Electron in a cube: Synthesis and characterization of perfluorocubane as an electron acceptor.

Fluorinated analogs of polyhedral hydrocarbons have been predicted to localize an electron within their cages upon reduction. Here, we report the synthesis and characterization of perfluorocubane, a stable polyhedral fluorocarbon. The key to the successful synthesis was the efficient introduction of multiple fluorine atoms to cubane by liquid-phase reaction with fluorine gas. The solid-state structure of perfluorocubane was confirmed using x-ray crystallography, and its electron-accepting character was corroborated electrochemically and spectroscopically. The radical anion of perfluorocubane was examined by matrix-isolation electron spin resonance spectroscopy, which revealed that the unpaired electron accepted by perfluorocubane is located predominantly inside the cage.

Case Report: A Rare Case of Elderly-Onset Adult-Onset Still's Disease in a Patient With Systemic Lupus Erythematosus.

The rare systemic inflammatory disorder 'adult-onset Still's disease (AOSD)' is characterized by recurrent fever, evanescent rash, arthralgia, and leukocytosis with neutrophilia. The Yamaguchi criteria are widely used to diagnose AOSD; these criteria can be used for diagnosis after a wide range of infectious, rheumatic, and neoplastic diseases have been excluded. AOSD generally does not overlap with other rheumatic diseases. We present the rare case of an 80-year-old Japanese woman who presented with arthralgia, fever, and skin rash during treatment for systemic lupus erythematosus (SLE), which was finally diagnosed as an overlap of AOSD. Blood tests revealed leukocytosis with neutrophilia, high C-reactive protein (CRP), and liver dysfunction. Her anti-ds-DNA antibody titer and serum complement titer were at the same level as before and remained stable. We suspected AOSD based on the high serum ferritin level but hesitated to diagnose AOSD because of the patient's SLE history. We measured serum interleukin (IL)-18; it was extremely high at 161,221 pg/mL, which was strongly suggestive of AOSD. We thus diagnosed AOSD complicated during the course of treatment for SLE. The patient's arthralgia and high CRP level persisted after we increased her oral prednisolone dose and added oral methotrexate, but her symptoms eventually improved with the addition of intravenous tocilizumab. We note that the presence of autoantibodies or other rheumatic diseases cannot be absolutely ruled out in the diagnosis of AOSD. Although high serum IL-18 levels are not specific for AOSD, the measurement of serum IL-18 may aid in the diagnosis of AOSD in similar rare cases.

Four-Year Teriparatide Followed by Denosumab vs. Continuous Denosumab in Glucocorticoid-Induced Osteoporosis Patients With Prior Bisphosphonate Treatment.

Objectives: In our previous 24-month study, we observed that teriparatide had some advantages over denosumab for bone mineral density (BMD) in glucocorticoid-induced osteoporosis (GIO) patients with prior bisphosphonate treatment. We conducted this extension study to investigate whether the advantage of teriparatide obtained in the first 2 years would be maintained after the switch to denosumab. Materials and Methods: We switched patients who had completed 24-month daily teriparatide treatment to denosumab (switch group, n=18) and compared their BMD every 6 months up to 48 months with the group who continued to receive denosumab (denosumab group, n=16). Results: At 48 months, the lumbar spine BMD was significantly increased from baseline in both groups (denosumab: 10.4 ± 8.7%, p<0.001; switch: 14.2 ± 6.8%, p<0.001). However, a significant increase in femoral neck BMD from baseline occurred only in the switch group (11.2 ± 14.6%, p<0.05); denosumab (4.1 ± 10.8%). The total hip BMD increased significantly from baseline in both groups (denosumab: 4.60 ± 7.4%, p<0.05; switch: 7.2 ± 6.9%, p<0.01). Femoral neck BMD was significantly increased in the switch versus the denosumab group (p<0.05). Conclusion: In GIO patients with prior bisphosphonate treatment, the advantage of teriparatide may be maintained after the treatment period. A continuous increase in BMD can be expected with teriparatide followed by denosumab.

