Search

From genetic and etiological studies, autoimmune mechanisms underlying schizophrenia are suspected; however, the details remain unclear. In this study, we describe autoantibodies against neural cell adhesion molecule (NCAM1) in patients with schizophrenia (5.4%, cell-based assay; 6.7%, ELISA) in a Japanese cohort (n = 223). Anti-NCAM1 autoantibody disrupts both NCAM1-NCAM1 and NCAM1-glial cell line-derived neurotrophic factor (GDNF) interactions. Furthermore, the anti-NCAM1 antibody purified from patients with schizophrenia interrupts NCAM1-Fyn interaction and inhibits phosphorylation of FAK, MEK1, and ERK1 when introduced into the cerebrospinal fluid of mice and also reduces the number of spines and synapses in frontal cortex. In addition, it induces schizophrenia-related behavior in mice, including deficient pre-pulse inhibition and cognitive impairment. In conclusion, anti-NCAM1 autoantibodies in patients with schizophrenia cause schizophrenia-related behavior and changes in synapses in mice. These antibodies may be a potential therapeutic target and serve as a biomarker to distinguish a small but treatable subgroup in heterogeneous patients with schizophrenia.

Recent studies have identified autoantibodies against synaptic molecules in patients with encephalitis. Autoantibodies against the N-Methyl-d-Aspartate receptor have been reported in patients with schizophrenia; however, autoantibodies against other molecules are yet to be identified. This study used a cell-based assay to examine serum samples from individuals with schizophrenia and healthy controls. The results showed that 5 (8.6%) of 57 patients with schizophrenia harbor autoantibodies against the α1 subunit of the γ-aminobutyric acid A receptor (GABAARα1), which are currently not know to be linked to the pathology of this disease. Some patients showed markedly high antibody titers (i.e., 1:10,000-100,000). None of the heathy control subjects were positive for GABAARα1 antibodies. Therefore, these autoantibodies may form the basis of GABA-mediated pathology in a subgroup of patients with schizophrenia.

Background Psoriasis is a chronic inflammatory skin disease characterized by IL-17-mediated immune responses. p38 is known to be highly activated in the psoriatic epidermis; however, whether p38 is involved in the development of psoriasis is unclear. Objective We sought to demonstrate that activation of p38 mitogen-activated protein kinase is sufficient to induce psoriatic inflammation in mice and that cutaneous p38 activities are the topical therapeutic targets for psoriasis. Methods A p38 activator, anisomycin, was applied daily to murine skin. Transcriptomic analyses were performed to evaluate the similarities of the skin responses to those in human psoriasis and the existing animal model. BIRB796, a small-molecule inhibitor targeting p38 activities, was applied to the murine psoriatic models topically or to human psoriatic skin specimens ex vivo. Results Topical treatment with anisomycin induced key signatures in psoriasis, such as epidermal thickening, neutrophil infiltration, and gene expression of Il1a, Il1b, Il6, Il24, Cxcl1, Il23a, and Il17a, in treated murine skin. These responses were fully abrogated by topical treatment with BIRB796, and were reduced in IL-17A–deficient mice. Transcriptomic analyses demonstrated the similarities of anisomycin-induced dermatitis to human psoriasis and imiquimod-induced murine psoriatic dermatitis. Furthermore, BIRB796 targeting of p38 activities reduced expression of psoriasis-related genes in both human keratinocytes stimulated with recombinant IL-17A in vitro and psoriatic skin specimens ex vivo. Conclusion Therefore our findings suggest that cutaneous p38 activation can be a key event in patients with psoriasis and a potential topical therapeutic target of a small molecule.

This study investigates the usefulness of machine learning for modeling complex relationships in a material library. We tested 81 types of active pharmaceutical ingredients (APIs) and their tablets to construct the library, which included the following variables: 20 types of API material properties, one type of process parameter (three levels of compression pressure), and two types of tablet properties (tensile strength (TS) and disintegration time (DT)). The machine learning algorithms boosted tree (BT) and random forest (RF) were applied to analysis of our material library to model the relationships between input variables (material properties and compression pressure) and output variables (TS and DT). The calculated BT and RF models achieved higher performance statistics compared with a conventional modeling method (i.e., partial least squares regression), and revealed the material properties that strongly influence TS and DT. For TS, true density, the tenth percentile of the cumulative percentage size distribution, loss on drying, and compression pressure were of high relative importance. For DT, total surface energy, water absorption rate, polar surface energy, and hygroscopicity had significant effects. Thus, we demonstrate that BT and RF can be used to model complex relationships and clarify important material properties in a material library.

