芜湖地区痛风急性发作诱因及临床生化特征初探

目的 探讨痛风性关节炎急性发作的诱因并对其临床特征进行总结。方法 对2017年11月~2018年12月就诊于皖南医学院第二附属医院内分泌科门诊及住院痛风性关节炎急性发作患者进行问卷调查并收集临床资料,将以上资料录入Excel数据库,对其急性发作诱因及临床特征进行分析。结果 50~60岁为发病年龄高峰,女性患者均为绝经后发病;88.03%的痛风患者急性发作前有诱因,高嘌呤饮食诱发的为61例（52.14%）,因饮酒诱发的为55例（47.01%）,上述两者中至少含有一项者为81例（69.23%）,同时含有两项者为32例（27.35%）;60例患者首发关节部位为足第一跖趾关节,下肢关节受累数目多于上肢关节（113例vs 14例）。发病年龄小的患者比发病年龄大的患者痛风发作频率高;病程长,有痛风石的患者易痛风发作频率高（P均＜0.05）;血尿酸水平高低与患者发作频率无关,两组其他临床生化检查比较,差异无统计学意义（P＞0.05）;年龄、BMI、血尿素氮是痛风石形成的危险因素,频发与长病程同样是痛风石形成的危险因素,差异均有统计学意义（P＜0.05）;Pearson直线相关分析发现:痛风急性发作时血尿酸水平与血尿素氮、血肌酐、胱抑素C相关（P＜0.05）;多因素Logistic分析显示年龄、频发和长病程是痛风石形成的独立危险因素（P＜0.05）。结论 痛风患者中老年居多,发病存在明显性别差异。痛风性关节炎急性发作诱因中以高嘌呤饮食和饮酒为其最常见诱因;发病年龄小,病程长,有痛风石的患者发作频率高。部分痛风性关节炎急性发作时血尿酸水平并不高。年龄偏大、频发和长病程的患者容易形成痛风石。     

膝关节痛风性关节炎的超声诊断价值

目的 探讨超声在痛风性关节炎诊断中的价值。方法 选取2015年3月~2018年12月我院确诊为痛风性关节炎且膝关节受累患者20例,均进行超声检查及关节镜检查,观察患者超声及关节镜下表现。结果 超声检查:声像图异常表现有滑膜增生、积液、尿酸结晶沉积、痛风石形成、“双轨征”、骨侵蚀,其中可见滑膜增生19例、积液15例、尿酸结晶沉积13例、痛风石形成5例、“双轨征”3例、骨侵蚀1例。关节镜检查:镜下可见大量白色尿酸盐结晶,沉积于关节腔内。结论 超声检查能有效、全面的评估痛风性关节炎患者受累关节情况,能够实时动态对不同病程阶段的关节情况进行监测,其可作为痛风性关节诊断的重要影像学手段。     

Self-treatment for gout.

After describing some of the symptoms of gout and considering some causes, such as an excess of ethanol, the source of the pain in the infected joint is discussed. This is known to be from urate crystals formed in the synovial fluid inside the joint. It is suggested herein that the pain is due to grinding from the crystals through the surface film of the joint, and possibly into the bone itself, which is relatively soft. The pain then stems in part from the resulting inflammation. The key hypothesis is that these urate crystals dissolve on warming. Hence, by warming the joint concerned in hot water, and moving the joint around to encourage diffusion, the urate concentration is reduced and crystals no longer form, provided the treatment is continued.     

Aortic valvular tophus: identification by X-ray diffraction of urate and calcium phosphates.

A typical gouty tophus with birefringent, dichroic, needle shaped crystals was found in a resected calcified aortic valve on routine histological examination. The patient, an elderly man, had a long history of gout. X-ray diffraction confirmed the presence of sodium acid urate monohydrate and identified hydroxyapatite and whitlockite in the accompanying dystrophic calcification of the aortic valves. Previous reports indicate that gouty tophi of the cardiac valves are rare: of the nine cases reported, eight occurred in the mitral valve.     

