Nagoya Journal of Medical Science

Recently, the effects of stem cell supernatants or exosomes, such as skin wounds, have attracted at- tention. However, the effects of the induced pluripotent stem (iPS) cell-derived exosomes (iPS-Exos) have not been investigated in detail. Here, we investigated the effects of iPS-Exos on skin wound healing using an animal model. We isolated iPS-Exos from the iPS cell culture media. Control exosomes were isolated from unused iPS cell culture media (M-Exos). We first observed the morphologic characteristics of the isolated exosomes and examined the expression of surface antigens. The effects of these exosomes on the migratory response and proliferation of fibroblasts were analyzed as well. Additionally, using a diabetic ulcer model, the effects of iPS-Exos and M-Exos on skin wound healing were investigated. Transmission electron microscope analysis demonstrated that the size of iPS-Exos (120 ± 25 nm) was significantly larger than that of M-Exos (≤ 100 nm). Flow cytometry analyses showed that iPS-Exos were positive for CD9, CD63, and CD81, whereas they were negative for HLA-ABC and -DR expression. The migratory ability of fibroblasts cocultured with iPS-Exos was shown to be higher than that of the cells cocultured with M-Exos, as demonstrated using scratch assay. Skin wound healing model results showed that the administration of iPS-Exos results in a faster wound closure compared with that observed in the M-Exo group. In conclusion, the results obtained here indicate that iPS-Exos may promote the migration of fibroblasts in vitro and in vivo, suggesting the possibility of using iPS-Exos for the treatment of diabetic ulcer.

The purpose of this study was to clarify the factors related to mental health and hearing in community- dwelling elderly. Elderly participants in a project to prevent long-term care need were given a self- administered questionnaire and tested by pure-tone audiometry. One hundred fifty were taken as subjects. Forty-one of these subjects (27.3%) were found to have poor mental health. The results of multiple logistic regression analysis with mental health level as the dependent variable indicated that subjects 65–74 years old who did not think their own hearing was bad had better mental health than those who did think their hearing was bad (odds ratio 10.800). Among subjects 75 years and older, those who had not been certified as needing long-term care had better mental health than those who had been certified (odds ratio 3.937). When planning mental health support for community-dwelling elderly in the future, it will be necessary to consider differences in background due to age group. The present results suggest that appropriate support for awareness of hearing and acceptance of decreased hearing ability in people in early old age (65–74 years old) may help to prevent declining mental health in later old age.

Providing safe drinking-water to human civilization is indispensable; it is one of the most cost-effective means of reducing the disease burden of diarrhea. Unfortunately, water supply quality monitoring from public water treatment plants (WTPs) is often neglected or taken for granted. To determine the produced water quality, WTPs in Sarawak, Malaysia were assessed for their protozoa removal ability. A self- administered questionnaire based on the regulations in the Drinking-water Standards for New Zealand (DWSNZ) was developed. Optional 10-liter raw water samples were collected from willing WTPs for the detection of protozoan cysts. Routine physical and microbial testing of WTP parameters were also requested for raw water quality overview. Two of the nine assessed WTPs achieved three log credits in the treatment component, one of which belonged to Peninsular Malaysia. No log credits were obtained in the other tested components for any samples. Most of the WTPs employed “Coagulation, Sedimentation, and Filtration” using rapid gravity filters without enhancement ( P < 0.05). Giardia cysts were detected in raw water sources used for treatment, and the geographical location was identified as an influencing factor for raw water quality. There is an urgent requirement for active collaboration and holistic approaches to review existing water management policies and interventions. WTPs in Sarawak did not achieve the log credits required to safeguard the microbial quality of the water supplied; however, only Giardia cysts were detected in 10-liter raw water samples despite routine microbial parameter monitoring showing disturbing contamination levels.

