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Rationale: Oculofaciocardiodental syndrome (OFCD) patients who show radiculomegaly are very rare. We treated a new OFCD patient orthodontically, and performed longitudinal observation for 30 years. New findings, termed calcified-dental-papillae (CDPs) beneath open-apices (OAs) of developing radiculomegalies, pulp-stone-like-calcifications (PSLCs) and the process of radiculomegaly development were observed. A novel mutation of BCL-6 interacting corepressor (BCOR) was identified. Cone-beam-computed-tomography (CBCT) images of the radiculomegalies clarified their morphology., Patient Concerns: A female patient and her parents were referred to orthodontic clinic for alignment of the teeth., Diagnosis: A CDP that harbored bulbous-round-calcified-tissue in the dental papilla beneath the OA of a developing radiculomegaly was found radiographically. PSLCs were observed in the dental pulp. Genetic analysis revealed a novel mutation c.265G>A on Exon 4 and diagnosed as OFCD. CBCT images confirmed round-calcified-tissue and PSLC and that the length of an affected canine was 38.0 mm and calculated as +14.8SD. These novel findings were not observed in lateral incisors and molars., Interventions: Observation was performed for 29 years and 3 months including orthodontic treatment for 2 years and 9 months., Outcome: Longitudinal follow-up for 26 years and 7 months after the treatment revealed that the development of radiculomegaly every few months or years, CDPs beneath OAs and PSLCs were observed. CDPs, PSLCs, and OAs were associated with radiculomegaly. The patient and the affected teeth including aligned teeth showed no particular change after the completion of the radiculomegaly. CBCT images showed bulbous-calcified-tissue and PSLCs in the mature dental pulp associated with radiculomegaly., Lessons: The radiographical findings of CDP, OA and PSLC help early diagnose of OFCD and have importance for initiating orthodontic treatment until radiculomegaly completion.

Interleukin (IL)-12 and IL-23 share a common subunit (p40) and function in T-helper (Th) 1 and Th17 immunity, respectively. Anti-IL-12/23p40 and specific anti-IL-23 antibodies are currently in clinical use for psoriasis and undergoing trials for autoimmune diseases. Since expression levels of the IL-23 receptor are likely to be much lower than those of IL-23, an anti-IL-23 receptor antibody might offer greater promise in inhibiting the IL-23-IL-17 pathways involved in inflammatory disorders. To our knowledge, no anti-IL-23 receptor antibody has been trialed in clinical studies to date. This study describes the generation and characterization of AS2762900-00, a fully human monoclonal antibody against the IL-23 receptor. AS2762900-00 bound both human and cynomolgus monkey IL-23 receptors. AS2762900-00 showed potent inhibitory effects on IL-23-induced Kit-225 cell proliferation compared to the existing anti-IL-12/23p40 antibody, ustekinumab. In a single dose administration pharmacodynamics study in cynomolgus monkeys, 1 mg/kg of AS2762900-00 significantly inhibited (> 85%) IL-23-induced STAT3 phosphorylation in blood for up to 84 days. Therefore, AS2762900-00 represents a potent novel IL-23-IL-17 pathway inhibitor with the potential to be developed into a new therapy for the treatment of autoimmune diseases., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Indomethacin (IND) suppresses the T-dependent antibody response (TDAR) in juvenile males when it is administered to pregnant rats during late gestation. In this study, the effect of IND on cytokine production in juvenile rats was examined to investigate the mechanism behind the suppression of antibody production. IND was orally administered to pregnant SD rats on days 18-21 of gestation. After parturition, the spleen cells isolated from 3-week-old pups were incubated with concanavalin A (Con A) or lipopolysaccharide (LPS). The level of cytokines in the culture supernatant was measured. IL-10 decreased significantly in the males, and IL-6 and TNF-alpha tended to decrease in both sexes. In order to examine the effect of IND on cytokine production in juvenile rats in vitro, spleen cells isolated from untreated 3-week-old rats were exposed to IND and a mitogen (Con A or LPS) simultaneously, and then the levels of cytokines were measured. IL-4 decreased in the males, and IL-6 tended to decrease in both sexes. These results indicated that treating dams with IND during late gestation causes a change in the release of Th2 cytokine, and suggested that this change involves the suppression of antibody production.

