KEIO JOURNAL OF MEDICINE最新文献

Patients with spinal deformities, both adolescents and adults, often experience pulmonary symptoms such as shortness of breath during physical exertion and reduced exercise tolerance. These symptoms significantly affect their daily functioning, and recent research by Van Kempen et al. (2022) involving 8,723 AIS patients found that declines in pulmonary function tests (PFTs) were linked to the severity of their spinal deformities.However, these clinically relevant pulmonary symptoms are not routinely monitored, which could have health implications as patients age, given the gradual deterioration of pulmonary function associated with the severity of their spinal deformities. PFTs have been used to quantify these symptoms, but a discrepancy exists between these objective measurements and the subjective experiences of patients, reducing their clinical value. To address this gap, patient-reported outcome measures (PROMs) capturing the patient's perspective are needed but are currently lacking.The presentation outlines ongoing efforts to rectify this situation, with a focus on measuring pulmonary function and exercise tolerance through structured patient interviews, the use of smart vests with sensors, and the development of a patient-reported outcome measure (PROM). These endeavors aim to improve the monitoring and management of pulmonary symptoms in spinal deformity patients, ultimately enhancing their quality of life and long-term health. (Presented at the 2009st Meeting, November 8, 2023).

The quest to cure cancer has been one of the Holy Grails of medicine. The discovery I am going to share with you, CAR T cells, is a promising new form of therapy of cancer that offers the prospect of curing cancer using the immune system. CAR T cells are the first form of synthetic biology to enter the practice of medicine. The notion of using the immune system to fight cancer is an old idea. Over a century ago, bacteria were ground up and injected into patients with late-stage cancers, and occasionally the cancer would disappear. However, we now have precise tools for genetic editing and gene insertion like CRISPR/Cas9 to rewrite the DNA code, offering the possibility to improve the immune system over what has evolved in a Darwinian fashion. In 2017 for the first time, CAR T cells were approved for the treatment of cancer. Today they are used worldwide in more than 15,000 patients and they offer the promise to move beyond cancer to other fields of medicine such as autoimmune disease and heart disease. Here I will discuss the promises and challenges faced by the evolving CAR T cell industry.

Our understanding of the biology of the intestinal epithelium has advanced since the establishment of an organoid culture system. Although organoids have enabled investigation of the mechanism of self-renewal of human intestinal stem cells in vitro, it remains difficult to clarify the behavior of human normal and diseased intestinal epithelium in vivo. Recently, we developed a xenotransplantation system in which human intestinal organoids are engrafted onto epithelium-depleted mouse colons. This xenograft recapitulated the original tissue structures. Upon xenotransplantation, normal colon organoids developed normal colon crypt structures without tumorigenesis, whereas tumor-derived organoids formed colonic tumors resembling the original tumors. The non-tumorigenicity of human intestinal organoids highlights the safety of organoid-based regenerative medicine. As an example of regenerative medicine for short bowel syndrome, we devised a unique organ-repurposing approach to convert colons into small intestines by organoid transplantation. In this approach, the transplanted rat small intestinal organoids not only engrafted onto the rat colons but also remodeled the colon subepithelial structures into a small intestine-like conformation. Luminal flow accelerated the maturation of villi in the small intestine, which promoted the formation of a lymphovascular network mimicking lacteals. In this review, we provide an overview of recent advances in gastrointestinal organoid transplantation and share our understanding of human disease biology and regenerative medicine derived from these studies.

Because recovery from upper limb paralysis after stroke is challenging, compensatory approaches have been the main focus of upper limb rehabilitation. However, based on fundamental and clinical research indicating that the brain has a far greater potential for plastic change than previously thought, functional restorative approaches have become increasingly common. Among such interventions, constraint-induced movement therapy, task-specific training, robotic therapy, neuromuscular electrical stimulation (NMES), mental practice, mirror therapy, and bilateral arm training are recommended in recently published stroke guidelines. For severe upper limb paralysis, however, no effective therapy has yet been established. Against this background, there is growing interest in applying brain-machine interface (BMI) technologies to upper limb rehabilitation. Increasing numbers of randomized controlled trials have demonstrated the effectiveness of BMI neurorehabilitation, and several meta-analyses have shown medium to large effect sizes with BMI therapy. Subgroup analyses indicate higher intervention effects in the subacute group than the chronic group, when using movement attempts as the BMI-training trigger task rather than using motor imagery, and using NMES as the external device compared with using other devices. The Keio BMI team has developed an electroencephalography-based neurorehabilitation system and has published clinical and basic studies demonstrating its effectiveness and neurophysiological mechanisms. For its wider clinical application, the positioning of BMI therapy in upper limb rehabilitation needs to be clarified, BMI needs to be commercialized as an easy-to-use and cost-effective medical device, and training systems for rehabilitation professionals need to be developed. A technological breakthrough enabling selective modulation of neural circuits is also needed.

Pluripotent stem cells (PSCs), which include embryonic stem cells and induced pluripotent stem cells, have the potential for unlimited self-renewal and proliferation and the ability to differentiate into all three embryonic germ layers. Human PSCs (hPSCs) are used in drug discovery screening, disease models, and regenerative medicine. These cells maintain a transcriptional regulatory network based on a set of unique transcription factors to maintain their stem cell properties. Downstream of such transcriptional regulatory networks, various stem cell-specific metabolic programs are used to produce energy and metabolites as necessary. hPSCs and differentiated cells utilize different metabolic programs for self-renewal ability and maintenance of quiescence. Understanding the different metabolic features of hPSCs and differentiated cells can contribute to the development of technologies that are useful for regenerative medicine, such as the purification of differentiated cells. This review describes the unique metabolic programs active in hPSCs and their differences from somatic cells, with a focus on cardiomyocytes.

