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Introduction: The watch-and-wait (WW) strategy is an alternative to anterior resection in patients with rectal cancer (RC) that have had a complete clinical response to neoadjuvant treatment. Few reports describe the quality of life and functional anorectal disorders (FADs) in that population. Aim: To analyze and compare the FADs and quality of life in patients with locally advanced adenocarcinoma of the rectum treated with neoadjuvant therapy, divided into two different strategy groups: group 1 (G1), WW; and group 2 (G2), anterior resection. Materials and methods: Thirty patients (G1: n = 20 and G2: n = 10) that had finished neoadjuvant therapy at least 12 months prior were included. Mean patient age was 59.5 years (range: 41-79) and 15 of the patients were men. The FADs were evaluated through: a) clinical history, b) 21-day bowel diary, c) Jorge and Wexner fecal incontinence scale, d) anorectal manometry (ARM), and fecal incontinence quality of life scale (FIQL). Results: Bowel diary: fecal incontinence (40%) and urge to defecate (45%) in G1 vs. fecal incontinence (60%) and urge to defecate (30%) in G2, with no significant differences (p = NS). Fecal incontinence scale: fecal incontinence in G1 was significantly less severe than that in G2 (median 6.5 points vs. 13 points [p = 0.0142]). ARM: no differences between the two groups. Quality of life: significantly different between the two groups (FIQL/G1: 3.7 vs. FIQL/G2: 2.8; p

Resumen: Introducción y objetivos: La estrategia watch and wait (WW) es una alternativa a la resección anterior (RA) en pacientes con cáncer de recto (CR), con respuesta clínica completa a la neoadyuvancia. Existen pocos reportes que describan la calidad de vida (CV) y los trastornos funcionales anorrectales (TFA) en esta población. Objetivo: Analizar y comparar los TFA y la CV en pacientes con adenocarcinoma de recto localmente avanzados tratados con neoadyuvancia con diferentes estrategias: grupo 1 (G1): WW y grupo 2 (G2): RA. Material y métodos: Se incluyeron 30 pacientes (G1: n = 20 y G2: n = 10) que cumplieron al menos 12 meses de finalizado el tratamiento neoadyuvante, edad mediana de 59.5 años (rango: 41-79), 15 son hombres. Los TFA fueron evaluados con: a) historia clínica, b) diario de continencia anal de 21 días, c) escala de continencia anal de Jorge y Wexner, d) manometría anorrectal (MAR) y la CV con el cuestionario de incontinencia fecal (FIQL). Resultados: Diario de continencia anal: G1: incontinencia fecal (40%) y urgencia defecatoria (45%) vs. G2 incontinencia fecal (60%) y urgencia defecatoria (30%), sin diferencias significativas (p = NS). Escala de continencia anal: la incontinencia fecal de G1 fue significativamente menos severa que la de G2 [mediana 6.5 puntos vs. 13 puntos; (p = 0.0142)]. MAR: sin diferencias entre los grupos. CV: es significativamente diferente entre ambos grupos (FIQL/G1: 3.7 vs. FIQL/G2: 2.8; p < 0.03). Conclusiones: La estrategia de seguimiento WW en pacientes con CR localmente avanzado estaría asociada con una mejor CV y menor incontinencia fecal. Abstract: Introduction: The watch-and-wait (WW) strategy is an alternative to anterior resection in patients with rectal cancer (RC) that have had a complete clinical response to neoadjuvant treatment. Few reports describe the quality of life and functional anorectal disorders (FADs) in that population. Aim: To analyze and compare the FADs and quality of life in patients with locally advanced adenocarcinoma of the rectum treated with neoadjuvant therapy, divided into two different strategy groups: group 1 (G1), WW; and group 2 (G2), anterior resection. Materials and methods: Thirty patients (G1: n = 20 and G2: n = 10) that had finished neoadjuvant therapy at least 12 months prior were included. Mean patient age was 59.5 years (range: 41-79) and 15 of the patients were men. The FADs were evaluated through: a) clinical history, b) 21-day bowel diary, c) Jorge and Wexner fecal incontinence scale, d) anorectal manometry (ARM), and fecal incontinence quality of life scale (FIQL). Results: Bowel diary: fecal incontinence (40%) and urge to defecate (45%) in G1 vs. fecal incontinence (60%) and urge to defecate (30%) in G2, with no significant differences (p = NS). Fecal incontinence scale: fecal incontinence in G1 was significantly less severe than that in G2 (median 6.5 points vs. 13 points [p = 0.0142]). ARM: no differences between the two groups. Quality of life: significantly different between the two groups (FIQL/G1: 3.7 vs. FIQL/G2: 2.8; p < 0.03). Conclusions: The WW follow-up strategy in patients with locally advanced rectal cancer was associated with better quality of life and reduced fecal incontinence.

Abstract Introduction Cerebrospinal fluid (CSF) analysis is important for detecting inflammation of the nervous system and the meninges, bleeding in the area of the subarachnoid space that may not be visualized by imaging, and the spread of malignant diseases to the CSF space. In the diagnosis and differential diagnosis of neurodegenerative diseases, the importance of CSF analysis is increasing. Measuring the opening pressure of CSF in idiopathic intracranial hypertension and at spinal tap in normal pressure hydrocephalus constitute diagnostic examination procedures with therapeutic benefits. Recommendations (most important 3-5 recommendations on a glimpse): 1. The indications and contraindications must be checked before lumbar puncture (LP) is performed, and sampling CSF requires the consent of the patient. 2. Puncture with an atraumatic needle is associated with a lower incidence of postpuncture discomfort. The frequency of postpuncture syndrome correlates inversely with age and body mass index, and it is more common in women and patients with a history of headache. The sharp needle is preferably used in older or obese patients, also in punctures expected to be difficult. 3. In order to avoid repeating LP, a sufficient quantity of CSF (at least 10 ml) should be collected. The CSF sample and the serum sample taken at the same time should be sent to a specialized laboratory immediately so that the emergency and basic CSF analysis program can be carried out within 2 h. 4. The indication for LP in anticoagulant therapy should always be decided on an individual basis. The risk of interrupting anticoagulant therapy must be weighed against the increased bleeding risk of LP with anticoagulant therapy. 5. As a quality assurance measure in CSF analysis, it is recommended that all cytological, clinical-chemical, and microbiological findings are combined in an integrated summary report and evaluated by an expert in CSF analysis. Conclusions In view of the importance and developments in CSF analysis, the S1 guideline “Lumbar puncture and cerebrospinal fluid analysis” was recently prepared by the German Society for CSF analysis and clinical neurochemistry (DGLN) and published in German in accordance with the guidelines of the AWMF ( https://www.awmf.org ). /uploads/tx_szleitlinien/030-141l_S1_Lumbalpunktion_und_Liquordiagnostik_2019-08.pdf). The present article is an abridged translation of the above cited guideline. The guideline has been jointly edited by the DGLN and DGN.

