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Soy protein has shown remarkable effectiveness in reducing fat mass compared with other protein sources, and exercise has the potential to further enhance this fat loss effect. Previous studies have demonstrated that soy protein intake leads to decreased fatty acid synthesis, which contributes to its fat-loss properties. However, the exact mechanism by which these lipids are consumed remains unclear. To investigate this, we conducted a comprehensive study using C57/BL6 male mice, comparing the effects of soy and casein proteins with and without exercise (Casein-Sed, Casein-Ex, Soy-Sed, and Soy-Ex groups) under high- and low-protein conditions (14% or 40% protein). Our findings revealed that combining soy protein intake with exercise significantly reduced epididymal white adipose tissue (eWAT) weight, particularly in the high-protein diet group. Further analysis revealed that exercise increased the expression of lipid oxidation-regulatory proteins, including mitochondrial oxidative phosphorylation protein (OXPHOS) complexes, in the plantaris muscle regardless of the protein source. Although soy protein intake did not directly affect muscle mitochondrial protein expression, the activity of OXPHOS complex I was additively enhanced by exercise and soy protein under the 40% protein condition. Notably, complex I activity inversely correlated with eWAT weight in the soy protein diet group. These results highlight the potential link between improved complex I activity induced by soy protein and fat mass reduction, which emphasizes the promising benefits of combining soy protein with exercise in promoting fat loss.NEW & NOTEWORTHY The findings revealed that soy protein intake combined with exercise resulted in reduced adipose tissue weight compared with that obtained with casein protein intake. Furthermore, the joint impact of exercise and soy protein consumption resulted in enhanced activity of oxidative phosphorylation protein (OXPHOS) complex I in fast-twitch muscles, which appears to be associated with fat mass reduction. These findings elucidate the potential additive effects of soy protein and exercise on body weight management.
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Caseínas , Proteínas de Soja , Masculino , Ratones , Animales , Proteínas de Soja/farmacología , Proteínas de Soja/metabolismo , Caseínas/metabolismo , Caseínas/farmacología , Grasa Intraabdominal , Dieta , Músculo Esquelético/metabolismo , Ingestión de Alimentos/fisiologíaRESUMEN
We describe the case of a 74-year-old man with severe aplastic anaemia who experienced persistent remission attributed to proliferation of HLA allele-deficient clones. Despite an initial worsening of pancytopenia with eltrombopag and ciclosporin treatment, gradual trilineage haematopoietic recovery occurred, with blood counts normalizing over 3 years. Flow cytometry and deep nucleotide sequencing revealed that haematopoiesis was primarily supported by several clones with somatic mutations that inactivated antigen presentation via HLA-A*0206. This suggests that monitoring haematopoietic regeneration by immune escape clones could be an alternative approach for immune aplastic anaemia patients who possess HLA allele-deficient clones and cannot tolerate standard therapy.
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BACKGROUND: Residents in nursing homes are prone to cognitive decline affecting memory, visuospatial cognition, and executive functions. Cognitive decline can lead to dementia, necessitating prioritized intervention. METHODS: The current study aimed to investigate whether an intervention using a digital game was effective for preserving and improving the cognitive function of residents in nursing homes. An intervention study was conducted using a single-case AB design with multiple baselines. The participants in the study were five older adults aged 65 and over who do not play digital games regularly. The study ran for 15 weeks, including a baseline (phase A) and an intervention phase (phase B). Phase A had five baselines (5 to 9 weeks) with random participant assignment. In phase B, participants engaged in a digital game (Space Invaders) individually. Cognitive function was assessed as the outcome, measured using the Brain Assessment (performed on a tablet through the Internet) at 16 measurement points. Four of five participants (two female and two male) were included in the analysis, using visual inspection and Bayesian statistics with multi-level modeling. RESULTS: Visual inspection of the graphs revealed cognitive function score improvements after the intervention for most layers in terms of memory of numbers, memory of words, mental rotation test (visuospatial ability), and total scores in the Brain Assessment. These effects were also significant in the analysis by multi-level modeling. CONCLUSIONS: The results suggest that the use of digital games may be effective for preserving and improving cognitive function among residents of nursing home. TRIAL REGISTRATION: This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000048677; public title: Effect of a Digital Game Intervention for Cognitive Functions in Older People; registration date: August 30, 2022).
