Promyelinating drugs ameliorate oligodendrocyte pathologies in a mouse model of Krabbe disease.

Krabbe disease (KD) is a rare inherited demyelinating disorder caused by a deficiency in the lysosomal enzyme galactosylceramide (GalCer) ß-galactosidase. Most patients with KD exhibit fatal cerebral demyelination with apoptotic oligodendrocyte (OL) death and die before the age of 2-4 years. We have previously reported that primary OLs isolated from the brains of twitcher (twi) mice, an authentic mouse model of KD, have cell-autonomous developmental defects and undergo apoptotic death accompanied by abnormal accumulation of psychosine, an endogenous cytotoxic lyso-derivative of GalCer. In this study, we aimed to investigate the effects of the preclinical promyelinating drugs clemastine and Sob-AM2 on KD OL pathologies using primary OLs isolated from the brains of twi mice. Both agents specifically prevented the apoptotic death observed in twi OLs. However, while Sob-AM2 showed higher efficacy in restoring the impaired differentiation and maturation of twi OLs, clemastine more potently reduced the endogenous psychosine levels. These results present the first preclinical in vitro data, suggesting that clemastine and Sob-AM2 can act directly and distinctly on OLs in KD and ameliorate their cellular pathologies associated with myelin degeneration.

Matrix-free laser desorption/ionization mass spectrometry imaging for rapid evaluation of wood biomass conversion.

RATIONALE: This study overcomes traditional biomass analysis limitations by introducing a pioneering matrix-free laser desorption/ionization (LDI) approach in mass spectrometry imaging (MSI) for efficient lignin evaluation in wood. The innovative acetic acid-peracetic acid (APA) treatment significantly enhances lignin detection, enabling high-throughput, on-site analysis. METHODS: Wood slices, softwood from a conifer tree (Japanese cypress) and hardwood from a broadleaf tree (Japanese beech), were analyzed using MSI with a Fourier transform ion cyclotron resonance mass spectrometer. The developed APA treatment demonstrated effectiveness for MSI analysis of biomass. RESULTS: Our imaging technique successfully distinguishes between earlywood and latewood and enables the distinct visualization of lignin in these and other wood tissues, such as the radial parenchyma. This approach reveals significant contrasts in MSI. It has identified intense ions from ß-O-4-type lignin, specifically in the radial parenchyma of hardwood, highlighting the method's precision and utility in wood tissue analysis. CONCLUSIONS: The benefits of matrix-free LDI include reduced peak overlap, consistent sample quality, preservation of natural sample properties, enhanced analytical accuracy, and reduced operational costs. This innovative approach is poised to become a standard method for rapid and precise biomass evaluation and has important applications in environmental research and sustainable resource management and is crucial for the effective management of diverse biomass, paving the way towards a sustainable, circular society.

Effect of simultaneous bilateral surgery or simultaneous arthroscopic ankle lateral ligament repair in hindfoot endoscopic surgery for posterior ankle impingement syndrome in athletes.

BACKGROUND: Posterior ankle impingement syndrome (PAIS) is sometimes complicated by bilateral cases and lateral ankle ligament injuries. Reports on bilateral surgery for PAIS and simultaneous surgery for lateral ankle ligament injury are scarce in the literature. METHODS: We present a 2-year follow-up of 76 athletic patients who underwent endoscopic hindfoot surgery for PAIS. Patients were divided into those who underwent unilateral or simultaneous bilateral surgery and PAIS surgery alone or simultaneous bilateral PAIS surgery without arthroscopic ankle lateral ligament repair. RESULTS: All patients returned to full athletic activities postoperatively. There was no difference in all subscales of the SAFE-Q score between groups except for mean days after surgery for full return to athletic activities. CONCLUSION: Simultaneous bilateral surgery and simultaneous arthroscopic lateral ankle ligament repair had no negative effect on subjective clinical evaluation 2 years after surgery in hindfoot endoscopic surgery for PAIS. LEVEL OF EVIDENCE: III, retrospective case-control study.

Analyzing the risk factors for disease progression within 2 years and histological transformation in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone as first-line treatment: A 15-year follow-up of patients with advanced follicular lymphoma in JCOG0203.

