Surveillance of seasonal influenza viruses during the COVID-19 pandemic in Tokyo, Japan, 2018-2023, a single-center study.

Introduction: COVID-19 pandemic led to significant reductions in influenza detection worldwide, fueling debates on whether influenza truly ceased circulating in communities. The number of influenza cases decreased significantly in Japan, raising concerns about the potential risk of decreased immunity to influenza in the population. Our single-center study aimed to investigate influenza trends before and during the COVID-19 pandemic in Tokyo, Japan. Materials and Methods: This cross-sectional study included patients of all ages who visited Tokyo Shinagawa Hospital between April 1, 2018, and March 31, 2023. Influenza and COVID-19 tests were conducted using Quick Navi-Flu2 and polymerase chain reaction (PCR). We analyzed data from before and during the COVID-19 epidemic, based on patient background, hospitalization, and deaths, collected from medical records. Results: A total of 12 577 influenza tests were conducted, with approximately 100 tests consistently performed each month even in the influenza off-season. Throughout the observation period, 962 positive cases were identified. However, no cases were observed for 27 months between March 2020 and November 2022. Influenza A cases were reobserved in December 2022, followed by influenza B cases in March 2023, similar to the influenza incidence reports from Tokyo. The positivity rate during the 2022-2023 winter season was lower than before the COVID-19 epidemic and decreased in elderly patients, with no hospitalizations or deaths observed. Conclusion: This single-center study provided actual trend data for influenza patients before and during COVID-19 outbreaks in Tokyo, which could offer insights into the potential impact and likelihood of influenza virus infection in Japan.

Reevaluation of Gastric Cancer Screening by Levin's Equation.

INTRODUCTION: This study aimed to reevaluate the effectiveness of fluoroscopy and endoscopy in reducing gastric cancer mortality at the population level. METHODS: Crude and age-adjusted mortality rates of gastric cancer and the introduction rates of gastric cancer screening were extracted from the Cancer Registry and Statistics database. The population-attributable risk (PAR) percent of no screening for gastric cancer mortality was calculated using Levin's equation. The PAR of each mortality rate in the no-screening group was estimated as follows: mortality × PAR%. The Jonckheere-Terpstra test for trends and linear regression were performed to compare the PAR of gastric cancer mortality rates among the decades. RESULTS: The PAR of crude and age-adjusted mortality rates in the no-screening group significantly decreased in the total population ( P for trend <0.001), as well as individually in the male ( P for trend <0.001) and female ( P for trend <0.001) populations. The PAR of the crude mortality rate in the female population significantly decreased in 2000-2009 and 2010-2019, compared with that in 1980-1989. There was no significant difference in the PAR of crude mortality rate in the male population among the decades. The PAR of the age-adjusted mortality rate significantly decreased in 2000-2009 and 2010-2019, compared with that in 1980-1989, in the male and female populations. DISCUSSION: PAR% and PAR of no screening for gastric cancer mortality could be estimated using Levin's equation, and the effectiveness of the present gastric cancer screenings with fluoroscopy and endoscopy has been decreasing, especially in the female population.

Prevalence of skin diseases and prognosis of atopic dermatitis in primary school children in populated areas of Japan from 2010 to 2019: The Asa Study in Hiroshima, Japan.

Skin diseases are common in children. However, the prevalence of childhood skin diseases in Japan has not been reported extensively. In this study, dermatologists conducted face-to-face examinations of primary school children over a 10-year period to determine the prevalence of each skin disease. Atopic dermatitis (AD, 12.3%) was the most common disease among first graders, followed by eczema other than AD (9.7%), molluscum contagiosum (1.9%), and verruca vulgaris (1.1%). Among sixth graders, acne vulgaris was most common (9.6%), followed by AD (8.9%), eczema other than AD (6.7%), and verruca vulgaris (3.1%). The prevalence of AD remained stable among first graders after 2010, at approximately 10%-15%, but it increased slightly among sixth graders. Of the 87 children who had AD in first grade, 51 (58.6%) were in remission in sixth grade. On the other hand, AD was diagnosed in 30 (4.5%) sixth graders who had been among the 665 children who did not have it in first grade. The more severe the symptoms were in first grade, the more likely a child was to still have AD in sixth grade, and the more severe the later symptoms tended to be. This study investigated recent trends in skin diseases in Japanese primary school children and found that the prevalence of some skin diseases differed between first and sixth graders. It was also found that children with moderate AD in first grade were more likely to be moderate in sixth grade than those with mild AD.