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Cognición , Disfunción Cognitiva , Casas de Salud , Juegos de Video , Humanos , Masculino , Femenino , Juegos de Video/psicología , Anciano , Anciano de 80 o más Años , Cognición/fisiología , Disfunción Cognitiva/terapia , Disfunción Cognitiva/psicología , Estudios de Casos Únicos como Asunto , Hogares para AncianosRESUMEN
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal thrombotic microangiopathy caused by autoantibody-mediated severe deficiency of ADAMTS13. Standardized definitions of response, exacerbation, remission, and relapse were initially proposed in 2003 and modified by the International Working Group for TTP in 2017. These definitions, which have been widely used in clinical practice and research, are based primarily on the platelet count and are benchmarked against the timing of discontinuation of therapeutic plasma exchange (TPE). They do not incorporate ADAMTS13 activity or the temporizing effects on the platelet count of caplacizumab, a novel anti-von Willebrand factor (VWF) nanobody. In light of these limitations, the IWG aimed to develop revised consensus outcome definitions that incorporate ADAMTS13 activity and the effects of anti-VWF therapy, by using an estimate-talk-estimate approach. The updated definitions distinguish clinical remission and clinical relapse (defined primarily by platelet count) from ADAMTS13 remission and ADAMTS13 relapse (defined by ADAMTS13 activity). The revised definitions of exacerbation and remission are benchmarked against not only the timing of discontinuation of TPE but also that of anti-VWF therapy. Retrospective validation of the revised definitions is described, although they have yet to be prospectively validated. Clinical implications of the updated outcome definitions are also discussed and an example of their application to clinical practice is provided to highlight their clinical relevance.
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Púrpura Trombocitopénica Trombótica/terapia , Proteína ADAMTS13/análisis , Adulto , Consenso , Manejo de la Enfermedad , Femenino , Fibrinolíticos/uso terapéutico , Humanos , Intercambio Plasmático , Recuento de Plaquetas , Púrpura Trombocitopénica Trombótica/sangre , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/patología , Recurrencia , Anticuerpos de Dominio Único/uso terapéutico , Resultado del Tratamiento , Factor de von Willebrand/antagonistas & inhibidoresRESUMEN
The neuronal nitric oxide synthase (nNOS; encoded by NOS1)-derived nitric oxide (NO) plays an important role in maintaining skeletal muscle mass. In adult skeletal muscle, nNOS localizes to the cell membrane, cytosol, and nucleus, and regulates muscle hypertrophy and atrophy in various subcellular fractions. However, its role in muscle stem cells (also known as muscle satellite cells), which provide myonuclei for postnatal muscle growth, maintenance, and regeneration, remains unclear. The present study aimed to determine nNOS expression in muscle satellite cell-derived primary myoblasts during differentiation and its DNA methylation levels, an epigenetic modification that controls gene expression. Undifferentiated and differentiated satellite cell-derived primary myoblasts were found to express nNOS. Immunohistochemical analysis revealed that nNOS colocalized with Pax7 (satellite cell marker) only in the undifferentiated myoblasts. Furthermore, nNOS immunoreactivity spread to the cytosol of Pax7-negative differentiated myotube-like cells. The level of Nos1µ mRNA, the main isoform of skeletal muscle nNOS, was increased in differentiated satellite cell-derived primary myoblasts compared to that in the undifferentiated cells. However, Nos1 methylation levels remained unchanged during differentiation. These findings suggest that nNOS induction and the appropriate transition of its subcellular localization may contribute to muscle differentiation.
