Kobe Journal of Medical Sciences最新文献

A machine learning model using Extreme Gradient Boosting (XGBoost) was developed to predict long-term nursing care needs among older adults, based on comprehensive claims and health checkup data from Japan's public insurance system. The model demonstrated strong predictive performance (AUC: 0.878; sensitivity: 0.784; specificity: 0.820) on the test dataset, supporting its use for early identification of high-risk individuals. Key risk factors identified through permutation importance and marginal effect analyses included advanced age, prior care needs, neurological and gastrointestinal diseases, as well as specific medical procedures and medications. In contrast, factors such as joint replacement surgery and the use of preventive care services were associated with lower risk. Lifestyle and biochemical indicators, including slower gait speed and low LDL cholesterol, also significantly influenced risk. Constipation, osteoporosis, and lower back pain had relatively small marginal effects, but was associated with a high incidence rate. This model provides a valuable tool for extending healthy life expectancy and optimizing long-term care planning in aging populations, supporting both public health policy and personalized prevention.

Apolipoprotein B48 (ApoB48) may be an indicator of residual cardiovascular risk beyond conventional lipid measures. However, its performance for detecting coronary artery disease (CAD), alone and in combination with the ankle-brachial index (ABI), remains to be investigated. This cross-sectional study (358 patients; 299 and 59 with and without CAD, respectively) assessed the value of ApoB48 (cutoff: ≥4.5 μg/mL) and ABI (cutoff: <0.9) in detecting CAD. Subgroup analyses were performed for patients with diabetes mellitus, hypertension, dyslipidemia, and low levels of low-density lipoprotein-cholesterol (LDL-C) (<100 mg/dL). Baseline characteristics, including lipid profiles and biomarker levels, were compared between patients with and without CAD. Patients with CAD exhibited significantly higher ApoB48 levels compared to those without (5.1 ± 3.2 vs. 4.0 ± 2.2 μg/mL, respectively, p = 0.001); there were no significant differences in ABI values. The sensitivity and specificity of ABI alone for CAD were 16.7% and 81.4%, respectively, while those for ApoB48 alone were 48.2% and 61.0%, respectively. Combining both markers improved sensitivity to 55.5%, though specificity declined to 47.5%. Subgroup analyses revealed that ApoB48 maintained superior sensitivity across groups with diabetes, hypertension, dyslipidemia, and low levels of LDL-C. Lipid parameters (LDL-C, non-high density lipoprotein-cholesterol, and triglycerides) showed minimal discriminatory power between patients with and without CAD. ApoB48 demonstrates superior sensitivity for CAD detection compared to ABI, particularly in high-risk patients. While combining ApoB48 and ABI enhances sensitivity, it compromises specificity, suggesting the need for balanced diagnostic strategies. ApoB48 may be a valuable marker of residual cardiovascular risk, particularly in patients with well-controlled LDL-C or comorbid metabolic conditions.

We previously demonstrated that interferon-stimulated gene 15 protein (ISG15) plays a role in enhancing hepatitis B virus (HBV) and hepatitis C virus (HCV) infections through the ISGylation of the HBV X protein (HBx) and the HCV NS5A protein. ISGylation is a post-translational modification where ISG15 is covalently attached to target proteins. These findings suggest that targeting ISGylation could be a potential therapeutic strategy for HBV and HCV infections. In this study, we evaluated the antiviral activity of HZ-6d, a quinoline derivative that inhibits HERC5-mediated ISGylation. Our results showed that HZ-6d did not inhibit HBx ISGylation and only modestly suppressed HBV replication in HBV-infected HepG2-NTCP cells and in HBV-replicating cells. Interestingly, HZ-6d also did not affect NS5A-ISGylation, however, it significantly suppressed HCV replication. These observations suggest that HZ-6d exerts its antiviral effects in HCV-replicating cells through mechanisms independent of HERC5-mediated NS5A-ISGylation. Furthermore, HZ-6d strongly activated the p53-mediated apoptosis signaling pathway, as evidenced by increased levels of phosphorylated p53, cleaved caspase-8, and cleaved caspase-3. Notably, activation of caspase-3 has been implicated in the proteolysis of HCV NS5A, indicating that apoptosis-related mechanisms may contribute to HCV suppression. Collectively, our findings suggest that HZ-6d induces antiviral activity against HCV through the p53-mediated apoptosis pathway, rather than by interfering with HERC5-mediated NS5A ISGylation.

