Functional connectivity between pre-supplementary motor area and inferior parietal lobule associated with impaired motor response inhibition in first-degree relatives of patients with obsessive-compulsive disorder.

Previous studies have suggested that specific fronto-striatal circuits are associated with impaired motor response inhibition in patients with obsessive-compulsive disorder (OCD) and their relatives. However, no study has investigated the underlying resting-state network associated with motor response inhibition in the unaffected first-degree relatives of patients with OCD. We measured motor response inhibition using stop-signal task, and obtained resting-state fMRI in 23 first-degree relatives and 52 healthy control participants. We explored the group differences in the functional network from seed regions-of-interest (ROIs) associated with motor response inhibition abilities. We used the inferior frontal gyrus (IFG) and pre-supplementary motor area (pre-SMA) as seed-ROIs. A significant group difference was observed in functional connectivity between the pre-SMA and inferior parietal lobule. In the relative group, reduced functional connectivity between these areas was associated with a longer stop-signal reaction time. Additionally, relatives showed significantly greater functional connectivity between the IFG and SMA, precentral, and postcentral areas. Our results could provide new insights into the resting-state neural activity of the pre-SMA underlying impaired motor response inhibition of unaffected first-degree relatives. In addition, our results suggested that relatives have an altered connectivity of the sensorimotor region, similar to that of patients with OCD shown in previous literature.

Gyrification of the medial and lateral orbitofrontal cortex in first-degree relatives of patients with obsessive-compulsive disorder.

Gyrification patterns reflect early neurodevelopment and could be highly heritable. While some discrepant results have been reported, the most consistent finding was that patients with obsessive-compulsive disorder showed altered gyrification patterns in the orbitofrontal cortex. Nevertheless, no study has investigated the alterations in gyrification in unaffected first-degree relatives of patients with obsessive-compulsive disorder. We measured local gyrification by the FreeSurfer software in 23 unaffected first-degree relatives of patients with obsessive-compulsive disorder and 52 healthy control participants. We explored differences in the local gyrification index using vertex-wise whole-brain analysis and a region of interest-based approach in the medial and lateral orbitofrontal cortex. There was no significant difference in the local gyrification index between the 2 groups in the vertex-wise whole-brain analysis. Region of interest analyses showed that, compared with healthy controls, first-degree relatives showed significantly reduced local gyrification index in the left medial and lateral orbitofrontal cortex. A negative correlation was observed between the reduced local gyrification index in lateral orbitofrontal cortex and the subclinical anxiety scores of first-degree relatives. Our results showed that first-degree relatives of patients with obsessive-compulsive disorder had an altered local gyrification index in the orbitofrontal cortex. Especially, reduced local gyrification index in lateral orbitofrontal cortex associated with subclinical anxiety symptom could be a potential neurodevelopmental marker for the illness onset.

GLUT9 as a potential drug target for chronic kidney disease: Drug target validation by a Mendelian randomization study.

Although chronic kidney disease (CKD) is recognized as a major public health concern, effective treatment strategies have yet to be developed. Identification and validation of drug targets are key issues in the development of therapeutic agents for CKD. Uric acid (UA), a major risk factor for gout, has also been suggested to be a risk factor for CKD, but the efficacy of existing urate-lowering therapies for CKD is controversial. We focused on five uric acid transporters (ABCG2, SLC17A1, SLC22A11, SLC22A12, SLC2A9) as potential drug targets and evaluated the causal association between serum UA levels and estimated glomerular filtration rate (eGFR) using single-SNP Mendelian Randomization. The results showed a causal association between genetically predicted changes in serum UA levels and eGFR when genetic variants were selected from the SLC2A9 locus. Estimation based on a loss-of-function mutation (rs16890979) showed that the changes in eGFR per unit increase in serum UA level was -0.0082 ml/min/1.73 m2 (95% CI -0.014 to -0.0025, P = 0.0051). These results indicate that SLC2A9 may be a novel drug target for CKD that preserves renal function through its urate-lowering effect.

High-Speed Tracking with Mutual Assistance of Feature Filters and Detectors.

