Differential dependence on microbiota of IL-23/IL-22-dependent gene expression between the small- and large-intestinal epithelia.

In the intestine, interleukin (IL)-23 and IL-22 from immune cells in the lamina propria contribute to maintenance of the gut epithelial barrier through the induction of antimicrobial production and the promotion of epithelial cell proliferation. Several previous studies suggested that some of the functions of the IL-23/IL-22 axis on intestinal epithelial cells are shared between the small and large intestines. However, the similarities and differences of the IL-23/IL-22 axis on epithelial cells between these two anatomical sites remain unclear. Here, we comprehensively analyzed the gene expression of intestinal epithelial cells in the ileum and colon of germ-free, Il23-/- , and Il22-/- mice by RNA-sequencing. We found that while the IL-23/IL-22 axis is largely dependent on gut microbiota in the small intestine, it is much less dependent on it in the large intestine. In addition, the negative regulation of lipid metabolism in the epithelial cells by IL-23 and IL-22 in the small intestine was revealed, whereas the positive regulation of epithelial cell proliferation by IL-23 and IL-22 in the large intestine was highlighted. These findings shed light on the intestinal site-specific role of the IL-23/IL-22 axis in maintaining the physiological functions of intestinal epithelial cells.

Rhodium-catalysed additive-free alkoxycarbonylation of indoles: 2,4,6-trimethylbenzoic acid-based carbonate anhydrides as a versatile alkoxycarboxyl source.

We report a CO-free approach to indole-2-carboxylic esters: rhodium-catalysed C(2)-alkoxycarbonylation of indoles with 2,4,6-trimethylbenzoic acid-based carbonate anhydrides. Selective C-O bond cleavage of the anhydrides facilitates the introduction of various alkoxycarbonyl groups. Control experiments suggest that merging a rhodium catalyst and KI promotes the in situ formation of the RhI species.

Killer cell lectin-like receptor G2 facilitates aggressive phenotypes of gastric cancer cells via dual activation of the ERK1/2 and JAK/STAT pathways.

BACKGROUND: Advanced gastric cancer (GC) has a poor prognosis. This study aimed to identify novel GC-related genes as potential therapeutic targets. METHODS: Killer cell lectin-like receptor G2 (KLRG2) was identified as a candidate gene by transcriptome analysis of metastatic GC tissues. Small interfering RNA-mediated KLRG2 knockdown in human GC cell lines was used to investigate KLRG2 involvement in signaling pathways and functional behaviors in vitro and in vivo. Clinicopathological data were analyzed in patients stratified according to tumor KLRG2 mRNA expression. RESULTS: KLRG2 knockdown in GC cells decreased cell proliferation, migration, and invasion; caused cell cycle arrest in G2/M phase; induced apoptosis via caspase activation; suppressed JAK/STAT and MAPK-ERK1/2 pathway activities; and upregulated p53 and p38 MAPK activities. In mouse xenograft models of peritoneal metastasis, the number and weight of disseminated GC nodules were decreased by KLRG2 knockdown. High tumor levels of KLRG2 mRNA were significantly associated with lower 5-year overall survival (OS) and relapse-free survival (RFS) rates in patients with Stage I-III GC (5-year OS rate: 64.4% vs. 80.0%, P = 0.009; 5-year RFS rate: 62.8% vs. 78.1%, P = 0.030). CONCLUSIONS: KLRG2 knockdown attenuated the malignant phenotypes of GC cells via downregulation of JAK/STAT and MAPK-ERK1/2 pathway activity and upregulation of p38 MAPK and p53. Targeted suppression of KLRG2 may serve as a new treatment approach for GC.

Effectiveness and safety of the simulation-based first-dose design of voriconazole.

