Nagoya Journal of Medical Science

The first Institute of Biochemistry in Japan was founded by Leonor Michaelis from Berlin at Nagoya in 1922, and there have been numerous interrelations between Japanese and German biochemists since. Some such relationships are presented here from a personal point of view as one illustrative example, which could be extended amply by the experience of many other scientists from the two countries. Fruitful exchanges are facilitated by organisations such as the Alexander von Humboldt Foundation (AvH) and the Deutscher Akademischer Austauschienst (DAAD) or the Japanese Society for the Promotion of Science (JSPS) and by the many bilateral agreements between universities and research institutions.

Central diabetes insipidus (CDI), characterized by polyuria and polydipsia, is caused by deficiency of arginine vasopressin (AVP), an antidiuretic hormone which acts on V2 receptors in kidney to promote reabsorption of free water. CDI is classified into three subtypes; idiopathic, secondary and familial. A previous study suggests that infundibulo-neurohypophysitis might be an underlying cause of idiopathic CDI. Among secondary CDI, the tumors in the central nervous system such as craniopharyngioma and germ cell tumors are the most frequent causes. Familial CDI is inherited mostly in an autosomal dominant mode, and the number of causal mutations in the AVP gene locus reported so far exceeds 80. CDI is treated with desmopressin, an analogue of vasopressin, and the tablet is preferred to the nasal form because it is easier to administer. It is also shown that the oral disintegrating tablet formula increases QOL and decreases the incidence of hyponatremia in CDI patients. In some CDI patients, the osmoreceptors in the hypothalamus do not function and patients do not sense thirst. These adipsic CDI patients are treated with desmopressin and adjusting the amount of daily water intake based on body weight measurement; but controlling the water balance is extremely difficult, and morbidity and mortality are shown to be high in these patients.

Rare progression to renal failure imposes a burden on children with IgA vasculitis (Henoch–Schönlein purpura, HSP). An abnormal urinalysis on day 7 (7d-UA) may be a surrogate marker for persistent nephritis, but this has not been established. We retrospectively analyzed the risk factors for persistent nephritis in a cohort of 138 children. Of 35 children with abnormal 7d-UA, 24 (69%) had an abnormal urinalysis 6 months after the diagnosis of HSP, which was significantly more than 6 of 103 children (6%) with normal 7d-UA (P < 0.0001). The negative predictive values for normal urinalysis and negative proteinuria 6 months after diagnosis were 0.94 (95% confidence interval [CI], 0.90–0.97) and 0.98 (95% CI, 0.95–0.99), respectively. When children with abnormal urinalysis 6 months after diagnosis were compared with those without, the following factors were significantly associated: age at diagnosis, abnormal urinalysis at diagnosis, abnormal 7d-UA, complement C3, steroid treatment, and presence of abdominal pain. However, multivariate analysis revealed that abnormal 7d-UA was the only significant risk factor for abnormal urinalysis 6 months after diagnosis (odds ratio 54.3, 95% CI 15.3–275, P = 1.89 × 10⁻⁶). Abnormal 7d-UA may be an independent risk factor for persistent nephritis, but this should be confirmed in a prospective study.

Mitral valve surgery has changed with the wide acceptance of mitral valve repair. The aim of this study is to obtain the long-term results of patients who underwent mitral valve replacement (MVR) using a biological prosthesis in contemporary practice in Japan. From January 1990 to December 2013, 76 patients underwent MVR using a biological prosthesis with or without concomitant surgery. Data were obtained by means of a questionnaire and a telephone interview. The mean follow-up period was 4.26 years. The etiologies of the patients included dilated cardiomyopathy (DCM) (n=20 [26.3%]), ischemic mitral regurgitation (n=7 [9.2%]). There is a trend towards decreasing number of rheumatic and degenerative disease and increasing number of DCM and ischemic mitral regurgitation. Three patients (3.9%) died in the perioperative period. The 5- and 10-year overall survival rates were 69.6% and 31.7%, respectively. The 5- and 10-year freedom from valve related death were 95.6% and 80.6 %, respectively. The linearized rates of valve-related complications were as follows: thromboembolism (0.63%/patient/year), bleeding (1.25%/patient/year). One patient underwent reoperation for structural degeneration 13 years after the first operation. The present study shows the long-term results of mitral valve replacement with bioproshtesis in a contemporary case series. The practice pattern is changing. The low rate of valve-related complication justify the current patient selection.

