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Background Systemic lupus erythematosus (SLE) disproportionately affects individuals of African ancestry (AA) compared to European ancestry (EA). In the general population, high risk (HR) variants in the apolipoprotein L1 ( APOL1) gene increase the risk of renal and hypertensive disorders in individuals of AA. Since SLE is characterized by an interferon signature and APOL1 expression is driven by interferon, we examined the hypothesis that APOL1 HR genotypes predominantly drive higher rates of renal and hypertensive-related comorbidities observed in SLE patients of AA versus those of EA. Methods We performed a retrospective cohort study in patients with SLE of EA and AA using a genetic biobank linked to de-identified electronic health records. APOL1 HR genotypes were defined as G1/G1, G2/G2, or G1/G2 and low risk (LR) genotypes as 1 or 0 copies of the G1 and G2 alleles. To identify renal and hypertensive-related disorders that differed in prevalence by ancestry, we used a phenome-wide association approach. We then used logistic regression to compare the prevalence of renal and hypertensive-related disorders in EA and AA patients, both including and excluding patients with the APOL1 HR genotype. In a sensitivity analysis, we examined the association of end stage renal disease secondary to lupus nephritis (LN-related ESRD) with ancestry and the APOL1 genotype. Results We studied 784 patients with SLE; 195 (24.9%) were of AA, of whom 27 (13.8%) had APOL1 HR genotypes. Eighteen renal and hypertensive-related phenotypes were more common in AA than EA patients ( p-value ≤ 1.4E-4). All phenotypes remained significantly different after exclusion of patients with APOL1 HR genotypes, and most point odds ratios (ORs) decreased only slightly. Even among ORs with the greatest decrease, risk for AA patients without the APOL1 HR genotype remained significantly elevated compared to EA patients. In the sensitivity analysis, LN-related ESRD was more prevalent in SLE patients of AA versus EA and AA patients with the APOL1 HR genotype versus LR ( p-value < .05 for both). Conclusion The higher prevalence of renal and hypertensive disorders in SLE patients of AA compared to those of EA is not fully explained by the presence of APOL1 high risk variants.

Some autoimmune (AI) conditions affect white blood cell (WBC) counts. Whether a genetic predisposition to AI disease associates with WBC counts in populations expected to have low numbers of AI cases is not known. We developed genetic instruments for 7 AI diseases using genome-wide association study summary statistics. Two-sample inverse variance weighted regression (IVWR) was used to determine associations between each instrument and WBC counts. Effect size represents change in transformed WBC counts per change in log odds-ratio of the disease. For AI diseases with significant associations by IVWR, polygenic risk scores (PRS) were used to test for associations with measured WBC counts in individuals of European ancestry in a community-based (ARIC, n = 8926), and a medical-center derived cohort (BioVU, n = 40,461). The IVWR analyses revealed significant associations between 3 AI diseases and WBC counts: systemic lupus erythematous (Beta = − 0.05 [95% CI, − 0.06, − 0.03]), multiple sclerosis (Beta = − 0.06 [− 0.10, − 0.03]), and rheumatoid arthritis (Beta = 0.02 [0.01, 0.03]). PRS for these diseases showed associations with measured WBC counts in ARIC and BioVU. Effect sizes tended to be larger among females, consistent with the known higher prevalence of these diseases among this group. This study shows that genetic predisposition to systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis was associated with WBC counts, even in populations expected to have very low numbers of disease cases.

In contrast to the main olfactory system that detects volatile chemicals in the nasal air, the vomeronasal system can detect nonvolatile chemicals as well as volatiles. In the vomeronasal system, chemicals are perceived by the vomeronasal organ (VNO) projecting axons to the accessory olfactory bulb (AOB). Beavers (Castor spp.) are semiaquatic mammals that have developed chemical communication. It is possible that the beaver's anal gland secretions, nonvolatile and insoluble substances, may work as a messenger in the water and that beavers may detect the nonvolatile chemicals floating on the water surface via the VNO. The present study aimed to clarify the specificities of the beaver vomeronasal system by histologically and immunohistochemically analyzing the VNO and AOB of 12 Eurasian beavers (C. fiber). The VNO directly opened to the nasal cavity and was independent of a narrow nasopalatine duct connecting the oral and nasal cavities. The VNO comprised soft tissues including sensory and nonsensory epithelium, glands, a venous sinus, an artery, as well as cartilage inner, and bone outer enclosures. The AOB had distinct six layers, and anti-G protein α-i2 and α-o subunits were, respectively, immunoreactive in rostral and caudal glomeruli layers indicating expressions of V1Rs and V2Rs. According to gene repertories analysis, the beavers had 23 and six intact V1R and V2R genes respectively. These findings suggested that beavers recognize volatile odorants and nonvolatile substances using the vomeronasal system. The beaver VNO was developed as well as in other rodents, and it had two specific morphological features, namely, disadvantaged contact with the oral cavity because of a tiny nasopalatine duct, and a double bone and cartilage envelope. Our results highlight the importance of the vomeronasal system in beaver chemical communication and support the possibility that beavers can detect chemicals floating on the water surface via the VNO.

Objectives The aim of this AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial subgroup analysis was to examine rivaroxaban monotherapy benefits and their relation to the time between stenting and enrollment among patients after coronary stenting. Background Of 2,215 patients with atrial fibrillation and stable coronary artery disease in the AFIRE trial, rivaroxaban monotherapy was noninferior to rivaroxaban plus antiplatelet therapy (combination therapy) in terms of efficacy and superior for safety endpoints. However, thrombotic risk after antiplatelet therapy cessation remained a concern among 1,444 patients who had undergone coronary stenting >1 year before enrollment. Methods The benefits of rivaroxaban monotherapy in coronary stenting subgroups were assessed for efficacy (a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death of any cause), safety (major bleeding defined according to International Society on Thrombosis and Haemostasis criteria), ischemic endpoints, net adverse clinical event, and time between stenting and enrollment. Results Efficacy and safety endpoints for monotherapy were superior to combination therapy, with HRs of 0.70 for efficacy (95% CI: 0.50-0.98; P = 0.036) and 0.55 for safety (95% CI: 0.33-0.92; P = 0.019). For ischemic endpoints, the HR was 0.82 (95% CI: 0.58-1.15; P = 0.240). The HR became smaller with longer time between stenting and enrollment (efficacy, P for interaction = 0.158; safety, P = 0.097). Conclusions In patients with atrial fibrillation after coronary stenting, the benefits of rivaroxaban monotherapy for efficacy and safety endpoints were consistent with those in the whole AFIRE trial population. The benefits became apparent with longer time between stenting and enrollment. (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study [AFIRE]; UMIN000016612 , NCT02642419 )

