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Conflicts arising from the consumption of anthropogenic foods by wildlife are increasing worldwide. Conventional tools for evaluating the spatial distribution pattern of large terrestrial mammals that consume anthropogenic foods have various limitations, despite their importance in management to mitigate conflicts. In this study, we examined the spatial distribution pattern of crop‐foraging sika deer by performing nitrogen stable isotope analyses of bone collagen. We evaluated whether crop‐foraging deer lived closer to agricultural crop fields during the winter and spring, when crop production decreases. We found that female deer in proximity to agricultural crop fields during the winter and spring were more likely to be crop‐foraging individuals. Furthermore, the likelihood of crop consumption by females decreased by half as the distance to agricultural crop fields increased to 5–10 km. We did not detect a significant trend in the spatial distribution of crop‐foraging male deer. The findings of spatial distribution patterns of crop‐foraging female deer will be useful for the establishment of management areas, such as zonation, for efficient removal of them., We examined the spatial distribution pattern of crop‐foraging sika deer by performing nitrogen stable isotope analyses. Female deer in proximity to agricultural crop fields were more likely to be crop‐foraging individuals and the likelihood of crop consumption decreased by half as the distance to agricultural crop fields increased to 5–10 km.

Conflicts arising from the consumption of anthropogenic foods by wildlife are increasing worldwide. Conventional tools for evaluating the spatial distribution pattern of large terrestrial mammals that consume anthropogenic foods have various limitations, despite their importance in management to mitigate conflicts. In this study, we examined the spatial distribution pattern of crop-foraging sika deer by performing nitrogen stable isotope analyses of bone collagen. We evaluated whether crop-foraging deer lived closer to agricultural crop fields during the winter and spring, when crop production decreases. We found that female deer in proximity to agricultural crop fields during the winter and spring were more likely to be crop-foraging individuals. Furthermore, the likelihood of crop consumption by females decreased by half as the distance to agricultural crop fields increased to 10 km and fell to essentially zero at a distance of approximately 40 km. We did not detect a significant trend in the spatial distribution of crop-foraging male deer. The findings of spatial distribution patterns of crop-foraging female deer will be useful for the establishment of management areas, such as zonation, for efficient removal of them.

Anthropogenic foods such as agricultural crops have potential to give large impacts on wildlife populations. However, few studies have addressed the impact of anthropogenic food consumption on the individual performance and then population of long‐lived mammals such as large herbivores. In this study, we investigated the effect of agricultural crop consumption on the physical characteristics and reproductive performances of sika deer (Cervus nippon) in central Japan. To investigate the relative dietary contribution of agricultural crops for each individual, we performed nitrogen stable isotope analysis of bone collagen. Our results suggest that nitrogen stable isotope ratios (δ15N) could be used as an index of the relative dietary contribution of agricultural crops. The δ15N value of agricultural crops was much higher than that of wild plants and that of bone collagen varied widely among individuals. Deer ≤4 yr old that were more likely to consume agricultural crops tended to be larger and have a higher reproductive rate. In contrast, body size and reproductive rate did not vary according to the relative dietary contribution of agricultural crops in individuals ≥5 yr old. These results indicate that consumption of anthropogenic foods can induce precocious maturity in younger individuals by improving their physical characteristics and reproductive performance. Agricultural crop consumption is therefore likely to be an important factor in the population dynamics of large herbivores living in agricultural landscapes.

Objectives Baloxavir marboxil (formerly S-033188) is a first-in-class, orally available, cap-dependent endonuclease inhibitor licensed in Japan and the USA for the treatment of influenza virus infection. We evaluated the efficacy of delayed oral treatment with baloxavir marboxil in combination with a neuraminidase inhibitor in a mouse model of lethal influenza virus infection. Methods The inhibitory potency of baloxavir acid (the active form of baloxavir marboxil) in combination with neuraminidase inhibitors was tested in vitro. The therapeutic effects of baloxavir marboxil and oseltamivir phosphate, or combinations thereof, were evaluated in mice lethally infected with influenza virus A/PR/8/34; treatments started 96 h post-infection. Results Combinations of baloxavir acid and neuraminidase inhibitor exhibited synergistic potency against viral replication by means of inhibition of cytopathic effects in vitro. In mice, baloxavir marboxil monotherapy (15 or 50 mg/kg twice daily) significantly and dose-dependently reduced virus titre 24 h after administration and completely prevented mortality, whereas oseltamivir phosphate treatments were not as effective. In this model, a suboptimal dose of baloxavir marboxil (0.5 mg/kg twice daily) in combination with oseltamivir phosphate provided additional efficacy compared with monotherapy in terms of virus-induced mortality, elevation of cytokine/chemokine levels and pathological changes in the lung. Conclusions Baloxavir marboxil monotherapy with 96 h-delayed oral dosing achieved drastic reductions in virus titre, inflammatory response and mortality in a mouse model. Combination treatment with baloxavir acid and oseltamivir acid in vitro and baloxavir marboxil and oseltamivir phosphate in mice produced synergistic responses against influenza virus infections, suggesting that treating humans with the combination may be beneficial.

