Effectiveness of intravenous methylprednisolone pulse in patients with severe microscopic polyangiitis and granulomatosis with polyangiitis.

OBJECTIVES: To evaluate the effectiveness and safety of two different intravenous methylprednisolone (IVMP) pulse doses in patients with severe microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). METHODS: We emulated a target trial using observational data from the nationwide registry in Japan. Patients with severe glomerulonephritis or diffuse alveolar haemorrhage were selected and pseudo-randomised into three groups using propensity score-based overlap weighting as follows: non-IVMP, IVMP 0.5 g/day, and IVMP 1.0 g/day. The primary outcome was all-cause death, and the secondary outcomes were composite all-cause death and kidney failure, severe relapse, and serious infection from 2 to 48 weeks after treatment initiation. To estimate the treatment effects, the Cox proportional hazard model and Fine-Gray subdistribution hazard model were used. RESULTS: In this emulated target trial, of 201 eligible patients (MPA, 175; GPA, 26), 6 (2.8%) died, 4 (2.0%) had kidney failure, 11 (5.3%) had severe relapse, and 40 (19.8%) had severe infections. Hazard ratios (HR) for IVMP 0.5 g/day and IVMP 1.0 g/day pulse groups compared with non-IVMP pulse were as follows: all-cause death = 0.46 (95% confidence interval [95%CI]: 0.07-2.81) and 0.07 (95%CI: 0.01-0.41); all-cause death/kidney failure = 1.18 (95%CI: 0.26-5.31) and 0.59 (95%CI: 0.08-4.52); subdistribution HRs for severe relapse = 1.26 (95%CI: 0.12-13.70) and 3.36 (95%CI: 0.49-23.29); and serious infection = 1.88 (95%CI: 0.76-4.65) and 0.94 (95%CI: 0.28-3.13). CONCLUSIONS: IVMP 1.0 g/day pulse may improve 48-week mortality in patients with severe MPA/GPA.

Association between hypogammaglobulinaemia and severe infections during induction therapy in ANCA-associated vasculitis: from J-CANVAS study.

OBJECTIVES: To investigate the association between decreased serum IgG levels caused by remission-induction immunosuppressive therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and the development of severe infections. METHODS: We conducted a retrospective cohort study of patients with new-onset or severe relapsing AAV enrolled in the J-CANVAS registry, which was established at 24 referral sites in Japan. The minimum serum IgG levels up to 24 weeks and the incidence of severe infection up to 48 weeks after treatment initiation were evaluated. After multiple imputations for all explanatory variables, we performed the multivariate analysis using a Fine-Gray model to assess the association between low IgG (the minimum IgG levels <500 mg/dl) and severe infections. In addition, the association was expressed as a restricted cubic spline (RCS) and analysed by treatment subgroups. RESULTS: Of 657 included patients (microscopic polyangiitis, 392; granulomatosis with polyangiitis, 139; eosinophilic granulomatosis with polyangiitis, 126), 111 (16.9%) developed severe infections. The minimum serum IgG levels were measured in 510 patients, of whom 77 (15.1%) had low IgG. After multiple imputations, the confounder-adjusted hazard ratio of low IgG for the incidence of severe infections was 1.75 (95% confidence interval: 1.03-3.00). The RCS revealed a U-shaped association between serum IgG levels and the incidence of severe infection with serum IgG 946 mg/dl as the lowest point. Subgroup analysis showed no obvious heterogeneity between treatment regimens. CONCLUSION: Regardless of treatment regimens, low IgG after remission-induction treatment was associated with the development of severe infections up to 48 weeks after treatment initiation.

Optimal Dose of Intravenous Cyclophosphamide during remission induction therapy in ANCA-associated vasculitis: a retrospective cohort study of J-CANVAS.