BACKGROUND: We investigated whether the initial voriconazole (VRCZ) dosing design, as determined using simulation software with a population pharmacokinetic model of Japanese patients, impacts the effectiveness and safety when compared with VRCZ initiation according to the package insert. METHODS: In this single-center retrospective observational study, we employed records from Tosei General Hospital (a 633-bed hospital), dated April 2017 to September 2023. Eligible patients were divided into the software-based simulation group, comprising patients administered initial VRCZ dosage adjustment by pharmacists using software-based simulation, and the standard therapy group, whose dosage was administered by a physician following the package insert recommendations without simulation. The primary objective of this study was to determine the efficacy of VRCZ first-dose design in reducing the incidence of hepatotoxicity and visual symptoms. RESULTS: The median ages of enrolled participants (n = 93) were 75 (68-79) and 72 (65-78) years in the software-based simulation and standard therapy groups, respectively. Regardless of formulation, initial trough concentrations were lower in the VRCZ software-based first dosage adjustment group and higher rate within the appropriate range (1-4 µg/mL). The incidence of all-grade hepatotoxicity or visual symptoms was significantly lower in the software-based simulation group. The log-rank test revealed a significant impact on the occurrence of ≥grade 2 hepatotoxicity in the software-based first dosage adjustment group compared to that in the standard therapy group. CONCLUSIONS: The initial VRCZ dosing design using simulation software improved the achievement of appropriate initial trough concentrations and resulted in fewer occurrences of hepatotoxicity (≥grade 2) when compared with the standard therapy.

Relationship between texture perception and oral function: A preliminary study in young, healthy adults.

BACKGROUND: Oral frailty, characterised by reduced oral function, is associated with systemic health issues in older adults. Although the criteria for diminished oral function often focus on motor and secretory abilities, texture perception also plays a crucial role in health due to its impact on food intake and palatability. OBJECTIVE: This study aimed to explore the relationship between thickness discrimination ability (TDA) and oral motor and secretory functions in healthy young individuals. METHODS: Twenty-eight adults were assessed for texture perception using eight concentrations of aqueous xanthan gum solutions to determine TDA scores. Measurements of occlusal force, masticatory performance, tongue pressure, stimulated salivary flow rate and tongue-lip motor function were conducted. Spearman's correlation analysis was used to evaluate the relationship between TDA scores and oral functions. Participants were divided into high-sensitivity and low-sensitivity groups based on their TDA scores to compare oral function test results. RESULTS: The TDA scores varied among the participants, with higher scores correlating with higher masticatory performance (r = 0.41, p < .05). Masticatory performance in the high-sensitivity group was significantly higher than in the low-sensitivity group (211.9 ± 59.2 mg/dL vs. 157.9 ± 43.0 mg/dL, p = .013), with no significant differences in other oral functions. CONCLUSION: Masticatory performance was correlated with TDA, suggesting a link between the selection function of mastication and thickness discrimination. These findings highlight the potential relevance of texture perception in oral function and indicate the need for further exploration, particularly in older adults with declining oral health.

The atypical Rab GTPase associated with Parkinson's disease, Rab29, is localized to membranes.

Several genetic studies have shown that the small GTPase Rab29 is involved in the pathogenesis of Parkinson's Disease (PD). It has also been shown that overexpression of Rab29 increases the activity of leucine-rich repeat kinase 2, a protein kinase often mutated in familial PD, although the mechanism underlying this activation remains unclear. Here, we employed biochemical analyses to characterize the localization of Rab29 and found that, unlike general Rab proteins, Rab29 is predominantly fractionated into the membrane fraction by ultracentrifugation. We also found that Rab29 is resistant to extraction from membranes by GDP-dissociation inhibitors (GDIs) in vitro. Furthermore, Rab29 failed to interact with GDIs, and its membrane localization was not affected by the knockout of GDIs in cells. We show that the knockout of Rab geranylgeranyltransferase decreased the hydrophobicity of Rab29, suggesting that Rab29 is geranylgeranylated at its carboxyl terminus as is with typical Rab proteins. Notably, we demonstrated that membrane-bound Rab29 retains some hydrophilicity, indicating that mechanisms other than geranylgeranylation might also be involved in the membrane localization of Rab29. Taken together, these findings uncover the atypical nature of Rab29 among Rab proteins, which will provide important clues for understanding how Rab29 is involved in the molecular pathomechanism of PD.

