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Inflammation driven by immune cells and pro-inflammatory cytokines is implicated in pancreatic β-cell injury, leading to the development of diabetes mellitus. IL-27, a cytokine consisting of IL-27p28 and Epstein-Barr virus-induced gene 3 (EBI3), binds a membrane-bound heterodimeric receptor consisting of the IL-27 receptor α chain (WSX-1) and gp130. IL-27 has anti-inflammatory properties that regulate T-cell polarization and cytokine production. We evaluated blood glucose and islet proinsulin concentrations, inflammatory cell infiltration in islets, and expression of IL-1β mRNA in pancreas in wild-type (WT), EBI3(-/-), and WSX-1(-/-) mice treated with streptozotocin (STZ). Hyperglycemia was augmented in EBI3(-/-) and WSX-1(-/-) mice compared with WT mice. Islet proinsulin levels after STZ treatment were lower in EBI3(-/-) and WSX-1(-/-) mice than in WT mice. The infiltration of islets by F4/80(+)CD11c(-)7/4(-) macrophages, CD4(+) T cells, and CD8(+) T cells was increased in EBI3(-/-) and WSX-1(-/-) mice compared with WT mice. The administration of recombinant IL-27, compared with control, decreased the blood glucose level, immune cell infiltration into islets, and IL-1β mRNA expression in the pancreas and increased islet proinsulin levels in WT and EBI3(-/-) mice. Thus, IL-27 inhibits STZ-induced hyperglycemia and pancreatic islet inflammation in mice and represents a potential novel therapeutic approach for β-cell protection in diabetes.

Summary Background Interleukin (IL)-27 and WSX-1, the receptor α-specific subunit, have been shown to play important roles in initiating Th1 responses and in inducing immune modulation, and the immunosuppressive effect of IL-27 appears to be exerted via suppression of IL-10 and IL-17, which may participate in the pathogenesis of human systemic lupus erythematosus (SLE). Objectives To examine the significance of IL-27/WSX-1 signalling in spontaneous skin inflammation of MRL/lpr mice, a model for SLE. Methods The severity and development of skin lesions, dermal inflammatory cells and epidermal–dermal depositions in the skin lesions of MRL/lpr mice with CD2-promoted WSX-1 overexpression (WSX-1 Tg mice) and those with globally disrupted WSX-1 (WSX-1 KO mice) were examined and compared with those of MRL/lpr mice. Results By 4 months of age, both WSX-1 KO mice and control MRL/lpr mice developed predominantly similar skin inflammation, while WSX-1 Tg mice hardly did so, demonstrating that intensifying IL-27/WSX-1 signalling on T cells prevents the spontaneous skin inflammation. WSX-1 KO mice showed Th2-type skin inflammation as evidenced by the Th2-prone dermal infiltrating cells and an absence of cutaneous Th1-type IgG deposition. Interestingly, there were significant IL-17+ dermal infiltrating cells in both WSX-1 KO and control MRL/lpr mice, which might potentially contribute to the formation of skin inflammation in these mice. Conclusions These data indicate that IL-27/WSX-1 signalling may play a protective role in the development of SLE-like skin inflammation, and modulating IL-27/WSX-1 signalling might be an interesting therapeutic strategy in the treatment of SLE.

Atherosclerotic lesions were observed in male and ovariectomized female Microminipig (MMP) fed a high fat and cholesterol diet with sodium cholate (HFCD/SC) for 3 months. HFCD/SC induced hypercholesterolemia accompanied by an increase in serum total cholesterol (T-Cho), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and cholesterol ester (CE). Unlike the mouse or rabbit, a dominant LDL-C fraction in the intact MMP, similar to that in humans, was observed by serum lipoprotein analysis. HFCD/SC increased body weight gain. At the end of the experiment, computed tomography scans of conscious animals showed that HFCD/SC had decreased liver attenuation values (Hounsfield unit) and increased subcutaneous and abdominal fat, suggesting the induction of fatty liver and obesity. HFCD/SC induced atherosclerotic lesions in systemic arteries, including the external and internal iliac arteries, abdominal aorta, coronary artery, and cerebral arterial circle. Atherosclerosis and pathological findings induced by HFCD/SC in MMP were similar to those in humans. The MMP is a potentially suitable tool for investigating human atherosclerosis. Keywords:: atherosclerosis, cholesterol, diet, life-style, Microminipig

We investigated whether habitual exercise (HE) (treadmill running) suppresses development of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA).Male Fischer 344 rats were divided into six groups: group I, saline treatment (12 weeks = initiation period) and non-HE; group II, Fe-NTA treatment (12 weeks) and non-HE; group III, saline treatment and short-term (12 weeks) HE; group IV, Fe-NTA treatment and short-term HE; group V, saline treatment and long-term (40 weeks) HE; and group VI, Fe-NTA treatment and long-term HE. Saline treatment groups did not develop RCC, therefore we investigated the effects of HE among Fe-NTA treatment groups.Gross nodules (diagnosed as RCC), RCC represented by microcarcinomas (Mcs), karyomegalic cells (KCs), and degenerative tubules (DTs) were seen in rats treated with Fe-NTA. The number of Mcs, KCs, and DTs were increased in the short-term HE group when compared with those in the non-HE group, but were decreased in the long-term HE group when compared with those in the short-term HE group.Short-term (initiation period) HE promoted renal carcinogenesis induced by Fe-NTA; however, long-term HE after the initiation period suppressed the promoted carcinogenesis.

