It has been reported that various clinical criteria indicate computed tomography (CT) examination for mild head injury (MHI). However, the decision to perform CT for MHI largely depends on the physician. Data on severe head injuries is available in sources such as the Japan Neurotrauma Data Bank, but only a few data has been collected on MHI. A total of 1688 patients with MHI (Glasgow Coma Scale 14 and 15) treated at our hospital from June 2017 to May 2019 were reviewed. CT was performed in 1237 patients (73.28%), and intracranial hemorrhage was detected in 50 patients. Three patients deteriorated, and all were surgically treated. Statistical analysis of the presence or absence of acute intracranial hemorrhage and "risk factors for complications of intracranial lesions in MHI" showed significant differences in unclear or ambiguous accident history (p = 0.022), continued post-traumatic amnesia (p < 0.01), trauma above the clavicles including clinical signs of skull fracture (skull base or depressed skull fracture) (p = 0.012), age <60 years (p < 0.01), coagulation disorders (p < 0.01), and alcohol or drug intoxication (p < 0.01). The 453 patients who did not satisfy these risk factors included only one patient with intracranial hemorrhage, so the negative predictive value was 99.78%. This study shows that the "risk factors for complications of intracranial lesions in MHI" are effective criteria for excluding acute intracranial hemorrhage and CT should be actively considered for patients with the above factors that showed significant differences.
Introduction: The objective of this study was to examine if halo vest fixation provides sufficient stabilization of cervical spine alignment to endorse its use through intraoperative positional changes in patients with cervical spine instability. Methods: The subjects of this study were 14 patients with cervical spine instability who were immobilized in halo vests until they underwent subsequent internal fixation surgery. After induction of anesthesia, the patients in halo vests were repositioned from the supine position to the prone position. The halo ring was fixed to the surgical table and the dorsal struts and vest were removed for surgery. Radiographs obtained in the preoperative sitting position and intraoperative prone position were compared for the following measures of cervical alignment: O-C2 angle, C2-C6 angle, pharyngeal inlet angle (PIA), atlantodental interval (ADI), Redlund-Johnell (R-J) value as a measure of O-C2 length, O-C6 length, and O-C2 length/O-C6 length (%). Results: There were no significant differences in O-C2 angle, C2-C6 angle, PIA, ADI, or O-C2 length/O-C6 length (%). However, the R-J value and O-C6 length were significantly higher in the intraoperative prone position than in the preoperative sitting position. None of the patients presented with any complications, including dysphagia or neurological deterioration. Conclusions: Our results suggest that when patients are repositioned to the prone position while immobilized in halo vests, the cervical spine is distracted in the cephalocaudal direction across all cervical segments but the cervical alignment is sufficiently maintained. Halo vests are a highly effective external fixation method for patients with cervical spine instability, allowing for a safe repositioning to the prone position for surgery while preserving cervical alignment and preventing neurological deterioration.
Background: Acute exacerbation of head injury in elderly patients due to use of antithrombotic agents has become a concern in countries with aging populations. Reversal agents are recommended for treatment, but its usage is unclear. Therefore, we conducted a prospective observational study in this patient population to monitor usage of reversal therapy. Methods: The subjects were 721 elderly patients aged ≥65 years old who were hospitalized in 15 centers from December 2019 to May 2021. Patients were divided into groups who did not receive antithrombotic agents (Group A), who received antithrombotic agents, but did not receive reversal therapy (Group B), and were treated with antithrombotic agents and reversal therapy (Group C). Age, gender, mechanism of injury, neurologic and imaging findings on admission, clinical course after admission and surgery, outcomes and complications were compared among these groups. Time from injury to reversal therapy was examined based on outcomes to investigate trends in the timing of administration of the reversal agent. Results: Acute exacerbation during the clinical course occurred in 9.8 %, 15.8 % and 31.0 % of cases in Groups A, B and C, respectively, and differed significantly among the groups. On head CT, the incidences of hematoma were 35.7 %, 36.5 % and 60.4 %, respectively, with this incidence being significantly higher in Group C; and the respective rates of craniotomy were 18.8 %, 14.0 % and 50.9 %, again with this rate being significantly higher in Group C. The good outcome and mortality rates were 57.1 %, 52.5 % and 35.8 %, and 14.5 %, 18.0 % and 24.5 %, respectively, and both were poorest in Group C. Times from injury to treatment with a reversal agent were significantly shorter in patients without compared to those with acute exacerbation (405.9 vs. 880.8 min) and in patients with favorable outcomes compared to those with unfavorable outcomes (261.9 vs. 543.4 min). Conclusion: Similarly to previous studies, the incidence of acute exacerbation was increased by use of antithrombotic agents. These results suggest that patients in Japan who require hematoma evacuation due to symptom exacerbation tend to be treated with reversal agents. Although it is difficult to assess the efficacy of reversal therapy from this study, earlier treatment with reversal agents before the occurrence of acute exacerbation may be useful to improve outcomes.
