Raphe glucose-sensing serotonergic neurons stimulate KNDy neurons to enhance LH pulses via 5HT2CR: rat and goat studies.

Dysfunction of central serotonergic neurons is known to cause depressive disorders in humans, who often show reproductive and/or glucose metabolism disorders. This study examined whether dorsal raphe (DR) serotonergic neurons sense high glucose availability to upregulate reproductive function via activating hypothalamic arcuate (ARC) kisspeptin neurons (= KNDy neurons), a dominant stimulator of gonadotropin-releasing hormone (GnRH)/gonadotropin pulses, using female rats and goats. RNA-seq and histological analysis revealed that stimulatory serotonin-2C receptor (5HT2CR) was mainly expressed in the KNDy neurons in female rats. The serotonergic reuptake inhibitor administration into the mediobasal hypothalamus (MBH), including the ARC, significantly blocked glucoprivic suppression of luteinizing hormone (LH) pulses and hyperglycemia induced by intravenous 2-deoxy-D-glucose (2DG) administration in female rats. A local infusion of glucose into the DR significantly increased in vivo serotonin release in the MBH and partly restored LH pulses and hyperglycemia in the 2DG-treated female rats. Furthermore, central administration of serotonin or a 5HT2CR agonist immediately evoked GnRH pulse generator activity, and central 5HT2CR antagonism blocked the serotonin-induced facilitation of GnRH pulse generator activity in ovariectomized goats. These results suggest that DR serotonergic neurons sense high glucose availability to reduce gluconeogenesis and upregulate reproductive function by activating GnRH/LH pulse generator activity in mammals.

Relationship between Treatment Choices according to the Modified Osteoporotic Fracture Score and Posttreatment Radiographic Outcomes.

STUDY DESIGN: Retrospective observational study. PURPOSE: To evaluate the modified osteoporotic fracture (mOF) scores in three treatment groups and compare imaging findings in patients treated and not treated according to the mOF score-based treatment recommendation. OVERVIEW OF LITERATURE: The osteoporotic fracture (OF) score was established by the AO Spine to guide therapeutic decisions. To enhance its applicability, a mOF score was recently introduced. METHODS: Consecutive patients diagnosed with OFs at Fujieda Heisei Memorial Hospital were divided into three groups: nonsurgical therapy, balloon kyphoplasty (BKP), and open surgery groups. The mOF score was calculated, and the levels of independence and posttreatment imaging data were compared between patients treated and not treated according to the mOF score-based treatment recommendation. RESULTS: In total, 118 patients were included (nonsurgical therapy, n=57; BKP, n=48; open surgery, n=13), of whom 100 (85%) received treatment consistent with the mOF score-based treatment recommendation. In the BKP and open surgery groups, the mOF scorebased treatment recommendations were consistent with the actual treatment in 93% of the patients. However, in the nonsurgical group, the mOF score-based treatment recommendation was not consistent with the actual treatment in 25% of the patients. In this group, patients not treated according to the mOF score had significantly shorter vertebral body height, greater local kyphosis, and smaller sacral slope after treatment than patients treated according to the mOF score-based treatment recommendation. CONCLUSIONS: In the BKP and open surgery groups, the mOF scores were consistent with actual clinical selection. In the nonsurgical therapy group, patients not treated according to the mOF score-based treatment recommendation exhibited severe vertebral body deformity and a less well-balanced spine shape after treatment. The mOF score may help in selecting suitable treatments for OFs.

Differences in the Demographics and Clinical Characteristics between the Ossification of the Posterior Longitudinal Ligament and Ossification of the Ligamentum Flavum in Patients Who Underwent Thoracic Spinal Surgery for Compressive Myelopathy.

Ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF) are related diseases associated with the ossification of spinal ligaments that can occasionally lead to thoracic myelopathy. We retrospectively analyzed the clinical data of 34 consecutive patients who underwent thoracic spinal surgeries for OPLL and/or OLF at our hospital between July 2010 and June 2022, and statistically compared data between patients with thoracic OPLL (TOPLL; n = 12) and those with thoracic OLF (TOLF; n = 22). The mean age of the TOPLL group was significantly lower than that of the TOLF group (53.7 vs. 68.4 years). The TOPLL group exhibited a greater female predominance than the TOLF group (58.3% vs. 18.2%). The median body mass index of the TOPLL group was significantly higher than that of the TOLF group (33.0 vs. 26.0 kg/m2). Patients with TOPLL significantly required instrumented fusion and repetitive surgical intervention more than those with TOLF (83.3% vs. 9.1%; 50.0% vs. 0.0%). Although neurological deterioration just after the intervention was more common in patients with TOPLL (41.7% vs. 4.6%), no difference was observed in thoracic Japanese Orthopaedic Association score and recovery rate in the chronic phase between TOPLL and TOLF. The TOPLL group had a younger onset, female dominance, and a greater degree of obesity when compared with the TOLF group. The surgery for TOPLL is challenging, considering that it requires long-range decompression and fusion, subsequent operations, careful management, and long-term follow-up, when compared to TOLF, which necessitates only simple decompression.

Characteristics of the most viewed Hybrid Assistive Limb-related videos on YouTube.

Objectives. YouTube is one of the most popular video-sharing tools and is used as a forum for sharing information about experiences with new technology-based exercise programs, such as the wearable cyborg Hybrid Assistive Limb (HAL). This study aimed to analyze the content and quality of HAL-related videos viewed by people to clarify the content required by YouTube viewers. Methods. We searched HAL-related YouTube videos and selected the top 100 most viewed videos. The number of views, video length, upload date, content, and uploaders of each video were recorded. In addition, DISCERN was used to evaluate the quality of videos. Results. Of the 100 videos, the most shared content was the training videos on HAL (n = 58). The videos uploaded by YouTubers had a significantly higher number of views than those uploaded by other uploaders (hospital, company, and municipality) (p < .001). Furthermore, they had significantly higher DISCERN Questions 16 scores, which serve as the basis for the overall evaluation of the publication's overall quality (p < .001). Conclusion. HAL-related videos on YouTube, featuring the experiences and feedback of YouTubers who are HAL users, are favored more by viewers than by service providers.

Screening for prostate cancer in a city in Japan: age-specific prostate-specific antigen cutoff thresholds.

PURPOSE: Older men have higher prostate-specific antigen levels than younger men. However, the current Japanese Urological Association guidelines recommend secondary screening at a cutoff value of 4.0 ng/mL, even in older men. Here, we reexamined the cutoffs for older men using a prostate screening cohort in Japan and first performed an analysis to determine the indication cutoffs for detecting positive biopsies. METHODS: Data from 68,566 prostate cancer screenings in the city in 2018 were combined with cancer registration data. The optimal prostate-specific antigen levels to predict prostate cancer in different age groups were calculated using receiver operating characteristic curves after determining whether a cancer was registered within one year of screening. RESULTS: At the conventional prostate-specific antigen threshold of 4.0 ng/mL, the sensitivity, specificity, and negative predictive value were 94.9%, 91.7%, and 91.7%, respectively. The optimal prostate-specific antigen cutoff values for patients aged 50-59 years, 60-69 years, 70-79 years, and over 80 years were 3.900 ng/mL, 4.014 ng/mL, 4.080 ng/mL, and 4.780 ng/mL, respectively. CONCLUSIONS: The sensitivity and specificity of prostate cancer screening in the city were high, indicating a highly accurate screening. The prostate-specific antigen threshold was 4.78 ng/mL in patients older than 80 years. A higher prostate-specific antigen threshold may be useful in men over 80 years of age to avoid excess biopsy and reduce costs. Our results suggest that the current Japanese method of using PSA 4.0 ng/mL as a cutoff regardless of age may not be preferable for older men.

Age group differences in psychological distress and leisure-time exercise/socioeconomic status during the COVID-19 pandemic: a cross-sectional analysis during 2020 to 2021 of a cohort study in Japan.