Needle biopsy in gout and pseudogout (author's transl)]

Introduction: Radiological and morphological findings in advanced arthritis urica and pyrophosphate arthropathy are well known. In contrast, the early changes of synovial membrane in these disturbances of metabolism pose diagnostic problems. With the assistance of various cytological techniques and polarizing microscopical as well as electron microscopical investigation it was examined to what extent needle biopsies can be helpful in the differential diagnosis of gout and pseudogout. Material and Methods: In 8 patients with gout and 11 patients with pseudogout synovial fluid and small tissue specimens could be obtained with the aid of the Parker-Pearson needle. Both fluid and tissue specimens were investigated light and electron microscopically. Cell counts were evaluated in a Rosenthal chamber. The differentiation of the cells in stained smears was done by counting 200-600 cells per case. Crystals were identified by polarizing microscopy in wet preparations of freshly aspirated synovial fluid. Results: Polarizing microscopy of synovial fluid detected intra- as well as extracellular urate and pyrophosphate crystals. The wedge-shaped urate crystals and the larger partly polygonal pyrophosphate crystals showed different polarizing microscopical properties and a negative birefringence. The absolute cell counts in gout were higher than those in pseudogout. The relative cell counts of the different cell types in synovial fluid showed more variation in gout than in pseudogout. Cases with acute gout developed a relative leukocytosis in contrast to a relative lymphocytosis in chronic gout. A relative leukocytosis was constant in all patients with pseudogout. Sclerosed areas with scarce and plump villi as well as sometimes hyperplastic and polymorphous synovial cell layers could be demonstrated histologically in the tissue specimens of the needle biopsies in cases with gout. Urate crystals were less frequent in specimens fixed in formalin. The histological alterations in pseudogout were uniform, 2-4 rows of slightly pleomorphic synovial cells lined the inner surface of the joint capsule, sclerosing alterations were less frequent. Pyrophosphate crystals and calcified particles were seen within the synovial lining cells, the connective tissue and the enodthelial cells of the blood vessels in pseudogout specimens. Intra- as well as extracellular crystals could also be demonstrated with the aid of scanning electron microscopy in sediments of synovial fluid in gout and pseudogout. Transmission electron microscopical investigations of synovial tissue specimens detected proliferated and pleomorphic synovial lining cells in gout in contrast to a more monomorphic appearance of these cells in pseudogout. The crystals were washed out during the preparation techniques for transmission electron microscopy so that needle-like empty spaces resulted within cytoplasm of the phagocytic cells. These clefts were surrounded by phagosomal structures and densified cytoplasmic ground substance; sometimes they were also lined by membranes...     

A young man with oligoarthritis: what is his cardiovascular risk?

Gout is the commonest cause of inflammatory arthritis among young men. A case of acute gout in a 39-year-old man is described. As part of his assessment, his cardiovascular risk factors were evaluated. He was found to have elevated body mass index, central obesity, hypertension, a family history of cardiovascular disease, and hypercholesterolemia. This case highlights the association between gout, hyperuricaemia and elevated cardiovascular risk. In young male patients, acute presentation with gout in primary care may provide the first opportunity for assessment of cardiovascular risk factors and primary prevention of ischaemic heart disease.     

The synovitis of acute gouty arthritis. A light and electron microscopic study

The synovium participates in the inflammatory process of acute gouty arthritis with intense polymorphonuclear leukocyte infiltration, but many chronic inflammatory cells are also seen even during the acute attack. Crystals in the synovial membrane were found in three patients and then only in well defined tophi. Tophus structure was consistent with crystal deposition in a collagen and amorphous matrix with little adjacent inflammatory reaction. Microtophi were superficial and thinly encapsulated, suggesting that crystals from these tophi might easily rupture into the joint space to initiate the inflammatory reaction. Crystals were seen in detached lining cells and other macrophages as well as in polymorphonuclear leukocytes in the synovial fluid. Clinically satisfactory doses of colchicine produced no detectable morphologic changes in microtubules or other structures.     

Altered Arachidonic Acid Metabolism in Urate Crystal Induced Inflammation

Gout is an acute rheumatic disorder that occurs in connection with the deposition of monosodium urate (MSU) crystals in the joints. This disease is characterized by intermittent episodes of severe pain and inflammatory joint swelling which are seemingly driven by prostaglandins. In this study we investigated the effect of MSU crystals on arachidonic acid (AA) metabolism in the mouse. We have demonstrated that prostaglandins and other AA metabolites were transiently formed after MSU crystal injection with peak levels occurring after 10 min. In contrast, free AA levels remained high for 2–4 hours after MSU crystal injection. By contrast, when exogenous AA was administered instead of MSU crystals, both the eicosanoids and AA diminished at the same high rates. The metabolism of exogenously administered AA to eicosanoids was inhibited by pretreatment with MSU crystals. No inhibition of AA metabolism was observed when mice were pretreated with AA itself, Ca²⁺ ionophore (A23187), or zymosan. We conclude that the MSU crystal treatment of mice results in a transient eicosanoid production which is followed by attenuated AA metabolism. It could be that MSU crystals similarly inhibit AA metabolism in gout and thereby limit the duration of gout attacks.     

