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1.
Indian J Pediatr ; 2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-33400135

RESUMEN

OBJECTIVE: To clarify the pathogenesis of sudden unexpected natural death (SUD) as well as biomarkers to differentiate the underlying diseases, by performing cytokine analysis in the acute phase of pediatric patients in whom viral infection led to SUD. METHODS: An acute phase cytokine analysis of pediatric patients in whom viral infection led to SUD was performed, and the data obtained were compared with those from SUD patients not associated with viral infections. Subjects included 4 boys aged 1-16 mo who died of cardiopulmonary arrest associated with viral infections. The causative viruses were identified as enterovirus, parainfluenza virus, respiratory syncytial virus, and rotavirus. The 4 other infants/children (aged 2-12 mo) died of non-infectious episodes, i.e., 1, 2, and 1 died of drowning, falling, and a traffic accident, respectively. Cerebrospinal fluid samples (CSF) of the subjects were collected during cardiopulmonary resuscitation or within 24 h of the events. RESULTS: The infection-induced sudden death group showed elevated CSF levels of inflammatory cytokines and chemokines. No increase was observed in interleukin-10 levels. Furthermore, in the infection-induced sudden death group, platelet-derived growth factor levels correlated with inflammatory cytokine levels. CONCLUSIONS: Infection-associated SUD may be differentiated from noninfectious SUD by measuring the levels of acute phase-inflammatory cytokines and chemokines at the onset of SUD.

2.
J Phys Ther Sci ; 32(11): 772-774, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33281295

RESUMEN

[Purpose] A case report in which we treated injured patellar cartilage using non-invasive electrical stimulation; we also used MRI to document the morphology of the patellar cartilage before and after the treatment. [Participant and Methods] A police officer suffered from right anterior knee pain that noticeably affected his firearms marksmanship in kneeling position. After a MRI scan he was diagnosed with grade I chondromalacia patella involving the lateral patellar facet. He received therapeutic electrical stimulation on right knee acupoints for four weeks. [Results] He responded positively to the treatment and his numerical rating scale reduced from 6 to 0 for the right knee pain. The MRI revealed that the signs of grade I chondromalacia patella disappeared. [Conclusion] The patellar cartilage is largely avascular; the chondrocytes in cartilage have a low metabolic rate due to limited nutrient supply. Mild cartilage repair may occur spontaneously but is undoubtedly slow. Although this is a case report, we believe that the micro-current stimulation may help enhance the local metabolism and repair process in the affected cartilage.

3.
J Clin Med ; 9(11)2020 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-33228144

RESUMEN

Although migraines are common in children and adolescents, they have a robustly negative impact on the quality of life of individuals and their families. The current treatment guidelines outline the behavioral and lifestyle interventions to correct common causative factors, such as negative emotional states, lack of exercise and sleep, and obesity; however, the evidence of their effectiveness is insufficient. To create a plan for disseminating optimal pediatric headache education, we reviewed the current evidence for factors correlated with migraine. We assessed three triggers or risk factors for migraines in children and adolescents: stress, sleep poverty, and alimentation (including diet and obesity). While there is a gradual uptick in research supporting the association between migraine, stress, and sleep, the evidence for diet-related migraines is very limited. Unless obvious dietary triggers are defined, clinicians should counsel patients to eat a balanced diet and avoid skipping meals rather than randomly limiting certain foods. We concluded that there is not enough evidence to establish a headache education plan regarding behavioral and lifestyle interventions. Clinicians should advise patients to avoid certain triggers, such as stress and sleep disorders, and make a few conservative dietary changes.

4.
Am J Med Genet A ; 2020 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-33251766

RESUMEN

Several patients with beta-propeller protein-associated neurodegeneration (BPAN)/static encephalopathy with neurodegeneration in adulthood have been reported to present Rett syndrome (RTT)-like features. This report presents an individual with BPAN showing clinical features of RTT. Psychomotor delay and epilepsy onset were noted at 1 year, and regression began at 4 years. Screening of the methyl-CpG binding protein 2 (MECP2) did not show variants. At 22 years, basal ganglia iron deposits were found on magnetic resonance imaging (MRI), and the WD-domain repeat 45 gene (WDR45) variant was identified. Review of the literature showed that BPAN with RTT-like features is associated with more epileptic seizures and less deceleration of head growth, breathing irregularities, and cold extremities than classic RTT with MECP2 variants. These clinical presentations may provide clues for differentiating between these two disorders. However, both WDR45 and MECP2 should be screened in patients presenting a clinical picture of RTT without specific MRI findings of BPAN.

