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1.
J Mol Cell Cardiol ; 177: 50-61, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36898499

RESUMEN

Genetic testing for inherited arrhythmias and discriminating pathogenic or benign variants from variants of unknown significance (VUS) is essential for gene-based medicine. KCNQ1 is a causative gene of type 1 long QT syndrome (LQTS), and approximately 30% of the variants found in type 1 LQTS are classified as VUS. We studied the role of zebrafish cardiac arrhythmia model in determining the clinical significance of KCNQ1 variants. We generated homozygous kcnq1 deletion zebrafish (kcnq1del/del) using the CRISPR/Cas9 and expressed human Kv7.1/MinK channels in kcnq1del/del embryos. We dissected the hearts from the thorax at 48 h post-fertilization and measured the transmembrane potential of the ventricle in the zebrafish heart. Action potential duration was calculated as the time interval between peak maximum upstroke velocity and 90% repolarization (APD90). The APD90 of kcnq1del/del embryos was 280 ± 47 ms, which was significantly shortened by injecting KCNQ1 wild-type (WT) cRNA and KCNE1 cRNA (168 ± 26 ms, P < 0.01 vs. kcnq1del/del). A study of two pathogenic variants (S277L and T587M) and one VUS (R451Q) associated with clinically definite LQTS showed that the APD90 of kcnq1del/del embryos with these mutant Kv7.1/MinK channels was significantly longer than that of Kv7.1 WT/MinK channels. Given the functional results of the zebrafish model, R451Q could be reevaluated physiologically from VUS to likely pathogenic. In conclusion, functional analysis using in vivo zebrafish cardiac arrhythmia model can be useful for determining the pathogenicity of loss-of-function variants in patients with LQTS.


Asunto(s)
Síndrome de QT Prolongado , Pez Cebra , Animales , Humanos , Canal de Potasio KCNQ1/genética , Síndrome de QT Prolongado/genética , Mutación , ARN Complementario , Virulencia , Pez Cebra/genética
2.
Europace ; 25(6)2023 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-37386841

RESUMEN

AIMS: Patients with particular mutations of type-2 long QT syndrome (LQT2) are at an increased risk for malignant arrhythmia during fever. This study aimed to determine the mechanism by which KCNH2 mutations cause fever-induced QT prolongation and torsades de pointes (TdP). METHODS AND RESULTS: We evaluated three KCNH2 mutations, G584S, D609G, and T613M, in the Kv11.1 S5-pore region, identified in patients with marked QT prolongation and TdP during fever. We also evaluated KCNH2 M124T and R269W, which are not associated with fever-induced QT prolongation. We characterized the temperature-dependent changes in the electrophysiological properties of the mutant Kv11.1 channels by patch-clamp recording and computer simulation. The average tail current densities (TCDs) at 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller and less increased with rising temperature from 35°C to 40°C than those for WT, M124T, and R269W. The ratios of the TCDs at 40°C to 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller than for WT, M124T, and R269W. The voltage dependence of the steady-state inactivation curve for WT, M124T, and R269W showed a significant positive shift with increasing temperature; however, that for G584S, WT+D609G, and WT+T613M showed no significant change. Computer simulation demonstrated that G584S, WT+D609G, and WT+T613M caused prolonged action potential durations and early afterdepolarization formation at 40°C. CONCLUSION: These findings indicate that KCNH2 G584S, D609G, and T613M in the S5-pore region reduce the temperature-dependent increase in TCDs through an enhanced inactivation, resulting in QT prolongation and TdP at a febrile state in patients with LQT2.


