RESUMEN
Aortitis is a rare adverse event of granulocyte colony-stimulating factor (G-CSF) treatment. Several previous studies have described recurrent aortitis caused by re-administration of the same G-CSF. However, no previous studies have examined the safety of switching between short-acting G-CSFs in patients who develop aortitis. We report the case of a 55-year-old man with refractory diffuse large B-cell lymphoma, who developed G-CSF-associated aortitis. The aortitis was triggered by filgrastim and recurred after treatment with lenograstim. The patient possessed human leukocyte antigen B52, which has been implicated in Takayasu arteritis. In addition, a drug-induced lymphocyte stimulation test for lenograstim performed upon detection of recurrent G-CSF-associated aortitis produced a positive result. Our case suggests that switching from one short-acting G-CSF to another does not prevent recurrence of G-CSF-associated aortitis. Although the etiology of G-CSF-associated aortitis has not been fully elucidated, our case also suggests that some patients may be genetically predisposed to aortitis.
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Aortitis , Factor Estimulante de Colonias de Granulocitos , Antígeno HLA-B52 , Linfoma de Células B Grandes Difuso , Humanos , Masculino , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Persona de Mediana Edad , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Aortitis/inducido químicamente , Aortitis/etiología , Antígeno HLA-B52/efectos adversos , Filgrastim/efectos adversos , Filgrastim/administración & dosificación , Lenograstim , Sustitución de Medicamentos , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéuticoRESUMEN
Patients with acute myeloid leukemia (AML) who have comorbidities have limited treatment options, thereby resulting in poor prognosis. Venetoclax, a specific B-cell lymphoma-2 inhibitor, has recently been approved for AML in combination with hypomethylating agents; however, only one report has described its use in patients undergoing dialysis. Herein, we report the effectiveness of combined venetoclax and azacitidine in a 73-year-old man with AML undergoing dialysis and who was ineligible for standard therapies. The safety of venetoclax and azacitidine in patients undergoing dialysis has been reported, and their combination may be a feasible option for patients with AML undergoing dialysis.
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OBJECTIVE: As of 2022, 36 anti-seizure medications (ASMs) have been licensed for the treatment of epilepsy, however, adverse effects (AEs) are commonly reported. Therefore, ASMs with a wide margin between therapeutic effects and AEs are preferred over ASMs that are associated with a narrow margin between efficacy and risk of AEs. E2730 was discovered using in vivo phenotypic screening and characterized as an uncompetitive, yet selective, inhibitor of γ-aminobutyric acid (GABA) transporter 1 (GAT1). Here, we describe the preclinical characteristics of E2730. METHODS: Anti-seizure effects of E2730 were evaluated in several animal models of epilepsy: corneal kindling, 6 Hz-44 mA psychomotor seizure, amygdala kindling, Fragile X syndrome, and Dravet syndrome models. Effects of E2730 on motor coordination were assessed in accelerating rotarod tests. The mechanism of action of E2730 was explored by [3 H]E2730 binding assay. The GAT1-selectivity over other GABA transporters was examined by GABA uptake assay of GAT1, GAT2, GAT3, or betaine/GABA transporter 1 (BGT-1) stably expressing HEK293 cells. To further investigate the mechanism for E2730-mediated inhibition of GAT1, in vivo microdialysis and in vitro GABA uptake assays were conducted under conditions of different GABA concentrations. RESULTS: E2730 showed anti-seizure effects in the assessed animal models with an approximately >20-|fold margin between efficacy and motor incoordination. [3 H]E2730 binding on brain synaptosomal membrane was abolished in GAT1-deficient mice, and E2730 selectively inhibited GAT1-mediated GABA uptake over other GABA transporters. In addition, results of GABA uptake assays showed that E2730-mediated inhibition of GAT1 positively correlated to the level of ambient GABA in vitro. E2730 also increased extracellular GABA concentration in hyperactivated conditions but not under basal levels in vivo. SIGNIFICANCE: E2730 is a novel, selective, uncompetitive GAT1 inhibitor, which acts selectively under the condition of increasing synaptic activity, contributing to a wide margin between therapeutic effect and motor incoordination.
