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Sarcopenia: Pathophysiology and Treatment Strategies. 肌肉疏松症:病理生理学与治疗策略。
IF 1.9 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-01-01 DOI: 10.2174/1871530323666230518105408
Chaoming Qiu, Xifei Yang, Pei Yu

Sarcopenia is becoming prevalent in older or inactive patients, which is placing a heavy burden on the social health system. Studies on the pathogenesis of sarcopenia mainly focus on adipose tissue, myoglobin autophagy, and mitochondrial dysfunction. Up to now, non-drug treatment has been the main way to treat sarcopenia, and there are no drugs specially approved for the treatment of sarcopenia. Here, the pathophysiology and treatment methods of sarcopenia have been summarized, and new drugs for sarcopenia to be researched and developed in the future have been prospected.

肌肉疏松症在年长或不活跃的患者中越来越普遍,给社会医疗系统带来沉重负担。有关 "肌肉疏松症 "发病机制的研究主要集中在脂肪组织、肌红蛋白自噬和线粒体功能障碍等方面。迄今为止,非药物治疗一直是治疗肌肉疏松症的主要方法,也没有专门批准用于治疗肌肉疏松症的药物。本文总结了肌肉疏松症的病理生理学和治疗方法,并展望了未来研究和开发的治疗肌肉疏松症的新药物。
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引用次数: 0
New Promising Routes in Peptic Ulcers: Toll-like Receptors and Semaphorins. 治疗消化性溃疡的新途径:Toll-like Receptors and Semaphorins.
IF 1.9 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-01-01 DOI: 10.2174/1871530323666230821102718
Teresa V Jacob, Gaurav M Doshi

Peptic ulcers (PU) are one of the commonest yet problematic diseases found to be existing in the majority of the population. Today, drugs from a wide range of therapeutic classes are available for the management of the disease. Still, the complications of the condition are difficult to tackle and the side effect profile is quite a concern. The literature indicates that Toll-like receptors (TLRs) and Semaphorins (SEMAs) have been under study for their various pharmacological actions over the past few decades. Both these signalling pathways are found to regulate immunological and inflammatory responses. Moreover, receptors and signalling molecules from the family of TLRs and SEMAs are found to have bacterial recognition and antibacterial properties which are essential in eradicating Helicobacter pylori (H. pylori), one of the major causative agents of PU. Our understanding of SEMAs, a class of proteins involved in cell signalling, is relatively less developed compared to TLRs, another class of proteins involved in the immune response. SEMAs and TLRs play different roles in biological processes, with SEMAs primarily involved in guiding cell migration and axon guidance during development, while TLRs are responsible for recognizing pathogens and initiating an immune response. Here, in this review, we will discuss in detail the signalling cascade of TLRs and SEMAs and thereby understand its association with PU for future therapeutic targeting. The review also aims at providing an overview of the study that has been into exploring the role of these signalling pathways in the management of PU.

消化性溃疡(PU)是大多数人最常见的疾病之一,但也是最棘手的疾病之一。如今,治疗该疾病的药物种类繁多。然而,该病的并发症仍然难以解决,其副作用也相当令人担忧。文献表明,在过去几十年中,人们一直在研究 Toll 样受体(TLRs)和 Semaphorins(SEMAs)的各种药理作用。研究发现,这两种信号通路都能调节免疫和炎症反应。此外,还发现 TLRs 和 SEMAs 家族的受体和信号分子具有细菌识别和抗菌特性,这对于根除幽门螺杆菌(H. pylori)至关重要,而幽门螺杆菌是 PU 的主要致病菌之一。与参与免疫反应的另一类蛋白质 TLRs 相比,我们对 SEMA(一类参与细胞信号传递的蛋白质)的了解相对较少。SEMAs和TLRs在生物过程中发挥着不同的作用,SEMAs主要参与发育过程中的细胞迁移和轴突导向,而TLRs则负责识别病原体并启动免疫反应。在本综述中,我们将详细讨论 TLRs 和 SEMAs 的信号级联,从而了解其与 PU 的关联,为今后的治疗提供靶点。本综述还旨在概述探索这些信号通路在治疗 PU 中的作用的研究。
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引用次数: 0
Autoimmune Responses and Therapeutic Interventions for Systemic Lupus Erythematosus: A Comprehensive Review. 系统性红斑狼疮的自身免疫反应和治疗干预:全面回顾。
IF 1.9 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-01-01 DOI: 10.2174/1871530323666230915112642
Surya Prakash Pandey, Rakesh Bhaskar, Sung Soo Han, Kannan Badri Narayanan

