Humanized anti-IL-26 monoclonal antibody as a novel targeted therapy for chronic graft-versus-host disease.

IL-26 is a Th17 cytokine, with its gene being absent in rodents. To characterize the in vivo immunological effects of IL-26 in chronic systemic inflammation, we used human IL26 transgenic (hIL-26Tg) mice and human umbilical cord blood mononuclear cells (hCBMC) in mouse allogeneic-graft-versus-host disease (GVHD) and chronic xenogeneic-GVHD model, respectively. Transfer of bone marrow and spleen T cells from hIL-26Tg mice into B10.BR mice resulted in GVHD progression, with clinical signs of tissue damage in multiple organs. IL-26 markedly increased neutrophil levels both in the GVHD-target tissues and peripheral blood. Expression levels of Th17 cytokines in hIL-26Tg mice-derived donor CD4 T cells were significantly increased, whereas IL-26 did not affect cytotoxic function of donor CD8 T cells. In addition, granulocyte-colony stimulating factor, IL-1ß, and IL-6 levels were particularly enhanced in hIL-26Tg mice. We also developed a humanized neutralizing anti-IL-26 monoclonal antibody (mAb) for therapeutic use, and its administration after onset of chronic xenogeneic-GVHD mitigated weight loss and prolonged survival, with preservation of graft-versus-leukemia effect. Taken together, our data elucidate the in vivo immunological effects of IL-26 in chronic GVHD models and suggest that a humanized anti-IL-26 mAb may be a potential therapeutic agent for the treatment of chronic GVHD.

Inhibited maturation of astrocytes caused by maternal n-3 PUFA intake deficiency hinders the development of brain glial cells in neonatal rats.

The brain is rich in long-chain PUFA, which play an essential role in its development and functions. Here, we examined the impact of maternal n-3 PUFA intake deficiency during gestation and lactation on the development of glial cells in the pup's developing cerebral cortex. In addition, using myelination as indicator and the anti-myelin basic protein as measurement to establish the relationship between the number of glial fibrillary acidic protein (GFAP)-positive cells and the development of oligodendrocytes, we determined the myelination state of the somatosensory cortex at postnatal day 14. Rat dams were fed either a control (Cont) or an n-3 PUFA-deficient (Def) diet for 60 d (acclimatisation: 14 d; gestation: 21 d; and lactation: 21 d). Pups lactated from dams throughout the experiment. The distribution pattern of astrocytes in pups on postnatal day 7 was immunohistochemically analysed using GFAP and brain lipid binding protein (BLBP) as markers for mature astrocytes and astrocyte-specific radial glial cells, respectively. It was observed that, when compared with Cont pups, GFAP-positive cells decreased, BLBP-positive cells increased and myelinated structures were sparser in the somatosensory cortices of Def pups. In the open field test on postnatal day 21, behavioural parameters did not differ between groups. Our results indicated that inhibited maturation of astrocytes caused by maternal n-3 PUFA deficiency hindered the development of brain glial cells of neonatal rats; hence, maternal n-3 PUFA intake during the gestation and lactation periods may have been crucial for the brain cell composition of pups.

Intracellular Storage of Duffy Antigen-Binding Chemokines by Duffy-Positive Red Blood Cells.

BACKGROUND: Duffy antigen/chemokine receptor (DARC) is a non-signaling receptor for multiple chemokines. The role of DARC on red blood cells (RBCs) has remained elusive. The purpose of this study was to analyze selective storage of DARC-binding chemokines in RBCs. METHODS: Peripheral blood from healthy volunteers with DARC-positive blood type was collected in EDTA tubes. The concentration of DARC binding chemokines (i.e., MCP-1, RANTES, eotaxin-1, TARC, and IL-8), DARC nonbinding chemokines (i.e., MIP-1α, IP-10), and several cytokines in the supernatant of purified RBCs before and after hemolysis was measured using Bio-Plex and ELISA assays. Storage of chemokines in RBCs and the expression of DARC were evaluated using flow-cytometry. RESULTS: The levels of all DARC-binding chemokines except TARC and IL-8 increased significantly after hemolysis. There was no significant increase in any of the DARC non-binding chemokines or in the other cytokines after hemolysis. RANTES, eotaxin-1, and MCP-1 were detectable intracellularly but not on the RBC surface. RANTES was absorbed by RBCs. DARC was expressed intracellularly in RBCs as well as on the surface. CONCLUSIONS: These data suggested that DARC-positive RBCs store RANTES, MCP-1 and eotaxin-1. DARC on RBC may be internalized from the surface in the process of chemokine absorption.