The Lewis acid-mediated direct carboxylation of aromatic compounds with CO2 is efficiently promoted by the addition of silyl chlorides bearing three alkyl and/or aryl substituents in total on the silicon atom. Thus, toluene, xylenes, mesitylene, and some other alkylbenzenes are treated with a 1:1 mixture of AlBr3 and Ph3SiCl in neat substrates under CO2 pressure (3.0 MPa) at room temperature, to give the corresponding carboxylic acids in 60-97% yields, based on AlBr3. Polycyclic arenes, including naphthalene, phenanthrene, and biphenyl, are regioselectively carboxylated in 91-98% yields with the aid of 1 molar equiv of AlBr3 and Ph3SiCl in an appropriate solvent, chosen from benzene, chlorobenzene, and fluorobenzene. These solvents, as well as bromobenzene, resist carboxylation; however, they are also carboxylated in moderate yields when treated with a 1:5 mixture of AlBr3 and (i)PrSiCl at elevated temperatures. The FT-IR spectrum of a mixture prepared by exposing a suspension of AlBr3 and Ph3SiCl in cyclohexane to CO2 exhibits an absorption band around 1650 cm(-1), assigned to the C═O stretching vibration of a species consisting of CO2, AlBr3, and Ph3SiCl, which suggests that the silyl chlorides activate CO2 in cooperation with AlBr3. (1)H NMR analysis of unworked-up reaction mixtures reveals that the products merge as aluminum carboxylates. The mass balance concerning silicon indicates that the silyl chlorides are recycled during the reaction sequence. On the basis of these observations, a feasible mechanism is proposed for the present carboxylation.

Migration routes of Na ions towards the surface and into SiN x films of Si cells during the potential-induced degradation (PID) test were analyzed by microscale measurements such as X-ray photoelectron spectroscopy, scanning electron microscopy, energy dispersive X-ray spectroscopy, and conductive atomic force microscopy. These measurements showed the appearance of high Na concentrations near the finger electrodes and at the top of texture structures of the SiN x film surface. However, a high current conductivity of SiN x films was observed at halfway between two finger electrodes and at the top of texture structures. These results suggest that focusing of electric fields originating from finger electrodes and the shape of texture structures affected the Na distributions and migration into the SiN x films. The influence of the PID recovery test on the Na ion migration and SiN x films is also discussed in the paper.

Although the apoptotic role of caspases has been largely understood, accumulating evidence in Drosophila suggests that caspases also control other processes than apoptotic cell death. However, how caspases contribute to the development of the mammalian nervous system remains obscure. Here, we provide unique evidence that Apaf-1/caspase-9–mediated caspase signaling regulates the development of olfactory sensory neurons (OSNs), which includes axonal projection, synapse formation, and maturation of these neurons. This caspase signaling leads to a cleavage of Semaphorin 7A, a membrane-anchored semaphorin that is required for the proper axonal projection. Mutant mice deficient for apaf-1 or caspase-9 exhibit misrouted axons, impaired synaptic formation, and defects in the maturation of OSNs without affecting the number of these cells. Our findings suggest that Apaf-1/caspase-9–mediated nonapoptotic caspase signaling is required for the proper neural network formation during olfactory development.

The nuclear factor-κB (NF-κB) plays a central role in the activation and survival of lymphocytes. NF-κB, therefore, is pivotal for acquired immunity, but the dysregulation of NF-κB signaling leads to inflammatory diseases and lymphomagenesis. Accumulating evidence has demonstrated that the mucosa-associated lymphoid tissue (MALT) lymphoma-related molecules, B-cell lymphoma 10 (BCL10) and MALT-lymphoma-translocation gene1 (MALT1), are essential signaling components for NF-κB and mitogen-activated protein kinase (MAPK) activation, mediated by the immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors involved in both innate and adaptive immunity. CARMA1 (also referred to as CARD11 and Bimp3) is a crucial regulator for ITAM-mediated signaling as it forms a complex with BCL10-MALT1 in lymphoid lineage cells such as T, B, natural killer (NK), and natural killer T (NKT) cells, known as the lymphoid CARMA1-BCL10-MALT1 (L-CBM) complex. In this review, recent understanding of the molecular and biological functions and the signal regulation mechanisms of the L-CBM complex are described and its role in disease development and potential as a therapeutic target is further discussed.

Study design Cerebrocortical culture and rat spinal cord injury (SCI) model were used to examine the expression of high mobility group box 1 (HMGB1), TNF-alpha, and Rage by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical examination. In addition, relationship between upregulation of HMGB1 and neural cells apoptosis was evaluated after SCI. Objective To evaluate the upregulation of HMGB1, TNF-alpha, and Rage after SCI. Summary of background data It is known that the mode of delayed neuronal cell death after SCI is apoptosis. Apoptotic cell death is influenced by several injury-promoting factors which include pro-inflammatory cytokines. Inhibition of apoptosis promotes neurologic improvement following SCI. However, the factors which transmit inflammatory signaling following SCI have not yet been clarified in detail. HMGB1 was reported as an important mediator of inflammation. We examined the expression of HMGB1, TNF-alpha and Rage following acute SCI. Methods Expression of HMGB1, TNF-alpha and Rage was examined by RT-PCR and immunohistochemical examination. Apoptotic cell death was evaluated by TUNEL methods. Results HMGB1 was exported from nuclei to cytoplasm in active caspase-3 positive apoptotic cell in vitro. In addition, HMGB1, TNF-alpha, and Rage was expressed in same cell after NMDA treatment. RT-PCR revealed that expression of HMGB1 and TNF-alpha was upregulated following SCI. Immunohistochemical examination revealed that the numbers of HMGB1-, TNF-alpha-, and Rage-positive cells were increased following SCI. The number of TUNEL-positive cells was significantly increased at 12 hours after injury, and was maximal at 72 hours after injury. However, HMGB1- and TNF-alpha-positive cells were maximal in number 48 hours after injury, while Rage-positive cells were maximal in number at 24 hours after injury. These data suggest that HMGB1, TNF-alpha, and Rage were upregulated following SCI but preceding the apoptotic cell death. Conclusion Our findings suggest that HMGB1 play a role in the induction of apoptosis via inflammatory reaction.

Life-support (particularly, advanced life-support) training is not included in pharmacist education; however, the life-support should be mastered since a pharmacist is a medical professional. We consider it to be important to master other skills before the life-support practicing, because a pharmacist does not check a patient to assess their clinical condition and administer drugs (suppository, intravenous injection etc.) The pharmacist prepares medicines, but does not administer medicines to treat the patient. Furthermore, the pharmacist is not interested in the vital signs of the patient receiving the medicines (the pharmacist has not identified the patient has complaint from changes in vital signs), which is why pharmacists can not develop themselves as medical professionals. Based on this observation, life-support training should be considered. In other words, to foster pharmacists with high clinical competence, pharmacy students should receive life-support training after training in drug administration and vital sign checks in a bedside training room. Drug administration using a pharmacy system versatile-type training model and pharmacy training model, vital signs check and auscultation using a physical assessment model and a cardiac disease disorder simulator in our bedside practice are useful for advanced life-support using a high-performance care simulator (monitoring vital signs, adrenalin administration and oxygen inhalation for ventricular fibrillation (VF). These training skills can improve the clinical competence of pharmacy students.

