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A number of devastating disasters have occurred in Japan since 2017, including heavy rains, wide ranging floods, a large typhoon, earthquakes, and landslides. Such disasters are beyond our imagination and our scientific assumptions. All of these come from global warming, which comes from human economic activities with CO2 emissions. There are interdependencies around the globe, between sea and land, ocean and air currents, and so on. In the twentieth century, we pushed technological innovation to conquer nature, but it only partly succeeded—and was actually almost in vain. We must recognize that human beings are a part of nature and must rethink our attitude towards nature. As citizens of the world, human beings must have a keen sensibility to find new virtue, “living together on the same globe.” It is the new ideal beyond boundaries and beyond differences between the rich and the poor, looking for the possibility of democracy.

According to Eco-ethica, our circumstances have a triple structure: 1)Nature, 2)Technological Conjuncture, and 3)Culture. In the twenty-first century we face the crisis of a global warming. It is because of human activities that create technological conjuncture: a diminishing time-process that aims at economic effects. Climate change is a cosmopolitan problem because it easily transcends boundaries. Practices must be subject to not only political regulation to promote public awareness, but also to individual consciousness-raising of personal responsibilities. Democracy must be rethought in order to promote joining the public and individuals to become World Citizens. In this information-society, Big Data must be available for everyone equally and freely. There is a social difference between rich and poor. Tocqueville suggested that rich citizens in a democracy are necessarily supported by the poor.

This study aimed to evaluate changes in the attitudes of Japan’s post-war youth towards gender equality and sexuality, and to examine whether these attitudes bore a relationship to school education...

In the case of Japan, we accepted the Chinese philosophy of morality when we received the Chinese character Yi: it means responsibility to Heaven (vertical) and, at the same time, responsibility to community (horizontal). An act having this structure might be our responsibility as human beings: yi means “justice”, keeping balance between Heaven and Earth. The Japanese people had such a balance until the Edo era. In 1868, when the Meiji Restoration occurred, the Japanese government tried to accept Western ideas. Cyoumin Nakae introduced the Western philosophy of law and the constitutional system. He translated Rousseau’s The Social Contract into Japanese and gave a series of lectures on the social contract. The fundament of his thought is concentrated in the “rights of Liberty”. He emphasized transcendental liberty beyond personal, phenomenal liberty and found the same structure in Mencius. His idea of ft suggests the way of justice. Unfortunately, this idea was crushed with the death of his talented disciple in prison. After the book of Bushido, ft was only translated as “duty” for the community (horizontal), and we lost the vertical perspective: transcendental liberty.

The characteristic feature of modernized systematic environment is realized by one little, thin box named a smart phone or iPhone. By touching the surface, it can open various kinds of technologically magnified internet environment, and bring us into so-called world-wide information society. Our surrounding world is changed to a “technologically developed imaginary world”, virtual reality, where we can live and enjoy. Through this instrument we will be an “anonymous person” for helping people but we may hurt another person’s dignity. It is possible to hide one’s own “self’ behind the technological tool. People always look at the surface of smart phone and concentrate upon outer world without consciousness. It is the crisis of “self’, because of a lack of thinking. Unfortunately, dehumanization will occur. But for solving transnational problems, for example global warming, refugees, etc., we must change our ethical attitude from nosism without any responsibility to an awakening consciousness or living together as “world citizens”.

A novel, practical protocol for the aerobic direct C–H acetoxylation of arenes, employing a recyclable heterogeneous rhodium catalyst, is reported herein. The trifluoroacetoxylation of 2-amido-substituted anthracenes proceeded at the 9-position with exclusive regioselectivity. The oxidation of variously substituted anthracenes and other polycyclic aromatics with molecular oxygen as a terminal oxidant proceeded under mild conditions, providing products in good to excellent yields.