Comparison of the pain-relieving effects of transcutaneous electrical nerve stimulation applied at the same dermatome levels as the site of pain in the wrist joint.

[Purpose] The purpose of this study was to develop a proposal for an effective interventional option for therapeutic stimulation sites by comparing the pain-relieving effect of transcutaneous electrical nerve stimulation (TENS) applied to the same dermatome level of the contralateral sites of the dorsal wrist joint with the pain or the neck, or both sites simultaneously. [Subjects and Methods] A control was first established by triggering pain in the left dorsal wrist joints of adult females by using heat stimulation. Three interventions were then performed, comprising the TENS to the contralateral wrist joint (CW) and to the neck (N) at the same dermatome level as the site of pain, and the TENS to both CW and N simultaneously (CWN). Levels of pain and cerebral blood flow were also measured. [Results] The pain levels of three interventions were found to be significantly decreased compared with the control; however, no significant differences in the levels of pain were seen between any combinations of three interventions. Furthermore, no significant differences were seen between any interventions in terms of cerebral blood flow. [Conclusion] The results suggest that in order for TENS to be effective, it is necessary to make effective use of the dermatome.

Possible involvement of reusable towels in the high rate of Bacillus species-positive blood cultures in Japanese hospitals.

BACKGROUND: A number of outbreaks caused by Bacillus species have been reported to date. Outbreaks reported in the last decade have predominantly arisen in Japanese hospitals. AIM: To elucidate factors contributing to these real or pseudo outbreaks by Bacillus species, and to evaluate the rate of Bacillus species-positive blood culture samples in Japan. METHODS: A systematic review of the literature was performed. Reports including data on outbreaks caused by Bacillus species were searched for in PubMed, Google Scholar and Evidence-based Medicine BMJ from inception through 10 Aug 2014. Japanese nationwide data on bacteriological tests were collected from Japan Nosocomial Infections Surveillance. Regional bacteriological data for Akita prefecture were collected using the Akita Regional Network for Infection Monitoring/Control System. FINDINGS: Contamination of reusable towels was suspected as a cause for the high rate of Bacillus-positive blood cultures in Japan. The rate of Bacillus species in blood cultures was much higher in Japan than in reports from other countries. CONCLUSIONS: The high contamination rate of blood culture samples by Bacillus species in Japan is a matter of concern for infection control and medical treatment. Bacteriological investigation of reusable towels should be considered in hospitals with a high frequency of Bacillus-positive blood cultures.

Coexistence of monochalocogen and dichalocogen ions in BiSe2 and BiS2 crystals prepared at high pressure.

A single crystal of bismuth diselenide, BiSe2, containing both monochalcogen (Se(2-)) and dichalcogen (Se2(2-)) ions, was prepared at a high pressure of 5.5 GPa. Its crystal structure, substitution chemistry, and physical properties were investigated. X-ray analysis showed that BiSe2 is in a monoclinic system (space group C2/m) with the following lattice parameters: a = 16.740(3) Å, b = 4.1410(11) Å, c = 12.027(3) Å, and ß = 127.658(13)°. A crystal structure of BiSe2 can be viewed as a layered structure with stacks of neutral BiSe2 blocks along the c-axis, or alternatively as a quasi-one-dimensional structure with double chains of BiSe5 pyramids along the b-axis. Each Bi is coordinated with three Se(2-) ions and two Se2(2-) ions, and the bond valence analysis indicated that Bi was trivalent. BiSe2 and BiS2 form a solid solution in the whole range while retaining the same structure, and the partial substitution of Sb for Bi is also achieved at 10%. All the compounds show a semiconducting property and diamagnetism that can be attributed to the closed-shell ion core. In spite of the compositional analogy with Bi2Se3, BiSe2 is proven by the first-principles calculations not to be a topological insulator.

Coadministration of polyinosinic:polycytidylic acid and immunostimulatory complexes modifies antigen processing in dendritic cell subsets and enhances HIV gag-specific T cell immunity.