6.
J Child Neurol ; 35(10): 667-673, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32476572

RESUMEN

BACKGROUND: Migraines are a broad spectrum of disorders classified by the type of aura with some requiring attentive treatment. Vasoconstrictors, including triptans, should be avoided in the acute phase of migraines with brainstem aura, in hemiplegic migraine, and in retinal migraine. This study investigated the characteristics and burden of these migraines. METHODS: Medical charts of 278 Japanese pediatric patients with migraines were retrospectively reviewed. Migraine burden of migraines with brainstem aura, hemiplegic migraines, and retinal migraine was assessed using the Headache Impact Test-6™ (HIT-6) and the Pediatric Migraine Disability Assessment scale (PedMIDAS). RESULTS: Of 278 patients screened, 12 (4.3%) patients with migraines with brainstem aura (n = 5), hemiplegic migraines (n = 2), and retinal migraine (n = 5) were enrolled in the study. All patients had migraine with/without typical aura, whereas some patients had coexisting migraine with another type of headache (chronic tension-type headache in 3 patients, and 1 each with frequent episodic tension-type headache, headache owing to medication overuse, and chronic migraine). Migraines with brainstem aura, hemiplegic migraines, and retinal migraine patients with coexisting headaches had higher HIT-6 or PedMIDAS scores, whereas migraines with brainstem aura, hemiplegic migraines, and retinal migraine patients without coexisting headache did not show high HIT-6 or PedMIDAS scores. CONCLUSION: All migraines with brainstem aura, hemiplegic migraines, and retinal migraine patients experienced migraine with or without typical aura, and some patients having other coexisting headaches also had high PedMIDAS and HIT-6 scores. PedMIDAS and HIT-6 should not be considered diagnostic indicators of migraines with brainstem aura, hemiplegic migraines, or retinal migraine. In clinical practice for headaches in children, careful history taking and proactive assessment of the aura are needed for accurate diagnosis of migraines with brainstem aura, hemiplegic migraines, and retinal migraine.

7.
Brain Dev ; 42(7): 523-528, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32336482

RESUMEN

BACKGROUND: Riboflavin may prevent migraine episodes; however, there is limited evidence of its effectiveness in pediatric populations. This study investigated the effectiveness of riboflavin and clinical predictors of response in children with migraines. METHODS: We retrospectively reviewed data from 68 Japanese children with migraines, of whom 52 also exhibited another type of headache. Patients received 10 or 40 mg/day of riboflavin. We evaluated the average migraine frequency per month as a baseline and after 3 months of riboflavin therapy to determine the effectiveness and clinical predictors of response. RESULTS: The frequency of migraine episodes was significantly lower at 3 months than at baseline (median, [interquartile range], 5.2 (3-7) vs. 4.0 (2-5); p < 0.01). Twenty-five patients (36.7%) showed 50% or greater reduction in episode frequency (responders), while 18 (26.5%) showed a 25%-50% reduction. We compared responders (n = 25) and non-responders (n = 43) and found no significant differences in sex, familial history, riboflavin dose, migraine type (i.e., presence or absence of aura), age at headache onset, or age at consultation. However, non-responders were more likely to have co-morbid non-migraine headaches (odds ratio, 4.11; 95% confidence interval [CI], 1.27-13.33; p = 0.02); this variable was also significant in a multivariate analysis (adjusted odds ratio, 3.8; 95% CI, 1.16-12.6; p = 0.03). Of the co-morbid headache types, only tension headaches were significant (odds ratio, 0.176; 95% CI, 0.04-0.73; p = 0.013). No adverse effects of riboflavin were identified. CONCLUSIONS: Low-dose riboflavin is safe and modestly effective for migraines in children. It may be especially beneficial for children without other co-morbid headache types.

