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INTRODUCTION/AIMS: Novel disease-modifying approaches for spinal muscular atrophy (SMA) have highlighted the patient's perspective on functional changes over time. In this study, we evaluated the impact of nusinersen on the health-related quality of life (HRQoL) of patients with later-onset SMA and the caregiver burden. METHODS: We assessed the changes in HRQoL using the Pediatric Quality of Life Inventory 4.0 Generic Core Scale (PedsQL GCS) and the Pediatric Quality of Life Inventory 3.0 Neuromuscular Module (PedsQL NMM) during 26 months of treatment. Caregiver burden was assessed using the Assessment of Caregiver Experience with Neuromuscular Disease. We also assessed motor function using the Hammersmith Functional Motor Scale-Expanded (HFMSE) and the Revised Upper Limb Module score. RESULTS: Twenty-four patients and their caregivers were included. The median age of patients at treatment onset was 148.8 (6.8 to 269.4) months. A significant improvement was observed in psychosocial health in proxy-reported PedsQL (P = .023). However, the physical health scores of the PedsQL GCS and About my neuromuscular disorder subscores of the PedsQL NMM did not change, although there was a significant increase in HFMSE scores. Regarding the caregiver burden, the financial burden was reduced, whereas time burden increased. A higher HFMSE score was associated with better self-reported PedsQL GCS total scores (P < .001). DISCUSSION: Our results provide insights into the multifaceted implications of disease-modifying therapies for SMA through patient-reported outcome measures (PROMs). PROMs should be taken into consideration to assess the clinical significance of the functional changes identified by clinician-reported scales.
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Carga del Cuidador , Atrofia Muscular Espinal , Niño , Humanos , Lactante , Calidad de Vida , Atrofia Muscular Espinal/tratamiento farmacológico , Relevancia ClínicaRESUMEN
Background: Evans blue dye (EBD) is the most common indicator to analyze the extent of blood-brain barrier (BBB) breakdown in several neurological disease models. However, the high-dose of EBD (51.9 mg/kg) is usually required for visualization of blue color by the human eye that brings potential safety issues. Methods: To solve this problem, low-dose of EBD was applied for the near-infrared (NIR) fluorescence-assisted quantitation of BBB breakdown in photothrombotic stoke model. Animals were allocated to seven dose groups ranging from 1.35 nmol (5.19 µg/kg) to 13.5 µmol (51.9 mg/kg) EBD. Results: EBD was undetectable in the non-ischemic brain tissue, and the fluorescence signals in the infarcted hemisphere seemed proportional to the injected dose in the dose range. Although the maximum fluorescence signals in brain tissue were obtained with the injections of 1.35 nmol ~ 13.5 µmol EBD, the background signals in the neighboring brain tissues were significantly increased as well. Since the high concentration of EBD is necessary for color-based identification of the infarcted lesion in brain tissues, even 10-fold diluted could not be distinguished visually by naked eye. Conclusions: NIR fluorescence-assisted method could potentially provide new opportunities to study BBB leakage just using small amount of EBD in different pathological conditions and to test the efficacy of various therapeutic strategies to protect the BBB.
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Barrera Hematoencefálica/diagnóstico por imagen , Azul de Evans , Accidente Cerebrovascular/diagnóstico por imagen , Animales , Isquemia Encefálica/diagnóstico por imagen , Fluorescencia , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , República de CoreaRESUMEN
INTRODUCTION: Duchenne and Becker muscular dystrophies (DMD and BMD) are allelic X-linked recessive muscle diseases caused by mutations in the large and complex dystrophin gene. METHODS: We analyzed the dystrophin gene in 507 Korean DMD/BMD patients by multiple ligation-dependent probe amplification and direct sequencing. RESULTS: Overall, 117 different deletions, 48 duplications, and 90 pathogenic sequence variations, including 30 novel variations, were identified. Deletions and duplications accounted for 65.4% and 13.3% of Korean dystrophinopathy, respectively, suggesting that the incidence of large rearrangements in dystrophin is similar among different ethnic groups. We also detected sequence variations in >100 probands. The small variations were dispersed across the whole gene, and 12.3% were nonsense mutations. CONCLUSIONS: Precise genetic characterization in patients with DMD/BMD is timely and important for implementing nationwide registration systems and future molecular therapeutic trials in Korea and globally. Muscle Nerve 55: 727-734, 2017.