Objective: This study aimed to determine the association between psychological distress and leisure-time exercise/socioeconomic status by age group, using data from a cohort study in Japan during the COVID-19 pandemic. Methods: This cross-sectional study was conducted among participants in the ME-BYO cohort, aged 20-85 years, living or working in Kanagawa, Japan. A questionnaire was disseminated to 1,573 participants (51.7% men) between December 2020 and March 2021. The questionnaire items included psychological distress (using the 6-item Kessler Psychological Distress Scale [K6]), leisure-time exercise, and socioeconomic status. Multivariate analyses were conducted using logistic regression analysis for each age group. Results: We found that 47.4% of 20-39-year-olds, 40.6% of 40-64-year-olds, and 28.3% of 65-85-year-olds experienced psychological distress (K6: ≥5 points). For those aged 20-39 years, leisure-time exercise (odds ratio [OR] (95% confidence interval) = 0.45 (0.28-0.73)) and higher annual household income [0.53 (0.32-0.90)] were associated with less psychological distress. For those aged 40-64 years, older age was associated with less psychological distress, while full-time work [1.98 (1.05-9.71)] was associated with more psychological distress. In the 65-85-year age group, higher education and higher annual income tended to be associated with less psychological distress. For those over 40 years of age, living with other(s) was associated with reduced psychological distress. Conclusion: In the general population of Japan, not engaging in leisure-time exercise and low income affect psychological distress among young adults. Further detailed studies are needed to consider overall physical activity, job type, and work style.

Treatment with Ligilactobacillus murinus lowers blood pressure and intestinal permeability in spontaneously hypertensive rats.

One feature of hypertension is a microbial imbalance with increased intestinal permeability. In this study, we examined whether an alteration in the microbiota affects blood pressure and intestinal permeability in spontaneously hypertensive rats (SHRs). We performed a 16S metagenome analysis of feces from 10- to 15-week-old SHRs using a synthetic long-read sequencing approach, and found a candidate for the microbiome treatment, Ligilactobacillus murinus (L. murinus), that was robustly decreased. Oral administration of L. murinus to SHRs for 2 weeks significantly inhibited blood pressure elevation and improved endothelium-dependent vasodilation but did not attenuate enhanced vascular contraction in SHR mesenteric arteries. The proximal colon of SHRs exhibited increased intestinal permeability with decreased levels of the tight junction protein claudin 4, morphological changes such as decreased intestinal crypts and elevated TNF-α levels, which was reversed by treatment with L. murinus. Consistent with these intestinal phenotypes, plasma lipopolysaccharides levels were elevated in SHR but decreased following L. murinus administration. We concluded that oral administration of L. murinus to SHRs exerts protective effects on intestinal permeability via restoration of claudin 4 expression and reversal of morphologic disorder, which may improve low-grade endotoxemia and thus reduce development of hypertension via recovery of endothelial vasodilating functions.

Analysis of Neurogenic Bowel and Bladder Dysfunction Following Decompression Surgery for Cervical Spondylotic Myelopathy: A Prospective Cohort Study.

STUDY DESIGN: A prospective observational study. OBJECTIVES: To investigate preoperative prevalence of neurogenic bowel dysfunction and neurogenic bladder in patients with degenerative cervical myelopathy (DCM) and examine the degree and timing of symptom improvement after cervical decompression surgery. Factors contributing to symptom improvement were also analyzed. METHODS: Among 75 patients with DCM who underwent cervical decompression, Constipation Scoring System (CSS) score, International Prostate Symptoms Score (IPSS), and Japanese Orthopaedic Association (JOA) score were assessed before surgery and 1, 3, 6, and 12 months after. Prevalence rates were calculated. Data regarding patient age, sex, disease status, disease duration, lesion level, and score changes was prospectively recorded and analyzed. RESULTS: The prevalence rates of defecation and urinary dysfunction before surgery were 41.3% and 34.7%, respectively. Among the patients with defecation dysfunction, the number of patients who improved 1, 3, 6, and 12 months after surgery was 10, 9, 9, and 6, respectively. Among the patients with urinary dysfunction, the corresponding number of patients was 12, 10, 11, and 11, respectively. None of the factors we examined were significantly associated with improvement in either CSS or IPSS score; however, improvement of lower extremity JOA score tended to be associated with improvement in both. CONCLUSIONS: The prevalence of symptoms of defecation and urinary dysfunction in patients with DCM was 41.3% and 34.7%, respectively. Decompression surgery improved symptoms in 20% to 46% of patients.

Isosteric Replacement of Ester Linkage of Lysophospholipids with Heteroaromatic Rings Retains Potency and Subtype Selectivity.

