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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.

Dysregulation of nicotinamide adenine dinucleotide (NAD +) metabolism contributes to the initiation and progression of age-associated diseases, including chronic kidney disease (CKD). Nicotinamide N-methyltransferase (NNMT), a nicotinamide (NAM) metabolizing enzyme, regulates both NAD + and methionine metabolism. Although NNMT is expressed abundantly in the kidney, its role in CKD and renal fibrosis remains unclear. We generated NNMT-deficient mice and a unilateral ureter obstruction (UUO) model and conducted two clinical studies on human CKD to investigate the role of NNMT in CKD and fibrosis. In UUO, renal NNMT expression and the degraded metabolites of NAM increased, while NAD + and NAD + precursors decreased. NNMT deficiency ameliorated renal fibrosis; mechanistically, it (1) increased the DNA methylation of connective tissue growth factor (CTGF), and (2) improved renal inflammation by increasing renal NAD + and Sirt1 and decreasing NF-κB acetylation. In humans, along with CKD progression, a trend toward a decrease in serum NAD + precursors was observed, while the final NAD + metabolites were accumulated, and the level of eGFR was an independent variable for serum NAM. In addition, NNMT was highly expressed in fibrotic areas of human kidney tissues. In conclusion, increased renal NNMT expression induces NAD + and methionine metabolism perturbation and contributes to renal fibrosis.

Regulatory T cells (Tregs) suppress the host immune response and maintain immune homeostasis. Tregs also promote cancer progression and are involved in resistance to immune checkpoint inhibitor treatments. Recent studies identified selective CCR8 expression on tumor-infiltrating Tregs; CCR8+ Tregs have been indicated as a possible new target of cancer immunotherapy. Here, we investigated the features of CCR8+ Tregs in lung cancer patients. CCR8+ Tregs were highly activated and infiltration of CCR8+ Tregs in tumors was associated with poor prognosis in lung cancer patients. We also investigated their immune suppressive function, especially the influence on cytotoxic T lymphocyte cell function. The Cancer Genome Atlas analysis revealed that CD8 T cell activities were suppressed in high CCR8-expressing tumors. Additionally, depletion of CCR8+ cells enhanced CD8 T cell function in an ex vivo culture of lung tumor-infiltrating cells. Moreover, CCR8+ Tregs, but not CCR8− Tregs, induced from human PBMCs markedly suppressed CD8 T cell cytotoxicity. Finally, we demonstrated the therapeutic effect of targeting CCR8 in a murine model of lung cancer. These findings reveal the significance of CCR8+ Tregs for immunosuppression in lung cancer, especially via cytotoxic T lymphocyte cell suppression, and suggest the potential value of CCR8-targeted therapy for cancer treatment.

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.