Asunto(s)
Síndrome de QT Prolongado , Torsades de Pointes , Humanos , Torsades de Pointes/diagnóstico , Torsades de Pointes/genética , Simulación por Computador , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/genética , Mutación , Proteínas de Unión al ADN , Canal de Potasio ERG1/genética
3.
Artículo en Inglés | MEDLINE | ID: mdl-37851159

RESUMEN

Objective structured clinical examination (OSCE) is widely used to assess medical students' clinical skills. Virtual OSCEs were used in place of in-person OSCEs during the COVID-19 pandemic; however, their reliability is yet to be robustly analyzed. By applying generalizability (G) theory, this study aimed to evaluate the reliability of a hybrid OSCE, which admixed in-person and online methods, and gain insights into improving OSCEs' reliability. During the 2020-2021 hybrid OSCEs, one examinee, one rater, and a vinyl mannequin for physical examination participated onsite, and a standardized simulated patient (SP) for medical interviewing and another rater joined online in one virtual breakout room on an audiovisual conferencing system. G-coefficients and 95% confidence intervals of the borderline score, namely border zone (BZ), under the standard 6-station, 2-rater, and 6-item setting were calculated. G-coefficients of in-person (2017-2019) and hybrid OSCEs (2020-2021) under the standard setting were estimated to be 0.624, 0.770, 0.782, 0.759, and 0.823, respectively. The BZ scores were estimated to be 2.43-3.57, 2.55-3.45, 2.59-3.41, 2.59-3.41, and 2.51-3.49, respectively, in the score range from 1 to 6. Although hybrid OSCEs showed reliability comparable to in-person OSCEs, they need further improvement as a very high-stakes examination. In addition to increasing clinical vignettes, having more proficient online/on-demand raters and/or online SPs for medical interviews could improve the reliability of OSCEs. Reliability can also be ensured through supplementary examination and by increasing the number of online raters for a small number of students within the BZs.

4.
Circ J ; 86(1): 118-127, 2021 12 24.
Artículo en Inglés | MEDLINE | ID: mdl-34615813

RESUMEN

BACKGROUND: The usefulness of electrocardiographic (ECG) voltage criteria for diagnosing hypertrophic cardiomyopathy (HCM) in pediatric patients is poorly defined.Methods and Results:ECGs at the 1st grade (mean [±SD] age 6.6±0.3 years) were available for 11 patients diagnosed with HCM at around the 7th grade (13.2±0.3 years). ECGs were available for another 64 patients diagnosed with HCM in the 1st (n=15), 7th (n=32), and 10th (n=17) grades. Fifty-one voltage criteria were developed by grade and sex using 62,841 ECGs from the general population. Voltage criteria were set at the 99.95th percentile (1/2,000) point based on the estimated prevalence of childhood HCM (2.9 per 100,000 [1/34,483]) to decrease false negatives. Conventional criteria were from guidelines for school-aged children in Japan. Of 11 patients before diagnosis, 2 satisfied conventional criteria in 1st grade; 5 (56%) of the remaining 9 patients fulfilled 2 voltage criteria (R wave in limb-lead I [RI]+S wave in lead V3 [SV3] and R wave in lead V3 [RV3]+SV3). Robustness analysis for sensitivity showed RV3+SV3 was superior to RI+SV3. For all patients after diagnosis, RI+SV4 was the main candidate. However, conventional criteria were more useful than voltage criteria. CONCLUSIONS: Early HCM prediction was possible using RV3+SV3 in >50% of patients in 1st grade. Voltage criteria may help diagnose prediagnostic or early HCM, and prevent tragic accidents, although further prospective studies are required.


Asunto(s)
Cardiomiopatía Hipertrófica , Adolescente , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/epidemiología , Niño , Electrocardiografía/métodos , Humanos , Japón , Estudios Prospectivos
5.
Heart Vessels ; 35(7): 985-995, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32161993

RESUMEN

Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy and is associated with high morbidity and mortality. However, the role and significance of school screening for LVNC have not been fully elucidated. In this multicenter, retrospective cohort study, a total of 105 children with LVNC were included from 2000 to 2017. At the initial presentation, 44 patients (41.9%) were diagnosed by school screening. One (1.0%) patient underwent heart transplantation and four (3.8%) patients died during the study. Electrocardiogram data showed a high prevalence of fragmented QRS (33.4%) and J wave (15.7%). Treatments were needed in eight (18.2%) patients who were detected by school screening. The multivariable proportional hazards model showed T-wave abnormality on electrocardiogram in first graders was independent risk factors for major adverse cardiac events (odds ratio 4.94, p value = 0.0007). Moreover, dilation of the left atrium on chest X-ray and low ejection fraction on echocardiogram at the initial treatment were independent risk factors for treatment (odds ratio 1.7 × 107 and 22.3, p = 0.0362 and 0.0028, respectively). This study is the first report focusing on school screening in a large pediatric cohort with LVNC. With the use of abnormalities in electrocardiogram, school screening may be a good detector of and predictor for LVNC.