OBJECTIVES: To identify the optimal dose of intravenous cyclophosphamide (IVCY) for induction therapy for anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: We retrospectively assessed patients with AAV who received IVCY every 2-3 weeks during the remission induction phase. The associations of the IVCY dose with infection-free survival and relapse-free survival were analysed using a Cox regression model. We compared patients in three categories: very low-dose (VLD), low-dose (LD), and conventional dose (CD) (<7.5 mg/kg, 7.5-12.5 mg/kg, and >12.5 mg/kg, respectively). The non-linear association between IVCY dose and the outcomes were also evaluated. RESULTS: Of the 80 patients (median age 72 years), 12, 42, and 26 underwent the VLD, LD, and CD regimens, respectively, of whom 4, 3, and 7 developed infection or died. The adjusted hazard ratios for infection or death were 4.3 (95% confidence interval (CI) 0.94-19.8) for VLD and 5.1 (95% CI 1.21-21.3) for CD, compared with LD. We found the hazard ratio for infection or death increased when the initial IVCY dose exceeded 9 mg/kg. Relapse-free survival did not differ clearly. CONCLUSION: Low-dose IVCY (7.5-12.5 mg/kg) may result in fewer infections and similar relapse rates compared with the conventional regimen (>12.5 mg/kg).

Soft tissue infection caused by Mycolicibacter kumamotonensis.

Mycolicibacter kumamotonensis (M. kumamotonensis), formerly Mycobacterium kumamotonense, is a nontuberculous mycobacteria species, which was first separated from Mycobacterium terrae complex in 2006. Reports about infections caused by M. kumamotonensis are extremely rare, with most of them being lung infection. Here, we report the case of a 68-year-old man with a hobby of gardening who developed swelling in his right middle finger. He underwent surgical debridement at a previous hospital and was diagnosed with nontuberculous mycobacteria infection based on positive findings of acid-fast staining of pus obtained from the surgical specimen. He was treated with rifampicin, ethambutol, and clarithromycin, but the swelling worsened. Therefore, he was referred to our hospital for further examination and treatment. We performed a second debridement and added isoniazid to the treatment regimen, but the swelling continued to worsen. We then administered levofloxacin, but his condition did not change. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry and DNA sequencing analysis confirmed M. kumamotonensis as the causative bacterium. Since the finger swelling did not improve, the patient underwent a third debridement and amikacin was added to the treatment regimen. Finally, the infection was controlled. He completed amikacin therapy and will continue treatment with the other five antibiotics for a total of 24 months. To the best of our knowledge, this is the first report of a patient with M. kumamotonensis soft tissue infection. We consider this case might provide important insights into the diagnosis and treatment of soft tissue infections caused by M. kumamotonensis.

Association between preexisting lung involvements and the risk of diffuse alveolar hemorrhage in patients with microscopic polyangiitis: A multi-center retrospective cohort study.

Objectives: To identify the factors associated with the risk of diffuse alveolar hemorrhage (DAH) in patients with microscopic polyangiitis (MPA), focusing on other preexisting lung involvements such as interstitial lung disease (ILD) and airway disease.Methods: In this retrospective cohort study, we analyzed consecutive patients with myeloperoxidase-antineutrophil cytoplasmic antibody-positive MPA who had undergone chest computed tomography (CT) before starting treatment between 2006 and 2016. Patients who already had DAH at initial CT imaging were excluded. CT images were evaluated for the presence of ILD and airway disease. The association between preexisting lung involvements and the development of DAH was assessed using logistic regression models adjusted for various clinical characteristics.Results: We identified 113 patients (median age 72 years; median follow-up duration 39 months), and 27 (24%) of them developed DAH during the follow-up. Airway disease was identified in 41 (36%) patients and was independently associated with the development of DAH (adjusted odds ratio 6.86, 95% confidence interval 1.85-25.4). However, ILD identified in 45 (40%) patients was not associated with DAH.Conclusion: Our findings suggest that DAH in MPA occurs frequently in patients with airway disease. Attention to preexisting airway disease may help predict the development of DAH.

Pigment epithelium-derived factor inhibits the growth of human esophageal squamous cell carcinoma by suppressing neovascularization.

