Post-intensive care syndrome: Recent advances and future directions.

Post-intensive care syndrome comprises physical, cognitive, and mental impairments in patients treated in an intensive care unit (ICU). It occurs either during the ICU stay or following ICU discharge and is related to the patients' long-term prognosis. The same concept also applies to pediatric patients, and it can greatly affect the mental status of family members. In the 10 years since post-intensive care syndrome was first proposed, research has greatly expanded. Here, we summarize the recent evidence on post-intensive care syndrome regarding its pathophysiology, epidemiology, assessment, risk factors, prevention, and treatments. We highlight new topics, future directions, and strategies to overcome post-intensive care syndrome among people treated in an ICU. Clinical and basic research are still needed to elucidate the mechanistic insights and to discover therapeutic targets and new interventions for post-intensive care syndrome.

Comparison of the pre-dilution and post-dilution methods for online hemodiafiltration.

Online hemodiafiltration (OL-HDF) is a treatment modality using diffusion and ultrafiltration. There are two types of dilution methods in OL-HDF: pre-dilution, which is commonly provided in Japan, and post-dilution, which is commonly provided in Europe. The optimal OL-HDF method for individual patients is not well studied. In this study, we compared the clinical symptoms, laboratory data, spent dialysate, and adverse events of pre- and post-dilution OL-HDF. We conducted a prospective study of 20 patients who underwent OL-HDF between January 1, 2019 and October 30, 2019. Their clinical symptoms and dialysis efficacy were evaluated. All patients underwent OL-HDF every 3 months in the following sequence: first pre-dilution, post-dilution, and second pre-dilution. We evaluated 18 patients for the clinical study and 6 for the spent dialysate study. No significant differences in spent dialysates regarding small and large solutes, blood pressure, recovery time, and clinical symptoms were observed between the pre- and post-dilution methods. However, the serum α1-microglobulin level in post-dilution OL-HDF was lower than that in pre-dilution OL-HDF (first pre-dilution: 124.8 ± 14.3 mg/L; post-dilution: 116.6 ± 13.9 mg/L; second pre-dilution: 125.8 ± 13.0 mg/L; first pre-dilution vs. post-dilution, post-dilution vs. second pre-dilution, and first pre-dilution vs. second pre-dilution: p = 0.001, p < 0.001, and p = 1.000, respectively). The most common adverse event was an increase in transmembrane pressure in the post-dilution period. Compared to pre-dilution, the post-dilution method decreased the α1-microglobulin level; however, there were no significant differences in clinical symptoms or laboratory data.

Evaluation of anticoagulant rodenticide sensitivity by examining in vivo and in vitro responses in avian species, focusing on raptors.

Anticoagulant rodenticides (ARs) are used to control pest rodent species but can result in secondary poisoning of non-target animals, especially raptors. In the present study, differences in AR sensitivity among avian species were evaluated by comparing in vivo warfarin pharmacokinetics and effects, measuring cytochrome P450s (CYPs) expression involved in AR metabolism, and conducting in vitro inhibition assays of the AR target enzyme Vitamin K 2,3-epoxide reductase (VKOR). Oral administration of warfarin at 4 mg/kg body weight did not prolong prothrombin time in chickens (Gallus gallus), rock pigeons (Columba livia), or Eastern buzzards (Buteo japonicus). Rock pigeons and buzzards exhibited shorter plasma half-life of warfarin compared to chickens. For the metabolite analysis, 4'-hydroxywarfarin was predominantly detected in all birds, while 10-hydroxywarfarin was only found in pigeons and raptors, indicating interspecific differences in AR metabolism among birds likely due to differential expression of CYP enzymes involved in the metabolism of ARs and variation of VKOR activities among these avian species. The present findings, and results of our earlier investigations, demonstrate pronounced differences in AR sensitivity and pharmacokinetics among bird species, and in particular raptors. While ecological risk assessment and mitigation efforts for ARs have been extensive, AR exposure and adverse effects in predatory and scavenging wildlife continues. Toxicokinetic and toxicodynamic data will assist in such risk assessments and mitigation efforts.

Assessment of developmental toxicity and the potential mode of action underlying single and binary exposure to estrogenic endocrine disrupting chemicals in zebrafish (Danio rerio).

