No strong association among epigenetic modifications by DNA methylation, telomere length, and physical fitness in biological aging.

Cellular senescence is greatly accelerated by telomere shortening, and the steps forward in human aging are strongly influenced by environmental and lifestyle factors, whether DNA methylation (DNAm) is affected by exercise training, remains unclear. In the present study, we investigated the relationships between physiological functions, maximal oxygen uptake (VO2max), vertical jump, working memory, telomere length (TL) assessed by RT-PCR, DNA methylation-based estimation of TL (DNAmTL), and DNA methylation-based biomarkers of aging of master rowers (N = 146) and sedentary subjects (N = 95), aged between 37 and 85 years. It was found that the TL inversely correlated with chronological age. We could not detect an association between telomere length and VO2max, vertical jump, and working memory by RT-PCR method, while these physiological test results showed a correlation with DNAmTL. DNAmGrimAge and DNAmPhenoAge acceleration were inversely associated with telomere length assessed by both methods. It appears that there are no strong beneficial effects of exercise or physiological fitness on telomere shortening, however, the degree of DNA methylation is associated with telomere length.

Treatment for the recurrent case of locking of the metacarpophalangeal joint of the thumb: A case report.

BACKGROUND: Locking of the metacarpophalangeal (MP) joint of the thumb is a rare condition caused by hyperextension injury. Cases are treated by closed reduction, but open reduction is occasionally required. CASE PRESENTATION: Herein, we report a recurrent case of locking of the MP joint. Closed reduction was successful for treatment of the first injury but unsuccessful for the second injury, and open reduction was performed. At the operation for the second injury, we observed a transverse groove on joint cartilage of the metacarpal head. CONCLUSION: In recurrent cases, we should assume the possibility of failure of closed reduction and prepare for open reduction.

Sulforaphane Attenuates Neutrophil ROS Production, MPO Degranulation and Phagocytosis, but Does Not Affect NET Formation Ex Vivo and In Vitro.

Sulforaphane has several effects on the human body, including anti-inflammation, antioxidation, antimicrobial and anti-obesity effects. In this study, we examined the effect of sulforaphane on several neutrophil functions: reactive oxygen species (ROS) production, degranulation, phagocytosis, and neutrophil extracellular trap (NET) formation. We also examined the direct antioxidant effect of sulforaphane. First, we measured neutrophil ROS production induced by zymosan in whole blood in the presence of 0 to 560 µM sulforaphane. Second, we examined the direct antioxidant activity of sulforaphane using a HOCl removal test. In addition, inflammation-related proteins, including an azurophilic granule component, were measured by collecting supernatants following ROS measurements. Finally, neutrophils were isolated from blood, and phagocytosis and NET formation were measured. Sulforaphane reduced neutrophil ROS production in a concentration-dependent manner. The ability of sulforaphane to remove HOCl is stronger than that of ascorbic acid. Sulforaphane at 280 µM significantly reduced the release of myeloperoxidase from azurophilic granules, as well as that of the inflammatory cytokines TNF-α and IL-6. Sulforaphane also suppressed phagocytosis but did not affect NET formation. These results suggest that sulforaphane attenuates neutrophil ROS production, degranulation, and phagocytosis, but does not affect NET formation. Moreover, sulforaphane directly removes ROS, including HOCl.

Vertical locking of the metacarpophalangeal joint of the little finger: A case report.

Locking of the metacarpophalangeal (MCP) joint is commonly caused by hyperextension of the thumb or moderate flexion of the index or middle finger. We report a rare case of vertical locking of the MCP joint of the little finger in a 16-year old female after blunt trauma to the little finger. The MCP joint was locked when positioned at approximately 90-degree-flexion and could not extend actively or passively. A manual reduction was easily achieved and no immobilization was applied. Vertical locking of the MCP joint can be easily reduced, and immobilization is unnecessary after reduction. Correct diagnosis prior to reduction and differentiation from other types of locking are essential to prevent overtreatment.

Lipase member H frequently overexpressed in human esophageal adenocarcinomas.