ABSTRACT Mosquito-transmitted viruses are spread globally and present a great risk to human health. Among the many approaches investigated to limit the diseases caused by these viruses are attempts to make mosquitos resistant to virus infection. Coinfection of mosquitos with the bacterium Wolbachia pipientis from supergroup A is a recent strategy employed to reduce the capacity for major vectors in the Aedes mosquito genus to transmit viruses, including dengue virus (DENV), Chikungunya virus (CHIKV), and Zika virus (ZIKV). Recently, a supergroup B Wolbachia wStri, isolated from Laodelphax striatellus, was shown to inhibit multiple lineages of ZIKV in Aedes albopictus cells. Here, we show that wStri blocks the growth of positive-sense RNA viruses DENV, CHIKV, ZIKV, and yellow fever virus by greater than 99.9%. wStri presence did not affect the growth of the negative-sense RNA viruses LaCrosse virus or vesicular stomatitis virus. Investigation of the stages of the ZIKV life cycle inhibited by wStri identified two distinct blocks in viral replication. We found a reduction of ZIKV entry into wStri-infected cells. This was partially rescued by the addition of a cholesterol-lipid supplement. Independent of entry, transfected viral genome was unable to replicate in Wolbachia-infected cells. RNA transfection and metabolic labeling studies suggested that this replication defect is at the level of RNA translation, where we saw a 66% reduction in mosquito protein synthesis in wStri-infected cells. This study’s findings increase the potential for application of wStri to block additional arboviruses and also identify specific blocks in viral infection caused by Wolbachia coinfection. IMPORTANCE Dengue, Zika, and yellow fever viruses are mosquito-transmitted diseases that have spread throughout the world, causing millions of infections and thousands of deaths each year. Existing programs that seek to contain these diseases through elimination of the mosquito population have so far failed, making it crucial to explore new ways of limiting the spread of these viruses. Here, we show that introduction of an insect symbiont, Wolbachia wStri, into mosquito cells is highly effective at reducing yellow fever virus, dengue virus, Zika virus, and Chikungunya virus production. Reduction of virus replication was attributable to decreases in entry and a strong block of virus gene expression at the translational level. These findings expand the potential use of Wolbachia wStri to block viruses and identify two separate steps for limiting virus replication in mosquitos that could be targeted via microbes or other means as an antiviral strategy.

Indroduction. At present, modern telemedicine methods are being introduced, that may contribute to reducing lack of qualified stroke patient care, particularly in less populated regions. With the help of video conferencing systems, a so-called neuromedical teleconsultation is carried out. Methods. The study included a multicentered, completely standardized survey of physicians in hospitals by means of a computerized on-line questionnaire. Descriptive statistical methods were used for data analysis. Results. 119 acute hospitals without neurology departments were included in the study. The most important reasons for participating in a teleneuromedical network is seen as the improvement in the quality of treatment (82%), the ability to avoid unnecessary patient transport (76%), easier and faster access to stroke expertise (72%) as well as better competitiveness among medical services (67%). The most significant problem areas are the financing system of teleneuromedicine with regard to the acquisition costs of the technical equipment (43%) and the compensation for the stroke-unit center with the specialists' consultation service (31%) as well as legal aspects of teleneuromedicine (27%). Conclusions. This investigation showed that there is a high acceptance for teleneuromedicine among co-operating hospitals. However these facilities have goals in addition to improved quality in stroke treatment. Therefore the use of teleneuromedicine must be also associated with long term incentives for the overall health care system, particularly since the implementation of a teleneuromedicine network system is time consuming and associated with high implementation costs.

Background: Extracorporeal shock wave therapy (ESWT) is an effective treatment for musculoskeletal pain, tendinopathy, and fasciitis with an anti-inflammatory effect. ESWT can be categorized into two groups: radial pressure wave (RPW) and focused shock wave (FSW). Although there have been several studies on the inflammation and pain-improvement mechanisms of FSW, there are few studies on the pain-improvement mechanisms of RPW. This study aimed to elucidate the efficacy of RPW in a rat model of adjuvant arthritis., Methods: Ninety-six rats were randomly categorized into three groups: RPW, control, and sham as follows: (I) RPW group, which received RPW application after complete Freund's adjuvant (CFA) injection; (II) Control group, which received only CFA injection; and (III) Sham group, which received only saline injection. All rats were evaluated at 0, 4, 7, 14, 28, and 56 days post-RPW application based on foot circumference, von Frey test, and immunohistochemistry of nerve fibers for calcitonin gene-related peptide (CGRP) and protein gene product (PGP) 9.5 in plantar skins., Results: There were no significant differences in foot circumference between the RPW and control groups at any time point. The RPW group showed significant improvements in the von Frey test results on days 7 and 14. The total CGRP-immunoreactive (ir) and PGP9.5-ir nerve fiber lengths in the RPW group decreased on day 0; however, both were increased in the control group. The CGRP-ir and PGP9.5-ir nerve fibers in the RPW group were significantly shorter than those in the control group until day 14 after RPW., Conclusions: RPW improved the mechanical hypersensitivity between days 7 and 14 after application. Like FSW, RPW also induced the degeneration of sensory nerve fibers in the skin in the early period after irradiation, and reinnervation occurred between 14 and 28 days. Thus, our results demonstrate one of the pain relief mechanisms after RPW application., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Proximal femoral fractures in geriatric patients are a major challenge in orthopedics, often leading to major functional impairment. Early surgical intervention is crucial for improving patient recovery and overall health outcomes. Thus, Japan's Ministry of Health, Labour and Welfare initiated a reimbursement policy in April 2022 to encourage early surgery for these fractures in patients aged ≥75 years. This study investigated the impact of this policy on early surgery rates in Japan and identified factors influencing the timing of surgical interventions., Methods: We retrospectively analyzed the data of patients who underwent surgery for proximal femoral fractures at our institution between April 2022 and March 2023. Patients were categorized into two groups based on the timing of surgery relative to the injury: ≤48 h and >48 h. Demographic and clinical data, including age, sex, fracture type, and various health- and admission-related factors, were assessed., Results: Of the 192 patients, 152 were included in the study. Among them, 38% underwent early surgery (≤48 h), and 15% of the patients arrived more than 48 h post-injury. Significant differences were found in admission routes and residence types between the groups. The ≤48 h group had shorter intervals from injury to admission and surgery than the >48 h group. Factors such as the admission process, day of the week, and C-reactive protein levels significantly influenced the timing of surgery., Conclusions: After introducing incentives for early surgery in Japan, 38% of patients with proximal femoral fractures underwent surgery within 48 h of injury. Factors contributing to patients not receiving early surgery included transport from another hospital, weekend hospitalization, and elevated CRP levels. These findings suggest that achieving surgery within 48 h of injury is challenging through hospital efforts alone, and the time criteria might be more appropriate if changed to "admission to surgery.", Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Study Design: Retrospective study., Purpose: To investigate the risk factors for allogeneic red blood cell (RBC) transfusion in adult spinal deformity (ASD) surgery., Overview of Literature: Studies have not thoroughly explored the roles of intraoperative hypothermia, autologous blood donation, and hemostatic agent administration, which would provide a better understanding of the risk for perioperative RBC transfusion in ASD surgery., Methods: The medical records of 151 patients with ASD who underwent correction surgery between 2012 and 2021 were retrospectively reviewed. Estimated blood loss and perioperative allogeneic transfusion were examined. Patients were categorized into two groups based on whether they received perioperative allogeneic blood transfusion. Logistic regression analysis was employed to investigate the effect of age, sex, blood type, body mass index, American Society of Anesthesiologists' physical status, preoperative hemoglobin level, autologous blood donation, global spine alignment parameters, preoperative use of anticoagulants or antiplatelet medicine and nonsteroidal anti-inflammatory drugs, number of instrumented fusion levels, total operative duration, three-column osteotomy, lateral interbody fusion, pelvic fixation, intraoperative hypothermia, use of gelatin-thrombin based hemostatic agents, and intraoperative tranexamic acid (TXA) with simultaneous exposure by two attending surgeons., Results: The estimated blood loss was 994.2±754.5 mL, and 71 patients (47.0%) received allogeneic blood transfusion. In the logistic regression analysis, the absence of intraoperative TXA use and simultaneous exposure (odds ratio [OR], 26.3; 95% confidence interval [CI], 7.6-90.9; p<0.001), lack of autologous blood donation (OR, 21.2; 95% CI, 4.4-100.0; p<0.001), and prolonged operative duration (OR, 1.6; 95% CI, 1.3-1.9; p<0.001) were significant independent factors for perioperative allogeneic blood transfusion in ASD surgery., Conclusions: Autologous blood storage, intraoperative TXA administration, and simultaneous exposure should be considered to minimize perioperative allogeneic blood transfusion in ASD surgery, particularly in patients with anticipated lengthy surgeries.

