Prostaglandin-related immune suppression in cattle.

Prostaglandins (PGs) are lipid mediators derived from arachidonic acid by several enzymes including cyclooxygenase (COX)-1 and COX-2. We have previously shown that PGE2 regulates immune responses, such as Th1 cytokine production and T-cell proliferation, in cattle. However, it is still unclear whether other PGs are involved in the regulation of immune responses in cattle. Here, immunosuppressive profiles of PGs (PGA1, PGB2, PGD2, PGE2, PGF1α and PGF2α) were firstly examined using bovine peripheral blood mononuclear cells (PBMCs). In addition to PGE2, PGA1 significantly inhibited Th1 cytokine production from PBMCs in cattle. Further analyses focusing on PGA1 revealed that treatment with PGA1 in the presence of concanavalin A (con A) downregulated CD69, an activation marker, and IFN-γ expression in both CD4+ and CD8+ T cells. Sorted CD3+ T cells stimulated with con A were cultivated with PGA1, and IFN-γ and TNF-α concentrations decreased upon PGA1 treatment. Taken together, these results suggest that the treatment with PGA1in vitro inhibits T-cell activation, especially Th1 cytokine production, in cattle.

Susceptibility of patients receiving chemotherapy for haematological malignancies to scabies.

BACKGROUND: Scabies is a contagious dermatosis. The risk factors for its transmission remain unclear. A scabies outbreak, involving patients who were receiving chemotherapy for haematological malignancies, occurred at our hospital. METHODS: The outbreak population was analysed to determine whether the incidence of scabies was higher among contact patients receiving chemotherapy for haematological malignancies. RESULTS: A patient with crusted scabies was the index case, and 18 of 78 contact healthcare workers (HCWs) and 22 of 135 contact patients were diagnosed with classical scabies. Ten of 17 contact patients with haematological malignancies and 12 of 118 contact patients with other diseases were infected with scabies. The incidence rate was significantly higher among the patients with haematological malignancies (P<0.001). The patients with haematological malignancies had a significantly lower mean minimum neutrophil count than those with other diseases (1159/µL vs 3761/µL, P=0.0012). Most haematological patients did not require special nursing assistance, suggesting that the higher incidence of scabies among these patients resulted from their immunodeficiency rather than greater skin-to-skin contact with infected HCWs. CONCLUSION: Our study suggests that patients receiving chemotherapy for haematological malignancies are more susceptible to scabies than patients with other diseases, and require stricter protection.

Efficacy, Immunogenicity, and Safety of a 9-Valent Human Papillomavirus Vaccine: Subgroup Analysis of Participants From Asian Countries.

Background: A 9-valent human papillomavirus-6/11/16/18/31/33/45/52/58 (9vHPV) vaccine extends coverage to 5 next most common oncogenic types (31/33/45/52/58) in cervical cancer versus quadrivalent HPV (qHPV) vaccine. We describe efficacy, immunogenicity, and safety in Asian participants (India, Hong Kong, South Korea, Japan, Taiwan, and Thailand) from 2 international studies: a randomized, double-blinded, qHPV vaccine-controlled efficacy study (young women aged 16-26 years; NCT00543543; Study 001); and an immunogenicity study (girls and boys aged 9-15 years; NCT00943722; Study 002). Methods: Participants (N = 2519) were vaccinated at day 1 and months 2 and 6. Gynecological samples (Study 001 only) and serum were collected for HPV DNA and antibody assessments, respectively. Injection-site and systemic adverse events (AEs) were monitored. Data were analyzed by country and vaccination group. Results: 9vHPV vaccine prevented HPV-31/33/45/52/58-related persistent infection with 90.4%-100% efficacy across included countries. At month 7, ≥97.9% of participants seroconverted for each HPV type. Injection-site AEs occurred in 77.7%-83.1% and 81.9%-87.5% of qHPV and 9vHPV vaccine recipients in Study 001, respectively, and 62.4%-85.7% of girls/boys in Study 002; most were mild to moderate. Conclusions: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Asian participants. Data support 9vHPV vaccination programs in Asia. Clinical Trials Registration: NCT00543543; NCT00943722.

Association between chronic musculoskeletal pain and executive function in community-dwelling older adults.