2-week and 4-week general toxicity studies of indomethacin, a nonselective inhibitor of cyclooxygenase 1 and 2, were performed using rats. A female fertility study was also conducted to compare the results to those of ovarian histopathological findings. The main purposes of the present studies are to assess whether a precise histopathological examination, taking the morphological changes the female reproductive organs undergo during each estrus phases into account, can evaluate toxicity to the ovaries, and to determine the optimal administration period for detecting ovarian toxicity. Indomethacin was administered on a daily basis to female Sprague-Dawley rats at doses of 0, 0.4, 1.3, or 4 mg/kg in the both the general toxicity studies and the female fertility study. In the general toxicity studies, unruptured follicles or luteinized cysts were observed histopathologically in the 4 mg/kg group in both the 2-week and 4-week studies. In addition, follicular cysts were found in the 4 mg/kg group in the 4-week study. Estrous cyclicity was not disturbed in both studies. There were no histopathological changes in the ovaries of the 1.3 mg/kg group in general toxicity studies. In the female fertility study, no toxic effects on female fertility parameters were detected in the 0.4 and 1.3 mg/kg group treated with indomethacin, but 8 of 10 rats in the 4 mg/kg group died or were sacrificed before completion of the dosing period. These results demonstrated that 2 weeks of indomethacin treatment is sufficient to detect unruptured follicles or luteinized cyst in the ovary. In addition, 4 weeks of dosing maybe required for induction of follicular cysts, although we could not clearly show that these histopathological changes would affect female fertility functions. These present studies suggest that a precise histopathological examination may be able to predict the effect of test articles on female reproductive functions.

Objective: To test the hypothesis that there is no difference in the pain associated with orthodontic force application after the application of local CO(2) laser irradiation to the teeth involved., Materials and Methods: Separation modules were placed at the distal contacts of the maxillary first molars in 90 patients in this single-blinded study. In 60 of these patients (42 females and 18 males; mean age = 19.22 years) this was immediately followed by laser therapy. The other 30 patients (18 females and 12 males; mean age = 18.8 years) did not receive active laser irradiation. Patients were then instructed to rate their levels of pain on a visual analog scale over time, and the amount of tooth movement was analyzed., Results: Significant pain reductions were observed with laser treatment from immediately after insertion of separators through day 4, but no differences from the nonirradiated control side were noted thereafter. No significant difference was noted in the amount of tooth movement between the irradiated and nonirradiated group., Conclusions: The hypothesis was rejected. The results suggest that local CO(2) laser irradiation will reduce pain associated with orthodontic force application without interfering with the tooth movement.

Objective: Recently, highly sensitive molecular-biological approaches using the 16S rRNA gene sequence have been carried out for the detection of bacteria. The aim of this study was to detect bacteremia in febrile patients with ulcerative colitis (UC) using a new molecular approach., Material and Methods: Fifteen febrile patients with relapsing UC were enrolled, and 15 healthy volunteers participated as normal controls. Blood samples were analyzed for bacteremia using nested polymerase chain reaction (PCR) with universal primers (27F, 529F, 1492R). We investigated the bacterial DNA by means of terminal restriction fragment length polymorphism (T-RFLP) with five restriction enzymes (Alu I, Hha I, Hae III, Msp I, and Rsa I). A terminal restriction fragment (TRF) profile database was created with the predicted profiles of 63 common bacteria isolated from blood cultures, using computer simulation based on sequence information. TRF lengths were analyzed using the TRF profile database and a T-RFLP profiler., Results: The bacterial gene was detected in 9 out of 15 UC patients (60%) and 8 of out 15 controls (53%). The numbers of Hae III- and Rsa I-digested T-RFs and the average number of five restriction enzyme-digested T-RFs were significantly higher in UC patients than in controls (p=0.0189, 0.0151, 0.0092, respectively). In UC patients, the most prevalent species included the 7 common species in controls and 10 other species., Conclusions: In febrile UC patients with relapse, bacteremia undetected by culture was found at high frequency by the PCR method. Therefore, antibiotic treatment for UC can be approved on the basis of the finding of bacteremia in this study.

Objective: The present study used a split-mouth design to compare the amount of canine movement and the retraction time between brackets with Clear Snap and brackets with stainless steel ligature wires for three different levels of retraction force., Materials and Methods: A sample of 30 patients was used. After initial leveling, the canine was retracted using a 50-g (n = 10), 100-g (n = 10), or 150-g (n = 10) closed-coil spring. The canine on one side was chosen at random, and Clear Snap was attached to the bracket during the retraction period. The other side was used as a control. The amount of canine retraction was measured with a digital vernier caliper. Statistical analysis was performed by analysis of variance., Results: The average canine retraction time was approximately 2 to 3 months less in all experimental groups (50, 100, and 150 g) compared to the control group. In the control group, 150 g resulted in a shorter duration of canine retraction compared to 50 g. There was no significant difference in the duration of canine retraction among the experimental groups. A greater amount of mean total canine movement was observed in all experimental groups compared to the control groups., Conclusion: A shorter duration of canine retraction time was observed with Clear Snap attached when compared with the control. The authors suggest that with the use of Clear Snap, less than 50 g of force may effectively retract a canine.

