Therapeutic potential of stem cells in subarachnoid hemorrhage.

Aneurysm rupture can result in subarachnoid hemorrhage, a condition with potentially severe consequences, such as disability and death. In the acute stage, early brain injury manifests as intracranial pressure elevation, global cerebral ischemia, acute hydrocephalus, and direct blood-brain contact due to aneurysm rupture. This may subsequently cause delayed cerebral infarction, often with cerebral vasospasm, significantly affecting patient outcomes. Chronic complications such as brain volume loss and chronic hydrocephalus can further impact outcomes. Investigating the mechanisms of subarachnoid hemorrhage-induced brain injury is paramount for identifying effective treatments. Stem cell therapy, with its multipotent differentiation capacity and anti-inflammatory effects, has emerged as a promising approach for treating previously deemed incurable conditions. This review focuses on the potential application of stem cells in subarachnoid hemorrhage pathology and explores their role in neurogenesis and as a therapeutic intervention in preclinical and clinical subarachnoid hemorrhage studies.

Treatment factors to suppress delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage based on VASOGRADE: multicenter cohort study.

Delayed cerebral ischemia (DCI) is one of the most important outcome determinants for aneurysmal subarachnoid hemorrhage (aSAH). VASOGRADE, which combines World Federation of Neurological Surgeons grade and modified Fisher grade, is a useful scale for predicting DCI after aSAH. However, no studies have investigated whether VASOGRADE influences the treatment options. We retrospectively analyzed 781 aSAH patients who were prospectively enrolled in 9 primary stroke centers from 2013 to 2021. The total cohort consisted of 76 patients (9.7%) with VASOGRADE-Green, 390 patients (49.9%) with VASOGRADE-Yellow, and 315 patients (40.3%) with VASOGRADE-Red. Worse VASOGRADE had higher incidences of DCI, which occurred in 190 patients (24.3%). As only 5 patients (6.6%) with VASOGRADE-Green developed DCI, we searched for DCI-associated factors in patients with VASOGRADEs-Yellow and -Red. Multivariate analyses revealed independent treatment factors suppressing DCI as follows: no postoperative hemorrhagic complication, combined administration of fasudil hydrochloride and cilostazol, combination of clipping and cisternal drainage, and coiling for VASOGRADE-Yellow; and clipping, and administration of fasudil hydrochloride with or without cilostazol for VASOGRADE-Red. The findings suggest that treatment strategies should be determined based on VASOGRADE to prevent DCI after aSAH.

Tramadol effects on brain activity during cognitive and emotional empathy for pain: a randomized controlled study.

Pain is perceived not only by personal experience, but also vicariously. Pain empathy is the ability to share and understand other's intentions and emotions in their painful conditions, which can be divided into cognitive and emotional empathy. It remains unclear how centrally acting analgesics would modulate brain activity related to pain empathy, and which component of pain empathy would be altered by analgesics. In this study, we examined the effects of the analgesic tramadol on the brain activity for pain empathy in healthy adults. We used two tasks to assess brain activity for pain empathy. In experiment 1, we used a well-established picture-based pain empathy task involving passive observation of other's pain. In experiment 2, we developed a novel pain empathy task to assess brain activity during cognitive and emotional empathy for pain separately in a single task. We conducted a double-blind, placebo-controlled within-subject cross-over study with functional magnetic resonance imaging for 33 participants in experiment 1 and 31 participants in experiment 2, respectively. In experiment 1, we found that tramadol decreased activation in the supramarginal gyrus (SMG) during observation of other's pain compared to placebo. SMG activation correlated negatively with the thermal pain threshold. In experiment 2, we found that tramadol decreased activation in angular gyrus in cognitive empathy for pain compared to placebo, but didn't change brain activity in emotional empathy for pain. PERSPECTIVE: Centrally acting analgesics such as tramadol may have not only analgesic effects on self-experienced pain, but also on the complex neural processing of pain empathy. DATA AVAILABILITY: Data are available on reasonable request from the corresponding author.

Impact of surgical treatment on patient reported outcome in patients with spinal metastases from prostate cancer.