Systemic Lupus Erythematosus (SLE) or Lupus is a multifactorial autoimmune disease of multiorgan malfunctioning of extremely heterogeneous and unclear etiology that affects multiple organs and physiological systems. Some racial groups and women of childbearing age are more susceptible to SLE pathogenesis. Impressive progress has been made towards a better understanding of different immune components contributing to SLE pathogenesis. Recent investigations have uncovered the detailed mechanisms of inflammatory responses and organ damage. Various environmental factors, pathogens, and toxicants, including ultraviolet light, drugs, viral pathogens, gut microbiome metabolites, and sex hormones trigger the onset of SLE pathogenesis in genetically susceptible individuals and result in the disruption of immune homeostasis of cytokines, macrophages, T cells, and B cells. Diagnosis and clinical investigations of SLE remain challenging due to its clinical heterogeneity and hitherto only a few approved antimalarials, glucocorticoids, immunosuppressants, and some nonsteroidal anti-inflammatory drugs (NSAIDs) are available for treatment. However, the adverse effects of renal and neuropsychiatric lupus and late diagnosis make therapy challenging. Additionally, SLE is also linked to an increased risk of cardiovascular diseases due to inflammatory responses and the risk of infection from immunosuppressive treatment. Due to the diversity of symptoms and treatment-resistant diseases, SLE management remains a challenging issue. Nevertheless, the use of next-generation therapeutics with stem cell and gene therapy may bring better outcomes to SLE treatment in the future. This review highlights the autoimmune responses as well as potential therapeutic interventions for SLE particularly focusing on the recent therapeutic advancements and challenges.

系统性红斑狼疮(SLE)或狼疮是一种影响多个器官和生理系统的多因素自身免疫性疾病,多器官功能失调,病因极为复杂且不明确。一些种族群体和育龄妇女更容易受到系统性红斑狼疮发病机制的影响。在更好地了解导致系统性红斑狼疮发病的不同免疫成分方面,已经取得了令人瞩目的进展。最近的研究发现了炎症反应和器官损伤的详细机制。各种环境因素、病原体和毒物,包括紫外线、药物、病毒病原体、肠道微生物代谢产物和性激素,都会诱发遗传易感人群的系统性红斑狼疮发病,并导致细胞因子、巨噬细胞、T 细胞和 B 细胞的免疫平衡被破坏。由于其临床异质性,系统性红斑狼疮的诊断和临床研究仍具有挑战性,迄今为止,只有少数几种经批准的抗疟药、糖皮质激素、免疫抑制剂和一些非甾体抗炎药(NSAIDs)可用于治疗。然而,肾性狼疮和神经精神性狼疮的不良反应以及诊断较晚使治疗面临挑战。此外,系统性红斑狼疮还与炎症反应导致的心血管疾病风险增加以及免疫抑制治疗带来的感染风险有关。由于系统性红斑狼疮的症状和耐药性多种多样,其治疗仍然是一个具有挑战性的问题。然而,干细胞和基因疗法等新一代疗法的使用可能会为系统性红斑狼疮的治疗带来更好的结果。本综述重点介绍系统性红斑狼疮的自身免疫反应以及潜在的治疗干预措施,尤其关注近期的治疗进展和面临的挑战。
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引用次数: 0
Emerging Insights and Global Trends in the Relationship between Selenium and Thyroid Diseases: A Bibliometric Analysis. 硒与甲状腺疾病关系的新见解和全球趋势:文献计量分析。
IF 1.9 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-01-01 DOI: 10.2174/1871530323666230918121353
Yuqing Wu, Tiantian Cai, Yuan Tao, Jing Zhao, Jinan Zhang

Objective: Selenium, a significant trace element needed by the human body, is closely related to thyroid. Therefore, this study aimed to explore the status of selenium and thyroid diseases, analyze emerging insights, and predict future trends.

Methods: Literature on selenium and thyroid included in the core database of Web of Science from January 1992 to October 2022 was retrieved. CiteSpace and VOSviewer software were used for visual analysis in terms of publication, author, country, institution, co-citation, and keywords.

Results: A total of 1,142 works of literature were included after the screening, and the annual publication showed a fluctuating upward trend. The country and the institution with the highest publication volume were the United States and Charité Universitätsmedizin Berlin, respectively. In terms of authors, Schomburg L has formed a cooperative network and has published the largest number of papers and made great contributions in this field. The biggest cluster of keywords was trace elements, and the hot keywords in recent years were oxidative stress, Hashimoto's thyroiditis, cadmium, copper, etc. Conclusion: This paper analyzes the current status, insights, and trends of the studies on selenium and thyroid diseases by the method of bibliometrics and delivers ideas and methods for subsequent research in this field. The therapeutic effect of selenium on Hashimoto's thyroiditis is controversial and needs further research, and oxidative stress is also a research hotspot in this field. The crossstudy of multiple trace elements and diseases may be the development trend in the future.