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Distrofina/genética , Distrofia Muscular de Duchenne/genética , Mutación , Adolescente , Adulto , Alelos , Niño , Preescolar , Exones , Humanos , Masculino , Polimorfismo Genético , República de Corea , Eliminación de Secuencia , Adulto JovenRESUMEN
Background: Since it is known that serum albumin-bound dyes can cross the blood-brain barrier (BBB) after ischemia, Evans Blue dye is commonly used to assess BBB disruption because of its rapid binding to serum albumin. In addition, indocyanine green (ICG), a clinically available dye, binds to serum proteins that could also be used for assessment of BBB impairment. Unlike these near-infrared (NIR) dyes, zwitterionic NIR fluorophore (ZW800-1) shows no serum binding, ultralow non-specific tissue uptake, and rapid elimination from the body via renal filtration. In this study, we report the use of ZW800-1 as a NIR fluorescence imaging agent for detecting BBB disruption in rat stroke models. Methods: Three types of NIR fluorophores, Evans Blue, ICG, and ZW800-1, were administered intraperitoneally into rat photothrombotic stroke models by using 4% concentration of each NIR dye. The NIR fluorescence signals in the infarcted brain tissue and biodistribution were observed in real-time using the Mini-FLARE® imaging system up to 24 h post-injection. Results: ZW800-1 provided successful visualization of the ischemic injury site in the brain tissue, while the remaining injected dye was clearly excreted from the body within a certain period of time. Although Evans Blue and ICG provided mapping of the infarcted brain lesions, they exhibited high non-specific uptake in most of the tissues and organs and persisted in the body over 24 h post-injection. Conclusion: Our results suggest the promising application of ZW800-1 as a new strategy in BBB experiments and future therapeutic development.
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Barrera Hematoencefálica/diagnóstico por imagen , Isquemia Encefálica/diagnóstico por imagen , Compuestos de Amonio Cuaternario/administración & dosificación , Accidente Cerebrovascular/diagnóstico por imagen , Ácidos Sulfónicos/administración & dosificación , Animales , Barrera Hematoencefálica/fisiopatología , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/fisiopatología , Azul de Evans/administración & dosificación , Humanos , Verde de Indocianina/administración & dosificación , Ratas , Espectrometría de Fluorescencia , Espectroscopía Infrarroja Corta , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/fisiopatologíaRESUMEN
OBJECTIVES: Intravenous levetiracetam (LEV) has been shown to be effective and safe in treating adults with refractory status epilepticus (SE). We sought to investigate the efficacy and safety of intravenous LEV for pediatric patients with refractory SE. METHODS: We performed a retrospective medical-record review of pediatric patients who were treated with intravenous LEV for refractory SE. Clinical information regarding age, sex, seizure type, and underlying neurological status was collected. We evaluated other anticonvulsants that were used prior to administration of intravenous LEV and assessed loading dose, response to treatment, and any adverse events from intravenous LEV administration. RESULTS: Fourteen patients (8 boys and 6 girls) received intravenous LEV for the treatment of refractory SE. The mean age of the patients was 4.4 ± 5.5 years (range, 4 days to 14.6 years). Ten of the patients were neurologically healthy prior to the refractory SE, and the other 4 had been previously diagnosed with epilepsy. The mean loading dose of intravenous LEV was 26 ± 4.6 mg/kg (range, 20-30 mg/kg). Seizure termination occurred in 6 (43%) of the 14 patients. In particular, 4 (57%) of the 7 patients younger than 2 years showed seizure termination. No immediate adverse events occurred during or after infusions. CONCLUSIONS: The current study demonstrated that the adjunctive use of intravenous LEV was effective and well tolerated in pediatric patients with refractory SE, even in patients younger than 2 years. Intravenous LEV should be considered as an effective and safe treatment option for refractory SE in pediatric patients.
