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Abstract Background Several studies have confirmed the advantages of delivering high doses of external beam radiotherapy to achieve optimal tumor-control outcomes in patients with localized prostate cancer. We evaluated the medium-term treatment outcome after high-dose, image-guided intensity-modulated radiotherapy (IMRT) using intra-prostate fiducial markers for clinically localized prostate cancer. Methods In total, 141 patients with localized prostate cancer treated with image-guided IMRT (76 Gy in 13 patients and 80 Gy in 128 patients) between 2003 and 2008 were enrolled in this study. The patients were classified according to the National Comprehensive Cancer Network-defined risk groups. Thirty-six intermediate-risk patients and 105 high-risk patients were included. Androgen-deprivation therapy was performed in 124 patients (88%) for a median of 11 months (range: 2–88 months). Prostate-specific antigen (PSA) relapse was defined according to the Phoenix-definition (i.e., an absolute nadir plus 2 ng/ml dated at the call). The 5-year actuarial PSA relapse-free survival, the 5-year distant metastasis-free survival, the 5-year cause-specific survival (CSS), the 5-year overall survival (OS) outcomes and the acute and late toxicities were analyzed. The toxicity data were scored according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up was 60 months. Results The 5-year PSA relapse-free survival rates were 100% for the intermediate-risk patients and 82.2% for the high-risk patients; the 5-year actuarial distant metastasis-free survival rates were 100% and 95% for the intermediate- and high-risk patients, respectively; the 5-year CSS rates were 100% for both patient subsets; and the 5-year OS rates were 100% and 91.7% for the intermediate- and high-risk patients, respectively. The Gleason score ( Conclusions These medium-term results demonstrate a good tolerance of high-dose image-guided IMRT. However, further follow-up is needed to confirm the long-term treatment outcomes.

Case: A 34-year-old man presented at our hospital with knee collapse. Magnetic resonance imaging (MRI) revealed posterior compression of the dural sac by a lumbar epidural lesion; however, a diagnosis could not be reached. Gadolinium (Gd)-enhanced 3-dimensional MRI (3D-MRI) clearly delineated the morphology, enabling us to make a preoperative diagnosis of posterior epidural migration of the lumbar disc fragment (PEMLDF). Furthermore, detailed location information enabled surgical removal of the lesion in a minimally invasive manner., Conclusions: PEMLDF is rare and often difficult to diagnose. Gd-enhanced 3D-MRI provides useful information for the diagnosis and surgical planning for PEMLDF., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C488)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

High-intensity intermittent training (HIIT) in a normobaric hypoxic environment enhances exercise capacity, possibly by increasing the mitochondrial content in skeletal muscle; however, the molecular mechanisms underlying these adaptations are not well understood. Therefore, we investigated whether HIIT under normobaric hypoxia can enhance the expression of proteins involved in mitochondrial biogenesis and dynamics in rat gastrocnemius muscle. Five-week-old male Wistar rats (n = 24) were randomly assigned to the following four groups: (1) sedentary under normoxia (20.9% O 2 ) (NS), (2) training under normoxia (NT), (3) sedentary under normobaric hypoxia (14.5% O 2 ) (HS), and (4) training under normobaric hypoxia (HT). The training groups in both conditions were engaged in HIIT on a treadmill five to six days per week for nine weeks. From the fourth week of the training period, the group assigned to hypoxic conditions was exposed to normobaric hypoxia. Forty-eight hours after completing the final training session, gastrocnemius muscles were surgically removed, and mitochondrial enzyme activity and mitochondrial biogenesis and dynamics regulatory protein levels were determined. Citrate synthase (CS) activity and mitochondrial oxygen phosphorylation (OXPHOS) subunits in the gastrocnemius muscle in the HT significantly exceeded those in the other three groups. Moreover, the levels of a master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and a mitochondrial fusion-related protein, optic atrophy 1 (OPA1), were significantly increased by HIIT under normobaric hypoxia. Our data indicates that HIIT and normobaric hypoxia increase the expression of mitochondrial biogenesis- and dynamics-related proteins in skeletal muscles., Competing Interests: Declarations. Compliance with ethical standards: This study was approved by the Juntendo University Animal Care Committee and was conducted according to the guiding principles for the care and use of Animals in the Field of Physiological Sciences of the Physiological Society of Japan. Conflict of interest: The authors declare no conflicts of interest., (© 2024. The Author(s) under exclusive licence to University of Navarra.)

