Search

Kyphotic deformity after cervical laminoplasty (CLP) often leads to unfavorable neurological recovery due to insufficient indirect decompression of the spinal cord. Existing literature has described that segmental cervical instability is a contraindication for CLP because it is a potential risk factor for kyphotic changes after surgery; however, this has never been confirmed in any clinical studies.To confirm whether segmental cervical instability was an independent risk factor for postoperative kyphotic change and to examine whether segmental cervical instability led to poor neurological outcomes after CLP for cervical spondylotic myelopathy (CSM).A retrospective study PATIENT SAMPLE: Patients who underwent CLP for CSM between January 2013 and January 2021 with a follow-up period of ≥1 year were enrolled.Cervical radiographic measurements including C2-C7 lordosis (C2-7 angle), cervical sagittal vertical axis, C7 slope, flexion range of motion (fROM) and extension ROM (eROM) were assessed using neutral and flexion-extension views. Segmental cervical instability was classified into anterolisthesis (AL) of ≥2 mm displacement, retrolisthesis (RL) of ≥2 mm displacement, and translational instability (TI) of ≥3 mm translational motion. The amount of C2-7 angle loss at the follow-up period compared to the preoperative measurements was defined as cervical lordosis loss (CLL). Neurological outcomes were assessed using the recovery rate of the Japanese Orthopedic Association score (JOA-RR).CLL was compared among patients with and without segmental cervical instability. Further, multiple linear regression model for CLL was built for the evaluation with adjustment of the reported risks, including cervical sagittal vertical axis, C7 slope, fROM, eROM, and patient age together with AL, RL, and TI, as independent variables. The JOA-RR was also compared between patients with and without segmental cervical instability.A total of 138 patients (mean age, 68.7 years; 65.9% male) were included in the analysis. AL, RL, and TI were found in 12 (8.7%), 33 (23.9%), and 16 (11.6%) patients, respectively. Comparisons among the groups showed that AL led to greater CLL; however, RL and TI did not. Multiple linear regression analysis revealed that greater CLL is significantly associated with greater fROM and smaller eROM (regression coefficient [β]=0.328, 95% confidence interval: 0.178 to 0.478, p.001; β=-0.372, 95% confidence interval: -0.591 to -0.153, p=.001, respectively). However, there were no significant statistical associations in the AL, RL, and TI. Whereas, patients with AL tended to exhibit lower JOA-RR than those without AL (37.8% vs. 52.0%, p=.108).Segmental cervical instability is not the definitive driver for loss of cervical lordosis after CLP in patients with CSM; thus, is not a contraindication in and of itself. However, it is necessary to consider the indications for CLP, according to individual cases of patients with AL on baseline radiograph, which is a sign of poor neurological recovery.

Aims The liver is the major organ shown to remove oxidized low-density lipoprotein (oxLDL) from the circulation. Given increased evidence that thermogenic adipose tissue has anti-effects, we used 123I-labelled oxLDL as a tracer to reveal oxLDL accumulation in the brown adipose tissue (BAT) of mice. We also explored the mechanisms of oxLDL accumulation in BAT. Methods and results We used high-resolution nanoSPECT/CT to investigate the tissue distribution of 123I-oxLDL and 123I-LDL (control) following intravenous injection into conscious mice. 123I-oxLDL distribution was discovered in BAT at an intensity equivalent to that in the liver, whereas 123I-LDL was detected mostly in the liver. Consistent with the function of BAT related to sympathetic nerve activity, administering anaesthesia in mice almost completely eliminated the accumulation of 123I-oxLDL in BAT, and this effect was reversed by administering β3-agonist. Furthermore, exposing mice to cold stress at 4°C enhanced 123I-oxLDL accumulation in BAT. Because in 123I-oxLDL, the protein of oxLDL was labelled, we performed additional experiments with DiI-oxLDL in which the lipid phase of oxLDL was fluorescently labelled and observed similar results, suggesting that the whole oxLDL particle was taken up by BAT. To identify the receptor responsible for oxLDL uptake in BAT, we analysed the expression of known oxLDL receptors (e.g. SR-A, CD36, and LOX-1) in cultured brown adipocyte cell line and primary brown adipocytes and found that CD36 was the major receptor expressed. Treatment of cells with CD36 siRNA or CD36 neutralizing antibody significantly inhibited DiI-oxLDL uptake. Finally, CD36 deletion in mice abolished the accumulation of 123I-oxLDL and DiI-oxLDL in BAT, indicating that CD36 is the major receptor for oxLDL in BAT. Conclusion We show novel evidence for the CD36-mediated accumulation of oxLDL in BAT, suggesting that BAT may exert its anti-atherogenic effects by removing atherogenic LDL from the circulation.