In order to investigate the effect of non-steroidal anti-inflammatory drugs (NSAIDs) on the development of rat immunity, indomethacin (IND; 0.25, 0.5, or 1.0 mg/kg/day), acetyl salicylic acid (ASA; 90, 180, or 360 mg/kg/day), or diclofenac sodium salt (DSS; 0.5, 1.0, or 2.0 mg/kg/day) suspended in 0.5% methylcellulose aqueous solution, was orally administered once daily to five pregnant Sprague-Dawley (IGS) rats per group on days 18-21 of gestation. After parturition, the serum IgM and IgG levels, the spleen weight, and the number of spleen cells were measured in 3- and 8-week-old pups. Afterwards, immunophenotyping analysis of splenocytes or peripheral blood lymphocytes and T-dependent antibody response were performed. The number of spleen cells in 3-week-olds increased when 1.0 mg/kg of IND and 180 mg/kg of ASA were administered. Immunophenotyping analysis using flow cytometry (FCM) indicated that the proportion and number of CD45RA(+) cells increased, and the proportion of CD3(-) NKR-P1A(+) cells decreased in males when dosed with IND at 1.0 mg/kg or ASA at 180 mg/kg. The serum anti-KLH IgG antibody titer decreased in the males of the IND 1.0 mg/kg dosing group, the serum levels of anti-KLH IgM, total IgM, and IgG were not changed at all. These changes disappeared in 8-week-old pups. There were no effects on any of the parameters in the 3- and 8-week-olds of the DSS treatment group. These results suggest that IND or ASA administration to dams during late gestation either causes a change in the lymphocyte subsets, or that they suppress the T-dependent antibody response in juvenile males. Both of these changes eventually recover to intact levels later on during development. These results will contribute to the development of a technique for the assessment of developmental immunotoxicity and generate data on the effect of prenatal administration of NSAIDs on the developmental immune system in pups.

Background: Valproic acid (VPA) causes the failure of neural tube closure in newborn mice. However, the molecular mechanism of its teratogenesis is unknown. This study was conducted to investigate the genomewide effects of VPA disruption of normal neural tube development in mice., Methods: Microarray analysis was performed on the head part of NMRI mouse embryos treated for 1 hr with VPA on gestational day (GD) 8. Subsequently, we attempted to isolate genes that changed in correlation with the teratogenic action of VPA by employing reduced teratogenic VPA analogs, valpromide (VPD) and valnoctamide (VCD), in a real-time PCR study., Results: Microarray results demonstrated that during neurulation, many genes, some of whose functions are known and some unknown, were either increased or decreased after VPA injection. Some genes were affected by VPD or VCD in the same way as VPA, but others were not changed by the analogs. In this way, our system identified 11 increased and 20 decreased genes. Annotation analysis revealed that the increased genes included gadd45b, ier5, per1, phfl3, pou3f1, and sox4, and the decreased genes included ccne2, ccnl, gas5, egr2, sirt1, and zfp105., Conclusions: These findings demonstrate that expression changes in genes having roles in the cell cycle and apoptosis pathways of neural tube cells were strongly expected to relate to the teratogenic, but not antiepileptic, activity of VPA. Our approach has allowed the expansion of the catalog of molecules immediately affected by VPA in the developing neural tube., ((c) 2005 Wiley-Liss, Inc.)

Clinicopathological features of mammary gland tumors (MGTs) in 101 dogs were evaluated retrospectively. The incidence of histological malignancy in 60 small- and 41 other-breed dogs were 25% and 58.5%, respectively. In 82 epithelial MGTs, small-sized tumors (< 3 cm) or non-invasive tumors were predominant in small breeds. In multivariate survival analysis, small breed (p=0.048) and lower stage of tumor cell invasion (p=0.006) were significantly associated with longer survival time. These results suggest that the incidence of histological or biological malignancy in MGTs is lower in small-breed dogs than in others.

