A case of sudden cardiac death due to mitochondrial disease

A 25-year-old, emaciated man without medical treatment was found to have died suddenly at home by his mother. At autopsy, there were no injuries to his body, but significant circulatory insufficiency was observed. Electron microscopy revealed abnormal mitochondria in cells of the cardiac conduction system. The conduction system was filled with mitochondrial size abnormalities and mitochondrial cristae abnormalities. No notable abnormal findings were observed in other organs. Genetic examination of the blood revealed the mitochondrial pathogenetic variant m.3243A>G. Epileptic seizures, diabetic ketoacidosis, and hyperosmolar hyperglycemic state were unlikely to be the cause of sudden death. The cause of death was diagnosed as arrhythmia possibly induced by the failure of the cardiac conduction system due to mitochondrial disease. This is a rare case of sudden death caused by an accumulation of abnormal mitochondria in the cardiac conduction system.     

COX20基因变异线粒体复合物Ⅳ缺乏症相关的遗传性周围神经病4例病例系列报告及文献复习

背景：原发性线粒体病具有高度的临床和遗传异质性，其中周围神经是线粒体病的常见受累器官之一。 目的：总结COX20基因变异相关周围神经病的临床表型及遗传学特征。 设计：病例系列报告。 方法：回顾性收集2018年5月至2020年5月复旦大学附属儿科医院诊治的COX20基因变异相关周围神经病患儿的临床资料，总结其临床表现、基因检测结果及治疗效果，并以“COX20”、“线粒体复合物Ⅳ缺乏症（Complex Ⅳ deficiency）”为关键词检索中英文数据库。检索时间均为从建库至2021年12月。总结已报道COX20基因变异与临床表型的关系。 主要结局指标：临床表型和COX20基因变异位点。 结果：4例患儿纳入分析，男、女各2例，其中3例自幼运动发育落后。4例均在儿童期起病，均以行走不稳为首发症状。肌电图均提示多发性周围神经损害改变，感觉神经轴索受累为主。4例患儿均携带COX20基因复合杂合变异，包括错义变异2个，无义变异和移码变异各1个，其中移码变异c.262delG(p.E88Kfs*35)尚未见报道。文献复习目前共报道COX基因变异18个家系22例患儿（包括本文病例）,起病中位年龄为5（1.0~17）岁，22例均以行走困难或步态不稳起病，11例（50.0%）有精神运动发育迟滞，病程中14例(63.6%)出现构音障碍，14例(63.6%)出现肌力下降和/或足部畸形，8例（36.4%）出现共济失调，6例(27.3%)出现肌张力障碍，5例（22.7%）存在认知倒退等。21例患儿行神经传导及肌电图检查，19例(90.5%)提示多发性周围神经病变。头颅（18例）及脊髓（10例）MR检查提示，脊髓萎缩4例（40%），小脑萎缩4例（22.2%）。9例患儿已无法独立行走，丧失独立行走能力中位年龄为10（7~21）岁。目前共报道9个变异位点，4种变异类型，其中错义变异5个，剪切变异2个，无义变异和移码变异各1个。 结论：COX20基因变异患者多早期起病，以周围神经系统病变为主要表现，可合并构音障碍、共济失调、肌张力障碍、认知倒退等，病情逐渐进展，致残率高。COX20基因变异类型以错义变异最常见。     

补中益气汤对于肝再生线粒体能量代谢的研究概况＊

肝再生的机制非常复杂，线粒体功能障碍所引起的能量供给不足是影响因素之一，但其机理亟待研究。严重肝损害时肝细胞ATP供应减少、线粒体能量代谢异常，导致肝再生受到抑制。补中益气汤为李东垣所创，其具补中益气、升阳举陷之功，有实验证实补中益气汤具有保护线粒体功能、增加线粒体能量代谢的作用，从而促进肝再生。本文综述补中益气汤总方与其中各类中药对线粒体能量代谢的保护作用，从而为促进肝再生提供新的治疗手段并对改善病人预后有重要意义。     

Methods improvement for diagnostics and treatment of inflammatory diseases in the temporomandibular joint

PurposeThe article subject relevance is conditioned by poor knowledge of the aetiology and pathogenesis of inflammatory diseases in this area. The purpose of this study was to identify the most rational approach to solving the issues of improving methods for treating arthritis and arthrosis.MethodsThe leading approach was the combination of the analysis results concerning the clinical examination of dental patients of various age groups with the logical construction of conclusions drawn from the research results. The paper presented the clinical examination data of patients with TMJ pathologies of various age groups and described the methods of their treatment.ResultsThe results include the main effective methods identification for the diagnostics and treatment of inflammatory diseases in the temporomandibular joint and the main prospects for improving these methods in the future, with the aim of a general expansion of ideas regarding the possibilities of diagnostics and treatment of such diseases.ConclusionThe study value lies in the possibility of using its results in practical dentistry to bring practical improvements to the currently available methods for diagnostics and treatment of inflammatory TMJ diseases.     