SUMMARYMounting evidence supports an instructive role for metabolism in stem cell fate decisions. However, much is yet unknown about how fetal metabolism changes during mammalian development and how altered maternal metabolism shapes fetal metabolism. Here, we present a descriptive atlas ofin vivofetal murine metabolism during mid-to-late gestation in normal and diabetic pregnancy. Using13C-glucose and LC-MS, we profiled the metabolism of fetal brains, hearts, livers, and placentas harvested from pregnant dams between embryonic days (E)10.5 and 18.5. Comparative analysis of our large metabolomics dataset revealed metabolic features specific to fetal tissues developed under a hyperglycemic environment as well as metabolic signatures that may denote developmental transitions during euglycemic development. We observed sorbitol accumulation in fetal tissues and altered neurotransmitter levels in fetal brains isolated from dams with maternal hyperglycemia. Tracing13C-glucose revealed disparate nutrient sourcing in fetuses depending on maternal glycemic states. Regardless of glycemic state, histidine-derived metabolites accumulated during late development in fetal tissues and maternal plasma. Our rich dataset presents a comprehensive overview ofin vivofetal tissue metabolism and alterations occurring as a result of maternal hyperglycemia.

Serum/glucocorticoid-regulated kinase 1 (SGK1) is predominantly expressed in endothelial cells of mouse embryos, and Sgk1 null mice show embryonic lethality due to impaired vascular formation. However, how the SGK1 expression is controlled in developing vasculature remains unknown. In this study, we first identified a proximal endothelial enhancer through lacZ reporter mouse analyses. The mouse Sgk1 proximal enhancer was narrowed down to the 5' region of the major transcription initiation site, while a human corresponding region possessed relatively weak activity. We then searched for distal enhancer candidates using in silico analyses of publicly available databases for DNase accessibility, RNA polymerase association and chromatin modification. A region approximately 500 kb distant from the human SGK1 gene was conserved in the mouse, and the mouse and human genomic fragments drove transcription restricted to embryonic endothelial cells. Minimal fragments of both proximal and distal enhancers had consensus binding elements for the ETS transcription factors, which were essential for the responsiveness to ERG, FLI1 and ETS1 proteins in luciferase assays and the endothelial lacZ reporter expression in mouse embryos. These results suggest that endothelial SGK1 expression in embryonic vasculature is maintained through at least two ETS-regulated enhancers located in the proximal and distal regions.

