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BACKGROUND: Malignant hyperthermia is a potentially lethal condition triggered by specific anesthetic drugs, especially a depolarizing muscle relaxant of succinylcholine (Suxamethonium). Despite the frequent use of succinylcholine with electroconvulsive therapy (ECT), there has been no reported case of potentially lethal malignant hyperthermia following ECT. In addition, the time interval between the administration of succinylcholine and the onset of malignant hyperthermia has not been outlined in the context of ECT. CASE PRESENTATION: We present the case of a 79-year-old woman suffering from severe depression, who experienced severe malignant hyperthermia due to succinylcholine administration during an ECT session. She presented with a high fever of 40.2 °C, tachycardia of 140/min, hypertension with a blood pressure exceeding 200 mmHg, significant muscle rigidity, and impaired consciousness. These symptoms emerged two hours after ECT, which occurred in a psychiatric ward rather than an operating room, and reached their peak in less than 24 h. She was given 60 mg of dantrolene, which quickly reduced the muscular rigidity. Subsequently, she received two additional doses of 20 mg and 60 mg of dantrolene, which brought her fever down to 36.2 °C and completely eased her muscle rigidity within two days after ECT. CONCLUSIONS: This is the first reported case of potentially lethal malignant hyperthermia after ECT. In addition, it highlights the delayed onset of malignant hyperthermia following an ECT procedure, emphasizing the necessity for psychiatrists to recognize its onset even after the treatment. In the light of potentially lethal consequences of malignant hyperthermia, it is critically important for psychiatrists to closely monitor both intraoperative and postoperative patient's vital signs and characteristic physical presentations, promptly identify any symptomatic emergence, and treat it immediately with dantrolene.
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Terapia Electroconvulsiva , Hipertermia Maligna , Fármacos Neuromusculares Despolarizantes , Succinilcolina , Anciano , Femenino , Humanos , Dantroleno/uso terapéutico , Dantroleno/efectos adversos , Terapia Electroconvulsiva/efectos adversos , Terapia Electroconvulsiva/métodos , Hipertermia Maligna/etiología , Fármacos Neuromusculares Despolarizantes/efectos adversos , Succinilcolina/efectos adversosRESUMEN
OBJECTIVE: This study aimed to compare the current handgrip strength (HGS) of Kendo athletes with their HGS when they were in university (up to 50 years). METHODS: Eighty male graduates who were Kendo club members during their university days performed anthropometric and HGS measurements, and these HGS were compared with those measured during their university days (mean age of 19.5 years old). RESULTS: There was no evidence of a statistical difference in HGS between the current measurement and the measurement taken during university [-0.64 (-1.9, 0.67) kg, p = .336]. There was, however, evidence that the difference in HGS depended upon the current age of the individual (t = -6.43, p < .001). When probing the interaction, there were statistical differences between the ages of 24.6 and 38.2 years and between the ages of 47.4 and 69.9 years. Strength increased across time in the younger participants and decreased for those who were older. Between the ages of 38.9 and 46.1 years, there was no evidence of a statistical difference indicating a maintenance of strength. CONCLUSION: The HGS of Kendo club graduates, which they acquired during their formative years, continued to increase even after they graduated from university and entered their 30s. However, their HGS decreased from age 50, even though they practiced Kendo.
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Magnetic semimetals form an attractive class of materials because of the nontrivial contributions of itinerant electrons to magnetism. Because of their relatively low-carrier-density nature, a doping level of those materials could be largely tuned by a gating technique. Here, we demonstrate gate-tunable ferromagnetism in an emergent van der Waals magnetic semimetal Cr3Te4 based on an ion-gating technique. Upon doping electrons into the system, the Curie temperature (TC) sharply increases, approaching near to room temperature, and then decreases to some extent. This non-monotonous variation of TC accompanies the switching of the magnetic anisotropy, synchronously followed by the sign changes of the ordinary and anomalous Hall effects. Those results clearly elucidate that the magnetism in Cr3Te4 should be governed by its semimetallic band nature.
