High oxygen exposure's impact on newborn mice: Temporal changes observed via micro-computed tomography.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) impacts life expectancy and long-term quality of life. Currently, BPD mouse models exposed to high oxygen are frequently used, but to reevaluate their relevance to human BPD, we attempted an assessment using micro-computed tomography (µCT). METHODS: Newborn wildtype male mice underwent either 21% or 95% oxygen exposure for 4 days, followed until 8 wk. Weekly µCT scans and lung histological evaluations were performed independently. RESULTS: Neonatal hyperoxia for 4 days hindered lung development, causing alveolar expansion and simplification. Histologically, during the first postnatal week, the exposed group showed a longer mean linear intercept, enlarged alveolar area, and a decrease in alveolar number, diminishing by week 4. Weekly µCT scans supported these findings, revealing initially lower lung density in newborn mice, increasing with age. However, the high-oxygen group displayed higher lung density initially. This difference diminished over time, with no significant contrast to controls at 3 wk. Although no significant difference in total lung volume was observed at week 1, the high-oxygen group exhibited a decrease by week 2, persisting until 8 wk. CONCLUSION: This study highlights µCT-detected changes in mice exposed to high oxygen. BPD mouse models might follow a different recovery trajectory than humans, suggesting the need for further optimization.

Genetic Ablation of Pyruvate Dehydrogenase Kinase Isoform 4 Gene Enhances Recovery from Hyperoxic Lung Injury: Insights into Antioxidant and Inflammatory Mechanisms.

BACKGROUND: Pyruvate dehydrogenase kinase isoform 4 (PDK4) plays a pivotal role in the regulation of cellular proliferation and apoptosis. The objective of this study was to examine whether the genetic depletion of the PDK4 gene attenuates hyperoxia-induced lung injury in neonatal mice. METHODS: Neonatal PDK4-/- mice and wild-type (WT) mice were exposed to oxygen concentrations of 21% (normoxia) and 95% (hyperoxia) for the first 4 days of life. Pulmonary histological assessments were performed, and the mRNA levels of lung PDK4, monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 were assessed. The levels of inflammatory cytokines in lung tissue were quantified. RESULTS: Following convalescence from neonatal hyperoxia, PDK4-/- mice exhibited improved lung alveolarization. Notably, PDK4-/- mice displayed significantly elevated MCP-1 protein levels in pulmonary tissues following 4 days of hyperoxic exposure, whereas WT mice showed increased IL-6 protein levels under similar conditions. Furthermore, neonatal PDK4-/- mice subjected to hyperoxia demonstrated markedly higher MCP-1 mRNA expression at 4 days of age compared to WT mice, while IL-6 mRNA expression remained unaffected in PDK4-/- mice. CONCLUSIONS: Newborn PDK4-/- mice exhibited notable recovery from hyperoxia-induced lung injury, suggesting the potential protective role of PDK4 depletion in mitigating lung damage.

Association of hyaluronan and proteoglycan link protein 1 gene with the need of home oxygen therapy in premature Japanese infants with bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) has a lasting effect on the respiratory function of infants, imposing chronic health burdens. BPD is influenced by various prenatal, postnatal, and genetic factors. This study explored the connection between BPD and home oxygen therapy (HOT), and then we examined the association between HOT and a specific single-nucleotide polymorphism (SNP) in the hyaluronan and proteoglycan link protein 1 (HAPLN1) gene among premature Japanese infants. MATERIALS AND METHODS: Prenatal and postnatal data from 212 premature infants were collected and analyzed by four SNPs (rs975563, rs10942332, rs179851, and rs4703570) around HAPLN1 using the TaqMan polymerase chain reaction method. The clinical characteristics and genotype frequencies of HAPLN1 were assessed and compared between HOT and non-HOT groups. RESULTS: Individuals with AA/AC genotypes in the rs4703570 SNP exhibited significantly higher HOT rates at discharge than those with CC homozygotes (odds ratio, 1.20, 95% confidence interval, 1.07-1.35, p = .038). A logistic regression analysis determined that CC homozygotes in the rs4703570 SNP did not show a statistically significant independent association with HOT at discharge. CONCLUSIONS: Although our study did not reveal a correlation between HAPLN1 and the onset of BPD, we observed that individuals with CC homozygosity at the rs4703570 SNP exhibit a reduced risk of HOT.

Designing artificial circadian environments with multisensory cares for supporting preterm infants' growth in NICUs.