Objective Substantial evidence suggests that human synovial mast cells (MCs) are involved in the pathogenesis of rheumatoid arthritis (RA). A plausible pathway for the activation of synovial MCs is through IgG receptors, given the prevalence of circulating IgG isotype autoantibodies and synovial immune complexes in patients with RA. However, IgG receptor expression on human synovial MCs remains uncharacterized. The aim of this study was to identify which IgG receptor(s) on synovial MCs are responsible for MC activation in immune complexes. Methods Synovial tissue specimens were obtained from patients with RA or patients with osteoarthritis (OA) who were undergoing joint replacement surgery, and synovial MCs were enzymatically dispersed. Cultured synovium-derived MCs were generated by culturing synovial cells with stem cell factor, and receptor expression was analyzed using fluorescence-activated cell sorting. Mediators released from MCs were measured using enzyme immunoassays or enzyme-linked immunosorbent assays. Results Primary synovial MCs and cultured synovium-derived MCs obtained from both patients with RA and patients with OA expressed Fce receptor I (FceRI), FcγRI, and FcγRII but not FcγRIII. Cultured synovium-derived MCs induced degranulation and the production of prostaglandin D2 and tumor necrosis factor α (TNFα) through FcγRI. The aggregation of FcγRII caused histamine release from cultured MCs but not from primary MCs. Histamine release induced by aggregated IgG was significantly inhibited by neutralizing anti-FcγRI monoclonal antibody and anti-FcγRII monoclonal antibody. Conclusion With regard to the FcR expression profile, synovial MCs from patients with RA and patients with OA were similar. FcγRI was responsible for producing abundant TNFα from synovial MCs in response to aggregated IgG. Immune complexes may activate synovial MCs through FcγRI and FcγRII.

This paper aims to determine via responses to three questionnaire surveys how sexuality education programs are conducted at junior high schools in Japan. Study 1 examined the practice of sexuality education in schools, Study 2 investigated junior high school students' (age 12–13 and 14–15 years) knowledge of sexuality, and Study 3 examined parents'/guardians' views on sexuality education. For Study 1, 703 principals of 5158 junior high schools returned an original questionnaire (13.6% recovery rate), and for Studies 2 and 3, 9492 students and 5374 parents returned questionnaires (86.2% and 60.3% recovery rate, respectively). In Study 1, an average of 9.19 hours of instruction was allocated to sexuality education over three grades. In Study 2, the average correct response rate was as low as 34.5% for boys and 39.4% for girls, with many answering ‘I don't know.’ Approximately one-half of the boys indicated there was nothing in particular they wanted to know about sex and no-one they wanted to consult. In St...

Background: Respiratory syncytial virus (RSV) infection in infants with Th2 predisposition is thought to increase the risk of allergic sensitization, recurrent wheezing, and bronchial asthma during childhood. We attempted to clarify the molecular mechanisms by which Th1/Th2 predisposition in the host alters RSV infection and facilitates airway inflammation. Methods: A549 human airway epithelial cells were inoculated with live or UV-treated RSV after pretreatment with either a combination of tumor necrosis factor (TNF)-α and interferon-γ (Th1-primed) or a combination of TNF-α and interleukin-4 (Th2-primed) for 48 h. The gene and protein expression profiles of RSV-infected A549 cells were examined. Results: GeneChip analysis indicated that, at 96 h after inoculation with RSV, the expression of 62 genes was specifically enhanced (more than 2-fold by normalized data) in Th2-primed cells compared to that in unprimed or Th1-primed cells. An increase in mRNA and protein levels of monocyte chemoattractant protein (MCP)-1/CCL2 among those 62 genes was confirmed by real-time PCR and cytometric bead assay, respectively. RSV replication was markedly diminished in Th1-primed airway epithelial cells but not in Th2-primed cells, which was presumably caused at least in part by the early induction of antiviral genes. Conclusions: These results suggest that Th1/Th2 predisposition in the host prior to RSV infection critically regulates inflammatory reactions in the airways through alteration of gene expression, and that MCP-1/CCL2 plays an important role in the pathogenesis of severe RSV infection and the subsequent development of asthma in Th2-predisposed hosts.

Background: Whileβ2-adrenoceptor agonists (β2-agonists) are widely used as bronchodilators in the treatment of asthma, there has been increasing concern that regular use of β2-agonists may adversely affect the control of asthma. However, the molecular mechanisms of such undesirable effects of β2-agonists are not fully understood. In this study, we examined the effects of β2-agonists on cytokine-induced production of thymic stromal lymphopoietin (TSLP), an indispensable cytokine in the development of allergic diseases, by lung tissue cells. Methods: Normal human bronchial epithelial cells (NHBE), smooth muscle cells (BSMC) and fibroblasts (NHLF) were stimulated with the IL-4 and TNF-α cytokines, alone and in combination, and their production of TSLP was examined by ELISA. The effects of β2-agonists (salmeterol, formoterol, salbutamol), intracellular cyclic adenosine monophosphate (cAMP)-elevating agents (8-bromo-cAMP, dibutyryl cAMP, forskolin) and a corticosteroid (fluticasone) on the cytokine-induced TSLP production were examined. Results: The following results were observed in all three types of lung tissue cells tested (that is, NHBE, BSMC and NHLF). Costimulation with IL-4 and TNF-α significantly induced TSLP production, and β2-agonists further enhanced it via upregulation of intracellular cAMP. However, addition of a corticosteroid to the cytokines and β2-agonist resulted in a marked decrease in TSLP production. Conclusions: β2-Agonists significantly enhanced the cytokine-induced TSLP production by primary human lung tissue cells. This may be partly responsible for the undesirable clinical effects of continuous β2-agonist monotherapy, and combination therapy with a corticosteroid might effectively inhibit TSLP-mediated allergic inflammation.