Endoscopic balloon dilation for the prevention of severe strictures caused by acute esophageal necrosis.

A 58-year-old man who had the history of alcohol dependence was referred to our emergency center due to severe nausea, vomiting, and subsequent onset of chest and back pain. Esophagogastroduodenoscopy (EGD) showed black-appearing esophagus mucosa extending from the cervical esophagus to the esophagogastric junction with clear margins, a condition typically referred to as a black esophagus. Alcohol abuse was considered an important factor associated with acute esophageal necrosis in this patient. After admission, he received fluid resuscitation and proton-pump inhibitors, with restriction of oral intake and treatment of alcohol dependence. Follow-up EGDs and endoscopic balloon dilation were performed for the management of esophageal narrowing before the development of severe strictures. Strictures were successfully treated endoscopically without complications such as perforation.

Outcomes in high and low volume hospitals in patients with acute hematochezia in a cohort study.

Outcomes of acute lower gastrointestinal bleeding have not been compared according to hospital capacity. We aimed to perform a propensity score-matched cohort study with path and mediation analyses for acute hematochezia patients. Hospitals were divided into high- versus low-volume hospitals for emergency medical services. Rebleeding and death within 30 days were compared. Computed tomography, early colonoscopy (colonoscopy performed within 24 h), and endoscopic therapies were included as mediators. A total of 2644 matched pairs were yielded. The rebleeding rate within 30 days was not significant between high- and low-volume hospitals (16% vs. 17%, P = 0.44). The mortality rate within 30 days was significantly higher in the high-volume cohort than in the low-volume cohort (1.7% vs. 0.8%, P = 0.003). Treatment at high-volume hospitals was not a significant factor for rebleeding (odds ratio [OR] = 0.91; 95% confidence interval [CI], 0.79-1.06; P = 0.23), but was significant for death within 30 days (OR = 2.03; 95% CI, 1.17-3.52; P = 0.012) on multivariate logistic regression after adjusting for patients' characteristics. Mediation effects were not observed, except for rebleeding within 30 days in high-volume hospitals through early colonoscopy. However, the direct effect of high-volume hospitals on rebleeding was not significant. High-volume hospitals did not improve the outcomes of acute hematochezia patients.

[A Case of Laparoscopy-Assisted Surgery for Intestinal Malignant Lymphoma with Bowel Obstruction].

An 83-year-old woman visited our emergency department with a chief complaint of abdominal pain and vomiting. Abdominal computed tomography showed thickening of the wall of the small intestine in the right middle abdomen and marked bowel dilation and fluid retention in the oral side of the small intestine. The patient was diagnosed with adhesive bowel obstruction and hospitalized for conservative treatment. However, the treatment was unsuccessful, and laparoscopic surgery was performed. The intraoperative findings included thickening of the wall and hardening of the obstructed part, suggestive of an intestinal tumor; thus, this part was resected. A histopathological examination revealed diffuse infiltration of large-sized atypical lymphocytes in the tumor, and diffuse large B-cell lymphoma was diagnosed through immunochemical staining. The postoperative course was uneventful, and the lymphoma has not recurred. Intestinal malignant lymphoma rarely causes bowel obstruction without invagination. Here, we report this case and review the literature.

Endoscopic treatment for a giant gastric bezoar: Sequential use of electrohydraulic lithotripsy, alligator forceps, and snares.