Esophageal cancer is one of the most frequent causes of cancer-related deaths worldwide. This is due to its asymptomatic nature or mild nonspecific symptoms. Most patients are diagnosed after appearance of prominent symptoms, and tumors are frequently accompanied by severe infiltration. Therefore, molecular biomarkers for the prognosis of early-stage esophageal cancer are desired. In this study, we examined the prognostic potential of lipase H (LIPH), a recently reported biomarker for lung adenocarcinoma and squamous carcinoma. We found that LIPH mRNA is also frequently upregulated in esophageal adenocarcinoma. Immunohistochemical analysis confirmed LIPH protein expression in various esophageal tumor tissue sections. Interestingly, higher expression of LIPH in esophageal adenocarcinoma showed a positive correlation with longer survival of patients. Our data suggest that LIPH may have prognostic value for esophageal cancer.

Lipase member H is a novel secreted protein selectively upregulated in human lung adenocarcinomas and bronchioloalveolar carcinomas.

Lung cancer is one of the most frequent causes of cancer-related death worldwide. However, molecular markers for lung cancer have not been well established. To identify novel genes related to lung cancer development, we surveyed publicly available DNA microarray data on lung cancer tissues. We identified lipase member H (LIPH, also known as mPA-PLA1) as one of the significantly upregulated genes in lung adenocarcinoma. LIPH was expressed in several adenocarcinoma cell lines when they were analyzed by quantitative real-time polymerase chain reaction (qPCR), western blotting, and sandwich enzyme-linked immunosorbent assay (ELISA). Immunohistochemical analysis detected LIPH expression in most of the adenocarcinomas and bronchioloalveolar carcinomas tissue sections obtained from lung cancer patients. LIPH expression was also observed less frequently in the squamous lung cancer tissue samples. Furthermore, LIPH protein was upregulated in the serum of early- and late-phase lung cancer patients when they were analyzed by ELISA. Interestingly, high serum level of LIPH was correlated with better survival in early phase lung cancer patients after surgery. Thus, LIPH may be a novel molecular biomarker for lung cancer, especially for adenocarcinoma and bronchioloalveolar carcinoma.

Performance evaluation of ChatGPT, GPT-4, and Bard on the official board examination of the Japan Radiology Society.

PURPOSE: Herein, we assessed the accuracy of large language models (LLMs) in generating responses to questions in clinical radiology practice. We compared the performance of ChatGPT, GPT-4, and Google Bard using questions from the Japan Radiology Board Examination (JRBE). MATERIALS AND METHODS: In total, 103 questions from the JRBE 2022 were used with permission from the Japan Radiological Society. These questions were categorized by pattern, required level of thinking, and topic. McNemar's test was used to compare the proportion of correct responses between the LLMs. Fisher's exact test was used to assess the performance of GPT-4 for each topic category. RESULTS: ChatGPT, GPT-4, and Google Bard correctly answered 40.8% (42 of 103), 65.0% (67 of 103), and 38.8% (40 of 103) of the questions, respectively. GPT-4 significantly outperformed ChatGPT by 24.2% (p < 0.001) and Google Bard by 26.2% (p < 0.001). In the categorical analysis by level of thinking, GPT-4 correctly answered 79.7% of the lower-order questions, which was significantly higher than ChatGPT or Google Bard (p < 0.001). The categorical analysis by question pattern revealed GPT-4's superiority over ChatGPT (67.4% vs. 46.5%, p = 0.004) and Google Bard (39.5%, p < 0.001) in the single-answer questions. The categorical analysis by topic revealed that GPT-4 outperformed ChatGPT (40%, p = 0.013) and Google Bard (26.7%, p = 0.004). No significant differences were observed between the LLMs in the categories not mentioned above. The performance of GPT-4 was significantly better in nuclear medicine (93.3%) than in diagnostic radiology (55.8%; p < 0.001). GPT-4 also performed better on lower-order questions than on higher-order questions (79.7% vs. 45.5%, p < 0.001). CONCLUSION: ChatGPTplus based on GPT-4 scored 65% when answering Japanese questions from the JRBE, outperforming ChatGPT and Google Bard. This highlights the potential of using LLMs to address advanced clinical questions in the field of radiology in Japan.

