Japanese value set for the EORTC QLU-C10D: A multi-attribute utility instrument based on the EORTC QLQ-C30 cancer-specific quality-of-life questionnaire.

PURPOSE: This study aimed to develop a Japanese value set for the EORTC QLU-C10D, a multi-attribute utility measure derived from the cancer-specific health-related quality-of-life (HRQL) questionnaire, the EORTC QLQ-C30. The QLU-C10D contains ten HRQL dimensions: physical, role, social and emotional functioning, pain, fatigue, sleep, appetite, nausea, and bowel problems. METHODS: Quota sampling of a Japanese online panel was used to achieve representativeness of the Japanese general population by sex and age (≥ 18 years). The valuation method was an online discrete choice experiment. Each participant considered 16 choice pairs, randomly assigned from 960 choice pairs. Each pair included two QLU-C10D health states and life expectancy. Data were analyzed using conditional logistic regression, parameterized to fit the quality-adjusted life-year framework. Preference weights were calculated as the ratio of each dimension-level coefficient to the coefficient for life expectancy. RESULTS: A total of 2809 eligible panel members consented, 2662/2809 (95%) completed at least one choice pair, and 2435/2662 (91%) completed all choice pairs. Within dimensions, preference weights were generally monotonic. Physical functioning, role functioning, and pain were associated with the largest utility weights. Intermediate utility weights were associated with social functioning and nausea; the remaining symptoms and emotional functioning were associated with smaller utility decrements. The value of the worst health state was - 0.221, lower than that seen in most other existing QLU-C10D country-specific value sets. CONCLUSIONS: The Japan-specific QLU-C10D value set is suitable for evaluating the cost and utility of oncology treatments for Japanese health technology assessment and decision-making.

Prostaglandin D2 metabolite is not a useful clinical indicator for assessing atopic dermatitis.

Prostaglandin D2 (PGD2 ) plays an important role in atopic dermatitis (AD), and 11,15-dioxo-9α-hydroxy-2,3,4,5-tetranorprostan-1,20-dioicacid (PGDM) is a major metabolite of PGD2 . We investigated the relationship between urinary PGDM levels and severity of paediatric AD. In total, 31 patients with AD and 21 healthy controls (HCs) without AD were recruited, and urinary PGDM levels were measured. Of the 31 patients with AD, 14 were reassessed for urinary PGDM after topical steroid therapy. There was no difference in urinary PGDM levels between patients with AD and HCs. Although there was a significant positive correlation between the SCORing Atopic Dermatitis (SCORAD) index and the serum level of thymus and activation-regulated chemokine (TARC), the urinary PGDM levels did not correlate with either SCORAD or serum TARC. Moreover, both SCORAD and serum TARC were significantly improved by topical steroid therapy; however, urinary PGDM levels were not changed. In conclusion, the level of urinary PGD2 metabolites in children with AD is substantially the same as that in HCs even if the disease is severe.

Inhibitory effects of Sanguisorba officinalis root extract on HYBID (KIAA1199)-mediated hyaluronan degradation and skin wrinkling.