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Anticonvulsivantes , Epilepsia , Proteínas Transportadoras de GABA en la Membrana Plasmática , Animales , Humanos , Ratones , Ataxia , Epilepsia/tratamiento farmacológico , Proteínas Transportadoras de GABA en la Membrana Plasmática/administración & dosificación , Ácido gamma-Aminobutírico/farmacología , Ácido gamma-Aminobutírico/metabolismo , Células HEK293 , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéuticoRESUMEN
BACKGROUND: Acquired hemophilia A (AHA) is a rare autoimmune disease characterized by bleeding events. Recombinant activated factor VII (rFVIIa) is a first-line bypassing agent, which is effective against clinically significant bleeding. However, there is no standard way of tapering and discontinuing rFVIIa, mainly because there is no established method for monitoring rFVIIa therapy for AHA. CASE PRESENTATION: Here, we report three AHA cases, in which we adjusted the rFVIIa dosing interval based on the results of thromboelastography (TEG) performed just before the administration of the next dose of rFVIIa. The dosing interval of rFVIIa was prolonged based on the reaction rate time (R) according to TEG, which is correlated with coagulation factor activity. The R-value reference range reported by the manufacturer of the TEG system was used as a threshold for making decisions. In these three cases, there was no rebleeding, and the patients' ability to perform activities of daily living did not decline. CONCLUSION: Our cases suggest that conducting TEG-based monitoring just before the administration of the next dose of rFVIIa may be useful for guiding increases in the rFVIIa dosing interval without causing rebleeding events. Further investigations are warranted to examine how TEG could be used to determine the most appropriate rFVIIa dosing interval, e.g., through regular TEG-based monitoring, and the optimal TEG-derived threshold for indicating changes to the rFVIIa dosing interval.
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Kabuki syndrome (KS) is a rare congenital disorder commonly complicated by humoral immunodeficiency. Patients with KS present with mutation in the histone-lysine N-methyltransferase 2D (KMT2D) gene. Although various KMT2D mutations are often identified in lymphoma and leukemia, those encountered in aplastic anemia (AA) are limited. Herein, we present the case of a 45-year-old Japanese man who developed severe pancytopenia and hypogammaglobulinemia. He did not present with any evident malformations, intellectual disability, or detectable levels of autoantibodies. However, B-cell development was impaired. Therefore, a diagnosis of very severe AA due to a hypoplastic marrow, which did not respond to granulocyte colony-stimulating factor, was made. The patient received umbilical cord blood transplantation but died from a Pseudomonas infection before neutrophil engraftment. Trio whole-exome sequencing revealed a novel missense heterozygous mutation c.15959G >A (p.R5320H) in exon 50 of the KMT2D gene. Moreover, Sanger sequencing of peripheral blood and bone marrow mononuclear cells and a skin biopsy specimen obtained from this patient identified this heterozygous mutation, suggesting that de novo mutation associated with KS occurred in the early embryonic development. Our case showed a novel association between KS mutation and adult-onset AA.
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Anomalías Múltiples/genética , Anemia Aplásica/genética , Proteínas de Unión al ADN/genética , Cara/anomalías , Enfermedades Hematológicas/genética , Mutación , Proteínas de Neoplasias/genética , Enfermedades Vestibulares/genética , Anomalías Múltiples/enzimología , Anomalías Múltiples/terapia , Aloinjertos , Anemia Aplásica/enzimología , Anemia Aplásica/terapia , Trasplante de Células Madre de Sangre del Cordón Umbilical , Resultado Fatal , Enfermedades Hematológicas/enzimología , Enfermedades Hematológicas/terapia , Humanos , Masculino , Persona de Mediana Edad , Gravedad del Paciente , Infecciones por Pseudomonas , Enfermedades Vestibulares/enzimología , Enfermedades Vestibulares/terapiaRESUMEN
Currently, the humanized anti-C5 monoclonal antibody, eculizumab, is widely used for treating paroxysmal nocturnal hemoglobinuria (PNH) due to its effects on suppression of intravascular hemolysis and resulting improvement in quality of life. However, in some cases, this treatment is refractory or is associated with meningococcal meningitis. No region-specific analyses have been published, and currently, information on region specificity and genetic factors is limited. We present here the results of a retrospective study involving eight patients with PNH who were treated with eculizumab in our hospital in Wakayama, Japan. The median age of these patients was 77 (range 23-88) years. Six patients had a complication of aplastic anemia, four patients had a history of thrombosis, and two experienced hemolytic episodes. Before initiating eculizumab treatment, the median serum LDH level was 1,192 IU/l (range 755-1,525 IU/l). Serum LDH levels normalized in five patients within a month of initiating therapy and PNH-related symptoms disappeared. C5 gene mutations were identified in the three patients who did not respond to eculizumab.