Proteinuria in hypertension is an early marker of renal disease and a predictor for the progression of end stage renal disease, and cardiovascular diseases. This study was designed to determine the prevalence of proteinuria and its association with cardiovascular risk factors among adult hypertensive patients in Afghanistan. Five hundred fifty-five patients with a high blood pressure recorded in an outpatient clinic in Andkhoy, Afghanistan from December 2014 to May 2015, were included in this study. Data obtained from each patient, included demographic characteristics, body mass index, blood pressure patterns, cardiovascular history, cardiovascular risk factors, comorbidity, and current drug-therapy. Dipstick screening for proteinuria was performed with reagent test strips. The mean age of the patients was 57.9 ± 13.3 years, and a female predominance was observed (n = 333, 60%). The prevalence of proteinuria was 67.2%. The predictors of proteinuria were found to be age ≥65 years (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.00–1.04), smoking (OR 1.88, 95% CI 1.17–3.02), heart failure (OR 2.23, 95% CI 1.13–4.41), and diabetes mellitus (OR 3.41, 95% CI 1.49–7.81). In conclusion, this study shows that proteinuria is highly prevalent among hypertensive outpatients in an outpatient clinic in Andkhoy, Afghanistan, especially in those with high cardiovascular risk.

Unsafe food is linked to the deaths of an estimated two million people annually. Food containing harmful agents is responsible for more than 200 diseases ranging from diarrhoea to cancers. A one-sample pilot intervention study was conducted to evaluate the role of courtyard counselling meetings as the means of intervention for improving food safety knowledge and practices among household food handlers in a district of Bangladesh. The study was conducted in three phases: a baseline survey, the intervention and an end-line survey between April and November 2015 where 194 food handlers took part. Data were collected through observations and face-to-face interviews. The mean age of the respondents was 38.8 (±12.4) years, all of whom were females. Hand washing before eating, and washing utensils with soap were significantly improved at the end-line in comparison to the baseline (57% vs. 40% and 83% vs. 69%, respectively). Hand washing with soap was increased by 4%. The mean score of food handling practices was significantly increased after the intervention (20.5 vs. 22.1; P<0.001). However, hand washing after use of toilet was unchanged after the intervention (75% vs.76%). Knowledge about safe food and the necessity of thorough cooking were significantly increased after the intervention (88% from 64% and 34% from 21%, respectively). Mean scores of knowledge and practice on food safety were significantly increased by 1.9 and 1.6, respectively after the one month intervention. Thus this food safety education in rural communities should be scaled up and, indeed, strengthened using the courtyard counselling meetings in Bangladesh.

The purpose of this study was to evaluate the acute and late toxicity as well as local control (LC) in T1 glottic cancer (GC) patients treated with hypofractionated radiotherapy (RT) in clinical practice. The Tokai Study Group for Therapeutic Radiology and Oncology started RT treatment with a dose of 2.25 Gy for T1 GC in 2011. Ten institutions combined data from 104 patients with T1 squamous cell carcinoma between 2011 and 2015. In total, 104 patients with T1 GC were irradiated with a standard radiation dose of 63 Gy in 28 fractions.The median follow-up duration was 18 (3.7–49.5) months. Acute grade 3 adverse events were observed in 7 patients, with 4 patients (5%) having dermatitis and 3 patients (4%) having mucositis. Late adverse events above grade 3 were not observed. Two patients developed local recurrence. The rates of acute adverse events in the present study were comparable to those in previous studies that have used 2 Gy fractions of RT.

