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1.
Artigo em Inglês | MEDLINE | ID: mdl-31928223

RESUMO

AIMS: Klotho interacts with various membrane proteins such as receptors for transforming growth factor (TGF) ß and insulin-like growth factor (IGF). Renal expression of klotho is diminished in polycystic kidney disease (PKD). In the present study, the effects of klotho supplementation on PKD were assessed. METHODS: Recombinant human klotho protein (10 µg/kg/day) or a vehicle was administered daily by subcutaneous injection to 6-week-old mice with PKD (DBA/2-pcy). Blood pressure was measured using tail-cuff methods. After 2 months, the mice were killed, and the kidneys were harvested for analysis. RESULTS: Exogenous klotho protein supplementation reduced kidney weight, cystic area, systolic blood pressure, renal angiotensin II levels, and 8-epi-prostaglandin F2α excretion (p<0.05). Klotho protein supplementation enhanced glomerular filtration rate, renal expressions of superoxide dismutase (SOD), klotho itself (p<0.05). Klotho supplementation attenuated renal expressions of TGFß and collagen I, and diminished renal abundance of Twist, phosphorylated Akt, and mTOR (p<0.05). Pathological examination revealed that klotho decreased the fibrosis index and nuclear staining of Smad in PKD kidneys (p<0.05). CONCLUSIONS: Our data indicate that klotho protein supplementation ameliorates the renin-angiotensin system, reducing blood pressure in PKD mice. Furthermore, the present results implicate klotho supplementation in the suppression of Akt/mTOR signaling, slowing cystic expansion. Finally, our findings suggest that klotho protein supplementation attenuated fibrosis at least partly by inhibiting epithelial mesenchymal transition in PKD.

2.
Nat Commun ; 10(1): 5386, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31772163

RESUMO

Myelodysplastic syndromes (MDS) arise in older adults through stepwise acquisitions of multiple somatic mutations. Here, analyzing 1809 MDS patients, we infer clonal architecture by using a stringent, the single-cell sequencing validated PyClone bioanalytic pipeline, and assess the position of the mutations within the clonal architecture. All 3,971 mutations are grouped based on their rank in the deduced clonal hierarchy (dominant and secondary). We evaluated how they affect the resultant morphology, progression, survival and response to therapies. Mutations of SF3B1, U2AF1, and TP53 are more likely to be dominant, those of ASXL1, CBL, and KRAS are secondary. Among distinct combinations of dominant/secondary mutations we identified 37 significant relationships, of which 12 affect clinical phenotypes, 5 cooperatively associate with poor prognosis. They also predict response to hypomethylating therapies. The clonal hierarchy has distinct ranking and the resultant invariant combinations of dominant/secondary mutations yield novel insights into the specific clinical phenotype of MDS.

4.
Nature ; 574(7780): 707-711, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31664194

RESUMO

In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.

5.
Nature ; 574(7780): 712-716, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31597163

RESUMO

Cancers are caused by genomic alterations known as drivers. Hundreds of drivers in coding genes are known but, to date, only a handful of noncoding drivers have been discovered-despite intensive searching1,2. Attention has recently shifted to the role of altered RNA splicing in cancer; driver mutations that lead to transcriptome-wide aberrant splicing have been identified in multiple types of cancer, although these mutations have only been found in protein-coding splicing factors such as splicing factor 3b subunit 1 (SF3B1)3-6. By contrast, cancer-related alterations in the noncoding component of the spliceosome-a series of small nuclear RNAs (snRNAs)-have barely been studied, owing to the combined challenges of characterizing noncoding cancer drivers and the repetitive nature of snRNA genes1,7,8. Here we report a highly recurrent A>C somatic mutation at the third base of U1 snRNA in several types of tumour. The primary function of U1 snRNA is to recognize the 5' splice site via base-pairing. This mutation changes the preferential A-U base-pairing between U1 snRNA and the 5' splice site to C-G base-pairing, and thus creates novel splice junctions and alters the splicing pattern of multiple genes-including known drivers of cancer. Clinically, the A>C mutation is associated with heavy alcohol use in patients with hepatocellular carcinoma, and with the aggressive subtype of chronic lymphocytic leukaemia with unmutated immunoglobulin heavy-chain variable regions. The mutation in U1 snRNA also independently confers an adverse prognosis to patients with chronic lymphocytic leukaemia. Our study demonstrates a noncoding driver in spliceosomal RNAs, reveals a mechanism of aberrant splicing in cancer and may represent a new target for treatment. Our findings also suggest that driver discovery should be extended to a wider range of genomic regions.