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Brain amyloid-ß (Aß) governs the pathogenic process of Alzheimer's disease. Clinical trials to assess the disease-modifying effects of inhibitors or modulators of ß- and γ-secretases have not shown clinical benefit and can cause serious adverse events. Previously, we found that the interleukin-like epithelial-to-mesenchymal transition inducer (ILEI, also known as FAM3C) negatively regulates the Aß production through a decrease in Aß immediate precursor, without the inhibition of ß- and γ-secretase activity. Herein, we found that MS-275, a benzamide derivative that is known to inhibit histone deacetylases (HDACs), exhibits ILEI-like activity to reduce Aß production independent of HDAC inhibition. Chronic MS-275 treatment decreased Aß deposition in the cerebral cortex and hippocampus in an Alzheimer's disease mouse model. Overall, our results indicate that MS-275 is a potential therapeutic candidate for efficiently reducing brain Aß accumulation.
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Enfermedad de Alzheimer , Piridinas , Ratones , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide , Péptidos beta-Amiloides , Benzamidas/farmacología , Precursor de Proteína beta-AmiloideRESUMEN
The aim of the present study was to investigate the perioperative and postoperative incidence of deep vein thrombosis (DVT) and validate the effectiveness of our own preventive treatment protocol for venous thromboembolism (VTE) occurrence in lower extremity arthroplasty patients. The subjects were 1,054 patients (mean age: 74.3 years) who underwent total hip arthroplasty (THA) or total knee arthroplasty (TKA) at our institutions between April 2014 and March 2017. We examined the frequencies of pre- and post-operative DVT by lower extremity Doppler images, and the incidence rate at proximal or distal regions as well as that according to preoperative DVT status were evaluated. Preoperative DVT was detected in 6.5% (69 cases) of our cohort and those were located 1.4% (15 cases) at proximal and 5.1% (54 cases) at distal regions. A significantly higher rate of postoperative DVT development was observed in preoperative DVT+ THA patients (P = 0.0075), but not in TKA patients only with a higher tendency (P = 0.56). The overall incidence of DVT up to 2 weeks after surgeries was 27.3% (288 cases); however, the rate in proximal femur regions was suppressed to 2.8% (30 cases), and there was no symptomatic pulmonary thromboembolism (PTE) case. The results demonstrated the importance of regular Doppler examination for early detection of postoperative DVT occurrence and the following immediate treatment initiation. Our own VTE preventive treatment protocol could reduce the development of proximal DVT, and the periodic monitoring as well as prompt treatment might prevent the fatal PTE. osteoarthritis (OA), rheumatoid arthritis (RA).
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Artritis Reumatoide , Artroplastia de Reemplazo de Cadera , Artroplastia de Reemplazo de Rodilla , Embolia Pulmonar , Tromboembolia Venosa , Trombosis de la Vena , Humanos , Anciano , Artroplastia de Reemplazo de Rodilla/efectos adversos , Tromboembolia Venosa/etiología , Incidencia , Trombosis de la Vena/diagnóstico por imagen , Trombosis de la Vena/epidemiología , Trombosis de la Vena/etiología , Artritis Reumatoide/complicaciones , Embolia Pulmonar/cirugía , Complicaciones Posoperatorias/etiología , Artroplastia de Reemplazo de Cadera/efectos adversos , Factores de RiesgoRESUMEN
Epidemiological studies have shown that cigarette smoking increases the risk of Alzheimer disease. However, inconsistent results have been reported regarding the effects of smoking or nicotine on brain amyloid ß (Aß) deposition. In this study, we found that stimulation of the nicotinic acetylcholine receptor (nAChR) increased Aß production in mouse brains and cultured neuronal cells. nAChR activation triggered the MEK/ERK pathway, which then phosphorylated and stabilized nuclear SP1. Upregulated SP1 acted on two recognition motifs in the BACE1 gene to induce its transcription, resulting in enhanced Aß production. Mouse brain microdialysis revealed that nAChR agonists increased Aß levels in the interstitial fluid of the cerebral cortex but caused no delay of Aß clearance. In vitro assays indicated that nicotine inhibited Aß aggregation. We also found that nicotine modified the immunoreactivity of anti-Aß antibodies, possibly through competitive inhibition and Aß conformation changes. Using anti-Aß antibody that was carefully selected to avoid these effects, we found that chronic nicotine treatment in Aß precursor protein knockin mice increased the Aß content but did not visibly change the aggregated Aß deposition in the brain. Thus, nicotine influences brain Aß deposition in the opposite direction, thereby increasing Aß production and inhibiting Aß aggregation.