Previous studies suggest the importance of stable circadian environments for fetuses to achieve sound physiology and intrauterine development. This idea is also supported by epidemiological and animal studies, in which pregnant females exposed to repeated shifting of light-dark cycles had increased rates of reproductive abnormalities and adverse pregnancy outcomes. In response to such findings, artificial circadian environments with light-dark (LD) cycles have been introduced to NICUs to promote better physical development of preterm infants. Such LD cycles, however, may not be fully effective for preterm infants who are less than 30 weeks gestational age (WGA) since they are too premature to be adequately responsive to light. Instead, circadian rhythmicity of incubated preterm infants less than 30 WGA may be able to be developed through stimulation of the non-visual senses such as touch and sound.

Roles of values in the risk factors of passive suicide ideation among young adults in the US and Japan.

The present study examined how the importance of values and perceived value congruence with families, friends, and country would be associated with the risk factors of passive suicide ideation. Specifically, the study investigated the associations that the values and perceived congruence had with thwarted belongingness and perceived burdensomeness during the COVID-19 pandemic after controlling for the impact of depression levels. The data from the US and Japan demonstrated that the values such as cherishing family and friends and value congruence played a protective factor for Japanese participants; however, the associations differed among those in the US. Values such as enduring challenges played a protective factor for perceived burdensomeness in Japan whereas values such as cherishing family and friends played a protective factor and improving society was a risk factor for thwarted belongingness for those in the US. These results can be used to further understand the roles of values in mental health.

Bronchopulmonary Dysplasia in Extremely Premature Infants: A Scoping Review for Identifying Risk Factors.

BACKGROUND: Over the years, bronchopulmonary dysplasia (BPD) affects the pulmonary function of infants, resulting in chronic health burdens for infants and their families. The aim of this scoping review was to screen available evidence regarding perinatal risk factors associated with the development and severity of BPD. METHODS: The eligibility criteria of the studies were year of publication between 2016 and 2021; setting of a developed country; English or Japanese as the study language; and randomized controlled, cohort, or case-control design. The titles and abstracts of the studies were screened by independent reviewers. RESULTS: Of 8189 eligible studies, 3 were included for severe BPD and 26 were included for moderate BPD. The risk factors for severe BPD were male sex, iatrogenic preterm birth, maternal hypertensive disorders of pregnancy (HDP), low gestational age, small-for-gestational-age (SGA) birth weight, mechanical ventilation on day 1, and need for patent ductus arteriosus (PDA) management. The risk factors for moderate or severe BPD included male sex, premature rupture of membranes, clinical chorioamnionitis, maternal HDP, SGA birth weight, bubbly/cystic appearance on X-ray, and PDA management. CONCLUSIONS: We identified several risk factors for BPD. We plan to confirm the validity of the new classification using the existing dataset.

The status of chronic lung disease diagnosis in Japan: Secondary publication.

BACKGROUND: In Japan, the definition and classification of neonatal chronic lung disease (CLD) used for its diagnosis are a combination of those used in Japan and abroad. METHODS: To clarify the current state of CLD diagnosis, a questionnaire survey was conducted. RESULTS: Half of the patients of the medical centers included in the study were diagnosed with CLD in real time, while the other half were diagnosed after discharge. In addition, in approximately 70% of the facilities, diagnosis was made after discussions various among medical teams. In approximately 80% of the centers, the chest radiography used for CLD diagnosis were evaluated by multiple doctors. Furthermore, some centers used chest X-rays that were taken at approximately 28 days of age for CLD diagnosis, whereas at other facilities, diagnosis was made regardless of time at which the chest radiography were obtained. Only a small number of centers have established criteria for determining the necessity of oxygen at the corrected age of 36 weeks, and the target saturation of peripheral oxygen levels also tend to vary for each facility. Whether the conditions wherein the patient receives respiratory support for apnea or respiratory tract diseases should be considered as CLD also differed among the facilities. CONCLUSIONS: It is necessary to reassess the definition and classification of CLD in Japan to accurately evaluate and improve the quality of respiratory management based on the long-term prognosis.

[Factors associated with behaviors to prevent COVID-19 infection during the declaration of emergency: A study among Tokyo residents].