VMAT with DIBH in hypofractionated radiotherapy for left-sided breast cancer after breast-conserving surgery: results of a non-inferiority clinical study.

The purpose of this study was to show the safety of volumetric modulated arc therapy (VMAT) with deep inspiration breath-hold (DIBH) in hypofractionated radiotherapy for left-sided breast cancer after breast-conserving surgery in a clinical setting. Twenty-five Japanese women, aged 20-59 years, who were enrolled in this prospective non-inferiority study received VMAT under the condition of DIBH with 42.4 Gy/16 fractions for whole-breast irradiation (WBI) ± boost irradiation for the tumor bed to show the non-inferiority of VMAT with DIBH to conventional fractionated WBI with free breathing. The primary endpoint was the rate of occurrence of radiation dermatitis of Grade 3 or higher or pneumonitis of Grade 2 or higher within 6 months after the start of radiotherapy. This study was registered with UMIN00004321. All of the enrolled patients completed the planned radiotherapy without interruption. The evaluation of adverse events showed that three patients (12.0%) had Grade 2 radiation dermatitis. There was no other Grade 2 adverse event and there was no patient with an adverse event of Grade 3 or higher. Those results confirmed our hypothesis that the experimental treatment method is non-inferior compared with our historical results. There was no patient with locoregional recurrence or metastases. In conclusion, VMAT under the condition of DIBH in hypofractionated radiotherapy for left-sided breast cancer after breast-conserving surgery can be performed safely in a clinical setting.

TIF1beta regulates the pluripotency of embryonic stem cells in a phosphorylation-dependent manner.

Transcription networks composed of various transcriptional factors specifically expressed in undifferentiated embryonic stem (ES) cells have been implicated in the regulation of pluripotency in ES cells. However, the molecular mechanisms responsible for self-renewal, maintenance of pluripotency, and lineage specification during differentiation of ES cells are still unclear. The results of this study demonstrate that a phosphorylation-dependent chromatin relaxation factor, transcriptional intermediary factor-1beta (TIF1beta), is a unique regulator of the pluripotency of ES cells and regulates Oct3/4-dependent transcription in a phosphorylation-dependent manner. TIF1beta is specifically phosphorylated in pluripotent mouse ES cells at the C-terminal serine 824, which has been previously shown to induce chromatin relaxation. Phosphorylated TIF1beta is partially colocalized at the activated chromatin markers, and forms a complex with the pluripotency-specific transcription factor Oct3/4 and subunits of the switching defective/sucrose nonfermenting, ATP-dependent chromatin remodeling complex, Smarcd1 [corrected], Brg-1, and BAF155, all of which are components of an ES-specific chromatin remodeling complex, esBAF. Phosphorylated TIF1beta specifically induces ES cell-specific genes and enables prolonged maintenance of an undifferentiated state in mouse ES cells. Moreover, TIF1beta regulates the reprogramming process of somatic cells in a phosphorylation-dependent manner. Our results suggest that TIF1beta provides a phosphorylation-dependent, bidirectional platform for specific transcriptional factors and chromatin remodeling enzymes that regulate the cell differentiation process and the pluripotency of stem cells.

Prevalence of sesamoid bones in the interphalangeal joint of the thumb and fingers: a radiographic study.

The prevalence of sesamoid bones in the hands has been reported in some previous articles. Most of them, however, have reported sesamoid bones of the metacarpophalangeal joint of the hand and of the interphalangeal (IP) joint of the thumb. The present study investigates the prevalence of sesamoid bones of the IP joint of the thumb and fingers. A retrospective review of radiologic views of the IP joints in the thumb or fingers was performed, including a total of 650 patients (1,096 thumbs or fingers). Sesamoid bones were found in the IP joint of the thumb at 67% (212 of 318), while the index, middle, ring, little fingers had sesamoid bones in the proximal interphlangeal (PIP) joint at 0% (0 of 172), 0.4% (1 of 244), 0.5% (1 of 183), and 1% (2 of 179), respectively. None of the four fingers had sesamoid bones in the distal IP joint. Previous articles have described the similar prevalence to the present study, of sesamoid bones of the IP joint of the thumb, while some others reported the different prevalence. About the PIP joint, no previous articles have found a sesamoid bone. Because the lateral X-ray view is more accurate and suitable to evaluate sesamoid bones, we used the lateral one for the present study. The knowledge that sesamoid bones occurs at these rates in the thumb IP joint and finger PIP joints is helpful to differentiate chip fractures from sesamoid bones near the IP joint, including the PIP joint.