Plasma urea, creatinine and uric acid concentrations in relation to feeding in peregrine falcons (Falco peregrinus)

Significant post-prandial increases in plasma uric acid and plasma urea concentrations were observed in peregrine falcons. Post-prandial uric acid concentrations were similar to those in birds suffering from hyperuricaemia and gout and were well above the theoretical limit of solubility of sodium urate in plasma. It is not clear why under normal circumstances no urate deposits occur in peregrine falcons (and probably other raptorial birds), which show hyperuricaemia for at least 12 h after ingesting a natural meal. It is important to evaluate renal function in peregrine falcons (and perhaps other birds) after a 24-h fast to avoid misinterpretation due to physiological food-induced elevated concentrations of nonprotein nitrogen substances.     

Fine needle aspiration of tophi in asymptomatic gout--a case report

Gout, a chronic hyperuricemic crystal induced arthropathy, may produce soft tissue masses (tophi). Tophi may be found in synovial membranes, periarticular ligaments, tendons, soft tissues as well as internal organs. We present a case in which diagnosis of gout was made by fine needle aspiration of tophus. The patient had a painless nodule over right ankle which was progressively increasing in size. He gave a past history of painful arthropathy, but serum uric acid levels were within normal limits. At this juncture, FNAC of the ankle tophus was performed which revealed aggregated and innumerable dissociated needle-shaped negatively birefringent crystals of monosodium urate (MSU) on polarization microscopy.     

Immunochemical and Ultrastructural Characterization of Serum Proteins Associated with Monosodium Urate Crystals (MSU) in Synovial Fluid Cells from Patients with Gout

Immunoelectron microscopic (IEM) analysis of the surface coats of intracellular and extracellular monosodium urate (MSU) crystals in synovial fluid (SF) in gouty arthritis was performed using the ferritin-bridge method. Cells from patients with acute gout were fixed in 1% glutaraldehyde containing 0.05% saponin to permeabilize membranes for access of immunochemicals to intracellular antigens. Intracellular MSU crystals were observed in phagosomes of greater than 75% of both polymorphonuclear (PMNs) and mononuclear cells. Coating of crystals with IgG was more prominent than with IgM or IgA. Other proteins such as C3, and fibrinogen were also found to a lesser extent. Albumin was not detected in appreciable amounts on MSU crystals. Extracellular crystals also showed IgG to be bound more prominently than other proteins. The various proteins, shown here for the first time to be clearly associated with intracellular crystals by EM, and other materials associated with MSU crystals May-Jun influence the phlogistic properties of these crystals.     

Gout: Joints and beyond,epidemiology, clinical features,treatment and co-morbidities

Gout is a common inflammatory arthritis precipitated by an inflammatory reaction to urate crystals in the joint. Gout is increasingly being recognised as a disease primarily of urate overload with arthritis being a consequence of this pathological accumulation. It is associated with a number of important co-morbidities including chronic kidney disease, obesity, diabetes and cardiovascular disease.     

Development of the gout tophus. An hypothesis

Sequential stages have been demonstrated in the development of individual focal deposits of crystalline urate and associated cell infiltrates within subcutaneous gout tophi. The findings suggest that acini of macrophages are formed and that active cellular transport of urate from the interstitial fluid into the central zones of these structures accounts for the focal nature of crystallization within the tophus. This process seems to account for the formation of focal urate deposits up to some 1.5-2 mm in diameter. The corona then commonly disappears and adjacent deposits may fuse. These events may lessen the consequences of hyperuricemia.     

虎贞痛风胶囊对家兔急性关节炎的影响

目的： 观察虎贞痛风胶囊对尿酸钠微晶（MSU）诱导的家兔急性关节炎的影响,对该药的抗炎作用进行药效学评价并初步探讨其机制,为临床应用提供科学依据。方法：将日本大耳白兔随机分成正常对照组（control）、急性关节炎模型组（AA）、不同剂量虎贞痛风胶囊治疗组（0.70 g/kg、0.35g/kg、0.20 g/kg）和痛风舒胶囊治疗组（药物对照组）,各组家兔分别灌胃给予溶剂、不同剂量的虎贞痛风胶囊悬液或痛风舒胶囊悬液,每天1次,连续灌胃5 d,于末次给药后30 min,模型组和各治疗组家兔膝关节内注射MSU复制急性关节炎模型,6 h后收集关节液进行白细胞计数,并取关节滑膜组织进行病理学检查。结果：正常对照组关节液未见炎症细胞浸润,镜下观察滑膜细胞连续平整、结构层次清晰;模型组关节液白细胞计数显著高于对照组,病理学观察有急性炎症发生,表现为表面滑膜组织肿胀、坏死、结缔组织水肿、炎症细胞弥漫性浸润等;虎贞痛风胶囊和痛风舒胶囊治疗组关节液白细胞计数低于模型组（P<0.05）,病理学观察镜下滑膜细胞连续平整、结构清晰,仅见少量炎症细胞浸润,其中虎贞痛风胶囊高剂量效果最好。结论： 虎贞痛风胶囊的高中剂量（0.70 g/kg、0.35 g/kg）明显抑制MSU所致的家兔急性关节炎,具有良好的抗炎作用,其效果优于痛风舒胶囊。     