6.
Nature ; 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31597162

RESUMO

Recurrent somatic single nucleotide variants (SNVs) in cancer are largely confined to protein-coding genes, and are rare in most paediatric cancers1-3. Here we report highly recurrent hotspot mutations of U1 spliceosomal small nuclear RNAs (snRNAs) in ~50% of Sonic hedgehog medulloblastomas (Shh-MB), which were not present across other medulloblastoma subgroups. This U1-snRNA hotspot mutation (r.3a>g), was identified in <0.1% of 2,442 cancers across 36 other tumour types. Largely absent from infant Shh-MB, the mutation occurs in 97% of adults (Shhδ), and 25% of adolescents (Shhα). The U1-snRNA mutation occurs in the 5' splice site binding region, and snRNA mutant tumours have significantly disrupted RNA splicing with an excess of 5' cryptic splicing events. Mutant U1-snRNA-mediated alternative splicing inactivates tumour suppressor genes (PTCH1), and activates oncogenes (GLI2, CCND2), represents a novel target for therapy, and constitutes a highly recurrent and tissue-specific mutation of a non-protein coding gene in cancer.

7.
Ren Fail ; 41(1): 893-898, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31557071

RESUMO

Background: Two types of global glomerulosclerosis, glomerular obsolescence and solidification, have been identified. A clinicopathological correlation between these glomerular changes and hypertensive nephrosclerosis has been reported; however, clinicopathological correlations with other kidney diseases are unknown. The aim of this study was to evaluate the correlation between the two glomerulosclerosis types and the clinical IgA nephropathy presentation. Methods: A single center, cross-sectional study of patients with IgA nephropathy was performed. Correlations between glomerulosclerosis and body mass index, mean blood pressure, creatinine-based estimated glomerular filtration rate (eGFR), total cholesterol, urinary protein corrected by urinary creatinine, and anti-hypertensive agent use were investigated using univariate and multivariate analyses. Results: Overall, 116 patients were enrolled (male/female, 59/57; mean age, 40.5 ± 15.0 years). Separate analyses were performed for solidification and obsolescence glomerulosclerosis. Univariate analysis demonstrated a significant correlation between the percentage of solidification glomerulosclerosis and patient age, mean blood pressure, eGFR, and use of antihypertensive drugs. Multivariate analysis showed that only eGFR and use of antihypertensive drugs maintained their independent predictive value. The amount of urinary protein emerged as a significant factor based on the multivariate analysis. However, although the univariate analysis demonstrated a statistically significant correlation between the percentage of obsolescence and eGFR for obsolescence glomerulosclerosis, a multivariate analysis indicated that none of the factors maintained their independent predictive value. Conclusions: The incidence of solidification was better correlated with some nephritis-related clinical parameters compared with the incidence of obsolescence. The emergence of solidification may influence the clinical activities that are associated with IgA nephropathy.

8.
Cancer Sci ; 110(10): 3358-3367, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385395

RESUMO

Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (ALL). Compared to children with ALL and no DS (non-DS-ALL), those with DS and ALL (DS-ALL) harbor uncommon genetic alterations, suggesting DS-ALL could have distinct biological features. Recent studies have implicated several genes on chromosome 21 in DS-ALL, but the precise mechanisms predisposing children with DS to ALL remain unknown. Our integrated genetic/epigenetic analysis revealed that DS-ALL was highly heterogeneous with many subtypes. Although each subtype had genetic/epigenetic profiles similar to those found in non-DS-ALL, the subtype distribution differed significantly between groups. The Philadelphia chromosome-like subtype, a high-risk B-cell lineage variant relatively rare among the entire pediatric ALL population, was the most common form in DS-ALL. Hypermethylation of RUNX1 on chromosome 21 was also found in DS-ALL, but not non-DS-ALL. RUNX1 is essential for differentiation of blood cells, especially B cells; thus, hypermethylation of the RUNX1 promoter in B-cell precursors might be associated with increased incidence of B-cell precursor ALL in DS patients.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Metilação de DNA , Síndrome de Down/complicações , Perfilação da Expressão Gênica/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Diferenciação Celular , Criança , Cromossomos Humanos Par 21/genética , Síndrome de Down/genética , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Cromossomo Filadélfia , Regiões Promotoras Genéticas , Análise de Sequência de DNA , Análise de Sequência de RNA
9.
Cancer Res ; 79(19): 4814-4827, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31431463