Association of frequent hypermethylation with high grade histological subtype in lung adenocarcinoma.

Lung adenocarcinoma is classified morphologically into five histological subtypes according to the WHO classification. While each histological subtype correlates with a distinct prognosis, the molecular basis has not been fully elucidated. Here we conducted DNA methylation analysis of 30 lung adenocarcinoma cases annotated with the predominant histological subtypes and three normal lung cases using the Infinium BeadChip. Unsupervised hierarchical clustering analysis revealed three subgroups with different methylation levels: high-, intermediate-, and low-methylation epigenotypes (HME, IME, and LME). Micropapillary pattern (MPP)-predominant cases and those with MPP components were significantly enriched in HME (p = 0.02 and p = 0.03, respectively). HME cases showed a significantly poor prognosis for recurrence-free survival (p < 0.001) and overall survival (p = 0.006). We identified 365 HME marker genes specifically hypermethylated in HME cases with enrichment of "cell morphogenesis" related genes; 305 IME marker genes hypermethylated in HME and IME, but not in LME, with enrichment "embryonic organ morphogenesis"-related genes; 257 Common marker genes hypermethylated commonly in all cancer cases, with enrichment of "regionalization"-related genes. We extracted surrogate markers for each epigenotype and designed pyrosequencing primers for five HME markers (TCERG1L, CXCL12, FAM181B, HOXA11, GAD2), three IME markers (TBX18, ZNF154, NWD2) and three Common markers (SCT, GJD2, BARHL2). DNA methylation profiling using Infinium data was validated by pyrosequencing, and HME cases defined by pyrosequencing results also showed the worse recurrence-free survival. In conclusion, lung adenocarcinomas are stratified into subtypes with distinct DNA methylation levels, and the high-methylation subtype correlated with MPP-predominant cases and those with MPP components and showed a poor prognosis.

Antiepileptic Drugs Modulate Alzheimer-Related Tau Aggregation in a Neuronal Activity-Independent Manner.

INTRODUCTION: A rapidly increasing number of patients with dementia present a serious social problem. Recently, the incidence of epilepsy in patients with Alzheimer's disease (AD) is increasing, drawing attention to the pathological relationship between the two conditions. Clinical studies have suggested the protective action of antiepileptic agents on dementia; however, the underlying mechanism remains unknown. We evaluated the effects of multiple antiepileptic drugs using tau aggregation assay systems to determine the effects of antiepileptic agents on tau aggregation, a major neuropathological finding associated with AD. METHODS: We evaluated the effects of seven antiepileptic agents on intracellular tau aggregation using a tau-biosensor cell-based high-throughput assay. Next, we tested these agents in a cell-free tau aggregation assay using thioflavin T (ThT). RESULTS: The assay results revealed that phenobarbital inhibited tau aggregation, whereas sodium valproate, gabapentin, and piracetam promoted tau aggregation. In the cell-free tau aggregation assay using ThT, we confirmed that phenobarbital significantly inhibited tau aggregation. CONCLUSION: Antiepileptic drugs may modify the tau pathology in AD in a neural activity-independent manner. Our finding may provide an important insight into the optimization of antiepileptic drug therapy in older adults with dementia.

Risk score for predicting death from other causes after curative gastrectomy for gastric cancer.

