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2.
PLoS One ; 15(1): e0227257, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31910242

RESUMO

PURPOSE: Multidrug-resistant Enterobacteriaceae in urinary tract infection (UTI) has spread worldwide; one cause is overuse of broad-spectrum antimicrobial agents such as fluoroquinolone antibacterials. To improve antimicrobial agent administration, this study aimed to calculate a probability prediction formula to predict the organism strain causing UTI in real time from dip-stick testing and flow cytometry. METHODOLOGY: We examined 372 outpatient spot urine samples with observed pyuria and bacteriuria using dip-stick testing and flow cytometry. We performed multiple logistic-regression analysis on the basis of 11 measurement items and BACT scattergram analysis with age and sex as explanatory variables and each strain as the response variable and calculated a probability prediction formula. RESULTS: The best prediction formula for discrimination of the bacilli group and cocci or polymicrobial group was a model with 5 explanatory variables that included percentage of scattergram dots in an angular area of 0-25° (P<0.001), sex (P<0.001), nitrite (P = 0.002), and ketones (P = 0.133). For a predicted cut-off value of Y = 0.395, sensitivity was 0.867 and specificity was 0.775 (cross-validation group: sensitivity = 0.840, specificity = 0.760). The best prediction formula for P. mirabilis and other bacilli was a model with percentage of scattergram dots in an angular area of 0-20° (P<0.001) and nitrite (P = 0.090). For a predicted cut-off value of Y = 0.064, sensitivity was 0.889 and specificity was 0.788 (cross-validation group: sensitivity = 1.000, specificity = 0.766). CONCLUSION: Simultaneous use of the calculated probability prediction formula with urinalysis results facilitates real-time prediction of organisms causing UTI, thus providing helpful information for empiric therapy.

3.
Lab Invest ; 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31857692

RESUMO

Men and women become infertile with age, but the mechanism of declining male fertility, more specifically, the decrease in in sperm quality, is not well known. Citrate synthase (CS) is a core enzyme of the mitochondrial tricarboxylic acid (TCA) cycle, which directly controls cellular function. Extra-mitochondrial CS (eCS) is produced and abundant in the sperm head; however, its role in male fertility is unknown. We investigated the role of eCS in male fertility by producing eCs-deficient (eCs-KO) mice. The initiation of the first spike of Ca2+ oscillation was substantially delayed in egg fused with eCs-KO sperm, despite normal expression of sperm factor phospholipase C zeta 1. The eCs-KO male mice were initially fertile, but the fertility dropped with age. Metabolomic analysis of aged sperm revealed that the loss of eCS enhances TCA cycle in the mitochondria with age, presumably leading to depletion of extra-mitochondrial citrate. The data suggest that eCS suppresses age-dependent male infertility, providing insights into the decline of male fertility with age.

4.
Sci Rep ; 9(1): 13587, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537874

RESUMO

Antimicrobial resistance is a global public threat and raises the need for development of new antibiotics with a novel mode of action. The dipeptidyl peptidase 11 from Porphyromonas gingivalis (PgDPP11) belongs to a new class of serine peptidases, family S46. Because S46 peptidases are not found in mammals, these enzymes are attractive targets for novel antibiotics. However, potent and selective inhibitors of these peptidases have not been developed to date. In this study, a high-resolution crystal structure analysis of PgDPP11 using a space-grown crystal enabled us to identify the binding of citrate ion, which could be regarded as a lead fragment mimicking the binding of a substrate peptide with acidic amino acids, in the S1 subsite. The citrate-based pharmacophore was utilized for in silico inhibitor screening. The screening resulted in an active compound SH-5, the first nonpeptidyl inhibitor of S46 peptidases. SH-5 and a lipophilic analog of SH-5 showed a dose-dependent inhibitory effect against the growth of P. gingivalis. The binding mode of SH-5 was confirmed by crystal structure analysis. Thus, these compounds could be lead structures for the development of selective inhibitors of PgDPP11.

