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Intestinal metaplasia induced by ectopic expression of caudal‐type homeobox (CDX)2 and/or CDX1 (CDX) is frequently observed around gastric cancer (GC). Abnormal expression of CDX is also observed in GC and suggests that inappropriate gastrointestinal differentiation plays essential roles in gastric tumorigenesis, but their roles on tumorigenesis remain unelucidated. Publicly available databases show that GC patients with higher CDX expression have significantly better clinical outcomes. We introduced CDX2 and CDX1 genes separately into GC‐originated MKN7 and TMK1 cells deficient in CDX. Marked suppression of cell growth and dramatic morphological change into spindle‐shaped flat form were observed along with induction of intestinal marker genes. G0‐G1 growth arrest was accompanied by changed expression of cell cycle‐related genes but not with apoptosis or senescence. Microarray analyses additionally showed decreased expression of gastric marker genes and increased expression of stemness‐associated genes. Hierarchical clustering of 111 GC tissues and 21 non‐cancerous gastric tissues by selected 18 signature genes based on our transcriptome analyses clearly categorized the 132 tissues into non‐cancer, “CDX signature”‐positive GC, and “CDX signature”‐negative GC. Gene set enrichment analysis indicated that “CDX signature”‐positive GC has lower malignant features. Immunohistochemistry of 89 GC specimens showed that 50.6% were CDX2‐deficient, 66.3% were CDX1‐deficient, and 44.9% were concomitant CDX2/CDX1‐deficient, suggesting that potentially targetable GC cases by induced intestinal differentiation are quite common. In conclusion, exogenous expression of CDX2/CDX1 can lead to efficient growth inhibition of CDX‐deficient GC cells. It is based on rapidly induced intestinal differentiation, which may be a future therapeutic strategy. Exogenous expression of CDX2/CDX1 can lead to G0‐G1 growth arrest in CDX‐deficient gastric cancer cells, accompanied by induction of intestinal genes and decreased expression of gastric genes. Publicly available databases and hierarchical clustering of gastric tissue showed that gastric cancer with CDX expression has significantly better clinical outcomes. A novel therapy against gastric cancer based on induced intestinal differentiation may be possible in the future.

BackgroundThe mechanism behind the pathogenesis and carcinogenesis of these neoplasms is not fully understood. The objective of this study was to identify genetic markers and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas through gene expression analysis.MethodsGene expression profiling was performed in 4 pairs of duodenal adenoma/adenocarcinomas and corresponding matched normal tissue. Genes with consistent expression differences were identified and confirmed in 7 independent pairs. Gene set enrichment analysis (GSEA) was performed to characterize gene expression profiles of duodenal adenoma/adenocarcinomas, together with immunohistochemical staining of candidate oncogenic genes.Results626 probes consistently demonstrated over a twofold expression difference between tumor–normal pairs. Reverse transcriptase polymerase chain reaction of genes with the most prominent difference in expression between tumors and normal mucosa (KLK7, KLK6, CEMIP, MMP7, KRT17, LGR5, G6PC, S100G, APOA1) validated the results of gene expression analysis. GSEA demonstrated a strong association between duodenal adenoma/adenocarcinomas with colorectal adenomas (p < 10−5) and gene expression patterns seen after APC gene knockout (p < 10−5), suggesting that the Wnt/β-catenin pathway plays a crucial role in the carcinogenesis of these neoplasms. Immunohistochemical staining of an independent group of duodenal adenomas confirmed over-accumulation of β-catenin in 80.0% (16/20).ConclusionsPrecancerous duodenal adenomas and early stage adenocarcinomas demonstrate gene expression characteristics with a strong resemblance to colorectal adenomas. The results of this study strongly suggest that upregulation of the Wnt/β-catenin pathway is the major factor involved in the initial stages of the carcinogenesis of duodenal adenocarcinomas.

Background Premature mortality, frequent relapse that easily leads to hospitalization, and discontinuous employment are key challenges for the treatment of schizophrenia. We evaluated risk factors for important clinical outcomes (death, hospitalization, resignation, and sick leave from work) in patients with schizophrenia in Japan. Methods A nested case–control study was conducted for patients with schizophrenia identified in a Japanese claims database. For each outcome, the case was matched with up to four controls of the same age, sex, index year, and enrollment status (employee or dependent family). Potential risk factors were defined by prescriptions or diagnoses within 3 months prior to or in the month of the event. The association among potential risk factors and each outcome was evaluated using multivariable conditional logistic regression analysis with stepwise variable selection. Results The number of cases and eligible patients for each outcome were 144 and 38,451 (death), 1,520 and 35,225 (hospitalization), 811 and 18,770 (resignation), and 4,590 and 18,770 (sick leave), respectively. Depression was a risk factor for death (odds ratio [OR]: 1.92; 95% confidence interval [CI]: 1.12, 3.29), hospitalization (OR: 1.22; 95% CI: 1.05, 1.42), and sick leave from work (OR: 1.46; 95% CI: 1.36, 1.57). Other risk factors for death were hospitalization history, Charlson Comorbidity Index (CCI) score, and prescription for laxatives. Prescriptions for hypnotics, laxatives, and anticholinergics were risk factors for hospitalization. Prescriptions for hypnotics and anticholinergics were risk factors for resignation. CCI score, prescription for hypnotics, laxatives, and antidiabetics were risk factors for sick leave from work. Conclusions Our findings suggest that depression and some physical symptoms, such as constipation and extrapyramidal symptoms, are risk factors for important clinical outcomes in patients with schizophrenia. Attention should be paid to both depression and physical symptoms for the treatment of schizophrenia.

