Nagoya Journal of Medical Science

Neurodegenerative diseases are disorders that are characterized by a progressive decline of the mo- tor and/or cognitive function caused by a selective loss of neurons within the central nervous system. Recent advancements in the translational research have facilitated extensive insights into the molecular pathophysiology of neurodegenerative diseases. Nonetheless, a myriad of compounds that suppressed the disease progression in cellular and animal models did not exhibit efficacy in clinical trials. Perhaps, vari- ous biological, medical, and methodological factors could be attributed to unfavorable results of clinical trials of such disease-modifying therapies. Primarily, the fact that pathological changes at molecular and cellular levels precede the clinical onset by several years underscores a pressing need for the initiation of interventions before the emergence of neurological symptoms. Using exquisite biomarkers, recent studies revealed the preclinical and prodromal progression of pathophysiology, as well as compensatory brain responses in several neurodegenerative diseases. This review aims to discuss the recent advancement of biomarker studies on presymptomatic subjects and the perspective on a preventive trial of disease-modifying therapies for devastating neurological disorders.

The Notch signaling pathway is highly conserved and essential for animal development. It is required for cell differentiation, survival, and proliferation. Regulation of Notch signaling is a crucial process for human health. Ligands initiate a signal cascade by binding to Notch receptors expressed on a neighboring cell. Notch receptors interact with ligands through their epidermal growth factor-like repeats (EGF repeats). Most EGF repeats are modified by O-glycosylation with residues such as O-linked N-acetylglucosamine (O-GlcNAc), O-fucose, and O-glucose. These O-glycan modifications are important for Notch function. Defects in O-glycosylation affect Notch-ligand interaction, trafficking of Notch receptors, and Notch stability on the cell surface. Although the roles of each modification are not fully understood, O-fucose is essential for binding of Notch receptors to their ligands. We reported an EGF domain-specific O-GlcNAc transferase (EOGT) localized in the endoplasmic reticulum. Mutations in genes encoding EOGT or NOTCH1 cause Adams-Oliver syndrome. Dysregulation of Notch signaling because of defects or mutations in Notch receptors or Notch signal-regulating proteins, such as glycosyltransferases, induce a variety of congenital disorders. In this review, we discuss O-glycosylation of Notch receptors and congenital human diseases caused by defects in O-glycans on Notch receptors.

The Japan Agency of Medical Research and Development (AMED) has approved the budget for the 5-year project called Establishment of the JAPAN Brain Bank Network, which commenced in 2016. This project was established with the aim of storing brain tissue samples to enable research on the etiologies and mechanisms of psychiatric diseases, which would eventually improve standards of clinical treatment for these diseases.
Japanese researchers in the field of biological psychiatry have historically depended on Western brain banks, particularly from Europe and the United States, which is regrettable. To remedy this situation and improve the Japanese research standards, attempts for establishing an autonomous Japanese brain bank are ongoing.
Reviews of the previous attempts on elucidating the etiopathology of neuropsychiatric diseases reveal that rapid advances result from studies on tissue samples from diseased brains. For example, in the Kraepelin era, i.e. in 1900 years before and after, long-term, resolute research on diseased brain specimens ultimately led to the discoveries of entities such as Alzheimer disease and Lewy body disease. The recent advances in techniques of neuroimaging and molecular biology have resulted in a shift of interest from brain tissue analysis. However, the integration of findings of all these techniques is recommended going forward, with a shift in focus back to brain tissue analysis.
The JAPAN Brain Bank Network project was launched under this setting. The success of this project largely depends on the will of patients and family members (for donating samples) as well as cooperation among many clinicians.
In this paper, we provide a brief overview of the history of biological psychiatric research and related perspectives, which will hopefully encourage further studies that will help bridge the gap between clinical and biological research on psychiatric diseases.