Object detection and tracking in camera images is a fundamental technology for computer vision and is used in various applications. In particular, object tracking using high-speed cameras is expected to be applied to real-time control in robotics. Therefore, it is required to increase tracking speed and detection accuracy. Currently, however, it is difficult to achieve both of those things simultaneously. In this paper, we propose a tracking method that combines multiple methods: correlation filter-based object tracking, deep learning-based object detection, and motion detection with background subtraction. The algorithms work in parallel and assist each other's processing to improve the overall performance of the system. We named it the "Mutual Assist tracker of feature Filters and Detectors (MAFiD method)". This method aims to achieve both high-speed tracking of moving objects and high detection accuracy. Experiments were conducted to verify the detection performance and processing speed by tracking a transparent capsule moving at high speed. The results show that the tracking speed was 618 frames per second (FPS) and the accuracy was 86% for Intersection over Union (IoU). The detection latency was 3.48 ms. These experimental scores are higher than those of conventional methods, indicating that the MAFiD method achieved fast object tracking while maintaining high detection performance. This proposal will contribute to the improvement of object-tracking technology.

Possible observation of quantum spin-nematic phase in a frustrated magnet.

Water freezes into ice in winter and evaporates into vapor in summer. Scientifically, the transformations between solid, liquid, and gas are called phase transitions and can be classified through the changes in symmetry which occur in each case. A fourth phase of matter was discovered late in the 19th century: the liquid crystal nematic, in which rod- or disk-shaped molecules align like the atoms in a solid, while continuing to flow like a liquid. Here we report thermodynamic evidence of a quantum analog of the classical nematic phase, the quantum spin nematic (SN). In an SN, the spins of a quantum magnet select a common axis, like a nematic liquid crystal, while escaping conventional magnetic order. Our state-of-the-art thermal measurements in high pulsed magnetic fields up to 33 T on the copper mineral volborthite with spin 1/2 on a frustrated lattice provide thermodynamic evidence for SN order, half a century after the theoretical proposal [Blume M, Hsieh YY (1969) J Appl Phys 40:1249; Andreev AF, Grishchuk IA (1984) J Exp Theor Phys 97:467-475].

Significant cases of central cusps, enamel pits, and oral fibromas in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder in which benign nodular tumors form in the cerebral cortex, cerebellum, and throughout the body causing various symptoms. In this study, we summarized the incidence of dental findings in patients with TSC at our hospital and its association with diseases in various organs. Patients diagnosed with TSC at our hospital between January 2013 and September 2017, and who were examined in the dental and oral surgery department were included in this study. The presence of intraoral manifestations (central cusps, enamel pits, oral fibromas) was examined by means of visual inspection, intraoral photography, and X-ray photography. In addition, the relationship with associated diseases (neurological, cutaneous, cardiac, renal, and pulmonary) according to organ and disease severity was examined. The mean age (± SD) of the 42 TSC patients (19 men and 23 women) was 27.8 ± 14.6 years, of which 24 patients (11 men and 13 women) presented with oral manifestations. Of these patients, seven had central cusps, 10 had enamel pits, and 17 had oral fibromas. The group with central cusps had significantly higher neurological issues in the relationship between intraoral manifestations and associated disease based on the involved organ. The prevalence of central cusps in TSC was 16.7%, which is significantly higher than the 2.6% reported in healthy Japanese subjects. The central cusp is a diagnostic factor alongside the presence of enamel pits and oral fibromas, which can aid in the early diagnosis of TSC by dentists.

JTZ-951, an HIF prolyl hydroxylase inhibitor, suppresses renal interstitial fibroblast transformation and expression of fibrosis-related factors.

