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排序方式: 共有429条查询结果,搜索用时 15 毫秒
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Ilias Karaiskos Maria Souli Helen Giamarellou 《Expert opinion on investigational drugs》2015,24(11):1501-1511
Introduction: Living in the ever-expanding era of multidrug-resistant (MDR), extensively drug-resistant (XDR), and even pandrug-resistant Gram-negative microorganisms, the medical community is facing the approaching fear of the “End of Antibiotics.” Plazomicin is a next-generation aminoglycoside designed to evade all clinically relevant aminoglycoside-modifying enzymes, the main mechanism of aminoglycoside resistance. A newer aminoglycoside active against several MDR-XDR microorganisms is herein presented and discussed.Areas covered: Herein, the authors present the currently available information on plazomicin. This includes the current knowledge concerning plazomicin’s: mechanisms of action, in vitro activity and interactions, its pharmacokinetics, its clinical efficacy in complicated urinary tract infections (cUTIs) and acute pyelonephritis, and its toxicity issues.Expert opinion: Plazomicin was developed to evade all clinically relevant aminoglycoside-modifying enzymes. Unfortunately, ribosomal enzymatic modification by ribosomal 16S-rRNA methyltransferases confers broad-spectrum high-level aminoglycoside resistance. Still, plazomicin demonstrates high activity against the Enterobacteriaceae including extended spectrum beta lactamase and most carbapenemase producers, as well as several of the non-fermenters. When compared to levofloxacin, the in vivo activity of plazomicin in complicated urinary tract infections (cUTIs) and in acute pyelonephritis in humans was very promising. Furthermore, regarding safety, no clinically significant effects on renal, vestibular, or cochlear function have been observed both at Phase I and II studies in humans, with mild to moderate adverse events being dose related. However, the authors believe that the real position of plazomicin in the MDR-XDR world will be revealed once pending Phase III studies are completed. 相似文献
3.
Min Zhong Wan-ling Song Ye-chun Xu Yang Ye Lin-yin Feng 《Acta pharmacologica Sinica》2015,36(3):298-310
Aim:
Paeoniflorin from Chinese herb Paeoniae Radix has been shown to ameliorate middle cerebral artery occlusion-induced ischemia in rats. The aim of this study was to investigate the mechanisms underlying the neuroprotective action of PF in cultured rat cortical neurons.Methods:
Primary cultured cortical neurons of rats were subjected to oxygen-glucose deprivation and reoxygenation (OGD/R) insult. Cell survival was determined using MTT assay. HEK293 cells stably transfected with A1R (HEK293/A1R) were used for detailed analysis. Phosphorylation of the signaling proteins was evaluated by Western blot or immunoprecipitation. Receptor interactions were identified using co-immunoprecipitation and immunofluorescence staining.Results:
Paeoniflorin (10 nmol/L to 1 μmol/L) increased the survival of neurons subjected to OGD/R. Furthermore, paeoniflorin increased the phosphorylation of Akt and ERK1/2 in these neurons. These effects were blocked by PI3K inhibitor wortmannin or MEK inhibitor U0126. Paeoniflorin also increased the phosphorylation of Akt and ERK1/2 in HEK293/A1R cells. Both A1R antagonist DPCPX and EGFR inhibitor AG1478 not only blocked paeoniflorin-induced phosphorylation of ERK1/2 and Akt in HEK293/A1R cells, but also paeoniflorin-increased survival of neurons subjected to OGD/R. In addition, paeoniflorin increased the phosphorylation of Src kinase and activation of MMP-2 in HEK293/A1R cells. Both Src inhibitor PP2 and MMP-2/MMP-9 inhibitor BiPs not only blocked paeoniflorin-induced phosphorylation of ERK1/2 (and Akt) in HEK293/A1R cells, but also paeoniflorin-increased survival of neurons subjected to OGD/R.Conclusion:
Paeoniflorin promotes the survival of cultured cortical neurons by increasing Akt and ERK1/2 phosphorylation via A1R-mediated transactivation of EGFR. 相似文献4.