Continuous recruitment, co-expression of tumour necrosis factor-α and matrix metalloproteinases, and apoptosis of macrophages in gout tophi

Gout tophi are characterised by foreign body granulomas consisting of mono- and multinucleated macrophages surrounding deposits of monosodium urate microcrystals. After primary formation, granulomas grow associated with degradation of the extracellular matrix. Based on this background, we have sought (1) to investigate whether during granuloma's growth new macrophages are recruited into the tophi, (2) to find in situ evidence for macrophages' active role in matrix degradation and (3) to examine whether shrunk cells seen within gout tophi are apoptotic. Immunohistochemistry showed that perivascular localised mononuclear cells are CD68+, S100A8+, S100A9+, 25F9-, representing freshly migrated monocytes/macrophages. In contrast, almost all CD68+ mono- and multinucleated cells arranged within granulomas were S100A8-, S100A9-, 25F9+, representing mature (non-migrating) macrophages. Serial sections revealed that macrophages co-express tumour necrosis factor (TNF)-alpha and matrix metalloproteinases (MMPs) 2 and 9. In situ end-labelling of fragmented DNA demonstrated that CD68+ macrophages undergo apoptosis within gout tophi. Our data show that macrophages are continuously recruited into the gout tophi. These macrophages co-produce the proinflammatory cytokine TNF-alpha and two TNF-alpha inducible lytic enzymes, MMP-2 and MMP-9, suggesting that TNF-alpha may induce MMP production followed by matrix degradation within foreign body granulomas. In parallel, macrophages undergo apoptosis, a phenomenon that may restrict the destructive potential of inflammatory macrophages.     

Crystal-induced neutrophil activation. IX. Syk-dependent activation of class Ia phosphatidylinositol 3-kinase

The deposition of monosodium urate (MSU) crystals in the joints of humans leads to an extremely acute, inflammatory reaction, commonly known as gout, characterized by a massive infiltration of neutrophils. Direct interactions of MSU crystals with human neutrophils and inflammatory mediators are crucial to the induction and perpetuation of gout attacks. The intracellular signaling events initiated by the physical interaction between MSU crystals and neutrophils depend on the activation of specific tyrosine kinases (Src and Syk, in particular). In addition, PI-3Ks may be involved. The present study investigates the involvement of the PI-3K family in the mediation of the responses of human neutrophils to MSU crystals. The results obtained indicate that the interaction of MSU crystals with human neutrophils leads to the stimulation of class Ia PI-3Ks by a mechanism that is dependent on the tyrosine kinase Syk. We also found an increase in the amount of p85 associated with the Nonidet P-40-insoluble fraction derived from MSU crystal-stimulated human neutrophils. Furthermore, MSU crystals induce the formation of a complex containing p85 and Syk, which is mediated by the Src family kinases. Finally, evidence is also obtained indicating that the activation of PI-3Ks by MSU crystals is a critical element regulating phospholipase D activation and degranulation of human neutrophils. The latter response is likely to be involved in the joint and tissue damage that occurs in gouty patients.     

Regulation of TRPV1 channel in monosodium urate-induced gouty arthritis in mice

Objective

The transient receptor potential vanilloid subtype 1 (TRPV1) channel is considered to play an important regulatory role in the process of pain. The purpose of this study is to observe the change characteristics of TRPV1 channel in MSU-induced gouty arthritis and to find a new target for clinical treatment of gout pain.

Methods

Acute gouty arthritis was induced by injection of monosodium urate (MSU) crystals into the ankle joint of mice. The swelling degree was evaluated by measuring the circumference of the ankle joint. Mechanical hyperalgesia was conducted using the electronic von Frey. Calcium fluorescence and TRPV1 current were recorded by applying laser scanning confocal microscope and patch clamp in dorsal root ganglion (DRG) neurons, respectively.