Several studies have investigated perceptual processes in patients with schizophrenia. Research confirms that visual impairments are one of the most important features of schizophrenia. Many studies, using behavioral and psychological experiments, confirm that visual impairments can be used to determine illness severity, state, and best treatments. Herein, we review recent research pertaining to visual function in patients with schizophrenia and highlight the relationship between laboratory findings and subjective, real-life reports from patients themselves. The purpose of this review is to 1) describe visual impairments that manifest in patients with schizophrenia, 2) examine the relationship between visual dysfunction, as- sessed by laboratory tests, and the experiences of patients themselves, and 3) describe real-life experiences related to visual function in this population. In this review, the impairments of motion and color perception, perceptual organization, and scan paths are summarized, along with the relationship between laboratory findings and patients’ real-world subjective experiences related to visual function.

Despite the increase in the number of drug treatment centers, patients with drug addicts have been increasing without the improvement of treatment in Afghanistan. This study aimed to examine the as- sociations of the completion of drug addiction treatment with motivational interviewing (MI) and other factors among male drug users in Afghanistan. Subjects were patients admitted to Jangalak Hospital in Kabul, Afghanistan in 2014 and 2015. Systematic sampling and supplementary sampling were applied. The records of 327 males aged 18 to 54 years were collected from those of 3,373 male inpatients. Completion of treatment was defined as presence and receiving treatment in the hospital for at least 45 days. Multiple logistic regression models were applied to estimate the adjusted odds ratio (AOR) and 95% confidence interval (CI) for the completion of drug addiction treatment. Among the patients, heroin was the most commonly used drug, followed by opium, crystal, hashish, and other drugs. Patients with treatment history for drug addiction (AOR 2.46; 95% CI 1.14–5.30), those attended MI before admission (AOR 43.98; 95% CI 17.21–112.39), and those used heroin (AOR 4.74; 95% CI 1.32–16.97) were more likely to complete the drug addiction treatment. Among the factors examined in this study, attending MI was most strongly associated with the completion of drug addiction treatment. Amendments to policies to include compulsory MI in standard operational procedures of drug addiction treatment before hospitalization may be recommended.

Falls are common in elderly patients and comprise 20–30% of all incident reports in hospitals. The current study examined falls in orthopedic patients among 212,617 inpatients admitted to our hospital from April 2012 to March 2017, using a prospective database in the hospital event reporting system. The risk of fall was evaluated using a fall assessment scoresheet at admission and during hospitalization, based on which patients were divided into risk grades 1, 2 and 3. Fall leading to fracture or a life-threatening injury was defined as an adverse event. The number of falls during the study period was 3,925, including 230 in orthopedic patients. Fall cases occurred at all times, but adverse events were significantly more common from 1–7 a.m. (67% vs. 24%, p<0.01). Patients hospitalized for orthopedic surgery had significantly higher fall rates compared to all other patients (3.12% vs. 1.80%, p<0.01), and were older (65.8 vs. 61.4 years, p<0.05) and more frequently >80 years old (23.4% vs. 17.9%, p<0.05). There was a significant difference in fall incidence between risk grades 2 and 3 for patients hospitalized for non-orthopedic surgery, but not for patients hospitalized for orthopedic surgery. We conclude that fall can occur in orthopedic patients with a low predicted risk of fall, and particularly for older patients. This may indicate that frequent specialized fall assessment is desirable after orthopedic surgery.

Anastomotic leakage is a major cause of prolonged hospitalization after gastrectomy and sometimes leads to fatal complications, such as abdominal abscess and sepsis. Arginine, glutamine, and β-hydroxy-β-methylbutyrate (HMB) are indispensable for biosynthesis of collagen, which plays an important role in the process of wound healing. However, treatment effects of amino acid supplements containing HMB on the healing process of anastomotic leakage after gastrectomy remain unclear. We designed an open-label, multicenter, phase II clinical trial to evaluate the therapeutic efficacy of an enteral amino acid supplement consisting of arginine, glutamine, and HMB (Abound, Abbott Japan Co., Ltd., Tokyo, Japan) in patients with anastomotic leakage after gastrectomy. Patients who are diagnosed with anastomotic leakage within 14 days after gastrectomy are eligible for this trial and the target sample size is 20. A pack of Abound is administered twice a day for 2 weeks. The primary objective of this clinical trial is to determine the length of time between diagnosis and cure of anastomotic leakage. The secondary endpoints include the safety of Abound, duration of drainage placement and fasting, postoperative hospital stay, surgical procedure, and blood test data. Variables are compared between enrolled patients and a historical control consisting of 20 patients who underwent gastrectomy between 2004 and 2016 at Nagoya University Hospital. We herein describe the study design and the concept in this protocol paper

