Effects of different exercise modes and intensities on cognitive performance, adult hippocampal neurogenesis, and synaptic plasticity in mice.

Exercise can induce beneficial improvements in cognition. However, the effects of different modes and intensities of exercise have yet to be explored in detail. This study aimed to identify the effects of different exercise modes (aerobic and resistance) and intensities (low and high) on cognitive performance, adult hippocampal neurogenesis and synaptic plasticity in mice. A total of 40 C57BL/6J mice were randomised into 5 groups (n = 8 mice per group): control, low-intensity aerobic exercise, high-intensity aerobic exercise, low-intensity resistance exercise, and high-intensity resistance exercise. The aerobic exercise groups underwent treadmill training, while the resistance exercise groups underwent ladder climbing training. At the end of the exercise period, cognitive performance was assessed by the Y-maze and Barnes maze. In addition, adult hippocampal neurogenesis was evaluated immunohistochemically by 5-bromo-2'-deoxyuridine (BrdU)/ neuronal nuclei (NeuN) co-labeling. The levels of synaptic plasticity-related proteins in the hippocampus, including synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95), were analyzed by western blotting. Our results showed no significant differences in cognitive performance among the groups. However, high-intensity aerobic exercise significantly increased hippocampal adult neurogenesis relative to the control. A trend towards increased adult neurogenesis was observed in the low-intensity aerobic group compared to the control group. No significant changes in synaptic plasticity were observed among all groups. Our results indicate that high-intensity aerobic exercise may be the most potent stimulator of adult hippocampal neurogenesis.

An anatomo-functional study of the interactivity between the paracentral lobule and the primary motor cortex.

OBJECTIVE: The purpose of this study was to understand the anatomical and functional connections between the paracentral lobule (PCL) and the primary motor cortex (M1) of the human brain. METHODS: This retrospective study included 16 patients who underwent resection of lesions located near M1. Nine patients had lesions in the dominant hemisphere. Tractography was performed to visualize the connectivity between two regions of interest (ROIs)-the convexity and the interhemispheric fissure-that were shown by functional MRI to be activated during a finger tapping task. The number, mean length, and fractional anisotropy (FA) of the fibers between the ROIs were estimated. During surgery, subdural electrodes were placed on the brain surface, including the ROIs, using a navigation system. Cortico-cortical evoked potentials (CCEPs) were evoked by applying electrical stimuli to the hand region of M1 using electrodes placed on the convexity and were measured with electrodes placed on the interhemispheric fissure. To verify CCEP bidirectionality, electrical stimuli were applied to electrodes on the interhemispheric fissure that showed CCEP responses. Correlations of CCEP amplitudes and latencies with the number, mean length, and mean FA value obtained from tractography were determined. The correlations between these parameters and perioperative motor functions were also analyzed. RESULTS: Fibers of 14 patients were visualized by diffusion tensor imaging (DTI). Unidirectional CCEPs between the PCL and M1 were measurable in all 16 patients, and bidirectional CCEPs between them were measurable in 14 patients. There was no significant difference between the two directions in the maximum CCEP amplitude or latency (amplitude, p = 0.391; latency, p = 0.583). Neither the amplitude nor latency showed any apparent correlation with the number, mean length, or mean FA value of the fibers obtained from tractography. Pre- and postoperative motor function of the hands was not significantly correlated with CCEP amplitude or latency. The number and mean FA value of fibers obtained by DTI, as well as the maximum CCEP amplitude, varied between patients. CONCLUSIONS: This study demonstrated an anatomical connection and a bidirectional functional connection between the PCL, including the supplementary motor area, and M1 of the human brain. The observed variability between patients suggests possible motor function plasticity. These findings may serve as a foundation for further studies.

Assessment of the accuracy of biparametric MRI/TRUS fusion-guided biopsy for index tumor evaluation using postoperative pathology specimens.

