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1.
Biol Pharm Bull ; 47(6): 1204-1208, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38910124

RESUMO

Guanfacine, used as a medication for attention-deficit/hyperactivity disorder (ADHD), leads to a high incidence of somnolence, in contrast to methylphenidate, which leads to a high incidence of insomnia. The impact of somnolence on continuing guanfacine treatment is unclear. Therefore, we investigated the reasons for discontinuing guanfacine and analyzed the factors associated with discontinuation caused by somnolence. We surveyed 96 patients under guanfacine from July 2017 to December 2021 at the Saga University Hospital. Patients who discontinued guanfacine by the end date of our study were divided into a median early and late group. We compared the reasons for discontinuation in both groups. Of all patients, 47 continued and 49 discontinued guanfacine. A higher percentage of patients discontinued guanfacine caused by somnolence for ≤70 d than for >70 d of treatment (44.0 vs. 8.3%; p = 0.008). When stratified by the concomitant use of other ADHD drugs, somnolence resulted in a higher discontinuation rate for ≤70 d than for >70 d of treatment without concomitant use (55.0 vs. 7.1%; p = 0.009). Nonetheless, concomitant use resulted in no difference. In conclusion, somnolence affects the early discontinuation of guanfacine as an ADHD drug. The combination of methylphenidate or atomoxetine may decrease withdrawal caused by somnolence.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Guanfacina , Guanfacina/efeitos adversos , Guanfacina/uso terapêutico , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Masculino , Feminino , Criança , Adolescente , Sonolência , Agonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Metilfenidato/efeitos adversos
2.
Mol Genet Metab ; 137(3): 239-248, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36182715

RESUMO

Niemann-Pick disease Type C (NPC) is a lysosomal storage disorder caused by mutation of the NPC1/NPC2 genes, which ultimately results in the accumulation of unesterified cholesterol (UEC) in lysosomes, thereby inducing symptoms such as progressive neurodegeneration and hepatosplenomegaly. This study determines the effects of 6-O-α-maltosyl-ß cyclodextrin (Mal-ßCD) on lipid levels and synthesis in Npc1-deficient (Npc1-KO cells) and vehicle CHO cells. Compared to vehicle cells, Npc1-KO cells exhibited high level of UEC, and low levels of esterified cholesterols (ECs) and long-chain fatty acids (LCFAs). The difference in lipid levels between Npc1-KO and CHO cells was largely ameliorated by Mal-ßCD administration. Moreover, the effects of Mal-ßCD were reproduced in the lysosomes prepared from Npc1-KO cells. Stable isotope tracer analysis with extracellular addition of D4-deuterated palmitic acid (D4-PA) to Npc1-KO cells increased the synthesis of D4-deuterated LCFAs (D4-LCFAs) and D4-deuterated ECs (D4-ECs) in a Mal-ßCD-dependent manner. Simultaneous addition of D6-deuterated UEC (D6-UEC) and D4-PA promoted the Mal-ßCD-dependent synthesis of D6-/D4-ECs, consisting of D6-UEC and D4-PA, D4-deuterated stearic acid, or D4-deuterated myristic acid, in Npc1-KO cells. These results suggest that Mal-ßCD helps to maintain normal lipid metabolism by restoring balance among UEC, ECs, and LCFAs through acting on behalf of NPC1 in Npc1-KO cells and may therefore be useful in designing effective therapies for NPC.


Assuntos
Doença de Niemann-Pick Tipo C , beta-Ciclodextrinas , Animais , Cricetinae , Humanos , Doença de Niemann-Pick Tipo C/genética , Doença de Niemann-Pick Tipo C/metabolismo , Cricetulus , Células CHO , Metabolismo dos Lipídeos , beta-Ciclodextrinas/farmacologia , Colesterol/metabolismo , Proteína C1 de Niemann-Pick/metabolismo
3.
J Gastroenterol Hepatol ; 37(9): 1719-1725, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35562319