Obese adipose tissue is characterized by an excessive production of inflammatory adipokines including tumor necrosis factor-alpha (TNF-alpha). TNF-alpha stimulates free fatty acid (FFA) secretion through adipocyte lipolysis, and increased plasma levels of FFA promote insulin resistance. In this report, we show that hesperetin and naringenin, two citrus flavonoids, inhibit TNF-alpha-stimulated FFA secretion from mouse adipocytes. These flavonoids block the TNF-alpha-induced activation of the NF-kappaB and ERK pathways. Moreover, hesperetin and naringenin prevent TNF-alpha from downregulating the transcription of two antilipolytic genes, perilipin and PDE3B. These effects are mediated through the inhibition of the ERK pathway. In contrast, the inhibition of the NF-kappaB pathway by hesperetin and naringenin suppresses the transcription of IL-6, which induces FFA secretion in an autocrine manner. Our results provide novel evidence that hesperetin and naringenin directly inhibit TNF-alpha-stimulated FFA secretion. These findings may be useful for ameliorating FFA-induced insulin resistance.

非ステロイド性抗炎症薬(NSAID)フルルビプロフェン(FP)の蛋白結合率は約99%であり、組織移行性が低い。6-メトキシ-2-ナフチル酢酸(6MNA)は、NSAIDの1つであるナブメトンの活性代謝産物である。これらの薬物は、ともにヒト血清アルブミン(HSA)のサイトIIに強く結合する。私たちは、LLC-PK1を用いて6MNA添加時のFPの細胞膜透過性について調べた。この実験では、細胞膜プレートの上側を組織側、下側を血管側と想定した。下側のFPを含むHSA溶液に6MNAを添加後、上側、下側のFP濃度を測定した。上側へのFPの移行量は6MNAの添加により、Total FPおよびFree FP濃度ともに有意な増加を示した。下側の量は変化が見られなかった。臨床におけるナブメトンの併用はFPのようなサイトII結合性薬物の標的組織への移行量を増加させ、少量においても効果を高める可能性が示唆された。, The protein binding rate of a nonsteroidal antiinflammatory drug (NSAID), flurbiprofen (FP), is about 99%, indicating its low tissue transfer. 6-Methoxy-2-naphthyl acetic acid (6MNA) is an active metabolite of an NSAID, nabumetone (Relifen ®). These drugs strongly bind to human serum albumin (HSA) site II, suggesting that protein binding inhibition by 6MNA may promote tissue transfer of FP. We investigated cell membrane permeability of FP in the presence of 6MNA using swine kidney cell line LLC-PK1, in which the upper and lower sides of the cell membrane plate (Transwell ®) were regarded as the tissue and vascular sides, respectively. After adding 6MNA to HSA solution containing FP on the lower side, the FP levels in the upper and lower solutions and cells were measured. FP transfer to the upper side was significantly promoted by the addition of 6MNA with regard to the total and free FP levels. No change in the FP level was noted in cells or wells. It was suggested that concomitant nabumetone may promote transfer of site II binding drugs, such as FP, to the target tissue, increasing the effect even at a low dose.

There are currently many on-going discussions on expanding the professional skills of pharmacists and in the future,pharmacists will need to be able to check the condition of patients.In view of this,we conducted a survey of the attitudes of community pharmacists towards further developing their professional skills and sent a questionnaire to 333 randomly selected community pharmacists in Japan.The questionnaire investigated attitudes toward checking vital signs,performing emergency medical procedures and expanding professional skills.The recovery rate was 26%.Analysis of the responses showed that there was a high level of interest in medical emergency education and expanding professional skills.However,it seemed that community pharmacists were experiencing difficulties in the current conduct of their duties and there was a general feeling that their profession was in a period of transition.There is therefore a need for innovative changes to be made in future pharmaceutical education and pharmacy practice programs and we feel that pharmacy schools need to devote energy to enhancing lifelong education for pharmacists designed to further develop their professional skills.

Many cells die during mammalian development and are engulfed by macrophages. In DNase II(-/-) embryos, the TUNEL-positive DNA of apoptotic cells is left undigested in macrophages, providing a system for studying programmed cell death during mouse development. Here, we showed that an Apaf-1-null mutation in the DNase II(-/-) embryos greatly reduced the number of macrophages carrying DNA at E11.5. However, at later stages of the embryogenesis, a significant number of macrophages carrying undigested DNA were present in Apaf-1(-/-) embryos, indicating that cells died and were engulfed in an Apaf-1-independent manner. In most tissues of the Apaf-1(-/-) embryos, no processed caspase-3 was detected, and the DNA of dead cells accumulated in the macrophages appeared intact. Many nonapoptotic dead cells were found in the tail of the Apaf-1(-/-) embryos, suggesting that the Apaf-1-independent programmed cell death occurred, and these dead cells were engulfed by macrophages. In contrast, active caspase-3 was detected in E14.5 thymus of Apaf-1(-/-) embryos. Treatment of fetal thymocytes with staurosporine, but not etoposide, induced processing of procaspases 3 and 9, indicating that the E14.5 thymocytes have the ability to undergo caspase-dependent apoptosis in an Apaf-1-independent manner. Thus, programmed cell death in mouse development, which normally proceeds in an efficient Apaf-1-depenent mechanism, appears to be backed up by Apaf-1-independent death systems.

Interleukin 27 has pro- and anti-inflammatory features and is a potent target for therapy of various immune diseases. Cytokine-mediated immunity plays a crucial role in the pathogenesis of various diseases including infection and autoimmune diseases. IL-27, along with IL-12, −23, and −35, belongs to the IL-12 cytokine family. These family members play roles in regulation of Th cell differentiation. IL-27 is unique in that although it induces Th1 differentiation, the same cytokine suppresses immune responses. In the absence of IL-27-mediated immunosuppression, hyperproduction of various proinflammatory cytokines concomitant with severe inflammation is observed. The immunosuppressive effects of IL-27 depend on IL-2 suppression, inhibition of Th17 development, and induction of IL-10 production. Administration of IL-27 suppresses some diseases of autoimmune or allergic origin, demonstrating its potential in therapy of diseases mediated by inflammatory cytokines. In this review, we discuss recent studies about the role of IL-27 in immune regulation in view of its pro- and anti-inflammatory properties and possible therapeutic application.