Background: Although there are reports on the recurrence prevention in the chronic phase using direct oral anticoagulants (DOACs) for deep vein thrombosis (DVT) in patients with cancer, acute thrombus regression effect using DOACs has not been assessed. This study aimed to assess the thrombus regression effect of initial treatment using edoxaban for acute lower-extremity DVT in patients with active cancer., Methods and Results: In this observational study, among the inpatients with cancer and lower-extremity DVT who underwent initial treatment with edoxaban at our hospital from November 2019 to December 2021, 34 consenting patients were recruited in this study. The quantitative ultrasound thrombus (QUT) score of thrombus volume was calculated at baseline (before administration) and 7-14 days after the start of edoxaban administration, using lower-extremity venous ultrasound to evaluate changes in thrombus volume. The primary and secondary endpoints were the acute thrombus regression effect of edoxaban and the impact of patients' clinical frailty on the thrombus regression effect, respectively. Anticoagulant therapy with edoxaban significantly reduced QUT score (p < 0.001). In addition, regardless of the Clinical Frailty Scale scores, QUT score decreased significantly., Conclusion: Initial treatment with edoxaban was effective for lower-extremity DVT in patients with cancer. In addition, the effect was the same independent of the degree of frailty., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

MOTS-c is a mitochondrial microprotein that improves metabolism. Here, we demonstrate CK2 is a direct and functional target of MOTS-c. MOTS-c directly binds to CK2 and activates it in cell-free systems. MOTS-c administration to mice prevented skeletal muscle atrophy and enhanced muscle glucose uptake, which were blunted by suppressing CK2 activity. Interestingly, the effects of MOTS-c are tissue-specific. Systemically administered MOTS-c binds to CK2 in fat and muscle, yet stimulates CK2 activity in muscle while suppressing it in fat by differentially modifying CK2-interacting proteins. Notably, a naturally occurring MOTS-c variant, K14Q MOTS-c, has reduced binding to CK2 and does not activate it or elicit its effects. Male K14Q MOTS-c carriers exhibited a higher risk of sarcopenia and type 2 diabetes (T2D) in an age- and physical-activity-dependent manner, whereas females had an age-specific reduced risk of T2D. Altogether, these findings provide evidence that CK2 is required for MOTS-c effects., Competing Interests: Pinchas Cohen is an advisor to and stockholder in CohBar Inc. UCLA has licensed the intellectual property on MOTS-c, on which Pinchas Cohen is listed as an inventor, to CohBar. None of the other authors has any conflicts of interest, financial or otherwise, to disclose., (© 2024 The Author(s).)

Purpose: Exercise benefits the body and mind, but its weight loss effect is less than generally expected. Although this phenomenon is likely due to an exercise intensity-dependent decrease in non-exercise physical activity (NEPA), resulting in a decrease in non-exercise activity thermogenesis, the underlying mechanisms and effects of exercise intensity remain unknown. Here we show that acute vigorous exercise decreases subsequent NEPA and body temperature (BT) in association with body weight gain., Methods: Adult male C57BL/6J mice were categorized into three groups: sedentary, moderate exercise, and vigorous exercise, with exercise groups undergoing a 30-min treadmill session. Using an intraperitoneally implanted activity monitor, NEPA and BT were monitored for 2 d before and 3 d after exercise. The daily synchrony between NEPA and BT was evaluated using a cross-correlation function. Plasma corticosterone was also detected 6 and 24 h after exercise., Results: Notably, only the vigorous exercise group exhibited a decline in both NEPA and BT, resulting in body weight gain the following day, despite no observed changes in food intake. Furthermore, vigorous exercise induces a distinct delay in the daily dynamics of NEPA compared with BT. A positive correlation was observed between plasma corticosterone levels and changes in NEPA levels before and after exercise across all exercise groups., Conclusions: Our findings provide evidence for vigorous exercise-specific reduction in subsequent NEPA, BT, and their synchrony linked to weight gain, likely due to the disturbed circadian rhythm of corticosterone. This is an initial investigation redefining the significance of exercise intensity in beneficial effects beyond the energy expenditure of the exercise itself., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

