RESUMEN
We report herein the case of a 79-year-old woman who experienced difficulties in swallowing, dysarthria, dropped head, and muscle weakness associated with diurnal and day-to-day variation. We made a diagnosis of generalized myasthenia gravis (MG) with anti-acetylcholine receptor antibodies. Contrast-enhanced computed tomography showed no sign of thymoma. As the MG worsened, the patient presented with severe bradycardia. Chest compressions were performed on days 6 and 7 after admission and she underwent implantation of a temporary pacemaker. The arrhythmia resolved after strong immunosuppressive treatment, and anti-striational antibodies, including anti-muscular voltage-gated potassium channel-complex (Kv1.4) antibody and anti-titin antibody, were subsequently detected. This case implies the possible involvement of anti-striational antibodies in bradycardia.
Asunto(s)
Miastenia Gravis , Timoma , Neoplasias del Timo , Anciano , Autoanticuerpos , Bradicardia/etiología , Femenino , Humanos , Miastenia Gravis/complicaciones , Miastenia Gravis/diagnóstico , Miastenia Gravis/terapiaRESUMEN
A 79-year-old woman presented 3 years' history of hand shaking while drinking a cup of tea. The tremor was seen bilaterally, more predominantly on the left, and it also appeared when reading a book or writing. It was also induced by flexing the elbow to about 90 degrees or more without any specific task. Although there was no family history, the tremor in the present case was clinically diagnosed as essential tremor, because there were no other movement abnormalities, and other causes of tremor were excluded by laboratory tests. The tremor was dependent on the position of the involved extremity regardless of the kind of tasks. Position-specific tremor is discussed in relation to postural tremor.
Asunto(s)
Trastornos del Movimiento , Temblor , Anciano , Extremidades , Femenino , Humanos , Temblor/diagnóstico , Temblor/etiologíaRESUMEN
OBJECTIVE: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM). METHODS: Participants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety. RESULTS: Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively). CONCLUSION: Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02573467. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Miositis por Cuerpos de Inclusión/tratamiento farmacológico , Accidentes por Caídas , Adulto , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fuerza Muscular/efectos de los fármacos , Miositis por Cuerpos de Inclusión/complicaciones , Tiempo , Resultado del Tratamiento , Prueba de PasoRESUMEN
A 52-year old woman first noted dysphagia four months before admission followed by dysarthria two months later. She then developed weakness of all limbs and became unable to walk. All these symptoms, associated with tongue atrophy, slowly progressed, leading to the initial clinical impression of a motor neuron disease, although her nerve conduction study and electromyography showed no abnormalities. Her brain MRI with T2 weighted/diffusion weighted image (DWI)/fluid attenuated inversion recovery (FLAIR) revealed a high signal lesion located at dorsal medulla oblongata. She proved positive for anti-aquaporin 4 antibody, which confirmed the diagnosis of neuromyelitis optica spectrum disorders (NMOSD). We conclude that NMOSD may initially present with progressive bulbar palsy and pyramidal tract disorder over a few months, mimicking a motor neuron disease. Awareness of this atypical presentation helps establish an early diagnosis of this treatable entity.
Asunto(s)
Parálisis Bulbar Progresiva/diagnóstico , Parálisis Bulbar Progresiva/etiología , Enfermedad de la Neurona Motora , Neuromielitis Óptica/complicaciones , Neuromielitis Óptica/diagnóstico , Acuaporina 4/inmunología , Atrofia/etiología , Autoanticuerpos/sangre , Biomarcadores/sangre , Encéfalo/diagnóstico por imagen , Diagnóstico Diferencial , Progresión de la Enfermedad , Disartria/etiología , Femenino , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Factores de Tiempo , Lengua/patologíaRESUMEN
A 33-year-old man admitted to our hospital for the evaluation of progressive muscular atrophy of his left lower leg. From his childhood, he had suffered from transient attacks of limb paralysis and myalgia lasting about 1 hour. At age 30, the muscle weakness and atrophy of his left lower leg emerged and progressed gradually. Muscle MR images showed atrophy and fat replacement in left lower leg, and muscle biopsy revealed tubular aggregates (TA). Genetic analysis showed heterozygous c.2111C>T/p.T704M missense mutation of SCN4A gene, which causes hyperkalemic periodic paralysis (HyperPP). Although HyperPP is rare, it is quite critical for clinicians to recognize that the patients of HyperPP often present progressive myopathy. We emphasize the importance of paying attention to progressive myopathy and discuss the pathological mechanism of myopathy through this case report.