Although the spontaneous regression of pseudotumors after posterior fusion has been reported, the predictive factors remain unclear. We examined the radiological features that predict for the regression of retro-odontoid pseudotumors after posterior fusion, with a specific focus on cyst formation.We included 28 patients with a diagnosis of retro-odontoid pseudotumor using preoperative magnetic resonance imaging. The radiographic parameters and pseudotumor thickness were measured pre- and postoperatively. The regression rate for each pseudotumor was calculated. The presence of a cyst around the retro-odontoid pseudotumor was investigated. If present, the cyst thickness was measured. To elucidate the predictors for the postoperative regression of pseudotumors, the patients were divided into 2 cohorts: the regression group with a regression rate40% and the no-regression group with a regression rate of40%. Multivariate logistic regression analysis, including the demographic data and preoperative radiographic parameters as independent variables, was performed.The mean pseudotumor size had decreased significantly from 8.8 ± 3.6 mm preoperatively to 5.3 ± 2.0 mm postoperatively (P0.0001). The mean regression rate was 35.9% during a magnetic resonance imaging follow-up period of 8.6 months (range, 6-12 months). Cystic lesions were noted in 10 patients (35.7%) preoperatively. The mean cyst size was 4.7 ± 1.9 mm. All cysts were located dorsal to the pseudotumors and were involved at the maximum spinal compression levels. Nevertheless, all the cysts had disappeared postoperatively. Multivariate logistic regression analysis revealed that the pseudotumor regression group had had a significantly greater proportion of cysts (57.1% vs. 14.3%; odds ratio, 11.7; P = 0.013).The presence of cystic lesions protruding from retro-odontoid pseudotumors might serve as a predictive factor for the spontaneous regression of pseudotumors after posterior fusion.

Study design A retrospective study. Objective To investigate the effects of surgery on the subjective perception of bodily unsteadiness and the objective measurements of postural instability in patients with cervical compressive myelopathy (CCM). Summary of background data Several studies have demonstrated that CCM patients have impaired postural stability and investigated its surgical outcomes. However, these studies have only objectively measured postural stability by using a stabilometer or three-dimensional motion capture system. There have been no studies examining the subjective perception of postural instability in CCM patients. Materials and methods We retrospectively reviewed patients who underwent decompressive surgery for CCM. The Fall Efficacy Scale-International (FES-I) and a self-prepared questionnaire were used to evaluate subjective perception of bodily unsteadiness. To objectively assess postural instability, a stabilometric analysis was performed with the following parameters: sway area (SwA, cm2), sway velocity (SwV, cm/s), and sway density (SwD, /cm). The evaluations were performed preoperatively, during the early postoperative period (3-6 mo postoperatively), and at 1-year postoperatively in patients with CCM. The evaluation results were compared with age-matched, sex-matched, and body mass index-matched healthy subjects. Results We included 70 CCM patients and 36 healthy subjects in this study. In both the FES-I and self-prepared questionnaire, CCM patients reported significantly milder postoperative bodily unsteadiness. The stabilometric parameters were significantly improved during the postoperative period when compared with preoperative values. Nevertheless, neither the self-reported outcome measures nor stabilometric parameters of CCM patients reached the levels of those in healthy controls in the postoperative period. Conclusion This was the first study to examine CCM surgical outcomes in terms of both subjective perception and objective postural instability. While both objective postural stability and subjective perception improved following decompressive surgery, they did not reach the levels seen in healthy participants. Level of evidence Level III.

STUDY DESIGN This was a retrospective study. OBJECTIVE The objective of this study was to investigate the diagnostic utility of percutaneous ultrasonography (PUS) for postoperative epidural hematoma (EH) as a postoperative complication. SUMMARY OF BACKGROUND DATA We investigated the usefulness of PUS for determining the need of surgical evacuation of postoperative EH by comparing the postoperative magnetic resonance imaging (MRI) and PUS of the spinal cord. MATERIALS AND METHODS This study included patients who underwent cervical laminoplasty using suture anchors. Regular MRI and PUS were performed 1 week postoperatively. Whenever the patients exhibited neurological deterioration, MRI and PUS were performed. The spinal cord decompression status was classified into 3 grades using MRI and PUS. The existence of spinal pulsation was determined by PUS. RESULTS One hundred thirty-one patients were investigated. The decompression status by MRI and PUS, and the pulsation status by PUS showed a correlation with neurological deterioration (P

In this study, we conducted a collaborative study on the classification between silicone oil droplets and protein particles detected using the flow imaging (FI) method toward proposing a standardized classifier/model. We compared four approaches, including a classification filter composed of particle characteristic parameters, principal component analysis, decision tree, and convolutional neural network in the performance of the developed classifier/model. Finally, the points to be considered were summarized for measurement using the FI method, and for establishing the classifier/model using machine learning to differentiate silicone oil droplets and protein particles.

