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Various studies have described epigenetic inheritance through sperms. However, the detailed mechanisms remain unclear. In this study, we focused on DNA methylation in mice treated with valproic acid (VPA), an inducer of epigenomic changes, and analyzed the treatment effects on the sperm from the next generation of mice. The administration of 200 mg/kg/day VPA to mice for 4 weeks caused transient histone hyperacetylation in the testes and DNA methylation changes in the sperm, including promoter CpGs of genes related to brain function. Oocytes fertilized with VPA-treated mouse sperm showed methylation fluctuations at the morula stage. Pups that were fathered by these mice also showed behavioral changes in the light/dark transition test after maturation. Brain RNA-seq of these mice showed that the expression of genes related to neural functions were altered. Comparison of the sperm DNA methylation status of the next generation of mice with that of the parental generation revealed the disappearance of methylation changes observed in the sperm of the parental generation. These findings suggest that VPA-induced histone hyperacetylation may have brain function-related effects on the next generation through changes in sperm DNA methylation.

Mammalian sleep comprises rapid eye movement (REM) sleep and non-REM (NREM) sleep. To functionally isolate from the complex mixture of neurons populating the brainstem pons those involved in switching between REM and NREM sleep, we chemogenetically manipulated neurons of a specific embryonic cell lineage in mice. We identified excitatory glutamatergic neurons that inhibit REM sleep and promote NREM sleep. These neurons shared a common developmental origin with neurons promoting wakefulness; both derived from a pool of proneural hindbrain cells expressing Atoh1 at embryonic day 10.5. We also identified inhibitory γ-aminobutyric acid–releasing neurons that act downstream to inhibit REM sleep. Artificial reduction or prolongation of REM sleep in turn affected slow-wave activity during subsequent NREM sleep, implicating REM sleep in the regulation of NREM sleep.

IntroductionHaemoglobin vesicles (HbVs) (product name, NMU-HbVs [Nara Medical University-Haemoglobin Vesicles]), which contain purified human haemoglobin encapsulated within liposomes, have been developed as a potential alternative to blood transfusions in emergency situations. A previous phase I study examined doses up to 100 mL in 11 healthy volunteers. Here, we describe the protocol for a phase Ib study, wherein we will evaluate the safety and pharmacokinetics of NMU-HbV in healthy Japanese adults.Methods and analysisThis single-centre, open-label, dose-escalation study will enrol 16 healthy volunteers divided into four cohorts. Planned doses are 100 mL for cohorts 1 and 2, 200 mL for cohort 3 and 400 mL for cohort 4, with infusion rates gradually increasing to a maximum of 5.0 mL/min. The primary endpoint will be safety, which will be assessed as the incidence of adverse events within 14 days and significant clinical changes within 72 hours after administration. Safety evaluations will include subjective symptoms, vital signs, electrocardiograms and laboratory test results compared with the baseline. The secondary endpoint will be pharmacokinetics, which will be assessed as changes in NMU-HbV concentration immediately after infusion until day 4 to determine the maximum blood concentration, time to reach the maximum blood concentration, area under the blood concentration-time curve and elimination half-life. This study will provide data on the safety and pharmacokinetic profiles of NMU-HbV at doses up to 400 mL. The findings are expected to support the further development of NMU-HbV as a viable alternative to emergency transfusions.Ethics and disseminationThe study protocol was approved by the Institutional Review Board of Nara Medical University on 10 December 2024. Dissemination plans include publishing in peer-reviewed scientific journals and presentation at international conferences.Trial registration numberJapan Registry of Clinical Trials (jRCT2051240249). Registered on 27 January 2025 (https://jrct.mhlw.go.jp/en-latest-detail/jRCT2051240249).

The COVID-19 pandemic is an unprecedented threat to humanity that has provoked global health concerns. Since the etiopathogenesis of this illness is not fully characterized, the prognostic factors enabling treatment decisions have not been well documented. Accurately predicting the progression of the disease would aid in appropriate patient categorization and thus help determine the best treatment option. Here, we have introduced a proteomic approach utilizing data-independent acquisition mass spectrometry (DIA-MS) to identify the serum proteins that are closely associated with COVID-19 prognosis. Twenty-seven proteins were differentially expressed between severely ill COVID-19 patients with an adverse or favorable prognosis. Ingenuity Pathway Analysis revealed that 15 of the 27 proteins might be regulated by cytokine signaling relevant to interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF), and their differential expression was implicated in the systemic inflammatory response and in cardiovascular disorders. We further evaluated practical predictors of the clinical prognosis of severe COVID-19 patients. Subsequent ELISA assays revealed that CHI3L1 and IGFALS may serve as highly sensitive prognostic markers. Our findings can help formulate a diagnostic approach for accurately identifying COVID-19 patients with severe disease and for providing appropriate treatment based on their predicted prognosis.