Bilirubin has antioxidant and anti-inflammatory properties in vitro and in animal studies and protects against inflammatory, cardiovascular, and other diseases in observational studies; therefore, bilirubin has potential as a therapeutic agent. However, observational studies could be confounded by many factors. We used a genetic (n = 61,281) and clinical (n = 234,670) approach to define the association between bilirubin and 19 conditions with a putative protective signal in observational studies. We also tested if individuals with genetically higher bilirubin levels underwent more diagnostic tests. We used a common variant in UGT1A1 (rs6742078) associated with an 26% increase in bilirubin levels in the genetic studies. Carriers of the variant had higher bilirubin levels (P = 2.2 × 10-16 ) but there was no significant association with any of the 19 conditions. In a phenome-wide association study (pheWAS) to seek undiscovered genetic associations, the only significant finding was increased risk of "jaundice-not of newborn." Carriers of the variant allele were more likely to undergo an abdominal ultrasound (odds ratio = 1.04, [1.00-1.08], P = 0.03). In contrast, clinically measured bilirubin levels were significantly associated with 15 of the 19 conditions (P

OBJECTIVES To determine if the implementation of a weight-based high-flow nasal cannula (HFNC) protocol for infants with bronchiolitis was associated with improved outcomes, including decreased ICU use. METHODS We implemented a weight-based HFNC protocol across a tertiary care children’s hospital and 2 community hospitals that admit pediatric patients on HFNC. We included all patients who were RESULTS Implementation of the weight-based HFNC protocol was associated with an immediate absolute decrease in ICU use of 4.0%. We also observed a 6.2% per year decrease in the slope of ICU admissions pre- versus postintervention. This was associated with an immediate reduction in median cost per bronchiolitis encounter of $661, a 2.3% immediate absolute reduction in the proportion of patients who received noninvasive ventilation, and a 3.4% immediate absolute reduction in the proportion of patients who received HFNC. CONCLUSIONS A multicenter, weight-based HFNC protocol was associated with decreased ICU use and noninvasive ventilation use. In hospitals where HFNC is used in non-ICU units, weight-based approaches may lead to improved resource use.

Simple Summary In this study, we clarified the evolutional features of the UGT gene family in Carnivora. We firstly analyzed the gene synteny of UGT1As, 2Bs, ana 2Es and further demonstrated the phylogenetic analysis to reveal the evolutional gene duplication and loss event in Carnivora. We found specific UGT1A duplication in Canidae, brown bear and black bear, and UGT2Bs duplication in Canidae, some Mustelidae, and Ursidae. In addition, we observed gene contraction of UGT1A7-12 in Phocidae, Otariidae, and Felidae. This study strongly suggested closely related Carnivorans also showed significant evolutional differences of UGTs, and further imply the importance of appropriate approaches to assess pharmacokinetics and toxicokinetic from experimental animals. UDP-glucuronosyltransferases (UGTs) are one of the most important enzymes for xenobiotic metabolism or detoxification. Through duplication and loss of genes, mammals evolved the species-specific variety of UGT isoforms. Among mammals, Carnivora is one of the orders that includes various carnivorous species, yet there is huge variation of food habitat. Recently, lower activity of UGT1A and 2B were shown in Felidae and pinnipeds, suggesting evolutional loss of these isoforms. However, comprehensive analysis for genetic or evolutional features are still missing. This study was conducted to reveal evolutional history of UGTs in Carnivoran species. We found specific gene expansion of UGT1As in Canidae, brown bear and black bear. We also found similar genetic duplication in UGT2Bs in Canidae, and some Mustelidae and Ursidae. In addition, we discovered contraction or complete loss of UGT1A7-12 in phocids, some otariids, felids, and some Mustelids. These studies indicate that even closely related species have completely different evolution of UGTs and further imply the difficulty of extrapolation of the pharmacokinetics and toxicokinetic result of experimental animals into wildlife carnivorans.

Study question Does the area of oocyte perivitelline space have an effect on fertilization and embryo development following intracytoplasmic sperm injection? Summary answer The area of oocyte perivitelline space has not an effect on the fertilization but the embryo development following intracytoplasmic sperm injection. What is known already Oocyte perivitelline space has a lot of variation at intracytoplasmic sperm injection (ICSI). Some researchers reported that the characteristics of perivitelline space (large or small) affect embryo development, pregnancy, and implantation. However, these studies did not accurately calculate the area of perivitelline space. Therefore, little information is available on the effect of the area of oocyte perivitelline space on fertilization and embryo development following ICSI. The purpose of this study was to calculate and classify the area of oocyte perivitelline space and investigate the effect of the area of perivitelline space on fertilization and embryo development following ICSI. Study design, size, duration 1. We retrospectively investigated 634 mature oocytes that were conducted ICSI between January 2021 and December 2021. The area of each oocyte perivitelline space was defined from between the area of circle calculated from the inner layer of zona pellucida and cytoplasm and divided into 3 groups (-9%, 10-19%, 20%-). 2. We retrospectively calculated the diameter of an inner layer of zona pellucida and cytoplasm and compared it with the 3 groups (-9%, 10-19%, 20%-). Participants/materials, setting, methods 1. The fertilization, survival, good quality day-3 embryo, blastocyst, good quality blastocyst rates following ICSI were compared with the 3 groups (-9%, 10-19%, 20%-). 2. The average diameter of an inner layer of zona pellucida and cytoplasm of each oocyte for the 3 groups (-9%, 10-19%, 20%-) were compared. The data were analyzed by Fisher’s exact test, residual analysis, one-way ANOVA test, with Bonferroni correction as appropriate to determine the statistical differences among groups. Main results and the role of chance 1. The survival rates of perivitelline space -9%, 10-19%, 20%- groups were 100% (109/109), 96% (363/378), 94% (138/147), the fertilization rates were 89% (97/109), 88% (331/378), 86% (127/147), the good quality day-3 embryo rates were 56% (54/97), 70% (232/331), 70% (89/127) respectively. No significant difference was observed between these comparison items. The blastocyst rates of perivitelline space -9%, 10-19%, 20%- groups were 51% (47/92), 69% (222/321), 82% (93/114), the good quality blastocyst rates were 22% (20/92), 40% (129/321), 52% (59/114) respectively. The blastocyst and good quality blastocyst rates of perivitelline space -9% group showed significantly lower results. On the other hand, the blastocyst and good quality blastocyst rates of perivitelline space 20%- group showed significantly higher results. 2. The average diameter of an inner layer of zona pellucida of perivitelline space -9%, 10-19%, 20%- groups were 125 ± 4 µm, 129 ± 5 µm, 136 ± 6 µm, the average diameter of the cytoplasm of perivitelline space were 121 ± 4 µm, 119 ± 4 µm, 118 ± 4 µm respectively. Significant differences were observed in all pairs of groups of the average diameter of an inner layer of zona pellucida and cytoplasm. Limitations, reasons for caution The area of oocyte perivitelline space was calculated at only one plane. Wider implications of the findings Oocytes with narrow perivitelline space might have a wide region of adhesive between the cytoplasm surface and an inner layer of the zona pellucida which resulted in a smaller diameter of the zona pellucida and lower blastocyst rate by forming cytoplasmic fragments (Yumoto K et al. JARG. 2020 ;37(6):1349-1354.). Trial registration number Not Applicable