Some preceding studies have provided evidence that hypoxia-inducible factor (HIF)-prolyl hydroxylase (PH) inhibitors have therapeutic potential against tubular interstitial fibrosis (TIF). Recently, transformation of renal interstitial fibroblasts (RIFs) into α-smooth muscle actin-positive myofibroblasts with loss of their hypoxia-inducible erythropoietin (EPO) expression has been hypothesized as the central mechanism responsible for TIF with renal anemia (the RIF hypothesis). These reports have suggested that HIF-PH inhibitors may suppress TIF via suppressing transformation of RIFs. However, the direct effect of HIF-PH inhibitors on transformation of RIFs has not been demonstrated because there has been no appropriate assay system. Here, we established a novel in vitro model of the transformation of RIFs. This model expresses key phenotypic changes such as transformation of RIFs accompanied by loss of their hypoxia-inducible EPO expression, as proposed by the RIF hypothesis. Using this model, we demonstrated that JTZ-951, a newly developed HIF-PH inhibitor, stabilized HIF protein in RIFs, suppressed transformation of RIFs, and maintained their hypoxia-inducible EPO expression. JTZ-951 also suppressed the expression of FGF2, FGF7, and FGF18, which are upregulated during transformation of RIFs. Furthermore, expression of Fgf2, Fgf7, and Fgf18 was correlated with TIF in an animal model of TIF. We also demonstrated that not only FGF2, which is a well-known growth-promoting factor, but also FGF18 promoted proliferation of RIFs. These data suggest that JTZ-951 has therapeutic potential against TIF with renal anemia. Furthermore, FGF2, FGF7, and FGF18, which faithfully reflect the anti-TIF effects of JTZ-951, have potential as TIF biomarkers.

Distinct transcriptional programs of SOX2 in different types of small cell lung cancers.

SOX2 is recognized as an oncogene in human small cell lung cancer (SCLC), which is an aggressive neuroendocrine (NE) tumor. However, the role of SOX2 in SCLC is not completely understood, and strategies to selectively target SOX2 in SCLC cells remain elusive. Here, we show, using next-generation sequencing, that SOX2 expressed in the ASCL1-high SCLC (SCLC-A) subtype cell line is dependent on ASCL1, which is a lineage-specific transcriptional factor, and is involved in NE differentiation and tumorigenesis. ASCL1 recruits SOX2, which promotes INSM1 and WNT11 expression. Immunohistochemical studies revealed that SCLC tissue samples expressed SOX2, ASCL1, and INSM1 in 18 out of the 30 cases (60%). Contrary to the ASCL1-SOX2 signaling axis controlling SCLC biology in the SCLC-A subtype, SOX2 targets distinct genes such as those related to the Hippo pathway in the ASCL1-negative, YAP1-high SCLC (SCLC-Y) subtype. Although SOX2 knockdown experiments suppressed NE differentiation and cell proliferation in the SCLC-A subtype, they did not sufficiently impair the growth of the SCLC-Y subtype cell lines in vitro and ex vivo. The present results support the importance of the ASCL1-SOX2 axis as a main subtype of SCLC, and suggest the therapeutic potential of targeting the ASCL1-SOX2 axis.

Significance of achaete-scute complex homologue 1 (ASCL1) in pulmonary neuroendocrine carcinomas; RNA sequence analyses using small cell lung cancer cells and Ascl1-induced pulmonary neuroendocrine carcinoma cells.

ASCL1 is one of the master transcription factors of small cell lung carcinoma (SCLC). To investigate the significance of ASCL1 in pulmonary neuroendocrine carcinoma, we performed 2 comparative RNA-seq studies between H69 (ASCL1-positive, classical type SCLC) and H69AR (ASCL1-negative, variant type SCLC) and between ASCL1-transfected A549 adenocarcinoma cell lines (A549(ASCL1+) cell lines) and A549(control) cell lines. RNA-seq analyses revealed that 940 genes were significantly different between the H69 and H69AR cell lines, and 728 between the A549(ASCL1+) and A549(control) cell lines. In total, 120 common genes between these analyses were selected as candidate ASCL1-related genes, and included genes with various cellular functions, such as neural development, secretion, growth, and morphology. Their expression degrees in three classical and two variant SCLC cell lines, two A549(ASCL1+) and two A549(control) cell lines were subjected to quantitative PCR analyses. Since the candidate ASCL1-related genes were strongly expressed in the classical SCLC and A549(ASCL1+) cell lines and more weakly expressed in the variant SCLC and A549(control) cell lines, the ASCL1-related 7 molecules INSM1, ISL1, SYT4, KCTD16, SEZ6, MS4A8, and COBL were further selected. These molecules suggested diverse functions for A549(ASCL1+): INSM1 and ISL1 are transcription factors associated with neuroendocrine differentiation, while SYT4, KTCD16, and SEZ6 may be related to neurosecretory functions and MS4A8 and COBL to cell growth and morphology. An immunohistochemistry of these seven molecules was performed on lung carcinoma tissues and the xenotransplanted tumors of A549(ASCL1+), and they were preferentially and positively stained in ASCL1-postive tumor tissues.