BACKGROUND: We examined the association of chronic musculoskeletal pain with executive function in community-dwelling older adults. METHOD: This cross-sectional study recruited 234 community-dwelling older adults in Japan (mean age: 72.7, women: 62.8%). Chronic musculoskeletal pain was defined as having moderate or more severe pain lasting ≥ 3 months. Executive function was assessed using the Digit Symbol Substitution Test (DSST), Trail Making Test (TMT) parts A and B, Letter Verbal Fluency Test (LVFT) and Category Verbal Fluency Test (CVFT). RESULTS: Prevalence of chronic musculoskeletal pain was 19% (n = 44). In the univariate analysis, the DSST and CVFT scores were significantly lower in the chronic musculoskeletal pain group than in the control group (DSST: chronic musculoskeletal pain group vs. control group, 40.2 vs. 45.4, respectively, p < 0.05; CVFT: 13.7 vs. 15.6, respectively, p < 0.05), whereas the TMT parts A and B and LVFT scores were not. The multivariate linear regression models adjusted for covariates showed that the chronic musculoskeletal pain group had significantly lower DSST (adjusted ß = -0.13, p < 0.05) and CVFT scores (adjusted ß = -0.17, p < 0.05) than the control group. CONCLUSION: Chronic musculoskeletal pain may interfere with the elements of executive function, processing speed and semantic fluency, in community-dwelling older adults. The association of chronic musculoskeletal pain with executive function requires further investigation. SIGNIFICANCE: Our results suggest an association between moderate-severe chronic musculoskeletal pain and impairments of semantic fluency and processing speed in community-dwelling older adults.

Relationship between the changes in blood flow and volume in the finger during a Braille character discrimination task.

PURPOSE: We hypothesized that skin blood flow (SBF) of fingers are modulated during concentrated finger perception and that the changes in SBF reflect fluctuations in finger volume (FV). The aim of this study, therefore, was examine the relationship between the changes in SBF and FV during Braille reading. METHODS: We measured SBF of the finger, cutaneous vascular conductance (CVC), FV, and arterial blood pressure during Braille reading performed under blind conditions in thirty healthy subjects. The subjects were instructed to read a flat plate with raised letters (Braille reading) for 15 seconds using their forefinger, and to touch a blank plate as a control for the Braille discrimination procedure. RESULTS: Arterial blood pressure slightly increased during Braille reading but remained unchanged during the touching of the blank plate. SBF, CVC, and FV were reduced during Braille reading (decreased by -26%, -29%, and -0.3 mL/100 mL respectively). Furthermore, a significant relationship was observed between the changes in SBF and FV (r=.613) during Braille reading. CONCLUSION: These results suggested that SBF of fingers is modulated during concentrated finger perception, and that the variability of blood flow reflects the response in FV.

BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4.

Although high brain and acute leukemia, cytoplasmic (BAALC) expression is a well-characterized poor prognostic factor in acute myeloid leukemia (AML), neither the exact mechanisms by which BAALC drives leukemogenesis and drug resistance nor therapeutic approaches against BAALC-high AML have been properly elucidated. In this study, we found that BAALC induced cell-cycle progression of leukemia cells by sustaining extracellular signal-regulated kinase (ERK) activity through an interaction with a scaffold protein MEK kinase-1 (MEKK1), which inhibits the interaction between ERK and MAP kinase phosphatase 3 (MKP3/DUSP6). BAALC conferred chemoresistance in AML cells by upregulating ATP-binding cassette proteins in an ERK-dependent manner, which can be therapeutically targeted by MEK inhibitor. We also demonstrated that BAALC blocks ERK-mediated monocytic differentiation of AML cells by trapping Krüppel-like factor 4 (KLF4) in the cytoplasm and inhibiting its function in the nucleus. Consequently, MEK inhibition therapy synergizes with KLF4 induction and is highly effective against BAALC-high AML cells both in vitro and in vivo. Our data provide a molecular basis for the role of BAALC in regulating proliferation and differentiation of AML cells and highlight the unique dual function of BAALC as an attractive therapeutic target against BAALC-high AML.

Suppressive effects of neutrophil by Salp16-like salivary gland proteins from Ixodes persulcatus†Schulze tick.