OBJECTIVES: Hyaluronan (HA), an important constituent of extracellular matrix in the skin, has many biological activities such as hydration that contributes to firmness and bounciness of the skin. We have reported that reduction in HA in the papillary dermis and over-expression of HYBID (HYaluronan Binding protein Involved in hyaluronan Depolymerization, alias KIAA1199 or CEMIP), a key molecule for HA degradation in skin fibroblasts, are implicated in facial skin wrinkling in Japanese and Caucasian women. However, little or no information is available for substances which inhibit the HYBID-mediated HA degradation. METHODS: Inhibition of Sanguisorba officinalis root extract and ziyuglycoside I, one of the components of Sanguisorba officinalis root extract, to the HYBID-mediated HA degradation was assessed by size-exclusion chromatography of HA depolymerized by stable transfectants of HYBID in HEK293 cells (HYBID/HEK293 cells) or normal human skin fibroblasts (Detroit 551 cells and NHDF-Ad cells). The HYBID mRNA and protein expression was examined by quantitative real-time PCR and immunoblotting in the skin fibroblasts treated with Sanguisorba officinalis root extract, and size distribution of newly produced HA was evaluated by preparing metabolically radiolabelled HA. A double-blind, randomized and placebo-controlled study was carried out in the 21 healthy Japanese women, who were topically treated with the formulation containing Sanguisorba officinalis root extract or the placebo on each side of the face including crow's foot area. RESULTS: Sanguisorba officinalis root extract, but not ziyuglycoside I, abolished HYBID-mediated HA degradation by HYBID/HEK293 cells. Sanguisorba officinalis root extract also inhibited HYBID-mediated HA degradation in skin fibroblasts by down-regulating HYBID mRNA and protein expression. Although control untreated skin fibroblasts produced polydispersed HA, the cells treated with Sanguisorba officinalis root extract produced only high-molecular-weight HA. Treatment with Sanguisorba officinalis root extract-formulated lotion significantly improved skin elasticity, and reduced skin wrinkling scores at the outer eye corner compared with the placebo formulation. CONCLUSION: Sanguisorba officinalis root extract showed an anti-HYBID-mediated HA degradation activity and anti-wrinkle activity on human facial skin, which is accompanied by the improvement in elasticity. Our study provides the possibility of a new strategy to inhibit HYBID-mediated HA degradation for anti-wrinkle care.

OBJECTIFS: l'acide hyaluronique (AH), un composant important de la matrice extracellulaire de la peau, assure de nombreuses activités biologiques, telles que l'hydratation qui contribue à la fermeté et l'élasticité de la peau. Nous avons rapporté que la réduction d'AH dans le derme papillaire et une surexpression de la protéine de liaison de l'AH impliquée dans la dépolymérisation de l'AH (HYBID, alias KIAA1199 ou CEMIP), une molécule clé de la dégradation de l'AH des fibroblastes cutanés, sont impliquées dans la formation des rides au niveau de la peau du visage chez les femmes d'origine japonaise et caucasienne. Cependant, peu ou aucune information n'est disponible concernant les substances qui inhibent la dégradation de l'AH provoquée par la protéine HYBID. MÉTHODES: l'inhibition de l'extrait de racine de la pimprenelle (Sanguisorba officinalis) et du ziyuglycoside I, l'un des composants de l'extrait de racine de Sanguisorba officinalis, sur la dégradation de l'AH provoquée par la protéine HYBID a été évaluée à l'aide d'une chromatographie par exclusion stérique de l'AH dépolymérisé par des transfectants stables de la protéine HYBID dans les cellules HEK293 (cellules HYBID/HEK293) ou les fibroblastes cutanés humains normaux (lignée cellulaire Detroit 551 et cellules des fibroblastes du derme humain chez l'adulte). L'expression de l'ARNm et de la protéine HYBID a été examinée par PCR quantitative en temps réel et par immuno-empreinte des fibroblastes cutanés traités avec de l'extrait de racine de Sanguisorba officinalis, et l'attribution des tailles des nouveaux échantillons produits de l'AH a été évaluée par préparation d'AH radiomarqué métaboliquement. Une étude en double aveugle, randomisée et contrôlée par placebo a été menée auprès des 21 femmes japonaises en bonne santé, qui ont été traitées localement avec la formulation élaborée à partir d'extraits de racine de Sanguisorba officinalis ou un placebo, sur chaque côté du visage, notamment sur la zone à pattes d'oie. RÉSULTATS: l'extrait de racine de Sanguisorba officinalis a permis d'arrêter la dégradation de l'AH provoquée par la protéine HYBID par les cellules HYBID/HEK293, mais ce n'était pas le cas du ziyuglycoside I. L'extrait de racine de Sanguisorba officinalis a également inhibé la dégradation de l'AH provoquée par la protéine HYBID des fibroblastes cutanés en diminuant l'expression de l'ARNm et des protéines HYBID. Bien que les fibroblastes cutanés témoins non traités aient produit de l'AH polydispersé, les cellules traitées aux extraits de racine de Sanguisorba officinalis ont produit uniquement de l'AH de haut poids moléculaire. Le traitement par lotion formulée à partir d'extraits de racine de Sanguisorba officinalis a amélioré de manière significative l'élasticité de la peau et réduit les scores de vieillissement du coin extérieur de la peau autour des yeux, par rapport à la formulation placebo. CONCLUSION: l'extrait de racine de Sanguisorba officinalis a démontré une action anti-dégradation de l'AH provoquée par la protéine HYBID et une activité antirides au niveau de la peau du visage humain, s'accompagnant d'une amélioration de l'élasticité. Notre étude fournit la possibilité d'une nouvelle stratégie pour inhiber la dégradation de l'AH provoquée par la protéine HYBID dans le cadre des soins antirides.