目的:硒是人体所需的重要微量元素,与甲状腺密切相关。因此,本研究旨在探讨硒与甲状腺疾病的现状,分析新的见解,预测未来趋势:方法:检索1992年1月至2022年10月Web of Science核心数据库中有关硒与甲状腺的文献。使用 CiteSpace 和 VOSviewer 软件从出版物、作者、国家、机构、共同引用和关键词等方面进行可视化分析:经过筛选,共收录了 1 142 篇文献,年发表量呈波动上升趋势。发表量最高的国家和机构分别是美国和柏林夏里特大学。在作者方面,Schomburg L形成了一个合作网络,发表的论文数量最多,在该领域做出了巨大贡献。最大的关键词群是微量元素,近年来的热门关键词是氧化应激、桥本氏甲状腺炎、镉、铜等。结论本文通过文献计量学的方法,分析了硒与甲状腺疾病研究的现状、启示和趋势,为该领域的后续研究提供了思路和方法。硒对桥本氏甲状腺炎的治疗效果尚存争议,有待进一步研究,氧化应激也是该领域的研究热点。多种微量元素与疾病的交叉研究可能是未来的发展趋势。
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引用次数: 0
Pre-implantation Genetic Testing in Inherited Metabolic Diseases? Stateof- the-art and current challenges 遗传代谢性疾病的植入前基因检测?最新进展和当前挑战
IF 1.9 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-12-19 DOI: 10.2174/0118715303279986231211090830
Ana Miguel Capela, Ana Cunha, Ana Maria Fortuna, Cláudia Falcão Reis
Introduction:: Inborn errors of metabolism (IEM) are genetic diseases involving congenital disorders of enzyme activities. Most follow Mendelian autosomal recessive inheritance and few follow mitochondrial inheritance. In many cases, after the birth of an affected child parents discover that have been the carriers for the condition and worry about the risk of recurrence in future offspring. Preimplantation genetic testing (PGT) can analyze embryos before their transfer to the uterus and prevent the transmission of hereditary conditions to descendants, however this procedure is of limited value in mtDNA conditions. Methods:: The list of diseases currently approved for PGT were reviewed. The process for eligibility, was as for the Comissão Nacional Procriação Medicamente Assistida (CNPMA), of Portugal (PT). Review of international practices for Assisted Reproductive Techniques (ART) in IEM was carried out. Results:: As of 07.2022, 23 IEM diseases associated with deleterious variants in nDNA were approved for PGT in PT. Couples at risk for conditions not included in the list can solicit an evaluation from an expert committee, after a medical genetics consultation. To qualify for approval, diseases must cause significant suffering and/or premature death. Due to a greater number of solicitations many more IEM conditions have been approved for PGT across the world. ART for mtDNA is not available in PT. International expert centers include PGT for specific well documented variants and mitochondrial donation. Conclusion:: PGT is a reliable approach to reduce the risk of transmission of a genetic condition to the offspring. The list of IEM disorders currently accepted for this technique in Portugal are small, but it is expanding, as many more diseases fit the necessary criteria. While appealing in theory, low success rates coupled with limited availability can be discouraging for patients. Genetic counselling is of paramount importance after the diagnosis of IEM diseases. It is important for both clinicians and patients to be made aware of the available reproductive options and their limitations.
