RESUMEN
KIF1A-related disorders (KRDs) encompass recessive and dominant variants with wide clinical variability. Recent genetic investigations have expanded the clinical phenotypes of heterozygous KIF1A variants. However, there have been a few long-term observational studies of patients with heterozygous KIF1A variants. A retrospective chart review of consecutive patients diagnosed with spastic paraplegia at Miyagi Children's Hospital from 2016 to 2020 identified six patients with heterozygous KIF1A variants. To understand the long-term changes in clinical symptoms, we examined these patients in terms of their characteristics, clinical symptoms, results of electrophysiological and neuroimaging studies, and genetic testing. The median follow-up period was 30 years (4-44 years). This long-term observational study showed that early developmental delay and equinus gait, or unsteady gait, are the first signs of disease onset, appearing with the commencement of independent walking. In addition, later age-related progression was observed in spastic paraplegia, and the appearance of axonal neuropathy and reduced visual acuity were characteristic features of the late disease phenotype. Brain imaging showed age-related progression of cerebellar atrophy and the appearance of hyperintensity of optic radiation on T2WI and FLAIR imaging. Long-term follow-up revealed a pattern of steady progression and a variety of clinical symptoms, including spastic paraplegia, peripheral neuropathy, reduced visual acuity, and some degree of cerebellar ataxia. Clinical variability between patients was observed to some extent, and therefore, further studies are required to determine the phenotype-genotype correlation.
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BACKGROUND: Lung sound analysis parameters have been reported to be useful biomarkers for evaluating airway condition. We developed an automatic lung sound analysis software program for infants and children based on lung sound spectral curves of frequency and power by leveraging machine learning (ML) technology. METHODS: To put this software program into clinical practice, in Study 1, the reliability and reproducibility of the software program using data from younger children were examined. In Study 2, the relationship between lung sound parameters and respiratory flow (L/s) was evaluated using data from older children. In Study 3, we conducted a survey using the ATS-DLD questionnaire to evaluate the clinical usefulness. The survey focused on the history of wheezing and allergies, among healthy 3-year-old infants, and then measured lung sounds. The clinical usefulness was evaluated by comparing the questionnaire results with the results of the new lung sound parameters. RESULTS: In Studies 1 and 2, the parameters of the new software program demonstrated excellent reproducibility and reliability, and were not affected by airflow (L/s). In Study 3, infants with a history of wheezing showed lower FAP0 and RPF75p (p < 0.001 and p = 0.025, respectively) and higher PAP0 (p = 0.001) than healthy infants. Furthermore, infants with asthma/asthma-like bronchitis showed lower FAP0 (p = 0.002) and higher PAP0 (p = 0.001) than healthy infants. CONCLUSIONS: Lung sound parameters obtained using the ML algorithm were able to accurately assess the respiratory condition of infants. These parameters are useful for the early detection and intervention of childhood asthma.
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Asma , Ruidos Respiratorios , Programas Informáticos , Humanos , Ruidos Respiratorios/fisiopatología , Asma/fisiopatología , Asma/diagnóstico , Lactante , Masculino , Preescolar , Femenino , Reproducibilidad de los Resultados , Aprendizaje Automático , Encuestas y Cuestionarios , NiñoRESUMEN
Juvenile myasthenia gravis (JMG) exhibits a more favorable response to glucocorticoids and has a better prognosis than adult myasthenia gravis. However, no established treatment exists for refractory JMG. Although thymectomy has been performed in several patients with refractory systemic JMG, there are few detailed clinical descriptions of patients who underwent thymectomy. Here, we present the case of a 10-year-old boy with refractory systemic JMG who was successfully treated with thymectomy. The patient developed symptoms, including dysphagia, malaise, diurnal ptosis, and weakness in the trunk muscles, and he was diagnosed with generalized JMG. Despite undergoing various treatments, including steroids, tacrolimus, steroid pulse therapy, intravenous immunoglobulin, azathioprine (AZT), and rituximab, his symptoms did not improve. Therefore, he underwent a thoracoscopic thymectomy 24 months after disease onset. Thymectomy led to remission, as demonstrated by a significant reduction in the quantitative myasthenia gravis score and anti-acetylcholine receptor antibody levels, which persisted for 43 months after surgery. Our case demonstrates the effectiveness of thymectomy in systemic JMG patients with positive anti-acetylcholine receptor antibodies, despite therapeutic failure with AZT and rituximab, within 2 years of disease onset.
