Nagoya Journal of Medical Science

Pregnancy is an excellent opportunity to provide medical interventions to women. It is also a stress test used to predict health. Numerous studies have demonstrated that the pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) are critical factors for pregnancy complications such as hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), large or small gestational age infants, and spontaneous preterm birth (sPTB). These complications are associated with an increased risk of cardiovascular disease (CVD), which is a leading cause of mortality in women. In addition, complications adversely affect the short- and long-term prognoses of children. Optimal GWG to reduce complications is recommended based on pre-pregnancy BMI; however, racial differences should also be noted. The values in the Japanese guidelines are lower than those in the American Institute of Medicine guidelines. The Asian BMI thresholds for CVD risk are also lower than those in Europe. Therefore, weight management should be based on racial/genetic background. Interpregnancy weight gain or loss has also been reported to be associated with the risk of pregnancy complications; however, few studies have been conducted in Asian populations. Our previous reports suggested that avoiding an excess of 0.6 kg/m²/year of annual BMI gain may reduce the risk of HDP or GDM, and insufficient gain of < 0.25 kg/m²/year may increase sPTB recurrence. Annual BMI is useful for practical weight control during interpregnancy. Based on these findings, effective approaches should be established to improve the health of women and their offspring.

Androgen receptor signaling inhibitors combined with androgen deprivation therapy have become the standard of care for metastatic castration-sensitive prostate cancer (mCSPC), regardless of tumor volume or risk. However, survival of approximately one-third of these patients has not improved, necessitating further treatment escalation. On the other hand, for patients with oligometastatic mCSPC, there is an emerging role for local radiation therapy. Although data remain scarce, it is expected that treatment of both primary tumor as well as metastasis-directed therapy may improve survival outcomes. In these patients, systemic therapy may be de-escalated to intermittent therapy. However, precise risk stratification is necessary for risk-based treatment escalation or de-escalation. In addition to risk stratification based on clinical parameters, research has been conducted to incorporate genomic and/or transcriptomic data into risk stratification. In future, an integrated risk model is expected to precisely stratify patients and guide treatment strategies. Here, we first review the transition of the standard treatment for mCSPC over the last decade and further discuss the newest concept of escalating or de-escalating treatment using a multi-modal approach based on the currently available literature.

As the Japanese population continues to age steadily, the number of older adults requiring healthcare has increased. Evidence demonstrates that hospitalization for acute care has a negative impact on the health outcomes of older adults. Frail older adults tend to have multifactorial conditions collectively known as “geriatric syndromes.” When those with these premorbid conditions are hospitalized for acute care, they tend to develop new problems such as delirium and new functional impairments. Adverse consequences of hospitalization include the risk of loss of functional independence and chronic disability. In 2019, the new concept of “hospital-associated complications” (HACs) was proposed to describe these new problems. HACs comprise five conditions: hospital-associated falls, delirium, functional decline, incontinence, and pressure injuries. This review discusses the important issues of HACs in relation to their classification, prevalence, risk factors, prevention, and management in older adults hospitalized for acute care. Robust prevention and management are imperative to address the serious consequences and escalating medical costs associated with HACs, and a multidimensional and multidisciplinary approach is key to achieving this goal. Comprehensive geriatric assessment (CGA) is the cornerstone of geriatric medicine and offers a holistic approach involving multidisciplinary and multidimensional assessments. Considerable evidence is accumulating regarding how CGA and coordinated care can improve the prognosis of hospitalized older adults. Further research is needed to understand the occurrence of HACs in this population and to develop effective preventive measures.

Patients with acute coronary syndrome (ACS), frequently caused by plaque rupture (PR), often have vulnerable plaques in residual lesions as well as in culprit lesions. However, whether this occurs in patients with plaque erosion (PE) as well is unknown. We retrospectively analyzed the data of 88 patients with ACS who underwent both optimal coherence tomography (OCT) and intravascular ultrasound (IVUS). Based on plaque morphology of the culprit lesions identified using OCT, patients were classified into PE (n=23) and PR (n=35) groups. The tissue characteristics of residual lesions evaluated using integrated backscatter IVUS were compared between both groups after percutaneous coronary intervention. The PE group had a significantly lower percent lipid volume and a higher percent fibrous volume than the PR group (35.0±17.8% vs 49.2±13.4%, p<0.001; 63.2±17.1% vs 50.3±13.1%, p=0.002, respectively). Receiver operating characteristic curve analysis revealed that percent lipid volume in the residual lesions was a significant discriminant factor in estimating the plaque morphology of the culprit lesion (optimal cut-off value, <43.5%; sensitivity and specificity values were 73.9% and 68.6%, respectively). In conclusion, patients with PE had a significantly lower percent lipid volume and a significantly higher percent fibrous volume in the residual lesions than those with PR, suggesting that the nature of coronary plaques in patients with PE is different from that of those with PR.