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Hemoglobinuria Paroxística , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados , Humanos , Japón , Persona de Mediana Edad , Calidad de Vida , Estudios Retrospectivos , Adulto JovenAsunto(s)
Cadenas Ligeras de Inmunoglobulina/aislamiento & purificación , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Placa Amiloide/diagnóstico , Anticuerpos Antiidiotipos/inmunología , Biopsia , Humanos , Cadenas Ligeras de Inmunoglobulina/inmunología , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/genética , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/inmunología , Masculino , Persona de Mediana Edad , Placa Amiloide/genética , Placa Amiloide/inmunologíaRESUMEN
We managed a patient with acute myeloid leukemia (AML) who showed refractory ascites that developed in late-phase cord blood transplantation (CBT). The ascites obverted 5 months after CBT. The liver was atrophic, and serum hyaluronic acid was elevated at the onset, suggesting fibrotic changes in the liver. The ascites were transiently improved by cell-free and concentrated ascites reinfusion therapy (CART) and corticosteroid administration; however, the patient died from anasarca and recurrent AML 378 d after CBT. The etiology of the ascites is not well understood; therefore, additional studies on similar patients should be explored for proper management.
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Ascitis/terapia , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Humanos , Cirrosis HepáticaRESUMEN
Porcine circovirus associated diseases (PCVAD) have multiple manifestations that have been attributed to porcine circovirus type 2 (PCV2). Recently, a novel porcine circovirus, PCV type 3 (PCV3), was identified in pigs with systemic inflammation of unknown etiology. In this study, we tried to detect the PCV3 genome in tissue samples collected from Japanese pig herds in 2016. The PCV3 genome was detected by PCR in 7 of 73 samples. The homology between each Japanese strain was 99.5% for the full-length sequence and 98.9 to 99.2% for the open reading frame 2. These results suggest that PCV3 has already invaded Japanese pig farms.
Asunto(s)
Infecciones por Circoviridae/veterinaria , Circovirus/aislamiento & purificación , Enfermedades de los Porcinos/diagnóstico , Animales , Infecciones por Circoviridae/diagnóstico , Circovirus/clasificación , Japón , Filogenia , PorcinosRESUMEN
BACKGROUND: Porcine epidemic diarrhea (PED) is a lethal infectious disease in suckling piglets with symptoms including watery diarrhea caused by PED virus (PEDV). Since the late 1990's, live vaccines based on genogroup 1 virus have been used in Japan, and a significant amount of the vaccine has been used even after new genogroups invaded in 2013. In this study, we evaluated the effect of a conventional PED live vaccine on a newly prevalent genogroup 2 field strain in experimental and field situations. METHODS: Two pregnant sows were administered twice the live vaccine before farrowing. A pregnant sow was served as a negative control. All newborn piglets were challenged with the genogroup 2 virus, and clinical signs were monitored for 7 days post challenge. PEDV-specific immune responses in serum and milk of the sows were assayed by virus neutralization assay. The efficacy of PED live vaccine in vaccinated or non-vaccinated farms was evaluated by comparing the mortality rate of suckling piglets after the onset of PED. RESULTS: The challenged piglets exhibited watery diarrhea with or without vaccination. However, the clinical score of piglets born from vaccinated sows significantly improved after the 4th day of the challenge. The survival rate of piglets in the vaccinated group at the end of the experimental period was 80%, whereas in the control group was 0%. Neutralizing antibody titers in serum and milk of control sow was negative throughout the experimental period, whereas high titers were observed in the vaccinated sows. The vaccinated farms significantly reduced the mortality rate of suckling piglets after the onset of PED, compared to farms not vaccinated. CONCLUSIONS: The conventional PED live vaccine induced the lactogenic immunity to vaccinated sows and showed partial protection against the genogroup 2 virus both under the experimental and field conditions.