Background: The diagnosis of rotator cuff tears (RCTs) using radiographs alone is clinically challenging; thus, the utility of deep learning algorithms based on convolutional neural networks has been remarkable in the field of medical imaging recognition. We aimed to evaluate the diagnostic performance of artificial intelligence (a deep learning algorithm; a convolutional neural network) to detect and classify RCTs using shoulder radiographs, and compare its diagnostic performance with that of orthopedic surgeons., Methods: A total of 1169 plain shoulder anteroposterior radiographs (1 image per shoulder) were included in the total dataset and divided into four groups: intact, small, medium, and large to massive tear groups. The sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and area under the receiver operating curve were measured for the detection of RCTs through binary classification. The average accuracy, recall, precision, and F1-score were divided into four groups by cuff tear size for multiclass classification., Results: The convolutional neural network demonstrated a high performance, with 92% sensitivity, 69% specificity, 86% accuracy, and an area under the receiver operating curve of 0.88 for the detection of RCTs. The average accuracy, recall, precision, and F1-score of the convolutional neural network for classification were 60%, 0.42, 0.49, and 0.45, respectively. The accuracy of the convolutional neural network for the detection and classification of RCTs was significantly better than that of orthopedic surgeons., Conclusion: The convolutional neural network demonstrated the diagnostic ability to detect and classify RCTs using plain shoulder radiographs, and the diagnostic performance exhibited equal to superior accuracy when compared with those of shoulder experts., (Copyright © 2024 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Purpose: Magnetic resonance imaging (MRI) is the most widely used imaging to diagnose lateral epicondylitis (LE). However, the importance of MRI findings in LE remains unclear. This study aimed to classify the signal intensity changes of the extensor carpi radialis brevis origin and the shape and length of the synovial fold using MRI and compare them with clinical symptoms. We hypothesized that MRI findings in LE are not associated with clinical symptoms., Methods: Two hundred and forty-three patients (261 elbows, mean age: 51.2 ± 8.5 years, mean duration of LE: 18.2 ± 11.3 months) who were evaluated using pretreatment MRI were included. The signal change of the extensor carpi radialis brevis origin was classified using coronal T2-weighted (T2) imaging and coronal fat-suppressed proton density T2 imaging, and the shape and length of the synovial folds were evaluated using coronal and sagittal T2 imaging. Furthermore, MRI findings were compared with clinical symptoms at the first visit., Results: The number of elbows with high signal intensity on fat-suppressed proton density T2 was 252 of 261 (96.5%), and those on T2 were 207 of 261 (79.3%). Synovial folds were observed in 231 of 261 (88.5%) of the elbows, and synovial folds having a dull shape were observed in 95 of 261 (36.4%) elbows. The length of the synovial fold was >1/3 of the radial head in 87 of 261 (33.3%) of the elbows. There was no statistically significant correlation between the MRI findings and clinical symptoms., Conclusions: A high rate of high signal intensity changes of the extensor carpi radialis brevis origin was observed, and fat-suppressed proton density T2 could detect finer signal changes than T2. Furthermore, synovial folds were found in many cases of LE. However, there was no association between MRI findings and clinical symptoms at first visit., Type of Study/level of Evidence: Prognostic IV., Competing Interests: No benefits in any form have been received or will be received related directly to this article., (© 2024 The Authors.)

