KEIO JOURNAL OF MEDICINE最新文献

The hair follicle is an appendage of the skin that undergoes hair cycles throughout life. Recently, numerous genes expressed in the hair follicles have been identified, and variants in some of these genes are now known to underlie hereditary hair diseases in humans. Hereditary hair diseases are classified into non-syndromic and syndromic forms. In the Japanese population, the non-syndromic form of autosomal recessive woolly hair, which is caused by founder pathogenic variants in the lipase H (LIPH) gene, is the most prevalent hereditary hair disease. In addition, other types of hereditary hair diseases are known in Japan, such as Marie-Unna hereditary hypotrichosis, hypohidrotic ectodermal dysplasia, and tricho-rhino-phalangeal syndrome. To ensure correct diagnoses and appropriate patient care, dermatologists must understand the characteristics of each hair disorder. Elucidation of the molecular basis of hereditary hair diseases can directly tell us which genes are crucial for morphogenesis and development of hair follicles in humans. Therefore, continuation of "wet laboratory" research for these diseases remains important. To date, several syndromic forms of hereditary hair diseases have been approved as designated intractable diseases in Japan. As part of our efforts in the Project for Research on Intractable Diseases through the Ministry of Health, Labour, and Welfare of Japan, we anticipate that more hereditary hair diseases be recognized as designated intractable diseases in the future, which will be to the benefit of the affected individuals.

Our Research Group for Rare and Intractable Skin Diseases operates within the Project for Research on Intractable Diseases of the Ministry of Health, Labour, and Welfare of Japan and is conducting research on eight rare intractable skin diseases. Five of these are monogenic disorders (epidermolysis bullosa, congenital ichthyoses, oculocutaneous albinism, pseudoxanthoma elasticum, and hereditary angioedema), and for a sixth [generalized pustular psoriasis (GPP)], genetic predisposing factors are important. This review introduces our activities for raising public awareness of these six intractable hereditary skin diseases and summarizes our recent achievements in clarifying the situation of medical treatments for these diseases in Japan. We note our current progress in elucidating the pathogeneses of these diseases and in developing new treatment methods, and we discuss our progress in establishing clinical practice guidelines. A nationwide survey on epidermolysis bullosa and a clinical survey on congenital ichthyoses are progressing. The Angioedema Activity Score and the Angioedema Quality-of-Life Questionnaire, the latter of which is a quality-of-life evaluation tool, have been established for hereditary angioedema. Registries of patients with oculocutaneous albinism and pseudoxanthoma elasticum have been created, and the registry for the latter has achieved its target of 170 cases. For GPP, the results of our survey on clinical practice were published in 2021. Information regarding all six of these hereditary skin diseases has been disseminated to academic societies, medical professionals, patients, and the general public.

A 75-year-old man underwent distal gastrectomy for advanced gastric cancer in September 2018. During the adjuvant chemotherapy, computed tomography (CT) revealed recurrence sites in the liver and para-aortic lymph nodes. Therefore, chemotherapy was initiated. After first-line (capecitabine with oxaliplatin) and second-line (paclitaxel with ramucirumab) treatments, nivolumab was used as third-line chemotherapy. This treatment showed a strong effect against the tumor. However, following an immune-related adverse effect (irAE) because of nivolumab, the therapy was halted. The irAE was diagnosed with central adrenal insufficiency that was controllable by oral intake of steroids. CPT-11 was started and showed a similarly strong effect to that observed for nivolumab. Eventually, the recurrent tumor lesions became too small to be detected by CT. We discontinued CPT-11 at the request of the patient. Even after discontinuation, no recurrent sites have been observed, allowing us to declare a case of clinical complete response (cCR). In conclusion, even if irAEs occur in a patient, continuing chemotherapy should be considered. However, if cCR is achieved, discontinuation of chemotherapy might be a strategic treatment option.