The track records of the use of anti-methicillin-resistant Staphylococcus aureus agents (anti-MRSA agents) in a 5-year period (2001.4-2006.3) were collected, and cases in which anti-MRSA agents were used for >4 days were selected. In each case, the results of laboratory data and bacterial examination before and after administering the anti-MRSA agents were investigated retrospectively. In addition, it was also investigated in each case whether therapeutic drug monitoring (TDM) was carried out. It was observed that the number of patients treated with anti-MRSA agents and the total dose of anti-MRSA agents used tended to increase over time, except for arbekacin sulfate. It was, however, shown that treatment with anti-MRSA agents resulted in significant decreases in body temperature, C-reactive protein, and white blood cell counts. Bacterial examination was conducted in 75.6% of the patients treated with anti-MRSA agents, with MRSA being detected in 72.4% of the cases examined. On the other hand, TDM was also conducted in 60% of the cases, but this was at a lower percentage than that of the other examinations. Quantitative bacterial examination after treatment with anti-MRSA agents indicates that TDM can be considered important for the appropriate use of anti-MRSA agents.

An expression plasmid containing the aglA gene encoding Aspergillus niger GN-3 α-glucosidase was constructed and inserted into Emericella nidulans JCM10259. The transformant secreted about 61 mg/L of the recombinant α-glucosidase into its culture medium. The recombinant enzyme was purified from the culture filtrate through ammonium sulfate precipitation and three chromatographic steps. It was confirmed that, like wild-type A. niger GN-3 α-glucosidase, the purified recombinant enzyme consisted of two subunits. Although the molecular mass of the recombinant enzyme was slightly smaller than that of wild-type A. niger α-glucosidase (attributed to differences in glycosylation), the pH optima and substrate specificities of the wild-type and recombinant enzymes were comparable.

Background The activation of liver X receptor (LXR) α or LXRβ negatively regulates the expression of pro-inflammatory genes in mammalian cells. We recently reported that 25-hydroxycholesterol, a representative LXR-activating oxysterol, suppresses IL-6 production in mouse mast cells (MCs) following its engagement of the high-affinity IgE receptor (FceRI). This finding suggests that murine MCs express functional LXRs; however, the mechanisms underlying the LXR-dependent repression of the MC-mediated production of pro-inflammatory cytokines, including IL-6, are poorly understood. Therefore, we employed the synthetic LXR ligand GW3965 to examine the functions of LXRα and LXRβ in the production of pro-inflammatory cytokines by murine bone marrow-derived MCs (BMMCs). Methods We prepared BMMCs from wild-type (WT), LXRα −/− , and LXRα/β −/− mice. Each group of BMMCs was pretreated with GW3965 and then stimulated with IgE+antigen (Ag) or lipopolysaccharide (LPS). Cytokine production was then analyzed using specific ELISA kits. Results The activation of LXRs by GW3965 significantly attenuated the production of IL-1α and IL-1β, but not of IL-6, in the WT and LXRα −/− BMMCs stimulated with IgE+Ag. However, GW3965 treatment decreased the production of IL-1α, IL-1β, and IL-6 in WT and LXRα −/− BMMCs upon stimulation with LPS, while the GW3965-mediated suppression of cytokine production was nearly absent from the LXRα/β −/− BMMCs. Conclusions These findings demonstrate, for the first time, that the activation of LXRs by GW3965 attenuates the antigen- or LPS-induced production of pro-inflammatory cytokines, such as IL-1α and IL-1β, in murine MCs and that LXRβ plays an important role in the LXR-mediated repression of cytokine production.

A novel stable organic radical, 2-(4-azaindol-2-yl)-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazoline-1-oxyl-3-oxide (2) was synthesized and its magneto-structural correlation is discussed. 2 crystallizes in the space group C2/c with hydrogen bonding between two independent molecules (A and B) having different dihedral angles between the azaindole rings and nitronyl nitroxide units in the asymmetric unit. The molecules are further linked together with axisymmetrically related molecules (A* and B*) through hydrogen bonds (A-B* and A*-B) and π stacking (A-A*). The temperature dependence of the magnetic susceptibility reveals that half of the radicals are antiferromagnetically coupled as a dimer (singlet-triplet energy gap: 2J = −64 cm−1) while the other half behaves as an isolated monomer. DFT calculations (UB3LYP/6–31G*) of the dimeric coordinates extracted from the X-ray analysis rationalize the fact that the π-stacked A-A* dimer contributes to the antiferromagnetic coupling by a close contact between nitronyl nitroxide units.

