BACKGROUND & AIMS: :Inborn errors of vitamin B(12) (cobalamin) metabolism are characterized by decreased production of active cobalamin cofactors and subsequent deficiencies in the activities of methionine synthase and methylmalonyl-CoA mutase. With the recent discovery of the cblJ defect in two patients with phenotypes mimicking the cblF defect, there are nine genes known to be involved in cobalamin metabolism. The new defect is caused by mutations in the ABCD4 gene, encoding an ABC transporter. At the moment, there is no clear distinction between the cblJ and cblF defects either clinically or biochemically, and both defects result in blocks in the transport of cobalamin from the lysosome to the cytoplasm. A patient was diagnosed with hyperhomocysteinemia and methylmalonic aciduria at the age of 8 years. Incorporations of both [(14)C]propionate and [(14)C]methyltetrahydrofolate in cultured fibroblasts were within reference ranges and thus too high to allow for complementation analysis. We observed decreased synthesis of both adenosylcobalamin and methylcobalamin and accumulation of unmetabolized cyanocobalamin. Exome sequencing was performed to identify causative mutation(s) and Sanger re-sequencing was performed to validate segregation of mutation in the family. By this approach, a homozygous mutation, c.423C>G, in the ABCD4 gene was identified. Here, we report the successful application of exome sequencing for diagnosis of a rare inborn error of vitamin B(12) metabolism in a patient whose unusual presentation precluded diagnosis using standard biochemical and genetic approaches. The patient represents only the third known patient with the cblJ disorder.

背景与目标： ：维生素B（12）（钴胺素）代谢的先天性错误的特征在于活性钴胺素辅因子的产生减少以及蛋氨酸合酶和甲基丙二酰辅酶A突变酶的活性随后不足。随着最近在两名模仿cblF缺陷的表型患者中发现cblJ缺陷，已知有9个基因与钴胺素代谢有关。新的缺陷是由编码ABC转运蛋白的ABCD4基因突变引起的。目前，在临床或生化方面，cblJ和cblF缺陷之间尚无明确区分，并且两种缺陷均导致钴胺素从溶酶体到细胞质的转运受阻。一名患者在8岁时被诊断出患有高同型半胱氨酸血症和甲基丙二酸尿症。 [（14）C]丙酸酯和[（14）C]甲基四氢叶酸在培养的成纤维细胞中的掺入均在参考范围内，因此含量过高，无法进行互补分析。我们观察到腺苷钴胺素和甲基钴胺素的合成减少以及未代谢的氰钴胺素的积累。进行了外显子组测序以鉴定致病突变，并进行了桑格重测序以验证家族中突变的分离。通过这种方法，鉴定出ABCD4基因中的纯合突变，即c.423C> G。在这里，我们报告外显子组测序成功诊断了罕见的先天性维生素B（12）代谢错误的患者，该患者的异常表现使得无法使用标准生化和遗传方法进行诊断。该患者仅代表第三位已知的cblJ疾病患者。

BACKGROUND & AIMS: :Glycogen storage disease type II (GSDII) is a lysosomal disorder caused by the deficient activity of acid alpha-glucosidase (GAA) enzyme, leading to the accumulation of glycogen within the lysosomes. The disease has been classified in infantile and late-onset forms. Most late-onset patients share a splicing mutation c.-32-13T > G in intron 1 of the GAA gene that prevents efficient recognition of exon 2 by the spliceosome. In this study, we have mapped the splicing silencers of GAA exon 2 and developed antisense morpholino oligonucleotides (AMOs) to inhibit those regions and rescue normal splicing in the presence of the c.-32-13T > G mutation. Using a minigene approach and patient fibroblasts, we successfully increased inclusion of exon 2 in the mRNA and GAA enzyme production by targeting a specific silencer with a combination of AMOs. Most importantly, the use of these AMOs in patient myotubes results in a decreased accumulation of glycogen. To our knowledge, this is the only therapeutic approach resulting in a decrease of glycogen accumulation in patient tissues beside enzyme replacement therapy (ERT) and TFEB overexpression. As a result, it may represent a highly novel and promising therapeutic line for GSDII.