Funder: GlaxoSmithKline; doi: http://dx.doi.org/10.13039/100004330, BACKGROUND AND OBJECTIVES: GSK2982772 is an oral small-molecule RIPK1 inhibitor with potential therapeutic efficacy in immune-mediated inflammatory diseases (IMIDs). An inter-ethnic comparison of GSK2982772 pharmacokinetics was conducted based on data from Western (Study 1) and Japanese subjects (Study 2). METHODS: Both studies were single-centre, randomised, double-blind, placebo-controlled studies with objectives to assess the safety and characterise the pharmacokinetics of GSK2982772. Western subjects in Study 1 (NCT03305419), Part A (N = 15), were randomly assigned to receive 120 mg three times daily (TID), 240 mg TID, or 360 mg twice daily (BID) doses of GSK2982772, or placebo (TID or BID) for 1 day. Part B subjects (N = 47) received GSK2982772 120 mg TID, 240 mg TID, or placebo TID for 14 days. Japanese subjects in Study 2 (N = 13) (NCT03590613) were randomly assigned to receive TID doses of GSK2982772 60, 120, 240 mg TID or placebo TID for 1 day. RESULTS: GSK2982772 was well tolerated and adverse events were generally mild. Maximum observed plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma drug concentration versus time curve after the first GSK2982772 dose (AUC(0-7)) of 120 and 240 mg, and (AUC(0-24)) values for the 120 and 240 mg TID doses over a single day were similar in Japanese and Western subjects. CONCLUSIONS: The pharmacokinetics and tolerability of GSK2982772 were similar between Western and Japanese subjects, justifying inclusion of Japanese subjects in future global clinical studies to assess the therapeutic potential of RIPK1 inhibition for the treatment of IMIDs. Clinical Trials: NCT03305419 and NCT03590613 available from http://www.clinicaltrials.gov .

Introduction: Osteoporotic vertebral fracture (OVF) is the most common osteoporotic fracture, and some patients require surgical intervention to improve their impaired activities of daily living with neurological deficits. However, many previous reports have focused on OVF around the thoracolumbar junction, and the surgical outcomes of lumbar OVF have not been thoroughly discussed. We aimed to investigate the surgical outcomes for lumbar OVF with a neurological deficit. Methods: Patients who underwent fusion surgery for thoracolumbar OVF with a neurological deficit were enrolled at 28 institutions. Clinical information, comorbidities, perioperative complications, Japanese Orthopaedic Association scores, visual analog scale scores, and radiographic parameters were compared between patients with lower lumbar fracture (L3-5) and those with thoracolumbar junction fracture (T10-L2). Each patient with lower lumbar fracture (L group) was matched with to patients with thoracolumbar junction fracture (T group). Results: A total 403 patients (89 males and 314 females, mean age: 73.8 ± 7.8 years, mean follow-up: 3.9 ± 1.7 years) were included in this study. Lower lumbar OVF was frequently found in patients with lower bone mineral density. After matching, mechanical failure was more frequent in the L group (L group: 64%, T group: 39%; p < 0.001). There was no difference between groups in the clinical and radiographical outcomes, although the rates of complication and revision surgery were still high in both groups. Conclusions: The surgical intervention for OVF is effective in patients with myelopathy or radiculopathy regardless of the surgical level, although further study is required to improve clinical and radiographical outcomes. Level of evidence: Level III