Necrotising fasciitis (NF) is a potentially lethal infection affecting subcutaneous tissue and superficial fascia that may progress to multiple organ failure, and the prognosis is often worse when the host is immunocompromised. The prognosis is influenced by early diagnosis and early surgical debridement (1). Biologic therapies have been used in treating intractable inflammatory diseases, including collagen disorders. When using such a treatment strategy, it is critical to be aware that the treated subject may be highly susceptible to infection. Tocilizumab is a humanised monoclonal antibody directed against the interleukin-6 (IL-6) receptor and is recognised as an excellent biologic treatment in inflammatory rheumatic conditions (2). However, we wish to highlight the fact that its use may be associated with serious adverse reactions such as NF. It is known that tocilizumab may completely suppress induced C-reactive protein (CRP) via neutralisation of IL-6 effects (3). In fact, there have been a few reports of infections and other adverse events in subjects treated with tocilizumab (4). CASE REPORT

The characteristic feature of the end of the twentieth century is a modernized, systematized society for the development of technology. By preserving the character of instrumentality, technological cohesion or conjuncture is our new circumstance. New phenomena have arisen such as technological abstraction, a separation of function from form, and cards with many functions. Until the twentieth century, technologists looked for new technology as a positive way to create artifacts. But in the twenty-first century, it is necessary to think about negative technology (technica negativa). Negative technology is no longer a theoretical idea but a practical project. After Fukushima, we must concern ourselves about safety and close the nuclear facilities. Such a project must be a negation of positive technology, but this negativity should be turned to be positive.

We previously reported the construction of an overexpression system of Candida tropicalis peroxisomal catalase (CTC) gene in the Saccharomyces cerevisiae cytoplasm using the GAL7 promoter (Kinoshita et al. , Appl. Microbiol. Biotechnol., 40: 682–686, 1994). To study the mechanism of the subcellular localization of peroxisomal catalase which is composed of four identical subunits and four heme molecules, the system was improved by changing the promoter used in order to express the catalase subunit accompanying the proliferation of peroxisomes in S. cerevisiae cells ( S. cerevisiae ΔAΔT strain), in which catalase A and catalase T genes were disrupted. On native-PAGE, besides the functional tetrameric form (220 kDa), other larger multimeric forms of recombinant CTC were observed in the cell-free extract. It was clearly demonstrated that only the tetrameric form, among the various forms, contained heme and exhibited catalase activity. Subcellular fractionation and protease protection experiments indicated that only the functionally active tetrameric form was present inside the peroxisomes even under conditions of overexpression of the catalase subunit, in which different multimeric forms including the active tetrameric form were produced outside the peroxisomes. The results indicated that C. tropicalis catalase subunit and heme stoichiometrically localize even in S. cerevisiae peroxisomes, suggesting a common regulatory role of peroxisomes themselves for the transport of the oligomeric form of catalase beyond yeast species.

先天性眼底疾患を伴った遠視性不同視弱視1例と近視性不同視弱視2例に弱視治療を行った。ぶどう膜欠損を伴った遠視性不同視弱視の1例は斜視はなく脈絡膜欠損も黄斑部には及んでいなかった為,弱視治療をはじめて11か月後(0.7)まで視力は向上した。網膜有髄神経繊維を伴った片眼高度近視による近視性不同視弱視の1例は弱視治療により17か月後(0.7)まで向上した。同じく網膜有髄神経繊維に軽度近視による近視性不同視弱視を伴った1例は治療開始年齢が低年齢でなかったこともあり,視力は弱視治療より20か月後(0.7)にとどまっている。それぞれの眼底疾患が視機能の発育と弱視治療の効果に影響を及ぼしていると考えられたが,3症例共に治療の結果,視力の向上をみた。このような弱視に対しても積極的に弱視治療を試みても良いのではないかと考えられた。

筆者らは1993年1月より1996年3月までに京都桂病院眼科を受診したEB服用開始者212名を対象にEB視神経症の初期症状について検討した。EB服用中止になった症例は9例で全体の4.2%であった。全例にCFF値の低下を見たが,視力,視野障害は2例,色覚の異常(パネルD-15)を認めたのは1例のみであった。CFF値の低下がEB視神経症の最初の症状と思われた。