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Hiperpotasemia/complicaciones , Hiperpotasemia/diagnóstico , Miopatías Estructurales Congénitas/etiología , Parálisis/complicaciones , Parálisis/diagnóstico , Periodicidad , Adulto , Progresión de la Enfermedad , Heterocigoto , Humanos , Hiperpotasemia/genética , Imagen por Resonancia Magnética , Masculino , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Mutación , Miopatías Estructurales Congénitas/diagnóstico por imagen , Miopatías Estructurales Congénitas/patología , Canal de Sodio Activado por Voltaje NAV1.4/genética , Parálisis/genética , LinajeRESUMEN
UNLABELLED: The voltage-gated H+ channel is a powerful H+ extruding mechanism of osteoclasts, but its functional roles and regulatory mechanisms remain unclear. Electrophysiological recordings revealed that the H+ channel operated on activation of protein kinase C together with cell acidosis. INTRODUCTION: H+ is a key signaling ion in bone resorption. In addition to H+ pumps and exchangers, osteoclasts are equipped with H+ conductive pathways to compensate rapidly for pH imbalance. The H+ channel is distinct in its strong H+ extrusion ability and voltage-dependent gatings. METHODS: To investigate how and when the H+ channel is available in functional osteoclasts, the effects of phorbol 12-myristate 13-acetate (PMA), an activator for protein kinase C, on the H+ channel were examined in murine osteoclasts generated in the presence of soluble RANKL (sRANKL) and macrophage-colony stimulating factor (M-CSF). RESULTS AND CONCLUSIONS: Whole cell recordings clearly showed that the H+ current was enhanced by increasing the pH gradient across the plasma membrane (delta(pH)), indicating that the H+ channel changed its activity by sensing delta(pH). The reversal potential (V(rev)) was a valuable tool for the real-time monitoring of delta(pH) in clamped cells. In the permeabilized patch, PMA (10 nM-1.6 microM) increased the current density and the activation rate, slowed decay of tail currents, and shifted the threshold toward more negative voltages. In addition, PMA caused a negative shift of V(rev), suggesting that intracellular acidification occurred. The PMA-induced cell acidosis was confirmed using a fluorescent pH indicator (BCECF), which recovered quickly in a K(+)-rich alkaline solution, probably through the activated H+ channel. Both cell acidosis and activation of the H+ channel by PMA were inhibited by staurosporine. In approximately 80% of cells, the PMA-induced augmentation in the current activity remained after compensating for the delta(pH) changes, implying that both delta(pH)-dependent and -independent mechanisms mediated the channel activation. Activation of the H+ channel shifted the membrane potential toward V(rev). These data suggest that the H+ channel may contribute to regulation of the pH environments and the membrane potential in osteoclasts activated by protein kinase C.