Follicular lymphoma (FL) is an indolent lymphoma that becomes aggressive due to histological transformation (HT), leading to reduced survival. Patients with FL have different clinical courses and various treatment options. Some patients exhibit shorter survival and experience disease progression within 24 months of diagnosis/treatment (POD24); the optimal treatment remains an unmet needs. Thus, identifying factors that predict shorter survival is essential to stratify treatment and prolong the survival of patients with FL. To analyze risk factors for POD24 and HT in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line treatment, we performed this post-hoc analysis of patients with advanced indolent B-cell lymphoma in a randomized clinical trial wherein six cycles of R-CHOP were administered every 2-3 weeks. The primary analysis showed no differences in outcomes, which enabled the analysis of 248 patients with FL, assigned to two arms. All histopathological specimens from the 300 enrolled patients were reviewed by three expert hematopathologists. Multivariable analysis implicated Follicular Lymphoma International Prognostic Index (FLIPI) intermediate (odds ratio [OR] 2.531, 95% confidence interval [CI] 0.676-9.466) and high- (OR 2.236, 95% CI 0.160-31.226) risks, B symptoms (OR 2.091, 95% CI 0.747-5.851), and grade 3A (G3A) (OR 1.833, 95% CI 0.634-5.299) as risk factors for POD24. Furthermore, multivariable analysis through a median follow-up of 15.9 years implicated G3A (OR 2.628, 95% CI 0.806-8.575) and high-risk FLIPI (OR 4.401, 95% CI 0.186-104.377) as risk factors for HT. However, an analysis limited to the first 10 years revealed that the prognostic factors elucidated from the longer-term analysis had a greater impact on HT. G3A and high-risk FLIPI may independently predict POD24 and HT, thereby informing treatment stratification of patients with untreated advanced-stage FL in future trials, particularly to address the unmet needs of patients with POD24.

Inhibition of BMP signaling pathway induced senescence and calcification in anaplastic meningioma.

PURPOSE: Meningiomas are the most common type of brain tumors and are generally benign, but malignant atypical meningiomas and anaplastic meningiomas frequently recur with poor prognosis. The metabolism of meningiomas is little known, so few effective treatment options other than surgery and radiation are available, and the targets for treatment of recurrence are not well defined. The Aim of this paper is to find the therapeutic target. METHODS: The effects of bone morphogenetic protein (BMP) signal inhibitor (K02288) and upstream regulator Gremlin2 (GREM2) on meningioma's growth and senescence were examined. In brief, we examined as follows: 1) Proliferation assay by inhibiting BMP signaling. 2) Comprehensive analysis of forced expression GREM2.3) Correlation between GREM2 mRNA expression and proliferation marker in 87 of our clinical samples. 4) Enrichment analysis between GREM2 high/low expressed groups using RNA-seq data (42 cases) from the public database GREIN. 5) Changes in metabolites and senescence markers associated with BMP signal suppression. RESULTS: Inhibitors of BMP receptor (BMPR1A) and forced expression of GREM2 shifted tryptophan metabolism from kynurenine/quinolinic acid production to serotonin production in malignant meningiomas, reduced NAD + /NADH production, decreased gene cluster expression involved in oxidative phosphorylation, and caused decrease in ATP. Finally, malignant meningiomas underwent cellular senescence, decreased proliferation, and eventually formed psammoma bodies. Reanalyzed RNA-seq data of clinical samples obtained from GREIN showed that increased expression of GREM2 decreased the expression of genes involved in oxidative phosphorylation, similar to our experimental results. CONCLUSIONS: The GREM2-BMPR1A-tryptophan metabolic pathway in meningiomas is a potential new therapeutic target.

Streamlining Considerations for Safety Measures: A Predictive Model for Addition of Clinically Significant Adverse Reactions to Japanese Drug Package Inserts.