OBJECTIVE: This study aimed to elucidate postoperative outcomes in patients with spinal metastases of prostate cancer, with a focus on patient-oriented assessments. METHODS: This was a prospective multicenter registry study involving 35 centers. A total of 413 patients enrolled in the Japanese Association for Spine Surgery and Oncology Multicenter Prospective Study of Surgery for Metastatic Spinal Tumors were evaluated for inclusion. The eligible patients were followed for at least 1 year after surgery. The Frankel Classification, Eastern Cooperative Oncology Group Performance Status, visual analog scale for pain, face scale, Barthel Index, vitality index, indications for oral pain medication, and the EQ-5D-5L questionnaire were used for evaluating functional status, activities of daily living, and patient motivation. RESULTS: Of the 413 eligible patients, 41 with primary prostate cancer were included in the study. The patient-oriented assessments indicated that the patients experienced postoperative improvements in quality of life and motivation in most items, with the improvements extending for up to 6 months. More than half of the patients with Frankel classifications B or C showed improved neurological function at 1 month after surgery, and most patients presented maintained or improved their classification at 6 months. CONCLUSION: Surgical intervention for spinal metastases of prostate cancer significantly improved neurological function, quality of life, and motivation of the patients. Consequently, our results support the validity of surgical intervention for improving the neurological function and overall well-being of patients with spinal metastases of prostate cancer.

Safety and feasibility of intravenous administration of a single dose of allogenic-Muse cells to treat human cervical traumatic spinal cord injury: a clinical trial.

INTRODUCTION: Spinal cord injury (SCI) is a devastating injury and remains one of the largest medical and social burdens because of its intractable nature. According to the recent advances in stem cell biology, the possibility of spinal cord regeneration and functional restoration has been suggested by introducing appropriate stem cells. Multilineage-differentiating stress enduring (Muse) cells are a type of nontumorigenic endogenous reparative stem cell. The positive results of Muse cell transplantation for SCI was shown previously. As a first step for clinical application in human SCI, we conducted a clinical trial aiming to confirm the safety and feasibility of intravenously injected donor-Muse cells. METHODS: The study design of the current trial was a prospective, multicenter, nonrandomized, nonblinded, single-arm study. The clinical trial registration number was JRCT1080224764. Patients with a cervical SCI with a neurological level of injury C4 to C7 with the severity of modified Frankel classification B1 and B2 were included. A primary endpoint was set for safety and feasibility. Our protocol was approved by the PMDA, and the trial was funded by the Life Science Institute, Tokyo, Japan. The present clinical trial recruited 10 participants (8 males and 2 females) with an average age of 49.3 ± 21.2 years old. All 10 participants received a single dose of allogenic CL2020 (a total of 15 × 106 cells, 2.1-2.7 × 105 cells/kg of body weight), which is a Muse cell-based product produced from human mesenchymal stem cells, by an intravenous drip. RESULTS: There were two reported severe adverse events, both of which were determined to have no causal relationship with Muse cell treatment. The change in the ISNCSCI motor score, the activity of daily living and quality of life scores showed statistically significant improvements compared to those data at the time of CL2020 administration. CONCLUSION: In the present trial, no safety concerns were identified, and Muse cell product transplantation demonstrated good tolerability. Future clinical trials with appropriate study designs incorporating a control arm will clarify the definitive efficacy of single-dose allogenic Muse cell treatment with intravenous administration to treat SCI. TRIAL REGISTRATION: jRCT, JRCT1080224764. Registered 03 July 2019, https://jrct.niph.go.jp/latest-detail/jRCT1080224764 .

Patient-specific mechanical analysis of pedicle screw insertion in simulated osteoporotic spinal bone models derived from medical images.

Study Design: Biomechanical study. Purpose: To investigate the mechanical characteristics of bone models created from medical images. Overview of Literature: Recent advancements in three-dimensional (3D) printing technology have affected its application in surgery. However, a notable gap exists in the analyses of how patient's dimorphism and variations in vertebral body anatomy influence the maximum insertional torque (MIT) and pullout strength (POS) of pedicle screws (PS) in osteoporotic vertebral bone models derived from medical images. Methods: Male and female patients with computed tomography data were selected. Dimensions of the first thoracic (T1), fourth lumbar (L4), and fifth lumbar (L5) vertebrae were measured, and bone models consisting of the cancellous and cortical bones made from polyurethane foam were created. PS with diameters of 4.5 mm, 5.5 mm, and 6.5 mm were used. T1 PS were 25 mm long, and L4 and L5 PS were 40 mm long. The bone models were secured with cement, and the MIT was measured using a calibrated torque wrench. After MIT testing, the PS head was attached to the machine's crosshead. POS was then calculated at a crosshead speed of 5 mm/min until failure. Results: The L4 and L5 were notably larger in female bone models, whereas the T1 vertebra was larger in male bone models. Consequently, the MIT and POS for L4 and L5 were higher in female bone models across all PS diameters than in male bone models. Conversely, the MIT for T1 was higher in male bone models across all PS; however, no significant differences were observed in the POS values for T1 between sexes. Conclusions: The mechanical properties of the proposed bone models can vary based on the vertebral structure and size. For accurate 3D surgical and mechanical simulations in the creation of custom-made medical devices, bone models must be constructed from patientspecific medical images.