Study question In the management of male infertility, we investigated whether urological consultation could improve the live birth rate, and who should visit urologists in the setting of IVF clinic. Summary answer Urologic consultation resulted in improvement of semen quality and live birth rate with more IVF use in those with adverse semen parameters. What is known already Male factor infertility exists in about a half of infertility couples. This accounts for about 8% in male reproductive age. Therefore, ideally every male partner of infertility couples attempting conception should have a urological evaluation. However, it is not very easy to access urologists who specialized in reproductive medicine in Japan because we have very few of such urologists. One the other hand, a certain number of couples are wasting their time during IVF failure without urological evaluation. Study design, size, duration This is a single-institution retrospective study. We enrolled male partners of infertility couples who visited Kameda IVF clinic Makuhari, Chiba, Japan, between May 2016 and December 2020 and followed at least one year. Live birth rate and the frequency of IVF use were investigated according to semen quality and urological consultation status. Chi-square tests and T tests were used to compare the results between groups. Participants/materials, setting, methods Among 2225 couples who visited Kameda IVF clinic Makuhari, 803 male partners (Group A, 36.0%) were evaluated by urologists who were specialized in male reproductive medicine. Remaining 1422 patients did not (Group B, 64.0%). Lifestyle evaluation, physical examination, semen analyses, scrotal ultrasonography, blood test including sexual hormones and zinc concentration were performed in Group A. Semen analyses and lifestyle evaluation were performed in Group B. Urological treatments were done according to factors of male infertility. Main results and the role of chance Semen quality was worse in Group A as compared to Group B (sperm motility, 28.5±16.9% vs. 46.0±17.0%; total sperm count, 105±108 million/mL vs. 176±155; total motile sperm count, 34±49 vs.87±98; mean±S.D.; p = 0.0001, 0.0001, 0.0001, A vs. B, respectively). After urologic consultation and managements, sperm motility was improved to 34±18% (p = 0.001). Live birth rate in groups A and B were similar (56.0% vs. 57.2%), however couples who obtained a child in Group A used IVF more often than those in Group B (70% vs. 49.9%, p 50 million, n = 900), 119 visited urologist (31.1%, Group 3) and 781 did not (Group 4). Live birth rate and the use of IVF were not different between Groups 3 and 4 (51.1% vs.60.9%; 50.4% vs. 62.9%). Limitations, reasons for caution This study is a single-institution, retrospective study in the setting of IVF clinic. There may be a selection bias since men first visit gynecologists. These could affect the study results. Wider implications of the findings In the setting of IVF clinic, urologic consultation resulted in improved semen quality and better live birth rate with the use of IVF, especially in those who have adverse semen parameters. The results of this study encourage patients to see urologists and physicians to introduce urologist to patients. Trial registration number not applicable

Wild carnivorans are one of the most important species due to their high positions in the food chain. They are also highly affected by numerous environmental contaminants through bioaccumulation and biomagnification. Xenobiotic metabolism is a significant chemical defense system from xenobiotics because it degrades the activity of a wide range of chemicals, generally into less active forms, resulting in their deactivation. Sulfotransferases (SULTs) are one of the most important xenobiotic metabolic enzymes, which catalyze the sulfonation of a variety of endogenous and exogenous chemicals, such as hormones, neurotransmitters, and a wide range of xenobiotic compounds. Although SULTs are of such high importance, little research has focused on these enzymes in wild carnivorans. In this study, we clarified the genetic properties of SULTs in a wide range of mammals, focusing on carnivorans, using in silico genetic analyses. We found genetic deficiencies of SULT1E1 and SULT1D1 isoforms in all pinnipeds analyzed and nonsense mutations in SULT1Cs in several carnivorans including pinnipeds. We further investigated the enzymatic activity of SULT1E1 in vitro using liver cytosols from pinnipeds. Using a SULT1E1 probe substrate, we found highly limited estradiol sulfonation in pinnipeds, whereas other mammals had relatively high sulfation. These results suggest that pinnipeds have severely or completely absent SULT1E1 activity, which importantly catalyzes the metabolism of estrogens, drugs, and environmental toxins. This further implies a high susceptibility to a wide range of xenobiotics in these carnivorans, which are constantly exposed to environmental chemicals throughout their lifetime.

Introduction: We clarified the renal uptake and urinary secretion mechanism of [99mTc]dimercaptosuccinic acid ([99mTc]DMSA) via drug transporters in renal proximal tubules. Methods: [99mTc]DMSA was added to human embryonic kidney 293 cells expressing human multidrug and toxin extrusion (MATE)1 and MATE2-K, carnitine/organic cation transporter (OCTN)1 and OCTN2, and organic cation transporter (OCT)2; to Flp293 cells expressing human organic anion transporter (OAT)1 and OAT3; and to vesicles expressing P-glycoprotein (P-gp), multidrug resistance associated protein (MRP)2, MRP4, or breast cancer resistance protein with and without probenecid (OAT inhibitor for both OATs and MRPs). Time activity curves of [99mTc]DMSA with and without probenecid were established using LLC-PK1 cells. Biodistribution and single photon emission computed tomography (SPECT) imaging in mice were conducted using [99mTc]DMSA with and without probenecid. Results: [99mTc]DMSA uptake was significantly higher in Flp293/OAT3 than in mock cells. Uptake via OAT3 was inhibited by probenecid. [99mTc]DMSA uptake into vesicles that highly expressed MRP2 was significantly higher in adenosine triphosphate (ATP) than in adenosine monophosphate (AMP), and probenecid decreased uptake to similar levels as that in AMP. In the time activity curves for [99mTc]DMSA in LLC-PK1 cells, probenecid loading inhibited accumulation from the basolateral side into LLC-PK1 cells, whereas accumulation from the apical side into cells gradually increased. Transport of [99mTc]DMSA from both sides was low. Biodistribution and SPECT imaging studies showed that [99mTc]DMSA with probenecid loading resulted in significantly higher accumulation in blood, heart, liver, and bladder after [99mTc]DMSA injection compared with control mice. Probenecid induced significantly lower accumulation in the kidney after [99mTc]DMSA injection. Conclusions: [99mTc]DMSA accumulates in renal proximal tubular epithelial cells from blood via OAT3 on the basolateral side, and then a small volume of [99mTc]DMSA will be excreted in urine via MRP2. Advances in knowledge: [99mTc]DMSA accumulates via OAT3 in renal proximal tubular epithelial cells and is slightly excreted from the cells via MRP2. Implications for patient care: [99mTc]DMSA may be useful for measuring renal transport function with OAT3 in patients.