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Óxido Nítrico Sintasa de Tipo I , Células Satélite del Músculo Esquelético , Humanos , Diferenciación Celular/fisiología , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo I/metabolismo , Células Satélite del Músculo Esquelético/metabolismoRESUMEN
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare autoimmune disorder caused by neutralizing anti-ADAMTS13 autoantibodies. In white individuals, HLA allele DRB1*11 is a predisposing factor for iTTP, whereas DRB1*04 is a protective factor. However, the role of HLA in Asians is unclear. In this study, we analyzed 10 HLA loci using next-generation sequencing in 52 Japanese patients with iTTP, and the allele frequency in the iTTP group was compared with that in a Japanese control group. We identified the following HLA alleles as predisposing factors for iTTP in the Japanese population: DRB1*08:03 (odds ratio [OR], 3.06; corrected P [Pc] = .005), DRB3/4/5*blank (OR, 2.3; Pc = .007), DQA1*01:03 (OR, 2.25; Pc = .006), and DQB1*06:01 (OR,: 2.41; Pc = .003). The estimated haplotype consisting of these 4 alleles was significantly more frequent in the iTTP group than in the control group (30.8% vs 6.0%; Pc < .001). DRB1*15:01 and DRB5*01:01 were weak protective factors for iTTP (OR, 0.23; Pc = .076; and OR, 0.23, Pc = .034, respectively). On the other hand, DRB1*11 and DRB1*04 were not associated with iTTP in the Japanese. These findings indicated that predisposing and protective factors for iTTP differ between Japanese and white individuals. HLA-DR molecules encoded by DRB1*08:03 and DRB1*11:01 have different peptide-binding motifs, but interestingly, bound to the shared ADAMTS13 peptide in an in silico prediction model.
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Proteína ADAMTS13/fisiología , Pueblo Asiatico/genética , Antígenos HLA-DR/genética , Púrpura Trombocitopénica Trombótica/genética , Alelos , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Simulación por Computador , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Antígenos HLA-DR/inmunología , Antígenos HLA-DR/metabolismo , Haplotipos , Secuenciación de Nucleótidos de Alto Rendimiento , Prueba de Histocompatibilidad , Humanos , Japón/epidemiología , Masculino , Modelos Moleculares , Fragmentos de Péptidos/metabolismo , Conformación Proteica , Mapeo de Interacción de Proteínas , Púrpura Trombocitopénica Trombótica/etnología , Púrpura Trombocitopénica Trombótica/inmunologíaRESUMEN
Running exercise has beneficial effects on brain health. However, the effects of relatively short-term running exercise (STEx) on behavior, and its underlying signaling pathways, are poorly understood. In this study, we evaluated the possibility that the regulation by STEx of brain-derived neurotrophic factor (BDNF) and neuronal nitric oxide synthase (nNOS, encoded by NOS1), which are important molecules for anxiety regulation, might involve mechanisms of epigenetic modification, such as DNA methylation. C57BL/6J male mice were divided into sedentary (SED, n = 12) and STEx (EX, n = 15) groups; STEx was conducted with the mice for a duration of 11 days. STEx reduced anxiety-like behaviors, and STEx reduced Nos1α and increased Bdnf exon I and IV mRNA levels in the hippocampus. Interestingly, behavioral parameters were associated with Bdnf exon I and IV and Nos1α mRNA levels in the ventral, but not dorsal, hippocampal region. However, STEx had no effect on peroxisome proliferator-activated receptor-γ coactivator 1α (Pgc-1α) or fibronectin type III domain-containing 5 (Fndc5) mRNA levels, which are relatively long-term exercise-induced upstream regulators of BDNF. In parallel with gene expression changes, we found, for the first time, that STEx downregulated Bdnf promoter IV and upregulated Nos1 DNA methylation levels in the hippocampus, and these patterns were partially different between the dorsal and ventral regions. These findings suggest that the beneficial effects of running exercise on mood regulation may be controlled by alterations in epigenetic mechanisms, especially in the ventral hippocampus. These effects occur even after a relatively short-term period of exercise.
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Ansiedad/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Condicionamiento Físico Animal/fisiología , Carrera/fisiología , Tejido Adiposo , Animales , Conducta Animal , Composición Corporal , Peso Corporal , Factor Neurotrófico Derivado del Encéfalo/genética , Metilación de ADN , Fibronectinas/genética , Fibronectinas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo I/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Distribución Aleatoria , Factores de TiempoRESUMEN
Thrombotic thrombocytopenic purpura (TTP) is an extremely rare and fatal thrombotic disorder characterized by impaired enzyme activity of von Willebrand factor cleaving protease, also known as ADAMTS13. Immune-mediated TTP (iTTP) is an acquired form of TTP caused by the production of auto-antibodies against ADAMTS13. The pathophysiology of autoimmune disorders is multifactorial, with several human leukocyte antigen (HLA) alleles identified as a genetic risk factor for autoimmune diseases known as susceptible HLA. In the early 2010s, three distinct European groups revealed that DRB1*11 is one of the most susceptible alleles in acquiring iTTP among Caucasians based on HLA typing data. Several in silico predictions for allele-restricted ADAMTS13 epitopes against T cells are made in this context, followed by an in vitro validation employing mass spectrometry using eluted peptides and T-cell assays. However, similar analyses in a genetically distinct Japanese population have not yet been conducted. We used next-generation sequencing to perform HLA typing for 52 Japanese patients with iTTP from 19 institutes. Our detailed analysis revealed that the specific allele DRB1*08:03 was identified as a genetic risk factor for iTTP in Japanese patients, but there were no statistically significant differences in the allele frequency of DRB1*11 between iTTP and healthy controls.