Some patients undergo postoperative chemotherapy despite showing impaired wound healing after a major surgery. We speculated that postoperative chemotherapy further delays wound healing in these patients. This study aimed to compare the effects of doxorubicin (DXR) in ischemic skin flap and normal incisional wound models after surgery. A 2-cm incisional wound was made in group 1 rats, and saline was injected intravenously, following surgery on the same day. Incisional wound was made in group 2–5 rats, and 8 mg/kg DXR was injected intravenously, following surgery on the same day and after 7, 14, and 21 days respectively. H-shaped double flaps were made in group 6 rats, and saline was injected intravenously, following surgery on the same day. Flaps were made in group 7–10 rats, and 8 mg/kg DXR was injected intravenously, following surgery on the same day and after 7, 14, and 21 days respectively. On days 7, 14, 21, and 28 after surgery, the suture wounds were removed, tensile wound strengths were measured, and tissue samples were collected for histopathological evaluation. The tensile strength was significantly lower in the DXR-treated groups than in the control groups for both ischemic skin flaps and incision wounds. Additionally, the cross effect between DXR and ischemia was not significant. On pathological examination, DXR showed atrophic skin changes and degeneration of skin appendages on days 14–21 after the surgery in both the models. DXR decreased the wound tensile strength and caused an atrophic change in the ischemic wound.

Increasing numbers of international students require Japanese universities to provide mental health support as one of their primary responsibilities. The problem with the provision of such support is that the stigma of mental disorder causes many individuals to avoid seeking help. We aim to clarify the association between stigma and mental illness to develop anti-stigma education. We performed a cross- sectional observational study. The target population comprised international students enrolled in a Japanese university. Online questionnaires were used to assess self-stigma, perceived stigma, recognized knowledge of schizophrenia and depression, gender, country and region, general mental health status, parents’ income, non-clinical and clinical help-seeking attitudes, and Japanese and English language ability. Logistic regres- sion model was used to estimate odds ratios (ORs) for self-stigma and perceived stigma after adjusting for the above factors. A total of 119 students were invited to participate, 61 (51.3%) of whom were enrolled. Students with good knowledge of depression/schizophrenia did not indicate more severe self-stigma compared with those without such knowledge. Students with good knowledge of schizophrenia indicated more severe perceived stigma compared with those without such knowledge (OR 3.78 [95% confidence intervals; CI, 1.21-11.78]). Students with good knowledge of depression indicated less severe perceived stigma compared with those without such knowledge (OR 0.31 [95% CI, 0.10–0.94]). In this study, among international students, higher perceived stigma was associated with knowledge of schizophrenia and lower knowledge of depression.

In Myanmar, the Control of Smoking and Consumption of Tobacco Products Law (Tobacco Control Law; TCL), which covers the prohibition of sale of tobacco to minors and all forms of tobacco advertisement, was enacted in 2006. This study aimed to examine the awareness of the TCL among high school students. A cross-sectional study was conducted in November 2015. Participants were 1,339 high school students (554 boys and 785 girls) from two regions and two states of Myanmar. Data were collected using anonymous self-administered questionnaires and revealed that 78.0% of boys and 86.5% of girls responded the sale of tobacco products in or within 100 feet from school, and 83.4% of boys had ever seen someone selling tobacco products to minors. More than half of the students had ever seen minors selling or distributing tobacco products, and had knowledge about the TCL, while only 9.7% knew about the penalties. The adjusted odds ratio (95% confidence interval) of awareness of the TCL was 2.12 (1.35–3.31) for students who had ever received tobacco products free of charge, or seen/heard about their distribution free of charge, 1.86 (1.20–2.89) for current smokeless tobacco users, and 0.58 (0.43–0.77) for students who had ever seen someone selling tobacco products to minors. The majority of high school students did not know that the violation of the TCL could be punished with a fine and/or imprisonment. These findings suggest that awareness of the TCL was very low among high school students, highlighting that TCL enforcement and compliance, and tobacco-related health education programs are not satisfactory in Myanmar.