The current study investigated the effect of single and binary exposure to distinct xenoestrogens, including diethylstilbestrol (DES) and zearalenone (ZEN), on zebrafish embryos subjected to continuous exposure for 4 days starting from 4 h post fertilization. Noteworthy impact on cumulative mortality, hatchability, spinal and tail curvature, pericardial edema, and reduction in blood circulation were observed in DES-treated embryos, with lower incidence and intensity shown for ZEN at the same nominal concentration (3 µM). An interactive effect was seen for the combined exposure to DES and ZEN, in which deformities and circulatory failure mediated by DES were mitigated by co-treatment with low concentrations of ZEN. Similarly, ZEN-induced spinal and tail curvature, pericardial edema, and blood flow reduction declined dramatically following DES co-exposure at low concentrations. A significant counteracting effect has been observed against DES- and ZEN-induced developmental anomalies following co-treatment with an estrogen receptor (ER) antagonist, fulvestrant (FUL). The assessment of the aromatase gene (CYP19A1b) showed that DES strongly upregulated mRNA expression of CYP19A1b with a lower EC50 (1.1 × 10-3 nM) than a natural estrogen, 17ß-estradiol (2.5 nM). Similarly, ZEN induced CYP19A1b mRNA expression with an EC50 of 57 nM. Exposure to 10 or 20 µM FUL inhibited the expression of CYP19A1b induced by a single treatment of DES or ZEN. Overall, the competitive action against ER could be the main mechanism underlying the developmental toxicity induced by DES and ZEN.

Return-to-Work Prevalence Among COVID-19 Patients After Receiving Intensive Care: A Systematic Review and Meta-Analysis.

Returning to work can be a serious issue for patients who have undergone intensive care. Previous studies have reported a relatively low return-to-work prevalence among such patients. Some patients with coronavirus disease 2019 (COVID-19) experience severe pneumonia and require intensive care, including mechanical ventilation. However, little is known about the return-to-work prevalence among such patients. Therefore, we conducted a systematic review and meta-analysis of the literature describing the return-to-work prevalence among COVID-19 patients who received intensive care. The eligibility criteria were determined based on the medical condition, context, and population framework of each study, as follows: (1) full-text observational studies, (2) context: COVID-19 patients admitted to ICU, (3) condition: return-to-work prevalence after ICU discharge, and (4) population: critically ill patients who are 18 years and older. Eligible studies included randomized controlled trials (RCTs) and observational studies. Review articles, case reports, letters to the editor, and comments without data involving return-to-work prevalence were excluded. We searched the Medical Literature Analysis and Retrieval System Online (MEDLINE, via PubMed), the Cumulated Index to Nursing and Allied Health Literature (CINAHL, via EBSCOhost), and the International Clinical Trials Registry Platform (ICTRP) databases from their inception till July 26, 2022, and updated the search on June 14, 2023. Specifically, we collected studies reporting data on the return-to-work prevalence among COVID-19 patients after receiving intensive care. Data extraction and quality assessment were performed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Prevalence Studies. Pre-developed standard forms were used for data collection, and pooled prevalence for return-to-work was calculated. Out of the 2221 available records, 42 full texts were reviewed, 20 of which were included in the qualitative synthesis. The number of return-to-work cases reported at 0-3 months, 4-6 months, and 7-12 months were three, 11, and nine, respectively. At 0-3 months, the pooled prevalence was 0.49 (three trials; n = 73; 95% CI: 0.15-0.84; I2 = 82%). At 4-6 months, the pooled prevalence was 0.57 (11 trials; n = 900; 95% CI: 0.40-0.73; I2 = 92%). Finally, at 7-12 months, the pooled prevalence was 0.64 (nine trials; n = 281; 95% CI: 0.50-0.77; I2 = 80%). However, the overall quality of the included studies was low. Based on the results, approximately one-third of COVID-19 patients did not return to work 12 months after receiving intensive care. Given the quality and limitations of the studies, a more detailed and extensive cohort study is required; also, concerned authorities should implement adequate measures in terms of providing integrated job support for this patient population.

Japanese Clinical Practice Guidelines for Rehabilitation in Critically Ill Patients 2023 (J-ReCIP 2023).