A 62-year-old woman with no past history was referred to our hospital for endoscopic treatment of a large gastric bezoar measuring 10 cm in diameter. The bezoar had a hard surface and huge volume. A tunnel was created at the center of the bezoar using electrohydraulic lithotripsy and was dilated using a through-the-scope balloon. The bezoar was then gradually crushed using alligator forceps and snares to decrease the risk of intestinal obstruction by the crushed bezoar fragments. The sequential use of electrohydraulic lithotripsy, alligator forceps, and snares according to the therapeutic plan enabled the endoscopic treatment of the giant gastric bezoar without surgery.

[Consideration on Industry-Academia Partnering in Drug Discovery Development: Based on a Questionnaire Survey of Pharmaceutical Companies and Academia].

Japanese pharmaceutical products continue to experience a trade deficit, since import values exceed export values. In drug discovery development, given the pace of technological innovations, there has been a major shift from low-molecular-weight compounds to biomedicine. It is anticipated that industry, academia and government will work more closely together in support of the pharmaceutical industry. Drug discovery requires much time and vast resources before the results can be put to practical use, and evidence suggests that many newly approved drugs derive from university-sourced technology. Pharmaceutical companies keep a close eye on technology evolving in universities. However, some reports state that there is a substantial difference compared to the development costs of the major Japanese pharmaceutical companies. Therefore, the authors hypothesized that there may be some issues hindering industrial-academic partnerships in drug discovery. In order to understand the actual situation and barriers to promoting industrial-academic collaboration, the Japan Pharmaceutical Manufacturers Association (JPMA), Japan Agency for Medical Research and Development (AMED), and the Medical Industry-Academia Collaboration Network (medU-net) Council will work together in issuing questionnaires and conducting an awareness survey. This survey sought the personal opinions of individuals belonging to JPMA and medU-net. Based on the results of this survey, we will introduce the issues related to industrial-academic collaboration and partnerships, and any gaps between industry and academia. Furthermore, we suggest solutions to promoting drug discovery innovation in Japan.

Discovery of 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazoles as novel class of corticotropin releasing factor 1 receptor antagonists.

A new class of corticotropin releasing factor 1 (CRF1) receptor antagonists characterized by a tricyclic core ring was designed and synthesized. Novel tricyclic derivatives 2a-e were designed as CRF1 receptor antagonists based on conformation analysis of our original 2-anilinobenzimidazole CRF1 receptor antagonist. The synthesized tricyclic derivatives 2a-e showed CRF1 receptor binding activity with IC50 values of less than 400 nM, and the 1,2,3,4-tetrahydropyrimido-[1,2-a]benzimidazole derivative 2e was selected as a lead compound with potent in vitro CRF1 receptor binding activity (IC50 = 7.1 nM). To optimize the pharmacokinetic profiles of lead compound 2e, we explored suitable substituents on the 1-position and 6-position, leading to the identification of compound 42c-R, which exhibited potent CRF1 receptor binding activity (IC50 = 58 nM) with good oral bioavailability (F = 68% in rats). Compound 42c-R exhibited dose-dependent inhibition of [125I]-CRF binding in the frontal cortex (5 and 10 mg/kg, p.o.) as well as suppression of locomotor activation induced by intracerebroventricular administration of CRF in rats (10 mg/kg, p.o.). These results suggest that compound 42c-R successfully binds CRF1 receptors in the brain and exhibits the potential to be further examined for clinical studies.

Characterization of CRF1 receptor antagonists with differential peripheral vs central actions in CRF challenge in rats.