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Acidosis/inducido químicamente , Activación del Canal Iónico/efectos de los fármacos , Canales Iónicos/metabolismo , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Acetato de Tetradecanoilforbol/farmacología , Acidosis/metabolismo , Animales , Conductividad Eléctrica , Concentración de Iones de Hidrógeno , Masculino , Potenciales de la Membrana/efectos de los fármacos , Ratones , Técnicas de Placa-Clamp , ProtonesRESUMEN
Osteoclasts secrete a large amount of proton (H+) ions and proteolytic enzymes into bone resorption pit to degrade bone matrix. In addition to H+ pumps and exchangers, voltage-gated H+ channels, which are H+ conductive pathways, are expressed in osteoclasts. H+ channels are distinct in their strong H+ extrusion ability, but the functional role is not clear. This is the first study of H+ channels in murine osteoclasts generated from mononuclear precursors in the presence of a soluble form of receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony stimulating factor (M-CSF). The H+ channel was characterized by voltage- and pH-dependent activation, slow activation kinetics, and outward rectification. The reversal potential (Vrev) was shifted to more positive potentials by decreasing the pH gradient across the plasma membrane (deltapH). Employing Vrev as a real time monitor of pH in clamped cells, it is revealed that the H+ channel activation could decrease deltapH by approximately 0.43 unit/s. Decline in the current during prolonged depolarizations was accompanied by a positive shift in Vrev. This implies that the H+ channel activity is auto-regulated by sensing deltapH, to compensate for pH imbalance. The H+ current-density in cells with 36 nuclei was significantly smaller than that in cells with < or =5 nuclei, although the activation rate was unaltered. Thus, the H+ channel activity may alter during osteoclastogenesis. These data suggest the H+ channel is a powerful mechanism for pH homeostasis of osteoclasts that are exposed to drastic change in pH environments during the bone resorption cycle.
Asunto(s)
Homeostasis/fisiología , Hidrógeno/metabolismo , Canales Iónicos/fisiología , Osteoclastos/fisiología , Animales , Electrofisiología , Concentración de Iones de Hidrógeno , Activación del Canal Iónico/fisiología , Ratones , Ratones Endogámicos C3HRESUMEN
Osteoclasts possess extracellular Ca2+-sensing machinery to regulate bone-resorbing activity. In murine osteoclasts, an elevation of the extracellular Ca2+ concentration activated a volume-sensitive outwardly rectifying Cl- (OR(Cl)) channel. Exposure to 40 mM Ca2+ activated the OR(Cl) current in association with an increase in the planar cell area. An actin-destabilizer (cytochalasin D), removal of a major extracellular osmolyte (Na+), and a blocker for the Na+/Ca2+ exchanger (2'4'-dichlorobenzamil hydrochloride) inhibited both swelling and activation of the OR(Cl) channel by extracellular Ca2+. There was a positive correlation between the current density and increment in the cell area. The extracellular Ca2+-induced swelling was confirmed in intact (unclamped) cells by three-dimensional analysis using confocal scanning microscopy with a fluorescent dye (BCECF) in the extracellular medium. These results suggest that swelling is an intermediate signal for extracellular Ca2+ sensing of osteoclasts, which leads to activation of the OR(Cl) channel. Cell volume may be a second-message in the regulation of osteoclast function.
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Calcio/metabolismo , Tamaño de la Célula/fisiología , Canales de Cloruro/fisiología , Osteoclastos/metabolismo , Receptores de Superficie Celular/fisiología , Animales , Soluciones Hipotónicas/farmacología , Masculino , Ratones , Ratones Endogámicos C3H , Microscopía Confocal , Receptores Sensibles al CalcioRESUMEN
Voltage-gated proton channels are found in many different types of cells, where they facilitate proton movement through the membrane. The mechanism of proton permeation through the channel is an issue of long-term interest, but it remains an open question. To address this issue, we examined the temperature dependence of proton permeation. Under whole cell recordings, rapid temperature changes within a few milliseconds were imposed. This method allowed for the measurement of current amplitudes immediately before and after a temperature jump, from which the ratios of these currents (Iratio) were determined. The use of Iratio for evaluating the temperature dependence minimized the contributions of factors other than permeation. Temperature jumps of various degrees (DeltaT, -15 to 15 degrees C) were applied over a wide temperature range (4-49 degrees C), and the Q10s for the proton currents were evaluated from the Iratios. Q10 exhibited a high temperature dependence, varying from 2.2 at 10 degrees C to 1.3 at 40 degrees C. This implies that processes with different temperature dependencies underlie the observed Q10. A novel resistivity pulse method revealed that the access resistance with its low temperature dependence predominated in high temperature ranges. The measured temperature dependence of Q10 was decomposed into Q10 of the channel and of the access resistances. Finally, the Q10 for proton permeation through the voltage-gated proton channel itself was calculated and found to vary from 2.8 at 5 degrees C to 2.2 at 45 degrees C, as expected for an activation enthalpy of 64 kJ/mol. The thermodynamic features for proton permeation through proton-selective channels were discussed for the underlying mechanism.