Cytohistology of morule in cribriform-morular variant of papillary thyroid carcinoma.

INTRODUCTION: Cribriform-morular variant (CMV) is a rare variant of papillary thyroid carcinoma. It frequently occurs in association with familial adenomatous polyposis (FAP), although some cases are sporadic. Herein, we report a case of CMV and analyse morule cytohistology. CASE REPORT: The patient was a 47-year-old woman with no familial history of FAP. A 3.0-cm unifocal mass was identified in the left thyroidal lobe. Fine-needle aspiration cytology revealed papillary clusters of atypical cells with nuclear grooves, which was suspected to be conventional papillary thyroid carcinoma. Histologically, the tumour comprised a papillary and cribriform growth of atypical cells with cytoplasmic accumulation and nuclear translocation of b-catenin. In addition, frequent morule formation was identified. DISCUSSION: In this case, we performed morule analysis through correlative light and electron microscopy (CLEM), and revealed its ultrastructure. Although CMV is a rare form of thyroid carcinoma, it should be considered along with its distinct clinicopathological characteristics.

Randomized phase III and extension studies: efficacy and impacts on quality of life of naldemedine in subjects with opioid-induced constipation and cancer.

BACKGROUND: The efficacy and safety of naldemedine (a peripherally acting µ-opioid receptor antagonist) for opioid-induced constipation (OIC) in subjects with cancer was demonstrated in the primary report of a phase III, double-blind study (COMPOSE-4) and its open-label extension (COMPOSE-5). The primary end point, the proportion of spontaneous bowel movement (SBM) responders, was met. Here, we report results from secondary end points, including quality of life (QOL) assessments from these studies. PATIENTS AND METHODS: In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned 1:1 to receive once-daily oral naldemedine 0.2 mg (n = 97) or placebo (n = 96) for 2 weeks, and those who continued on to COMPOSE-5 received naldemedine for 12 weeks (n = 131). Secondary assessments in COMPOSE-4 included the proportion of complete SBM (CSBM) responders, SBM or CSBM responders by week, and subjects with ≥1 SBM or CSBM within 24 h postinitial dose. Changes from baseline in the frequency of SBMs or CSBMs per week were assessed at weeks 1 and 2. Time to the first SBM or CSBM postinitial dose was also evaluated. In both studies, QOL impact was evaluated by Patient Assessment of Constipation-Symptoms (PAC-SYM) and PAC-QOL questionnaires. RESULTS: Naldemedine improved bowel function for all secondary efficacy assessments versus placebo (all P ≤ 0.0002). The timely onset of naldemedine activity versus placebo was evidenced by median time to the first SBM (4.7 h versus 26.6 h) and CSBM (24.0 h versus 218.5 h) postinitial dose (all P < 0.0001). In COMPOSE-4, significant differences between groups were observed with the PAC-SYM stool domain (P = 0.045) and PAC-QOL dissatisfaction domain (P = 0.015). In COMPOSE-5, significant improvements from baseline were observed for overall and individual domain scores of PAC-SYM and PAC-QOL. CONCLUSIONS: Naldemedine provided effective and timely symptomatic relief from OIC and improved the QOL of subjects with OIC and cancer. TRIAL REGISTRATION ID: www.ClinicalTrials.jp: JAPIC-CTI-132340 (COMPOSE-4) and JAPIC-CTI-132342 (COMPOSE-5).