Japanese apricot ( Prunus mume ; ume ) is a traditional food in Japan that has been shown to have various beneficial health effects. There is some evidence to suggest that ume is also effective against allergic disease. Here, we conducted a cross-sectional epidemiological pilot study to examine the association between ume intake frequency and allergic symptoms including rhinitis in 563 adults (288 men and 275 women) who resided in Wakayama, Japan. After adjusting for age, present illness and medication, women with high ume intake had significantly lower odds ratio (OR) for the presence of symptoms of allergy [OR: 0.49 with 95% confidence interval (CI): 0.25–0.97]. Therefore, we investigated the anti-allergic effect of ume on passive cutaneous anaphylaxis (PCA) reaction in immunoglobulin E (IgE)-sensitized mice. The animal study demonstrated that oral administration of ume extract attenuated the PCA reaction and mast cell degranulation. Furthermore, RBL-2H3 mast cells were used to identify anti-allergic ume compounds. The following ume compounds inhibited IgE-mediated mast cell degranulation: vanillin, syringic acid, protocatechuic aldehyde, lyoniresinol and p -coumaric acid. These results suggested that ume has the potential to inhibit mast cell degranulation and may be associated with reduced risk of allergic symptoms in women.

This study aimed to evaluate the impact of the number of psychotropic medications on short-term neonatal outcomes in pregnancies complicated by maternal psychiatric disorders, focusing on the effect of non-opioid psychotropic polypharmacy and co-exposure. A retrospective study was conducted on pregnancies complicated by maternal mental disorders that resulted in full-term singleton deliveries at a tertiary perinatal hospital between 2019 and 2023. Among 4,367 deliveries during the study period, 358 were identified. Pregnant women prescribed three or more psychotropic medications had significantly higher rates of adverse neonatal outcomes. Significantly, most infants exhibiting neonatal abstinence syndrome (NAS)-related symptoms were exposed in utero to selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines (BZs). Furthermore, neonates exposed to CYP2D6-inhibiting psychotropic drugs had significantly lower Apgar scores and higher rates of neonatal intensive care unit admission, respiratory ventilator use, and NAS compared to those not exposed to such drugs. Full-term neonates born to women with mental illness taking three or more psychotropic drugs were significantly more likely to experience adverse short-term outcomes. Particular attention should be given to neonatal adaptation in infants exposed in utero to CYP2D6-inhibiting psychotropic drugs, as well as SSRIs and BZs, especially in cases of multiple psychotropic medications.

Purpose: Lithium (Li), which is extensively used in the treatment of mood disorders such as bipolar disorder, has been associated with hyperparathyroidism. However, the relationship between the serum Li concentration and hyperparathyroidism remains unclear. This study aimed (1) to investigate the incidence of hyperparathyroidism and hypercalcemia in consecutive patients treated with Li, (2) to assess the correlation between serum Li concentration and hyperparathyroidism/hypercalcemia, and (3) to establish cutoff values for predicting hyperparathyroidism and hypercalcemia based on serum Li concentration. Methods: This retrospective cross‐sectional study was conducted at the Department of Psychiatry and Department of Medicine at Tokyo Women’s Medical University. Ninety‐seven consecutive individuals without renal impairment and with an estimated glomerular filtration rate (eGFR) equal to or greater than 45 mL/min/1.73 m 2 were included. Results: Hyperparathyroidism and hypercalcemia were observed in 35.1% and 9.3% of the patients on Li, respectively. The serum Li concentration showed a significant positive correlation with hyperparathyroidism and hypercalcemia, independent of other factors. The cutoff values for predicting hyperparathyroidism and hypercalcemia were 0.52 and 0.62 mEq/L, respectively. Conclusions: This study confirmed that the high incidence of hyperparathyroidism and hypercalcemia in patients treated with Li. Clinicians should be aware that Li treatment may induce hyperparathyroidism, and a serum Li concentration exceeding 0.52 mEq/L may pose an increased risk. Monitoring serum calcium and Li concentrations is recommended in patients undergoing Li treatment.