Resolving a 150-year-old paternity case in Mormon history using DTC autosomal DNA testing of distant relatives

Although autosomal DNA testing has been available for a number of years, its use to reconstruct genetic profiles of people that lived centuries in the past is relatively recent and there are no published cases where it was employed to verify a kinship relation, likely to be an alleged paternity, that occurred one and a half century ago.DNA testing has already been employed to study the ancestry and posterity of Joseph Smith Jr., founder of the Latter-day Saint (Mormon) movement. Thanks to information found on the paternally inherited Y chromosome, a number of alleged paternities have been disproved, but obviously this analysis is not effective for alleged daughters. Likewise, his reconstructed mitogenome sequence, reported here for the first time, provides information about his maternal ancestry, but is useless in any paternity questions due to the strict maternal inheritance. Among all the children attributed to Joseph Smith Jr., Josephine Lyon, born in 1844, is perhaps the most frequently mentioned.In the current study, 56 individuals, mostly direct descendants of Joseph Smith Jr. and Josephine Lyon, had their autosomal DNA tested to verify Josephine’s biological paternity. Nearly 600,000 autosomal SNPs from each subject were typed and detailed genealogical data were compiled. The absence of shared DNA between Josephine’s grandson and Joseph Smith Jr.’s five great-grandchildren together with various amounts of autosomal DNA shared by the same individual with four other relatives of Windsor Lyon is a clear indication that Josephine was not related to the Smith, but to the Lyon’s family. These inferences were also verified using kinship analyses and likelihood ratio calculations.     

Methodological considerations for near-infrared spectroscopy to assess mitochondrial capacity after spinal cord injury

Background: Skeletal muscle mitochondrial activity is reduced by?～?50–60% after SCI, resulting in impaired energy expenditure, glucose utilization and insulin sensitivity. Near infra-red spectroscopy (NIRS) is a non-invasive tool that can be used to assess mitochondrial capacity.

Objectives: (1) Highlight methodological limitations impacting data acquisition and analysis such as subcutaneous adipose tissue (SAT) thickness, movement artifacts, inadequate muscle stimulation, light interference, and ischemic discomfort. (2) Provide technical considerations to improve data acquisition and analysis. This may serve as guidance to other researchers and clinicians using NIRS.

Study Design: cross-sectional observational design.

Settings: Clinical research medical center.

Participants: Sixteen men with 1?>?year post motor complete SCI.

Methods: NIRS signals were obtained from right vastus lateralis muscle utilizing a portable system. Signals were fit to a mono-exponential curve.

Outcome Measures: Rate constant and r ² values for the fit curve, indirectly measures mitochondrial capacity.

Results: Only four participants produced data with accepted rate constants of 0.002–0.013?s^?1 and r ² of 0.71–0.87. Applications of studentized residuals ≥2.5 resulted in sparing data from another four participants with rate constants of 0.010–0.018?s^?1and r ² values ranging from 0.86–0.99.

Conclusions: Several limitations may challenge the use of NIRS to assess mitochondrial capacity after SCI. Acknowledging these limitations and applying additional data processing techniques may overcome the discussed limitations and facilitate data sparing.     

Does perturbation in the mitochondrial protein folding pave the way for neurodegeneration diseases?

Mitochondria, which are cell compartments that are widely present in eukaryotic cells, have been shown to be involved in a variety of synthetic, metabolic, and signaling processes, thereby playing a vital role in cells. The mitochondrial unfolded protein response (mtUPR) is a response in which mitochondria reverse the signal to the nucleus and maintain mitochondrial protein homeostasis when unfolded and misfolded proteins continue to accumulate. Multiple neurodegeneration diseases, including Alzheimer's disease (AD), Parkinson’s disease (PD), and familial amyotrophic lateral sclerosis (fALS), are public health challenges. Every year, countless efforts are expended trying to clarify the pathogenesis and treatment of neurological disorders, which are associated with mitochondrial dysfunction to some extent. Numerous studies have shown that mtUPR is involved in and plays an important role in the pathogenesis of neurological disorders, but the exact mechanism of the disorders is still unclear. Further study of the process of mtUPR in neurological disorders can help us more accurately understand their pathogenesis in order to provide new therapeutic targets. In this paper, we briefly review mtUPR signaling in Caenorhabditis elegans (C. elegans) and mammals and summarize the role of mtUPR in neurodegeneration diseases, including AD, PD and fALS.     