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Anticonvulsivantes/administración & dosificación , Piracetam/análogos & derivados , Estado Epiléptico/tratamiento farmacológico , Adolescente , Anticonvulsivantes/farmacología , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Levetiracetam , Masculino , Piracetam/administración & dosificación , Piracetam/farmacología , Resultado del TratamientoRESUMEN
BACKGROUND/AIM: This study investigated the treatment patterns and prognosis of patients with metastatic or unresectable colorectal cancer (mCRC) treated with chemotherapy with targeting agents. PATIENTS AND METHODS: This longitudinal multicenter study included 963 patients with mCRC who were treated in Korea between 2016 and 2020. Treatment patterns and efficacy were compared according to the mutation status and clinical factors. RESULTS: As first-line therapy, most of the patients (83.5%) received FOLFOX plus bevacizumab (35.4%), followed by FOLFIRI plus bevacizumab (18.8%), FOLFIRI plus cetuximab (17.0%), and FOLFOX plus cetuximab (12.3%). Bevacizumab was the most frequent agent (78.8%) combined with chemotherapy in RAS-mutated CRC, while cetuximab (57.2%) in RAS wild-type CRC. Cetuximab was frequently combined with a doublet regimen in patients with left-sided CRC than in those with right-sided CRC (34.4% vs. 16%). As second-line therapy, most patients (63.4%) also received doublet regimens with bevacizumab, and FOLFIRI plus aflibercept was administered in 15.1%. The objective response rate with FOLFIRI plus cetuximab was significantly higher in patients with left-sided CRC than in those with right-sided CRC (59.2% vs. 30.8%, p=0.008) and marginally higher in patients with RAS wild-type CRC than in those with RAS-mutated CRC (55.6% vs. 0.0%, p=0.092). Progression-free survival (PFS) with FOLFOX plus bevacizumab was significantly shorter than that with FOLFIRI plus bevacizumab (p=0.030) in RAS-mutated CRC, whereas there were no significant differences between regimens in RAS wild-type CRC. CONCLUSION: In patients with unresectable metastatic colorectal cancer, doublet chemotherapy with targeting agents is the most common therapy and efficacy depends on the mutation status as well as clinical factors.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Cetuximab , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Pronóstico , Neoplasias del Recto/tratamiento farmacológicoRESUMEN
We evaluated the efficacy and tolerability of rufinamide adjunctive therapy in children with refractory generalised epilepsy. The study cohort consisted of 20 patients with Lennox-Gastaut syndrome, 5 with Dravet syndrome, and 28 with unclassified refractory generalised epilepsy. Patients with more than 50% seizure reduction at three and six months were defined as responders. The overall response rate was 37.7% at three months and 34.0% at six months. At three months, patients with Lennox-Gastaut syndrome (40.0%) and epilepsy with spasms/tonic seizures (38.5%) showed higher response rates than those with Dravet syndrome (20.0%) and epilepsy with myoclonic seizures (20.0%). High response rates in patients with Lennox-Gastaut syndrome (30.0%) and epilepsy with spasms/tonic seizures (38.5%) were sustained throughout the six-month study. The accuracy of, and differences between, responder rates should, however, be interpreted with caution due to the small number of patients. Overall, rufinamide appeared to be effective and reasonably well tolerated in this group of children with refractory generalised epilepsies, although a subgroup of patients with Dravet syndrome and epilepsy with myoclonic seizures were less responsive to rufinamide treatment.
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Anticonvulsivantes/uso terapéutico , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsia Generalizada/tratamiento farmacológico , Discapacidad Intelectual/tratamiento farmacológico , Espasmos Infantiles/tratamiento farmacológico , Triazoles/uso terapéutico , Adolescente , Niño , Preescolar , Femenino , Humanos , Síndrome de Lennox-Gastaut , Masculino , Resultado del TratamientoRESUMEN
INTRODUCTION: Schinzel-Giedion syndrome (SGS) is a rare multiple congenital malformation syndrome defined by characteristic facial features, profound developmental delay, severe growth failure, and multiple congenital anomalies. Most individuals affected by SGS die in early childhood mainly because of progressive neurodegeneration and respiratory failure. The causative gene of SGS, SETBP1, was identified, but there are few reports of SGS with molecular confirmation worldwide. PATIENT AND METHOD: In this study, we present a 10-month-old boy presenting with SGS complicated by epilepsy and profound developmental delay. RESULTS: Typical facial features, multiple anomalies, and associated neurological findings suggested a clinical diagnosis of SGS. Unusually in our patient, generalized tonic seizure occurred and has been controlled well by combined antiepileptic therapy during 7 months of follow-up. Electroencephalography findings were compatible with partial seizures, and ventriculomegaly, thinning of the corpus callosum, and delayed myelination were identified on brain MR images. SETBP1 mutational analysis revealed the presence of a recurrent mutation, p.Gly870Ser. Thus, the diagnosis of our patient was molecularly confirmed as SGS. CONCLUSIONS: Although this syndrome is extremely rare, it is important to consider SGS in the differential diagnosis of infantile-onset epilepsy with progressive neurodevelopmental retardation, especially in patients with multiple anomalies and facial dysmorphism.