背景与目标： ：II型糖原贮积病（GSDII）是一种溶酶体疾病，由酸性α-葡萄糖苷酶（GAA）酶的活性不足引起，导致糖原在溶酶体内积累。该疾病已被分类为婴儿期和晚期发作形式。大多数晚期发病的患者在GAA基因内含子1中共有一个剪接突变c.-32-13T> G，该剪接突变阻止剪接体有效识别外显子2。在这项研究中，我们已经绘制了GAA外显子2的剪接沉默基因，并开发了反义吗啉代寡核苷酸（AMO）以抑制这些区域并在存在c.-32-13T> G突变的情况下拯救正常剪接。通过使用小基因方法和患者成纤维细胞，我们通过结合AMO靶向特定的沉默子，成功增加了外显子2在mRNA和GAA酶生产中的含量。最重要的是，在患者的肌管中使用这些AMO会导致糖原积累减少。据我们所知，这是唯一一种减少酶替代疗法（ERT）和TFEB过表达的导致患者组织中糖原积累减少的治疗方法。结果，它可能代表了GSDII的一种非常新颖和有希望的治疗方法。

BACKGROUND & AIMS: OBJECTIVES:To describe the prevalence of oral diseases and their impact on oral-health-related quality of life in people with severe mental illness undertaking community-based psychiatric care. METHODS:A survey was conducted at eight outpatient psychiatric care clinics in Tower Hamlets, London, UK. One hundred and twelve consecutive patients with mental illness were invited to participate in this study. They were clinically examined and asked to complete the oral health impact profile (OHIP) questionnaire. RESULTS:The response rate was 79% (n = 89); 57 (64%) males and 58 persons over 45 years of age (65%) participated in this survey. Overall OHIP score was 25.4 (95% CI 23.3, 27.4), 70 (78%) were smokers and 45 (51%) had been to the dentist in the last two years. Forty-seven (53%) respondents had caries in at least one tooth, 60 (67%) had 21 teeth and more, and 14 (16%) used dentures. Advanced periodontal treatment was indicated in 42 (55%) of patients and 52.8% (n = 47) patients reported current pain. CONCLUSION:Overall, this survey found that oral health has a great impact on patients with severe mental illness being treated in the community setting and their oral health is poorer than the national adult general population. Future research should consider the causes that relate to the poorer oral health in this population and potential health promotion mechanisms in this population to encourage an upstream approach to health.

背景与目标： 目的：描述接受社区精神病治疗的重度精神疾病患者的口腔疾病患病率及其对口腔健康相关生活质量的影响。
方法：在英国伦敦塔哈姆雷特市的八家门诊精神病诊所进行了一项调查。连续邀请112名精神疾病患者参加这项研究。对他们进行了临床检查，并要求他们填写口腔健康影响概况（OHIP）问卷。
结果：回应率为79％（n = 89）；男性（57％）（64％）和58岁以上的58人（65％）参加了这项调查。 OHIP总体得分为25.4（95％CI 23.3、27.4），吸烟者为70（78％），最近两年去牙医的患者为45（51％）。 47名（53％）的被调查者的至少一颗牙齿上有龋齿； 60（67％）的人有21颗及以上的牙齿，以及14颗（16％）的假牙。 42名（55％）患者表示进行了牙周治疗，目前有疼痛的患者占52.8％（n = 47）。
结论：总体而言，该调查发现，口腔健康对在社区环境中接受治疗的严重精神疾病患者有很大影响，并且其口腔健康比全国成年人口还差。未来的研究应考虑与该人群口腔健康较差的原因以及该人群中潜在的健康促进机制，以鼓励采用上游健康方法。

