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This study aimed to determine the results of radiolunate arthrodesis for rheumatoid arthritis (RA) after a long-term follow-up period of up to 20 years under tight postoperative medical control of RA. We also compared the results between patients with and without degenerative changes in the midcarpal joints at follow-up. We determined the radiologic factors predictive of secondary degenerative changes in the midcarpal joint. This was a long-term retrospective analysis of 16 wrists of 14 patients with RA treated with radiolunate arthrodesis first reported in 2013. The mean follow-up period was 14 years (range, 8–23 years; SD, 4.6 years). Ten wrists had a Larsen classification of grade III, whereas 6 wrists had grade IV. The range of motion was assessed, and clinical outcomes were graded using the Mayo Wrist Score and Stanley classification system. The Carpal Height Index, Ulnar Translation Index, and changes in the midcarpal joint contour were determined from radiographs. We categorized the changes in the midcarpal joint as unchanged or degenerative. At final follow-up, the clinical scores improved; however, the extension and flexion range of motion was significantly reduced compared with that before surgery. The Carpal Height Index and Ulnar Translation Index improved immediately after surgery and remained stable at final follow-up. The changes in the midcarpal joint were categorized as unchanged in 6 wrists and degenerative in 10 wrists. The clinical outcomes were similar between the groups. The mean preoperative Ulnar Translation Index was significantly higher in the degenerative group than in the unchanged group. Radiolunate arthrodesis in patients with RA maintained good clinical results and corrected alignment, even during long-term follow-up. Preoperative severe ulnar translation deformity was a risk factor for postoperative degeneration of the midcarpal joint, and pre-existing degenerative changes at the midcarpal joint might lead to loss of wrist range of motion. Therapeutic IV. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To clarify the mechanism underlying the effect of polaprezinc on hypogeusia, we investigated the uptake of polaprezinc by the tongue in rats. Main methods: Rats were fed a zinc-sufficient (Zn(+)) or zinc-deficient (Zn(−)) diet. After 4weeks on the Zn(−) diet, polaprezinc (1, 3, or 10mg/kg) or [65Zn] polaprezinc (10mg/kg) was administered orally once a day. The zinc concentration or the 65Zn radioactivity of the tongue was measured by inductively-coupled plasma mass spectrometry or gamma counting, respectively. In addition, the distribution of 65Zn in the tongue was analyzed by microautoradiography and the proliferative activity of taste bud cells was measured from the uptake of 5-bromo-2′-deoxyuridine. Key findings: The zinc concentration of the lingual epithelium, but not the whole tongue, was markedly decreased in Zn(−) rats compared with Zn(+) rats. After administration of polaprezinc to Zn(−) rats at doses of 1, 3, and 10mg/kg, the zinc concentration in the lingual epithelium increased significantly from 85±4 to 105±7 (p <0.05), 120±3 (p <0.001), and 124±3 (p <0.001) µg/g, respectively. After administration of [65Zn] polaprezinc, the 65Zn radioactivity of the tongue and serum were higher in Zn(−) rats than in Zn(+) rats. 65Zn was mainly detected in the epithelium on microautoradiograms of the tongue in Zn(−) rats. In addition, polaprezinc (3 and 10mg/kg) improved the reduced proliferation of taste bud cells due to zinc deficiency. Significance: Polaprezinc is distributed to the lingual epithelium and restores its zinc concentration in Zn(−) rats resulting in improvement of cellular functions, especially proliferation. [Copyright &y& Elsevier]

• Immunoglobulin A vasculitis (IgAV) induces acute encephalopathy. • Neurological sequelae can be caused by IgAV, even extremely rare. • MRI showed unusual biphasic features and reduced cerebral blood flow. • Cerebrospinal fluid interleukin-6 level was markedly elevated. Immunoglobulin A vasculitis (IgAV) occasionally induces central nervous system (CNS) involvement, which is usually transient with no sequelae except for hemorrhagic stroke. It is thought to be useful to measure serum and cerebrospinal fluid (CSF) cytokine levels for better understanding the pathological condition in encephalopathy, but there have been no reports in acute encephalopathy with IgAV. We describe an 8-year-old boy with IgAV who had neurological sequelae after complication of acute encephalopathy, focusing on the cytokine profiles and unique biphasic findings of magnetic resonance imaging. He presented with status epilepticus and mildly intensified