Objectives　The COVID-19 pandemic spread rapidly across the globe during the first half of 2020. In Japan, a state of emergency was declared on April 7, 2020, which had a significant impact on the life of citizens. This study focused on behaviors like avoiding going out or coming in contact with others and frequent hand-washing to prevent the infection and the spread of COVID-19 among people living in Tokyo. We also examined the factors associated with these behaviors during the declaration of emergency.Methods　An online survey was conducted from April 26 to 29, 2020, approximately 20 days after the declaration of the emergency, among men and women aged 20-69 years living in Tokyo. The study framework was based on the protection motivation theory, which explains the risk-reducing behaviors, and focus theory of normative conduct, which explains the effect of others' behavior on one's own behavior. The frequency of behaviors like avoiding going out or coming in contact with others and frequent hand-washing, as well as the perception of the risk of COVID-19 during the week preceding the survey, were assessed. Each preventive action was evaluated based on the following factors: perceived effectiveness (response efficacy), perceived practicability (self-efficacy), necessary cost (response cost), and perceptions of how much should be done (injunctive norm) and how well others are doing it (descriptive norm). Hierarchical multiple regression analysis with these behaviors as outcomes were performed.Results　This study included 1,034 participants (50.3% male, mean age 44.82 years, standard deviation 14.00 years). The analyses of the frequency of avoiding going out or coming in contact with others showed that the injunctive norm was positively associated with the behavior (standardized partial regression coefficient (ß)=0.343, P<0.001), while the descriptive norm was negatively associated with the behavior (ß=-0.074, P=0.010). Furthermore, the two-way interaction between risk perception, response efficacy, and self-efficacy was significant (ß=0.129, P<0.001), indicating that risk perception was positively associated with the behavior only when either response efficacy or self-efficacy was low. A similar analysis conducted for hand-washing behavior revealed that injunctive norm (ß=0.256, P<0.001) and response efficacy (ß=0.132, P<0.001) were positively associated with the behavior, while the response cost (ß=-0.193, P<0.001) was negatively associated with the behavior.Conclusion　Some variables in the protection motivation theory and the focus theory of normative conduct were related to the behavior for the prevention of COVID-19. The results suggest that the application of these theories is useful in future studies.

Detection of Pathologic Heart Murmurs Using a Piezoelectric Sensor.

This study aimed to evaluate the capability of a piezoelectric sensor to detect a heart murmur in patients with congenital heart defects. Heart sounds and murmurs were recorded using a piezoelectric sensor and an electronic stethoscope in healthy neonates (n = 9) and in neonates with systolic murmurs caused by congenital heart defects (n = 9) who were born at a hospital. Signal data were digitally filtered by high-pass filtering, and the envelope of the processed signals was calculated. The amplitudes of systolic murmurs were evaluated using the signal-to-noise ratio and compared between healthy neonates and those with congenital heart defects. In addition, the correlation between the amplitudes of systolic murmurs recorded by the piezoelectric sensor and electronic stethoscope was determined. The amplitudes of systolic murmurs detected by the piezoelectric sensor were significantly higher in neonates with congenital heart defects than in healthy neonates (p < 0.01). Systolic murmurs recorded by the piezoelectric sensor had a strong correlation with those recorded by the electronic stethoscope (ρ = 0.899 and p < 0.01, respectively). The piezoelectric sensor can detect heart murmurs objectively. Mechanical improvement and automatic analysis algorithms are expected to improve recording in the future.

Higher-order structure of polymer melt described by persistent homology.

The optimal method of the polymer Materials Informatics (MI) has not been developed because the amorphous nature of the higher-order structure affects these properties. We have now tried to develop the polymer MI's descriptor of the higher-order structure using persistent homology as the topological method. We have experimentally studied the influence of the MD simulation cell size as the higher-order structure of the polymer on its electrical properties important for a soft material sensor or actuator device. The all-atom MD simulation of the polymer has been calculated and the obtained atomic coordinate has been analyzed by the persistent homology. The change in the higher-order structure by different cell size simulations affects the dielectric constant, although these changes are not described by a radial distribution function (RDF). On the other hand, using the 2nd order persistent diagram (PD), it was found that when the cell size is small, the island-shaped distribution become smoother as the cell size increased. There is the same tendency for the condition of change in the monomer ratio, the polymer chain length or temperature. As a result, the persistent homology may express the higher-order structure generated by the MD simulation as a descriptor of the polymer MI.

Use of pleural cryobiopsy for tissue culture specimens: a case report.

A 43-year-old man presented with cough. His chest X-ray showed a left-sided pleural effusion. We suspected tuberculous pleurisy (TP), and thoracoscopy under local anaesthesia was performed. It showed entire pleura with scattered nodules. Nodules were biopsied by conventional biopsy forceps, but the tissue sample was small. Therefore, the nodules were biopsied with a cryoprobe. The tissue size obtained was 2 mm by conventional biopsy forceps, and 6 mm at 5 sec by cryobiopsy. Histological analysis of the conventional biopsy forceps and cryobiopsy specimen showed inflammation with lymphocytes and caseating granulomas. Tissue culture of conventional biopsy forceps was positive for Mycobacterium tuberculosis, and all sensitivity tests were positive. But, the tissue culture of the cryobiopsy sample was negative. There is a possibility that cryobiopsy is not useful for tissue culture for TP.