The addition of clinically significant adverse reactions (CSARs) to Japanese package inserts (PIs) is an important safety measure that can be used to inform medical personnel of potential health risks; however, determining the necessity of their addition can be lengthy and complex. Therefore, we aimed to construct a machine learning-based model that can predict the addition of CSARs at an early stage due to the accumulation of both Japanese and overseas adverse drug reaction (ADR) cases. The target comprised CSARs added to PIs from August 2011 to March 2022. The control group consisted of drugs without the same CSARs in their PIs by March 2022. Features were generated using ADR case accumulation data obtained from the Japanese Adverse Drug Event Report and the U.S. Food and Drug Administration Adverse Event Reporting System databases. The model was constructed using DataRobot, and its performance evaluated using the Matthews correlation coefficient. The target for the addition of CSARs included 414 cases, comprising 302 due to domestic case accumulation, 22 due to both domestic and overseas case accumulation, 12 due to overseas case accumulation, and 78 due to revisions of the company core data sheet. The best model was a generalized linear model with informative features, achieving a cross-validation of 0.8754 and a holdout of 0.8995. In conclusion, the proposed model effectively predicted CSAR additions to PIs resulting from the accumulation of ADR cases using data from both Japan and the United States.

Evaluation of Environmental Factor Effects on the Polyphenol and Flavonoid Content in the Leaves of Chrysanthemum indicum L. and Its Habitat Suitability Prediction Mapping.

The leaves of Chrysanthemum indicum L. are known to have various bioactive compounds; however, industrial use is extremely limited. To overcome this situation by producing high-quality leaves with high bioactive content, this study examined the environmental factors affecting the phytochemical content and antioxidant activity using C. indicum leaves collected from 22 sites in Kochi Prefecture, Japan. Total phenolic and flavonoid content in the dry leaves ranged between 15.0 and 64.1 (mg gallic acid g-1) and 2.3 and 11.4 (mg quercetin g-1), while the antioxidant activity (EC50) of the 50% ethanol extracts ranged between 28.0 and 123.2 (µg mL-1) in 1,1-Diphenyl-2-picrylhydrazyl radical scavenging assay. Among the identified compounds, chlorogenic acid and 1,5-dicaffeoylquinic acid were the main constituents in C. indicum leaves. The antioxidant activity demonstrated a positive correlation with 1,5-dicaffeoylquinic acid (R2 = 0.62) and 3,5-dicaffeoylquinic acid (R2 = 0.77). The content of chlorogenic acid and dicaffeoylquinic acid isomers varied significantly according to the effects of exchangeable magnesium, cation exchange capacity, annual temperature, and precipitation, based on analysis of variance. The habitat suitability map using the geographical information system and the MaxEnt model predicted very high and high regions, comprising 3.2% and 10.1% of the total area, respectively. These findings could be used in future cultivation to produce high-quality leaves of C. indicum.

Targeting cholesterol biosynthesis for AT/RT: comprehensive expression analysis and validation in newly established AT/RT cell line.

Atypical teratoid/rhabdoid (AT/RT) is a rare and highly malignant tumor of the central nervous system (CNS). It is most commonly found in children less than 5 years of age and is associated with inactivation of loss of function of SMARCB1/INI1. An experimental model for AT/RT is necessary to develop new and effective therapies. We established a patient-derived new cell line (MZ611ATRT), which showed loss of BAF-47. MZ611ATRT genetically features somatic heterozygous deletion of SMARCB1 and single nucleotide deletion of the residual allele, exon 5 ([c.541delC]), resulting in a stop codon at codon 954 by frameshift. We assessed the RNA-sequencing data of the other two AT/RT cell lines with forced expression of SMARCB1 available from public databases. We found SMARCB1 overexpression significantly down-regulates the expression of a group of enzymes related to cholesterol biosynthesis. Simvastatin was highly sensitive against MZ611ATRT cells and induced apoptosis (IC50 was 3.098 µM for MZ611ATRT, 41.88uM for U-87 MG, 23.34uM for IOMM-Lee, and 18.12uM for U-251 MG.). Pathways involved in cholesterol biosynthesis may be new targets for adjuvant therapy of AT/RT.

Arthroscopic Modified Lasso-Loop Stitch Technique for Chronic Lateral Ankle Instability in Skeletally Immature vs Mature Patients.