The standard method for sleep state classification is thresholding the amplitudes of electroencephalography (EEG) and electromyography (EMG) data, followed by manual correction by an expert. Although popular, this method has some shortcomings: (1) the time-consuming manual correction by human experts is sometimes a bottleneck hindering sleep studies, (2) EEG electrodes on the skull interfere with wide-field imaging of the cortical activity of a head-fixed mouse under a microscope, (3) invasive surgery to fix the electrodes on the thin mouse skull risks brain tissue injury, and (4) metal electrodes for EEG and EMG recording are difficult to apply to some experimental apparatus such as that for functional magnetic resonance imaging. To overcome these shortcomings, we propose a pupil dynamics-based vigilance state classification method for a head-fixed mouse using a long short-term memory (LSTM) model, a variant of a recurrent neural network, for multi-class labeling of NREM, REM, and WAKE states. For supervisory hypnography, EEG and EMG recording were performed on head-fixed mice. This setup was combined with left eye pupillometry using a USB camera and a markerless tracking toolbox, DeepLabCut. Our open-source LSTM model with feature inputs of pupil diameter, pupil location, pupil velocity, and eyelid opening for 10 s at a 10 Hz sampling rate achieved vigilance state estimation with a higher classification performance (macro F1 score, 0.77; accuracy, 86%) than a feed-forward neural network. Findings from a diverse range of pupillary dynamics implied possible subdivision of the vigilance states defined by EEG and EMG. Pupil dynamics-based hypnography can expand the scope of alternatives for sleep stage scoring of head-fixed mice.

Inflammatory bowel diseases (IBD) are currently recognized to involve chronic intestinal inflammation in genetically susceptible individuals. Patients with IBD mainly develop gastrointestinal inflammation, but it is sometimes accompanied by extraintestinal manifestations such as arthritis, erythema nodosum, episcleritis, pyoderma gangrenosum, uveitis, and primary sclerosing cholangitis. These clinical aspects imply the importance of interorgan networks in IBD. In the gastrointestinal tract, immune cells are influenced by multiple local environmental factors including microbiota, dietary environment, and intercellular networks, which further alter molecular networks in immune cells. Therefore, deciphering networks at interorgan, intercellular, and intracellular levels should help to obtain a comprehensive understanding of IBD. This review focuses on the intestinal immune system, which governs the physiological and pathological functions of the digestive system in harmony with the other organs.

Patients with tracheostomy who undergo a full sternotomy have an increased risk of mediastinitis and sternal infection. This report describes a reoperative aortic valve replacement (re-AVR) for structural valve deterioration (SVD) through a lower hemisternotomy. This procedure was performed on a 71-year-old man with a tracheostomy who had previously undergone a Bentall procedure with a bioprosthetic valve to replace an enlarged ascending aortic aneurysm. Comorbidities included chronic renal failure requiring hemodialysis. Fourteen months after the Bentall procedure, the patient presented with sudden dyspnea and was transferred to another hospital. Upon suffering acute heart failure, the patient required mechanical ventilation and was transferred to our hospital for intubation. The patient subsequently developed severe pneumonia. As a result of prolonged ventilation, the patient underwent tracheostomy and was administered antibiotic medication (piperacillin/tazobactam) for pneumonia. Echocardiography revealed severe aortic regurgitation caused by SVD. There was a risk that a full sternotomy in a patient with tracheostomy could cause mediastinitis; therefore, we performed a re-AVR through a lower hemisternotomy (second T incision). The re-AVR surgery proceeded without complications, and the bioprosthetic valve was removed while preserving the vascular graft from the previous Bentall procedure. The postoperative course was uneventful, and the patient was discharged from hospital 31 days after the tracheostomy was closed. The success of this procedure demonstrates the viability of re-AVR through a lower hemisternotomy in patients with SVD who are at risk of additional surgical complications.

Food protein-induced enterocolitis syndrome (FPIES) is a type of non-IgE-mediated gastrointestinal food allergy. FPIES is characterized by repetitive vomiting without classic IgE-mediated allergic skin or respiratory symptoms 1-4 h after causative food ingestion. The condition may be classified as acute or chronic, typical or atypical, and liquid or solid according to the course of symptoms, presence of IgE antibodies, and causative food, respectively. Since the development of international consensus guidelines in 2017, epidemiological studies have been conducted in many countries. FPIES is a relatively rare disease, with a prevalence of 0.015%-0.7%. However, the number of patients has been increasing in recent years. Most patients develop the disease in infancy. The natural history of FPIES is generally favorable, with most FPIES cases resolving before school age. FPIES is diagnosed using symptoms such as vomiting or diarrhea, or via an oral food challenge (OFC). Currently, no validated biomarker is available for diagnosis, and the mechanisms related to gastrointestinal manifestations and immune system involved in the development of FPIES have not yet been elucidated. Treatment with intravenous fluids and ondansetron is recommended in the acute phase. Long-term management consists of complete causative food elimination and periodic OFC to confirm tolerance. Given that many diagnoses are delayed because of a lack of awareness of the condition, FPIES must be widely recognized by healthcare providers. In the future, it is expected that FPIES pathogenesis will be further clarified, and more objective diagnostic criteria will be developed.