Peripheral tetrahydrobiopterin is involved in the pathogenesis of mechanical hypersensitivity in a rodent postsurgical pain model.

Because treatment for postsurgical pain (PSP) remains a major unmet medical need, the emergence of safe and innovative nonopioid drugs has been strongly coveted. Tetrahydrobiopterin (BH4) is an interesting molecule for gaining a better understanding the pathological mechanism of neuropathic pain. However, whether BH4 and its pathway are involved in the pathogenesis of PSP remains unclear. In this study, we found that early in a rat paw incision model, the gene expression of GTP cyclohydrolase 1 (GTPCH) and sepiapterin reductase (SPR), BH4-producing enzymes in the de novo pathway, were significantly increased in incised compared with naive paw skin. Although a significant increase in GTPCH protein levels was observed in incised paw skin until only 1 day after incision, a significant increase in BH4 levels was observed until 7 days after incision. In vivo, Spr-knockout mice showed an antinociceptive phenotype in the hind paw incision compared with the wild-type and Spr heterozygote groups. Furthermore, QM385, the SPR inhibitor, showed a significant dose-dependent, antinociceptive effect, which was supported by a reduction in BH4 levels in incised skin tissues, with no apparent adverse effects. Immunohistochemical analysis demonstrated that macrophages expressing GTPCH protein were increased around the injury site in the rat paw incision model. These results indicate that BH4 is involved in the pathogenesis of PSP, and that inhibition of the BH4 pathway could provide a new strategy for the treatment of acute PSP.

Study protocol for a nationwide questionnaire survey of physical activity among breast cancer survivors in Japan.

INTRODUCTION: A major concern is that few cancer survivors meet the guidelines for recommended levels of physical activity. No studies have investigated physical activity among breast cancer survivors nationwide in Japan. Therefore, the aims of this study are to identify the levels of physical activity among breast cancer survivors, to examine factors-related physical activity among breast cancer survivors and to identify breast cancer survivors' preferences for and interest in exercise programmes in order to inform the future programme development. METHODS AND ANALYSIS: We will administer a cross-sectional survey using a self-report questionnaire to breast cancer survivors. At each of 50 facilities selected to include a variety of institutional backgrounds according to the population distribution of different regions throughout Japan, we will consecutively distribute the questionnaire to 30 outpatients who have completed initial treatments, except for hormone therapy. The target sample size is 1500 survivors. We will calculate descriptive statistics for each measurement item and perform univariate and multivariate analyses using outcome measures (eg, physical activity and quality of life) related to physical, psychological, social and environmental factors. DISCUSSION: This is the first nationwide survey of physical activity levels among breast cancer survivors in Japan. Identifying the factors associated with physical activity will help us to develop, disseminate and implement programmes that encourage more survivors to adhere to physical activity guidelines. ETHICS AND DISSEMINATION: The protocol was approved by the Institutional Review Board (IRB) of the National Cancer Center on 11 January 2019 (ID: 2018-295). In addition, many of the participating facilities required ethical approval from their local IRBs, while others did not. Accordingly, approval from the local IRBs of individual facilities was obtained when required. The findings will be disseminated through peer-reviewed publications and conference presentations.

An Early-Onset Neuronopathic Form of Acid Sphingomyelinase Deficiency: A SMPD1 p.C133Y Mutation in the Saposin Domain of Acid Sphingomyelinase.