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Anomalías Múltiples/diagnóstico , Proteínas Portadoras/genética , Anomalías Craneofaciales/diagnóstico , Deformidades Congénitas de la Mano/diagnóstico , Discapacidad Intelectual/diagnóstico , Uñas Malformadas/diagnóstico , Proteínas Nucleares/genética , Convulsiones/diagnóstico , Anomalías Múltiples/genética , Anomalías Craneofaciales/genética , Deformidades Congénitas de la Mano/genética , Humanos , Lactante , Discapacidad Intelectual/genética , Masculino , Uñas Malformadas/genética , Convulsiones/genéticaRESUMEN
INTRODUCTION: Spinal muscular atrophy (SMA) is a degenerative neuromuscular disorder long recognized as the most common genetic cause of infantile mortality described so far. However, the emergence of some innovative therapies, such as nusinersen and onasemnogene abeparvovec (AVXS-101), have made it possible to change the disease course of SMA. METHODS: In this study, five SMA type 1 and one SMA type 2 patients who received AVXS-101 were enrolled (7-24 months of age when administered). They were all previously treated with nusinersen, 4-5 times including loading doses, but stopped nusinersen maintenance after injection of AVXS-101. Patients were regularly followed up with laboratory tests and functional assessments after administration. RESULTS: Liver enzymes (aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase) and monocyte count tended to be elevated but normalized after several weeks. Platelets and white blood cells were transiently decreased for a few weeks after injection. Prolonged elevation of liver enzymes was associated with steroid tapering earlier than 1 month post treatment. During the follow-up period (ranging from 5 to 17 months after injection), all patients showed improved motor function and there was no case of mortality or requirement for permanent ventilatory support. For one patient, use of bilevel positive airway pressure could be reduced from 16 h to 8 h a day during sleep at 6 months post treatment. CONCLUSION: Our experience of AVXS-101 treatment has shown that a single intravenous dose could be safe and effective for SMA patients without the need for any maintenance treatment.
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Productos Biológicos/farmacología , Proteínas Recombinantes de Fusión/farmacología , Atrofias Musculares Espinales de la Infancia/terapia , Productos Biológicos/administración & dosificación , Productos Biológicos/efectos adversos , Preescolar , Femenino , Humanos , Lactante , Masculino , Evaluación de Resultado en la Atención de Salud , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversosRESUMEN
Currently, the expanding recreational use of synthetic cannabinoids (SCBs) threatens public health. SCBs produce psychoactive effects similar to those of tetrahydrocannabinol, the main component of cannabis, and additionally induce unexpected pharmacological side effects. SCBs are falsely advertised as legal and safe, but in reality, SCB abuse has been reported to cause acute intoxication and addictive disorders. However, because of the lack of scientific evidence to elucidate their dangerous pharmacological effects, SCBs are weakly regulated and continue to circulate in illegal drug markets. In the present study, the intravenous self-administration (IVSA) paradigm was used to evaluate the abuse potential of three SCBs (AM-1248, CB-13, and PB-22) in rats. All three SCBs maintained IVSA with a large number of infusions and active lever presses, demonstrating their reinforcing effects. The increase of active lever presses was particularly significant during the early IVSA sessions, indicating the reinforcementenhancing effects of the SCBs (AM-1248 and CB-13). The number of inactive lever presses was significantly higher in the SCB groups (AM-1248 and CB-13) than that in the vehicle group, indicating their impulsive effects. In summary, these results demonstrated that SCBs have distinct pharmacological properties and abuse potential.
