 87 can be suggested as an indicator of nutritional support need in an acute-care setting.
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