Prediction of hematoma expansion in spontaneous intracerebral hemorrhage using a multimodal neural network.

Hematoma expansion occasionally occurs in patients with intracerebral hemorrhage (ICH), associating with poor outcome. Multimodal neural networks incorporating convolutional neural network (CNN) analysis of images and neural network analysis of tabular data are known to show promising results in prediction and classification tasks. We aimed to develop a reliable multimodal neural network model that comprehensively analyzes CT images and clinical variables to predict hematoma expansion. We retrospectively enrolled ICH patients at four hospitals between 2017 and 2021, assigning patients from three hospitals to the training and validation dataset and patients from one hospital to the test dataset. Admission CT images and clinical variables were collected. CT findings were evaluated by experts. Three types of models were developed and trained: (1) a CNN model analyzing CT images, (2) a multimodal CNN model analyzing CT images and clinical variables, and (3) a non-CNN model analyzing CT findings and clinical variables with machine learning. The models were evaluated on the test dataset, focusing first on sensitivity and second on area under the receiver operating curve (AUC). Two hundred seventy-three patients (median age, 71 years [59-79]; 159 men) in the training and validation dataset and 106 patients (median age, 70 years [62-82]; 63 men) in the test dataset were included. Sensitivity and AUC of a CNN model were 1.000 (95% confidence interval [CI] 0.768-1.000) and 0.755 (95% CI 0.704-0.807); those of a multimodal CNN model were 1.000 (95% CI 0.768-1.000) and 0.799 (95% CI 0.749-0.849); and those of a non-CNN model were 0.857 (95% CI 0.572-0.982) and 0.733 (95% CI 0.625-0.840). We developed a multimodal neural network model incorporating CNN analysis of CT images and neural network analysis of clinical variables to predict hematoma expansion in ICH. The model was externally validated and showed the best performance of all the models.

Temporal Shape Changes of Pedicle screw-rod Constructs After Lumbar Interbody Fusion.

STUDY DESIGN: Retrospective multicenter study. OBJECTIVE: To examine the shape change of screw-rod constructs over time following short-segment lumbar interbody fusion and to clarify its relationship to clinical characteristics. SUMMARY OF BACKGROUND DATA: No study has focused on the shape change of screw-rod constructs after short-segment fusion and its clinical implications. METHODS: One hundred and eight patients who had single-level lumbar interbody fusion with pedicle screws and cages were enrolled. Three-dimensional (3D) images of screw-rod constructs were generated from baseline CT on the day after surgery and follow-up CT, and were superposed on the right and left side, respectively, using the iterative closest point algorithm. The shape change was quantitatively assessed by computing the median distance between the 3D images, which was defined as the shape change value. Among the five time-course categories of follow-up CT (≤1 month, 2-3 months, 4-6 months, 7-12 months, ≥13 months), the shape change values were compared. The relationships between the shape change values and clinical characteristics, such as age, CT-derived vertebral bone mineral density, screw and rod materials, and postoperative interbody fusion status, cage subsidence, and screw loosening, were evaluated. RESULTS: A total of 237 follow-up CTs were included (≤1 month [34 scans], 2-3 months [33 scans], 4-6 months [80 scans], 7-12 months [48 scans], ≥13 months [42 scans]) because many patients underwent multiple follow-up CTs. There were significant differences in shape change values among the time-course categories (P<0.001 in Kruskal-Wallis test). Most shape changes occurred within 6 months postoperatively, with no significant changes observed at 7 months or more. There were no significant relationships between the shape change values and each clinical characteristic. CONCLUSION: The temporal shape changes of screw-rod constructs following short-segment lumbar interbody fusion progressed up to 6 months after surgery but not significantly thereafter.

Prospective Registration Study for Establishing Minimal Clinically Important Differences in Patients Undergoing Surgery for Spinal Metastases.