Acid sphingomyelinase (ASM) is a lysosomal hydrolase that degrades sphingomyelin into ceramide and phosphocholine. Recent crystallographic studies revealed the functional role of the N-terminal ASM saposin domain. ASM deficiency due to mutations in the ASM-encoding sphingomyelin phosphodiesterase 1 (SMPD1) gene causes an autosomal recessive sphingolipid-storage disorder, known as Niemann-Pick disease Type A (NPA) or Type B (NPB). NPA is an early-onset neuronopathic disorder, while NPB is a late-onset non-neuronopathic disorder. A homozygous one-base substitution (c.398G>A) of the SMPD1 gene was identified in an infant with NPA, diagnosed with complete loss of ASM activity in the patient's fibroblasts. This mutation is predicted to substitute tyrosine for cysteine at amino acid residue 133, abbreviated as p.C133Y. The patient showed developmental delay, hepatosplenomegaly and rapid neurological deterioration leading to death at the age of 3 years. To characterize p.C133Y, which may disrupt one of the three disulfide bonds of the N-terminal ASM saposin domain, we performed immunoblotting analysis to explore the expression of a mutant ASM protein in the patient's fibroblasts, showing that the protein was detected as a 70-kDa protein, similar to the wild-type ASM protein. Furthermore, transient expression of p.C133Y ASM protein in COS-7 cells indicated complete loss of ASM enzyme activity, despite that the p.C133Y ASM protein was properly localized to the lysosomes. These results suggest that the proper three-dimensional structure of saposin domain may be essential for ASM catalytic activity. Thus, p.C133Y is associated with complete loss of ASM activity even with stable protein expression and proper subcellular localization.

Bubbly and cystic appearance on chest radiograph of extremely preterm infants with bronchopulmonary dysplasia is associated with wheezing disorder.

AIM: Bubbly/cystic appearance on chest X-ray (CXR) is an important factor in cases of severe bronchopulmonary dysplasia (BPD). We aimed to determine whether CXR -based BPD classifications obtained in extremely preterm infants with oxygen dependency at 28 days after birth (BPD28) is associated with wheezing disorders. METHODS: This was a multicentre retrospective cohort study of population data from infants (body weight, <1500 g) enrolled in the Neonatal Research Network of Japan. Of the 15 480 infants born at <28 weeks of gestation between 2003 and 2012, 8979 met the BPD28 criteria, and 4007 were classified as the no BPD28 group. BPD28 infants were classified according to the bubbly/cystic or no bubbly/cystic appearance on CXR at postnatal ≧28 days. The effects on wheezing disorder at 3 years of age were analysed. RESULTS: Bubbly/cystic BPD28 infants showed higher rates of wheezing disorders compared with no BPD28 infants. Bubbly/cystic BPD28 (odds ratio 1.7; 95% confidence interval, 1.3-2.2) was a significant independent factor for wheezing disorders. CONCLUSION: A bubbly/cystic appearance on CXR with BPD28 was a potential risk factor of wheezing disorders at 3 years of age. This may be a useful early diagnostic tool at ≧28 postnatal days in extremely preterm infants.

Impact of chest radiography-based definition of bronchopulmonary dysplasia.

BACKGROUND: Bubbly/cystic appearance on chest radiograph is an important factor in severe-type bronchopulmonary dysplasia (BPD) in Japan. The aim of this study was to determine the perinatal characteristics and neonatal complications of the bubbly/cystic(+) group in extremely preterm infants with BPD, that is, oxygen dependency at day 28 after birth (BPD28). METHODS: This was a multicenter retrospective cohort study of population data from infants (birthweight, <1,500 g) enrolled in the Neonatal Research Network of Japan. Of the 15 480 infants born at <28 weeks' gestational age (GA) between 2003 and 2012, 8,979 met the BPD28 criteria. The BPD28 infants were classified according to bubbly/cystic appearance on radiograph (±) at >28 postnatal days. RESULTS: The bubbly/cystic(+) group had lower GA and birthweight and required longer mechanical ventilation and oxygen dependency than the bubbly/cystic(-) group. After adjustment for confounding factors, bubbly/cystic appearance was an independent risk factor for home oxygen therapy at discharge. CONCLUSION: Bubbly/cystic appearance on chest radiograph was a predictor of short-term respiratory outcomes in infants with BPD28, which is diagnosed much earlier (≥28 postnatal days), and has a potentially different etiology to BPD36 (oxygen and/or positive pressure respiratory support dependency at 36 weeks' postmenstrual age).

Discovery of a novel 2-(1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole derivative as an EP1 receptor antagonist and in vivo studies in a bone fracture model.

We describe a medicinal chemistry approach to the discovery of a novel EP1 antagonist exhibiting high potency and good pharmacokinetics. Our starting point is 1, an EP1 receptor antagonist that exhibits pharmacological efficacy in cystometry models following intravenous administration. Despite its good potency in vitro, the high lipophilicity of 1 is a concern in long-term in vivo studies. Further medicinal chemistry efforts identified 4 as an improved lead compound with good in vitro ADME profile applicable to long term in vivo studies. A rat fracture study was conducted with 4 for 4 weeks to validate its utility in bone fracture healing. The results suggest that this EP1 receptor antagonist stimulates callus formation and thus 4 has potential for enhancing fracture healing.