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Miastenia Gravis , Timectomía , Niño , Humanos , Masculino , Autoanticuerpos , Progresión de la Enfermedad , Glucocorticoides/uso terapéutico , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/cirugía , Rituximab , Resultado del TratamientoRESUMEN
This study aimed to clarify the characteristics of patients with lung cancer undergoing treatment until the onset of tuberculosis. Between 2005 and 2019, patients who were admitted to Tokyo National Hospital due to tuberculosis during lung cancer treatment were examined retrospectively. There were 42 patients, and detailed medical information was obtained in 39 patients. The median age of the 39 patients were 75 years (range: 47-92 years), of which 33 were males and 36 were Japanese Baby Boomers or older. Regarding risk factors for developing tuberculosis, smoking was noted in 34 cases, oral corticosteroid use in 13, and previous tuberculosis in six. Thirty-seven patients had one risk factor and 19 had two or more risk factors, but diagnosis of latent tuberculosis infection (LTBI) was obtained in only one patients, and none had received LTBI treatment. The first-line treatment for lung cancer was resection in 13 cases, chemoradiotherapy in 6, chemotherapy in 10, radiation therapy in 3, laser therapy in 1, and best supportive care (BSC) alone in 6. At tuberculosis onset, BSC accounted for 17 cases, but other situations were considerably existed such as anticancer medication (12 cases), and observation after lung cancer treatment (10 cases). Tuberculosis occurred in various situations in elderly patients with lung cancer. It is critical to actively evaluate the risk of tuberculosis and consider LTBI screening and treatment.
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Tuberculosis Latente , Neoplasias Pulmonares , Tuberculosis , Anciano , Anciano de 80 o más Años , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/epidemiología , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Estudios Retrospectivos , Tuberculosis/diagnóstico , Tuberculosis/epidemiologíaRESUMEN
Human metapneumovirus (hMPV) is a common cause of upper and lower respiratory tract infections in children. A few case reports have described hMPV encephalitis or encephalopathy. Neuroimaging data on patients with hMPV encephalitis are scarce. We report a patient with trisomy 13 who developed severe hMPV pneumonia, multifocal cerebral and cerebellar hemorrhagic infarctions and extensive cerebral white matter demyelination. Although adult respiratory distress syndrome and disseminated intravascular coagulation contributed to the devastating central nervous system (CNS) lesions, endothelial dysfunction of the CNS caused by hMPV infection probably also played a pathophysiological role in this case.
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Encefalitis , Metapneumovirus , Infecciones por Paramyxoviridae , Neumonía Viral , Infecciones del Sistema Respiratorio , Sustancia Blanca , Adulto , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/diagnóstico por imagen , Niño , Encefalitis/complicaciones , Humanos , Lactante , Infecciones por Paramyxoviridae/complicaciones , Neumonía Viral/complicaciones , Síndrome de la Trisomía 13/complicaciones , Sustancia Blanca/diagnóstico por imagenRESUMEN
Cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4) is early onset neuromotor disorder and intellectual disabilities caused by variants of ATP8A2. We report sibling cases and systematically analyze previous literature to increase our understanding of CAMRQ4. Japanese siblings presented with athetotic movements at 1 and 2 months of age. They also had ptosis, ophthalmoplegia, feeding difficulty, hypotonia, and severely delayed development. One patient had retinal degeneration and optic atrophy. Flattening of the auditory brainstem responses and areflexia developed. At the last follow-up, neither patient could sit or achieve head control, although some nonverbal communication was preserved. Whole exome sequencing revealed compound heterozygous variants of ATP8A2: NM_016529.6:c.[1741C>T];[2158C>T] p.[(Arg581*)];[(Arg720*)]. The p.(Arg581*) variant has been reported, while the variant p.(Arg720*) was novel. The symptoms did not progress in the early period of development, which makes it difficult to distinguish from dyskinetic cerebral palsy, particularly in solitary cases. However, visual and hearing impairments associated with involuntary movements and severe developmental delay may be a clue to suspect CAMRQ4.