The purpose of this study was to develop and test the reliability and validity of a brief and comprehensive instrument to assess self-management, decision-making, and coping by chronic obstructive pulmonary disease (COPD) patients. A web-based questionnaire was administered to 300 COPD patients and a retest was administered to 100 COPD patients. Cronbach’s alpha was used to assess internal consistency, and an intraclass correlation coefficient was calculated to test the reliability of the retest. The convergent and discriminant validities were also examined. Valid responses were obtained from 279 participants in the first survey and 70 participants in the retest. From our analysis, a COPD self-care assessment scale (CSCS) was developed, consisting of seven subscales and 14 items. Cronbach’s alpha for the total CSCS score, intraclass correlation coefficient, and scale success rate were 0.80, 0.79, and 100%, respectively. A multivariate analysis showed that CSCS was associated with current smoking (standardized partial regression coefficient [std β] = −0.30; p < 0.001), long-term oxygen therapy (std β = 0.23; p < 0.001), and social support (std β = 0.24; p < 0.001), but not psychological symptoms or quality of life. The CSCS is also useful in assessing self-management, decision-making, and coping in Japanese COPD patients, and the scale has high reliability and validity.

Psychiatric disorders are highly inheritable, and most psychiatric disorders exhibit genetic overlap. Recent studies associated the 3q29 recurrent deletion with schizophrenia (SCZ) and autism spectrum disorder (ASD). In this study, we investigated the association of genes in the 3q29 region with SCZ and ASD. TM4SF19 and PAK2 were chosen as candidate genes for this study based on evidence from previous research. We sequenced TM4SF19 and PAK2 in 437 SCZ cases, 187 ASD cases and 524 controls in the Japanese population. Through targeted sequencing, we identified 6 missense variants among the cases (ASD & SCZ), 3 missense variants among controls, and 1 variant common to both cases and controls; however, no loss-of-function variants were identified. Fisher’s exact test showed a significant association of variants in TM4SF19 among cases (p=0.0160). These results suggest TM4SF19 variants affect the etiology of SCZ and ASD in the Japanese population. Further research examining 3q29 region genes and their association with SCZ and ASD is thus needed.

Cleft palate is the most common facial birth defect worldwide. It is caused by environmental factors or genetic mutations. Environmental factors such as pharmaceutical exposure in women are known to induce cleft palate. The aim of the present study was to investigate the protective effect of Sasa veitchii extract against medicine-induced inhibition of proliferation of human embryonic palatal mesenchymal cells. We demonstrated that all-trans-retinoic acid inhibited human embryonic palatal mesenchymal cell proliferation in a dose-dependent manner, whereas dexamethasone treatment had no effect on cell proliferation. Cotreatment with Sasa veitchii extract repressed all-trans-retinoic acid-induced toxicity in human embryonic palatal mesenchymal cells. We found that cotreatment with Sasa veitchii extract protected all-trans-retinoic acid-induced cyclin D1 downregulation in human embryonic palatal mesenchymal cells. Furthermore, Sasa veitchii extract suppressed all-trans-retinoic acid-induced miR-4680-3p expression. Additionally, the expression levels of the genes that function downstream of the target genes (ERBB2 and JADE1) of miR-4680-3p in signaling pathways were enhanced by cotreatment with Sasa veitchii extract and all-trans-retinoic acid compared to all-trans-retinoic acid treatment. These results suggest that Sasa veitchii extract suppresses all-trans-retinoic acid-induced inhibition of cell proliferation via modulation of miR-4680-3p expression.