[This corrects the article DOI: 10.22603/ssrr.2023-0045.].
BACKGROUND: In patients with cervical spinal cord injury (SCI), we need to make accurate prognostic predictions in the acute phase for more effective rehabilitation. We hypothesized that a multivariate prognosis would be useful for patients with cervical SCI. METHODS: We made two predictive models using Multiple Linear Regression (MLR) and Artificial Neural Networks (ANNs). We adopted MLR as a conventional predictive model. Both models were created using the same 20 clinical parameters of the acute phase data at the time of admission. The prediction results were classified by the ASIA Impairment Scale. The training data consisted of 60 cases, and prognosis prediction was performed for 20 future cases (test cohort). All patients were treated in the Spinal Injuries Center (SIC) in Fukuoka, Japan. RESULTS: A total of 16 out of 20 cases were predictable. The correct answer rate of MLR was 31.3%, while the rate of ANNs was 75.0% (number of correct answers: 12). CONCLUSION: We were able to predict the prognosis of patients with cervical SCI from acute clinical data using ANNs. Performing effective rehabilitation based on this prediction will improve the patient's quality of life after discharge. Although there is room for improvement, ANNs are useful as a prognostic tool for patients with cervical SCI.
PURPOSE: The purpose of this study is to investigate the effects of denture adhesives on masticatory performance via a 10-center, parallel, randomized, controlled trial of complete denture wearers in Japan. METHODS: The trial was conducted between September 2013 and October 2016. The inclusion criteria were complete edentulism, willingness to undergo new complete denture treatment, and willingness to return for recall treatment. The exclusion criteria were age 90 years or older, presence of severe systemic illness, inability to understand the questionnaires, wearing metal base complete dentures, denture adhesive user, wearing prosthetics for maxillofacial defects, wearing complete dentures with tissue conditioners, and severe xerostomia. Randomization of the powder-type denture adhesive (powder), cream-type denture adhesive (cream), and control (saline) groups was performed using a sealed envelope system. Masticatory performance was measured using color-changeable chewing gum. Intervention blinding was not feasible. RESULTS: Sixty-seven control, 69 powder, and 64 cream participants are analyzed using the intention-to-treat principle. The participants in all groups show significantly improved masticatory performance at post-intervention (paired t-test with Bonferroni correction P < 0.0001). However, no significant difference in masticatory performance is detected among the three groups (one-way analysis of variance). A significant negative correlation between pre- and post-changes in masticatory performance and intraoral condition scores is observed (Pearson's correlation coefficient, P < 0.0001). CONCLUSIONS: Although denture adhesives improved the masticatory performance of complete denture wearers, their clinical effects are comparable to those of saline solution. The use of denture adhesives is more effective in complete denture wearers with unsatisfactory intraoral conditions.