RESUMO

BACKGROUND AND AIM: Smart Gene™ was developed based on the concept of point-of-care genetic testing. We evaluated the detection performance of a reagent for Helicobacter pylori (H. pylori) clarithromycin (CAM)-resistant mutation assessment and determined the association between the results of Smart Gene™ and those of eradication therapy for H. pylori. METHODS: In 2020, the present study was conducted on participants of the H. pylori test and treat project in Saga Prefecture. The submitted stool samples were measured for H. pylori gene and CAM-resistant mutation by Smart Gene™, and the results were compared with real-time polymerase chain reaction (PCR) and sequencing analysis. Finally, the results of the eradication therapy were examined for each result of Smart Gene™. RESULTS: Stool samples were obtained from 139 patients who were tested positive by stool antigen test and were analyzed. The H. pylori detection rate was 95.7% by Smart Gene™, 92.8% by real-time PCR (P < 0.01), and 89.2% by sequencing analysis (P = 0.06). The overall concordance rate for CAM-resistant mutation between Smart Gene™ and sequencing analysis was 96.7%. Moreover, 35 of 48 students with CAM-resistant mutation and 33 of the 35 students with a mutation without CAM resistance succeeded in CAM-containing triple therapy, and the success rate was significantly higher for the mutation without CAM resistance (P = 0.012). CONCLUSIONS: The detection performance of Smart Gene™ was comparable with that of real-time PCR and sequencing analysis. It is expected that the success rate of eradication would be further improved by using the reagent.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Claritromicina/farmacologia , Farmacorresistência Bacteriana/genética , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/genética , Humanos , Mutação , Testes Imediatos
4.
Pediatr Int ; 64(1): e15358, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36564216

RESUMO

BACKGROUND: In children, relationships between developmental disorders such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder and allergic diseases remain controversial, because these diseases show age- and sex-related differences. A proper understanding of the relationships between developmental disorders and allergic diseases should improve medical care for both diseases. We confirmed the prevalence of allergic diseases in elementary school-age children with developmental disorders by grade and sex. METHODS: The subjects were 446 lower grade and 312 upper grade elementary school-age children who had visited our hospital. The prevalence of allergic diseases among subjects with and without developmental disorders by grade and sex was examined using the diagnostic names on medical records. RESULTS: The prevalence of allergic diseases was significantly higher in lower grade boys and girls with developmental disorders than in those without developmental disorders (boys: OR 3.22, 95%; CI 1.49-6.95; girls: OR: 3.87, 95% CI: 1.27-11.82). The prevalence of allergic diseases was significantly higher in higher grade boys with developmental disorders than in those without developmental disorders (OR: 3.46, 95% CI: 1.59-7.53). Multiple logistic regression analysis in lower grades revealed that ADHD correlated with bronchial asthma (adjusted OR: 3.72, 95% CI: 1.42-9.69) and that autism spectrum disorder correlated with atopic dermatitis (adjusted OR: 4.26, 95% CI: 1.36-13.36). Analyses of children in the upper grades showed that ADHD correlated with atopic dermatitis (adjusted OR: 5.06, 95% CI: 1.28-20.05). CONCLUSIONS: Elementary school-age children with developmental disorders were more likely to have allergic diseases. The types of allergic diseases related to developmental disorders differed by grade and sex.


Assuntos
Asma , Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Dermatite Atópica , Hipersensibilidade , Masculino , Feminino , Humanos , Criança , Dermatite Atópica/epidemiologia , Dermatite Atópica/complicações , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/complicações , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/complicações , Hipersensibilidade/epidemiologia , Hipersensibilidade/complicações , Asma/epidemiologia , Asma/complicações , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Prevalência
5.
Pediatr Int ; 64(1): e15120, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35616152

RESUMO

BACKGROUND: Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma of the face, small stature, sparse scalp hair, juvenile cataract, radial aplasia, and predisposition to cancers. Due to the rarity of RTS, the situation of patients with RTS in Japan has not been elucidated. METHODS: In 2010 and 2020, following the results of a primary questionnaire survey, a secondary questionnaire survey on RTS was conducted nationwide to investigate the number of RTS cases and their associated skin lesions, bone lesions, other clinical features, and quality of life in Japan. RESULTS: In 2010 and 2020, 10 and eight patients with RTS were recruited, respectively. Skin lesions such as poikiloderma, erythema, pigmentation, and abnormal scalp hair were observed in almost all cases. Bone lesions were observed in four cases in the 2010 and 2020 surveys, respectively. Two cases had mutations in the RECQL4 gene in the 2020 survey. CONCLUSIONS: Two nationwide surveys have shown the actual situation of patients with RTS in Japan. Cutaneous and bone manifestations are important for the diagnosis of RTS. However, many patients have no RECQL4 mutations. The novel causative gene of RTS should be further elucidated.