5.
Endosc Int Open ; 7(9): E1187-E1191, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31475238

RESUMO

Background and study aims Although colorectal endoscopic submucosal dissection (ESD) has enabled high en bloc resection rates regardless of tumor size, colorectal ESD is still a challenging procedure. We developed a novel device called the Nelaton Attachment, which allows endoscopists to manipulate the ESD knives using two fingers of their left hand while holding the endoscope with their right hand. We retrospectively investigated the efficacy and safety of the Nelaton Attachment for colorectal ESD. We compared efficacy and safety between Nelaton Attachment and non-Nelaton Attachment groups, and also conducted an ex vivo experiment to evaluate the effect of the Nelaton Attachment. Patients and methods We retrospectively reviewed 36 consecutive patients with 37 colorectal tumors who had undergone ESD at Kishiwada Tokushukai Hospital and Naritatomisato Tokushukai Hospital between April 2016 and September 2018. The Nelaton Attachment was used for 22 of the 37 colorectal ESDs. In the ex vivo experiment, endoscopists inserted and withdrew an ESD knife 2 cm using two fingers of their left hand with and without the Nelaton Attachment. Results Median procedure time was significantly shorter in the Nelaton Attachment group (38 min [range 6 - 195 min]) compared to the non-Nelaton Attachment group (75 min [range 17 - 198 min]; P  = 0.030). Median time to complete the ex vivo experiment five times was significantly faster with the Nelaton Attachment than without the Nelaton Attachment ( P  = 0.001). Conclusions Use of the Nelaton Attachment for colorectal ESD is feasible and safe, and may facilitate colorectal ESD procedures.

6.
Cancer Med ; 8(12): 5524-5533, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31385432

RESUMO

Protoporphyrin IX-fluorescence measurement is a powerful in situ approach for cancer detection after oral/topical administration of 5-aminolevulinic acid. However, this approach has not been clinically established for breast cancer, probably due to insufficient delivery of 5-aminolevulinic acid to the mammary glands. In the present study, we directly exposed breast cancer cells to 5-aminolevulinic acid to assess their discrimination via protoporphyrin IX-fluorescence. Fluorescence intensity (FI) was measured in the human breast cancer cell lines MCF7 and MDA-MB-231 and breast epithelial cell line MCF10A by confocal microscopy and flow cytometry. After 5-aminolevulinic acid exposure for 2 hours, protoporphyrin IX-FI in MCF7 and MDA-MB-231 cells significantly increased with marked cell-to-cell variability, whereas that in MCF10A cells increased moderately. Combined exposure of the cancer cells to 5-aminolevulinic acid and Ko143, a specific inhibitor of ATP-binding cassette transporter G2, further increased protoporphyrin IX-FI and alleviated the cell-to-cell variability in MCF7 and MDA-MB-231 cells, indicating improvement in the reproducibility and accuracy for fluorescence-based cancer detection. The increased FI by combined administration of these two drugs was also demonstrated in cells obtained via fine needle aspiration from mouse xenograft models inoculated with MDA-MB-231 cells. Furthermore, a cutoff value for increased protoporphyrin IX-FI ratio, before and after exposure to these drugs, clearly discriminated between cancer and noncancer cells. Taken together, direct exposure to 5-aminolevulinic acid and Ko143 may be a promising strategy for efficient fluorescence-based detection of breast cancer cells ex vivo using fine needle aspiration.

7.
Front Pediatr ; 7: 244, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31316950

RESUMO

Kawasaki disease (KD) is a pediatric vasculitis syndrome that is often involves coronary artery lesions (e. g., coronary artery aneurysms). Although its causal factors and entire pathogenesis remain elusive, the available evidence indicates that the pathogenesis of KD is closely associated with dysregulation of immune responses to various viruses or microbes. In this short review, we address several essential aspects of the etiology of KD with respect to the immune response to infectious stimuli: 1) the role of viral infections, 2) the role of bacterial infections and the superantigen hypothesis, 3) involvement of innate immune response including pathogens/microbe-associated molecular patterns and complement pathways, and 4) the influence of genetic background on the response to infectious stimuli. Based on the clinical and experimental evidence, we discuss the possibility that a wide range of microbes and viruses could cause KD through common and distinct immune processes.

9.
Stem Cell Reports ; 12(6): 1366-1379, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31155506

RESUMO

Zygotic genome activation (ZGA) begins after fertilization and is essential for establishing pluripotency and genome stability. However, it is unclear how ZGA genes prevent mitotic errors. Here we show that knockout of the ZGA gene Zscan5b, which encodes a SCAN domain with C2H2 zinc fingers, causes a high incidence of chromosomal abnormalities in embryonic stem cells (ESCs), and leads to the development of early-stage cancers. After irradiation, Zscan5b-deficient ESCs displayed significantly increased levels of γ-H2AX despite increased expression of the DNA repair genes Rad51l3 and Bard. Re-expression of Zscan5b reduced γ-H2AX content, implying a role for Zscan5b in DNA damage repair processes. A co-immunoprecipitation analysis showed that Zscan5b bound to the linker histone H1, suggesting that Zscan5b may protect chromosomal architecture. Our report demonstrates that the ZGA gene Zscan5b is involved in genomic integrity and acts to promote DNA damage repair and regulate chromatin dynamics during mitosis.

