The parathyroid hormone-vitamin D 3 endocrine system, as well as dietary phosphorus, plays an important role in regulating renal and gastrointestinal absorption of phosphate. Recently, emerging evidence suggests that other systemic and/or paracrine/autocrine factors are present in bones for maintaining phosphate homeostasis, such as fibroblast growth factor-23 (FGF-23), 1 frizzled-related protein-4 (FRP-4), and matrix extracellular phosphoglycoprotein (MEPE) (1-11). These three factors were highly expressed in tumors isolated from oncogenic osteomalacia patients and reduced phosphate transport in kidney. Among these factors, FGF-23 strongly suppressed 1␣,25(OH) 2 D 3 production and elicited hypophosphatemia. Administration of the recombinant FGF-23 protein reduced serum phosphorus without affecting serum calcium, as well as increasing renal phosphorus excretion in mice (12). Mice bearing FGF-23-expressing Chinese hamster ovary cells showed suppressed 25-hydroxyvitamin D 3 1␣-hydroxylase mRNA expression in the kidney (3). FGF-23 mRNA is expressed in a variety of tissues such as thymus, brain, bone, thyroid/parathyroid gland, and heart (2, 3, 13). Recent studies (13, 14) indicated FGF-23 mRNA as well as FGF-23 protein was elevated in bones from patients with McCune-Albright syndrome and also in bones from HYP mouse, mouse homologue to X-linked hypophosphatemic (XLH) rickets. However, the level of serum FGF-23 in hypophosphatemic patients with XLH is still controversial (15-17). Hyperphosphatemic patients with chronic kidney disease showed significant elevation in circulating FGF-23, which correlated with serum phosphorus and creatinine (16, 18 -20), suggesting (a) serum phosphorus was a possible regulator of FGF-23 production or (b) circulating FGF-23 accumulated in chronic renal failure.The purpose of this study was to evaluate the effects of dietary phosphorus and 1␣,25(OH) 2 D 3 on FGF-23 production. Administration of FGF-23 protein or overexpression of Fgf23 gene in rodent suppressed 1␣,25(OH) 2 D 3 production by reducing 25-hydroxyvitamin D 3 1␣-hydroxylase in the proximal tubules (12, 21-23). On the contrary, Fgf23-null mice reported increased circulating 1␣,25(OH) 2 D 3 despite hyperphosphatemia, hypercalcemia, and low PTH levels (24). Administration of 1␣,25(OH) 2 D 3 increased serum FGF-23 in normal mice (25). These observations suggested mutual regulation between FGF-23 and 1␣,25(OH) 2 D 3 ; however, 1␣,25(OH) 2 D 3 administration also increases intestinal phosphate uptake and suppresses PTH. Thus, we used thyroparathyroidectomized rats as well as 5/6 nephrectomized rats fed a diet with various kinds of phosphorus content to examine the direct effect of 1␣,25(OH) 2 D 3 administration on serum FGF-23.* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.§ To whom correspondence should be addressed. Tel.: 81-550-87-6735; Fax: 81-550-8...

SUMMAR Y Epidemiological studies have shown that playing a computer game at night delays bedtime and shortens sleeping hours, but the effects on sleep architecture and quality have remained unclear. In the present study, the effects of playing a computer game and using a bright display on nocturnal sleep were examined in a laboratory. Seven male adults (24.7 ± 5.6 years old) played exciting computer games with a bright display (game-BD) and a dark display (game-DD) and performed simple tasks with low mental load as a control condition in front of a BD (control-BD) and DD (control-DD) between 23:00 and 1:45 hours in randomized order and then went to bed at 2:00 hours and slept until 8:00 hours. Rectal temperature, electroencephalogram (EEG), heart rate and subjective sleepiness were recorded before sleep and a polysomnogram was recorded during sleep. Heart rate was significantly higher after playing games than after the control conditions, and it was also significantly higher after using the BD than after using the DD. Subjective sleepiness and relative theta power of EEG were significantly lower after playing games than after the control conditions. Sleep latency was significantly longer after playing games than after the control conditions. REM sleep was significantly shorter after the playing games than after the control conditions. No significant effects of either computer games or BD were found on slow-wave sleep. These results suggest that playing an exciting computer game affects sleep latency and REM sleep but that a bright display does not affect sleep variables.k e y w o r d s circadian rhythm, electroencephalogram, heart rate, mental task, rectal temperature, video display terminal

The basis of extracorporeal photopheresis is the reinfusion of leukocytes previously exposed to 8-methoxypsoralen (8-MOP) and UVA radiation. It has been approved for the palliative treatment of cutaneous T cell lymphoma and has reported benefits in autoimmune diseases, transplant rejection, and graft-vs-host disease. However, the underlying mechanism of photopheresis remains unresolved. Because UVB radiation can cause immune tolerance via induction of regulatory T cells, we studied whether photopheresis exerts a similar effect extracorporeally. Therefore, we established a model of photopheresis using a murine model of contact hypersensitivity. Splenocytes and lymph node cells of mice that were sensitized with dinitrofluorobenzene were exposed to 8-MOP plus UVA in vitro. Intravenous injection of these cells into naive mice caused inhibition of a hapten immune response, which was lost upon depletion of CD11c+ cells but not T cells. Mice that received untreated cells or cells exposed to UVA or 8-MOP alone were not affected. Inhibition was cell-mediated and Ag-specific as demonstrated by transfer of tolerance from the primary recipients into naive animals, which could, however, properly respond to the unrelated hapten oxazolone. Transfer activity was lost when cells were depleted of CD4+ or CD25+ subpopulations. These data suggest that photopheresis exerts its immunomodulatory effects via the induction of Ag-specific regulatory T cells.