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Secretasas de la Proteína Precursora del Amiloide , Péptidos beta-Amiloides , Ácido Aspártico Endopeptidasas , Nicotina , Receptores Nicotínicos , Factor de Transcripción Sp1 , Animales , Humanos , Masculino , Ratones , Péptidos beta-Amiloides/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Ratones Endogámicos C57BL , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Fosforilación/efectos de los fármacos , Receptores Nicotínicos/metabolismo , Factor de Transcripción Sp1/metabolismoRESUMEN
Despite the success of total knee arthroplasty (TKA), current implant designs could not consistently restore the physiological knee kinematics, especially in cruciate-retaining (CR) implants. This study aimed to investigate the short-term clinical outcomes, particularly patient satisfaction, of primary TKA employing a new-type kinematic retaining (KR) implant. We analyzed 149 cases applied the KR implant at our institutions during June 2017 to May 2019. The effectiveness of this implant design was compared with another CR one (171 cases). Both groups underwent primary TKA in the same period and all patients completed 2 years of follow-up. Perioperative changes in range of motion (ROM), Knee Score, function score, and patient satisfaction by Forgotten Joint Score-12 (FJS-12) method were evaluated. Postoperative ROM, Knee Score, and function score were significantly improved at 1 year after surgeries and maintained for another year in both KR and CR groups. The improvement rate of ROM in KR group (108.1%) was substantially higher than that in CR (104.5%), even 4% increase could have affected patients' satisfaction in a real-world setting. Regarding the patient satisfaction, such 4 items as climbing stairs, walking on a bumpy road, doing housework or gardening, and taking a walk or hiking were significantly enhanced in KR cases compared to CR. There were no loosening or revision cases and the short-term survivorships of both implants were 100%. In addition, there has been no case of obvious complications in both groups during and after surgeries. The results of the present study suggest that this novel KR prosthesis can reproduce physiological knee kinematics, recover its functions, and contribute to pain relief after TKA. TKA procedure using the KR implant should be a good surgical option to improve postoperative outcomes.
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Artroplastia de Reemplazo de Rodilla , Miembros Artificiales , Humanos , Fenómenos Biomecánicos , Articulación de la Rodilla/cirugía , Tareas del HogarRESUMEN
Melatonin, a neurohormone nocturnally produced by the pineal gland, is known to regulate the circadian rhythm. It has been recently reported that variants of melatonin receptors are associated with an increased risk of hyperglycemia and type 2 diabetes, suggesting that melatonin may be involved in the regulation of glucose homeostasis. Insulin is a key hormone that regulates circulating glucose levels and cellular metabolism after food intake in many tissues, including the brain. Although cells actively uptake glucose even during sleep and without food, little is known regarding the physiological effects of nocturnal melatonin on glucose homeostasis. Therefore, we presume the involvement of melatonin in the diurnal rhythm of glucose metabolism, independent of insulin action after food intake. In the present study, goldfish (Carassius auratus) was used as an animal model, since this species has no insulin-dependent glucose transporter type 4 (GLUT4). We found that in fasted individuals, plasma melatonin levels were significantly higher and insulin levels were significantly lower during the night. Furthermore, glucose uptake in the brain, liver, and muscle tissues also significantly increased at night. After intraperitoneal administration of melatonin, glucose uptake by the brain and liver showed significantly greater increases than in the control group. The administration of melatonin also significantly decreased plasma glucose levels in hyperglycemic goldfish, but failed to alter insulin mRNA expression in Brockmann body and plasma insulin levels. Using an insulin-free medium, we demonstrated that melatonin treatment increased glucose uptake in a dose-dependent manner in primary cell cultures of goldfish brain and liver cells. Moreover, the addition of a melatonin receptor antagonist decreased glucose uptake in hepatocytes, but not in brain cells. Next, treatment with N1-acetyl-5-methoxykynuramine (AMK), a melatonin metabolite in the brain, directly increased glucose uptake in cultured brain cells. Taken together, these findings suggest that melatonin is a possible circadian regulator of glucose homeostasis, whereas insulin acquires its effect on glucose metabolism following food intake.
