Deposition Of Monosodium Urate Crystals Research Articles

Monosodium urate crystals alter the circadian clock in macrophages leading to loss of NLRP3 inflammasome repression: Implications for timing of the gout flare.

Gout is caused by monosodium urate (MSU) crystal deposition within joints. This leads to acute episodes of inflammation ("gout flares") driven by NLRP3 inflammasome activation in macrophages. Gout flares are frequently present during late night/early morning. The reason for this timing is unclear. Recent evidence suggests the NLRP3 inflammasome is under circadian control. The purpose of this study was to determine whether MSU crystals cause changes in the circadian clock in macrophages leading to time-of-day differences in NLRP3 inflammasome activation. Levels of circadian clock components were measured in undifferentiated "monocytic" and PMA-differentiated "macrophagic" THP-1 cells cultured with/without MSU crystals. Caspase-1 activity was measured to assess NLRP3 inflammasome activity. MSU crystal exposure resulted in minimal effects on clock genes in THP-1 monocytes but BMAL1, CRY1, PER2, and REV-ERBα showed altered expression with reduced protein levels of BMAL1 and REV-ERBα in THP-1 macrophages. REV-ERBα activation or BMAL1 over-expression resulted in reduced MSU crystal-induced caspase-1 activity. BMAL1 knockdown resulted in a further increase in MSU crystal-induced caspase-1 activity, but only at times of day when BMAL1 levels were naturally high. MSU crystal-induced NLRP3 inflammasome activation was greatest at the time of day when BMAL1 levels were naturally low. MSU crystals alter the expression of circadian clock components in THP-1 macrophages leading to loss of BMAL1 and REV-ERBα-mediated repression of NLRP3 inflammasome activity and time-of-day differences in susceptibility to inflammasome activation. Our findings suggest that the nocturnal risk of gout flare is at least partially a consequence of altered circadian control of immune cell function.

Detailed analysis of the association between urate deposition and bone erosion in gout: a dual-energy computed tomography study.

This study aimed to analyze the effect of urate deposition (UD) on bone erosion and examine the association between the volume of monosodium urate (MSU) crystals and an improved bone erosion score method, as measured in the metatarsophalangeal (MTP) joints of patients with gout. Fifty-six patients diagnosed with gout using the 2015 European League Against Rheumatism and American College of Rheumatology criteria were enrolled. MSU crystals volume at each MTP joint was measured using dual-energy computed tomography (DECT) images. The degree of bone erosion was evaluated with the modified Sharp/van der Heijde (SvdH) erosion scoring system based on CT images. Differences in clinical features between patients with (UD group) and without (non-UD group) UD were assessed, and the correlation between erosion scores and urate crystal volume was analyzed. The UD and non-UD groups comprised 30 and 26 patients, respectively. Among the 560 MTP joints assessed, 80 showed MSU crystal deposition, and 108 showed bone erosion. Bone erosion occurred in both groups but was significantly less severe in the non-UD group (p <0.001). Both groups had equivalent levels of serum uric acid (p=0.200). Symptom duration was significantly longer in the UD group (p=0.009). The UD group also had a higher rate of kidney stones (p=0.023). The volume of MSU crystals was strongly and positively associated with the degree of bone erosion (r=0.714, p <0.001). This study found that patients with UD show significant increased bone erosion than those without UD. The volume of MSU crystals is associated with the improved SvdH erosion score based on CT images, regardless of serum uric acid level, demonstrating the potential of combining DECT and serum uric acid measurements in helping optimize the management of patients with gout.

Can We Take Hyperuricemia as a Cardiovascular Risk?