Merkel cell polyomavirus (MCPyV) is the causative agent of an aggressive skin tumor, Merkel cell carcinoma. The viral genome is integrated into the tumor genome and harbors nonsense mutations in the helicase domain of large T antigen. However, the molecular mechanisms by which the viral genome gains the tumor-specific mutations remain to be elucidated. Focusing on host cytosine deaminases APOBEC3s, we find that A3A, A3B, or A3G introduces A3-specific mutations into episomal MCPyV genomes in MCPyV-replicating 293-derivative cells. Sequence analysis of MCPyV genomes retrieved from the NCBI database revealed a decrease of TpC dinucleotide, a preferred target for A3A and A3B, in the 3'-region of the large T antigen‒coding sequence. The viral DNA isolated from tumors contained mutated cytosines, with a remarkable bias toward TpC dinucleotide. Analysis of publicly available microarray data showed that expression of IFN-γ and cytotoxic T lymphocyte markers was positively correlated with the A3A, A3B, and A3G levels in MCPyV-positive but not in MCPyV-negative tumors. Finally, IFN-γ treatment induced A3B and A3G expression in the MCPyV-positive Merkel cell carcinoma cell line MS-1. These results suggest that the IFN-γ-A3B axis plays pivotal roles in evolutionally shaping MCPyV genomic sequences and in generating tumor-specific large T antigen mutations during development of Merkel cell carcinoma.

Recent studies have identified autoantibodies against synaptic molecules in patients with encephalitis. Autoantibodies against the N-Methyl-d-Aspartate receptor have been reported in patients with schizophrenia; however, autoantibodies against other molecules are yet to be identified. This study used a cell-based assay to examine serum samples from individuals with schizophrenia and healthy controls. The results showed that 5 (8.6%) of 57 patients with schizophrenia harbor autoantibodies against the α1 subunit of the γ-aminobutyric acid A receptor (GABA

Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family consists of deaminases. Some isozymes of APOBEC3 are induced upon human papillomavirus infection or development of psoriasis skin lesions. However, the involvement of APOBEC3 in keratinocyte differentiation has not been addressed. We herein sought to evaluate the roles of APOBECs in mouse primary keratinocyte differentiation. We found that expression levels of APOBEC1 and APOBEC3 were increased during calcium-induced keratinocyte differentiation. Unexpectedly, however, the expression levels of keratinocyte differentiation markers keratin 1/10, involucrin, loricrin and filaggrin were higher in keratinocytes treated with APOBEC3 siRNAs than in those treated with control RNAs. In addition, the treatment of keratinocytes with APOBEC3 siRNAs increased the gene expression levels of Notch3, a master regulator of keratinocyte differentiation. Moreover, calcium-induced increase in Notch3 expression and keratinocyte differentiation were impaired by transfection with an APOBEC3 expression plasmid. Furthermore, co-treatment with Notch3 siRNAs reduced the APOBEC3 siRNA-mediated upregulation of Notch3 expression and in part attenuated the increased expression levels of keratinocyte differentiation markers. These results suggest that APOBEC3 is induced upon keratinocyte differentiation and negatively regulates the keratinocyte differentiation in part by its inhibitory role for Notch3 expression.

The purpose of this study was to explore the potential of a quantitative structure–property relationship (QSPR) model to predict tablet density. First, we calculated 3381 molecular descriptors for 81 active pharmaceutical ingredients (API). Second, we obtained data that were merged with a dataset including powder properties that we had constructed previously. Next, we prepared 81 types of tablet, each containing API, microcrystalline cellulose, and magnesium stearate using direct compression at 120, 160, and 200 MPa, and measured the tablet density. Finally, we applied the boosted-tree machine learning approach to construct a QSPR model and to identify crucial factors from the large complex dataset. The QSPR model achieved statistically good performance. A sensitivity analysis of the QSPR model revealed that molecular descriptors related to the average molecular weight and electronegativity of the API were crucial factors in tablet density, whereas the effects of powder properties were relatively insignificant. Moreover, we found that these descriptors had a positive linear relationship with tablet density. This study indicates that a QSPR approach is possibly useful for in silico prediction of tablet density for tablets prepared using more than a threshold compression pressure, and to allow a deeper understanding of tablet density.