Assuntos
Síndrome de Rothmund-Thomson , Humanos , Japão/epidemiologia , Mutação , Qualidade de Vida , Síndrome de Rothmund-Thomson/diagnóstico , Síndrome de Rothmund-Thomson/epidemiologia , Síndrome de Rothmund-Thomson/genética , Inquéritos e Questionários
6.
J Clin Microbiol ; 59(7): e0324520, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-33910960

RESUMO

The recent increase in macrolide-resistant Mycoplasma pneumoniae in Asia has become a continuing problem. A point-of-care testing method that can quickly detect M. pneumoniae and macrolide-resistant mutations (MR mutations) is critical for proper antimicrobial use. Smart Gene (Mizuho Medy Co., Ltd., Tosu City, Saga, Japan) is a compact and inexpensive fully automatic gene analyzer that combines amplification with PCR and the quenching probe method to specify the gene and MR mutations simultaneously. We performed a clinical evaluation of this device and its reagents on pediatric patients with suspected M. pneumoniae respiratory infections and evaluated the impact of the assay on antimicrobial selection. Using real-time PCR as a comparison control, the sensitivity of Smart Gene was 97.8% (44/45), its specificity was 93.3% (98/105), and its overall concordance rate was 94.7% (142/150). The overall concordance rate of Smart Gene diagnosis of MR mutations in comparison with sequence analysis was 100% (48/48). The ratio of MR mutations was significantly higher at high-level medical institutions than at a primary medical clinic (P = 0.023), and changes in antibiotic therapy to drugs other than macrolides were significantly more common in patients with MR mutations (P = 0.00024). Smart Gene demonstrated excellent utility in the diagnosis of M. pneumoniae and the selection of appropriate antimicrobials for MR mutations at primary medical institutions, which play a central role in community-acquired pneumonia care. The use of this device may reduce referrals to high-level medical institutions for respiratory infections, thereby reducing the medical and economic burdens on patients.


Assuntos
Mycoplasma pneumoniae , Pneumonia por Mycoplasma , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Ásia , Criança , Farmacorresistência Bacteriana/genética , Humanos , Japão , Macrolídeos/farmacologia , Mutação , Mycoplasma pneumoniae/genética , Pneumonia por Mycoplasma/diagnóstico , Pneumonia por Mycoplasma/tratamento farmacológico , Sistemas Automatizados de Assistência Junto ao Leito , RNA Ribossômico 23S
7.
Helicobacter ; 26(2): e12776, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33368891

RESUMO

BACKGROUND: The screening and treatment of Helicobacter pylori infection for all junior high students in Saga Prefecture, Japan, were started in 2016. The present study aims to evaluate the influence of adverse reactions on the success of the eradication therapy. METHODS: From 2017 to 2019, 25,006 third-grade junior high school students were tested for urinary anti-H. pylori antibodies. Positive cases were confirmed by H. pylori stool antigen tests. Of the 531 students who were found to be H. pylori-positive, 390 (358 in first-line and 32 in second-line therapy) underwent eradication therapy, and 274 (242 in first-line and 32 in second-line) students actually completed a self-reported form to rate stool consistency (based on the Bristol Stool Scale), the maximum number of bowel movements, and abdominal symptoms during the 7 days of treatment. RESULTS: Among the 274 students, the total of primary and secondary eradication success rates was 87% (95% confidential interval: 82.9-90.1) in intention-to-treat analysis. On days 4, 5, and 6, stool consistency was looser in the primary eradication failure group than in the success group (p < .05). Looser stool consistencies were observed in male students with abdominal pain compared to those who did not experience pain (p < .05). Abdominal pain and diarrhea were detected in 28.5% and 42.7% of the subjects, respectively. The overall incidence of other adverse events was low (n = 8/274, 2.9%), and only two students discontinued treatment because of adverse events. CONCLUSIONS: Softening of the stool was related to the eradication failure in the junior high school students, especially in males with abdominal pain. Adverse effects did not induce discontinuation of the eradication treatment.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Claritromicina/uso terapêutico , Quimioterapia Combinada , Infecções por Helicobacter/tratamento farmacológico , Humanos , Japão , Masculino , Estudos Prospectivos , Inibidores da Bomba de Prótons/uso terapêutico , Resultado do Tratamento
8.
Int J Mol Sci ; 22(1)2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33466390