Study conducted for Gouty arthritis at Pan Pakistan level in 2017 showed mean Uric Acid levels of 6.11±1.7mg/dl with frequency of hyperuricemia of 39% and having 27.9% male and 49.35 women respectively.1 This type of arthritis results from monosodium urate crystal deposition in and around the joints affecting big toe around the joints of hands and feet. Gout has been shown to increase with age and associated with diabetes &amp; hypertension.2,3 It has also been shown that hyperuricemia may be tied to increased risk of cardiovascular disease mortality.4 Hyperuricemia has also shown to increase atherosclerosis by systemic inflammation and oxidative stress. It also causes endothelial dysfunction and oxidation of lipoproteins with formation of atherosclerotic plaques.5 Recent studies have shown hypertension, coronary artery disease, cardiovascular diseases, vascular dementia and preclampsia to be associated with high uric acid levels. The studies include Rotterdam (Serum Uric Acid Level and Myocardial infraction),2 PUMA study (Serum Uric Acid levels with cardiovascular events and deaths in hypertensive patients),6 PAMELA study (increased risk of cardiovascular deaths with increase of every 1mg /dl).4 Three important co-relation i.e. Hyperuricemia, atherosclerosis and heart failure need bit of understanding. In one study elevated uric acid levels (75.5mg/dl) in 90% of adolescents with essential hypertension7 and lower uric acid levels in teens with either white coat or secondary hypertension.7 Secondly association between increased uric acid levels and coronary artery calcification has shown an independent risk factor for subclinical atherosclerosis in young adults.8 Similar association was also seen in atherosclerotic vulnerable carotid plaque.9 Thirdly in cardiovascular health study incidence of heart failure was 21% with Chronic hyperuricemia and 18% without.10 For management of hyperuricemia (gout) multidisciplinary approach involving primary care physicians, rheumatologist and cardiologists might improve associated cardiovascular diseases other than primary pathology. Drugs like non-steroidal anti-inflammatory drug (NSAIDS), steroids &amp; colchicine may improve Gout but improvement in cardiovascular comorbids are questionable.11,12 Though different epidemiological studies have shown hyperuricemia as an independent risk factor for cardiovascular diseases and hypertension. Further studies are needed that my elucidate association of increased uric acid level with cardiovascular diseases. Multidisciplinary approach, awareness and counselling patient will hopefully prevent onset of heart disease and improve survival outcomes for gouty patients.

A review on gout: Looking back and looking ahead.

Gout is a metabolic disease caused by the deposition of monosodium urate (MSU) crystals inside joints, which leads to inflammation and tissue damage. Increased concentration of serum urate is an essential step in the development of gout. Serum urate is regulated by urate transporters in the kidney and intestine, especially GLUT9 (SLC2A9), URAT1 (SLC22A12) and ABCG. Activation of NLRP3 inflammasome bodies and subsequent release of IL-1β by monosodium urate crystals induce the crescendo of acute gouty arthritis, while neutrophil extracellular traps (NETs) are considered to drive the self-resolving of gout within a few days. If untreated, acute gout may eventually develop into chronic tophaceous gout characterized by tophi, chronic gouty synovitis, and structural joint damage, leading the crushing burden of treatment. Although the research on the pathological mechanism of gout has been gradually deepened in recent years, many clinical manifestations of gout are still unable to be fully elucidated. Here, we reviewed the molecular pathological mechanism behind various clinical manifestations of gout, with a view to making contributions to further understanding and treatment.

Clinical case of severe visceral complications with atypical localization in a patient with gout