Towards a unified model of neutrino-nucleus reactions for neutrino oscillation experiments.

A precise description of neutrino-nucleus reactions will play a key role in addressing fundamental questions such as the leptonic CP violation and the neutrino mass hierarchy through analyzing data from next-generation neutrino oscillation experiments. The neutrino energy relevant to the neutrino-nucleus reactions spans a broad range and, accordingly, the dominant reaction mechanism varies across the energy region from quasi-elastic scattering through nucleon resonance excitations to deep inelastic scattering. This corresponds to transitions of the effective degree of freedom for theoretical description from nucleons through meson-baryon to quarks. The main purpose of this review is to report our recent efforts towards a unified description of the neutrino-nucleus reactions over the wide energy range; recent overall progress in the field is also sketched. Starting with an overview of the current status of neutrino-nucleus scattering experiments, we formulate the cross section to be commonly used for the reactions over all the energy regions. A description of the neutrino-nucleon reactions follows and, in particular, a dynamical coupled-channels model for meson productions in and beyond the [Formula: see text](1232) region is discussed in detail. We then discuss the neutrino-nucleus reactions, putting emphasis on our theoretical approaches. We start the discussion with electroweak processes in few-nucleon systems studied with the correlated Gaussian method. Then we describe quasi-elastic scattering with nuclear spectral functions, and meson productions with a [Formula: see text]-hole model. Nuclear modifications of the parton distribution functions determined through a global analysis are also discussed. Finally, we discuss issues to be addressed for future developments.

Three-dimensional evaluation of subclinical extension of extramammary Paget disease: visualization of the histological border and its comparison to the clinical border.

BACKGROUND: In extramammary Paget disease (EMPD), Paget cells are sometimes detected outside the clinical border (subclinical extension). However, the spreading pattern of Paget cells in subclinical extension remains unclear. In addition, the macroscopic appearances of lesions accompanied by subclinical extension are totally unknown. OBJECTIVES: To characterize the spreading pattern of Paget cells as well as the macroscopic appearance of lesions of EMPD with subclinical extension. METHODS: Nineteen patients with primary anogenital EMPD underwent mapping biopsies and excisional surgeries; biopsy samples were then taken at the periphery of well-demarcated lesions. Samples were transparentized and subjected to whole-mount immunostaining with anticytokeratin 7 antibody to label Paget cells. The histological border was evaluated in three dimensions by two-photon microscopy. The shape and location of the histological border were compared with those of the clinical border. RESULTS: In 21 samples taken at the lesion where subclinical extension was not shown by mapping biopsy, the shape and location of the histological border were almost identical to those of the clinical border. However, two samples exhibited small foci of Paget cells outside the clinical border, showing subclinically extended satellite lesions. In the two samples taken at the lesions where subclinical extension was shown by mapping biopsy, a continuous arrangement of Paget cells extending beyond the clinical border was identified. Subclinically extended Paget cells were detected solely outside hypopigmented patches with erythema. CONCLUSIONS: In EMPD, at least two patterns of subclinical extension exist: continuous and satellite lesions. Subclinical extension might exist preferentially outside hypopigmented patches with erythema.

Economic evaluation of a preemptive treatment strategy for invasive fungal infection in neutropenic patients with hematological diseases.

We compared the expected medical costs of empirical and preemptive treatment strategies for invasive fungal infection in neutropenic patients with hematological diseases. Based on the results of two clinical trials with different backgrounds reported by Oshima et al. [J Antimicrob Chemother 60(2):350-355; Oshima study] and Cordonnier et al. [Clin Infect Dis 48(8):1042-1051; PREVERT study], we developed a decision tree model that represented the outcomes of empirical and preemptive treatment strategies, and estimated the expected medical costs of medications and examinations in the two strategies. We assumed that micafungin was started in the empirical group at 5 days after fever had developed, while voriconazole was started in the preemptive group only when certain criteria, such as positive test results of imaging studies and/or serum markers, were fulfilled. When we used an incidence of positive test results of 6.7 % based on the Oshima study, the expected medical costs of the empirical and preemptive groups were 288,198 and 150,280 yen, respectively. Even in the case of the PREVERT study, in which the incidence of positive test results was 32.9 %, the expected medical costs in the empirical and preemptive groups were 291,871 and 284,944 yen, respectively. A sensitivity analysis indicated that the expected medical costs in the preemptive group would exceed those in the empirical group when the incidence of positive test results in the former was over 34.4 %. These results suggest that a preemptive treatment strategy can be expected to reduce medical costs compared with empirical therapy in most clinical settings.