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Infecciones por Coronavirus/veterinaria , Virus de la Diarrea Epidémica Porcina/inmunología , Enfermedades de los Porcinos/prevención & control , Enfermedades de los Porcinos/virología , Vacunas de Productos Inactivados/inmunología , Vacunas Virales/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Chlorocebus aethiops , Femenino , Genotipo , Inmunización , Japón , Pruebas de Neutralización , Evaluación de Resultado en la Atención de Salud , Filogenia , Virus de la Diarrea Epidémica Porcina/genética , Embarazo , Porcinos , Enfermedades de los Porcinos/diagnóstico , Enfermedades de los Porcinos/inmunología , Células VeroRESUMEN
N-Cyclopropylmethyl-7-(2,6-dimethoxy-4-methoxymethylphenyl)-2-ethyl-N-(tetrahydro-2H-pyran-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-amine tosylate (E2508) is a newly discovered selective corticotropin-releasing factor 1 receptor antagonist. Here, we investigated the effects of E2508 on wrap restraint stress-induced defecation and visceral pain in rats. Oral pretreatment with E2508 dose-dependently decreased stool weights after 20min wrap restraint stress and significant effects were observed at doses of 30 and 100mg/kg. However, E2508 did not affect basal defecation at doses up to 100mg/kg. In contrast, alosetron, a 5-HT3 receptor antagonist, decreased both wrap restraint stress-induced and basal stool output at a dose of 0.1mg/kg. In a rat visceral pain model, subcutaneous injections of both E2508 (0.01 and 0.1mg/kg) and alosetron (0.001 and 0.01mg/kg) significantly decreased the number of abdominal muscle contractions induced by colonic distention, suggesting these drugs reduced visceral pain. Together, these results demonstrate E2508 has the potential to be an effective therapy for the treatment of irritable bowel syndrome with a lower risk of adverse events such as constipation compared with the current clinically used 5-HT3 receptor antagonist.
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Defecación/efectos de los fármacos , Síndrome del Colon Irritable/tratamiento farmacológico , Pirazoles/farmacología , Piridinas/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Antagonistas del Receptor de Serotonina 5-HT3/farmacología , Estrés Psicológico/complicaciones , Dolor Visceral/tratamiento farmacológico , Animales , Carbolinas/administración & dosificación , Carbolinas/farmacología , Modelos Animales de Enfermedad , Masculino , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Ratas , Ratas Endogámicas F344 , Antagonistas del Receptor de Serotonina 5-HT3/administración & dosificación , Dolor Visceral/etiologíaRESUMEN
Corticotropin-releasing factor (CRF) is a hormone secreted by the hypothalamus in response to stress, and CRF antagonists may be effective for the treatment of stress-related disorders including major depressive and anxiety disorders. Here, we investigated the in vivo pharmacological profile of N-cyclopropylmethyl-7-(2,6-dimethoxy-4-methoxymethylphenyl)-2-ethyl-N-(tetrahydro-2H-pyran-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-amine tosylate (E2508), a recently synthesized, orally active CRF1 receptor antagonist. Oral administration of a single dose of E2508 (3 or 10mg/kg), but not fluoxetine (30mg/kg), a selective serotonin reuptake inhibitor (SSRI), significantly shortened immobility time in rats in the forced swim test. E2508 (10, 30, or 100mg/kg) also showed an antidepressant-like effect in the forced swim test in mice, with no sedative or muscle relaxant effects for doses up to 100mg/kg. Moreover, E2508 (5 or 20mg/kg) significantly reduced anxiety-like behavior in the rat defensive burying test. Diazepam, a benzodiazepine anxiolytic agent, also showed an anxiolytic effect in the defensive burying test at the same dose that induced a muscle relaxant effect in mice. Administration of E2508 (30mg/kg) for 14 consecutive days did not affect sexual behavior. By contrast, fluoxetine (30mg/kg) administration for ≥7 consecutive days decreased sexual behavior. These results indicate that E2508 has both potent antidepressant-like and anxiolytic-like effects in rodent models, and is well tolerated compared with a commonly prescribed therapeutic SSRI or benzodiazepine.
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Ansiolíticos/administración & dosificación , Antidepresivos/administración & dosificación , Trastornos de Ansiedad/prevención & control , Trastorno Depresivo Mayor/prevención & control , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Acetilcolina/sangre , Administración Oral , Animales , Trastornos de Ansiedad/metabolismo , AMP Cíclico/metabolismo , Trastorno Depresivo Mayor/metabolismo , Diazepam/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Fluoxetina/administración & dosificación , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Fuerza Muscular/efectos de los fármacos , Pirimidinas/administración & dosificación , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Ratas Wistar , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Conducta Sexual Animal/efectos de los fármacosRESUMEN
Several studies have shown that glycine transporter 1 (GlyT1) inhibitors have anxiolytic actions. There are two types of glycine receptor: the strychnine-sensitive glycine receptor (GlyA) and the strychnine-insensitive glycine receptor (GlyB); however, which receptor is the main contributor to the anxiolytic actions of GlyT1 inhibitors is yet to be determined. Here, we clarified which glycine receptor is the main contributor to the anxiolytic effects of GlyT1 inhibitors by using maternal separation-induced ultrasonic vocalization (USV) by rat pups as an index of anxiety. We confirmed that administration of the benzodiazepine diazepam or the selective serotonin reuptake inhibitor escitaloplam, which are both clinically proven anxiolytics, or the GlyT1 inhibitor SSR504734 (2-chloro-N-[(S)-phenyl[(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide), decreases USV in rat pups. In addition, we showed that another GlyT1 inhibitor, ALX5407 ((R)-N-[3-(4'-fluorophenyl)-3(4'-phenylphenoxy)propyl]sarcosine) also decreases USV in rat pups. SSR504734- or ALX5407-induced decreases in USV were dose-dependently reversed by administration of the GlyA antagonist strychnine, whereas the diazepam- or escitalopram-induced decreases in USV were not. Furthermore, GlyT1-induced decreases in USV were not reversed by administration of the GlyB antagonist L-687,414. Together, these results suggest that GlyA activation is the main contributor to the anxiolytic actions of GlyT1 inhibitors and that the anxiolytic actions of diazepam and escitalopram cannot be attributed to GlyA activation. Our findings provide new insights into the importance of the activation of GlyA in the anxiolytic effects of GlyT1 inhibitors.