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BACKGROUND: Recently, the recreational use of substituted phenethylamines has grown rapidly. Among these are 2-(3,5-dimethoxy-4-((2-methylallyl)oxy)phenyl)ethanamine (MAL) and 2-(2,5-dimethoxy-4-methylphenyl)-2-methoxyethan-1-amine (BOD). However, studies characterizing their abuse potential are still lacking. AIM: The purpose of this study was to investigate the abuse potential of MAL and BOD. METHODS: The psychostimulant, reinforcing, and rewarding properties of MAL and BOD were analyzed using locomotor sensitization, self-administration, and conditioned place preference tests. Dopamine antagonists (i.e. SCH23390, haloperidol) were administered during conditioned place preference to evaluate the involvement of the mesolimbic dopamine system. Furthermore, dopamine-related protein expression in the nucleus accumbens and the ventral tegmental area was measured along with dopamine concentrations in the nucleus accumbens. Electroencephalography was conducted to determine effects of MAL and BOD on brain wave activity. RESULTS: MAL induced psychostimulant effects and sensitization, while BOD induced locomotor depression in mice. Only MAL was self-administered by rats. Both drugs induced conditioned place preference in mice at different doses; dopamine receptor antagonists blocked MAL- and BOD-induced conditioned place preference. Both the compounds altered the expression of dopamine receptor D1 and D2 proteins in the nucleus accumbens and tyrosine hydroxylase (TH) and dopamine transporter in the ventral tegmental area, enhanced dopamine levels in the nucleus accumbens, and increased delta and gamma wave activities in the brain. CONCLUSIONS: MAL may induce abuse potential via the mesolimbic dopaminergic system and possibly accompanied by alterations in brain wave activity. Moreover, the lack of rewarding and reinforcing effects in BOD suggest that this drug may have little to no capability to engender compulsive behavior, though having found to induce alterations in dopaminergic system and brain wave activities.
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Conducta Animal/efectos de los fármacos , Ondas Encefálicas/efectos de los fármacos , Sensibilización del Sistema Nervioso Central/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Locomoción/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Fenetilaminas/farmacología , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Área Tegmental Ventral/efectos de los fármacos , Animales , Estimulantes del Sistema Nervioso Central/administración & dosificación , Antagonistas de Dopamina/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Fenetilaminas/administración & dosificaciónRESUMEN
RATIONALE: Depressive syndrome or depression is a debilitating brain disorder affecting numerous people worldwide. Although readily available, current antidepressants have low remission rates and late onset times. Recently, N-methyl-D-aspartate (NMDA) receptor antagonists, like ketamine and methoxetamine (MXE), were found to elicit rapid antidepressant effects. As the search for glutamatergic-based antidepressants is increasing, we synthesized three novel MXE analogs, N-ethylnorketamine hydrochloride (NENK), 2-MeO-N-ethylketamine hydrochloride (2-MeO-NEK), and 4-MeO-N-ethylketamine hydrochloride (4-MeO-NEK). OBJECTIVES: To determine whether the three novel MXE analogs induce antidepressant effects and explore their mechanistic correlation. METHODS: We examined their affinity for NMDA receptors through a radioligand binding assay. Mice were treated with each drug (2.5, 5, and 10 mg/kg), and their behavior was assessed 30 min later in the forced swimming test (FST), tail suspension test (TST), elevated plus-maze (EPM) test, and open-field test (OFT). Another group of mice were pretreated with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione (NBQX), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, or ketanserin (KS), a 5-HT2 receptor antagonist, during the FST. We also measured mRNA levels of the AMPA receptor subunits GluA1 and GluA2, brain-derived neurotrophic factor (BDNF), and mammalian target of rapamycin (mTOR) in the hippocampus and prefrontal cortex. RESULTS: The MXE analogs showed affinity to NMDA receptors and decreased immobility time during the FST and TST. NBQX and KS blocked their effects in the FST. The compounds did not induce behavioral alteration during the EPM and OFT. The compounds altered GluA1, GluA2, and BDNF mRNA levels. CONCLUSION: These results suggest that the novel MXE analogs induce antidepressant effects, which is likely via AMPA and 5-HT2 receptor activation.