Periostin of human periodontal ligament fibroblasts promotes migration of human mesenchymal stem cell through the αvß3 integrin/FAK/PI3K/Akt pathway.

BACKGROUND AND OBJECTIVE: The periodontal ligament (PDL) is characterized by rapid turnover, high remodeling capacity and high inherent regenerative potential compared with other connective tissues. Periostin, which is highly expressed in the fibroblasts in the PDL, has been widely discussed in relation to collagen fibrillogenesis in the PDL. Recently, several reports have indicated periostin in cell migration. The aim of this study was to examine whether human PDL fibroblasts (hPDLFs) with high levels of periostin expression promote the migration of human bone marrow mesenchymal stem cells (hMSCs). MATERIAL AND METHODS: The migration of hMSCs was examined by transwell chamber migration assay under different conditions: medium alone, hPDLFs, human dermal fibroblasts, recombinant periostin, integrin αvß3 blocking antibody (anti-CD51/61 antibody) and inhibitors of FAK (PF431396) and PI3K (LY294002). Phosphorylation of FAK and Akt in hMSCs under stimulation of periostin was examined by western blotting. RESULTS: The migration assay revealed that the number of migrated hMSCs by hPDLFs was significantly larger than those by dermal fibroblasts, periostin small interfering RNA hPDLFs and medium alone. Furthermore, recombinant periostin also strongly induced hMSC migration. The addition of anti-CD51/61 antibody, PF431396 and LY294002 caused a significant reduction in the number of migrated hMSCs respectively. The anti-CD51/61 antibody inhibited both FAK and Akt phosphorylations under periostin stimulation. PF431396 inhibited both FAK and Akt phosphorylations. LY294002 inhibited only Akt phosphorylation, and FAK phosphorylation was not influenced under periostin stimulation. CONCLUSION: Periostin expression in hPDLFs promotes the migration of hMSCs through the αvß3 integrin/FAK/PI3K/Akt pathway in vitro.

Cyclic nucleotide phosphodiesterases: important signaling modulators and therapeutic targets.

By catalyzing hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), cyclic nucleotide phosphodiesterases are critical regulators of their intracellular concentrations and their biological effects. As these intracellular second messengers control many cellular homeostatic processes, dysregulation of their signals and signaling pathways initiate or modulate pathophysiological pathways related to various disease states, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication, chronic obstructive pulmonary disease, and psoriasis. Alterations in expression of PDEs and PDE-gene mutations (especially mutations in PDE6, PDE8B, PDE11A, and PDE4) have been implicated in various diseases and cancer pathologies. PDEs also play important role in formation and function of multimolecular signaling/regulatory complexes, called signalosomes. At specific intracellular locations, individual PDEs, together with pathway-specific signaling molecules, regulators, and effectors, are incorporated into specific signalosomes, where they facilitate and regulate compartmentalization of cyclic nucleotide signaling pathways and specific cellular functions. Currently, only a limited number of PDE inhibitors (PDE3, PDE4, PDE5 inhibitors) are used in clinical practice. Future paths to novel drug discovery include the crystal structure-based design approach, which has resulted in generation of more effective family-selective inhibitors, as well as burgeoning development of strategies to alter compartmentalized cyclic nucleotide signaling pathways by selectively targeting individual PDEs and their signalosome partners.

Neuropeptide Y loses its orexigenic effect in rats with lesions of the hypothalamic paraventricular nucleus.