Modification of lifestyle habits, including diet and physical activity, is essential for the prevention and control of type 2 diabetes mellitus (T2DM) in elderly patients. However, individualized treatment is more critical for the elderly than for general patients. This study aimed to determine lifestyle interventions that resulted in lowering hemoglobin A_1c (HbA_1c) in Japanese pre- and early diabetic elderly subjects. The BEST-LIFE trial is an ongoing, open-label, 6-month, randomized (1:1) parallel group trial. Subjects with HbA_1c of ≥5.6%—randomly assigned to the intervention or control group —use wearable monitoring devices loaded with Internet of things (IoT) systems that aids them with self-management and obtaining monthly remote health guidance from a public health nurse. The primary outcome is changes in HbA_1c after a 6-month intervention relative to the baseline values. The secondary outcome is the change of behavior modification stages. The background, rationale, and study design of this trial are also presented. One hundred forty-five subjects have already been enrolled in this lifestyle intervention program, which will end in 2019. The BEST-LIFE trial will provide new evidence regarding the effectiveness and safety of our program on lowering HbA_1c in elderly subjects with T2DM. It will also investigate whether information communication technology tools and monitoring devices loaded with IoT can support health care in elderly subjects. The trial registration number is UMIN-CTR: UMIN 000023356.

Therapeutic response to neoadjuvant chemotherapy (NAC) for breast cancer based on Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.0 with FDG-PET/CT measurements was evaluated, and the results compared to those obtained with currently widely used Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, based on MRI measurements. MRI and FDG-PET/CT examina- tions were performed in 32 breast cancer patients before and after the NAC prior to a surgical resection. Chemotherapeutic response of the primary tumor and relapse-free survival (RFS) were investigated using RECIST 1.1 and PERCIST 1.0. Pathological complete response (pCR) was seen in 14 (43.8%) patients, while complete response (CR) was noted in 5, partial response in 25, stable disease in 2, and progressive disease in 0 with RECIST 1.1, and in 28, 2, 1, and 1, respectively, with PERCIST 1.0. For pCR prediction, the sensitivity, specificity, and accuracy with RECIST 1.1 were 28.6% (4/14), 94.4% (17/18), and 65.6% (21/32), and those with PERCIST 1.0 were 100% (14/14), 22.2% (4/18), and 56.3% (18/32). Five patients (15.6%) had recurrent development after a median period of 24 months (range 7.8–66.8 months). Patients who achieved CR shown by RECIST 1.1 showed slightly longer RFS than those who did not (p=0.46), whereas those with complete metabolic response (CMR) based on PERCIST 1.0 showed a relatively longer RFS than non-CMR patients (p=0.087). For prediction of pathological response to NAC in breast cancer, RECIST 1.1 and PERCIST 1.0 have complementary functions, however, FDG-PET as a post-NAC treatment assessment modality remains to be confirmed.

This multicenter cross-sectional study aimed to determine the differences in distribution and fracture pattern between low-energy and high-energy groups in distal humeral fractures in Japan. Retrospectively, 133 patients (48 males, 85 females) with distal humeral fractures were enrolled in this study. The age, sex, fracture classification, injury mechanism, preoperative therapy for osteoporosis, and nature of soft-tissue injury were recorded for all patients. The Mann-Whitney U test and chi-square test or Fisher’s exact test were used for non-normally distributed variables and categorical variables, respectively, to compare differences between the two groups. The mean age of the patients at the time of surgery was 66 years (range 21–99 years). Marked differences were observed between the two groups in terms of age, sex, and fracture pattern. The mean age of patients with AO classification type A2 fractures was significantly higher than that of the patients with other fracture types. In contrast, the mean age of patients with AO classification type C2 fractures was slightly lower than that of the remainder of the population. In the low-energy trauma group, females accounted for 72.2% of fractures and their mean age at the time of surgery was 76 years. Low-energy trauma among elderly individuals was prominent.