Asunto(s)
Canales Iónicos/metabolismo , Microglía/metabolismo , Protones , Temperatura , Animales , Células Cultivadas , Citosol/metabolismo , Técnicas de Placa-Clamp , RatasRESUMEN
Voltage-gated proton (H+) channels play a pivotal role in compensating charge and pH imbalances during respiratory bursts in phagocytes. Lactic acidosis is a clinically important metabolic condition accompanying various tissue disorders in which the extracellular pH and the intracellular pH often change in parallel. In this study, we investigated the responses of the H+ channel in microglia to lactate-induced pH disturbances using the perforated-patch recordings. Na-lactate (pH 6.8) acidified the cells and activated the H+ channel within 5 min. This early activation was correlated with increases in the pH gradient across the plasma membrane (DeltapH) and was dose-dependent over a concentration range of 10-150 mM. At 10 mM, the change in DeltapH was only slight, but the H+ currents continued to increase over an hour after the cell acidosis was stabilized. Prolonged exposure to lactate (10-20 mM, >1 h) increased the amplitude by two to threefold. The late activation was not explained by increased DeltapH but by changes in the property of the channel per se. Pretreatment with staurosporine and chelerythrine, inhibitors for protein kinase C, prevented the late activation. These results suggest that the H+ channel could be activated greatly during long-lasting lactic acidosis through both DeltapH-dependent and -independent mechanisms.
Asunto(s)
Acidosis Láctica/fisiopatología , Concentración de Iones de Hidrógeno , Activación del Canal Iónico/fisiología , Canales Iónicos/fisiología , Microglía/fisiología , Protones , Equilibrio Ácido-Base/fisiología , Animales , Línea Celular , Tamaño de la Célula , Estimulación Eléctrica , Inhibidores Enzimáticos/farmacología , Ácido Láctico/farmacología , Microglía/citología , Técnicas de Placa-Clamp , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Ratas , Estaurosporina/farmacologíaRESUMEN
The vacuolar-type H(+)-ATPase (V-ATPase) in the plasma membrane of a variety of cells serves as an acid-secreting pathway, and its activity is closely related to cellular functions. Massive proton secretion often leads to electrolyte disturbances in the vicinity of the cell and may in turn affect the activity of the V-ATPase. We characterized, for the first time, the proton currents mediated by plasmalemmal V-ATPase in murine osteoclast-like cells and investigated its activity over a wide range of pH gradients across the membrane (DeltapH = extracellular pH - intracellular pH). The V-ATPase currents were identified as outward H(+) currents and were dependent on ATP and sensitive to the inhibitors bafilomycin A(1) and N,N'-dicyclohexylcarbodiimide. Although H(+) was transported uphill, the electrochemical gradient for H(+) affected the current. The currents were increased by elevating DeltapH and depolarization, and were reduced by lowering DeltapH and hyperpolarization. Elevation of extracellular Ca(2+) (5-40 mm) diminished the currents in a dose-dependent manner and made the voltage dependence more marked. Extracellular Mg(2+) mimicked the inhibition. With 40 mm Ca(2+), the currents decreased to < 40% at 0 mV and to < 10% at about -80 mV. Increases in the intracellular Ca(2+) (0.5-5 microm) did not affect the current. The data suggest that acid secretion through the plasmalemmal V-ATPase is regulated by a combination of the pH gradient, the membrane potential and the extracellular divalent cations. In osteoclasts, the activity-dependent accumulation of acids and Ca(2+) in the closed extracellular compartment might serve as negative feedback signals for regulating the V-ATPase.