Hepatitis C virus (HCV) infection induces chaperone-mediated autophagy (CMA), where the HCV NS5A protein promotes the binding of the molecular chaperone HSC70 to substrate proteins containing a KFERQ motif. HSC70 recognizes this pentapeptide motif and transports substrates to lysosomes for degradation. In this study, we identified a KFERQ motif (³²⁴ELLRQ³²⁸) in the YAP1 protein, a key regulator of the Hippo pathway, and examined its interaction with HSC70 during HCV infection. To determine whether HSC70 directly binds to this motif, we generated four YAP1 mutants with specific alterations in the KFERQ motif and assessed their binding to HSC70. Among these, the R327A/Q328A mutant showed the greatest reduction in HSC70 binding, indicating that the sequence ³²⁴ELLRQ³²⁸ functions as the KFERQ motif in YAP1. Further analysis revealed that YAP1 binds to the substrate-binding domain of HSC70. Moreover, shRNA-mediated knockdown of LAMP2A, a critical receptor for CMA, led to increased levels of YAP1, confirming that YAP1 is indeed a CMA substrate. Notably, HSC70 was also found to interact with phosphorylated YAP1 at serine 127 (S127). Although NS5A did not bind directly to YAP1, NS5A expression reduced the binding between YAP1 and HSC70. This suggests that under normal conditions, YAP1 is recognized by HSC70 and degraded via CMA. However, during HCV infection, NS5A interferes with YAP1-HSC70 interaction, preventing YAP1 from being degraded. As a result, YAP1 accumulates in the cytoplasm and subsequently translocates to the nucleus, where YAP1 may activate genes involved in cell proliferation and survival. This mechanism may contribute to HCV-induced pathogenesis.

Aim: We previously reported that broad-band and specific wavelengths of ultraviolet B (UVB) limit the development of atherosclerosis by augmenting anti-inflammatory immune responses in hypercholesterolemic mice. This study aimed to elucidate the effect of 284 nm UVB on the stabilization of atherosclerotic plaques and the underlying mechanisms.

Methods and results: Six- to eight-week-old male LDL receptor-deficient (Ldlr ^-/-) mice were fed a high-fat and high-cholesterol diet for 8 weeks to form atherosclerotic lesions, and the diet was changed to a standard diet. The mice were subsequently irradiated with 284 nm UVB at 5 kJ/m² twice weekly for 2 or 4 weeks. The effects of 284 nm UVB irradiation on atherosclerotic plaque size and components and immunoinflammatory responses were evaluated by histological analysis and flow cytometry. Normalization of plasma cholesterol levels did not prevent the development of atherosclerotic lesions in the aortic sinus of UVB-irradiated or nonirradiated mice, whereas it markedly reduced the lipid content in the aortic sinus lesions of these mice, which was more prominent in UVB-irradiated mice. The accumulation of CD4⁺ T cells in atherosclerotic lesions and aortic immunoinflammatory responses were reduced in UVB-irradiated mice, although no beneficial effects of UVB treatment on macrophage accumulation or collagen content were observed. The plaque-stabilizing effect of UVB treatment was associated with augmented regulatory T cell immune responses in lymphoid tissues.

Conclusions: 284 nm UVB irradiation in combination with lipid-lowering therapy improves the stability of atherosclerotic plaques by augmenting anti-inflammatory Treg immune responses. The combination of aggressive lipid-lowering therapies and 284 nm UVB phototherapy may serve as an attractive therapeutic approach for high-risk patients with vulnerable atherosclerotic plaques.

Around 9.4% of infants born in Japan have a low birthweight. While some studies have clarified the developmental progress of very-low-birthweight (VLBW) and extremely-low-birthweight (ELBW) infants at 18 months, less is known about how these children fare in preschool. This study aimed to identify VLBW and ELBW infants without major complications and their behavioral and emotional characteristics as preschoolers compared to their infantile development. Participants were the parents of 28 VLBW and ELBW children without major complications. The Child Behavior Checklist (CBCL) 1.5-5 was administered at ages 3-5, and the results were compared with the Modified Checklist for Autism in Toddlers (M-CHAT). The examination outcomes were assessed at 18-24 months. Of these, 11 had normal scores on all CBCL scales, but the outcomes of the other 17 children were borderline or in the clinical range on either of the CBCL scales. Twenty-one children were screened negative on M-CHAT. Eleven had normal scores on all CBCL scales, but the outcomes of the other 10 children were borderline or in the clinical range on either of the CBCL scales. Seven children screened positive on M-CHAT, and all scored in the borderline or clinical range on either of the CBCL scales. Seven of the 23 M-CHAT items demonstrated relevance between 6 out of 10 CBCL-1.5-5 scales. M-CHAT-positive infants are likely to continue facing behavioral and emotional problems as preschoolers. Even in infants with a negative M-CHAT screening, the underlying problems may become apparent during the preschool years.

