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Yoichi Tanaka,1,2 Ren Fujii,2,3 Hayato Shigetoh,2,4 Gosuke Sato,2 Shu Morioka2 1Department of Occupational Therapy, School of Rehabilitation, Hyogo Medical University, Hyogo, Japan; 2Neuro Rehabilitation Research Center, Kio University, Nara, Japan; 3Musashigaoka Clinical Research Center, Musashigaoka Hospital, Kumamoto, Japan; 4Department of Physical Therapy, Faculty of Health Science, Kyoto Tachibana University, Kyoto, JapanCorrespondence: Yoichi Tanaka, Department of Occupational Therapy, School of Rehabilitation, Hyogo Medical University, 1-3-6 Minatojima Chuo-ku, Kobe, Hyogo, Japan, Tel +81 78-304-3180, Email yi-tanaka@hyo-med.ac.jpPurpose: This study aimed to juxtapose the circadian rhythm of pain with the conventional 7-day assessment and ascertain the feasibility of condensing the evaluation of the circadian rhythm of pain into a 3-day timeframe.Patients and Methods: Seventy-three patients with pain persisting for a minimum of 3 months and a numerical rating scale (NRS) score of ≥ 2 were recruited from three medical centers. The circadian patterns of pain were appraised over a 7-day period by quantifying the intensity of pain at six temporal junctures each day using a 10-cm visual analog scale (VAS). Cluster analysis was performed using six standardized variables derived from the VAS score of each participant at six designated time points to identify cohorts with analogous circadian rhythms of pain. The clusters were discerned for the 7- and 3-day assessments (Tuesday–Thursday, Friday–Sunday, and Sunday–Tuesday), according to the research objectives. Cohen’s kappa coefficient was calculated to gauge the intra-observer variability to assess the consistency between the outcomes of the cluster analysis for the 7-day assessment and each of the 3-day assessments.Results: The highest Cohen’s kappa coefficient was observed for the 3-day evaluation spanning from Friday to Sunday, indicating a substantial concordance with the results of the 7-day assessment.Conclusion: Our results suggest that it may be prudent to consider implementing a condensed 3-day evaluation of the circadian rhythm of pain that is tailored to individual characteristics. This approach will allow a better understanding of the diurnal rhythms of chronic pain in patients and implement more targeted and specific pain management strategies. Furthermore, it will contribute to increased patient satisfaction through early intervention.Keywords: pain, chronic pain, physical activity, circadian rhythm

Takashi Hoshikawa,1 Naomichi Okamoto,1 Tomoya Natsuyama,1 Rintaro Fujii,1 Atsuko Ikenouchi,1 Yuichi Honma,2 Masaru Harada,2 Reiji Yoshimura1 1Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, 8078555, Japan; 2 3rd Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, 8078555, JapanCorrespondence: Reiji YoshimuraDepartment of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, 8078555, Japan, Tel +81936917253, Fax +81936924894, Email yoshi621@med.uoeh-u.ac.jpPurpose: We investigated the serum levels of cytokines, including interleukin 1β (IL-β), IL-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-α), and growth factors, including brain-derived neurotrophic factor, vascular endothelial growth factor, and insulin-like growth factor 1, and their association with major depression in patients with and without type 2 diabetes mellitus. We also investigated the response to antidepressant treatment in both groups.Patients and Methods: Forty-one patients with major depression were recruited at the University Hospital of Occupational and Environmental Health. All patients were diagnosed with major depression using the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition. Type 2 diabetes mellitus was diagnosed according to the criteria of the Japan Diabetes Society. Six healthy controls with no history of psychiatric or physical diseases were also enrolled. Serum levels of several cytokines, growth factors, and high-sensitivity C-reactive protein (hs-CRP) were measured. The clinical symptoms of patients with major depression were assessed using the Montgomery-Asberg Depression Rating Scale.Results: Significant differences in cytokines, growth factors, and hs-CRP were observed between the major depression and healthy control groups. Serum TNF-α levels were significantly higher in patients with major depression and type 2 diabetes mellitus than in those without type 2 diabetes mellitus. In the major depression group, serum IL-6 and hs-CRP levels tended to be higher in patients with type 2 diabetes mellitus than in those without. Several correlations among cytokines, growth factors, and hs-CRP were observed in patients with major depression with and without type 2 diabetes mellitus. Responses to pharmacological interventions for major depression did not differ between patients with and without type 2 diabetes mellitus.Conclusion: Serum levels of TNF-α, hs-CRP, and IL-6 were different between patients with major depression with and without type 2 diabetes mellitus. Also, correlations were found between serum levels of cytokines, growth factors, and hs-CRP in patients with major depression. Inflammatory factors, which may be associated with growth factors, may be involved in the pathophysiology of major depression, particularly among patients with comorbid type 2 diabetes mellitus.Keywords: major depression, diabetes mellitus, cytokine, growth factor, high-sensitivity C-reactive protein, brain-derived neurotrophic factor