导言先天性代谢错误(IEM)是一种先天性酶活性紊乱的遗传疾病。大多数为孟德尔常染色体隐性遗传,少数为线粒体遗传。在许多情况下,患儿出生后,父母会发现自己是该病的携带者,并担心后代复发的风险。胚胎植入前基因检测(PGT)可在胚胎移植到子宫前对其进行分析,防止遗传病遗传给后代,但这一程序对 mtDNA 遗传病的价值有限。方法对目前获准进行 PGT 的疾病清单进行了审查。资格审查程序与葡萄牙国家辅助生殖委员会(CNPMA)相同。对国际辅助生殖技术(ART)在 IEM 中的应用进行了回顾。结果截至 2022 年 7 月,有 23 种与 nDNA 中的有害变异有关的 IEM 疾病获准在葡萄牙进行 PGT。有可能患上未列入清单的疾病的夫妇,可在进行医学遗传学咨询后,请求专家委员会进行评估。要获得批准,疾病必须造成重大痛苦和/或过早死亡。由于申请数量增加,全球已有更多的 IEM 疾病获准进行 PGT。PT 不提供针对 mtDNA 的 ART。国际专家中心包括针对有据可查的特定变异和线粒体捐赠的 PGT。结论PGT 是降低遗传病遗传给后代风险的可靠方法。目前,葡萄牙接受这种技术的 IEM 疾病不多,但随着符合必要标准的疾病越来越多,这种技术的范围也在不断扩大。虽然在理论上很有吸引力,但低成功率和有限的可用性会让患者望而却步。确诊 IEM 疾病后,遗传咨询至关重要。临床医生和患者都必须了解现有的生殖选择及其局限性。
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引用次数: 0
Pharmacogenetic Variants Can Influence Optical Medication Use 药物基因变异可影响光学用药
IF 1.9 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-12-19 DOI: 10.2174/0118715303271934231211085226
Diana Alves, Filipa Ferreira, Cristina Pereira, Altina Lopes, Célia Nogueira, Laura Vilarinho
Introduction:: Single Nucleotide Polymorphisms (SNPs) are used as drug susceptibility biomarkers in metabolic diseases. Alterations in the gene encoding triggers the enzyme flavin monooxygenase 3 (FMO3), involved in the Sulindac metabolization, which also is responsible for the inherited metabolic disorder. Trimethylaminuria (TMAu, OMIM: 602079). DPYD gene variants are associated with the enzyme dihydropyrimidine dehydrogenase deficiency (DPD; OMIM: 274270). This autosomal recessive metabolic disorder, ultimately leads to the inability to metabolize fluoropyrimidines, which causes severe toxicity in individuals treated with these drugs. Methods:: Variants in genes responsible for the expression of enzymes that encode transporters or receptors involved in the metabolization pathways of certain drugs may condition the individuals response to certain drugs, compromising the therapeutic response and clinical prognosis. Thus the sequencing and identification of variants become relevant, not only gain knowledge on effects of these variants’ on disease causality but also in terms of its side effects resulting from the coding enzymes responsible for drug metabolization. Results:: It was found that patients with the c.472G>A (p.Glu158Lys) and c.923A>G (p.Glu308Gly) polymorphisms, in homozygosity, in FMO3 gene did not develop polyps, thus have a protective effect in the treatment of Familial Adenomatous Polyposis (PAF). However, in the case of the DPYD gene, c.1905+1G>A (IVS14+1G>A), c.1679T>G (p.Ile560Ser), c.2846A>T (p.Asp949Val) e c.1236G>A/HapB3 variants can be lethal in cancer patients indicated for fluoropyrimidine-based chemotherapy. Conclusion:: Knowledge on the drug mechanisms will affect the therapeutic response of patients treated with a given drug. Thus, pharmacogenetics is an essential tool in personalized medicine, since molecular studies allows the clinician to predict the probability of efficacy and toxicity of certain drugs, resulting higher efficiency in individualizing treatment and also improving the safety of the patient. From a personalized medicine perspective, the study of the characteristics of the drug and its metabolization site, the genes involved in the encoding of enzymes responsible for its metabolization will be of great interest.