Meropenem (MEPM) is a broad-spectrum antibiotic prescribed to patients with moderate or severe pneumonia. It is well recognized that appropriate medicine reduces the burden on not only young patients but elderly ones as well. We enrolled 56 patients aged 75 and over who were diagnosed with moderate or severe pneumonia (body temperature: ≧37.5 °C; white blood cell (WBC) count: ≧10,000/μL; C-reactive protein (CRP): ≧4 mg/dL) on the basis of Clinical Evaluation Methods for New Antimicrobial Agents to Treat Respiratory Infections defined by the Japanese Society of Chemotherapy, at the National Hospital Organization Kanazawa Medical Center from January 1, 2007 to May 31, 2010. Forty-two patients were given MEPM twice a day and 14 were given the same drug three times a day in a Japanese community hospital. After four days, the three times a day group showed significant decreases in body temperature, WBC count, and CRP level, which are commonly used indices for evaluating therapeutic effects. Similarly, the twice a day group showed decreases of those indices, and both treatments had no serious adverse effects. Simulation analysis based on the pharmacokinetics-pharmacodynamics (PK/PD) theory revealed that both treatments effectively inhibited the activities of Pneumococcus, Haemophilus influenzae, Providencia stuartii, and Staphylococcus aureus, which are the major bacteria in the patients. In this retrospective study, simulation analysis based on the PK/PD theory revealed that even the twice a day MEPM administration has sufficient effectiveness against pneumonia. It also may pave the way for the use of personalized medicine in the patients.

The standardized uptake value (SUV) is a marker of tumor glucose metabolism, detected using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and may reflect tumor aggressiveness. The purpose of this study was to evaluate the clinical significance of maximum SUV (SUVmax) of primary esophageal cancer (EC) lesions. A total of 86 patients with EC who underwent pre-treatment FDG-PET and R0-resection were included in our study. The mean patient age was 65 years, and 87% were men. Histologically, cancers included squamous cell carcinomas, adenocarcinomas, and other tumors in 72, 3, and 11 patients, respectively. Preoperative chemotherapy with or without radiotherapy was performed in 4 and 37 patients, respectively. Measured patient outcomes included the correlation between the SUVmax of the primary EC lesion and clinicopathological factors in patients who did not undergo preoperative treatment (n = 45), and the investigation of relapse-free survival (RFS) according to SUVmax and the relationship between SUVmax and recurrence sites in all patients (n=86). The mean SUVmax was 8.9 ± 4.6, and SUVmax values significantly correlated with tumor invasion depth and stage. The 5-year RFS for the enrolled patients was 57%, and the RFS of patients with SUVmax < 7.0 was better than that of patients with SUVmax ≥ 7.0, with a marginal difference (p = 0.0892). Lymph node recurrences were significantly more common in patients with SUVmax ≥ 7.0, compared to patients with SUVmax < 7.0. Therefore, the SUVmax value of the primary EC lesion before preoperative treatment may be predictive of RFS and lymph node recurrence.

Argon-plasma coagulation, high-frequency electrosurgical snare, laser therapy, and microwave treatment are therapeutic options to reduce tumor-related stenosis of the central airway. These treatments may cause airway fire under a high concentration of oxygen, so FiO2 levels must be ≤40%. This restriction may be dangerous when treating patients with respiratory failure. The cryosurgery unit, ERBE-CRYO2, facilitates treatment under an FiO₂ level of 100%, safely reducing this risk. In Japan, CRYO2 has been approved for cryobiopsy and foreign body removal, but not for tissue removal at the site of obstruction or stenosis due to lack of sufficient evidence. Since CRYO2 may be useful for reducing airway stenosis, the present study was designed to increase indications for this unit in Japan.