area in the occipital lobe on the fluid-attenuated inversion recovery view. Arterial spin labeling (ASL) revealed the reduction of cerebral blood flow in the left hemisphere. On day 5 of illness, these abnormal findings disappeared, but delayed hyperintensity lesions on diffusion-weighted images newly emerged. Furthermore, CSF interleukin (IL)-6 levels markedly increased without elevated levels of IL-10 during the acute phase of disease. He suffered from long-lasting hemiparesis and intellectual impairment. In conclusion, acute encephalopathy with IgAV could cause neurological sequelae by prolonged seizure, and elevated IL-6 in CSF and laterality of cerebral blood flow in ASL might be useful to predict the prognosis of CNS dysfunction of IgAV. [ABSTRACT FROM AUTHOR]

Abstract The treatment of juvenile osteoporosis has not been established due to a lack of data regarding the efficacy and adverse effects of therapeutic agents. The possible adverse effects of the long-term use of antiresorptive therapies on skeletal growth in children is of particular concern. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immunoreceptor that regulates osteoclast development and bone resorption, and its deficiency suppresses bone remodeling in the secondary spongiosa, but not in the primary spongiosa, due to a compensatory mechanism of osteoclastogenesis. This prompted us to develop an anti-Siglec-15 therapy for juvenile osteoporosis because most anti-resorptive drugs have potential adverse effects on skeletal growth. Using growing rats, we investigated the effects of an anti-Siglec-15 neutralizing antibody (Ab) on systemic bone metabolism and skeletal growth, comparing this drug to bisphosphonate, a first-line treatment for osteoporosis. Male 6-week-old F344/Jcl rats were randomized into six groups: control (PBS twice per week), anti-Siglec-15 Ab (0.25, 1, or 4 mg/kg every 3 weeks), and alendronate (ALN) (0.028 or 0.14 mg/kg twice per week). Treatment commenced at 6 weeks of age and continued for the next 6 weeks. Changes in bone mass, bone metabolism, bone strength, and skeletal growth during treatment were analyzed. Both anti-Siglec-15 therapy and ALN increased bone mass and the mechanical strength of both the femora and lumbar spines in a dose-dependent manner. Anti-Siglec-15 therapy did not have a significant effect on skeletal growth as evidenced by micro-CT-based measurements of femoral length and histology, whereas high-dose ALN resulted in growth retardation with histological abnormalities in the growth plates of femurs. This unique property of the anti-Siglec-15 Ab can probably be attributed to compensatory signaling for Siglec-15 inhibition in the primary spongiosa, but not in the secondary spongiosa. Thus, anti-Siglec-15 therapy could be a safe and effective for juvenile osteoporosis. Highlights • Anti-Siglec-15 Ab does not result in adverse effects on skeletal growth in growing rats. • Anti-Siglec-15 Ab increases bone mass and mechanical properties of long bones and lumbar vertebral bodies in growing rats. • Anti-Siglec-15 Ab could be safe and effective for juvenile osteoporosis. [ABSTRACT FROM AUTHOR]

Osteoclastogenesis requires immunoreceptor tyrosine-based activation motif signaling. Multiple immunoreceptors associated with immunoreceptor tyrosine-based activation motif adaptor proteins, including DNAX-activating protein 12 kDa (DAP12) and Fc receptor common γ (FcRγ), have been identified in osteoclast lineage cells, and some are involved in arthritis-induced bone destruction. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immunoreceptor that regulates osteoclast development and bone resorption in association with DAP12. Whether Siglec-15 is involved in arthritis-induced bone lesions, however, remains unknown. Here we used a murine antigen-induced arthritis model to examine the role of Siglec-15 in the development of bone lesions induced by joint inflammation. Arthritis was unilaterally induced in the knee joints of 8-week-old female wild-type (WT) and Siglec-15 −/− mice, and the contralateral knees were used as a control. The degree of joint inflammation, and cartilage and subchondral bone destruction in Siglec-15 −/− mice was comparable to that in WT mice, indicating that Siglec-15 is not involved in the development of arthritis and concomitant cartilage and subchondral bone destruction. On the other hand, the degree of periarticular bone loss in the proximal tibia of the arthritic knee was significantly lower in Siglec-15 −/− mice compared to WT mice. Although osteoclast formation in the metaphysis was enhanced in both WT and Siglec-15 −/− mice after arthritis induction, mature multinucleated osteoclast formation was impaired in Siglec-15 −/− mice, indicating impaired osteoclast bone resorptive function in the periarticular regions of the arthritic joint in Siglec-15 −/− mice. Confirming this result, Siglec-15 −/− primary unfractionated bone marrow cells harvested from arthritic femurs and tibiae failed to develop into mature multinuclear osteoclasts. Our findings suggest that Siglec-15 is a therapeutic target for periarticular bone loss, but not for joint destruction, in inflammatory arthritis, such as rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immunoreceptor that regulates osteoclast development and bone resorption in association with an immunoreceptor tyrosine-based activation motif (ITAM) adaptor protein, DNAX-activating protein 12 kDa (DAP12). Although Siglec-15 has an important role in physiologic bone remodeling by modulating RANKL signaling, it is unclear whether it is involved in pathologic bone loss in which multiple osteoclastogenic factors participate in excessive osteoclastogenesis. Here we demonstrated that Siglec-15 is involved in estrogen deficiency-induced bone loss. WT and Siglec-15 −/− mice were ovariectomized (Ovx) or sham-operated at 14 wk of age and their skeletal phenotype was evaluated at 18 and 22 wk of age. Siglec-15 −/− mice showed resistance to estrogen deficiency-induced bone loss compared to WT mice. Although the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts increased after ovariectomy in both WT and Siglec-15 −/− mice, the increase was lower in Siglec-15 −/− mice than in WT mice. Importantly, osteoclasts in Siglec-15 −/− mice were small and failed to spread on the bone surface, indicating impaired osteoclast differentiation. Because upregulated production of TNF-α as well as RANKL is mainly responsible for estrogen deficiency-induced development of osteoclasts, we examined whether Siglec-15 deficiency affects TNF-α-induced osteoclastogenesis in vitro . The TNF-α mediated induction of TRAP-positive multinucleated cells was impaired in Siglec-15 −/− cells, suggesting that Siglec-15 is involved in TNF-α induced osteoclastogenesis. We also confirmed that signaling through osteoclast-associated receptor/Fc receptor common γ chain, which is an alternative ITAM adaptor to DAP12, rescues multinucleation but not cytoskeletal organization of TNF-α and RANKL-induced Siglec-15 − / − osteoclasts, indicating that the Siglec-15/DAP12 pathway is especially important for cytoskeletal organization of osteoclasts in both RANKL and TNF-α induced osteoclastogenesis. The present findings indicate that Siglec-15 is involved in estrogen deficiency-induced differentiation of osteoclasts and is thus a potential therapeutic target for postmenopausal osteoporosis. [ABSTRACT FROM AUTHOR]

Abstract: Teriparatide (PTH1–34) promotes skeletal repair and increases bone mass. Vitamin K is involved in bone mineralization as a coenzyme of γ-carboxylase for Gla proteins, and therefore vitamin K insufficiency caused by malnutrition or therapeutic intake of the vitamin K antagonist warfarin could affect the efficacy of PTH1–34 therapy for bone repair. In the present study, we investigated whether vitamin K influences the efficacy of PTH1–34 therapy for bone repair in a rat osteotomy model. Female 12-week-old Sprague–Dawley rats were subjected to a closed midshaft osteotomy of the femur and randomized into four groups (n=10 per group): vehicle, PTH1–34 (daily 30μg/kg/day subcutaneous injection)+solvent (orally, three times a week), PTH1–34 +warfarin (0.4mg/kg/day orally, three times a week), and PTH1–34 +vitamin K2 (menatetrenone, 30mg/kg/day orally, three times a week). Serum γ-carboxylated and uncarboxylated osteocalcin (Gla-OC and Glu-OC) levels and radiographic healing were monitored every 2weeks. Skeletal repair was assessed by micro-computed tomography, mechanical testing, and histology at 8weeks after surgery. PTH1–34 amplified the osteotomy-induced increase in Gla-OC and improved the mechanical properties as well as the volumetric bone mineral tissue density of the fracture callus. Concurrent use of warfarin decreased the response to PTH1–34 therapy in terms of mechanical recovery, probably by impairing mineralization due to the lack of Gla-OC. Although the effects of combination therapy with PTH1–34 and vitamin K2 on bone repair did not significantly exceed those of PTH1–34 monotherapy in rats fed sufficient dietary vitamin K, postoperative Gla-OC levels were correlated with the mechanical properties of the osteotomized femur in PTH1–34-treated rats regardless of the use of warfarin or vitamin K2. These findings suggest the importance of vitamin K dependent γ-carboxylation of OC for realizing the full effects of PTH1–34 on skeletal repair. [Copyright &y& Elsevier]