导言单核苷酸多态性(SNPs)被用作代谢性疾病的药物易感性生物标志物。编码引发黄素单加氧酶 3(FMO3)的基因发生了改变,该酶参与舒林酸的代谢,也是导致遗传性代谢紊乱的原因。三甲胺尿症(TMAu,OMIM:602079)。DPYD 基因变异与二氢嘧啶脱氢酶缺乏症(DPD;OMIM: 274270)有关。这种常染色体隐性遗传代谢紊乱最终导致无法代谢氟嘧啶类药物,从而使接受此类药物治疗的患者产生严重毒性。研究方法某些药物的代谢途径中编码转运体或受体的酶的基因表达存在变异,这可能会影响个体对某些药物的反应,从而影响治疗反应和临床预后。因此,对变异基因进行测序和鉴定具有重要意义,不仅可以了解这些变异基因对疾病因果关系的影响,还可以了解负责药物代谢的编码酶所产生的副作用。研究结果研究发现,FMO3 基因中 c.472G>A(p.Glu158Lys)和 c.923A>G(p.Glu308Gly)多态性同源的患者不会出现息肉,因此对治疗家族性腺瘤性息肉病(PAF)具有保护作用。然而,在 DPYD 基因中,c.1905+1G>A(IVS14+1G>A)、c.1679T>G(p.Ile560Ser)、c.2846A>T(p.Asp949Val)e c.1236G>A/HapB3 变异在接受氟嘧啶类化疗的癌症患者中可能是致命的。结论对药物机制的了解会影响患者对特定药物的治疗反应。因此,药物遗传学是个性化医疗的重要工具,因为分子研究可以让临床医生预测某些药物的疗效和毒性,从而提高个性化治疗的效率,并改善患者的安全性。从个体化医学的角度来看,研究药物的特性及其代谢部位、参与药物代谢酶编码的基因将是非常有意义的。
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引用次数: 0
Increasing Sanfilippo Syndrome Awareness through Children's Literature and Music 通过儿童文学和音乐提高对桑菲利波综合症的认识
IF 1.9 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-12-19 DOI: 10.2174/0118715303272345231211094632
Raquel Marques, Rodrigo Carlson, Guilhain Higonnet
: There is an ongoing effort to increase rare disease awareness amongst healthcare providers. This front is important and can help to address several challenges faced by rare disease patients, such as lengthy diagnosis times, difficulty in finding adequate providers of medical services and experts, and adequate treatment if one exists. On another front, there is the need for awareness among citizens and their support in the advocacy for public policies towards rare disease patients and families. Awareness campaigns are prevalent in social networks and fundraising events. In this poster, we present a complementary approach to engage society and promote rare disease awareness through children’s literature and music. A Portuguese teenager wrote a book (‘My Life with my sister’), describing simple and daily moments spent with her teenage sister affected by Sanfilippo syndrome. A professional illustrator designed and illustrated the book. The book is bilingual in Portuguese and English. The author, with the assistance of her music teacher, also composed a song which was recorded with the participation of professional musicians and made into a video clip telling their story and the books. The book and song promote the inclusion and love for people affected by rare diseases and their families. To increase outreach, sister organizations translated the book, adapted the song, and published/ recorded the material in Brazilian Portuguese and French. The proceeds from the sales go towards the Sanfilippo foundations in their respective countries to fund common research projects. The material is being advertised on social media, television, interviews, newspapers, podcasts, libraries, schools, bookshops, book fairs, and others. To date, more than eight hundred books have been sold to individuals and companies. The interviews and video clips add to more than twelve hundred views. The target audience is children, parents, teachers but also companies, and their employees.
:我们一直在努力提高医疗保健提供者对罕见病的认识。这一方面非常重要,有助于解决罕见病患者面临的一些挑战,如诊断时间过长、难以找到足够的医疗服务提供者和专家,以及即使存在也难以得到适当治疗等。另一方面,需要提高公民的认识,并支持他们宣传针对罕见病患者和家庭的公共政策。在社交网络和筹款活动中,宣传活动非常普遍。在本海报中,我们介绍了一种通过儿童文学和音乐吸引社会参与并提高人们对罕见病认识的补充方法。一位葡萄牙青少年写了一本书(《我和姐姐的生活》),描述了她与患有桑菲利波综合症的姐姐一起度过的简单而日常的时光。一位专业插图画家为这本书设计了插图。该书以葡萄牙语和英语双语撰写。在音乐老师的协助下,作者还创作了一首歌曲,并在专业音乐家的参与下录制成视频短片,讲述他们的故事和这本书。这本书和歌曲促进了对罕见疾病患者及其家人的包容和关爱。为了扩大影响,姊妹组织翻译了这本书,改编了歌曲,并用巴西葡萄牙语和法语出版/录制了材料。销售收入将捐给各自国家的圣菲利波基金会,用于资助共同的研究项目。这些资料正在社交媒体、电视、访谈、报纸、播客、图书馆、学校、书店、书展等进行宣传。迄今为止,已向个人和公司出售了八百多本书。访谈和视频剪辑的浏览量超过一千二百次。目标受众是儿童、家长、教师,也包括公司及其员工。
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引用次数: 0
Challenges in Genetic Diagnosis of Mitochondrial Diseases: What Can Functional Genomics' Studies Do? 线粒体疾病基因诊断的挑战:功能基因组学研究能做些什么?