RESUMO

Gliomas are classified by combining histopathologic and molecular features, including isocitrate dehydrogenase (IDH) status. Although IDH-wild-type diffuse astrocytic glioma (DAG) shows a more aggressive phenotype than IDH-mutant type, lack of knowledge regarding relevant molecular drivers for this type of tumor has hindered the development of therapeutic agents. Here, we examined human IDH-wild-type DAGs and a glioma mouse model with a mosaic analysis with double markers (MADM) system, which concurrently lacks p53 and NF1 and spontaneously develops tumors highly comparable with human IDH-wild-type DAG without characteristic molecular features of glioblastoma (DAG-nonMF). During tumor formation, enhancer of zeste homolog (EZH2) and the other polycomb repressive complex 2 (PRC2) components were upregulated even at an early stage of tumorigenesis, together with an increased number of genes with H3K27me3 or H3K27me3 and H3K4me3 bivalent modifications. Among the epigenetically dysregulated genes, frizzled-8 (Fzd8), which is known to be a cancer- and stem cell reprogramming-related gene, was gradually silenced during tumorigenesis. Genetic and pharmacologic inhibition of EZH2 in MADM mice showed reactivation of aberrant H3K27me3 target genes, including Fzd8, together with significant reduction of tumor size. Our study clarifies a pathogenic molecular pathway of IDH-wild-type DAG-nonMF that depends on EZH2 activity and provides a strong rationale for targeting EZH2 as a promising therapeutic approach for this type of glioma. SIGNIFICANCE: EZH2 is involved in the generation of IDH-wild-type diffuse astrocytic gliomas and is a potential therapeutic target for this type of glioma. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/19/4814/F1.large.jpg.

11.
PLoS One ; 14(7): e0219819, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31310615

RESUMO

Rapid identification of causative agents from positive blood culture media is a prerequisite for the timely targeted treatment of patients with sepsis. The GENECUBE (TOYOBO Co., Ltd.) is a novel, fully-automated gene analyzer that can purify DNAs and amplify target DNAs. In this study, we evaluated the ability of two newly developed GENECUBE assays to directly detect the nuc and mecA genes in blood culture medium; nuc is specific to Staphylococcus aureus, and mecA indicates methicillin resistance. We examined 263 positive blood culture samples taken at three hospitals from patients suspected of having staphylococcal bacteremia. The results were then compared with those obtained using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, antimicrobial susceptibility testing (Microscan system or Dry-plate EIKEN), and sequencing analysis. The GENECUBE assays had sensitivity and specificity of 100% in detecting both S. aureus and methicillin resistance in positive blood culture. The turnaround time of the examination was evaluated for 36 positive blood culture samples. The time between the initiation of incubation and completion of the GENECUBE examination was 23 h (interquartile range: IQR 21-37 h); the time between reporting of Gram stain examination and completion of the GENECUBE examination was 52 min (IQR 48-62 min). These findings show that the GENECUBE assays significantly reduce the assay time with no loss of sensitivity or specificity.

12.
Nature ; 572(7767): 67-73, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31043743

RESUMO

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin+ stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.


Assuntos
Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Evolução Molecular , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Transcrição Genética , Animais , Neoplasias Cerebelares/classificação , Cerebelo/citologia , Cerebelo/embriologia , Cerebelo/metabolismo , Criança , Feminino , Feto/citologia , Glioma/classificação , Glioma/genética , Glioma/patologia , Humanos , Meduloblastoma/classificação , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos , Análise de Sequência de RNA , Análise de Célula Única , Fatores de Tempo , Transcriptoma/genética
13.
J Infect Chemother ; 25(8): 578-583, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30905631

RESUMO

Recently, rapid molecular detection systems have been used for point-of-care testing for the diagnosis of influenza worldwide. Here, we evaluated the performance of the cobas Liat system and the cobas Influenza A/B assay (Liat) using fresh nasopharyngeal samples collected from a Japanese population between December 2017 and February 2018. The performance of the examination was compared with that of antigen testing and a conventional polymerase chain reaction (nested-PCR) method. A total of 159 patients were included in this study, and 77 tested positive using Liat. The concordance rate between Liat and nested PCR was 97.5%. The median time between the ordering of testing and completion of molecular analyses using Liat was 30 min (interquartile range: 28-35 min). The overall sensitivity and specificity of antigen testing were 57.1% and 100%, respectively. The duration from symptom onset to examination did not alter antigen testing sensitivity. The current study demonstrates the high performance of Liat for the rapid molecular identification of the influenza virus.