The diagnosed gout is a signal to search for unrecognized concomitant conditions and their underlying causes and mechanisms of development. Due to the fact that gout is a common metabolic disorder with symptoms of localized inflammation caused by chronic and/or episodic deposition of monosodium urate crystals (MSU) in joints and soft tissues, the understanding of the inflammation interaction in metabolic disorders has changed. In cases of severe visceral complications of gout, the most common sites of tophl are kidneys, liver, spleen, lungs, pericardium, subcutaneous tissue and other soft tissues. The aim of this study was to outline the features of severe visceral complications with atypical localization in a patient with gout (identification of MSU crystals with polarization microscopy) and to determine the role of videothoracoscopy in this case. Patient N., 55 years old, complained of moderate chest pain, shortness of breath during exercise, general weakness and occasional cough. The patient was hospitalized in a multidisciplinary clinical institution. Examinations were performed, including polarization microscopy, spiral computed tomography (polytopic foci, formations), videothoracoscopy. Endoscopic resection of SVII of the lower lobe of the left lung with a biopsy of the lungs formations and mediastinal lymph nodes was performed. Results of histologic examination: amorphous masses are presented in combination with the organized chronic giant cell granulomatous structure (tophus), which contains clusters of crystals of MSU. Cytological examination of pleural cavity fluid revealed the presence of crystals of MSU. The presence of crystals of MSU was confirmed by polarization microscopy. From the anamnesis of the disease it became known that at the age of 38 the patient consulted a rheumatologist for moderate joint syndrome. On the basis of anamnesis, laboratory and instrumental data (X-ray, ultrasound examination) the diagnosis of gout, chronic gouty arthritis was established. Urate lowering therapy was prescribed. The patient took the drugs periodically without re-consultation with the doctor. The presented case of untreated gout has led to significant structural disorders in organs such as lungs, pleura. Endoscopic resection of the lower lobe of the left lung and revision of the thoracic cavity revealed atelectasis, hemorrhage, inflammatory infiltration, fibrous changes in tissues, amorphous masses with organized chronic giant cell granulomatous structure, presented by crystals of MSU. During the surgery, a powdery substance was found on the pleura surfaces. A video thoracoscopy in this case was a means to present a visceral damage in gout. The search for diagnostic tools to diagnose a severe visceral complications with atypical localization in gout still remains unsolved. Undoubtedly, the central role in the development of gout is played by the deposition of numerous crystals of MSU. In the patient under observation, crystals of MSU were found in pleural fluid and sputum consisting of sodium urate, like the known facts of their appearance in the joint fluid and urine. Uric acid salt crystals were also detected in the areas of pulmonary fibrosis formation according to the results of radiological examination, as well as endoscopic intervention in the lower lobe of the left lung.

Role of NLRP3 in the pathogenesis and treatment of gout arthritis.

Gout arthritis (GA) is a common and curable type of inflammatory arthritis that has been attributed to a combination of genetic, environmental and metabolic factors. Chronic deposition of monosodium urate (MSU) crystals in articular and periarticular spaces as well as subsequent activation of innate immune system in the condition of persistent hyperuricemia are the core mechanisms of GA. As is well known, drugs for GA therapy primarily consists of rapidly acting anti-inflammatory agents and life-long uric acid lowering agents, and their therapeutic outcomes are far from satisfactory. Although MSU crystals in articular cartilage detected by arthrosonography or in synovial fluid found by polarization microscopy are conclusive proofs for GA, the exact molecular mechanism of NLRP3 inflammasome activation in the course of GA still remains mysterious, severely restricting the early diagnosis and therapy of GA. On the one hand, the activation of Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome requires nuclear factor kappa B (NF-κB)-dependent transcriptional enhancement of NLRP3, precursor (pro)-caspase-1 and pro-IL-1β, as well as the assembly of NLRP3 inflammasome complex and sustained release of inflammatory mediators and cytokines such as IL-1β, IL-18 and caspase-1. On the other hand, NLRP3 inflammasome activated by MSU crystals is particularly relevant to the initiation and progression of GA, and thus may represent a prospective diagnostic biomarker and therapeutic target. As a result, pharmacological inhibition of the assembly and activation of NLRP3 inflammasome may also be a promising avenue for GA therapy. Herein, we first introduced the functional role of NLRP3 inflammasome activation and relevant biological mechanisms in GA based on currently available evidence. Then, we systematically reviewed therapeutic strategies for targeting NLRP3 by potentially effective agents such as natural products, novel compounds and noncoding RNAs (ncRNAs) in the treatment of MSU-induced GA mouse models. In conclusion, our present review may have significant implications for the pathogenesis, diagnosis and therapy of GA.