The rat mono-iodoacetate (MIA) arthritis model has been used in studies on the hip, knee, and ankle joints. Few studies have explored its utility in shoulder arthritis research, and none have evaluated the effects of time and different MIA doses on arthritis progression. Therefore, we developed a rat MIA shoulder arthritis model to evaluate articular changes through radiological and histological analyses. Sprague-Dawley rats (n = 108) were equally divided into groups that were intra-articularly injected with 0.5 mg of MIA (in 50 µL of purified water), 2.0 mg of MIA (in 50 µL of purified water), or purified water (50 µL; sham group). Throughout the study period, 18 rats (six per group) were evaluated by computed tomography and assessed using the Larsen's classification system; 90 rats were further evaluated histologically using the Osteoarthritis Research Society International scoring system. Computed tomography revealed that the groups injected with MIA developed arthritis and osteophytes 14 days after injection, which progressed temporally. The Larsen's grades worsened over time; at all time points, the scores were higher in the group injected with 2.0 mg of MIA than in the group injected with 0.5 mg of MIA. Furthermore, concurrent with the worsening Larsen's grades, the Osteoarthritis Research Society International scores also significantly increased over time; at all time points, they were higher in the group injected with 2.0 mg of MIA than in the group injected with 0.5 mg of MIA. Our rat MIA shoulder arthritis model revealed radiologically and histologically confirmed temporal and MIA dose-dependent arthritic changes., (© 2023 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Background: Ulnar collateral ligament (UCL) injuries occur frequently in baseball players, and UCL reconstruction is performed when nonoperative treatment fails., Purpose: To compare a novel all-suture anchor method of UCL reconstruction with a method using bone tunnels (Ito method) by investigating the displacement against valgus torque and the failure strength., Study Design: Controlled laboratory study., Methods: Eight fresh-frozen cadaveric upper extremities (mean age, 82.0 years) were utilized in this study. To evaluate the displacement against valgus torque, the valgus stability test was performed for 4 anterior oblique ligament (AOL) conditions: intact AOL, resected AOL, reconstructed using the anchor method, and reconstructed using the Ito method. The load-to-failure test was performed to evaluate the failure strength of the anchor and Ito methods. Displacement against valgus load was compared between conditions using the repeated-measures 2-way analysis of variance with Bonferroni post hoc test, and failure strength between the anchor and Ito methods was compared using the unpaired t test., Results: Displacements of the intact AOL and anchor method were significantly greater than those of the resected AOL at both 60° and 90° of flexion (intact AOL: P  = .005 and P  < .001, respectively; and anchor method: P  = .024 and P  < .001, respectively). The displacement of the Ito method at 90° of flexion was significantly greater than that of the resected AOL ( P =  .003), but no significant difference was observed at 60° of flexion ( P =  .109). There were no significant differences in displacement between the anchor and Ito methods at any flexion angle, nor was there a significant difference in failure torque between the anchor and Ito methods (16.3 ± 3.1 vs 17.6 ± 2.3 N·m, respectively; P  = .537)., Conclusion: The displacement and failure strength against a valgus load after UCL reconstruction using a suture anchor on the ulnar side were equal to those using bone tunnels., Clinical Relevance: UCL reconstruction using a suture anchor on the ulnar side is simpler and less invasive than using bone tunnels, with similar outcomes., Competing Interests: The authors have declared that there are no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2023.)

Background: Reverse total shoulder arthroplasty (RSA) has been approved since 2014 in Japan, and the number of RSA cases has been accumulating. However, only short-to medium-term outcomes have been reported, with a small number of case series, because of its short history in Japan. This study aimed to evaluate complications after RSA in hospitals affiliated with our institute, with comparison to those in other countries., Methods: A multicenter retrospective study was performed at 6 hospitals. In total, 615 shoulders (mean age: 75.7 ± 6.2 years; mean follow-up: 45.2 ± 19.6 months) with at least 24 months of follow-up were included in this study. The active range of motion was assessed pre-and postoperatively. The 5-year survival rate was evaluated for reoperation for any reason in 137 shoulders with at least 5 years of follow-up using Kaplan-Meier analysis. Postoperative complications were evaluated, including dislocation; prosthesis failure; deep infection; periprosthetic, acromial, scapular spine, and clavicle fractures; neurological disorders; and reoperation. Furthermore, imaging assessments, including scapular notching, prosthesis aseptic loosening, and heterotopic ossification were evaluated on postoperative radiography at the final follow-up., Results: All range of motion parameters were significantly improved postoperatively ( P  < .001). The 5-year survival rate was 93.4% (95% confidence interval: 87.8%-96.5%) for reoperation. Complications occurred in 256 shoulders (42.0%), with reoperation in 45 (7.3%), acromial fracture in 24 (3.9%), neurological disorders in 17 (2.8%), deep infection in 16 (2.6%), periprosthetic fracture in 11 (1.8%), dislocation in 9 (1.5%), prosthesis failure in 9 (1.5%), clavicle fracture in 4 (0.7%), and scapular spine fracture in 2 (0.3%). Regarding imaging assessments, scapular notching was observed in 145 shoulders (23.6%), heterotopic ossification in 80 (13.0%), and prosthesis loosening in 13 (2.1%)., Conclusion: This is the first large case series to investigate the complications after RSA in Japan, and the overall frequency of complications after RSA was similar to that in other countries., (© 2023 The Author(s).)

Background: A comparison of changes in the long head of the biceps tendon for different types of rotator cuff tears has not been previously performed. Furthermore, the correlation between the thickening and degeneration of the long head of the biceps tendon and the cause of these changes have not been fully clarified. We evaluated the relationship between degenerative changes in the long head of the biceps tendon and rotator cuff tears in a rat model using imaging and histology., Methods: Ninety-six 12-week-old Sprague-Dawley rats were divided into anterior (subscapularis tear), anterosuperior (subscapularis, supraspinatus, and infraspinatus tears), superior (supraspinatus and infraspinatus tears), and control groups. The long head of the biceps tendon was harvested at 4 or 12 weeks postoperatively. The cross-sectional areas of the intra- and extra-capsular components of the tendon were measured using micro-computed tomography, and the affected/normal ratio of the cross-sectional area was calculated. Masson's trichrome staining and Alcian blue staining were performed for histologic analysis, with degenerative changes described using the modified Bonar scale. The correlation between the affected/normal ratio and Bonar scores was evaluated., Results: The affected/normal ratio was higher for the anterior and anterosuperior groups than for the control group at 4 and 12 weeks. The ratio increased for the intra-articular portion in the superior group and for both the intra- and extra-articular portions in the anterior and anterosuperior groups. Degeneration considerably progressed in the anterior and anterosuperior groups compared with the control group from weeks 4 to 12 and was greater in the intra- than in the extra-articular portion. The ratio correlated with extracellular matrix score., Conclusions: Subscapularis tears were associated with progressive thickening and degeneration of the long head of the biceps tendon at 4 and 12 weeks postoperatively, which was more significant in the intra- than in the extra-articular portion. Histologic evaluation indicated that the extracellular matrix likely caused these degenerative changes., (© 2023. The Author(s).)

Background: Although arthroscopic subacromial decompression (ASD) is a commonly used procedure during arthroscopic rotator cuff repair (ARCR), the effect of ASD on the clinical outcomes for ARCR is controversial. The purpose of this study was to compare the clinical outcomes of ARCR with or without ASD., Methods: Patients (n = 315 with 320 shoulders) who underwent ARCR for small to medium-sized rotator cuff tears were followed for at least 24 months. ARCR was performed with ASD (180 shoulders, group A) or without ASD (140 shoulders, group N). There were no significant differences in patient demographics, including mean age and mean follow-up time. Rotator cuff repair was performed using the suture-bridge technique in all shoulders, and all patients were treated using the same rehabilitation protocol after surgery. University of California at Los Angeles score, Constant score, re-tear rates, revision surgery rates, and operating time were compared between groups. Re-tear was defined as Sugaya classification Types 4 and 5 using postoperative magnetic resonance imaging at more than 12 months., Results: There was no statistically significant difference in clinical outcomes before and after ARCR between groups. However, the University of California at Los Angeles scores and Constant scores significantly improved in both groups after surgery ( P  < .001). Furthermore, there was no major difference in the re-tear rates between groups A (7/180 shoulders, 3.9%) and N (11/140 shoulders, 7.9%) ( P  = .146). Revision surgeries were performed on 3/180 shoulders (1.7%) in group A (due to postoperative deep infection in one shoulder and revision ARCR for re-tear in two shoulders). No revisions surgeries were needed in group N patients ( P  = .259). The mean surgical time for group A was 62.0 ± 27.0 minutes (29-138 min.) and 52.4 ± 26.1 minutes (17-124 min.) for group N ( P  = .007)., Conclusion: These results suggest that ASD has a limited effect on clinical outcomes of ARCR for small to medium-sized rotator cuff tears., (© 2022 The Authors.)