Currently approved adjuvants induce protective Ab responses but are more limited for generating cellular immunity. In this study, we assessed the effect of combining two adjuvants with distinct mechanisms of action on their ability to prime T cells: the TLR3 ligand, polyinosinic:polycytidylic acid (poly I:C), and immunostimulatory complexes (ISCOMs). Each adjuvant was administered alone or together with HIV Gag protein (Gag), and the magnitude, quality, and phenotype of Gag-specific T cell responses were assessed. For CD8 T cells, all adjuvants induced a comparable response magnitude, but combining poly I:C with ISCOMs induced a high frequency of CD127(+), IL-2-producing cells with decreased expression of Tbet compared with either adjuvant alone. For CD4 T cells, combining poly I:C and ISCOMs increased the frequency of multifunctional cells, producing IFN-γ, IL-2, and TNF, and the total magnitude of the response compared with either adjuvant alone. CD8 or CD4 T cell responses induced by both adjuvants mediated protection against Gag-expressing Listeria monocytogenes or vaccinia viral infections. Poly I:C and ISCOMs can alter Ag uptake and/or processing, and we therefore used fluorescently labeled HIV Gag and DQ-OVA to assess these mechanisms, respectively, in multiple dendritic cell subsets. Poly I:C promoted uptake and retention of Ag, whereas ISCOMs enhanced Ag degradation. Combining poly I:C and ISCOMs caused substantial death of dendritic cells but persistence of degraded Ag. These data illustrate how combining adjuvants, such as poly I:C and ISCOMs, that modulate Ag processing and have potent innate activity, can enhance the magnitude, quality, and phenotype of T cell immunity.

Comparative analysis of the magnitude, quality, phenotype, and protective capacity of simian immunodeficiency virus gag-specific CD8+ T cells following human-, simian-, and chimpanzee-derived recombinant adenoviral vector immunization.

Recombinant adenoviral vectors (rAds) are the most potent recombinant vaccines for eliciting CD8(+) T cell-mediated immunity in humans; however, prior exposure from natural adenoviral infection can decrease such responses. In this study we show low seroreactivity in humans against simian- (sAd11, sAd16) or chimpanzee-derived (chAd3, chAd63) compared with human-derived (rAd5, rAd28, rAd35) vectors across multiple geographic regions. We then compared the magnitude, quality, phenotype, and protective capacity of CD8(+) T cell responses in mice vaccinated with rAds encoding SIV Gag. Using a dose range (1 × 10(7)-10(9) particle units), we defined a hierarchy among rAd vectors based on the magnitude and protective capacity of CD8(+) T cell responses, from most to least, as: rAd5 and chAd3, rAd28 and sAd11, chAd63, sAd16, and rAd35. Selection of rAd vector or dose could modulate the proportion and/or frequency of IFN-γ(+)TNF-α(+)IL-2(+) and KLRG1(+)CD127(-)CD8(+) T cells, but strikingly ∼30-80% of memory CD8(+) T cells coexpressed CD127 and KLRG1. To further optimize CD8(+) T cell responses, we assessed rAds as part of prime-boost regimens. Mice primed with rAds and boosted with NYVAC generated Gag-specific responses that approached ∼60% of total CD8(+) T cells at peak. Alternatively, priming with DNA or rAd28 and boosting with rAd5 or chAd3 induced robust and equivalent CD8(+) T cell responses compared with prime or boost alone. Collectively, these data provide the immunologic basis for using specific rAd vectors alone or as part of prime-boost regimens to induce CD8(+) T cells for rapid effector function or robust long-term memory, respectively.

Structural abnormalities of corpus callosum and cortical axonal tracts accompanied by decreased anxiety-like behavior and lowered sociability in spock3- mutant mice.

Spock3/Testican-3 is a nervous system-expressed heparan sulfate proteoglycan belonging to a subgroup of the BM-40/SPARC/osteonectin family, the role of which in brain development is unclear. Because Spock1, a member of the Spock family, inhibits their attachment to substrates and the neurite outgrowth of cultured neuronal cells, Spock3 is also thought to be similarly involved in the neuronal development. In the present study, we established a Spock3-mutant mouse harboring a deletion extending from the presumptive upstream regulatory region to exon 4 of the Spock3 locus and performed histological and behavioral studies on these mutant mice. In wild-type (WT) mice, all Spock members were clearly expressed during brain development. In adults, intense Spock1 and Spock2 expressions were observed throughout the entire brain; whereas, Spock3 expression was no longer visible except in the thalamic nuclei. Thus, Spock3 expression is mostly confined to the developmental stage of the brain. In adult mutant mice, the cells of all cortical layers were swollen. The corpus callosum was narrowed around the central region along the rostral-caudal axis and many small spaces were observed without myelin sheaths throughout the entire corpus callosum. In addition, the cortical input and output fibers did not form into thick bundled fibers as well as the WT counterparts did. Moreover, a subpopulation of corticospinal axonal fibers penetrated into the dorsal striatum with moderately altered orientations. Consistent with these modifications of brain structures, the mutant mice exhibited decreased anxiety-like behavior and lowered sociability. Together, these results demonstrate that Spock3 plays an important role in the formation or maintenance of major neuronal structures in the brain.