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Diabetes Mellitus Tipo 2 , Melatonina , Animales , Melatonina/metabolismo , Carpa Dorada/fisiología , Glucosa/metabolismo , Encéfalo/metabolismoRESUMEN
Although tapered-wedge short stem has been widely employed with its availability for minimally invasive surgeries in total hip arthroplasty (THA), post-operative stress shielding matter remains unresolved in cementless procedures. This study aimed to clarify the most optimal femoral canal contact regions of the stem design taking stress shielding incidence into consideration. This investigation included 60 joints from 60 patients (mean age at operation: 65.9 years), of which follow-up duration after primary THA had been more than 2 years. Frequencies of spot welds, subsidence, and stress shielding were examined 2 years after surgery. The most suitable femoral canal contact regions were evaluated by plain radiograph (2D) and 3D-computed tomography analyses according to Nakata's division for fitting manners. Spot welds were observed in 38 cases (63.3%), and no subsidence case was seen. Respective number of stress shielding cases, based on Engh's classification, categorized as degree 0, 1, and 2, were 2 (3.3%), 31 (51.7%), and 27 (45.0%), while no cases for degree 3 or 4 were found. When assessed by 3D fitting analysis, 27 cases of stress shielding degree 2 were constituted by 13/42 cases of mediolateral (ML) fit, 2/4 cases of flare fit, and 12/14 cases of multi point fit. In 42 cases of ML fitting, stem contact rate of the most proximedial region in stress shielding degree 0 and 1 was significantly higher compared to stress shielding degree 2 cases. Meanwhile, the rates of distal regions were significantly lower or absent in stress shielding degree 0 and 1 cases. The initial fixation of this stem design was very good in our cohort regardless of fitting manners. This study successfully revealed that ML fitting with femoral component, especially the most proximedial calcar site restricted fitting, would be optimal for reducing stress shielding occurrence in cementless short, tapered-wedge stem THA. Thus, the ideal stem contact region should be considered during THA procedures in light of the reduction of stress shielding development.
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Although nitric oxide (NO) is a known factor that regulates the bone physiology, few and discordant results have been obtained in human studies evaluating the effect of nitrates on bone health. We investigated for the relationship between serum NOx level and incident osteoporotic fracture rate prospectively in a cohort consisting of Japanese women. A total of 871 subjects (67.5 ± 10.8 y/o) were analyzed. During the observation period (8.8 ± 7.2 yrs), incident osteoporotic fractures occurred in 267 participants (209 vertebral fractures, 57 long-bone fractures, and 1 both types). Hazard ratio, by the Cox proportional hazards model, of serum NOx for incident fracture was 0.64 (95% confidence interval 0.53-0.78, p < 0.001) after adjustment for baseline age (1.13, 1.06-1.21, p < 0.001), lumbar bone mineral density (L-BMD; 0.85, 0.78-0.92, p < 0.001), presence of prevalent fracture (3.27, 2.49-4.32, p < 0.001), and treatment of osteoporosis (0.70, 0.53-0.92, p = 0.010). The relationships between serum level of NOx and bone-related parameters were examined by multiple regression analysis; body mass index (p < 0.001) and L-BMD (p = 0.011) were significantly associated with serum NOx level. These results suggest that the low circulating NOx is one of the independent predictors for osteoporotic fracture occurrence in postmenopausal women.