The aim of this study was to examine the effects of regular high-cocoa chocolate consumption on arterial stiffness and fat oxidation during light- to moderate-intensity exercise.This randomized, controlled, parallel-group intervention study included 32 Japanese college students (mean age, 20.7 ± 0.3 y; men, n = 24; women, n = 8) who were assigned to either control or intervention groups (n = 16 each). The control group did not alter their habitual diet or physical activity throughout the study period. The intervention group consumed 20 g/d (508 mg of cacao polyphenol) of high-cocoa chocolate for 4 wk. Blood pressure, heart-ankle pulse wave velocity, cardio-ankle vascular index, body composition, and metabolic characteristics during exercise at 50% maximal oxygen uptake level were assessed before and after the intervention.Four weeks of high-cocoa chocolate ingestion significantly reduced heart-ankle pulse wave velocity and cardio-ankle vascular index (%change, intervention versus control: -2.3 ± 0.9% versus 0.9 ± 0.9%, and -4.8 ± 1.8% versus 0.7 ± 1.3%, respectively; both P0.05). However, blood pressure, weight, body mass index, body fat, waist circumference, and metabolic characteristics during exercise such as respiratory exchange ratio did not significantly change in either group.Four weeks of regular high-cocoa chocolate consumption reduced arterial stiffness after considering blood pressure in healthy young men and women. However, the habitual consumption of high-cocoa chocolate for 4 wk did not affect metabolic characteristics during light- to moderate-intensity exercise and body composition.

Epithelial cells are the first line of defense against external dangers, and contribute to induction of adaptive immunity including Th17 responses. However, it is unclear whether specific epithelial signaling pathways are essential for the development of robust IL-17–mediated immune responses. In mice, the development of psoriatic inflammation induced by imiquimod required keratinocyte TRAF6. Conditional deletion of TRAF6 in keratinocytes abrogated dendritic cell activation, IL-23 production, and IL-17 production by γδ T cells at the imiquimod-treated sites. In contrast, hapten-induced contact hypersensitivity and papain-induced IgE production were not affected by loss of TRAF6. Loss of psoriatic inflammation was not solely due to defective imiquimod sensing, as subcutaneous administration of IL-23 restored IL-17 production but did not reconstitute psoriatic pathology in the mutant animals. Thus, TRAF6 was required for the full development of IL-17–mediated inflammation. Therefore, epithelial TRAF6 signaling plays an essential role in both triggering and propagating IL-17–mediated psoriatic inflammation.

Oncolytic viruses (OVs) are novel cancer therapeutics with great promise, but host antiviral immunity represents the hurdle for their efficacy. Immunosuppression by cyclophosphamide (CP) has thus been shown to enhance the oncolytic efficacy of many OVs, but its effects on OVs armed with therapeutic genes remain unknown. We have previously reported on the efficacy of AxE1CAUP, an oncolytic adenovirus (OAd) expressing uracil phosphoribosyltransferase (UPRT), an enzyme that markedly enhanced the toxicity of 5-fluorouracil (5-FU), in immunodeficient, Ad-nonpermissive nude mice. Here we explored the efficacy and safety of intratumoral (i.t.) AxE1CAUP/5-FU therapy and of its combination with CP for syngenic HaP-T1 pancreatic cancers in immunocompetent, Ad-permissive Syrian hamsters. AxE1CAUP infected, replicated, expressed UPRT, and increased the sensitivity to 5-FU in HaP-T1 cells in vitro. I.t. AxE1CAUP/5-FU treatment inhibited the growth of subcutaneous HaP-T1 allografts. The combination with high-dose CP inhibited serum Ad-neutralizing antibody formation, increased intratumoral AxE1CAUP replication and UPRT expression, and resulted in further enhanced therapeutic effects with 5-FU. Neither body weight nor histology of the liver and lung changed during these treatments. A clinically-approved, intermediate-dose CP also enhanced the efficacy of i.t. AxE1CAUP/5-FU treatment in these hamsters, which was not affected by preexisting immunity to the vector. These data demonstrate the excellent antitumor efficacy and safety of an OAd armed with a suicide gene in combination with CP for treating syngenic tumors in immunocompetent, Ad-permissive animals, indicating the efficacy of CP in overcoming the hurdle of antiviral immunity for effective OV-mediated gene therapy.

