Pharmacological evaluation of E2730, a novel selective uncompetitive GAT1 inhibitor, on epileptiform activities in resected brain tissues from human focal cortical dysplasia ex vivo.

Focal cortical dysplasia (FCD) is an important etiology of focal epilepsy in children and adults. However, only a few preclinical models sufficiently reproduce the characteristic histopathologic features of FCD. To improve the success rate of clinical trials for antiseizure medications (ASMs) in patients with FCD, more human-relevant preclinical models are needed, and epileptic foci resected from patients are a powerful tool for this purpose. Here, we conducted ex vivo studies using epileptic foci resected from patients with FCD type II to evaluate the pharmacologic effects of the ASM candidate E2730, a selective uncompetitive inhibitor of γ-aminobutyric acid transporter 1. We used the same ex vivo assay system to assess carbamazepine (CBZ), an ASM often prescribed for focal epilepsy, as a reference. At the higher dose tested (200 µM), both E2730 and CBZ suppressed spontaneous epileptiform activities almost completely. At the lower dose (100 µM), CBZ reduced the area of brain tissue showing epileptiform activity, whereas E2730 significantly decreased the number of epileptiforms. These findings suggest that E2730-both as a single agent and in combination with CBZ-merits evaluation in clinical trials involving patients with FCD.

Identification of a Biallelic Missense Variant in Gasdermin D (c.823G > C, p.Asp275His) in a Patient of Atypical Gorham-Stout Disease in a Consanguineous Family.

Gorham-Stout disease (GSD), also called vanishing bone disease, is a rare osteolytic disease, frequently associated with lymphangiomatous tissue proliferation. The causative genetic background has not been noted except for a case with a somatic mutation in KRAS. However, in the present study, we encountered a case of GSD from a consanguineous family member. Whole-exome sequencing (WES) analysis focusing on rare recessive variants with zero homozygotes in population databases identified a homozygous missense variant (c.823G > C, p.Asp275His) in gasdermin D (GSDMD) in the patient and heterozygous in his unaffected brother. Because this variant affects the Asp275 residue that is involved in proteolytic cleavage by caspase-11 (as well as -4 and -5) to generate an activating p30 fragment required for pyroptotic cell death and proinflammation, we confirmed the absence of this cleavage product in peripheral monocytic fractions from the patient. A recent study indicated that a shorter p20 fragment, generated by further cleavage at Asp88, has a cell-autonomous function to suppress the maturation of osteoclasts to resorb bone matrix. Thus, the present study suggests for the first time the existence of hereditary GSD cases or novel GSD-like diseases caused by GSDMD deficiency. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Evaluation of Ulnar Setting of Volar Locking Plates for Distal Radius Fractures Using Modified Skyline View.

Purpose: Volar lunate facet fragments in distal radius fractures are located at the center of the load in the wrist joint and, therefore, should be properly supported by the distal ulnar setting of volar locking plates to obtain better postoperative outcomes. This study evaluated the usefulness of the modified skyline view (MSV) in intraoperative fluoroscopy for the ulnar setting of volar locking plates by comparing it with that of the anteroposterior view (APV). Methods: Sixty-five patients with distal radius fractures who underwent open reduction and plate fixation as well as follow-up intraoperative fluoroscopy and postoperative computed tomography (CT) at our institution between April 2019 and March 2022 were included. The distance between the ulnar edge of the plate and the distal radius (d-value) was measured retrospectively using intraoperative fluoroscopy (distance measured from MSV and distance measured from APV) or postoperative CT (distance measured using postoperative CT). The distance measured from MSV and that measured from APV were compared with those measured using CT as the true values. Each measurement was performed twice by 2 examiners at an interval of 1 month. The comparison scores were evaluated using the intraclass correlation coefficient. Results: The distance measured from MSV showed a difference of 0.6 ± 0.5 mm from that measured using CT, which was significantly smaller than that measured from APV (1.2 ± 0.9 mm; P < .001). Neither postoperative volar subluxation nor dislocation of bone fragments was found during the study period. Both intraclass correlation coefficient (1,1) and intraclass correlation coefficient (2,1) reliabilities were substantial to almost perfect. Conclusions: Modified skyline view is an effective and versatile imaging method for estimating the ulnar setting of volar locking plates; it provides measurements more similar to those provided by postoperative CT compared with APV. The use of MSV may reduce postoperative complications, such as volar subluxation and dislocation of bone fragments, especially in cases with volar lunate facet fragments in which the ulnar setting of the plate is significant. Type of study/level of evidence: Diagnostic III.