The aim of this study was to investigate peripheral and central roles of corticotropin-releasing factor (CRF) in endocrinological and behavioral changes. Plasma adrenocorticotropin (ACTH) concentration was measured as an activity of hypothalamic-pituitary-adrenal (HPA) axis. As behavioral changes, locomotion and anxiety behavior were measured after CRF challenge intravenously (i.v.) for the peripheral administration or intracerebroventricularly (i.c.v.) for the central administration. Plasma ACTH concentration was significantly increased by both administration routes of CRF; however, hyperlocomotion and anxiety behavior were induced only by the i.c.v. administration. In the drug discovery of CRF1 receptor antagonists, we identified two types of compounds, Compound A and Compound B, which antagonized peripheral CRF-induced HPA axis activation to the same extent, but showed different effects on the central CRF signal. These had similar in vitro CRF1 receptor binding affinities (15 and 10nM) and functional activities in reporter gene assay (15 and 9.5nM). In the ex vivo binding assays using tissues of the pituitary, oral treatment with Compound A and Compound B at 10mg/kg inhibited [125I]-CRF binding, whereas in the assay using tissues of the frontal cortex, treatment of Compound A but not Compound B inhibited [125I]-CRF binding, indicating that only Compound A inhibited central [125I]-CRF binding. In the peripheral CRF challenge, increase in plasma ACTH concentration was significantly suppressed by both Compound A and Compound B. In contrast, Compound A inhibited the increase in locomotion induced by the central CRF challenge while Compound B did not. Compound A also reduced central CRF challenge-induced anxiety behavior and c-fos immunoreactivity in the cortex and the hypothalamic paraventricular nucleus. These results indicate that the central CRF signal, rather than the peripheral CRF signal would be related to anxiety and other behavioral changes, and CRF1 receptor antagonism in the central nervous system may be critical for identifying drug candidates for anxiety and mood disorders.

Potent and selective oxytocin receptor agonists without disulfide bridges.

Oxytocin (OT) is a neuropeptide involved in a wide variety of physiological actions, both peripherally and centrally. Many human studies have revealed the potential of OT to treat autism spectrum disorders and schizophrenia. OT interacts with the OT receptor (OTR) as well as vasopressin 1a and 1b receptors (V1aR, V1bR) as an agonist, and agonistic activity for V1aR and V1bR may have a negative impact on the therapeutic effects of OTR agonism in the CNS. An OTR-selective agonistic peptide, FE 202767, in which the structural differences from OT are a sulfide bond instead of a disulfide bond, and N-alkylglycine replacement for Pro at position 7, was reported. However, the effects of amino acid substitutions in OT have not been comprehensively investigated to compare OTR, V1aR, and V1bR activities. This led us to obtain a new OTR-selective analog by comprehensive amino acid substitutions of OT and replacement of the disulfide bond. A systematic amino acid scanning (Ala, Leu, Phe, Ser, Glu, or Arg) of desamino OT (dOT) at positions 2, 3, 4, 5, 7, and 8 revealed the tolerability for the substitution at positions 7 and 8. Further detailed study showed that trans-4-hydroxyproline (trans-Hyp) at position 7 and γ-methylleucine [Leu(Me)] at position 8 were markedly effective for improving receptor selectivity without decreasing the potency at the OTR. Subsequently, a combination of these amino acid substitutions with the replacement of the disulfide bond of dOT analogs with a sulfide bond (carba analog) or an amide bond (lactam analog) yielded several promising analogs, including carba-1-[trans-Hyp7,Leu(Me)8]dOT (14) with a higher potency (7.2pM) at OTR than that of OT and marked selectivity (>10,000-fold) over V1aR and V1bR. Hence, we investigated comprehensive modification of OT and obtained new OT analogs that exhibited high potency at OTR with marked selectivity. These OTR-selective agonists could be useful to investigate OTR-mediated effects on psychiatric disorders.

Discovery of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole, a novel CRF1 receptor antagonist.

Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF1) receptor (IC50=9.5nM) and in vitro antagonistic activity (IC50=88nM) but is rapidly metabolized by human hepatic microsomes (182µL/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity. Structure-activity relationship (SAR) studies considering in vitro metabolic stability revealed that 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole 24d was more stable in human microsomes (87µL/min/mg) than compound 1. Compound 24d demonstrated potent CRF binding inhibitory activity (IC50=4.1nM), in vitro antagonistic activity (IC50=44nM), and slow dissociation from the CRF1 receptor. Orally administered compound 24d (6-24µmol/kg) showed ex vivo CRF1 receptor binding in the rat pituitary, olfactory bulb, and frontal cortex and suppressed stress-induced adrenocorticotropic hormone (ACTH) secretion. In this report, we discuss SAR studies on the metabolic stability as well as CRF binding inhibitory activity of the benzimidazole series as CRF1 receptor antagonists and the pharmacological profiles of compound 24d.