Epicutaneous application of haptens to UV-exposed skin induces hapten-specific tolerance. This is mediated via regulatory T cells (Tr), as i.v. injection of T cells from UV-tolerized mice into naive animals renders the recipients unresponsive to the respective hapten. However, when UV-induced Tr are injected i.v. into sensitized mice, contact hypersensitivity (CHS) is not suppressed, suggesting that Tr inhibit the induction, but not the elicitation, of CHS and are inferior to T effector cells. As sensitization takes place in the lymph nodes, but elicitation occurs in the area of challenge, we postulated that Tr injected i.v. locate to the lymph nodes and not to the periphery and therefore only suppress the induction, not the elicitation, of CHS. Indeed, i.v. injection of Tr into sensitized mice did not inhibit CHS, although injection of Tr into the ears of sensitized mice suppressed the challenge. Inhibition was hapten specific, as injection of dinitrofluorobenzene (DNFB)-specific Tr into the ears of oxazolone (OXA)-sensitized mice did not affect challenge with OXA. However, when ears of OXA-sensitized mice were injected with DNFB-specific Tr and painted with DNFB before OXA challenge, CHS was suppressed. Inhibition correlated with the local expression of IL-10. Depletion studies and FACS analysis revealed that Tr express the lymph node-homing receptor L-selectin, but not the ligands for the skin-homing receptors E- and P-selectin, suggesting that UV-induced Tr, although able to inhibit T effector cells, do not suppress the elicitation of CHS upon i.v. injection, because they obviously do not migrate into the skin.

To investigate intraarticular lesions producing persistent postoperative pain, we arthroscopically examined 31 ankles in 31 patients (15 women and 16 men) with lateral ligament injury. The patients ranged in age from 15 to 33 years, with a mean of 20 years. Nine patients were freshly injured, and 22 patients had chronic injuries. All of the patients underwent arthroscopic examination immediately before the ligament operation. Chondral lesions were found in 89% of the freshly injured ankles and 95% of the ankles with chronic injuries. Most of these lesions were in the medial half of the ankle joint, especially in the anteromedial edge of the tibial plafond. After followup for 1 year postoperatively, persistent pain was noted in 4 patients who had chondral lesions of greater than one-half the thickness of the articular cartilage. Pain and tenderness were localized at the anteromedial joint line, corresponding to the location of the chondral lesions. Chondral lesions of greater than one-half the thickness of the articular cartilage were found in 8 ankles in the chronic injury group, but there were none in the fresh injury group. Thus, in lateral ligament injuries of the ankle, the longer the time elapsed from the initial injury, the more severe the associated chondral lesions became. These chondral lesions appear to cause persistent pain.

The immunostimulatory cytokine IL-12 is able to antagonize immunosuppression induced by solar/ultraviolet (UV) radiation via yet unknown mechanisms. IL-12 was recently found to induce deoxyribonucleic acid (DNA) repair. UV-induced DNA damage is an important molecular trigger for UV-mediated immunosuppression. Thus, we initiated studies into immune restoration by IL-12 to discern whether its effects are linked to DNA repair. IL-12 prevented both UV-induced suppression of the induction of contact hypersensitivity and the depletion of Langerhans cells, the primary APC of the skin, in wild-type but not in DNA repair-deficient mice. IL-12 did not prevent the development of UV-induced regulatory T cells in DNA repair-deficient mice. In contrast, IL-12 was able to break established UV-induced tolerance and inhibited the activity of regulatory T cells independent of DNA repair. These data identify a new mechanism by which IL-12 can restore immune responses and also demonstrate a link between DNA repair and the prevention of UV-induced immunosuppression by IL-12.

We evaluated 41 knees 24 to 48 months after anterior cruciate ligament reconstruction was performed using multiple autogenous semitendinosus tendons. The ipsilateral free semitendinosus tendon was tripled or quadrupled to make a graft 7 to 10 mm in diameter and more than 60 mm long. When the diameter of the graft was less than 7 mm, an ipsilateral doubled gracilis tendon was also used (in seven cases). Twenty-three patients (56%) returned to their preinjury activity levels. According to the patients' subjective assessment, 34 (83%) graded themselves as normal or nearly normal. No patient reported giving way of the knee or limitation of knee motion. The average anterior laxity difference between the involved knee and contralateral uninjured knee was 1.5 mm at 200 N. Twenty-nine patients (71%) demonstrated an anterior laxity difference of 3 mm or less when the involved knee was compared with the contralateral uninjured knee. Quadriceps muscle strength was 90% compared with the contralateral healthy limb, and hamstring muscle strength was equivalent to the contralateral limb. In our study, tripled or quadrupled semitendinosus free tendons were excellent anterior cruciate ligament grafts for restoring knee stability, recovering thigh muscle power, and preserving knee motion.

Background: Osteocytes, the most abundant cells in adult bone, express PPR. Results: Mice with constitutive PPR deletion in osteocytes demonstrate blunted anabolic and catabolic bone responses and the inability to recruit osteoblasts and osteoclasts upon PTH administration. Conclusion: PPR in osteocytes is needed for a full skeletal response to PTH administration. Significance: PPR signaling in osteocytes is necessary for PTH-driven anabolic effects during osteoporosis therapy.