Asunto(s)
Arritmias Cardíacas/diagnóstico , Programas de Detección Diagnóstica , Electrocardiografía , No Compactación Aislada del Miocardio Ventricular/diagnóstico , Servicios de Salud Escolar , Adolescente , Factores de Edad , Arritmias Cardíacas/mortalidad , Arritmias Cardíacas/terapia , Niño , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Trasplante de Corazón , Humanos , No Compactación Aislada del Miocardio Ventricular/mortalidad , No Compactación Aislada del Miocardio Ventricular/terapia , Japón/epidemiología , Masculino , Valor Predictivo de las Pruebas , Prevalencia , Pronóstico , Estudios Retrospectivos , Medición de Riesgo
6.
J Mol Cell Cardiol ; 114: 234-242, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29175505

RESUMEN

RATIONALE: Induced pluripotent stem cells (iPSCs) have been generated from patients with various forms of disease, including Danon disease (DD); however, few reports exist regarding disease-specific iPSCs derived from clinically divergent monozygotic twins. OBJECTIVE: We examined the characteristics of iPSCs and iPSC-derived cardiomyocytes (iPSC-CMs) generated from clinically divergent monozygotic female twins with DD. METHODS AND RESULTS: We generated iPSCs derived from T-cells isolated from clinically divergent, 18-year-old female twins with DD harboring a mutation in LAMP2 at the intron 6 splice site (IVS6+1_4delGTGA). Two divergent populations of iPSCs could prepare from each twin despite of their clinical divergence: one with wild-type LAMP2 expression (WT-iPSCs) and a second with mutant LAMP2 expression (MT-iPSCs). The iPSCs were differentiated into iPSC-CMs and then autophagy failure was observed only in MT-iPSC-CMs by electron microscopy, tandem fluorescent-tagged LC3 analysis, and LC3-II western blotting. Under these conditions, X-chromosome inactivation (XCI) was determined by PCR for the (CAG)n repeat in the androgen receptor gene, revealing an extremely skewed XCI pattern with the inactivated paternal wild-type and maternal mutant X-chromosomes in MT-iPSCs and WT-iPSCs, respectively, from each twin. CONCLUSION: Regardless of their clinical differences, we successfully established two sets of iPSC lines that expressed either wild-type or mutant LAMP2 allele from each monozygotic twin with DD, of which only the populations expressing mutant LAMP2 showed autophagic failure.


Asunto(s)
Enfermedad por Depósito de Glucógeno de Tipo IIb/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Gemelos Monocigóticos , Animales , Autofagia , Secuencia de Bases , Línea Celular , Femenino , Enfermedad por Depósito de Glucógeno de Tipo IIb/genética , Enfermedad por Depósito de Glucógeno de Tipo IIb/patología , Humanos , Células Madre Pluripotentes Inducidas/ultraestructura , Proteína 2 de la Membrana Asociada a los Lisosomas/genética , Proteína 2 de la Membrana Asociada a los Lisosomas/metabolismo , Ratones , Proteínas Mutantes/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/ultraestructura , ARN Mensajero/genética , ARN Mensajero/metabolismo , Inactivación del Cromosoma X/genética
8.
Pediatr Emerg Care ; 33(8): 564-569, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27261952