Crystal structure and properties of perovskite-type rubidium niobate, a high-pressure phase of RbNbO3.

We synthesized a perovskite-type RbNbO3 at 1173 K and 4 GPa from non-perovskite RbNbO3 and investigated its crystal structure and properties towards ferroelectric material design. Single-crystal X-ray diffraction analysis revealed an orthorhombic cell in the perovskite-type structure (space group Amm2, no. 38) with a = 3.9937(2) Å, b = 5.8217(3) Å, and c = 5.8647(2) Å. This non-centrosymmetric space group is the same as the ferroelectric BaTiO3 and KNbO3 but with enhanced distortion. Structural transition from orthorhombic to two successive tetragonal phases (Tetra1 at 493 K, Tetra2 at 573 K) was observed, maintaining the perovskite framework before reverting to the triclinic ambient phase at 693 K, with no structural changes between 4 and 300 K. The first transition is similar to that of KNbO3, whereas the second to Tetra2, marked by c-axis elongation and a significant cp/ap ratio jump (from 1.07 to 1.43), is unique. This distortion suggests a transition similar to that of PbVO3, where an octahedron's oxygen separates along the c-axis, forming a pyramid. Ab initio calculations simulating negative pressure like thermal expansion predicted this phase transition (cp/ap = 1.47 at -1.2 GPa), aligning with experimental findings. Thermal analysis revealed two endothermic peaks, with the second transition entailing a greater enthalpy change and volume alteration. Strong second harmonic generation signals were observed across Ortho, Tetra1, and Tetra2 phases, similar to BaTiO3 and KNbO3. Permittivity increased during the first transition, although the second transition's effects were limited by thermal expansion-induced bulk sample collapse. Perovskite-type RbNbO3 emerges as a promising ferroelectric material.

Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine.

A systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole-sporozoite PfSPZ vaccine in African infants. Innate immune activation and myeloid signatures at prevaccination baseline correlated with protection from P. falciparum parasitemia in placebo controls. These same signatures were associated with susceptibility to parasitemia among infants who received the highest and most protective PfSPZ vaccine dose. Machine learning identified spliceosome, proteosome, and resting DC signatures as prevaccination features predictive of protection after highest-dose PfSPZ vaccination, whereas baseline circumsporozoite protein-specific (CSP-specific) IgG predicted nonprotection. Prevaccination innate inflammatory and myeloid signatures were associated with higher sporozoite-specific IgG Ab response but undetectable PfSPZ-specific CD8+ T cell responses after vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against infection by sporozoite injection in malaria-naive mice while diminishing the CD8+ T cell response to radiation-attenuated sporozoites. These data suggest a dichotomous role of innate stimulation for malaria protection and induction of protective immunity by whole-sporozoite malaria vaccines. The uncoupling of vaccine-induced protective immunity achieved by Abs from more protective CD8+ T cell responses suggests that PfSPZ vaccine efficacy in malaria-endemic settings may be constrained by opposing antigen presentation pathways.

Melanogenesis-inhibitory activity of aromatic glycosides from the stem bark of Acer buergerianum.