RESUMO

Niemann-Pick disease type C (NPC) is a recessive hereditary disease caused by mutation of the NPC1 or NPC2 gene. It is characterized by abnormality of cellular cholesterol trafficking with severe neuronal and hepatic injury. In this study, we investigated the potential of glycoprotein nonmetastatic melanoma protein B (GPNMB) to act as a biomarker reflecting the therapeutic effect of 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) in an NPC mouse model. We measured serum, brain, and liver expression levels of GPNMB, and evaluated their therapeutic effects on NPC manifestations in the brain and liver after the intracerebroventricular administration of HP-ß-CD in Npc1 gene-deficient (Npc1-/-) mice. Intracerebroventricular HP-ß-CD inhibited cerebellar Purkinje cell damage in Npc1-/- mice and significantly reduced serum and cerebellar GPNMB levels. Interestingly, we also observed that the intracerebral administration significantly reduced hepatic GPNMB expression and elevated serum ALT in Npc1-/- mice. Repeated doses of intracerebroventricular HP-ß-CD (30 mg/kg, started at 4 weeks of age and repeated every 2 weeks) drastically extended the lifespan of Npc1-/- mice compared with saline treatment. In summary, our results suggest that GPNMB level in serum is a potential biomarker for evaluating the attenuation of NPC pathophysiology by intracerebroventricular HP-ß-CD treatment.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/administração & dosagem , Cerebelo/efeitos dos fármacos , Proteínas do Olho/metabolismo , Fígado/efeitos dos fármacos , Melanoma/metabolismo , Glicoproteínas de Membrana/metabolismo , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Doença de Niemann-Pick Tipo C/metabolismo , Animais , Biomarcadores/metabolismo , Cerebelo/metabolismo , Colesterol/metabolismo , Modelos Animais de Doenças , Feminino , Glicoproteínas/metabolismo , Infusões Intraventriculares , Fígado/metabolismo , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/metabolismo
9.
Hum Mol Genet ; 27(8): 1421-1433, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29432562

RESUMO

Calcineurin is a calcium (Ca2+)/calmodulin-regulated protein phosphatase that mediates Ca2+-dependent signal transduction. Here, we report six heterozygous mutations in a gene encoding the alpha isoform of the calcineurin catalytic subunit (PPP3CA). Notably, mutations were observed in different functional domains: in addition to three catalytic domain mutations, two missense mutations were found in the auto-inhibitory (AI) domain. One additional frameshift insertion that caused premature termination was also identified. Detailed clinical evaluation of the six individuals revealed clinically unexpected consequences of the PPP3CA mutations. First, the catalytic domain mutations and frameshift mutation were consistently found in patients with nonsyndromic early onset epileptic encephalopathy. In contrast, the AI domain mutations were associated with multiple congenital abnormalities including craniofacial dysmorphism, arthrogryposis and short stature. In addition, one individual showed severe skeletal developmental defects, namely, severe craniosynostosis and gracile bones (severe bone slenderness and perinatal fractures). Using a yeast model system, we showed that the catalytic and AI domain mutations visibly result in decreased and increased calcineurin signaling, respectively. These findings indicate that different functional effects of PPP3CA mutations are associated with two distinct disorders and suggest that functional approaches using a simple cellular system provide a tool for resolving complex genotype-phenotype correlations.


Assuntos
Artrogripose/genética , Calcineurina/genética , Anormalidades Craniofaciais/genética , Nanismo/genética , Mutação com Ganho de Função , Mutação com Perda de Função , Espasmos Infantis/genética , Sequência de Aminoácidos , Artrogripose/metabolismo , Artrogripose/patologia , Sequência de Bases , Calcineurina/química , Calcineurina/metabolismo , Criança , Pré-Escolar , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/patologia , Nanismo/metabolismo , Nanismo/patologia , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética , Humanos , Masculino , Modelos Moleculares , Linhagem , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios Proteicos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Espasmos Infantis/metabolismo , Espasmos Infantis/patologia , Adulto Jovem
10.
Helicobacter ; 25(3): e12690, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32207209