BACKGROUND & AIMS: BACKGROUND:Early and late dumping are complications of gastric bypass surgery. Early dumping occurs within an hour after eating, when the emptying of food into the small intestine triggers rapid fluid shifts into the intestinal lumen and the release of gastrointestinal hormones, resulting in gastrointestinal and vasomotor symptoms. Late dumping occurs between 1 and 3 hours after carbohydrate ingestion and is caused by an exaggerated insulin release, resulting in hypoglycemia. Almost no data are currently available on the prevalence of early and late dumping or their impact on health-related quality of life (QoL). OBJECTIVES:To study the prevalence of early and late dumping in a large population of patients having undergone a primary Roux-en-Y gastric bypass (RYGB) and its effect on QoL. SETTING:Cross-sectional study at a single bariatric department in the Medical Center Leeuwarden, The Netherlands between 2008 and 2011. METHODS:In 2013, this descriptive cohort study approached by email or post all patients who underwent a primary RYGB in the setting between 2008 and 2011 in one hospital. These patients were asked to fill in standardized questionnaires measuring their QoL (RAND-36), anxiety and depression (HADS), fatigue (MFI-20) and any disease specific indicators of early and late dumping syndrome. RESULTS:The questionnaire was completed and returned by 351 of 613 patients (57.1%) and 121 nonobese volunteers. Participants were mostly female (80%), aged 42 (40-54 years), with an excess weight loss of 76.8% [IQR 61-95] after RYGB surgery 2.3 [ IQR 1.6-3.4] years earlier. Self-reported complaints of moderate to severe intensity suggestive of early and late dumping were present in 18.8% and 11.7% of patients, respectively. Patients with early and late dumping demonstrated significantly lower scores on the RAND-36 and HADS compared with patients without dumping. No differences were seen in the MFI-20 scores between patients with or without early and late dumping. CONCLUSION:In this descriptive cohort, self-reported complaints suggestive of early and late dumping of moderate-to-severe intensity were, respectively, 18.8% and 11.7% in a cohort after primary gastric bypass surgery. These complaints were associated with markedly reduced health-related QoL.

背景与目标： 背景：早期和晚期倾倒是胃搭桥手术的并发症。进食后一小时内会发生早期倾倒，这是因为食物排入小肠会触发液体快速进入肠腔并释放胃肠激素，从而导致胃肠道和血管舒缩症状。延迟进食发生在摄入碳水化合物后的1至3个小时之间，并且是由于胰岛素释放过大引起的，从而导致低血糖症。目前几乎没有关于早期和晚期倾倒的流行率及其对健康相关生活质量（QoL）的影响的数据。
目的：研究大量初次Roux-en-Y胃搭桥术（RYGB）患者的早期倾倒和晚期倾倒的患病率及其对生活质量的影响。
地点：2008年至2011年，在荷兰吕伐登医学中心的单个减肥科进行横断面研究。
方法：2013年，该描述性队列研究通过电子邮件或将所有在2008年至2011年之间在某医院接受原发性RYGB治疗的患者纳入研究。这些患者被要求填写标准化问卷，以测量他们的生活质量（RAND-36），焦虑和抑郁（HADS），疲劳（MFI-20）以及早期和晚期倾倒综合征的任何疾病特异性指标。
结果：613例患者中的351例（占57.1％）和121例非肥胖志愿者完成了问卷调查并返回。参与者主要是女性（80％），42岁（40-54岁），在RYGB手术2.3年[IQR 1.6-3.4]之前，体重减轻了76.8％[IQR 61-95]。自我报告的中度至重度暗示早期和晚期倾倒的投诉分别占患者的18.8％和11.7％。与没有倾倒的患者相比，早期和晚期倾倒的患者在RAND-36和HADS上的得分明显较低。在有或没有早期和晚期倾倒的患者之间，MFI-20评分均未见差异。
结论：在这个描述性队列中，自我报告的关于初次胃旁路手术后队列中早期至晚期倾倒中度至重度的抱怨分别为18.8％和11.7％。这些投诉与健康相关的生活质量显着降低有关。