Eco-ethica was presented by Tomonobu Imamichi (1922–2012) in 1965. In 1981, he created a research team on Eco-ethica, which, for the past 6 years has been under the aegis of Peter Kemp and has met at international symposia. Eco-ethica is the new ethics for the technological environment (technological conjuncture). We have developed ideas for “the New World Order”: “Cosmopolitanism”. We must rethink “What is eco-ethica?” After Fukushima, we must recognize that not only is Nature out of our control, so is technology. The huge earthquake and subsequent tsunami destroyed not only Fukushima’s nuclear facilities but the traditional relationship between human beings. The idea of promoting peace through atomic energy and safety through technology must be changed. After Fukushima, I am sure that the minds of the Japanese people have changed. They are trying to re-conceive human relations by living with compassion and sympathy with others as a World Citizen. In this situation, I am trying to re-conceive Eco-ethica for future generations.

In an n-alkane assimilating yeast, Candida tropicalis, carnitine acetyltransferase (CAT; EC 2.3.1.7) was localized in both peroxisomes and mitochondria. Both CATs were encoded by one gene, CT-CAT, although the initiation sites of translation were suggested to be different. In the present study, the genes corresponding to the supposed C. tropicalis peroxisomal and mitochondrial CATs, which were truncated from the CT-CAT gene, were individually expressed in Saccharomyces cerevisiae, using the C. tropicalis isocitrate lyase promoter (UPR-ICL), which is inducible by oleic acid in concert with proliferation of peroxisomes in S. cerevisiae [Umemura, K., Atomi, H., Kanai, T., Teranishi, Y., Ueda, M., and Tanaka, A. (1995) Appl. Microbiol. Biotechnol. 43, 489-492]. The 71 kDa precursor of mitochondrial CAT, initiating at the first Met, was found to be processed to the mature size (66 kDa) in S. cerevisiae and immunoelectronmicroscopical observation revealed that this enzyme was localized in mitochondria. On the other hand, 68 kDa CAT, initiating at the second Met (residue No. 19), had no cleavable signal and was translocated into peroxisomes and cytosol, but not into mitochondria. The amino-terminal amino acid sequences of individually expressed CATs were identical to those of CATs isolated from alkane-grown C. tropicalis cells, respectively. These results demonstrated that only the 71 kDa protein yielded the 66 kDa protein and that peroxisomal and mitochondrial CATs arose from the difference in the initiation sites of translation.

Background A large body of evidence has demonstrated that treatment with omalizumab is clinically effective for the management of moderate to severe allergic asthma, emphasizing the importance of IgE in the pathogenesis of allergic asthma. We hypothesized that IgE accelerates FceRI-mediated responsiveness of "immature" human mast cells (MCs) and that omalizumab downregulates the acceleration. Objectives To examine when MC progenitors acquired the ability to degranulate following FceRI aggregation, whether IgE accelerates the responsiveness of immature MCs following FceRI aggregation, and whether omalizumab regulates such an acceleration. Methods Gene expression was examined using a microarray and quantitative reverse transcription polymerase chain reaction. Protein expression was investigated using FACS. Histamine release was examined using an EIA. Results The time-course analysis of the mRNA expression of MC-related genes, including FceRI, in Kit + sorted cells during the differentiation and histamine experiments revealed that the expression level of FceRI in 5 week (w)-cultured MCs was not sufficient to induce degranulation following FceRI aggregation but that 5 w-cultured MCs were fully responsive to calcium ionophore. By addition of IgE in culture medium FceRI expression level and FceRI-mediated histamine release of 5 w-cultured MCs were significantly increased compared with those without addition of IgE, whereas the expression level of tryptase and number of MCs was not affected. Omalizumab significantly inhibited IgE-dependent enhancement of FceRI expression level and FceRI-mediated histamine release. Conclusions High levels of IgE in the microenvironment in vivo may upregulate the responsiveness of immature MCs to allergens. Omalizumab may inhibit the IgE-mediated responsiveness of not only mature MCs, but also immature MCs.