A fall may cause trauma and bone fracture, which can affect ADL and QOL. Therefore, countermea- sures to prevent falls are important. There are many reports on falls in hospitalized patients, but few for outpatients. Therefore, the purpose of this study is to report the characteristics of outpatient falls that occurred in hospital over five years to identify factors associated with fall in these patients. From April 2012 to March 2017, we investigated fall cases in outpatients using a hospital database. Fall that led to fracture or a life-threatening injury was defined as an adverse event. A total of 3,758 patients had falls in the hospital, and this included 146 outpatients, giving an incidence of 3.9% (146/3,758). Most falls involved outpatients in their 70s, and most occurred in operating rooms (15%), followed by examination rooms (13%), escalators (10%), and waiting rooms (7%). Falls in neurology patients accounted for 12%, followed by neurosurgery (10%), and ophthalmology (8%). Among all falls, 5% occurred in patients wearing slippers, and 54% and 46% occurred in patients without and with a need for assistance with mobility, respectively. There were 6 adverse events (4%) due to fall in outpatients: 4 femoral neck fractures, 1 teeth injury, and 1 pubic bone fracture. In conclusion, a fall accident occurs most commonly in outpatients suffering from a neurological disease and in ophthalmologic outpatients aged about 70 years old, and is likely to occur in the operating room, examination room, escalator and waiting room. Our findings suggest that countermeasures for each location are necessary.

Hepatic carcinosarcoma (HCS) generally presents in advanced stages, demonstrates aggressive behavior, and has a poor prognosis. Other than curative primary resection, no effective treatment options exist. We present a case of resected HCS with four repeat resections for solitary lymph node recurrence followed by chemoradiotherapy with doxorubicin and ifosfamide. A 67-year-old Japanese man was admitted to our hospital for evaluation of an asymptomatic hepatic tumor. The patient underwent right hepatectomy with a presumptive preoperative diagnosis of atypical hepatocellular carcinoma. Based on histopathological and immunohistochemical findings, the tumor was diagnosed as HCS containing osteosarcoma and chondro- sarcoma components. After the initial surgery, the patient underwent four additional resections for solitary lymph node HCS recurrence, and then underwent chemoradiotherapy with doxorubicin and ifosfamide for an unresectable lymph node recurrence. Chemotherapy was stopped after two cycles because of severe adverse events, although chemoradiotherapy markedly reduced the size of the lymph node recurrence and provided a progression-free survival of 12 months. Thirty-seven months after the initial surgery, the patient died of cardiac invasion of multiple mediastinal lymph node metastases. The clinical course outlined in this case report suggests that chemoradiotherapy with doxorubicin and ifosfamide for metastatic HCS may prolong survival in patients with unresectable lesions.

Meningiomas rarely exhibit cystic lesions with mural nodules, and may be misdiagnosed as intrapa- renchymal cystic tumors. We herein present a 64-year-old woman with a cystic lesion and enhancing mural nodule in the left temporal lobe accompanied by peritumoral brain edema. Differential diagnoses included low-grade gliomas, hemangioblastoma, and cystic meningioma. Gross total resection of the tumor was achieved through a temporal surgical approach. Intraoperative findings showed that the tumor was an extraparenchymal tumor. The cyst was covered by an extraparenchymal thin membrane and the cystic fluid was yellowish in color. The final result of the pathological examination was microcystic meningioma, WHO grade I. Although intraparenchymal tumors, such as hemangioblastoma, ganglioglioma, pilocytic astrocytoma, and pleomorphic xanthoastrocytoma, commonly display this MRI pattern, meningioma needs to be included in the differential diagnosis.