An Internally Validated Nomogram for Predicting the Likelihood of Improvement of Clinical Global Impression in Patients With Lifelong Premature Ejaculation Treated With Dapoxetine

BackgroundAlthough the introduction of dapoxetine has ushered in a new era in the treatment of premature ejaculation, many patients with lifelong premature ejaculation (LPE) exhibit an unimproved clinical global impression even after treatment with dapoxetine.AimTo investigate independent predictors of the improvement of Clinical Global Impression (iCGI) in patients with LPE treated with dapoxetine and develop a nomogram to predict a patient's likelihood of achieving iCGI.MethodsData of 243 patients with LPE diagnosed at Xijing Hospital (Xi'an, China) and Northwest Women's and Children's Hospital (Xi'an, China) from January 2019 to May 2020 were analyzed. Independent predictors of iCGI were identified, and a nomogram was developed using R software based on a multivariate logistic regression model. The predictive accuracy of the nomogram was measured using the area under the receiver operating characteristic curve. The nomogram was calibrated by comparing predictions with observations.Main Outcome MeasuresThe primary outcome was the patient-rated Clinical Global Impression of Change scale score after a 4-week course of dapoxetine treatment, which was collected via an online questionnaire. A Clinical Global Impression of Change score of ≥1 was defined as iCGI in this study.ResultsPatients with LPE with at least a bachelor's degree, a self-reported intravaginal ejaculation latency time of >1 minute, and an International Index of Erectile Function question 5 score of ≥3 were independent factors associated with achieving iCGI, whereas a Premature Ejaculation Diagnostic Tool question 1 score of ≥2 was an independent factor negatively associated with achieving iCGI. The predictive accuracy of the nomogram, which was developed by integrating all variables with independent predictive significance, was 0.710 (95% confidence interval: 0.702–0.718). In addition, the calibration plot demonstrated excellent agreement between predictions and observations.Clinical ImplicationsIf the predictive performance of our nomogram is further proven in multiple external validations, it can be used to select suitable patients for dapoxetine treatment, thereby reducing the number of patients discontinuing treatment.Strengths & LimitationsThis study developed the first nomogram for predicting the likelihood of achieving iCGI in patients with LPE treated with dapoxetine. However, our nomogram was not externally validated using independent cohorts from other institutions.ConclusionThis study identified several independent predictors of iCGI in patients with LPE treated with dapoxetine. An effective nomogram was developed to predict their likelihood of achieving iCGI. External validations using data of Western patients with LPE are required to test the broader applicability of this Chinese patient-based tool.Hou G, Gao M, Zhang L, et al. An Internally Validated Nomogram for Predicting the Likelihood of Improvement of Clinical Global Impression in Patients With Lifelong Premature Ejaculation Treated With Dapoxetine. J Sex Med 2020;17:2341–2350.     

Family History for Cardio-Metabolic Diseases: A Predictor of Major Adverse Cardiovascular Events in Men With Erectile Dysfunction

BackgroundFamily history (FH) of cardiovascular (CV) disease is a known CV risk factor. However, it is rarely considered for CV risk stratification. Furthermore, FH for metabolic diseases is generally overlooked.AimTo evaluate, in a population of men with erectile dysfunction (ED), whether FH for cardio-metabolic diseases could provide insights into metabolic and sexual features and predict the occurrence of forthcoming major adverse CV events (MACE).MethodsA consecutive series of 4,693 individuals (aged 51.3 ± 13.3 years) attending an Andrology outpatient clinic for ED was studied. A subset of these (n = 1,595) was evaluated retrospectively for MACE occurrence.OutcomesSeveral metabolic and sexual function–related parameters were studied. For the retrospective study, information on an incident MACE was collected over a mean follow-up of 4.2 ± 2.5 years.ResultsA greater number of cardio-metabolic FH factors were associated with a worse metabolic profile, including higher waist circumference, triglycerides, glucose, glycosylated hemoglobin, and diastolic blood pressure, as well as lower high-density lipoprotein cholesterol. An increased number of FH factors were associated with worse erectile function (odds ratio = 1.14[1.07;1.23], P < .0001), impaired penile dynamic peak systolic velocity, and lower testosterone levels. In the retrospective study, a positive cardiometabolic FH was associated with a significantly higher incidence of MACEs, even after adjusting for age and comorbidities (hazard ratio = 1.51[1.06-2.16], P = .023). Interestingly, when dividing the sample into high- and low-risk categories according to several CV risk factors (age, previous MACEs, high-density lipoprotein cholesterol, and comorbidities), FH was confirmed as a predictor of incident MACE only among the low-risk individuals.Clinical ImplicationsInvestigating FH for cardio-metabolic diseases is a quick and easy task that could help clinicians in identifying, among individuals with ED, those who deserve careful evaluation of CV and metabolic risk factors. Moreover, considering FH for CV risk stratification could predict MACEs in individuals who, according to conventional CV risk factors, would be erroneously considered at low risk.Strengths & LimitationsThe large sample size and the systematic collection of MACEs through an administrative database, with no risk of loss at follow-up, represent strengths. The use of administrative database for MACE collection may lead to some misclassifications. The specific population of the study limits the generalizability of the results.ConclusionFH is simple and inexpensive information that should be part of the CV risk assessment in all men with ED because it helps in the identification of those who need lifestyle and risk factor modifications and whose risk would otherwise be overlooked.Rastrelli G, Yannas D, Mucci B, et al. Family History for Cardio-Metabolic Diseases: A Predictor of Major Adverse Cardiovascular Events in Men With Erectile Dysfunction. J Sex Med 2020;17:2370–2381.