Mouth, Edentulous , Tooth Loss , Humans , Aged, 80 and over , Powders , Denture, Complete , Chewing Gum , Mastication
Introduction: Older adults with cervical spinal cord injury (CSCI) often have a poor prognosis due to the high number of complications, decreased motivation to rehabilitation, and poor response to treatment. This study aimed to investigate the characteristics of CSCI in Japanese older adults and examined the factors influencing their discharge home. Methods: In this retrospective cohort study, we extracted data on consecutive cases with CSCI between 2005 and 2020 from the study hospital's database. Patients over 65 years old who were admitted to the hospital within 14 days of injury were selected. A univariate analysis was performed between the home discharge and out-of-home discharge groups. In addition, binary logistic regression analysis of admission findings and patient background was performed to examine independent factors influencing home discharge. Results: Of the 219 patients included, 90 (41.1%) were eventually discharged to home. Comparing home discharge and out-of-home discharge groups revealed significant differences in age at injury, length of hospital stay, neurological level of injury (NLI), percentage of American Spinal Injury Association (ASIA) Impairment Scale (AIS: A), percentage of living alone, ASIA motor score (AMS), and Spinal Cord Independence Measure (SCIM) at initial visit and discharge. Binary logistic regression analysis revealed that old age (over 75 years old) at injury (odds ratio [OR]: 0.31, 95% CI: 0.16-0.60, P<.001), living alone (OR: 0.22, 95% CI: 0.03-0.42, P<.01), high level of injury (i.e., NLI: C1-4; OR: 0.22, 95% CI: 0.09-0.53, P<.0001), and percentage of AIS: A at admission (OR: 0.09, 95% CI: 0.04-0.24, P<.001) were independent factors that influenced home discharge. Conclusions: More than 50% older adults with CSCI were discharged to a place other than their own home. Age, percentage of AIS: A, living alone, and high level of injury at admission were independent factors that influenced home discharge.
Introduction: Intraoperative three-dimensional (3D) imaging guide technology, such as the O-arm surgical imaging system, is a beneficial tool in spinal surgery that provides real-time 3D images of a patient's spine. This study aims to determine the exposure dose from intraoperative O-arm imaging. Methods: A consecutive retrospective review of all patients undergoing spinal surgery was conducted between June 2019 and August 2022. Demographic and operative data were collected from electronic medical records. Results: Intraoperative O-arm imaging was conducted in 206 (12.9%) of 1599 patients, ranging from one to 4 scans per patient (1.17±0.43 scans). Single O-arm imaging enabled navigation of seven vertebrae in the cervical spine, seven in the thoracic spine, five in the thoracolumbar spine, and four in the lumbar spine on average. The number of O-arm shots per surgery was 1.15±0.36, 1.06±0.24, 1.61±0.7, and 1.07±0.25 for cervical, thoracic, thoracolumbar, and lumbar spinal cases, respectively. The exposure doses represented by dose length products in single O-arm imaging were 377±19 mGy-cm, 243±22 mGy-cm, 378±38 mGy-cm, and 258±11 mGy-cm for cervical, thoracic, thoracolumbar, and lumbar spine cases, respectively. We observed a weak positive correlation between the number of fused spinal levels and the exposure dose. Conclusions: Intraoperative radiation exposure from O-arm imaging was lower than the national diagnostic reference levels in Japan established based on the International Commission on Radiological Protection publication, demonstrating its safety from the standpoint of radiological protection in most cases. In surgeries with a large range of fixations, such as corrective deformity surgery, the number of imaging sessions and the amount of intraoperative radiation exposure would increase, leading surgeons to pay attention to the risk of radiation in spinal surgery.
Background: Spinal cord injury (SCI) is a devastating disease that results in permanent paralysis. Currently, there is no effective treatment for SCI, and it is important to identify factors that can provide therapeutic intervention during the course of the disease. Zinc, an essential trace element, has attracted attention as a regulator of inflammatory responses. In this study, we investigated the effect of zinc status on the SCI pathology and whether or not zinc could be a potential therapeutic target. Methods: We created experimental mouse models with three different serum zinc concentration by changing the zinc content of the diet. After inducing contusion injury to the spinal cord of three mouse models, we assessed inflammation, apoptosis, demyelination, axonal regeneration, and the number of nuclear translocations of NF-κB in macrophages by using qPCR and immunostaining. In addition, macrophages in the injured spinal cord of these mouse models were isolated by flow cytometry, and their intracellular zinc concentration level and gene expression were examined. Functional recovery was assessed using the open field motor score, a foot print analysis, and a grid walk test. Statistical analysis was performed using Wilcoxon rank-sum test and ANOVA with the Tukey-Kramer test. Results: In macrophages after SCI, zinc deficiency promoted nuclear translocation of NF-κB, polarization to pro-inflammatory like phenotype and expression of pro-inflammatory cytokines. The inflammatory response exacerbated by zinc deficiency led to worsening motor function by inducing more apoptosis of oligodendrocytes and demyelination and inhibiting axonal regeneration in the lesion site compared to the normal zinc condition. Furthermore, zinc supplementation after SCI attenuated these zinc-deficiency-induced series of responses and improved motor function. Conclusion: We demonstrated that zinc affected axonal regeneration and motor functional recovery after SCI by negatively regulating NF-κB activity and the subsequent inflammatory response in macrophages. Our findings suggest that zinc supplementation after SCI may be a novel therapeutic strategy for SCI.