Aim Patients with cancer often experience nausea and vomiting (N/V), but may have difficulty using olanzapine (OLZ), a common antiemetic. Asenapine (ASE) is a multi‐acting receptor‐targeted antipsychotic like OLZ, although there is little evidence that ASE serves as an antiemetic. The aim of this study was to evaluate the efficacy and tolerability of ASE compared to those of OLZ for the treatment of N/V in patients with cancer. Methods This retrospective study involved patients who received 5 mg ASE, 5 mg OLZ, or 2.5 mg OLZ for 2 days. Daily worst N/V was rated on a scale of 0 (none) to 3 (very much). The primary endpoint was the proportion of patients who had a response, defined as any reduction in N/V score. A complete response (CR) was defined as a score reduction to 0. Secondary endpoints included the proportion of patients with CR and adverse events. Results Between April 2017 and March 2023, 212 patients were enrolled to receive treatment: 5 mg ASE (n = 34), 5 mg OLZ (n = 102), or 2.5 mg OLZ (n = 76). No significant differences in response rates (52.9% vs. 58.8% vs. 52.6%, p = 0.671) or secondary endpoints were observed between the groups. Patients receiving ASE were more likely to experience oral hypoesthesia (p = 0.004). Conclusion This preliminary study suggests that ASE may be effective for N/V. Further studies are required to confirm these findings. Patients with cancer often experience nausea and vomiting (N/V), but may have difficulty using olanzapine (OLZ), a common antiemetic. Asenapine (ASE) is a multi‐acting receptor‐targeted antipsychotic like OLZ, although there is little evidence that ASE serves as an antiemetic. The aim of this study was to evaluate the efficacy and tolerability of 5mg ASE compared to those of 5 mg OLZ and 2.5 mg OLZ. This study suggests that ASE may be effective for N/V.

Background Pro re nata (PRN) medication is used “as needed” for symptoms such as agitation and insomnia, in addition to regular daily pharmacotherapy of mental disorders. However, there is no high-quality evidence on the effectiveness of psychotropic PRN medications and concerns have been raised about their potential to contribute to polypharmacy. This study introduced a psychotropic PRN prescription-monitoring programme for psychiatric inpatients with the aim of examining the change before and after the implementation of the programme. Method This study included 389 patients admitted to the psychiatric department between 1 July 2021 and 30 June 2023. The psychotropic PRN prescription-monitoring programme was implemented in July 2022, and the participants were classified into monitoring and non-monitoring groups. Demographic data (age, sex, and diagnosis), regular prescriptions before admission and at discharge, psychotropic PRN prescriptions before admission and at discharge, and the total number of psychotropic PRN prescriptions during hospitalisation were compared between the two groups. Data on psychotropic prescription were collected by psychotropic category. The significance level of 5% was set at 1.67 × 10 −3 using the Bonferroni correction for multiple testing. Results The psychotropic PRN prescription ratio at discharge in the monitoring group was 9.3%, which was significantly lower than the 28.1% in the non-monitoring group. The percentage of patients with a PRN prescription during hospitalisation in the monitoring group was 29.8%, which was significantly lower than the 64.5% in the non-monitoring group. In the non-monitoring group, there was no statistically significant difference in the number of psychotropic drugs prescribed regularly before and after admission. However, in the monitoring group, the number of psychotropic drugs in the regular prescriptions at discharge was 1.87 ± 1.24, which was significantly lower than 2.47 ± 1.90 in the regular prescription before admission. Conclusions Our findings suggest that a psychotropic PRN prescription-monitoring programme may contribute to the elimination of polypharmacy, including regular prescriptions. Further research is required to optimise psychotropic PRN prescriptions and reduce polypharmacy.