Primary peritoneal carcinoma (PPC) is treated similarly to advanced epithelial ovarian carcinoma (aEOC); however, the standard approach for the management of PPC is controversial. The objective of this study was to evaluate the clinical features and prognosis of those patients. A retrospective analysis was performed of eight patients with PPC between January 2008 and December 2015. Clinicopathologic parameters, the diagnostic modality, treatment, and oncologic outcome were analyzed. The median age at the time of diagnosis was 72.5 years (range: 55–79), with a median follow-up of 26.5 months (range, 5–74). Most of the PPC developed with carcinomatosis peritonei involving ascites, while some cases developed sporadically in the peritoneal or extraperitoneal cavity without ascites. The most common initial symptom was abdominal fullness, and other symptoms were inguinal tumor, paralysis of the extremities, and respiratory disorder. The preoperative CA125 value was elevated in all patients. In four patients who did not undergo primary surgery, the final diagnoses were determined by the ascites cytology and radiological image. Initial or interval debulking surgery was performed in only two patients. All patients were treated with paclitaxel or docetaxel plus carboplatin. Five showed a complete response (CR), and one showed a partial response (PR). Among the five patients with CR, the median progression-free and overall survival periods were 15 (12–26) and 41.5 (32–74) months, respectively. Three patients without carcinomatosis peritonei showed a relatively favorable prognosis. The management of PPC is generally consistent with that of aEOC; however, in atypical cases, the treatment method should be considered individually.

The aim of this study was to examine the associations of alcohol use with sociodemographic factors, mental health and alcohol exposure among school-going adolescents in Cambodia. The analysis included 3,806 school children, mean age 15.7 years (SD=1.8), from Cambodia who participated in the “Global School-based Student Health Survey” (GSHS) in 2013. The results indicate that overall, 10.0% of the students reported current alcohol use, 10.8% lifetime drunkenness, and 2.8% problem drinking. In multivariate logistic regression analysis, sociodemographic factors (older age and being male), mental health and other variables (bullying victimization, OR (odds ratio) = 1.99; 95% Confidence Interval (CI) [1.50, 2.65] and OR = 2.15; 95% CI [1.58, 3.21], respectively; having attempted suicide, OR = 2.04; 95% CI [1.35, 3.08] and OR = 2.06; 95% CI [1.29, 3.28], respectively and illicit drug use, OR = 4.97; 95% CI [2.41, 10.24] OR = 5.05; 95% CI [2.14, 11.98], respectively) and alcohol exposure variables (peer influence on drinking alcohol, OR = 6.68; 95% CI [4.75, 9.39] and OR = 7.83; 95% CI [5.73, 10.66], respectively and daily or almost daily to alcohol advertising in the past 30 days OR = 1.61; 95% CI [1.03, 2.51] and OR = 2.30; 95% CI [1.40, 3.77], respectively) were significantly positively associated with current alcohol use and drunkenness. Moreover, older age, being male, bullying victimization, having close friends, suicide attempt, drug use, father or male guardian drinks alcohol and peer influence were associated with problem drinking. There is a need to implement public health interventions with a special focus on the determinants of alcohol consumption, including exposure to alcohol advertising, in this age group.