BACKGROUND: In recent years, arthroscopic lateral ankle ligament repair has become increasingly popular. However, reports on the clinical outcomes of arthroscopic ankle stabilization for skeletally immature patients remain scarce. This study investigated the clinical outcomes of arthroscopic lateral ankle ligaments repair in skeletally immature patients compared to skeletally mature patients. METHODS: Our retrospective analysis compared skeletally immature patients and skeletally mature adults who underwent arthroscopic repair of the ankle lateral ligaments with a modified lasso-loop stitch using a suture anchor. Skeletal immaturity was defined as patients whose epiphyseal line of the distal fibula remained open on plain radiography. Clinical outcomes were evaluated using the Self-Administered Foot Evaluation Questionnaire (SAFE-Q) at 2 years after surgery. The time to postoperative walking, jogging, and return to full sports activities were also evaluated. RESULTS: Sixty-four skeletally immature patients (IM group) and 103 skeletally mature adults (M group) were included. No significant differences were observed during both walking and jogging after surgery between the groups; however, return to full athletic activities was significantly earlier in IM group (P = .05). The mean scores in all SAFE-Q subscales significantly improved in both groups after surgery (P < .001). There were also no statistically significant differences between the groups in the mean postoperative SAFE-Q scores for all subscales. All patients in the IM group returned to playing sports at their preinjury levels postoperatively. CONCLUSION: We found that skeletally immature patients with chronic lateral ankle instability had generally similar responses to arthroscopic lateral ankle as skeletally mature adult patients at minimally 2 years' follow-up with a high rate of successful return to sport. LEVEL OF EVIDENCE: Level III, retrospective case control study.

[Exploration of Risk Factors of the Onset of Antibiotics-induced Acute Kidney Injury and Its Transfer to Chronic Kidney Disease Using the Medical Information Database].

Drug-induced acute kidney injury (AKI) is a serious adverse drug reaction, which results in a significant decline in renal function and is known to progress to chronic kidney disease (CKD). Therefore, appropriate drug therapy is important to avoid the risk of drug-induced AKI and CKD, which are serious concerns in clinical practice. In this study, using the medical information database of Hamamatsu University Hospital, we investigated the risk factors that accelerate the onset of drug-induced AKI or its progression to CKD in patients who received aminoglycoside antibiotics (AGs) or glycopeptide antibiotics (GPs), which are strongly associated with drug-induced AKI and CKD. We performed logistic regression analysis using patients' background, laboratory test results, and concomitant drug use, among other such factors as explanatory variables and drug-induced AKI or CKD onset as objective variables to explore the risk factors for drug-induced AKI and CKD. Our results showed that co-administration of amphotericin B, piperacillin-tazobactam and other AGs and GPs, increased serum creatinine (Scr) and chloride concentrations, serum lactate dehydrogenase activity, and decreased serum albumin concentration were risk factors for drug-induced AKI onset. Moreover, a reduced blood urea nitrogen : Scr ratio at drug-induced AKI onset served as a risk factor for CKD. These results suggest that careful monitoring of the aforementioned factors is important to ensure appropriate usage of these drugs in patients treated with AGs and GPs.

Close relationships between neck and upper-back stiffness and transverse cervical artery flow velocity.

PURPOSE: Neck and upper-back stiffness is encountered in daily life, with symptoms appearing as dullness or aches predominantly in the trapezius muscle (TM). Our previous study demonstrated that TM hardness as measured with a muscle hardness meter correlates well with transverse cervical artery (TCA) flow supplying the TM. Muscle hardness meters, however, cannot measure hardness in the TM alone. Meanwhile, recent advances in ultrasound elastography have enabled the evaluation of localized hardness in targeted tissues. The present study, therefore, aimed to clarify the relationship between TM hardness as measured by elastography and TCA hemodynamics as measured on Doppler sonography, with reference to daily symptoms of upper-back stiffness. METHODS: The study population comprised 66 healthy young adults (32 males, 34 females; mean age, 21 ± 1 years). Relationships were evaluated between TM hardness as a negative correlate of strain ratio from elastography and TCA hemodynamics on Doppler sonography. Hemodynamics in the TCA were evaluated according to the frequency of neck and upper-back stiffness. RESULTS: TM strain ratio correlated with peak systolic velocity (PSV) in the TCA (r = 0.273, p = 0.036), particularly in symptomatic subjects (r = 0.417, p = 0.022). PSV in the TCA decreased with increasing frequency of daily symptoms (p = 0.045). CONCLUSION: TCA hemodynamics correlated with muscle hardness when evaluating localized TM hardness. This relationship and low PSV in the TCA were evident in symptomatic subjects. These results suggest that PSV in the TCA is associated with neck and upper-back stiffness.