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Ataxia Cerebelosa , Discapacidad Intelectual , Adenosina Trifosfatasas , Humanos , Discapacidad Intelectual/genética , Hipotonía Muscular , Náusea , Proteínas de Transferencia de Fosfolípidos , Hermanos , SíndromeRESUMEN
We synthesize optically active (R)-terbutaline 2, which is an anti-asthmatic drug, through recyclable catalytic asymmetric transfer hydrogenation (RCATH). Various chloroketones 4 were prepared and RCATH was performed on them. The products exhibit moderate to high enantioselectivity. In particular, the hydrogenation of acyl substituted substrates 4c yields chiral secondary alcohols 5c in good yield and enantioselectivity. Furthermore, (R)-terbutaline 2 can be synthesized in one step from the resulting secondary alcohol 5 without racemization.
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Antiasmáticos/síntesis química , Tecnología Química Verde , Líquidos Iónicos/química , Terbutalina/síntesis química , Antiasmáticos/química , Catálisis , Hidrogenación , Estructura Molecular , Estereoisomerismo , Terbutalina/químicaRESUMEN
Several types of muscular dystrophy are caused by defective linkage between α-dystroglycan (α-DG) and laminin. Among these, dystroglycanopathy, including Fukuyama-type congenital muscular dystrophy (FCMD), results from abnormal glycosylation of α-DG. Recent studies have shown that like-acetylglucosaminyltransferase (LARGE) strongly enhances the laminin-binding activity of α-DG. Therefore, restoration of the α-DG-laminin linkage by LARGE is considered one of the most promising possible therapies for muscular dystrophy. In this study, we generated transgenic mice that overexpress LARGE (LARGE Tg) and crossed them with dy(2J) mice and fukutin conditional knockout mice, a model for laminin α2-deficient congenital muscular dystrophy (MDC1A) and FCMD, respectively. Remarkably, in both the strains, the transgenic overexpression of LARGE resulted in an aggravation of muscular dystrophy. Using morphometric analyses, we found that the deterioration of muscle pathology was caused by suppression of muscle regeneration. Overexpression of LARGE in C2C12 cells further demonstrated defects in myotube formation. Interestingly, a decreased expression of insulin-like growth factor 1 (IGF-1) was identified in both LARGE Tg mice and LARGE-overexpressing C2C12 myotubes. Supplementing the C2C12 cells with IGF-1 restored the defective myotube formation. Taken together, our findings indicate that the overexpression of LARGE aggravates muscular dystrophy by suppressing the muscle regeneration and this adverse effect is mediated via reduced expression of IGF-1.
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Regulación hacia Abajo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Músculo Esquelético/fisiopatología , Distrofia Muscular Animal/metabolismo , Distrofia Muscular Animal/fisiopatología , N-Acetilglucosaminiltransferasas/metabolismo , Regeneración , Animales , Fusión Celular , Línea Celular , Distroglicanos/metabolismo , Glicosilación , Humanos , Ratones , Ratones Transgénicos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Mioblastos/metabolismo , Mioblastos/patología , Fenotipo , Proteínas/metabolismo , Transfección , TransferasasRESUMEN
The oxidation of (Z)-1,2-bis(arylseleno)-1-alkenes is known to afford alkynyl selenoxides via a unique selenoxide anti-elimination mechanism; however, to date, there have been no mechanistic studies of this reaction. During our studies of this transformation, monoselenoxides 6 and 7 were unexpectedly isolated as stable reaction intermediates. In addition, (77)Se NMR studies of the reaction mixture revealed the presence of an intramolecular Se···O interaction and the formation of alkynyl selenoxides. Meanwhile, even at higher temperatures, the reaction of a (Z)-1,2-bis(arylsulfinyl)-1-alkene, the sulfur analog of (Z)-1,2-bis(arylseleninyl)-1-alkenes, did not proceed via sulfoxide elimination but proceeded via isomerization and disproportionation. Therefore, the intramolecular Se···O interaction can be concluded to play a pivotal role in the anti-elimination reaction.