Providing standardized, high-quality rehabilitation for critically ill patients is a crucial issue. In 2017, the Japanese Society of Intensive Care Medicine (JSICM) promulgated the "Evidence-Based Expert Consensus for Early Rehabilitation in the Intensive Care Unit" to advocate for the early initiation of rehabilitations in Japanese intensive care settings. Building upon this seminal work, JSICM has recently conducted a rigorous systematic review utilizing the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. This endeavor resulted in the formulation of Clinical Practice Guidelines (CPGs), designed to elucidate best practices in early ICU rehabilitation. The primary objective of this guideline is to augment clinical understanding and thereby facilitate evidence-based decision-making, ultimately contributing to the enhancement of patient outcomes in critical care settings. No previous CPGs in the world has focused specifically on rehabilitation of critically ill patients, using the GRADE approach. Multidisciplinary collaboration is extremely important in rehabilitation. Thus, the CPGs were developed by 73 members of a Guideline Development Group consisting of a working group, a systematic review group, and an academic guideline promotion group, with the Committee for the Clinical Practice Guidelines of Early Mobilization and Rehabilitation in Intensive Care of the JSICM at its core. Many members contributed to the development of the guideline, including physicians and healthcare professionals with multiple and diverse specialties, as well as a person who had been patients in ICU. Based on discussions among the group members, eight important clinical areas of focus for this CPG were identified. Fourteen important clinical questions (CQs) were then developed for each area. The public was invited to comment twice, and the answers to the CQs were presented in the form of 10 GRADE recommendations and commentary on the four background questions. In addition, information for each CQ has been created as a visual clinical flow to ensure that the positioning of each CQ can be easily understood. We hope that the CPGs will be a useful tool in the rehabilitation of critically ill patients for multiple professions.

Instruments to assess post-intensive care syndrome assessment: a scoping review and modified Delphi method study.

BACKGROUND: The assessment of post-intensive care syndrome (PICS) is challenging due to the numerous types of instruments. We herein attempted to identify and propose recommendations for instruments to assess PICS in intensive care unit (ICU) survivors. METHODS: We conducted a scoping review to identify PICS follow-up studies at and after hospital discharge between 2014 and 2022. Assessment instruments used more than two times were included in the modified Delphi consensus process. A modified Delphi meeting was conducted three times by the PICS committee of the Japanese Society of Intensive Care Medicine, and each score was rated as not important (score: 1-3), important, but not critical (4-6), and critical (7-9). We included instruments with ≥ 70% of respondents rating critical and ≤ 15% of respondents rating not important. RESULTS: In total, 6972 records were identified in this scoping review, and 754 studies were included in the analysis. After data extraction, 107 PICS assessment instruments were identified. The modified Delphi meeting reached 20 PICS assessment instrument recommendations: (1) in the physical domain: the 6-min walk test, MRC score, and grip strength, (2) in cognition: MoCA, MMSE, and SMQ, (3) in mental health: HADS, IES-R, and PHQ-9, (4) in the activities of daily living: the Barthel Index, IADL, and FIM, (5) in quality of life: SF-36, SF-12, EQ-5D-5L, 3L, and VAS (6), in sleep and pain: PSQI and Brief Pain Inventory, respectively, and (7) in the PICS-family domain: SF-36, HADS, and IES-R. CONCLUSION: Based on a scoping review and the modified Delphi method, 20 PICS assessment instruments are recommended to assess physical, cognitive, mental health, activities of daily living, quality of life, sleep, and pain in ICU survivors and their families.

Analysis of Crop Consumption Using Scatological Samples from the Red-Crowned Crane Grus japonensis in Eastern Hokkaido, Japan.

Total DNA extracts from the intestinal contents of 60 flying red-crowned cranes (juveniles, subadults and adults) found dead in 2006-2021, and the feces of 25 chicks collected in June and July of 2016-2018, were used for PCR reactions with primers specific for 16 crops, followed by high-throughput sequencing. The most predominant crop detected was corn in adult and subadult cranes (61.7%). Other grains (barley, wheat, soybean) (5.0-8.3%) and vegetables (tomatoes, Chinese cabbage, etc.) (1.7-6.7%) were also detected in flying cranes. Surprisingly, some of the detected crops were not grown in the Kushiro and Nemuro regions. There was no significant difference in crop intake status in winter and that in other seasons for most of the crops. Corn (28.0%), soybeans (8.0%), wheat and beet (4.0%) were detected in crane chicks in summer, though the detection rates were generally lower than those in flying cranes. Alfalfa, which is not grown in eastern Hokkaido but is used in some cattle feed, was detected in some cranes. Rice, buckwheat, adzuki beans, common beans, potatoes and carrots were not detected at any life stage, indicating the preferences of red-crowned cranes. The results suggest that red-crowned cranes in Hokkaido are dependent on dairy farmers for their feed supply.