Background: Valproic acid (VPA) is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its teratogenic mechanisms are unknown. We have attempted to describe a fundamental role of the Polycomb group (Pc-G) in VPA-induced transformations of the axial skeleton., Methods: Pregnant NMRI mice were given a single subcutaneous injection of vehicle or VPA (800 mg/kg) on gestation day (GD) 8. The expression of genes encoding Polycomb and trithorax groups was measured by quantitative real-time RT-PCR using total RNA isolated from the embryos exposed to vehicle or VPA for 1, 3, and 6 hr. In addition, the use of two less teratogenic antiepileptic chemicals valpromide (VPD) and valnoctamide (VCD) provide reliable evidence to support the relationship between VPA teratogenicity and the Polycomb group., Results: At a teratogenic level, VPA inhibits the expression of the Polycomb group genes, including Eed, Ezh2, Zfp144, Bmi1, Cbx2, Rnf2, and YY1 in the mouse embryos. In contrast, neither VPD nor VCD have significant effects on the expression of those genes affected by VPA. The trithorax group (trx-G) gene MLL, which is known to be required to maintain homeobox gene expression such as the Polycomb gene, is not affected by a teratogenic dose of VPA., Conclusions: We propose that, during embryonic development, VPA may affect the gene silencing pathway mediated by the Polycomb group complex. The epigenetic mechanism of VPA teratogenicity on anteroposterior patterning is suspected.

A new mouse monoclonal antibody (mAb), HUKT was raised against chicken peripheral blood thrombocytes. The mAb HUKT appeared to detect a specific marker on the surface of chicken thrombocytes. Flow cytometry (FCM) analysis revealed that it did not react with cells from the normal thymus, bursa of Fabricius, six kinds of chicken cell lines, chicken erythrocytes or human platelets. In addition, HUKT(+) cells in peripheral blood leukocytes (PBL) were CD45(low), Bu-1a(-) and CD3(-) cells. Immunoblotting analysis showed that the molecule recognized by HUKT is a monomer with an apparent molecular weight of 150 kDa under non-reducing and reducing conditions. Tissue distribution studies revealed that only cells of thrombocyte lineage in bone marrow and embryonic blood cells were stained by HUKT. The HUKT mAb presented here may be useful for both ontogenetic studies of thrombocyte lineage and immunological studies in the chicken.

The existence of CD3(+)CD4(-)CD8(-) T cells in thymus and spleen has already been known. However, because of the presence of large amounts of thrombocytes in peripheral blood (PB), the proportion of CD3(+)CD4(-)CD8(-) T cells in PB has yet to be investigated. Therefore, the proportion of peripheral T cell-subsets was investigated in 6-week-old chickens. The percentage of CD3(+) cells, CD4(+) cells, CD8 alpha(+) cells, CD8 beta(+), and CD3(+)CD4(-)CD8(-) cells was 76%, 41%, 14%, 5%, and 15%, respectively. The proportion of CD3(+)CD4(-)CD8(-) cells in PB increased during egg-laying periods and in chickens treated with an analog of estrogen, while it decreased with age and in response to restraint stress. All of the CD3(+)CD4(-)CD8(-) cells expressed TCR1, and did not have NK activity. CD3(+)CD4(-)CD8(-) cells represent about 60% of peripheral TCR1(+) cells. These findings indicate that the proportion of CD3(+)CD4(-)CD8(-) cells is regulated by the endocrine and nerve systems.

Immune system is organized by the influence of both neural and endocrine systems. NK activity plays an important role in the innate immunity. In this study, we observed the effects of restraint stress on chicken peripheral blood NK activity. Viability of FITC-labeled RP9 was measured with PI after treatment with the effector cells. Chicken peripheral blood CD8alpha+ cells expressed strong cytotoxic activity, in contrast to thrombocytes, while peripheral blood CD3+ CD8alpha+ cells and CD4+ cells had little cytotoxic activity. Con A supernatant enhanced the cytotoxic activity of CD8alpha+ cells. Therefore, it is considered that these cytotoxic activities measured by flow cytometry (FCM) analysis are NK activity. When chickens were exposed to restraint stress, the levels of serum corticosterone increased transiently over a short period of time while the NK activity decreased. The decreased NK activity, however, did not recover to the intact levels for a long time, even once the serum corticosterone levels had recovered. These data indicate that chicken NK activity is able to be measured by flow cytometric analysis and that restraint stress causes severe damage to the chicken NK activity.