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Antidepresivos/uso terapéutico , Ciclohexanonas/uso terapéutico , Ciclohexilaminas/uso terapéutico , Depresión/metabolismo , Ketamina/análogos & derivados , Ketamina/uso terapéutico , Receptores AMPA/metabolismo , Anestésicos Disociativos/farmacología , Anestésicos Disociativos/uso terapéutico , Animales , Antidepresivos/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Ciclohexanonas/farmacología , Ciclohexilaminas/farmacología , Depresión/tratamiento farmacológico , Depresión/psicología , Relación Dosis-Respuesta a Droga , Suspensión Trasera/efectos adversos , Suspensión Trasera/psicología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ketamina/farmacología , Masculino , Ratones , Ratones Endogámicos ICR , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Receptores de Serotonina 5-HT2 , Natación/psicologíaRESUMEN
Herein, we address repurposing hybrids of mosloflavone or 5,6,7-trimethoxyflavone with amide analogs of resveratrol from anticancer leads to novel potent anti-inflammatory chemical entities. To unveil the potent anti-inflammatory molecules, biological evaluations were initiated in LPS-induced RAW 264.7 macrophages at 1⯵M concentration. Promising compounds were further evaluated at various concentrations. Multiple proinflammatory mediators were assessed including NO, PGE2, IL-6, TNF-α and IL-1ß. Compound 5z inhibited the induced production of NO, PGE2, IL-6, TNF-α and IL-1ß at the low 1⯵M concentration by 44.76, 35.71, 53.48, 29.39 and 41.02%, respectively. Compound 5z elicited IC50 values as low as 2.11 and 0.98⯵M against NO and PGE2 production respectively. Compounds 5q and 5g showed potent submicromolar IC50 values of 0.31 and 0.59⯵M respectively against PGE2 production. Reverse docking of compound 5z suggested p38-α MAPK, which is a key signaling molecule within the pathways controlling the transcription of proinflammatory mediators, as the molecular target. Biochemical testing confirmed these compounds as p38-α MAPK inhibitors explaining its potent inhibition of proinflammatory mediators' production. Collectively, the results presented 5z as a promising compound for further development of anti-inflammatory agents for treatment of macrophages-and/or immune mediated inflammatory diseases.
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Antiinflamatorios no Esteroideos/farmacología , Flavonas/farmacología , Flavonoides/farmacología , Mediadores de Inflamación/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Resveratrol/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Flavonas/química , Flavonoides/química , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Células RAW 264.7 , Resveratrol/química , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
PURPOSE: There is no regimen that is strongly recommended for more than second-line treatment. We investigated the efficacy and safety of platinum/vinorelbine as more than second-line treatment. MATERIALS AND METHODS: We selected patients with advanced non-small cell lung cancer (NSCLC) who received treatment with platinum/vinorelbine at Chungnam National University Hospital from August 2001 to December 2013. The primary end point was the response rate, and secondary end points were progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: Thirty-five patients were enrolled. Response rate was 22.9% (complete response, 0 patients [0%]; partial response, eight patients [22.9%]; stable disease, 10 patients [28.6%]; progressive disease, 14 patients [40.0%]). A significantly higher response rate was observed for patients who had responded to previous chemotherapy than for those who did not (34.8% [8/23] vs. 0% [0/12], p=0.020). The median PFS was 4 months (range, 1 to 21 months). Patients with adenocarcinoma and non-smokers had a significantly longer PFS than patients with non-adenocarcinoma and smokers (5 months vs. 2 months, p=0.007; 4.5 months vs. 2 months, p=0.046, respectively). The median OS was 10 months (range, 1 to 41 months). Patients with good performance status and non-smokers had a significantly longer OS than patients with poor performance status and smokers (14 months vs. 4 months, p=0.02; 18.5 months vs. 6 months, p=0.049, respectively). The main serious adverse event (grade 3 or 4) was neutropenia (15 events, 13.3%) in a total of 113 cycles. CONCLUSION: Platinum/vinorelbine was effective as more than second-line chemotherapy, and the toxicity was tolerable, in patients with advanced NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Platino (Metal)/efectos adversos , Platino (Metal)/farmacología , Vinblastina/análogos & derivados , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Platino (Metal)/administración & dosificación , Estudios Retrospectivos , Vinblastina/administración & dosificación , Vinblastina/efectos adversos , Vinblastina/farmacología , VinorelbinaRESUMEN