9.
J Infect Chemother ; 26(4): 393-396, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31879187

RESUMEN

We report a first case of respiratory syncytial virus (RSV) infection-associated encephalopathy in which RS virus was detected in the patient's intratracheal aspiration and cerebrospinal fluid despite negative rapid test results of the nasal swab. The patient's findings and clinical course coincided with those of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) with severe subsequent sequelae. Our case indicates that clinicians should consider RSV infection when patients have AESD with unknown etiology.

10.
ChemMedChem ; 14(22): 1894-1910, 2019 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-31657130

RESUMEN

The ß-site amyloid precursor protein cleaving enzyme 1 (BACE1, also known as ß-secretase) is a promising target for the treatment of Alzheimer's disease. A pKa lowering approach over the initial leads was adopted to mitigate hERG inhibition and P-gp efflux, leading to the design of 6-CF3 dihydrothiazine 8 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide). Optimization of 8 led to the discovery of 15 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide) with an excellent balance of potency, hERG inhibition, P-gp efflux, and metabolic stability. Oral administration of 8 elicited robust Aß reduction in dog even at 0.16 mg/kg. Reflecting the reduced hERG inhibitory activity, no QTc prolongation was observed at high doses. The potential for reactive metabolite formation of 15 was realized in a nucleophile trapping assay using [14 C]-KCN in human liver microsomes. Utilizing covalent binding (CVB) in human hepatocytes and the maximum projected human dosage, the daily CVB burden of 15 was calculated to be at an acceptable value of below 1 mg/day. However, hepatotoxicity was observed when 15 was subjected to a two-week tolerance study in dog, which prevented further evaluation of this compound.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Oxazinas/farmacología , Tiazinas/farmacología , Secretasas de la Proteína Precursora del Amiloide/deficiencia , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/deficiencia , Ácido Aspártico Endopeptidasas/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Hepatocitos/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Noqueados , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Oxazinas/química , Ratas , Relación Estructura-Actividad , Tiazinas/administración & dosificación , Tiazinas/química
11.
J Med Chem ; 62(20): 9331-9337, 2019 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-31549838

RESUMEN

Genetic evidence points to deposition of amyloid-ß (Aß) as a causal factor for Alzheimer's disease. Aß generation is initiated when ß-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead 1, we describe the discovery of a thiazine-based BACE1 inhibitor 5 with robust Aß reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where 5 achieved sustained Aß reduction of 80% at trough level.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores de Proteasas/química , Tiazinas/química , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP2C9/metabolismo , Perros , Evaluación Preclínica de Medicamentos , Femenino , Semivida , Haplorrinos , Corazón/efectos de los fármacos , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Ratas , Ratas Sprague-Dawley , Tiazinas/metabolismo , Tiazinas/farmacología
12.
Biol Pharm Bull ; 42(10): 1651-1657, 2019 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-31341143

RESUMEN

Patients with myelodysplastic syndrome (MDS) often require blood transfusion and anticancer therapy; however, elderly patients are intolerant to the associated side effects of anticancer therapy. Because L-leucine can be used to treat Diamond-Blackfan anemia, which is caused by defects in ribosomal protein (RP) genes, resulting in increased in vivo hemoglobin synthesis, it is possible that some MDS patients who have aberrations in their RP genes could also be effectively treated with L-leucine. In the present study, we investigated the effects of L-leucine on hematopoietic function (reticulocyte count), red blood cell count, and hemoglobin level in MDS patients. We administered L-leucine (1.8 g, twice daily, 3 d/week) with oral vitamin B6 supplements to a final cohort of eight MDS patients for 15 (interquartile range: 11-18) weeks. We assessed the patients at 10 ± 2 weeks after therapy initiation. Only the absolute reticulocyte count was affected, improving in 6/8 (75%) patients. The median absolute reticulocyte count was 3.5 × 104 (range: 2.7-6.4 × 104) cells/µL, an increase of 0.5 × 104 (range: 0.2-0.7 × 104) cells/µL. At 10 weeks, there was only one case of an improved hemoglobin level. Non-hematological adverse events of grade 3 were observed one raised triglycerides. These data suggest that L-leucine has little effect on MDS. However, it may contribute to the recovery of hematopoietic function, futher study be desired.