Results

MSU treatment resulted in significant inflammatory response and mechanical hyperalgesia. The peak swelling degree appeared at 12 h, and the minimum pain threshold appeared at 8 h after MSU treatment. The fluorescence intensity of capsaicin-induced calcium response and TRPV1 current were increased in DRG cells from MSU-treated mice. The number of cells that increased calcium response after MSU treatment was mainly distributed in small-diameter DRG cells. However, the action potential was not significantly changed in small-diameter DRG cells after MSU treatment.

Conclusions

These findings identified an important role of TRPV1 in mediating mechanical hyperalgesia in MSU-induced gouty arthritis and further suggest that TRPV1 can be regarded as a potential new target for the clinical treatment of gouty arthritis.

     

Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis

Hyperuricemia-mediated uric acid crystal formation may cause joint inflammation and provoke the destruction of joints through the activation of inflammasome-mediated innate immune responses. However, the immunopathological effects and underlying intracellular regulatory mechanisms of uric acid crystal-mediated activation of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) have not been elucidated. Therefore, we investigated the in vitro effects of monosodium urate crystals, alone or in combination with the inflammatory cytokines tumor-necrosis factor (TNF)-α or interleukin (IL)-1β, on the activation of human FLS from RA patients and normal control subjects and the underlying intracellular signaling mechanisms of treatment with these crystals. Monosodium urate crystals were able to significantly increase the release of the inflammatory cytokine IL-6, the chemokine CXCL8 and the matrix metalloproteinase (MMP)-1 from both normal and RA-FLS (all P<0.05). Moreover, the additive or synergistic effect on the release of IL-6, CXCL8 and MMP-1 from both normal and RA-FLS was observed following the combined treatment with monosodium urate crystals and TNF-α or IL-1β. Further experiments showed that the release of the measured inflammatory cytokine, chemokine and MMP-1 stimulated by monosodium urate crystals were differentially regulated by the intracellular activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase pathways but not the p38 mitogen-activated protein kinase pathway. Our results therefore provide a new insight into the uric acid crystal-activated immunopathological mechanisms mediated by distinct intracellular signal transduction pathways leading to joint inflammation in RA.     

膝关节液pH值与痛风结晶的形成

背景：引起痛风结晶析出的原因除了尿酸盐浓度升高之外还应有其他的影响因素。 目的：探讨膝关节液pH值在痛风结晶形成中的意义。 方法：选择2008-08/2010-12桂林医学院附属医院脊柱骨病外科因膝关节疾病就诊的患者40例,分为2组,实验组：关节镜检见关节内白垩样结晶沉积者。对照组：关节镜检关节内无明显白垩样结晶形成。其中实验组膝关节液25份,对照组膝关节液15份。检测并比较两组患者的关节液pH值。 结果与结论：实验组pH值7.8±0.2,对照组pH值8.5±0.3。镜检有痛风结晶形成的膝关节液pH值较无痛风结晶形成的膝关节液pH值明显偏低,差异有显著性意义(P < 0.001)。提示有痛风结晶形成的膝关节液pH值较无痛风结晶形成的膝关节液pH值明显偏酸性,膝关节液pH值降低是痛风结晶析出的危险因素之一。     

祛湿除痹复方对急性痛风性关节炎模型大鼠关节症状的作用及其机制

目的: 探讨祛湿除痹复方对大鼠急性痛风性关节炎的可能作用机制,验证急性痛风性关节炎的湿热痹阻病机。方法: 将40只Wistar大鼠随机分5组,每组8只,即空白组、模型组、秋水仙碱组、中药低剂量组和中药高剂量组。采用尿酸单钠晶体溶液踝关节注射法建立急性痛风性关节炎模型。以祛湿除痹复方与秋水仙碱对比治疗,观察祛湿除痹复方对大鼠关节各种症状(炎症、肿胀度及活动障碍)及大鼠关节组织内白细胞介素1β(IL-1β)、白细胞介素1受体(IL-1R)和髓样分化因子88(MyD88)表达水平的影响。结果: 灌胃给药7 d后秋水仙碱组和中药各剂量组与模型组比较,大鼠关节肿胀程度差异显著(P<0.01), 秋水仙碱组和中药高剂量组比较差异有统计学意义(P<0.05)。各组大鼠关节炎症指数及功能障碍指数积分比较,模型组积分最高。造模后8和72 h各组积分均降低(P<0.05),模型组与各用药组比较差异显著 (P<0.05)。关节软组织内IL-1β、IL-1R及MyD88的平均吸光度以模型组为最高,中药低剂量组和秋水仙碱组比较无明显差异(P>0.05),而与中药高剂量组比较有显著差异(P<0.05)。结论: 祛湿除痹复方能有效抑制实验性急性痛风性关节炎大鼠关节组织内炎症因子的表达,从而改善模型大鼠各种关节症状。