Approximately 30% of patients with moyamoya disease (MMD) have presented with involvement of the posterior circulation, mainly the posterior cerebral artery (PCA). Diagnosis of delayed progression of PCA stenosis in MMD may be difficult due to the diversity in clinical features. The goal of this study was to evaluate pediatric MMD patients with delayed PCA involvement after completion of revascularization of the anterior circulation. Forty-one pediatric MMD patients who underwent revascularization of the PCA territory due to delayed posterior circulation insufficiency MMD from 2006 to 2011 were retrospectively reviewed. The average interval between the initial operation and the occipital artery (OA) procedure was 5.0 years. Common symptoms were headaches and transient visual symptoms. The decision to operate was made based on a combination of diagnostic tools. The results obtained with perfusion MRI, SPECT, MR angiography, and EEG supported posterior circulation insufficiency in 78, 41, 73, and 71% of patients, respectively. Encephaloduroarteriosynangiosis (EDAS) using the OA was performed in 15 patients, and 26 patients received multiple burr hole trephination of the occipital area. All patients showed clinical improvement. Clinicians should be aware of the possibility of delayed involvement of the PCA in pediatric MMD patients. The clinical decision regarding treatment should be based on a combination of symptomatology and the results obtained with various tools to assess whether the blood flow in the PCA territory is insufficient. Surgical treatment using indirect revascularization appears to be effective for patients with delayed PCA involvement.
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Revascularización Cerebral/métodos , Enfermedad de Moyamoya/cirugía , Procedimientos Neuroquirúrgicos/métodos , Arteria Cerebral Posterior/cirugía , Insuficiencia Vertebrobasilar/cirugía , Adolescente , Angiografía Cerebral , Circulación Cerebrovascular , Niño , Preescolar , Electroencefalografía , Femenino , Estudios de Seguimiento , Cefalea/etiología , Cefalea/terapia , Humanos , Lactante , Angiografía por Resonancia Magnética , Masculino , Enfermedad de Moyamoya/complicaciones , Enfermedad de Moyamoya/fisiopatología , Estudios Retrospectivos , Tomografía Computarizada de Emisión de Fotón Único , Resultado del Tratamiento , Insuficiencia Vertebrobasilar/complicaciones , Insuficiencia Vertebrobasilar/etiología , Insuficiencia Vertebrobasilar/fisiopatología , Visión Ocular , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: The aim of this study was to identify and describe the pediatric autoimmune encephalitis cases positive for anti-neuronal antibody tests. METHODS: Screening of six anti-neuronal antibodies in 23 children with suspected autoimmune encephalitis was performed by cell-based indirect immunofluorescence test with patients' serum or cerebrospinal fluid. RESULTS: Among the 23 cases enrolled here, eight patients (35%) were positive for the anti-N-methyl-d-aspartate (NMDA) receptor antibody and one patient (4%) was positive for the anti-contactin-associated protein-like 2 (CASPR2) antibody. In the anti-NMDA receptor antibody-positive group, seizure and movement disorders were the most prominent features and were present in all patients. A tumor was present in only one patient. Three patients with infant- and toddler-onset disease did not exhibit a classic multistage illness. In addition to seizure and dyskinesia, aphasia or mutism without severe consciousness impairment was present in all three patients. These atypical clinical presentations may suggest different pathomechanism of anti-NMDA receptor encephalitis among these age groups. The patient who was positive for the anti-CASPR2 antibody was an 8-year-old girl who presented with fever, encephalopathy, and seizure. Neuromyotonia or other dyskinesia was not present. CONCLUSIONS: Eight anti-NMDA receptor antibody positive patients and one CASPR2 positive patient were identified from the screening of six anti-neuronal antibodies in pediatric patients suspected with autoimmune encephalitis. Developmental regression specifically for language skills was suggested as one of the atypical clinical features in infants and toddler onset anti-NMDA receptor antibody positive patients.