The necessity of routine screening for deep vein thrombosis before surgery.

Background: Pulmonary embolism (PE) from deep venous thrombosis (DVT) can be a fatal postoperative complication. Preventive measures for venous thromboembolism (VTE) was evaluated in this hospital. Materials and methods: Preoperative DVT screening following surgery under general anesthesia in 2009-2016 was examined, and then, 217 patients diagnosed with DVT by preoperative leg-ultrasound (US) between 2014 and 2016 were retrospectively analyzed. Results: There were 24,826 operations under general anesthesia in the study period. Preoperative leg-US was performed in 5345 (21.5%) patients, and 648 (12.1% of patients, 2.6% of total operations) were diagnosed with DVT. In 2014-2016, 217 patients, which is 11.7% of patients undergoing leg-US, were diagnosed with DVT. DVT was found in the proximal veins (upper popliteal vein) in 86 (39.6%) patients. A total of 143 (62%) patients were considered to have organized thrombi, no patient developed pulmonary embolism, and 133 (58%) patients were discharged without follow-up examination for DVT. Ninety-six patients were evaluated for changes on leg-US, with no difference in the results with and without anticoagulant use. On multivariate logistic regression analysis, anticoagulants appeared effective for non-organized thrombi, higher D-dimer levels (≥10 µg/mL), or orthopedic surgery. Conclusion: Preoperative screening for DVT did not appear useful, and treatment of asymptomatic DVT was not always necessary.

Impact of body mass index on surgical outcomes and complications in adult spinal deformity.

BACKGROUND: Several studies have reported that overweightness and obesity are associated with higher complication rates in lumbar spine surgery. However, little is known about the effect of obesity on postoperative complications in adult spinal deformity (ASD) surgery, especially in the elderly. This study aimed to examine the effect of body mass index (BMI) on surgical outcomes and postoperative complications in elderly ASD patients undergoing surgical correction in Japan. METHODS: We conducted a retrospective, multicenter, observational study of 234 consecutive patients diagnosed with ASD who underwent corrective surgery. Patients were divided into two groups according to BMI, BMI <25 (153 patients, mean age 71.9 years) and BMI ≥ 25 (overweight/obese, 81 patients, mean age 73.3 years). Radiographic results and perioperative complications were compared between the two groups. RESULTS: Surgical complications occurred in approximately 20% of patients in each group; complications did not significantly differ between the two groups. A greater proportion of patients in the BMI ≥ 25 group experienced mechanical failure and DJK, although the difference was not significant. Preoperative mean lumbar lordosis (LL), pelvic incidence (PI) minus LL, sacral slope (SS) and sagittal vertical axis (SVA) were similar in the BMI < 25 and BMI ≥ 25 groups. However, the BMI ≥25 group had lower mean LL (p = 0.015) and higher PI minus LL (p = 0.09) postoperatively. The BMI ≥25 groups also had significantly smaller LL (p = 0.026), smaller SS (p = 0.049) and higher SVA (p = 0.041) at the final follow-up, compared to the BMI < 25 group. CONCLUSIONS: In the present study, no difference in medical or surgical complications after ASD surgery was found between overweight/obese patients (BMI ≥ 25) and those with BMI < 25. However, correction of LL and SVA was smaller in patients with overweight/obese patients.

Comparison of Lateral Lumbar Interbody Fusion and Posterior Lumbar Interbody Fusion as Corrective Surgery for Patients with Adult Spinal Deformity-A Propensity Score Matching Analysis.

Lateral lumbar interbody fusion (LLIF) is increasingly performed as corrective surgery for patients with adult spinal deformity (ASD). This paper compares the surgical results of LLIF and conventional posterior lumbar interbody fusion (PLIF)/transforaminal lumbar interbody fusion (TLIF) in ASD using a propensity score matching analysis. We retrospectively reviewed patients with ASD who received LLIF and PLIF/TLIF, and investigated patients' backgrounds, radiographic parameters, and complications. The propensity scores were calculated from patients' characteristics, including radiographic parameters and preoperative comorbidities, and one-to-one matching was performed. Propensity score matching produced 21 matched pairs of patients who underwent LLIF and PLIF/TLIF. All radiographic parameters significantly improved in both groups at the final follow-up compared with those of the preoperative period. The comparison between both groups demonstrated no significant difference in terms of postoperative pelvic tilt, lumbar lordosis (LL), or pelvic incidence-LL at the final follow-up. However, the sagittal vertical axis tended to be smaller in the LLIF at the final follow-up. Overall, perioperative and late complications were comparable in both procedures. However, LLIF procedures demonstrated significantly less intraoperative blood loss and a smaller incidence of postoperative epidural hematoma compared with PLIF/TLIF procedures in patients with ASD.