Introduction: Myeloid/Natural killer (NK) cell precursor acute leukemia (MNKPL) is a rare hematologic malignancy prevalent in East Asia. MNKPL is characterized by extramedullary involvement, immature lymphoblastoid morphology without myeloperoxidase (MPO) reactivity, the CD7+/CD33+/CD34+/CD56+/HLA−DR+ phenotype. MNKPL is classified as mixed phenotype acute leukemia, and not otherwise specified rare types (MPAL NOS rare types) in WHO classification. However, its characteristic clinical feature and undetermined genetic feature suggests that MNPKL leaves open the possibility of a new independent disease concept. Here, we report clinical features and genetic alterations in patients with MNKPL. Methods: The Leukemia and Lymphoma Committee of the Japanese Society of Pediatric Hematology and Oncology (JSPHO) sent out questionnaires to 110 JSPHO affiliated hospitals and collected cases of MNPKL diagnosed during the period 2000-2013. Besides, the cases published as literature were recruited. The data of clinical features, cell surface antigen profiling, overall survival (OS), and event-free survival (EFS) defined as relapse or death were also collected as a secondary survey. The protocol of this retrospective study was approved by the review boards of JSPHO and Ehime Prefectural Central Hospital. Comprehensive genetic analysis including 13 whole-exome sequences (WES), 2 target sequence, 6 RNA sequence (RNA-seq), and 8 DNA methylation analysis was performed. We also performed single-cell RNA-seq using 1 sample of MNKPL patients and a normal bone marrow sample as the reference. The research protocol was approved by the review board of TMDU. Results: Sixteen children or young adults (< 39 years old) and 2 older adults with MNKPL were identified. The median age of MNKPL patients was 11 (0.5-75) years old. There are 12 males and 6 females. The extramedullary involvement was observed in 7 patients. Complete remission after induction therapy was achieved in 8/14 (57%) patients treated with acute myeloid leukemia (AML) type chemotherapy and 2/4 (50%) patients treated with acute lymphoblastic leukemia (ALL)/non-Hodgkin lymphoma type chemotherapy, respectively. Fifteen patients underwent hematopoietic cell transplantation (HCT). The median follow-up period was 3.8 (0.1-16.0) years. 5-year OS and 5-year EFS was 49.5% and 40.7%, respectively. In genetic analysis, median 388 somatic mutations in MNKPL were identified by WES. The recurrent mutations were observed in NOTCH1 (n=5), MAML3 (n=4), NRAS, MAP3K4, RECQL4, CREBBP, ASXL2, and KMT2D (n=3, respectively), and MAML2, MAP3K1, FLT3, CARD11, MSH4, FANCI, WT1, ZNF384, and ERG (n=2, respectively). The distinct expression pattern, higher expression of RUNX3 and NOTCH1, and lower expression of BCL11B were identified in MNKPL samples which were compared to MPAL, AML, and T cell ALL in RNA-seq. The distinct methylation profile, hypomethylation of RUNX3 regulatory region, and hypermethylation of BCL11B regulatory region were identified in DNA methylation analysis. Single-cell RNA-seq analysis also showed distinct 4 subsets of MNKPL. Discussion and Conclusions: NK cells are the founding member of a family of innate lymphoid cells (ILC). Genetic abnormality of NOTCH1 pathway is a hallmark of MNPKL. RUNX3 is required for NK cell survival and proliferation in response to IL-15 signaling. RUNX3 high expression and hypomethylation of RUNX3 regulatory region also characterize MNKPL. Currently, MNKPL is classified as MPAL NOS, our genetic analysis revealed that MNKPL is a distinct group from MPAL. The prognosis of MNKPL was not satisfactory even though HCT was performed. The development of new therapeutic approaches based on these genetic analyses is highly expected. Disclosures Saito: Toshiba Corporation: Research Funding. Nakazawa:Toshiba Corporation: Research Funding.

Background Depression in old age is an increasing contributor to poor health and accompanying health care costs. Although there is an abundance of literature on later-life depression (LLD), the neural correlates have not been clarified. The aim of this study was to determine whether patients with LLD show abnormal gray matter volume (GMV) and white matter integrity by using multiple image analysis methods. Methods The study included 45 patients with LLD and 61 healthy participants who were matched for age, sex, years of education, and vascular risk factors. GMV was examined using voxel-based morphometry, while the white matter integrity was determined by tract-based spatial statistics and tract-specific analysis, which were obtained from high-resolution magnetic resonance images. Results Patients with LLD showed significantly less GMV in the orbitofrontal cortex, anterior cingulate, insula, amygdala, and temporal regions, as well as higher fractional anisotropy in the uncinate fasciculus, compared with healthy participants. Patients with LLD who had reduced orbitofrontal and insular GMV had more severe clinical variables. The reduced orbitofrontal GMV was associated with higher fractional anisotropy in the uncinate fasciculus. Limitation The effects of medication should also be considered when interpreting the results of this study. Conclusion Our results suggest that regional GMV is linked to white matter integrity of the uncinate fasciculus in the orbitomedial prefrontal limbic network, and the disruption of this network may be involved in the pathophysiology of LLD.