A new benzyl glucoside, 3-O-demethylnikoenoside (1), along with eleven known compounds, including seven aromatic glycosides, 2-8, three lignans, 9-11, and one cyclitol, 12, were isolated from the BuOH-soluble fraction of a MeOH extract of Acer buergerianum stem bark. The structures of the new compound were elucidated on the basis of extensive spectroscopic analyses and comparison with literature. Upon evaluation of compounds 1-12 on melanogenesis in B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH), three compounds, i.e., hovetrichoside B (8), pinoresinol 4-O-ß-D-glucopyranoside (9), and pinoresinol 4-O-ß-D-apiofuranosyl-(1→2)-ß-D-glucopyranoside (10), have been found to exhibit inhibitory effects with 41-49% melanin content compared to the control at 100 µM and low cytotoxicity to the cells (81-92% cell viability at 100 µM). Western blot analysis showed that compound 8 reduced the protein levels of MITF (=microphtalmia-associated transcription factor) and tyrosinase, in a concentration-dependent manner, suggesting that 8 inhibits melanogenesis in α-MSH-stimulated B16 melanoma cells by, at least in part, inhibiting the expression of MITF, followed by decreasing the expression of tyrosinase. On the other hand, upon Western blotting, compound 9 was found to reduce the protein levels of tyrosinase and TRP-2, while it increased MITF and TRP-1 (=tyrosine-related protein 1), in a concentration-dependent manner, indicating that 9 inhibits melanogenesis in α-MSH-stimulated B16 melanoma cells by, at least in part, inhibiting the expression of tyrosinase and TRP-2.

Antioxidative and melanogenesis-inhibitory activities of caffeoylquinic acids and other compounds from moxa.

The MeOH extract of moxa, the processed leaves of Artemisia princeps PAMP. (Asteraceae), exhibited potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity and melanogenesis-inhibitory activity in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16 melanoma cells. Eight caffeoylquinic acids, 1 and 6-12, five flavonoids, 13-17, two benzoic acid derivatives, 18 and 19, three coumarin derivatives, 20-22, four steroids, 23-26, and six triterpenoids, 27-32, were isolated from the MeOH extract. Upon evaluation of compounds 1, 6-23, and four semisynthetic caffeoylquinic acid esters, 2-5, for their DPPH radical-scavenging activity, 15 compounds, 1-13, 17, and 19, showed potent activities (IC(50) 3.1-16.8 µM). The 15 compounds exhibited, moreover, potent inhibitory activities (51.1-92.5% inhibition) against peroxidation of linoleic acid emulsion at 10 µg/ml concentration. In addition, when 27 compounds, 1-8, 10, 12, 13, 15-18, 20-25, and 27-32, were evaluated for their inhibitory activity against melanogenesis in α-MSH-stimulated B16 melanoma cells, five caffeoylquinic acids, i.e., chlorogenic acid (1), ethyl chlorogenate (3), propyl chlorogenate (4), isopropyl chlorogenate (5), and butyl chlorogenate (6), along with homoorientin (17) and vanillic acid (18), exhibited inhibitory activities with 33-62% reduction of melanin content at 100 µM concentration with no or almost no toxicity to the cells (89-114% of cell viability at 100 µM). Western blot analysis showed that compound 6 reduced the protein levels of microphtalmia-associated transcription factor (MITF), tyrosinase, tyrosine-related protein 1 (TRP-1), and TRP-2 mostly in a concentration-dependent manner, suggesting that this compound inhibits melanogenesis on α-MSH-stimulated B16 melanoma cells by, at least in part, inhibiting the expression of MITF, followed by decreasing the expression of tyrosinase, TRP-1, and TRP-2. Furthermore, four compounds, 13, 15, 16, and 30, exhibited cytotoxicities against HL60 human leukemia cell line (IC(50) 7.0-11.1 µM), and nine compounds, 14-16, 23, 26-28, 31, and 32, showed inhibitory effects (IC(50) 272-382 mol ratio/32 pmol 12-O-tetradecanoylphohrbol-13-acetate (TPA)) against Epstein-Barr virus early antigen (EBV-EA) activation induced by TPA in Raji cells.

Glycosidic inhibitors of melanogenesis from leaves of Passiflora edulis.