RESUMO

BACKGROUND: Probiotics are beneficial to patients with Helicobacter pylori infections by modulating the gut microbiota. Biofermin-R (BFR) is a multiple antibiotic-resistant lactic acid bacteria preparation of Enterococcus faecium 129 BIO 3B-R and is effective in normalizing the gut microbiota when used in combination with antibiotics. This study aimed to determine the effect of BFR in combination with vonoprazan (VPZ)-based therapy on gut microbiota. METHODS: Patients with positive urinary anti-H pylori antibody test (primary test) and fecal H pylori antigen test (secondary test) were examined. Patients in group 1 (BFR- ) received VPZ (20 mg twice daily), amoxicillin (750 mg twice daily), and clarithromycin (400 mg twice daily) for 7 days. Patients in group 2 (BFR+ ) received BFR (3 tablets/day) for 7 days, in addition to the aforementioned treatments. Following treatment, the relative abundance, α-diversity, and ß-diversity of gut microbiota were assessed. RESULTS: Supplementation with BFR prevented the decrease in a-diversity after eradication therapy (Day 7). ß-diversity was similar between groups. The incidence rate of diarrhea was non-significantly higher in the BFR- than in the BFR+ group (73.1% vs 56.5%; P = .361). Stool consistency was comparable in the BFR+ group on Days 7 and 1 (3.86 ± 0.95 vs 3.86 ± 1.46; P = .415). CONCLUSION: Biofermin-R combined with VPZ-based therapy resulted in higher microbial α-strain diversity and suppressed stool softening during H pylori eradication therapy.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Infecções por Helicobacter , Helicobacter pylori/efeitos dos fármacos , Probióticos/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Adolescente , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Claritromicina/uso terapêutico , Diarreia/tratamento farmacológico , Quimioterapia Combinada , Feminino , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Humanos , Masculino
11.
BMC Gastroenterol ; 20(1): 397, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33228552

RESUMO

BACKGROUND: The resistance rate of Helicobacter pylori to clarithromycin (CAM) is high among infected children in Japan. Therefore, a new method for detecting CAM-resistant H. pylori using a minimally invasive technique is strongly desired. We aimed to investigate the clinical usefulness of our newly developed nested polymerase chain reaction-quenching probe (Nested PCR-QP) method using stool specimens. METHODS: We first evaluated our method using a residual solution of the H. pylori stool antigen test for adolescents. Then, we evaluated our method using culture testing for adults. RESULTS: Among 57 middle school students with H. pylori, the Nested PCR-QP test results of 53 (90.3%) were able to be analyzed. A total of 28 students had CAM resistance mutations. We found a genetic mutation in 28 students and no mutation in 23 students, and these results were consistent with those of PCR-direct sequencing. In the 23 adults who were diagnosed with H. pylori infection using the rapid urease test and culture testing, we were able to use Nested PCR-QP for analyzing 21 adults who tested positive in the stool H. pylori antigen test. The results obtained for all 21 adults were consistent with those obtained via the drug susceptibility test. CONCLUSIONS: Our novel method could be useful for non-invasively detecting CAM resistance mutations in H. pylori. This may help select a drug to reduce eradication failure rates against H. pylori. Trial registration This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (no. UMIN000030632, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034977 ) on 29 December 2017.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Adolescente , Adulto , Antibacterianos/farmacologia , Criança , Claritromicina/farmacologia , Farmacorresistência Bacteriana/genética , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/genética , Humanos , Indicadores e Reagentes , Japão , Testes de Sensibilidade Microbiana
12.
J Med Genet ; 56(6): 396-407, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842224

RESUMO

BACKGROUND: Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (MECP2). Our objective to investigate the genetic landscape of MECP2-negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES). METHODS: We performed WES on 77 MECP2-negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria. RESULTS: Pathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including MECP2) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes: a de novo variant in each of ATPase H+ transporting V0 subunit A1 (ATP6V0A1), ubiquitin-specific peptidase 8 (USP8) and microtubule-associated serine/threonine kinase 3 (MAST3), as well as biallelic variants in nuclear receptor corepressor 2 (NCOR2). CONCLUSIONS: Our study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.


Assuntos
Sequenciamento do Exoma , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Fenótipo , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Ontologia Genética , Redes Reguladoras de Genes , Estudos de Associação Genética/métodos , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Polimorfismo de Nucleotídeo Único
13.
J Epidemiol ; 29(8): 282-287, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30344199