Kyphotic deformity is a rare but serious complication after cervical laminoplasty (CLP), and several studies have investigated its predictors. In these studies, a kyphotic Cobb angle of 0°-5° between C2 and C7 at a certain postoperative time-point was often used to detect kyphotic deformity. However, studies considering the amount of cervical lordosis loss compared to the preoperative measurement are scarce. This study aimed to elucidate risk factors for kyphotic change after CLP by comparing patients with and without marked loss of cervical lordosis postoperatively. The study population was divided into seven patients with and 92 patients without a loss of10° of the C2-7 angle during the follow-up period compared to the preoperative measurements [cervical lordosis loss (CLL) group and no CLL (NCLL) group, respectively]; demographic characteristics, surgical information, preoperative radiographic sagittal parameters of the cervical spine, and posterior paravertebral muscle morphology evaluated by magnetic resonance imaging were compared between two groups. A univariate analysis revealed that the CLL group had significantly greater flexion range of motion (fROM) than the NCLL group (43.0° vs. 25.8°, P 0.001); however, no statistical significance was identified for other parameters. The fROM had a high capacity to discriminate between the CLL and NCLL groups (area under the receiver-operating characteristic curve, 0.880; P 0.001; 95% confidence interval, 0.589-0.974) with an optimal cutoff point of 37°. This study suggests that greater fROM is a risk factor for the development of kyphotic changes after CLP. For patients with preoperative fROM exceeding 40°, CLP should be carefully indicated.

Development of multi-chambered heart is associated with spatio-temporal regulation of gene expression. A basic helix-loop-helix transcription factor Hey2 is specifically expressed in the embryonic mouse ventricles and is indispensable for ventricular myocyte differentiation, compartment identity and morphogenesis of the heart. However, how Hey2 transcription is precisely regulated in the heart remains unclear. In this study, we identified a distal Hey2 enhancer conserved in the mouse and human to possess specific transcriptional activity in ventricular free wall myocytes at the looping stage of cardiac development. Deletion of the enhancer significantly decreased endogenous Hey2 expression in the ventricular myocardium but not in other tissues of mouse embryos. Mutation/deletion of the conserved binding sites for T-box and Gata proteins, but not NK-2 proteins, abolished the enhancer activity, and Tbx20 null mice completely lost the enhancer activity in the embryonic ventricles. Luciferase reporter analysis suggested that the ventricular enhancer activity was controlled by Tbx20 through its DNA binding and cooperative function with cardiac Gata proteins. These results delineate a regulatory mechanism of ventricular Hey2 expression and help fully understand molecular cascades in myocardial cell differentiation and cardiac morphogenesis during embryonic development.

Levocetirizine is classified as a second‐generation antihistamine. Levocetirizine is available for the treatment of allergic disorders such as allergic rhinitis and chronic idiopathic urticaria. This was a single‐center, single‐dose, open‐label, randomized, 2‐way crossover study in healthy Japanese male subjects consisting of 2 parts. Part 1 compared the bioavailability of levocetirizine oral disintegrating tablet (ODT) and levocetirizine immediate‐release tablet (IRT) taken with water in the fasted state in 24 subjects; all subjects completed this part of the trial. In part 2, the bioavailability of levocetirizine ODT without water was compared with that of levocetirizine IRT with water in the fasted state in 48 subjects; 47 subjects completed this part of the trial. Bioequivalence was demonstrated between levocetirizine IRT 5 mg and ODT 5 mg. The safety profiles were generally similar between levocetirizine ODT and levocetirizine IRT, with no serious adverse events, deaths, or adverse events leading to withdrawal reported during the study.