INTRODUÇÃO: A Fasceite Necrotizante é uma infecção multibacteriana em região perineal, de rápida progressão e difícil tratamento, sobretudo em pacientes diabéticos, desnutridos e imunossuprimidos. Seu tratamento inclui inicialmente anti-bioticoterapia de amplo espectro e desbridamento precoce, levando a perda tecidualem escroto e períneo, muitas vezes com exposição testicular. A reconstrução perineoescrotal se baseia em retalhos bem vascularizados visando reestabelecimento estético e funcional, porém complicações são frequentes, tornando-se um desafio ao cirurgião plástico. OBJETIVO: Relatar caso de reconstrução de região perineoescrotal realizado no Serviço de Cirurgia Plástica Dr. Linneu Mattos Silveira – PUC-SP bem como as suas intercorrências e terapêutica usada para resolução. METODOLOGIA: relatar método de reconstrução perineoescrotal com retalho fasciocutâneo supero-medial da coxa bem como o tratamento de suas complicações. RESULTADOS: Bom resultado estético-funcional , com integração de enxerto de pele parcial e cobertura total de testículos. Paciente se mostrou satisfeito e retomou suas atividades de vida diária, dando sequência ao seu tratamento para Neoplasia de Reto. CONCLUSÃO: A reconstrução perineal se mostra bastante complexa visto as adversidades apresentadas pelos pacientes acometidos com fasceíte necrotizante, devendo o cirurgião plástico dispor de vasto arsenal terapêutico para melhor resultado estético-funcional.

INTRODUÇÃO: O mamilo invertido é definido como um mamilo não projetado, mais deprimido do que a pele circunjacente, podendo ter etiologia congênita, como na hipoplasia dos ductos lactíferos, ou adquiridas, como nas patologias malignas da mama. Tem incidência entre 1,8% e 3,1%, variando conforme a literatura. Muitas são as técnicas para correção deste defeito, mostrando a dificuldade em se obter resultados satisfatórios. O autor descreve neste trabalho técnica preconizada em nosso serviço. OBJETIVO: Relatar técnica cirúrgica preconizada em nosso serviço para a correção do mamilo invertido. METODOLOGIA: Foram realizadas 5 correções, sendo quatro de origem congênita e uma adquirida. A média de idade situou-se em 35,6 anos e foram corrigidos 3 mamilos direitos e 2 mamilos esquerdos ao todo. Realizada anestesia local com lidocaína a 2% com vasoconstrictor. Após, é realizada a exteriorização e tração do mamilo invertido, sendo realizada incisão infra-areolar semicircular através da pele e tecido subcutâneo e posterior transecção dos ductos lactíferos e bandas fibróticas, revisão da hemostasia e realização de sutura em bolsa de tabaco retro-areolar, distando entre 4mm e 5mm da papila para preservar a projeção do mamilo, e finalizando com o fechamento da pele. RESULTADOS: Obteve-se resultado satisfatório na correção do mamilo invertido mediante uso desta técnica. Não houveram recidivas ou complicações pós-operatórias até o presente momento. Nenhuma paciente engravidou após o procedimento. CONCLUSÃO: Pode-se apontar como vantagens da técnica apresentada a simples execução, podendo ser realizada de forma ambulatorial, com boa reprodutibilidade. Obteve-se projeção e formato do mamilo de maneira satisfatória, com cicatrizes reduzidas e sem complicações relativas à perda de sensibilidade ou prejuízo na vascularização, com boa manutenção do resultado final a longo prazo.

