Mediation of Ferroptosis Suppressor Protein 1 Expression via 4-Hydroxy-2-Nonenal Accumulation Contributes to Acquisition of Resistance to Apoptosis and Ferroptosis in Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. New therapeutic strategies are needed for the treatment of refractory DLBCL. 4-Hydroxy-2-nonenal (4-HNE) is a cytotoxic lipid peroxidation marker, which alters intracellular signaling and induces genetic mutations. Lipid peroxidation is associated with nonapoptotic cell death, called ferroptosis. However, the relationship between 4-HNE accumulation and feroptotic regulators in DLBCL has not been fully evaluated. Here, we aimed to evaluate the accumulation of lipid peroxide and the expression of ferroptosis suppressor protein 1 (FSP1) in DLBCL using immunohistochemistry. We found a significant increase in the expression of FSP1 in cases with nuclear 4-HNE accumulation (P = .021). Both nuclear and cytoplasmic 4-HNE accumulation and FSP1 positivity were independent predictors of worse prognosis. In vitro exposure to 4-HNE resulted in its concentration- and time-dependent intracellular accumulation and increased expression of FSP1. Furthermore, short-term (0.25 and 1.0 µM) or long-term (0.25 µM) exposure to 4-HNE induced resistance to not only apoptosis but also ferroptosis. Taken together, regulation of FSP1 through 4-HNE accumulation may attenuate resistance to cell death in treatment-resistant DLBCL and might help develop novel therapeutic strategies for refractory DLBCL.

[A curatively resectable case of cholangiocarcinoma 52 years after cholecystoduodenostomy for biliary atresia].

A 52-year-old female had cholecystoduodenostomy for biliary atresia of type I cyst at 120 days of age. The patient's surgery recovery was uneventful;however, the patient had recurring cholangitis at the age of 27. The patient had high hepatobiliary enzymes in the outpatient clinic and was diagnosed with cholangitis. In general, the Kasai method is the mainstream for biliary atresia, since it has a much-reduced incidence of both early and late postoperative problems. However, this patient had biliary atresia of type I cyst and had undergone cholecystoduodenostomy. We suspected that the obstructive cholangitis was caused by the relatively wide anastomosis opening into the duodenal bulb, where the stomach contents pass through the most, and the poor clearance owing to the convoluted cystic duct;therefore, we chose to place a stent endoscopically. However, to our surprise, Class V was detected in the bile cytology performed as a precaution. Although no tumor was seen on imaging such as contrast-enhanced CT, EUS, and PET/CT, mapping biopsy results showed the presence of cancer at the bifurcation of the cystic duct. The patient had cholangiocarcinoma confined to the extrahepatic bile ducts only;thus, extrahepatic bile duct resection was conducted. The patient was discovered to have biliary intraepithelial neoplasia-3, and the tumor was entirely respectable. The patient had a good postoperative course, with normalization of liver function and no recurrence of cholangitis. In this case, cholangiocarcinoma was detected at an early stage by cytological examination performed as a precaution during endoscopic therapy for recurrent cholangitis. In addition to the fact that the long-term pathogenesis of biliary atresia is still unknown, it is important to note the presence of malignancy, which has the greatest effect on the patient prognosis, considering that the course of the disease varies depending on the operation carried out. Because cholecystoduodenostomy for biliary atresia is a rare approach, and there has been no previous report of related cholangiocarcinoma, we report this case for the benefit of gastroenterologists who may encounter similar cases in the future.

Predictive grade of ultrasound synovitis for diagnosing rheumatoid arthritis in clinical practice and the possible difference between patients with and without seropositivity.

