Nagoya Journal of Medical Science

CD4⁺ regulatory T cells (Tregs) expressing the transcription factor forkhead box P3 (FoxP3) play an important role in self-tolerance and immune homeostasis. Tregs have evolved to protect the host from aberrant immune responses against self-components and collateral damages occurring in the process of defense against invading pathogens by softening immune responses. However, they turned to be a scourge in malignant tumors by not only allowing and promoting tumor growth but also suppressing effective antitumor actions, both inherent (host’s immune surveillance) and extrinsic (anticancer therapy). An increase in the number of Tregs infiltrating into tumor sites and a concomitant decrease in the number of CD8⁺ cytotoxic T lymphocytes are associated with a poor prognosis for various types of cancers, marking Tregs as notorious meddlers with an effective antitumor response. Various cancer immunotherapy approaches are often dampened by meddling Tregs, making them one of the major targets in the treatment of cancer. The recent success of immune checkpoint inhibitors (ICIs) that target immune checkpoint molecules expressed by Tregs or effector T cells implies, that “meddling with meddlers” represents an effective strategy in cancer immunotherapy. However, clinical responses to ICIs are effective and durable only in some patients with cancer, whereas more than half of them do not show significant clinical improvement. This implies that a therapeutic approach based on the use of a single ICI, or targeting Tregs alone, is insufficient, highlighting the need for combinatorial approaches. With regard to antitumor immune stimulation, several approaches, such as vaccination with peptides (or the corresponding DNA) to stimulate antigen-presenting CD8⁺ T cells with tumor-specific neoantigens, cancer/testis antigens, or cancer stem cell antigens, that eventually boost effective cytotoxic antitumor responses are being tested. This review describes the immunosuppressive physiology of Tregs and their meddling with the host’s antitumor immunity; current and prospective approaches to curb Tregs; and approaches to augment antitumor immunity.

Pulmonary hypertension (PH) is a hemodynamic state that is characterized by a resting mean pulmonary artery pressure ≧ 25 mmHg. The common forms of PH are pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), PH caused by left-heart disease, and PH due to lung disease. Previously regarded as untreatable, the treatment of PAH has dramatically advanced since the introduction of the drug epoprostenol in 1999, with three-year survival rates improving from 30%–40% to over 85%. Drugs available for the specific treatment of PAH include endothelin-receptor antagonists, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, prostacyclin analogs, and prostacyclin-receptor agonists. In the past decade, management and treatment of CTEPH have also improved. While pulmonary endarterectomy used to be the only option for the treatment of CTEPH, newer treatments include a soluble guanylate cyclase stimulator, which has proven to be an efficacious targeted therapy. Other cases benefit from balloon pulmonary angioplasty.

In order to reduce child mortality, recommendations for diarrhea management practices have been widely promoted by various methods, including mass media. This study examined whether mother’s exposure to mass media was associated with child’s diarrhea, and with the diarrhea management practiced by their mothers. Data on 7,068 women, whose youngest child was under five years old, were extracted from the Bangladesh Demographic and Health Survey, 2011, together with information on the child. The outcome variables were an episode of diarrhea in the two weeks prior to the survey and diarrhea management practices; exposure to mass media was used as the major explanatory variable. They were descriptively summarized, and logistic regression analyses were performed. Television was found to be the most common form of media. Among 346 children who had experienced an episode of diarrhea in the previous 2 weeks, less than 42.5% were given zinc and only 26.3% of the mothers provided sufficient fluids. No significant associations between mother’s mass media exposure and child’s diarrhea were observed. Women who read newspapers/magazines were more likely to provide sufficient fluids and food, and those exposed to the radio were more likely to provide zinc supplementation. Since mother’s exposure to newspaper/magazines and radio showed associations with some recommended practices for the treatment of childhood diarrhea, mass media clearly has the potential to improve diarrhea management practices. More effective use of mass media is anticipated; in particular, promotion of zinc supplementation and increasing fluid intake during diarrhea, neither of which were currently well practiced.