BACKGROUND: The number of patients who die from causes other than gastric cancer after R0 resection is increasing in Japan, due in part to the aging population. However, few studies have comprehensively investigated the clinicopathological risks associated with deaths from other causes after gastrectomy. This study aimed to build a risk score for predicting such deaths. METHODS: We retrospectively reviewed clinical data for 3575 patients who underwent gastrectomy for gastric cancer at nine institutions in Japan between January 2010 and December 2014. RESULTS: The final study population of 1758 patients were assigned to Group A (n = 187): patients who died from other causes within 5 years of surgery, and Group B (n = 1571): patients who survived ≥ 5 years after surgery. Multivariate analysis identified nine characteristics as risk factors for poor survival: age ≥ 75 years, male sex, body mass index < 22 kg/m2, Eastern Cooperative Oncology Group Performance Status (≥ 1), diabetes mellitus, cardiovascular/cerebrovascular disease, other malignant diseases, preoperative albumin level < 3.5 g/dL, and total gastrectomy. Patients with risk scores of 0-2, 3-4, or 5-9 (based on 1 point per characteristics) were classified into Low-risk, Intermediate-risk, and High-risk groups, respectively. The 5-year survival rates were 96.5%, 85.3%, and 56.5%, for the Low-, Intermediate-, and High-risk groups, respectively, and the hazard ratio (95% confidence intervals) was 16.33 (10.85-24.58, p < 0.001) for the High-risk group. CONCLUSIONS: The risk score defined here may be useful for predicting deaths from other causes after curative gastrectomy.

Quantitative Measurement of Phthalate Exposure Biomarker Levels in Diaper-Extracted Urine of Japanese Toddlers and Cumulative Risk Assessment: An Adjunct Study of JECS Birth Cohort.

Phthalate exposure monitoring and risk assessment in non-toilet-trained children are rarely reported. This adjunct study of the Japan Environment and Children's Study assessed cumulative health risks in 1.5-year-old toddlers in the Aichi regional subcohort by biomonitoring 16 urinary metabolites of eight phthalate plasticizers. Overnight urine was extracted from toddlers' diapers (n = 1077), and metabolites were quantified using ultraperformance liquid chromatography coupled with tandem mass spectrometry. The analyses' quality was assured by running quality control samples. The highest geometric mean concentration was found for mono-(2-ethyl-5-carboxypentyl) phthalate, followed by mono-isobutyl phthalate (23 and 21 µg/L, respectively). Di-2-ethylhexyl phthalate (DEHP) and di-butyl phthalate exhibited higher risks [hazard quotient (HQ) > 1] than the cutoff level in a small proportion of toddlers; 8 and 14% of toddlers were at cumulative risk of multiple phthalates beyond the cutoff level [hazard index, (HI) > 1], based on the tolerable daily intake of the European Food Safety Authority and the United States Environmental Protection Agency Reference Dose. HI > 1 for antiandrogenicity in creatinine-unadjusted and -adjusted estimations were exhibited by 36 and 23% of the children, respectively. Thus, identifying exposure sources and mitigating exposure are necessary for risk management. Additionally, continuous exposure assessment and evaluation of health outcomes, especially antiandrogenic effects, are warranted.

Residue levels of organophosphate pesticides and dialkylphosphates in agricultural products in Japan.

High urinary levels of dialkylphosphates (DAPs), which are common structures of organophosphate pesticides (OPs), have been associated with several adverse health outcomes in human biomonitoring studies. Previous studies have indicated that dietary OP exposure and ingestion of environmentally degraded DAP, which is inactive with acetylcholinesterase, can lead to an increase in urinary DAP levels in the general population. However, the specific food sources contributing to the intake of OPs and DAPs have not been identified. In this study, we analyzed the levels of OPs and preformed DAPs in various food items. DAP levels were markedly high in certain fruits, such as persimmon, apple juice, kiwi, and mandarin. In contrast, only moderate levels of OPs were detected in these foods. Furthermore, the levels of OPs and DAPs were positively associated with vegetables, whereas no such association was observed in fruits. Increased consumption of certain fruits presumably leads to a marked increase in urinary DAP levels in individuals despite limited exposure to OPs, resulting in reduced reliability of urinary DAPs as a marker of OP exposure. Therefore, the possible effects of dietary habits and the resulting intake of preformed DAPs should be considered when interpreting biomonitoring data of urinary DAPs. Additionally, DAP levels in most organic foods were much lower than those in conventional foods, suggesting that the reduction in urinary DAPs by organic diet intervention may be mainly attributed to the reduced intake of preformed DAPs rather than reduced exposure to OPs. Therefore, urinary DAP levels may not be suitable indicators for evaluating ingested OP exposure.