We investigated the association between CYP2C19 genotype and additional effect of cilostazol on clopidogrel resistance (CR) in neuroendovascular therapy. Between January 2012 and January 2016, 447 consecutive patients were administered with 75-mg cilostazol/day. The VerifyNow System was used for evaluating P2Y12 reaction units (PRU) > 230 and/or percentage inhibition of platelet function (% Inhibi- tion) ≤ 20 as CR. Among 158 patients with CR, 31 were administered with additional 100- or 200-mg cilostazol/day and their platelet function was evaluated. According to CYP2C19 genotypes revealed using the Spartan RX and DNeasy Blood & Tissue Kit, patients were classified into three phenotypic groups: extensive metabolizer (EM, three patients), intermediate metabolizer (IM, 12 patients), and poor metabolizer (PM, 16 patients). Administration of additional cilostazol decreased PRU (EM group: 160.7 ± 85.2 after vs 278.3 ± 40.1 before, P = 0.15; IM group: 205.6 ± 74.0 vs 254.3 ± 35.0, P = 0.02; and PM group: 227.8 ± 52.2 vs 282.1 ± 30.4, P = 0.003), and increased % Inhibition (EM group: 40.0 ± 27.9 vs 9.3 ± 3.8, P = 0.25; IM group: 31.4 ± 18.0 vs 11.8 ± 8.2, P = 0.001; and PM group: 24.6 ± 15.0 vs 10.4 ± 9.3, P = 0.001). However, the rate of normalized-clopidogrel response, thromboembolic lesions, and bleeding complications were not significantly different among the three groups. Thus, the addition of cilostazol was effective on CR in terms of PRU, % Inhibition, rate of change of normalized-clopidogrel response, thromboembolic events, and bleeding complications irrespective of phenotype.

Information on patterns of clinical care for elderly breast cancer patients is lacking. The aims of this study are two-fold, firstly, to clarify daily practice treatments for elderly breast cancer patients in Japan, and secondly, to plan a prospective clinical trial to address unresolved clinical questions. We investigated practice care of elderly breast cancer patients in 38 institutions of the Japan Clinical Oncology Group (JCOG). Questionnaires asked: (1) definition of “elderly” for each treatment, (2) clinical standard anti-HER2 therapy in each age-group, (3) recommended docetaxel dose in each age-group, (4) considerations for future clinical trials, and (5) other information about geriatric oncology concerning breast cancer. The upper age-limit for surgery and irradiation therapy was generally 80 years, while many physicians considered anti-cytotoxic adjuvant therapy unsuitable for patients >70–75 years. For HER2-positive metastatic breast cancer, 82% of physicians recommended docetaxel (DTX) plus trastuzumab plus pertuzumab (DTP) as standard care for patients aged 65–70, although 54% of physicians avoided DTP for those aged 71–75 as first-line standard preference. Most physicians recommended 75 mg/m² DTX for both 65–70 (63%) and 70–75 (52%) age-groups, but not for those over 75. Many physicians (73%) recommended 60 mg/m² DTX first. Most (97%) agree that the vulnerability of each elderly patient in a clinical trial should be assessed by comprehensive geriatric assessment. This is the first questionnaire study of care patterns for elderly breast cancer patients. Physicians considered different drug regimens and dosages according to patients’ fragility.

Vietnam is facing a problem of over-crowding in public hospitals. Long waiting time is a major dis- satisfaction for patients. Reducing waiting time benefits not only patients but also hospitals in decreasing overall workload. To identify factors contributing to long waiting time in outpatient clinics, a cross-sectional study was conducted at a national hospital in Vietnam. The time for each process of 7,931 patients who visited the outpatient clinics within Thong Nhat Hospital from 5 to 9 September 2016 was collected from the computerized clinical database. Characteristics of patients (age, sex, address, day of visit, registration time, visited department and test) and waiting times were studied at the outcome measures. Multivariate analyses using the linear regression model was carried out to evaluate the contribution of these factors to the total waiting time. Among 7,931 patients, 52.3% were women, 46.3% were 60–80 years, and 64.8% registered between 5:30 and 9:30. The mean total waiting time was 104.1 minutes. The analysis on total waiting time among 4,564 patients who visited one department without any test showed that department group and registration time were significantly associated with a total waiting time. In 1,259 patients who visited one department with one test, early registration and undergoing blood tests were significantly associated with a longer total waiting time. These results showed that old age, visiting internal medicine departments, early registration time, and undergoing blood tests were factors contributing to a longer total waiting time in the outpatient clinics within Thong Nhat Hospital.