Single-Cell Analysis in Blood Reveals Distinct Immune Cell Profiles in Gouty Arthritis.

Gout is a chronic disease caused by monosodium urate crystal deposition. Previous studies have focused on the resident macrophage, infiltrating monocyte, and neutrophil responses to monosodium urate crystal, yet the mechanisms of the potential involvement of other immune cells remain largely unknown. In this study, we enrolled seven gout patients and five age-matched healthy individuals and applied single-cell mass cytometry to study the distribution of immune cell subsets in peripheral blood. To our knowledge, our study reveals the immune cell profiles of gout at different stages for the first time. We identified many immune cell subsets that are dysregulated in gout and promote gouty inflammation, especially those highly expressing CCR4 and OX40 (TNFR superfamily member 4), including CCR4+OX40+ monocytes, CCR4+OX40+CD56high NK cells, CCR4+OX40+CD4+ NK T cells, and CCR4+CD38+CD4+ naïve T cells. Notably, the plasma levels of CCL17 and CCL22, measured by ELISA, increased in the acute phase of gout and declined in the interval. We also found a clue that Th2-type immune responses may participate in gout pathology. Moreover, the subset of granzyme B+ (GZMB+) CD38+ NK cells is positively correlated with serum urea acid level, and another two γδT subsets, GZMB+CD161+ γδT cells and GZMB+CCR5+ γδT cells, are negatively correlated with erythrocyte sedimentation rate. In sum, gouty arthritis is not a disease simply mediated by macrophages; multiple types of immune cell may be involved in the pathogenesis of the disease. Future research needs to shift attention to other immune cell subsets, such as NK cells and T cells, which will facilitate the identification of novel therapeutic targets.

Downregulation of Sox8 mediates monosodium urate crystal-induced autophagic impairment of cartilage in gout arthritis

The deposition of monosodium urate (MSU) crystals in arthritic joints of gout seriously damages cartilage. This study aimed to investigate whether MSU crystal-induced cartilage impairment was related to autophagic signaling. mRNAs of cartilage from MSU-induced gouty arthritis rat model were sequenced. MSU crystal-treated human chondrocytes were used to evaluate the function of Sox8. The recombinant Sox8 lentiviral vector (lenti-Sox8) was applied to upregulate the expression of Sox8. Transfection of the mRFP-GFP-LC3 plasmid was evaluated by confocal microscopy. The autophagic vacuoles were stained with monodansylcadaverine and examined by flow cytometry. The morphology of autophagosomes was observed by transmission electron microscopy. The ratio of LC3-II/I in the presence or absence of bafilomycin A1 and the expression levels of Beclin1, Sox8, p-PI3K, PI3K, p-AKT, AKT, p-mTOR, and mTOR were detected by Western blot. In vivo, the effect of Sox8 on cartilage of acute gouty model rats was evaluated by safranin-O/fast green staining and Western blot. The expression of Sox8 was significantly downregulated both in vivo and in vitro. In chondrocytes, MSU crystals reduced the expression of Sox8, inhibited the PI3K/AKT/mTOR signaling pathway, and increased the level of autophagy. Overexpression of Sox8 notably inhibited MSU crystal-induced autophagy by rescuing the phosphorylation levels in the PI3K/AKT/mTOR signaling pathway. In vivo, overexpression of Sox8 remarkably alleviated cartilage damage in acute gouty model rats. These results indicate that downregulation of Sox8 plays an important role in MSU-induced chondrocyte autophagy by modulating PI3K/AKT/mTOR signaling, and overexpression of Sox8 may serve as a novel therapy to prevent the impairment of cartilage in gout arthritis.

Changes in Tophus Composition During Urate-Lowering Therapy: A Dual-Energy Computed Tomography Study.