Side Effects of COVID-19 Vaccines in Patients with Inflammatory Bowel Disease in Japan.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are recommended to receive the coronavirus disease 2019 (COVID-19) vaccine. However, a recent survey showed that patients with IBD are more hesitant to receive the vaccine than the general population. Detailed information on the side effects of the COVID-19 vaccine is necessary to encourage vaccination among patients with IBD. AIM: To investigate the frequency of side effects following COVID-19 vaccination in patients with IBD in Japan. STUDY DESIGN: a cross-sectional survey was conducted using a questionnaire administered to adult patients with IBD in a tertiary medical facility. RESULTS: Among the participants who answered the questionnaire, 92.6%, 91.5%, and 41.5% of the participants had received their first, second, and third doses of the COVID-19 vaccine, respectively. Of the vaccinated participants, 88.3%, 86.3%, and 89.0% experienced side effects after receiving the first, second, and third doses of the vaccine, respectively. The incidences of fever, chills, and headaches were significantly higher among female participants than among male participants (p < 0.05). However, the frequencies of most side effects were comparable between the BNT162b2 mRNA and mRNA-1273 vaccines. CONCLUSION: The findings of our survey can help encourage patients with IBD to receive the COVID-19 vaccine.

Changes in choriocapillaris structure occurring in idiopathic macular hole before and after vitrectomy.

PURPOSE: The aim of this study was to analyze the anatomical choroidal vascular layers and the changes in idiopathic macular hole (IMH) eyes over time after vitrectomy. METHODS: This is a retrospective observational case-control study. Fifteen eyes from 15 patients who received vitrectomy for IMH and age-matched 15 eyes from 15 healthy controls were enrolled in this study. Retinal and choroidal structures were quantitatively analyzed before vitrectomy and 1 and 2 months after surgery using spectral domain-optical coherence tomography. Each choroidal vascular layer was divided into the choriocapillaris, Sattler's layer, and Haller's layer, and then, the choroidal area (CA), luminal area (LA), stromal area (SA), and central choroidal thickness (CCT) were calculated using binarization techniques. The ratio of LA to CA was defined as the L/C ratio. RESULTS: The CA, LA, and L/C ratios were 36.9 ± 6.2, 23.4 ± 5.0, and 63.1 ± 7.2 in the choriocapillaris of IMH and were 47.3 ± 6.6, 38.3 ± 5.6, and 80.9 ± 4.1 in that of control eyes, respectively. Those values were significantly lower in IMH eyes than in control eyes (each P < 0.01), whereas there was no significant difference in total choroid, Sattler's layer, and Haller's layer or CCT. The ellipsoid zone defect length showed a significant negative correlation with the L/C ratio in total choroid and with CA and LA in the choriocapillaris of IMH (R = - 0.61, P < 0.05, R = - 0.77, P < 0.01, and R = - 0.71, P < 0.01, respectively). In the choriocapillaris, the LA were 23.4 ± 5.0, 27.7 ± 3.8, and 30.9 ± 4.4, and the L/C ratios were 63.1 ± 7.2, 74.3 ± 6.4, and 76.6 ± 5.4 at baseline, 1 month, and 2 months after vitrectomy, respectively. Those values showed a significant increase over time after surgery (each P < 0.05), whereas the other choroidal layers did not alter consistently with respect to changes in choroidal structure. CONCLUSIONS: The current OCT-based study demonstrated that the choriocapillaris was exclusively disrupted between choroidal vascular structures in IMH, which may correlate with the ellipsoid zone defect. Furthermore, the L/C ratio of choriocapillaris recovered after IMH repair, suggesting an improved balance between supply and demand of oxygen that has collapsed due to temporary loss of central retinal function by IMH.