Molecular sensing using stimuli-responsive viscoelastic property of amphiphilic polymer hydrogel was demonstrated. Thermo-responsive poly(N-isopropylacrylamide); NIPA, hydrogel immobilizing bovine serum albumin (BSA) in its polymer chain was synthesized on the AT-cut QCM (Quartz crystal microbalance). The device was provided to the sensing of anti-BSA antibody. The resonance behavior of QCM in response to the adsorption of anti-BSA antibody on the hydrogel was observed based on both the resonance frequency and resistance of QCM with impedance analysis. The QCM device coated with the LCST polymer hydrogel revealed a characteristic resonance behavior in response to the adsorption of anti-BSA antibody in the collapse phase of gel at which the gel lost most of its hydrated water. The resonance frequency and resistance in the collapsed gel were highly sensitive and their changes in response to the target adsorption were much larger than in the swelling state of gel. The use of the device at the LCST of NIPA gel is ideal because the largest amplification of the adsorption signal is available along with the largest phase change of NIPA gel.

In zebrafish, Rohon-Beard (RB) neurons are primary sensory neurons present during the embryonic and early larval stages. At 2 days post-fertilization (dpf), wild-type zebrafish embryos respond to mechanosensory stimulation and swim away from the stimuli, whereas mi310 mutants are insensitive to touch. During ~2-4 dpf, wild-type RB neurons undergo programmed cell death, which is caused by sodium current-mediated electrical activity, whereas mutant RB cells survive past 4 dpf, suggesting a defect of sodium currents in the mutants. Indeed, electrophysiological recordings demonstrated the generation of action potentials in wild-type RB neurons, whereas mutant RB cells failed to fire owing to the reduction of voltage-gated sodium currents. Labeling of dissociated RB neurons with an antibody against voltage-gated sodium channels revealed that sodium channels are expressed at the cell surface in wild-type, but not mutant, RB neurons. Finally, in mi310 mutants, we identified a mis-sense mutation in pigu, a subunit of GPI (glycosylphosphatidylinositol) transamidase, which is essential for membrane anchoring of GPI-anchored proteins. Taken together, biogenesis of GPI-anchored proteins is necessary for cell surface expression of sodium channels and thus for firings of RB neurons, which enable zebrafish embryos to respond to mechanosensory stimulation.

In recent years there have been many reports on studies related to the temporomandibular joint (TMJ) in orthodontic treatment, but an adequate system of diagnosis and treatment has yet to be established, and they often cause considerable difficulty clinically. The patient in this case report sustained generalized contusions, a cerebral concussion, a midline fracture of the mandibular corpus, and bilateral fractures of the condylar process of the mandible when he fell asleep while driving a car and collided with a truck. Because non-surgical reduction was impossible, mandibular condylectomy was performed, and when orthodontic treatment was attempted to improve the open bite that persisted as a sequela of the accident, the favorable results were obtained, as described below. 1. The open bite was corrected by the orthodontic treatment, and the impairment that remained as a sequela resolved. 2. The mandibular condyles were removed during surgical reduction, and the mouth opening disturbance, the TMJ pain, and the TMJ noise resolved. The patient was able to go about his everyday life unimpaired, with hardly any awareness of limitation of jaw movement, and this situation remained unchanged even after the orthodontic treatment was performed. (J. Oral Sci. 40, 1-8, 1998)

We analyzed clinically 36 patients in whom dental implants were unsuccessful. The patients presented for implants treatment at the Department of Oral Surgery, Nihon University School of Dentistry at Matsudo from January 1989 through December 1993.The results were as follows:1. The male: female ratio of the patients was 1: 1 and the largest age group was from 40 to 69 years.2. Type of implant: endosteal implant (31 cases), subperiosteal implant (3 cases), endodontic implant (1 case), endosteal implant and endodontic implant concurrently (1 case).3. Chief complaint: excessive implant mobility (8 cases), gingival swelling (7 cases), occlusal pain (6 cases), spontaneous pain (5 cases).4. Present condition: excessive implant mobility (23 cases), resorption of alveolar bone (17 cases), pus discharge (12 cases), swelling (9 cases), spontaneous pain (9 cases), occlusal pain (7 cases), bleeding (4 cases), paralysis (4 cases).5. Secondary conditions: alveolar ostitis (28 cases), maxillary sinusitis (5 cases), ostitis of the jaw (3 cases), temporomandibular arthrosis (3 cases), paralysis of the inferior alveolar nerve (3 cases).6. Some symptoms developed in 15 patients from immediately after implant operation. In spite of discomfort, implants were used for an average of 5.1 years.

