KEIO JOURNAL OF MEDICINE最新文献

Many powerful molecular biology tools have their origin in nature. From restriction enzymes to CRISPR-Cas9, microbes utilize a diverse array of systems to get ahead evolutionarily. We are exploring this natural diversity through bioinformatics, biochemical, and molecular work to better understand the fundamental ways in which microbes and other living organisms sense and respond to their environment and as possible to develop these natural systems as molecular tools and to improve human health. Building on our demonstration that Cas9 can be repurposed for precision genome editing in mammalian cells, we look for novel CRISPR-Cas systems that are different and may have other useful properties. This led to the discovery of several new CRISPR systems, including the CRISPR-Cas13 family that target RNA, rather than DNA. We have developed a toolbox for RNA modulation based on Cas13, including methods for precision base editing, adding to our robust toolbox for DNA based on Cas9 and Cas12. We are expanding our biodiscovery efforts to search for new microbial proteins that may be adapted for applications beyond genome and transcriptome modulation, capitalizing on the growing volume of microbial genomic sequences. We are particularly interested in identifying new therapeutic modalities and vehicles for delivering them into patients. We hope that additional robust tools and delivery options will further accelerate research into human disease and open up new therapeutic possibilities.

Mesenchymal stem cells (MSCs) have generated great interest in the fields of regenerative medicine and immunotherapy because of their unique biological properties. Among MSCs, amniotic fluid stem cells (AFS) have a number of characteristics that make them attractive candidates for tissue engineering and cell replacement strategies, particularly for perinatal medicine. If various neonatal conditions, including birth asphyxia, preterm birth, and congenital abnormalities, which result in long-lasting severe impairments, could be predicted during pregnancy, it would allow collection of small samples of amniotic fluid cells by amniocentesis. In vitro culture of these autologous AFS during pregnancy would make them available for use soon after birth. Hypoxic-ischemic encephalopathy (HIE) and myelomeningocele (MMC) are neonatal conditions that cause permanent neurological disability, for which the treatment options are extremely limited. Experiments using animal models of HIE and MMC and human clinical trials have demonstrated that MSCs, including AFS, have beneficial effects on the central nervous system through paracrine influences, indicating that autologous AFS treatment may be applicable for intractable neurological diseases, including HIE and MMC, during the perinatal period. In this review, we focus on recent research related to the therapeutic potential of AFS for perinatal neurological diseases such as HIE and MMC.

Obturator hernia (OH) is a rare condition that accounts for 0.073-1% of abdominal hernias and 0.48% of bowel obstructions. OH frequently occurs in elderly women, with an incidence that increases with age. The only treatment for OH is surgical intervention, and the approaches used vary greatly. Consequently, a well-defined consensus has not yet emerged. We assessed the efficiency and safety of the midline extraperitoneal approach for OH. Six patients with OH repaired using the midline extraperitoneal approach at KKR Sapporo Medical Center between April 2011 and January 2016 were included in the study. We retrospectively evaluated the patient characteristics, intraoperative findings, and the postoperative course. All patients were elderly women [median age, 90 (range, 79-92) years], with a median body mass index of 17.0 (range, 15.6-18.3) kg/m² at presentation. All had symptoms associated with bowel obstruction: two patients presenting with leg pain had the Howship-Romberg sign. In two patients, bowel resection was required because of irreversible ischemic changes. Five patients had coexisting femoral and inguinal hernias that were repaired by bilateral mesh repair. One patient had aspiration pneumonia as a postoperative complication. All patients were discharged alive, without infection or recurrence. OH can be efficiently and safely repaired using the midline extraperitoneal approach. This approach establishes the diagnosis of OH, avoids injuring obturator vessels, gives improved exposure of the obturator canal, enables identification and simultaneous repair of other pelvic hernias, and facilitates bowel resection. This approach reduces the risk of mesh infection in patients undergoing bowel resection.