Assuntos
Vírus da Influenza A/genética , Vírus da Influenza B/genética , Influenza Humana/diagnóstico , Adolescente , Adulto , Idoso , Feminino , Humanos , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular/métodos , Nasofaringe/virologia , Sistemas Automatizados de Assistência Junto ao Leito , Reação em Cadeia da Polimerase/métodos , Estudos Prospectivos , Sensibilidade e Especificidade , Adulto Jovem
14.
Blood Adv ; 3(4): 588-595, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30792187

RESUMO

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of peripheral T-cell lymphoma affecting younger patients and associated with hemophagocytic lymphohistiocytosis. To clarify the molecular pathogenesis of SPTCL, we analyzed paired tumor and germline DNAs from 13 patients by whole-exome sequencing. All cases were Asians and were phenotypically sporadic with no family history of SPTCL. Consistent with a recent report, germline mutations in HAVCR2, encoding T-cell immunoglobulin mucin 3 (TIM3), were identified in 11 of 13 (85%) cases. All mutated cases were primary SPTCL, whereas the 2 cases without mutation were secondary SPTCL associated with underlying diseases, including viral infection and autoimmune disease. Ten patients harbored homozygous p.Y82C mutations, and 1 showed compound heterozygous mutations (p.Y82C and p.T101I). Both missense mutations altered highly conserved residues located in the extracellular immunoglobulin variable-like domain. According to the Genome Aggregation Database of >138 500 general individuals, both mutations were documented with minor allele frequencies < 0.007, indicating remarkable enrichment of these HAVCR2 alleles in SPTCL. SPTCL cells also harbored somatic mutations (6.2 per patient) that are frequently identified in genes associated with epigenetic regulation and signal transduction. In conclusion, individuals harboring biallelic HAVCR2 (TIM3) germline mutations were highly susceptible to sporadic SPTCL, which was also associated with clonal somatic mutations.

15.
Hypertens Res ; 42(5): 699-707, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30626932

RESUMO

Hypertensive disorders of pregnancy (HDP) represent a frequent disorder among pregnancies. Women with severe hypertension in pregnancy are at increased risk of maternal complications and require antihypertensive drug therapy. This study aimed to systematically review randomized control trials of antihypertensive drug(s) treating non-severe hypertension during pregnancy to estimate the effectiveness and safety of this intervention. On May 8, 2018, we searched PubMed, Cochrane Library, and Ichu-Shi with no restriction on publication year. We selected randomized control trials that involved women with HDP being treated with antihypertensive drug(s) as intervention. Fourteen trials (1804 women) were identified for meta-analysis. There were no significant differences in the risk of maternal death (373 women; risk ratio (RR) 0.70; 95% confidence interval (CI) 0.04 to 11.45), proteinuria (1214 women; RR 1.00; 95% CI 0.67 to 1.49), side effects (360 women; RR 2.69; 95% CI 0.32 to 22.64), cesarean section (1239 women; RR 0.97; 95% CI 0.82 to 1.15), neonatal and birth death (1548 women; RR 0.80; 95% CI 0.43 to 1.49), preterm birth (904 women; RR 0.86; 95% CI 0.53 to 1.39), or small for gestational age infants (1082 women; RR 1.04; 95% CI 0.66 to 1.63) with antihypertensive drug therapy versus placebo or no treatment. The current review suggests that antihypertensive drug therapy does not reduce or increase the risk of maternal or perinatal outcomes. Further studies are needed to build reliable estimates of the effectiveness and safety of antihypertensive drug therapy for women with HDP.