Discovery of a 7-arylaminobenzimidazole series as novel CRF1 receptor antagonists.

A promising lead compound 1 of a benzimidazole series has been identified as a corticotropin-releasing factor 1 (CRF1) receptor antagonist. In this study, we focused on replacement of a 7-alkylamino group of 1, predicted to occupy a large lipophilic pocket of a CRF1 receptor, with an aryl group. During the course of this examination, we established new synthetic approaches to 2,7-diarylaminobenzimidazoles. The novel synthesis of 7-arylaminobenzimidazoles culminated in the identification of compounds exhibiting inhibitory activities comparable to the alkyl analog 1. A representative compound, p-methoxyanilino analog 16g, showed potent CRF binding inhibitory activity against a human CRF1 receptor and human CRF1 receptor antagonistic activity (IC50=27nM, 56nM, respectively). This compound exhibited ex vivo (125)I-Tyr(0) ((125)I-CRF) binding inhibitory activity in mouse frontal cortex, olfactory bulb, and pituitary gland at 20mg/kg after oral administration. In this report, we discuss the structure-activity-relationship of these 7-arylamino-1H-benzimidazoles and their synthetic method.

Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists.

Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF1) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF1 receptor antagonists. In a structure-activity relationship study, 4-chloro-N(2)-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-N(7),N(7)-dipropyl-1H-benzimidazole-2,7-diamine 29g had the most potent binding activity against a human CRF1 receptor and the antagonistic activity (IC50 = 9.5 and 88 nM, respectively) without concerns regarding cytotoxicity at 30 µM. Potent CRF1 receptor-binding activity in brain in an ex vivo test and suppression of stress-induced activation of the hypothalamus-pituitary-adrenocortical (HPA) axis were also observed at 138 µmol/kg of compound 29g after oral administration in mice. Thus, the newly designed benzimidazole 29g showed in vivo CRF1 receptor antagonistic activity and good brain penetration, indicating that it is a promising lead for CRF1 receptor antagonist drug discovery research.

Discovery of pyrrolo[2,3-d]pyrimidin-4-ones as corticotropin-releasing factor 1 receptor antagonists with a carbonyl-based hydrogen bonding acceptor.

A new class of pyrrolo[2,3-d]pyrimidin-4-one corticotropin-releasing factor 1 (CRF(1)) receptor antagonists has been designed and synthesized. In general, reported CRF(1) receptor antagonists possess a sp(2)-nitrogen atom as hydrogen bonding acceptor (HBA) on their core scaffolds. We proposed to use a carbonyl group of pyrrolo[2,3-d]pyrimidin-4-one derivatives as a replacement for the sp(2)-nitrogen atom as HBA in classical CRF(1) receptor antagonists. As a result, several pyrrolo[2,3-d]pyrimidin-4-one derivatives showed CRF(1) receptor binding affinity with IC(50) values in the submicromolar range. Ex vivo (125)I-sauvagine binding studies showed that 2-(dipropylamino)-3,7-dimethyl-5-(2,4,6-trimethylphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (16b) (30 mg/kg, p.o.) was able to penetrate into the brain and inhibit radioligand binding to CRF(1) receptors (frontal cortex, olfactory bulb, and pituitary) in mice. We identified pyrrolo[2,3-d]pyrimidin-4-one derivatives as the first CRF(1) antagonists with a carbonyl-based HBA.

Developmental expression of RFamide-related peptides in the rat central nervous system.