Demyelinating Diseases , Spinal Cord Injuries , Mice , Animals , NF-kappa B/metabolism , Spinal Cord Injuries/pathology , Macrophages/metabolism , Disease Models, Animal , Minerals/therapeutic use , Zinc/metabolism , Demyelinating Diseases/metabolism
The photophysical properties of dyes composed of two squaraine chromophores fused with a benzodipyrrole central moiety (BS1 and BS2), were investigated using steady-state absorption, fluorescence, and transient absorption spectroscopy. The dyes exhibit solvent-independent split electronic absorption due to exciton-coupling. Interestingly significant solvent-dependent fluorescence properties were observed. In toluene, they emit from the lowest excited state, while in methanol, they show weak emission in the higher energy region. In the low-temperature glass matrix, emission from the lowest excited state dominates similarly to that in toluene. The transient absorption spectra exhibit similar ground-state bleaching in toluene and methanol, revealing the formation of delocalized excited states by exciton coupling independent of solvent. However, the excited state deactivates rapidly in ultrafast time scale in methanol, likely due to solvent interaction, leading to rapid non-radiative deactivation. The PEG film doped with the exciton-coupled bis-squaraine shows a distinct fluorescence response to methanol vapor.
Spasticity-defined as involuntary movements caused by insult to upper motor neurons after spinal cord injury (SCI)-interferes with patients' activities of daily living. Spasticity is generally identified and managed in the chronic phase of SCI, but few reports have examined the onset of spasticity after injury. The purpose of this study is to elucidate serial changes in spasticity after SCI and clarify the timing of severe spasticity. We prospectively examined individuals with acute traumatic SCI admitted within two weeks after injury. Severity of spasticity was evaluated using the Modified Ashworth Scale (MAS) at 2, 4, 6, and 8 weeks, followed by 3, 4, 5, and 6 months after injury. After completing evaluation of the cohort, the patients were divided into two groups: a spasticity group with MAS scores ≥3 (marked increase in muscle tone through most of the range of motion (ROM)) in at least one joint movement within 6 months of injury and a control group with MAS scores ≤2 in all joint movements throughout the 6 months after injury. Neurological findings such as the American Spinal Injury Association (ASIA) Impairment Scale grades and ASIA motor scores were also assessed at all time points, and the correlations between the onset of spasticity, severity of spasticity, and neurological findings were analyzed. There were 175 patients with traumatic SCI who were assessed consecutively for 6 months after injury. The MAS scores of the group significantly increased over time until 4 months after injury. The spasticity group had significantly higher MAS scores compared with the control group as early as 2 weeks post-injury. We found that the patients with earlier onset of spasticity had higher final MAS scores. No correlation was found between the ASIA Impairment Scale grade and the onset of spasticity. Our results reveal that the development of severe spasticity may be predictable from as early as 2 weeks after SCI, suggesting that early therapeutic intervention to mitigate problematic spasticity may enhance the benefits of post-injury rehabilitation.
Introduction: Aspiration pneumonia is one of the most frequent and fatal life-threatening complications among individuals with acute traumatic cervical spinal cord injury (CSCI). However, the mechanism of dysphagia among individuals with CSCI is not well understood. Morbidity and mortality associated with CSCI may result from the interplay between respiratory dysfunction and dysphagia. This study aimed to elucidate the effect of respiratory dysfunction on the swallowing function of individuals with acute traumatic CSCI. Methods: A prospective cohort study was conducted involving 54 individuals with acute traumatic CSCI who were admitted within 2 weeks following injury. Dysphagia was evaluated using the Dysphagia Severity Scale (DSS) and the Functional Oral Intake Scale (FOIS). Respiratory function was evaluated by measuring the cough peak flow (CPF), forced expiratory volume in 1 s (FEV1.0), FEV1.0/forced vital capacity (FEV1.0%), and percent vital capacity (%VC). We recorded these parameters at weeks 2, 4, 8, and 12 following injury and analyzed pertinent changes over time and significant correlations. Results: Among 54 individuals (46 men and 8 women) recruited in this study, 48 (88.9%) had restrictive ventilatory impairment and 17 (31.5%) had severe dysphagia (DSS level 1-4) 2 weeks following injury. However, respiratory function and swallowing function significantly improved thereafter. CPF, FEV1.0, and %VC were significantly correlated with the severity of dysphagia during each period. Conclusions: Restrictive ventilatory impairment, poor cough force, and dysphagia are closely related, and the evaluation of respiratory function plays an important role in evaluating dysphagia.