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Osteoporosis Posmenopáusica , Osteoporosis , Fracturas Osteoporóticas , Fracturas de la Columna Vertebral , Humanos , Femenino , Fracturas Osteoporóticas/epidemiología , Óxido Nítrico , Pueblos del Este de Asia , Osteoporosis/complicaciones , Densidad Ósea , Fracturas de la Columna Vertebral/epidemiología , Factores de Riesgo , Osteoporosis Posmenopáusica/complicacionesRESUMEN
Cyclic guanosine 3',5'-monophosphate (cGMP) is a ubiquitous important second messenger involved in various physiological functions. Here, intracellular cGMP (cGMPi) was visualized in chemotactic Dictyostelium cells using the fluorescent probe, D-Green cGull. When wild-type cells were stimulated with a chemoattractant, fluorescence transiently increased, but guanylate cyclase-null cells did not show a change in fluorescence, suggesting that D-Green cGull is a reliable indicator of cGMPi. In the aggregation stage, the responses of cGMPi propagated in a wave-like fashion from the aggregation center. The oscillation of the cGMPi wave was synchronized almost in phase with those of other second messengers, such as the intracellular cAMP and Ca2+. The phases of these waves preceded those of the oscillations of actomyosin and cell velocity, suggesting that these second messengers are upstream of the actomyosin and chemotactic migration. An acute increase in cGMPi concentration released from membrane-permeable caged cGMP induced a transient shuttle of myosin II between the cytosol and cell cortex, suggesting a direct link between cGMP signaling and myosin II dynamics.
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Dictyostelium , Dictyostelium/fisiología , Quimiotaxis/fisiología , Actomiosina , GMP Cíclico/farmacología , GMP Cíclico/fisiología , Miosina Tipo IIRESUMEN
INTRODUCTION: Available evidence on favorable nutritional factors for preventing osteoporosis remains controversial. Considering the recent increases in life expectancy, we investigated the relationship between incident osteoporotic fractures and dietary habits in early and late postmenopausal phase women. MATERIALS AND METHODS: Subjects were Japanese postmenopausal outpatients recruited at a primary care institution in Nagano Prefecture (Nagano Cohort Study). Patients with critical or acute illness or secondary osteoporosis were not included in this study. In total, 1,071 participants were prospectively followed for a mean of 5.8 years. The cohort was divided into early (≤ 70 years) and late (> 70 years) postmenopausal phases based on median age. Dietary nutrient intake was estimated by the food frequency questionnaire method. According to baseline nutrient intake characteristics, we focused on protein/energy and Ca/NaCl intake ratios, which were also divided by the median values. RESULTS: Kaplan-Meier plots revealed a significantly higher occurrence of fractures for the high protein/energy intake group in early postmenopausal subjects (P = 0.009), whereas the low Ca/NaCl intake group in late postmenopausal subjects exhibited a significantly earlier occurrence of fractures (P = 0.002). Multivariate Cox regression uncovered significant independent risks of higher protein/energy (HR 1.35; 95% CI 1.04-1.74) and lower Ca/NaCl (HR 0.79; 95% CI 0.63-0.99) intake ratios for incident osteoporotic fractures in the early and late postmenopausal cohorts, respectively. CONCLUSION: Distinct dietary risk factors for osteoporotic fractures were identified in early and late postmenopausal phase women. Appropriate nutritional guidance according to patient age will be important for maintaining bone health and quality of life.