Our group has reported various derivatives of lysophosphatidylserine (LysoPS) as potent and subtype-selective agonists for G-protein-coupled receptors (GPCRs). However, the ester linkage between the glycerol moiety and fatty acid or fatty acid surrogate is present in all of them. In order to develop these LysoPS analogs as drug candidates, appropriate pharmacokinetic consideration is essential. Here, we found that the ester bond of LysoPS is highly susceptible to metabolic degradation in mouse blood. Accordingly, we examined isosteric replacement of the ester linkage with heteroaromatic rings. The resulting compounds showed excellent retention of potency and receptor subtype selectivity, as well as increased metabolic stability in vitro.

Unrecognized dural tear during percutaneous endoscopic lumbar surgery confirmed with myelography.

Iatrogenic dural tear is usually recognized during the surgery. We describe a rare case of unrecognized dural tear caused by percutaneous endoscopic lumbar surgery at another hospital clearly confirmed with dynamic myelography. Although magnetic resonance imaging of the lumbar spine showed no obvious fluid collection suggesting dural tear, dynamic myelography revealed leakage of intradural subarachnoid contrast medium along root sleeve into the intervertebral disc space. In the setting of endoscopic spine surgery, incidental dural tear might be overlooked due to the narrow and fluid-filled surgical field. Dynamic myelography is useful to evaluate the precise condition caused by unrecognized dural tear.

Postoperative intractable leg pain caused by dislocation of drainage tube.

Background: A wide variety of conditions can cause recurrent postoperative lumbar radiculopathy. Case Description: A 49-year-old female developed sudden recurrent postoperative right leg pain after a right-sided L5S1 microdiskectomy for a herniated disc. Emergent magnetic resonance and computed tomography studies demonstrated migration of the drainage tube into the right L5S1 lateral recess compromising the S1 nerve root. Following drain removal, the patient's right reg pain immediately resolved. Conclusion: Migration of a lumbar wound drain into the operated lateral recess following a lumbar diskectomy may result in acute, recurrent/intractable radicular pain that was readily resolved with drain removal.

Intraoperative complications of vertebral body stenting system.

Background: Vertebral body stenting systems (VBSs) are superior to balloon kyphoplasty for performing vertebral augmentation and height restoration. However, VBS may likely result in more material-related complications that have been under-reported. Here, an 84-year-old female's vertebral stents "toppled over" before the filling cement was fully applied, thus necessitating an additional posterior fusion. Case Description: An 84-year-old female presented with low back pain after a fall. Dynamic standing and decubitus X-rays revealed a vertebral compression fracture at T12 resulting in an intravertebral vacuum cleft (i.e., the lowermost level of diffuse idiopathic skeletal hyperostosis). When the VBS was performed, the stents "toppled over" just after removing the balloon catheters; we successfully restored with the cement volume in one stent but not the other, thus warranting an additional posterior fusion to maintain stability. Conclusion: The proper injection of cement into a VBS requires dual correct stent positioning, and careful control of requisite stent expansion. In an 84-year-old female with a T12 vertebral body fracture and a remarkable vacuum cleft, the VBS procedure resulted in an inadvertent injection into one stent thus warranting a secondary posterior fusion.

Effectiveness of a targeted primary preventive intervention in a high-risk group identified using an efficiency score from data envelopment analysis: a randomised controlled trial of local residents in Japan.

