This review article summarizes my work as a researcher over the past 40 years. I began my life as a researcher at Hokkaido University as a graduate student, and remained there, first as a post-doctoral fellow and later as a research associate, until 1987. My major discovery during this period was that the GTP binding protein was involved in not only the adenylyl cyclase coupling receptor system, but also the Ca²⁺ mobilizing hormone receptor system. I later moved to Gunma University and investigated, first as an associate professor and later as a professor, the role of ATP, sphingosine 1-phosphate (S1), and protons as extracellular signaling ligands of GTP binding protein-coupled receptors. Although our group was not the first to discover that the proton is a signaling ligand, ATP and S1P had not been recognized as signaling molecules at the time of my initial investigations. The discovery that SIP mediates anti-atherogenic actions of high-density lipoprotein is internationally recognized. On the other hand, research on the proton is still relatively new, and many topics remain unsolved.

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Vitreoretinal interface diseases commonly occur in the macula. However, the mechanism of this preferential distribution was not known for many years. We used scanning electron microscopy to examine postmortem eyes with posterior vitreous detachment, and found vitreous cortex remnants at the macula with high frequency. We discovered the "posterior precortical vitreous pocket" when we observed the three-dimensional structure of the vitreous in postmortem eyes with fluorescein staining technique. Based on this anatomical finding, we explained the clinical mechanism of macular hole, premacular membrane, and ring shaped proliferation in diabetic retinopathy. Optical coherence tomography (OCT), introduced in 1997, enabled visualization of the premacular vitreous cortex, i.e. the posterior wall of the "pocket", proving our hypothesis. The swept source OCT, which became commercially available in 2012, enabled visualization of the entire "pocket". It also showed the "pocket" was connected to Cloquet's canal (Cloquet's canal traverses the vitreous from the optic nerve disc to the lens). This anatomical finding suggests that aqueous humor may flow into the premacular pocket.

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Aging of the Japanese population is at an unprecedented level. The increasing number of disabled elderly needing support or long term care places enormous social and economic burdens on our society. The epidemiology, natural history, and symptoms of age related locomotive organ disorders was not well known. Medical checkups, originally intended for early detection of cancer and as a preventive measure against lifestyle-related disease, were conducted in Katashina Village, Gunma Prefecture. The Department of Orthopedic Surgery, Gunma University, randomly selected several hundred subjects from participants of these medical checkups to receive orthopedic examinations. This has been done every year since 2006. In this article, we introduce several articles from our Katashina Study, which published new findings on locomotive organ disorders. Some of these studies showed new ideas for treatment or prevention of aging-related diseases. Our group hopes to publish additional cohort studies.

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Background: Risk factors have been reported for osteoarthritis (OA) after anterior cruciate ligament (ACL) reconstruction, but previous studies did not include a control group, and may have included OA that would have naturally developed even in the absence of ACL injury. This study investigated risk factors compared with the patient's own contralateral knee.
Methods: Three hundred forty-nine patients who had undergone ACL reconstruction at least 15 years previously were invited to visit the hospital. After exclusion criteria were applied, 40 patients were included in the study, including 16 with progressive OA and 24 without OA. Progressive OA was defined as OA that was more advanced on the affected side than on the contralateral side. The variables evaluated included age at the time of surgery, time from injury to surgery, sex, graft material, cartilage damage, and meniscectomy.
Results: No significant differences between groups were seen in terms of age, time from injury to surgery, sex, graft material, or cartilage damage. Meniscectomy was ultimately performed significantly more frequently in the OA group (88%) than in the non-OA group (38%; p< 0.01).
Conclusions: Meniscectomy was found to constitute a risk factor for the progression of OA after ACL reconstruction.

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Background: Prognosis of HIV-infected patients has dramatically improved through advances of antiretroviral therapy (ART). As a result, the number of long-term survivors has increased, and the regional cooperation in managing common chronic diseases, securing places for employment, chronic hemodialysis, nursing care, and recuperation have become important issues for HIV-infected patients. Methods: A questionnaire survey was conducted on Japanese HIV-infected patients who were under medical care in the outpatient clinic of Gunma University Hospital. The questionnaire sheet was distributed to 90 patients between April and November 2015, and responses were obtained from 83 patients. Results: Twenty-three percent of the patients answered that they have difficulty in regularly visiting our hospital and need regional clinics close to their home where they can easily receive HIV medication. Two-thirds of the patients had visited other clinics such as dentistry, general medicine and dermatology. Seventy percent, however, did not tell medical staff that they were HIV-infected under the fear that they might be refused treatment and receive some sort of discrimination. Many of the patients strongly requested medical care services in residential areas close to their home where general medicine consultation, chronic hemodialysis, dental treatment, and nursing care could be provided at any time if necessary. Conclusion: Based on the results of the present survey, we will try to establish medical care network for HIV-infected patients in Gunma, thereby allowing them to access residential care more easily.