Background: Allergic rhinitis is the most common allergic disease, displaying the typical nasal symptom of congestion. Prostaglandin D2 (PGD2), a chemical mediator released in large amounts by mast cells upon allergic stimulation in humans, is known to be involved in nasal congestion. However, the mechanism by which this congestion occurs remains unclear. Methods: The effect of PGD2 on the nasal airflow in guinea pigs was measured using a noninvasive approach that avoided any anesthetic effect. Isometric tension of isolated nasal mucosa and the nasal vascular corrosion resin cast technique were used to clarify the area of nasal mucosal vessels affected by PGD2, and to examine the mechanism of PGD2-induced nasal congestion. Moreover, the involvement of second messengers in PGD2-induced mucosal relaxation was investigated. Results: PGD2 induced an increase in intranasal pressure in a guinea pig model of rhinitis. Additionally, sinusoidal microvessel dilatation appeared around the septum using the vascular corrosion resin cast technique in the nasal mucosa. Moreover, relaxation of the nasal mucosa following stimulation of the prostanoid DP-1 receptor was associated with cAMP levels in the tissue. Conclusions: PGD2-induced nasal congestion is caused by direct dilatation of the sinusoid vessels through the increase of cAMP levels in the nasal mucosa, demonstrating that the mechanism of PGD2-induced nasal congestion is different from other chemical mediators. Consequently, antagonists for the prostanoid DP-1 receptor would be an alternative approach for the relief of nasal congestion. Alternatively, the combined administration with antagonists for other mediators involved in nasal congestion may also be a valuable therapy for allergic rhinitis.

Introduction: Myeloid/Natural killer cell precursor acute leukemia (MNKPL) and myeloid/NK cell acute leukemia (MNKL) is a rare hematologic malignancy prevalent in East Asia. MNKPL is characterized by marked extramedullary involvement, immature lymphoblastoid morphology without myeloperoxidase (MPO) reactivity, a CD7+/CD33+/CD34+/CD16−/CD15−/+/HLA-DR+ phenotype, myeloid chemosensitivity, and a poor prognosis. By contrast, MNKL shows no extramedullary involvement, a HLA‐DR−/CD33+/CD16−/CD34−/+ phenotype, myeloid chemosensitivity, and a good prognosis. However, analysis of outcome and genetic alterations in these leukemias are limited. Here, we report outcome and genetic alterations in the patients with MNKPL and MNKL. Methods: The Leukemia and Lymphoma Committee of the Japanese Society of Pediatric Hematology and Oncology (JSPHO) sent out two questionnaires to 110 JSPHO affiliated hospitals. The first questionnaire requested details of the number of pediatric patients with MNKPL or MNKL had been diagnosed during the period 2000-2013. The second questionnaire requested more detailed information about clinical curses. Overall survival (OS) and event free survival (EFS) defined as relapse or death was analyzed. The protocol of this retrospective study was approved by the review boards of JSPHO and Ehime Prefectural Central Hospital. We also performed whole exome sequence (WES) using 7 children's samples (5 MNKPL, 2 MNKL) and target sequence using 2 adult's samples (2 MNKPL) from this and another independent cohort. The research protocol was approved by the review board of TMDU. Results: Thirteen children with MNKPL and 6 children with MNKL were identified. Median age of MNKPL was 8 year-old (range; 0.5-17) and median age of MNKL was 10 year-old (range; 2-13). There are 8 males and 5 females in MNKPL and 4 males and 2 females in MNKL. In MNKPL, central nervous system, mediastinum and lymph node involvement was observed in 1 case respectively. Nasal sinus involvement was observed in 1 case in MNKL. Eleven patients with MNKPL and 3 patients with MNKL were treated with acute myeloid leukemia style chemotherapy and 1 MNKPL patients and 3 MNKL patients were treated with acute lymphoblastic leukemia/non-Hodgkin lymphoma style chemotherapy. Complete remission after induction therapy was achieved in 8/13 MNKPL children and 4/6 MNKL children. Twelve out of 13 MNKPL children and all 6 MNKL children underwent hematopoietic cell transplantation (HCT) with myeloablative conditioning regimen. Median follow up period was 5.3 years in MNKPL and 3.8 years in MNKL patients. 5-year OS of MNKPL and MNKL was 67.3 % and 41.7 %, 5-year EFS of MNKPL and MNKL was 52.7 % and 41.7 % respectively. In genetic analysis, average 148 somatic mutations in MNKPL and 88 somatic mutations in MNKL were identified by WES. In combined analysis using adult cases, the recurrent mutations were observed in NOTCH1, NRAS (n=3, respectively), MAML2, MAP3K1, SIRPA (n=2, respectively) as activating signal genes, and CLTCL1 (n=2) as cell adhesion molecules, and RECQL4 (n=2) as cell cycle/DNA repair molecules, and PRDM2, CREBBP, SETBP1 (n=2, respectively) as epigenetic modifiers, and WT1, ZNF384, BCLAF1 (n=2, respectively) as transcription factors. Conclusions: Previously, it has been reported that outcome of MNKL is relatively good than MNKPL. MNKPL and MNKL children had a poor prognosis in our cohort even though most patients received HCT. We identified alteration of molecules involved in NOTCH signaling and RAS-MAPK pathways. In addition, mutations of several transcription factors such as WT1 were identified. The drugs targeting RAS pathway and epigenetic factors may have the potential to improve outcome. An international collaboration for clinical and cytogenetic research of MNKPL and MNKL is needed as they are complex and rare diseases. Disclosures No relevant conflicts of interest to declare.

