Usefulness of platelet count to predict concomitant valvular heart disease in patients with systemic lupus erythematosus.

Background: Although the prevalence rate of valvular heart disease (VHD) is high in patients with systemic lupus erythematosus (SLE), the predictive factors of concomitant VHD have not been fully evaluated. Methods and results: Among 288 patients with SLE who underwent transthoracic echocardiography at Kumamoto University Hospital from 2016 to 2021, 241 patients with sufficient echocardiographic data were retrospectively analysed. Among them, 22 (9 %) had VHD (10 had mitral regurgitation, 3 had aortic regurgitation, 6 had tricuspid regurgitation, 1 had mitral regurgitation and tricuspid regurgitation, and 2 had a prosthetic cardiac valve). After excluding the two patients with a prosthetic cardiac valve, we divided the remaining patients into two groups: the VHD group and non-VHD group. Multivariate logistic regression analysis revealed that age and the platelet count were significantly and independently associated with having VHD (age: odds ratio, 1.06; 95 % confidence interval, 1.02-1.10; p < 0.01) (platelet count: odds ratio, 0.99; 95 % confidence interval, 0.98-1.00; p < 0.05). After excluding 95 patients aged < 40 years, receiver operating characteristic analysis revealed that the area under the curve of the platelet count for prediction of VHD was 0.73 with an optimal cut-off value of 166.5 × 103/µL (sensitivity: 76.6 %, specificity: 60.0 %). Among patients with a low platelet count (<166.5 × 103/µL), the rate of having VHD was 29 % (12/41 patients). However, among those with a high platelet count (≥166.5 × 103/µL), this rate was only 8 % (8/103 patients). Conclusion: The platelet count is useful to predict concomitant VHD in middle-aged and older patients with SLE.

Formal Total Synthesis of Batrachotoxin Enabled by Radical and Weix Coupling Reactions.

Batrachotoxin (1), originally isolated from a Columbian poison-dart frog, is a steroidal alkaloid. Its 6/6/6/5-membered carbocycle (ABCD-ring) contains two double bonds, one nitrogen, and five oxygen functionalities. We developed a radical-based convergent strategy and realized the total synthesis of 1 in 28 steps. The AB-ring and D-ring fragments were efficiently synthesized and linked by exploiting a powerful Et3B/O2-mediated radical coupling reaction. Vinyl triflate and vinyl bromide were then utilized for a Pd/Ni-promoted Weix coupling reaction to cyclize the C-ring. A hydroxy group of the C-ring was stereoselectively installed by a decarboxylative hydroxylation reaction to prepare an advanced intermediate of our previous total synthesis of 1.

Design of Novel Series of Antimalarial PMX Inhibitors with Increased Half-Life via Molecular Property Optimization.

Plasmepsin X (PMX) has been identified as a multistage antimalarial target. PMX is a malarial aspartyl protease essential for merozoite egress from infected red blood cells and invasion of the host erythrocytes. Previously, we reported the identification of PMX inhibitors by structure-based optimization of a cyclic guanidine core. Preclinical assessment of UCB7362, which displayed both in vitro and in vivo antimalarial activity, revealed a suboptimal dose paradigm (once daily dosing of 50 mg for 7 days for treatment of uncomplicated malaria) relative to current standard of care (three-dose regime). We report here the efforts toward extending the half-life (t1/2) by reducing metabolic clearance and increasing volume of distribution (Vss). Our efforts culminated in the identification of a biaryl series, with an expected longer t1/2 in human than UCB7362 while maintaining a similar in vitro off-target hit rate.

Possible Association of Mutations in the MEFV Gene with the Intestinal Phenotype of Behçet's Disease and Refractoriness to Treatment.

BACKGROUND: Mediterranean fever (MEFV) gene mutations are responsible for familial Mediterranean fever (FMF) and associated with other inflammatory diseases. However, the effects of MEFV gene mutations on intestinal Behçet's disease (BD) are unknown. In this study, we investigated these mutations and clinical features in patients with intestinal BD. METHODS: MEFV gene analysis was performed in 16 patients with intestinal BD, 10 with BD without intestinal lesions, and 50 healthy controls. Clinical features of patients with intestinal BD were retrospectively assessed. RESULTS: The rates of MEFV gene mutations in patients with intestinal BD, BD without intestinal lesions, and healthy controls were 75%, 50%, and 38%, respectively. Only 2 of 12 patients with intestinal BD harboring MEFV gene mutations (17%) were controlled without immunosuppressive treatment, while 8 patients (67%) required therapy with tumor necrosis factor (TNF) inhibitors. Among patients with intestinal BD without MEFV gene mutations (four patients), three (75%) were controlled by the administration of 5-aminosalicylic acid with or without colchicine, and one (25%) required TNF inhibitors. All patients who underwent intestinal resection had MEFV gene mutations. Immunohistochemical analysis and in situ hybridization with interleukin-1ß (IL-1ß) showed a high expression of IL-1ß only in injured areas, suggesting that IL-1ß may be involved in the formation of ulcers in patients with intestinal BD carrying MEFV gene mutations. CONCLUSION: Mutations in the MEFV gene may be associated with intestinal lesions of BD and refractoriness to treatment.