The gouty tophus is an organized structure composed of monosodium urate (MSU) crystals and chronic inflammatory soft tissue. This dual-energy computed tomography (DECT) study aimed to determine whether the composition of the tophus changes during urate-lowering therapy. Serial DECT scans from 32 people with gout were obtained over 2 years of allopurinol therapy, dose-escalated to serum urate of <0.36 mmoles/liter. Up to 5 index tophi were selected for each patient, with 103 separate tophi included in the analysis. Using manual outlining methods of conventional CT and DECT scans, the same index tophi were serially measured for total tophus volume and urate volume. For each tophus, the soft tissue volume was then calculated by subtracting the urate volume from the total tophus volume. The mean ± SD serum urate reduced from 0.43 ± 0.03 mmoles/liter at baseline to 0.31 ± 0.02 mmoles/liter at year 2. The mean ± SD total tophus volume reduced over the 2-year period from 5.17 ± 5.55 cm3 to 2.61 ± 2.73 cm3 (P < 0.0001). Greater reductions in tophus urate volumes than tophus soft tissue volumes were observed; the tophus urate volume decreased by 70.6%, and tophus soft tissue volume decreased by 37.8% (P < 0.0001). The mean tophus urate:soft tissue ratio reduced from 0.15 at baseline to 0.05 at year 2 (P < 0.001). The composition of the tophus is dynamic and changes during urate-lowering therapy for gout management. The soft tissue component of the tophus is slower to respond and may persist without measurable MSU crystal deposition.

COMPARISON OF URIC ACID LEVELS IN MAN AND WOMAN AGED 45-60 YEARS

Gout arthritis is a progressive disease due to the deposition of monosodium urate (MSU) crystals in joints, kidneys, and other connective tissues as a result of chronic hyperuricemia. The purpose of this study was to compare uric acid levels in men and women aged 45-60 years.The type of research used in this research is observational analytic with a quantitative approach and the method used in this research is Enzymatic Colorimetric (Uricase). This method uses the aid of a spectrophotometer to measure uric acid levels. The spectrophotometer used in this research is Pentra C200.The results of the research conducted at the UPTD Balai LABKESDA Gorontalo Province showed that abnormal uric acid levels were more in men than uric acid levels in women where the abnormal number in men was 7 respondents and in women only 4 respondents. This is because men have a higher risk of developing gout compared to women whose risk will be the same as men when entering the age or period of menopause.

The application of a novel hydrodynamic cavitation device to debride intra-articular monosodium urate crystals

IntroductionEfficient and complete debridement of intra-articular deposits of monosodium urate crystals is rarely achieved by existing arthroscopic tools such as shavers or radiofrequency ablation, while cavitation technology represents a prospective solution for the non-invasive clearance of adhesions at intra-articular interfaces.MethodsSimulation modeling was conducted to identify the optimal parameters for the device, including nozzle diameters and jet pressures. Gouty arthritis model was established in twelve rats that were equally and randomly allocated into a cavitation debridement group or a curette debridement group. A direct injection nozzle was designed and then applied on animal model to verify the effect of the cavitation jet device on the removal of crystal deposits. Image analysis was performed to evaluate the clearance efficiency of the cavitation device and the pathological features of surrounding tissue were collected in all groups.ResultsTo maximize cavitation with the practical requirements of the operation, an experimental rig was applied, including a 1 mm direct injection nozzle with a jet pressure of 2.0 MPa at a distance of 20 mm and a nitrogen bottle as high-pressure gas source. With regards to feasibility of the device, the clearance rates in the cavitation group were over 97% and were significantly different from the control group. Pathological examination showed that the deposition of monosodium urate crystals was removed completely while preserving the normal structure of the collagen fibers.ConclusionsWe developed a promising surgical device to efficiently remove intra-articular deposits of monosodium urate crystals. The feasibility and safety profile of the device were also verified in a rat model. Our findings provide a non-invasive method for the intraoperative treatment of refractory gouty arthritis.

Biomineralized Nanoscavenger Abrogates Proinflammatory Macrophage Polarization and Induces Neutrophil Clearance through Reverse Migration during Gouty Arthritis.