Release of large amounts of adenosine triphosphate (ATP), a gliotransmitter, into the extracellular space by traumatic brain injury (TBI) is considered to activate the microglia followed by release of inflammatory cytokines resulting in excessive inflammatory response that induces secondary brain injury. The present study investigated whether antagonists of ATP receptors (P2X4 and/or P2X7) on microglia are beneficial for reducing the post-injury inflammatory response that leads to secondary injury, a prognostic aggravation factor of TBI. Adult male Sprague-Dawley rats were subjected to cortical contusion injury (CCI) and randomly assigned to injury and drug treatment conditions, as follows: i) No surgical intervention (naïve group); ii) dimethyl sulfoxide treatment after CCI (CCI-control group); iii) 5-BDBD (antagonist of P2X4 receptor) treatment after CCI (CCI-5-BDBD group); iv) CCI-AZ11645373 (antagonist of P2X7 receptor) treatment after CCI (CCI-AZ11645373 group); v) or 5-BDBD and AZ11645373 treatment after CCI (CCI-5-BDBD + AZ11645373 group). In the CCI-5-BDBD, CCI-AZ11645373, and CCI-5-BDBD + AZ11645373 groups, expression of activated microglia was suppressed in the ipsilateral cortex and hippocampus 3 days after the CCI. Western blotting with ionized calcium-binding adaptor molecule 1 antibody revealed that administration of CCI-5-BDBD and/or CCI-AZ11645373 suppressed expression of microglia and reduced expression of inflammatory cytokine mRNA 3 days after the CCI. Furthermore, the plus maze test, which reflects the spatial memory function and involves the hippocampal function, showed improvement 28 days after secondary injury to the hippocampus. These findings confirmed that blocking the P2X4 and P2X7 receptors, which are ATP receptors central in gliotransmission, suppresses microglial activation and subsequent cytokine expression after brain injury, and demonstrates the potential as an effective treatment for reducing secondary brain injury.
Neonatal spinal cord injury (SCI) shows better functional outcomes than adult SCI. Although the regenerative capability in the neonatal spinal cord may have cues in the treatment of adult SCI, the mechanism underlying neonatal spinal cord regeneration after SCI is unclear. We previously reported age-dependent variation in the pathogenesis of inflammation after SCI. Therefore, we explored differences in the pathogenesis of inflammation after SCI between neonatal and adult mice and their effect on axon regeneration and functional outcome. We established two-day-old spinal cord crush mice as a model of neonatal SCI. Immunohistochemistry of the spinal cord revealed that the nuclear translocation of NF-κB, which promotes the expression of chemokines, was significantly lower in the astrocytes of neonates than in those of adults. Flow cytometry revealed that neonatal astrocytes secrete low levels of chemokines to recruit circulating neutrophils (e.g., Cxcl1 and Cxcl2) after SCI in comparison with adults. We also found that the expression of a chemokine receptor (CXCR2) and an adhesion molecule (ß2 integrin) quantified by flow cytometry was lower in neonatal circulating neutrophils than in adult neutrophils. Strikingly, these neonate-specific cellular properties seemed to be associated with no neutrophil infiltration into the injured spinal cord, followed by significantly lower expression of inflammatory cytokines (Il-1ß, Il-6 and TNF-α) after SCI in the spinal cords of neonates than in those of adults. At the same time, significantly fewer apoptotic neurons and greater axonal regeneration were observed in neonates in comparison with adults, which led to a marked recovery of locomotor function. This neonate-specific mechanism of inflammation regulation may have potential therapeutic applications in controlling inflammation after adult SCI.