IF 1.9 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-12-19 DOI: 10.2174/0118715303273290231211062420
Marta Simões, Maria João Santos, Sara Martins, Maria do Carmo Macário, João Durães, Luísa Diogo, João Paulo Oliveira, José Carlos Ferreira, Manuela Grazina
Introduction:: Mitochondrial oxidative phosphorylation (OXPHOS) diseases are challenging both from clinical and therapeutic perspectives. The advent of next-generation sequencing (NGS) boosted the discovery of new genetic defects affecting OXPHOS, with pathogenic variants identified in >350 genes to date [1]. However, in many patients, novel variants of unknown clinical significance are found. Subsequent functional studies may clarify its pathogenic consequences and modify the variant’s classification, establishing a genetic diagnosis [2, 3]. Methods:: Analysis of data obtained from patients (P1-P5) with novel genetic causes and functional genomics’ studies performed, namely OXPHOS respiratory/glycolytic rates (Seahorse XF), enzymatic activity and assembly (BN-page), protein levels (SDS-WB), single muscle fiber assay, NGS and bioinformatics. Results/Case Report:: P1-Leigh syndrome (40y, male); Complex IV activity deficiency (full assembly absent), homozygous deletion (c.-11_13del, SURF1), not detected by NGS[2]. P2- Epileptic encephalopathy (8y, male); homozygous c.882-1G>A, FASTKD2; OXPHOS decrease; reduced FASTKD2 expression and abnormal respiratory/glycolytic rates. P3-Cardiomyopathy/ nephropathy (39y, male); c.29G>C, FASTKD2; OXPHOS decrease; reduced FASTKD2 levels. P4-CPEO (62y, female); multiple OXPHOS deficiency; mtDNA alterations (m.7486G>A, MTTS1; 4,977bp del); higher levels of mutant mtDNA alterations in COX-deficient fibers [3]. P5- Polyneuropathy (15y, female); heterozygous c.1437C>A, POLG; combined def. or normal OXPHOS activity/respiratory capacity (tissue variable), raised CI assembly; normal POLG levels. Also, proteins’ expression levels were reduced (P1-4), confirming pathogenicity. In P5, data do not support pathogenicity. Conclusion:: If specific functional results are similar to controls, one might inquire about the pathogenicity of the studied variant and more genetic or bioinformatics analyses and family investigations are needed. There are also limitations of NGS in mutation detection that Sanger sequencing can overcome (P1). When performed first, the OXPHOS activity may guide to genetic screening or interpretation, concordant to later assembly results. All cases were solved and data may be crucial for genetic counseling.
导言线粒体氧化磷酸化(OXPHOS)疾病在临床和治疗方面都具有挑战性。下一代测序技术(NGS)的出现促进了影响 OXPHOS 的新基因缺陷的发现,迄今已在 350 个基因中发现了致病变异[1]。然而,在许多患者中还发现了临床意义不明的新型变体。随后的功能研究可能会明确其致病后果并修改变异体的分类,从而确定基因诊断[2, 3]。方法分析新型遗传因子患者(P1-P5)的数据,并进行功能基因组学研究,即 OXPHOS 呼吸/糖酵解率(Seahorse XF)、酶活性和装配(BN-page)、蛋白质水平(SDS-WB)、单肌纤维测定、NGS 和生物信息学。结果/病例报告::P1-Leigh 综合征(40 岁,男性);复合体 IV 活性缺乏(完全组装缺失),同基因缺失(c.-11_13del,SURF1),NGS 未检测到[2]。P2-癫痫性脑病(8 岁,男性);同基因 c.882-1G>A,FASTKD2;OXPHOS 减少;FASTKD2 表达减少,呼吸/糖酵解速率异常。P3-心肌病/肾病(39 岁,男性);c.29G>C,FASTKD2;OXPHOS 减少;FASTKD2 水平降低。P4-CPEO(62 岁,女性);多种 OXPHOS 缺乏;mtDNA 改变(m.7486G>A,MTTS1;4,977bp del);COX 缺乏纤维中突变 mtDNA 改变水平较高 [3]。P5-多发性神经病(15 岁,女性);杂合子 c.1437C>A,POLG;OXPHOS 活性/呼吸能力合并缺陷或正常(组织可变),CI 组装提高;POLG 水平正常。此外,蛋白质表达水平降低(P1-4),证实了致病性。在 P5 中,数据不支持致病性。结论如果特定功能结果与对照组相似,人们可能会询问所研究变异体的致病性,需要进行更多的遗传学或生物信息学分析和家族调查。在突变检测方面,NGS 也存在桑格测序可以克服的局限性(P1)。如果先进行 OXPHOS 活动,则可指导基因筛选或解释,与后来的组装结果一致。所有病例均已解决,数据可能对遗传咨询至关重要。
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引用次数: 0
Italian Guidelines for the Management of Sporadic Primary Hyperparathyroidism 意大利散发性原发性甲状旁腺功能亢进症治疗指南