We carried out a microscopic examination of stools from a 2-month-old female puppy with bloody diarrhea, and this revealed large numbers of different spiral-shaped bacteria. To isolate these organisms, a rectal swab specimen was inoculated onto plates of Skirrow's agar and incubated at 37 degrees C for 6 days in a microaerobic atmosphere. Finally, a total of six different spiral-shaped bacteria (strains G1104, 94105, FR106, B0101, 3J102, and J2103) were isolated. Based on their morphology, biochemical traits, whole-cell protein profiles, and analysis of their 16S rDNA sequences, they were identified as Campylobacter upsaliensis, Helicobacter cinaedi, 'Flexispira rappini', two Anaerobiospirillum spp. with different morphologies, and Helicobacter sp., respectively. Analysis of 16S rRNA gene sequence data for strains 94150 (H. cinaedi) and FR106 (F. rappini) revealed that this approach has limitations when identifying isolates to the species level because of a high degree of sequence homology between these species (>99%) and considerable sequence variation among different isolates within these species. The dog was treated orally with amoxicillin for 3 days, which resolved the diarrhea. However, 1 day after the last dose the bloody diarrhea recurred but regarded to six more days amoxicillin treatment. This suggests a bacterial cause for the diarrhea. The approach to identification to microaerobic spiral-shaped bacteria in diarrheic dogs can be applied further to characterize their role in diarrhea illness.

In order to investigate the immunological aspects of silent thyroiditis, T lymphocyte subsets were analyzed by two-color flow cytometry in 10 patients with silent thyroiditis in the thyrotoxic phase, 12 patients with silent thyroiditis in the recovery phase, and 11 healthy volunteers as a control. The percentages of CD3+, CD4+, and CD8+ cells were similar in all three groups. In contrast, activated matured T (HLA-DR+CD3+), activated helper/inducer T (HLA-DR+CD4+) and activated suppressor/cytotoxic T (HLA-DR+CD8+) cells were more numerous in both the thyrotoxic and the recovery phases of patients with silent thyroiditis when compared with healthy controls. In a serial study of 6 patients with silent thyroiditis, the percentage of activated helper/inducer T (HLA-DR+CD4+) cells was higher in the thyrotoxic phase than in the recovery phase. These data indicate that the activation of T cells, especially of helper/inducer T cells, might be important for the induction of silent thyroiditis.

Cerebrovascular accidents due to Moyamoya disease, a disorder characterized by arterial stenosis at the base of the brain accompanied by typical net-like collateral vessels, occurred in two young Japanese women with Graves' disease when they were in thyrotoxicosis. In one patient, a second attack of cerebral infarction occurred with the recurrence of thyrotoxicosis. Association of Moyamoya disease and Graves' thyrotoxicosis is rare and the pathegenetic relationship is discussed.

Alopecia areata universalis developed gradually over nine months in a 25-year-old woman. When her scalp hairs were totally lost and other body hair began to fall out, the symptoms of insulin dependent diabetes mellitus, an organ-specific autoimmune disease, developed rapidly and progressed to diabetic coma. Alopecia did not regress after the metabolic state improved following insulin therapy. Biopsy of the scalp skin revealed significant reduction of the total number of hair bulbs and prominent lymphocyte infiltration into the remaining hair follicles. Insulin dependent diabetes mellitus and alopecia areata universalis are both thought to be related to the autoimmune mechanism and sometimes coexist. However, simultaneous development of these two disorders is extremely rare.

Attempts were made to purify the LH-releasing substance extracted from the leaves of Avena sativa by means of two-step chromatographic procedures using a weakly acidic ion-exchange resin (CG-50,type II) and DEAE-Sephadex A-25 (coarse) with successful results. For preliminary fractionation of such starting materials as dried leaves, fresh leaves, and acetone-extracted powder(crude extracts), 5% acetate-buffered active carbon proved to be more effective than starch zone electrophoresis. From its behavior on chromatography with weakly acidic ion-exchange resins as well as Sephadex gel filtration, the active fraction extracted from the leaves of Avena saliva was assumed to be different from the LH-RH present in the hypothalamus. This partially purified material, however, was demonstrated to have an LH-releasing activity by the ovarian ascorbic acid depletion method using Wistar-Imamichi strain rats. Evidence was presented that its site of action is in the adenohypophysis.

Muramyl dipeptide (MDP), a minimal structure in bacterial cell walls essential for their adjuvant activity, was incorporated in a water-in-oil emulsion and injected into the footpads of nude rats devoid of functional T cells. MDP thus injected evoked massive epithelioid granulomas in the draining lymph nodes, indicating that MDP induced epithelioid granuloma formation requires no T cells. This finding with other data available strongly suggest that epithelioid granulomas can be induced without immunologic reactions.