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。     

Flavocoxid is as effective as naproxen for managing the signs and symptoms of osteoarthritis of the knee in humans: a short-term randomized,double-blind pilot study

Flavocoxid (Limbrel), a proprietary mixture of flavonoid molecules (baicalin and catechin), was tested against a traditional nonsteroidal anti-inflammatory drug, naproxen, for the management of the signs and symptoms of moderate osteoarthritis (OA) in humans. Discomfort and global disease activity were used as the primary end points, and safety assessments were also taken for both treatments as a secondary endpoint. In this double-blind study, 103 subjects were randomly assigned to receive either flavocoxid [500 mg twice daily (BID)] or naproxen (500 mg BID) in a 1-month onset of action trial. Outcome measures included the short Western Ontario and McMaster University Osteoarthritis Index, subject Visual Analogue Scale for discomfort and global response, and investigator Visual Analogue Scale for global response and fecal occult blood. Both flavocoxid and naproxen showed significant reduction in the signs and symptoms of knee OA (P ≤ .001). There were no statistically detectable differences between the flavocoxid and naproxen groups with respect to any of the outcome variables. Similarly, there were no statistically detectable differences between the groups with respect to any adverse event, although there was a trend toward a higher incidence of edema and nonspecific musculoskeletal discomfort in the naproxen group. In this short-term pilot study, flavocoxid was as effective as naproxen in controlling the signs and symptoms of OA of the knee and would present a safe and effective option for those individuals on traditional nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors. A low incidence of adverse events was reported for both groups.     

老年性聋大鼠耳蜗COX活性的研究

目的:探讨线粒体呼吸链细胞色素C氧化酶(COX)活性异常在老年性聋发病中的作用机制.方法:免疫组化法检测老年性聋大鼠耳蜗COX活性.结果:与正常对照组相比,实验组老年性聋大鼠耳蜗中COX活性降低.结论:耳蜗组织中COX活性降低在老年性聋的发病中起一定作用.     

Pathophysiology of idiopathic dystonia: findings from genetic animal models

Dystonia is a common movement disorder which is thought to represent a disease of the basal ganglia. However, the pathogenesis of the idiopathic dystonias, i.e. the neuroanatomic and neurochemical basis, is still a mystery. Research in dystonia is complicated by the existence of various phenotypic and genotypic subtypes of idiopathic dystonia, probably related to heterogeneous dysfunctions.In neurological diseases in which no obvious neuronal degeneration can be found, such as in idiopathic dystonia, the identification of a primary defect is difficult, because of the large number of chemically distinct, but functionally interrelated, neurotransmitter systems in the brain.The variable response to pharmacological agents in patients with idiopathic dystonia supports the notion that the underlying biochemical dysfunctions vary in the subtypes of idiopathic dystonia. Hence, in basic research it is important to clearly define the involved type of dystonia.Animal models of dystonias were described as limited. However, over the last years, there has been considerable progress in the evaluation of animal models for different types of dystonia.Apart from animal models of symptomatic dystonia, genetic animal models with inherited dystonia which occurs in the absence of pathomorphological alterations in brain and spinal cord are described.This review will focus mainly on genetic animal models of different idiopathic dystonias and pathophysiological findings. In particular, in the case of the mutant dystonic (dt) rat, a model of generalized dystonia, and in the case of the genetically dystonic hamster (dt^sz), a model of paroxysmal dystonic choreoathetosis has been used, as these show great promise in contributing to the identification of underlying mechanisms in idiopathic dystonias, although even a proper animal model will probably never be equivalent to a human disease.Several pathophysiological findings from animal models are in line with clinical observations in dystonic patients, indicating abnormalities not only in the basal ganglia and thalamic nuclei, but also in the cerebellum and brainstem. Through clinical studies and neurochemical data several similarities were found in the genetic animal models, although the current data indicates different defects in dystonic animals which is consistent with the notion that dystonia is a heterogenous disorder.Different supraspinal dysfunctions appear to lead to manifestation of dystonic movements and postures. In addition to increasing our understanding of the pathophysiology of idiopathic dystonia, animal models may help to improve therapeutic strategies for this movement disorder.     