FDG-PET/CT and Auricular Cartilage Biopsy Are Useful for Diagnosing with Relapsing Polychondritis in Patients without Auricular Symptoms.

Relapsing polychondritis (RP) is a rare autoimmune inflammatory disease characterized by recurrent inflammation and destruction of cartilage. Although auricular chondritis is a characteristic finding in RP, it can be difficult to diagnose in the absence of auricular symptoms. A 64-year-old Japanese male was referred to our hospital with fever and respiratory distress. Contrast-enhanced computed tomography (CT) revealed bronchial wall thickening and we suspected RP; however, he had no auricular symptoms and did not meet the diagnostic McAdam criteria for RP, so we used 18F-fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) to search for other cartilage lesions. This analysis revealed FDG accumulation not only in the bronchial walls, but also in the left auricle. Instead of a bronchial biopsy using a bronchoscope, we performed a biopsy of the left auricular cartilage, which is considered a relatively less invasive site. Even though the auricle was asymptomatic, the pathology results revealed chondritis. He was diagnosed with RP, and his symptoms rapidly improved with corticosteroid therapy. A biopsy of asymptomatic auricular cartilage may be useful in the diagnosis of RP. FDG-PET/CT is a powerful tool for the early diagnosis of RP, identifying inflammatory areas even in the absence of symptoms, and guiding the selection of appropriate biopsy sites.

Propylthiouracil-Induced Antineutrophil Cytoplasmic Antibody-Associated Vasculitis after COVID-19 Vaccination.

We report the case of a patient who developed antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) after receiving the coronavirus disease 2019 (COVID-19) vaccine BNT162b (Pfizer-BioNTech). A 37-year-old Japanese woman had been taking propylthiouracil for Graves' disease. She had erythema on her forearm on the 12th day after receiving the first dose of the vaccine, fever on the 13th day, and redness and swelling of her left auricle on the 25th day. Her serum myeloperoxidase-ANCA and proteinase 3-ANCA levels, which were negative before the Graves' disease treatment, were elevated. She had unilateral auricular symptoms but no other typical relapsing polychondritis findings. She was diagnosed with propylthiouracil-induced AAV. She was treated with oral glucocorticoids, and her symptoms improved. Propylthiouracil is considered to be the main cause of the onset of AAV in this case, but it cannot be ruled out that BNT162b may have had some effect on the onset of the disease. Although the development of propylthiouracil-induced AAV in this case may have been incidental and unrelated to the vaccination, this report provides important data for evaluating the safety of the vaccine.

Foxp3-Positive Regulatory T Cells Contribute to Antifibrotic Effects in Renal Fibrosis via an Interleukin-18 Receptor Signaling Pathway.

Renal interstitial fibrosis is a common lesion in the process of various progressive renal diseases. Interleukin (IL)-18 is a proinflammatory cytokine that plays an important role in the induction of Th1 responses and is associated with renal interstitial fibrosis, but the mechanism of fibrosis remains unclear. Here we used IL-18 receptor alpha knockout (IL-18Rα KO) mice to investigate the role of an IL-18Rα signaling pathway in renal fibrosis in a murine model of unilateral ureteral obstruction. IL-18 Rα KO mice showed decreased renal interstitial fibrosis and increased infiltration of CD4+ T cells and Foxp3+ regulatory T cells (Tregs) compared to wildtype (WT) mice. The expression of renal transforming growth factor beta 1 (TGF-ß1, which is considered an important cytokine in renal interstitial fibrosis) was not significantly different between WT and IL-18Rα KO mice. The adoptive transfer of CD4+ T cells from the splenocytes of IL-18Rα KO mice to WT mice reduced renal interstitial fibrosis and increased the number of Foxp3+ Tregs in WT mice. These results demonstrated that Foxp3+ Tregs have a protective effect in renal interstitial fibrosis via an IL-18R signaling pathway.

Effects of denosumab versus teriparatide in glucocorticoid-induced osteoporosis patients with prior bisphosphonate treatment.