In our previous study, we reported that cerulein-induced acute pancreatitis is aggravated in pancreatic β-cell-specific pituitary adenylate cyclase-activating polypeptide (PACAP) transgenic mice, showing that an increase in pancreatic PACAP is a risk factor for progression of acute pancreatitis. Accordingly, in this study, we examined the progression of cerulein-induced acute pancreatitis in PACAP knockout (KO) mice. Unexpectedly, after cerulein, about 60% of the KO mice showed severe hypothermia below 30°C by 12 h and most of them died within 72 h. In contrast, the remaining KO and wild-type mice showed normothermia with no mortality. Thus, KO mice could be classified into two groups as hypothermic (HT-KO) and normothermic (NT-KO) to cerulein. Only HT-KO mice subsequently showed severe mortality, although both HT-KO and NT-KO mice exhibited similar susceptibility of lungs to cerulein toxicity, comparable to that in wild-type mice. Regarding pancreatitis, HT-KO mice showed ameliorated pancreatic damage without any rise in serum enzyme activities, whereas NT-KO mice exhibited a similar degree of pancreatitis to wild-type mice. Taken together, the present results indicate that lack of pancreatic PACAP did not aggravate, but rather ameliorated, cerulein-induced pancreatitis. In addition, about half of KO mice showed a novel phenotype in which cerulein caused rapid and severe hypothermia, followed by death.

Development of human chronic pancreatitis is associated with intrapancreatic accumulation of pituitary adenylate cyclase–activating polypeptide (PACAP) accompanied with an altered inflammatory response (Michalski et al., Am J Physiol Gastrointest Liver Physiol. 2008;294:G50–G57). To investigate the role of pancreatic PACAP in the development of acute pancreatitis, we employed transgenic mice over-expressing PACAP in pancreatic β-cells (PACAP-Tg). In comparison to wild-type mice, PACAP-Tg mice exhibited more severe pathophysiological signs of the cerulein-induced pancreatitis at 12 h, as evidenced by higher serum amylase and lipase levels accompanied by the exacerbation of pancreatic edema, necrosis, and inflammation. Cerulein treatment increased mRNA expression of several proinflammatory cytokines (TNFα, IL-1β, and IL-6) at 12 h with similar magnitude both in wild-type and PACAP-Tg mice. In addition, the mRNA and protein levels of regenerating gene III β (RegIIIβ), a key factor in the pancreatic response to acute pancreatitis, were up-regulated at 24 h in wild-type mice upon cerulein administration, whereas they were attenuated in PACAP-Tg mice. These data indicate that over-expressed PACAP in pancreas enhances the cerulein-induced inflammatory response of both acinar cells, leading to aggravated acute pancreatitis, which was accompanied by a down-regulation of RegIIIβ, an anti-inflammatory factor. Keywords:: pituitary adenylate cyclase–activating polypeptide (PACAP), cerulein, acute pancreatitis, regenerating gene III β (RegIIIβ)

Obese diabetes was induced by monosodium aspartate (MSA) administration in KK male mice and the diabetic KK mice were divided into two groups, younger (12-week-old) and older (35-week-old). The diabetic KK mice were castrated and administered with androgen and effect of androgen on glycosuria appearance was investigated. Androgen dependent tear proteins (Mtp-M) were detected by the method of polyacrylamide gel electrophoresis. Blood androgen level was estimated by observation of change of the pattern of Mtp-M. In the younger mice group, glycosuria disappeared temporarily after castration and then appeared naturally again. The Mtp-M declined with castration, but did not disappear in this experimental period. In the older mice group, glycosuria and Mtp-M disappeared completely and blood glucose level decreased considerably after castration. However, in the castrated older mice, the glycosuria and the Mtp-M appeared again after the administration of dehydroepiandrosterone (DHEA), and the increasing of blood glucose level was observed. These results strongly suggested that androgen had an important role in the onset of diabetes in the KK mice treated with MSA.