Autophagy as a potential mechanism underlying the biological effect of 1,25-Dihydroxyvitamin D3 on periodontitis: a narrative review.

The major active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D3), is known for its wide bioactivity in periodontal tissues. Although the exact mechanisms underlying its protective action against periodontitis remain unclear, recent studies have shown that 1,25D3 regulates autophagy. Autophagy is vital for intracellular pathogen invasion control, inflammation regulation, and bone metabolic balance in periodontal tissue homeostasis, and its regulation could be an interesting pathway for future periodontal studies. Since vitamin D deficiency is a worldwide health problem, its role as a potential regulator of autophagy provides new insights into periodontal diseases. Based on this premise, this narrative literature review aimed to investigate the possible connection between 1,25D3 and autophagy in periodontitis. A comprehensive literature search was conducted on PubMed using the following keywords (e.g., vitamin D, autophagy, periodontitis, pathogens, epithelial cells, immunity, inflammation, and bone loss). In this review, the latest studies on the protective action of 1,25D3 against periodontitis and the regulation of autophagy by 1,25D3 are summarized, and the potential role of 1,25D3-activated autophagy in the pathogenesis of periodontitis is analyzed. 1,25D3 can exert a protective effect against periodontitis through different signaling pathways in the pathogenesis of periodontitis, and at least part of this regulatory effect is achieved through the activation of the autophagic response. This review will help clarify the relationship between 1,25D3 and autophagy in the homeostasis of periodontal tissues and provide perspectives for researchers to optimize prevention and treatment strategies in the future.

Ligneous periodontitis exacerbated by Behçet's disease in a patient with plasminogen deficiency and a stop-gained variant PLG c.1468C > T: a case report.

BACKGROUND: Plasminogen serves as the precursor to plasmin, an essential element in the fibrinolytic process, and is synthesized primarily in the liver. Plasminogen activation occurs through the action of plasminogen activator, converting it into plasmin. This conversion greatly enhances the fibrinolytic system within tissues and blood vessels, facilitating the dissolution of fibrin clots. Consequently, congenital deficiency of plasminogen results in impaired fibrin degradation. Patients with plasminogen deficiency typically exhibit fibrin deposits in various mucosal sites throughout the body, including the oral cavity, eyes, vagina, and digestive organs. Behcet's disease is a chronic recurrent systemic inflammatory disease with four main symptoms: aphthous ulcers of the oral mucosa, vulvar ulcers, skin symptoms, and eye symptoms, and has been reported worldwide. This disease is highly prevalent around the Silk Road from the Mediterranean to East Asia. We report a case of periodontitis in a patient with these two rare diseases that worsened quickly, leading to alveolar bone destruction. Genetic testing revealed a novel variant characterized by a stop-gain mutation, which may be a previously unidentified etiologic gene associated with decreased plasminogen activity. CASE PRESENTATION: This case report depicts a patient diagnosed with ligneous gingivitis during childhood, originating from plasminogen deficiency and progressing to periodontitis. Genetic testing revealed a suspected association with the PLG c.1468C > T (p.Arg490*) stop-gain mutation. The patient's periodontal condition remained stable with brief intervals of supportive periodontal therapy. However, the emergence of Behçet's disease induced acute systemic inflammation, necessitating hospitalization and treatment with steroids. During hospitalization, the dental approach focused on maintaining oral hygiene and alleviating contact-related pain. The patient's overall health improved with inpatient care and the periodontal tissues deteriorated. CONCLUSIONS: Collaborative efforts between medical and dental professionals are paramount in comprehensively evaluating and treating patients with intricate complications from rare diseases. Furthermore, the PLG c.1468C > T (p.Arg490*) stop-gain mutation could contribute to the association between plasminogen deficiency and related conditions.