INTRODUCTION: Osteoporosis is one of the serious adverse effects associated with glucocorticoid therapy. Although bisphosphonates have been used for glucocorticoid-induced osteoporosis (GIO), some patients have shown an inadequate response. In such cases, denosumab or teriparatide are used. However, there is no consensus on which of these two drugs is superior. We prospectively compared denosumab's and teriparatide's effects on the bone mineral density (BMD) in GIO patients with prior bisphosphonate treatment. MATERIALS AND METHODS: After receiving oral bisphosphonates for ≥2 years, GIO patients with low T-score BMD (<-2.5) were switched from bisphosphonates to denosumab (n = 20) or daily teriparatide (n = 21). We measured the BMD (lumbar spine, femoral neck, and total hip) in both groups every 6 months for 24 months. RESULTS: At 24 months of treatment, the lumbar spine BMD increased significantly from baseline in both the denosumab and teriparatide groups (baseline vs. denosumab and teriparatide; 5.9 ± 5.6%, P < 0.001 and 7.9 ± 5.4%, P < 0.001). A significant increase in femoral neck BMD from baseline occurred only in the teriparatide group (6.6 ± 10.8%, P < 0.05); denosumab (1.5 ± 5.0%). No significant changes occurred in the total hip BMD from baseline in either group (-0.1 ± 5.6% and 3.3 ± 7.5%, respectively). There was no significant difference between the denosumab and teriparatide groups at 24 months in lumbar spine and femoral neck BMD, but was significantly higher in the teriparatide group at 12 months (P < 0.01 and P < 0.05 in the lumbar spine and femoral neck, respectively). CONCLUSION: Teriparatide might have some advantages over denosumab and be a good alternative for treating GIO patients with prior bisphosphonate treatment.

Synthesis of Fluorinated Dialkyl Carbonates from Carbon Dioxide as a Carbonyl Source.

Fluorinated dialkyl carbonates (DACs), which serve as environmentally benign phosgene substitutes, were produced successfully from carbon dioxide either directly or indirectly. Nucleophilic addition of 2,2,2-trifluoroethanol to carbon dioxide and subsequent reaction with 2,2,2-trifluoroethyltriflate (3 a) afforded bis(2,2,2-trifluoroethyl) carbonate (1) in up to 79 % yield. Additionally, carbonate 1 was obtained through the stoichiometric reaction of 3 a and cesium carbonate. Although bis(1,1,1,3,3,3-hexafluoro-2-propyl) carbonate (4) was difficult to obtain by either of the above two methods, it could be synthesized through the transesterification of carbonate 1.

Long-Term Levocarnitine Ameliorates Left Ventricular Diastolic as Well as Systolic Dysfunction in Hemodialysis Patients　- Multi-Center Study.

Background: Levocarnitine has been reported to improve the left ventricular (LV) systolic function and decrease LV hypertrophy in hemodialysis (HD) patients. Its effect on LV diastolic dysfunction, however, has not yet been clarified. Methods and Results: HD patients (n=88) were given levocarnitine i.v. 1,000 mg for 12 months at the end of every dialysis session through the dialysis circuit of the venous site. LV ejection fraction (EF), E/A, E/e', left atrial volume index (LAVI) and LV mass index (LVMI) were measured before and 3, 6, 9, and 12 months after the start of levocarnitine on echocardiography. We regarded E/A≤0.8, E/e'>14 and LAVI>34 mL/m2 as LV diastolic dysfunction, and LVEF<55% as LV systolic dysfunction. We also investigated the effect of levocarnitine on HFpEF. Plasma brain natriuretic peptide, total carnitine, free carnitine, and acyl-carnitine and biochemistry parameters were measured. Levocarnitine significantly improved LV diastolic function in HD patients with LV diastolic dysfunction, but did not affect LV diastolic function in those with normal LV diastolic function. Levocarnitine significantly improved HFpEF. Levocarnitine significantly improved the LV systolic function in HD patients with LV systolic dysfunction but did not affect the LV systolic function in those with normal LV systolic function. Levocarnitine significantly decreased LVMI and increased plasma total, free, and acyl-carnitine. Conclusions: Levocarnitine ameliorates LV diastolic as well as LV systolic dysfunction in HD patients.