STUDY DESIGN: Multicenter, prospective registry study. OBJECTIVE: To clarify minimal clinically important differences (MCIDs) for surgical interventions for spinal metastases, thereby enhancing patient care by integrating quality of life (QoL) assessments with clinical outcomes. SUMMARY OF BACKGROUND DATA: Despite its proven usefulness in degenerative spinal diseases and deformities, the MCID remains unexplored regarding surgery for spinal metastases. METHODS: This study included 171 (out of 413) patients from the multicenter "Prospective Registration Study on Surgery for Metastatic Spinal Tumors" by the Japan Association of Spine Surgeons. These were evaluated preoperatively and at 6 months postoperatively using the Face scale, EuroQol-5 Dimensions-5 Levels (EQ-5D-5L), including the visual analog scale (VAS), and performance status. The MCIDs were calculated using an anchor-based method, classifying participants into the improved, unchanged, and deteriorated groups based on the Face scale scores. Focusing on the improved and unchanged groups, the change in the EQ-5D-5L values from before to after treatment was analyzed, and the cutoff value with the highest sensitivity and specificity was determined as the MCID through receiver operating characteristic curve analysis. The validity of the MCIDs was evaluated using a distribution-based calculation method for patient-reported outcomes. RESULTS: The improved, unchanged, and deteriorated groups comprised 121, 28, and 22 participants, respectively. The anchor-based MCIDs for the EQ-5D-5L index, EQ-VAS, and domains of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression were 0.21, 15.50, 1.50, 0.50, 0.50, 0.50, and 0.50, respectively; the corresponding distribution-based MCIDs were 0.17, 15,99, 0.77, 0.80, 0.78, 0.60, and 0.70, respectively. CONCLUSION: We identified MCIDs for surgical treatment of spinal metastases, providing benchmarks for future clinical research. By retrospectively examining whether the MCIDs are achieved, factors favoring their achievement and risks affecting them can be explored. This could aid in decisions on surgical candidacy and patient counseling.

Current Concepts of Cervical Spine Alignment, Sagittal Deformity, and Cervical Spine Surgery.

There are not many reports on cervical spine alignment, and only a few analyze ideal surgical approaches and optimal amounts of correction needed for the various types of deformity. We comprehensively reviewed the present literature on cervical spinal deformities (with or without myelopathy) and their surgical management to provide a framework for surgical planning. A general assessment of the parameters actually in use and correlations between cervical and thoracolumbar spine alignment are provided. We also analyzed posterior, anterior, and combined cervical surgical approaches and indications for the associated techniques of laminoplasty, laminectomy and fusion, and anterior cervical discectomy and fusion. Finally, on the basis of the NDI, SF-36, VAS, and mJOA questionnaires, we fully evaluated the outcomes and measures of postoperative health-related quality of life. We found the need for additional prospective studies to further enhance our understanding of the importance of cervical alignment when assessing and treating cervical deformities with or without myelopathy. Future studies need to focus on correlations between cervical alignment parameters, disability scores, and myelopathy outcomes. Through this comprehensive literature review, we offer guidance on practical and important points of surgical technique, cervical alignment, and goals surgeons can meet to improve symptoms in all patients.

Three-dimensional Images Fusion Method Useful for Preoperative Simulation of Clipping Surgery for Cerebral Aneurysms.

This study aimed to introduce a three-dimensional (3D) images fusion method for preoperative simulation of aneurysm clipping. Consecutive unruptured aneurysm cases treated with surgical clipping from March 2021 to October 2023 were included. In all cases, preoperative images of plain computed tomography (CT), CT angiography, magnetic resonance imaging (MRI) 3D fluid-attenuated inversion recovery, 3D heavily T2-weighted images, and 3D rotational angiography were acquired and transported into a commercial software (Ziostation2 Plus, Ziosoft, Inc. Tokyo, Japan). The software provided 3D images of skull, arteries including aneurysms, veins, and brain tissue that were freely rotated, magnified, trimmed, and superimposed. Using the 3D images fusion method, two operators predicted clips to be used in the following surgery. The predicted clips and actually used ones were compared to give agreement scores for the following factors: (1) type of clips (simple or fenestrated), (2) shape of clips (straight, curved, angled, or bayonet), and (3) clipping strategy (single or multiple). The agreement score ranged from 0 to 3 because a score of 1 or 0 was given for agreement or disagreement on each factor. Interoperator reproducibility was also evaluated. During the study period, 44 aneurysms from 37 patients were clipped. All procedures were successfully completed, thanks to the precisely reproduced surgical corridors with the 3D images fusion method. Agreement in clip prediction was good with mean agreement score of 2.4. Interobserver reproducibility was also high with the kappa value of 0.79. The 3D images fusion method was useful for preoperative simulation of aneurysm clipping.