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The efficacy of electroconvulsive therapy (ECT) is superior to that of repetitive transcranial magnetic stimulation (rTMS), particularly for the treatment of major depression with psychotic features. However, ECT is sometimes terminated for several reasons, including patient refusal. Here, the authors present the case of a 57-year-old woman who recovered from major depression with psychotic features with one course of rTMS after ECT was discontinued due to patient refusal. She had been suffering from depression with psychotic features (e. g., tactile hallucinations) for three years prior to admission. During the most recent episode, she was admitted to the authors' hospital and was eventually treated with one course of ECT; however, there was no change in her reported symptoms. Four weeks later, she refused a second course of ECT but agreed to a course of rTMS therapy. She demonstrated gradual recovery from depression three weeks after the initial rTMS therapy session. She demonstrated significant improvement and was discharged from the hospital after 55 days following the first rTMS session. Although the relationship between ECT and rTMS remains unclear, rTMS may be an option for major depression with psychotic features when the patient does not consent to continuing with ECT.

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Sometimes, the cause of vertigo might be central nervous system disorder, although most vertigo patients are introduced to a Ear-Nose Throat (ENT) doctor because they are supposed to have inner ear diseases, i.e. benign paroxysmal positional vertigo and Meniere's disease. Ninety-three patients of vertigo symptoms took an examination of MRI scan, and 2 patients (2.1%) had a fresh cerebral infarction. All of them were examined by ENT doctor previously, and denied to have an inner ear disease. Herein, we report these 2 cases with some literature review. To prevent a wrong diagnosis of cerebral infarction, diffusion-weighted image of MRI was useful for vertigo patients.

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We report a case of lower rectal cancer in an 88-year-old woman with severe kyphosis treated with laparoscopic abdominoperineal resection. As she had severe kyphosis, tumor excision with laparotomy was difficult owing to narrow working space and limited visual field. Therefore, we planned a laparoscopic abdominoperineal resection after careful evaluation of simulated CT images. During surgery, it was difficult to move the small bowels from the pelvic cavity because of obstruction from the lower limbs. Furthermore, since the Douglas pouch was displaced upwards, laparoscopic dissection between vagina and rectum was difficult, and was therefore, performed from the perineal side. The surgery was performed safely and without any complication. The patient was discharged on postoperative day 24. We conclude that laparoscopic surgery is effective for severe kyphosis patients having rectal cancer.

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We report a case of splenic metastasis from an endometrial cancer. The patient was a 66-year-old female who underwent hysterectomy for endometrial cancer 3 years prior. The CT scan showed multiple splenic tumors and tumor thrombi in the splenic hilum, and the PET-CT scan showed a strong accumulation in the same site, and also confirmed an accumulation in the right diaphragm. Distal pancreatectomy, splenectomy, diaphragmatic tumor resection was performed. Pathological examination results confirmed diagnosis of endometrial carcinoma metastasis and diaphragmatic tumors. She received adjuvant chemotherapy, and has had no sign of recurrence for 3 years after surgery. Extension of prognosis can be expected by excision including splenic metastasis.

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Liposarcoma is the most common soft tissue malignant tumor. It mostly arises in the subcutaneous tissue of shoulders, limbs, neck, and retroperitoneal space, but abdominal wall occurrence is very rare. Atypical lipomatous tumor (ALT) is a well-differentiated liposarcoma (WDLPS) and constitutes 40-45% of all liposarcoma cases. A 47-year-old male was admitted due to subcutaneous tumor. MR examination showed a mass with heterogeneous contrast in the lower abdominal wall. The patient was operated under spinal anesthesia. Adipose tissue of the lower abdominal tissue was removed. Postoperative course was uneventful. The final histopathological diagnosis was atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDLPS). The patient remains under surgical care.

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Alopecia areata (AA) is usually characterized by areas of patchy hair loss on the scalp, although in severe cases, the total loss of scalp or body hair may occur. While the association between AA and Graves' disease is described in textbooks, few reports have been published. We herein report a case of AA associated with Graves' disease, in which a skin biopsy revealed marked perifollicular infiltration of mononuclear cells and pigment incontinence in the dermis. Slight staining of IgG and IgM was observed in the follicle on a direct immunofluorescence test. Pulse corticosteroid therapy followed by contact immunotherapy with squaric acid dibutylester (SADBE) was effective.

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