The Circulating Level of Klotho Is Not Dependent upon Physical Fitness and Age-Associated Methylation Increases at the Promoter Region of the Klotho Gene.

(1) Background: Higher levels of physical fitness are believed to increase the physiological quality of life and impact the aging process with a wide range of adaptive mechanisms, including the regulation of the expression of the age-associated klotho (KL) gene and protein levels. (2) Methods: Here, we tested the relationship between the DNA methylation-based epigenetic biomarkers PhenoAge and GrimAge and methylation of the promoter region of the KL gene, the circulating level of KL, and the stage of physical fitness and grip force in two groups of volunteer subjects, trained (TRND) and sedentary (SED), aged between 37 and 85 years old. (3) Results: The circulating KL level is negatively associated with chronological age in the TRND group (r = -0.19; p = 0.0295) but not in the SED group (r = -0.065; p = 0.5925). The age-associated decrease in circulating KL is partly due to the increased methylation of the KL gene. In addition, higher plasma KL is significantly related to epigenetic age-deceleration in the TRND group, assessed by the biomarker of PhenoAge (r = -0.21; p = 0.0192). (4) Conclusions: The level of physical fitness, on the other hand, does not relate to circulating KL levels, nor to the rate of the methylation of the promoter region of the KL gene, only in males.

Recent Postoperative Radiotherapy for Left-sided Breast Cancer Does Not Increase Mortality of Heart Disease in Asians or Pacific Islanders: SEER Database Analysis.

BACKGROUND/AIM: The purpose of this study was to evaluate the impact of recent radiotherapy on mortality from heart disease in Asians or Pacific islanders with breast cancer using the Surveillance, Epidemiology, and End Results (SEER) database. PATIENTS AND METHODS: Asians or Pacific islanders with stage 0 or I (AJCC 6th) breast cancer between 2000 and 2015 were analyzed. The impact of radiotherapy for mortality from heart disease after treatment was evaluated by comparing patients who received radiotherapy for left-sided breast cancer, patients who received radiotherapy for right-sided breast cancer and patients who did not receive radiotherapy. RESULTS: In 25,684 Asians or Pacific islanders, the incidence of cardiac death was higher in patients who did not receive radiotherapy than in patients who received radiotherapy. Among patients who received external beam irradiation, the incidence of cardiac death was 2.00% for patients with left-sided breast cancer and 1.69% for patients with right-sided breast cancer, with no significant difference (chi-square test, p=0.427). In the period from 2000 to 2008, there was no significant difference between the cumulative heart-related death rates in patients who received radiotherapy and in patients who did not receive radiotherapy (Tarone-Ware test, p=0.406); however, in 2009-2015, the cumulative heart-related death rate in patients who did not receive radiotherapy was significantly higher than that in patients who received radiotherapy (log-rank test, p<0.001). CONCLUSION: Heart-related death after treatment for breast cancer is relatively rare in Asians or Pacific islanders. Since at least 2000, the cardiac impact of postoperative radiotherapy has not been significant.

An 81-Year-Old Man Presenting with Asthenia and Anorexia After an Alcohol-Induced Hypoglycemic Coma and a Diagnosis of Central Adrenal Insufficiency: A Case Report.