RESUMEN
An 18-year-old boy was admitted with chest discomfort, nausea, and dyspnea at rest. At the age of 3 years, he underwent muscle biopsy and dystrophin gene analysis owing to an enlarged calf muscle and elevated serum kinase level (6,378 U/L) without overt weakness; based on the results, Becker muscular dystrophy (BMD) was diagnosed. The dystrophin gene showed deletion of exons 45 to 49. He remained ambulant and could step upstairs without significant difficulties. A chest roentgenogram showed cardiomegaly (cardiothoracic ratio, 54%), and his electrocardiogram (ECG) showed abnormal ST-T wave, biatrial enlargement, and left ventricular hypertrophy. The 2-dimensional and M-mode ECGs showed a severely dilated left ventricular cavity with diffuse hypokinesis. The systolic indices were reduced, including fractional shortening (9%) and ejection fraction (19%). Despite receiving intensive medical treatment, he died from congestive heart failure 5 months after the initial cardiac symptoms. We report a case of BMD with early-onset dilated cardiomyopathy associated with deletion of exons 45 to 49. Early cardiomyopathy can occur in BMD patients with certain genotypes; therefore, careful follow-up is required even in patients with mild phenotypes of BMD.
RESUMEN
PURPOSE: We performed this study to evaluate the frequency, types, and ictal electroencephalography (EEG) findings of coexisting seizures in patients with infantile spasms at the onset of spasms. We also evaluated the effect of coexisting seizures on short-term seizure control. METHODS: We retrospectively reviewed the long-term video-EEG and electronic medical records of 109 patients (58 boys and 51 girls) diagnosed with infantile spasms at the Seoul National University Children's Hospital. Coexisting seizure types were classified according to the International League Against Epilepsy seizure and epilepsy classification. Ictal EEG findings were also reviewed. Short-term seizure control rates were compared between groups with or without coexisting seizures. RESULTS: We identified 27 coexisting seizures in 24 of the 109 patients (22%). The most common type of seizure was generalized tonic seizure followed by myoclonic, focal tonic, tonic-clonic, hypokinetic, and versive seizures. Rates of preterm birth and birth asphyxia were significantly higher in patients with coexisting seizures. Initial anticonvulsant was vigabatrin (103 patients), valproic acid (five patients), and topiramate (one patient). There was no significant difference in short-term seizure freedom (overall seizure-free rates in patients without coexisting seizures vs. those with: 29.2% vs. 11.1% at 2 months, 36.1% vs. 22.2% at 4 months, and 41.7% vs. 27.8% at 6 months). Seizure freedom was significantly lower in the symptomatic groups compared with non-symptomatic groups. CONCLUSIONS: Long-term video-EEG monitoring is required as an initial evaluation in patients with infantile spasms, especially when there are reports of coexisting seizures, or a history of preterm birth or birth asphyxia. Presence of coexisting seizures was not related to poor seizure control in the short-term treatment period.
Asunto(s)
Convulsiones/complicaciones , Espasmos Infantiles/complicaciones , Edad de Inicio , Anticonvulsivantes/uso terapéutico , Electroencefalografía , Electromiografía , Femenino , Duplicación de Gen , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Monitoreo Fisiológico , Estudios Retrospectivos , Convulsiones/genética , Convulsiones/fisiopatología , Espasmos Infantiles/genética , Espasmos Infantiles/fisiopatología , Grabación de Cinta de VideoRESUMEN
BACKGROUND/AIMS: Antiphospholipid antibodies (aPL) have been detected in various proportions of patients with primary immune thrombocytopenia (ITP), but the clinical significance of this is debatable. The present study aimed to determine the frequency and clinical implications of elevated aPL in adult patients with ITP. METHODS: We prospectively studied newly diagnosed adult patients with ITP who were enrolled between January 2003 and December 2008 at Chungnam National University Hospital. They were evaluated for the presence of lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) at diagnosis and were followed for the development of thrombosis. RESULTS: Seventy consecutive patients with ITP (median age, 48 years; range, 18 to 79) were enrolled. Twenty patients (28.5%) were positive for aPL at the time of diagnosis: aCL alone in 15 (75%), aCL and LA in two (10%), and LA alone in three (15%). Patients who had platelet counts < 50,000/µL were administered oral prednisolone with or without intravenous immune globulin. No difference was found between the aPL-positive and -negative groups regarding gender, initial platelet count, and response to the therapy. After a median follow-up of 20 months (range, 2 to 68), two of 20 patients who were aPL-positive (10%) developed thrombosis, whereas no thrombotic event was found among those who were aPL-negative. CONCLUSIONS: Our data suggest that aPL levels should be determined at the initial presentation of ITP and that patients found to be aPL-positive should receive closer follow-up for thrombotic events.