This study investigated lifestyle changes and the self-reported mental health status of Japanese community residents during the COVID-19 pandemic. Differences in demography, daily lifestyle changes, and approaches to problem solving were analyzed in two age cohorts (<60 vs ≥60 years). The prevalence of moderate/increased psychological distress was 31.7%, with no significant difference between the cohorts. Compared with the pre-COVID-19 era, more than 80% of the participants stopped eating out and spent more time at home, and more than 70% used public transport less frequently. There were significant differences between the cohorts for the time spent at home, opportunities to eat meals outside of home, and shopping in stores. Participants aged under 60 years were less likely to use television and newspapers or to consult a family doctor. Those aged over 60 years were less likely to consult friends/colleagues or to use the Internet/social networking services. Identifying the risk factors for psychological distress is warranted for implementing measures to maintain and improve the physical and mental health of residents.

Emerging infections are caused when microorganisms that are maintained in a reservoir where they cause no harm, transmit from the reservoir to a new host. I have been studying the replication, molecular basis for pathogenesis, and host responses to emerging viruses, including influenza virus, Ebola virus, and SARS-CoV-2, and using the knowledge gained from these studies to develop antivirals and vaccines.Influenza viruses cause epidemics every winter, but occasionally new influenza viruses emerge and spread worldwide (pandemic). We established a technique that allows us to make influenza viruses artificially. This technique is now widely used for basic research and for the development of vaccines against highly pathogenic avian influenza virus for pandemic preparedness and live attenuated influenza vaccines. Using this technique, we elucidated the mechanisms of emergence of pandemic viruses, viral replication, and the molecular mechanism of pathogenesis.Ebola virus causes severe disease with a mortality rate of up to 90%. In 2013, a major outbreak of Ebola virus began in West Africa that led to nearly 30,000 people being infected and a death toll of over 10,000 people. During the outbreak, we established a laboratory in Sierra Leone and used samples from Ebola patients to study host responses and identify biomarkers for severe infection. We also established a technology to artificially make Ebola virus and used this technology to make an Ebola virus that grows only in a particular cell line. Using this virus, we produced an inactivated Ebola vaccine, which was shown to be safe and effective in a Phase I clinical trial.Late in 2019, SARS-CoV-2 emerged in Wuhan, China and has since caused unprecedented damage globally. In our laboratory, we established an animal model for this infection and have used it to evaluate pathogenicity, efficacy of therapeutic monoclonal antibodies and antivirals, and to develop vaccines.In my presentation, I will discuss our findings regarding these emerging viral infections.

Virtual reality (VR) is emerging as a groundbreaking tool in the treatment of congenital heart diseases. This innovative technology offers a transformative approach by creating immersive, interactive, and personalized environments for both patients and healthcare professionals. In the pediatric cardiology institute in Safra Children's hospital in Sheba Medical Center in Israel, VR is being utilized for patient education, pre-operative planning, and intraoperative guidance. Patients can explore 3D visualizations of their own hearts, gaining a better understanding of their condition and proposed treatments. Surgeons and medical teams benefit from VR simulations that enhance their surgical planning and decision-making processes observing complex cases and evaluating printed models. Furthermore, Augmented reality AR can be employed in the operating room for observing the rib cage and reviewing the patient anatomy. The 3D visualization program is led by the Engineering in Medicine (EiM) tech-lab which cooperates with different specialties in the hospital including plastic surgery, ENT, ObGyn and more. The most critical topic addressed by the lab, cooperating with engineers from the Israeli Institute of technology deals with registration of the holographic image on the real patient body allowing intra-operative guidance. (Presented at the 2008th Meeting, September 27, 2023).