RESUMO

BACKGROUND: Selection of test-negative controls takes less time and costs less than traditional control selection for evaluating vaccine effectiveness (VE). Here, rotavirus VE was evaluated using hospital controls and compared with test-negative controls to determine whether using the latter can substitute for the former. METHODS: We recorded gastroenteritis in children from 2 months to 2 years of age at six medical facilities in Saga City between January 4th and May 31st, 2014. Stools from all identified acute gastroenteritis patients were tested for rotavirus using immunochromatography. Rotavirus gastroenteritis (RVGE) cases had test-positive stool, whereas test-negative controls had gastroenteritis but no rotavirus infection; hospital controls were outpatients visiting the same facility for indications other than gastroenteritis. Vaccination status was verified by inspecting maternal and child health records, and demographic data were obtained from a questionnaire completed by the patients' guardians or from the medical records. Unconditional logistic regression analysis was used to adjust for possible confounding factors. RESULTS: Sixty-four RVGE cases, 260 test-negative controls, and 589 hospital controls were enrolled. The characteristics of the two control groups, including RV vaccination history, were similar. The RVGE cases were more likely to have used daycare services than children from either of the two control groups. The VE against RVGE estimated using hospital controls was 86.6% (95% confidence interval [CI], 55.9-96.0%), very similar to the VE using test-negative controls (84.9% [95% CI, 49.6-95.5%]). CONCLUSIONS: The estimated VE using test-negative controls and hospital controls is similar. Therefore, test-negative controls are considered appropriate for establishing VE.


Assuntos
Gastroenterite/virologia , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/imunologia , Rotavirus/isolamento & purificação , Estudos de Casos e Controles , Pré-Escolar , Fezes/virologia , Feminino , Gastroenterite/epidemiologia , Humanos , Lactente , Japão/epidemiologia , Masculino , Infecções por Rotavirus/epidemiologia , Vacinas contra Rotavirus/administração & dosagem
14.
Int J Mol Sci ; 20(5)2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30845767

RESUMO

Niemann-Pick disease Type C (NPC) is a rare lysosomal storage disease characterized by the dysfunction of intracellular cholesterol trafficking with progressive neurodegeneration and hepatomegaly. We evaluated the potential of 6-O-α-maltosyl-ß-cyclodextrin (G2-ß-CD) as a drug candidate against NPC. The physicochemical properties of G2-ß-CD as an injectable agent were assessed, and molecular interactions between G2-ß-CD and free cholesterol were studied by solubility analysis and two-dimensional proton nuclear magnetic resonance spectroscopy. The efficacy of G2-ß-CD against NPC was evaluated using Npc1 deficient Chinese hamster ovary (CHO) cells and Npc1 deficient mice. G2-ß-CD in aqueous solution showed relatively low viscosity and surface activity; characteristics suitable for developing injectable formulations. G2-ß-CD formed higher-order inclusion complexes with free cholesterol. G2-ß-CD attenuated dysfunction of intercellular cholesterol trafficking and lysosome volume in Npc1 deficient CHO cells in a concentration dependent manner. Weekly subcutaneous injections of G2-ß-CD (2.9 mmol/kg) ameliorated abnormal cholesterol metabolism, hepatocytomegaly, and elevated serum transaminases in Npc1 deficient mice. In addition, a single cerebroventricular injection of G2-ß-CD (21.4 µmol/kg) prevented Purkinje cell loss in the cerebellum, body weight loss, and motor dysfunction in Npc1 deficient mice. In summary, G2-ß-CD possesses characteristics favorable for injectable formulations and has therapeutic potential against in vitro and in vivo NPC models.


Assuntos
Colesterol/metabolismo , Proteína C1 de Niemann-Pick/deficiência , Doença de Niemann-Pick Tipo C/tratamento farmacológico , beta-Ciclodextrinas/administração & dosagem , Animais , Células CHO , Cricetinae , Cricetulus , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Injeções Subcutâneas , Camundongos , Doença de Niemann-Pick Tipo C/metabolismo , Ressonância Magnética Nuclear Biomolecular , Resultado do Tratamento , beta-Ciclodextrinas/farmacologia
15.
Hum Mol Genet ; 25(7): 1406-19, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26908620

RESUMO

Uniparental disomy (UPD) is defined as the inheritance of both homologs of a given genomic region from only one parent. The majority of UPD includes an entire chromosome. However, the extent of UPD is sometimes limited to a subchromosomal region (segmental UPD). Mosaic paternal UPD (pUPD) of chromosome 11 is found in approximately 20% of patients with Beckwith-Wiedemann syndrome (BWS) and almost all pUPDs are segmental isodisomic pUPDs resulting from mitotic recombination at an early embryonic stage. A mechanism initiating a DNA double strand break (DSB) within 11p has been predicted to lead to segmental pUPD. However, no consensus motif has yet been found. Here, we analyzed 32 BWS patients with pUPD by SNP array and searched for consensus motifs. We identified four consensus motifs frequently appearing within breakpoint regions of segmental pUPD. These motifs were found in another nine BWS patients with pUPD. In addition, the seven motifs found in meiotic recombination hot spots could not be found within pUPD breakpoint regions. Histone H3 lysine 4 trimethylation, a marker of DSB initiation, could not be found either. These findings suggest that the mechanism(s) of mitotic recombination leading to segmental pUPD are different from that of meiotic recombination. Furthermore, we found seven patients with paternal uniparental diploidy (PUD) mosaicism. Comparison of clinical features between segmental pUPDs and PUDs showed that developmental disability and cardiac abnormalities were additional characteristic features of PUD mosaicism, along with high risk of tumor development. We also found that macroglossia was characteristic of segmental pUPD mosaicism.