The deposition of monosodium urate (MSU) crystals induces the overexpression of reactive oxygen species (ROS) and proinflammatory cytokines in residential macrophages, further promoting the infiltration of inflammatory leukocytes in the joints of gouty arthritis. Herein, a peroxidase-mimicking nanoscavenger was developed by forming manganese dioxide over albumin nanoparticles loaded with an anti-inflammatory drug, indomethacin (BIM), to block the secretion of ROS and COX2-induced proinflammatory cytokines in the MSU-induced gouty arthritis model. In the MSU-induced arthritis mouse model, the BIM nanoparticles alleviated joint swelling, which is attributed to the abrogation of ROS and inflammatory cytokine secretions from proinflammatory macrophages that induces neutrophil infiltration and fluid building up in the inflammation site. Further, the BIM nanoparticle treatment reduced the influx of macrophages and neutrophils in the injured region by blocking migration and inducing reverse migration in the zebrafish larva tail amputation model as well as in MSU-induced peritonitis and air pouch mouse models. Overall, the current strategy of employing biomineralized nanoscavengers for arthritis demonstrates clinical significance in dual blocking of peroxides and COX2 to prevent influx of inflammatory cells into the sites of inflammation.

Anti-Inflammatory Effects of Polyphenols from Plum (Prunus salicina Lindl) on RAW264.7 Macrophages Induced by Monosodium Urate and Potential Mechanisms.

Acute gouty arthritis is an acute inflammatory reaction caused by the deposition of monosodium urate (MSU) crystals in joints and surrounding soft tissues. Controlling inflammation is the key to preventing acute gouty arthritis. Anti-inflammatory activities and the possible molecular mechanisms of plum (Prunus salicina Lindl cv. "furong") polyphenols (PSLP) on RAW264.7 macrophage cells induced by monosodium urate were investigated. PPSF significantly inhibited the activity of inflammatory factors such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18). In addition, PPSF exhibited excellent activation of superoxide dismutase (SOD) activity and reduction of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels in RAW264.7 macrophages. The results of global screening of all transcripts by RNA-seq revealed 8585 differentially expressed genes between the PSLP-treated group and the MUS group. From GO analysis, PSLP could affect the occurrence and development of RAW264.7 macrophage inflammation through biological processes, such as organic substance metabolism, intracellular organelles, and binding function. The regulation mechanism of PSLP on MSU-induced RAW264.7 macrophage inflammation may be achieved through the HIF-1 signaling pathway, renal cell carcinoma, the ErbB signaling pathway, and the FoxO signaling pathway. Therefore, PSLP has great prospects in the prevention of gout and similar inflammatory diseases.

Crystal deposition disease as an unusual cause of knee pain in an adult male: Report of a rare case

Abstract Gout is a monosodium urate crystal deposit disease which generally occurs in middle aged male and post-menopausal females. It is typically characterized by episodic acute and chronic arthritis due to deposition of monosodium urate crystals in joints and connective tissue. Palpable deposits of crystals known as tophi may form particularly around joints but also elsewhere. This is a single case based prospective work-up and follow up study done at our institute of a middle-aged male having chronic right knee pain since 1 year year. Meticulous history and clinical examination ,laboratory investigations were done like ESR (erythrocyte sedimentation rate) and CRP (c- reactive protein) and radiological investigation including plain radiograph and MRI (Magnetic resonance imaging) right knee was done and was suggestive of giant cell tumor of patella. Excision and curettage of the lesion was done and sample was sent for HPE (histopathological examination) which showed fibrocartilaginous tissue with features of gouty arthritis. Serum uric acid was done which came out to be raised (10.14 mg/dl). At final follow-up patient had satisfactory outcome. It is important to have in mind that tophus of patella can cause chronic knee pain in patients with gouty arthritis. Early diagnosis and treatment are essential. Patients with tophaceous gout require strict disease control and close follow-up.

HQL6 serves as a novel P2Y14 receptor antagonist to ameliorate acute gouty arthritis through inhibiting macrophage pyroptosis.