The aim of this study was to explore the prevalence and relationship of anticipated chronic illness stigma among patients diagnosed with a variety of chronic diseases in three Southeast Asian countries (Cambodia, Myanmar and Vietnam). A cross-sectional survey was conducted in 4,803 adult chronic disease patients (mean age 49.3 years; SD=16.5) recruited systematically from health facilities. Overall, the results indicate that 20.7% of patients reported that for any of the 12 stigma items, they anticipated they were likely or very likely to experience chronic disease stigma. A multivariate analysis of sociodemographics revealed the following were associated with anticipated chronic disease stigma: older versus younger age, OR (odds ratio) = 0.71; 95% Confidence Interval (CI) [0.58, 0.87]; higher versus lower education, OR = 2.23; 95% CI [1.81, 2.75]; origin from Myanmar or Vietnam, being single, divorced or widowed, rural residence, and health status (having three or more chronic conditions versus having one chronic condition), OR = 1.93; 95% CI [1.58, 2.35]; lower versus higher quality of life, OR = 0.73; 95% CI [0.63, 0.85]); health risk behavior (physical inactivity, poor diet, current smoking, and problem drinking) and low versus medium or high medication adherence (OR = 0.69; 95% CI [0.55,0.86]). This study demonstrated the possible consequences of anticipated stigma on the health and behavior of people living with chronic diseases, and several factors for chronic disease stigma were identified that can help guide interventions to reduce chronic illness stigma in this population.

Cardiac sarcoidosis (CS) can cause sudden death, which is the leading cause of mortality in patients with sarcoidosis in Japan. However, it is difficult to diagnose CS because of the lack of a sensitive diagnostic method for the condition. Late gadolinium-enhanced cardiac magnetic resonance (MR) imaging demonstrates improved sensitivity for diagnosing CS. Therefore, it is important to know the late gadolinium-enhancement (LGE) characteristics of CS on cardiac MR images in order to diagnose CS accurately. In this study, we investigated the most common sites of LGE on cardiac MR images in CS. Late gadolinium-enhanced MR images of 9 consecutive patients with CS (obtained between August 2009 and July 2015) were reviewed by two radiologists. The distribution of LGE was evaluated using the American Heart Association 17-segment model of the left ventricle. The LGE in each segment was also classified into 4 patterns according to the myocardial layer in which it occurred (the subepicardial, subendocardial, intramural, and transmural layer patterns). All 9 patients exhibited LGE in their left ventricle, and 70 of 153 (46%) myocardial segments were enhanced. All of the patients displayed LGE in the basal septal wall. The patients’ LGE layer patterns were as follows: subepicardial: 40% (28/70), intramural: 30% (21/70), subendocardial: 16% (11/70), and transmural: 14% (10/70). The basal septum wall and subepicardial layer often exhibit LGE on cardiac MR images in CS patients. LGE can be observed in other segments and layers in some cases.

Thoracoscopic lobectomy has recently become a widely used surgical treatment for congenital cystic lung disease, but significant issues can arise in some cases, such as a limited working space in neonates, a limited view in cases involving large cystic lesions. We reviewed the treatment outcomes of neonates that underwent complete thoracoscopic lobectomy or segmentectomy and evaluated the operative difficulties. From January 2008 to October 2015, 38 patients under the age of 1 year underwent complete thoracoscopic lobectomy or segmentectomy for cystic lung disease at our institution. We compared the intra- and postoperative data of the neonate group (N group) with those of the infant group (I group). Fourteen and 24 patients underwent thoracoscopic lobectomy or segmentectomy in the N group and I group, respectively. The operative time and amount of intraoperative blood loss did not differ significantly between the two groups (p=0.694 and p=0.878, respectively), but the duration of the postoperative hospitalization period was significantly longer (p<0.01) in the N group. The frequencies of postoperative complications did not differ significantly between the two groups. The operative time of thoracoscopic lobectomy was significantly longer in cases involving incomplete lobar fissures than in those involving normal lobar fissures. Surgical outcomes of complete thoracoscopic lobectomy for neonatal cases are almost equivalent compared with infantile cases, and thoracoscopic lobectomy takes longer in cases involving incomplete lobar fissures.