RESUMEN

OBJECTIVES: To assess the effectiveness of pediatric simulation by remote facilitation. We hypothesized that simulation by remote facilitation is more effective compared to simulation by an on-site facilitator. We defined remote facilitation as a facilitator remotely (1) introduces simulation-based learning and simulation environment, (2) runs scenarios, and (3) performs debriefing with an on-site facilitator. METHODS: A remote simulation program for medical students during pediatric rotation was implemented. Groups were allocated to either remote or on-site facilitation depending on the availability of telemedicine technology. Both groups had identical 1-hour simulation sessions with 2 scenarios and debriefing. Their team performance was assessed with behavioral assessment tool by a trained rater. Perception by students was evaluated with Likert scale (1-7). RESULTS: Fifteen groups with 89 students participated in a simulation by remote facilitation, and 8 groups with 47 students participated in a simulation by on-site facilitation. Participant demographics and previous simulation experience were similar. Both groups improved their performance from first to second scenario: groups by remote simulation (first [8.5 ± 4.2] vs second [13.2 ± 6.2], P = 0.003), and groups by on-site simulation (first [6.9 ± 4.1] vs second [12.4 ± 6.4], P = 0.056). The performance improvement was not significantly different between the 2 groups (P = 0.94). Faculty evaluation by students was equally high in both groups (7 vs 7; P = 0.65). CONCLUSIONS: A pediatric acute care simulation by remote facilitation significantly improved students' performance. In this pilot study, remote facilitation seems as effective as a traditional, locally facilitated simulation. The remote simulation can be a strong alternative method, especially where experienced facilitators are limited.


Asunto(s)
Reanimación Cardiopulmonar/educación , Pediatría/educación , Entrenamiento Simulado/métodos , Estudiantes de Medicina , Adulto , Niño , Femenino , Humanos , Masculino , Evaluación de Procesos y Resultados en Atención de Salud , Proyectos Piloto , Adulto Joven
9.
Circ J ; 78(3): 701-7, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24463758

RESUMEN

BACKGROUND: Circumstances and outcomes of out-of-hospital cardiac arrest (OHCA) in elementary and middle school students while at school in the era of public-access defibrillation are unknown. METHODS AND RESULTS: We conducted a nationwide hospital-based survey of elementary and middle school students who had had OHCA of cardiac origin and received prehospital resuscitation in 2005-2009. Among 58 cases recruited, 90% were witnessed by bystanders; 86% had ventricular fibrillation as the initial rhythm; 74% were resuscitated by bystanders; 24% were defibrillated by bystanders; 55% occurred at school; 66% were exercise-related; 48% were followed up before the event; 67% had structural heart disease. In total, 53% of overall patients and 79% of those initially defibrillated by bystanders had a favorable neurological outcome. Patients were more likely to be defibrillated by bystanders (38% vs. 8%, P=0.012) and had a more favorable neurological outcome in schools (69% vs. 35%, P=0.017) than in other locations. The majority of arrests in schools were exercise-related (84% vs. 42%, P=0.001), occurred at sports venues, and students were resuscitated by teachers; half of the cases at school occurred in patients with a pre-event follow-up. CONCLUSIONS: After OHCA, children were more likely to be defibrillated by bystanders and had a better outcome in schools than in other locations, which may be relevant to the circumstances of events.


Asunto(s)
Desfibriladores , Paro Cardíaco Extrahospitalario/mortalidad , Paro Cardíaco Extrahospitalario/terapia , Resucitación , Estudiantes , Fibrilación Ventricular/mortalidad , Fibrilación Ventricular/terapia , Adolescente , Niño , Femenino , Humanos , Masculino
10.
Europace ; 15(9): 1259-66, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23603306

RESUMEN

AIMS: The purpose of this study was to determine whether implementation of public access defibrillation (PAD) improves the outcome after out-of-hospital cardiac arrest (OHCA) in school-age children at national level. METHODS AND RESULTS: We conducted a prospective, nationwide, population-based Japanese Utstein registry study of consecutive OHCA cases in elementary and middle school children (7-15 years of age) who had a bystander-witnessed arrest of presumed cardiac origin during 2005-09 and received pre-hospital resuscitation by emergency responders. The primary endpoint was a favourable neurological outcome 1 month after an arrest. Among 230 eligible patients enrolled, 128 had ventricular fibrillation (VF) as an initial rhythm. Among these 128 patients, 29 (23%) children received a first shock by a bystander. Among these 29 patients, the proportion of the favourable neurological outcome after OHCA was 55%. During the study period, the proportion of patients initially shocked by a bystander among eligible patients increased from 2 to 21% (P = 0.002 for trend). The proportion of patients with a favourable neurological outcome after OHCA increased from 12 to 36% overall (P = 0.006). The collapse to defibrillation time was shorter in bystander-initiated defibrillation when compared with defibrillation by emergency responders (3.3 ± 3.7 vs. 12.9 ± 5.8 min, P < 0.001), and was independently associated with a favourable neurological outcome after OHCA [P = 0.03, odds ratio (OR) per 1 min increase, 0.90 (95% confidence interval 0.82-0.99)]. A non-family member's witness was independently associated with VF as the initial rhythm [P < 0.001, OR 4.03 (2.08-7.80)]. CONCLUSION: Implementation of PAD improved the outcome after OHCA in school-age children at national level in Japan.