A case with a trend of QT interval prolongation due to the introduction of methadone to a pancreatic cancer patient on levofloxacin.

BACKGROUND: As methadone can prevent the development of opioid resistance, it has application in alleviating cancer-related pain that proves challenging to manage with other opioids. QT interval prolongation is a serious side effect of methadone treatment, with some reported deaths. In particular, owing to the increased risk of QT interval prolongation, caution should be exercised when using it in combination with drugs that also prolong the QT interval. CASE PRESENTATION: This study presents a case in which methadone was introduced to a patient (a man in his 60s) already using levofloxacin, which could prolong the QT interval-a serious side effect of methadone treatment-and whose QTc value tended to increase. Given that levofloxacin can increase the risk of QT interval prolongation, we considered switching to other antibacterial agents before introducing methadone. However, because the neurosurgeon judged that controlling a brain abscess was a priority, low-dose methadone was introduced with continuing levofloxacin. Owing to the risks, we performed frequent electrocardiograms. Consequently, we responded before the QTc increased enough to meet the diagnostic criteria for QT interval prolongation. Consequently, we prevented the occurrence of drug-induced long QT syndrome. CONCLUSIONS: When considering the use of methadone for intractable cancer pain, it is important to eliminate possible risk factors for QT interval prolongation. However, as it may be difficult to discontinue concomitant drugs owing to comorbidities, there could be cases in which the risk of QT interval prolongation could increase, even with the introduction of low-dose methadone. In such cases, frequent monitoring, even with simple measurements such as those used in this case, is likely to prevent progression to more serious conditions.

Temporal trends in antipsychotic prescriptions for pediatric patients using an administrative hospital database in Japan: a retrospective study.

BACKGROUND: Schizophrenia is a psychiatric disorder characterized by hallucinations, delusions, and other symptoms. Although treatment guidelines for schizophrenia have been established in Japan, drugs are not recommended for pediatric schizophrenia. Additionally, the temporal trends in prescribing antipsychotics for pediatric patients with schizophrenia are unclear. Therefore, we aimed to clarify the trends in antipsychotic prescriptions for Japanese pediatric outpatients from 2015 to 2022. METHODS: Administrative data (as of November 2023) of Japanese pediatric outpatients with schizophrenia aged 0-18 years who visited acute-care diagnosis procedure combination hospitals between January 1, 2015, and December 31, 2022, were included in this study. The target drugs for schizophrenia were all indicated for treating schizophrenia and marketed in Japan as of December 2022. Annual prescription trends for antipsychotics during this period were calculated based on their proportions. The Cochran-Armitage trend test was used to evaluate the proportion of prescriptions for each antipsychotic. RESULTS: The main drugs prescribed for these patients were aripiprazole and risperidone. Among male patients, the proportion of prescriptions for aripiprazole increased significantly from 21.2% in 2015 to 35.9% in 2022, whereas that for risperidone decreased significantly from 47.9% in 2015 to 36.7% in 2022 (both P < 0.001). Among female patients, the proportion of prescriptions for aripiprazole increased significantly from 21.6% in 2015 to 35.6% in 2022, whereas that for risperidone decreased significantly from 38.6% in 2015 to 24.8% in 2022 (both P < 0.001). CONCLUSIONS: Aripiprazole and risperidone were primarily prescribed for pediatric schizophrenia in Japan during the study period. Additionally, the proportion of aripiprazole prescriptions increased over time.

Enhancing Bioethanol Production from Rice Straw through Environmentally Friendly Delignification Using Versatile Peroxidase.