Background: The Alcohol Use Disorders Identification Test (AUDIT) is commonly used in clinical settings to assess the severity of alcohol-related problems, with the effectiveness of alcohol reduction interventions varying across this spectrum. In a recent study, we demonstrated that a 12-week intervention involving the provision of free non-alcoholic beverages reduced alcohol consumption among heavy drinkers for up to 8 weeks post-intervention. However, it remains unclear whether this effect was consistent across different AUDIT score ranges. Therefore, this secondary analysis aimed to examine whether the severity of alcohol-related problems, as indicated by AUDIT scores, influences the effectiveness of non-alcoholic beverage provision in reducing alcohol consumption., Methods: This was a single-center, open-label, randomized, parallel-group study. Participants were Japanese individuals who frequently consumed large quantities of alcohol (at least 40 g/day for men and 20 g/day for women) but were not diagnosed with alcohol dependence. Participants were randomly assigned to either an intervention or control group. The intervention group received free non-alcoholic beverages once every 4 weeks over a 12-week period (24 bottles of 350 mL per case, up to three cases per session, for a total of three sessions). Alcohol and non-alcoholic beverage consumption over the previous 4 weeks was tracked using a drinking diary. For this secondary analysis, participants were categorized into four groups based on their AUDIT scores (group 1: ≤ 7 points, group 2: 8-11 points, group 3: 12-14 points, and group 4: ≥ 15 points), and changes in alcohol consumption were compared across these groups in both the intervention and control participants., Results: The provision of non-alcoholic beverages significantly increased non-alcoholic beverage consumption in all groups. However, alcohol consumption was significantly reduced in the intervention groups compared to controls only in groups 1-3. The reduction in alcohol consumption was less pronounced in groups 3 and 4 compared to group 1 (both, p < 0.05). Importantly, the provision of non-alcoholic beverages did not lead to an increase in alcohol consumption, even among individuals with higher AUDIT scores., Conclusions: These findings suggest that individuals with higher AUDIT scores may experience a reduced benefit from a 12-week non-alcoholic beverage intervention in terms of alcohol consumption reduction. Nevertheless, this intervention appears to be a safe and effective strategy for reducing alcohol consumption in heavy drinkers who do not have alcohol dependence., Trial Registration: UMIN UMIN000047949. Registered 4 June 2022., (© 2024. The Author(s).)

Background: It is unclear whether brief interventions using the combined classification of alcohol-metabolizing enzymes aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) together with behavioral changes in alcohol use can reduce excessive alcohol consumption. This study aimed to examine the effects of a brief intervention based on the screening of ALDH2 and ADH1B gene polymorphisms on alcohol consumption in Japanese young adults., Methods: In this open-label randomized controlled trial, we enrolled adults aged 20-30 years who had excessive drinking behavior (average amount of alcohol consumed: men, ≥  4 drinks/per day and women, ≥  2 drinks/per day; 1 drink = 10 g of pure alcohol equivalent). Participants were randomized into intervention or control group using a simple random number table. The intervention group underwent saliva-based genotyping of alcohol-metabolizing enzymes (ALDH2 and ADH1B), which were classified into five types. A 30-min in-person or online educational counseling was conducted approximately 1 month later based on genotyping test results and their own drinking records. The control group received traditional alcohol education. Average daily alcohol consumption was calculated based on the drinking diary, which was recorded at baseline and at 3 and 6 months of follow-up. The primary endpoint was average daily alcohol consumption, and the secondary endpoints were the alcohol-use disorder identification test for consumption (AUDIT-C) score and behavioral modification stages assessed using a transtheoretical model., Results: Participants were allocated to the intervention (n = 100) and control (n = 96) groups using simple randomization. Overall, 28 (29.2%) participants in the control group and 21 (21.0%) in the intervention group did not complete the follow-up. Average alcohol consumption decreased significantly from baseline to 3 and 6 months in the intervention group but not in the control group. The reduction from baseline alcohol consumption values and AUDIT-C score at 3 months were greater in the intervention group than in the control group (p < 0.001). In addition, the behavioral modification stages were significantly changed by the intervention (p < 0.001)., Conclusions: Genetic testing for alcohol-metabolizing enzymes and health guidance on type-specific excessive drinking may be useful for reducing sustained average alcohol consumption associated with behavioral modification., Trial Registration: R000050379, UMIN000044148, Registered on June 1, 2021., (© 2024. The Author(s).)

