24 research outputs found
ALS mutations in the TIA-1 prion-like domain trigger highly condensed pathogenic structures
筋萎縮性側索硬化症(ALS)の発症機構の一端を解明 --タンパク質の高密度な凝縮構造が鍵--. 京都大学プレスリリース. 2022-09-13.T cell intracellular antigen-1 (TIA-1) plays a central role in stress granule (SG) formation by self-assembly via the prion-like domain (PLD). In the TIA-1 PLD, amino acid mutations associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) or Welander distal myopathy (WDM), have been identified. However, how these mutations affect PLD self-assembly properties has remained elusive. In this study, we uncovered the implicit pathogenic structures caused by the mutations. NMR analysis indicated that the dynamic structures of the PLD are synergistically determined by the physicochemical properties of amino acids in units of five residues. Molecular dynamics simulations and three-dimensional electron crystallography, together with biochemical assays, revealed that the WDM mutation E384K attenuated the sticky properties, whereas the ALS mutations P362L and A381T enhanced the self-assembly by inducing β-sheet interactions and highly condensed assembly, respectively. These results suggest that the P362L and A381T mutations increase the likelihood of irreversible amyloid fibrillization after phase-separated droplet formation, and this process may lead to pathogenicity
Effects of monthly intravenous ibandronate on bone mineral density and microstructure in patients with primary osteoporosis after teriparatide treatment: The MONUMENT study
Purpose: To investigate the effects of sequential therapy with monthly intravenous ibandronate on bone mineral density (BMD) and microstructure in patients with primary osteoporosis who received teriparatide treatment. Methods: Sixty-six patients with primary osteoporosis who had undergone teriparatide treatment for more than 12 months (mean 18.6 months) received sequential therapy with 1 mg/month intravenous ibandronate for 12 months. The patients were evaluated using dual-energy X-ray absorptiometry (DXA), quantitative ultrasound, bone turnover markers, and high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and 6 and 12 months after beginning administration. Results: At 12 months after beginning sequential therapy,the bone resorption marker, tartrate-resistant acid phosphatase-5b, decreased by 39.5%, with 82.3% of the patients exhibiting levels within the normal limit. DXA revealed that the BMD of the lumbar spine increased by 3.2%, with 79.0% of the patients exhibiting a response, and 40.3% experiencing an increase in BMD over 5%. HR-pQCT revealed that the cortical thickness of the distal tibia was increased by 2.6%. The cortical area increased by 2.5%, and the buckling ratio (an index of cortical instability) decreased by 2.5%. Most parameters of the trabecular bone showed no significant changes. These changes in the cortical bone were observed in both the distal radius and tibia and appeared beginning 6 months after treatment initiation. Conclusions: Sequential therapy with monthly intravenous ibandronate increased the BMD and improved the cortical bone microstructure of osteoporotic patients who had undergone teriparatide treatment
Randomized controlled trial of daily teriparatide, weekly high-dose teriparatide, or bisphosphonate in patients with postmenopausal osteoporosis: The TERABIT study
Purpose: The effects of daily teriparatide (20 μg) (D-PTH), weekly high-dose teriparatide (56.5 μg) (W-PTH), or bisphosphonates (BPs) on areal bone mineral density (aBMD), bone turnover markers (BTMs), volumetric BMD (vBMD), microarchitecture, and estimated strength were investigated in postmenopausal osteoporosis patients.Methods: The study participants were 131 women with a history of fragility fractures. They were randomized to receive D-PTH, W-PTH, or BPs (alendronate or risedronate) for 18 months. Dual-energy X-ray absorptiometry (DXA), BTMs, and high-resolution peripheral quantitative CT (HR-pQCT) parameters were evaluated at baseline and after 6 and 18 months of treatment. The primary endpoint was the change (%) in cortical thickness (Ct.Th) after 18 months\u27 treatment compared with baseline.Results: DXA showed that D-PTH, W-PTH, and BPs increased lumbar spine aBMD (+12.0%, +8.5%, and +6.8%) and total hip aBMD (+3.0%, +2.1%, and +3.0%), but D-PTH and W-PTH decreased 1/3 radius aBMD (− 4.1%, − 3.0%, − 1.4%) after 18 months. On HR-pQCT, D-PTH increased trabecular vBMD (Tb.vBMD) at the distal radius and tibia after 18 months (+6.4%, +3.7%) compared with the BPs group, decreased cortical volumetric tissue mineral density (Ct.vTMD) (− 1.8%, − 0.9%) compared with the other groups, increased Ct.Th (+1.3%, +3.9%), and increased failure load (FL) (+4.7%, +4.4%). W-PTH increased Tb.vBMD (+5.3%, +1.9%), maintained Ct.vTMD (− 0.7%, +0.2%) compared with D-PTH, increased Ct.Th (+0.6%, +3.6%), and increased FL (+4.9%, +4.5%). The BPs increased Tb.vBMD only in the radius (+2.0%, +0.2%), maintained Ct.vTMD (− 0.6%, +0.3%), increased Ct.Th (+0.5%, +3.4%), and increased FL (+3.9%, +2.8%).Conclusions: D-PTH and W-PTH comparably increased Ct.Th, the primary endpoint. D-PTH had a strong effect on trabecular bone. Although D-PTH decreased Ct.vTMD, it increased Ct.Th and total bone strength. W-PTH had a moderate effect on trabecular bone, maintained Ct.vTMD, and increased Ct.Th and total bone strength to the same extent as D-PTH
Fulminant Myocarditis 24 Days after Coronavirus Disease Messenger Ribonucleic Acid Vaccination
Fulminant Myocarditis 24 Days after Coronavirus Disease Messenger Ribonucleic Acid Vaccination
A 60-year-old Japanese woman was hospitalized for cardiogenic shock 24 days after receiving the second dose of the coronavirus disease 2019 BNT162b2 vaccine. Impella CP left ventricular assist device implantation and venoarterial peripheral extracorporeal membranous oxygenation were immediately initiated along with inotropic support and steroid pulse therapy, as an endomyocardial biopsy specimen showed myocarditis. Three weeks later, her cardiac function had recovered, and she was discharged. An immune response associated with the presence of spike protein in cardiac myocytes may be related to myocarditis in the present case because of positive immunostaining for severe acute respiratory syndrome coronavirus 2 spike protein and C4d in the myocardium