OBJECTIVE: To determine whether a minimal intervention based on the data envelopment analysis (DEA)-identified efficiency score effectively prevents hypertension. DESIGN: Randomised controlled trial. SETTING: Takahata town (Yamagata, Japan). PARTICIPANTS: Residents aged 40-74 years belonged to the information provision group for specific health guidance. Participants with a blood pressure ≥140/90 mm Hg, those taking antihypertensive medication, or those with a history of cardiac diseases were excluded. Participants were consecutively assigned based on their health check-up visit at a single centre from September 2019 to November 2020 and were followed up at the check-up in the following year, until 3 December 2021. INTERVENTION: A targeted approach using minimal intervention. Target was identified using DEA and 50% of participants with higher risk were targeted. The intervention was notifying the results of their risk of hypertension according to the efficiency score obtained by the DEA. PRIMARY OUTCOME MEASURES: A reduction in the proportion of participants who developed hypertension (≥140/90 mm Hg or taking antihypertensive medication). RESULTS: A total of 495 eligible participants were randomised, and follow-up data were available for 218 and 227 participants in the intervention and control groups, respectively. The risk difference for the primary outcome was 0.2% (95% CI -7.3 to 6.9) with 38/218 (17.4%) and 40/227 (17.6%) events in the intervention and control group, respectively (Pearson's χ2 test, p=0.880). The adjusted OR of the effect of the intervention was 0.95 (95% CI 0.56 to 1.61, p=0.843), and that of the efficiency score (10-rank increase) was 0.81 (95% CI 0.74 to 0.89, p<0.0001). CONCLUSIONS: Minimal intervention to a high-risk population stratified by DEA was not effective in reducing the onset of hypertension in 1 year. The efficiency score could predict the risk of hypertension. TRIAL REGISTRATION NUMBER: UMIN000037883.

The ME-BYO index: A development and validation project of a novel comprehensive health index.

Quantifying health status and identifying modifiable factors are essential for effective and individualized prevention of age-related conditions and for promoting health during aging. The ME-BYO concept from Kanagawa Prefecture, one of Japan's largest prefectures, can be used to establish a healthy aging society. In disease etiology, ME-BYO considers the status of an individual's body and mind as changing continuously from healthy to sick instead of being a dichotomy between the two. ME-BYO conceptualizes the entire process of this change. The ME-BYO index was developed in 2019 to comprehensively and numerically measure and visualize an individual's current health status and future disease risk by quantifying data on the four domains of metabolic function, locomotor function, cognitive function, and mental resilience. The ME-BYO index has been implemented in the personal health management application "My ME-BYO." However, scientific validation of this index and the development of a practical application using healthcare data remain to be completed. In 2020, our research team started a project to refine the ME-BYO index using data from the Kanagawa ME-BYO prospective cohort study, which is a large population-based genomic cohort study. This project will scientifically evaluate the ME-BYO index and develop a practical application for promoting healthy aging.

Effect of a neurokinin 3 receptor-selective agonist administration on the embryos recovered from superovulated cows.

Superovulation (SOV) treatment of cows results in unovulated follicles and inconsistent quality of the recovered embryos. It has been demonstrated that luteinizing hormone (LH) secretion is suppressed during SOV treatment of cows, which may cause insufficient follicle development and variation in the development of recovered embryos and unovulated follicles. Pulsatile gonadotropin-releasing hormone/LH secretion is controlled by the activity of kisspeptin, neurokinin B and dynorphin (KNDy) neurons in the arcuate nucleus in many mammals. As neurokinin B promotes the activity of KNDy neurons, we hypothesized that senktide, a neurokinin B receptor agonist, has the potential as a therapeutic drug to improve the ovulation rate and quality of recovered embryos in SOV-treated cows via stimulation of LH secretion. Senktide was administered intravenously (30 or 300 nmol/min) for 2 h, beginning from 72 h after the start of SOV treatment. LH secretion was examined before and after administration, and embryos were collected 7 d after estrus. Senktide administration increased LH secretion in SOV-treated cows. The ratios of code 1, code 1 and 2, and blastocyst stage embryos to recovered embryos were increased by senktide (300 nmol/min) administration. Moreover, the mRNA levels of MTCO1, COX7C, and MTATP6 were upregulated in recovered embryos of senktide (300 nmol/min)-administered animals. These results indicate that the administration of senktide to SOV-treated cows enhances LH secretion and upregulates the expression of genes involved in mitochondrial metabolism in embryos, thereby improving embryo development and embryo quality.

Effects of gene-lifestyle interactions on obesity based on a multi-locus risk score: A cross-sectional analysis.