Overlap syndrome involving anti-OJ antibody-positive polymyositis, systemic lupus erythematosus and Sjögren's syndrome: A case report and literature review.

Anti-OJ antibody is relatively rarely detected in patients with the anti-synthetase syndrome, which is polymyositis (PM)/dermatomyositis (DM) with anti-aminoacyl transfer ribonucleic acid (RNA) synthetase antibodies. There have been few case reports of anti-OJ antibody-positive PM/DM complicated by other connective tissue disorders. Herein, we report the case of a 33-year-old woman who was admitted to our hospital with fever, muscle weakness, and dyspnoea on exertion. She was diagnosed with anti-OJ antibody-positive PM, overlapping systemic lupus erythematosus, and Sjögren's syndrome (SS). Her symptoms and clinical findings improved after treatment with prednisolone 1 mg/kg/day without immunosuppressive agents. This is the first case of overlap syndrome with anti-OJ antibody-positive PM, systemic lupus erythematosus, and Sjögren's syndrome.

Electrochemical Synthesis of Substituted Morpholines via a Decarboxylative Intramolecular Etherification.

An efficient method for the synthesis of 2,6-multisubstituted morpholines via an electrochemical intramolecular etherification has been developed. The method, which is operationally simple and easy to scale up, provides various substituted morpholine derivatives in high yields. The utility of this method is showcased by the synthesis of 2,2,6,6-tetrasubstituted morpholines, which are difficult to synthesize efficiently using previously reported strategies.

Refractory IgG4-related Pleural Disease with Chylothorax: A Case Report and Literature Review.

We herein report a rare case of a 66-year-old man with refractory chylothorax. Although he had been treated with moderate doses of prednisolone (PSL) on suspicion of pleuritis with Sjögren syndrome, the pleural effusion expanded after the reduction of PSL. Further workup including histopathological examinations of pleura led to the diagnosis of IgG4-RD with bilateral chylothorax without any leakage from the thoracic duct. Combination therapy with high-dose PSL plus rituximab successfully decreased the pleural effusion. This is a very rare case of IgG4-related pleuritis with chylothorax and the first report of its successful treatment with rituximab.

Safety and tolerability of ultrasound-guided synovial needle biopsy in Japanese arthritis patients.

OBJECTIVES: We sought to clarify the safety and tolerability of ultrasound (US)-guided synovial needle biopsy in hand and knee joints in Japanese arthritis patients. METHODS: A total of nine consecutive arthritis patients were recruited and scheduled for US-guided synovial needle biopsies. Patients completed a safety questionnaire and patient-reported outcomes (PRO) data of joint pain, stiffness, and swelling pre- and postbiopsy. We also recorded patients' characteristics and willingness to undergo a second biopsy by the same technique. All synovial needle biopsy samples were assessed with pathological and microbial examination to verify whether clinical evaluation was possible. RESULTS: Five and 4 patients underwent US-guided biopsy from hand and knee joints, respectively. PRO data showed no significant differences in pain, swelling, or stiffness levels before and after biopsy, with a mean 11.8 samples collected per procedure. No significant complications, including joint infection, bleeding, or vasovagal signs, were reported. Histologically adequate synovial tissue was identified in 83 (78%) samples. We were able to submit the biopsy samples to pathological and bacterial analysis to exclude septic arthritis. CONCLUSION: We demonstrated that a minimally invasive US-guided needle biopsy is a safe and well-tolerated procedure and the synovial tissue collected was of adequate quality for pathological analysis.

Decreased activation of ataxia telangiectasia mutated (ATM) in monocytes from patients with systemic sclerosis.

OBJECTIVES: The regulation system for oxidative stress in systemic sclerosis (SSc) remains unclear. This study aimed to clarify the possible involvement of ataxia telangiectasia mutated (ATM), which plays a key role in DNA repair and redox balance, in the pathogenesis of SSc. METHODS: Thirty patients with SSc and 15 healthy controls were enrolled. Expression of ATM and phosphorylated ATM (pATM), an activated form of ATM, in phagocytes in whole blood samples was analysed by FACS. Correlations between expression levels of ATM/pATM and clinical parameters of SSc patients were statistically analysed. Peripheral monocytes were cultured with an ATM-specific inhibitor (KU55933), and reactive oxygen species production in the cells was measured. RESULTS: Expression level of pATM in peripheral monocytes and neutrophils from SSc patients was significantly lower than those in healthy controls (P = 0.04 and P < 0.001, respectively), while no significant difference in total ATM expression was observed between SSc and healthy controls. In addition, pATM expression in monocytes of SSc patients with interstitial lung disease or digital pitting scar was remarkably lower than in the patients without these clinical features (P = 0.02 and P = 0.03), respectively. Moreover, pATM expression in monocytes positively correlated with forced vital capacity and negatively correlated with the serum Krebs von den Lungen-6 level. Notably, KU55933, an ATM-specific inhibitor, enhanced reactive oxygen species production by monocytes under oxidative stress. CONCLUSION: Our data revealed that decreased ATM activation in monocytes was associated with SSc-interstitial lung disease and that impaired ATM activation in monocytes may contribute to the disease process of SSc via uncontrolled reactive oxygen species production.