BACKGROUND: Multiparametric MRI (mpMRI) is widely used for the diagnosis, surveillance, and staging of prostate cancer. However, it has several limitations, including higher costs, longer examination times, and the use of gadolinium-based contrast agents. This study aimed to investigate the accuracy of preoperatively assessed index tumors (ITs) using biparametric MRI (bpMRI)/transrectal ultrasound (TRUS) fusion biopsy compared with radical prostatectomy (RP) specimens. METHODS: We included 113 patients diagnosed with prostate cancer through bpMRI/TRUS fusion-guided biopsies of lesions with a Prostate Imaging Reporting and Data System (PI-RADS) category ≥ 3. These patients underwent robot-assisted laparoscopic radical prostatectomy (RARP) at our institution between July 2017 and March 2023. We examined the localization of preoperative and postoperative ITs, the highest Gleason score (GS), and tumor diameter in these patients. RESULTS: The preoperative cT stage matched the postoperative pT stage in 53 cases (47%), while 31 cases (27%) were upstaged, and 29 cases (26%) were downstaged (Weighted Kappa = 0.21). The preoperative and postoperative IT localizations were consistent in 97 cases (86%). The concordance rate between Gleason groups in targeted biopsies and RP specimens was 51%, with an upgrade in 25 cases (23%) and a downgrade in 27 cases (25%) (Weighted Kappa = 0.42). The maximum diameter of the IT and the maximum cancer core length on biopsy were correlated with the RP tumor's maximum diameter (p < 0.001 for both). CONCLUSION: The diagnostic accuracy of bpMRI/TRUS fusion biopsy is comparable to mpMRI, suggesting that it can be a cost-effective and time-saving alternative.

Alcohol-Associated Liver Disease Outcomes: Critical Mechanisms of Liver Injury Progression.

Alcohol-associated liver disease (ALD) is a substantial cause of morbidity and mortality worldwide and represents a spectrum of liver injury beginning with hepatic steatosis (fatty liver) progressing to inflammation and culminating in cirrhosis. Multiple factors contribute to ALD progression and disease severity. Here, we overview several crucial mechanisms related to ALD end-stage outcome development, such as epigenetic changes, cell death, hemolysis, hepatic stellate cells activation, and hepatic fatty acid binding protein 4. Additionally, in this review, we also present two clinically relevant models using human precision-cut liver slices and hepatic organoids to examine ALD pathogenesis and progression.

High expression of autotaxin is associated with poor recurrence-free survival in cholangiocarcinoma.

BACKGROUND AND AIM: Autotaxin (ATX) is an extracellular lysophospholipase D that catalyzes the hydrolysis of lysophosphatidylcholine into lysophosphatidic acid (LPA). Recent accumulating evidence indicates the biological roles of ATX in malignant tumors. However, the expression and clinical implications of ATX in human cholangiocarcinoma (CCA) remain elusive. METHODS: In this study, the expression of ATX in 97 human CCA tissues was evaluated by immunohistochemistry. Serum ATX levels were determined in CCA patients (n = 26) and healthy subjects (n = 8). Autotaxin expression in cell types within the tumor microenvironment was characterized by immunofluorescence staining. RESULTS: High ATX expression in CCA tissue was significantly associated with a higher frequency of lymph node metastasis (p = 0.050). High ATX expression was correlated with shorter overall survival (p = 0.032) and recurrence-free survival (RFS) (p = 0.001) than low ATX expression. In multivariate Cox analysis, high ATX expression (p = 0.019) was an independent factor for shorter RFS. Compared with low ATX expression, high ATX expression was significantly associated with higher Ki-67-positive cell counts (p < 0.001). Serum ATX levels were significantly higher in male CCA patients than in healthy male subjects (p = 0.030). In the tumor microenvironment of CCA, ATX protein was predominantly expressed in tumor cells, cancer-associated fibroblasts, plasma cells, and biliary epithelial cells. CONCLUSIONS: Our study highlights the clinical evidence and independent prognostic value of ATX in human CCA.

Modification of ibuprofen to improve the medicinal effect; structural, biological, and toxicological study.