INTRODUCTION: Neovascularization consists of angiogenesis and vasculogenesis during which bone marrow-derived endothelial progenitor cells (EPCs) are mobilized for blood vessel formation. Pigment epithelium-derived factor (PEDF) is known to be a potent inhibitor of angiogenesis in some solid carcinomas. However, the effects of PEDF on human esophageal squamous cell carcinoma (ESCC) and vasculogenesis are still unknown. The purpose of this research was to investigate the effect of PEDF on angiogenesis, tumor growth, and vasculogenesis in ESCC. MATERIALS AND METHODS: The PEDF gene was transduced to the TE8 ESCC cell line not secreting endogenous PEDF and the HEC 46 cell line originally secreting endogenous PEDF by lentivirus-based vectors expressing PEDF. In vitro endothelial cell proliferation and migration assays were performed using the supernatant derived from PEDF-overexpressing cells. In in vivo experiments, the effects of PEDF on chronological tumor growth, intratumoral microvessel density (MVD), tumor cell apoptosis, and the frequency of EPCs in peripheral blood and tumor tissues were examined in murine subcutaneous tumor models. RESULTS: PEDF inhibited endothelial cell proliferation and migration in vitro and showed potent in vivo antitumor properties by inhibiting MVD in the human ESCC cell line that did not secrete endogenous PEDF. However, in the cell line secreting endogenous PEDF, additional PEDF gene transfer showed no inhibition of angiogenesis and no subsequent antitumor properties. With respect to vasculogenesis, PEDF was found to have potential to suppress vasculogenesis; the frequency of EPCs both in peripheral blood and tumor tissue was decreased in mice implanted with PEDF-overexpressing TE8 and HEC46 cells. CONCLUSION: PEDF may have potent antiangiogenic and antitumor effects in ESCC cells naturally not secreting endogenous PEDF and can be expected to be applied as gene therapy in the future.

Allograft inflammatory factor-1 stimulates chemokine production and induces chemotaxis in human peripheral blood mononuclear cells.

Allograft inflammatory factor-1 (AIF-1) is expressed by macrophages, fibroblasts, endothelial cells and smooth muscle cells in immune-inflammatory disorders such as systemic sclerosis, rheumatoid arthritis and several vasculopathies. However, its molecular function is not fully understood. In this study, we examined gene expression profiles and induction of chemokines in monocytes treated with recombinant human AIF (rhAIF-1). Using the high-density oligonucleotide microarray technique, we compared mRNA expression profiles of rhAIF-1-stimulated CD14(+) peripheral blood mononuclear cells (CD14(+) PBMCs) derived from healthy volunteers. We demonstrated upregulation of genes for several CC chemokines such as CCL1, CCL2, CCL3, CCL7, and CCL20. Next, using ELISAs, we confirmed that rhAIF-1 promoted the secretion of CCL3/MIP-1α and IL-6 by CD14(+) PBMCs, whereas only small amounts of CCL1, CCL2/MCP-1, CCL7/MCP-3 and CCL20/MIP-3α were secreted. Conditioned media from rhAIF-1stimulated CD14(+) PBMCs resulted in migration of PBMCs. These findings suggest that AIF-1, which induced chemokines and enhanced chemotaxis of monocytes, may represent a molecular target for the therapy of immune-inflammatory disorders.

Seasonal Influence on Development of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Retrospective Cohort Study Conducted at Multiple Institutions in Japan (J-CANVAS).

OBJECTIVE: To clarify seasonal and other environmental effects on the onset of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: We enrolled patients with new-onset eosinophilic granulomatosis with polyangiitis (EGPA), microscopic polyangiitis (MPA), and granulomatosis with polyangiitis (GPA) registered in the database of a Japanese multicenter cohort study. We investigated the relationship between environmental factors and clinical characteristics. Seasons were divided into 4 (spring, summer, autumn, and winter), and the seasonal differences in AAV onset were analyzed using Pearson chi-square test, with an expected probability of 25% for each season. RESULTS: A total of 454 patients were enrolled, with a mean age of 70.9 years and a female proportion of 55.5%. Overall, 74, 291, and 89 patients were classified as having EGPA, MPA, and GPA, respectively. Positivity for myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA was observed in 355 and 46 patients, respectively. Overall, the seasonality of AAV onset significantly deviated from the expected 25% for each season (P = 0.001), and its onset was less frequently observed in autumn. In ANCA serotypes, seasonality was significant in patients with MPO-ANCA (P < 0.001), but not in those with PR3-ANCA (P = 0.97). Additionally, rural residency of patients with AAV was associated with PR3-ANCA positivity and biopsy-proven pulmonary vasculitis. CONCLUSION: The onset of AAV was influenced by seasonal variations and was less frequently observed in autumn. In contrast, the occurrence of PR3-ANCA was triggered, not by season, but by rural residency.

Spontaneous pneumothorax in a patient with dendriform pulmonary ossification: report of a case.