Asunto(s)
Recuento de Eritrocitos , Hematopoyesis/efectos de los fármacos , Leucina/farmacología , Síndromes Mielodisplásicos/sangre , Anciano , Anciano de 80 o más Años , Femenino , Hemoglobinas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Reticulocitos , Proteínas Ribosómicas/genética
13.
CEN Case Rep ; 8(2): 75-78, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30293132

RESUMEN

We herein report 2 Japanese patients with X-linked Alport syndrome (XLAS), with a novel variant in COL4A5. Patient 1 was a 16-year-old Japanese girl with a history of microscopic hematuria, without proteinuria, renal dysfunction, deafness, or ocular abnormalities. At 13 years of age, renal biopsy was performed; however, a diagnosis of AS was not considered. When her mother (patient 2) was 40 years of age (3 years after patient 1 underwent a renal biopsy), patient 2 was found to have asymptomatic hematuria, proteinuria, and an increased serum creatinine level, without deafness and ocular abnormalities. Subsequently, immunofluorescence staining for alpha 5 chains of type IV collagen was performed in patient 1. Pathological findings were consistent with AS, and genetic analysis demonstrated that both patients had a heterozygous mutation in COL4A5 (NM_000495.4: exon41:c.C3769T: p.Q1257X). To date, more than 900 different COL4A5 mutations have been identified; however, this variant has not been previously described. Physicians have to consider AS when they perform a renal biopsy in all patients with hematuria despite absent/present of family history, hearing loss, and ocular abnormality. Especially, when findings of light microscopy and immunofluorescence microscope are unclear, it should be considered carefully. Electron microscopy findings are very important.


Asunto(s)
Colágeno Tipo IV/genética , Nefritis Hereditaria/genética , Adolescente , Adulto , Femenino , Humanos , Riñón/patología , Masculino , Nefritis Hereditaria/patología
14.
J Pediatr Hematol Oncol ; 41(5): e325-e328, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30130274

RESUMEN

Therapeutic phlebotomy is recommended for treating hereditary hemochromatosis. However, the procedure and its efficacy for children remain unclear. We describe a young female patient with ferroportin disease, which was confirmed from excess iron deposition within hepatocytes and by identifying a heterozygous variant p.Cys326Phe in SLC40A1. She had been followed without phlebotomy. Liver histology at age 13 years revealed iron deposition progression. Phlebotomy was initiated and her iron markers and imaging findings improved without severe adverse effects. Therapeutic phlebotomy for children is effective and well-tolerated and should be considered as early as possible after a hemochromatosis diagnosis.


Asunto(s)
Proteínas de Transporte de Catión/deficiencia , Hemocromatosis/diagnóstico , Hemocromatosis/terapia , Mutación , Flebotomía/métodos , Adolescente , Proteínas de Transporte de Catión/genética , Femenino , Hemocromatosis/genética , Heterocigoto , Humanos , Resultado del Tratamiento
15.
J Org Chem ; 84(8): 4893-4897, 2019 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-30371078

RESUMEN

The synthesis of a 6-CF3-substituted 2-amino-dihydro-1,3-thiazine via N, N-diethylaminosulfur trifluoride (DAST)-mediated cyclization of N-hydroxypropyl thiourea 6 is described. This reaction gave 6-CF3-1,3-thiazine 7 with high chemical yield and chemoselectivity, suppressing the common byproduct of oxazine 8. This new protocol enabled access to 6-CF3-substituted 1,3-thiazine ß-secretase inhibitor 2.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Dietilaminas/farmacología , Inhibidores Enzimáticos/farmacología , Flúor/farmacología , Tiazinas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ciclización , Dietilaminas/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Flúor/química , Humanos , Estructura Molecular , Tiazinas/síntesis química , Tiazinas/química
18.
Bioorg Med Chem ; 25(7): 2177-2190, 2017 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-28284871

RESUMEN

A novel series of (6-aminopyridin-3-yl)(4-(pyridin-2-yl)piperazin-1-yl) methanone derivatives were identified as selective transient receptor potential vanilloid 4 (TRPV4) channel antagonist and showed analgesic effect in Freund's Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig and rat. Modification of right part based on the compound 16d which was disclosed in our previous communication led to the identification of compound 26i as a flagship compound. In this paper, we described the details about design, synthesis and structure-activity relationship (SAR) analysis at right and left part of these derivatives (Fig. 1).