Ibuprofen is classified as a non-steroidal anti-inflammatory drug (NSAID) that is employed as an initial treatment option for its non-steroidal anti-inflammatory, pain-relieving, and antipyretic properties. However, Ibuprofen is linked to specific well-known gastrointestinal adverse effects like ulceration and gastrointestinal bleeding. It has been linked to harmful effects on the liver, kidney, and heart. The purpose of the study is to create novel and potential IBU analogue with reduced side effects with the enhancement of their medicinal effects, so as to advance the overall safety profile of the drug. The addition of some novel functional groups including CH3, F, CF3, OCF3, Cl, and OH at various locations in its core structure suggestively boost the chemical as well as biological action. The properties of these newly designed structures were analyzed through chemical, physical, and spectral calculations using Density Functional Theory (DFT) and time-dependent DFT through B3LYP/6-31 g (d,p) basis set for geometry optimization. Molecular docking and non-bonding interaction studies were conducted by means of the human prostaglandin synthase protein (PDB ID: 5F19) to predict binding affinity, interaction patterns, and the stability of the protein-drug complex. Additionally, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) and PASS (Prediction of Activity Spectra for Substances) predictions were employed to evaluate the pharmacokinetic and toxicological properties of these structures. Importantly, most of the analogues displayed reduced hepatotoxicity, nephrotoxicity, and carcinogenicity in comparison to the original drug. Moreover, molecular docking analyses indicated improved medicinal outcomes, which were further supported by pharmacokinetic calculations. Together, these findings suggest that the modified structures have reduced adverse effects along with improved therapeutic action compared to the parent drug.

Comparison of hemostatic ability between spray coagulation and forced coagulation modes in endoscopic submucosal dissection in patients with early gastric neoplasms: a study protocol for multicenter randomized controlled trial (Spray-G trial).

BACKGROUND: Endoscopic submucosal dissection (ESD) is the standard treatment for early gastric neoplasms (EGN). Controlling intraoperative bleeding is crucial for ensuring safe and reliable procedures. ESD using the spray coagulation mode (SCM-ESD) has been developed to control bleeding more effectively than ESD using the conventional forced coagulation mode (FCM-ESD). This study aims to compare the hemostatic efficacies of SCM-ESD and FCM-ESD. METHODS: This multicenter, prospective, parallel, randomized, open-label superiority trial will be conducted in five Japanese institutions. Patients with a preoperative diagnosis of intramucosal EGC will be randomized to undergo either SCM-ESD or FCM-ESD. The primary outcome measure is the completion of ESD with an electrosurgical knife alone, without the use of hemostatic forceps. Secondary outcomes include the number and duration of hemostasis using hemostatic forceps, procedure time, curability, and safety. A total of 130 patients will be enrolled in this study. DISCUSSION: This trial will provide evidence on the hemostatic efficacy of SCM-ESD compared with FCM-ESD in patients with intramucosal EGN, potentially improving the safety and reliability of ESD procedures. TRIAL REGISTRATION: The trial has been registered at the University Hospital Medical Information Network Clinical Trials Registration (UMIN-CTR) as UMIN000040518. The reception number is R000054009.

Two-devices-in-one-channel method for fractured pancreatic duct stent retrieval in a case of severe chronic pancreatitis.

When a pancreatic plastic stent for symptomatic chronic pancreatitis breaks during its removal, severe pancreatic duct stenosis may complicate its retrieval. Takuma and colleagues report on the successful retrieval of a fragmented and displaced pancreatic plastic stent by applying the two-device-in-one-channel method using forceps and a snare.

Pathological features of primary cardiac myxoid tumour in dogs: a review of 11 cases (2002-2022).

This report documents the pathological features of primary cardiac myxoid tumour (MT) in 11 dogs. Macroscopically, all the tumours were located in the tricuspid valve (TV), its septal leaflet being predominantly affected. Therefore, it appears that the TV is the most common site of occurrence for cardiac MT in dogs. Two gross anatomical types of canine valvular MT were evident. Seven of the 11 tumours were round or oval with a smooth or gently lobulated and glistening surface, while the other four were gelatinous, multilobulated and polypoid, with an irregular surface. Microscopically, in nine cases the tumours had an abundant myxoid matrix within which elongated spindle-shaped cells with no remarkable cytological atypia were sparsely embedded, suggesting a benign character (ie, myxoma). In the other two cases the tumours consisted of variably dense, haphazardly arranged, interlacing streams of anaplastic spindle-shaped or polygonal cells containing many mitotic figures, indicative of a malignant form of myxoma (ie, myxosarcoma). Isolated or clustered collections of myxoma cells (eg, cords, rings, syncytia) characteristic of human atrial myxoma were only rarely evident or lacking in all 11 cases, indicating that rarity or absence of such structural features may be specific to valvular MTs. Immunohistochemical findings were indicative of smooth muscle differentiation of the neoplastic cells. Tumour embolization to the intrapulmonary arteries and/or tumour implantation on the endocardium of the right heart chambers was evident only in the four cases of irregular-surfaced MT.