Diagnostic Performance of Endoscopic Ultrasonography with Water-Filled Balloon Method for Superficial Esophageal Squamous Cell Carcinoma.

BACKGROUND: Endoscopic ultrasonography (EUS) is a commonly used tool for preoperative depth diagnosis of superficial esophageal squamous cell carcinoma (ESCC). Probing EUS using the water-filled balloon method is a simple and safe examination. AIM: The aim of this study was to clarify the diagnostic performance of EUS with the water-filled balloon method for superficial ESCC compared to magnifying narrow-band imaging (ME-NBI). METHODS: We retrospectively examined 403 lesions in 393 consecutive patients diagnosed with ESCC and evaluated them with ME-NBI and EUS. Clinicopathological findings were collected, and the accuracy of the preoperative diagnosis was compared between ME-NBI and EUS-B. EUS examiners were not blinded to prior ME-NBI results, and EUS results may have been influenced by ME-NBI results. RESULTS: The pathological tumor depth of the EP/LPM in 152 lesions, MM/SM1 in 130 lesions, and deep submucosa (SM2/SM3) in 121 lesions was examined. The proportion of total lesions with an accurate diagnosis was significantly higher in EUS than in ME-NBI (67.7% versus 62.0%, P = 0.015). When analyzed by clinical depth diagnosis using ME-NBI, the proportion of lesions with an accurate diagnosis was significantly higher for EUS in MM/SM1 (55.7% versus 46.1%, P = 0.033). The sensitivity was significantly higher in EUS for SM2/SM3 lesions (76.0% versus 54.5%, P < 0.001). The accuracy and specificity of EUS, which differentiate MM/SM1 from EP/LPM or SM2/SM3, were significantly higher than those of ME-NBI. The median endoscopic ultrasonography procedure time was approximately 6.5 min. CONCLUSIONS: EUS with the water-filled balloon method is a safe and straightforward method that can be performed on lesions clinically diagnosed as MM/SM1 using ME-NBI. We retrospectively reviewed lesions in patients diagnosed with ESCC and evaluated them using magnifying endoscopy with narrow-band imaging (ME-NBI) and endoscopic ultrasound using the water-filled balloon method (EUS-B). We conclude that EUS-B can increase the diagnostic accuracy.

Safety of Cold Snare Polypectomy during Continuous Use of Antithrombotic Drugs for Delayed Post-Polypectomy Bleeding: A Pilot Study.

BACKGROUND: Cold snare polypectomy is a high-risk endoscopic procedure with a low delayed post-polypectomy bleeding rate. However, it is unclear whether delayed post-polypectomy bleeding rates increase during continuous antithrombotic treatment. This study aimed to determine the safety of cold snare polypectomy during continuous antithrombotic treatment. METHODS: This single-center, retrospective cohort study enrolled patients who underwent cold snare polypectomy during antithrombotic treatment between January 2015 and December 2021. Patients were divided into continuation and withdrawal groups based on whether they continued with antithrombotic drugs or not. Propensity score matching was performed using age, sex, Charlson comorbidity index, hospitalization, scheduled treatment, type of antithrombotic drugs used, multiple medications used, indication for antithrombotic drugs, and gastrointestinal endoscopist qualifications. The delayed polypectomy bleeding rates were compared between the groups. Delayed polypectomy bleeding was defined as the presence of blood in stools and requiring endoscopic treatment or a decrease in hemoglobin level by 2 g/dL or more. RESULTS: The continuation and withdrawal groups included 134 and 294 patients, respectively. Delayed polypectomy bleeding was observed in 2 patients (1.5%) and 1 patient (0.3%) in the continuation and withdrawal groups, respectively (p = 0.23), before propensity score matching, with no significant difference. After propensity score matching, delayed polypectomy bleeding was observed in 1 patient (0.9%) in the continuation group but not in the withdrawal group, with no significant difference. CONCLUSION: Cold snare polypectomy during continuous antithrombotic treatment did not significantly increase delayed post-polypectomy bleeding rates. Therefore, this procedure may be safe during continuous antithrombotic treatment.