English translation team: (affiliation as of May 2021) Ryota Hashimoto, Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry Junichi Iga, Department of Neuropsychiatry, Ehime University Graduate School of Medicine Ken Inada, Department of Psychiatry, Tokyo Women’s Medical University Taro Kishi, Department of Psychiatry, Fujita Health University School of Medicine Hiroshi Kimura, Department of Psychiatry, International University of Health and Welfare/Gakuji-kai Kimura Hospital Yuki Matsuda, Department of Psychiatry, Jikei University School of Medicine Nobumi Miyake, Department of Neuropsychiatry, St. Marianna University School of Medicine Kiyotaka Nemoto, Department of Psychiatry, Faculty of Medicine, University of Tsukuba Shusuke Numata, Department of Psychiatry, Graduate School of Biomedical Science, Tokushima University Shinichiro Ochi, Department of Neuropsychiatry, Molecules and Function, Ehime University Graduate School of Medicine Hideki Sato, National Center Hospital, National Center of Neurology and Psychiatry Seiichiro Tarutani, Department of Psychiatry, Shin-Abuyama Hospital, Osaka Institute of Clinical Psychiatry Hiroyuki Uchida, Department of Neuropsychiatry, Keio University School of Medicine English translation team: (COI as of 2018-2020) Ryota Hashimoto: Received research grants from Otsuka Pharmaceutical Co., Ltd., Japan Tobacco Inc., and Takeda Pharmaceutical Company Ltd.; rewards for lectures from Takeda Pharmaceutical Company Ltd., Lundbeck Japan K.K., Dainippon Sumitomo Pharma Co., Ltd., and Mochida Pharmaceutical.Co., Ltd.; manuscript fees for writing from Dainippon Sumitomo Pharma Co., Ltd. Junchi Iga: Received rewards for lectures from Otsuka Pharmaceutical Co. Ltd., Meiji Seika Pharma Co. Ltd., Sumitomo Dainippon Pharma Co. Ltd., Kyowa Pharmaceutical Industry Co. Ltd., Shionogi & Co. Ltd., Mochida Pharmaceutical Co. Ltd., Eisai Co. Ltd., Mylan Inc., Sawai Pharmaceutical Co. Ltd., Novartis Pharma K.K., Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Janssen Pharmaceutical K.K., Sanofi K.K., Viatris Inc., and Yoshitomiyakuhin Co. Ken Inada: Received research grants, rewards for lectures, manuscript fees for writing, and donations from Astellas Pharma Inc., Eisai Co. Ltd., MSD K.K., Otsuka Pharmaceutical Co. Ltd., Shionogi & Co. Ltd., Sumitomo Dainippon Pharma Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Novartis Pharma K.K., Pfizer Inc., Meiji Seika Pharma Co. Ltd., Mochida Pharmaceutical Co. Ltd., Janssen Pharmaceutical K.K., and Yoshitomiyakuhin Co. Taro Kishi: Received speaker’s honoraria from Sumitomo Dainippon, Otsuka, Eisai, Daiichi Sankyo, Janssen, Takeda, Kyowa, Kissei, Meiji, Pfizer, Mochida, Eli Lilly, MSD, Janssen, and Tanabe-Mitsubishi (Yoshitomi); as well as research grants from Eisai, the Japanese Ministry of Health, Labour and Welfare, Grant-in-Aid for Scientific Research, and Fujita Health University School of Medicine. Before reading this guideline (For experts, patients, families, and supporters) This guideline was written for specialists in the treatment of schizophrenia, but patients, as well as their families and supporters, may also use this guideline. [...]a very simple explanation will first be given on the aims of this guideline. [...]one may have the impression from reading the individual texts that it is recommended to treat schizophrenia with pharmacological therapy alone, or that pharmacological therapy has a larger effect than other therapies. [...]the available drugs and their administration and the medical system can vary between Japan and other countries. [...]a clinical guideline that is aligned with the medical circumstances in Japan was needed.

Background Laxative use has recently been indicated as a risk factor for hospitalization in patients with schizophrenia. Oral antipsychotic therapy for patients with schizophrenia treated with laxatives may be problematic due to gastrointestinal dysfunction, which affects absorption. Therefore, transdermal patches of antipsychotics may be a suitable alternative. We herein compared the efficacies of a blonanserin (BNS) patch and BNS oral formulation in patients with schizophrenia treated with laxatives. Methods A retrospective cohort study was performed using a claims database in Japan provided by DeSC Healthcare Inc. Subjects were BNS patch‐ or BNS oral formulation‐prescribed patients with schizophrenia. The primary outcome was hospitalization to psychiatric wards. The hazard ratio (HR) for hospitalization was estimated using Cox proportional hazards model and adjusted by propensity scores. Results Among the 3896 patients identified, 1407 were prescribed laxatives (BNS patch group: n = 538, BNS oral group: n = 869). Mean ages in the BNS patch and BNS oral groups were 74 and 58 years, respectively. The adjusted HR for hospitalization (BNS patch group vs. BNS oral group) was 1.31 (95% confidence interval; 0.88, 1.94), with no significant difference. Conclusions No significant difference was observed in the risk of hospitalization for patients with schizophrenia treated with laxatives between the BNS patch and BNS oral groups. The effectiveness of antipsychotic patches in these patients warrants further research that considers factors such as patch preference in the elderly. Laxative use has recently been identified as a risk factor for hospitalization in patients with schizophrenia, and oral antipsychotic medication may be problematic due to gastrointestinal dysfunction affecting absorption, suggesting that transdermal antipsychotic patches could be a suitable alternative. A retrospective cohort study compared the efficacies of a blonanserin (BNS) patch and BNS oral formulation in patients with schizophrenia treated with laxatives, with the primary outcome being hospitalization to psychiatric wards. The study found no significant difference in the risk of hospitalization between the BNS patch and BNS oral groups, and further research is warranted to consider factors such as patch preference in the elderly.