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Alquenos/química , Compuestos de Organoselenio/química , Óxidos/química , Compuestos de Azufre/química , Catálisis , Cristalografía por Rayos X , Isomerismo , Modelos Moleculares , Oxidación-ReducciónAsunto(s)
Personal Administrativo/psicología , COVID-19/terapia , Enfermeras y Enfermeros/psicología , Médicos/psicología , Trabajo de Rescate , Trastornos por Estrés Postraumático/psicología , Personal Administrativo/estadística & datos numéricos , Adulto , Ansiedad/epidemiología , Ansiedad/psicología , Carga del Cuidador/epidemiología , Carga del Cuidador/psicología , Estudios Transversales , Medicina de Desastres , Femenino , Humanos , Japón/epidemiología , Masculino , Salud Mental , Persona de Mediana Edad , Enfermeras y Enfermeros/estadística & datos numéricos , Médicos/estadística & datos numéricos , Cuarentena , Trastornos por Estrés Postraumático/epidemiología , Encuestas y Cuestionarios , Carga de TrabajoRESUMEN
OBJECTIVE: Trauma informed care (TIC) is an important approach for people who have experienced trauma. Although psychological first aid (PFA) may be effective training in TIC, no study reported an association between PFA training and TIC. This study aimed to investigate the association between PFA training and attitudes toward TIC among health care professionals in Japan. METHODS: Japanese health care professionals were recruited for a survey conducted from May 21 to June 18, 2021. TIC was assessed by the Attitudes Related to Trauma Informed Care Scale 10-item short form (ARTIC-10). A question about PFA training participation was originally developed through discussion among researchers. Univariate and multiple linear regression analyses were used to examine the association between the PFA experience and ARTIC-10. RESULTS: In total, 484 (3.6%) health care professionals completed all questions. Among them, 77 (15.9%) had experienced PFA training. Univariate and multiple linear regression analyses showed that PFA experience (B = 0.19, 95% CI: 0.02-0.36, P = 0.03; B = 0.17, 95% CI: 0.01-0.34, P = 0.04) was significantly associated with ARTIC-10. CONCLUSIONS: This study was the first to show an association between PFA training and attitudes toward TIC among health care professionals, which was a significant result for future research on PFA training, TIC, and trauma care.
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Personal de Salud , Primeros Auxilios Psicológicos , Humanos , Japón , Personal de Salud/psicología , Actitud del Personal de Salud , Encuestas y CuestionariosRESUMEN
OBJECTIVES: Translation of the Professional Fulfillment Index (PFI) into Japanese would be more useful than the currently developed scales for appropriately measuring burnout and professional fulfillment in healthcare professionals. This study aimed to develop the Japanese version of the PFI and examine its internal consistency, structural validity, and convergent validity in healthcare professionals. METHODS: Healthcare professionals in Japan were recruited online. The survey was conducted from October to November 2022. Internal consistency was tested using Cronbach's α. Structural validity was tested using confirmatory factor analysis (CFA) and exploratory factor analysis (EFA). Convergent validity was tested using Pearson's correlation coefficients, which were calculated between each score of the PFI scale and burnout (the Japanese Burnout Scale: JBS), depressive symptoms (the Patient Health Questionnaire-9), and QOL (the General Health Questionnaire-12). RESULTS: The Cronbach's alpha was .91 in professional fulfillment, .80 in burnout: work exhaustion, .90 in burnout: interpersonal disengagement, and .89 in burnout: total score. Confirmatory factor analysis demonstrated a modest fit, and EFA yielded a three-factor structure the same as the original PFI. The all three subscales and total score of burnout were significantly correlated with the scores of all the scales (p < .001; e.g., burnout: work exhaustion correlated emotional exhaustion in JBS, r = .71). CONCLUSIONS: The Japanese version of the PFI demonstrated acceptable high internal consistency, structural validity, and convergent validity of the scale with a three-factor structure the same as in the original PFI. The Japanese version of PFI proved to be reliable and valid for use in healthcare professionals.