A retrospective multicenter study. Body mass index (BMI) is recognized as an important determinant of osteoporosis and spinal postoperative outcomes; however, the specific impact of BMI on surgery for osteoporotic vertebral fractures (OVFs) remains inconclusive. This retrospective multicenter study investigated the impact of BMI on clinical outcomes following fusion surgery for OVFs. 237 OVF patients (mean age, 74.3 years; 48 men and 189 women) with neurological symptoms who underwent spinal fusion were included in this study. Patients were grouped by World Health Organization BMI categories: low BMI (18.5 kg/m2), normal BMI (≥18.5 and 25 kg/m2), and high BMI (≥25 kg/m2). Patients' backgrounds, surgical method, radiological findings, pain measurements, activities of daily living (ADL), and postoperative complications were compared after a mean follow-up period of 4 years. As results, the proportion of patients able to walk independently was significantly smaller in the low BMI group (75.0%) compared with the normal BMI group (89.9%; P = .01) and the high BMI group (94.3%; P = .04). Improvement in the visual analogue scale for leg pain was significantly less in the low BMI group than the high BMI group (26.7 vs 42.8 mm; P = .046). Radiological evaluation, the Frankel classification, and postoperative complications were not significantly different among all 3 groups. Improvement of pain intensity and ADL in the high BMI group was equivalent or non-significantly better for some outcome measures compared with the normal BMI group. Leg pain and independent walking ability after fusion surgery for patients with OVFs improved less in the low versus the high BMI group. Surgeons may want to carefully evaluate at risk low BMI patients before fusion surgery for OVF because poor clinical results may occur.

Abstract Among neonatal cardiomyopathies, primary endocardial fibroelastosis (pEFE) remains a mysterious disease of the endomyocardium that is poorly genetically characterized, affecting 1/5000 live births and accounting for 25% of the entire pediatric dilated cardiomyopathy (DCM) with a devastating course and grave prognosis. To investigate the potential genetic contribution to pEFE, we performed integrative genomic analysis, using whole exome sequencing (WES) and RNA-seq in a female infant with confirmed pathological diagnosis of pEFE. Within regions of homozygosity in the proband genome, WES analysis revealed novel parent-transmitted homozygous mutations affecting three genes with known roles in cilia assembly or function. Among them, a novel homozygous variant [c.1943delA] of uncertain significance in ALMS1 was prioritized for functional genomic and mechanistic analysis. Loss of function mutations of ALMS1 have been implicated in Alstrom syndrome (AS) [OMIM 203800], a rare recessive ciliopathy that has been associated with cardiomyopathy. The variant of interest results in a frameshift introducing a premature stop codon. RNA-seq of the proband’s dermal fibroblasts confirmed the impact of the novel ALMS1 variant on RNA-seq reads and revealed dysregulated cellular signaling and function, including the induction of epithelial mesenchymal transition (EMT) and activation of TGFβ signaling. ALMS1 loss enhanced cellular migration in patient fibroblasts as well as neonatal cardiac fibroblasts, while ALMS1-depleted cardiomyocytes exhibited enhanced proliferation activity. Herein, we present the unique pathological features of pEFE compared to DCM and utilize integrated genomic analysis to elucidate the molecular impact of a novel mutation in ALMS1 gene in an AS case. Our report provides insights into pEFE etiology and suggests, for the first time to our knowledge, ciliopathy as a potential underlying mechanism for this poorly understood and incurable form of neonatal cardiomyopathy. Key message Primary endocardial fibroelastosis (pEFE) is a rare form of neonatal cardiomyopathy that occurs in 1/5000 live births with significant consequences but unknown etiology. Integrated genomics analysis (whole exome sequencing and RNA sequencing) elucidates novel genetic contribution to pEFE etiology. In this case, the cardiac manifestation in Alstrom syndrome is pEFE. To our knowledge, this report provides the first evidence linking ciliopathy to pEFE etiology. Infants with pEFE should be examined for syndromic features of Alstrom syndrome. Our findings lead to a better understanding of the molecular mechanisms of pEFE, paving the way to potential diagnostic and therapeutic applications.