Depression is common among cancer patients and their families, and may lead to substantial clinical consequences. Clinicians should routinely screen cancer patients for comorbid depression and should provide appropriate care at both primary and specialized care levels. Good quality care is beneficial not only for cancer patients themselves but also for their family members. It includes good communication between patients and health providers, and addressing of unmet needs of cancer patients. Specialized care comprises pharmacotherapy and psychotherapy. The advancement of psychotherapy for cancer patients parallels the advancement of general psychotherapy. Among the many types of psychotherapies, mindfulness-based interventions have been attracting growing attention. Some relevant studies that have been conducted in Keio University Hospital are described herein.

The aim of this study was to evaluate the effects of transcorneal electrical stimulation in subjects with primary open-angle glaucoma. Five eyes of four male subjects with primary open-angle glaucoma (average age: 52.25 ± 14.68 years) were enrolled. The subjects underwent transcorneal electrical stimulation every 3 months according to the following procedure. A Dawson-Trick-Litzkow electrode was placed on the cornea, and biphasic electric current pulses (10 ms, 20 Hz) were delivered using a stimulator (BPG-1,BAK Electronics) and a stimulus isolation unit (BSI-2). A current that evoked a phosphene that the subject perceived in the whole visual area was delivered continuously for 30 min. Humphrey visual field testing was performed after every third transcorneal electrical stimulation treatment. Changes in mean deviation (MD) values were evaluated with a linear regression model. Transcorneal electrical stimulation was performed 18.2 ± 9.4 times over a period of 49.8 ± 23.0 months. The average pretranscorneal electrical stimulation intraocular pressure, best corrected visual acuity, and MD values were 11.8 ± 1.79 mmHg, 0.14 ± 0.19 (logMAR) and -17.28 ± 6.24 dB, respectively. No significant differences were observed in intraocular pressure before and after transcorneal electrical stimulation. However, there was a significant positive linear relationship between changes in MD values and the number of transcorneal electrical stimulation treatments (R² = 0.176, P = 0.005, Spearman correlation R =0.294, P = 0.008). Transcorneal electrical stimulation treatment may improve glaucomatous visual field defects in subjects with primary open-angle glaucoma. Large-scale studies are necessary to confirm these preliminary findings.

In this study, we investigated the correlations between biochemical and hematological test results obtained using microliter-scale fingertip blood samples collected with a newly developed blood collection device and those obtained using conventional venous blood. Eighty volunteer subjects were enrolled in this study. Blood samples were drawn from the fingertip of the ring finger by a single puncture, and 60-µL samples were promptly and accurately aspirated into a blood collection chip. Then the chip was tightly sealed in a chip container and was shaken to mix the contents without dispersion. For biochemical tests other than that for HbA1c, blood was collected without anticoagulant and centrifuged to obtain 15 µL of serum which was then diluted with 190 µL of physiological saline for the assay. For hematological tests and the test for HbA1c, the sample was assayed with blood collected using EDTA-2 K. Good correlations were obtained between the test results of the assay using fingertip blood and that using venous blood. The correlation coefficients were ≥0.97 for TG, T-CHO, HDL-C, LDL-C, GLU, ALT, γ-GTP, UA, BUN, and HbA1c and ≥0.95 for WBC, RBC, Hgb, and Hct. These results suggest that our microliter-scale blood testing system is comparable to assays using venous blood and may be useful as a rapid and simple test to determine basic clinical parameters that are close to the reference intervals.

Unlinked total elbow arthroplasty (TEA), which has no mechanical connection between the humeral and ulnar components, has theoretical advantages based on its near-normal elbow kinematics and the preservation of bone stock. Unlinked TEA is appropriate only for patients who have limited bone loss or limited deformity and good ligamentous function. This is because postoperative instability has been a major complication of unlinked prostheses. The concept and goal of unlinked TEA is to share the loading stress on the bone implant interface with the surrounding tissues. Although the loosening rate of unlinked prostheses theoretically should be lower than that of linked prostheses (which have a mechanical connection between the humeral and ulnar components), there is no clear evidence that unlinked TEAs are superior to linked TEAs in this respect. However, we believe that primary TEA should be performed using an unlinked TEA, especially for younger patients, because revision surgery for unlinked TEA results in longer prosthesis survival than revision surgery for linked TEA. Improvement of the design of unlinked prostheses and the introduction of less invasive surgical techniques are required to reduce postoperative instability.