We report herein the rare case of a patient with dendriform pulmonary ossification (DPO) who developed spontaneous pneumothorax. A 33-year-old male with a history of bronchial asthma presented with pneumothorax of the left lung. An intraoperative inspection revealed no findings of bullae in the entire left lung, but inflammatory pleural changes were identified on the interlobular surface of the left lower lobe. In addition, hard, twig-like configurations were clearly palpable in the subpleural parenchyma and were resected. A histological examination showed acicular bone formations containing myeloid tissue and marrow fat in the lung. DPO was thus diagnosed, and the bony spines were considered to have caused a rupture of the elastic fiber layer of the visceral pleura. DPO may thus have been directly responsible for the pneumothorax in this case.

Posterior scleritis with choroidal detachments and periaortitis associated with IgG4-related disease: A case report.

BACKGROUND: IgG4-related diseases (IgG4-RDs) are known to disrupt the functioning of multiple organs and are usually associated with mass lesions. Periaortitis, an inflammation of the adventitia and tissues surrounding the aorta, is an example of an IgG4-RD. In ophthalmology, an enlargement of the lacrimal gland is a well-known IgG4-RD, and scleritis has also been reported to be an IgG4-RD although it is rare. We report our findings in a case with periaortitis and posterior scleritis that were present at the same time, and they responded well to systemic steroid therapy. PATIENTS CONCERNS: A 79-year-old man with dementia and Lewy bodies was referred to our hospital because of uveitis in both eyes that did not respond to topical steroid therapy. DIAGNOSIS: We found anterior scleritis in the right eye and uveitis with shallow anterior chambers in both eyes. B-mode echography showed choroidal detachments (CDs) and a T sign in the right eye. The CDs were assumed to have progressed to the posterior scleritis which then caused the severe vision reduction. The patient was referred to the Internal Medicine Department because the systemic inflammatory disease was suspected due to the high levels of C-reactive protein (CRP) and the fast erythrocyte sedimentation rate. Systemic CT scans showed periaortitis only at the lumbar region. Because of the high levels of IgG4, the patient was diagnosed with IgG4-RD. INTERVENTIONS: The patient received intravenous and oral steroid therapy. The first 125 mg of methylprednisolone (mPSL) for 3 days was intravenous, after which it was switched to oral prednisolone (PSL) therapy and the dosage was gradually reduced. OUTCOMES: The posterior scleritis and periaortitis responded well to the systemic steroid therapy. One year and a half after the onset of the disease, the patient is still taking 5 mg of PSL. CONCLUSIONS: Scleritis with multiple CDs and periaortitis were strongly suspected to be due to IgG4-RD although no definitive diagnosis was made by biopsy of the lesions. Clinicians should be aware that IgG4-RD should be considered as one of the causes of posterior scleritis.

Treatment of rheumatoid arthritis and its outcomes in an aging society: a single-center cohort study in Japan from 2011 to 2020.

BACKGROUND: We conducted a single-center cohort study of rheumatoid arthritis (RA) patients from 2011 to 2020 to understand their real world treatment and outcomes, especially changes in physical function and quality of life (QOL) in elderly patients, including those aged ≥ 80 years. METHODS: For RA patients attending our outpatient clinic, we annually recorded tender and swollen joint counts, laboratory findings, therapeutic drugs, and scores from the Japanese Health Assessment Questionnaire and EuroQoL-5 Dimensions questionnaire. We examined changes in treatment and outcomes over time, by age group, in patients enrolled over a 10-year period, from 2011 to 2020. RESULTS: One thousand eight hundred thirty RA patients were enrolled and data were recorded once a year, and a total of 9299 patient records were evaluated. The average age of patients increased by 3.7 years during the study period; the patients aged rapidly. Intensive pharmacological treatment was more frequent in younger patients. Disease activity, physical function, and QOL showed improvement in all age groups over the study period. Physical function and QOL showed greater changes with aging, compared with disease activity. This may be due to the effects of accumulated RA damage, disability due to aging, and depression. CONCLUSIONS: Intensive pharmacological treatment contributes to not only control of disease activity but also the improvement of physical activity and QOL, even in elderly patients. Relieving age-related physical impairment and depression may improve the QOL of very elderly RA patients.

Latent trajectory modelling of pulmonary artery pressure in systemic sclerosis: a retrospective cohort study.