10.
Sci Rep ; 9(1): 8555, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31189981

RESUMO

The global pandemic of ESBL-producing Escherichia coli is associated with sequence type 131 (ST131). However, mechanisms of ST131 spread remain unclear. This study searched for proteins with amino acid substitutions specific for ST131 and used proteomics analysis to clarify ST131 characteristics. Five proteins had ST131-specific amino acid substitutions: uncharacterized protein YahO with E34A (m/z 7655); UPF0337 protein YjbJ with V59D, D60S and T63K (m/z 8351); uncharacterized protein YnfD with S106T (m/z 8448); and acid stress chaperone HdeA with Q92K and N94S (m/z 9714). Soluble cytochrome b562 (m/z 11783) showed seven amino acid substitutions, and the sequence differed between clade C of the pandemic clade and non-C. In silico analysis showed YahO protein-protein interaction with YjbJ, possibly related to biofilm formation. Although the function of soluble cytochrome b562 is electron transport of unknown function, its involvement in biofilm formation was predicted. HdeA was a gastric acid resistance-related protein. The function of YnfD was completely unclear. In conclusion, ST131-specific protein amino acid substitutions consisted mainly of a gastric acid resistance protein and proteins of unknown function (possibly involved in biofilm formation), which might be mechanisms for long-term colonization in the human intestinal tract.

11.
Commun Biol ; 2: 226, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31240264

RESUMO

Calaxin is a Ca2+-binding dynein-associated protein that regulates flagellar and ciliary movement. In ascidians, calaxin plays essential roles in chemotaxis of sperm. However, nothing has been known for the function of calaxin in vertebrates. Here we show that the mice with a null mutation in Efcab1, which encodes calaxin, display typical phenotypes of primary ciliary dyskinesia, including hydrocephalus, situs inversus, and abnormal motility of trachea cilia and sperm flagella. Strikingly, both males and females are viable and fertile, indicating that calaxin is not essential for fertilization in mice. The 9 + 2 axonemal structures of epithelial multicilia and sperm flagella are normal, but the formation of 9 + 0 nodal cilia is significantly disrupted. Knockout of calaxin in zebrafish also causes situs inversus due to the irregular ciliary beating of Kupffer's vesicle cilia, although the 9 + 2 axonemal structure appears to remain normal.

13.
Insects ; 10(5)2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31058867

RESUMO

Although elevational gradients of biodiversity have long been the topic of scientific research, information on patterns of, and processes that shape insect community structure across elevation is still lacking. Addressing this gap requires the use of both taxonomic and functional approaches when studying diversity across elevational gradients. In this study, we examined taxonomic and functional alpha and beta diversity of ant assemblages sampled along tropical, subtropical, and subalpine elevational transects in Yunnan Province, southwest China. Species richness was used to quantify taxonomic alpha diversity, and two indices (FD and FRic) were calculated using morphological measurements to quantify functional alpha diversity. Taxonomic and functional beta diversity were partitioned into their turnover- and nestedness-resultant components. Though temperature and functional alpha diversity decreased linearly with increasing elevation, taxonomic alpha diversity showed a significant logarithmic decrease, with few species present at elevations greater than 3000 m a.s.l. The turnover-resultant component of taxonomic beta diversity increased with increasing elevational distance, while the nestedness-resultant component of functional beta diversity increased with increasing elevational distance in the subtropical transect. The observed patterns of taxonomic and functional diversity reflected ants' thermophilic nature, implying functional adaptations (i.e., nested functional diversity) at higher elevations where environmental conditions were unfavorable.