The suprapatellar approach for intramedullary tibial nailing has become widely accepted over the past decade. A round sleeve is passed beneath the patella to protect the surface of the patellofemoral joint (PFJ). However, the round sleeve cannot be easily stabilized in the PFJ because it does not conform to the shape of the patellar apex. Consequently, we produced a heart-shaped sleeve to simplify the insertion of the entry sleeve during the suprapatellar approach. Using the new sleeve, the following procedure is used: (1) make a longitudinal 4 cm skin incision proximal to the patella to reach the PFJ, (2) insert the guide pin manually to the ventral edge of the tibial plateau, (3) insert the cannulated trocar along the guide pin, (4) insert the heart-shaped sleeve along the cannulated trocar, (5) remove the cannulated trocar, (6) ream the entry point through the heart-shaped sleeve. Then, continue insertion of the nail in the standard manner. Among 44 patients (29 men, mean age 45.6 years, range 26-87 years) with tibial fractures treated between 2010 and 2015, the first 18 consecutive cases were performed using a round sleeve and the rest were performed using the heart-shaped sleeve. The surgery time until entry reaming commenced was 8.9 min (range 6-12 min) using the round sleeve and 6.2 min (range 3-12 min) using the heart-shaped sleeve (P < 0.05). The heart-shaped sleeve is easily stabilized in the PFJ and greatly simplifies the intramedullary nailing of tibial shaft fractures using the suprapatellar approach.

The hypoxia response is a fundamental phenomenon mainly regulated by hypoxia-inducible factors (HIFs). For more than a decade, we have investigated and revealed the roles of the hypoxia response in the development, physiology, and pathophysiology of the retina by generating and utilizing cell-type-specific conditional knockout mice. To investigate the functions of genes related to the hypoxia response in cells composing the retina, we generated various mouse lines that lack HIFs and/or related genes specifically in retinal neurons, astrocytes, myeloid cells, or retinal pigment epithelium cells. We found that these genes in the different types of retinal cells contribute in various ways to the homeostasis of ocular vascular and visual function. We hypothesized that the activation of HIFs is likely involved in the development and progress of retinal diseases, and we subsequently confirmed the pathological roles of HIFs in animal models of neovascular and atrophic ocular diseases. Currently, anti-vascular endothelial growth factor (anti-VEGF) therapy is a first-line treatment widely used for neovascular retinal diseases. However, alternative or additional targets are now required because several recent large-scale clinical trials and animal studies, including our own research, have indicated that VEGF antagonism may induce retinal vascular and neuronal degeneration. We have identified and confirmed a microRNA as a candidate for an alternative target against neovascular retinal diseases, and we are now working to establish a novel HIF inhibitor for clinical use based on the disease mechanism that we identified.

Graft-versus-host disease (GVHD) is a major contributor to early and late morbidity and mortality after allogeneic stem cell transplantation. Despite results from a randomized controlled trial demonstrating an increased risk of chronic GVHD with use of growth factor-mobilized peripheral blood stem cells (PBSC) compared with bone marrow, PBSCs are the most widely used graft source in allogeneic transplantation for hematologic neoplasms in the U.S. This lecture will review established, recent, and novel strategies for GVHD prevention in unrelated donor PBSC transplantation and will highlight ongoing clinical research at Fred Hutchinson Cancer Research Center. Clinical trials aimed at defining standard-of-care GVHD prophylaxis after myeloablative and nonmyelablative conditioning will be presented. In addition, novel pharmacologic agents and graft manipulation strategies under investigation will be discussed. (Presented at the 1962nd Meeting, May 12, 2018).