The difference between X-ray-induced photodarkening (X-PD) and 451 nm laser diode (LD) induced PD (LD-PD) was investigated in DyAlGe-doped silica glasses. The same defect species (Al-OHC, Dy2+, GEC, and GLPC+) are generated in X-PD and LD-PD, although the LD-PD defect population is 10−3 of the X-PD defect population. There is a big difference in the defect population ratio of GEC and Al-OHC and its dependence on Ge concentration. The ratio in LD-PD is higher than that in X-PD. The GEC population of X-PD almost saturates when Ge > 2 wt%. On the other hand, GEC of LD-PD continues to increase even if Ge exceeds 2 wt%. Based on these facts, possible mechanisms of LD-PD and the role of Ge codoping were proposed.

This study aimed to establish zebrafish-based in vivo and in silico assay systems to evaluate the antiandrogenic potential of environmental chemicals. Zebrafish embryos were exposed to 17α-methyltestosterone (TES) alone or coexposed to TES and representative antiandrogens including flutamide, p,p'-DDE, vinclozolin, fenitrothion, and linuron. We assessed the transcript expression of the androgen-responsive gene sulfotransferase family 2, cytosolic sulfotransferase 3 (sult2st3). The expression of sult2st3 was significantly induced by TES in the later stages of embryonic development. However, the TES-induced expression of sult2st3 was inhibited by flutamide in a concentration-dependent manner (IC

application/pdf, Artiodactyl livestock animals have a vomeronasal system that detects pheromones. Vomeronasal receptors comprise type 1 (V1R) coupled with G protein α-i2 (Gαi2) and type 2 (V2R) coupled with G protein α-o (Gαo). Laboratory rodents have two segregated V1R and V2R pathways that reach separately to the accessory olfactory bulb (AOB). In contrast, the AOBs of goats and sheep are entirely positive for Gαi2, indicating that they have only the V1R pathway. However, we detected a few V2R genes in the genome of cattle, goats, sheep and pigs by genome assembly. Thus, we immunohistochemically analyzed the AOBs of cattle and pigs to confirm which type of the vomeronasal system is present in artiodactyl livestock species. The glomerular layer of the AOB in cattle and pigs was entirely positive for anti-Gαi2 and weakly positive for anti-Gαo, as in the V1R uniform type of vomeronasal system in other mammal species. These findings indicated that artiodactyl livestock species have a uniform type of vomeronasal system composing the V1R pathway. Therefore, caution is advised when extrapolating knowledge of laboratory rodents with two vomeronasal pathways to livestock animals that have one. © 2022 Elsevier Ltd

Objective This study was undertaken to investigate the hypothesis that a genetic predisposition toward rheumatoid arthritis (RA) increases the risk of 10 cardiometabolic and autoimmune disorders previously associated with RA in epidemiologic studies, and to define new genetic pleiotropy present in RA. Methods Two approaches were used to test our hypothesis. First, we constructed a weighted genetic risk score (wGRS) and then examined its association with 10 prespecified disorders. Additionally, a phenome-wide association study (PheWAS) was carried out to identify potential new associations. Second, inverse variance-weighted regression (IVWR) meta-analysis was used to characterize the association between genetic susceptibility to RA and the prespecified disorders, with the results expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs). Results The wGRS for RA was significantly associated with type 1 diabetes mellitus (DM) (OR 1.10 [95% CI 1.04-1.16]; P = 9.82 × 10-4 ) and multiple sclerosis (OR 0.82 [95% CI 0.77-0.88]; P = 1.73 × 10-8 ), but not with other cardiometabolic phenotypes. In the PheWAS, wGRS was also associated with an increased risk of several autoimmune phenotypes including RA, thyroiditis, and systemic sclerosis, and with a decreased risk of demyelinating disorders. In the IVWR meta-analyses, RA was significantly associated with an increased risk of type 1 DM (P = 1.15 × 10-14 ), with evidence of horizontal pleiotropy (Mendelian Randomization-Egger intercept estimate P = 0.001) likely driven by rs2476601, a PTPN22 variant. The association between type 1 DM and RA remained significant (P = 9.53 × 10-9 ) after excluding rs2476601, with no evidence of horizontal pleiotropy (intercept estimate P = 0.939). RA was also significantly associated with type 2 DM and C-reactive protein levels. These associations were driven by variation in the major histocompatibility complex region. Conclusion This study presents evidence of pleiotropy between the genetic predisposition to RA and associated phenotypes found in other autoimmune and cardiometabolic disorders, including type 1 DM.

Sea turtles can detect airborne and waterborne odors, but whether they recognize scents from the same species and if so, how they affect their behavior remains unknown. The present study evaluated the behavioral effects of odorants on juvenile green sea turtles (Chelonia mydas). The odorants were derived from Rathke glands (external scent glands) of mature male green sea turtles, and from two types of food. The activity of the juveniles increased when exposed to food scents, and significantly decreased compared with controls when exposed to scents from Rathke glands. These findings indicated that scents from the same species affect behavior, and that chemical communication via olfaction has important outcomes for sea turtles.

TPMT and NUDT15 variants explain less than 25% of azathioprine-associated myelotoxicity. There are 25 additional genes in the thiopurine pathway that could also contribute to azathioprine myelotoxicity. We hypothesized that among TPMT and NUDT15 normal metabolizers, a score combining the genetically predicted expression of other proteins in the thiopurine pathway would be associated with a higher risk for azathioprine discontinuation due to myelotoxicity. We conducted a retrospective cohort study of new users of azathioprine who were normal TPMT and NUDT15 metabolizers. In 1201 White patients receiving azathioprine for an inflammatory disease, we used relaxed Least Absolute Shrinkage and Selection Operator (LASSO) regression to select genes that built a score for discontinuing azathioprine due to myelotoxicity. The score incorporated the predicted expression of AOX1 and NME1. Patients in the highest score tertile had a higher risk of discontinuing azathioprine compared to those in the lowest tertile (hazard ratio [HR] = 2.15, 95% confidence interval [CI] = 1.11-4.19, p = 0.024). Results remained significant after adjusting for a propensity score, including sex, tertile of calendar year at initial dose, initial dose, age at baseline, indication, prior TPMT testing, and the first 10 principal components of the genetic data (HR = 2.11, 95% CI = 1.08-4.13, p = 0.030). We validated the results in a cohort (N = 517 non-White patients and those receiving azathioprine to prevent transplant rejection) that included all other patients receiving azathioprine (HR = 2.00, (95% CI = 1.09-3.65, p = 0.024). In conclusion, among patients who were TPMT and NUDT15 normal metabolizers, a score combining the predicted expression of AOX1 and NME1 was associated with an increased risk for discontinuing azathioprine due to myelotoxicity.