Implementation and effectiveness of a physician-focused peer support program.

BACKGROUND: The practice of medicine faces a mounting burnout crisis. Physician burnout leads to worse mental health outcomes, provider turnover, and decreased quality of care. Peer support, a viable strategy to combat burnout, has been shown to be well received by physicians. METHODS: This study evaluates the Peer Outreach Support Team (POST) program, a physician-focused peer support initiative established in a 2-hospital system, using descriptive statistical methodologies. We evaluate the POST program using the Practical Robust Implementation and Sustainability Model (PRISM) framework to describe important contextual factors including characteristics of the intervention, recipients, implementation and sustainability infrastructure, and external environment, and to assess RE-AIM outcomes including reach, effectiveness, adoption, implementation, and maintenance. RESULTS: This program successfully trained 59 peer supporters across 11 departments in a 2-hospital system over a 3-year period. Trained supporters unanimously felt the training was useful and aided in general departmental culture shift (100% of respondents). After 3 years, 48.5% of physician survey respondents across 5 active departments had had a peer support interaction, with 306 successful interactions recorded. The rate of interactions increased over the 3-year study period, and the program was adopted by 11 departments, representing approximately 60% of all physicians in the 2-hospital system. Important implementation barriers and facilitators were identified. Physician recipients of peer support reported improved well-being, decreased negative emotions and stigma, and perceived positive cultural changes within their departments. CONCLUSIONS: We found that POST, a physician-focused peer support program, had widespread reach and a positive effect on perceived physician well-being and departmental culture. This analysis outlines a viable approach to support physicians and suggests future studies considering direct effectiveness measures and programmatic adaptations. Our findings can inform and guide other healthcare systems striving to establish peer support initiatives to improve physician well-being.

Combined endoscopic endonasal and transcranial approach for internal carotid artery aneurysms: usefulness and safety of endonasal proximal control.

It is necessary to secure both the proximal and distal sides of the parent artery to prevent premature rupture when clipping cerebral aneurysms. Herein, we describe four cases in which the proximal internal carotid artery (ICA), affected by a paraclinoid aneurysm, was secured using an endoscopic endonasal approach. We used various tools, including a surgical video, cadaver dissection picture, artist's illustration, and intraoperative photographs, to elucidate the process. No patient experienced postoperative complications at our institution. Compared to the cervical or cavernous ICA, the ICA adjacent to the clivus (paraclival ICA) can be anatomically safely and easily exposed using an endoscopic endonasal approach because there is no need to consider cerebrospinal fluid leakage or hemorrhage from the cavernous sinus. Securing the proximal side of the parent artery using an endoscopic endonasal approach may be a viable method for clipping selected ICA aneurysms, such as paraclinoid aneurysms especially for upward or outward aneurysms of the C2 portion.

Effect of a Low Concentration of Sevoflurane Combined With Propofol on Transcranial Electrical Stimulation Motor Evoked Potential: A Case Series.

Transcranial electrical motor evoked potential (TCeMEP) is used to monitor the integrity of intraoperative motor function. Total intravenous anesthesia (TIVA) is the preferred method because its effect on MEP is relatively smaller than volatile anesthetics. However, maintaining the balanced anesthesia in long-time surgery using TIVA is challenging and may sometime cause problems including body movement during microsurgery. Such problems can be avoided by intraoperative anesthesia management using a mixture of propofol and a low concentration of sevoflurane. We recorded TCeMEP under a mixture of propofol and low concentration of sevoflurane anesthesia in three cases of neurosurgery. Anesthesia was induced with a 5.0 µg/mL target-controlled infusion of propofol and 0.6 mg/kg rocuronium. General anesthesia was maintained by propofol and 0.1-0.25 µg/kg/min remifentanil infusion. After the recording of control TCeMEP, sequential inhalation of 0.2 minimum alveolar concentration (MAC) and 0.5 MAC of sevoflurane was performed. The duration of each sevoflurane inhalation was 10 minutes, and the MACs were adjusted by the patient's age. In our cases, the combination of propofol and 0.2 MAC sevoflurane suppressed the amplitude of TCeMEP to 38.0±21.7% (379.8±212.0 µV), but the amplitude was high enough for evaluation of motor function monitoring. On the other hand, the combination of 0.5 MAC sevoflurane greatly decreased the amplitude of TCeMEP to 6.3±6.0% (71.9±66.9 µV) resulting in less than 150 µV, and it was difficult to record the change in TCeMEP amplitude over time. The combination of 0.2 MAC sevoflurane with TIVA might enable TCeMEP monitoring with TIVA.