Thrombotic thrombocytopenic purpura (TTP) can rapidly become a life-threatening condition, and the importance of its appropriate diagnosis and treatment cannot be overstated. Until recently, TTP has mainly been diagnosed by clinical findings such as thrombocytopenia and hemolytic anemia. In addition to these clinical findings, however, reduced activity of a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) below 10% has become internationally accepted as a diagnostic criterion for TTP. TTP is classified as immune-mediated TTP (iTTP) if the patient is positive for anti-ADAMTS13 autoantibodies, and as congenital TTP (cTTP) if ADAMTS13 gene abnormalities are detected. Fresh frozen plasma (FFP) transfusion is performed in patients with cTTP to supplement ADAMTS13. Plasma exchange therapy using FFP is conducted in patients with iTTP to supplement ADAMTS13 and to remove both anti-ADAMTS13 autoantibodies and unusually large von Willebrand factor (VWF) multimers. To suppress autoantibody production, corticosteroid therapy is administered in conjunction with plasma exchange. The monoclonal anti-CD-20 antibody rituximab is effective in patients with iTTP. In addition, caplacizumab, an anti-VWF A1 domain nanobody, has a novel mechanism of action, involving direct inhibition of platelet glycoprotein Ib–VWF binding. The recommended first-line treatments of iTTP in Japan are plasma exchange and corticosteroids, as well as caplacizumab.

Immune thrombotic thrombocytopenic purpura (iTTP) is caused by ADAMTS13 deficiency due to anti-ADAMTS13 autoantibodies. Rituximab, an anti-CD20 monoclonal antibody, is often used to suppress these autoantibodies. This retrospective study, conducted in an iTTP cohort in Japan, evaluated the long-term efficacy of rituximab as off-label treatment for refractory or relapsed cases. A total of 252 iTTP patients with severe ADAMTS13 deficiency (< 10%) and its inhibitor were enrolled, and 169 episodes in 156 patients were analyzed. Sixty-five episodes with relapse or resistance to conventional treatment were treated with rituximab, while 104 episodes received conventional treatment only. The rituximab group had a significantly higher inhibitor titer than the rituximab-untreated group. During the median follow-up period of 3.9 years, there were 8 relapses in the rituximab group and 17 relapses in the rituximab-untreated group. The median time to relapse in the rituximab group (2.9 years) was significantly longer than that in the rituximab-untreated group (1.2 years). Relapse-free survival at 2 years was significantly higher in the rituximab group than in the rituximab-untreated group. The incidence of relapse at 5 years did not differ between the 2 groups. Rituximab reduced the risk of relapse in refractory or relapsed iTTP patients for 2 years.

Congenital thrombotic thrombocytopenic purpura (cTTP) is an extremely rare disease characterized by the severe deficiency of a disintegrin and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13), caused by ADAMTS13 mutations. While ADAMTS13 supplementation by fresh frozen plasma (FFP) infusion immediately corrects platelet consumption and resolves thrombotic symptoms in acute episodes, FFP treatment can lead to intolerant allergic reactions and frequent hospital visits. Up to 70% of patients depend on regular FFP infusions to normalize their platelet counts and avoid systemic symptoms, including headache, fatigue, and weakness. The remaining patients do not receive regular FFP infusions, mainly because their platelet counts are maintained within the normal range or because they are symptom-free without FFP infusions. However, the target peak and trough levels of ADAMTS13 to prevent long-term comorbidity with prophylactic FFP and the necessity of treating FFP-independent patients in terms of long-term clinical outcomes are yet to be determined. Our recent study suggests that the current volumes of FFP infusions are insufficient to prevent frequent thrombotic events and long-term ischemic organ damage. This review focuses on the current management of cTTP and its associated issues, followed by the importance of upcoming recombinant ADAMTS13 therapy.