Nonmagnetic Ground States and a Possible Quadrupolar Phase in 4d and 5d Lacunar Spinel Selenides GaM_{4}Se_{8} (M=Nb, Ta).

Structural and magnetic properties of cubic spinel selenides GaM_{4}Se_{8} (M=Nb, Ta), which are candidates for the molecular J_{eff}=3/2 Mott insulators, are investigated. The effective magnetic moments are reduced compared to the spin only value, indicating the presence of sizable spin-orbit coupling. GaNb_{4}Se_{8} and GaTa_{4}Se_{8} exhibit phase transitions into the nonmagnetic ground states with orthorhombic and tetragonal structures, respectively, which are robust against magnetic field up to at least 60 T. A cubic-cubic phase transition is observed in GaNb_{4}Se_{8} preceding the magnetic transition, suggesting the existence of a quadrupolar-ordered phase theoretically predicted in the J_{eff}=3/2 Mott insulator.

Synthesis, Structure, and Anomalous Magnetic Ordering of the Spin-1/2 Coupled Square Tetramer System K(NbO)Cu4(PO4)4.

Quasi-zero-dimensional antiferromagnets with weakly coupled clusters of multiple spins can provide an excellent platform for exploring exotic quantum states of matter. Here, we report the synthesis and the characterization of a copper-based insulating antiferromagnet, K(NbO)Cu4(PO4)4. Single-crystal X-ray diffraction measurements reveal that the crystal structure belongs to the tetragonal space group P4/nmm, in which Cu2+ ions align to form a quasi-two-dimensional layer of spin-1/2 coupled square tetramers. The structure is quasi-isostructural to recently reported magnetoelectric antiferromagnets, A(TiO)Cu4(PO4)4 (A = Ba, Sr, and Pb) with the P4212 space group. Despite their structural similarities, whereas the antiferromagnetic transition in A(TiO)Cu4(PO4)4 produces conventional anomalies in magnetization and heat capacity, that in K(NbO)Cu4(PO4)4 has several unusual features such as an upturn in magnetic susceptibility and a very weak specific heat anomaly that corresponds to a spin entropy release as small as 3%. These results indicate that the magnetism of K(NbO)Cu4(PO4)4 is far different from that of A(TiO)Cu4(PO4)4 and suggest that the ground state is very close to a quantum nonmagnetic singlet state. The origin of the distinct magnetism in K(NbO)Cu4(PO4)4 is discussed in terms of structural modifications of a Cu4O12 unit forming a square tetramer. Our study demonstrates that the present material family, represented by an extended chemical formula A(BO)Cu4(PO4)4 (AB = KNb, BaTi, SrTi, and PbTi), has broad chemical controllability of their magnetism. This makes this system an attractive material platform to study the physics of quantum spin-1/2 coupled square tetramers.

Ascl1-induced Wnt11 regulates neuroendocrine differentiation, cell proliferation, and E-cadherin expression in small-cell lung cancer and Wnt11 regulates small-cell lung cancer biology.