Salp16, a 16-kDa tick salivary gland protein, is known to be the molecule involved in the transmission of Anaplasma phagocytophilum, an obligate intracellular pathogen causing zoonotic anaplasmosis, from its mammalian hosts to Ixodes scapularis. Recently, the presence of A. phagocytophilum was documented in Japan and Ixodes persulcatus was identified as one of its vectors. The purpose of this study was to identify Salp16 genes in I. persulcatus and characterize their function. Two cDNA clones encoding the Salp16-like sequences were obtained from the salivary glands of fed female I. persulcatus ticks and designated Salp16 Iper1 and Iper2. Gene expression analyses showed that the Salp16 Iper genes were expressed specifically in the salivary glands and were up-regulated by blood feeding. These proteins attenuated the oxidative burst of activated bovine neutrophils and inhibited their migration induced by the chemoattractant interleukin-8 (IL-8). These results demonstrate that Salp16 Iper proteins contribute to the establishment of blood feeding as an immunosuppressant of neutrophil, an essential factor in innate host immunity. Further examination of the role of Salp16 Iper in the transmission of pathogens, including A. phagocytophilum, will increase our understanding of the tick-host-pathogen interface.

Hyperthermic intraperitoneal chemotherapy using a combination of mitomycin C,5-fluorouracil, and oxaliplatin in patients at high risk of colorectal peritoneal metastasis: A Phase I clinical study.

INTRODUCTION: The drugs and protocols used for hyperthermic intraperitoneal chemotherapy (HIPEC) vary among institutions. Here we show the efficacy of the 3-drug combination of mitomycin C (MMC), 5-fluorouracil (5FU), and oxaliplatin (OHP) in an in vitro simulation of HIPEC and the safety of HIPEC with these drugs during a Phase I study of patients at high risk of developing colorectal peritoneal metastasis. METHODS: To simulate HIPEC, we used HCT116 and WiDr cells to assess the growth inhibitory efficacy of MMC 2 µg/mL, 5FU 200 µg/mL, and OHP 40 µg/mL as single drugs or their combination after an exposure time of 30 min at 37 or 42 °C. In addition, nine patients underwent surgical resection of tumors and HIPEC with MMC, 5FU, and an escalating dose of OHP (90/110/130 mg/m²). Dose-limiting toxicity was monitored. RESULTS: In the simulation, the 3-drug combination showed marked tumor-suppressive effects compared with those from ten times higher dose of OHP 400 µg/mL, with significant augmentation under hyperthermic conditions. No dose-limiting toxicity occurred in the clinical study. Dose escalation was completed at the final level of OHP. CONCLUSIONS: The MMC-5FU-OHP combination showed marked growth inhibition against colorectal cancer cells under hyperthermic conditions in vitro. In the phase I study, the recommended dose of OHP was determined as 130 mg/m² when used with MMC and 5FU; HIPEC using MMC-5FU-OHP appears to be safe and feasible for patients at high risk of colorectal peritoneal metastasis.

Successful treatment for Cronkhite-Canada syndrome with endoscopic mucosal resection and salazosulfapyridine.

A 79-year-old woman was referred to our hospital because numerous polyps were found in her stomach and large intestine at an ambulatory clinic. Although there were no characteristic symptoms or signs of Cronkhite-Canada syndrome (CCS), endoscopic and pathological findings indicated CCS. Moreover, colonoscopy showed two polypoid lesions (Is type), which appeared neoplastic by magnifying observation with image-enhanced endoscopy (IEE), in the ascending colon. Histologically, the resected specimens revealed tubular adenomas arising in the CCS inflammatory polyps. Remarkable remission of the polyps and edematous mucosa in the stomach and colon was seen after 8 months of administration of salazosulfapyridine (SASP) (3 g/day). Another adenoma was detected and removed endoscopically in the sigmoid colon. This is the first report to describe an asymptomatic case of CCS probably detected in the early phase of the disease, by magnifying IEE which enabled detection and treatment for associated colonic adenomas. SASP was effective in eradication of the inflammatory polyposis, and an additional adenoma was successfully found and removed by surveillance colonoscopy thereafter.

Hiatal hernia following total gastrectomy with Roux-en-Y reconstruction.