Rice straw (RS), an agricultural residue rich in carbohydrates, has substantial potential for bioethanol production. However, the presence of lignin impedes access to these carbohydrates, hindering efficient carbohydrate-to-bioethanol conversion. Here, we expressed versatile peroxidase (VP), a lignin-degrading enzyme, in Pichia pastoris and used it to delignify RS at 30 °C using a membrane bioreactor that continuously discarded the degraded lignin. Klason lignin analysis revealed that VP-treatment led to 35% delignification of RS. We then investigated the delignified RS by SEC, FTIR, and SEM. The results revealed the changes of RS caused by VP-mediated delignification. Additionally, we compared the saccharification and fermentation yields between RSs treated with and without VP, VP-RS, and Ctrl-RS, respectively. This examination unveiled an improvement in glucose and bioethanol production, VP-RS exhibiting up to 1.5-fold and 1.4-fold production, respectively. These findings underscore the potential of VP for delignifying RS and enhancing bioethanol production through an eco-friendly approach.

Epidemiological Study of Metastatic Brain Tumors in Miyazaki Prefecture: A Regional 10-year Survey in Southern Japan.

Advances in cancer treatment have improved the survival of patients with cancer, with a concomitant increase in the proportion of patients with metastatic brain tumors (MBTs). In this study, we used cancer registries established in Japan after 2016 and available patient data by organ in order to conduct an accurate epidemiological study. To the best of our knowledge, this is the first study to report on the detailed epidemiological data on MBT at the prefectural level in Japan using the Miyazaki Brain Tumor Database and Miyazaki Cancer Registry. This study included 425 new cases of MBTs diagnosed in Miyazaki Prefecture from 2007 to 2016. As per our findings, the most frequent primary tumor in Miyazaki Prefecture was found to be in the lung (49.4%), followed by colon/rectum/anus (9.4%) and breast (8.5%). Among patients with MBTs, 59.1% were males, a number closely similar to that of Japan, as shown in the Japanese Brain Tumor Registry (55.5%). The median age at diagnosis was 68 and 63 years in Miyazaki Prefecture and Japan, respectively. Although more patients were symptomatic in Miyazaki Prefecture than in Japan (88.5% vs. 15.5%), fewer patients opted for surgery (33.6% vs. 61.9%), probably because of their advanced age at diagnosis. As per the findings of this study, the annual incidence rate of new MBTs (i.e., ratio of the number of new cancer registrations to that of new MBT patients in Miyazaki Prefecture) was at 0.41%. The number of tumor sites in MBTs was independent of the total number of cancers per organ. Considering the expansion of cancer registries worldwide, including those on brain tumors, further epidemiological analysis of MBTs is deemed warranted.

The etherase system of Novosphingobium sp. MBES04 functions as a sensor of lignin fragments through phenylpropanone production to induce specific transcriptional responses.

The MBES04 strain of Novosphingobium accumulates phenylpropanone monomers as end-products of the etherase system, which specifically and reductively cleaves the ß-O-4 ether bond (a major bond in lignin molecules). However, it does not utilise phenylpropanone monomers as an energy source. Here, we studied the response to the lignin-related perturbation to clarify the physiological significance of its etherase system. Transcriptome analysis revealed two gene clusters, each consisting of four tandemly linked genes, specifically induced by a lignin preparation extracted from hardwood (Eucalyptus globulus) and a ß-O-4-type lignin model biaryl compound, but not by vanillin. The most strongly induced gene was a 2,4'-dihydroxyacetophenone dioxygenase-like protein, which leads to energy production through oxidative degradation. The other cluster was related to multidrug resistance. The former cluster was transcriptionally regulated by a common promoter, where a phenylpropanone monomer acted as one of the effectors responsible for gene induction. These results indicate that the physiological significance of the etherase system of the strain lies in its function as a sensor for lignin fragments. This may be a survival strategy to detect nutrients and gain tolerance to recalcitrant toxic compounds, while the strain preferentially utilises easily degradable aromatic compounds with lower energy demands for catabolism.

Sex-dependent impact of a short rest after lunch on hemodynamics as assessed by Doppler sonography.