Background: Blood vessels have the Windkessel effect and are involved in blood circulation. The breakdown of this mechanism is also involved in the pathogenesis of heart failure (HF); however, the relationship between vascular dysfunction and HF prognosis is not fully understood. Methods : We evaluated 214 patients hospitalized for HF at our institution who underwent a cardio-ankle vascular index (CAVI), which evaluates vascular function, between January 2012 and July 2018. To investigate factors (including CAVI) associated with major adverse cardiac events (MACE) during 1 year after patients with HF were discharged, we evaluated clinical profiles, blood tests, chest X-P, 12-lead electrocardiography, and transthoracic echocardiographic findings. MACE was defined as cardiovascular death or readmission for HF. Results : The severity of HF between the MACE and non-MACE was not significantly different. Previous HF and chronic kidney disease were significantly more common in the MACE group. CAVI and % mean atrial pressure in the MACE group were statistically higher than those in the non-MACE group. The cardiac shadow as shown by chest X-P and left ventricular size in the MACE group were significantly bigger, and HF preserved ejection fraction (EF) (EF > 50%) was significantly more common in the MACE group. In multivariate analysis, CAVI was an independent predictive factor for the occurrence of MACE (model 1; hazard ratio (HR): 1.33, 95% confidence interval (CI): 1.05-1.68, p = 0.018; model 2; HR: 1.31, 95% CI: 1.07-1.60, p = 0.009). Conclusions : Because high CAVI is associated with poor prognosis of HF, these patients require more careful treatment.

Background: We recently demonstrated that a 12-week intervention consisting of the provision of free non-alcoholic beverages reduced alcohol consumption in excessive drinkers for 8 weeks after the intervention. However, gender differences in this effect were not explored. Thus, this secondary analysis investigated gender differences in the influence of non-alcoholic beverage provision on alcohol consumption., Methods: Individuals who frequently drank excessively (at least 40 g/day in men and 20 g/day in women) and who were not diagnosed with alcoholism were recruited. Participants were randomized into the intervention or control group by simple randomization using a random number table. In the intervention group, free non-alcoholic beverages were provided once every 4 weeks for 12 weeks (three times in total). The consumption of alcoholic and non-alcoholic beverages was calculated based on a drinking diary submitted with the previous 4 weeks' of data. In this study, we compared the longitudinal changes in alcohol consumption between genders in both groups., Results: The provision of non-alcoholic beverages significantly reduced alcohol consumption in both genders; however, significant differences in alcohol consumption between the control and intervention groups were observed only in men. The average alcohol consumption during the intervention fell below the level associated with a high risk of non-communicable diseases in men (32.7 g/day), but not in women (24.8 g/day). Correlation coefficient analysis showed that replacing alcoholic beverages with the provided non-alcoholic beverages resulted in different drinking patterns according to gender. The percent changes in the consumption of alcoholic and non-alcoholic beverages relative to baseline levels did not differ between genders., Conclusions: Our results suggest that the provision of non-alcoholic beverages reduced alcohol consumption irrespective of gender. Of note, providing non-alcoholic beverages might be particularly useful for reducing high-risk alcohol consumption in male excessive drinkers., Trial Registration: UMIN UMIN000047949. Registered 4 June 2022., (© 2024. The Author(s).)