IF 1.9 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-12-15 DOI: 10.2174/0118715303260423231122111705
Fabio Vescini, Giorgio Borretta, Iacopo Chiodini, Marco Boniardi, Marina Carotti, Elena Castellano, Cristiana Cipriani, Cristina Eller-Vainicher, Sandro Giannini, Maurizio Iacobone, Antonio Stefano Salcuni, Federica Saponaro, Stefano Spiezia, Annibale Versari, Guido Zavatta, Zuzana Mitrova, Rosella Saulle, Simona Vecchi, Debora Antonini, Michele Basile, Alexia Giovanazzi, Agostino Paoletta, Enrico Papini, Agnese Persichetti, Irene Samperi, Alessandro Scoppola, Roberto Novizio, Giorgio Calò, Filomena Cetani, Luisella Cianferotti, Sabrina Corbetta, Maria Luisa De Rimini, Alberto Falchetti, Giovanni Iannetti, Stefano Laureti, Celestino Pio Lombardi, Bruno Madeo, Claudio Marcocci, Sandro Mazzaferro, Vittorio Miele, Salvatore Minisola, Andrea Palermo, Jessica Pepe, Alfredo Scillitani, Laura Tonzar, Franco Grimaldi, Renato Cozzi, Roberto Attanasio
Aim:: This guideline (GL) is aimed at providing a clinical practice reference for the management of sporadic primary hyperparathyroidism (PHPT) in adults. PHPT management in pregnancy was not considered. Methods:: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) and Società Italiana dell’Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro (SIOMMMS) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as “critical” and “important” were considered in the systematic review of evidence. Those classified as “critical” were considered for the clinical practice recommendations. Results:: The present GL provides recommendations about the roles of pharmacological and surgical treatment for the clinical management of sporadic PHPT. Parathyroidectomy is recommended in comparison to surveillance or pharmacologic treatment in any adult (outside of pregnancy) or elderly subject diagnosed with sporadic PHPT who is symptomatic or meets any of the following criteria: • Serum calcium levels >1 mg/dL above the upper limit of normal range. • Urinary calcium levels >4 mg/kg/day. • Osteoporosis disclosed by DXA examination and/or any fragility fracture. • Renal function impairment (eGFR <60 mL/min). • Clinic or silent nephrolithiasis. • Age ≤50 years. Monitoring and treatment of any comorbidity or complication of PHPT at bone, kidney, or cardiovascular level are suggested for patients who do not meet the criteria for surgery or are not operated on for any reason. Sixteen indications for good clinical practice are provided in addition to the recommendations. Conclusion:: The present GL is directed to endocrinologists and surgeons - working in hospitals, territorial services or private practice - and to general practitioners and patients. The recommendations should also consider the patient’s preferences and the available resources and.
目的本指南(GL)旨在为成人散发性原发性甲状旁腺功能亢进症(PHPT)的治疗提供临床实践参考。未考虑妊娠期的 PHPT 治疗。方法本 GL 是按照《意大利国家指南系统手册》中描述的方法制定的。对于每个问题,由内分泌医学协会(AME)和意大利骨质疏松症、矿物质代谢疾病和骨质疏松症协会(SIOMMMS)任命的专家小组都会确定潜在的相关结果,然后根据其对治疗选择的影响进行评级。系统性证据审查只考虑被列为 "关键 "和 "重要 "的结果。临床实践建议中考虑了被列为 "关键 "的结果。结果本 GL 就药物治疗和手术治疗在散发性 PHPT 临床治疗中的作用提出了建议。与监测或药物治疗相比,建议对任何确诊为散发性 PHPT 的成人(妊娠除外)或老年患者进行甲状旁腺切除术,这些患者应无症状或符合以下任一标准:- 血清钙水平超过正常范围上限 1 mg/dL。- 尿钙水平>4毫克/千克/天。- 通过 DXA 检查发现骨质疏松症和/或任何脆性骨折。- 肾功能受损(eGFR 为 60 毫升/分钟)。- 临床或无症状肾结石。- 年龄小于 50 岁。对于不符合手术标准或因故未接受手术的患者,建议对 PHPT 在骨、肾或心血管方面的任何合并症或并发症进行监测和治疗。除建议外,还提供了 16 项良好临床实践指征。结论本《全球指南》面向在医院、地区服务机构或私人诊所工作的内分泌科医生和外科医生,以及全科医生和患者。这些建议还应考虑到患者的偏好和可用资源。
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引用次数: 0