Bird death is often caused by renal lesions induced by chemicals. The avian kidney has a renal portal system with significant blood flow that is sensitive to many chemicals. However, early avian bio-markers for kidney injury are yet to be identified. This study aimed to identify novel renal biomarkers. Acute kidney injury (AKI) can be divided into acute intersti-tial nephritis (AIN) and acute tubular necrosis (ATN). A chicken model of kidney damage was created by an injection of diclofenac or cisplatin, which caused either AIN or ATN, respectively. Microarray analysis was per-formed to profile the gene expression patterns in the chickens with nephropathy. A gene enrichment analysis suggested that the genes related to responses to external stimuli showed expression changes in both AIN and ATN. However, hierarchical clustering analyses sug-gested that gene expression patterns differed between AIN and ATN, and the number of biomarkers relating to renal damage was low. To identify early biomarkers for nephropathy, we focused on genes that were induced at various levels of renal damage. The gene, vanin-1 (VNN1) was highly induced in the early stages of renal damage. A quantitative real-time PCR analysis sup-ported this finding. These results suggest VNN1 could be a useful early biomarker of kidney injury in avian species.

Azathioprine is used frequently to treat several inflammatory conditions. However, treatment is limited by adverse events-in particular, myelotoxicity. Thiopurine-S-methyltransferase (TPMT) and nudix hydrolase-15 (NUDT15) are enzymes involved in azathioprine metabolism; variants in the genes encoding these enzymes increase the risk for azathioprine myelotoxicity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has recommended dose adjustments based on the results of TPMT and NUDT15 genotyping. However, little is known about the importance of this genetic information in routine clinical care. We hypothesized that in patients with inflammatory diseases, TPMT and NUDT15 genotype data predict the risk of discontinuing azathioprine due to myelotoxicity. This was a retrospective cohort study in 1,403 new adult azathioprine users for the management of inflammatory conditions for whom we had genetic information and clinical data. Among patients who discontinued azathioprine, we adjudicated the reason(s). Genotyping was performed using the Illumina Infinium Expanded Multi-Ethnic Genotyping Array plus custom content. We used CPIC guidelines to determine TPMT and NUDT15 metabolizer status; patients were grouped as either: (i) poor/intermediate, or (ii) normal/indeterminate metabolizers. We classified 110 patients as poor/intermediate, and 1,293 patients as normal/indeterminate metabolizers. Poor/intermediate status was associated with a higher risk for azathioprine discontinuation due to myelotoxicity compared to normal/indeterminate metabolizers (hazard ratio (HR) = 2.90, 95% confidence interval (CI): 1.58-5.31, P = 0.001). This association remained significant after adjustment for race, age at initiation, sex, primary indication, and initial daily dose of azathioprine (adjusted HR (aHR) = 2.67, 95% CI: 1.44-4.94, P = 0.002). In conclusion, TPMT and NUDT15 metabolizer status predicts discontinuation due to myelotoxicity for patients taking azathioprine for inflammatory conditions.

Background Acute coronary syndrome (ACS) with occlusion of the circumflex coronary artery (LCX) poses diagnostic dilemma that may lead to a delay in reperfusion. Purpose We sought to assess the diagnostic significance of initial electrocardiography (ECG) changes in patients with acute LCX occlusion in relation to its clinical characteristics and the management. Methods From consecutive 1269 patients with ACS who were admitted to our institution during a 5-year period (2015–2019), 138 patients with ACS due to LCX occlusion were analyzed for clinical, ECG and angiographic presentation, and the door-to-balloon (DTB) time. ECG changes were classified into 4 different patterns: 1) ST-elevation in inferior/lateral leads (ST-E); 2) ST-depression in V1-V4 (ST-D); 3) no significant ST changes (No-ST); and 4) others. Results (1) No-ST pattern was found in 47 patients (34%), ST-E in 47 patients (34%), ST-D in 25 patients (18%) and others in 19 patients (14%). (2) Occlusion site: Proximal LCX; 16 patients with No-ST (34%), 6 patients with ST-E (13%), 13 patients with ST-D (52%). Distal LCX; 28 patients with No-ST (60%), 35 patients with ST-E (74%), 11 patients with ST-D (44%) (p=0.007). (Table) (3) Echocardiographic identification of left ventricular asynergy; 31 patients with No-ST (66%), 38 patients with ST-E (81%), 22 patients with ST-D (88%). (4) No-ST group was associated with longer DTB time; 245 min (170–562 min), compared to 93 min (83–121 min) in ST-E group and 97 min (70–129 min) in ST-D group (p Conclusion One-third of the patients with LCX-ACS showed no ST changes, resulting in significantly longer DTB time. Improving diagnostic accuracy with anticipation for LCX-ACS and the use of echocardiographic examination and also the possible application of posterior leads (V7-V9) recording is challenging but critical to avoid delayed reperfusion and to improve outcomes in these patients without ECG changes. Funding Acknowledgement Type of funding sources: None.

The UDP-glucuronosyltransferase (UGT) gene family is responsible for the transfer of glucuronic acid to exogenous and endogenous chemicals. Based on the highly diversified number of genes, the mammalian UGT1A and UGT2B subfamily genes are believed to be involved in the conjugation reactions of xenobiotic metabolism. However, it is speculated that the UGT2 family genes are not involved in the xenobiotic metabolism of avian species due to the less diverse number of genes. In this study, we aimed to investigate the evolutionary history of mammalian UGT1 and UGT2 family genes and determine when the diversification of UGT2B genes occurred. We also attempted to identify the main factors responsible for the diversification of UGT genes. By examining the genomic information and feeding habits of 67 species representing each mammalian family, we discovered that the UGT2B genes emerged in the Eutheria on or after Cretaceous period and that their number were higher in plant-eating mammals (herbivore or omnivore) than in carnivorous mammals. We also found that the UGT2B genes in some herbivorous mammals underwent positive selection. In contrast, the diversity of the UGT1 family genes was inherited from the common ancestor of birds and mammals. Thus, our findings suggest that the emergence of angiosperms (flowering plants) and the occurrence of “animal–plant warfare” influenced the evolution of this gene family involved in the xenobiotic metabolism of eutherians. Furthermore, future research investigating the marsupials and birds that do not possess UGT2B genes is required to elucidate the mechanisms underlying the metabolism of chemical substances in these species.