15.
J Med Ultrason (2001) ; 46(4): 503-511, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31011935

RESUMO

PURPOSE: We examined the influences of age and gender on flow-mediated endothelial function and the involvement of the competitive inhibition of L-arginine in endothelial function. METHODS: We measured brachial and popliteal flow-mediated vasodilation (FMD) responses, nitrate/nitrite (NOx) concentrations, and plasma levels of asymmetric dimethylarginine (ADMA) in four healthy, nonsmoking groups: young men (mean 26 ± 2 years, n = 17), middle-aged men (mean 50 ± 3 years, n = 19), young women (mean 27 ± 2 years, n = 16), and middle-aged women (mean 51 ± 2 years, n = 18). RESULTS: In young men, we found no significant differences between brachial and popliteal artery FMDs (10.6 ± 1.5 vs 8.7 ± 1.6%, p = 0.06). However, the popliteal artery FMD was significantly lower than the brachial artery FMD in middle-aged men (11.4 ± 1.5 vs 6.4 ± 1.0%, p < 0.001). In women, we found no significant differences between brachial and popliteal artery FMDs in young and middle-aged individuals (young, p = 0.17; middle-aged, p = 0.08). Popliteal artery FMD correlated with plasma NOx and ADMA levels as well as with the NOx/ADMA ratio in men but not in women (r = 0.485, - 0.544, and 0.672, respectively). CONCLUSION: We concluded that a decrease in flow-mediated endothelial function in arteries of the lower extremities was evident in healthy middle-aged men, but not in middle-aged women. The competitive inhibition of L-arginine may contribute to this decrease in men.


Assuntos
Envelhecimento/fisiologia , Arginina/análogos & derivados , Artéria Braquial/fisiologia , Endotélio Vascular/fisiologia , Artéria Poplítea/fisiologia , Vasodilatação/fisiologia , Adulto , Fatores Etários , Arginina/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Fatores Sexuais
16.
Respir Care ; 64(5): 502-508, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30890628

RESUMO

BACKGROUND: Intrapulmonary percussive ventilation (IPV) is used for airway clearance and delivery of aerosol medications, including bronchodilators. Despite the common use of IPV for drug delivery, few data are available regarding optimization of inhalation therapy with IPV. In this study, we investigated the influence of IPV setting parameters and lung mechanics on drug delivery via IPV alone. METHODS: An IPV device was connected to a lung model via a trachea model and a flow analyzer. Albuterol nebulized from the IPV device was collected onto a filter attached between the trachea and lung models, and was quantitated by spectrophotometry (230 nm). RESULTS: Albuterol delivery to the lung model was increased up to 2.1-fold, with decreasing percussion frequency. Decreasing percussion frequency concomitantly increased the tidal volume, and albuterol delivery was correlated with tidal volume (r = 0.91, P < .001). Airway resistance had a negative impact on albuterol delivery, whereas lung compliance had no significant effect. Increasing operational pressure increased albuterol delivery while increasing peak inspiratory pressure. CONCLUSIONS: Albuterol delivery and tidal volume with IPV can be improved by maintaining low levels of percussion frequency and increasing operational pressure. When increasing operational pressure, the peak inspiratory pressure and airway resistance levels need to be carefully monitored for safe inhalation therapy with IPV.

17.
J Infect Chemother ; 25(9): 731-734, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30905630

RESUMO

Recently, basidiomycete Schizophyllum commune has been reported as a cause of allergic bronchopulmonary mycosis. However, it is rare as a cause of otitis externa. We experienced a very rare case of otitis externa caused by S. commune in a 68-year-old man with a history of chronic otitis media. We performed Gram staining at the first consultation and follow-up treatment and found fungal cells on the smear and treated him with an appropriate antifungal drug. The results of identification and antifungal susceptibility testing obtained in cooperation with clinical microbiologists at other facilities was very important for future treatment planning decisions. Medical practitioners worldwide should introduce a Gram staining tool into their workflow and cooperate closely with clinical microbiologists to achieve antimicrobial stewardship.


Assuntos
Aspergilose Pulmonar Invasiva/etiologia , Otite Externa/microbiologia , Otite Média/complicações , Schizophyllum/isolamento & purificação , Idoso , Antifúngicos/uso terapêutico , Gestão de Antimicrobianos , Violeta Genciana , Humanos , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Aspergilose Pulmonar Invasiva/microbiologia , Masculino , Fenazinas
18.
Chem Pharm Bull (Tokyo) ; 67(1): 71-74, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30606952

RESUMO

A facile and convenient synthesis of trisubstituted (E)-α,ß-unsaturated esters was developed by improving our previously established method. The new method circumvented the separation of the intermediates, which have an activating group of the hydroxyl group in ß-hydroxy esters, furnishing α,ß-unsaturated esters in shorter steps than the previous method: an acetylation of ß-hydroxy group and subsequent E1cB reaction proceeded in tandem. In addition, the new method can not only employ a diastereomeric mixture of the substrate for the E1cB reaction, it has a wide substrate scope as well, which would enable the synthesis of various trisubstituted (E)-α,ß-unsaturated esters.