Cell-penetrating peptides (CPPs) are promising delivery vehicles. These short peptides can transport wide range of cargos into cells, although their usage has often limitations. One of them is the endosomatic internalisation and thus the vesicular entrapment. Modifications which increases the direct delivery into the cytosol is highly researched area. Among the oligoarginines the longer ones (n > 6) show efficient internalisation and they are well-known members of CPPs. Herein, we describe the modification of tetra- and hexaarginine with (4-((4-(dimethylamino)phenyl)azo)benzoyl) (Dabcyl) group. This chromophore, which is often used in FRET system increased the internalisation of both peptides, and its effect was more outstanding in case of hexaarginine. The modified hexaarginine may enter into cells more effectively than octaarginine, and showed diffuse distribution besides vesicular transport already at low concentration. The attachment of Dabcyl group not only increases the cellular uptake of the cell-penetrating peptides but it may affect the mechanism of their internalisation. Their conjugates with antitumor drugs were studied on different cells and showed antitumor activity.

Although sedation for bronchoscopy improves patient comfort, there is a risk of oversedation in elderly patients. Only a few studies have evaluated the efficacy and safety of sedation for bronchoscopy in elderly patients.This study retrospectively analyzed records of 210 patients who underwent transbronchial brushing and/or biopsy under midazolam sedation at National Hospital Organization Omuta National Hospital between June 2017 and October 2019. Patients were administered 1 mg midazolam following 10 mL 4% lidocaine inhalation. When sedation was insufficient, 0.5 mg midazolam was administered additionally. Diagnostic yield, incidence of complications, amount of oxygen supplementation, decreases in percutaneous oxygen saturation (SpO2), changes in blood pressure, and degree of comfort were analyzed.Patients were divided into the elderly (n = 102) and non-elderly (n = 108) groups. No significant differences were observed in diagnostic yield and procedure time between the 2 groups, and no severe adverse events were noted in the elderly group. The degree of comfort during bronchoscopy was significantly higher in the elderly group. In patients administered < 2 mg midazolam, the amount of oxygen supplementation and decreases in SpO2 were significantly smaller in the elderly group compared to the non-elderly group.The risk of adverse events related to midazolam sedation in bronchoscopy does not increase with age, and sedation improves comfort during flexible bronchoscopy in elderly patients. Moreover, a total dose of midazolam <2 mg is safe for elderly patients undergoing bronchoscopy.

Marked promotion of membrane permeation of a cell-penetrating peptide, octaarginine (R8), was attained by attachment to a single 2,2'-dipicolylamine moiety (DPA-R8) that forms 1:1 complexes with metal ions. Studies using giant unilamellar vesicles demonstrated that DPA targets phospholipids and enhances R8 binding to the membranes in the presence of metal ions. While DPA/Zn(II) complex has been most frequently employed for chelate formation with phosphates, Ni(II) had the most prominent effect on the membrane binding and penetration of DPA-R8. Facile cytosolic distribution of DPA-R8 was also attained in a few minutes in the presence of Ni(II). Analysis of the cellular uptake methods of DPA-R8/Ni(II) suggested the involvement of direct permeation through cell membrane without the use of endocytosis. The applicability of this system to the intracellular delivery of bioactive compounds was exemplified using a peptidomimetic farnesyltransferase inhibitor, FTI277.

Background and Purpose: Acute respiratory distress syndrome (ARDS) complication has long been considered a factor associated with poor prognosis in patients with miliary tuberculosis. However, few reports exist on the prognostic factors of miliary tuberculosis including those complicating ARDS., Subjects and Methods: We retrospectively examined prognoses and other clinical information obtained from medical records of a total of 68 patients diagnosed with miliary tuberculosis. Clinical findings were compared between patients who died within three months (non-survivor group) and those who survived beyond three months (survivor group), and risk factors for death within three months of diagnosis were examined using logistic regression analysis., Results: Fifteen of 68 patients diagnosed with miliary tuberculosis died within three months. Most patients were aged 60 years or older (63 patients; 91.2%), with a peak in the 80 s (32 patients; 47.1%). Of the 68 patients with miliary tuberculosis, 13 (19%) had ARDS. The risk of death within three months increased with increasing age and ARDS onset during the disease course. The results of multivariate analysis revealed that, in addition to age (odd ratio (OR): 15.5) and the presence/absence of ARDS (OR: 12.0), consciousness disturbance (OR: 81.53) and high BUN levels (OR: 5.71) were independent factors for death within three months., Conclusion: In patients with miliary tuberculosis, old age, ARDS, consciousness disturbance, and high BUN levels were factors associated with poor prognosis., (© 2018 The Authors. Published by Elsevier Ltd.)

Background: The prognostic significance of serial measurements of serum KL-6 levels in patients with idiopathic pulmonary fibrosis (IPF) is unclear; hence, it was assessed in this study., Methods: Medical records of 66 patients with IPF, who were not treated with pirfenidone prior to enrollment, were retrospectively reviewed for information on clinical progress, forced vital capacity (FVC), survival, and serum KL-6 levels. We assessed initial serum levels of KL-6, serial changes in serum KL-6 levels, yearly decline in FVC (ΔFVC), and the rate of decline (%ΔFVC)., Results: Patients with increased serum KL-6 levels during follow-up had a significantly steeper decline in ΔFVC than those with no KL-6 increase (-201 vs. -50.7ml/year; p=0.0001). Patients with both initial serum KL-6 ≥1000U/ml and serial increases in serum KL-6 had the steepest decline, while those with both initial serum KL-6 <1000ml and no serial increases in KL-6 had the least decline in ΔFVC and %ΔFVC. Relative to the non-increased KL-6 group, survival in the increased KL-6 group tended to be poorer (p=0.0530). Patients with both initial serum KL-6 values <1000U/ml and no serial increase in KL-6 had more favorable prognoses than those with serial increases in KL-6 or initial serum KL-6 values ≥1000U/ml (p<0.0044). Prognosis was significantly poorer in patients with serial KL-6 changes >51.8U/ml/year than in those with serial KL-6 changes <51.8U/ml/year (p=0.0009)., Conclusion: Thus, serial serum KL-6 measurements can be useful for assessing prognosis in patients with IPF., (Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Far-out syndrome was reported by Wiltse et al. in 1984, which is a condition characterized by L5 spinal nerve radiculopathy due to nerve compression between the L5 transverse process and sacral alar. Although many cases of far-out syndrome have been reported, to our knowledge, the present case firstly showed far-out syndrome due to assimilated L4 hemivertebra and L5 vertebra through which abnormal nerve root passed., Case Presentation: A 71-year-old man presented with left lower back pain and intermittent claudication accompanied by severe left buttock pain. Radiological examination showed assimilation between the L4 hemivertebra and L5 vertebra, which had two pedicles on the right side, with no canal stenosis. However, computed tomography and magnetic resonance imaging of coronal sections showed extraforaminal stenosis between the L5 transverse process and sacral alar, whereby the L5 spinal nerve was pinched ("far-out lesion"), and an abnormal nerve root passage in the assimilated vertebral corpus. We performed transforaminal lumbar interbody fusion, then resected the L5 transverse process to decompress the extraforaminal stenosis, and finally installed pedicle screws, but not at the one of pedicles of the assimilated vertebra in order to prevent nerve injury. Postoperatively, the patient had no symptoms up to 1.5 years after the surgery., Conclusion: The current case suggests the importance of detailed preoperative examination of patients with anatomical abnormalities such as assimilated vertebrae, which may result in incorrect diagnosis and failed surgery.