Acute gouty arthritis (AGA) has been classified as an autoinflammatory disease caused by deposition of monosodium urate crystals (MSU), accompanied by swellingofjoint and severe pain. Limited clinical therapy and highincidence indicate that the development of effective drugs for AGA is an urgent need. Our previous study found that P2Y14 receptor (P2Y14R) was a potential target in anti-gout treatment through regulating pyroptosis of macrophages under exposure of MSU. Based on previous work, we carried out further structure modifications and led to a more effective antagonist HQL6 with IC50 of 3.007nM. Extensive profiling of HQL6 has demonstrated that its high selectivity, good pharmacokinetic properties, and reliable in vivo anti-gout efficacy. Moreover, P2Y14R has been demonstrated to be the key target of HQL6 since the diminished effects on adenylate cyclase inhibitor-induced acute gouty arthritis in P2Y14R knockout rats. More importantly, results of single point mutant experiments exhibited that HQL6 might interact with Lys277 as favorable residue in the binding pocket of P2Y14R. Therefore, we confirmed that P2Y14R was a promising drug target for AGA, and HQL6 would be an available candidate for further drug development.

РАЗРАБОТКА И АПРОБАЦИЯ ПРОТОТИПА ЭКСПЕРТНОЙ СИСТЕМЫ ДЛЯ ДИАГНОСТИКИ ПОДАГРЫ

Significance. Gout is a rheumatological disease that affects up to 2% of the population of the Russian Federation according to various sources. The pathogenesis of the disease is associated with a disturbance in uric acid metabolism and manifests itself in the deposition of monosodium urate crystals in various tissues of the body. Timely diagnosis and treatment of the disease can prevent the development of gout complications and disability of the patient, however, according to various sources, it takes from 44 to 8 years to diagnose gout. One possible way to improve the quality of gout diagnosis is to develop and implement an expert system for preliminary diagnosis, diagnostic techniques and consultations, and final diagnosis. The purpose of the study is to develop and test a prototype expert system for gout diagnosis. Material and methods. The study used system analysis methods, including decomposition, analysis and synthesis methods, knowledge engineering methods, including knowledge representation methods (frames, semantic networks), ontological approach, fuzzy logic, hierarchical structuring methods and effective evaluation methods, including ROC analysis. Results. A prototype expert system for gout diagnosis has been developed. The prototype consists of a knowledge base, a logical solver, and an explanation subsystem. A specialized knowledge base editor was created for the development and subsequent maintenance of the knowledge base. The knowledge base was filled using 2 information objects jointly developed with a group of experts: the nomenclature of medical concepts (495 basic and 679 synonymous concepts) and logical schemes (40 schemes) related to gout diagnosis. The structure of the knowledge base is a combination of frames and semantic networks and includes 18 objects (7 types of concepts and 11 types of relationships). A graph database is used to store the knowledge base that determines the logic of the logical solver and the explanation subsystem. The logical solver analyzes the patient's clinical data and searches the optimal path, the end points of which are the recommendations of the expert system prototype. The explanation subsystem uses this path to argue the selected solution. The prototype expert system was tested on two depersonalized samples containing 1725 patients provided by the Tyumen Healthcare Department. Conclusion. A prototype expert system has been developed to determine the preliminary diagnosis of gout, prescribe diagnostic techniques and consultations for its verification, and make a final diagnosis. The prototype includes 1174 concepts and 5,640,522 relationships. Testing of the prototype expert system with ROC-analysis showed that its sensitivity was 91.3% CI [89.1%; 93.1%], specificity was 85.4% CI [82.9%; 87.6%], and AUROC was 0.954 CI [0.944; 0.963]. Scope of application. The research results can be used to integrate the prototype expert system into the doctor’s automated workplace of a medical information system in a medical organization.

WHEN TOPHACEOUS GOUT INVOLVES MULTIPLE ORGANS: CHALLENGES AND SOLUTIONS.