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Púrpura Trombocitopénica Trombótica , Alelos , Susceptibilidad a Enfermedades/complicaciones , Prueba de Histocompatibilidad/efectos adversos , Humanos , Púrpura Trombocitopénica Trombótica/genética , Factores de RiesgoRESUMEN
Neuropsychiatric symptoms comprise one of the five classic symptoms of autoimmune thrombotic thrombocytopenic purpura (aTTP). Although aTTP is typically transient, it is sometimes complicated by cerebral infarction with residual disability. This report presents the case of an 87-year-old man previously admitted to a different hospital with fever and transient consciousness loss. After receiving platelet transfusion with diagnosis of Evans syndrome, he was transferred to our hospital with worsening consciousness disturbance. He was subsequently diagnosed with aTTP with a PLASMIC score of 6 points, ADAMTS13 activity of less than 0.5%, and its inhibitor of 7.4 BU/ml. Platelet count and consciousness were rapidly improved with plasmapheresis and steroids, but motor aphasia emerged. MRI showed multiple cerebral infarctions, including a large infarction in the left frontal lobe. Thus, unfractionated heparin was administered. When his platelet count dropped once again on the 20th day, rituximab was added. The treatment eventually proved to be successful, and his aTTP remained in remission one year after the onset. Treatment for cerebral infarctions was switched to DOAC, and rehabilitation was continued. However, his ADL has not yet recovered. Advances in aTTP treatment have cured many similar cases. Thus, rituximab is now considered a treatment option for refractory cases. However, ischemic organ damage in acute phase and sequelae are observed. Therefore, early diagnosis and novel therapy are required.
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Púrpura Trombocitopénica Trombótica , Proteína ADAMTS13 , Anciano de 80 o más Años , Infarto Cerebral/diagnóstico por imagen , Infarto Cerebral/tratamiento farmacológico , Infarto Cerebral/etiología , Heparina , Humanos , Masculino , Intercambio Plasmático , Púrpura Trombocitopénica Trombótica/complicaciones , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Rituximab/uso terapéuticoRESUMEN
Congenital thrombotic thrombocytopenic purpura (cTTP), known as Upshaw-Schulman syndrome, is an ultrarare thrombotic disorder caused by ADAMTS13 gene mutations; however, its long-term outcomes have not been widely studied. A questionnaire survey was administered to physicians of patients in the Japanese cTTP registry to characterise these outcomes. We analysed 55 patients in remission, with 41 cases receiving prophylactic fresh frozen plasma (FFP; median dosage: 13·2 ml/kg per month) and 14 receiving on-demand FFP. Patients receiving prophylactic FFP were considered as having a more severe form of the disease and had lower platelet counts and higher serum creatinine levels than those receiving on-demand FFP (median 138 × 109 /l vs. 243 × 109 /l, P = 0·003 and 0·71 mg/dl vs 0·58 mg/dl, P = 0·009, respectively). Patients who received prophylactic FFP more commonly developed organ damage, including renal impairment, cerebral infarctions, and cardiac hypofunction, than those who did not. Adverse FFP-related events were seen in 78% of the prophylactic FFP group, with allergic reactions being most common. Since current protocols for FFP administration to the prophylactic FFP group in Japan may be insufficient for preventing cumulative organ damage, a higher dosage of ADAMTS13 supply using recombinant ADAMTS13 agent is needed in these patients.