The relationship between demographic/clinical characteristics, clinical outcomes and the development of hemorrhagic complications in patients with ischemic stroke who underwent reperfusion therapy has not been studied sufficiently. We have aimed to compare genders and age groups in terms of clinical features and outcome; and types of reperfusion treatments and clinical features regarding the development of hemorrhagic complications in patients with ischemic stroke who underwent recombinant tissue plasminogen activator (rtPA) and/or thrombectomy. Patients with acute ischemic stroke undergoing rtPA and/or thrombectomy were divided into six age groups. Parameters including hemorrhagic complications, anticoagulant and antiaggregant use, hyperlipidemia, smoking status, biochemical parameters, and comorbidities were documented. National Institutes of Health Stroke Scale (NIHSS) scores, modified Rankin Score (mRS) and Glasgow Coma Scale scores were recorded. Etiological classification of stroke was done. These parameters were compared in terms of age groups, genders, and hemorrhagic complications. Significant differences were found between age groups concerning hypertension, coronary artery disease, smoking status, and antiaggregant use. Rate of hemorrhagic complications in rtPA group was significantly lower when compared with other treatment groups. Hemorrhagic complications developed mostly in the rtPA+thrombectomy group. Among the patients who developed hemorrhagic complications, NIHSS scores on admission were found to be significantly lower in men than women. Admission, discharge, and 3^rd month mRS values in men were significantly lower than those of women. Knowing demographic and clinical features of patients that may have an impact on the clinical course of ischemic stroke managed with reperfusion therapy will be useful in predicting the hemorrhagic complications and clinical outcomes.

Until recently, the Thai national program of seasonal influenza vaccination for high-risk people has been using a walk-in service system. However, in 2020, an online registration system was introduced in Bangkok to improve vaccine coverage. This study aimed to compare the coverage of influenza vaccination between the walk-in service and online registration systems. The study participants included 374,710 Thai individuals who obtained an influenza vaccination from the national program in the Bangkok health region in 2018 (n = 162,214) and in 2020 (n = 212,496). The registration systems that were examined were the walk-in service system in 2018 and the online registration system in 2020. The characteristics of vaccine recipients and the vaccine coverage in each risk group and health facility level were compared between the two systems. Coverage comparison in Bangkok between the years 2018 and 2020 showed an increase in coverage, particularly among individuals who had an influenza vaccination at health facilities of the primary level and in the elderly and obesity groups. The coverage among children was lowest among all high-risk groups. To improve coverage in Thailand, the online registration system should be introduced in all regions. Additionally, information about influenza vaccination for children should be disseminated to parents using handbooks or by word-of-mouth from healthcare workers.

Despite encouraging multi-generational cohabitation, the population of Japanese people living alone has increased. However, little is known about the association between health and multigenerational cohabitation. This study examined the relationship between self-rated health and living arrangements among Japanese adults using data from the Japan Multi-Institutional Collaborative Cohort Study (2013–2017). The analysis employed multivariate logistic regression to examine the associations. Our results showed no association between living arrangements and self-rated health when stratified by gender. Living alone was found to be associated with poor self-rated health among women aged 65 and above. A similar association may exist among men in the same age group. Among women aged < 65 years, two-generation cohabitation was associated with a good self-rated health, similar to those living alone. Among men aged < 65 years, neither living alone nor two-generation cohabitation was significantly associated with good self-rated health. We found no association between three- or plus-generation cohabitation and self-rated health. Therefore, our findings indicate associations between multigenerational cohabitation and self-rated health, but they vary by gender and age. Invested stakeholders in the public health field should consider the potential impact of living arrangements on health based on gender and age.

Enterovesical fistula (EVF) in Crohn’s disease (CD) often does not improve with medical treatment and requires surgical treatment. The surgical treatment strategy for EVF in CD is definitive resection of the intestinal tract side, and performing a leak test using dye injection into the bladder after EVF dissection to determine the appropriate surgical procedure for the bladder side. This study aimed to evaluate the outcomes of surgical treatment for EVF in CD. Twenty-one patients who underwent surgery for EVF between 2006 and 2021 were included and retrospectively evaluated for clinical background, surgical procedures, and postoperative complications. The most common origin of EVF was the ileum (17 cases; 81%), and the most common site of EVF formation was the apex (12; 57%). Surgical approaches were laparotomy in 11 (52%) cases and laparoscopy in 10 (48%). Surgical procedures on the bladder side were fistula dissection in 13 (62%) cases and sutured closure of fistula in 8 (38%). A comparison of approaches revealed no significant difference in operative time, but the amount of blood loss was significantly less in the laparoscopy (p < 0.01). There was no significant difference in the occurrence of postoperative complications between approaches. Postoperative anti-TNF-α antibody agents were used in 17 (81%) cases, and there were no cases of recurrent EVF. In conclusion, definitive resection of the intestinal tract and minimal treatment on the bladder side were sufficient to achieve satisfactory outcomes for EVF in CD.