An efficient synthesis of (R)- and (S)-α-(hydroxymethyl)pyroglutamic acid esters from L -proline has been achieved. Each step was carried out on a decagram scale to access the N-protected (R)-ester in a highly efficient manner (44% overall yield from a proline-derived bicyclic substrate).

Caspases are essential in multicellular organisms for inducing cell death during normal development and in the immune system. However, caspases can also trigger the degenerative process under certain conditions such as pathophysiological conditions and aging. Here, we identified Semaphorin 7A (Sema7A) as a novel substrate for caspase-9 that can be used to monitor caspase-9 activity in mice, and found nonapoptotic caspase-9 activation in the aged olfactory bulb (OB). Immunostaining of the OB for the caspase-9-cleaved form of Sema7A revealed abundant caspase-9-activated cells in 2-year-old (aged) but not in 2-month-old (young) mice. In fact, various regions of the aged brain, including the OB, exhibited an increased level of caspase-9 activity. However, the number of dying cells in the aged OB was, intriguingly, much lower (

IL-27 was first discovered as a factor supporting initial Th1 immune responses. Subsequent studies revealed that this cytokine has pleiotropic effects, including inhibition of certain immune cells, a regulatory role in hemopoietic stem cell differentiation, and antitumor activities. However, the role of human IL (hIL)-27 in human osteoclast precursors and inflammatory bone disease is unclear. Here, we examined the direct effect of hIL-27 on human osteoclastogenesis. Human bone marrow cells cultured in MethoCult medium containing human (h) GM-CSF, human stem cell factor, and hIL-3 expressed Mac-1, c-kit, and c-Fms. These cells, called hCFU-GMs, also expressed the IL-27 receptor, an IL-27Rα (WSX-1)/gp130 heterodimer. Cultivation in hM-CSF and human receptor activator of NF-κB ligand induced the differentiation of tartrate-resistant acid phosphatase-positive multinucleated cells (osteoclasts) from hCFU-GMs, and hIL-27 inhibited this osteoclastogenesis in a dose-dependent manner. hIL-27 also repressed bone resorption by osteoclasts on a dentine slice. hIL-27 caused a remarkable increase in STAT1 phosphorylation and enhanced the STAT1 protein level. It also inhibited the expression of receptor activator of NF-κB ligand-induced c-Fos and cytoplasmic, calcineurin-dependent 1 NFAT (NFATc1), which are indispensable transcription factors for osteoclastogenesis. Fludarabine, a STAT1 inhibitor, and STAT1 small interfering RNA partially rescued the inhibition of osteoclastogenesis by IL-27. A WSX-1 deficiency caused severe inflammatory bone destruction primed by Escherichia coli cell wall lysate in vivo. Therefore, hIL-27 may act as an anti-inflammatory cytokine in human bone destruction, by inhibiting osteoclastogenesis from hCFU-GMs via STAT1-dependent down-regulation of the transcription factor c-Fos. Our results suggest that hIL-27 may prove useful as a therapeutic target for inflammatory bone destruction.

Interleukin (IL-) 27 is a member of IL-12 cytokine family with Th1-promoting and anti-inflammatory effects. IL-27 has been shown to facilitate tumor-specific cytotoxic T lymphocyte (CTL) induction against various tumors. However, IL-27 suppresses cytokine production of lymphocytes and antigen-presenting function of dendritic cells (DCs). To examine the in vivo role of IL-27 in generation of anti-tumor immunity, we examined IL-27-mediated antitumor-effects using WSX-1 (IL-27 receptor alpha chain)-deficient (WSX-1(-/-)) mice. In WSX-1(-/-) mice inoculated with B16 melanoma cells, tumor growth was higher than in wild-type (WT) mice. Accordingly, tumor-specific CTL generation was lower in WSX-1(-/-) mice than in WT mice. CTL induction in WSX-1(-/-) mice was not restored by transfer of WT DCs pulsed with TRP2 peptide, indicating that IL-27 is directly required for generation of tumor-specific CTLs. However, when transferred into tumor-bearing mice, WSX-1(-/-) DCs pulsed with TRP2 peptide was more potent than WT DCs in tumor growth inhibition and generation of CTLs, indicating suppressive effects of IL-27 on DC function. Finally, the combination of WT CD8(+) T cells and KO DCs is more potent in generation of antigen-specific CTLs than any other combinations. Expression of perforin gene and percentages of tumor-specific CD8(+) T cells were also the highest in the combination of WT CD8+ T cells and WSX-1(-/-) DCs. It was thus revealed that IL-27 promotes CTL generation while suppressing DC function during generation of tumor immunity. The combination of WT T cells and IL-27 signal-defective DCs may have therapeutic potential against tumors.

We previously reported that a neonatal administration of diethylstilbestrol or 17β-estradiol affected the mammary carcinogenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) in rats. The aim of this present study was to investigate the effects of 4- n-octylphenol (OP), a weak estrogenic disruptor, on the induction of mammary carcinomas (MC) and benign proliferative lesions (PL) induced by DMBA in rats. All female rats were administered at 0, 0.1, 10, 100, and 1,000 μg OP once at birth, given 10 mg DMBA at 50 days after birth, and thereafter underwent necropsy at 351 days after birth. All male rats were given 10 mg DMBA at 28, 42, and 56 days after birth, and 0, 10, 100, and 1,000 ppm OP fed from day 70-153; they underwent necropsy at 153 days after birth. Neonatal single administration of OP in female rats showed no effects such as persistent estrus, anovulatory ovaries, or PL. A slight increase in numbers of rats with MC occurred at the highest dosage. Feeding a large dose of OP for a long period in male rats induced atrophy of testes and slightly increased numbers of affected MC but not increased numbers of males while it showed no effects on PL. These results suggested that administration of a large dose of OP for a long period may have had a minimal effect on mammary carcinogenesis in male rats.