OBJECTIVE: To determine the degree of contribution and the contributing factors of ultrasound in the diagnosis of rheumatoid arthritis (RA) in daily clinical practice and the predictive differences depending on seropositivity. METHODS: We included 122 patients who presented with the main complaint of finger and/or wrist joint pain but for whom no definite diagnosis was reached or treatment strategy was provided. Ultrasound was performed on at least 22 joints (both wrist joints, proximal interphalangeal joint, and metacarpophalangeal joints), and patients were followed for ≥6 months. Factors contributing to RA diagnosis were determined and compared between seropositive and seronegative RA patients. RESULTS: RA was diagnosed in 52 of 122 patients, in whom the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria (odds ratio [OR] = 4.74, P = 0.01) and gray scale (GS) grade of 3 (OR = 3.64, P = 0.04) for ≥ 1 joint were the contributing factors. In seropositive RA, the ACR/EULAR criteria (OR = 15.53, P < 0.001) and power Doppler (PD) ≥ 2 for ≥ 1 joint (OR = 10.48, P = 0.0048) were the contributing factors. In seronegative RA, PD ≥ 1 for ≥ 1 joint contributed the most (OR = 20.00, P = 0.0044), but the ACR/EULAR criteria did not contribute to RA diagnosis (P = 0.57). CONCLUSION: Ultrasound findings contributed to RA diagnosis in clinical practice. The contributing factors are different in the presence or absence of seropositivity, and ultrasound complementation was particularly useful in seronegative RA patients.

The synovial grade corresponding to clinically involved joints and a feasible ultrasound-adjusted simple disease activity index for monitoring rheumatoid arthritis.

OBJECTIVES: To determine which grade of ultrasound (US) synovitis corresponds to clinically involved joints in rheumatoid arthritis (RA) and develops a new US-adjusted composite measure. METHODS: Clinical and US examinations were performed on 137 patients with RA (28 joints). Synovial effusion, hypertrophy, and blood flow were semiquantitatively graded from 0 to 3 using gray scale (GS) and power Doppler (PD) modes. We calculated US-adjusted simple disease activity index (SDAI) and assessed feasibility, and external validity by comparing with erythrocyte sedimentation rate (ESR), and modified health assessment questionnaires (MHAQ). RESULTS: GS ≥2 and PD ≥0 corresponds to clinically swollen joints, and GS ≥2 and PD ≥1 corresponds to tender joints. The US-adjusted SDAI showed the highest correlation when US-determined swollen joints were defined as PD ≥2 with ESR, and GS ≥3 and PD ≥2 with MHAQ. A feasible US-adjusted SDAI examining only clinically involved joints still showed a higher correlation with ESR and MHAQ than SDAI. CONCLUSION: Our composite measure complemented by US only for clinically involved joints is feasible and reliable for monitoring disease activity.

Clinical features and pregnancy outcome in antiphospholipid syndrome patients with history of severe pregnancy complications.

Abstract Objective. To clarify the clinical significance of antiphospholipid antibody (aPL) profile in patients with obstetric antiphospholipid syndrome (APS). Methods. Clinical records of 13 pregnant patients (15 pregnancies) with obstetrical APS were reviewed over 10 years. Patients who met the Sapporo Criteria fully were studied, whereas those with only early pregnancy loss were excluded. In addition to classical aPL: lupus anticoagulant (LA), anticardiolipin antibody (aCL), and anti-ß2-glycoprotein I (aß2GPI); phosphatidylserine-dependent anti-prothrombin antibody (aPS/PT) and kininogen-dependent anti-phosphatidylethanolamine antibody (aPE) were also examined in each case. Results. Cases were divided into two groups according to patient response to standard treatment: good and poor outcome groups. All cases with poor outcome presented LA, with IgG aß2GPI and IgG aPS/PT were also frequently observed. IgG aPE did not correlate with pregnancy outcome. Conclusion. aPL profile may predict pregnancy outcome in patients with this subset of obstetric APS.

Predictive value of bone destruction and duration of clinical remission for subclinical synovitis in rheumatoid arthritis patients.

OBJECTIVES: Treatment for rheumatoid arthritis (RA) should aim to achieve full remission. The aim of this study was to investigate predictors of persistent subclinical synovitis and whether longer clinical remission is effective in reducing subclinical synovitis. METHODS: Forty-four RA patients who achieved DAS28ESR clinical remission for at least 3 months were enrolled in this study and underwent ultrasound examination of 22 joints (bilateral proximal interphalangeal joints, metacarpophalangeal joints, and wrists); bilateral hand X-ray; and blood examination. The severity of synovial effusion, synovial hypertrophy, and blood flow were semi-quantitatively graded from 0 to 3 using gray-scale (GS) and power Doppler (PD) modes. RESULTS: Among patients with DAS28ESR-defined clinical remission, 59.1% (26/44) demonstrated residual synovitis (≥ PD1) in at least one joint. Genant-modified total Sharp score (TSS) demonstrated the highest statistical difference between patients with and without residual subclinical synovitis (p = 0.0057), and full remission was only observed in patients with low TSS. A nonsignificant trend for decreased residual synovitis with longer sustained clinical remission was also observed (p = 0.724). CONCLUSION: Residual synovitis can persist during clinical remission, particularly in patients with progressive bone destruction. Early treatment and longer sustained clinical remission prior to bone destruction are critical for full remission.