An on-cell aptamer sensor has the potential to reveal cell-cell communications by signalling molecules. We attempted to design new fluorescent aptamer sensors for the sensing of IFN-γ and adenine compounds on cells. BODIPY-labeled external quencher-free aptamer sensors have allowed a turn-on detection of the target molecule with improved off/on efficiency.

Purpose: To investigate the changes in subfoveal thickness after switching to intravitreal aflibercept injection for polypoidal choroidal vasculopathy (PCV)., Methods: We retrospectively reviewed 66 eyes of 65 PCV patients (mean age 75.7 years) which were refractory to ranibizumab. The choroidal thickness was measured by optical coherence tomography (OCT) using an enhanced depth imaging technique. Intravitreal aflibercept (2 mg/0.05 ml) was administered with three consecutive monthly injections as a loading dose, followed by further injections bimonthly (every two months)., Results: The mean subfoveal choroidal thickness significantly decreased from 203 μm at baseline to 171 μm at month 6 (P < 0.0001). The mean logMAR best-corrected visual acuity levels significantly improved from 0.40 at baseline to 0.33 at 6 months (P < 0.001). The central retinal thickness significantly decreased from 249 μm at baseline to 161 μm at 6 months (P < 0.0001). At month 6, 41 (62.1%) eyes had dry macula by OCT. Of 46 eyes with polypoidal lesions at baseline, complete regression of polypoidal lesions was achieved in 26 (56.5%) eyes at 3 months., Conclusions: The choroidal thickness in PCV eyes significantly decreased after switching to intravitreal aflibercept injection. Aflibercept may help prevent choroidal neovascularization near or under the retinal pigment epithelium, which might help achieve greater occlusion of polypoidal lesions compared with ranibizumab.

The structural complexity and diversity of natural products make them attractive sources for potential drug discovery, with their characteristics being derived from the multi-step combination of enzymatic and non-enzymatic conversions of intermediates in each biosynthetic pathway. Intermediates that exhibit multipotent behaviour have great potential for use as starting points in diversity-oriented synthesis. Inspired by the biosynthetic pathways that form complex metabolites from simple intermediates, we developed a semi-synthetic process that combines heterologous biosynthesis and artificial diversification. The heterologous biosynthesis of fungal polyketide intermediates led to the isolation of novel oligomers and provided evidence for ortho-quinonemethide equivalency in their isochromene form. The intrinsic reactivity of the isochromene polyketide enabled us to access various new chemical entities by modifying and remodelling the polyketide core and through coupling with indole molecules. We thus succeeded in generating exceptionally diverse pseudo-natural polyketides through this process and demonstrated an advanced method of using biosynthetic intermediates.

Copy number variations on human chromosome 15q11-q13 have been implicated in several neurodevelopmental disorders. A paternal loss or duplication of the Prader-Willi syndrome/Angelman syndrome (PWS/AS) region confers a risk of obesity, although the mechanism remains a mystery due to a lack of an animal model that accurately recreates the obesity phenotype. We performed detailed analyses of mice with duplication of PWS/AS locus (6 Mb) generated by chromosome engineering and found that animals with a paternal duplication of this region (patDp/+) show late-onset obesity, high sensitivity for high-fat diet, high levels of blood leptin and insulin without an increase in food intake. We show that prior to becoming obese, young patDp/+ mice already had enlarged white adipocytes. Transcriptome analysis of adipose tissue revealed an up-regulation of Secreted frizzled-related protein 5 (Sfrp5), known to promote adipogenesis. We additionally generated a new mouse model of paternal duplication focusing on a 3 Mb region (3 Mb patDp/+) within the PWS/AS locus. These mice recapitulate the obese phenotypes including expansion of visceral adipose tissue. Our results suggest paternally expressed genes in PWS/AS locus play a significant role for the obesity and identify new potential targets for future research and treatment of obesity., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Obesity is not only associated with unhealthy lifestyles, but also linked to genetic predisposition. Previously, we generated an autism mouse model (patDp/+) that carries a 6.3 Mb paternal duplication homologous to the human 15q11-q13 locus. Chromosomal abnormalities in this region are known to cause autism spectrum disorder, Prader-Willi syndrome, and Angelman syndrome in humans. We found that, in addition to autistic-like behaviors, patDp/+ mice display late-onset obesity and hypersensitivity to a high-fat diet. These phenotypes are likely to be the results of genetic perturbations since the energy expenditures and food intakes of patDp/+ mice do not significantly differ from those of wild-type mice. Intriguingly, we found that an enlargement of adipose cells precedes the onset of obesity in patDp/+ mice. To understand the underlying molecular networks responsible for this pre-obese phenotype, we performed transcriptome profiling of white adipose tissue from patDp/+ and wild-type mice using microarray. We identified 230 genes as differentially expressed genes. Sfrp5 - a gene whose expression is positively correlated with adipocyte size, was found to be up-regulated, and Fndc5, a potent inducer of brown adipogenesis was identified to be the top down-regulated gene. Subsequent pathway analysis highlighted a set of 35 molecules involved in energy production, lipid metabolism, and small molecule biochemistry as the top candidate biological network responsible for the pre-obese phenotype of patDp/+. The microarray data were deposited in NCBI Gene Expression Omnibus database with accession number GSE58191. Ultimately, our dataset provides novel insights into the molecular mechanism of obesity and demonstrated that patDp/+ is a valuable mouse model for obesity research.