Yuki Nishi,1,2 Hayato Shigetoh,1 Ren Fujii,1 Michihiro Osumi,1,3 Shu Morioka1,3 1Department of Neurorehabilitation, Graduate School of Health Science, Kio University, Nara, Japan; 2Department of Rehabilitation Medicine, Nishiyamato Rehabilitation Hospital, Nara, Japan; 3Neurorehabilitation Research Center, Kio University, Nara, JapanCorrespondence: Yuki NishiDepartment of Neurorehabilitation, Graduate School of Health Science, Kio University, 4-2-2 Umaminaka, Koryo-cho, Kitakatsuragi-gun, Nara, 635-0832, JapanTel +81-74-554-1601Fax +81-74-554-1600Email y.nishi.pt@gmail.comBackground: Individuals with chronic low back pain (CLBP) experience changes in gait control due to pain and/or fear. Although CLBP patients’ gait has been performed in laboratory environments, changes in gait control as an adaptation to unstructured daily living environments may be more pronounced than the corresponding changes in laboratory environments. We investigated the impacts of the environment and pathology on the trunk variability and stability of gait in CLBP patients.Methods: CLBP patients (n=20) and healthy controls with no low-back pain history (n=20) were tasked with walking in a laboratory or daily-living environment while wearing an accelerometer on the low back. We calculated the stride-to-stride standard deviation and multiscale sample entropy as indices of “gait variability” and the maximum Lyapunov exponent as an index of “gait stability” in both the anterior-posterior and medial-lateral directions. The participants were assessed on the numerical rating scale for pain intensity, the Tampa Scale for Kinesiophobia, and the Roland–Morris Disability Questionnaire for quality of life (QOL).Results: In a repeated-measures ANOVA, the standard deviation was affected by environment in the anterior-posterior direction and by group and environment in the medial-lateral direction. Multiscale sample entropy showed no effect in the anterior-posterior direction and showed both effects in the medial-lateral direction. Maximum Lyapunov exponents showed both effects in the anterior-posterior direction, but none in the medial-lateral direction. These changes of trunk motor control by CLBP patients were found to be related to pain intensity, fear of movement, and/or QOL in the daily-living environment but not in the laboratory environment.Conclusion: These results revealed that CLBP patients exhibit changes in trunk variability and stability of gait depending on the environment, and they demonstrated that these changes are related to pain, fear, and QOL. We propose useful accelerometer-based assessments of qualitative gait in CLBP patients’ daily lives, as it would provide information not available in a general practice setting.Keywords: chronic low back pain, daily-living gait, variability index, stability index, inertial sensor

Takanori Kumai,1 Naoko Yui,1 Kanaka Yatabe,1 Chizuko Sasaki,2 Ryoji Fujii,3 Mitsuko Takenaga,3 Hiroto Fujiya,1 Hisateru Niki,4 Kazuo Yudoh3 1Department of Sports Medicine, St Marianna University School of Medicine, Miyamae-ku, Kawasaki 216-8511, Japan; 2Institute for Ultrastructural Morphology, St Marianna University Graduate School of Medicine, Miyamae-ku, Kawasaki 216-8512, Japan; 3Department of Frontier Medicine, Institute of Medical Science, St Marianna University School of Medicine, Miyamae-ku, Kawasaki 216-8512, Japan; 4Department of Orthopaedic Surgery, St Marianna University School of Medicine, Miyamae-ku, Kawasaki 216-8512, Japan Purpose: We previously created a self-assembled cartilage-like complex in vitro from only three cartilage components, hyaluronic acid (HA), aggrecan (AG) and type II collagen, without other materials such as cross-linking agents. Based on this self-organized AG/HA/collagen complex, we have created three novel types of biphasic cartilage and bone-like scaffolds combined with hydroxyapatite (HAP) for osteochondral tissue engineering. These scaffolds have been developed from self-assembled cartilage component molecules and HAP at the nanometer scale by manipulating the intermolecular relations. Patients and methods: The surface structure of each self-organized biphasic cartilage and bone-like scaffold was evaluated by scanning electron microscopy, whereas the viscoelasticity was also analyzed in vitro. Three types of artificial cartilage–HAP conjugates were implanted into an osteochondral defect in rat knee joints, and bone and cartilage tissues of the implanted site were examined 4 and 8 weeks after implantation. The tissues were examined histopathologically to evaluate the effects of the implantation on the articular cartilage and subchondral bone tissues. Results: Our in vitro and in vivo data reveal that the self-organized biphasic cartilage and bone-like scaffold conjugated with HAP are superior to the scaffold with no HAP in both cartilage regeneration and subchondral bone regeneration. Conclusion: Our present study indicates that the self-organized biphasic cartilage and bone-like scaffold, which is conjugated with an HAP layer, may have potential not only to repair articular cartilage defects but also to ameliorate the degeneration of subchondral bone in the diseases with osteochondral defect. Keywords: cartilage tissue engineering, subchondral bone, articular cartilage, osteoarthritis, self assembly, hydroxyapatite