Skeletal muscle is a highly plastic tissue. The role of heat shock protein 72 (Hsp72) in heat stress-induced skeletal muscle hypertrophy has been well demonstrated; however, the precise mechanisms remain unclear. Essential amino acids, such as leucine, mainly mediate muscle protein synthesis. We investigated the effects of pre-heating and increased Hsp72 expression on the mechanistic target of rapamycin (mTOR) signaling and protein synthesis following leucine administration in rat gastrocnemius muscle. To ensure increased Hsp72 expression in both the red and white portions of the muscle, one leg of male Wistar rats (10-week-old, n = 23) was heat-stressed in 43 °C water for 30 min twice at a 48-h-interval (heat-stressed leg, HS leg). The contralateral leg served as a non-heated internal control (CT leg). After the recovery period (48 h), rats were divided into the pre-administration or oral leucine administration groups. We harvested the gastrocnemius muscle (red and white parts) prior to administration and 30 and 90 min after leucine treatment (n = 7-8 per group) and intramuscular signaling responses to leucine ingestion were determined using western blotting. Heat stress significantly upregulated the expression of Hsp72 and was not altered by leucine administration. Although the phosphorylation levels of mTOR/S6K1 and ERK were similar regardless of heating, 4E-BP1 was less phosphorylated in the HS legs than the CT legs after leucine administration in the red portion of the muscles (P < 0.05). Moreover, c-Myc expression differed significantly after leucine administration in both the red and white portions of the muscles. Our findings indicate that following oral leucine administration, pre-heating partially blunted the muscle protein synthesis signaling response in the rat gastrocnemius muscle., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Heat stress (HS) induces Akt/mTOR phosphorylation and FoxO3a signaling; however, whether a prior increase in heat shock protein 72 (HSP72) expression affects intracellular signaling following eccentric exercise remains unclear. We analyzed the effects of HS pretreatment on intramuscular signaling in response to acute exercise in 10-week-old male Wistar rats (n = 24). One leg of each rat was exposed to HS and the other served as an internal control (CT). Post-HS, rats were either rested or subjected to downhill treadmill running. Intramuscular signaling responses in the red and white regions of the gastrocnemius muscle were analyzed before, immediately after, or 1 h after exercise (n = 8/group). HS significantly increased HSP72 levels in both deep red and superficial white regions. Although HS did not affect exercise-induced mTOR signaling (S6K1/ERK) responses in the red region, mTOR phosphorylation in the white region was significantly higher in CT legs than in HS legs after exercise. Thr308 phosphorylation of Akt showed region-specific alteration with a decrease in the red region and an increase in the white region immediately after downhill running. Overall, a prior increase in HSP72 expression elicits fiber type-specific changes in exercise-induced Akt and mTOR phosphorylation in rat gastrocnemius muscle., (© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: The evaluation of arteriosclerosis (vascular function) is important when treating heart failure (HF). Vascular dysfunction is associated with anemia through renal function and endothelial nitric oxide synthase. Additionally, blood pressure (BP) variability (BPV) caused by vascular dysfunction is also associated with HF prognosis. However, how anemia and BPV may affect HF prognosis is unclear., Methods: Between January 2012 and July 2018, 214 patients with HF were hospitalized. The cardio-ankle vascular index (CAVI) as an index of arteriosclerosis of these patients was measured. The patients were divided into the elevated and preserved CAVI groups. We investigated the factors related to major adverse cardiovascular events (MACEs) as cardiovascular death or rehospitalization within 1 year after discharge., Results: In the elevated CAVI group, significant differences in body mass index (BMI), BPV, left ventricular dimension, and hemoglobin levels were observed between patients with and without MACEs. In the preserved CAVI group, significant differences in BMI, diastolic/mean BP, and hemoglobin levels were observed between those with and without MACEs. The multivariate analysis showed an independent association between hemoglobin levels and MACE occurrence in both the elevated and preserved CAVI groups (elevated CAVI group: hazard ratio [HR] = 0.800, p = .045 [model 1], HR = 0.802, p = .035 [model 2]; preserved CAVI group: HR = 0.783, p = .049 [model 1], HR = 0.752, p = .023 [model 2], and HR = 0.754, p = .024 [model 3])., Conclusions: Anemia was independently associated with HF prognosis with or without arteriosclerosis., (© 2023 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)