Can routine clinical measures predict ultrasound-determined synovitis and remission in rheumatoid arthritis patients?

OBJECTIVES: The purpose of this study was to determine if routine clinical measures can predict the presence and severity of ultrasound synovitis in rheumatoid arthritis (RA) patients. METHODS: Bilateral 1-5 MCP (metacarpopharangeal) and wrist joints were examined using power Doppler (PD) ultrasound (US). Correlations between PD scores and routine clinical measures of RA - swollen joint count (SJC), tender joint count, patient's global assessment (GA), physician's GA, CRP, ESR, MMP-3, RF and anti-CCP antibody - were determined and used to identify significant predictors of PD score. Clinical measures were then compared between two groups (patients with and without PD) and analysed using multiple logistic regression, to derive a model that predicted the absence of PD signals. RESULTS: SJC was the most significant predictor of PD score (R2 = 0.4566, p value <0.0001), but was an inadequate predictor of PD signal remission. However, the combination of Steinbrocker's stage I or II (odds ratio [OR] 9.23, p=0.0049), SJC=0 in 1-5 MCP and wrist joints on both sides (OR 6.60, p=0.0039), and SDAI (or CDAI) remission (OR 5.06, p=0.0450) had a positive predictive value of 100%, predicting the absence of PD signals in all study patients meeting the 3 criteria. CONCLUSIONS: PD score and absence of PD signals can be predicted using routine clinical measures. When used in combination, Steinbrocker's stage, SJC and SDAI (or CDAI) can estimate disease activity and identify patients likely to have synovitis and requiring US.

Weighting with the Lansbury articular index improves the correlation of ultrasound score with serum matrix metalloproteinase-3 level in rheumatoid arthritis patients.

OBJECTIVE: To determine whether weighting improves the correlation of ultrasound (US) score with serum matrix metalloproteinase-3 (MMP-3) level in rheumatoid arthritis (RA). METHODS: As ultrasound examination was performed on 100 RA patients, and the severity of synovial effusion and synovial hypertrophy and the blood flow were semi-quantitatively graded from 0 to 3 by using the gray-scale (GS) and power Doppler (PD) modes. We then calculated the sums of the scores of the 28 joints of each patient in the 2 modes, that is, the GS28 and PD28 scores, as well as the respective scores weighted using the Lansbury articular index (LAI, shoulder and elbow, × 12; wrist, × 8; and knee, × 24)-Lans GS28 and Lans PD28 scores. RESULT: The Lans PD28 score showed a higher correlation with MMP-3 (r = 0.591; 95% confidence interval, 0.446-0.705, p < 0.0001) than the existing measures. The scores of the large joints-the knee, shoulder, and elbow-correlated well with the serum MMP-3 level. CONCLUSION: Weighting with the LAI can improve the correlation of US findings with serum MMP-3 level. Bidirectional approach based on both serum MMP-3 level and US scores can further improve the assessment of disease activity in RA patients.

Hemophagocytic lymphohistiocytosis complicated by central nervous system lesions in a patient with dermatomyositis: a case presentation and literature review.

We report a case of dermatomyositis (DM) and hemophagocytic lymphohistiocytosis (HLH) complicated by central nervous system (CNS) lesions and review eight literature cases of DM and HLH. A 17-year-old woman, admitted to our hospital because of severe muscle weakness and high fever, was diagnosed with DM based on elevated serum levels of muscle enzymes and a typical skin rash. Pancytopenia, high serum ferritin and soluble interleukin (IL)-2 receptor, and hepatosplenomegaly were also noted. Bone-marrow examination was negative for hemophagocytosis. Steroid therapy combined with immunoglobulin i.v. was ineffective against the DM, pancytopenia, hepatic dysfunction, and hyperferritinemia. On the 27th hospital day, seizures and acute respiratory failure occurred. In the course of improving muscle enzyme levels after starting adjunctive treatment with cyclosporine, the patient suffered disturbed consciousness, dyskinesia, and tremor. Brain magnetic resonance imaging (MRI) revealed T2 hyperintense lesions in the pons. Additional cyclophosphamide pulse therapy successfully decreased serum ferritin. Unfortunately, the diffuse alveolar damage (DAD) confirmed by biopsy progressed and the patient died. Autopsy findings revealed DAD throughout both lungs, HLH liver lesions, and a hemorrhagic necrotic lesion of the pons in the brain. Even when pathological examination yields no findings of hemophagocytosis, it is important to comprehensively and rapidly diagnose HLH based on the clinical picture. Because DM complicated by HLH may be associated with abnormal production of cytokines and systemic autoimmune responses, it may be necessary to immediately administer additional immunosuppressive therapy. We describe and discuss the extraordinary, severe form of DM in our patient, along with cases in the literature.

