Macrophages (MФ) residing in the adipose tissue have garnered attention for their role in regulating adipocyte function and controlling systemic metabolism. These macrophages are typically classified into two subtypes, M1 and M2, based on their distinct functions. M1 MФ, whose counts are increased in obesity, originate from the bone marrow; they secrete pro-inflammatory cytokines and induce insulin resistance. In contrast, M2 MФ predominantly reside in the adipose tissue of non-obese individuals and secrete anti-inflammatory cytokines, such as interleukin-10 (IL-10), which are believed to play a role in maintaining insulin sensitivity. The widely accepted “phenotypic switch theory” posits that obesity induces a shift in macrophage polariztion, i.e., from the anti-inflammatory M2 phenotype to the inflammatory M1 phenotype. However, our 2017 study challenged this view. We generated transgenic mice where M2 MФ could be selectively eliminated at will and found that depletion of M2 MФ unexpectedly resulted in improved glucose tolerance and insulin resistance. This was associated with increased number of smaller adipocytes and enhanced proliferation of adipocyte progenitors. Using a mechanistic approach, we demonstrated that M2 MФ inhibit the proliferation and differentiation of adipocyte progenitors into mature adipocytes through the secretion of TGFβ, thereby preventing unnecessary cell division and cellular senescence, maintaining progenitor cell quality, and regulating both systemic obesity and insulin sensitivity. This study has prompted a revision of the traditional “phenotypic switch theory.” Additionally, our research revealed that the depletion of M2 MФ facilitates recovery from skeletal muscle injury by inducing the activation of fibro-adipogenic progenitors (FAPs), which are mesenchymal stem cell-like cells within the skeletal muscle, challenging the generally accepted view that M2 MФ play a more reparative role during the recovery phase of injury. These findings suggest that targeting M2 MФ and reducing TGFβ signaling could offer a therapeutic breakthrough, addressing both obesity-induced insulin resistance and sarcopenia in aging populations.

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　Pathogenesis of schizophrenia still remains to be elucidated, which limits its accurate diagnosis and efficacious treatment. Neuroimaging and other studies have revealed that the progressive brain changes such as cerebral gray matter loss occur during early stages of schizophrenia. The early intervention is critical to improve the long-term outcome of schizophrenia. In addition, it is desirable to develop more accurate methods for early diagnosis as well as novel treatments to prevent progressive brain pathology in the early stages of schizophrenia. Research strategy in subjects with clinical high-risk state for developing psychosis was described, and the current status and future perspective of the research in this field were summarized.

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　The goal of many observational studies in epidemiology and clinical epidemiology is to establish and quantify the magnitude of exposures and risk factors that have a causal relationship to health and social factors. In epidemiology and statistics, the methodology used to establish causal relationships is generally referred to as causal inference. I introduce triangulation, which has been attracting a topic in recent years as a method of causal inference in observational studies. Triangulation is a method to strengthen causal inference by integrating research results obtained from several different statistical approaches. This paper provided an overview of triangulation in epidemiology, its relation to Mendelian randomization analysis in genetic epidemiology studies, examples of studies, and discusses future developments.

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Background
　Majority of the patients with cancer are older in age. Although real-world registry data provide additional evidence to support cancer management, few such studies have been conducted in local Japanese areas. We analyzed hospital-based cancer registry data to reveal the present situation of older patients with non-small cell lung cancer in the Hokushin region.
Methods
　The Hokushin Ganpro database was constructed based on data from 21 hospitals engaged in cancer management in the Hokushin area from 2010 to 2015. We analyzed patient demographics, clinical stage, pathological histology, detection methods, and initial therapeutic options.
Results
　The total number of patients with non-small cell lung cancer was 13,721 with a median age of 72 years. The ratio of adenocarcinomas decreased with age, while that of squamous cell carcinomas increased.
　The proportion of medical check-ups decreased with age. The proportion of best supportive care alone in the initial therapeutic strategy increased with age.
Conclusion
　This is one of the few reports describing a large registry set of patients with non-small cell lung cancer in a Japanese local area. These data may help consider future strategies for cancer therapy in the older population residing in local areas of Japan.