Metachronous Multiple Gastric Cancer Discovered as Endoscopic Curability C2 during Regular Follow-Up after Gastric Endoscopic Submucosal Dissection.

INTRODUCTION: The objective of this study was to clarify characteristics of metachronous endoscopic curability C2 (eCura C2) cancer during post-endoscopic submucosal dissection (ESD) follow-up. METHODS: Of 4,355 gastric lesions treated by ESD at our hospital during 2005-2021, 657 were metachronous. After excluding lesions found ≥2 years since the prior examination or in the gastric remnant, the remaining 515 were analyzed. Study 1: We compared 35 eCura C2 cancers and 480 eCura A-C1 cancers. Study 2: Endoscopic findings of the 35 lesions were examined to determine why they had been missed. RESULTS: Mean tumor size was larger (34.0 mm vs. 12.1 mm, p < 0.01) and the proportions of mixed-type and poorly differentiated cancers were higher (highly:mixed:poorly, 34.3:57.1:8.6 vs. 94.2:5.0:0.8, p < 0.01) in the eCura C2 group. Study 2: At the prior examination, 4 lesions were noticed but considered benign, 2 lacked sufficient imaging, 19 were detectable on imaging but missed, and 10 were not detectable on imaging. Over half the lesions that were detectable but missed at the prior examination were in the lesser curvature, many being type IIa-IIb lesions with color similar to the background mucosa. All lesions not detectable on imaging at the prior examination were mixed-type or poorly differentiated type. DISCUSSION: Metachronous cancer detected as eCura C2 cancers was significantly larger, and a significantly higher proportion was mixed-type or poorly differentiated cancers, compared with eCura A-C1 cancers. Possible reasons why these lesions were missed include rapid progression of mixed-type and poorly differentiated cancers, and poor recognition that lesions showing only slight color changes may be present at the lesser curvature.

In vivo and in silico assessments of estrogenic potencies of bisphenol A and its analogs in zebrafish (Danio rerio): Validity of in silico approaches to predict in vivo effects.

This study assessed the estrogen-like potencies of bisphenol A (BPA) and its analogs (BPs) using in vivo and in silico approaches in zebrafish. Zebrafish embryos were exposed to 16 BPs, most of which concentration-dependently induced cytochrome P450 19A1b (CYP19A1b) expression. BPs-induced CYP19A1b expression was suppressed by fulvestrant, a nonselective high affinity antagonist for estrogen receptor (Esr) subtypes. For BPs that concentration-dependently induced CYP19A1b expression, we estimated their 50 % effective concentration (EC50) and relative potencies (REPs) with respect to the potency of BPA for inducing CYP19A1b expression. BP C2, Bis-MP, and BPAF showed lower EC50 than BPA, BPE, and BPF, while BPZ and BPB showed moderate EC50. The REP order of the BPs was BP C2 (26) > Bis-MP (24) > BPAF (21) > BPZ (5.8) > BPB (2.7) > BPE (1.5) > BPF (0.63) > 2,4'-BPF (0.22), indicating that some BPs showed greater estrogenic potencies than BPA in our system. We also constructed in silico homology models of ligand binding domains for zebrafish Esr subtypes, including Esr1, Esr2a, and Esr2b. Molecular docking simulations of ligands with the Esr subtypes revealed the interaction energies of some BPs were lower than that of BPA. The interaction energies showed significant positive correlations with their EC50 values for inducing CYP19A1b expression in vivo. This study showed that some BPA analogs have greater estrogenic potencies than BPA and that in silico simulations of interactions between ligands and Esr subtypes may help predict in vivo estrogenic potencies of untested chemicals.

The Impact of Tunneled Central Venous Hemodialysis Catheter on Mortality of Elderly Hemodialysis Patients Hospitalized in a Long-Term Care Hospital.