Deletion of IL-1ß exacerbates acrylamide-induced neurotoxicity in mice.

Acrylamide is a neurotoxicant in human and experimental animals. Interleukin-1ß (IL-1ß) is a proinflammatory cytokine known as a critical component of brain reaction to any insult or neurodegenerative pathologies, though its role in electrophile-induced neurotoxicity remains elusive. The aim of this study was to investigate the role of IL-1ß in acrylamide-induced neurotoxicity in mice. Ten-week-old male wild-type and IL-1ß knock-out mice were allocated into 3 groups each and exposed to acrylamide at 0, 12.5, 25 mg/kg body weight by oral gavage for 28 days. Compared with wild-type mice, the results showed a significant increase in landing foot spread test and a significant decrease in density of cortical noradrenergic axons in IL-1ß KO mice exposed to acrylamide at 25 mg/kg body weight. Exposure to acrylamide at 25 mg/kg significantly increased cortical gene expression of Gclc, Gpx1, and Gpx4 in wild-type mice but decreased them in IL-1ß KO mice. The same exposure level significantly increased total glutathione and oxidized glutathione (GSSG) in the cerebellum of wild-type mice but neither changed total glutathione nor decreased GSSG in the cerebellum of IL-1ß KO mice. The basal level of malondialdehyde in the cerebellum was higher in IL-1ß KO mice than in wild-type mice. The results suggest that IL-1ß protects the mouse brain against acrylamide-induced neurotoxicity, probably through suppression of oxidative stress by glutathione synthesis and peroxidation. This unexpected result provides new insight on the protective role of IL-1ß in acrylamide-induced neurotoxicity.

Development of non-electrically controlled SalivaDirect LAMP (NEC-SD-LAMP), a new nonelectrical infectious disease testing method.

In this study, non-electrically controlled SalivaDirect loop-mediated isothermal amplification (NEC-SD-LAMP), which can detect infections by amplifying viral DNA expression in saliva without using electrical control systems, was developed. By this method, only by adding water to the device, viral DNA was extracted from saliva using SalivaDirect, the extracted DNA was amplified via loop-mediated isothermal amplification (LAMP), and the results were visually confirmed. Melting palmitic acid maintained the optimal temperature for the LAMP reaction, as the temperature of palmitic acid is maintained at 62.9 °C, its melting point. By exploiting the proximity of the melting point to the optimal temperature for LAMP, LAMP can be performed without electricity. We detected several viruses in the saliva using this method. NEC-SD-LAMP could clearly distinguish 3 types of viral DNA, indicating the high specificity of this reaction. Furthermore, the viral concentration detection limit of the device was 2 copies per µL, indicating that it is possible to detect DNA viral infections in saliva even before the onset of viral infection.

Role of Nrf2 in 1,2-dichloropropane-induced cell proliferation and DNA damage in the mouse liver.

1,2-Dichloropropane (1,2-DCP) is recognized as the causative chemical of occupational cholangiocarcinoma in printing workers in Japan. However, the cellular and molecular mechanisms of 1,2-DCP-induced carcinogenesis remains elusive. The present study investigated cellular proliferation, DNA damage, apoptosis, and expression of antioxidant and proinflammatory genes in the liver of mice exposed daily to 1,2-DCP for 5 weeks, and the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in these responses. Wild-type and Nrf2-knockout (Nrf2-/-) mice were administered 1,2-DCP by gastric gavage, and then the livers were collected for analysis. Immunohistochemistry for BrdU or Ki67 and TUNEL assay revealed that exposure to 1,2-DCP dose-dependently increased proliferative cholangiocytes, whereas decreased apoptotic cholangiocytes in wild-type mice but not in Nrf2-/- mice. Western blot and quantitative real-time PCR showed that exposure to 1,2-DCP increased the levels of DNA double-strand break marker γ-H2AX and mRNA expression levels of NQO1, xCT, GSTM1, and G6PD in the livers of wild-type mice in a dose-dependent manner, but no such changes were noted in Nrf2-/- mice. 1,2-DCP increased glutathione levels in the liver of both the wild-type and Nrf2-/- mice, suggesting that an Nrf2-independent mechanism contributes to 1,2-DCP-induced increase in glutathione level. In conclusion, the study demonstrated that exposure to 1,2-DCP induced proliferation but reduced apoptosis in cholangiocytes, and induced double-strand DNA breaks and upregulation of antioxidant genes in the liver in an Nrf2-dependent manner. The study suggests a role of Nrf2 in 1,2-DCP-induced cell proliferation, antiapoptotic effect, and DNA damage, which are recognized as key characteristics of carcinogens.