BACKGROUND & AIMS: OBJECTIVE:Studies have reported that up to 60% of individuals with schizophrenia are overweight or obese. This study explored the relationship between obesity and health-related quality of life (HRQoL) in Chinese patients with schizophrenia. METHODS:A total of 1,108 patients with schizophrenia aged 18-50 years were recruited from 10 different sites in China. Demographic and medical information were collected; the Mandarin version of Short Form 36 Health Survey questionnaire (SF-36) was used to assess HRQoL; in addition,height and weight were measured to calculate body mass index (BMI). BMI was categorized into underweight, normal weight, overweight and obese using cutoffs for Asian populations recommended by the World Health Organization. RESULTS:Fifty-six percent of participants with schizophrenia were overweight or obese. A higher BMI was associated with significantly lower scores in physical functioning, role-physical, and physical component summary (p's ≤ 0.010). Obese patients with schizophrenia had significantly lower scores in 3 domains and physical component summary of the SF-36 compared with normal weight patients (p's ≤ 0.007). CONCLUSION:Obesity is associated with decreased HRQoL in Chinese patients with schizophrenia. Our findings suggest that the prevention and management of weight gain and obesity is important in improving HRQoL in patients who suffer from this devastating mental illness.

背景与目标： 目的：研究报告称，多达60％的精神分裂症患者超重或肥胖。这项研究探讨了肥胖与中国精神分裂症患者健康相关生活质量（HRQoL）之间的关系。
方法：从中国10个不同地区招募了1108名18至50岁的精神分裂症患者。收集了人口和医疗信息；简短的36号健康调查问卷的中文版（SF-36）用于评估HRQoL；另外，测量身高和体重以计算体重指数（BMI）。根据世界卫生组织（WHO）推荐的针对亚洲人群的临界值，将BMI分为体重过轻，正常体重，超重和肥胖。
结果：精神分裂症参与者中有56％是超重或肥胖。较高的BMI与身体机能，角色-身体和身体组成部分摘要中的得分明显较低有关（p≤0.010）。与正常体重的患者相比，肥胖的精神分裂症患者在3个领域和SF-36的物理成分摘要方面得分明显较低（p≤0.007）。
结论：肥胖与中国精神分裂症患者的HRQoL降低有关。我们的研究结果表明，预防和控制体重增加和肥胖对改善患有这种毁灭性精神疾病的患者的HRQoL很重要。

BACKGROUND & AIMS: OBJECTIVE:To compare EuroQol 5-Dimensions (EQ-5D) utility and quality-adjusted life-years (QALYs) in patients with early, methotrexate (MTX) refractory rheumatoid arthritis (RA), randomised to addition of infliximab (IFX) or sulfasalazine and hydroxychloroquine (SSZ+HCQ). METHODS:RA-patients with symptoms <1 year were enrolled between 2002 and 2005 at 15 Swedish centres. After 3-4 months of MTX monotherapy, patients with a remaining DAS28>3.2 were randomised to addition of IFX or SSZ+HCQ and followed for 21 months. EQ-5D profiles were collected every 3 months. Between-group comparisons of utility change and accumulated QALYs were performed, using last observation carried forward (LOCF) following protocol breach. Missing data were imputed by linear interpolation or LOCF. Sensitivity analyses applying baseline observation carried forward (BOCF) or restricted to completers were conducted. RESULTS:Of 487 patients initially enrolled, 128 and 130 were randomised to IFX or SSZ+HCQ, respectively. Mean utility in the IFX and SSZ+HCQ groups increased from 0.52 (SD 0.27) and 0.55 (SD 0.27) at randomisation to 0.66 (SD 0.25) and 0.63 (SD 0.27) at 21 months (adjusted mean difference favouring IFX 0.04; 95% CI -0.01, 0.09; p=0.15). Average accumulated QALYs were 1.10 (SD 0.37) and 1.07 (SD 0.42) in the IFX and SSZ+HCQ groups, respectively (adjusted mean difference favouring IFX 0.07; 95%CI -0.01, 0.14; p=0.07). BOCF analysis showed similar results, while differences were reversed, though remained statistically non-significant among completers. Dropout rates in the IFX/SSZ+HCQ groups were 30%/43% (p=0.01). CONCLUSIONS:Comparing addition of IFX or SSZ+HCQ to MTX in active early RA, no statistically significant differences in utility or QALY gain could be detected over 21 months. TRIAL REGISTRATION:Registered in WHO database at the Karolinska University Hospital, number CT20080004.