BACKGROUND: The relationship between lifestyle and obesity is a major focus of research. Personalized nutrition, which utilizes evidence from nutrigenomics, such as gene-environment interactions, has been attracting attention in recent years. However, evidence for gene-environment interactions that can inform treatment strategies is lacking, despite some reported interactions involving dietary intake or physical activity. Utilizing gene-lifestyle interactions in practice could aid in optimizing interventions according to genetic risk. METHODS: This study aimed to elucidate the effects of gene-lifestyle interactions on body mass index (BMI). Cross-sectional data from the Japan Multi-Institutional Collaborative Cohort Study were used. Interactions between a multi-locus genetic risk score (GRS), calculated from 76 ancestry-specific single nucleotide polymorphisms, and nutritional intake or physical activity were assessed using a linear mixed-effect model. RESULTS: The mean (standard deviation) BMI and GRS for all participants (n = 12,918) were 22.9 (3.0) kg/m2 and -0.07 (0.16), respectively. The correlation between GRS and BMI was r(12,916) = 0.13 (95% confidence interval [CI] 0.11-0.15, P < 0.001). An interaction between GRS and saturated fatty acid intake was observed (ß = -0.11, 95% CI -0.21 to -0.02). An interaction between GRS and n-3 polyunsaturated fatty acids was also observed in the females with normal-weight subgroup (ß = -0.12, 95% CI -0.22 to -0.03). CONCLUSION: Our results provide evidence of an interaction effect between GRS and nutritional intake and physical activity. This gene-lifestyle interaction provides a basis for developing prevention or treatment interventions for obesity according to individual genetic predisposition.

Correction: Takeuchi et al. Predictive Factors for Poor Outcome following Chemonucleolysis with Condoliase in Lumbar Disc Herniation. Medicina 2022, 58, 1868.

In the original publication [...].

Association of 25-hydroxyvitamin D with risk of overall and colorectal cancer among Japanese using a Mendelian randomization approach.

The association between vitamin D and total and colorectal cancer risk was inconsistent in observational studies. We conducted Mendelian randomization approach in which the effect of confounding might be reduced. 110 single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D concentrations were systematically selected according to the "GWAS Catalog" from all ethnic populations. For the SNP-vitamin D concentration association, 3978 individuals from two Japanese cohorts were included. Regarding SNP-total and colorectal cancer association, 4543 cancer cases and 14,224 controls and 7936 colorectal cancer cases and 38,042 controls, respectively were included from the Japanese Consortium of Genetic Epidemiology and other studies in Japan. There was no significant association between the genetically predicted plasma 25-hydroxyvitamin D concentration and total or colorectal cancer in any of the MR analyses. Odds ratios per doubling in vitamin D concentration were 0.83 (95% confidence interval [CI] 0.63-1.09) for total cancer and 1.00 (95% CI 0.80-1.24) for colorectal cancer in inverse variance weighted method, 0.83 (95% CI 0.57-1.19) for total cancer and 1.01 (95% CI 0.75-1.37) for colorectal cancer in MR-Egger method. Consistent with previous MR analyses among European ancestries, there was no significant association identified between 25-hydroxyvitamin D levels and total or colorectal cancer among Asians.

Deterioration of mitochondrial biogenesis and degradation in the endometrium is a cause of subfertility in cows.

To investigate possible causes of reproductive failure, we conducted global endometrial gene expression analyses in fertile and subfertile cows. Ingenuity pathway analysis showed that RICTOR and SIRT3 are significant upstream regulators for highly expressed genes in fertile cows, and are predicted to be activated upstream regulators of normal mitochondrial respiration. Canonical pathway analysis revealed that these highly expressed genes are involved in the activation of mitochondrial oxidative phosphorylation. Therefore, in subfertile cows, the inactivation of RICTOR and SIRT3 may correlate with decreased capacity of mitochondrial respiration. Furthermore, the expression levels of most mitochondrial DNA genes and nuclear genes encoding mitochondrial proteins were higher in subfertile cows. The mitochondrial DNA copy number was significantly higher in the endometrium of subfertile cows, whereas the ATP content did not differ between fertile and subfertile cows. Quantitative reverse transcription-PCR analysis demonstrated that the expression of PGC1a, TFAM, MFN1, FIS1, and BCL2L13 were significantly lower in subfertile cows. In addition, transmission electron microscopy images showed mitochondrial swelling in the endometrial cells of the subfertile cow. These results suggest that poor-quality mitochondria accumulate in the endometrium owing to a reduced capacity for mitochondrial biogenesis, fusion, fission, and degradation in subfertile cows, and may contribute to infertility.