INTRODUCTION: The association between tunneled central venous hemodialysis catheters (TCVCs) and mortality in hospitalized elderly hemodialysis (HD) patients remains unclear. METHODS: This retrospective observational study was conducted in a long-term care hospital. We evaluated the association between TCVC and mortality in HD patients hospitalized between 2015 and 2020. RESULTS: A total of 463 patients were compared: TCVC group (n = 53) and non-TCVC group (n = 410) including arteriovenous fistula (AVF, n = 369), arteriovenous graft (AVG, n = 30), and superficialized brachial artery (SBA, n = 11). The mean ages were 80 and 78 years in the TCVC and non-TCVC groups, respectively. Overall mortality rates for all-cause and cardiovascular diseases (CVDs) were higher in the TCVC group than in the non-TCVC group (log-rank, p = 0.01, and p = 0.009). Overall mortality was higher in the TCVC group than in the AVF group (p = 0.04), but there were no significant differences between the TCVC, AVG, and SBA groups. In Cox proportional hazards regression models, age, dialysis vintage, male sex, Charlson Comorbidity Index (CCI), and serum albumin level were associated with all-cause, CVD, and infectious disease (ID) mortalities, but TCVC was not associated with all-cause (hazard ratio, 1.31; 95% confidence interval, 0.95-1.80; p = 0.1), CVD (1.54; 0.99-2.39; p = 0.051), and ID (0.91; 0.48-1.70; p = 0.8) mortalities. Among patients aged ≥80 years, with dialysis vintage ≥7 years and CCI ≥10, the overall mortality rates were comparable between the two groups. CONCLUSIONS: Among elderly HD patients in the long-term care hospital, TCVC was not associated with mortality.

The predictive markers of severity and mortality in hospitalized hemodialysis patients with COVID-19 during Omicron epidemic.

INTRODUCTION: Predictive markers and prognosis remain unclear in hospitalized hemodialysis (HD) patients with coronavirus disease 2019 (COVID-19) during the Omicron epidemic. METHODS: We evaluated characteristics, laboratory parameters, and outcomes in hospitalized HD patients with COVID-19 (n = 102) at two centers between January and April 2022. RESULTS: The 30-day mortality rate was higher in moderate-critical group (n = 43) than mild group (n = 59) (16.3% vs. 1.7%; p = 0.007), and higher in patients with lower CC chemokine ligand 17 (CCL17) levels (<95.0 pg/mL) compared with normal CCL17 levels (19.0% versus 4.9%; p = 0.03). In multivariate analyses, a low CCL17 level (p = 0.003) was associated with moderate-critical conditions, and moderate-critical conditions (p = 0.04) were associated with 30-day mortality, whereas CCL17 was not associated with 30-day mortality. CONCLUSIONS: COVID-19 remains a fatal complication, and CCL17 was a predictive marker of severity in hospitalized HD patients during the Omicron epidemic.

Sulfotransferases (SULTs), enzymatic and genetic variation in Carnivora: Limited sulfation capacity in pinnipeds.

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.

Efficient in vivo and in silico assessments of antiandrogenic potential in zebrafish.

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 (IC50: 5.7 µM), suggesting that the androgen receptor (AR) plays a role in sult2st3 induction. Similarly, p,p'-DDE, vinclozolin, and linuron repressed the TES-induced expression of sult2st3 (IC50s: 0.35, 3.9, and 52 µM, respectively). At the highest concentration tested (100 µM), fenitrothion also suppressed sult2st3 expression almost completely. Notably, p,p'-DDE and linuron did not inhibit sult2st3 induction due to higher concentrations of TES; instead, they potentiated TES-induced sult2st3 expression. Fenitrothion and linuron, which had relatively low antiandrogenic potentials in terms of sult2st3 inhibition, induced broader toxicities in zebrafish embryos; thus, the relationship between developmental toxicities and antiandrogenic potency was unclear. Additionally, an in silico docking simulation showed that all five chemicals interact with the zebrafish AR at relatively low interaction energies and with Arg702 as a key amino acid in ligand binding. Our findings suggest that a combination of zebrafish-based in vivo and in silico assessments represents a promising tool to assess the antiandrogenic potentials of environmental chemicals.

Characteristics of cytochrome P450-dependent metabolism against acetamiprid in the musk shrew (Suncus murinus).