The Usefulness and Reliability of Coagrasper for Artery Bleeding during Endoscopic Necrosectomy.

Although endoscopic necrosectomy (EN) is a less invasive therapy for walled-off necrosis (WON), arterial bleeding can occur during EN. A 60-year-old man with infected WON underwent the EN procedure. During EN, the artery in the WON cavity was injured. As the artery was directly visible, we grasped it using a Coagrasper and coagulated the bleeding point. However, the bleeding was aggravated after coagulation owing to an extension of the vessel damage. The entire vessel was grasped, and complete hemostasis was achieved. The Coagrasper is useful for managing arterial bleeding; however, it should be employed only on the basis of its characteristics and in suitable scenarios.

A globin-family protein, Cytoglobin 1, is involved in the development of neural crest-derived tissues and organs in zebrafish.

The zebrafish is an excellent model animal that is amenable to forward genetics approaches. To uncover unknown developmental regulatory mechanisms in vertebrates, we conducted chemical mutagenesis screening and identified a novel mutation, kanazutsi (kzt). This mutation is recessive, and its homozygotes are embryonic lethal. Mutant embryos suffered from a variety of morphological defects, such as head flattening, pericardial edema, circulation defects, disrupted patterns of melanophore distribution, dwarf eyes, a defective jaw, and extensive apoptosis in the head, which indicates that the main affected tissues are derived from neural crest cells (NCCs). The expression of tissue-specific markers in kzt mutants showed that the early specification of NCCs was normal, but their later differentiation was severely affected. The mutation was mapped to chromosome 3 by linkage analyses, near cytoglobin 1 (cygb1), the product of which is a globin-family respiratory protein. cygb1 expression was activated during somitogenesis in somites and cranial NCCs in wild-type embryos but was significantly downregulated in mutant embryos, despite the normal primary structure of the gene product. The kzt mutation was phenocopied by cygb1 knockdown with low-dose morpholino oligos and was partially rescued by cygb1 overexpression. Both severe knockdown and null mutation of cygb1, established by the CRISPR/Cas9 technique, resulted in far more severe defects at early stages. Thus, it is highly likely that the downregulation of cygb1 is responsible for many, if not all, of the phenotypes of the kzt mutation. These results reveal a requirement for globin family proteins in vertebrate embryos, particularly in the differentiation and subsequent development of NCCs.

Influence of Change of Full-Time Equivalents on Post-prescription Review with Feedback Interventions in an Antimicrobial Stewardship.

Few studies have investigated the influence of more full-time equivalents (FTEs) of infectious disease (ID) pharmacists on the likelihood of a post-prescription review with feedback (PPRF) intervention. This study focused on this in community hospitals before and after the Japanese medical reimbursement system was revised to introduce antimicrobial stewardship (AS) fees. We collected data for two periods: before (April 2017 to March 2018) and after (April 2018 to March 2019) AS fee implementation. The efficacy of the PPRF by the ID pharmacist was assessed based on the usage of broad-spectrum antimicrobials in days of therapy (DOT) per 100 patient-days. Further, we generated the susceptibility rate for antimicrobial-resistant organisms. The number of PPRF drugs was 2336 (2596 cases) before AS fee implementation and 2136 (1912 cases) after implementation. The overall monthly FTE for AS for an ID pharmacist increased from [median (interquartile range; IQR)] 0.34 (0.33-0.36) to 0.63 (0.61-0.63) after AS fee implementation. The DOT of the broad-spectrum antibiotics decreased from 10.46 (9.61-12.48) to 8.68 (8.14-9.18). The DOT of carbapenems and quinolones decreased significantly from 4.11 (3.69-4.41) to 3.07 (2.79-3.22) and 0.96 (0.61-1.14) to 0.37 (0.19-0.46), respectively (p < 0.05). Furthermore, the rate of levofloxacin (LVFX)-susceptible Pseudomonas (P.) aeruginosa improved from 71.5 to 84.8% (p < 0.01). We observed that increasing the FTE of ID pharmacists influences the DOTs of broad-spectrum antibiotics; a higher FTE contributes to fewer DOTs. Further, the susceptibility of P. aeruginosa to meropenem and LVFX increased as the FTE increased.