Assuntos
Mitose , Recombinação Genética , Dissomia Uniparental/genética , Síndrome de Beckwith-Wiedemann , Cromossomos Humanos Par 11/genética , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Mosaicismo , Dissomia Uniparental/etiologia
16.
Pediatr Int ; 60(1): 70-75, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28796925

RESUMO

BACKGROUND: The aim of this study was to determine the frequency of central nervous system comorbidities in children with neurofibromatosis type 1 (NF1). METHODS: We performed a nationwide survey to investigate neurological comorbidities in 3-15-year-old children with NF1 in Japan by sending questionnaires to pediatricians and pediatric neurologists. A secondary questionnaire was sent to the parents of identified NF1 patients to assess neurological comorbidities including headache, attention deficit-hyperactivity disorder (ADHD) Rating Scale (RS), and the Social Responsiveness Scale 2. RESULTS: The primary survey identified 760 NF1 patients, and the parents of 565 patients were sent the secondary questionnaire. The parental response rate was 25.7% (145; 63 girls, 81 boys, one unspecified). Among the patients, 42.9% (55/128; 35 girls, 20 boys) were reported to exhibit intellectual problems. On the ADHD-RS, 40.2% (47/117) of NF1 patients aged 6-15 had ADHD (RS score >93rd percentile), with a rate of 47.7% in boys and 30.8% in girls. Furthermore, 20.2% of patients had suspected autism spectrum disorder (29/143; 10 girls, 19 boys), with Social Responsiveness Scale score ≥76. Headache was reported by 49.6% (61/123) of children over 5 years old, and 25.2% (31/123; 10 girls, 21 boys) reported migraine. Other neurological comorbidities included 20 cases of epilepsy (13.8%), 11 cases of optic nerve glioma (7.6%), five cases of brain tumor (3.4%), six cases of cerebrovascular disease (4.1%), and two cases of hydrocephalus (1.4%). CONCLUSION: Intellectual problems, ADHD, autism spectrum disorder, and migraine are major neurological comorbidities in NF1.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Espectro Autista/epidemiologia , Cefaleia/epidemiologia , Deficiência Intelectual/epidemiologia , Neurofibromatose 1/epidemiologia , Adolescente , Criança , Pré-Escolar , Comorbidade , Feminino , Inquéritos Epidemiológicos , Humanos , Japão/epidemiologia , Masculino
17.
J Hum Genet ; 62(12): 1031-1035, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28878338

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder that shows a characteristic progeria phenotype. We conducted a questionnaire survey of 1173 tertiary hospitals in Japan and reviewed the academic reports, to identify the characteristics of Asian patients with classical HGPS. As a result, four Japanese patients were identified; this was estimated to account for approximately two-third of the prevalence in Japan. Three Asian patients who had definitively been diagnosed with classical HGPS were identified in the literature; in total, the clinical characteristics of seven patients were evaluated. Most of the clinical phenotypes of Asian patients were essentially similar to those of patients of other ethnicities, such as sclerodermatous skin, growth failure, loss of scalp hair or severe complications of cardiovascular and cerebral ischemic disease. In conclusion, to circumvent or minimalize severe vascular complication, an early diagnosis, careful observation and, promisingly, new intervention with farnesylation inhibitors may improve the prognosis of classical HGPS patients.


Assuntos
Anormalidades Múltiplas/genética , Povo Asiático/genética , Doenças Cardiovasculares/genética , Progéria/genética , Dermatopatias/genética , Anormalidades Múltiplas/diagnóstico , Adolescente , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/diagnóstico , Criança , Pré-Escolar , Evolução Fatal , Feminino , Humanos , Japão , Masculino , Fenótipo , Progéria/complicações , Progéria/diagnóstico , Dermatopatias/complicações , Dermatopatias/diagnóstico , Inquéritos e Questionários
18.
Pediatr Int ; 59(2): 237-239, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28211222

RESUMO

Hemophilic pseudotumor is a rare complication, even in patients with severe hemophilia. Herein we report on a case of hemophilic pseudotumor in a patient with mild hemophilia A and allergic rhinitis, initially suspected to be a nasal tumor. The pseudotumor was cured by supplementation with recombinant factor VIII concentrates, and medication for allergic rhinitis. Pseudotumor should always be considered in hemophiliac patients, even in those with only mild deficiency of coagulation factors.


