•Coronavirus disease has emerged as a global pandemic.•Japan has experienced two waves of the disease.•The second wave had a lower proportion of severe cases on admission.
The role of histamine in various murine disease models has been clarified using histidine decarboxylase gene knockout mice. The mice were generated using conventional gene-targeting methods. Studies, ...including ours, using knockout mice have shown that the activity of histamine is not limited to allergic, peptic and neurologic functions as in the old paradigm, but extends to other processes related to wound healing, circulatory disease, immunology, oncology and infectious disease. The recent observation of the activity of newly cloned histamine receptors and a pathophysiologic effect of histamine has dramatically expanded our understanding of the scope of histamine function.
Aim: Cardiovascular disease (CVD) is the second largest cause of death in Japanese women. Pregnancy and childbirth are events that put a strain on the cardiovascular system. When postpartum weight ...retention is insufficient, weight gain due to fat deposition during pregnancy might lead to obesity. Thus, we examined the effects of body mass index (BMI) in middle and older ages and the number of children on CVD and metabolic disorders.Methods: From the Tohoku Medical Megabank database, we used data from 32,000 women aged ≥ 50 years. This database contains obstetrical history, medical history, and laboratory data obtained once from 2013 to 2015.Results: The mean age of participants was 64.2 years, and 47.7% of women had two children. Compared with nulliparous women, those who had a higher number of children had higher BMI and systolic blood pressure. The prevalence of CVD was highest in obese class I (30 kg/m2 ≤ BMI) women with three or more children and the prevalence of hypertension was high in pre-obese (25 kg/m2 ≤ BMI ＜30 kg/m2) and obese class I women with children. Conversely, the prevalence of diabetes and proportion of women whose HbA1c values were ＞6.5% was highest in obese class I women with no children.Conclusion: In this study, we found that not only BMI but also the number of children influenced the health status of middle- and older-aged women, suggesting the importance of childbirth history in the health management of women.
Highlights • Histamine regulates microglia in vivo in the striatum. • The H4 receptor activates microglia. • Histamine deficiency leads to reduce neuroprotective microglia. • Histamine deficiency ...leads to a potentiated response to inflammatory challenge.
ObjectivesTo investigate the risk factors contributing to severity on admission. Additionally, risk factors of worst severity and fatality were studied. Moreover, factors were compared based on three ...points: early severity, worst severity and fatality.DesignAn observational cohort study using data entered in a Japan nationwide COVID-19 inpatient registry, COVIREGI-JP.SettingAs of 28 September 2020, 10480 cases from 802 facilities have been registered. Participating facilities cover a wide range of hospitals where patients with COVID-19 are admitted in Japan.ParticipantsParticipants who had a positive test result on any applicable SARS-CoV-2 diagnostic tests were admitted to participating healthcare facilities. A total of 3829 cases were identified from 16 January to 31 May 2020, of which 3376 cases were included in this study.Primary and secondary outcome measuresPrimary outcome was severe or nonsevere on admission, determined by the requirement of mechanical ventilation or oxygen therapy, SpO2 or respiratory rate. Secondary outcome was the worst severity during hospitalisation, judged by the requirement of oxygen and/orinvasive mechanical ventilation/extracorporeal membrane oxygenation.ResultsRisk factors for severity on admission were older age, men, cardiovascular disease, chronic respiratory disease, diabetes, obesity and hypertension. Cerebrovascular disease, liver disease, renal disease or dialysis, solid tumour and hyperlipidaemia did not influence severity on admission; however, it influenced worst severity. Fatality rates for obesity, hypertension and hyperlipidaemia were relatively lower.ConclusionsThis study segregated the comorbidities influencing severity and death. It is possible that risk factors for severity on admission, worst severity and fatality are not consistent and may be propelled by different factors. Specifically, while hypertension, hyperlipidaemia and obesity had major effect on worst severity, their impact was mild on fatality in the Japanese population. Some studies contradict our results; therefore, detailed analyses, considering in-hospital treatments, are needed for validation.Trial registration numberUMIN000039873. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000045453
Abstract
Here, we report the results of a phase I/II, single-arm study (UMIN-CTR Clinical Trial Registry UMIN000002661) assessing the safety (primary endpoint) of G47∆, a triple-mutated oncolytic ...herpes simplex virus type 1, in Japanese adults with recurrent/progressive glioblastoma despite radiation and temozolomide therapies. G47Δ was administered intratumorally at 3 × 10
8
pfu (low dose) or 1 × 10
9
pfu (set dose), twice to identical coordinates within 5–14 days. Thirteen patients completed treatment (low dose,
n
= 3; set dose,
n
= 10). Adverse events occurred in 12/13 patients. The most common G47Δ-related adverse events were fever, headache and vomiting. Secondary endpoint was the efficacy. Median overall survival was 7.3 (95%CI 6.2–15.2) months and the 1-year survival rate was 38.5%, both from the last G47∆ administration. Median progression-free survival was 8 (95%CI 7–34) days from the last G47∆ administration, mainly due to immediate enlargement of the contrast-enhanced area of the target lesion on MRI. Three patients survived >46 months. One complete response (low dose) and one partial response (set dose) were seen at 2 years. Based on biopsies, post-administration MRI features (injection site contrast-enhancement clearing and entire tumor enlargement) likely reflected tumor cell destruction via viral replication and lymphocyte infiltration towards tumor cells, the latter suggesting the mechanism for “immunoprogression” characteristic to this therapy. This study shows that G47Δ is safe for treating recurrent/progressive glioblastoma and warrants further clinical development.