Voxel-based analysis (VBA) of diffusion tensor images (DTI) and voxel-based morphometry (VBM) in patients with multiple sclerosis (MS) can sensitively detect occult tissue damage that underlies pathological changes in the brain. In the present study, both at the start of fingolimod and post-four months clinical remission, we assessed four patients with MS who were evaluated with VBA of DTI, VBM, and fluid-attenuated inversion recovery (FLAIR). DTI images for all four patients showed widespread areas of increased mean diffusivity (MD) and decreased fractional anisotropy (FA) that were beyond the highintensity signal areas across images. After four months of continuous fingolimod therapy, DTI abnormalities progressed; in particular, MD was significantly increased, while brain volume and high-intensity signals were unchanged. These findings suggest that VBA of DTI (e.g., MD) may help assess MS demyelination as neuroinflammatory conditions, even though clinical manifestations of MS appear to be in complete remission during fingolimod.

MBD5 (Methyl-CpG-binding domain 5) is a critical gene for normal development. While deletion or duplication of MBD5 may contribute to a genetic predisposition to autism spectrum disorders (ASD), intellectual disability, or epilepsy, the impact of rare MBD5 single nucleotide variants (SNVs) on neurodevelopmental features, particularly features with late onset, has not been fully explored. In this study, we conducted exon-targeted resequencing of MBD5 with next-generation sequencing technology in 562 Japanese patients (192 with idiopathic ASD and 370 with schizophrenia (SCZ)) and detected 16 MBD5 SNVs with allele frequencies of ≤1%. We then performed phenotype analyses with 12 novel variants of these 16 SNVs. SCZ patients with these variants exhibited mainly within normal development ranges until the first psychosis and ASD patients with SNVs did not precisely overlap with the core characteristics described in previous literature as being associated with MBD5 SNVs. Our results suggested that MBD5 variants might contribute to a broad spectrum of neurodevelopmental pathophysiology. Further research and assessment of clinical diagnostic screening are necessary for understanding the burden of rare MBD5 SNVs for these neurodevelopmental disorders.

We aimed to investigate the prevalence and predictors of diabetes and prediabetes among adults in Palau. We used data of 1915 adults, aged 25 to 64 years, who participated in the World Health Organization’s (WHO) STEPwise Approach to Risk Factor Surveillance (STEPS) study in Palau. Information on behavioral risk factors of NCDs and physical and biochemical measurements were obtained using standard methods of the WHO. The diagnosis of diabetes and prediabetes was based on the recent American Diabetes Association criteria. Predictors of the prevalence of diabetes and prediabetes were identified using multinomial logistic regression analysis. The overall age-standardized prevalence of prediabetes and diabetes were 40.4% (43.6% for men, 37.4% for women) and 17.7% (18.6% for men, 17% for women), respectively. Old age, overall obesity (high BMI), central obesity (large waist circumference or waist-hip ratio), hypertension and hypertriglyceridemia were significant predictors of prediabetes and/or diabetes. Diabetes occurred at a younger age in “obese” individuals than that of their “non-obese” counterparts. We confirmed that prediabetes and diabetes are highly prevalent in Palau affecting 40% and 18% adults, respectively. Introducing public health interventions to reduce and prevent obesity as early as possible could prove useful to curb the problem.

Darier’s disease (DD, keratosis follicularis: OMIM#124200) is an autosomal dominant skin disorder characterized by multiple dark brown keratotic plaques and warty papules covered by thick crusts. Most cases of DD are caused by mutations in ATP2A2, which is expressed in both the skin and the brain. ATP2A2 encodes the cardiac muscle SERCA2a protein and the ubiquitously expressed SERCA2b. SERCA2 plays an important role as a calcium pump. It is thought that a mutation in ATP2A2 causes dyskeratosis and abnormality of cell-cell adhesion. Here, we report five DD patients from five independent families who presented or were referred to the Nagoya University Hospital in the past five years. We detected five mutations in ATP2A2, including a previously unreported mutation. We observed no apparent genotype/ phenotype correlation between types and sites of the ATP2A2 mutations and DD phenotypes in the present series of DD patients. Genetic diagnosis from ATP2A2 mutation search is useful for the definite diagnosis of DD, although it is difficult to predict the severity and prognosis of skin symptoms from the results of the ATP2A2 mutation analysis in DD patients.