Background: CCL23 (MPIF1/CK-BETA-8) is a novel CC chemokine that plays important roles in the inhibition of myeloid progenitor cell development, the selective recruitment of resting T lymphocytes and monocytes, and the potentiation of VEGF-induced proliferation and migration of human endothelial cells. Since eosinophils participate in the pathogenesis of airway remodeling, we examined CCL23 production and release by human eosinophils in vitro. Methods: Using Ficoll and antibody-coated immunomagnetic beads, eosinophils and other blood cells were purified from peripheral blood samples obtained from normal subjects and mildly allergic patients. Eosinophils were cultured in the presence of 10 ng/ml granulocyte-macrophage colony-stimulating factor (GM-CSF), 10 ng/ml IL-5, 100 ng/ml IFN-γ, 100 ng/ml IFN-α, or immobilized secretory IgA (sIgA). Total mRNA was extracted after 6 h of culture, and mRNA expression was measured using a microarray and RT-PCR. The CCL23 concentrations in the supernatants and cell lysates after 24 and 48 h of culture were measured by ELISA. Results: CCL23 mRNAs (both CK-β8-1 and CK-β8) were constitutively expressed in fresh eosinophils, and their expression levels were higher than in other types of blood cells. CCL23 mRNAs were significantly increased by stimulation with GM-CSF and IL-5 and slightly by IFN-α and immobilized sIgA. Fresh eosinophils contained trace amounts of CCL23 protein. CCL23 was significantly released into the supernatant when the eosinophils were stimulated with GM-CSF or IL-5 but not with IFN-γ or immobilized sIgA. Conclusion: Our data suggest that eosinophils produce and release CCL23 and may be involved in some in vivo physiological and pathological conditions.

Lens epithelium-derived growth factor (LEDGF)/dense fine speckles 70 kDa protein (DFS70) is a transcription cofactor that enhances growth and is overexpressed in various cancers. In the epidermis, LEDGF/DFS70 localizes to the nucleus of keratinocytes (KCs) in the basal layers and to the cytoplasm of cells in the upper layers. However, the biological and pathological relevance of LEDGF/DFS70 in the epidermis is virtually unknown. Compared with normal epidermis, we detected strong nuclear staining of LEDGF/DFS70 in both the spinous and basal layers of the epidermis of psoriatic skin. To investigate the roles of LEDGF/DFS70 in the epidermis of psoriatic skin, we generated HaCaT cells that constitutively express enhanced green fluorescence protein (EGFP)-LEDGF (EGFP-LEDGF-HaCaT) or EGFP alone (EGFP-HaCaT) as a control. EGFP-LEDGF-HaCaT cells had increased expression of IL-6, which was attenuated by LEDGF-specific RNA interference and the p38-specific inhibitors SB-239063 and SB-203580. Furthermore, EGFP-LEDGF-HaCaT cells had increased expression of S100A7 and S100A9 and decreased expression of filaggrin. These findings are compatible with the expression pattern in psoriatic tissues. Taken together, these results strongly suggest that ectopic expression of LEDGF/DFS70 in KCs could be involved in the pathology of psoriasis vulgaris.

Background In recent years, it has been reported that stem cells exist in the mesenchymal tissues of the bone marrow and adipose. These stem cells are thought to express specific cell surface markers such as CD44, CD54, CD105, CD90, and CD271 and have been confirmed to be pluripotent. Furthermore, although it has been reported that stem cells are also present in the dermis, their cell surface markers and characteristics are not fully understood. Objective To confirm the presence of stem cells in the dermis and their ability, employing the mesenchymal stem cell markers which have previously been reported as an indication. Methods We analyzed the percentages of CD44 (+), CD54 (+), CD90 (+), CD105 (+), and CD271 (+) cells in the dermis of neonatal mice (HR-1 mouse) by performing immunostaining and FACS. Secondly, we isolated each type of marker-positive and -negative cells from dermal tissues and evaluated their proliferation potential and their ability to differentiate into adipocytes, osteoblasts, and chondrocytes. Results According to the immunostaining and FACS results, we confirmed that stem cells that express CD44, CD54, CD90, CD105, and CD271 are present in the dermal tissues of neonatal mice. In addition, when we measured the proliferation and differentiation potentials of each type of marker-positive cells, it was revealed that cells expressing CD54 or CD271 have a high proliferation potential and are able to differentiate into adipocytes, osteoblasts, and chondrocytes. Conclusions These results indicated that dermal tissues contain stem cells that express CD44, CD54, CD90, CD105, and CD271 which are stem cell markers. More precisely, it was suggested that both CD54 (+) and CD271 (+) stem cells have high proliferation and differentiation potentials.