Cells display distinct metabolic characteristics depending on its differentiation stage. The fuel type of the cells serves not only as a source of energy but also as a driver of differentiation. Glucose, the primary nutrient to the cells, is a critical regulator of rapidly growing embryos. This metabolic change is a consequence as well as a cause of changes in genetic program. Disturbance of fetal glucose metabolism such as in diabetic pregnancy is associated with congenital heart disease. In utero hyperglycemia impacts the left-right axis establishment, migration of cardiac neural crest cells, conotruncal formation and mesenchymal formation of the cardiac cushion during early embryogenesis and causes cardiac hypertrophy in late fetal stages. In this review, we focus on the role of glucose in cardiogenesis and the molecular mechanisms underlying heart diseases associated with hyperglycemia.

Introduction: Using intraoperative computed tomography (iCT), we aimed to clarify the course of the esophagus and pharynx during anterior cervical spine surgery to estimate the risk of intraoperative injury. Methods: Sixteen patients who underwent anterior cervical spine surgery with intraoperative CT for registration of a navigation system without release of blade retraction were included. To investigate the status of the retracted esophagus and pharynx, the distance between the nasogastric tube and center of the vertebra (NVD) was measured at each disc and vertebral level (C4-7) using axial CT. The location of the cricoid cartilage, which may affect the shift of the esophagus and pharynx, was noted. Presence or absence of contact between the esophagus and the edge of the surgical blade was investigated. Results: The NVDs were 28.0, 28.3, 28.9, 27.2, 24.7, 19.9, and 13.8 mm at C4, C4/5, C5, C5/6, C6, C6/7, and C7, respectively; NVDs at C6/7 or more caudal levels were significantly shorter than those at C6 or more cranial levels (P < 0.001). The cricoid cartilage was observed at the C4-C5/6 level. Esophageal contact with the edge of the blade was observed in nine cases at C6 or more caudal levels. Conclusions: The esophagus, which was placed at C6 or more caudal levels, was directly retracted by the blade. Nevertheless, the pharynx, which was placed at C6 or more cranial levels, was mostly retracted with the cricoid cartilage. Thus, the risk of direct esophageal injury was higher at C6 or more caudal levels than at cranial levels.

A four-year atmospheric exposure test was performed on steel with a Zn–30 mass%Al thermal-sprayed coating using an accelerated atmospheric exposure test, and then the atmospheric corrosion properties were evaluated. X-ray diffraction results showed that the corrosion products formed on the coating owing to the accelerated atmospheric exposure test were the same as those formed in a typical atmospheric exposure test. The corrosion weight loss of the thermally sprayed coatings in the accelerated atmospheric exposure test was promoted by approximately 1.5 to 2.0 times compared to the atmospheric exposure test. This Paper was Originally Published in Japanese in Zairyo-to-Kankyo 68 (2019) 187–193.

Background Controversy exists regarding surgical treatment of high-grade spondylolisthesis (HGS) in terms of decompression with surgical reduction or in situ fusion. In situ fusion has the advantage of being less technically demanding. However, the residual bone graft area is extremely limited, and posterolateral bone grafting is complex as the transverse process of the slipped vertebrae is located anterior to the sacral ala, which correlates with high rates of pseudoarthrosis. Methods Four cases of L5/S1 HGS complaining of low back pain were treated using our new bone graft technique with an exposed osseous end plate. Transdiskal screw holes were made from the S1 pedicle, and bone chips were packed into the L5/S disk space through the screw holes. The slipped L5 vertebra was fixed with a combination of L5/S1 transdiskal and L5 pedicle screws. Results All cases exhibited good bony fusion, and the low back pain disappeared in all patients up to the 12-month follow-up. This technique involved packing the bone into the closed space, relieving any concerns regarding bone graft migration. Conclusions Transpedicular bone graft via transdiskal screw holes is an easy and practical technique for raising the fusion rate in surgical treatment of HGS.