We evaluated the progression of interstitial lung disease (ILD) by three-dimensional curved highresolution computed tomography (3D-cHRCT) at a constant depth from the chest wall and compare the results to pulmonary function test (PFT) results on a follow-up assessment. We reviewed the patients with ILD who underwent HRCT and concurrent PFTs at least twice from April 2008 to December 2014. Fortyfive patients with ILD were enrolled. 3D-cHRCT images of the lung at various depths from the chest wall were reconstructed, and total area (TA), high-attenuation area (HAA) >-500 HU, and %HAA ([HAA/TA] × 100) were calculated. The TA, HAA, and %HAA ratios (follow-up to baseline) were assessed for use in the diagnosis of physiologically progressive ILD (defined as; forced vital capacity [FVC] ratio <0.9 or %diffusing capacity of the lung for carbon monoxide [%DLCO] ratio <0.85 [follow-up to baseline]). Of all ratios obtained from 3D-cHRCT images at 5–30mm depths, the %HAA ratio at 20-mm had the largest area under the receiver operating characteristic curve (0.815, 95 % confidence interval 0.677–0.953). By univariate logistic regression analysis, TA, HAA, and %HAA ratios at 20-mm showed significant correlations with physiologically progressive ILD. 3D-cHRCT imaging performed in parallel with the chest wall offers novel quantitative parameters that are useful for following ILD.

The major hallmarks of Alzheimer’s disease (AD) are the extracellular accumulation of pathological amyloid beta (Aβ) in the brain parenchyma and Aβ deposition in cerebral blood walls (cerebral amyloid angiopathy; CAA). Although CAA occurs in more than 80% of AD patients, the mechanisms of Aβ deposition and clearance around the vessel walls are unknown. We found Aβ-degrading activity in human serum during analysis of the regulatory mechanism of Aβ production in human endothelial cells. To elucidate the metabolic dynamics of Aβ surrounding the brain microvessels, we identified Aβ-degrading activity in human serum (blood Aβ-degrading activity: BADA) by column chromatography and LC/MS. BADA exhibited characteristics of an acidic protein, pI 4.3, which had two different protein surface charges (low and high affinity cations). Both BADA fractions had a relative molecular mass of greater than 400 kDa. Furthermore, BADA in the low affinity cation fraction was inhibited by the serine protease inhibitor 4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF). We clarified alpha-2-macroglobulin (a2M) and several serine proteases from this BADA by LC-MS. Moreover, we demonstrated that BADA is increased by approximately 5000-fold in human serum by column chromatography. Therefore, BADA may play an important role in the circulation and metabolism of Aβ in human brain microvessels.

In Myanmar, although the law prohibits the sale of tobacco products to and by those aged less than 18 years, the use of smoking and smokeless tobacco among high school students is a social problem. There has been no previous study on tobacco use or knowledge of tobacco law among students in Nay Pyi Taw. A survey was conducted to assess the knowledge, attitude, and usage pattern of tobacco among high school students in Nay Pyi Taw, Myanmar. The data were collected in three high schools, from 300 students of Grade 10 and 11, in September 2015, using anonymous self-administered questionnaires which included characteristics of students, knowledge, attitude, and usage pattern of tobacco. Of the 300 students, 104 (34.7%) were smokers and 85 (28.3%) were users of smokeless tobacco. The average age of first use of tobacco was 14 years. Although most students knew about the ill effects of tobacco, only 25% knew about the Tobacco Product Law. The most common source of tobacco was friends and male family members were main smokers in families. Most students had seen male teachers and headmasters smoking in schools. The usage of tobacco and smokeless tobacco was associated with sex and the students’ attitude towards tobacco. This study indicated that the high school students knew about the ill effects of tobacco, but not about the Tobacco Product Law. Schools need to educate students and teachers about tobacco and the Tobacco Product Law and the enforcement of the law is also needed.