Asunto(s)
Desfibriladores/estadística & datos numéricos , Paro Cardíaco Extrahospitalario/mortalidad , Paro Cardíaco Extrahospitalario/prevención & control , Sistema de Registros , Estudiantes/estadística & datos numéricos , Adolescente , Niño , Femenino , Humanos , Incidencia , Japón/epidemiología , Factores de Riesgo , Tasa de Supervivencia , Resultado del Tratamiento
12.
ScientificWorldJournal ; 2012: 748572, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22645447

RESUMEN

Specific strains of Lactobacillus have been found to be beneficial in treating some types of diarrhea and vaginosis. However, a high mortality rate results from underlying immunosuppressive conditions in patients with Lactobacillus casei bacteremia. Cyclic AMP (cAMP) is a small second messenger molecule that mediates signal transduction. The onset and progression of inflammatory responses are sensitive to changes in steady-state cAMP levels. L. casei cell wall extract (LCWE) develops arteritis in mice through Toll-like receptor-2 signaling. The purpose of this study was to investigate whether intracellular cAMP affects LCWE-induced pathological signaling. LCWE was shown to induce phosphorylation of the nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways and cell proliferation in mice fibroblast cells. Theophylline and phosphodiesterase inhibitor increased intracellular cAMP and inhibited LCWE-induced cell proliferation as well as phosphorylation of NF-κB and MAPK. Protein kinase A inhibitor H89 prevented cAMP-induced MAPK inhibition, but not cAMP-induced NF-κB inhibition. An exchange protein activated by cAMP (Epac) agonist inhibited NF-κB activation but not MAPK activation. These results indicate that an increase in intracellular cAMP prevents LCWE induction of pathological signaling pathways dependent on PKA and Epac signaling.


Asunto(s)
Lacticaseibacillus casei/enzimología , Hidrolasas Diéster Fosfóricas/metabolismo , Animales , Proliferación Celular , Pared Celular/metabolismo , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Activación Enzimática , Fibroblastos/metabolismo , Sistema de Señalización de MAP Quinasas , Ratones , FN-kappa B/metabolismo , Células 3T3 NIH , Fosforilación , Transducción de Señal , Teofilina/farmacología , Receptor Toll-Like 2/metabolismo
13.
Sci Transl Med ; 14(628): eabf3274, 2022 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-35044787

RESUMEN

Dilated cardiomyopathy (DCM) is a major cause of heart failure, characterized by ventricular dilatation and systolic dysfunction. Familial DCM is reportedly caused by mutations in more than 50 genes, requiring precise disease stratification based on genetic information. However, the underlying genetic causes of 60 to 80% of familial DCM cases remain unknown. Here, we identified that homozygous truncating mutations in the gene encoding Bcl-2­associated athanogene (BAG) co-chaperone 5 (BAG5) caused inherited DCM in five patients among four unrelated families with complete penetrance. BAG5 acts as a nucleotide exchange factor for heat shock cognate 71 kDa protein (HSC70), promoting adenosine diphosphate release and activating HSC70-mediated protein folding. Bag5 mutant knock-in mice exhibited ventricular dilatation, arrhythmogenicity, and poor prognosis under catecholamine stimulation, recapitulating the human DCM phenotype, and administration of an adeno-associated virus 9 vector carrying the wild-type BAG5 gene could fully ameliorate these DCM phenotypes. Immunocytochemical analysis revealed that BAG5 localized to junctional membrane complexes (JMCs), critical microdomains for calcium handling. Bag5-mutant mouse cardiomyocytes exhibited decreased abundance of functional JMC proteins under catecholamine stimulation, disrupted JMC structure, and calcium handling abnormalities. We also identified heterozygous truncating mutations in three patients with tachycardia-induced cardiomyopathy, a reversible DCM subtype associated with abnormal calcium homeostasis. Our study suggests that loss-of-function mutations in BAG5 can cause DCM, that BAG5 may be a target for genetic testing in cases of DCM, and that gene therapy may potentially be a treatment for this disease.