The Relationship between Circulating Polyunsaturated Fatty Acid Levels and Exercise Responses of Patients with Non-ischemic Heart Failure
Objective Polyunsaturated fatty acids (PUFAs) are associated with heart failure (HF) as well as coronary artery disease. However, little is known about the relationships between PUFAs and the exercise responses of patients with HF. We evaluated the relationships between PUFAs and the parameters of cardiopulmonary exercise tests (CPETs) in patients with non-ischemic HF. Methods Fifty patients with stable non-ischemic HF underwent CPETs at our hospital. Data were analyzed to evaluate the relationships between PUFAs and echocardiographic findings as well as CPET and other test parameters. Results Correlations were significant and negative between dihomo-γ-linolenic acid (DGLA) + arachidonic acid (AA) and minute ventilation versus carbon dioxide production (VE/VCO2) slope, and positive between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and VE/VCO2 slope. A multivariate regression analysis selected DGLA+AA and AA as independent predictors of VE/VCO2 slope. However, eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) were not significantly correlated with the CPET parameters. Conclusion Low levels of circulating DGLA+AA and AA among PUFAs were associated with decreased exercise responses in patients with stable non-ischemic HF. These findings suggest that high levels of omega-6 PUFAs may improve the clinical outcomes of patients with non-ischemic HF via their effects on exercise responses
Cardiogenic Shock due to Left Ventricular Outflow Obstruction and Complete Atrioventricular Block in a Patient with Hypertrophic Cardiomyopathy with Acute Myocarditis
A 67-year-old woman was referred to our hospital with a sudden syncopal attack. She suffered from cardiogenic shock due to left ventricular (LV) outflow stenosis with simultaneous complete atrioventricular (AV) block. An endomyocardial biopsy of the left ventricle demonstrated myocardial disarray and myocardial fibrous and edematous tissue with infiltration of mononuclear cells. Cardiac magnetic resonance imaging (cMRI) detected a damaged septal area that was likely associated with the conduction disturbance. The diagnosis was hypertrophic cardiomyopathy accompanied by acute myocarditis. Although the LV outflow stenosis was transient, the complete AV block was persistent, thus requiring permanent pacemaker implantation
The Relationship between Circulating Polyunsaturated Fatty Acid Levels and Exercise Responses of Patients with Non-ischemic Heart Failure
Objective Polyunsaturated fatty acids (PUFAs) are associated with heart failure (HF) as well as coronary artery disease. However, little is known about the relationships between PUFAs and the exercise responses of patients with HF. We evaluated the relationships between PUFAs and the parameters of cardiopulmonary exercise tests (CPETs) in patients with non-ischemic HF. Methods Fifty patients with stable non-ischemic HF underwent CPETs at our hospital. Data were analyzed to evaluate the relationships between PUFAs and echocardiographic findings as well as CPET and other test parameters. Results Correlations were significant and negative between dihomo-γ-linolenic acid (DGLA) + arachidonic acid (AA) and minute ventilation versus carbon dioxide production (VE/VCO2) slope, and positive between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and VE/VCO2 slope. A multivariate regression analysis selected DGLA+AA and AA as independent predictors of VE/VCO2 slope. However, eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) were not significantly correlated with the CPET parameters. Conclusion Low levels of circulating DGLA+AA and AA among PUFAs were associated with decreased exercise responses in patients with stable non-ischemic HF. These findings suggest that high levels of omega-6 PUFAs may improve the clinical outcomes of patients with non-ischemic HF via their effects on exercise responses
Cyclophosphamide-induced Cardiotoxicity with a Prolonged Clinical Course Diagnosed on an Endomyocardial Biopsy
A 31-year-old woman with primary mediastinal large B-cell lymphoma refractory to conventional chemotherapy was treated with high-dose chemotherapy containing cyclophosphamide (CY). Subsequently, she was treated with auto peripheral blood stem cell transplantation. Although a complete remission was obtained, heart failure developed two months later. Echocardiography showed an impaired systolic function with peri-cardial effusion. A biopsy of the endomyocardial region from the left ventricle demonstrated spotty myocar-dial hemorrhage and myocardial fibrosis with disruption and aggregation of mitochondrial cristae. Based on these findings, CY-induced cardiotoxicity was diagnosed. The patient was treated with conventional therapy for heart failure, which required approximately one year to improve her condition
Fulminant Myocarditis and Acute Appendicitis after COVID-19 Vaccination
A 19-year-old Japanese man was hospitalized for cardiogenic shock 28 days after receiving a second dose of the coronavirus disease 2019 (COVID-19) mRNA-1273 vaccine. He had had a high fever for three days with vomiting and abdominal pain before arriving at our hospital. The patient visited a local hospital and was diagnosed with heart failure and acute appendicitis. An endomyocardial biopsy specimen showed myocarditis. Thereafter, Impella CP left ventricular assist device implantation and venoarterial peripheral extracorporeal membranous oxygenation were initiated immediately along with inotropic support and steroid pulse therapy. Given these findings, he was finally diagnosed with multiple inflammatory syndrome and fulminant myocarditis