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Kai Ushio,1,2 Kazuyoshi Nakanishi,3,4 Yukio Mikami,1,5 Atsuo Yoshino,6 Masahiro Takamura,7 Kazuhiko Hirata,2 Yuji Akiyama,8 Hiroaki Kimura,1,2 Yasumasa Okamoto,6 Nobuo Adachi2,3 1Department of Rehabilitation, Hiroshima University Hospital, Hiroshima, Japan; 2Sports Medical Center, Hiroshima University Hospital, Hiroshima, Japan; 3Department of Orthopedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; 4Department of Orthopedic Surgery, Nihon University School of Medicine, Nihon University, Tokyo, Japan; 5Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan; 6Department of Psychiatry and Neurosciences, Hiroshima University, Hiroshima, Japan; 7Brain, Mind and KANSEI Sciences Research Center, Hiroshima University, Hiroshima, Japan; 8Department of Clinical Radiology, Hiroshima University Hospital, Hiroshima, JapanCorrespondence: Kazuyoshi NakanishiDepartment of Orthopedic Surgery, Nihon University School of Medicine, Nihon University, Oyaguchi-Kamimachi 30-1, Itabashi-Ku, Tokyo 173-8610, JapanTel +81-3-3972-8111Fax +81-3-3957-6186Email nakanishi.kazuyoshi@nihon-u.ac.jpPurpose: Expectation affects pain experience in humans. Numerous studies have reported that pre-stimulus activity in the anterior insular cortex (aIC), together with prefrontal and limbic regions, integrated pain intensity and expectations. However, it is unclear whether the resting-state functional connectivity (rs-FC) between the aIC and other brain regions affects chronic pain. The purpose of this study was to examine the rs-FC between the aIC and the whole brain regions in female patients with severe knee osteoarthritis (OA).Patients and Methods: Nineteen female patients with chronic severe knee OA and 15 matched controls underwent resting-state functional magnetic resonance imaging. We compared the rs-FC from the aIC seed region between the two groups. A disease-specific measurement of knee OA was performed.Results: The aIC showed stronger rs-FC with the right orbitofrontal cortex (OFC), subcallosal area, and bilateral frontal pole compared with controls. The strength of rs-FC between the left aIC and the right OFC was positively correlated with the knee OA pain score (r = 0.49, p = 0.03). The strength of rs-FC between the right aIC and right OFC was positively correlated with the knee OA total score (r = 0.48, p = 0.036) and pain score (r = 0.46, p = 0.049). The OFC, subcallosal area, and frontal pole, together with the aIC, were activated during anticipation of pain stimulus. These areas have been reported as representative pain-related expectation regions.Conclusion: This was the first study to show the stronger rs-FCs between the aIC and other pain-related expectation regions in female patients with severe knee OA. Female sex and preoperative pain intensity are risk factors of persistent postoperative pain after total knee arthroplasty. It is suggested that the functional relationship between pain-related expectation regions affects the formation of severe knee OA and persistent postoperative pain following total knee arthroplasty.Keywords: functional magnetic resonance imaging, chronic pain, insular cortex, orbitofrontal cortex

Hironi Makita,1,2,* Masaru Suzuki,1,* Satoshi Konno,1 Kaoruko Shimizu,1 Yasuyuki Nasuhara,1 Katsura Nagai,1,3 Yasushi Akiyama,3 Satoshi Fuke,4 Hiroshi Saito,5 Takeshi Igarashi,5 Kimihiro Takeyabu,6 Masaharu Nishimura1,2 1Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 2Hokkaido Medical Research Institute for Respiratory Diseases, Sapporo, Japan; 3Center for Respiratory Diseases, JCHO Hokkaido Hospital, Sapporo, Japan; 4Department of Internal Medicine, KKR Sapporo Medical Center, Sapporo, Japan; 5Department of Internal Medicine, Hokkaido Chuo Rosai Hospital, Iwamizawa, Japan; 6Department of Respiratory Medicine, Otaru Kyokai Hospital, Otaru, Japan*These authors contributed equally to this workCorrespondence: Masaharu NishimuraDepartment of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, JapanTel +81 11 706 5911Fax +81 11 706 7899Email ma-nishi@med.hokudai.ac.jpPurpose: Causes of death may be unique and different in Japanese patients with COPD because they are generally older, thinner, experience fewer exacerbations, and live longer than those in other countries. We investigated the detailed mortality profile in the Hokkaido COPD cohort study, which completed a 10-year follow-up with a very low dropout rate.Patients and Methods: We prospectively examined the 10-year natural history in 279 Japanese patients with COPD (GOLD 1, 26%; GOLD 2, 45%; GOLD 3, 24%; and GOLD 4, 5%). The majority of patients were male, and the average age at baseline was 69 years old. About 95% of all patients had accurate mortality data. The risk factors for mortality were also analyzed.Results: During the 10 years, 112 patients (40%) died. Their median survival time was 6.1 years (interquartile range: 4.7– 7.9 years), and age at death was 79 ± 6 years old (mean ± SD). Respiratory diseases, including pneumonia, were the leading causes of death in 45 (40%), followed by lung cancer in 24 (21%), other cancers in 18 (16%), and cardiovascular diseases in 12 (11%). In particular, lung cancer-related death was equally distributed across all COPD stages, with a higher proportion of lung cancer in the relatively younger generation (< 64 years old). Older age at baseline, lower BMI, and severer emphysema were significant risk factors for all-cause mortality.Conclusion: The unique mortality profile observed in this study should be considered when designing strategies for the management of patients with COPD in any geographic region.Keywords: chronic obstructive pulmonary disease, mortality, cause of death, cohort study

Yumi Harano,1 Atsuko Kitano,2 Yurika Akiyama,1 Lisa Kotajima,1 Kazufumi Honda,1 Hiroko Arioka11Department of General Internal Medicine, 2Department of Medical Oncology, St Luke’s International Medical Center, Tokyo, JapanAbstract: A 52-year-old woman presented with an 8-month history of epigastric pain, nausea, and weight loss. One year before, she was diagnosed with breast cancer. During the postoperative chemotherapy, she developed epigastric pain and nausea. As a result, she gradually lost 12 kg of her body weight. We performed upper gastrointestinal endoscopy, which revealed mild erosive gastritis. After the treatment with a proton pump inhibitor, her symptoms persisted. Before the admission, mild hypercalcemia was pointed out. Fluid replacement didn't improve hypercalcemia. We assessed adrenocortical function, which showed that her serum cortisol and adrenocorticotropic hormone were decreased. Through loading tests, we established diagnosis of isolated adrenocorticotropic hormone deficiency. She was treated with hydrocortisone. Soon after the treatment, her serum calcium level returned to normal and her symptoms improved. In a case of hypercalcemia unresponsive to fluid replacement, we recommend ruling out adrenal insufficiency after excluding more common diseases which induce hypercalcemia.Keywords: hypercalcemia, breast cancer, chemotherapy, adrenocorticotropic hormone deficiency, adrenocortical insufficiency

All cells must adapt to rapidly changing conditions. The heat shock response (HSR) is an intracellular signaling pathway that maintains proteostasis (protein folding homeostasis), a process critical for survival in all organisms exposed to heat stress or o