The early diagnosis of central nervous system infections is of great importance to minimize morbidity and mortality. Neurogranin is a postsynaptic neural protein, and when the blood-brain barrier is damaged, neurogranin levels increase in both the cerebrospinal fluid and serum. The aim of this study was to evaluate the level of serum neurogranin and to investigate its utility in the diagnosis of central nervous system infections. This study was conducted as a prospective case-control study of patients diagnosed with meningitis. The study initially included 55 patients, and 15 patients with proven central nervous system infection were ultimately included in the patient group. The results in the patient group were compared with those of the control group of 15 healthy subjects. The 15 patients comprised 4 women and 11 men with a mean cerebrospinal fluid neurogranin level of 432.4 ± 123.5 ng/ml. Correlation analysis revealed a moderate positive correlation between cerebrospinal fluid neurogranin levels and serum neurogranin levels. The mean serum neurogranin level was 198.6 ± 51.7 ng/ml in the control group but was significantly higher at 429.2 ± 104.3 ng/ml in the patient group. In conclusion, it may be useful to measure blood neurogranin levels in patients suspected of having central nervous system infections, especially in those for whom computed tomography, magnetic resonance imaging, or lumbar puncture cannot be performed.

Many operative procedures have been reported for the management of chronic lateral ankle instability, and anatomical reconstructions are an excellent option. However, if the remnants of the ligaments are considerably damaged, anatomical reconstructions using such remnants can be difficult. In cases such as these, tenodesis stabilization may be required. However, tenodesis stabilization often restricts the range of ankle movement. The purpose of this study was to determine the effectiveness of a new procedure that we developed to mitigate the problems associated with tenodesis stabilization procedures. We installed grafts in the original anatomical position by devising a system for positioning the drill holes in the bones so that our procedure did not restrict the range of ankle movement. A retrospective review of 37 patients (13 men, 24 women) with a mean age of 30.2 (range, 16-66) years was performed at an average of 69 (range, 47-77) months after the surgery. The average American Orthopaedic Foot and Ankle Society ankle-hindfoot score improved significantly from 65.6 (range, 47-77) points preoperatively to 98.0 (range, 87-100) points postoperatively (P < 0.001). With the number of subjects available, no significant differences were detected between the postoperative mean ranges of movement of the ankle and subtalar joints and those of the preoperative ankle. Patients who underwent anatomical tenodesis reconstructions with a free split peroneal brevis tendon showed good outcomes after a 69-month follow-up period.

Infection with Yersinia pseudotuberculosis, a known causal pathogen of human bacterial gastroenteritis, causes various symptoms and complications. A previously healthy 7-year-old girl was admitted because of fever and gastrointestinal symptoms. She was initially diagnosed with intussusception by abdominal ultrasonography. Although the patient was successfully treated by air enema, the fever persisted. The patient was then diagnosed with incomplete Kawasaki disease based on the presence of four principal clinical features. Intravenous immunoglobulin and oral aspirin were initiated. The patient defervesced and the other symptoms subsided after the treatment. Cardiac ultrasound results showed normal coronary arteries. Because of the gastrointestinal symptoms, stool samples were cultured repeatedly, only to yield normal flora. However, serum levels of anti-Y. pseudotuberculosis-derived mitogen antibody were elevated between the 7th and 18th days of the disease, thereby confirming Y. pseudotuberculosis infection. Because Y. pseudotuberculosis infection results in various clinical manifestations, we must be aware of each symptom and address them systematically.

Uterus transplantation (UTx) is now a potential option to allow women with uterine factor infertility to give birth. However, UTx is still at an experimental stage, and basic animal studies, including in non-human primates, are needed for the accumulation of data prior to clinical application. Considering that UTx may provide new hope to Japanese women, we launched UTx research in 2009 and have since accumulated a large archive of results in the UTx research field. Furthermore, we have carried out various activities aimed at the implementation of clinical applications of UTx in Japan while clarifying the ethical and social issues involved. Currently, the clinical application of UTx in Japan is just around the corner, and it is expected that UTx research will develop further in the future. Herein, we summarize our basic experiences using non-human primates and our activities with the goal of future clinical applications.

In this study, the complicated reasoning and processes inherent in diagnostic testing were analyzed, and a mathematical theory was developed for effectively stopping the transmission of infection in the context of coronavirus disease 2019 (COVID-19). As a result of this work, a new formula was developed for the "boundary condition for contagion containment," which, based on a horizontal transmission model, gives the lower limit of sensitivity for a diagnostic test to stop the virus spreading. Two parameters are considered in the model: the level of transmission and the effective reproduction number. In example computations, the formula indicated that a one-off polymerase chain reaction-based test with a sensitivity of 85% would not be sufficient to contain highly contagious infections such as the Delta variant of SARS-CoV-2, which would likely require a sensitivity close to 100% for its containment. Furthermore, a cascade judgment system for multiple tests was proposed and examined as a form of triplet test system. This approach can enhance the accuracy of COVID-19 testing up to the minimum level needed to stop the virus spreading. The theory developed in this study will not only contribute as an academic exercise, but also be useful for making evidence-based decisions on public policy for pandemic control.