Asunto(s)
Cardiomiopatía Dilatada , Trasplante de Corazón , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/metabolismo , Humanos , Ratones , Mutación/genética , Miocitos Cardíacos/metabolismo , Fenotipo
14.
Pediatr Int ; 53(5): 747-753, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21410592

RESUMEN

BACKGROUND: Balloon angioplasty has recently been adopted as an acceptable form of treatment for stenotic vessel lesions of congenital heart diseases. However, precise mechanisms of restenosis and thrombosis, which are the most common complications after these procedures, are unknown. METHODS: We examined the effects of antithrombin III (ATIII) on inflammation, thrombus formation, and remodeling of vascular wall after guidewire-induced injury in the femoral artery of mice. ATIII or saline was administered as a bolus intravenous infusion before injury. RESULTS: Seventy-two hours after injury, approximately half of the saline-treated vessels showed macroscopic thrombus formation. In contrast, no thrombi were seen in the arteries pretreated with ATIII. Significantly higher levels of inflammation were induced in the injured vessels than in the sham-operated controls, as determined by CD11b-positive cell density in the adventitial area. ATIII treatment resulted in marked reduction of inflammatory cell infiltration. Twenty-eight days after injury, similar levels of neointimal proliferation were found in the injured arteries in both groups. CONCLUSIONS: Our results suggested that a high dose of ATIII may influence the sequelae of arterial injury by reducing mural thrombus formation and limiting the inflammatory reaction of the vessel wall without altering the process of vascular remodeling.


Asunto(s)
Angioplastia de Balón/efectos adversos , Antitrombina III/uso terapéutico , Antitrombinas/uso terapéutico , Arteria Femoral/lesiones , Trombosis/prevención & control , Lesiones del Sistema Vascular/tratamiento farmacológico , Animales , Arteria Femoral/patología , Masculino , Ratones , Ratones Endogámicos C3H , Trombosis/etiología , Túnica Íntima/patología , Lesiones del Sistema Vascular/etiología , Lesiones del Sistema Vascular/patología
15.
Pediatr Cardiol ; 32(7): 1040-2, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21789477

RESUMEN

Pulmonary arterial hypertension (PAH) when associated with systemic sclerosis (SSc) (SSc-PAH) is one of the leading causes of mortality and is found in 10-15% of adult patients with SSc. The ET receptor antagonist bosentan has been shown to be effective in the treatment of adult patients with SSc-PAH. Furthermore, it has been shown that bosentan ameliorates decreased skin perfusion and digital ulceration secondary to SSc. However, the effectiveness and safety of bosentan for treatment of juvenile SSc still remains unclear. We describe a case of juvenile SSc-PAH successfully treated with bosentan. The present case shows that bosentan ameliorated PAH and peripheral circulation as evaluated by cold stress thermography. No bosentan-related adverse events such as liver dysfunction were observed. Prospective randomized trials are required to validate the effectiveness of bosentan for patients with juvenile SSc; however, bosentan might be useful for the management of patients with juvenile SSc.


