Atopic dermatitis is characterized by three factors: decreased skin barrier function, type 2 immune response, and itching. In recent years, the elucidation of the pathological condition of atopic dermatitis has progressed from the immunological aspect. Type 2 cytokines, such as interleukin (IL)-4 and IL-13, produced from cells such as Th2 cells and type 2 innate lymphocytes, play a crucial role in the lesion areas of atopic dermatitis. These type 2 cytokines decrease the antibacterial peptide levels, weaken the barrier of epidermal keratinocytes, and induce inflammation. Currently, antibody preparations that suppress targeted cytokines, Janus kinase (JAK) inhibitors that inhibit the JAK-signal transducer and activator of transcription pathway and system, and anti-Phosphodiesterase 4 inhibitors, developed based on the pathological condition of atopic dermatitis, are available. The existing topical drug therapies are the anticipated treatment methods for refractory atopic dermatitis affecting children and adults.

This report is a secondary publication of my previous review report "J Tokyo Wom Med Univ (in Japanese). 2024;94 (2): 35-40".

In recent years, osteoporosis has become a significant issue in developed countries. Romosozumab, which was introduced in 2019, is a relatively novel drug used for osteoporosis treatment. In particular, it can enhance bone mineral density and has new fracture inhibitory effects. Hypocalcemia is a contraindication to romosozumab. The drug should also be administered with caution in patients at high risk of cardiovascular disorders. To maximize its effect, it is better to use romosozumab before starting other osteoporosis medications. Currently, there are no clinical reports on the ability of romosozumab to promote fracture healing. With the use of this drug in combination with others, we can treat as many patients with osteoporosis as possible.

This article is based on our study first reported in the Journal of Tokyo Women's Medical University (in Japanese), 2024; 94 (4):71-5.

Natriuretic peptides are among the most important discoveries in cardiovascular medicine, revealing the endocrine properties of the heart. Natriuretic peptides are activated in heart failure (HF) and play important cardioprotective roles. Atrial and brain natriuretic peptides are abundantly expressed and secreted in the atria and ventricles, respectively. They exert antagonistic effects on angiotensin II by inhibiting aldosterone secretion and exerting diuretic, natriuretic, and vasodilatory effects. Identifying natriuretic peptides has led to a burgeoning field of research characterizing their physiological roles in cardiovascular homeostasis and disease and their potential as biomarkers and therapeutic agents. Carperitide and sacubitril/valsartan effectively treat HF by modulating the physiological effects of natriuretic peptides. Understanding the role of natriuretic peptides in maintaining cardiovascular homeostasis and their pathophysiological significance in the development and progression of HF is fundamental for understanding the clinical relevance of natriuretic peptides in developing diagnostic and therapeutic agents for HF.

This article is based on our study first reported in the "J Tokyo Wom Med Univ (in Japanese). 2024; 94 (3): 55-63."

Modern Western legal theories are based on the idea that "people" generally refer to males. Consequently, modern civil law ensured that men were treated equally and acted freely in public spheres. However, women were confined to the private sphere (home). Under a male-dominated legal system, women are considered inferior and face persistent challenges in securing equal rights. This was evident in the struggles of Ginko Ogino, Japan's first female doctor, to qualify for the national medical exam and in the efforts of Yayoi Yoshioka, founder of Tokyo Women's Medical University. This paper reviews the history of male chauvinism in Japan. Based on the understanding that gender bias is a barrier to the career progression of female medical professionals, we discuss the significance of increasing the number of female doctors to help improve medical services and benefit society more broadly. We also review the efforts of Tokyo Women's Medical University to support the development and advancement of female medical professionals.

Background: Hypotension during general anesthesia increases perioperative morbidity and mortality. Sensitivity to sevoflurane anesthesia is reduced in mice deficient in guanylate cyclase-1, suggesting nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway involvement. Here, we investigated whether sevoflurane induces hypotension via NO-cGMP activation.

Methods: Blood pressure, heart rate, and temperature were monitored in telemetry-implanted, spontaneously breathing male Sprague-Dawley rats during sevoflurane administration at 2.0% or 4.5% (20 min). Sevoflurane was administered to the intubated and mechanically ventilated rats and cardiac blood was withdrawn. Plasma and erythrocytic nitrite/nitrate and cGMP levels were measured using high-performance liquid chromatography and enzyme-linked immunosorbent assays, respectively.