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Transfusión de Componentes Sanguíneos , Púrpura Trombocitopénica Trombótica/terapia , Proteína ADAMTS13/genética , Adolescente , Adulto , Transfusión de Componentes Sanguíneos/efectos adversos , Niño , Estudios de Cohortes , Femenino , Humanos , Japón/epidemiología , Masculino , Mutación , Puntuaciones en la Disfunción de Órganos , Plasma/química , Púrpura Trombocitopénica Trombótica/epidemiología , Púrpura Trombocitopénica Trombótica/genética , Adulto JovenRESUMEN
BACKGROUND: Coronavirus disease 2019 (COVID-19) pneumonitis associated with severe respiratory failure is associated with high mortality. The pathogenesis of COVID-19 is associated with microembolism or microvascular endothelial injuries. Here, we report that syndecan-1 (SDC-1), a component of the endothelial glycocalyx, may be a biomarker of severity classification for COVID-19 related to endothelial injury. METHODS AND ANALYSIS: We analyzed the data of COVID-19 patients for 1 year from February 2020 at Yokohama City University Hospital and Yokohama City University Medical Center Hospital. We selected COVID-19 patients who required admission care, including intensive care, and analyzed the classification of severe and critical COVID-19 retrospectively, using various clinical data and laboratory data with SDC-1 by ELISA. RESULTS: We analyzed clinical and laboratory data with SDC-1 in five severe COVID-19 and ten critical COVID-19 patients. In the two groups, their backgrounds were almost the same. In laboratory data, the LDH, CHE, and CRP levels showed significant differences in each group (P = 0.032, P < 0.0001, and P = 0.007, respectively) with no significant differences in coagulation-related factors (platelet, PT-INR, d-dimer, ISTH score; P = 0.200, 0.277, 0.655, and 0.36, respectively). For the clinical data, the SOFA score was significantly different from admission day to day 14 of admission (p < 0.0001). The SDC-1 levels of critical COVID-19 patients were significantly higher on admission day and all-time course compared with the levels of severe COVID-19 patients (P = 0.009 and P < 0.0001, respectively). CONCLUSIONS: Temporal change of SDC-1 levels closely reflect the severity of COVID-19, therefore, SDC-1 may be a therapeutic target and a biomarker for the severity classification of Covid-19.
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INTRODUCTIONS: Patients with acquired thrombotic thrombocytopenic purpura (TTP) show no severe abnormalities in coagulation or fibrinolysis. However, the exact extent of the abnormalities is unclear. MATERIALS AND METHODS: This study analyzed 138 patients with acquired TTP and 46 patients with septic disseminated intravascular coagulation (DIC) who were included in a Japanese registry. Complete blood cell counts and 8 coagulation or fibrinolysis parameters were compared between the 2 groups. RESULTS: Platelet counts in the acquired TTP group were significantly lower than those in the septic DIC group (P < .001). The international normalized ratio of prothrombin time and the activated partial thromboplastin time in the septic DIC group were significantly higher and longer, respectively, than those in the acquired TTP group (P < .01). The antithrombin (AT) values were significantly lower in the septic DIC group than in the acquired TTP group (P < .001), the latter of which were almost normal. Although both groups revealed elevations of fibrinogen degradation product (FDP) and D-dimer, these levels were significantly higher in the septic DIC group than in the acquired TTP group (P < .001). Of 138 patients with acquired TTP, 25 (18.1%) were diagnosed with septic DIC by the diagnostic criteria of the Japanese Ministry Health, Labour and Welfare, and 78 (56.5%) by those of the Japanese Association of Acute Medicine. Receiver operating characteristic curve analysis showed that acquired TTP could be diagnosed based on severe thrombocytopenia (<20 × 109/L), normal AT level (>87%), and mildly elevated FDP (<23 µg/mL). CONCLUSIONS: Our results indicate that 3 routine laboratory tests could differentiate between acquired TTP and septic DIC.