Recent evidence has revealed that organophosphorus flame retardants (OPFRs) elicit a variety of toxic effects, including endocrine disruption. The present study examined estrogenic and growth inhibitory responses to OPFR metabolites in comparison to their parent compounds using zebrafish eleutheroembryos.1 Exposure to 4-hydroxylphenyl diphenyl phosphate (HO-p-TPHP) but not its parent compound triphenyl phosphate (TPHP) elicited upregulation of a marker gene of estrogenic responses, cytochrome P450 19A1b (CYP19A1b), and this upregulation was reversed by co-exposure to an estrogen receptor antagonist. Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), as well as 3-hydroxylphenyl diphenyl phosphate (HO-m-TPHP) and diphenyl phosphate (DPHP), did not elicit significant changes in the CYP19A1b expression. Reduction in body length was induced by TPHP and to a lesser extent by its hydroxylated metabolites. Altered expression of genes involved in the synthesis and action of thyroid hormones, including iodothyronine deiodinases 1 and 2, thyroid hormone receptor alpha, and transthyretin, were commonly observed for TPHP and its hydroxylated metabolites. Reduction in the body length was also seen in embryos exposed to TDCIPP but not BDCIPP. The transcriptional effect of TDCIPP was largely different from that of TPHP, with decreased expression of growth hormone and prolactin observed only in TDCIPP-exposed embryos. Considering the concentration response relationships for the growth retardation and gene expression changes, together with existing evidence from other researchers, it is likely that prolactin is in part involved in the growth inhibition caused by TDCIPP. The present study showed similarities and differences in the endocrine disruptive effects of OPFRs and their metabolites.

Cytochrome P450s are among the most important xenobiotic metabolism enzymes that catalyze the metabolism of a wide range of chemicals. Through duplication and loss events, CYPs have created their original feature of detoxification in each mammal. We performed a comprehensive genomic analysis to reveal the evolutionary features of the main xenobiotic metabolizing family: the CYP1-3 families in Carnivora. We found specific gene expansion of CYP2Cs and CYP3As in omnivorous animals, such as the brown bear, the black bear, the dog, and the badger, revealing their daily phytochemical intake as providing the causes of their evolutionary adaptation. Further phylogenetic analysis of CYP2Cs revealed Carnivora CYP2Cs were divided into CYP2C21, 2C41, and 2C23 orthologs. Additionally, CYP3As phylogeny also revealed the 3As’ evolution was completely different to that of the Caniformia and Feliformia taxa. These studies provide us with fundamental genetic and evolutionary information on CYPs in Carnivora, which is essential for the appropriate interpretation and extrapolation of pharmacokinetics or toxicokinetic data from experimental mammals to wild Carnivora.

Anticoagulant rodenticides have been widely used to eliminate wild rodents, which as invasive species on remote islands can disturb ecosystems. Since rodenticides can cause wildlife poisoning, it is necessary to evaluate the sensitivity of local mammals and birds to the poisons to ensure the rodenticides are used effectively. The Bonin Islands are an archipelago located 1000 km southeast of the Japanese mainland and are famous for the unique ecosystems. Here the first-generation anticoagulant rodenticide diphacinone has been used against introduced black rats (Rattus rattus). The only land mammal native to the archipelago is the Bonin fruit bat (Pteropus pse-laphon), but little is known regarding its sensitivity to rodenticides. In this study, the Egyptian fruit bats (Rou-settus aegyptiacus) was used as a model animal for in vivo pharmacokinetics and pharmacodynamics analysis and in vitro enzyme kinetics using their hepatic microsomal fractions. The structure of vitamin K epoxide reductase (VKORC1), the target protein of the rodenticide in the Bonin fruit bat, was predicted from its genome and its binding affinity to rodenticides was evaluated. The Egyptian fruit bats excreted diphacinone slowly and showed similar sensitivity to rats. In contrast, they excreted warfarin, another first-generation rodenticide, faster than rats and recovered from the toxic effect faster. An in silico binding study also indicated that the VKORC1 of fruit bats is relatively tolerant to warfarin, but binds strongly to diphacinone. These results suggest that even chemicals with the same mode of action display different sensitivities in different species: fruit bat species are relatively resistant to warfarin, but vulnerable to diphacinone.

Simple Summary Hedgehogs have a sensitive olfaction, but little is known about their vomeronasal organ, which detects specific chemicals such as pheromones. This is the first study to reveal the morphological and histological features of the vomeronasal organ in the African pygmy hedgehog. Notably, unlike other mammals, the hedgehog has a large, well-developed serous gland in the vomeronasal organ. This gland seems to allow flushing out odorous substances from the vomeronasal organ and might be favorable for subsequent stimulus reception. Abstract The vomeronasal organ (VNO) detects specific chemicals such as pheromones and kairomones. Hedgehogs (Eulipotyphla: Erinaceidae) have a well-developed accessory olfactory bulb that receives projections from the VNO, but little is known about the hedgehog VNO. Here, we studied the histological features of the VNO in five individual African pygmy hedgehogs by hematoxylin-eosin, periodic acid-Schiff, and Alcian blue stains. The hedgehog VNO comprises a hyaline cartilage capsule, soft tissue and epithelial lumen, and it branches from the site just before the incisive duct opening into the nasal cavity. The soft tissues contain several small mucous (or mucoserous) glands and a large serous gland, and many venous sinuses all around the lumen. The VNO lumen is round to oval throughout the hedgehog VNO, and the sensory epithelium lines almost the entire rostral part and medial wall of the middle part. These findings indicate that the VNO is functional and plays an important role in the hedgehog. Notably, the VNO apparently has a characteristic flushing mechanism with serous secretions like those of gustatory glands, which the hedgehog might frequently use to recognize the external environment.

Objectives To test the hypothesis that genetic predisposition to systemic lupus erythematosus (SLE) increases the risk of cardiometabolic disorders. Methods Using 41 single nucleotide polymorphisms (SNPs) associated with SLE, we calculated a weighted genetic risk score (wGRS) for SLE. In a large biobank we tested the association between this wGRS and 9 cardiometabolic phenotypes previously associated with SLE: atrial fibrillation, ischemic stroke, coronary artery disease, type 1 and type 2 diabetes, obesity, chronic kidney disease, hypertension, and hypercholesterolemia. Additionally, we performed a phenome-wide association analysis (pheWAS) to discover novel clinical associations with a genetic predisposition to SLE. Findings were replicated in the Electronic Medical Records and Genomics (eMERGE) Network. To further define the association between SLE-related risk alleles and the selected cardiometabolic phenotypes, we performed an inverse variance weighted regression (IVWR) meta-analysis. Results The wGRS for SLE was calculated in 74,759 individuals of European ancestry. Among the pre-selected phenotypes, the wGRS was significantly associated with type 1 diabetes (OR [95%CI] =1.11 [1.06, 1.17], P-value = 1.05x10−5). In the PheWAS, the wGRS was associated with several autoimmune phenotypes, kidney disorders, and skin neoplasm; but only the associations with autoimmune phenotypes were replicated. In the IVWR meta-analysis, SLE-related risk alleles were nominally associated with type 1 diabetes (P = 0.048) but the associations were heterogeneous and did not meet the adjusted significance threshold. Conclusion A weighted GRS for SLE was associated with an increased risk of several autoimmune-related phenotypes including type I diabetes but not with cardiometabolic disorders.