BACKGROUND: Both neuropeptide Y (NPY) and ghrelin can enhance the feeding behavior. The purpose of this study was to determine whether NPY and ghrelin are involved in hyperphagia and obesity induced by lesions of the hypothalamic paraventricular nucleus (PVN). METHODS: Sham-operated control rats and rats subjected to bilateral electrolytic lesions of the PVN were administered NPY (5 µg/rat) by intracerebroventricular infusion or ghrelin (20 µg/kg) by intraperitoneal (i.p.) injection. Control rats were administered the appropriate vehicle by the same route as the drug. We measured the cumulative food intake (FI) for 2 h after infusion of NPY and for 4 h after ghrelin injection. RESULTS: NPY significantly increased the cumulative FI in sham-operated rats. In PVN-lesioned rats, however, the cumulative FI at each time point (15 min, 30 min, 1 h, and 2 h) after NPY infusion was not significantly different from vehicle infusion, showing that NPY lost its orexigenic effect in PVN-lesioned rats. Following ghrelin injection, the cumulative FI was greater in PVN-lesioned rats than sham-operated rats, indicating that PVN lesions enhanced the orexigenic effects of ghrelin. CONCLUSION: These results suggest that the hyperphagia and obesity induced by PVN lesions may be related to an increased orexigenic action of ghrelin, but not NPY.

Protein-Ligand Interaction Analyses with Nuclear Magnetic Resonance Spectroscopy Enhanced by Dissolution Triplet Dynamic Nuclear Polarization.

Solution-state nuclear magnetic resonance spectroscopy (NMR) is a powerful method for the analysis of intermolecular interactions within a biomolecular system. However, low sensitivity is one of the major obstacles of NMR. We improved the sensitivity of solution-state 13C NMR for the observation of intermolecular interactions between protein and ligand using hyperpolarized solution samples at room temperature. Eutectic crystals composed of 13C-salicylic acid and benzoic acid doped with pentacene were hyperpolarized by dynamic nuclear polarization using photoexcited triplet electrons, and a 13C nuclear polarization of 0.72 ± 0.07% was achieved after dissolution. The binding of human serum albumin and 13C-salicylate was observed with several hundred times sensitivity enhancement under mild conditions. The established 13C NMR was applied for pharmaceutical NMR experiments by observation of the partial return of the 13C chemical shift of salicylate by competitive binding with other non-isotope-labeled drugs.

Evaluation of a moisturising micro-gel spray for prevention of cell dryness in oral mucosal cells: an in vitro study and evaluation in a clinical setting.

A moisturising micro-gel spray for prevention of dryness was compared with commercial products and artificial saliva in vitro and in a clinical setting in patients with cancer. Survival of cultured human gingival epithelial cells was evaluated after treatment with each product for 15 min. A dry test was performed for products giving a 50% survival rate, in which cell survival was measured after drying of cells treated with each product. The survival rates of cells treated with the micro-gel spray and artificial saliva were significantly higher than those of control cells. The micro-gel spray was then evaluated for 1 week in patients with symptoms of dry mouth caused by cancer treatment. There was significant improvement of these symptoms at night and on awakening and of subjective symptoms of decreased salivary volume (P < 0.05). Mean visual analogue scale scores also significantly decreased (P < 0.01). These data suggest that evaluation of moisturising products for dryness prevention can be performed in cultured cells, since products that performed well in vitro also showed good efficacy for symptoms of dry mouth. The micro-gel spray was particularly effective for relieving symptoms of dry mouth in patients with cancer.

Oral malodorous compound triggers mitochondrial-dependent apoptosis and causes genomic DNA damage in human gingival epithelial cells.