Whilebeta(2)-adrenoceptor agonists (beta(2)-agonists) are widely used as bronchodilators in the treatment of asthma, there has been increasing concern that regular use of beta(2)-agonists may adversely affect the control of asthma. However, the molecular mechanisms of such undesirable effects of beta(2)-agonists are not fully understood. In this study, we examined the effects of beta(2)-agonists on cytokine-induced production of thymic stromal lymphopoietin (TSLP), an indispensable cytokine in the development of allergic diseases, by lung tissue cells.Normal human bronchial epithelial cells (NHBE), smooth muscle cells (BSMC) and fibroblasts (NHLF) were stimulated with the IL-4 and TNF-alpha cytokines, alone and in combination, and their production of TSLP was examined by ELISA. The effects of beta(2)-agonists (salmeterol, formoterol, salbutamol), intracellular cyclic adenosine monophosphate (cAMP)-elevating agents (8-bromo-cAMP, dibutyryl cAMP, forskolin) and a corticosteroid (fluticasone) on the cytokine-induced TSLP production were examined.The following results were observed in all three types of lung tissue cells tested (that is, NHBE, BSMC and NHLF). Costimulation with IL-4 and TNF-alpha significantly induced TSLP production, and beta(2)-agonists further enhanced it via upregulation of intracellular cAMP. However, addition of a corticosteroid to the cytokines and beta(2)-agonist resulted in a marked decrease in TSLP production.beta(2)-Agonists significantly enhanced the cytokine-induced TSLP production by primary human lung tissue cells. This may be partly responsible for the undesirable clinical effects of continuous beta(2)-agonist monotherapy, and combination therapy with a corticosteroid might effectively inhibit TSLP-mediated allergic inflammation.

The unfolded protein response (UPR), which is induced by stress to the endoplasmic reticulum (ER), is involved in the functional alteration of certain cells, such as the differentiation of B cells to plasma cells. The aim of this study is to determine whether the UPR is activated during epidermal keratinocyte (KC) differentiation. Here, we show that the expression of the UPR-induced proteins Bip/GRP78 and HRD1 was increased in cells in the supra-basal layers of normal human epidermis that contain KCs undergoing differentiation as well as in skin-equivalent cultured KCs. However, Bip/GRP78 and HRD1 were poorly expressed in proliferating KCs in squamous cell carcinoma and psoriasis vulgaris tissues. The epidermal growth factor receptor tyrosine kinase inhibitor, PD153035, which induces KC differentiation, upregulated UPR-induced marker mRNAs and proteins. Furthermore, microarray analyses and quantitative PCR revealed that ER stress-inducing reagents, tunicamycin (TU), thapsigargin, and brefeldin A, altered the expression of genes essential for human epidermal KC differentiation, including C/EBPbeta, KLF4, and ABCA12 in vitro. However, ABCA12 and KLF4 mRNA did not increase with TU treatment after siRNA-mediated knockdown of XBP-1. Taken together, our findings strongly suggest that the UPR is activated during normal epidermal KC differentiation and induces C/EBPbeta, KLF4, and ABCA12 mRNAs.

The track records of the use of anti-methicillin-resistant Staphylococcus aureus agents (anti-MRSA agents) in a 5-year period (2001.4-2006.3) were collected, and cases in which anti-MRSA agents were used for4 days were selected. In each case, the results of laboratory data and bacterial examination before and after administering the anti-MRSA agents were investigated retrospectively. In addition, it was also investigated in each case whether therapeutic drug monitoring (TDM) was carried out. It was observed that the number of patients treated with anti-MRSA agents and the total dose of anti-MRSA agents used tended to increase over time, except for arbekacin sulfate. It was, however, shown that treatment with anti-MRSA agents resulted in significant decreases in body temperature, C-reactive protein, and white blood cell counts. Bacterial examination was conducted in 75.6% of the patients treated with anti-MRSA agents, with MRSA being detected in 72.4% of the cases examined. On the other hand, TDM was also conducted in 60% of the cases, but this was at a lower percentage than that of the other examinations. Quantitative bacterial examination after treatment with anti-MRSA agents indicates that TDM can be considered important for the appropriate use of anti-MRSA agents.

In this paper, we derive an exact test for linear restrictions on regression coefficients in seemingly unrelated regressions with the same regressors in each equation. The test statistic is distributed as the T 2 distribution, and thus critical values can be obtained from the F distribution. Since the test for symmetry in demand systems is a special case of the test for linear restrictions, our test gives an exact test for symmetry.

Follicle-associated epithelium (FAE) covering Peyer's patches contains specialized epithelial M cells that take up ingested macromolecules and microorganisms from the lumen of the gut by transcytosis. Using high-density oligonucleotide microarrays, we analyzed the gene expression profiles of FAE and M cells in order to characterize their cellular phenotypes. The microarray data revealed that, among approximately 14,000 genes, 409 were expressed in FAE at twofold or higher levels compared to the intestinal epithelial cells (IECs) of the villi. These included genes involved in membrane traffic, host defense and transcriptional regulation, as well as uncharacterized genes. Real-time PCR and in situ hybridization analyses identified three molecules, ubiquitin D (Ub-D), tumor necrosis factor receptor superfamily 12a (TNFRsf12a), and transmembrane 4 superfamily 4 (Tm4sf4), which were predominantly distributed throughout FAE, but were expressed little, if at all, in IECs. By contrast, transcripts of secretory granule neuroendocrine protein 1 (Sgne-1) were scattered in FAE, and were co-localized with Ulex europaeus agglutinin-1 (UEA-1)-positive cells. This clearly suggests that expression of Sgne-1 in the gut is specific to M cells. Such a unique pattern of gene expression distinguishes FAE and M cells from IECs, and may reflect their cellular phenotype(s) associated with specific functional features.