FTY720, a sphingosine-derived immunomodulator, causes immunosuppression via enhancement of lymphocyte sequestration into secondary lymphoid organs, thereby preventing their antigen-activated T cell egress to sites of inflammation. FTY720 is highly effective in inhibiting autoimmunity in various animal models. However, there is little known about how FTY720 controls the migration property of memory T cells. Here, we demonstrated that FTY720 pre%nts the development of colitis induced by the adoptive transfer of lamina propria (LP) colitogenic effector memory CD[4.sup.+] T cells ([T.sub.EM] cells; CD45R[B.sup.low]WCD[44.sup.high]CD62[L.sup.-]) into severe combined immunodeficiency (SCID) mice and suppresses interferon-% interleukin-2, and tumor necrosis factor-a production by LP CD[4.sup.+] T cells. The numbers of spleen, peripheral blood, mesentefic lymph node, and LP CD[4.sup.+] T cells in FTY720-treated mice were significantly reduced compared with those in control mice. Notably, LP CD[4.sup.+] [T.sub.EM] cells as well as splenic CD[4.sup.+]CD45R[B.sup.high] T cells expressed several spingosine-l-phosphate receptors that are targets for FRY720. Furthermore, FTY720 also prevented the development of colitis induced by the adoptive transfer of splenic CD[4.sup.+]CD45R[B.sup.high] T cells into SCID mice. Collectively, the present data indicate that FTY720 treatment may offer the potential not only to prevent the onset of disease but also to treat memory T cell-mediated autoimmune diseases including inflammatory bowel diseases. therapy; migration; I cell doi:10.1152/ajpgi.00496.2005

Naturally arising [CD4.sup.+][CD25.sup.+] regulatory T ([T.sub.R]) cells have been shown to prevent and cure murine T cell-mediated colitis. However, their exact mechanism of controlling colitogenic memory [CD4.sup.+] T cells in in vivo systems excluding the initial process of naive T cell activation and differentiation has not been examined to date. Using the colitogenic effector memory ([T.sub.EM]) [CD4.sup.+] cell-mediated colitis model induced by adoptive transfer of colitogenic [CD4.sup.+][CD44.sup.high][CD62L.sup.-] lamina propria (LP) T cells obtained from colitic [CD4.sup.+] [CD45RB.sup.high] T cell-transferred mice, we have shown in the present study that [CD4.sup.+][CD25.sup.+] TR cells are able not only to suppress the development of colitis, Th1 cytokine production, and the expansion of colitogenic LP [CD4.sup.+] [T.sup.EM] cells but also to expand these cells by themselves extensively in vivo. An in vitro coculture assay revealed that [CD4.sup.+][CD25.sup.+] TR cells proliferated in the presence of IL-2-producing colitogenic LP [CD4.sup.+] [T.sub.EM] cells at the early time point (48 h after culture), followed by the acquisition of suppressive activity at the late time point (96 h after culture). Collectively, these data suggest the distinct timing of the IL-2-dependent expansion of [CD4.sup.+][CD25.sup+] [T.sub.R] cells and the their suppressive activity on colitogenic LP [CD4.sup.+] [T.sub.EM] cells. murine colitis model; interleukin-2

Elevated As concentrations in shallow groundwater in parts of the Tulare Basin, California, are a concern because of potential migration into deeper aquifers that could serve as a source of future drinking water. The objectives of this study were to evaluate adsorbed As and the potential contribution to groundwater using (i) isotopic dilution, (ii) successive extraction with an electrolyte solution resembling the pore-water chemical composition, and (iii) P[O.sub.4] exchange for As. Sediment samples collected from 2 to 4 m below land surface in the Tulare Lake bed area contained a total As concentration of 24 mg As [kg.sup.-1]. Pore water extracted under hydraulic pressure contained a total As concentration of 590 [micro]g As [L.sup.-1], which predominantly contained As as arsenate [As(V), 97%], a minor amount of arsenite [As(III), 3%], and non-detectable organic As. The isotopic dilution method [[sup.73]As(V)] estimated that the concentration of adsorbed As(V) on the sediment was 5.7 mg As [kg.sup.-1] at pH 8.5 and 6.7 mg As [kg.sup.-1] at pH 7.5, respectively. Fourteen successive 24-h extractions with the artificial pore water released up to 57 to 61% of the adsorbed AS(V) that was determined by isotopic dilution, indicating that only a portion of the adsorbed As could be released to groundwater. The phosphate-exchangeable As (0.1M P[O.sub.4], pH 8.5 or 7.5) was 63% of the isotopically exchangeable As(V). Thus, extraction of As by 0.1 M P[O.sub.4] at ambient pHs is recommended as a method to determine the potential mount of As(V) on sediments that could be released to the solution phase. The overall results indicated that adsorbed As could be a significant source of As to groundwater. However, other factors that affect As transport such as the leaching rate need to be considered.