PURPOSE: Taking a short rest after lunch suppresses increases in blood flow to the digestive organs and maintains blood flow to the brain in the afternoon, possibly providing beneficial effects in preventing post-prandial drowsiness. The present study investigated sex-dependent influences on changes in hemodynamics produced by taking a short rest after lunch. METHODS: Subjects comprised 20 healthy young adults (10 men, 10 women; mean age 21 ± 1 years). Doppler sonography was performed to measure blood flow in the superior mesenteric artery (SMA) and common carotid artery (CCA) before and after lunch every hour on each day, with and without a 15-min rest with eyes closed after lunch. Blood pressure and heart rate (HR) were also measured. RESULTS: For both men and women, peak systolic velocity (PSV) in the SMA was suppressed by taking a rest. PSV in the CCA in men was increased at 0.5 h after lunch in the resting condition but was decreased in the non-resting condition (median 109%, interquartile range [IQR] 102-120% vs. median 98%, IQR 90-107%; P = 0.037). No such differences were observed in women. Although post-prandial increases in HR were observed in women, a similar increase was only found for men in the resting condition. CONCLUSION: An increase in CCA blood flow was observed only in men. The present study suggests that a short rest after lunch could better promote the maintenance of blood flow to the brain in men than in women.

Investigation of vertical margin involvement in endoscopic resection for T1 colorectal cancer.

OBJECTIVES: The resection of vertical margin-negative submucosally invasive colorectal cancer (CRC) relies on the pathological risk assessment of lymph node metastasis. However, no large-scale study has clarified the endoscopic resection (ER) outcome for submucosally invasive CRC, focusing on the vertical margin status. This retrospective study aimed to examine vertical margin involvement in ER for submucosally invasive CRC and explore the treatment consequences associated with vertical margin status. METHODS: We analyzed 395 submucosally invasive CRC cases in 389 patients who underwent ER at our hospital between 2008 and 2020. The presence of residual tumors and simultaneous lymph node metastasis in patients who underwent additional surgery was assessed and compared between the vertical incomplete ER and the vertical margin-negative groups. RESULTS: Among the patients, 270 were men, with a median age of 69 years. The vertical incomplete ER rate was 21.5%, with positive vertical margins and unclear vertical margins identified in 12.2% and 9.3% of the cases, respectively. Among 154 patients who underwent additional surgery after ER, the vertical incomplete ER group had a significantly higher residual tumor rate than the vertical margin-negative group (P = 0.001). The vertical incomplete ER group had a significantly higher lymph node metastasis rate than the vertical margin-negative group (P = 0.029). CONCLUSION: This study clarified the substantial risk of vertical incomplete ER in submucosally invasive CRC and revealed the high risk of residual tumor and lymph node metastasis in vertical incomplete ER for submucosal CRC.

R-CHOP treatment for patients with advanced follicular lymphoma: Over 15-year follow-up of JCOG0203.

Anti-CD20 antibody in combination with chemotherapy extends overall survival (OS) in untreated advanced-stage follicular lymphoma (FL), yet the optimal associated therapy is unclear. Data on the cumulative incidence of secondary malignancies postrelapse after conventional immunochemotherapy are scarce. A long-term analysis of rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) as first-line treatment was conducted in a randomised clinical trial. A six-cycle R-CHOP regimen was administered every 2 or 3 weeks without rituximab maintenance. A prespecified evaluation was conducted 15 years after the completion of enrolment, following initial analysis results that showed no significant differences in outcomes at the 3-year mark. In-depth analyses were performed on the cohort of 248 patients with FL who were allocated to the two treatment arms. With a median follow-up period of 15.9 years, the 15-year OS was 76.2%. There were no protocol treatment-related deaths, nor were there any fatal infections attributable to subsequent lymphoma treatment. At 15 years, the cumulative incidence of non-haematological and haematological malignancies was 12.8% and 3.7% respectively. Histological transformation appeared after a median of 8 years. R-CHOP maintains safety and efficacy in patients with advanced FL over extended follow-up, making it a viable first-line option for patients with advanced-stage FL.