Background and aim: Abemaciclib, a CDK4/6 inhibitor, is used for estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Interstitial lung disease (ILD) is a frequent adverse event of abemaciclib, particularly in Asian patients, though limited information is available on its incidence and risk factors. This study aimed to identify the incidence and risk factors of abemaciclib-induced ILD through a single-center retrospective analysis.

Methods: We analyzed ER-positive, HER2-negative inoperable or metastatic breast cancer patients treated with abemaciclib at Kakogawa Central City Hospital between November 1, 2018, and March 31, 2022. At least two respiratory medicine specialists evaluated computed tomography and examined the development of ILD after the initiation of abemaciclib. We conducted univariate analysis to examine factors associated with the development of ILD.

Results: Forty-nine patients were analyzed. The median (range) observation period was 27.0 (10-49) months, and the median (range) duration of abemaciclib was 11.0 (1-43) months. Fourteen patients (28.6%) received abemaciclib as a 3rd-line treatment or later. Ten patients (20.4%) were diagnosed with abemaciclib-induced ILD; 7 were diagnosed within 6 months of the initiation of abemaciclib and 3 developed severe ILD during the same period. We identified lung metastasis as a risk factor for the development of ILD (odds ratio = 5.00, 95% confidence interval: 1.15-21.70; p = 0.032).

Conclusion: The incidence of abemaciclib-induced ILD was 20.4%, which was higher than previously reported values. Today, as abemaciclib is one of the standard treatments for ER-positive, HER2-negative breast cancer, we should be more careful about ILD.

Background: Enteral nutrition therapy in the early postoperative period is essential for patients with esophageal cancer following esophagectomy. HINEX® E-gel LC is an oligomeric formula with various nutrients, including dietary fiber pectin. It is expected to reduce symptoms, such as diarrhea, resulting in improved adherence and a decreased rate of weight loss. However, no reports have examined the adherence to or efficacy of nutritional support therapy using HINEX® E-gel LC after esophagectomy.

Methods: This is a single-institution, single-arm phase II trial. We plan to recruit 32 patients with esophageal cancer who have undergone minimally invasive esophagectomy (MIE) and place an enteral feeding tube. Enteral feeding is to be initiated on the second postoperative day, and the patient is to remain on enteral feeding at 300 kcal/day after discharge. The primary endpoint is adherence to enteral nutrition with HINEX® E-gel LC for up to 2 months postoperatively. The secondary endpoint is the association between the adherence to HINEX® E-gel LC and each nutritional parameter, such as hematological examination, body weight, and psoas muscle.

Discussion: Although enteral nutrition is usually initiated in the early postoperative period after esophagectomy, the use of fat-containing digestive agents in the early postoperative period is a novel approach. To the best of our knowledge, this study is the first to evaluate the safety and nutritional status of early postoperative enteral nutrition using fat-containing digestive agents after MIE. Efficient nutritional support therapy using fat-containing digestive agents is expected to be especially useful after esophagectomy when oral intake is significantly decreased.

We report a rare case of pseudohypercalcemia associated with multiple myeloma in a 77-year-old woman. Despite elevated albumin-corrected calcium levels (12.6 mg/dL), ionized calcium levels remained normal (1.25 mmol/L). Differential diagnoses excluded common causes of hypercalcemia, and the findings suggested calcium binding to negatively charged immunoglobulins and confirmed pseudohypercalcemia due to IgG-type myeloma. Treatment with isatuximab plus dexamethasone normalized albumin-corrected calcium levels as IgG levels decreased. This report highlights the importance of recognizing pseudohypercalcemia to prevent misdiagnosis of true hypercalcemia due to myeloma. Measuring ionized calcium levels is crucial for accurate diagnosis when hypercalcemia is suspected without corresponding clinical symptoms.

Primary hyperparathyroidism (PHPT) during pregnancy is rare, causing severe pregnancy complications. We report a pregnant woman with PHPT and a pregnancy complication history who underwent a single-gland parathyroidectomy during the second trimester and delivered at term. A 28-year-old pregnant woman, gravida 3, para 2, was referred to our hospital at 9 gestational weeks (GWs) because of previous intrauterine fetal death, preterm birth, and fetal growth restriction. She was diagnosed with PHPT during her second pregnancy, and her baby experienced neonatal hypocalcemia. However, she received no PHPT treatment afterward. Laboratory tests and neck ultrasound revealed hyperparathyroidism and an enlarged right superior parathyroid gland. She underwent a right superior parathyroidectomy at 24 GWs. She delivered a 2,136 g (-1.74 SD) healthy female infant at 37 GWs, and her baby demonstrated no neonatal hypocalcemia. Parathyroidectomy, even during pregnancy, should be considered among pregnant women with PHPT having a pregnancy or neonatal complication history.