The involvement of Wnt signaling in human lung cancer remains unclear. This study investigated the role of Wnt11 in neuroendocrine (NE) differentiation, cell proliferation, and epithelial-to-mesenchymal transition (EMT) in human small-cell lung cancer (SCLC). Immunohistochemical staining of resected specimens showed that Wnt11 was expressed at higher levels in SCLCs than in non-SCLCs; 58.8% of SCLC, 5.2% of adenocarcinoma (ADC), and 23.5% of squamous cell carcinoma tissues stained positive for Wnt11. A positive relationship was observed between Achaete-scute complex homolog 1 (Ascl1) and Wnt11 expression in SCLC cell lines, and this was supported by transcriptome data from SCLC tissue. The expression of Wnt11 and some NE markers increased after the transfection of ASCL1 into the A549 ADC cell line. Knockdown of Ascl1 downregulated Wnt11 expression in SCLC cell lines. Ascl1 regulated Wnt11 expression via lysine H3K27 acetylation at the enhancer region of the WNT11 gene. Wnt11 controlled NE differentiation, cell proliferation, and E-cadherin expression under the regulation of Ascl1 in SCLC cell lines. The phosphorylation of AKT and p38 mitogen-activated protein kinase markedly increased after transfection of WNT11 into the SBC3 SCLC cell line, which suggests that Wnt11 promotes cell proliferation in SCLC cell lines. Ascl1 plays an important role in regulating the Wnt signaling pathway and is one of the driver molecules of Wnt11 in human SCLC. Ascl1 and Wnt11 may employ a cooperative mechanism to control the biology of SCLC. The present results indicate the therapeutic potential of targeting the Ascl1-Wnt11 signaling axis and support the clinical utility of Wnt11 as a biological marker in SCLC.

Role of dental sleep medicine in management of patients with obstructive sleep apnea disorders using a team approach.

OBJECTIVE: Obstructive sleep apnea (OSA) is a significant social and health issue. An integrated multidisciplinary approach to OSA management may be the most effective owing to its multifactorial etiology. In this study, we evaluated the frequency and efficacy of various treatment modalities for OSA administered via an integrated care delivery model, and assessed the role of dental sleep medicine as part of a multidisciplinary team. MATERIALS AND METHODS: We retrospectively evaluated 1115 patients with OSA treated at the Tokyo Medical University Hospital's Outpatient Clinic for OSA by a multidisciplinary team under one roof. The various treatment methods included the following: continuous positive airway pressure (CPAP), oral appliance (OA), surgery, and behavioral treatment. RESULTS: The patient number of study group was as follows: 771 (69.1%) CPAP; 240 (21.5%) OA; 76 (6.8%) behavioral treatment and 28 (3%) surgery. Because significantly fewer patients underwent surgery, there was a discrepancy between the recommended first-choice treatment and the actual treatment. A statistically significant number of younger patients in each treatment group underwent surgery. Success rate of OA and MMA were 74.4 and 80%, respectively. CONCLUSIONS: Proper selection of primary treatment to manage patients with OSA was possible under one-roof system that included dental sleep medicine.

Magnetoelectric Behavior from S=1/2 Asymmetric Square Cupolas.

Magnetoelectric properties are studied by a combined experimental and theoretical study of a quasi-two-dimensional material composed of square cupolas, Ba(TiO)Cu_{4}(PO_{4})_{4}. The magnetization is measured up to the field above the saturation, and several anomalies are observed depending on the field directions. We propose a S=1/2 spin model with Dzyaloshinskii-Moriya interactions, which reproduces the full magnetization curves well. Elaborating the phase diagram of the model, we show that the anomalies are explained by magnetoelectric phase transitions. Our theory also accounts for the scaling of the dielectric anomaly observed in the experiments. The results elucidate the crucial role of the in-plane component of Dzyaloshinskii-Moriya interactions, which is induced by the noncoplanar buckling of a square cupola. We also predict a "hidden" phase and another magnetoelectric response, both of which appear in a nonzero magnetic field.

Giant Exchange Coupling Evidenced with a Magnetization Jump at 52 T for a Gadolinium-Nitroxide Chelate.