The annual meeting of the Mammalogical Society of Japan was held from September 20th to 23rd, 2012 at Azabu University. To mark this occasion, an exhibition entitled “Mammalogy at a Glance,” celebrating the hosting of the 2012 annual meeting of the Mammalogical Society of Japan by Azabu University, in 2012” was held from September 18th to December 26th, 2012. The senior author (ST) prepared the overall design and asked the contributors to prepare exhibits on the following five topics representing important fields of mammalogy. S. Takatsuki wrote an introduction of mammalogy focusing on its history in Japan. K. Koyasu and S. Oda wrote a history of the Mammalogical Society of Japan. K. Mori described the morphology by exhibiting the hind leg of a zebra (Equus grevyi). Exhibitions of muscle are uncommon and this exhibit attracted the visitors’ attention. H. Tamate explained the genetics by showing genetic variations of sika deer (Cervus nippon). Arrangements of DNA base sequences of sika deer were exhibited in the glass of exhibition cases. Tamate also explained the concept of the subspecies and mitochondria DNA. Skulls of three subspecies of sika deer were exhibited. N. Higuchi and M. Minami presented a study on the behavioral ecology of sika deer on Kinkazan Island based on individual identification. The social rank of male deer strongly affects their reproductive success. Y. Sato introduced the research and conservation activities concerning the brown bear (Ursus arctos) in Hokkaido. A leaflet and a GPS collar were exhibited.

Although counting cementum annuli of lower incisor is a reliable method for age estimation in cervids, it inevitably involves the destruction of specimens. Here we studied the relationship between cranial suture closure patterns and age to test the possibility of cranial suture closure as a non-destructive age indicator in sika deer (Cervus nippon) specimens from Kinkazan Island, Japan, for which extensive life records were available. A strong positive relationship between the sum of suture closure level scores and age was found. We found that this relationship was even stronger than the relationship between age and the crown height of the first molar, which is frequently used for non-destructive age determination. Our study highlights the potential of cranial suture closure as an alternative valid tool for age estimation.

The temporal pattern of estrus shows considerable variation in different mammalian species, and sometimes within species. In any mating systems, social organizations, environmental, or physiological conditions, females may adopt different reproductive strategies to achieve successful insemination (McClintock 1981; Kawata 1983; Wade and Schneider 1992). This variability also promotes diverse mating systems (Emlen and Oring 1977). Sika deer (Cervus nippon) in Japan are seasonal breeders, mating over 2–4 months from autumn to winter (Koizumi 1992; Asada and Ochiai 1996; Suzuki et al. 1996; Koizumi et al. 2009; Ohnishi et al. 2009). Like most cervid species, sika deer are polyestrous, and repeat estrus if conception is unsuccessful (e.g., Cowan 1965; Armstrong et al. 1969; Asher 1985; Sadlier 1987; Curlewis et al. 1988). Existing information about the temporal pattern, duration and estrous cycle of sika deer has been derived from captive animals or from hormone analysis. Authors report different length for the estrous cycle, up to 21 days (Yamauchi et al. 1997; Liu et al. 2002; Takahashi et al. 2002). Information on the pattern of estrus can be inferred from symptoms such as frequent urination, tail lifting, visible changes in external genitalia, color and swelling, and vaginal discharge (Bergerud 1975; Liu et al. 2002). Despite these observations, the receptive period (when females receive mounting and copulation) and the timing of copulation(s) of deer is unknown. Few data on estrous conditions in wild animals exist

Incisor size is associated with feeding efficiency in herbivorous ungulates and may have been under selection in correspondence with food habits. In the meantime, males of polygynous, dimorphic species have smaller cheek teeth than females, possibly because their reproductive span is much shorter than that of females. Thus, males are not under selection for more durable teeth when there is no reproductive return. Therefore, incisor size is expected to be under natural selection against wear and under the influence of sex-based differences in reproductive strategy. We first investigated incisor wear in Japanese sika deer (Cervus nippon) and compared wear rates between the sexes and two ecologically contrasting populations on Kinkazan Island and Mt. Goyo. We then compared unworn incisor size to test the hypotheses that female deer have relatively larger incisors than males and a population with faster incisor wear has larger incisors. The Kinkazan deer showed significantly faster wear than those on Mt. Goyo, and Kinkazan males had faster wear than Kinkazan females. Unworn incisor size was relatively larger for females than that for males and was larger for Kinkazan deer than that for Mt. Goyo deer. The sex-based difference in incisor size was greater in Mt. Goyo deer than that in Kinkazan deer. These findings support the hypothesis that sex-based differences in reproductive span result in larger incisor size for female sika deer and imply that strong natural selection against rapid tooth wear diminishes sex-based differences in incisor size in Kinkazan deer. © 2013 The Linnean Society of London, Biological Journal of the Linnean Society, 2013, 110, 384–397.