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Coagulación Sanguínea , Coagulación Intravascular Diseminada , Fibrinólisis , Púrpura Trombocitopénica Trombótica , Antitrombinas/sangre , Diagnóstico Diferencial , Coagulación Intravascular Diseminada/sangre , Coagulación Intravascular Diseminada/diagnóstico , Humanos , Tiempo de Tromboplastina Parcial , Tiempo de Protrombina , Púrpura Trombocitopénica Trombótica/sangre , Púrpura Trombocitopénica Trombótica/diagnósticoRESUMEN
This paper reviews the presence, localization and characteristics of state-specific neurons in the mouse forebrain, midbrain and hindbrain that are involved in the control of ultradian sleep-wake cycles and shows that all these regions contain basic neural elements capable of generating the sleep-wake cycle. The chronic single-unit recording method in unanaesthetized animals is useful for unravelling the dynamics of sleep-wake switching, in particular because it can analyse events at the level of single neurons, thereby decoding information used by the brain in determining its functional state. A prerequisite is to record a large number of all types of neurons, identify critical wake- and sleep-promoting neurons and determine their activity profiles during the sleep-wake cycle and their trends in spike activity during the state transitions from wakefulness to sleep and from sleep to wakefulness in the same species. Here, I argue that single-unit recordings in unanaesthetized mice help us to (a) determine key neural elements controlling sleep-wake dynamics, (b) elucidate the roles of forebrain and brainstem neurons in ultradian sleep-wake cyclicity and (c) gain a new insight into the functional significance of wakefulness, slow-wave sleep and paradoxical (or rapid eye movement) sleep. I also discuss the merits and limitations of single-unit recording compared with more recent genetic approaches, and I suggest that findings from studies using the classic electrophysiological technique will provide the foundation for future studies using new genetic techniques to dissect the neural networks responsible for the initiation, maintenance and cessation of each wake and sleep state.
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Sueño de Onda Lenta , Vigilia , Animales , Tronco Encefálico , Ratones , Sueño , Sueño REMRESUMEN
von Willebrand factor (VWF) is a blood glycoprotein that plays an important role in platelet thrombus formation through interaction between its A1 domain and platelet glycoprotein Ib. ARC1779, an aptamer to the VWF A1 domain, was evaluated in a clinical trial for acquired thrombotic thrombocytopenic purpura (aTTP). Subsequently, caplacizumab, an anti-VWF A1 domain nanobody, was approved for aTTP in Europe and the United States. We recently developed a novel DNA aptamer, TAGX-0004, to the VWF A1 domain; it contains an artificial base and demonstrates high affinity for VWF. To compare the effects of these three agents on VWF A1, their ability to inhibit ristocetin- or botrocetin-induced platelet aggregation under static conditions was analyzed, and the inhibition of thrombus formation under high shear stress was investigated in a microchip flow chamber system. In both assays, TAGX-0004 showed stronger inhibition than ARC1779, and had comparable inhibitory effects to caplacizumab. The binding sites of TAGX-0004 and ARC1779 were analyzed with surface plasmon resonance performed using alanine scanning mutagenesis of the VWF A1 domain. An electrophoretic mobility shift assay showed that R1395 and R1399 in the A1 domain bound to both aptamers. R1287, K1362, and R1392 contributed to ARC1779 binding, and F1366 was essential for TAGX-0004 binding. Surface plasmon resonance analysis of the binding sites of caplacizumab identified five amino acids in the VWF A1 domain (K1362, R1392, R1395, R1399, and K1406). These results suggested that TAGX-0004 possessed better pharmacological properties than caplacizumab in vitro and might be similarly promising for aTTP treatment.
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Aptámeros de Nucleótidos , Trombosis , Europa (Continente) , Humanos , Complejo GPIb-IX de Glicoproteína Plaquetaria/genética , Anticuerpos de Dominio Único , Trombosis/tratamiento farmacológico , Factor de von Willebrand/genéticaRESUMEN
We investigated the clinical course of individuals with 2019 novel coronavirus disease (COVID-19) who were transferred from the Diamond Princess cruise ship to 12 local hospitals. The conditions and clinical courses of patients with pneumonia were compared with those of patients without pneumonia. Among 70 patients (median age: 67 years) analyzed, the major symptoms were fever (64.3%), cough (54.3%), and general fatigue (24.3%). Forty-three patients (61.4%) had pneumonia. Higher body temperature, heart rate, and respiratory rate as well as higher of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and C-reactive protein (CRP) levels and lower serum albumin level and lymphocyte count were associated with the presence of pneumonia. Ground-glass opacity was found in 97.7% of the patients with pneumonia. Patients were administered neuraminidase inhibitors (20%), lopinavir/ritonavir (32.9%), and ciclesonide inhalation (11.4%). Mechanical ventilation and veno-venous extracorporeal membrane oxygenation was performed on 14 (20%) and 2 (2.9%) patients, respectively; two patients died. The median duration of intubation was 12 days. The patients with COVID-19 transferred to local hospitals during the outbreak had severe conditions and needed close monitoring. The severity of COVID-19 depends on the presence of pneumonia. High serum LDH, AST and CRP levels and low serum albumin level and lymphocyte count were found to be predictors of pneumonia. It was challenging for local hospitals to admit and treat these patients during the outbreak of COVID-19. Assessment of severity was crucial to manage a large number of patients.