Dengue fever during pregnancy is an expanding issue in Southeast Asia; however, the knowledge of adverse effects on mothers and neonates remains limited. Therefore, we aimed to determine the impact of dengue fever. The clinical information of 20 patients of dengue fever during pregnancy in Vietnam from January 1, 2015 to December 31, 2015 was collected and their outcomes were retrospectively investigated. A total of 18 patients (90%) presented with positivity of nonstructural protein 1, and a primary infection. Additionally, 4 patients (20%) had preterm deliveries and 1 (5%) had a stillborn child. All live-born neonates were discharged from the hospital uneventfully. Also, 6 patients (30%) required platelet transfu- sion and 3 of them received transfusion before delivery, but there were no maternal death. In addition, 3 cases of patients (15%) developed to postpartum hemorrhage (PPH), and their platelet concentrations were significantly lower than those of patients without PPH [90.0 (19.0 – 374.0) × 10³ vs. 40.0 (12.0 – 57.0) × 10³ cell/μl, p = 0.001]. In addition, patients with PPH also presented with elevated liver enzymes. Pregnant patients with low platelet counts should be recognized as being at high risk for PPH.

Left ventricular hypertrophy (LVH) and proteinuria are known as independent predictors of cardiovascu- lar death in hypertension. However, LVH and its association with proteinuria have not been investigated in adult hypertensive patients in Afghanistan. The objective of this research was to determine the prevalence of LVH and the correlation between LVH and proteinuria among the Afghan adult hypertensive popula- tion visiting an outpatient clinic in Afghanistan. We retrospectively evaluated 789 hypertensive patients (mean age is 56 years and 46% were men) who visited the clinic between December 2014 and August 2016. Patient characteristics and laboratory and clinical findings were recorded. The rate of LVH among hypertensive patients was 54.4%. Patients with proteinuria had a significantly higher LVH percentage compared to those without proteinuria (73.2% versus 55.8%; P<0.001). There was a significant correlation between LVH and proteinuria among hypertensive patients (r=0.182, P<0.001). Based on a multivariate regression analysis, age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.02–1.05), proteinuria (OR, 1.69; 95% CI, 1.19–2.41), and female sex (OR, 0.09; 95% CI, 0.06–0.13) were significant factors. In conclusion, the prevalence of LVH was more than 50% in the Afghan adult hypertensive population. This study indicates that there is a significant relationship between LVH detected by ECG and the presence of proteinuria among such subjects.

Fecal calprotectin (FC) has drawn attention as a biomarker in the evaluation of Crohn’s disease (CD). However, few reports have provided a detailed examination of the relationship between small-bowel CD lesions and FC levels. The present study aimed to examine the entire small bowel using double-balloon endoscopy (DBE) and to determine the relationship between the endoscopic activity in small-bowel CD and FC levels. Twenty small-bowel CD patients, who underwent DBE, were prospectively enrolled. Endoscopic evaluation was based on the simple endoscopic score for CD, with the small bowel divided into four regions. This score was defined as the double-balloon endoscopic score for CD (DES-CD). Furthermore, to focus on mucosal membrane damage, we used the partial DES-CD (pDES-CD), in which presence of stenosis was excluded from DES-CD. DES-CD revealed a correlation with FC (γ = 0.691, P = 0.001) and C-reactive protein (CRP) (γ = 0.631, P = 0.003) levels. Furthermore, pDES-CD showed a correlation with the FC level (γ = 0.747, P < 0.001), erythrocyte sedimentation rate (γ = 0.492, P = 0.028), and the CRP level (γ = 0.605, P = 0.005). CD Activity Index and endoscopic score showed no correlation. Our results revealed a correlation between the endoscopic activity in small-bowel CD and FC levels. Furthermore, pDES-CD showed a strong correlation with FC levels. This may be because FC levels were elevated due to mucosal membrane damages, rather than stenoses.