The Gd-radical complex [GdIII(hfac)3(6bpyNO)] (6bpyNO = 2,2'-bipyridin-6-yl tert-butyl nitroxide; Hhfac = 1,1,1,5,5,5-hexafluoropentane-2,4-dione) showed a magnetization jump at 52 T observed in a pulsed-field facility, corresponding to an exchange coupling constant of -17.4 K. Furthermore, hysteretic behavior due to a relatively slow magnetization reversal was recorded around 2 T. From the high-frequency EPR study, the exchange coupling between Gd and radical spins accompanies an anisotropic character, which is responsible for both the broad jump and the slow magnetization reversal.

Evaluation of dental implants as a risk factor for the development of bisphosphonate-related osteonecrosis of the jaw in breast cancer patients.

It remains unclear whether dental implants are a risk factor for the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We retrospectively evaluated the status of dental implants in patients given intravenous bisphosphonates (BPs) in a breast cancer cohort to elucidate the risk for BRONJ at the implant site. We established a BRONJ oral monitoring program for 247 breast cancer patients given intravenous BP in our institution. The 3-year cumulative incidence rate was determined. The systemic and local risk factors of 44 patients who completed comprehensive oral examinations were evaluated by logistic regression analysis. The 3-year cumulative incidence rate of the 247 patients was 0.074 % (8/247, 95 % CI 0.0081-0.014). In the 44 orally examined patients, 6 (13.6 %: 6/44) had dental implants. Of these 6 patients, 1 developed BRONJ at the implant site. There were no significant differences in the age, total BP treatment period, number of residual teeth, time of regular oral monitoring, oral hygiene level, or dental implant insertion. Although a case of ONJ was identified, dental implants which were inserted before intravenous BP administration were not a risk factor for the development of ONJ in breast cancer patients.

Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo.

OBJECTIVE: To evaluate the pharmacological properties of JTE-052, a novel Janus kinase (JAK) inhibitor. METHODS: The JAK inhibitory activity of JTE-052 was evaluated using recombinant human enzymes. The inhibitory effects on cytokine signaling pathways were evaluated using primary human inflammatory cells. The in vivo efficacy and potency of JTE-052 were examined in a mouse interleukin (IL)-2-induced interferon (IFN)-γ production model and a rat collagen-induced arthritis model. RESULTS: JTE-052 inhibited the JAK1, JAK2, JAK3, and tyrosine kinase (Tyk)2 enzymes in an adenosine triphosphate (ATP)-competitive manner and inhibited cytokine signaling evoked by IL-2, IL-6, IL-23, granulocyte/macrophage colony-stimulating factor, and IFN-α. JTE-052 inhibited the activation of inflammatory cells, such as T cells, B cells, monocytes, and mast cells, in vitro. Oral dosing of JTE-052 resulted in potent suppression of the IL-2-induced IFN-γ production in mice with an ED50 value of 0.24 mg/kg, which was more potent than that of tofacitinib (ED50 = 1.1 mg/kg). In the collagen-induced arthritis model, JTE-052 ameliorated articular inflammation and joint destruction even in therapeutic treatments where methotrexate was ineffective. CONCLUSIONS: The present results indicate that JTE-052 is a highly potent JAK inhibitor, and represents a candidate anti-inflammatory agent for suppressing various types of inflammation.

A randomized trial to identify the most effective dose of remifentanil during Le Fort I osteotomy.

PURPOSE: The Le Fort I osteotomy (L-I) requires extensive dissection and manipulation of tissue, causing hemodynamic instability and an undesirable postoperative stress response. This study aimed to clarify the most effective dose of remifentanil during L-I. MATERIALS AND METHODS: This study was designed as a prospective, randomized, controlled double-blinded study. Patients (American Society of Anesthesiologists physical status I to II) undergoing L-I were randomly assigned to receive anesthesia with propofol and remifentanil under 3 remifentanil dose conditions: 0.25 µg/kg/minute (group 1), 0.5 µg/kg/minute (group 2), and 0.75 µg/kg/minute (group 3). All patients underwent L-I with propofol and remifentanil target-controlled anesthesia. The study endpoints were mean arterial pressure (MAP) and heart rate. Data were recorded before L-I (20-minute period before surgery), during L-I (from the beginning of surgery to downfracture), and after L-I (20-minute period after downfracture). Average age, gender, average body mass index, aimed maxillary position, average bispectral index, average surgery time, and average blood loss also were examined. Data were analyzed using the Bartlett test and then 1-way analysis of variance with the Bonferroni multiple comparison test. RESULTS: Data were obtained from 20 patients (9 men, 11 women). The average operating times for groups 1, 2, and 3 were 53.1, 46.7, and 49 minutes, respectively. The age range was 18 to 46 years (average, 26.05 yr). The rate of MAP increase from before to during L-I in group 1 was 10.8% (n = 7). The rate of MAP increase from before to during L-I in group 3 was 2.1% (n = 6). Group 3 showed a significantly lower rate of MAP increase during and after L-I compared with group 1 (P < .05). CONCLUSION: Remifentanil administration at 0.75 µg/kg/minute stabilized hemodynamics during L-I without major side effects. Results indicated that the standard index of remifentanil administration during L-I should be 0.75 µg/kg/minute when using oxygen, propofol, and remifentanil for general anesthesia.