Spinal Cord Injuries , Spinal Cord Regeneration , Mice , Animals , Neutrophils/metabolism , Animals, Newborn , Neuroinflammatory Diseases , Axons/pathology , Astrocytes/metabolism , Spinal Cord/metabolism , Inflammation/etiology , Chemokines
After spinal cord injury (SCI), inflammatory cells such as macrophages infiltrate the injured area, and astrocytes migrate, forming a glial scar around macrophages. The glial scar inhibits axonal regeneration, resulting in significant permanent disability. However, the mechanism through which glial scar-forming astrocytes migrate to the injury site has not been clarified. Here we show that migrating macrophages attract reactive astrocytes toward the center of the lesion after SCI. Chimeric mice with bone marrow lacking IRF8, which controls macrophage centripetal migration after SCI, showed widely scattered macrophages in the injured spinal cord with the formation of a huge glial scar around the macrophages. To determine whether astrocytes or macrophages play a leading role in determining the directions of migration, we generated chimeric mice with reactive astrocyte-specific Socs3-/- mice, which showed enhanced astrocyte migration, and bone marrow from IRF8-/- mice. In this mouse model, macrophages were widely scattered, and a huge glial scar was formed around the macrophages as in wild-type mice that were transplanted with IRF8-/- bone marrow. In addition, we revealed that macrophage-secreted ATP-derived ADP attracts astrocytes via the P2Y1 receptor. Our findings revealed a mechanism through which migrating macrophages attract astrocytes and affect the pathophysiology and outcome after SCI.
Gliosis , Spinal Cord Injuries , Animals , Mice , Interferon Regulatory Factors , Macrophages
Introduction: This retrospective cohort study aimed to examine the nutritional time course and elucidate the critical period of undernutrition following acute traumatic cervical spinal cord injury (CSCI). Methods: The study was performed at a single facility that treated spinal cord injuries. We examined individuals with acute traumatic CSCI admitted to our hospital within 3 days of injury. Both prognostic nutritional index (PNI) and controlling nutritional status (CONUT) scores, which objectively reflect nutritional and immunological conditions, were assessed at admission and 1, 2, and 3 months after the injury. The American Spinal Injury Association impairment scale (AIS) categorizations and severity of dysphagia were evaluated at these time points. Results: A total of 106 patients with CSCI were evaluated consecutively for 3 months after injury. Individuals with AIS categorizations of A, B, or C at 3 days after injury were significantly more undernourished than those with an AIS categorization of D at 3 months after injury, indicating that individuals with mild paresis better maintained their nutritional condition after injury. Nutritional conditions, as assessed by both PNI and CONUT scores, improved significantly between 1 and 2 months after injury, whereas no significant differences were found between admission and 1 month after injury. Nutritional status and dysphagia were significantly correlated at each time point (p<0.001), indicating that swallowing dysfunction is an important factor associated with malnutrition. Conclusions: Nutritional conditions showed significant gradual improvements from 1 month after the injury. We must pay attention to undernutrition, which is associated with dysphagia, especially in individuals with severe paralysis during the acute phase following injury.
Synthesis of three derivatives of danicalipin A, tetrachloride, trisulfate and a fluorescent probe was achieved through Wittig reaction strategy. Toxicity of the derivatives against brine shrimp (Artemia salina) as also investigated to provide useful information for the biological activity; i) less chloride derivative showed similar toxicity to danicalipin A, ii) the amphiphilic property, a characteristic feature of danicalipin A, was crucial because trisulfate considerably decreased the toxicity and iii) fluorescent derivative kept brine shrimp toxicity of danicalipin A.
Artemia , Lipids , Animals , Fluorescent Dyes
INTRODUCTION: Central neuropathic pain (CNeP) is difficult to treat and has diverse etiology, including spinal cord injury (CNePSCI), Parkinson's disease (CNePPD), and central post-stroke pain (CPSP). The safety and efficacy of mirogabalin have been demonstrated in short-term trials, including patients with CNePSCI. The objective of our study was to confirm the safety/efficacy of mirogabalin in patients with CNePPD and CPSP, and obtain long-term data for CNePSCI. METHODS: This 52-week, open-label extension of a previous randomized controlled study was conducted across Japan, Korea, and Taiwan. Patients with CNePSCI, CNePPD, or CPSP received twice daily (BID) 5-10 mg mirogabalin for a 4-week titration period, after which the dosage was maintained for 47 weeks at a maximum of 15 mg BID, followed by a 1-week taper period receiving the same dose but only administered once daily. The primary endpoint was safety, assessed primarily by incidence and severity of treatment-emergent adverse events (TEAEs). Efficacy was assessed in a post hoc analysis of data obtained by the short-form McGill Pain Questionnaire (SF-MPQ). RESULTS: Of the 210 patients enrolled, 106, 94, and 10 had CNePSCI, CPSP, and CNePPD, respectively. The mean overall age of patients was 62.9 years, and most patients were male and of Japanese ethnicity. TEAEs occurred in 84.8% of patients, the most common being somnolence (16.7%), peripheral edema (12.4%), edema (11.4%), nasopharyngitis (11.0%), and dizziness (7.6%). Most TEAEs were mild. Severe and serious TEAEs occurred in 6.2% and 13.3% of patients, respectively. All patient groups experienced reductions in SF-MPQ visual analog scores for pain: mean ± standard deviation changes from baseline at week 52 were -2.3 ± 21.13 mm (CNePSCI), -17.0 ± 24.99 mm (CPSP), and -17.1 ± 35.32 mm (CNePPD). CONCLUSION: Mirogabalin was generally safe, well tolerated, and effective for treatment of CNeP in this long-term study. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03901352.