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Agotamiento Profesional , Calidad de Vida , Humanos , Reproducibilidad de los Resultados , Pueblos del Este de Asia , Encuestas y Cuestionarios , Atención a la Salud , PsicometríaRESUMEN
The use of biologic agents has enabled control of severe asthma, but there is a risk that eosinophilic granulomatosis with polyangiitis (EGPA) may be masked in some cases. We herein report a 71-year-old man who was administered dupilumab for 2 years to stabilize his asthma symptoms. A few months after discontinuation of dupilumab administration, an increase in the eosinophil count in peripheral blood, leg pain, and a rash appeared. Based on pathology, he was diagnosed with EGPA. EGPA in this case was considered to have become apparent due to the discontinuation of dupilumab administration.
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Asma , Síndrome de Churg-Strauss , Granulomatosis con Poliangitis , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Asma/diagnóstico , Asma/tratamiento farmacológico , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/tratamiento farmacológico , Granulomatosis con Poliangitis/diagnóstico , Granulomatosis con Poliangitis/tratamiento farmacológico , Humanos , MasculinoRESUMEN
This study aimed to compare the longitudinal change in depressive symptoms among healthcare professionals in Japan who are willing to receive novel coronavirus disease (COVID-19) vaccination and those who are unwilling to receive COVID-19 vaccination. The baseline survey was conducted in October 2020 (Survey time 1: T1); respondents in T1 were invited to participate in May 2021 (Survey time 2: T2). Depressive symptoms were assessed by the Patient Health Questionnaire-9 (PHQ-9). Group comparisons of the estimated mean of PHQ-9 score at T1 and T2 were estimated by the analysis of covariance. In T1, 597 participants (response rate: 4.4%) completed all questions. In T2, 211 participants (follow up rate: 35.3%) completed all questions. The group and time interaction effect was significant (F(1, 207)=3.9, p=0.049); depressive symptoms were worse among healthcare professionals who were unwilling to receive vaccination than among those who were willing to receive vaccination. This study showed that depressive symptoms were worse among healthcare professionals who were unwilling to receive COVID-19 vaccination than those who are willing to receive COVID-19 vaccination. This suggests that it is important to take care of healthcare professionals who are unwilling to receive vaccination to prevent mental health deterioration.
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Vacunas contra la COVID-19 , COVID-19 , COVID-19/prevención & control , Vacunas contra la COVID-19/uso terapéutico , Depresión/epidemiología , Humanos , Japón/epidemiología , Vacunación , Vacilación a la VacunaciónRESUMEN
Histone deacetylase inhibitors (HDACIs) are known to promote skeletal muscle formation. However, their mechanisms that include effects on the expression of major muscle components such as the dystrophin-associated proteins complex (DAPC) or myogenic regulatory factors (MRFs) remain unknown. In this study, we investigated the effects of HDACIs on skeletal muscle formation using the C2C12 cell culture system. C2C12 myoblasts were exposed to trichostatin A (TSA), one of the most potent HDACIs, and differentiation was subsequently induced. We found that TSA enhances the expression of myosin heavy chain without affecting DAPC expression. In addition, TSA increases the expression of the early MRFs, Myf5 and MEF2, whereas it suppresses the expression of the late MRF, myogenin. Interestingly, TSA also enhances the expression of Id1, Id2, and Id3 (Ids). Ids are myogenic repressors that inhibit myogenic differentiation. These findings suggest that TSA promotes gene expression in proliferation and suppresses it in the differentiation stage of muscle formation. Taken together, our data demonstrate that TSA enhances myogenesis by coordinating the expression of MRFs and myogenic repressors.