A new flavonoid glycoside, chrysin 6-C-ß-rutinoside (chrysin α-L-rhamnopyranosyl-(1→6)-C-ß-glucopyranoside; 2), and two new triterpene glycosides, (31R)-31-O-methylpassiflorine (7) and (31S)-31-O-methylpassiflorine (8), along with 14 known glycosides, including three flavonoid glycosides, 1, 3, and 4, six triterpene glycosides, 5, 6, and 9-12, three cyano glycosides, 13-15, and two other glycosides, 16 and 17, were isolated from a MeOH extract of the leaves of Passiflora edulis (passion flower; Passifloraceae). The structures of new compounds were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. Upon evaluation of compounds 1-17 against the melanogenesis in the B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH), three compounds, isoorientin (1), 2, and (6S,9R)-roseoside (17), exhibited inhibitory effects with 37.3-47.2% reduction of melanin content with no, or almost no, toxicity to the cells (90.8-100.2% cell viability) at 100 µM. Western blot analysis showed that compound 2 reduced the protein levels of MITF, TRP-1, and tyrosinase, in a concentration-dependent manner while exerted almost no influence on the level of TRP-2, suggesting that this compound inhibits melanogenesis on the α-MSH-stimulated B16 melanoma cells by, at least in part, inhibiting the expression of MITF, followed by decreasing the expression of TRP-1 and tyrosinase. In addition, compounds 1-17 were evaluated for their inhibitory effects against the EpsteinBarr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells.

Biological activities of phenolic compounds and triterpenoids from the galls of Terminalia chebula.

Nine phenolic compounds, including two phenolic carboxylic acids, 1 and 2, seven hydrolyzable tannins, 3-9, eight triterpenoids, including four oleanane-type triterpene acids, 10-13, and four of their glucosides, 14-17, isolated from a MeOH extract of the gall of Terminalia chebula Retz. (myrobalan tree; Combretaceae), were evaluated for their inhibitory activities against melanogenesis in B16 melanoma cells induced by α-melanocyte-stimulating hormone (α-MSH), against the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) in Raji cells, and against TPA-induced inflammation in mice. Their 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activities and cytotoxic activities against four human cancer cell lines were also evaluated. Compounds 6-9 and 12 exhibited potent inhibitory activities against melanogenesis (39.3-66.3% melanin content) with low toxicity to the cells (74.5-105.9% cell viability) at a concentration of 10 µM. Western-blot analysis revealed that isoterchebulin (8) reduced the protein levels of MITF (=microphtalmia-associated transcription factor), tyrosinase, and TRP-1 (=tyrosine-related protein 1), mostly in a concentration-dependent manner. Eight triterpenoids, 10-17, showed potent inhibitory effects on EBV-EA induction with the IC50 values in the range of 269-363 mol ratio/32 pmol TPA, while these compounds exhibited no DPPH scavenging activities (IC50 >100 µM). On the other hand, the nine phenolic compounds, 1-9, exhibited potent radical-scavenging activities (IC50 1.4-10.9 µM) with weak inhibitory effects on EBV-EA induction (IC50 460-518 mol ratio/32 pmol TPA). The tannin 6 and seven triterpenoids, 10-16, have been shown to inhibit TPA-induced inflammation (1 µg/ear) in mice with the ID50 values in the range of 0.06-0.33 µmol/ear. Arjungenin (10) exhibited inhibitory effect on skin-tumor promotion in an in vivo two-stage mouse-skin carcinogenesis test based on 7,12-dimethylbenz[a]anthracene (DMBA) as initiator and with TPA as promoter. Compounds 1, 2, 4, 5, 7-9, 12, and 13, against HL60 cell line, compounds 1 and 4, against AZ521 cell line, and compounds 1, 11, and 12, against SK-BR-3 cell line, showed moderate cytotoxic activities (IC50 13.9-73.2 µM).

[Role of university hospitals in regional infection control network].

Activities and the understanding of infection control in healthcare facilities have improved in the past decade since a certification system for medical personnel, such as infection control nurse and infection control doctor, were introduced in Japan. These specialists are distributed among tertiary general hospitals, while many small and mid-scale hospitals have no infection control specialists. In 2012, the Japanese Ministry of Health, Labour and Welfare launched a new strategy for further improvement of infection control by supporting a regional network of infection control activities. Through the infection control network, small or mid-scaled hospitals can utilize infection control specialists in tertiary general hospitals, enter educational programs on infection control and consult in cases of nosocomial infection outbreaks. As part of the regional infection control network, we established an information network system, named ReNICS, to share the bacteriological test results of the hospitals in Akita prefecture. ReNICS offers epidemiological data on bacteria identified in the region. We can identify the spread of multi-drug resistant bacteria and can roughly estimate the quality of infection control activities in each facility. As a similar information network is being prepared in Hirosaki University Hospital Infection Control Center in Aomori, a prefecture neighboring Akita, we discussed the roles of university hospitals for a regional infection control network.