Respiratory epithelial cells play important roles not only in host defense mechanisms, but also in inflammatory responses. Inhaled corticosteroids are widely used for the treatment of patients with inflammatory lung disorders, including asthma, chronic obstructive pulmonary disease, and sarcoidosis. Corticosteroids effectively reduce the production of inflammatory mediators, such as cytokines and chemokines. Although these molecules are also essential for host defense responses, there is no convincing evidence that inhaled corticosteroids increase susceptibility to lower respiratory tract infections. To test the involvement of Toll-like receptor (TLR) family molecules in this phenomenon, we examined the effects of various cytokines and corticosteroid on the expression of TLRs in human respiratory epithelial cells. Among the TLRs tested, TLR2 expression was significantly enhanced after stimulation with a combination of tumor necrosis factor-alpha and interferon-gamma. Dexamethasone synergistically enhanced TLR2 expression in combination with tumor necrosis factor-alpha and interferon-gamma in terms of both mRNA and protein levels. Furthermore, increased cell-surface TLR2 was functional, judging from the remarkable induction of interleukin-6, interleukin-8, and beta-defensin-2 after stimulation with peptidoglycan. These results provide evidence for a novel function of corticosteroids in airway inflammatory disorders, and indicate that the use of inhaled corticosteroids in such disorders may have a beneficial role in host defense mechanisms.

Esophageal squamous cell carcinoma has heterogeneous clinical outcomes that cannot be predicted well using any existing clinical or molecular prognostic factors. Gene expression profiling may enable more precise prediction of the clinical outcome of these patients. We developed a new approach using gene expression ratios of paired cancerous and normal tissue specimens from the same patient to reduce the effects of variation among individuals. Using oligonucleotide microarrays, we analyzed total RNA expression levels corresponding to 12,600 transcript sequences in 24 paired cancerous and normal tissue operative specimens from 12 patients with esophageal squamous cell carcinoma. Hierarchical clustering analysis using gene expression ratios (cancer:normal) divided the 12 patients into two groups; all 7 patients in the first cluster survived without relapse (median follow-up, 483 days), whereas all 5 patients in the second cluster relapsed (median relapse-free survival time, 280 days; log-rank test, P = 0.006). In contrast, clustering either with cancerous tissue alone or with normal tissue alone did not show significant differences in the outcomes. The expressions of a variety of genes related with cell cycle, gene-repair, apoptosis and chemoradiotherpay resistance were up-regulated in the poor prognostic cluster. These results suggest that ratios of paired gene expression profiles may more efficiently predict relapse-free survival of esophageal squamous cell carcinoma than existing prognostic factors or than gene expression profiling with cancerous tissue alone.

Background Oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODN) are known to exert a strong adjuvant effect on Th1 immune responses. Although several genes have been reported, no comprehensive study of the gene expression profiles in human cells after stimulation with CpG ODN has been reported. Results This study was designed to identify a CpG-inducible gene cluster that potentially predicts for the molecular mechanisms of clinical efficacy of CpG ODN, by determining mRNA expression in human PBMC after stimulation with CpG ODN. PBMCs were obtained from the peripheral blood of healthy volunteers and cultured in the presence or absence of CpG ODN 2006 for up to 24 hours. The mRNA expression profile was evaluated using a high-density oligonucleotide probe array, GeneChip®. Using hierarchical clustering-analysis, out of a total of 10,000 genes we identified a cluster containing 77 genes as having been up-regulated by CpG ODN. This cluster was further divided into two sub-clusters by means of time-kinetics. (1) Inflammatory cytokines such as IL-6 and GM-CSF were up-regulated predominantly 3 to 6 hours after stimulation with CpG ODN, presumably through activation of a transcription factor, NF-κB. (2) Interferon (IFN)-inducible anti-viral proteins, including IFIT1, OAS1 and Mx1, and Th1 chemoattractant IP-10, were up-regulated predominantly 6 to 24 hours after stimulation. Blocking with mAb against IFN-α/β receptor strongly inhibited the induction of these IFN-inducible genes by CpG ODN. Conclusion This study provides new information regarding the possible immunomodulatory effects of CpG ODN in vivo via an IFN-α/β receptor-mediated paracrine pathway.