Objective: This study aimed to examine the nutritional status and nutrient intake of patients with MAC lung disease with a focus on visceral fat area., Patients and Methods: Among 116 patients of our hospital with nontuberculous mycobacteriosis who were registered between May 2010 and August 2011, 103 patients with MAC lung disease were included in this study. In all patients, nutritional status and nutrient intake were prospectively examined., Results: Patients were 23 men and 80 women (mean age, 72.3±10.9 years). BMI (kg/m2) at the time of registration was 20.4±2.7 in men and 19.2±2.9 in women. Visceral fat area (cm2) was significantly lower in women (35.7±26.6) than in men (57.5±47.4) (p=0.0111). The comparison with general healthy adults according to age revealed a markedly reduced visceral fat area among patients with MAC lung disease. With respect to nutrient intake, energy adequacy (86.1±15.7%), protein adequacy (82.4±18.2%), lipid adequacy (78.1±21.8%), and carbohydrate adequacy (89.6±19.2%) ratios were all low at the time of registration. BMI was significantly correlated with protein adequacy (p=0.0397) and lipid adequacy (p=0.0214) ratios, while no association was found between visceral fat area and nutrient intake., Conclusion: Patients with MAC lung disease had a low visceral fat area and low nutrient intake.

Inhibition of the amyloid β aggregation process could possibly prevent the onset of Alzheimer's disease. In this article, we report a structure-activity relationship study of curcumin analogues for anti amyloid β aggregation activity. Compound 7, the ideal amyloid β aggregation inhibitor in vitro among synthesized curcumin analogues, has not only potent anti amyloid β aggregation effects, but also water solubility more than 160 times that of curcumin. In addition, new approaches to improve water solubility of curcumin-type compounds are proposed., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

To research a new non-peptidyl inhibitor of beta-site amyloid precursor protein cleaving enzyme 1, we focused on the curcumin framework, two phenolic groups combined with an sp2 carbon spacer for low-molecular and high lipophilicity. The structure-activity relationship study of curcumin derivatives is described. Our results indicate that phenolic hydroxy groups and an alkenyl spacer are important structural factors for the inhibition of beta-site amyloid precursor protein cleaving enzyme 1 and, furthermore, non-competitive inhibition of enzyme activity is anticipated from an inhibitory kinetics experiment and docking simulation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A 74-year-old man was referred to our hospital with a high grade fever, a left abdominal tumor and bloody sputum since the beginning of April 2006. We made an incision of the abdominal tumor, and the Gram-stain smear demonstrated Gram-positive rods. Actinomycosis was diagnosed because tissue culture demonstrated Actinomyces israelii. Penicillin was administered, and his clinical features improved. It is difficult to distinguish actinomycosis from malignancy or tuberculosis, therefore actinomycosis should be considered in the differential diagnosis of a mass shadow, and it can be cured with penicillin.

We recently identified 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), the first allosteric metabotropic glutamate (mGlu) 7 receptor-selective negative allosteric modulator. In this study, we examined the in vivo pharmacological effects of MMPIP on the central nervous system. MMPIP was distributed into the brain after systemic administration in both mice and rats. Pharmacokinetic study revealed that the half-life of MMPIP in circulation was about 1h in rats. Results of various behavioral studies revealed that MMPIP impaired non-spatial and spatial cognitive performances in the object recognition test and the object location test in mice, respectively. In rats, MMPIP increased time to complete the task in the 8-arm radial maze test without increasing error. In addition to impairing cognition, MMPIP decreased social interaction with reduction of line crossing in rats, while MMPIP had no effects on locomotor activity in rats and mice, rota-rod performance in mice, prepulse inhibition in rats, maternal separation-induced ultrasonic vocalization in rat pups, stress-induced hyperthermia in mice, or the tail suspension test in mice. No analgesic effects of MMPIP were detected in either the tail immersion test or formalin test in mice. MMPIP did not alter the threshold for induction of seizures by electrical shock or pentylenetetrazole in mice. These findings suggest that blockade of mGlu(7) receptors by MMPIP may modulate both non-spatial and spatial cognitive functions without non-selective inhibitory effects on the central nervous system., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

The present study investigated how frequency distribution of maternal separation-induced ultrasonic vocalization was altered by environmental stimuli and pharmacological agents. Sprague-Dawley rat pups at 10 days were used to measure numbers and frequencies of the ultrasonic vocalizations under various ambient temperatures and with pharmacological manipulations of the corticotropin-releasing factor (CRF) and GABAergic systems. The ultrasonic vocalization consisted of two distinct peaks in the frequency range of 30 kHz to 50 kHz. The area under the curve (AUC) in the high-frequency range and the number of the ultrasonic vocalizations increased when ambient temperature was lowered. Systemic administration of a selective CRF1 receptor antagonist, NBI27914, and a typical anxiolytic, diazepam, decreased the AUC in the high-frequency range and the number of the ultrasonic vocalizations in a dose-dependent manner at an ambient temperature of 24 degrees C. The AUC in the low-frequency range did not change with an alteration in ambient temperature or treatment with NBI27914 and diazepam except a high dose (1 mg/kg) of diazepam. These results demonstrated that emotional levels of isolated pups reflected not only the number but also the frequency distribution of maternal separation-induced ultrasonic vocalizations. High-frequency components, but not low-frequency components, of the ultrasonic vocalization were sensitive to changes in negative affective state of isolated pups.

Substantial evidence suggests that chromosomal abnormalities contribute to the risk of autism. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We have modeled this genetic change in mice by using chromosome engineering to generate a 6.3 Mb duplication of the conserved linkage group on mouse chromosome 7. Mice with a paternal duplication display poor social interaction, behavioral inflexibility, abnormal ultrasonic vocalizations, and correlates of anxiety. An increased MBII52 snoRNA within the duplicated region, affecting the serotonin 2c receptor (5-HT2cR), correlates with altered intracellular Ca(2+) responses elicited by a 5-HT2cR agonist in neurons of mice with a paternal duplication. This chromosome-engineered mouse model for autism seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human chromosome abnormality. This model will facilitate forward genetics of developmental brain disorders and serve as an invaluable tool for therapeutic development.

This paper investigates the source-distance dependency of head-related transfer functions (HRTFs) on the horizontal and median sagittal planes using the boundary-element method and a dummy head scanned with laser and computer tomography scanners. First, the HRTF spectra are compared among various source positions in a head-centered coordinate system, confirming that the major HRTF spectral features vary with source distance as stated in previous works. Furthermore, the HRTF spectra are compared in an ear-centered coordinate system, revealing how the outer ear angle of incidence affects the source-distance dependency of the HRTFs. Next, the comparison across coordinate systems reveals that the source-distance dependency of the ipsilateral HRTFs on the horizontal plane is mainly attributable to the outer ear angle of incidence, whereas the contralateral HRTFs vary with the source distance mainly due to the head's presence. Finally, results also show that, in an ear-centered coordinate system, the ipsilateral HRTFs do not depend strongly on a source distance greater than 0.2 m from the center of the head, whereas the contralateral HRTFs depend on source distance less than 1.8 m. Results also show that HRTFs on the median sagittal plane depend on a source distance of less than 0.4 m.