Optimal timing for intubating patients with coronavirus disease 2019 (COVID-19) has been debated throughout the pandemic. Early use of high-flow nasal cannula (HFNC) can help reduce the need for intubation, but delay can result in poorer outcomes. This study examines trends in laboratory parameters and serum severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA levels of patients with COVID-19 in relation to HFNC failure. Patients requiring HFNC within three days of hospitalization between July 1 and September 30, 2021 were enrolled. The primary outcome was HFNC failure (early failure ≤Day 3; late failure ≥Day 4), defined as transfer to intensive care just before/after intubation or in-hospital death. We examined changes in laboratory markers and SARS-CoV2-RNAemia on Days 1, 4, and 7, together with demographic data, oxygenation status, and therapeutic agents. We conducted a univariate logistic regression with the explanatory variables defined as 10% change rate in each laboratory marker from Day 1 to 4. We utilized the log-rank test to assess the differences in HFNC failure rates, stratified based on the presence of SARS-CoV2 RNAemia. Among 122 patients, 17 (13.9%) experienced HFNC failure (early: n = 6, late: n = 11). Seventy-five patients (61.5%) showed an initial SpO 2 /FiO 2 ratio ≤243, equivalent to PaO 2 /FiO 2 ratio ≤200, and the initial SpO 2 /FiO 2 ratio was significantly lower in the failure group (184 vs. 218, p = 0.018). Among the laboratory markers, a 10% increase from Day 1 to 4 of lactate dehydrogenase (LDH) and interleukin (IL)-6 was associated with late failure (Odds ratio [OR]: 1.42, 95% confidence interval [CI]: 1.09–1.89 and OR: 1.04, 95%CI: 1.00–1.19, respectively). Furthermore, in patients with persistent RNAemia on Day 4 or 7, the risk of late HFNC failure was significantly higher (Log-rank test, p<0.01). In conclusion, upward trends in LDH and IL-6 levels and the persistent RNAemia even after treatment were associated with HFNC failure.

The increasing requirement of mechanical ventilation (MV) due to the novel coronavirus disease (COVID-19) is still a global threat. The aim of this study is to identify markers that can easily stratify the impending use of MV in the emergency room (ER). A total of 106 patients with COVID-19 requiring oxygen support were enrolled. Fifty-nine patients were provided MV 0.5 h (interquartile range: 0.3 to 1.4) post-admission. Clinical and laboratory data before intubation were collected. Using a multivariate logistic regression model, we identified four markers associated with the impending use of MV, including the ratio of peripheral blood oxygen saturation to fraction of inspired oxygen (SpO 2 /FiO 2 ratio), alanine aminotransferase, blood glucose (BG), and lymphocyte counts. Among these markers, SpO 2 /FiO 2 ratio and BG, which can be measured easily and immediately, showed higher accuracy (AUC: 0.88) than SpO 2 /FiO 2 ratio alone (AUC: 0.84), despite no significant difference (DeLong test: P = 0.591). Moreover, even in patients without severe respiratory failure (SpO 2 /FiO 2 ratio > 300), BG (> 138 mg/dL) was predictive of MV use. Measuring BG and SpO 2 /FiO 2 ratio may be a simple and versatile new strategy to accurately identify ER patients with COVID-19 at high risk for the imminent need of MV.

Pachychoroid neovasculopathy (PNV) is a new concept of macular disorder. Some cases diagnosed as age-related macular degeneration (AMD) have been re-diagnosed as PNV. However, the biological features of PNV are still uncertain. The purpose of this study was to compare PNV and AMD by analyses focusing on von Willebrand factor (VWF) and complement factor H ( CFH ). Ninety-seven patients who were previously diagnosed with treatment naïve AMD were enrolled in this study. They were re-classified as either PNV or AMD based on the clinical criteria and 33 patients were classified as PNV and 64 patients as AMD. We examined the clinical data, analyzed VWF multimer and two genetic polymorphisms (I62V and Y402H) in the CFH . PNV group was significantly younger than AMD group ( P  = 0.001). In both I62V and Y402H, there were no significant differences between PNV and AMD while the recessive homozygous (AA) was found only in PNV group in I62V . The presence of unusually large VWF multimers (UL-VWFMs) and subretinal hemorrhages were significantly higher in PNV than in AMD ( P  = 0.045, P  = 0.020, respectively). Thus, the residual UL-VWFMs may result in platelet thrombosis and hemorrhages in the choriocapillaris of PNV. In conclusion, our results suggest the biological differences between PNV and AMD.