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Osteoporosis Posmenopáusica , Osteoporosis , Fracturas Osteoporóticas , Humanos , Femenino , Fracturas Osteoporóticas/etiología , Fracturas Osteoporóticas/complicaciones , Densidad Ósea , Posmenopausia , Calidad de Vida , Cloruro de Sodio , Osteoporosis Posmenopáusica/epidemiología , Osteoporosis Posmenopáusica/complicaciones , Factores de Riesgo , Osteoporosis/complicacionesRESUMEN
Background: Some patients are reported to develop depression immediately after COVID-19 infection. Typically, hospitalization is arranged a week to 10 days after symptom onset to avoid outbreak in the psychiatric ward when infectivity is almost eliminated. However, in patients on immunosuppressive drugs, infection is known to persist beyond the 10th day after testing positive with a polymerase chain reaction (PCR) test. Case Presentation: We present a patient with follicular lymphoma who was receiving immune-suppressing medication and contracted a COVID-19 infection; she developed severe depression and eventually required hospitalization 10 days after symptom onset or 5 days after the COVID-19 infection-related symptoms disappeared. Although the patient did not exhibit any symptom of pneumonia upon admission, she developed COVID-19 pneumonia 3 weeks after the initial positive test. She received intravenous infusion of the antiviral drug remdesivir, which led to the improvement of pneumonia, and she was discharged on day 32 from testing COVID-19 positive. However, COVID-19 pneumonia recurred on days 64 and 74. Conclusion: This is the first report of COVID-19 pneumonia developing in a psychiatric ward in a patient on immunosuppressive drugs, weeks to months after testing positive with a PCR test. When patients with compromised immune function, such as those on immunosuppressant medication or those with human immunodeficiency virus disease, are admitted to a psychiatric ward, careful monitoring of the risk of recurrence and sufficient consideration for infection control measures are necessary to avoid outbreaks.
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In a conventional magnetic material, a long-range magnetic order develops in three dimensions, and reducing a layer number weakens its magnetism. Here we demonstrate anomalous layer-number-independent ferromagnetism down to the two-dimensional (2D) limit in a metastable phase of Cr3Te4. We fabricated Cr3Te4 thin films by molecular-beam epitaxy and found that Cr3Te4 could host two distinct ferromagnetic phases characterized with different Curie temperatures (TC). One is the bulk-like "high-TC phase" showing room-temperature ferromagnetism, which is consistent with previous studies. The other is the metastable "low-TC phase" with TC ≈ 160 K, which exhibits a layer-number-independent TC down to the 2D limit in marked contrast with the conventional high-TC phase, demonstrating a purely 2D nature of its ferromagnetism. Such significant differences between two distinct phases could be attributed to a small variation in the doping level, making this material attractive for future ultracompact spintronics applications with potential gate-tunable room-temperature 2D ferromagnetism.
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Congenital scoliosis (CS) is a lateral curvature of the spine characterized by the presence of vertebral anomalies. Pathogenic genetic variants in the TBX6 gene are one of the causes of CS. However, since many clinically diagnosed cases of CS are without known TBX6 gene variations, this study aims to uncover new genes related to disease susceptibility of CS by exome sequencing (ES). This study employed ES in a cohort of 5 Japanese patients with CS and their healthy parents or a sister for a total of 16 samples among 5 families. Variant interpretation was performed using SIFT, PolyPhen-2, Mutation Taster, and CADD. Four de novo variants were identified by ES and confirmed by Sanger sequencing: 1 frameshift variant ( SHISA3 ) and 3 missense variants ( AGBL5 , HDAC4 , and PDE2A ). ES also uncovered 1 homozygous variant in the MOCOS gene. All of these variants were predicted to be deleterious by SIFT, PolyPhen-2, Mutation Taster, and/or CADD. The number of de novo variants identified in this study was exactly what would be expected by chance. Additional functional studies or gathering matched patients using Gene Matcher are needed.