Soricidae spp. (shrews) play an essential role in soil ecosystems and, due to their habitat and behavior, are exposed to soil pollutants, such as pesticides. Still, toxicity risk in Soricidae spp. has not been appropriately assessed. In this study, the musk shrew (Suncus murinus) was used as a model organism for toxicity assessment in Soricidae. Considering their carnivorous diet, it is reasonable to assume that the musk shrew has unique metabolic traits that are different from those of other common experimental models. This study describes the cytochrome P450 (CYP)-dependent metabolism affected by acetamiprid (ACP), a neonicotinoid insecticide. Pharmacokinetics analysis, an in vitro metabolic assay, and genetic analysis of CYP were performed and compared with data from mice and rats. Through phylogenetic and syntenic analyses, three families of CYP were identified in the musk shrew. Pharmacokinetic analysis showed that the blood concentration of ACP decreased more quickly in musk shrews than in mice. Moreover, the in vitro metabolic assay suggested more efficient metabolic responses toward ACP in musk shrews than in mice or rats. One of the CYP2A isoforms in musk shrews might be linked to a better ACP metabolism. From the results above, we describe novel metabolic traits of the musk shrew. Future research on recombinant CYP enzymes is necessary to fully understand CYP-dependent metabolism of xenobiotics in musk shrews.

Third-Generation High-Vision Ultrathin Endoscopy Using Texture and Color Enhancement Imaging and Narrow-Band Imaging to Evaluate Barrett's Esophagus.

It remains unclear whether texture- and color-enhancement imaging (TXI) and narrow-band imaging (NBI) provide an advantage over white-light imaging (WLI) in Barrett's esophagus. We compared endoscopic findings and color differences between WLI and image-enhanced endoscopy (IEE) using a third-generation ultrathin endoscope. We retrospectively enrolled 40 patients who evaluated Barrett's esophagus using WLI, TXI, and NBI. Color differences determined using the International Commission on Illumination 1976 (L∗, a∗, b∗) color space among Barrett's epithelium, esophageal, and gastric mucosa were compared among the endoscopic findings. As the secondary outcome, we assessed the subjective visibility score among three kinds of endoscopic findings. The prevalence of Barrett's esophagus and gastroesophageal reflux disease (GERD) in WLI was 82.5% and 47.5%, respectively, and similar among WLI, TXI, and NBI. Color differences between Barrett's epithelium and esophageal or gastric mucosa on NBI were significantly greater than on WLI (all p < 0.05). However, the color difference between Barrett's epithelium and esophageal mucosa was significantly greater on NBI than TXI (p < 0.001), and the visibility score of Barrett's epithelium detection was significantly greater on TXI than NBI (p = 0.022), and WLI (p = 0.016). High-vision, third-generation ultrathin endoscopy using NBI and TXI is useful for evaluating Barrett's epithelium and GERD compared with WLI alone.

Duplication, Loss, and Evolutionary Features of Specific UDP-Glucuronosyltransferase Genes in Carnivora (Mammalia, Laurasiatheria).

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.

Investigation of the New Advantages of Colonoscope Insertion with an Endoscopic Position Detection Unit.

BACKGROUND: The use of an endoscopic position detection unit (UPD) enables better and more objective understanding of the shape and position of the colonoscope. Here, we investigated the reproducibility of the insertion of a colonoscope with UPD. MATERIALS AND METHODS: Study participants were 122 patients who received a colonoscopy with UPD twice for the purpose of large bowel screening and surveillance. The mean age of participants was 69.7 ± 10.4 years, and the male-to-female ratio was 9.2:1. The colonoscope insertion technique was primarily based on the shaft-holding, shortening insertion method. The cecal intubation time was recorded; the method used for passing through the sigmoid/descending colon junction (SDJ) and the hepatic flexure. RESULTS: The mean cecal intubation time was 990 ± 511 s. The cecal intubation time and the patterns for passing through the SDJ and hepatic flexure were significantly correlated between the first and second colonoscopies. CONCLUSION: Use of a UPD revealed good reproducibility of colonoscope insertion. This is the first time we have proved that both time and pattern are inserted in much the same way for the first and second times. In patients' conducted UPD combination TCS after the second time, it was suggested that individual tailor-made insertions are possible based on the information from the first time.