Background Allergic rhinitis is 1 of the most common atopic diseases with strong similarity to asthma. Interleukin (IL) 27 is an immunosuppressive cytokine, and lack of the IL-27 receptor (WSX-1) resulted in exacerbation of allergic airway hyperresponsiveness. Objective To address the role of IL-27/WSX-1 in the rhinitis model compared with the asthma model. Methods Wild-type or WSX-1 −/− female mice were immunized intraperitoneally 4 times with ovalbumin adsorbed to aluminum potassium sulfate at a 1-week interval. The sensitized mice were then challenged for 14 days with ovalbumin intranasally from days 22 to 35. Clinical scores, serum antigen specific IgE levels, and cytokine production in the nasal lavage fluid were examined. Cytokine and chemokine expression in the cervical lymph nodes, nasopharynx-associated lymphoid tissues, and nasal mucosa was also examined. Results WSX-1 −/− mice developed augmented immune responses in the serum (IgE production), cervical lymph nodes (cytokine and chemokine expression), and nasopharynx-associated lymphoid tissues (cytokine and chemokine expression), whereas local responses, such as clinical scores and nasal lavage fluid cytokine production, were reduced in WSX-1 −/− mice. Expression of some chemokines was also reduced in the nasal mucosal tissues of WSX-1 −/− mice. Conclusion In contrast to the immunosuppressive role observed in the asthma model, IL-27/WSX-1 topically plays an exacerbating role in the pathogenesis of allergic rhinitis, presumably through differential expression of chemokines.

Drug efficacy depends on the amount of a preparation reaching the target tissue (grade of tissue transfer). In this experiment, we established the normal albumin concentration of a healthy adult (600 μ M) or a low-albumin state indicating marked liver hypofunction (100 μ M) on a cell membrane plate, and evaluated the cell membrane permeability of the probe agents. The cell membrane permeability of phenytoin or valproate depended on the concentration of albumin. Probe agent site-I and -II inhibitors, bucolome and oleic acid, respectively, increased the cell membrane permeability. In the future, the cell membrane permeability of probe agents should be further investigated to estimate the tissue transfer of agents based on various laboratory data (albumin, free fatty acids, uremic toxins, and bilirubin).

Current status of elemental research on a laser fusion reactor with a liquid wall in Japan is summarized. Cascade scheme was found to be useful to obtain a continuous protective liquid LiPb layer. Formation of micro particles in a plume ablated by alpha particle heating is discussed based on experimental results obtained by backside irradiation of a lead membrane. Our numerical simulation results for formation of aerosols matched experimental results obtained with electric discharge through a thin lead membrane. Protection of beam port is described. A magnetic field generated with a pulse current successfully shields the tip of beam port from alpha particles. Tracking of cone target with diverging beam showed 0.2 μm resolution at 10m separation.

The aim of this study was to investigate the effect of exposure period and dose of diethylstilbestrol (DES), which has strong estrogenic activity, on pregnancy in rats. All rats with observed vaginal plugs or sperm in vaginal smear tests after mating were divided into 3 groups: those fed a normal diet, a diet mixed with DES throughout pregnancy and a diet mixed with DES from day 13 of pregnancy. DES was mixed into the diet at 0.1, 1, 10 and 100 ppm. All bred rats fed the normal diet and 0.1 ppm DES from day 13 of pregnancy delivered pups, while none of the rats treated with 1-100 ppm DES during pregnancy and 100 ppm DES from day 13 of pregnancy delivered any pups. The number of male and female pups born decreased in rats treated with 10 ppm DES from day 13 of pregnancy. These results suggest that DES could affect pregnancy and that the exposure period and dose may result in sterility, abortion, poor fetal growth and reduced number of pups born.

The taking of vital signs and medical emergency procedures are taught as a part of bedside practice at the Department of Pharmacy of Kyushu University of Health and Welfare to aid pharmacists in providing medication for patients.Conducting a survey on the attitudes of hospital pharmacists and pharmacy students regarding their involvement in checking vital signs and medical emergency procedures produced the following results.Both hospital pharmacists and pharmacy students at our university were very interested in learning how to take vital signs and medical emergency procedures,in order to expand their role in treating patients.Hospital pharmacists were more aware of the need to have injection sets for pharmacists and instruction in emergency procedures than students.The taking of vital signs enables pharmacists to understand the conditions of patients better and helps them to evaluate drug efficacy and adverse effects.It also allows pharmacists to be more active members of the medical team and optimizes their role in patient-centered care.

A questionnaire survey of hospital pharmacists was performed to investigate their awareness with regard to expanding the professional role of pharmacists and the factors which influence this were analyzed by means of multiple regression analysis.Three significant factors were indicated,“Physical condition measurements”,“Guidance in medical emergencies”,and “Expansion of existing pharmacist work procedures”.Further,based on the model formula,“Guidance in medical emergencies” was the most influential factor (p=0.00177).These results suggest that pharmacists are interested in expanding their role,in particular with respect to providing guidance in medical emergencies,and we consider that they will be useful in curriculum development by professional organizations with the aim of expanding the professional role of pharmacists in the future.

The aim of this study was to investigate the effects of neonatal administration of a relatively high dose of diethylstilbestrol (DES) on the induction of mammary carcinomas (MCs) and benign proliferative lesions (PLs) induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female rats. Three different terms of daily administration of DES (10 μg) were used: 0–14, 0–5, and 6–14 days after birth. Control animals were administered solvent (oil) alone once daily from 0 to 14 days after birth. Rats were given DMBA (10 mg) at 50 days after birth. All rats administered DES showed persistent estrus and anovulatory ovaries. In rats administered DES from 0 to 14 and 0 to 5 days after birth there was protection from development of MCs and PLs, and serum levels of both estrogen and progesterone were significantly lower than in the control animals at 100 days after birth. In rats administered DES from 6 to 14 days after birth, the incidence of MCs was equal to that of the control animals (100%), and the number of PLs was significantly higher than in the control animals. The critical period for exposure to endocrine disruptors, such as DES, affecting the induction of MCs and PLs may be from 0 to 5 days after birth.