Tics, such as are seen in Tourette syndrome (TS), are common and can cause profound morbidity, but they are poorly understood. Tics are potentiated by psychostimulants, stress, and sleep deprivation. ...Mutations in the gene histidine decarboxylase (Hdc) have been implicated as a rare genetic cause of TS, and Hdc knockout mice have been validated as a genetic model that recapitulates phenomenological and pathophysiological aspects of the disorder. Tic-like stereotypies in this model have not been observed at baseline but emerge after acute challenge with the psychostimulant d-amphetamine. We tested the ability of an acute stressor to stimulate stereotypies in this model, using tone fear conditioning. Hdc knockout mice acquired conditioned fear normally, as manifested by freezing during the presentation of a tone 48h after it had been paired with a shock. During the 30min following tone presentation, knockout mice showed increased grooming. Heterozygotes exhibited normal freezing and intermediate grooming. These data validate a new paradigm for the examination of tic-like stereotypies in animals without pharmacological challenge and enhance the face validity of the Hdc knockout mouse as a pathophysiologically grounded model of tic disorders.
Depression during pregnancy is relatively undertreated; however, the relationship between prenatal exposure to antidepressants and neonatal outcomes remains controversial.
This retrospective cohort ...study used a Japanese nationwide claims database. Data of 114,359 singletons born between January 2005 and November 2019 were used to evaluate the relationship between prenatal exposure to antidepressants and neonatal morbidity.
Of 2892 mothers with a history of depression before delivery, 352 (12.1%) received prescriptions within three months before delivery (MP3), and 2540 did not (non-MP3). The participants were propensity score matched (PSM) in a ratio of 1:3 using logistic regression (MP3_PSM n = 351 vs non-MP3_PSM n = 1052), and maternal prescriptions of antidepressants within three months before delivery were associated with neonatal morbidity indicators, including admission to the neonatal intensive care unit (NICU) (15.7 vs. 9.1%, odds ratio (OR) 1.9 95% confidence interval (CI): 1.3–2.6), poor neonatal adaptation syndrome (6.0 vs 1.0%, OR 6.6 95% CI: 3.1–14.2), transient tachycardia (15.7 vs. 6.7%, OR 2.6 95% CI: 1.8–3.8), and meconium aspiration syndrome (3.1 vs 0.7%, OR 4.8 95% CI, 1.9–12.5). There were no significant differences in the long-term duration of stay at the NICU (>15 days).
Confounding factors may remain even after the propensity matching.
Maternal prescription of antidepressants within three months before delivery was associated with increased admission to the NICU. However, the absolute risk of severe neonatal morbidity was low. Therefore, collaborative care for prenatal depression and the neonatal intensive care is warranted.
•Depression during pregnancy is often untreatable.•The claims data showed an association between prenatal antidepressants and NICU admission.•The absolute risk of severe neonatal morbidity is low.•Collaborative care for prenatal depression and neonatal morbidities is warranted.
The hypocretins (Hcrts) (also called orexins) are two neuropeptides expressed in the lateral hypothalamus that play a crucial role in the stability of wakefulness. Previously, our laboratory ...demonstrated that in vivo photostimulation of Hcrt neurons genetically targeted with ChR2, a light-activated cation channel, was sufficient to increase the probability of an awakening event during both slow-wave sleep and rapid eye movement sleep. In the current study, we ask whether Hcrt-mediated sleep-to-wake transitions are affected by light/dark period and sleep pressure. We found that stimulation of Hcrt neurons increased the probability of an awakening event throughout the entire light/dark period but that this effect was diminished with sleep pressure induced by 2 or 4 h of sleep deprivation. Interestingly, photostimulation of Hcrt neurons was still sufficient to increase activity assessed by c-Fos expression in Hcrt neurons after sleep deprivation, although this stimulation did not cause an increase in transitions to wakefulness. In addition, we found that photostimulation of Hcrt neurons increases neural activity assessed by c-Fos expression in the downstream arousal-promoting locus ceruleus and tuberomammilary nucleus but not after 2 h of sleep deprivation. Finally, stimulation of Hcrt neurons was still sufficient to increase the probability of an awakening event in histidine decarboxylase-deficient knock-out animals. Collectively, these results suggest that the Hcrt system promotes wakefulness throughout the light/dark period by activating multiple downstream targets, which themselves are inhibited with increased sleep pressure.
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