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A proximity effect at a van der Waals (vdW) interface enables creation of an emergent quantum electronic ground state. Here we demonstrate that an originally superconducting two-dimensional (2D) NbSe2 forms a ferromagnetic ground state with spontaneous spin polarization at a vdW interface with a 2D ferromagnet V5Se8. We investigated the anomalous Hall effect (AHE) of the NbSe2/V5Se8 magnetic vdW heterostructures, and found that the sign of the AHE was reversed as the number of the V5Se8 layer was thinned down to the monolayer limit. Interestingly, the AHE signal of those samples was enhanced with the in-plane magnetic fields, suggesting an additional contribution to the AHE signal other than magnetization. This unusual behavior is well reproduced by band structure calculations, where the emergence of the Berry curvature along the spin-degenerate nodal lines in 2D NbSe2 by the in-plane magnetization plays a key role, unveiling a unique interplay between magnetism and Zeeman-type spin-orbit interaction in a non-centrosymmetric 2D quantum material.
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Peficitinib, a pan-JAK inhibitor, is known to suppress the activation of fibroblast-like synoviocytes (FLSs) and thereby reduces joint inflammation associated with rheumatoid arthritis (RA). However, the effect on osteoporosis in RA remains to be elucidated. In this study, the effect of peficitinib or etanercept on joint inflammation, and consequently decreased bone mineral density (BMD) was evaluated in mice with collagen-induced arthritis (CIA). Additionally, the effect on RANKL production from osteoblasts differentiated from the mesenchymal stem cells of RA patients was evaluated. Administration of peficitinib for established CIA ameliorated arthritis and improved BMD in the femoral metaphysis, but not in the femoral diaphysis. Conversely, etanercept suppressed an increase in synovial inflammatory markers but did not improve arthritic conditions or the reduction of BMD in either region. All elevated bone formation and bone resorption markers were decreased with peficitinib but only partially decreased with etanercept. Furthermore, production of RANKL by human osteoblasts was suppressed by peficitinib but enhanced by etanercept. Unlike etanercept, peficitinib is thought to increase BMD by ameliorating the high bone turnover associated with RA states, resulting in improvement of bone fragility. Our data provide evidence that peficitinib would be expected to show efficacy for osteoporosis associated with RA.
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Adamantano/análogos & derivados , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Densidad Ósea/efectos de los fármacos , Remodelación Ósea/efectos de los fármacos , Huesos/metabolismo , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/uso terapéutico , Niacinamida/análogos & derivados , Osteoporosis/tratamiento farmacológico , Adamantano/farmacología , Adamantano/uso terapéutico , Animales , Artritis Reumatoide/complicaciones , Resorción Ósea/prevención & control , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos DBA , Niacinamida/farmacología , Niacinamida/uso terapéutico , Osteoblastos/metabolismo , Osteoporosis/etiología , Osteoporosis/prevención & control , Ligando RANK/metabolismoRESUMEN
The family with sequence similarity 3 (FAM3) superfamily represents a distinct class of signaling molecules that share a characteristic structural feature. Mammalian FAM3 member C (FAM3C) is abundantly expressed in neuronal cells and released from the synaptic vesicle to the extracellular milieu in an activity-dependent manner. However, the neural function of FAM3C has yet to be fully clarified. We found that the protein sequence of human FAM3C is similar to that of the N-terminal tandem domains of Caenorhabditis elegans FAMP-1 (formerly named M70.4), which has been recognized as a tentative ortholog of mammalian FAM3 members or protein-O-mannose ß-1,2-N-acetylglucosaminyltransferase 1 (POMGnT1). Missense mutations in the N-terminal domain, named Fam3L2, caused defects in memory-based thermotaxis but not in chemotaxis behaviors; these defects could be restored by AFD neuron-specific exogenous expression of a polypeptide corresponding to the Fam3L2 domain but not that corresponding to the Fam3L1. Moreover, human FAM3C could also rescue defective thermotaxis behavior in famp-1 mutant worms. An in vitro assay revealed that the Fam3L2 and FAM3C can bind with carbohydrates, similar to the stem domain of POMGnT1. The athermotactic mutations in the Fam3L2 domain caused a partial loss-of-function of FAMP-1, whereas the C-terminal truncation mutations led to more severe neural dysfunction that reduced locomotor activity. Overall, we show that the Fam3L2 domain-dependent function of FAMP-1 in AFD neurons is required for the thermotaxis migration of C. elegans and that human FAM3C can act as a substitute for the Fam3L2 domain in thermotaxis behaviors.