背景与目标： 目的：比较早期甲氨蝶呤（MTX）难治性类风湿关节炎（RA）患者的EuroQol 5-Dimensions（EQ-5D）效用和质量调整生命年（QALYs），随机添加英夫利昔单抗（IFX）或柳氮磺吡啶和羟氯喹（SSZ HCQ）。
方法：2002年至2005年间，在瑞典的15个中心招募了症状<1年的RA患者。在MTX单药治疗3-4个月后，将DAS28> 3.2的患者随机添加IFX或SSZ HCQ，然后随访21个月。每3个月收集一次EQ-5D配置文件。进行了效用变化和累积QALY的组间比较，使用违反协议后的最新结转结果（LOCF）。缺失数据通过线性插值或LOCF估算。进行了敏感性分析，采用基线观察结转（BOCF）或仅限于完成者。
结果：在最初入组的487例患者中，分别有128例和130例被随机分配到IFX或SSZ HCQ。 IFX和SSZ HCQ组的平均效用从随机分配时的0.52（SD 0.27）和0.55（SD 0.27）增加到21个月时的0.66（SD 0.25）和0.63（SD 0.27）（调整后的平均差异有利于IFX 0.04; 95％CI -0.01，0.09； p ＝ 0.15）。 IFX和SSZ HCQ组的平均累积QALYs分别为1.10（SD 0.37）和1.07（SD 0.42）（校正后的平均差异有利于IFX 0.07; 95％CI -0.01，0.14; p = 0.07）。 BOCF分析显示了相似的结果，尽管差异在统计学上没有显着差异，但差异却可以逆转。 IFX / SSZ HCQ组的辍学率为30％/ 43％（p = 0.01）。
结论：在活跃的早期RA中，将IFX或SSZ HCQ加入MTX的比较，在21个月内未发现效用或QALY增益有统计学意义的差异。
试验注册：在卡罗林斯卡大学医院的世界卫生组织数据库中注册，编号CT20080004。

BACKGROUND & AIMS: :Although affective disorders have been known to have sex differences in the associated clinical characteristics and quality of life (QOL), sex differences among patients with panic disorder (PD) have remained relatively unexplored in Korea. We examined the sex differences in different types of stressful life events (SLEs), coping styles, symptom severity, and health-related QOL (HRQOL) in patients with PD. Data from 291 female and 254 male participants diagnosed with PD were analyzed using a structured clinical interview following the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria. Females with PD reported more SLEs including separation issues, physical illness or disability, and pregnancy-related problems than males. They also reported lower levels of confrontation and help-seeking coping strategies and higher levels of agoraphobia in symptom severity than males. The HRQOL of females with PD was significantly lower than male in physical functioning of HRQOL. This study suggests that the patient's sex is relevant to the assessment and treatment of PD.

背景与目标： ：尽管已知情感障碍在相关的临床特征和生活质量（QOL）中存在性别差异，但在韩国，恐慌症（PD）患者之间的性别差异仍未得到开发。我们检查了PD患者不同类型的应激性生活事件（SLE），应对方式，症状严重程度和健康相关的QOL（HRQOL）的性别差异。根据《精神障碍诊断和统计手册》第4版标准，使用结构化临床访谈分析了291名诊断为PD的女性和254名男性参与者的数据。患有PD的女性比男性报告了更多的SLE，包括分离问题，身体疾病或残疾以及与怀孕有关的问题。他们还报告说，与男性相比，对抗和寻求帮助的应对措施水平较低，症状严重程度的恐惧症水平更高。女性的PD的HRQOL在HRQOL的身体机能上明显低于男性。这项研究表明，患者的性别与PD的评估和治疗有关。