Measurement of urinary biomarkers in a case of tubulointerstitial nephritis and uveitis syndrome during glucocorticoid treatment.

Tubulointerstitial nephritis and uveitis (TINU) is a rare syndrome in which idiopathic interstitial nephritis coexists with chronic recurrent uveitis. This syndrome often represents systemic disorders such as arthralgia, rash, prolonged fever, anaemia and ocular symptoms that require medication including glucocorticoid administration. Recently, novel urinary biomarkers, such as kidney injury molecule-1, neutrophil gelatinase-associated lipocalin and liver-type fatty acid-binding protein, were shown to be associated with tubulointerstitial damage and were elevated in interstitial nephritis. We evaluated these urinary biomarkers in a case of TINU syndrome before and during treatment and found that their levels were elevated at onset and decreased during treatment, especially NGAL. We conclude that these urinary biomarkers are useful to evaluate and predict prognosis in interstitial nephritis.

[The pathogenic role of macrophage in lupus nephritis].

Lupus nephritis is major manifestation of systemic lupus erythematosus and could cause nephrotic syndrome or chronic kidney disease might lead to end-stage renal failure. The pathogenesis of macrophage as well as lymphocyte impairment had been described in lupus nephritis. The interstitial macrophage accumulation and interstitial change or fibrosis is more important than glomerular immunoglobulin deposition or glomerular macrophage accumulation in terms of renal outcome and survival proportion. The expressions of macrophage associated proteins such as CCL2/MCP-1, MIP-1 family and their receptors, CCR2, CCR1 and CCR5 are major target of therapeutic strategy for improving renal illness. The blockade of these chemokines or chemokine receptors ameliorates renal impairment without reducing glomerular immunoglobulin deposition. Deletion of CSF-1 signaling pathway represented more excellent effect in experimental lupus nephritis. The effect of specific antagonist for macrophage associated proteins, specific thyrosine kinase inhibitor for macrophage signaling pathway on glomerulonephritis in lupus prone mice had been reported with evaluation of renal leukocyte infiltration, anti-DNA antibody reduction, the amount of proteinuria, and their survival. The depletion of macrophage could be useful therapeutic tool including M2 macrophage and have synergistic effect with other immunomodulating agents.

[A case of agranulocytosis caused by rifampicin during treatment of tuberculous lymphadenitis in a chronic renal failure patient].

A 52-year-old woman was admitted to our hospital because of intermittent high fever and chronic renal failure. Computed tomography of the thorax showed swelling of the paratracheal lymph nodes that was confirmed by gallium scintigraphy. Biopsy of the supraclavicular lymph node on the right side showed necrotizing lymphadenitis with Langhans giant cells surrounded by epithelioid cells. Anti-tuberculosis treatment, including isoniazid, rifampicin, ethambutol, and pyrazinamide was initiated. One month after treatment, the patient developed agranulocytosis (white blood cell [WBC], 2100 cells/microl; neutrophils, 5%) accompanied by severe diarrhea. Bone marrow histology showed poor development of granulocytes, but no atypical cells were observed. Therefore, rifampicin was discontinued, and treatment with granulocyte colony-stimulating factor (G-CSF) was initiated. Subsequently, the white blood cell count and the proportion of neutrophils increased to 12500 cells/microL and 80%, respectively. Rifampicin in the anti-tuberculosis chemotherapy regimen was replaced with levofloxacin. This is a rare case of agranulocytosis caused by rifampicin administered during anti-tuberculosis treatment in a chronic renal failure patient.

Therapeutic effect of retinoic acid on unilateral ureteral obstruction model.