Association of radiographic findings in hand X-ray with clinical features and autoantibodies in patients with systemic sclerosis.

Musculoskeletal involvement is one of the major causes of impairment in daily life of patients with systemic sclerosis (SSc). Several hand radiographic findings can be seen in SSc patients; however, their association with clinical features and autoantibodies remains unclear. Here, we analyzed 124 SSc patients with their hand X-rays and clinical and serological features. Abnormal findings in hand X-rays including acro-osteolysis, calcinosis, flexion contracture, erosive change, joint space narrowing, and subluxation were observed in 110 patients (68%). These X-ray findings were more prevalent in patients with longer disease duration and digital ischemic changes. The majority of erosions were typical for erosive hand osteoarthritis, which was seen in 19% of patients. Hand X-ray findings were associated with involved organs; acro-osteolysis with interstitial lung disease, calcinosis with pulmonary arterial hypertension and gastrointestinal tract involvement, and flexion contracture with gastrointestinal tract involvement. Those findings were also relevant to autoantibodies; acro-osteolysis was more common in SSc patients with anti-Scl70 antibody but less in patients with anticentromere antibody. Calcinosis was more prevalent in patient with anticentromere antibody. In our study, organ involvements and SSc-associated autoantibodies showed associations with hand radiographic abnormalities. Hand X-ray findings might reflect underlying pathogenesis and autoantibody profiles in SSc patients.Key Points• Hand X-ray abnormalities were observed in approximately two-thirds of patients with SSc.• Erosive osteoarthritis was more prevalent in SSc patients than general population.• Hand X-ray findings were associated with disease duration, organ involvements, and SSc-associated autoantibodies, reflecting underlying pathogenesis.

Impact of subclinical synovitis in ankles and feet detected by ultrasonography in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the impact of subclinical synovitis detected by ultrasonography (US) on the ankles and feet of patients with rheumatoid arthritis. METHODS: We retrospectively reviewed the data of patients (n = 59) who underwent US. RESULTS: The functional ability and quality of life (QoL) of patients in the subclinical group were impaired. While the physician visual analog scale (VAS) scores significantly decreased in the subclinical group, patient and pain VAS scores significantly decreased only in patients without synovitis. CONCLUSION: US-detected subclinical foot and ankle synovitis considerably affected patient functional status and QoL; however, it was often unnoticed by physicians.

Synthesis of the Tetracyclic Structure of Batrachotoxin Enabled by Bridgehead Radical Coupling and Pd/Ni-Promoted Ullmann Reaction.

The steroidal ABCD-ring system of the potent neurotoxin batrachotoxin was efficiently assembled in a convergent fashion. Bridgehead radical coupling between the simple AB-ring and D-ring fragments (3 and 4) formed the sterically congested linkage at the C9-oxygen-attached tetrasubstituted carbon. The C-ring was then cyclized by the Pd/Ni-promoted Ullmann reaction of the vinyl triflate and vinyl bromide of 19, giving rise to tetracyclic structure 1.

Total synthesis and complete structural assignment of yaku'amide A.

Here we report the first total synthesis and the complete stereochemical assignment of yaku'amide A. Yaku'amide A (1) was isolated from a sponge Ceratopsion sp. as an extremely potent cytotoxin. Its structure was determined except for the C4-stereochemistry in the N-terminal acyl group (NTA). This tridecapeptide consists of 2 proteinogenic and 11 nonproteinogenic amino acid residues and is capped with NTA and a C-terminal amine (CTA). α,ß-Dehydrovaline, E- and Z-α,ß-dehydroisoleucines are the most unusual nonproteinogenic residues of 1 and necessitated development of new methodologies for their assembly. Consequently, Cu-mediated cross-coupling reactions were efficiently employed for E/Z-selective syntheses of the three dipeptides with the dehydroisoleucines and for construction of the tetrapeptide with the dehydrovaline. The peptide was then elongated from the tetrapeptide in a stepwise fashion to deliver the two possible C4-epimers of 1. Extensive NMR studies revealed that the natural 1 possessed the C4S-stereochemistry, and biological assays using P388 mouse leukemia cells demonstrated that both C4-epimers possessed comparable toxicities. The present synthetic methodologies for construction of the highly unsaturated peptide sequence of 1 will allow studies of the relationships between the conformational properties of dehydro amino acid residues and cytotoxicity.