BACKGROUND & AIMS: OBJECTIVE:To explore the prognostic value of the postsurgical half-life (HL) of serum alpha-fetoprotein (AFP). BACKGROUND:There is still a paucity of early surrogate indicators of clinical endpoints after liver resection of hepatocellular carcinoma (HCC). METHODS:The analysis was based on cohorts of 225 (exploration set) and 117 (validation set) treatment-naïve HCC patients undergoing curative liver resection. We defined 3 categories of AFP HL: early complete resolution of AFP, normal HL, and prolonged HL if the HL exceeded 7 days. Overall, probabilities of recurrence and survival were estimated and compared across the AFP HL categories. RESULTS:In the exploration cohort, 48 patients (21.3%) achieved early AFP complete resolution, 116 (51.6%) had normal HL, and 61 (27.1%) had prolonged HL. Long AFP HL was significantly associated with early postoperative recurrence (P < 0.001), as was microvascular invasion. Early recurrence within 2 years of resection was observed in 59% of the patients with prolonged AFP HL compared with only 29.3% of those with normal AFP HL (P < 0.001). A log-rank test followed by multivariate Cox analysis identified an independent function of prolonged AFP HL in predicting shorter recurrence-free survival and overall survival time after HCC resection (hazard ratios, 2.81 and 3.58; P < 0.001). When AFP HL analysis was applied to the validation cohort, the association between prolonged AFP HL and survival endpoints (hazard ratio, 11.63 and 16.39; P < 0.001) was confirmed.

背景与目标： 目的：探讨血清甲胎蛋白（AFP）的术后半衰期（HL）的预后价值。
背景：肝切除肝细胞癌（HCC）后仍缺乏临床终点的早期替代指标。
方法：该分析基于225例（探索组）和117例（验证组）未进行过根治性肝切除的未接受治疗的HCC患者的分析。我们定义了AFP HL的3个类别：AFP的早期完全消退，正常HL和如果HL超过7天则延长HL。总体而言，估计并比较了AFP HL类别中复发和存活的可能性。
结果：在探索队列中，有48例（21.3％）的患者达到了AFP的早期完全缓解，HL正常的116例（51.6％），HL延长的61例（27.1％）。长期AFP HL与微血管浸润与术后早期复发显着相关（P <0.001）。 AFP HL延长的患者中有59％的患者在切除后2年内出现了早期复发，而AFP HL正常的患者中只有29.3％（P <0.001）。对数秩检验和随后的多元Cox分析确定了AFP HL延长在预测肝癌切除术后较短的无复发生存期和总生存期方面具有独立的功能（危险比，2.81和3.58； P <0.001）。当将AFP HL分析应用于验证队列时，证实了延长的AFP HL与生存终点之间的关联（危险比：11.63和16.39； P <0.001）。

BACKGROUND & AIMS: :A 31-year-old woman complained of dyspnea and orthopnea at 38 weeks of gestation. A grade 3/6 pansystolic murmur was heard, and echocardiography revealed severe mitral regurgitation with a hyperechoic obstacle on the posterior mitral valve leaflet, consistent with a diagnosis of acute heart failure due to a ruptured chordae tendineae or an infectious endocarditis. An emergency cesarean section was performed under general anesthesia. A male infant was born weighing 2928 g with Apgar scores of 7 and 8 at 1 and 5 min, respectively. The patient was managed in the intensive care unit and underwent open-heart surgery for mitral valve repair on postpartum day 3. The two chordal tendineae appeared torn and frail, and a mitral annuloplasty was performed. No finding of infectious endocarditis was observed. Because it is a dramatic and life-threatening clinical situation, proper diagnosis and treatment in the intensive care unit assure a good outcome for both mother and fetus.

背景与目标： ：一名31岁妇女在妊娠38周时主诉呼吸困难和正气呼吸。听到了3/6级的收缩期杂音，超声心动图显示二尖瓣反流严重，二尖瓣后叶上有高回声障碍，与诊断为腱索破裂或感染性心内膜炎导致的急性心力衰竭相符。全身麻醉下进行紧急剖宫产。一名男婴出生时体重为2928微克，在1分钟和5分钟时Apgar得分分别为7和8。患者在重症监护病房接受治疗，并在产后第3天接受心脏直视手术以修复二尖瓣。两个腱腱均出现撕裂和脆弱，并进行了二尖瓣瓣环成形术。没有发现感染性心内膜炎。由于这是一种戏剧性且危及生命的临床情况，因此在重症监护室进行正确的诊断和治疗可确保母亲和胎儿均获得良好的治疗效果。