Assuntos
Hemofilia A/complicações , Doenças Nasais/etiologia , Nariz/patologia , Rinite Alérgica/complicações , Adolescente , Humanos , Imageamento por Ressonância Magnética , Masculino , Nariz/diagnóstico por imagem , Doenças Nasais/diagnóstico por imagem , Doenças Nasais/patologia , Tomografia Computadorizada por Raios X
19.
Mol Genet Metab ; 118(3): 214-219, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27184436

RESUMO

This study was conducted to evaluate the attenuating potential of 2-hydroxypropyl-ß-cyclodextrin (HPBCD) against Niemann-Pick Type C (NPC) disease, as well as the physical and chemical properties, particularly the cholesterol-solubilizing ability, in an NPC disease model in vitro. As parameters of NPC abnormalities, intracellular free and esterified cholesterol levels and lysosome volume were measured in Npc1 null Chinese hamster ovary cells. HPBCD showed dose-dependent effects against dysfunctional intracellular cholesterol trafficking, such as the accumulation and shortage of free and esterified cholesterols, respectively, in Npc1 null cells. However, the effectiveness was gradually offset by exposure to ≥8mM HPBCD. The same effect was also observed for increasing lysosome volume in Npc1 null cells. The degree of substitution of the hydroxypropyl group had little influence on the attenuating effects of HPBCD against the NPC abnormalities, at least in the range between 2.8 and 7.4. Next, we compared the effects of other hydroxyalkylated ß-cyclodextrin derivatives with different cholesterol-solubilizing abilities, such as 2-hydroxyethyl-ß-cyclodextrin (HEBCD) and 2-hydroxybutyl-ß-cyclodextrin (HBBCD). The cholesterol solubilizing potential, attenuating effects against NPC abnormalities and cytotoxicity induction were HBBCD≫HPBCD>HEBCD, HBBCD=HPBCD>HEBCD and HBBCD≫HPBCD=HEBCD, respectively. HPBCD may be superior in terms of safety and efficacy in Npc1 null cells compared with HEBCD and HBBCD. The results of this study will provide a rationale for the optimization of HPBCD therapy for NPC disease.


Assuntos
Proteínas de Transporte/metabolismo , Colesterol/metabolismo , Doença de Niemann-Pick Tipo C/metabolismo , beta-Ciclodextrinas/farmacologia , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Modelos Biológicos , Doença de Niemann-Pick Tipo C/tratamento farmacológico , beta-Ciclodextrinas/uso terapêutico
20.
Stem Cells ; 33(4): 1075-88, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25522247

RESUMO

Niemann-Pick disease type C (NPC) is a lysosomal storage disease characterized by abnormal accumulation of free cholesterol and glycolipids. Here, we established induced pluripotent stem cell (iPSC) lines from NPC patients. Hepatocyte-like cells (HLCs) and neural progenitors derived from the iPSC lines accumulated cholesterol and displayed impaired autophagy and ATP production. A molecular signature related to lipid metabolism was also impaired in the NPC-iPSC-derived HLCs. These findings indicate that iPSC-derived cells can phenocopy human NPC. We also newly found that 2-hydroxypropyl-γ-cyclodextrin (HPGCD) could reduce the cholesterol accumulation and restore the functional and molecular abnormalities in the NPC patient-derived cells, and do so more effectively than 2-hydroxypropyl-ß-cyclodextrin treatment. In addition, NPC model mice showed an improved liver status and prolonged survival with HPGCDs. Thus, iPSC lines derived from patient cells are powerful tools to study cellular models of NPC, and HPGCD is a potential new drug candidate for future treatment of this disease.


Assuntos
Células-Tronco Pluripotentes Induzidas/patologia , Doença de Niemann-Pick Tipo C/patologia , beta-Ciclodextrinas/farmacologia , gama-Ciclodextrinas/farmacologia , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Técnicas de Cocultura , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Doença de Niemann-Pick Tipo C/metabolismo , Resultado do Tratamento , beta-Ciclodextrinas/uso terapêutico , gama-Ciclodextrinas/uso terapêutico
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