Comparative analysis of clinical factors associated with pedicle screw pull-out during or immediately after surgery between intraoperative cone-beam computed tomography and postoperative computed tomography.

BACKGROUND: No studies to date have elucidated the clinical factors associated with pedicle screw pull-out during or immediately after surgery. The aim of this study was to assess the frequency of pedicle screw pull-out by comparing intraoperative scans obtained using cone-beam computed tomography (CBCT) with postoperative scans obtained using computed tomography (CT). We also sought to determine the incidence of pedicle screw pull-out and identify relevant risk factors. METHODS: This was a retrospective analysis of prospectively collected data for 742 pedicle screws placed in 76 consecutive patients who underwent at least triple-level posterior fixation for thoracic or lumbar spinal injury, spinal metastasis, or pyogenic spondylitis between April 2014 and July 2020. Pedicle screw pull-out distance in the axial and sagittal planes was compared between CT scans obtained 2 days postoperatively and CBCT images acquired intraoperatively. Risk factors associated with pedicle screw pull-out were investigated by multivariate logistic regression analysis. RESULTS: Pedicle screw pull-out was seen with 58 pedicle screws (7.8%) in 26 patients (34.2%). There were significant differences in age, number of fused segments, frequency of diffuse idiopathic skeletal hyperostosis (DISH), and medical history of osteoporosis for pedicle screw pull-out. Risk factors for pedicle screw pull-out were older age (odds ratio 1.07, 95% confidence interval 1.02-1.130) and a diagnosis of DISH (odds ratio 3.35, 95% confidence interval 1.12-10.00). Several cases suggest that use of connecting rods was an important factor in intraoperative pedicle screw pull-out. CONCLUSIONS: Our findings suggest that age, number of fused segments, presence of DISH, and medical history of osteoporosis are risk factors for pedicle screw pull-out, with the greatest being older age and DISH.

Functional Characterization of Acetylcholine Receptors Expressed in Human Neurons Differentiated from Hippocampal Neural Stem/Progenitor Cells.

Neurotransmission mediated by acetylcholine receptors (AChRs) plays an important role in learning and memory functions in the hippocampus. Impairment of the cholinergic system contributes to Alzheimer's disease (AD), indicating the importance of AChRs as drug targets for AD. To improve the success rates for AD drug development, human cell models that mimic the target brain region are important. Therefore, we characterized the functional expression of nicotinic and muscarinic AChRs (nAChRs and mAChRs, respectively) in human hippocampal neurons differentiated from hippocampal neural stem/progenitor cells (HIP-009 cells). Intracellular calcium flux in 4-week differentiated HIP-009 cells demonstrated that the cells responded to acetylcholine, nicotine, and muscarine in a concentration-dependent manner (EC50 = 13.4 ± 0.5, 6.0 ± 0.4, and 35.0 ± 2.5 µM, respectively). In addition, assays using subtype-selective compounds revealed that major AD therapeutic target AChR subtypes-α7 and α4ß2 nAChRs, as well as M1 and M3 mAChRs-were expressed in the cells. Furthermore, neuronal network analysis demonstrated that potentiation of M3 mAChRs inhibits the spontaneous firing of HIP-009 neurons. These results indicate that HIP-009 cells are physiologically relevant for AD drug screening and hence are loadstars for the establishment of in vitro AD models.

A case of graft infection 10 years after ascending aorta replacement.

A 52-year-old man was admitted with anemia and slight fever, which he had for the last 2 months. He had undergone replacement of the ascending aorta for acute aortic dissection 10 years previously. Echocardiography demonstrated a flailing thin structure in the anterior wall of the ascending aorta corresponding to the proximal portion of the prosthetic graft. This abnormal echocardiographic finding led us to repeat blood cultivation. We finally detected Enterococcus facium and Staphylococcus epidermidis in his blood sample. We diagnosed this as a graft infection and prepared for surgical re-replacement of the infected graft. While he was waiting for the operation, an infectious aneurysm of a tibialis posterior artery ruptured and an emergency operation was done. Replacement of the infected ascending aorta graft was done thereafter. In surgery, 2-cm-long vegetation was found. It stuck to the graft wall near the former hole used for air removal in the first surgery. The patient recovered fully and left our hospital after 3 months of postoperative antibiotics therapy. This rare case of aortic graft infection long after the original replacement surgery suggests the importance of thorough echocardiographic investigation of prosthetic graft infection as a possible cause of fever of unknown origin.