RFamide-related peptides (RFRP-1 and RFRP-3) have been recently identified in mammals and considered to play significant functional roles in the rat brain. In this study, we report the developmental expression of RFRP mRNA and its immunoreactive neuronal cells and fibers in the rat brain. The RFRP mRNA was expressed in the brain from embryonic day 15 (E15) according to reverse transcription-polymerase chain reaction analysis. We first detected RFRP mRNA expressing neurons in the caudal portion of the hypothalamus at E16 by in situ hybridization analysis. Immunohistochemical analysis showed that RFRP-3 or RFRP-1 immunoreactive neuronal cell bodies were first detected at E16 or E17, respectively. Double-labeling fluorescent immunohistochemical analysis showed that neurons containing both RFRP-1 immunoreactivity (ir) and RFRP-3-ir were detected from E18. We also detected RFRP-1 immunoreactive nerve fiber processes in the forebrain, hypothalamus, thalamus, midbrain, pons and medulla oblongata at prenatal day and the distribution of RFRP-1 immunoreactive nerve fibers in postnatal day 0 (P0) were almost coincident with that in adult. However, localization of RFRP-3 immunoreactive nerve fibers was limited around the RFRP-3 immunoreactive neuronal cell bodies during prenatal days. The distribution of RFRP-3 immunoreactive nerve fibers was first detected in the above areas at P0. The nerve fibers containing only RFRP-3-ir in the thalamus or spinal cord were first appeared at P21 or P28. Our results show that RFRP mRNA was expressed during the neonates and the distribution of RFRP-1 or RFRP-3 immunoreactive nerve fibers would be distinctly regulated in the developing rat brain.

Intracerebroventricular administration of urotensin II promotes anxiogenic-like behaviors in rodents.

We identified urotensin II (U-II) as the endogenous ligand for the orphan G-protein-coupled receptor GPR14 or SENR. Both U-II and GPR14 are expressed not only in peripheral tissues but also in the brain of rodents, suggesting that U-II plays a physiological role in the central nervous system. In the present study, we investigated the central effects of U-II in rodents. Intracerebroventricular administration of U-II induced anxiogenic-like behaviors in the elevated plus maze test and the hole-board test in mice in a dose-dependent manner, as did corticotropin releasing factor (CRF). The effective doses of U-II were 10-100-fold higher than these of CRF in these tests. Our results suggest that U-II is a candidate for the mediator of some aspect of stress or anxiety in the central nervous system.

Localization and neuronal response of RFamide related peptides in the rat central nervous system.

RFamide related peptides (RFRP)-1 and RFRP-3 are neuropeptides derived from the same preproprotein. We have examined the distribution of RFRP-1 and RFRP-3 immunoreactivities (irs) in the rat central nervous system using specific antibodies. Neuronal cell bodies containing both RFRP-1 and RFRP-3 were detected within the caudal portion of the hypothalamus, the periventricular nucleus (PerVN), and the portion around or above the ventromedial nucleus of the hypothalamus. Both immunohistochemical and in situ hybridization analyses showed that neurons containing RFRP immunoreactivity and mRNA were distinct from those of neuropeptide FF, which contains the same structure at the C-terminus, Pro-Glu-Arg-Phe-NH2, as RFRP-3. Fibers containing both RFRP-1 and RFRP-3 were widely distributed in the brain: the lateral septal nucleus in the telencephalon, the paraventricular thalamic nucleus, various hypothalamic nuclei, the periaqueductal gray in the midbrain, the parabrachial nucleus in the pons, and the nucleus tractus solitarius (NTS) in the medulla oblongata. Only RFRP-1-ir was detected within the posterior gray horn in the spinal cord. Only RFRP-3-ir was detected in several thalamic nuclei and the spinal cord, especially at the posterior intermediate sulcus and within the anterior gray horn. Intracerebroventricular administration of RFRPs induced c-Fos expression in the anterior portion of the NTS, locus coeruleus, the nucleus of incertus, supraoptic nucleus, PerVN and the arcuate nucleus of the hypothalamus. These results show that RFRP-1 and RFRP-3 are widely distributed in the rat central nervous system and might be involved in various functions such as the neuroendocrine system or pain modulation.