A case of paraganglioma of the cauda equina is reported. The patient was a 55-year-old Japanese woman who complained of lower back pain and gradual weakening of the left lower extremity, she was diagnosed as having a spinal cord tumor, and the tumor was removed surgically. Histologically, the tumor was encapsulated, and consisted of solid nests of large, polyhedral epithelioid cells with abundant eosinophilic cytoplasm. The nests were separated from each other by a thin fibrovascular stroma. Grimelius staining revealed neurosecretory granules in the cytoplasm of the tumor cells. This was further confirmed by electron microscopic observation. The tumor cells were immunohistochemically positive for neuron-specific enolase (NSE), but negative for glial fibrillary acidic protein (GFAP). On the basis of the histologic, immunohistochemical and electron microscopic features of the tumor cells, the tumor was diagnosed as paraganglioma. The cauda equina is a rare location for this type of tumor, and only a limited number of cases have been reported.

Cytokine-mediated immunity plays a crucial role in the pathogenesis of various diseases including autoimmunity. Recently, interleukin-27 (IL-27) was identified, which, along with IL-12, IL-23, and IL-35, belongs to the IL-12 cytokine family. These family members play roles in the regulation of T helper (Th) cell differentiation. IL-27 is unique in that while it induces Th1 differentiation, the same cytokine suppresses immune responses. In the absence of IL-27-mediated immunosuppression, hyper-production of various pro-inflammatory cytokines concomitant with severe inflammation in affected organs was observed in IL-27 receptor alpha chain (WSX-1)-deficient mice infected with Trypanosoma cruzi. Experimental allergic or inflammatory responses were also enhanced in WSX-1-deficient mice. The immunosuppressive effects of IL-27 depend on inhibition of the development of Th17 cells (a newly identified inflammatory T-helper population) and induction of IL-10 production. Moreover, administration of IL-27 or augmentation of IL-27 signaling suppresses some diseases of autoimmune or allergic origin, demonstrating its potential in therapy of diseases mediated by inflammatory cytokines. In this review, we discuss recent studies on the role of IL-27 in immunity to parasitic and bacterial infections as well as in allergy and autoimmunity in view of its pro- and anti-inflammatory properties.

Objective: In the present work, we investigate the role of interleukin (IL)27/IL27 receptor a (Ra) (WSX-1) in the development of autoimmune disorders in the MRL/lpr mouse, which is considered as an experimental model of systemic lupus erythaematosus (SLE) in humans. Methods: We generated two strains of WSX-1 transgenic mice in the MRL/lpr background with different expression levels of WSX-1, and investigated the effect of WSX-1 overexpression on survival, glomerulonephritis and immunological properties. Results: In comparison with wild type (WT) MRL/lpr and transgenic (Tg) low (TgL) mice, Tg high (TgH) mice exhibited a prolonged lifespan and no apparent development of autoimmune nephritis. Production of anti-dsDNA antibody and total IgG and IgG2a were significantly lower in TgH mice than those of TgL and WT mice. The expressed amounts of interferon (IFN)c and IL4 mRNA by CD4 + T cells from Tg mice decreased in a dose-dependent fashion. CD4 + splenic lymphocytes in TgH mice were more subject to the IL27-mediated suppression of cytokine production. In vitro stimulation of CD4 + T cells by IL27 resulted in over phosphorylation of STAT3 in TgH cells than in WT cells. Conclusion: WSX-1 overexpression in the MRL/lpr background rendered the autoimmune prone mice protected from the development of autoimmune diseases. Our results suggest that IL27 signalling may be a therapeutic target against autoimmune diseases, including human SLE.

The performance of the Texaco gasifier in hydrogen production was studied numerically. To estimate the accurate carbon conversion, a two-stage equilibrium model was proposed. In the proposed model, the two reactions which determined the carbon conversion were separated from other vapor–vapor reactions. The governing equations of the proposed model were derived and a self-consistent method was developed to solve the governing equations. The %AAD of the calculated carbon conversions from the measured values was 2.89 and that of the calculated gas production rate was 0.64. Calculated gas compositions showed a fairly good agreement with the experimental ones for commercial scale plants. It was found that the chemical reactions that occurred in the Texaco gasifier possess a mechanism for keeping the carbon conversion close to unity against a wide variation in the H 2 O to coal ratios.

Activating NK cell receptors transduce signals through ITAM-containing adaptors, including FcRγ and DAP12. Although the caspase recruitment domain (CARD)9-Bcl10 complex is essential for FcRγ/DAP12-mediated NF-κB activation in myeloid cells, its involvement in NK cell receptor signaling is unknown. Herein we show that the deficiency of CARMA1 or Bcl10, but not CARD9, resulted in severe impairment of cytokine/chemokine production mediated by activating NK cell receptors due to a selective defect in NF-κB activation, whereas cytotoxicity mediated by the same receptors did not require CARMA1-Bcl10-mediated signaling. IκB kinase (IKK) activation by direct protein kinase C (PKC) stimulation with PMA plus ionomycin (P/I) was abrogated in CARMA1-deficient NK cells, similar to T and B lymphocytes, whereas CARD9-deficient dendritic cells (DCs) exhibited normal P/I-induced IKK activation. Surprisingly, CARMA1 deficiency also abrogated P/I-induced IKK activation in DCs, indicating that CARMA1 is essential for PKC-mediated NF-κB activation in all cell types, although the PKC-CARMA1 axis is not used downstream of myeloid ITAM receptors. Consistently, PKC inhibition abrogated ITAM receptor-mediated activation only in NK cells but not in DCs, suggesting PKC-CARMA1-independent, CARD9-dependent ITAM receptor signaling in myeloid cells. Conversely, the overexpression of CARD9 in CARMA1-deficient cells failed to restore the PKC-mediated NF-κB activation. Thus, NF-κB activation signaling through ITAM receptors is regulated by a cell type-specific mechanism depending on the usage of adaptors CARMA1 and CARD9, which determines the PKC dependence of the signaling.