Genetic variations and their relationships to individual fitness have been the major topics in studies of ecology and evolution. The concept that a reduction in genetic variations leads to lower fecundity termed “inbreeding depression” has been predominantly supported by studies involving laboratory organisms, but has rarely been tested in wild populations. We therefore examined whether the individual genetic diversity among a population of wild sika deer (Cervus nippon) on Kinkazan Island, northern Japan, affected neonatal weight that is often considered as a fitness-related trait. First, the neonatal weights of fawns born during 1994–2004 were recorded, and 11 microsatellite loci were genotyped to obtain 5 different estimates of an individual's genetic diversity. To test whether the genetic diversities of fawns correlated with their neonatal weights, multivariate analyses using a generalized linear mixed model were performed. The neonatal weights were significantly affected by standardized mul...

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.

We performed hyperbaric oxygen (HBO) therapy for 3 patients with delayed neuropsychiatric encephalopathy induced by carbon monoxide (CO) poisoning. All patients were male and around 50 years old, and they had not received HBO therapy within 24 h after CO poisoning, even though they showed severe consciousness disturbance. In these patients, delayed neuropsychiatric encephalopathy appeared about 25 days after acute CO poisoning, and HBO therapy was initiated within 8 days after disease onset. Although the condition of 2 of the patients worsened initially, they showed significant improvement of neurocognitive impairment after 30 sessions of HBO therapy. The clinical courses of these patients suggest that the effect of HBO therapy can be evaluated after 30 sessions. To evaluate the validity of the indices of the clinical effect of HBO therapy, we performed brain magnetic resonance imaging, single photon emission computed tomography, electroencephalography (EEG), and neurocognitive tests (HDS-R, and Wechsler Adult Intelligence Scale-Revised or III). Our results showed that changes in EEG signals and neurocognitive tests were closely correlated with the patients' clinical courses.

The costs of parturition and lactation of female sika deer on Kinkazan Island (9.6 km2 in size), northern Japan, which live at a high density (about 50 deer/km2), were evaluated by comparison of body weights of 481 females measured during a 15 year study (1993–2008). Weight data were chosen from only females that did not give birth in the preceding year. The mean body weight of females that did not give birth (“yelds”) was significantly lower (P < 0.001) than that of females who gave birth (“milks”); yelds' body weight was 93.1% and 83.5% that of milks in the preceding and parturition years, respectively. The yelds increased in body weight by the following March by 8.2% (P < 0.001), whereas milks did not. Among the milks, those whose fawns survived until the following May (“rearing milks”) lost body weight by 14.9% (P < 0.001). Milks who lost fawns within a week after birth (“early fawn-less milks”) did not lose body weight (P = 0.583), while those whose fawns died after the first autumn but died before May (“late fawn-less milks”) lost body weight by 19.9% (P < 0.001). These results indicate that sika deer females do not enter estrus unless they are heavy enough, and that both parturition and rearing are costly for sika deer mothers living in high-density conditions.

Allergic rhinitis is the most common allergic disease, displaying the typical nasal symptom of congestion. Prostaglandin D(2) (PGD(2)), 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.The effect of PGD(2) 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 PGD(2), and to examine the mechanism of PGD(2)-induced nasal congestion. Moreover, the involvement of second messengers in PGD(2)-induced mucosal relaxation was investigated.PGD(2) 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.PGD(2)-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 PGD(2)-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.

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)

Life-time reproductive success (LRS) of female sika deer (Cervus nippon) on Kinkazan Island (9.6 km 2 in area), northern Japan, was studied based on individually identified females for 17 years from 1989 to 2005. Birth rate was almost zero for females under four years age, while at four it suddenly increased to 39%. Birth rates were about 50% thereafter. Individual females gave birth usually every second year. In the years when mothers were nursing offspring they neither gained body weight nor came into estrus. In the next "yeld" year (no fawn), they came into estrus after gaining body weight. When a mother lost a fawn within 10 days after birth, she recovered body weight. As many as 63% of females died without giving birth to any offspring. A LRS of three offspring was most frequent (16.3%), and more or fewer offspring were less common. No female gave birth to more than six fawns. LRS was greater in longer-living females, and neither con- centrating parturition in the prime age classes nor skipping parturition to achieve a longer life was observed. These results seemed to reflect poor food-quality habitat due to the extremely high deer density on the island.

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.