Results: Hypotension was induced in a concentration-dependent manner, and increases in heart rate were more pronounced with 2.0% sevoflurane than with 4.5%. Plasma nitrate levels were significantly higher with 2.0% than 4.5% (14.1 ± 2.7 μM vs. 10.7 ± 1.0 μM; p = 0.03). No differences in nitrite or cGMP were observed between the two groups.

Conclusions: Sevoflurane's hypotensive effects are accompanied by increases in plasma nitrate levels, which is indicative of systemic NO generation. However, the lack of changes in circulating nitrite/cGMP levels implies that sevoflurane-induced hypotension also involves NO-cGMP-independent pathways. Further studies need to elucidate the underlying mechanisms.

Background: The in vitro human skeletal muscle model is a valuable tool for studying muscle physiology and mechanisms underlying muscle diseases. Our previous work demonstrated that a tissue-engineering approach could produce contractile human muscle tissue, with electrical pulse stimulation (EPS) enhancing its contractility. However, challenges remain in achieving maturation levels that closely mimic native muscles.

Methods: We performed contractility analysis and mRNA sequencing of muscle tissues subjected to different EPS-induced exercise protocols and antioxidant supplementation.

Results: Although an appropriate amount of EPS enhanced contractility, excessive EPS caused tissue damage and reduced functionality. Both types of EPS promoted extracellular matrix reconstitution, skeletal muscle tissue development, oxidative stress response, and myokine production. However, specific genes, including ACTN3, were differentially expressed. EPS also led to hydrogen peroxide accumulation in the medium. The contractility assays and transcriptomic profiles suggested that the negative effects of accumulated hydrogen peroxide were mitigated by catalase supplementation. Although catalase effectively degraded extracellular hydrogen peroxide, transcriptomic data indicated that the intracellular oxidative stress caused by excessive EPS still negatively affected tissue maturation.

Conclusion: These findings highlight the need to optimize EPS-induced exercise protocols, balancing extracellular and intracellular oxidative stress to improve the maturation of in vitro muscle tissue.

Background: Kidney transplantation (KT) is an effective treatment for end-stage renal disease. The demand for living-donor kidney transplantation (LDKT) in the elderly is increasing in Japan. However, evidence of long-term outcomes remains limited. This study aimed to investigate long-term graft survival in elderly donors.

Methods: This retrospective cohort study, conducted as part of the Japan Academic Consortium of Kidney Transplantation, analyzed data from 933 adult LDKT recipients between 1995 and 2011. Recipients were categorized by age at LDKT as follows: < 64, 65-69, and > 70 years. The primary outcomes were graft loss (not censored for death) and recipient survival (death with a functioning graft). Statistical analyses included Kaplan-Meier survival curves and log-rank tests.

Results: The 10-year graft survival rates were 86.3%, 77.7%, and 68.1% for donors aged < 64, 65-69, and > 70 years, respectively (p < 0.001). However, the recipient 10-year survival rates were comparable across the groups.

Conclusions: Although advanced donor age was associated with lower graft survival, long-term recipient outcomes remained favorable. Compared to dialysis, elderly LDKT provides significantly better survival outcomes, making it an acceptable option amid Japan's prolonged donor shortage.

This study was approved by the Ethics Review Committee of Tokyo Women's Medical University (Approval No. #3366) and registered with the University Hospital Medical Information Network (UMIN000018327).

Background: Conventional diagnoses of neuromuscular disorders (NMD) are insufficient for patients with absent or atypical symptoms. However, genetic diagnosis provides individualized insights for treatment and management. This study aimed to establish definitive diagnoses using next-generation sequencing (NGS) and to implement clinical management. This study also examines important considerations in NGS analyses.

Methods: Targeted sequencing with the NMD panel was performed for 21 undiagnosed cases, followed by comprehensive NGS analysis using the clinical exome sequencing panel.

Results: A girl with fukutin (FKTN) pathogenic variants and a boy with a dystrophin (DMD) pathogenic variant were genetically diagnosed with dilated cardiomyopathy (DCM) and underwent strict management by pediatric cardiologists. The oldest reported case of a bcl-2-associated athanogene-3 (BAG3) pathogenic variant was diagnosed with myofibrillar myopathy 6. A man with mild symptoms was diagnosed with congenital myasthenic syndrome 7A due to a synaptotagmin 2 (SYT2) pathogenic variant, which showed potential for treatment. A patient with nemaline myopathy 2, caused by nebulin (NEB) pathogenic variants, is under respiratory monitoring.