Clinical pharmacy training III (bedside training) in the School of Pharmaceutical Sciences, Kyushu University of Health and Welfare is intended to train pharmacists who can also cope with medical emergencies. Therefore we produced original scenarios that provide experience of various medical emergencies using emergency care simulators. As a result, these simulators enabled students to experience dealing with various medical emergencies such as cardiopulmonary resuscitation, automated external defibrillation (AED), adrenalin administration, and oxygen inhalation. In addition, a survey on the necessity for and the degree of the understanding of training contents associated with emergency care simulators was performed before and at the end of clinical training. After clinical training, the necessity for and the degree of the understanding of these training contents significantly increased (p

The purpose of this paper is to determine the shape of an oscillating body by minimising drag and lift forces, located in a transient incompressible viscous fluid flow by means of the Arbitrary Lagrangian Eulerian finite element method and an optimal control theory. A performance function is expressed by the drag and lift forces. The performance function should be minimised satisfying the state equation and the constant volume condition. Therefore, this problem can be transformed into a minimisation problem without constraint by the Lagrange multiplier method. The adjoint equation and the gradient of the performance function are used to update the shape of the body. In this study, as a minimisation technique, the weighted gradient method is applied. The final shape is obtained of which drag and lift forces are reduced by 66.2% and 92.8%, respectively. The final shape obtained by this study is compared with the final shape of the non-oscillating body. The obtained final shape of the oscillating body is significantly different from the non-oscillating body.

The aim of this study was to investigate the effects of repeated administrations of relatively low doses of 7,12-dimethylbenz[a]anthracene (DMBA) on the induction of mammary carcinomas (MCs) and dysplasias (MDs) in rats. DMBA at 0, 0.1, 0.2, 0.5 and 1 mg for female rats, and at 0, 0.5, 1 and 2 mg for male rats was administered twice weekly after weaning. In female rats, repeated administration of 1 mg DMBA induced MCs while 0.1 mg DMBA induced MDs in all animals. The incidence of MCs increased and the latent period shortened while the incidence of MDs decreased in a dose-dependent manner. In male rats, repeated administration of 2 mg DMBA induced MCs in all animals. The incidence of MCs increased and the latent period shortened in a dose-dependent manner while the incidence of MDs increased by repeated administration of 1 mg DMBA. These results suggest that the total exposure of chemical carcinogens may be responsible for the induction of MCs or MDs, and that MDs may be more dependent on female sex hormones than MCs.

In Japan,prescription costs account for more than 20% of the national health care budget.In order to curtail such expenditure as much as possible,the government recommends switching from branded products to generics.However,the information available regarding the equivalence of branded products and generics is often insufficient.With this in mind,we evaluated the equivalence of the branded benidipine hydrochloride tablets and generics of it,by comparing such aspects as their passage through a nasogastric tube,and the characteristics of divided tablets.Further,since drug information (DI) is a vital factor for evaluating generics,we conducted an objective evaluation of the adequacy of DI supplied for them.Among sixteen generic products,the passage through a nasogastric tube was significantly delayed for 2 products and for 1 of these products,there was a large variation in the weight of the halves of divided tablets.Further,the amount of information supplied by the manufacturers of the generics was less than that supplied by the manufacturer of the original product and for most of the former,it took longer to obtain.In the clinical setting,tablets are often divided or made into suspensions and our results suggest that the generics are not necessarily equivalent to the branded product when used in these ways.We therefore conclude that generics should be evaluated not just from the aspect of bioequivalence with no change in dosage form but from a wider overall perspective.

We improved the universal training model that had been used for bedside training at the School of Pharmaceutical Sciences,Kyushu University of Health and Welfare,making it into a pharmaceutical universal training model for checking various administration routes.The advantages of the model are as follows : (1)various gastric tubes can be inserted into gastric and intestinal fistulae ; (2)training on more organs is possible ; (3)suppositories can be simply inserted ; (4)easy to change bedsore pads,and (5)puncture site facilitates the checking of subcutaneous,intramuscular,and intravenous injections and intravenous hyperalimentation.We conducted a questionnaire survey of students regarding the following points before and after the training : checking of various administration routes (tubal feeding,injection routes),practice in rectal administration to patients,bedsore care procedures and drug selection based on bedsore stage.Since there was a significant increase in the recognition of the necessity of these items and students understanding of them (p

We examined the effects of a diuretic, isotonic saline, and chelating agent, catechol-3, 6-bis (methyleiminodiacetic acid) (CBMIDA), on the excretion and prevention of renal damage of depleted uranium (DU). Male Wistar rats (8 weeks old) divided into seven groups were preinjected intraperitoneally with 4 mg/kg DU and then the six groups were injected intraperitoneally with a diuretic, a diuretic plus isotonic saline, 480 mg/kg or 720 mg/kg CBMIDA alone, or 480 mg/kg or 720 mg/kg CBMIDA plus a diuretic and saline for three days, and the one group was as the control (no treatment). The rats were killed 6 days after DU injection. The results indicated that the diuretic alone and the diuretic with isotonic saline were not effective in removing uranium from the body and protecting the renal function, and also did not help to increase significantly the effects of CBMIDA.

IL-17-producing CD4(+) T cells, so called T(h)17 cells, constitute a newly identified inflammatogenic cell population, which is critically involved in some inflammatory diseases. To explore the role of T(h)17 cells in murine experimental autoimmune uveoretinitis (EAU), a model of human autoimmune uveitis where T(h)1 responses predominantly participate in the pathogenesis, IL-17(-/-) mice were immunized with interphotoreceptor retinoid-binding protein peptide 1-20 for disease induction. Funduscopic examination revealed that EAU was induced in IL-17(-/-) mice just like in wild-type (WT) mice at early phases of the disease. However, at later/maintenance phases, the severity was significantly reduced in IL-17(-/-) mice. Expression of IFN-gamma and MCP-1 was comparable between WT and IL-17(-/-) mice during the time course. In vivo blockade of IFN-gamma and IL-4 resulted in exacerbation of EAU at later phases with augmented IL-17 production. Taken together, our data demonstrated that IL-17/T(h)17 participates in the late phases of EAU and also that T(h)1 and T(h)17 responses are differentially required for EAU.