application/pdf, The morphological and histological features of the nasal cavity are diverse among animal species, and the nasal cavities of terrestrial and semiaquatic turtles possess 2 regions lined with each different type of sensory epithelium. Sea turtles can inhale both of volatile and water-soluble odorants with high sensitivity, but details of the architectural features and the distribution of the sensory epithelia within the sea turtle nasal cavity remain uncertain. The present study analyzed the nasal cavity of green sea turtles using morphological, computed tomographic, and histological methods. We found that the middle region of the sea turtle nasal cavity is divided into anterodorsal, anteroventral, and posterodorsal diverticula and a posteroventral excavation by connective tissue containing cartilages. The posterodorsal diverticulum was lined with a thin sensory epithelium, and the anterodorsal and anteroventral diverticula were occupied by a single thick sensory epithelium. In addition, a relatively small area on the posteroventral excavation was covered by independent sensory epithelium that differed from other 2 types of epithelia, and a single thin bundle derived from the posteroventral excavation comprised the most medial nerve that joins the anterior end of the olfactory nerve tract. These findings suggested that the posteroventral excavation identified herein transfers stimuli through an independent circuit and plays different roles when odorants arise from other nasal regions.

Overexpression of HER2 in breast cancer is correlated with poor prognosis. HER2-targeted drugs, such as trastuzumab and lapatinib, have been successful to treat HER2-positive breast cancers, however, the acquisition of the drug resistance of the cells is recognized. Here we suggest the novel molecular targets to cure HER2-positive breast cancers. The oncogenic roles of Rac1, a Rho family small GTPase, in a variety of cancers have been demonstrated. For example, the elevated expression or hyperactivation of Rac1 is frequently observed in human cancers, correlating with their aggressiveness and poor prognosis. In breast cancers, upregulation of Rac1 GEF (GTP exchange factor) and downregulation of Rac1 GAP (GTPase activating protein) have been reported. Moreover, activation of Rac1 contributed to trastuzumab resistance, which poses a serious problem during chemotherapy. In the present study, we first investigated in detail in which subtypes of breast cancers mRNA expression of Rac1 is correlated with their poor prognosis. Using the METABRIC database, we found that high mRNA expression of Rac1 significantly correlated with the poor prognosis of HER2-positive breast cancer (p=0.0012, High: n=49, Low: n=171). On the other hands, other three types (basal, claudin-low, or luminal-B type) did not show significant correlation between the expression levels of Rac1 mRNA and their prognosis (p=0.15, High: n=97, Low: n=102; p=0.052, High: n=110, Low: n=89; p=0.17, High: n=70, Low: n=391; respectively). In luminal-A type breast cancer, low mRNA expression of Rac1 significantly correlated with poor prognosis (p=0.0046, High: n=492, Low: n=187). We next investigated the molecular mechanism underlying Rac1 activation in HER2-positive breast cancer cells, SKBR-3 cells. We found that Cullin-3 (CUL3, a subunit of a RING ubiquitin E3 ligase complex) and its adaptor protein KCTD10 are essential for Rac1 activation. Mechanistically, CUL3/KCTD10 ubiquitinate RhoB, a Rho family small GTPase that suppresses the activation of Rac1, leading to the degradation RhoB. We also found that HER2 signaling is essential for the activation of Rac1. Conclusions: This study reveals that the novel molecular axis CUL3/KCTD10/RhoB regulates the Rac1 activation in HER2-positive breast cancer cells. The interference of CUL3/KCTD10 complex formation may be a new strategy to the treatment of HER2- and Rac1-positive breast cancers. Citation Format: Murakami A, Maekawa M, Kusakabe E, Yamasawa H, Aoki R, Komatsu S, Taguchi K, Nishiyama K, Yamashita M, Sugimori W, Kawai K, Nakayama J, Araki N, Semba K, Taguchi T, Kamei Y, Takada Y, Higashiyama S. Novel mechanisms of Rac1 activation by the Cullin-3/KCTD10 ubiquitin E3 complex in HER2-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-05-02.

Increasing use of zebrafish in biomedical, toxicological and developmental studies requires explicit knowledge of cytochrome P450 (CYP), given the central role of CYP in oxidative biotransformation of xenobiotics and many regulatory molecules. A full complement of CYP genes in zebrafish and their transcript expression during early development have already been examined. Here we established a comprehensive picture of CYP gene expression in the adult zebrafish liver using a RNA-seq technique. Transcriptional profiling of a full complement of CYP genes revealed that CYP2AD2, CYP3A65, CYP1A, CYP2P9 and CYP2Y3 are major CYP genes expressed in the adult zebrafish liver in both sexes. Quantitative real-time RT-PCR analysis for selected CYP genes further supported our RNA-seq data. There were significant sex differences in the transcript levels for CYP1A, CYP1B1, CYP1D1 and CYP2N13, with males having higher expression levels than those in females in all cases. A similar feature of gender-specific expression was observed for CYP2AD2 and CYP2P9, suggesting sex-specific regulation of constitutive expression of some CYP genes in the adult zebrafish liver. The present study revealed several "orphan" CYP genes as dominant isozymes at transcript levels in the adult zebrafish liver, implying crucial roles of these CYP genes in liver physiology and drug metabolism. The current results establish a foundation for studies with zebrafish in drug discovery and toxicology.