Conclusions: In presymptomatic or atypical cases, a definitive diagnosis was achieved using clinical information, conventional testing, and NGS analysis, and specific clinical management strategies were developed. Individualized interventions, including revisiting conventional testing based on NGS findings, are useful.

Background: We previously developed a rapid three-dimensional (3-D) tissue fabrication method using centrifugation. In this study, we fabricated 3-D HepG2 liver tissues using a scaffold-free centrifugation method and analyzed them biochemically.

Methods: We investigated the conditions for fabricating HepG2 tissues by varying the number of seeded cells (1.25-20 × 10⁶ cells/169 mm²). After two days of cultivation, cultured tissue cross-sections were examined. In addition, HepG2 tissues were cultured for an extended period (10 days), and biochemical metabolic analyses were performed.

Results: Thick HepG2 tissue was rapidly fabricated by centrifugation. Optical coherence tomography observations indicated that tissue thickness increased with a higher number of seeded cells. However, after two days of cultivation, biochemical analyses and observations of the paraffin section indicated that tissues fabricated with over 5.0 × 10⁶ cells were weak and damaged. However, the liver tissues fabricated using 1.25-2.5 × 10⁶ cells were compact with high cell density. HepG2 tissue was cultured for 10 days; however, albumin production remained minimal.

Conclusion: This study established optimal conditions for the rapid fabrication of HepG2 liver tissue. The proposed method holds significant potential for advancing liver tissue engineering and hepatocyte biology.

Purpose: The ability of large language models (LLMs) to determine the tumor, node, and metastasis (TNM) classification of cancer from radiological reports based on simple prediction is limited. This study aimed to evaluate the performance of a reasoning language model (RLM)-an LLM with critical thinking, logical deduction, and multi-step reasoning-in identifying the TNM classification of cancer from unstructured radiological reports.

Materials and Methods: We retrospectively screened 100 consecutive radiology reports, written in Japanese, from computed tomography (CT) scans for pancreatic cancer conducted between April 2020 and June 2022. The cohort included 62 male and 38 female patients, with a mean age of 70.3 ± 10.8 years. OpenAI o1, the first RLM, was used to classify the TNM staging from the radiology reports based on the General Rules for the Study of Pancreatic Cancer, seventh edition. The accuracy and kappa coefficients of the TNM classifications by o1 were assessed and compared with the evaluations of two board-certified radiologists.

Results: The accuracy values for T, N, and M classification were 0.87, 0.99, and 0.97, respectively. The corresponding kappa coefficients were 0.74, 0.97, and 0.93.

Conclusions: The reasoning language model accurately determined the TNM classification for pancreatic cancer from unstructured Japanese radiology reports.

Background: Salubrinal, which inhibits the dephosphorylation of eukaryotic translation initiation factor 2 subunit α (eIF2α), protects against cadmium toxicity. However, the underlying mechanisms of salubrinal concerning endoplasmic reticulum (ER) stress and autophagy in SH-SY5Y human neuroblastoma cells following exposure to cadmium remain unknown.

Methods: Cells were exposed to 1.0 μmol/L CdCl₂ and 10 μmol/L salubrinal for 24 h. Cytotoxicity was evaluated using WST-8 assays. ER stress- and autophagy-related genes were analyzed by PCR and immunoblotting. To evaluate lysosomal pH and autophagosome formation, fluorescence signals were detected using confocal laser scanning microscopy. Flux assays were performed to distinguish autophagic impairment from autophagic activation.

Results: Salubrinal suppressed cadmium-induced cell death. Treatment with salubrinal led to increased levels of phosphorylated eIF2α and GRP78 and a decrease in the mRNA level of CHOP in cadmium-exposed cells. p62 and LC3B-II levels increased in cells treated with both cadmium and salubrinal. Flux assays revealed that the increase in LC3B-II expression was impaired by treatment with cadmium and enhanced by salubrinal treatment.

Conclusions: Salubrinal suppressed cadmium-induced CHOP expression and activated autophagic flux, thereby promoting cell survival.