Although exposure-directed busulfan (BU) dosing can improve allogeneic hematopoietic stem cell transplantation outcomes, there is still large variability in BU exposure with test dose alone due to changes in BU clearance caused by drug interactions. We conducted a single-arm phase II trial using the combined test dose and therapeutic drug monitoring strategy (PK-guided group) and compared the outcomes with an external historical cohort receiving a fixed-dose (fixed-dose group). The first eight and second eight doses were adjusted based on the area under the blood concentration-time curve (AUC) of the test and first doses, respectively, targeting a total AUC of 82.1 mg·h/L. All patients received either BU and cyclophosphamide conditioning (BU/CY) or fludarabine (FLU)-containing conditioning. The BU clearance at the first dose decreased more in patients receiving FLU than in those receiving BU/CY; however, BU clearance also declined over time in patients who received BU/CY. The simulated total AUC (sAUC) with test dose only was significantly higher in patients who received FLU than in those who received BU/CY, but sAUC with the combined strategy was comparable. The 100-day progression-free survival was 85.5% (95% confidence interval [CI]: 71.9-92.8%), and was not inferior to that in the fixed-dose group. For the FLU-containing regimens, the PK-guided group showed decreased relapse (0.0% vs. 26.9%, p = 0.03), and favorable overall survival (75.1% vs. 57.0%, p = 0.07) at 1 year. The combined strategy effectively controlled the BU exposure close to the target levels, potentially improving efficacy, especially in patients receiving the FLU-containing regimen. Clinical evaluation of efficacy of dose-modified intravenous busulfan in allogeneic hematopoietic stem cell transplantation for hematological malignancy (#UMIN000014077, June 15th, 2014).
Hematologic Neoplasms , Hematopoietic Stem Cell Transplantation , Humans , Busulfan , Cyclophosphamide , Drug Monitoring , Hematologic Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Transplantation Conditioning , Vidarabine
Joint contracture causes distressing permanent mobility disorder due to trauma, arthritis, and aging, with no effective treatment available. A principal and irreversible cause of joint contracture has been regarded as the development of joint capsule fibrosis. However, the molecular mechanisms underlying contracture remain unclear. We established a mouse model of knee joint contracture, revealing that fibrosis in joint capsules causes irreversible contracture. RNA-sequencing of contracture capsules demonstrated a marked enrichment of the genes involved in the extracellular region, particularly periostin (Postn). Three-dimensional magnetic resonance imaging and immunohistological analysis of contracture patients revealed posterior joint capsule thickening with abundant type I collagen (Col1a2) and POSTN in humans. Col1a2-GFPTG ; Postn-/- mice and chimeric mice with Col1a2-GFPTG ; tdTomatoTG bone marrow showed fibrosis in joint capsules caused by bone marrow-derived fibroblasts, and POSTN promoted the migration of bone marrow-derived fibroblasts, contributing to fibrosis and contracture. Conversely, POSTN-neutralizing antibody attenuated contracture exacerbation. Our findings identified POSTN as a key inducer of fibroblast migration that exacerbates capsule fibrosis, providing a potential therapeutic strategy for joint contracture.
Bone Marrow , Contracture , Humans , Mice , Animals , Bone Marrow/pathology , Range of Motion, Articular , Contracture/genetics , Contracture/drug therapy , Fibrosis , Fibroblasts/pathology