OBJECTIVES: To visualise the trajectories of pulmonary arterial pressure (PAP) in systemic sclerosis (SSc) and identify the clinical phenotypes for each trajectory, by applying latent trajectory modelling for PAP repeatedly estimated by echocardiography. METHODS: This was a multicentre, retrospective cohort study conducted at four referral hospitals in Kyoto, Japan. Patients with SSc who were treated at study sites between 2008 and 2021 and who had at least three echocardiographic measurements of systolic PAP (sPAP) were included. A group-based trajectory model was applied to the change in sPAP over time, and patients were classified into distinct subgroups that followed similar trajectories. Pulmonary hypertension (PH)-free survival was compared for each trajectory. Multinomial logistic regression analysis was performed for baseline clinical characteristics associated with trajectory assignment. RESULTS: A total of 236 patients with 1097 sPAP measurements were included. We identified five trajectories: rapid progression (n=9, 3.8%), early elevation (n=30, 12.7%), middle elevation (n=54, 22.9%), late elevation (n=24, 10.2%) and low stable (n=119, 50.4%). The trajectories, in the listed order, showed progressively earlier elevation of sPAP and shorter PH-free survival. In the multinomial logistic regression analysis with the low stable as a reference, cardiac involvement was associated with rapid progression, diffuse cutaneous SSc was associated with early elevation and anti-centromere antibody was associated with middle elevation; older age of onset was associated with all three of these trajectories. CONCLUSION: The pattern of changes in PAP over time in SSc can be classified into five trajectories with distinctly different clinical characteristics and outcomes.

Hypertrophic pachymeningitis in ANCA-associated vasculitis: a cross-sectional and multi-institutional study in Japan (J-CANVAS).

BACKGROUND: This study investigated the characteristics of hypertrophic pachymeningitis (HP) in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), using information from a multicenter study in Japan. METHODS: We analyzed the clinical information of 663 Asian patients with AAV (total AAV), including 558 patients with newly diagnosed AAV and 105 with relapsed AAV. Clinical findings were compared between patients with and without HP. To elucidate the relevant manifestations for HP development, multivariable logistic regression analyses were additionally performed. RESULTS: Of the patients with AAV (mean age, 70.2 ± 13.5 years), HP was noted in 30 (4.52%), including 20 (3.58%) with newly diagnosed AAV and 10 (9.52%) with relapsed AAV. Granulomatosis with polyangiitis (GPA) was classified in 50% of patients with HP. A higher prevalence of GPA was significantly observed in patients with HP than in those without HP in total AAV and newly diagnosed AAV (p < 0.001). In newly diagnosed AAV, serum proteinase 3 (PR3)-ANCA positivity was significantly higher in patients with HP than in those without HP (p = 0.030). Patients with HP significantly had ear, nose, and throat (ENT) (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.03-2.14, p = 0.033) and mucous membrane/eye manifestations (OR 5.99, 95% CI 2.59-13.86, p < 0.0001) in total AAV. Moreover, they significantly had conductive hearing loss (OR 11.6, 95% CI 4.51-29.57, p < 0.0001) and sudden visual loss (OR 20.9, 95% CI 5.24-85.03, p < 0.0001). CONCLUSION: GPA was predominantly observed in patients with HP. Furthermore, in newly diagnosed AAV, patients with HP showed significantly higher PR3-ANCA positivity than those without HP. The ear and eye manifestations may be implicated in HP development.

[Eosinophilic granulomatosis with polyangiitis presenting with Guillain-Barré syndrome-like acute course. A case report].

A 57-years-old man with a history of bronchial asthma and pansinusitis developed acute progressive muscle weakness and sensory disturbance of the distal limbs after upper respiratory infection. On day 15 after onset of sensory disturbance and muscle weakness, the patient admitted to our hospital. A neurological examination revealed asymmetry weakness of both proximal and distal muscles, "glove and stocking type" hypoesthesia, and paresthesia without obvious pain. Blood tests and a nerve conduction study demonstrated eosinophilia and elevation of MPO-ANCA, axonal multiple mononeuropathy, respectively. The cerebrospinal fluid was normal. Eosinophilic granulomatosis with polyangiitis (EGPA) or Guillain-Barré syndrome (GBS) were suspected. So intravenous immunoglobulin therapy (IVIg) and high dose methylprednisolone pulse therapy (HDMP) followed by oral prednisolone were started. However, neurological symptoms did not improve. Sural nerve biopsy on day 31 revealed varying myelinating fiber loss at every nerve bundle and perivascular lymphocytic infiltration. The results did not fulfill the pathologic criteria for EGPA, but supported the changes of vasculitis. Cyclophosphamide (CPA) pulse therapy was administered for the additional therapy. Neurological symptoms did not improve and worsened again after decreasing oral prednisolone; therefore, combined therapy with IVIg, HDMP, and CPA was administered. Neurological symptoms then diminished gradually and the MPO-ANCA level and number of eosinophils normalized. This case suggests the importance of early nerve biopsy to obtain pathological findings supportive of EGPA diagnosis to allow introduction of aggressive immunosuppressive therapy such as CPA in a case with acute progressive motor-sensory neuropathy due to EGPA mimicking GBS.