An infant animal isolated from its mother emits vocalizations spanning from the audible to the ultrasonic. These vocalizations are believed to represent distress signals from the pup. However, the neurobiological basis for vocalizations elicited by isolation has not been well characterized under different environmental conditions. The present study was designed to clarify the role of the corticotropin-releasing factor (CRF) system in vocalizations elicited by isolating a rat pup at ambient temperatures of 37 degrees C (temperature of the nest in which the mother and littermates are present) and 24 degrees C (room temperature). Sprague-Dawley rat pups at 7 days old were isolated from their dam, then the number of vocalizations was measured for 5 min. The number of vocalizations increased when ambient temperature was changed from 37 degrees C to 24 degrees C. Systemic administration of CRF (3 or 10 mg/kg) increased the number of vocalizations at 37 degrees C in a dose-dependent manner. CRF-induced increases in the number of vocalizations at 3 mg/kg were completely blocked by a selective CRF1 receptor antagonist, NBI27914 (3 mg/kg), but not by a selective CRF2 receptor antagonist, K41498 (3 mg/kg). NBI27914 (30 mg/kg), but not K41498 (3 mg/kg), suppressed the increased number of vocalizations at 24 degrees C. These results demonstrate involvement of the CRF-CRF1 receptor regulatory system on the modulation of ultrasonic vocalizations by rat pups separated from their dam.

The functional roles of metabotropic glutamate receptor (mGluR) 1 in integrative brain functions were investigated using a potent and selective mGluR1 allosteric antagonist, FTIDC [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide], in comparison with the mGluR5 allosteric antagonist and the mGluR2/3 orthosteric agonist in rodents. FTIDC reduced maternal separation-induced ultrasonic vocalization and stress-induced hyperthermia without affecting behaviors in the elevated plus maze. An mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and an mGluR2/3 agonist, LY379268 [(1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid], showed anxiolytic activities in these models, suggesting involvement of postsynaptic mGluR1 in stress-related responses comparable with mGluR5 and mGluR2/3. Analgesic effects of FTIDC were seen in the formalin test but not in the tail immersion test. FTIDC selectively blocked methamphetamine-induced hyperlocomotion and disruption of prepulse inhibition, whereas MPEP and LY379268 did not alter those behaviors, suggesting that pharmacological blockade of mGluR1 could result in antipsychotic-like effects. FTIDC did not elicit catalepsy or impair motor functions at 10 times higher dose than doses showing antipsychotic-like action. In conclusion, blockade of mGluR1 showed antipsychotic-like effects without impairing motor functions, whereas blockade of mGluR5 and activation of mGluR2/3 did not display such activities.

The over-expression of P-glycoprotein (P-gp) has been associated with the development of multidrug resistance (MDR) in cancer cells. In this study, we examined whether transferrin receptor (Tf-R) targeted liposomes can efficiently deliver encapsulated doxorubicin (DXR) into MDR cells (SBC-3/ADM) via Tf-R-mediated endocytosis thus overcoming MDR by by-passing P-gp-mediated drug efflux. We prepared four types of liposome, i.e. untargeted and Tf-R-targeted, made of either egg-PC/cholesterol or hydrogenated egg PC/cholesterol. Only with the targeted EPC-liposome we achieved significant delivery of encapsulated DXR and increased cytotoxicity of encapsulated DXR on the MDR cells (3.5-fold higher than free DXR). Confocal microscopy and an intracellular drug-accumulation assay indicated that the targeted liposomes efficiently delivered DXR into cells where it readily accumulated in the nucleus, in both drug-sensitive and MDR cells. These findings suggest that the targeted liposomes are rapidly internalized via Tf-R-mediated endocytosis followed by release of their contents into the cytoplasm. The rapid internalization and content release, most likely facilitated by the higher fluidity of the EPC-based liposomes, may explain why only targeted EPC-liposomes were able to prevent drug efflux by P-gp and to consequently circumvent MDR. Our results indicate that in order to achieve MDR circumvention by means of liposomal encapsulation of DXR the liposomes not only need to be targeted, but also to have the proper physicochemical properties for adequate release of the drug. Furthermore, these in vitro results suggest that Tf-R targeted EPC-liposomes are a potentially useful drug delivery system to circumvent P-gp-mediated MDR of tumors.

Recently, development of a numerical calculation of the head-related transfer function (HRTF) has been conducted using a computer model of a human head and the boundary element method. The reciprocity theorem is incorporated into the computational process in order to shorten the computational time, which is otherwise very long. On the other hand, another fast HRTF calculation method for any source position, which is realized by calculating factors independent of the source position in advance, has been suggested by the authors. Using this algorithm, the HRTF for any source position can be obtained in a few seconds with a common PC. The resulting HRTFs are more precise and are calculated faster than those by using the reciprocity theorem. However, speeding the process up even further is required in order to respond to a head movement and rotation or to moving sources during binaural sound reproduction. In this paper, a faster calculation method by incorporating a time domain operation into the authors' previous algorithm is proposed. Additionally, the new formulation, which eliminates the extra computational time in the preprocess, is proposed. This method is shown to be faster than the previous ones, but there are some discrepancies at higher frequencies.

Theophylline, a nonselective phosphodiesterase inhibitor, has long been regarded as a major bronchodilator in the treatment of human asthma. Using front-surface fluorometry with fura-2 and alpha-toxin permeabilization, the effects of theophylline on intracellular Ca2+ concentration ([Ca2+]i), tension development and Ca2+ sensitivity of the contractile apparatus were investigated in porcine tracheal smooth muscle strips. Application of theophylline induced a relaxation without a significant decrease in [Ca2+]i when strips were precontracted by 40 mm K+ depolarization, while theophylline significantly decreased both [Ca2+]i and tension induced by carbachol. The effects of theophylline on the increases in [Ca2+]i and tension induced by carbachol were significantly inhibited by iberiotoxin, an inhibitor of large-conductance Ca2+-activated K+ channels. In the absence of extracellular Ca2+, theophylline significantly attenuated carbachol-induced transient increases in tension development, while it did not affect carbachol-induced transient increase in [Ca2+]i. The [Ca2+]i-force relationship, which was determined by cumulative applications of extracellular Ca2+ (0-5 mm) during 40 mm K+ depolarization, was significantly shifted to the right by theophylline. In alpha-toxin permeabilized strips, theophylline significantly increased the EC50 value of [Ca2+]i for contraction and enhanced the effect of cAMP, but not of cGMP. These results indicate that theophylline induces relaxation of the porcine tracheal smooth muscle through an activation of BK channels, and a resultant decrease in [Ca2+]i and an attenuation of Ca2+ sensitivity, presumably through the action of cAMP.