18 Months of Treatment with Triheptanoin in 2 Patients with Long Chain Fatty Acid Oxidation Disorders 对两名长链脂肪酸氧化紊乱患者进行为期 18 个月的三庚酸治疗
IF 1.9 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-12-14 DOI: 10.2174/0118715303279681231122104925
Helena Santos, Ana Vieira, Joana Tenente, Ana Carriço, Esmeralda Rodrigues
Introduction:: Long-chain fatty acid oxidation disorders (LC-FAOD) are inborn errors of metabolism, also identified in newborn screening in Portugal. They interfere with adequate energy utilization, namely by muscles, heart, and liver. Treatment aims to maintain patients in an anabolic state, with increased caloric intake, using carbohydrates and medium-chain fatty acids. Treatment with triheptanoin (THP), a synthetic seven-carbon fatty acid triglyceride compound with an anaplerotic effect that increases energy availability to the cell, has been advocated as an efficacious and safe therapy in LC-FAOD. Methods:: Retrospective revision of clinical records of 2 LC-FAOD patients comparing number, severity and admissions for rhabdomyolysis crises, maximum CK values and weight gain in a period of 18 months before and after treatment with THP. Results/Case Report:: Patient 1 is a 12 year old male with VLCADD, with main manifestation being rhabdomyolysis crises. After he started THP we found a decrease in admissions (6 to 2), less rhabdomyolysis crises treated at home (5 to 3), and lower maximum CK values (72352 U/L to 13.000U/L). He had a large increase in weight - 13kg in 18 months. He was able to start pool exercises with no rhabdomyolysis associated. Patient 2 is an 8 year old male with LCAHDD, with main manifestations being rhabdomyolysis crises and retinopathy. After he started THP we found a decrease in admissions (4 to 1), no rhabdomyolysis crises treated at home, and lower maximum CK values (100.000U/L to 19848 U/L). He also increased his weight - 7kg in 18 months. He plays football in school and swims with no rhabdomyolysis associated. In both patients, no major side effects were observed. Conclusion:: In our patients, we could observe a reduction in the number of admissions, and less severe rhabdomyolysis crises after THP use. The weight gain was significant. There were no major side effects. Despite regarding only two patients, our findings are in line with the latest literature on THP and LC-FAOD, reinforcing the utility of THP as one more tool in the treatment of these disorders with rhabdomyolysis as the main manifestation. The weight increase is an issue to be aware of and to address from the start of the treatment.
导言长链脂肪酸氧化紊乱(LC-FAOD)是一种先天性代谢紊乱,在葡萄牙的新生儿筛查中也被发现。它们会影响肌肉、心脏和肝脏对能量的充分利用。治疗的目的是利用碳水化合物和中链脂肪酸增加热量摄入,使患者保持合成代谢状态。三庚酸(THP)是一种人工合成的七碳脂肪酸甘油三酯化合物,具有促进合成代谢的作用,可增加细胞的能量供应。方法回顾性修改 2 名 LC-FAOD 患者的临床记录,比较使用 THP 治疗前后 18 个月期间横纹肌溶解症的数量、严重程度和入院情况、肌酸激酶最高值和体重增加情况。结果/病例报告::患者 1 是一名 12 岁的男性,患有 VLCADD,主要表现为横纹肌溶解症。在他开始接受 THP 治疗后,我们发现入院次数减少了(从 6 例减少到 2 例),在家治疗的横纹肌溶解症减少了(从 5 例减少到 3 例),CK 最大值降低了(从 72352 U/L 降至 13.000U/L)。他的体重在 18 个月内大幅增加了 13 公斤。他可以开始泳池运动,而且没有发生横纹肌溶解症。患者 2 是一名 8 岁男性,患有 LCAHDD,主要表现为横纹肌溶解症和视网膜病变。在他开始接受 THP 治疗后,我们发现他的入院次数减少了(从 4 例减少到 1 例),没有发生在家治疗的横纹肌溶解症危象,肌酸激酶最高值也降低了(从 100.000U/L 降至 19848U/L)。他的体重也在 18 个月内增加了 7 千克。他在学校踢足球和游泳,没有发生横纹肌溶解症。两名患者均未出现严重的副作用。结论在我们的患者中,我们可以观察到,使用 THP 后,入院次数减少,横纹肌溶解症危机的严重程度降低。体重明显增加。没有出现严重的副作用。尽管只涉及两名患者,但我们的研究结果与有关 THP 和 LC-FAOD 的最新文献一致,加强了 THP 作为治疗这些以横纹肌溶解为主要表现的疾病的另一种工具的实用性。体重增加是一个需要注意的问题,从治疗一开始就要解决。
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引用次数: 0
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Endocrine, metabolic & immune disorders drug targets
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