Remitting seronegative symmetrical synovitis with pitting edema syndrome in maintenance hemodialysis.

INTRODUCTION: The remitting seronegative symmetrical synovitis with pitting edema syndrome primarily occurs in elderly individuals to represent symptoms of edema, pain, and joint swelling. It could be misdiagnosed in elderly maintenance hemodialysis patients, as hemodialysis patients often present with pain and joint swelling induced by hypervolemia, inflammation, amyloidosis, and/or chronic kidney disease. Here, we describe a maintenance hemodialysis patient with remitting seronegative symmetrical synovitis with pitting edema syndrome. CASE PRESENTATION: A 71-year-old man on maintenance hemodialysis who complained of continuous pain and swelling of joints was diagnosed with remitting seronegative symmetrical synovitis with pitting edema syndrome on his clinical findings that revealed tenosynovitis at the joint without joint erosions and no elevation of anti-cyclic citrullinated peptide antibody and rheumatoid factor. After administration of prednisolone, systemic edema, and pain improved in 2 days. CONCLUSION: Remitting seronegative symmetrical synovitis with pitting edema syndrome should be considered as a differential diagnosis in hemodialysis patients with edema and/or arthralgia.

Feedback Control of the Arachidonate Cascade in Osteoblastic Cells by 15-deoxy-Delta-Prostaglandin J(2).

15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and an anti-diabetic thiazolidinedione, troglitazone (TRO) are peroxisome proliferator-activated receptor (PPAR)-gamma ligands, which regulate immuno-inflammatory reactions as well as adipocyte differentiation. We previously reported that 15d-PGJ(2) can suppress interleukin (IL)-1beta-induced prostaglandin E(2) (PGE(2)) synthesis in synoviocytes of rheumatoid arthritis (RA). IL-1 also stimulates PGE(2) synthesis in osteoblasts by regulation of cyclooxygenase (COX)-2 and regulates osteoclastic bone resorption in various diseases such as RA and osteoporosis. In this study, we investigated the feedback mechanism of the arachidonate cascade in mouse osteoblastic cells, MC3T3-E1 cells, which differentiate into mature osteoblasts. Treatment with 15d-PGJ(2) led to a significant increase in IL-1alpha-induced COX-2 expression and PGE(2) production in a dose dependent manner. The effect of 15d-PGJ(2) was stronger than that of TRO. However, it did not affect the expression of COX-1. In addition, cell viability of MC3T3-E1 cells was not changed in the condition we established. This means that 15d-PGJ(2) exerts a positive feedback regulation of the arachidonate cascade of PGE(2) in osteoblastic cells. These results may provide important information about the pathogenesis and treatment of bone resorption in a variety of diseases such as RA and osteoporosis.

Eicosapentaenoic Acid suppresses the proliferation of synoviocytes from rheumatoid arthritis.

Eicosapentaenoic acid (EPA) is essential for normal cell growth, and may play an important role in inflammatory and autoimmune disorders including rheumatoid arthritis. We investigate that EPA could suppress the proliferation of fibroblast like synoviocytes in vitro. We treated synoviocytes with 1 to 50 microM EPA and measured cell viabilities by the modified MTT assay. We sorted the number of them in sub G1 stage by fluorescence-activated cell sorting caliber. And we stained them by light green or Hoechst 33258, and investigate microscopic appearance. The cell viabilities were decreased at 30 microM, 40 microM, and 50 microM of EPA comparing to 0 microM of EPA. The half maximal concentration of synoviocytes inhibition was approximately 25 microM. At day 1 and day 3, cell number was also decreased at 50 microM EPA comparing to control. FACS caliber indicated the number of synoviocytes in sub G1 stage did not increase in each concentration of EPA. Hoechst staining indicated normal chromatin pattern and no change in a nuclear morphology both in EPA treated synoviocytes and in untreated synoviocytes. These findings suggest that EPA could suppress the proliferation of synoviocytes in vivo dose dependently and time dependently, however, the mechanism is not due to apoptosis.