Allergenicity and Bioavailability of Nickel Nanoparticles Compared to Nickel Microparticles in Mice.

Metal allergy is a common disease that afflicts many people. Nevertheless, the mechanism underlying metal allergy development has not been completely elucidated. Metal nanoparticles might be involved in the development of a metal allergy, but the associated details are unknown. In this study, we evaluated the pharmacokinetics and allergenicity of nickel nanoparticles (Ni-NPs) compared with those of nickel microparticles (Ni-MPs) and nickel ions. After characterizing each particle, the particles were suspended in phosphate-buffered saline and sonicated to prepare a dispersion. We assumed the presence of nickel ions for each particle dispersion and positive control and orally administered nickel chloride to BALB/c mice repeatedly for 28 days. Results showed that compared with those in the Ni-MP administration group (MP group), the Ni-NP administration group (NP group) showed intestinal epithelial tissue damage, elevated serum interleukin (IL)-17 and IL-1ß levels, and higher nickel accumulation in the liver and kidney. Additionally, transmission electron microscopy confirmed the accumulation of Ni-NPs in the livers of both the NP and nickel ion administration groups. Furthermore, we intraperitoneally administered a mixed solution of each particle dispersion and lipopolysaccharide to mice and then intradermally administered nickel chloride solution to the auricle after 7 days. Swelling of the auricle was observed in both the NP and MP groups, and an allergic reaction to nickel was induced. Particularly in the NP group, significant lymphocytic infiltration into the auricular tissue was observed, and serum IL-6 and IL-17 levels were increased. The results of this study showed that in mice, Ni-NP accumulation in each tissue was increased after oral administration and toxicity was enhanced, as compared to those with Ni-MPs. Orally administered nickel ions transformed into nanoparticles with a crystalline structure and accumulated in tissues. Furthermore, Ni-NPs and Ni-MPs induced sensitization and nickel allergy reactions in the same manner as that with nickel ions, but Ni-NPs induced stronger sensitization. Additionally, the involvement of Th17 cells was suspected in Ni-NP-induced toxicity and allergic reactions. In conclusion, oral exposure to Ni-NPs results in more serious biotoxicity and accumulation in tissues than Ni-MPs, suggesting that the probability of developing an allergy might increase.

Diffuse alveolar damage in patients with dermatomyositis: a six-case series.

The clinical course of diffuse alveolar damage (DAD) was studied in six consecutive cases of dermatomyositis (DM) based on our hospital records over 8 years. Three patients had severe myopathy at presentation, and the other three patients showed clinically amyopathic DM (CADM). Interstitial pneumonia in all patients developed shortly after they manifested DM. DAD in five deceased patients, which was proven pathologically, did not respond to steroid therapy combined with cyclosporine or tacrolimus. Of these, two patients began receiving combination therapy before suffering respiratory symptoms, and one of them had elevated serum Krebs von der Lungen-6 (KL-6) levels before visible abnormalities appeared on a plain chest X-ray. Only one patient with CADM survived; this patient received intravenously administered pulse cyclophosphamide (IVCY) therapy intravenously for DAD from the early stage. Delayed adjunctive IVCY was ineffective for progressed DAD in the remaining five patients. Elevated serum ferritin levels were observed in all four patients examined and might have predicted the lethal DAD, as in a previous report. In conclusion, promptly beginning IVCY therapy may be beneficial for patients with DM and interstitial pneumonia who show elevated serum levels of ferritin or KL-6 with minimal pulmonary abnormalities.