16.
Nature ; 565(7739): 312-317, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30602793

RESUMO

Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale oesophageal samples and show, in physiologically normal oesophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with ageing, and ultimately replace almost the entire oesophageal epithelium in the extremely elderly. Compared with mutations in oesophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal oesophageal epithelia; these mutations can be acquired before late adolescence (as early as early infancy) and significantly increase in number with heavy smoking and drinking. The remodelling of the oesophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which-depending on lifestyle risks-may affect cancer development.


Assuntos
Envelhecimento/genética , Envelhecimento/patologia , Epitélio , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Mutação , Lesões Pré-Cancerosas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/genética , Biópsia , Contagem de Células , Transformação Celular Neoplásica/genética , Criança , Pré-Escolar , Células Clonais/metabolismo , Células Clonais/patologia , Variações do Número de Cópias de DNA , Epitélio/metabolismo , Epitélio/patologia , Evolução Molecular , Feminino , Interação Gene-Ambiente , Genoma Humano/genética , Humanos , Lactente , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Acúmulo de Mutações , Proteína Fosfatase 2C/genética , Receptor Notch1/genética , Fatores de Risco , Análise de Sequência de DNA , Análise de Célula Única , Fumar/genética , Adulto Jovem
17.
Acta Physiol (Oxf) ; 225(2): e13190, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30251773

RESUMO

AIMS: Klotho interacts with various membrane proteins, such as receptors for transforming growth factor (TGF)-ß and insulin-like growth factor (IGF), to alter their function. Renal expression of klotho is diminished in diabetes. The present study examined whether exogenous klotho protein supplementation ameliorates kidney injury and renin-angiotensin system (RAS) in db/db mice. METHODS: We investigated the effects of klotho supplementation on diabetic kidney injury and RAS. Recombinant human klotho protein (10 µg/kg/d) was administered to db/db mice daily. RESULTS: Klotho protein supplementation reduced kidney weight, systolic blood pressure (SBP), albuminuria, glomerular filtration rate, and 8-epi-prostaglandin F2α excretion without affecting body weight. Although klotho supplementation did not alter glycated albumin, it reduced renal angiotensin II levels associated with reduced renal expression of angiotensinogen. Klotho supplementation improved renal expression of superoxide dismutase (SOD), and endogenous renal expression of klotho. Klotho supplementation reduced the levels of hypoxia-inducible factor, phosphorylated Akt, and phosphorylated mTOR and decreased the renal expression of TGF-ß, tumour necrosis factor (TNF), and fibronectin. CONCLUSIONS: These data indicate that klotho supplementation reduces blood pressure and albuminuria along with ameliorating renal RAS activation in db/db mice. Furthermore, these results suggest that klotho inhibits IGF signalling, induces SOD expression to reduce oxidative stress, and suppresses Akt-mTOR signalling to inhibit abnormal kidney growth. Collectively, the results suggest that klotho inhibits TGF-ß and TNF signalling, resulting in a decline in renal fibrosis.

18.
Tohoku J Exp Med ; 246(4): 225-231, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30541996

RESUMO

Mycoplasma pneumoniae is a leading causative pathogen of pneumonia among pediatric patients, and its accurate diagnosis may aid in the selection of appropriate antimicrobial agents. We established a rapid reporting system of a polymerase chain reaction (PCR) examination for M. pneumoniae that enables physicians to obtain test results approximately 90 minutes after ordering the test. In this study, we evaluated the impact of this system on antimicrobial prescriptions for pediatric pneumonia patients after its implementation from May 2016 to April 2017. In total, we identified 375 pediatric pneumonia patients, and the results of the rapid PCR examinations for Mycoplasma pneumoniae were reported immediately in 90.7% of patients (340/375), with physicians able to use these results to decide on patients' management before the prescription of antimicrobial agents. Of the 375 pediatric pneumoniae patients, M. pneumoniae was detected in 223 (59.5%). Among the 223 M. pneumoniae-positive pneumonia cases, antimicrobial agents for atypical pathogens (macrolides, tetracyclines or quinolones) were prescribed in 97.3% (217/223) at the initial evaluation, and their prescription rates increased to 99.1% (221/223) during management. In contrast, antimicrobial agents for atypical pathogens were prescribed only in 10.5% of 152 M. pneumoniae-negative pneumonia cases at the initial evaluations, and only 1 additional case was prescribed clarithromycin for persistent symptoms during management. In conclusion, we show that molecular technology could be applicable in the field of point-of-care testing in infectious disease, and its implementation will ensure the correct antimicrobial prescription for pediatric pneumonia patients.