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Betacoronavirus , Infecciones por Coronavirus/fisiopatología , Infecciones por Coronavirus/terapia , Brotes de Enfermedades , Neumonía Viral/fisiopatología , Neumonía Viral/terapia , Anciano , COVID-19 , Infecciones por Coronavirus/complicaciones , Complicaciones de la Diabetes/complicaciones , Femenino , Humanos , Hipertensión/complicaciones , Japón , Masculino , Persona de Mediana Edad , Pandemias , Gravedad del Paciente , Neumonía Viral/complicaciones , Neumonía Viral/virología , Pronóstico , SARS-CoV-2 , NavíosRESUMEN
KEY POINTS: DNA methylation may play an important role in regulating gene expression in skeletal muscle to adapt to physical activity and inactivity. Neuronal nitric oxide synthase (nNOS) in skeletal muscle is a key regulator of skeletal muscle mass; however, it is unclear whether nNOS expression is regulated by DNA methylation. We found that 1 week of cast immobilization increased nNOS DNA methylation levels and downregulated nNOS gene expression in atrophic slow-twitch soleus muscle from the mouse leg. These changes were not detected in non-atrophic fast-twitch extensor digitorum longus muscle. Twelve hours of cast immobilization decreased nNOS gene expression, whereas nNOS DNA methylation levels were unchanged, suggesting that downregulation of nNOS gene expression by short-term muscle inactivity is independent of the DNA methylation pattern. These findings contribute to a better understanding of the maintenance of skeletal muscle mass and prevention of muscle atrophy by epigenetic mechanisms via the nNOS/NO pathway. ABSTRACT: DNA methylation is a mechanism that controls gene expression in skeletal muscle under various environmental stimuli, such as physical activity and inactivity. Neuronal nitric oxide synthase (nNOS) regulates muscle atrophy in skeletal muscle. However, the mechanisms regulating nNOS expression in atrophic muscle remain unclear. We hypothesized that nNOS expression in atrophic muscle is regulated by DNA methylation of the nNOS promotor in soleus (Sol; slow-twitch fibre dominant) and extensor digitorum longus (EDL; fast-twitch fibre dominant) muscles. One week of cast immobilization induced significant muscle atrophy in Sol but not in EDL. We showed that 1 week of cast immobilization increased nNOS DNA methylation levels in Sol, although only a minor change was detected in EDL. Consistent with the increased DNA methylation levels in atrophic Sol, the gene expression levels of total nNOS and nNOSµ (i.e. the major splicing variant of nNOS in skeletal muscle) decreased. The abundance of the nNOS protein and cell membrane (especially type IIa fibre) immunoreactivity also decreased in atrophic Sol. These changes were not observed in EDL after 1 week of cast immobilization. Furthermore, despite the lack of significant atrophy, 12 h of cast immobilization decreased gene expression levels of total nNOS and nNOSµ in Sol. However, no association was detected between nNOS DNA methylation and gene expression. The expression of the nNOSß gene, another splicing variant of nNOS, in EDL was unchanged by cast immobilization, whereas its expression was not detected in Sol. We concluded that chronic adaptation of nNOS gene expression in cast immobilized muscle may involve nNOS DNA methylation.