Clinical cases of cysts of the jaw treated in the Department of Oral Surgery of our university during the 10 y between 1980 and 1989 were studied clinically. Patients with radicular cyst, dentigerous cyst, odontogenic keratocyst and postoperative maxillary cyst, which were found at relatively high frequencies, were further analyzed with regard to age, sex and anatomical distribution. A diagnosis of cyst was established in 1,444 patients during the above period, and 1,234 (85.5%) of them had cysts of the jaw. According to a pathological classification by Ishikawa's method, these patients included 509 (41.2%) with radicular cyst, 259 (27.0%) with dentigerous cyst, 95 (7.7%) with odontogenic keratocyst and 267 (21.6%) with postoperative maxillary cyst. The pattern of age distribution in cases of radicular cyst, odontogenic keratocyst and postoperative maxillary cyst was similar to that found in previous studies. Among patients with dentigerous cyst, those aged under 20 y accounted for about 60%. Radicular cyst occurred most frequently in the maxillary lateral incisors, dentigerous cyst in the mandibular wisdom teeth, and odontogenic keratocyst in the region between the mandibular molar and the ramus of the mandible.

Genetic materials are one of the most important and fundamental research resources for studying biological phenomena. Scientific need for genetic materials has been increasing and will never cease. Ever since it was established as RIKEN DNA Bank in 1987, the Gene Engineering Division of RIKEN BioResource Center (BRC) has been engaged in the collection, maintenance, storage, propagation, quality control, and distribution of genetic resources developed mainly by the Japanese research community. When RIKEN BRC was inaugurated in 2001, RIKEN DNA Bank was incorporated as one of its six Divisions, the Gene Engineering Division. The Gene Engineering Division was selected as a core facility for the genetic resources of mammalian and microbe origin by the National BioResource Project (NBRP) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan in 2002. With support from the scientific community, the Division now holds over 3 million clones of genetic materials for distribution. The genetic resources include cloned DNAs, gene libraries (e.g., cDNA and genomic DNA cloned into phage, cosmid, BAC, phosmid, and YAC), vectors, hosts, recombinant viruses, and ordered library sets derived from animal cells, including human and mouse cells, microorganisms, and viruses. Recently genetic materials produced by a few MEXT national research projects were transferred to the Gene Engineering Division for further dissemination. The Gene Engineering Division performs rigorous quality control of reproducibility, restriction enzyme mapping and nucleotide sequences of clones to ensure the reproducibility of in vivo and in vitro experiments. Users can easily access our genetic materials through the internet and obtain the DNA resources for a minimal fee. Not only the materials, but also information of features and technology related to the materials are provided via the web site of RIKEN BRC. Training courses are also given to transfer the technology for handling viral vectors. RIKEN BRC supports scientists around the world in the use of valuable genetic materials.

Thermoresponsive viscoelastic behavior of poly(N-isopropylacrylamide) (PNIPA) hydrogel was investigated using quartz crystal microbalance (QCM) with the impedance analysis as a function of temperat...

We describe 4 cases of gingival hyperplasia induced by nifedipine, together with clinical and histological findings. Hyperplasia of the interdental papillae was observed in all cases. Histologic examination showed multilayered epithelial parakeratosis with variations in the width, proliferation, reticulation and elongation of the rete pegs. Substitution of another drug and improvement of oral hygiene led to reduction of the gingival overgrowth without gingivectomy. These treatments are essential for gingival hyperplasia induced by nifedipine.

A rare case of central cemento-ossifying fibroma of the mandibular medial region in a 38-year-old female was present. The histopathological examination showed that tumor consisted of fibrous connective tissue, containing cementicle-like tissues, woven and lamellar bones, and osteoid tissues. The literatures on cemento-ossifying fibroma were reviewed. Futhermore, both clinical and histopathological differences of several fibro-osseous lesions were also discussed.