WSX-1 is the α subunit of the IL-27R complex expressed by T, B, NK/NKT cells, as well as macrophages and dendritic cells (DCs). Although it has been shown that IL-27 has both stimulatory and inhibitory effects on T cells, little is known on the role of IL-27/WSX-1 on DCs. LPS stimulation of splenic DCs in vivo resulted in prolonged CD80/CD86 expression on WSX-1-deficient DCs over wild-type DCs. Upon LPS stimulation in vitro, WSX-1-deficient DCs expressed Th1-promoting molecules higher than wild-type DCs. In an allogeneic MLR assay, WSX-1-deficient DCs were more potent than wild-type DCs in the induction of proliferation of and IFN-γ production by responder cell proliferation. When cocultured with purified NK cells, WSX-1-deficient DCs induced higher IFN-γ production and killing activity of NK cells than wild-type DCs. As such, Ag-pulsed WSX-1-deficient DCs induced Th1-biased strong immune responses over wild-type DCs when transferred in vivo. WSX-1-deficient DCs were hyperreactive to LPS stimulation as compared with wild-type DCs by cytokine production. IL-27 suppressed LPS-induced CD80/86 expression and cytokine production by DCs in vitro. Thus, our study demonstrated that IL-27/WSX-1 signaling potently down-regulates APC function and Th1-promoting function of DCs to modulate overall immune responses.

Clear cell hidradenoma of the breast is rare. A 55-year-old woman demonstrated a left breast tumor during follow-up examination of the right breast. Focal asymmetric density was shown on mammogram, and ultrasonography showed an intracystic tumor. Since the diagnosis was not clear on aspiration cytology, excisional biopsy was performed. The lesion was an intracystic tumor macroscopically. Histological examination demonstrated characteristic histological features of clear cell hidradenoma, such as proliferation of uniform epithelial cells, clear or slightly eosinophilic cytoplasm, and cuboidal cell-lined ductal structures. Immunohistochemically, these proliferating epithelial cells were negative for myoepithelial markers, such as alpha-smooth muscle actin, CD 10 and anti-muscle actin, but positive for p63. These features were consistent with clear cell hidradenoma.

We report a case of primary giant cell malignant fibrous histiocytoma (GCMFH) of the breast. A 56-year-old Japanese woman presented with a firm mass in the right breast. Mammography and ultrasonography revealed a well-circumscribed and lobulated mass in the upper outer quadrant of the right breast, indicative of a benign breast tumor or mucinous carcinoma. Magnetic resonance imaging revealed a restricted breast tumor without intraductal spread. Computed tomography and bone scintigraphy found no sites of distant metastases. Fine needle aspiration biopsy showed several clusters of atypical cells associated with numerous multinucleated giant cells. Breast-conserving surgery with axillary lymph nodes dissection was performed. Histological examination showed primary GCMFH of the breast. No metastases were identified in any of the 15 left axillary lymph nodes resected and surgical margins were free from tumor cells. The tumor was negative for both estrogen and progesterone receptor. Neither adjuvant chemoendocrine therapy nor postoperative radiotherapy was given, and the patient has remained disease free for 30 months postoperatively. To our knowledge, only 30 cases of primary MFH of the breast have been reported in the literature.

Influenza virus (IFV) infection is a common cause of severe viral pneumonia associated with acute respiratory distress syndrome (ARDS), which is difficult to control with general immunosuppressive therapy including corticosteroids due to the unfavorable effect on viral replication. Studies have suggested that the excessive activation of the innate immunity by IFV is responsible for severe pathologies. In this study, we focused on CARD9, a signaling adaptor known to regulate innate immune activation through multiple innate sensor proteins and investigated its role in anti-IFV defense and lung pathogenesis in a mouse model recapitulating severe influenza pneumonia with ARDS. We found that influenza pneumonia was dramatically attenuated in Card9-deficient mice, which showed improved mortality with reduced inflammatory cytokines and chemokines in the infected lungs. However, viral clearance, type-I interferon production and the development of anti-viral B and T cell immunity were not compromised by CARD9 deficiency. Syk or CARD9-deficient DCs but not macrophages showed impaired cytokine but not type-I interferon production in response to IFV in vitro, indicating a possible role for the Syk-CARD9 pathway in DCs in excessive inflammation of IFV-infected lungs. Therefore, inhibition of this pathway is an ideal therapeutic target for severe influenza pneumonia without affecting viral clearance.

Hydrogenosomes and mitosomes are mitochondrion-related organelles (MROs) that have highly reduced and divergent functions in anaerobic/microaerophilic eukaryotes. Entamoeba histolytica, a microaerophilic, parasitic amoebozoan species, which causes intestinal and extraintestinal amoebiasis in humans, possesses mitosomes, the existence and biological functions of which have been a longstanding enigma in the evolution of mitochondria. We previously demonstrated that sulfate activation, which is not generally compartmentalized to mitochondria, is a major function of E. histolytica mitosomes. However, because the final metabolites of sulfate activation remain unknown, the overall scheme of this metabolism and the role of mitosomes in Entamoeba have not been elucidated. In this study we purified and identified cholesteryl sulfate (CS) as a final metabolite of sulfate activation. We then identified the gene encoding the cholesteryl sulfotransferase responsible for synthesizing CS. Addition of CS to culture media increased the number of cysts, the dormant form that differentiates from proliferative trophozoites. Conversely, chlorate, a selective inhibitor of the first enzyme in the sulfate-activation pathway, inhibited cyst formation in a dose-dependent manner. These results indicate that CS plays an important role in differentiation, an essential process for the transmission of Entamoeba between hosts. Furthermore, we show that Mastigamoeba balamuthi, an anaerobic, free-living amoebozoan species, which is a close relative of E. histolytica, also has the sulfate-activation pathway in MROs but does not possess the capacity for CS production. Hence, we propose that a unique function of MROs in Entamoeba contributes to its adaptation to its parasitic life cycle.

Interleukin-27 (IL-27) is a cytokine with strikingly diverse influences on the immune response. Although it was initially linked with the development of Th1 responses, it is now recognized as a potent antagonist of different classes of inflammation through its ability to directly modify CD4+ and CD8+ T cell effector functions, to induce IL-10, and to promote specialized T regulatory cell responses. Although this aspect of IL-27 biology has provided insights into how the immune system prevents hyperactivity in the setting of infectious and autoimmune inflammation, in vaccination and cancer models the stimulatory effects of IL-27 on CD8+ T cell function appear prominent. Additionally, associations between IL-27 and antibody-mediated disease have led to an interest in defining the impact of IL-27 on innate immunity and humoral responses in different disease states. The maturation of this literature has been accompanied by attempts to translate these findings from experimental models into human diseases and by efforts to define where IL-27 might represent a viable therapeutic target.