Improvement of spontaneous locomotor activity with JAK inhibition by JTE-052 in rat adjuvant-induced arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint destruction, disability, and decreased quality of life (QOL). Inhibition of Janus kinase (JAK) signaling ameliorates articular inflammation and joint destruction in animal models of RA, but its effects on behaviors indicating well-being are poorly understood. In this study, we evaluated the effect of JAK inhibition on spontaneous locomotor activity in rats with adjuvant-induced arthritis, a rodent model of RA. METHODS: Arthritis was induced in male Lewis rats by a single subcutaneous injection of Freund's complete adjuvant. The novel JAK inhibitor JTE-052 was orally administered for 7 days after the onset of arthritis. RESULTS: Induction of arthritis suppressed the spontaneous locomotor activity of the rats. Administration of JTE-052 completely improved the spontaneous locomotor activity, with partial reductions in articular inflammation and joint destruction. Hyperalgesia and motor functions were also improved, but the efficacy was not complete. However, serum interleukin (IL)-6 levels were completely decreased at 4 h after administration of the first dose of JTE-052. CONCLUSIONS: This study demonstrated that JAK inhibition improved the spontaneous locomotor activity of rats with adjuvant-induced arthritis, in association with amelioration of pain and physical dysfunction as a consequence of suppression of joint inflammation. Moreover, although further studies are needed, there was possible participation of IL-6 downregulation in the improvement of locomotor activity by JAK inhibition.

The utility of the phosphate binder, ferric citrate hydrate (JTT-751), about phosphorus absorption-reducing effect in normal rats.

Hyperphosphatemia is a risk factor for arterial calcification contributing to the high-cardiovascular mortality in patients with chronic kidney disease (CKD). Ferric citrate hydrate (JTT-751) is being developed as a treatment for hyperphosphatemia with chronic renal failure and has shown a serum phosphorus-lowering effect in CKD patients. In this study, we evaluated the combination effect of JTT-751 with the phosphorus absorption-reducing effect of calcium carbonate and compared phosphorus absorption-reducing efficacy between three phosphate binders including JTT-751. Normal rats were fed a diet containing either 1% calcium carbonate, 1% JTT-751 or 1% JTT-751 with 1% calcium carbonate, for 7 days. Both 1% calcium carbonate and 1% JTT-751 alone reduced urinary phosphorus excretion, and the combined treatment reduced it more than each single-treatment, without clearly influencing calcium or iron-metabolism. Next, normal rats were fed a diet containing either 0.3, 1 and 3% lanthanum carbonate or 2.3% JTT-751, for 7 days. Either 3% lanthanum carbonate or 2.3% JTT-751 reduced urinary phosphorus excretion. Finally, we compared the reduced amount of urinary phosphorus excretion per dose of compound, of which JTT-751 is comparable to that of calcium carbonate and is greater than that of the lanthanum carbonate. In conclusion, JTT-751 showed an additive effect on the phosphorus absorption-reducing effect of calcium carbonate without influencing calcium- and iron-metabolism, and had a phosphorus absorption-reducing efficacy comparable to or greater than other existing phosphate binders.