Assuntos
Ésteres/síntese química , Acetilação , Ésteres/química , Estrutura Molecular , Estereoisomerismo
19.
Ann Rheum Dis ; 78(1): 111-121, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30287418

RESUMO

OBJECTIVES: We recently identified microRNA-181a-5p (miR-181a-5p) as a critical mediator involved in the destruction of lumbar facet joint (FJ) cartilage. In this study, we tested if locked nucleic acid (LNA) miR-181a-5p antisense oligonucleotides (ASO) could be used as a therapeutic to limit articular cartilage degeneration. METHODS: We used a variety of experimental models consisting of both human samples and animal models of FJ and knee osteoarthritis (OA) to test the effects of LNA-miR-181a-5p ASO on articular cartilage degeneration. Histopathological analysis including immunohistochemistry and in situ hybridisation were used to detect key OA catabolic markers and microRNA, respectively. Apoptotic/cell death markers were evaluated by flow cytometry. qPCR and immunoblotting were applied to quantify gene and protein expression. RESULTS: miR-181a-5p expression was increased in human FJ OA and knee OA cartilage as well as injury-induced FJ OA (rat) and trauma-induced knee OA (mouse) cartilage compared with control cartilage, correlating with classical OA catabolic markers in human, rat and mouse cartilage. We demonstrated that LNA-miR-181a-5p ASO in rat and mouse chondrocytes reduced the expression of cartilage catabolic and chondrocyte apoptotic/cell death markers in vitro. Treatment of OA-induced rat FJ or mouse knee joints with intra-articular injections of in vivo grade LNA-miR-181a-5p ASO attenuated cartilage destruction, and the expression of catabolic, hypertrophic, apoptotic/cell death and type II collagen breakdown markers. Finally, treatment of LNA-miR-181a-5p ASO in cultures of human knee OA chondrocytes (in vitro) and cartilage explants (ex vivo) further demonstrated its cartilage protective effects. CONCLUSIONS: Our data demonstrate, for the first time, that LNA-miR-181a-5p ASO exhibit cartilage-protective effects in FJ and knee OA.


Assuntos
Cartilagem Articular/efeitos dos fármacos , MicroRNAs/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Osteoartrite/genética , Substâncias Protetoras/farmacologia , Animais , Apoptose/genética , Condrócitos/metabolismo , Humanos , Articulação do Joelho/efeitos dos fármacos , Vértebras Lombares , Camundongos , Ratos , Articulação Zigapofisária/efeitos dos fármacos
20.
Lab Invest ; 99(2): 200-209, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30401958

RESUMO

Tetraspanin CD9 is essential for sperm-egg fusion and also contributes to uterine repair through microexosome formation. Microexosomes share CD9 with exosomes and are released from eggs and uterine epithelial cells. However, the mechanism for the formation of microexosomes remains unknown. To address this issue, we examined membrane localization and extracellular release of CD9 proteins using uterine epithelial cells and secretions in mice and humans. In mice, CD9 localized predominantly on the basal region of the plasma membrane and relocated to the apical region upon embryo implantation. Furthermore, extracellular CD9 proteins were detected in uterine secretions of mice and women undergoing infertility treatment, but were below detectable levels in supernatants of pluripotent stem cells. Ultrastructural analysis demonstrated that membrane projections were shortened and the number of mitochondria was reduced in uterine epithelial cells lacking Cd9 genes. Our results suggest that CD9 repositioning and release affect both membrane structures and mitochondrial state in the uterus, and contribute to female fertility.


Assuntos
Tetraspanina 29 , Útero , Animais , Secreções Corporais/química , Secreções Corporais/citologia , Linhagem Celular , Ciclo Estral , Exossomos/química , Exossomos/metabolismo , Feminino , Humanos , Infertilidade Feminina , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/química , Mitocôndrias/metabolismo , Tetraspanina 29/química , Tetraspanina 29/metabolismo , Tetraspanina 29/fisiologia , Útero/química , Útero/citologia , Útero/metabolismo , Útero/fisiologia
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