《Pathology, research and practice》2020,216(8):153021
Acute allograft rejection is the most common complication in organ transplantation leading to organ loss. Treg cells play an important role in preventing acute rejection, but they are unstable and easily lose function. Poly(ADP-ribose) polymerase 1(PARP-1) is involved in the differentiation stabilization of Treg cells, it has been suggested that PARP-1 inhibition could prevent acute rejection and prolong allograft survival. This study investigated AG14361 effects on acute allograft rejection. We used a fully MHC-mismatched murine heart transplantation model to compare the effect of PARP-1 inhibitor-AG14361 on alloimmunity to the control. Mice treated with PARP-1 inhibitors showed a longer median survival time of allografts (MS14 compared with the control group, MST was 8 days, and AG14361 was 6 days, P = 0.019). The combination of sirolimus and AG14361 significantly delayed allograft MST (AG14361 + sirolimus for 30 days, sirolimus for 16 days, P = 0.002). AG14361 markedly augmented the number of the CD25+FoxP3+ Treg cells in the graft and periphery. In addition, it could enhance the suppressive function of Treg cells by upregulating the level of CTLA-4, PD-1 and ICOS. In vivo, the Treg/Th17 ratio increased significantly in the AG14351 group compared to the control. In the combination with sirolimus treatment, AG14361 promoted the long-term allograft survival. Our results highlight novel effects of a PARP-1 inhibitor. PARP-1 inhibitor AG14361 may be a promising agent to attenuate acute allograft rejection as it can maintain the number and function of Treg cells in allografts. 相似文献
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Monitoring recovery from diaphragm paralysis with ultrasound 总被引:1,自引:0,他引:1
BACKGROUND: Diaphragmatic paralysis is an uncommon, yet underdiagnosed cause of dyspnea. Data regarding the time course and potential for recovery has come from a few small case series. The methods that have been traditionally employed to diagnose diaphragmatic weakness or paralysis are either invasive or limited in sensitivity and specificity. A new technique utilizing two-dimensional, B-mode ultrasound (US) measurements of diaphragm muscle thickening during inspiration (Deltatdi%) has been validated in the diagnosis of diaphragm paralysis (DP). The purpose of this study was to assess whether serial US evaluation might be utilized to monitor the potential recovery of diaphragm function. METHODS: Twenty-one consecutive patients with clinically suspected DP were referred to the pulmonary physiology laboratory. Sixteen patients were found to have DP by US (unilateral, 10 patients; bilateral, 6 patients). Subjects were followed up for up to 60 months. On initial and subsequent visits, Deltatdi% was measured by US. Additional measurements included upright and supine vital capacity (VC), maximal inspiratory pressure (Pimax), and maximal expiratory pressure. RESULTS: Eleven of 16 patients functionally recovered from DP. The mean (+/- SD) recovery time was 14.9 +/- 6.1 months. No diaphragm thickening was noted in those patients who did not recover. Positive correlations were found between improvement in Deltatdi% and interval changes in VC, Pimax, and end-expiratory measurements of diaphragm thickness. CONCLUSIONS: US may be used to assess for potential functional recovery from diaphragm weakness or DP. As in previous series, recovery occurs in a substantial number of individuals, but recovery time may be prolonged. 相似文献
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8.
Hayat HaratiMonique Majchrzak Brigitte CosquerRodrigue Galani Christian KelcheJean-Christophe Cassel Alexandra Barbelivien 《Neurobiology of aging》2011,32(4):718-736
Aged rodents exhibit memory and attention dysfunctions. Environmental enrichment (EE) attenuates memory impairments. Whether it may reduce attention deficits is not known. At the age of 1 month, Long-Evans female rats were placed in standard or EE conditions and tested after 3 (young), 12 (middle-aged) or 24 (aged) months of differential housing. Spatial reference memory was assessed in a water-maze task. Attention performance was evaluated in the five-choice serial reaction time (5-CSRT) task. EE improved spatial memory at all ages, but did not ameliorate 5-CSRT performance in young and middle-aged rats; it prevented, however, the degradation of attention performances detected in aged rats. The number of ChAT (+30 to +64%)- and p75NTR-positive (+35 to +44%) neurons was higher in the basal forebrain of aged enriched vs. standard rats, suggesting their EE-mediated protection. The weaker deficit of attention found in aged EE rats might be linked to a better survival in the very long term of neurons in the basalo-cortical system. 相似文献
9.