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Ansiolíticos/uso terapéutico , Ansiedad de Separación/tratamiento farmacológico , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Privación Materna , Moduladores del Transporte de Membrana/uso terapéutico , Receptores de Glicina/agonistas , Vocalización Animal/efectos de los fármacos , Animales , Animales Recién Nacidos , Ansiolíticos/administración & dosificación , Ansiolíticos/efectos adversos , Ansiolíticos/química , Ansiedad de Separación/etiología , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Benzamidas/antagonistas & inhibidores , Benzamidas/uso terapéutico , Temperatura Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Moduladores del Transporte de Membrana/administración & dosificación , Moduladores del Transporte de Membrana/efectos adversos , Moduladores del Transporte de Membrana/química , Terapia Molecular Dirigida , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Piperidinas/antagonistas & inhibidores , Piperidinas/uso terapéutico , Pirrolidinonas/uso terapéutico , Ratas Sprague-Dawley , Receptores de Glicina/antagonistas & inhibidores , Receptores de Glicina/metabolismo , Sarcosina/administración & dosificación , Sarcosina/efectos adversos , Sarcosina/análogos & derivados , Sarcosina/antagonistas & inhibidores , Sarcosina/uso terapéutico , Estricnina/farmacología , UltrasonidoRESUMEN
OBJECTIVE: To evaluate the clinical benefits of the endothelin receptor antagonist bosentan on interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) who are ineligible for cyclophosphamide (CYC) therapy. METHODS: In this prospective open-label study, 9 patients with SSc and ILD received bosentan for 24 months. The main reasons for avoiding CYC included severely impaired lung function, long disease duration, and relapse after CYC treatment. Pulmonary function tests and Doppler echocardiograms were evaluated every 6 months, and high-resolution computed tomography (HRCT) was performed every 12 months. For an extended survival analysis, 17 historical controls who met the inclusion criteria at referral and had not used any immunosuppressive or antifibrotic agents thereafter were selected from the SSc database. RESULTS: Two patients did not finish the study; one developed vasculitis requiring high-dose corticosteroids and another died of bacterial pneumonia. The remaining 7 patients tolerated bosentan and completed the study period. There were trends toward mildly reduced forced vital capacity, total lung capacity, and diffusing capacity for carbon monoxide over time. Two patients developed pulmonary hypertension during the 24-month period. HRCT scores for ground-glass opacity, pulmonary fibrosis, and honeycomb cysts gradually increased. In the extended study, there was no difference in cumulative survival rate between the bosentan-treated and historical control groups. CONCLUSION: The gradual worsening of pulmonary function and HRCT findings in patients treated with bosentan was consistent with the natural course of SSc-associated ILD. This study does not support the use of bosentan for SSc-associated ILD even when CYC treatment is inadvisable.
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Antihipertensivos/uso terapéutico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Esclerodermia Sistémica/complicaciones , Sulfonamidas/uso terapéutico , Adulto , Anciano , Bosentán , Ciclofosfamida/uso terapéutico , Femenino , Humanos , Pulmón/fisiopatología , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pruebas de Función Respiratoria , Esclerodermia Sistémica/fisiopatología , Resultado del TratamientoRESUMEN
Interleukin-6 (IL-6) is a pleiotropic cytokine with a wide range of biologic activities in immune regulation, hematopoiesis, inflammation, and oncogenesis. Recent accumulating evidence indicates a pathologic role for IL-6 in promoting proliferation of both smooth muscle and endothelial cells in the pulmonary arterioles, resulting in development of pulmonary arterial hypertension (PAH). Here, we describe a patient with mixed connective tissue disease and severe, refractory PAH. Her functional activity and hemodynamic parameters dramatically responded to tocilizumab, a humanized monoclonal antibody to human IL-6 receptor, which was aimed at treating multicentric Castleman's disease. It appears that IL-6 blockade may hold promise as an adjunct drug in treatment of PAH in idiopathic form as well as in association with connective tissue disease.