BackgroundSystemic lupus erythematosus (SLE) is a chronic relapsing autoimmune disorder that is challenging to diagnose due to its heterogeneous presentation of a combination of non-specific clinical manifestations and laboratory findings. This heterogeneity and lack of granularity is a major cause of treatment failure. With the advent of precision medicine, there is a need for accurate methods to identify cases of SLE in large clinical databases, and to recognize constellations of pathological characteristics (or fingerprints) that allow a better understanding of the disease. Computational phenotype discovery aims to solve this problem by using unbiased, data-driven machine learning methods to disentangle the fingerprints of disease that hide within the noisy, sparse and incomplete electronic health record data.ObjectivesTo generate data-driven phenotypic fingerprints of SLE and validate them by assessing their ability to distinguish records of patients with SLE vs. ‘near miss’ patients without the disease.MethodsRecords of 716 patients that published, expert-curated algorithms [1] indicated as likely SLE patients were reviewed by 3 clinicians and labeled as positive (490 records), negative (261), or indeterminate (55). Those labeled positive by an algorithm but negative by clinician chart review were considered ‘near misses’ and should be among the more difficult cases to classify. We trained an ElasticNet (regularized logistic regression) model to distinguish the true positive records from the near misses and evaluated it under 10x cross validation.Inputs to the predictive model were the projections of each patient record into the space of 2000 latent variables. These features had been inferred separately by an unsupervised machine-learning algorithm from a much larger dataset of 646,716 randomly sampled temporal cross sections of 63,775 longitudinal records of patients with an antinuclear antibody test. Each of the 2000 variables constitutes the phenotypic fingerprint of an unobserved, independent potential disease mechanism. Formally, they represent linear combinations of demographic data, laboratory test results, billing code intensities, and medication exposures [2].ResultsOur predictive model achieved an area under the Receiver Operating Characteristic Curve of 0.90, 95% CI: [0.879, 0.922], an area under the Precision-Recall Curve of 0.94, 95% CI: [0.926, 0.954], and an Integrated Calibration Index of 0.074, 95% CI: [0.067, 0.080].The model selected 61 of the 2000 potential latent mechanisms to distinguish positive SLE records from near-misses. All of the phenotypes selected to be predictive exhibit high face-validity from a clinical interpretation perspective. They include recognizable patterns of variables representing different clinical features of SLE (Figure 1).Figure 1.Detail of the estimated changes in the clinical features representing one of the 61 potential fingerprints found to distinguish records of patients with SLE vs. near misses.ConclusionWe found unbiased, data-driven fingerprints of potential latent disease mechanisms that were highly informative in differentiating records of patients with SLE from near-miss presentations, with performance surpassing existing expert-curated algorithms. Our methods found dozens of variable constellations that may lead to a more precise understanding of this complex and heterogeneous disease. That these results were obtained from cases that should be the most difficult for an algorithm to distinguish (positive vs. near-miss) suggests that our model’s accuracy is a lower bound on what would be expected from a more balanced cohort.References[1]Barnado et al. Developing Electronic Health Record Algorithms That Accurately Identify Patients With Systemic Lupus Erythematosus. Arthritis care & research, 2017[2]Thomas A. Lasko and Diego A. Mesa. Computational Phenotype Discovery via Probabilistic Independence. Proc KDD Appl Data Sci for Healthcare (DSHealth), 2019.AcknowledgementsMBM would like to acknowledge the Fulbright Spanish Comission for funding his graduate studies and the research that made this work possible. VKK would like to acknowledge NIAMS/NIH R01 AR076516 and Lupus Research Alliance BMS Accelerator Award for their financial support.Disclosure of InterestsNone declared

There have been many reports regarding toxic chemicals in birds. Chemicals are mainly metabolized in the liver through phase I oxidation by cytochrome P450 (CYP) and phase II conjugation by conjugated enzymes, such as UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), glutathione-S-transferase (GST), etc. Xenobiotic metabolism differs among bird species, but little detailed information is available. In the present study, the four-ring polycyclic aromatic hydrocarbon (PAH), pyrene, was used as a model xenobiotic to clarify the characteristics of xenobiotic metabolism in birds compared with laboratory animals by in vivo and in vitro studies. Plasma, bile, and excreta (urine and feces) were collected after oral administration of pyrene and analyzed to clarify xenobiotic metabolism ability in chickens and quails. Interestingly, pyrenediol-glucuronide sulfate (PYDOGS) and pyrenediol-diglucuronide (PYDOGG) were present in chickens and quails but not in rats. In addition, the area under the curve (AUC), maximum plasma concentration (Cmax), and time to maximum plasma concentration (Tmax) of pyrene-1-sulfate (PYOS) were higher than those of the parent molecule, pyrene, while the elimination half-life (t1/2) and mean residence time (MRT) were faster than those of the parent pyrene. With regard to sulfation of 1-hydroxypyrene (PYOH), the maximum velocity (Vmax) and Michaelis constant (Km) of rat liver cytosol were greater than those of chicken and quail liver cytosol. Furthermore, Vmax/Km of UGT activity in rat liver microsomes was also greater than those of chicken and quail liver microsomes. Characterization of xenobiotic metabolism revealed species differences between birds and mammals, raising concerns about exposure to various xenobiotics in the environment.

We analyzed the internal structure of the nasal cavities of hawksbill, olive ridley and black sea turtles from computed tomography images. The nasal cavities of all three species consisted of a vestibule, nasopharyngeal duct and cavum nasi proprium that included anterodorsal, posterodorsal and anteroventral diverticula, and a small posteroventral salience formed by a fossa of the wall. These findings were similar to those of green and loggerhead sea turtles (Cheloniidae), but differed from those of leatherback sea turtles (Dermochelyidae). Compared to the Cheloniidae species, the nasal cavity in leatherback sea turtles was relatively shorter, wider and larger in volume. Those structural features of the nasal cavity of leatherback sea turtles might help to suppress heat dissipation and reduce water pressure within the nasal cavity in cold and deep waters.

Background/Introduction High platelet reactivity (HPR) is associated with adverse cardiovascular events, primarily intrastent thrombosis, after a percutaneous coronary intervention (PCI). However, the relationship between hyperacute postprocedural HPR with prasugrel loading and clinical outcomes in acute coronary syndrome (ACS) remains unclear. Moreover, factors contributing to HPR in ACS with prasugrel loading are also unknown. Purpose To assess the effects of post-procedural HPR with prasugrel loading on clinical outcomes in ACS during hospitalization, and to define the appropriate cut-off values and identify factors contributing to HPR. Methods A single-center, retrospective observational study that enrolled 154 patients who underwent emergent PCI for ACS with prasugrel loading was performed. The P2Y12 reaction unit (PRU) value was measured immediately after PCI using the VerifyNowR system. The primary end-point was major adverse cardiac events (MACE, defined as the composite of death, myocardial infarction, stroke, heart failure, ventricular arrhythmia needing defibrillation). Results The mean patient age (standard deviation) was 70.7 (±12.5) years, 76.6% were men, and the average time from the prasugrel intake to PRU calculation was 103.2 (±48.5) min. During the mean hospital stay of 15.6 (±8.5) days, 24 in-hospital MACE (15.5%) and 8 deaths (5.2%) occurred. Thrombosis events, including myocardial infarction recurrence, did not occur (only one case of spontaneous coronary artery dissection was considered as myocardial infarction recurrence). PRU was significantly higher in the MACE group than that in Non-MACE group (287±55 and 232±64, respectively, p293) immediately after the emergent PCI. Kaplan-Meier curve showing MACE events occurred in the HPR group than that in the non-HPR group (40.5% vs 7.6%, p Conclusion PRU was significantly higher in the MACE group, with an appropriate cut-off value of HPR of 293 in this study. HPR was an independent predictor of MACE during hospitalization; however, thrombosis events were not significant. HPR predictors were old age, female sex, low systolic blood pressure, short prasugrel intake to measure time, and large acute gain. This study shows the post-procedural HPR with prasugrel loading in patients with ACS can be a useful predictive marker of adverse events during hospitalization. Funding Acknowledgement Type of funding source: None

Unconfind compression tests, in which the suction in the specimens was measured, were carried out for statically compacted specimens of silty clay. The effect of degree of saturation on the unconfined compressive strength and deformation were examined. It was found that the suction stress affects the unconfined compressive strength, and that the relationship between the suction and the suction stress can be estimated by using the soil-water characteristic curve.