Background: This retrospective study was conducted to evaluate the safety and efficacy of ambrisentan combination therapy with phosphodiesterase type 5 (PDE5) inhibitors in Japanese patients with pulmonary arterial hypertension (PAH). Methods and Results: PAH patients who received ambrisentan for the first time in combination with a PDE5 inhibitor between January 2013 and the end of August 2015 were included in this study. Adverse drug reaction (ADR) safety analysis, as well as the efficacy analysis focusing on changes in clinical parameters, were investigated for overall cases and cases stratified by patient background. Forty-eight consecutive patients (n=21, 43.8% with idiopathic PAH; male/female, 18/30; average age, 43.3±17.4 years; World Health Organization functional class III/IV, n=22, 45.8%) who were treated with ambrisentan and a PDE5 inhibitor in Japan underwent the safety analysis. A total of 14 ADR occurred in 10 patients (20.8%). ADR included headache (8.3%), face edema (4.2%), angina pectoris (2.1%), hyperemia (2.1%), dyspnea (2.1%), pulmonary hypertension (i.e., worsening of PAH, 2.1%), nausea (2.1%), hepatic function abnormal (2.1%), edema (2.1%), and sudden death (2.1%). On analysis of hemodynamics parameters, there was a significant improvement in the mean pulmonary arterial pressure (-13.5 mmHg, P=0.0001) and pulmonary vascular resistance (-563.53 dyn·s·cm-5, P=0.0033). Conclusions: Ambrisentan combination therapy is safe and effective in hemodynamics improvement.

Diabetes mellitus (DM) can cause left ventricular (LV) diastolic dysfunction, leading to heart failure with preserved ejection fraction (HFpEF). Dipeptidyl peptidase IV (DPP-IV) inhibitors have failed to reduce hospitalization due to HF in type 2 DM (T2D) patients in a large-scale clinical trial, despite their cardiovascular protective effects. Therefore, it is important to investigate whether DPP-IV inhibitors can improve LV diastolic dysfunction in T2D patients. The aim of the study was to evaluate whether teneligliptin, the strongest of the DPP-IV inhibitors, improves LV dysfunction or prevents the worsening of LV diastolic function in T2D patients. The TOPLEVEL study is designed as an open-labeled, marker-stratified randomized, parallel-group comparison, standard treatment-controlled multicenter study. TOPLEVEL includes two marker-defined subgroups to give treatment recommendations for T2D patients with normal (E/e′

Introduction: Approximately 3% of osteoporotic vertebral fractures develop osteoporotic vertebral collapse (OVC) with neurological deficits, and such patients are recommended to be treated surgically. However, a proximal junctional fracture (PJFr) following surgery for OVC can be a serious concern. Therefore, the aim of this study is to identify the incidence and risk factors of PJFr following fusion surgery for OVC. Methods: This study retrospectively analyzed registry data collected from facilities belonging to the Japan Association of Spine Surgeons with Ambition (JASA) in 2016. We retrospectively analyzed 403 patients who suffered neurological deficits due to OVC below T10 and underwent corrective surgery; only those followed up for ≥2 years were included. Potential risk factors related to the PJFr and their cut-off values were calculated using multivariate logistic regression analysis and receiver operating characteristic (ROC) analysis. Results: Sixty-three patients (15.6%) suffered PJFr during the follow-up (mean 45.7 months). In multivariate analysis, the grade of osteoporosis (grade 2, 3: adjusted odds ratio (aOR) 2.92; p=0.001) and lower instrumented vertebra (LIV) level (sacrum: aOR 6.75; p=0.003) were independent factors. ROC analysis demonstrated that lumbar bone mineral density (BMD) was a predictive factor (area under curve: 0.72, p=0.035) with optimal cut-off value of 0.61 g/cm(2) (sensitivity, 76.5%; specificity, 58.3%), but that of the hip was not (p=0.228). Conclusions: PJFr was found in 16% cases within 4 years after surgery; independent risk factors were severe osteoporosis and extended fusion to the sacrum. The lumbar BMD with cut-off value 0.61 g/cm(2) may potentially predict PJFr. Our findings can help surgeons select perioperative adjuvant therapy, as well as a surgical strategy to prevent PJFr following surgery.