The purpose of the study was to investigate perceived teeth health status and oral health behavior, as well as their correlates, among adolescents in Cambodia. The analysis included 3806 Cambodian school children (mean age 15.7 years, SD=1.8 years) who took part in the “Global School-based Student Health Survey” (GSHS) in 2013. Overall, 7.8% of the students reported poor perceived teeth status, 18.0% had missed school in the past year because of a toothache, 26.7% engaged in combined oral health behavior (brushing teeth twice daily or more often = 79.8%, using fluoride toothpaste = 59.9%, and drinking soft drinks less than once a day = 53.6%), and 59.9% had never visited a dentist for a routine examination or other dental work. In the multivariate logistic regression analysis, older age, being female, missing school because of a toothache, having a toothache in the past 12 months, poor oral health behavior and sedentary leisure time were associated with poor perceived teeth status. Older age, good perceived teeth status, having had a dental check-up, washing hands before eating and after toilet use, and not eating fast food were associated with a positive oral health behavior (brushing teeth twice daily or more often, using fluoride toothpaste, and drinking soft drinks less than once a day). Significant proportions of poor perceived teeth status and poor oral health behavior were found among school children in Cambodia. Various risk factors (sociodemographic, dental variables, general health risk behaviors) for perceived poor teeth status, oral health behavior and never having had a dental check-up were identified, which can be utilized for intervention programs.

We report a long-term survivor of colorectal cancer who underwent aggressive, frequent resection for peritoneal recurrences. A 58-year-old woman was diagnosed with descending colon cancer. Resection of the descending colon along with lymph node dissection was performed in September 2006. The pathological findings revealed Stage IIA colorectal cancer. The following peritoneal recurrences were removed: two in July 2007, two in the omental fat and two in the pouch of Douglas in June 2008 resected by low anterior resection of the rectum, one in the uterus and right ovarian recurrence resected via bilateral adnexectomy and Hartmann’s procedure in May 2011, and one in the ascending colon by partial resection of the colon wall in December 2011. Postoperative adjuvant chemotherapy (uracil and tegafur/leucovorin, fluorouracil/ levofolinate/oxaliplatin/bevacizumab, 5-fluorouracil/leucovorin/bevacizumab, irinotecan/bevacizumab, and irinotecan/panitumumab) was administered. The patient did not desire postoperative adjuvant chemotherapy after the fourth operation. The long-term survival was 6 years and 7 months.

Pulmonary blastoma (PB) is a rare form of lung tumour and is accountable for 0.25–0.5% of primary pulmonary malignancies. Initially pulmonary blastoma was divided into three subtypes: biphasic pulmonary blastoma (BPB) consisting of an epithelial and mesenchymal component, well differentiated fetal adenocarcinoma (WDFA) built of well differentiated epithelium and a mesenchymal component and malignant pleuropulmonary blastoma (PPB). Prognosis in this type of cancer is really poor. We present a current review of literature and a clinical case report. Treatment of PB is very difficult. Data and recommendations about the treatment of pulmonary blastoma are still available therefore we should use only observations and clinical case reports.

Aneurysms arising from the distal anterior inferior cerebellar artery (AICA) are very rare. When the parent artery is an AICA−posterior inferior cerebellar artery (PICA) variant, occlusion of the artery, even distal to the meatal loop, leads to a significant area of cerebellar infarction. We report two cases of ruptured partially thrombosed distal AICA aneurysms. In both cases, the parent artery was an AICA−PICA variant. The aneurysms were clipped in one case and trapped following occipital artery (OA)−AICA anastomosis in another case. It is important to keep the OA as a donor artery for revascularization in the treatment of the AICA−PICA variant aneurysms, especially when the absence of intra-aneurysmal thrombus is not comfirmed preoperatively.