Improper healthcare waste management (HCWM) poses a serious public health problem worldwide. Primary health centres (PHCs) provide public health and medical care services as the basic structural and functional units of healthcare services in Myanmar. However, no study has been conducted in Myanmar about HCWM at PHCs. This study aims to assess the practice of HCWM at PHCs in Mon State, Myanmar. A cross-sectional study was conducted in all ten townships in Mon State, Myanmar. In total, 93 PHCs (71 non-hospitals and 22 hospitals) were selected using simple random sampling. The observational checklist which was developed based on the World Health Organization’s standard guideline procedure of HCWM was used to determine the practice of HCWM at PHCs. Binary logistic regression was used for final data analysis. The burning in pits method was used as the final disposal method of healthcare waste in 78.5% of PHCs. Non-hospital type PHC were more likely not to have colour coding system for HCWM (odds ratio [OR] 7.54; 95% confidence interval [CI] 2.15–26.52), did not have equipment for accidental spillage of healthcare waste (OR 3.92; 95% CI 1.3–11.77) and did not have separate staff for HCWM (OR 8.27; 95% CI 2.77–24.64), relative to hospitals. Non-hospital type PHCs practices poorly on the colour coding for waste segregation, assigning separate staff for HCWM, and possessing equipment for accidental spillage of healthcare waste than hospital type PHCs. The Ministry of Health and Sports should issue technical guidelines of safe HCWM as a compulsory policy for both hospitals and non-hospital type PHCs.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Despite multiple treatment strategies, the prognosis is still poor. This study aimed to evaluate the efficacy of combination treatment of GBM with the histone deacetylase (HDAC) inhibitor panobinostat and dual phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235. GBM cells were exposed to panobinostat and BEZ235 treatment alone or in combination, after which cell viability, proliferation and apoptosis were detected. Furthermore, the inhibitory mechanisms were investigated by Caspase-Glo assay, Western blot and qPCR analysis. We found that combination treatment with panobinostat and BEZ235 synergistically inhibited cell viability, markedly inhibited cell proliferation and induced apoptosis in GBM cells. Mechanistically, cotreatment with panobinostat and BEZ235 increased caspase 3/7 activity, suppressed proliferation- and antiapoptosis-related markers and AKT signaling in GBM cells. Cotreatment with panobinostat and BEZ235 warrants further evaluation in GBM therapy.

This study aims at describing oral health-related quality of life (OHRQoL) and determining its associated factors in a middle-aged and older adult community dwelling population in Myanmar. In a cross-sectional community survey, 633 individuals (men 55% and women 45%), aged 35–65 years, selected by multi-stage random sampling, responded to a structured questionnaire on the Oral Health Impact Profile-short form (OHIP-14), health status, health behavior and socio-demographic information. Participants had an overall mean score of 8.1(item mean=0.65) on the OHIP-14, 57.2% had impaired OHRQoL and 16.6% frequent impaired OHRQoL. The highest prevalence of problems was found to be psychological discomfort (60.2%), followed by physical pain (51.7%) and physical disability (40.9%). In adjusted logistic regression analysis, poor oral health status (tooth loss, having one or more cavities, and poor perceived periodontal health), and poor general health status (depressive symptoms) were positive while oral health behavior (drinking piped or bottled water, using toothpaste with fluoride, and never visited a dentist) were negatively associated with both impaired and frequent impaired OHRQoL. In addition, frequent soft drink consumption was associated with impaired OHRQoL, and having a high household income and being physically inactive were associated with frequent impaired OHRQoL. A high prevalence of impaired OHRQoL was found among this middle-aged and older adult population in central Myanmar. Several risk factors (poor oral health status, poor general health status, poor oral and general health behavior) for impaired OHRQoL were identified, which could help in guiding oral health interventions among the populace.

Surgical intervention for the treatment of acetabular fracture non-union is often challenging. Here, we present a case of acetabular fracture non-union with pelvic discontinuity in a patient who underwent cemented total hip arthroplasty (THA) after intra- and extra-articular plate fixation. The case was a 70-year-old male with left T-shaped acetabular fracture non-union neglected for 5 months after the injury. The anterior and posterior columns were not healed, and the articular surface was displaced toward the medial side with a protrusion of the collapsed femoral head. As the first surgical intervention, we performed intra- and extra-articular plate fixation after femoral head decapitation. We fixed non-union regions from the inferior acetabular margin to the anterior column using a pelvic reconstruction plate bent three-dimensionally at the acetabular curvature on the intra-articular side. Furthermore, we fixed that of the posterior column on the outside of the acetabulum using a bent pelvic reconstruction plate. Union of the anterior and posterior columns was observed at 4 and 6 months after the first surgical intervention. At 7 months, we performed a cemented THA without additional bone grafting. At 1-year follow-up, the patient did not have left coxalgia and could walk without any gait supports. Based on our experience, we propose this surgical protocol as a useful treatment option for cases of acetabular fracture non-union.