Asunto(s)
Antihipertensivos/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Presión Esfenoidal Pulmonar/efectos de los fármacos , Esclerodermia Sistémica/complicaciones , Sulfonamidas/uso terapéutico , Resistencia Vascular , Antihipertensivos/administración & dosificación , Bosentán , Niño , Relación Dosis-Respuesta a Droga , Ecocardiografía , Femenino , Estudios de Seguimiento , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Esclerodermia Sistémica/fisiopatología , Sulfonamidas/administración & dosificación , Termografía
16.
Int Immunopharmacol ; 38: 139-43, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27268285

RESUMEN

Shiga toxin (STX) is one of the main factors inducing hemorrhagic colitis and hemolytic-uremic syndrome (HUS) in infections with STX-producing Escherichia coli (STEC). Approximately 62% of patients with HUS showed symptoms of encephalopathy in the 2011 Japanese outbreak of STEC infections. At that time, we reported elevated serum concentrations of tumor necrosis factor (TNF)-α in patients with acute encephalopathy during the HUS phase. In the current study, we investigated whether TNF-α augments the effects of STX in glial cell lines and primary glial cells. We found that TNF-α alone or STX in combination with TNF-α activates nuclear factor-κB (NF-κB) signaling and inhibits growth of glial cells. The magnitude of the NF-κB activation and the inhibition of cell growth by the STX and TNF-α combination was greater than that obtained with TNF-α alone or STX alone. Thus, this in vitro study reveals the role of TNF-α in glial cells during STEC infections.


Asunto(s)
Encefalopatías/inmunología , Escherichia coli Enterotoxigénica/inmunología , Infecciones por Escherichia coli/inmunología , Neuroglía/inmunología , Toxina Shiga/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Línea Celular , Proliferación Celular , Humanos , FN-kappa B/metabolismo , Ratas , Toxina Shiga/inmunología , Transducción de Señal , Factor de Necrosis Tumoral alfa/inmunología
17.
JACC Clin Electrophysiol ; 2(3): 279-287, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29766885

RESUMEN

OBJECTIVES: In this study, we scored patients with long QT syndrome (LQTS) according to the different Schwartz diagnostic criteria from 1993, 2006, and 2011, and to examine the validation of the criteria in relevance to the frequency of LQTS-related gene mutation. BACKGROUND: Although updated diagnostic criteria have been used in clinical settings, few data exist regarding their impact on the diagnosis of LQTS. METHODS: We used a cohort of 132 patients who presented with prolonged QTc intervals and/or abnormal clinical history in cardiac screening and who underwent exercise stress testing. LQTS scores of ≥3.5 points according to the 2006 and the 2011 criteria were considered to indicate a high probability of LQTS, as opposed to the 4 points used by the 1993 criteria. The 2011 criteria were updated by adding the evaluation of the recovery phase of exercise. RESULTS: The 2011 criteria significantly increased the number of high probability patients (n = 62) compared with the 1993 criteria (n = 32; p = 0.0002) or the 2006 criteria (n = 36; p = 0.0014). The percentage of mutation carriers in those with an intermediate score, which was rather high using the 1993 (53%) and 2006 criteria (53%), was greatly reduced with the 2011 criteria (15%, p = 0.0014 vs. the 1993 criteria, and p = 0.0013 vs. the 2006 criteria). Among 54 mutation carriers, the 1993, the 2006, and the 2011 criteria identified a high probability of carriers in 25 patients (46% sensitivity and 91% specificity), 27 patients (50% sensitivity and 88% specificity), and 48 patients (89% sensitivity and 82% specificity), respectively. CONCLUSIONS: The use of the 2011 criteria will facilitate the diagnosis of LQTS and will decrease the number of false negative results.

18.
J Cardiol ; 66(2): 168-74, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25458169

RESUMEN

INTRODUCTION: Danon disease is an extremely rare X-linked dominant disorder characterized by progressive cardiomyopathy, muscle weakness, and mild mental retardation. Most cases harbor nonsense, frameshift, or splice-site mutations in LAMP2 that result in lysosome-associated membrane protein-2 (LAMP-2) deficiency and lysosomal defects. The identification of LAMP2 mutations makes it possible to detect female carriers with significant cardiomyopathy. Therefore, it is of paramount importance to develop useful carrier detection methods. METHODS: To screen for diminished LAMP-2 expression among female patients with progressive cardiomyopathy, we developed a flow cytometric method to detect LAMP-2-deficient leukocytes. RESULTS: In healthy controls, all circulating leukocyte populations, including granulocytes, monocytes, and lymphocytes, expressed significant levels of LAMP-2. In contrast, cells from a male patient with Danon disease lacked detectable LAMP-2. His younger twin sisters showed reduced levels of LAMP-2 expression with characteristic bimodal fluorescence intensity patterns. The percentage of LAMP-2-negative cells in the asymptomatic sibling was nearly the same as that in the symptomatic sibling. CONCLUSION: We developed a flow cytometric assay for LAMP-2 expression that can serve as a rapid primary screening method to detect carriers of LAMP-2 deficiencies. This assay will narrow the target population before subjecting patients to more laborious and expensive gene mutation analysis.