RESUMEN
OBJECTIVE: To evaluate the effects of i.v. CYC on the number of circulating endothelial progenitor cells (EPCs) in patients with SSc, and the potential association of the EPC response with CYC's effect for treating interstitial lung disease (ILD). METHODS: This open-label, prospective study involved 12 patients with SSc and alveolitis (CYC group). All patients received six courses of i.v. CYC (0.5 g/m2) at 4-week intervals in combination with low-dose prednisolone. Ten patients were followed for 24 months. Seven SSc patients treated with low-dose prednisolone alone were used as a control for the EPC measurement (control group). Five patients with non-SSc CTD who received i.v. CYC and prednisolone also served as disease controls. EPCs were quantified by the partial enrichment of CD34+ cells followed by three-colour flow cytometry. The circulating levels of vascular injury markers were measured by immunoassay. RESULTS: The EPC count was significantly increased at 2 weeks after treatment in the CYC group (P=0.02), but not in the control group, while CYC increased EPC count in all disease controls. The SSc patients in the CYC group were divided into five EPC responders and seven EPC non-responders. Circulating vascular injury markers were reduced in the responders, but not in the non-responders. During the 24-month follow-up, 3 of 10 patients developed end-stage lung disease, and all of them were EPC non-responders. CONCLUSION: A low-dose i.v. CYC induces EPC mobilization, which may contribute to the efficacy for treating SSc-associated ILD.
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Ciclofosfamida/administración & dosificación , Células Endoteliales/efectos de los fármacos , Esclerodermia Sistémica/tratamiento farmacológico , Células Madre/efectos de los fármacos , Anciano , Biomarcadores , Humanos , Inyecciones Intravenosas , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Here, we report an adult patient with IgA-related enteropathy complicated with massive intestinal bleeding and acute renal failure, but without skin lesions. Surgical resection of the small intestine and steroid pulse therapy was performed. Histopathology revealed significant deposition of IgA and C3 in the small vessels of the intestine and the kidney mesangium. Although skin purpura was absent, the histopathology and clinical manifestations suggested that the pathophysiology was similar to Henoch-Schönlein purpura (HSP), implying IgA-related enteropathy as a subclass of HSP. Retrospective analysis indicates that terminal ileum lesions may be a poor prognostic indicator.
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Progresión de la Enfermedad , Hemorragia Gastrointestinal/diagnóstico , Glomerulonefritis por IGA/diagnóstico , Vasculitis por IgA/diagnóstico , Inmunoglobulina A , Diagnóstico Diferencial , Resultado Fatal , Hemorragia Gastrointestinal/complicaciones , Glomerulonefritis por IGA/complicaciones , Humanos , Vasculitis por IgA/complicaciones , Inmunoglobulina A/efectos adversos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
We have previously reported a novel peptide, hippocampal cholinergic neurostimulating peptide (HCNP), which induces acetylcholine synthesis by increasing the amount of cholineacetyltransferase (ChAT) in medial septal nuclei. The HCNP precursor protein, composed of 186 amino acids, is an inhibitory factor of the c-Raf/ MEK cascade and may be involved in the development of the fetal rat brain via the inhibition of Erk phosphorylation. To clarify the involvement of HCNP in hippocampal cholinergic circuitry, we previously generated HCNP precursor protein (HCNP-pp) transgenic mice using the promoter of the alpha subunit of Ca(2+) calmodulin-dependent protein kinase II (CaMKIIalpha). These mice showed increased levels of ChAT in medial septal nuclei. Here, we investigated the behavioral phenotype of these mice, such as locomotor activity, mood and working/spatial memory. We demonstrate that HCNP-pp transgenic mice show a depressive-like phenotype at 30 weeks of age, but not at 12 weeks of age. We suggest that either HCNP and/or HCNP precursor protein may evoke the depressive-like phenotype via cholinergic hyperactivity from early neonatal life and/or inhibition of phosphorylated Erk in the neonatal hippocampus.