Surgical treatment of celiac-splenic aneurysms without arterial reconstruction.

We report a case of multiple sequential celiacsplenic aneurysms which we removed completely without arterial reconstruction. The patient was a 67-year-old man. During work-up for hypertension and diabetes, a splenic artery aneurysm was identified on abdominal ultrasonography. Follow-up examination 1 year and 3 months later showed enlargement of the aneurysm. The patient was referred to our Radiology Department for treatment. Abdominal computed tomography and angiography of the celiac trunk showed that the celiac artery was narrowed and then dilated to form a fusiform aneurysm. Splenic artery aneurysms were identified immediately distal to the bifurcation with the common hepatic artery, measuring about 5 cm and 3 cm. These findings ruled out treatment by interventional radiology, and surgery was performed. At laparotomy, a white, 5-cm aneurysm was densely adherent to the pancreas, and separation was impossible. We performed en bloc resection of the pancreatic body and tail, spleen, celiac artery, and common hepatic artery. Since pulsation in the replaced right hepatic artery and the color of the stomach were good, we did not perform an arterial reconstruction. Although the surgical treatment of aneurysms generally consists of resection and arterial reconstruction, we resected the lesion safely and completely without arterial reconstruction.

Pigment epithelium-derived factor gene therapy inhibits human pancreatic cancer in mice.

PURPOSE: Pigment epithelium-derived factor (PEDF), which has recently been shown to be the most potent inhibitor of angiogenesis in the mammalian eye, is also expressed in the pancreas. Previously, we have screened the expression of PEDF by immunohistochemical analysis and showed that low expression of PEDF is associated with increased risk of hepatic metastasis and short survival. The purpose of this study was to investigate whether PEDF gene is a potent tumor suppressor and a potential candidate for cancer gene therapy. EXPERIMENTAL DESIGN: We investigated both in vitro and in vivo growth characteristics of human pancreatic adenocarcinoma cell lines that were stably transfected to overexpress human PEDF and therapeutic effects of lentivirus-based vectors expressing PEDF on tumor growth in murine s.c. tumor model. RESULTS: We discovered that cells secreted PEDF protein in the media and this exhibited strong inhibitory effects on proliferation and migration of human umbilical vein endothelial cells. The size of PEDF-overexpressing pancreatic adenocarcinoma tumors was significantly smaller than that of control tumors in s.c. tumor models. Moreover, the growth of PEDF-overexpressing pancreatic adenocarcinoma cells was significantly suppressed in comparison with control cells in peritoneal metastasis models. In gene transfer models, intratumoral injection of a lentivirus vector encoding PEDF (LV-PEDF) caused significant inhibition of tumor growth. The antitumor effect observed after treatment with LV-PEDF was associated with decreased microvessel density in tumors. CONCLUSION: Our data suggest that PEDF may exert a biological effect on tumor angiogenesis and PEDF gene therapy may provide a new approach for treatment of pancreatic adenocarcinoma.

[A case of motor dominant neuropathy and focal segmental glomerulosclerosis associated with Sjögren's syndrome].

A 49-year-old woman was admitted to our hospital with gradually progressive weakness of the limbs for about 20 days. She presented with weakness of the limbs, predominantly in the proximal portion, and slight dysesthesia of the limbs, predominantly in the distal portion. Repeated nerve conduction examination revealed axonopathy dominantly in the motor neurons. Therefore, we suspected her as having Guillain-Barré syndrome, and initiated intravenous administration of high-dose immunoglobulin. However, her symptoms progressed gradually and finally she found it difficult to walk. Her urine analysis simultaneously demonstrated albuminuria, and a kidney biopsy indicated focal segmental glomerulosclerosis. At that point, laboratory examination showed high levels of anti SS-A antibody and salivary gland biopsy revealed infiltration of a significant number of lymphocytes around the gland, which led to the diagnosis of Sjögren's syndrome. We considered the etiology of the neural and renal dysfunction as due to the inflammatory mechanism associated with Sjögren's syndrome. Therefore, we administered a second course of immunoglobulin therapy and steroid therapy, which included both pulse and oral administration. Her neurologic symptoms and albuminuria improved rapidly after steroid therapy. The present case indicates that both motor dominant neuropathy and focal segmental glomerulosclerosis can occur in patients with Sjögren's syndrome.