Asunto(s)
Cardiomiopatía Hipertrófica/diagnóstico , Enfermedad por Depósito de Glucógeno de Tipo IIb/diagnóstico , Proteína 2 de la Membrana Asociada a los Lisosomas/metabolismo , Adolescente , Cardiomiopatía Hipertrófica/sangre , Estudios de Casos y Controles , Niño , Diagnóstico Precoz , Femenino , Citometría de Flujo , Enfermedad por Depósito de Glucógeno de Tipo IIb/sangre , Humanos , Leucocitos/metabolismo , Masculino , Linaje
19.
J Infect Chemother ; 5(1): 16-20, 1999 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11810485

RESUMEN

There is an increasing spread and incidence of penicillin-resistant bacteria that are becoming less susceptible to commonly prescribed oral antimicrobials, including extended-spectrum cephalosporins. Against this background, we undertook this study to determine the prevalence of penicillin resistance in Streptococcus pneumoniae and the in-vitro activity of oral antimitrobials. Between April 1996 and December 1997, in 245 children with respiratory tract infections (bronchitis in 61, pharyngitis in 115, and tonsillitis in 69), 119 strains of Haemophilus influenzae, 89 strains of Streptococcus pyogenes, 61 strains of Streptococcus pneumoniae, 36 strains of Staphylococcus aureus, and 34 strains of Moraxella catarrhalis were isolated from the pharynx. The antimicrobial susceptibility of these isolates was assessed by a broth microdilution method. The isolation incidence of penicillin-intermediately resistant S. pneumoniae (PISP) and penicillin-highly resistant S. pneumoniae (PRSP) was 59.0% and 13.1%, respectively. Most strains of PISP and PRSP were highly resistant to cefaclor, cefpodoxime, cefteram, cefdinir, clarithromycin, ampicillin, and minocycline, but susceptibile to ofloxacin and cefditoren (CDTR). The in-vitro activity of CDTR was superior to that of other cephalosporins, such as cefaclor, cefdinir, and cefpodoxime, when tested against both the beta-lactamase-positive and -negative H. influenzae isolated. CDTR was also active against all the other strains, including methicillin-sensitive S. aureus, S. pyogenes, and M. catarrhalis. This study suggested that CDTR was a useful oral antibiotic for pediatric respiratory tract infections.

20.
J Microbiol Immunol Infect ; 46(5): 389-92, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22572003

RESUMEN

Kawasaki disease is an acute illness of early childhood that is characterized by prolonged fever and vasculitis of unknown pathogenesis. Lactobacillus casei cell wall extract (LCWE)-induced vasculitis in mice is a well-validated model of Kawasaki disease. In the nervous system, glial cells play an important role in fever development. This study investigated whether LCWE directly stimulates glial cells, resulting in the induction of cyclooxygenase-2 (COX2), which is required for prostaglandin synthesis and fever development. We found that LCWE induced COX2 expression and activated the nuclear factor-κB signaling pathway in rat B92 glial cells, but Toll-like receptor-2, which is one of the receptors for LCWE, could not be detected in the cells. These results suggest that LCWE activates the nuclear factor-κB signaling pathway and induces COX2 in rat B92 glial cells through another LCWE receptor other than Toll-like receptor-2.


Asunto(s)
Pared Celular/inmunología , Ciclooxigenasa 2/biosíntesis , Interacciones Huésped-Patógeno , Lacticaseibacillus casei/inmunología , Neuroglía/inmunología , Neuroglía/microbiología , Animales , Línea Celular , Expresión Génica , Ratones , Ratas , Transducción de Señal , Receptor Toll-Like 2/biosíntesis
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