Survival impact of sequential chemotherapy following pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Pembrolizumab alone or combined with chemotherapy is the standard of care for first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) with positive programmed death-ligand 1 combined positive scores. However, data on second-line chemotherapy following pembrolizumab are scarce. METHODS: A single-center, retrospective study was conducted to determine the efficacies of pembrolizumab and pembrolizumab plus chemotherapy as first-line treatments and the efficacy of second-line chemotherapy for patients with R/M HNSCC who were refractory or intolerant to first-line treatment. RESULTS: Fifty-four patients were treated with pembrolizumab, and 29 received second-line therapy, with 27 opting for cetuximab-containing regimens. The median progression-free survival (PFS), overall survival (OS), and PFS on next-line therapy for first-line treatment were 4.7 (95% confidence interval [CI], 2.1-8.7), 22.1 (95% CI, 12.6-not reached), and 15.6 months (95% CI, 9.7-not reached) in the pembrolizumab group and 5.4 (95% CI, 3.3-6.8), 15.8 (95% CI, 8.6-not reached), and 13.7 months (95% CI, 8.1-not reached) in the pembrolizumab plus chemotherapy group, respectively. The overall response rate and median PFS for second-line treatment were 48.3% (95% CI, 30.4-67.0) and 6.1 months (95% CI, 2.30-8.84). The median OS for patients who received second-line treatment was 18.4 months, which was superior to the median OS of 6.0 months for patients who received the best supportive care (log-rank p = 0.10). CONCLUSION: This study indicates that cetuximab-containing second-line chemotherapy can improve outcomes in R/M HNSCC, even after first-line therapy failure or intolerance.

A novel approach to evaluation of lumbar bone density using Hounsfield units in volume of interest on computed tomography imaging.

OBJECTIVE: The purpose of this retrospective study was to evaluate the relationship between bone mineral density (BMD), as assessed with dual-energy x-ray absorptiometry (DEXA), and Hounsfield units (HU) measured in volumes of interest (VOIs) and regions of interest (ROIs) on lumbar spine CT. METHODS: A retrospective analysis was performed on data of lumbar vertebrae obtained from patients who underwent both DEXA and lumbar spine CT scan within a 6-month period. Vertebrae with a history of compression fracture, infectious spondylitis, cement reinforcement, or lumbar surgery were excluded. HU measurements were performed in the VOI and ROI (midaxial, midcoronal, and midsagittal sections) with CT, whereas BMD was assessed with DEXA. Statistical analyses, including correlation assessments and receiver operating characteristic (ROC) curve analyses, were performed. RESULTS: This analysis included 712 lumbar vertebrae, with a median patient age of 72.0 years. BMD values and HU measurements in the VOI increased sequentially from L1 to L4, whereas HU values in the ROI did not show a consistent pattern. HU values in the VOI consistently showed a stronger correlation with BMD than those in the ROI. ROC analysis revealed patient-level cutoff values for the diagnosis of osteoporosis at different lumbar vertebral levels with high sensitivity and specificity, as well as an excellent area under the curve. CONCLUSIONS: This is the first study to introduce a novel approach using the HU value in the VOI to assess bone health at the lumbar spine. There is a strong correlation between the HU value in the VOI and BMD, and the HU value in the VOI can be used to predict osteoporosis.

Impact of malnutrition on mortality and neurological recovery of older patients with spinal cord injury.