Efficacy of lumiracoxib in relieving pain associated with knee osteoarthritis: a 6‐week,randomized, double‐blind,parallel‐group study

Aim: The aim of the current study was to assess the efficacy, safety, and tolerability of lumiracoxib 200 mg once daily (o.d.) in relieving osteoarthritis (OA) knee pain in patients in China, Taiwan, and South Korea. Methods: Patients of either sex (aged ≥ 18 years) with symptomatic, primary OA of the knee for ≥ 3 months were eligible for inclusion if they had OA pain intensity of ≥ 40 mm (100 mm visual analogue scale [VAS]) in the target knee joint during the previous 24 h. Patients were required to undergo regular non‐steroidal anti‐inflammatory drug therapy for ≥ 6 weeks. After 3–7 days of screening, patients were randomized (1 : 1) to receive either lumiracoxib 200 mg o.d. or celecoxib 200 mg o.d. The primary efficacy comparison between the study groups was overall OA pain intensity (VAS) in the target knee after 6 weeks of treatment. Results: The mean overall OA pain intensity (VAS) in the target knee after 6 weeks decreased from 60.6 mm to 35.7 mm and 60.5 mm to 36.1 mm in the lumiracoxib and celecoxib groups, respectively. Both study groups showed similar results in terms of improvement in both patient's and physician's global assessment of disease activity and functional health status. The percentage of adverse events (AEs) in the lumiracoxib and celecoxib groups (40.3% and 37.9%, respectively) was similar, as was the proportion of treatment‐related AEs (21.0% and 18.2%, respectively). Conclusions: Lumiracoxib 200 mg o.d. provided effective and well‐tolerated pain relief similar to that achieved with celecoxib 200 mg o.d. in knee OA patients.     

Cyclooxygenase-2 inhibition increases gastric tone and delays gastric emptying in rats.

We evaluated the effects of cyclooxygenase-2 (COX-2) selective inhibitors, COX-1 selective inhibitor, or COX non-selective inhibitor on gastric emptying and intestinal transit of liquids, and evaluated the effect of a COX-2 selective inhibitor on gastric tonus (GT). Male Wistar rats were treated per os with saline (control), rofecoxib, celecoxib, ketorolac, rofecoxib + ketorolac, celecoxib + ketorolac, or indomethacin. After 1 h, rats were gavage-fed (1.5 mL) with the test meal (5% glucose solution with 0.05 g mL(-1) phenol red) and killed 10, 20 or 30 min later. Gastric, proximal, medial or distal small intestine dye recovery (GDR and IDR, respectively) were measured by spectrophotometry. The animals of the other group were treated with i.v. valdecoxib or saline, and GT was continuously observed for 120 min using a pletismomether system. Compared with the control group, treatment with COX-2 inhibitors, alone or with ketocolac, as well as with indomethacin increased GDR (P < 0.05) at 10-, 20- or 30-min postprandial intervals. Ketorolac alone did not change the GDR, but increased the proximal IDR (P < 0.05) at 10 min, and decreased medial IDR (P < 0.05) at 10 and 20 min. Valdecoxib increased (P < 0.01) GT 60, 80 and 100 min after administration. In conclusion, COX-2 inhibition delayed the gastric emptying of liquids and increased GT in rats.     

The COX-2 inhibitor, rofecoxib, ameliorates dextran sulphate sodium induced colitis in mice

Objective: We have evaluated the efficacy of the selective cyclo-oxygenase (COX)-2 inhibitor, rofecoxib, for the prevention of experimental colitis.Material and methods: To induce colitis BALB/c mice received 5% dextran sulphate sodium (DSS) in their drinking water continuously for 7 days. Rofecoxib (2.5–10 mg/kg body weight, p.o.) was administered throughout the treatment period with DSS. Colitis was quantified by a clinical damage score, colon length, weight loss, stool consistency and rectal bleeding. Inflammatory response was assessed by neutrophil infiltration, determined by histology and myeloperoxidase (MPO) activity. Interleukin (IL)-1, prostaglandin (PG)E₂ and PGD₂ levels in colon mucosa and the immunohistochemical expression of COX-1 and –2 were also studied.Results: The COX-2 inhibitor ameliorated severe colitis, reduced the degree of inflammation through reduction of neutrophil infiltration and IL-1 levels. PGE₂, and PGD₂ synthesis were significantly reduced in DSS-treated groups. Indeed, treatment with rofecoxib diminished the lost of COX-1 caused by DSS in the crypt epithelium whereas expression of COX-2 remained unaffected.Conclusions: Rofecoxib is protective in acute DSS – induced colitis, probably by reducing neutrophil infiltration, inhibiting up-regulation of IL-1 and returning to normal COX-1 expression in the inflamed colonic mucosa.Received 19 April 2004; returned for revision 17 June 2004; accepted by I. Ahnfelt-Rønne 23 November 2004     