Assuntos
Antibacterianos/uso terapêutico , Prescrições de Medicamentos , Mycoplasma pneumoniae/isolamento & purificação , Patologia Molecular/métodos , Pneumonia/tratamento farmacológico , Pneumonia/microbiologia , Sistemas Automatizados de Assistência Junto ao Leito , Adolescente , Antibacterianos/farmacologia , Criança , Feminino , Humanos , Macrolídeos/farmacologia , Macrolídeos/uso terapêutico , Masculino , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Tetraciclina/farmacologia , Tetraciclina/uso terapêutico , Fatores de Tempo
19.
J Gen Fam Med ; 19(6): 191-197, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30464865

RESUMO

Background: Mycoplasma pneumoniae is a common pathogen causing pneumonia; macrolide-resistant strains are rapidly spreading across Japan. However, the clinical features of macrolide-resistant M. pneumoniae pneumonia have not been well established. Here, we evaluated the clinical characteristics and seasonal variations in the prevalence of M. pneumoniae with macrolide-resistant mutations (MRM). Methods: The monthly prevalence of MRM in M. pneumoniae strains isolated from May 2016 to April 2017 was retrospectively analyzed, and the clinical characteristics of pneumonia cases with MRM were compared to those of cases without MRM. The M. pneumoniae isolates and point mutations at site 2063 or 2064 in domain V of 23S rRNA were evaluated by the GENECUBE system and GENECUBE Mycoplasma detection kit. Results: Mycoplasma pneumoniae infection was identified in 383 cases, including 221 cases of MRM (57.7%). The MRM prevalence was 86.3% (44/51) between May and July 2016, demonstrating an apparent decrease in September 2016, subsequently reaching 43.0% (34/79) in November 2016. Mycoplasma pneumoniae pneumonia was diagnosed in 275 cases, including 222 pediatric and 53 adult cases. Macrolide use preceding evaluation was found to be the only feature of MRM pneumonia cases both in children (odds ratio [OR] 3.86, 95% confidence interval [CI]:1.72-8.66) and in adults (OR 7.43, 95% CI: 1.67-33.1). Conclusions: The determination rate of MRM varied widely throughout the year, and our study demonstrated the challenges in predicting M. pneumoniae with MRM based on clinical features at diagnosis. Therefore, continuous monitoring of the prevalence of MRM is warranted, which may help in selecting an effective treatment.

20.
Clin Exp Hypertens ; : 1-7, 2018 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-30466333

RESUMO

OBJECTIVE: This simulation study attempted to infer the systolic blood pressure (SBP) levels at which subjects with hypertension, health nurses, and primary physicians should switch their preference of their treatment policies from lifestyle modifications to antihypertensive medications in virtual Japanese sample populations. METHODS: We assumed that SBP levels were normally distributed and that the incidence rate of cardiovascular disease (IRCVD, events/year) increased exponentially according to SBP. The total IRCVD was calculated by the definite integral for the product of the distribution of SBP multiplied by IRCVD at each SBP level. The success rates were calculated according to SBP and metabolic risk profiles in the two approaches, respectively. We deduced the hypothetical SBP levels by solving differential equations of ∆(IRCVD)/ ∆(SBP) = 0 using numerical analysis. RESULTS: In the realistic situations where the subjects were not affirmative to antihypertensive medications, the inferred SBP level to switch from lifestyle modifications to antihypertensive medications should be around 150 mmHg. If the subjects are affirmative to antihypertensive medications, the SBP level should be lowered to 140 mm Hg. CONCLUSION: This success rate-oriented simulation proposes that the SBP level to switch from lifestyle modifications to antihypertensive medications can be modulated according to the behavioral propensity for taking antihypertensive medications. ABBREVIATIONS: The following abbreviations are used in this manuscript: CVD: cardiovascular disease; LM: lifestyle modifications; AM: antihypertensive medications; IRCVD: incidence rate of cardiovascular disease (events/year); SBP: systolic blood pressure; ∆IRCVD: the improvements in the incidence rate of cardiovascular disease by lifestyle modifications and/or by antihypertensive medications.

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