This retrospective cohort study established malnutrition's impact on mortality and neurological recovery of older patients with cervical spinal cord injury (SCI). It included patients aged ≥ 65 years with traumatic cervical SCI treated conservatively or surgically. The Geriatric Nutritional Risk Index was calculated to assess nutritional-related risk. Overall, 789 patients (mean follow-up: 20.1 months) were examined and 47 had major nutritional-related risks on admission. One-year mortality rate, median survival time, neurological recovery, and activities of daily living (ADL) at 1 year post-injury were compared between patients with major nutrition-related risk and matched controls selected using 1:2 propensity score matching to adjust for age, pre-traumatic neurological impairment, and activity. In the Kaplan-Meier analysis, the median survival times were 44.9 and 76.5 months for patients with major nutrition-related risk and matched controls, respectively (p = 0.015). Matched controls had more individuals with a neurological improvement of American Spinal Injury Association Impairment Scale ≥ 1 grade (p = 0.039) and independence in ADL at 1 year post-injury than patients with major nutrition-related risk (p < 0.05). In conclusion, 6% of older patients with cervical SCI had major nutrition-related risks; they showed a significantly higher 1 year mortality rate, shorter survival time, poorer neurological improvement, and lower ADL at 1 year post-injury than matched controls.

UDP-Glucose/P2Y14 Receptor Signaling Exacerbates Neuronal Apoptosis After Subarachnoid Hemorrhage in Rats.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a severe subtype of stroke with poor outcomes. Abnormal glucose metabolism often occurs after SAH, but the strict control of blood glucose levels is not always beneficial. This study aimed to investigate the contribution of uridine diphosphate glucose (UDP-G), an intermediate of glucose/glycogen metabolism, and its receptor P2Y14 (P2Y purinoceptor 14) to SAH pathology and explored the potential targeted treatments in rats. METHODS: A total of 218 Sprague-Dawley male rats were used. SAH was induced by endovascular perforation. Brain expressions of P2Y14, uridine diphosphate glucose (UDP-G), and its converting enzyme UGP2 (UDP-G pyrophosphorylase-2) were evaluated. Exogenous UDP-G or selective P2Y14 inhibitor was administered intranasally at 1 hour after SAH to explore their potential effects. Intranasal Ugp2 or P2ry14 siRNA was delivered 24 hours before SAH for mechanistic evaluation. Primary neuron culture and hemoglobin stimulation were used as in vitro model of SAH. Post-SAH evaluation included liquid chromatography-mass spectrometry measurement of brain endogenous UDP-G level, neurobehavioral assessments, Western blotting, immunohistochemistry, TUNEL staining, and Nissl staining. RESULTS: There was an acute elevation of endogenous brain UDP-G and UGP2 after SAH, and P2Y14 was expressed in neurons. Although P2Y14 inhibitor decreased neurological dysfunction, neuronal apoptosis, and proapoptotic molecules, exogenous UDP-G exacerbated these outcomes at 24 hours after SAH. Early inhibition of P2Y14 preserved long-term neuronal survival in the hippocampus, amygdala, and cortex with improved neurocognition and depressive-like behavior. In addition, in vivo knockdown of Ugp2- and P2ry14-reduced neurological deficits and proapoptotic molecules at 24 hours after SAH, and furthermore in vitro knockdown of P2ry14-reduced apoptosis in hemoglobin stimulated primary neuron. CONCLUSIONS: These findings suggest a detrimental role of brain UDP-G/P2Y14 signaling in SAH, as a part of glucose metabolic pathology at the tissue level. P2Y14 inhibitor 4-[4-(4-piperidinyl)phenyl]-7-[4-(trifluoromethyl)phenyl]-2-naphthalenecarboxylic acid hydrochloride may serve as a potential therapeutic target in treating patients with SAH.

Fracture risk assessment of vascularized medial femoral condylar bone graft: A finite element analysis.

BACKGROUND: Vascularized medial femoral condyle (MFC) bone graft is useful for pseudarthrosis and osteonecrosis, but has the risk of fracture as a complication. This study aimed to create multiple three-dimensional (3D) finite element (FE) femur models to biomechanically evaluate the fracture risk in the donor site of a vascularized MFC bone graft. METHODS: Computer tomography scans of the femurs of nine patients (four males and five females) with no left femur disease were enrolled in the study. A 3D FE model of the left femur was generated based on the CT images taken from the patients. The descending genicular artery (DGA), the main nutrient vessel in vascularized MFC bone grafts, divides into the proximal transversal branch (TB) and the distal longitudinal branch (LB) before entering the periosteum. Thirty-six different bone defect models with different sizes and locations of the harvested bone were created. RESULTS: The highest stress was observed in the proximal medial and metaphyseal portions under axial and external rotation, respectively. In the bone defect model, the stress was most elevated in the extracted region's anterior or posterior superior part. Stress increased depending on proximal location and harvested bone size. CONCLUSION: Increasing the size of the bone graft proximally raises the stress at the site of bone extraction. For bone grafting to non-load-bearing areas, bone grafting distally using LB can reduce fracture risk. If TB necessitates a larger proximal bone extraction, it is advisable to avoid postoperative rotational loads.