BACKGROUND AND OBJECTIVE: Volatile sulfur compounds are the main compounds causing halitosis. One of these compounds, hydrogen sulfide (H(2)S), which is responsible for physiological halitosis, is reported also to have periodontal pathogenic activities. Hydrogen sulfide has been shown to activate the apoptotic process in different tissues. Apoptosis plays an important role in the development of periodontitis. The aim of this study was to determine whether H(2)S causes apoptosis in human gingival epithelial cells and to examine the cellular signaling pathway initiating the process. MATERIAL AND METHODS: Human gingival epithelial cells were incubated with 50 ng/mL H(2)S in air contining 5% CO(2) for 24, 48 or 72 h. To detect apoptosis, the cells were stained with annexin V and 7-amino actinomycin D, and analyzed using flow cytometry. Reactive oxygen species, mitochondrial membrane depolarization and release of cytochrome C into the cytosol were assessed using flow cytometry and enzyme-linked immunosorbent assay. Activity levels for the key apoptotic enzymes caspase-9, -8 and -3 were also determined. Genomic DNA damage was detected using single-cell gel electrophoresis. RESULTS: Apoptosis was significantly increased to 24.5 +/- 5.7 at 24 h and 41.5 +/- 8.9% at 48 h (p < 0.01). Reactive oxygen species were enhanced and mitochondrial membrane depolarization was collapsed. Cytochrome C release was dramatically increased (0.12 +/- 0.02 vs. 0.02 +/- 0.01 at 24 h and 0.21 +/- 0.02 vs. 0.02 +/- 0.01 ng/mL at 48 h; p < 0.05). Caspase-9 and -3 were strongly activated, while caspase-8 activity remained low. The percentage of DNA strand breaks increased, especially at 48 h. CONCLUSION: Hydrogen sulfide induces apoptosis in human gingival epithelial cells by activating the mitochondrial pathway.

Abnormal expression of the genes involved in cytokine networks and mitochondrial function in systemic juvenile idiopathic arthritis identified by DNA microarray analysis.

OBJECTIVES: Systemic juvenile idiopathic arthritis (sJIA) is a rheumatic disease in childhood characterised by systemic symptoms and a relatively poor prognosis. Peripheral leukocytes are thought to play a pathological role in sJIA although the exact cause of the disease is still obscure. In this study, we aimed to clarify cellular functional abnormalities in sJIA. METHODS: We analysed the gene expression profile in peripheral leukocytes from 51 patients with sJIA, 6 patients with polyarticular type JIA (polyJIA) and 8 healthy children utilising DNA microarrays. Gene ontology analysis and network analysis were performed on the genes differentially expressed in sJIA to clarify the cellular functional abnormalities. RESULT: A total of 3491 genes were differentially expressed in patients with sJIA compared to healthy individuals. They were functionally categorised mainly into a defence response group and a metabolism group according to gene ontology, suggesting the possible abnormalities in these functions. In the defence response group, molecules predominantly constituting interferon (IFN)gamma and tumour necrosis factor (TNF) network cascades were upregulated. In the metabolism group, oxidative phosphorylation-related genes were downregulated, suggesting a mitochondrial disorder. Expression of mitochondrial DNA-encoded genes including cytochrome c oxidase subunit 1(MT-CO1) and MT-CO2 were suppressed in patients with sJIA but not in patients with polyJIA or healthy children. However, nuclear DNA-encoded cytochrome c oxidases were intact. CONCLUSION: Our findings suggest that sJIA is not only an immunological disease but also a metabolic disease involving mitochondria disorder.

A novel fibronectin binding site required for fibronectin fibril growth during matrix assembly.

Fibronectin (FN) assembly into a fibrillar extracellular matrix is a stepwise process requiring participation from multiple FN domains. Fibril formation is regulated in part by segments within the first seven type III repeats (III1-7). To define the specific function(s) of this region, recombinant FNs (recFNs) containing an overlapping set of deletions were tested for the ability to assemble into fibrils. Surprisingly, recFN lacking type III repeat III1 (FNDeltaIII1), which contains a cryptic FN binding site and has been suggested to be essential for fibril assembly, formed a matrix identical in all respects to a native FN matrix. Similarly, displacement of the cell binding domain in repeats III9-10 to a position close to the NH2-terminal assembly domain, as well as a large deletion spanning repeats III4-7, had no effect on assembly. In contrast, two deletions that included repeat III2, DeltaIII1-2 and DeltaIII2-5, caused significant reductions in fibril elongation, although binding of FN to the cell surface and initiation of assembly still proceeded. Using individual repeats in binding assays, we show that III2 but not III1 contains an FN binding site. Thus, these results pinpoint repeat III2 as an important module for FN-FN interactions during fibril growth.