Asunto(s)
Metilación de ADN/genética , Músculo Esquelético/fisiología , Óxido Nítrico Sintasa de Tipo I/genética , Regiones Promotoras Genéticas/genética , Animales , Membrana Celular/genética , Expresión Génica/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Fibras Musculares de Contracción Rápida/fisiología , Fibras Musculares de Contracción Lenta/fisiología , Atrofia Muscular/genéticaRESUMEN
Congenital thrombotic thrombocytopenic purpura is an autosomal recessive inherited disease with a clinically heterogeneous course and an incompletely understood genotype-phenotype correlation. In 2006, the Hereditary TTP Registry started recruitment for a study which aimed to improve the understanding of this ultra-rare disease. The objective of this study is to present characteristics of the cohort until the end of 2017 and to explore the relationship between overt disease onset and ADAMTS13 activity with emphasis on the recurring ADAMTS13 c.4143_4144dupA mutation. Diagnosis of congenital thrombotic thrombocytopenic purpura was confirmed by severely deficient ADAMTS13 activity (≤10% of normal) in the absence of a functional inhibitor and the presence of ADAMTS13 mutations on both alleles. By the end of 2017, 123 confirmed patients had been enrolled from Europe (n=55), Asia (n=52, 90% from Japan), the Americas (n=14), and Africa (n=2). First recognized disease manifestation occurred from around birth up to the age of 70 years. Of the 98 different ADAMTS13 mutations detected, c.4143_4144dupA (exon 29; p.Glu1382Argfs*6) was the most frequent mutation, present on 60 of 246 alleles. We found a larger proportion of compound heterozygous than homozygous carriers of ADAMTS13 c.4143_4144dupA with overt disease onset at < 3 months of age (50% vs 37%), despite the fact that ADAMTS13 activity was <1% in 18 of 20 homozygous, but in only 8 of 14 compound heterozygous carriers. An evaluation of overt disease onset in all patients with an available sensitive ADAMTS13 activity assay (n=97) shows that residual ADAMTS13 activity is not the only determinant of age at first disease manifestation. Registered at clinicaltrials.gov identifier NCT01257269.
Asunto(s)
Proteína ADAMTS13 , Alelos , Heterocigoto , Homocigoto , Mutación , Púrpura Trombocitopénica Trombótica , Proteína ADAMTS13/sangre , Proteína ADAMTS13/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Trombótica/enzimología , Púrpura Trombocitopénica Trombótica/genéticaRESUMEN
The medullary reticular formation (RF) is involved in the maintenance of several vital physiological functions and level of vigilance. In this study, in nonanesthetised, head-fixed mice, I examined the role of medullary RF neurons in the control of sleep-wake states, that is, wakefulness (W), slow-wave sleep (SWS) and paradoxical (or rapid eye movement) sleep (PS). I showed, for the first time, that the mouse medullary RF contains presumed SWS-promoting, SWS-on neurons that remain silent during W, display a sharp increase in discharge rate at sleep onset, and discharge tonically and selectively during SWS. In addition, I showed the presence in the medullary RF of both PS-on and PS-off neurons, which, respectively, commence discharging or cease firing selectively just prior to, and during, PS. PS-off neurons were located in the raphe nuclei and ventral medulla, while PS-on neurons were found in both the lateral part of the ventral gigantocellular reticular nucleus and the raphe nuclei, as were SWS-on neurons. PS-off and SWS-on neurons appear to play an important role in both the W-SWS and SWS-PS switches, while PS-on and PS-off neurons play an important role in the PS-W switch. The present findings on the trends in spike activity at the transitions from SWS to PS and from PS to W are in line with the reciprocal interaction hypothesis according to which PS occurs as a result of the cessation of discharge of PS-off neurons, while PS ends as a result of the start of discharge of PS-off neurons.
Asunto(s)
Bulbo Raquídeo/fisiología , Neuronas/fisiología , Formación Reticular/fisiología , Sueño REM/fisiología , Sueño de Onda Lenta/fisiología , Vigilia/fisiología , Animales , Electroencefalografía , Masculino , Ratones , Ratones Endogámicos C57BL , Núcleos del Rafe/fisiologíaRESUMEN
Testicular toxicity is a frequent adverse effect of cancer chemotherapy that has no effective clinical biomarker. To find new biomarkers, we focused on epigenetic mechanisms in the male germline. We investigated the DNA methylation status of the male germline during testicular toxicity induced by doxorubicin (DXR), a widely used anticancer agent. We established mouse models of early stage testicular toxicity and testicular pre-toxicity by the administration of 0.2â¯mg/kg and 0.02â¯mg/kg DXR, respectively, twice weekly for 5 weeks. Histological analysis showed sparse abnormalities in testicular tissue; however, western blotting analysis revealed reduced testicular expression levels of DNA methyltransferases DNMT3a and DNMT3b in both DXR-treated groups. Interestingly, comprehensive sperm DNA methylation analysis using Methyl-CpG binding domain protein-enriched genome sequencing revealed that hypomethylation was the most frequent change induced by DXR. These findings suggest that sperm DNA methylation status may be used as an early diagnostic marker for testicular changes not detected by conventional toxicity analysis.