Hiatal hernias after total gastrectomy for advanced gastric cancer are very rare. We review a case of a 44-year-old male who presented with dyspnea and chest pain 2 days after total gastrectomy, lower esophagectomy, and splenectomy with retrocolic Roux-en-Y reconstruction approached by a left thoracoabdominal incision for gastric cancer at the cardia. Plain and cross-sectional imaging identified a large hiatal hernia protruding into the right thorax containing left-sided transverse colon and small intestine. Our patient underwent a laparotomy, and after hernia reduction the hiatal defect was repaired by direct suturing. He experienced anastomotic leakage and right pyothorax, but recovered. The potential cause is discussed here and the published literature on this rare complication is reviewed briefly.

Glue embolization for gastroduodenal ulcer bleeding: contribution to hemodynamics and healing process.

BACKGROUND: Although the morbidity of bowel ischemic events after glue embolization has been suggested, a causal relationship between glue and ischemia has not been clearly established. PURPOSE: To evaluate the efficiency and safety of transcatheter arterial embolization with n-butyl cyanoacrylate (NBCA-TAE) for upper gastrointestinal hemorrhage (GIH). MATERIAL AND METHODS: Between October 2006 and October 2012, 21 patients with upper GIH underwent NBCA-TAE, and endoscopic data were obtained within 30 days of follow-up. Shock index prior to and immediately after NBCA-TAE were compared to determine changes in hemodynamics. Days to Forrest type III, as assessed by follow-up endoscopy, was used as an indicator of the healing process. Other clinical outcomes included days for starting ingestion and for hospital discharge. RESULTS: Sixteen gastric and five duodenal ulcers, classified into Forrest type I, were treated. Immediate hemostasis was achieved in all the patients, and no re-bleeding occurred within the follow-up period. Shock index significantly (P < 0.001) improved from before (0.99 ± 0.076) to immediately after NBCA-TAE (0.67 ± 0.038). Sequential mucosal healing processes were observed in all the patients, and the number of days to Forrest type III was 9.6 ± 7.1. The number of days for starting ingestion and hospital discharge was 9.0 ± 4.5 and 15 ± 7.7 days, respectively. CONCLUSION: NBCA-TAE is an effective and safe method for the control of nonvariceal upper GIH, in terms of contribution to hemodynamics and healing process of the gastroduodenal mucosa.

Relationship between abdominal fat content and avian uncoupling protein gene expression in skeletal muscle of Japanese quail Coturnix japonica.

1. The genetic architecture of the avian uncoupling protein (avUCP) was investigated and the relationship between avUCP gene expression and the amount of abdominal fat of Japanese quail was determined by quantitative real-time PCR. 2. The Japanese quail avUCP gene consists of six exons and five introns. Sequences of nucleotides and amino acids were 94·6% and 86·0% identical to those of the chicken avUCP gene, and phylogenetic analysis showed that the Japanese quail avUCP gene consists of the same clusters as the chicken and turkey avUCP. 3. Expression of the avUCP gene was significantly higher in the Pectoralis major (1·28 ± 0·24) than in the Biceps femoris (0·63 ± 0·14). 4. A positive correlation coefficient between the avUCP gene expression in the Pectoralis major and Biceps femoris was observed (r = 0·79, P = 0·02), whereas a negative correlation coefficient was observed between the abdominal fat percentage (AFP) and gene expression in both the Pectoralis major (r = -0·82, P = 0·01) and Biceps femoris (r = -0·61, P = 0·11). 5. The avUCP gene was associated with the accumulation of abdominal fat in Japanese quail and it was concluded that modulation of avUCP gene expression could be utilised to control abdominal fat accumulation in poultry.

High-dose zoledronic acid narrows the periodontal space in rats.

The aim of this experiment was to evaluate the histological effects of zoledronic acid on the periodontal space in rats. 40 male Wistar rats were divided into three zoledronic acid groups and a control group. Zoledronic acid was injected subcutaneously at doses of 10, 50, or 500 µg/kg once a week for 3 weeks. The rats were killed 1 or 9 weeks after the last injection. Histological examination of the periodontal space around the incisor tooth revealed that zoledronic acid did not inhibit tooth development. In the rats killed 1 week after treatment discontinuation, the periodontal space gradually narrowed in response to increasing zoledronic acid doses, and the changes were statistically significant according to ANOVA but not according to ANOVA with post hoc tests. The changes persisted in the high-dose zoledronic acid group despite zoledronic acid discontinuation, with significant differences identified by ANOVA and ANOVA with post hoc tests. Therefore, although zoledronic acid had an insignificant effect on tooth development, it had a significant effect on the periodontal space when high doses were administered. The results of this experiment may provide useful information for future investigations on the role of zoledronic acid in the osteonecrosis of the jaw.