Exploration for Blood Biomarkers of Human Long Non-coding RNAs Predicting Oxaliplatin-Induced Chronic Neuropathy Through iPS Cell-Derived Sensory Neuron Analysis.

Oxaliplatin, a platinum-based chemotherapeutic agent, frequently causes acute and chronic peripheral sensory neuropathy, for which no effective treatment has been established. In particular, chronic neuropathy can persist for years even after treatment completion, thus worsening patients' quality of life. To avoid the development of intractable adverse effects, a predictive biomarker early in treatment is awaited. In this study, we explored extracellular long non-coding RNAs (lncRNAs) released from primary sensory neurons as biomarker candidates for oxaliplatin-induced peripheral neuropathy. Because many human-specific lncRNA genes exist, we induced peripheral sensory neurons from human induced pluripotent stem cells. Oxaliplatin treatment changed the levels of many lncRNAs in extracellular vesicles (EVs) released from cultured primary sensory neurons. Among them, the levels of release of lncRNAs that were considered to be selectively expressed in dorsal root ganglia were correlated with those of lncRNAs in plasma EV obtained from healthy individuals. Several lncRNAs in plasma EVs early after the initiation of treatment showed greater changes in patients who did not develop chronic neuropathy that persisted for more than 1 year than in those who did. Therefore, these extracellular lncRNAs in plasma EVs may represent predictive biomarkers for the development of chronic peripheral neuropathy induced by oxaliplatin.

Cerebral activation caused by dental sounds: a functional magnetic resonance imaging study.

Dental drilling sounds can induce anxiety in some patients. This study aimed to use functional magnetic resonance imaging (fMRI) to assess the relationship between dental fear and auditory stimuli. Thirty-four right-handed individuals (21 women and 13 men; average age, 31.2 years) were selected. The level of dental fear was assessed using the dental fear survey (DFS). Based on a threshold DFS score > 52, participants were categorized into two groups: dental fear (DF) group (n = 12) and control group (n = 22). Two types of stimuli were presented in a single session: dental and neutral sounds. Cerebral activation during the presentation of these sounds was evaluated using contrast-enhanced blood oxygenation level-dependent fMRI. In the DF group, dental sounds induced significantly stronger activation in the left inferior frontal gyrus and left caudate nucleus (one-sample t test, P < 0.001). In contrast, in the control group, significantly stronger activation was observed in the bilateral Heschl's gyri and left middle frontal gyrus (one-sample t test, P < 0.001). Additionally, a two-sample t test revealed that dental sounds induced a significantly stronger activation in the left caudate nucleus in the DF group than in the control group (P < 0.005). These findings suggest that the cerebral activation pattern in individuals with DF differs from that in controls. Increased activation of subcortical regions may be associated with sound memory during dental treatment.

Acute-Phase Plasma Pigment Epithelium-Derived Factor Predicting Outcomes after Aneurysmal Subarachnoid Hemorrhage in the Elderly.

Aneurysmal subarachnoid hemorrhage (SAH) has increased with the aging of the population, but the outcome for elderly SAH patients is very poor. Therefore, predicting the outcome is important for determining whether to pursue aggressive treatment. Pigment epithelium-derived factor (PEDF) is a matricellular protein that is induced in the brain, and the plasma levels could be used as a biomarker for the severity of metabolic diseases. This study investigated whether acute-phase plasma PEDF levels could predict outcomes after aneurysmal SAH in the elderly. Plasma samples and clinical variables were collected over 1-3 days, post-SAH, from 56 consecutive elderly SAH patients ≥75 years of age registered in nine regional stroke centers in Japan between September 2013 and December 2016. The samples and variables were analyzed in terms of 3-month outcomes. Acute-phase plasma PEDF levels were significantly elevated in patients with ultimately poor outcomes, and the cutoff value of 12.6 µg/mL differentiated 3-month outcomes with high sensitivity (75.6%) and specificity (80.0%). Acute-phase plasma PEDF levels of ≥12.6 µg/mL were an independent and possibly better predictor of poor outcome than previously reported clinical variables. Acute-phase plasma PEDF levels may serve as the first biomarker to predict 3-month outcomes and to select elderly SAH patients who should be actively treated.