Endothelial dysfunction is important in the pathology of pulmonary hypertension, and circulating endothelial progenitor cells (EPCs) have been studied to evaluate endothelial dysfunction. In patients with chronic thromboembolic pulmonary hypertension (CTEPH), riociguat reportedly increases the number of circulating EPCs. However, the relationship between EPC numbers at baseline and changes in clinical parameters after riociguat administration has not been fully elucidated. Here, we evaluated 27 treatment-naïve patients with CTEPH and analyzed the relationships between EPC number at diagnosis and clinical variables (age, hemodynamics, atrial blood gas parameters, brain natriuretic peptide, and exercise tolerance) before and after riociguat initiation. EPCs were defined as CD45^dim CD34⁺ CD133⁺ cells and measured by flow cytometry. A low number of circulating EPCs at diagnosis was significantly correlated with increased reductions in mean pulmonary arterial pressure (mPAP) (correlation coefficient = 0.535, P = 0.004) and right atrial pressure (correlation coefficient = 0.618, P = 0.001) upon riociguat treatment. We then divided the study population into two groups according to the mPAP change: a weak-response group (a decrease in mPAP of 4 mmHg or less) and a strong-response group (a decrease in mPAP of more than 4 mmHg). The number of EPCs at diagnosis was significantly lower in the strong-response group than in the weak-response group (P = 0.022), but there were no significant differences in other clinical variables or in medication profiles. In conclusion, circulating EPC numbers could be a potential predictor of the therapeutic effect of riociguat in CTEPH patients.

Radiotherapy combined with temozolomide (TMZ+RT) is the primary treatment for high-grade glioma. TMZ is classified as a moderate emetic risk agent and, thus, supportive care for nausea and vomiting is important. In Nagoya University Hospital, all patients are treated with a 5-hydroxy-tryptamine 3 receptor antagonist (5-HT₃RA) for the first 3 days. The daily administration of 5-HT₃RA is resumed after the 4th day based on the condition of patients during TMZ+RT. Therefore, the present study investigated risk factors for nausea and vomiting in patients requiring the daily administration of 5-HT₃RA. Patients with high-grade glioma who received TMZ+RT between January 2014 and December 2019 at our hospital were included. Patients were divided into two groups: a control group (patients who did not resume 5-HT₃RA) and resuming 5-HT₃RA group (patients who resumed 5-HT₃RA after the 4th day), and both groups were compared to identify risk factors for nausea and vomiting during TMZ+RT. There were 78 patients in the control group (68%) and 36 in the resuming 5-HT₃RA group (32%). A multivariate analysis of patient backgrounds in the two groups identified age <18 years, PS 2 or more, and occipital lobe tumors as risk factors for nausea and vomiting. Nausea and vomiting were attenuated in 30 patients (83%) in the resuming 5-HT₃RA group following the resumption of 5-HT₃RA. The results obtained highlight the importance of extracting patients with these risk factors before the initiation of therapy and the early resumption or daily administration of 5-HT₃RA according to the condition of each patient.

Advanced glycation end products (AGEs) have been reported to be associated with osteoporosis, aging, sarcopenia, and frailty. This study aimed to investigate the association AGEs with locomotive syndrome (LS). Participants were Japanese individuals aged 39 years or older who participated in the Yakumo Study (n=230). AGEs were measured by skin autofluorescence (SAF) using an AGE reader. We investigated SAF values for each locomotive stage. Multivariate logistic regression models were used to calculate the odds ratios of LS-associated factors. The relationships between SAF and physical performance and bone mineral density (BMD) were investigated. A receiver operating characteristic (ROC) curves were generated to determine the optimal cut-off value of SAF for predicting LS. SAF values tended to increase correspondingly with LS severity. SAF was an independently explanatory factor for LS (odds ratio 2.70; 95% confidence interval [CI] 1.040–6.990). SAF was positively correlated with the 10-m walking speed, The Timed Up and Go test results, and was negatively correlated with BMD. ROC curve represented by SAF for the presence or absence of LS risk had an area under the curve of 0.648 (95% CI: 0.571–0.726). High SAF values were identified as an independent risk factor for LS. AGEs could be a potential screening tool for people for LS.