BACKGROUND Alcohol abuse inhibits the ability of the liver to release glucose into the bloodstream, primarily by inhibiting gluconeogenesis, so chronic alcohol abusers exhibit hypoglycemia after drinking alcohol without eating; this is called alcohol-induced hypoglycemia. Central adrenal insufficiency (AI) is characterized by cortisol deficiency due to a lack of adrenocorticotropic hormone. It is challenging to diagnose central AI, as it usually presents with nonspecific symptoms, such as asthenia, anorexia, and a tendency toward hypoglycemia. Here, we report a rare case of central AI that presented with AI symptoms shortly after an alcohol-induced hypoglycemic coma. CASE REPORT An 81-year-old Japanese man who had been a moderate drinker for >40 years developed a hypoglycemic coma after consuming a large amount of sake (alcohol, 80 g) without eating. After the hypoglycemia was treated with a glucose infusion, he rapidly recovered consciousness. After stopping alcohol consumption and following a balanced diet, he had normal plasma glucose levels. However, 1 week later, he developed asthenia and anorexia. The endocrinological investigation results indicated central AI. He was started on oral hydrocortisone (15 mg/day), which relieved his AI symptoms. CONCLUSIONS Cases of central AI associated with alcohol-induced hypoglycemic attacks have been reported. Our patient developed AI symptoms following an alcohol-induced hypoglycemic attack. His alcohol-induced hypoglycemic attack likely occurred in combination with a developing cortisol deficiency. This case highlights the importance of considering central AI in chronic alcohol abusers presenting with nonspecific symptoms, including asthenia and anorexia, especially when patients have previously experienced alcohol-induced hypoglycemic attacks.

Hypoglycemic Hemiplegia Associated with Reversible Narrowing of the Contralateral Middle Cerebral Artery in a Patient with Adrenal Insufficiency.

A 56-year-old man with a 2.5-month history of anorexia developed sweating, weakness, and left hemiplegia and hemispatial neglect. Brain magnetic resonance imaging detected no abnormalities, but magnetic resonance angiography revealed narrowing of the right middle cerebral artery (MCA). The focal neurological signs and narrowing of the MCA resolved after detection and correction of hypoglycemia. Endocrinological examinations indicated adrenal insufficiency. Hemiplegia is a rare but important neurological manifestation of hypoglycemia, although the mechanisms involved remain unknown. Combined hypoglycemia and decreased MCA blood flow associated with vasospasm probably induced regionally severe neuroglycopenia with ischemia, which presented as focal neurological symptoms.

Clinical, imaging, and molecular features of radiation-induced glioblastomas developing more than 20 years after radiation therapy for intracranial germinomatous germ cell tumor: illustrative cases.

BACKGROUND: Germinomatous germ cell tumor is highly sensitive to chemoradiotherapy; patients are expected to survive for decades. Many radiation-induced malignant gliomas (RIMGs) occur >10 years after radiotherapy. Standard therapy for RIMGs has not been established because of the lesion's rarity, the patient's shorter survival period, and the risk of radiation necrosis by repeat radiation. OBSERVATIONS: Two patients, a 32-year-old man and a 50-year-old man, developed glioblastomas more than 20 years after radiation monotherapy for germinoma with or without mature teratoma. The first patient showed a tumor in the left frontotemporal region with disseminated lesions and died 2 months after partial resection of the tumor without responding to the chemotherapy with temozolomide and bevacizumab. Methylation classifier analysis classified the pathology as closest to diffuse pediatric-type high-grade glioma, Rtk1 subtype. The second patient showed a tumor mass in the brainstem and left cerebellar peduncle, which worsened progressively during chemotherapy with temozolomide and bevacizumab. The tumor transiently responded to stereotactic radiotherapy with the CyberKnife. However, the patient died of RIMG recurrence-related aspiration pneumonia 11 months after the biopsy. Methylation classifier analysis classified the pathology as closest to infratentorial pilocytic astrocytoma. LESSONS: Chemoradiotherapy may improve the survival of patients with RIMGs. Furthermore, molecular features may influence the clinical, locoregional, and pathological features of RIMG.

DNA methylation clock DNAmFitAge shows regular exercise is associated with slower aging and systemic adaptation.