[Trials for early intervention in Mie Prefectural Mental Care Center].

Mie Prefectural Mental Care Center is a public psychiatric hospital that has 400 beds and 250 outpatients a day. The main catchment area is Tsu City (population: 290,000). Our hospital started early intervention in Aug 2008, and opened the Youth Mental Support Center MIE (YMSC MIE) in Oct 2008. This article reports an early intervention trial in a regional area of Japan. The mission of YMSC MIE is the education, consultation, staff training, and intervention for mental health problems and early psychosis of youths. In Jul 2009, we set up the Youth Assist Clinic (YAC) to support youths with mental health problems and early psychoses. Our activities consist of school-based, community-based, and hospital-based approaches. Specific programs are as follows: 1) School-based approaches: Outreach consultation to school. Mental health lessens. Creating mental health textbooks. Education for parents and teachers. 2) Community-based approaches: To enlighten primary physicians and mental clinic psychiatrists about the importance of early psychosis. To survey their concerns regarding early psychosis. Promoting awareness of community staff and the general public. 3) Hospital-based approaches: YAC. Case manager system. Family meetings for the family including the young with mental disorders. Peer group. Looking back over our 3-year trials, especially in school and the community, we find several problems, as follows: 1) Lack of consultation skills of medical staff outside the hospital. 2) Limiting number of schools which have mental support system. 3) Support for school attendance and learning. 4) Lack of concern about early psychosis of primary physicians and mental clinic psychiatrists. 5) Staff training for early intervention. We are now getting close to improving these issues.

Case report: Evolution of catatonic mutism and psychotic symptoms in an adolescent with Down syndrome: transition from Down syndrome disintegrative disorder to anti-N-methyl-D-aspartate receptor encephalitis.

During her first year of junior high school, a 12-year-old Japanese girl with Down syndrome experienced dizziness, gait disruption, paroxysmal weakness in her hands, and sluggish speaking. Regular blood tests and a brain MRI revealed no abnormalities, and she was tentatively diagnosed with adjustment disorder. Nine months later, the patient experienced a subacute sickness of chest pain, nausea, sleep problem with night terrors, and delusion of observation. Rapid deterioration then developed with simultaneous fever, akinetic mutism, loss of facial expression, and urine incontinence. These catatonic symptoms improved after a few weeks after admission and treatment with lorazepam, escitalopram, and aripiprazole. After discharge, nonetheless, daytime slumber, empty eyes, paradoxical laughter, and declined verbal communication persisted. Upon confirmation of the cerebrospinal N-methyl-D-aspartate (NMDA) receptor autoantibody, methylprednisolone pulse therapy was tried, but it had little effect. Visual hallucinations and cenesthopathy, as well as suicidal thoughts and delusions of death, have predominated in the following years. Cerebrospinal IL-1ra, IL-5, IL-15, CCL5, G-CSF, PDGFbb, and VFGF were raised in the early stage of initial medical attention with nonspecific complaints, but were less prominent in the later stages of catatonic mutism and psychotic symptoms. We suggest a disease concept of progression from Down syndrome disintegrative disorder to NMDA receptor encephalitis, based on this experience.

Novel regulation of parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson's disease.

Mutations in parkin, an E3 ubiquitin ligase, are the most common cause of autosomal-recessive Parkinson's disease (PD). Here, we show that the stress-signaling non-receptor tyrosine kinase c-Abl links parkin to sporadic forms of PD via tyrosine phosphorylation. Under oxidative and dopaminergic stress, c-Abl was activated in cultured neuronal cells and in striatum of adult C57BL/6 mice. Activated c-Abl was found in the striatum of PD patients. Concomitantly, parkin was tyrosine-phosphorylated, causing loss of its ubiquitin ligase and cytoprotective activities, and the accumulation of parkin substrates, AIMP2 (aminoacyl tRNA synthetase complex-interacting multifunctional protein 2) (p38/JTV-1) and FBP-1.STI-571, a selective c-Abl inhibitor, prevented tyrosine phosphorylation of parkin and restored its E3 ligase activity and cytoprotective function both in vitro and in vivo. Our results suggest that tyrosine phosphorylation of parkin by c-Abl is a major post-translational modification that leads to loss of parkin function and disease progression in sporadic PD. Moreover, inhibition of c-Abl offers new therapeutic opportunities for blocking PD progression.