We previously reported the Marimo cell line, which was established from the bone marrow cells of a patient with essential thrombocythemia (ET) at the last stage after transformation to acute myeloid leukemia (AML). This cell line is widely used for the biological analysis of ET because it harbors CALR mutation. However, genetic processes during disease progression in the original patient were not analyzed. We sequentially analyzed the genetic status in the original patient samples during disease progression. The ET clone had already acquired CALR and MPL mutations, and TP53 and NRAS mutations affected the disease progression from ET to AML in this patient. Particularly, the variant allele frequency of the NRAS mutation increased along with the disease progression after transformation, and the NRAS-mutated clone selectively proliferated in vitro, resulting in the establishment of the Marimo cell line. Although CALR and MPL mutations co-existed, MPL was not expressed in Marimo cells or any clinical samples. Furthermore, mitogen-activated protein kinase (MAPK) but not the JAK2-STAT pathway was activated. These results collectively indicate that MAPK activation is mainly associated with the proliferation ability of Marimo cells.

To the best of our knowledge, this is the first case of pregnancy with a healthy baby after treatment with an oral gonadotropin-releasing hormone (GnRH) antagonist in women with premature ovarian insufficiency. A 36-year-old female presented at our hospital after being diagnosed with premature ovarian insufficiency by a previous doctor. We administered clomiphene, human menopausal gonadotropin (hMG), and GnRH antagonist (injection) together with estrogen replacement for 11 cycles (27 months), but no follicular development was observed. When the oral GnRH antagonist (relugolix), which has recently become available, was used in the 12^th cycle, follicular growth of 13 mm was confirmed on the 14^th day of stimulation. After stimulation, the use of hMG and GnRH antagonist (injection) was continued, and a maturation trigger, human chorionic gonadotropin 10000 IU, was administered. Oocyte retrieval was performed successfully, intracytoplasmic sperm injection and frozen embryo transfer were performed, and fetal heartbeat was confirmed. The patient was admitted to the perinatal management facility. She delivered a healthy baby of 3,732 g via cesarean section at 41 weeks +2. This case shows the possibility of using an oral GnRH antagonist as an option for infertility treatment.

We describe a case of erythema induratum of Bazin (EIB) that presented recurrently on the extremities during treatment with anti-tuberculosis medications. The anti-tuberculosis medications were effective, so they were continued despite the occurrence of the EIB lesions, and those lesions disappeared 5 months after first appearing. EIB is currently considered a multifactorial disorder with many different causes, with tuberculosis being an example, and it is thought to be a hypersensitive immune response to Mycobacterium tuberculosis. The clinical manifestations may fluctuate depending on the immune response of the host. Our patient was affected with myelodysplastic syndrome, and we believe that this was a major factor that interfered with a normal immune response. This case illustrates the importance of providing intensive anti-tuberculosis treatment from the start, and in cases where EIB co-presents, to continue this treatment until the end, in order to prevent relapse.

Exercise induced anaphylaxis (EIA) is a rare and potentially life-threatening syndrome characterized by anaphylaxis provoked by exercise. Although vaginal delivery with labor pain is a physical strain for women and a possible trigger for EIA, no consensus exists on the management strategy of delivery in patients with EIA. A 28-year-old primigravida was referred to our hospital because of history of EIA, associated with pruritus, urticaria, and respiratory distress, exacerbated during physical activity. To avoid physical stress, we chose scheduled labor induction with epidural anesthesia, and administered prophylactic intravenous hydrocortisone. She delivered vaginally with no symptoms suggestive of EIA during labor. Since it is quite possible for patients with EIA to develop anaphylaxis during vaginal delivery with labor pain, epidural anesthesia and prophylactic steroid administration may be the most rational approaches for delivery in pregnant women with EIA.