[Assessment of Motor and Language Function during Awake Surgery].

Awake surgery enables the evaluation of neurological functions that are difficult to assess with a conventional electrophysiological examination and is useful in the evaluation of language function. Awake surgery is a team effort involving anesthesiologists and rehabilitation physicians who evaluate motor and language functions, and information sharing during the perioperative period is important. Some points regarding surgical preparation and anesthesia methods are unique and must be well understood. For example, supraglottic airway devices must be used to secure the airway, and ventilation must be checked for availability when positioning the patient. Preoperative neurological evaluation is important in determining the method of intraoperative neurological evaluation, including choosing the simplest possible method of evaluation and sharing the information with the patient prior to surgery. Motor function assessment evaluates small movements that do not affect the surgery. Visual naming and auditory comprehension are useful in the evaluation of language function.

Rapid acquisition of absorption spectra to monitor proton migration in nanoliter space using the RGB-spectrum-conversion method with a 10 ms interval.

Acquisition protocol of absorption spectra at nanoliter spaces from the RGB values preserved in video data at 10 ms intervals was established using the principal-component-analysis-based RGB-conversion method. Proton behavior was monitored using a camera to acquire the video footage to monitor colorimetric change in the nanoliter space. The RGB values observed in the video were converted into a score vector using a conversion matrix. A linear combination of the predetermined loading vectors with the score values was calculated to reproduce the absorption spectra. The reproduced absorption spectra correlated well with those acquired using a conventional spectrophotometer during a short period. This method was applied to monitor the proton diffusion from a single cationic ion-exchange resin into hydrogels at low concentrations. The rapid acquisition and quick response of this method may enable the monitoring of the initial diffusion of protons, which is challenging with conventional spectrophotometry and electrochemical approaches.

Transcranial electrical stimulation technique for induction of unilateral motor evoked potentials.

OBJECTIVE: Transcranial electrical stimulation motor evoked potentials (TES-MEP) are widely used to monitor motor function; however, broad current spread and induced body movement are limitations of this technique. We herein report a localized stimulation technique for TES-MEP that induces unilateral MEP responses. METHODS: The stimulation of C1(+)-C4(-) or C2(+)-C3(-) was performed to induce right- or left-sided muscle contraction, respectively, in 70 patients. Electromyography was recorded by placing electrodes on the bilateral abductor pollicis brevis (APB) and abductor hallucis (AH) muscles. Stimulation conditions were regulated in the range to induce unilateral muscle contractions contralateral to the anodal stimulation. The thresholds and amplitudes of TES-MEP were retrospectively analyzed. RESULTS: The thresholds of APB were lower than those of AH in 47 patients, AH thresholds were lower than those of APB in 6 patients, and both APB and AH started to respond at the same intensity in 15 patients. This technical stimulation induced contralateral limb contractions with a suprathreshold stimulation of 129.4 ± 35.6 mA (mean ± standard deviation) in 68 patients (97%). Amplitudes in the suprathreshold stimulation of APB and AH responses were 727.5 ± 695.7 and 403.3 ± 325.7 µV, respectively. CONCLUSIONS: The C1(+)-C4/C2(+)-C3(-) stimulation in TES-MEP enables a localized stimulation to induce unilateral MEP responses. SIGNIFICANCE: Our stimulation technique enables the stable and safe monitoring of unilateral limbs, and contributes to the reliable monitoring of motor function in neurosurgery.