Asunto(s)
Analgésicos/farmacología , Compuestos de Azabiciclo/farmacología , Manejo del Dolor/métodos , Canales Catiónicos TRPV/antagonistas & inhibidores , Tiazoles/farmacología , Analgésicos/química , Animales , Compuestos de Azabiciclo/química , Cobayas , Humanos , Microsomas/efectos de los fármacos , Espectroscopía de Protones por Resonancia Magnética , Ratas , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad , Tiazoles/química
19.
Bioorg Med Chem Lett ; 26(20): 4936-4941, 2016 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-27634196

RESUMEN

A series of 2',4'-dimethyl-[4,5'-bithiazol]-2-yl amino derivatives have been identified as selective TRPV4 antagonists that display inhibition potencies against 4α-phorbol 12,13-didecanoate (4αPDD), well known as a TRPV4 selective agonist and/or a hypotonicity. In particular, 9-(6-((2',4'-dimethyl-[4,5'-bithiazol]-2-yl)amino)nicotinoyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one showed an analgesic effect in Freund's Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig (reported in Part 1). However, there are some concerns such as species differences and the need for higher plasma exposure to achieve target efficacy for evaluation by an in vivo pain model. In this Letter, we report the resolution of some of the problems by further optimizing the chemical scaffold.


Asunto(s)
Canales Catiónicos TRPV/antagonistas & inhibidores , Tiazoles/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Cricetinae , Descubrimiento de Drogas , Relación Estructura-Actividad , Tiazoles/administración & dosificación , Tiazoles/química , Tiazoles/farmacocinética
20.
J Hepatobiliary Pancreat Sci ; 23(10): 622-627, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27474864

RESUMEN

BACKGROUND: Gallstones are detected in about 5% of healthy Japanese. We followed up individuals showing gallstones upon screening, investigating features of those requiring surgery. METHODS: In 2002 we performed health evaluations for 21,550 persons (13,986 men and 7,564 women), detecting gallstones ultrasonographically in 837 or 3.9% (561 men, or 4.0%; 276 women, or 3.6%). Up until 2012, we followed up 720 of the 837 persons with gallstones (86.0%) and compared individuals requiring or not requiring cholecystectomy as to age, gender, body mass index, diabetes, liver function, lifestyle, abdominal symptoms, and ultrasonographic findings. We also compared laboratory data obtained before and after surgery. The study was reviewed and approved by our institutional review board, and registered on UMIN-CTR (ID: UMIN000021995). RESULTS: Among 720 persons with gallstones, 55 (7.6%) were treated by surgery. Men tended to undergo surgery more frequently than women (P = 0.086, 43 of 488, or 8%, vs. 12 of 232, or 5.2%). Need for cholecystectomy was significantly more likely among ethanol drinkers (P = 0.008). Gallstone diameters between 6 to 15 mm were more frequent in the surgical group (51.5%) than in subjects requiring only observation (29.5%; P = 0.002). Adenomyomatosis or gallbladder wall thickening was more frequent in the surgical group (P = 0.002), as was presence of abdominal symptoms (P = 0.0002). Hemoglobin A1c was significantly higher after surgery (5.4 ± 0.6) than before (5.3 ± 0.5; P = 0.001). CONCLUSIONS: Among persons with gallstones detected by screening, men who drank, had abdominal symptoms, and showed gallbladder wall thickening or adenomyomatosis were more likely to require surgery within 4 years.


Asunto(s)
Colecistectomía/métodos , Cálculos Biliares/diagnóstico por imagen , Cálculos Biliares/cirugía , Tamizaje Masivo/métodos , Espera Vigilante/métodos , Adulto , Análisis Químico de la Sangre , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Cálculos Biliares/terapia , Humanos , Japón , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Ultrasonografía Doppler/métodos
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