BACKGROUND: Retinoic acids, a group of natural and synthetic vitamin A derivatives, have potent anti-proliferative, anti-inflammatory and anti-fibrotic properties. We investigated the therapeutic effect of all-trans-retinoic acid (ATRA) on unilateral ureteral obstruction (UUO) model mice. METHODS: First, to evaluate the prophylactic effect, we administered 0.5 mg of ATRA for 3 days before UUO (UUO ATRA). Then, to evaluate the therapeutic effects, we administered 0.5 mg of ATRA 3 days after UUO (Day 3 ATRA). We compared the histological changes and immunostaining of macrophages, α-smooth muscle actin (α-SMA) and collagen I, and mRNA expression of monocyte chemotactic protein-1 (MCP-1), transforming growth factor (TGF)-ß(1) and TGF-ß R-II by RT-PCR 7 days after UUO. RESULTS: In the UUO ATRA and Day 3 ATRA groups, we observed a significant improvement in histological and immunological findings, including macrophage infiltration and improved expression of MCP-1, TGF-ß(1), α-SMA and collagen I compared with the UUO Day 7 group. CONCLUSION: ATRA treatment is not only an effective prophylactic strategy, but also a therapeutic strategy for the treatment of progressive renal fibrosis in diseased kidneys.

Effect of combining ACE inhibitor and statin in lupus-prone mice.

MRL-Fas(lpr) mice spontaneously develop a systemic autoimmune disease resembling human systemic lupus erythematosus. The glomerulonephritis in MRL-Fas(lpr) mice is mediated by autoantibodies and autoreactive lymphocytes. To investigate the effect of combination therapy by angiotensin-converting enzyme inhibitor (ACEI) and hydroxymethylglutaryl-coenzyme A reductase inhibitor (statin) for lupus nephritis, we treated MRL-Fas(lpr) mice with imidapril, pravastatin or both agents. Compared with other groups, the mice treated by combination therapy survived longer and showed a significant reduction in proteinuria, renal pathology, including glomerular IgG deposit, and serum anti-DNA Ab. Furthermore, monocyte chemoattractant protein-1 (MCP-1) in the kidney was reduced significantly in the combination therapy group, compared with that in the control group. We conclude that combination therapy with ACEI and statin for MRL-Fas(lpr) mice significantly alleviates autoimmune renal disorder and prolongs survival. These results suggest that combination therapy by ACEI and statin may represent a new approach to the treatment of patients with lupus.

Successful treatment with retinoids in patients with lupus nephritis.

Lupus nephritis is a major manifestation of systemic lupus erythematosus. Treatment with such immunosuppressive agents as corticosteroids or cyclophosphamide can decrease the progression of lupus nephritis; however, these agents have potentially severe adverse reactions. Therefore, the development of new drugs with fewer side effects is needed. Here, we report 2 patients with lupus that were treated successfully with retinoids. Initially, both patients were treated with 60 mg/d of prednisolone. However, nephrotic syndrome was not improved. Subsequently, treatment with 10 mg/d of all-trans-retinoic acid was started orally and elicited a good response, showing a decrease in proteinuria. Although additional controlled clinical studies are needed to confirm these findings, we suggest that therapy using retinoids may represent a novel approach to the treatment of patients with lupus nephritis.

Sudden death from ischaemic heart disease in a female patient with Sjögren syndrome: a case report.

Primary Sjögren syndrome (SjS) has a comparatively good prognosis except when it is complicated by non-Hodgkin's lymphoma. We performed an autopsy on a young female patient with primary SjS who had died suddenly during a meal, and we discuss the relationship between primary SjS and the cause of death. Eosinophilic change of the cardiomyocytes and severe arteriolosclerosis were observed within the myocardium. In the conduction system, lymphocyte infiltration was detected in the bundle of His, in addition to arteriosclerosis in the sinoatrial node and atrioventricular node arteries. The cause of death was diagnosed as ischaemic heart disease induced by arteriolosclerosis: its development can probably be attributed mostly to primary SjS. It should thus be kept in mind that primary SjS can occasionally result in the development of cardiovascular complications, such as ischaemic heart disease, as well as systemic lupus erythematosus or rheumatoid arthritis.