Immunohistochemical characteristics of duodenal adenomas in familial adenomatous polyposis with special reference to cell kinetics

The duodenum is the second most frequent site of cancer in patients with familial adenomatous polyposis (FAP). The main objective of this study was to evaluate the cell kinetics in duodenal and ampullary adenomas in FAP. The endoscopic and biopsy findings of duodenal adenomas in 22 FAP subjects and 18 non-FAP subjects were compared. Adenomas in FAP included 15 ampullary adenomas and 17 nonampullary adenomas. The cell kinetics was evaluated by immunohistochemistry for Ki-67, p53, bcl-2, and cyclooxygenase 2 (COX2), and the apoptotic index (AI) as determined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) method. Any correlations between the indices for cell kinetics and the endoscopic findings were identified. All 50 adenomas were histologically verified to be tubular adenoma with low-grade dysplasia. Neither the expression of Ki-67, p53, bcl-2, and COX2 nor the AI differed substantially between FAP and non-FAP subjects. In patients with FAP, duodenal adenoma tended to have a higher Ki-67-labeling index than the ampullary adenoma (54.3 +/- 11.3 versus 46.8 +/- 12.7; .05 < P < .1). In addition, the Ki-67-labeling index in endoscopically normal or slightly enlarged ampullary adenoma was significantly higher than that in markedly enlarged ampullary adenoma (51.8 +/- 11.4 versus 39.4 +/- 11.3; P < .05). Duodenal adenoma in FAP subjects was not found to have a higher proliferative activity or a smaller degree of apoptosis compared with those in non-FAP subjects. The smaller proliferative activity in larger ampullary adenoma may thus be related to the static nature of ampullary adenoma in FAP.     

Molecular targets of dietary polyphenols with anti-inflammatory properties

There is persuasive epidemiological and experimental evidence that dietary polyphenols have anti-inflammatory activity. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) have long been used to combat inflammation. Recently, cyclooxygenase (COX) inhibitors have been developed and recommended for treatment of rheumatoid arthritis (RA) and osteoarthritis (OA). However, two COX inhibitors have been withdrawn from the market due to unexpected side effects. Because conventional therapeutic and surgical approaches have not been able to fully control the incidence and outcome of many inflammatory diseases, there is an urgent need to find safer compounds and to develop mechanism-based approaches for the management of these diseases. Polyphenols are found in many dietary plant products, including fruits, vegetables, beverages, herbs, and spices. Several of these compounds have been found to inhibit the inflammation process as well as tumorigenesis in experimental animals; they can also exhibit potent biological properties. In addition, epidemiological studies have indicated that populations who consume foods rich in specific polyphenols have lower incidences of inflammatory disease. This paper provides an overview of the research approaches that can be used to unravel the biology and health effects of polyphenols. Polyphenols have diverse biological effects, however, this review will focus on some of the pivotal molecular targets that directly affect the inflammation process.     

Brain prostaglandin formation is increased by α-synuclein gene-ablation during global ischemia

We have previously demonstrated that α-synuclein (Snca) gene ablation reduces brain arachidonic acid (20:4n − 6) turnover rate in phospholipids through modulation of endoplasmic reticulum-localized acyl-CoA synthetase activity. Although 20:4n − 6 is a precursor for prostaglandin (PG), Snca effect on PG levels is unknown. In the present study, we examined the effect of Snca ablation on brain PG level at basal conditions and following 30 s of global ischemia. Brain PG were extracted with methanol, purified on C₁₈ cartridges, and analyzed by LC–MS/MS. We demonstrate, for the first time, that Snca gene ablation did not affect brain PG mass under normal physiological conditions. However, total PG mass and masses of individual PG were elevated ∼2-fold upon global ischemia in the absence of Snca. These data are consistent with our previously observed reduction in 20:4n − 6 recycling through endoplasmic reticulum-localized acyl-CoA synthetase in the absence of Snca, which may result in the increased 20:4n − 6 availability for PG production in the absence of Snca during global ischemia and suggest a role for Snca in brain inflammatory response.