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The efficacy of romosozumab for severe osteoporosis is uncertain in patients with osteogenesis imperfecta (OI). This report introduced a severe osteoporotic case of OI to examine the effect of romosozumab on bone fragility. A 64-year-old man with OI was referred to our department for finding out the cause of his repeated fractures. He was medicated with alendronate for only 1 year, 8 years ago, but it did not prevent repeated fractures, and thus, he had not received any treatments for osteoporosis since then. However, recently, the frequency of fractures had increased. At presentation, his lumbar and bilateral total hip bone mineral density (BMD) values were severely decreased to 0.546 and 0.209 g/cm2, respectively. Because of his severe osteoporosis, we started romosozumab treatment with eldecalcitol. Romosozumab (210 mg) was injected subcutaneously every month. At 12 months after drug initiation, his lumbar and total hip BMD increased by 22.0% and 136.4% versus pre-treatment levels, respectively. Bone formation markers increased, and bone resorption markers decreased at 12 months of the therapy. Neither hypocalcaemia nor any other severe adverse effects were observed in this severe osteoporotic case. This study revealed good responses of BMD and bone turnover markers to romosozumab treatment, which can be considered as an effective treatment option for osteoporotic OI patients.
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Conservadores de la Densidad Ósea , Osteogénesis Imperfecta , Osteoporosis , Anticuerpos Monoclonales , Biomarcadores , Conservadores de la Densidad Ósea/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Osteogénesis Imperfecta/complicaciones , Osteogénesis Imperfecta/tratamiento farmacológico , Osteoporosis/tratamiento farmacológicoRESUMEN
There are no published clinical reports comparing ibandronate (IBN) treatment and zoledronic acid (ZOL) treatment in Japanese postmenopausal osteoporotic patients. This investigation therefore compared the efficacy and safety of the drugs on improving bone metabolism and bone mineral density (BMD) in Japanese postmenopausal women with primary osteoporosis. Eighty-two treatment-naïve primary osteoporotic female patients were randomly divided into IBN-treated or ZOL-treated groups. Bone turnover markers and BMD were examined immediately prior to treatment (baseline) and at 6, 12, 18, 24, and 30 months of therapy. Compared with baseline levels, the values of type 1 procollagen N-terminal propeptide, bone-specific alkaline phosphatase (BAP), urinary type-I collagen amino-terminal telopeptide (NTX), and tartrate-resistant acid phosphatase 5b were all significantly decreased at every time point in both groups apart from BAP at 30 months in the ZOL group, urinary NTX at 12 months in the ZOL group and at 24 and 30 months in both groups. Lumbar BMD values were significantly increased at 6, 12, 18, and 24 months in the IBN group and at 6 and 12 months in the ZOL group compared with pre-treatment levels. Hip BMD values were also significantly increased at 6, 12, 18, and 24 months in the IBN group and at 6, 12, and 18 months in the ZOL group compared with baseline values. The percentage changes of hip BMD at 18 and 24 months in the ZOL group were significantly higher than those in the IBN group (both p < 0.05). No remarkable adverse events were noted in either group. In conclusion, both IBN and ZOL significantly and safely improved bone turnover markers and BMD during 30 months of treatment in Japanese osteoporosis patients. The ZOL group tended to exhibit greater gains in BMD as compared with the IBN group, which merits further investigation.