SSEA-4 is a marker of human deciduous periodontal ligament stem cells.

Although human deciduous teeth are an ideal source of adult stem cells, no method for identifying deciduous periodontal ligament (D-PDL) stem cells has so far been developed. In the present study, we investigated whether stage-specific embryonic antigen (SSEA)-4 is a marker that could be used to isolate D-PDL stem cells. The isolated D-PDL cells met the minimum criteria for mesenchymal stem cells (MSCs): They showed plastic adherence, specific-surface antigen expression, and multipotent differentiation potential. SSEA-4+ D-PDL cells were detected in vitro and in vivo. A flow cytometric analysis demonstrated that 22.7% of the D-PDL cells were positive for SSEA-4. SSEA-4+ clonal D-PDL cells displayed multilineage differentiation potential: They were able to differentiate into adipocytes, osteoblasts, and chondrocytes in vitro. A clonal assay demonstrated that 61.5% of the SSEA-4+ D-PDL cells had adipogenic, osteogenic, and chondrogenic potential. Our present study demonstrated that SSEA-4+ D-PDL cells are a subset of multipotent stem cells. Hence, SSEA-4 is a specific marker that can be used to identify D-PDL stem cells.

Kinetics of regulatory dendritic cells in inflammatory responses during Trypanosoma evansi infection.

Trypanosoma evansi (T. evansi) causes a wasting disease in almost all mammals. Trypanosoma evansi infection gives rise to the inflammatory responses that contribute to the development of inflammation-associated tissue injury. To determine what kinds of inflammatory molecules play roles in the pathogenicity of T. evansi infection, polymerase chain reaction array analysis was performed on samples from the infected and uninfected mice. The inflammatory cytokine and chemokine storm, caused mainly by macrophages, was observed. On the other hand, the expression levels of Ccl8 and Il10 in splenocytes were also markedly increased. These results suggested an augmentation in the number and activity of regulatory dendritic cells (DCs). Therefore, the kinetics of regulatory DCs in T. evansi-infected mice were investigated. During T. evansi infection, the regulatory DCs became prevalent, with reducing the amount of inflammatory DCs. Interestingly, when the regulatory DCs were implanted into T. evansi-infected mice, the survival was prolonged, and the expression levels of inflammatory molecules were suppressed. Taken together, these results showed that a subset of regulatory DCs acted as a potential regulator of the inflammatory responses.

Molecular cloning and characterization of Th1 and Th2 cytokines of African buffalo (Syncerus caffer).

The African buffalo (Syncerus caffer) has been implicated as the reservoir of several bovine infectious agents. However, there is insufficient information on the protective immune responses in the African buffalo, particularly in infected animals. In this study, we analysed Th1 cytokines IL-2 and IFN-γ, and Th2 cytokines IL-4 and IL-10. The cloned cDNA of IL-2, IL-4, IL-10 and IFN-γ contained an open reading frame of 468, 501, 408 and 540 nucleotides, encoding polypeptides of 155, 166, 135 and 179 amino acids, respectively. Nucleotide sequence homology of IL-2, IFN-γ and IL-4 was more than 98% between the African buffalo and cattle, which resulted in identical polypeptides. Meanwhile, IL-10 gene of African buffalo and cattle had 95% homology in nucleotide sequence, corresponding to thirteen amino acid residues substitution. Cysteine residues and potential glycosylation sites were conserved within the family Bovinae. Phylogenetic analyses including cytokines of the African buffalo placed them within a cluster comprised mainly of species belonging to the order Artiodactyla, including cattle, water buffalo, sheep, goat, pig and artiodactyl wildlife. A deeper understanding of the structure of these cytokines will shed light on their protective role in the disease-resistant African buffalo in comparison with other closely related species.