Ramón Rodríguez-Olivares Nahid El Faquir Zouhair Rahhab Lennart van Gils Ben Ren Rafi Sakhi Marcel L. Geleijnse Ron van Domburg Peter P.T. de Jaegere Jose L. Zamorano Gómez Nicolas M. Van Mieghem 《Cardiovascular Revascularization Medicine》2019,20(2):126-132
Aims
We sought to evaluate the interaction of different aortic root phenotypes with self-expanding (SEV), balloon-expandable (BEV) and mechanically expanded (MEV) and the impact on significant aortic regurgitation.Methods and results
We included 392 patients with a SEV (N?=?205), BEV (N?=?107) or MEV (N?=?80). Aortic annulus eccentricity index and calcification were measured by multi-slice CT scan. Paravalvular aortic regurgitation was assessed by contrast aortography (primary analysis) and transthoracic echocardiography (secondary analysis).In mildly calcified roots paravalvular regurgitation incidence was similar for all transcatheter heart valves (SEV 8.4%; BEV 9.1%; MEV 2.0% p?=?0.27). Conversely, in heavily calcified roots paravalvular regurgitation incidence was significantly higher with SEV (SEV 45.9%; BEV 0.0%; MEV 0.0% p?<?0.001). When paravalvular regurgitation was assessed by TTE, the overall findings were similar although elliptic aortic roots were associated with more paravalvular regurgitation with SEV (20.5% vs. BEV 4.5% vs. MEV 3.2%; p?=?0.009).Conclusions
In heavily calcified aortic roots, significant paravalvular aortic regurgitation is more frequent with SEV than with BEV or MEV, but similar in mildly calcified ones. These findings may support patient-tailored transcatheter heart valve selection.Classifications
Aortic stenosis; multislice computed tomography; transcatheter aortic valve replacement; paravalvular aortic regurgitation.Condensed abstract
We sought to evaluate the interaction of different aortic root phenotypes with self-expanding (SEV), balloon-expandable (BEV) and mechanically expanded (MEV) and the impact on significant aortic regurgitation. We included 392 patients with a SEV (N?=?205), BEV (N?=?107) or MEV (N?=?80). Aortic annulus eccentricity index and calcification were measured by multi-slice CT scan. Paravalvular aortic regurgitation was assessed by contrast aortography and transthoracic echocardiography. We found that in heavily calcified aortic roots, significant paravalvular aortic regurgitation is more frequent with SEV than with BEV or MEV, but similar in mildly calcified ones. 相似文献10.
Päivi Kankkunen Elina Välimäki Johanna Rintahaka Jaana Palomäki Tuula Nyman Harri Alenius Henrik Wolff Sampsa Matikainen 《Human immunology》2014
Inflammasome is an intracellular molecular platform of the innate immunity that is a key mediator of inflammation. The inflammasome complex detects pathogens and different danger signals, and triggers cysteine protease caspase-1-dependent processing of pro-inflammatory cytokines IL-1β, and IL-18 in dendritic cells and macrophages. Previously, we have shown that water-damaged building associated trichothecene mycotoxins, including roridin A, trigger IL-1β and IL-18 secretion in human macrophages. However, the molecular basis as well as mechanism behind this trichothecene-induced cytokine secretion has remained uncharacterized. Here, we show that the trichothecene-induced IL-1β secretion is dependent on NLRP3 inflammasome in human primary macrophages. Pharmacological inhibition and small interfering RNA approach showed that the trichothecene-induced NLRP3 inflammasome activation is mediated through ATP-gated P2X7 receptor. Moreover, we show that trichothecene-triggered NLRP3 inflammasome activation is dependent on Src tyrosine kinase activity. In addition, gene silencing of c-Cbl, a negative autophagy-related regulator of c-Src, resulted in enhanced secretion of IL-1β and IL-18 in response to trichothecene mycotoxin stimulation in human macrophages. In conclusion, our results suggest that roridin A, a fungal trichothecene mycotoxin, acts as microbial danger signals that trigger activation of NLRP3 inflammasome through P2X7R and Src tyrosine kinase signaling dependent pathway in human primary macrophages. 相似文献