Afghanistan is one of the countries with the poorest maternal mortality ratio in the world. Inadequate utilization of antenatal care (ANC) services increases the risk of maternal mortality. This study aimed to identify the factors associated with ANC visits in Afghanistan. The dataset of the Afghanistan Demographic and Health Survey (AfDHS) 2015 were used for taking the socio-demographic factors, cultural factors, and the number of ANC visits. The subjects of this study were 18,790 women who had at least one live birth in the last five years, and 10,554 women (56.2%) had availed of at least one ANC visit. Most women were 20-29 years old (53.3%), poor (41.7%), had 2–4 children (43.9%), lived in rural areas (76.1%), and had no education (85.0%) or no job (86.7%). Most women answered that husbands made a decision about their healthcare and that getting permission from their husbands was a major challenge. Multivariate analysis showed that age, ethnicity, area of residence, parity, women’s education, husband’s education, literacy, having a job, wealth, the decision maker for healthcare, and difficulty in getting permission from the husband were significantly correlated with availing of the ANC visits. This study showed that not only the socio-demographic factors but also the cultural factors were associated with ANC visits. The Afghanistan government should improve the education programs at schools and healthcare facilities, for both men and women. To augment women’s propensity to take a decision, the programs for women’s empowerment need to be supported and extended across the country.

Due to rapid economic growth in China, many gambling sites have emerged along the neighboring countries, including Myanmar, which place migrants at risk of developing gambling problems. This study aimed at identifying: i) types of gambling, ii) gambling involvement and intensity, and iii) the associations with problem gambling. A community-based cross-sectional study was conducted in Muse, Myanmar. A convenience sample of 273 internal migrants (18–49 years) filled a self-administered questionnaire. Chisquare tests and multiple logistic regression explored associations between gambling practices and problem gambling. Among the categories of gambling, the popular gambling types were lottery games (Aung Bar Lay, Thone-Lone and Nhit-Lone) and card games, as well as the use of Electronic Gambling Machines (EGMs). An average number of past-year gambling types involved and of gambling types engaged in regularly were 1.61 (SD=0.95) and 1.22 (SD=0.70), respectively. In association with PG, Nhit-Lone, EGMs, cards, and dice games were strongly associated among the gambling types. Those with PG had a higher number of involvement by past-year gambling types (1.92 vs. 1.18 for no PG) and spent 5 times higher amount of money on gambling. In conclusion, this study showed that types of gambling, such as Nhit-Lone, cards and dice games and higher involvement and intensity were associated with problem gambling. The findings provide new and important insights into gambling behavior among internal migrant workers in the border area with China and highlight the need for culturally specific preventive measures for the Myanmar population, with preference to gambling types.

Previous epidemiological studies have shown that coffee consumption may reduce liver cancer risk. The present study aimed to summarize the evidence for this association in the Japanese population by performing a meta-analysis of the results of relevant cohort studies conducted in Japan. We searched studies published prior to September 1, 2018 in PubMed. Extracted data were analyzed using a random effects model. A total of six cohort studies from five publications were included in the final analysis. The pooled estimate of relative risk with 95% confidence interval (CI) for the group with highest coffee consumption was 0.50 (95% CI: 0.38–0.66, p < 0.001) compared with non-coffee drinkers or those who almost never drink coffee. No evidence of publication bias was observed (p for Begg’s test = 0.85). This meta-analysis suggested that coffee consumption among Japanese people has a significant role in preventing liver cancer.