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Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Desarrollo de Músculos/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Factores Reguladores Miogénicos/metabolismo , Animales , Línea Celular , Complejo de Proteínas Asociado a la Distrofina/metabolismo , Expresión Génica/efectos de los fármacos , Proteína 1 Inhibidora de la Diferenciación/metabolismo , Proteína 2 Inhibidora de la Diferenciación/metabolismo , Proteínas Inhibidoras de la Diferenciación/metabolismo , Ratones , Desarrollo de Músculos/genética , Músculo Esquelético/crecimiento & desarrollo , Músculo Esquelético/metabolismo , Factor 5 Regulador Miogénico/metabolismo , Cadenas Pesadas de Miosina/metabolismoRESUMEN
α-Dystroglycan (α-DG) plays crucial roles in maintaining the stability of cells. We demonstrated previously that the N-terminal domain of α-DG (α-DG-N) is secreted by cultured cells into the culture medium. In the present study, to clarify its function in vivo, we generated a monoclonal antibody against α-DG-N and investigated the secretion of α-DG-N in human cerebrospinal fluid (CSF). Interestingly, we found that a considerable amount of α-DG-N was present in CSF. α-DG-N in CSF was a sialylated glycoprotein with both N- and O-linked glycan. These observations suggest that secreted α-DG-N may be transported via CSF and have yet unidentified effects on the nervous system.
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Distroglicanos/líquido cefalorraquídeo , Distroglicanos/metabolismo , Glicoproteínas/líquido cefalorraquídeo , Glicoproteínas/metabolismo , Neuronas/metabolismo , Células Cultivadas , Distroglicanos/química , Glicoproteínas/química , Glicosilación , Humanos , Ácido N-Acetilneuramínico/química , Estructura Terciaria de ProteínaRESUMEN
This study aimed to compare longitudinal change of the psychological distress of a group with psychological first aid (PFA) experience and a group without PFA experience among physicians and other healthcare professionals from before the novel coronavirus disease (COVID-19) pandemic to during the pandemic. The baseline survey was conducted in January 2020 (T1). The respondents in T1 were invited to participate in March (T2) and November 2020 (T3). Psychological distress was assessed by the Kessler 6 Scale. Participants were divided into two categories: a group with and a group without PFA experience. Participants were further divided between physicians and healthcare professionals other than physicians, because physicians are more likely to experience morally injurious events. A mixed-model repeated-measures ANOVA was conducted as an indicator of the group differences. In T1, 398 healthcare professionals participated. The longitudinal analysis of healthcare professionals other than physicians showed that psychological distress was significantly greater in the group without PFA experience than in the group with PFA experience (T1 vs. T3). This study showed psychological distress among healthcare professionals other than physicians was significantly greater in the group without PFA experience than in the group with PFA experience during the COVID-19 pandemic, but the results were not consistent among physicians.
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COVID-19 , Distrés Psicológico , Atención a la Salud , Humanos , Pandemias , Primeros Auxilios Psicológicos , SARS-CoV-2RESUMEN
People with severe motor and intellectual disabilities syndrome (SMIDS) have multiple comorbidities and high mortality rates. This study examined whether there is a difference in the efficacy and tolerability of perampanel (PER) between patients with drug-resistant epilepsy with or without SMIDS. The study identified 65 patients with drug-resistant epilepsy who underwent PER treatment as adjunctive therapy. The 50 % responder rate was 22 % (14/65) overall and 11 % (5/44) in patients with SMIDS versus 43 % (9/21) in patients without SMIDS (p <0.01). Although the overall 50 % responder rate was similar to those of previous reports, PER was less efficacious in the patients with SMIDS; nevertheless, PER was tolerated in the patients with SMIDS.
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Epilepsia Refractaria , Discapacidad Intelectual , Anticonvulsivantes/uso terapéutico , Epilepsia Refractaria/tratamiento farmacológico , Quimioterapia Combinada , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/tratamiento farmacológico , Japón , Nitrilos , Piridonas/uso terapéutico , Resultado del TratamientoRESUMEN
Molecular-targeted drugs (MTDs), such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and anaplastic lymphoma kinase inhibitors, are used to treat non-small-cell lung cancer (NSCLC). The incidence of rash caused by EGFR-TKIs and discontinuation of MTDs because of rash are issues. Rapid desensitization therapy (RDT) was performed in five patients who developed severe rash after introduction of MTDs and was successful in four, all of whom showed no rash relapse. RDT may thus be useful for treating rash in patients receiving MTDs for NSCLC.