Increased serum anti-CYP2E1 IgG autoantibody levels may be involved in the pathogenesis of occupational trichloroethylene hypersensitivity syndrome: a case-control study.

Occupational exposure to trichloroethylene (TCE) causes a systemic skin disorder with hepatitis known as TCE hypersensitivity syndrome (TCE-HS). Human Leukocyte Antigen (HLA)-B*13:01 is its susceptibility factor; however, the immunological pathogenesis of TCE-HS remains unknown. We herein examined the hypothesis that autoantibodies to CYP2E1 are primarily involved in TCE-HS. A case-control study of 80 TCE-HS patients, 186 TCE-tolerant controls (TCE-TC), and 71 TCE-nonexposed controls (TCE-nonEC) was conducted to measure their serum anti-CYP2E1 antibody (IgG) levels. The effects of TCE exposure indices, such as 8-h time-weighted-average (TWA) airborne concentrations, urinary metabolite concentrations, and TCE usage duration; sex; smoking and drinking habits; and alanine aminotransferase (ALT) levels on the antibody levels were also analyzed in the two control groups. There were significant differences in anti-CYP2E1 antibody levels among the three groups: TCE-TC > TCE-HS patients > TCE-nonEC. Antibody levels were not different between HLA-B*13:01 carriers and noncarriers in TCE-HS patients and TCE-TC. The serum CYP2E1 measurement suggested increased immunocomplex levels only in patients with TCE-HS. Multiple regression analysis for the two control groups showed that the antibody levels were significantly higher by the TCE exposure. Women had higher antibody levels than men; however, smoking, drinking, and ALT levels did not affect the anti-CYP2E1 antibody levels. Anti-CYP2E1 antibodies were elevated at concentrations lower than the TWA concentration of 2.5 ppm for TCE exposure. Since HLA-B*13:01 polymorphism was not involved in the autoantibody levels, the possible mechanism underlying the pathogenesis of TCE-HS is that TCE exposure induces anti-CYP2E1 autoantibody production, and HLA-B*13:01 is involved in the development of TCE-HS.

Alterations of choroidal circulation and vascular morphology in a patient with chronic myeloid leukemia before and after chemotherapy.

BACKGROUND: Chronic myeloid leukemia (CML) is known to cause leukemic retinopathy due to leukemia cell invasion into the choroid; however, details of the circulatory dynamics and morphological changes in the choroid are unknown. The aim of this study was to present a case of leukemic retinopathy and examine choroidal circulatory and structural analyses using laser speckle flowgraphy (LSFG) and optical coherence tomography with a binarization method, respectively. CASE PRESENTATION: A 15-year-old male diagnosed with CML complained of blurred vision in his right eye. He was ophthalmologically diagnosed with leukemic retinopathy due to retinal hemorrhage in both eyes. Tyrosine kinase inhibitors achieved complete cytogenetic remission and resolution of retinal hemorrhages at 6 months after treatment. After the treatment, the best-corrected visual acuity had recovered from 0.1 to 1.2 oculus dexter (OD) and remained at 1.5 oculus sinister (OS). The rate of change in macular blood flow assessed by the mean blur rate on LSFG was 18.3% increase OD and 25.2% decrease OS 19 months after treatment. The central choroidal thickness showed 0.4 and 3.1% reductions OD and OS, respectively. The binarization technique demonstrated that the rate of luminal areas in choroidal areas exhibited 3.2% increase OD but 4.8% decrease OS. CONCLUSION: Choroidal blood flow improved OD after treatment for CML, while it deteriorated OS, together with choroidal thinning due to reduction of luminal areas. The degrees of leukemia cell invasion into the choroidal tissue and tissue destruction might be different between the eyes in this case.