Recent epidemiological or immunopathological studies demonstrate the possible association between giant cell arteritis and infectious agents including Chlamydia pneumoniae. A 62-year-old Japanese man with type 1 diabetes mellitus developed biopsy-proven giant cell arteritis after acute upper respiratory infection. Serological examination indicated concurrent re-infection with C. pneumoniae. Clinical manifestations of the vasculitis subsided within a month without any immunosuppressive therapy, and no relapse was observed for the following 12 months. The natural history of this disease is unclear and spontaneous remission is rarely reported. The self-limiting nature of the infection could contribute to this phenomenon.

The periacetabular gap is an inherent consequence of the peripheral rim press-fit of the porous tantalum acetabular component. The circumference of the prosthesis is clearly depicted with computed tomography (CT) images that have been optimised to reduce metal artefacts. This case report highlights the utility of single-energy metal artefact reduction (SEMAR) for CT evaluation of the periacetabular gap by comparing CT images with and without SEMAR. A 70-year-old woman with a 5-year history of rheumatoid arthritis underwent total hip arthroplasty with a porous tantalum modular acetabular component. A periacetabular gap was suspected by plain radiography 2 weeks postoperatively. The metal artefacts rendered evaluation of the circumference of the acetabular component difficult in CT images acquired without SEMAR. In contrast, there were fewer metal artefacts, and a periacetabular gap (depth of 6.5 mm in DeLee and Charnley zone 2) was clearly depicted in CT images with SEMAR 2 weeks postoperatively. The porous surface of the acetabular component was in contact with the anterior and posterior rims of the acetabulum. Gap filling with bone and bone ingrowth into the porous surface were observed on CT images with SEMAR 24 weeks postoperatively. In conclusion, SEMAR reduces metal artefacts and improves CT image quality around the circumference of the acetabular component. The periacetabular gap and its filling with bone are clearly depicted in CT images with SEMAR, but not without SEMAR.

We report a very rare case of resected subsegmental lymph node metastasis of unknown origin. Hilar (N1) lymph node metastasis of unknown origin has previously been reported, but intrapulmonary lymph node metastasis has not been reported to date. At this patient’s first visit to our hospital, an abnormal nodule was found on the upper lung lobe on a chest radiograph. After 4 years’ follow-up, the nodule vanished, but a tiny nodule had emerged. 2-Fluoro-2-deoxy-D-glucose positron-emission tomography (FDG-PET) computed tomography was performed, and abnormal accumulation was observed only in the newly emerged intrapulmonary nodule. Right upper lobectomy was performed and a metastatic subsegmental lymph node, but no primary lesion, was found. Our observations suggest that evanescence of a suspicious primary lesion indicates the possibility of metastasis. FDG-PET was useful in this case for detecting lymph node metastases and demonstrating that the primary and further metastatic lesions were absent.

Fibrosarcoma is an extremely rare malignant sex-cord stromal tumor. Fibrosarcoma is generally unknown as an estrogen producing tumor. This report presents, for the first time, a case of estrogen producing ovarian fibrosarcoma in an 83-year-old female. We performed total hysterectomy, bilateral salpingo-oophorectomy and omentectomy. Histopathologically, the tumor of the left ovary had high cellularity, cellular atypia and 10–15 mitotic counts per 10 high power fields. The tumor contained small components composed of cells that were similar to Sertoli cells. In an effort to examine which component was producing estrogen, we checked aromatase expression; but both components were positive. We could not explain which component was producing estrogen. Postoperative clinical stage was IA. As she was geriatric patient, we did not recommend adjuvant chemotherapy. There were no signs of recurrence or increase in serum estradiol level at two years after the operation.

Like standard stenting in an unresectable malignant stricture of the biliary or digestive tract, minimally invasive modality for portal stenosis is indispensable for palliation. We describe here a safe and practical procedure of portal stenting in a case of metastatic hilar strictures developed nine years after the radical resection of sigmoid colon cancer. After urgent delivery of the biliary tract stenting for the relief of jaundice, the patient received palliative stenting for the stricture of the portal trunk. Transhepatic approach, via the anterior branch, of the portal vein intervention may fit into the standard aspects for portal stenting.