Uncontrolled chronic gout can lead to deposition of monosodium urate crystals, better known as tophi. Such depositions can involve several organ systems, including unusual locations such as the vertebrae. Nevertheless, certain complications, such as hypercalcemia, can arise because of tophi. Despite an aggressive intervention, hypercalcemia might not resolve spontaneously, as long as an ongoing inflammatory process secondary to gouty tophi is taking place. Herein, we present the case of a 62-year-old man with a long history of gouty tophi who presented for back pain and was found to have spinal cord involvement with PTH-independent hypercalcemia which only resolved with pegloticase therapy.

Targeted treatment of gouty arthritis by biomineralized metallic nanozyme-mediated oxidative stress-mitigating nanotherapy.

Gouty arthritis is characterized by chronic deposition of monosodium urate (MSU) crystals in the joints and other tissues, resulting in the production of excess reactive oxygen species (ROS) and proinflammatory cytokines that intensify synovial inflammation. This condition is mainly associated with inflammatory M1 macrophage activation and oxidative stress production. Hence, gout symptoms can often be resolved by eliminating M1 macrophage activation and scavenging oxidative stress in the inflamed areas. Herein, we developed M1-macrophage-targeting biomineralized metallic nanozymes (FALNZs) that deplete oxidative stress and reduce the M1 macrophage levels to mitigate gouty arthritis. Intra-articular injection of the FALNZs targets inflammatory macrophages and suppresses ROS levels in joints with MSU-crystal-induced arthritis. In addition, the FALNZs alleviate joint swelling, inflammatory cytokine production, and pathological features of the joints. Overall, the proposed therapeutic approach is biocompatible and is an effective ROS scavenger for the treatment of gouty pathogenesis.

Uric acid en route to gout.

Gout and hyperuricemia (HU) have generated immense attention due to increased prevalence. Gout is a multifactorial metabolic and inflammatory disease that occurs when increased uric acid (UA) induce HU resulting in monosodium urate (MSU) crystal deposition in joints. However, gout pathogenesis does not always involve these events and HU does not always cause a gout flare. Treatment with UA-lowering therapeutics may not prevent or reduce the incidence of gout flare or gout-associated comorbidities. UA exhibits both pro- and anti-inflammation functions in gout pathogenesis. HU and gout share mechanistic and metabolic connections at a systematic level, as shown by studies on associated comorbidities. Recent studies on the interplay between UA, HU, MSU and gout as well as the development of HU and gout in association with metabolic syndromes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular, renal and cerebrovascular diseases are discussed. This review examines current and potential therapeutic regimens and illuminates the journey from disrupted UA to gout.

Improvement Effect of Soyeom Pharmacopuncture on Gout via NLRP3 Inflammasome Regulation.

Gout is an inflammatory arthritis of the joints and soft tissues occurring due to deposition of monosodium urate (MSU) crystals, which are caused by persistent hyperuricemia. Soyeom pharmacopuncture is one treatment method that has been traditionally used for pain management in Oriental medicine. However, studies on its effect in reducing gout pain have been insufficient. Therefore, we selected Soyeom pharmacopuncture among natural products used in Korea as the new target of our study. The effects of Soyeom pharmacopuncture were examined in mouse models of acute gout induced by injection of MSU crystals into footpads. IL-1β, IL-6, and TNF-α production were examined by immunoblotting and enzyme-linked immunosorbent assay as hallmarks of NLRP3 inflammasome and cytokine activation. Soyeom pharmacopuncture reduced foot edema in gout-induced mice, as well as IL-1β, nitrite, IL-6, and TNF-α production. Moreover, Soyeom pharmacopuncture also reduced MSU-induced gout inflammatory gene expressions, specifically those in the NF-kB pathway. Pharmacopuncture may serve as a new solution for other inflammatory diseases as well. Through active follow-up studies, we could thoroughly understand the clinical value of Soyeom pharmacopuncture.