Dyschromatosis symmetrica hereditaria (DSH) is one of the genetic pigmentation disorders and shows characteristic mixture of hyper- and hypo-pigmented small macules on the extremities. Heterozygous mutations in the adenosine deaminase acting on RNA1 gene (ADAR1 ) cause DSH. In the present study, we report five cases of DSH and identify a distinct known mutation in each patient. Furthermore, we review previously described cases with the five ADAR1 mutations found in the present study. We reviewed clinical and molecular findings in the present and previously reported cases and found an identical mutation can result in various phenotypic severities, even in one family. We found novel phenotype-genotype correlations between the presence/absence of facial lesions and the ADAR1 mutation c.3286C>T. The absence of freckle- like macules in the face was found to be more commonly associated with the mutation c.3286C>T than with the other 4 ADAR1 mutations (odds ratio = 0.056 [95% CI: 0.007–0.47, p < 0.005]). We objectively evaluated the severity of skin manifestations in the extremities using our definition of severity levels for such manifestations. This is the first semi-quantitative evaluation of skin manifestations in DSH. Using our definition, we found that patients with facial lesions with or without hypopigmented macules tend to show more severe symptoms on the extremities than patients without facials lesions show. Furthermore, no significant difference in the severity of the skin lesions was observed between the upper and the lower extremities, suggesting that sun exposure does not affect significantly the pathogenesis of DSH skin lesions.

The authors present a 60-year-old man with a partially thrombosed, intracranial vertebral artery aneurysm. A vascular channel in intra-aneurysmal thrombus was effectively identified with high-resolution cone beam CT (DynaCT Micro: Siemens Medical Solutions, Erlangen, Germany). Pre-procedural vertebral angiogram implied a perforating artery arising from near neck of the aneurysm and DynaCT Micro performed before approaching to the lesion demonstrated a vascular channel running in intra-aneurysmal thrombus which could not be distinguished from perforators with other imaging modalities. It was confirmed that perforators around the aneurysm were not identified and safely treated the aneurysm with stent-assisted coil embolization. High-resolution cone beam CT is enable to sharply visualize vessel lumens, thrombus, and intra-thrombus structures, and is useful to identify a vascular channel in intracranial partially thrombosed aneurysm.

Nivolumab, a new immune checkpoint inhibitor that has been found to improve outcomes for patients with some advanced cancers, is being increasingly used. Immune checkpoint inhibitors can cause immune- related adverse events, including dermatitis, enterocolitis, hepatitis and hypophysitis, but adrenal insufficiency rarely occurs. We present a case of Nivolumab-induced adrenal insufficiency in a man who complained of refractory hypotension. A 52-year-old man with non-small cell lung cancer visited our emergency depart- ment complaining of fatigue and diarrhea. He had received Nivolumab every 2 weeks as third-line therapy for a total of 10 times. On arrival, his vital signs revealed shock: blood pressure, 68/48 mmHg; heart rate, 141 beats per minutes. Laboratory examination showed severe hemoconcentration with a hemoglobin level of 19.9 g/dL, normal electrolyte levels and hyperglycemia. We started intravenous infusion of 4.5 L of extracellular fluid, but his vital signs remained unstable. After admission, endocrine examination revealed abnormally low values of serum cortisol (4.86 μg/dL) and ACTH (<1.0 pg/mL), which had been normal at 2 months before admission (21.14 μg/dL and 20.1 pg/mL, respectively). We therefore made a diagnosis of adrenal insufficiency induced by Nivolumab and administered 100 mg hydrocortisone succinate sodium intravenously. He recovered soon after hydrocortisone replacement therapy. Nivolumab is a new immune checkpoint inhibitor and general physicians are not familiar with it. However, adverse events caused by Nivolumab, especially adrenal insufficiency, can lead to serious adverse outcomes if overlooked. We should recognize Nivolumab-induced adrenal insufficiency and administer a glucocorticoid immediately in cancer patients treated with immune checkpoint inhibitors.