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Background: Locomotive dysfunction, and neuropathy are often noted as risk factors for the declining quality of life (QOL), in the elder, with particular associations reported with impaired gait, lower limb muscle weakness, and balance dysfunction. However, there is a lack of clarity about the role of toe function in this regard. Therefore, this study investigated the relationships between toe function, lower limb muscle strength, and locomotive dysfunction in the elder.

Methods: Seventy elderly patients (45 males, 25 females; average age, 68.5±12.8 years) underwent physical assessment of bilateral toe function (using toe-gap force and “rock-paper-scissors” exercise), lower limb muscle strength (using manual muscle testing [MMT]), and balance (using the static standing balance [SSB]) test and the 3m-timed up and go [3m-TUG] test).

Results: The average toe-gap force was 2.5±2.0kg in the right leg and 2.1±1.6kg in the left foot. The toe-gap force was significantly associated with the total MMT score (right: p<0.001; left: p<0.05) and the SSB test (right: r=0.574, p<0.001; left: r=0.415, p<0.001). However, it was not associated with the rock-paper-scissors exercise of the toes, and the total MMT score was correlated with the 3m-TUG time (lower limb: p<0.001, foot: p<0.05).

Conclusion: Toe-gap force is associated with lower limb muscle strength and SSB time. Therefore, training for toe-gap force might help improve lower limb function and enhance QOL in the elder.

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　The prefrontal cortex integrates inputs from multiple brain regions, and sleep consolidates memories through synchronized activity between these regions. However, conventional methods have difficulty in extracting the dynamics of inter-regional circuits from complex neural networks. This study aimed to establish a multi-fiber photometry system for freely moving mice to measure the integration of information from multiple brain regions in the prefrontal cortex during learning and sleep. Using retrograde adeno-associated virus, genetically encoded Ca²⁺ indicators were expressed in neurons projecting to the prefrontal cortex. The activity of neurons projecting to the prefrontal cortex was observed in four cortical sub-regions, the thalamus, amygdala, and hippocampus, all involved in emotional memory. Electric shock during fear conditioning activated multiple brain regions. Some pairs of brain regions exhibited more synchronized activity during wakefulness, while others showed greater synchronization during sleep. Multi-fiber photometry can contribute to understanding the integration of information across brain regions through direct circuits in a brain state-dependent manner.

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［Background］Pulmonary pleomorphic carcinoma is a rare type of tumor, accounting for less than 1% of all lung cancer cases. ［Case］A 68-year-old woman visited a hospital for an examination of a tumor in her left upper lobe. Although lung cancer was suspected, several transbronchial biopsies did not reveal significant findings. Subsequently, she developed left upper lobe atelectasis and respiratory failure. A mucus plug was aspirated from the upper left segment by bronchoscopy, and adenocarcinoma cells floating solitarily within the mucus were detected by cytology. Owing to repeated airway obstruction, a left pneumonectomy was performed, and the patient was diagnosed as having pulmonary pleomorphic carcinoma. An epidermal growth factor gene mutation and anaplastic lymphoma kinase fusion gene were not detected. ［Conclusion］Lung cancer presenting with abundant mucinous production is often difficult to diagnose by bronchoscopy using small specimens and may require surgical resection.

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　Skin flaps are commonly used for reconstruction to restore function and esthetics following oral cancer resection. Reportedly, malignant tumors may originate within skin flaps, although this is extremely rare. We report a case of squamous cell carcinoma (SCC) that originated in a forearm skin flap used for reconstruction following buccal carcinoma resection.
　A 58-year-old man with left buccal SCC (cT3N2bM0) was referred to our hospital. The patient had a history of resection of cancerous buccal mucosa, left-sided neck dissection, and reconstruction using a forearm flap and developed flap erosion 8 years postoperatively. Biopsy revealed SCC, and the lesion was resected. To date, the patient has had no recurrence 3 years postoperatively.
　In this case, the tumor was confined to the epidermis and dermis at the central part of the skin flap and was clinically diagnosed as a primary carcinoma of the skin flap. Genetic testing revealed shared mutational identity between the primary tumor and the tumor that originated from the forearm skin flap. Therefore, we conclude that both tumors were genetically associated and perhaps had a common origin.

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