DNAmPhenoAge, DNAmGrimAge, and the newly developed DNAmFitAge are DNA methylation (DNAm)-based biomarkers that reflect the individual aging process. Here, we examine the relationship between physical fitness and DNAm-based biomarkers in adults aged 33-88 with a wide range of physical fitness (including athletes with long-term training history). Higher levels of VO2max (ρ = 0.2, p = 6.4E - 4, r = 0.19, p = 1.2E - 3), Jumpmax (p = 0.11, p = 5.5E - 2, r = 0.13, p = 2.8E - 2), Gripmax (ρ = 0.17, p = 3.5E - 3, r = 0.16, p = 5.6E - 3), and HDL levels (ρ = 0.18, p = 1.95E - 3, r = 0.19, p = 1.1E - 3) are associated with better verbal short-term memory. In addition, verbal short-term memory is associated with decelerated aging assessed with the new DNAm biomarker FitAgeAcceleration (ρ: - 0.18, p = 0.0017). DNAmFitAge can distinguish high-fitness individuals from low/medium-fitness individuals better than existing DNAm biomarkers and estimates a younger biological age in the high-fit males and females (1.5 and 2.0 years younger, respectively). Our research shows that regular physical exercise contributes to observable physiological and methylation differences which are beneficial to the aging process. DNAmFitAge has now emerged as a new biological marker of quality of life.

Successful treatment of bilateral vertebral artery dissecting aneurysms with subarachnoid hemorrhage: report of three cases.

Vertebral artery dissecting aneurysm (VADA) is a relatively rare cause of subarachnoid hemorrhage (SAH). Bilateral VADAs are even rare, and management strategies for this type of VADAs are still controversial. Here, we report 3 cases of bilateral VADAs with SAH. All 3 patients were treated conservatively under strict sedation and blood pressure control during the acute stage. During the course, rebleeding was not observed in any case. One patient underwent trapping of the ruptured VADA on day 28, because this lesion was considered to have a high tendency to rebleed, even in the chronic stage. In the other 2 patients, after conservative treatment, the VADAs spontaneously resolved on the both sides. As for the therapeutic strategy for bilateral VADAs presenting with SAH, at the acute stage, considering the difficulty of bypass surgery, we recommend conservative treatment with sedation and strict control of blood pressure. At the chronic stage, however, when the VADA is still large and growing in size, surgical treatment such as proximal occlusion or trapping of the affected VA with or without distal revascularization should be considered to avoid rebleeding.

Ulnar Nerve Injury Following Distal Radius Fracture Assessed by Ultrasonography: Management of an Ulnar Nerve Lesion.

A fracture of the distal radius with an associated injury to the ulnar nerve is rare. The management of the ulnar nerve lesion is unclear. We present a patient with a closed distal radius fracture related to an injury to the ulnar nerve associated with diminished sensation and a claw deformity. This was assessed by ultrasonography (US) that showed the nerve to be in continuity without any evidence of compression. The nerve was deviated towards the volar side at the distal end of the ulna and was enlarged at the same point. Open reduction and internal fixation was performed for the fracture. Emergent nerve exploration was not performed. The function of the ulnar nerve was completely restored at 16 weeks after injury. In cases presenting with ulnar nerve injury, we recommend US to evaluate the condition of the ulnar nerve. Nerve exploration should be performed when neurological deficits were found on US or symptoms did not recover over 4 months observation. Level of Evidence: Level V (Therapeutic).

Entrapment of the Ulnar Nerve and Artery Associated with Closed Distal Radius and Ulna Fracture: A Case Report.

CASE: We encountered a case of entrapment of the ulnar nerve and artery associated with displaced distal radius and ulna fracture. After the closed reduction, a patient noted a severe sensory deficit and had claw hand. Intraoperatively, the proximal edge of the fractured radius was positioned in the space between the ulnar artery and the nerve, and the nerve was entrapped. The entrapment was released surgically with a good 1-year outcome. CONCLUSION: In cases of distal radius fracture, there is a possibility of entrapment of the ulnar nerve. When neurological symptoms worsen after the reduction maneuver, early nerve exploration is needed.