Bendtsenthuesen8292

Nitrofurantoin (NIT) has long been a drug of choice in the treatment of lower urinary tract infections. Recent emergence of NIT resistant Enterobacteriaceae is a global concern. An ordinal logistic regression model based on PCR amplification patterns of five genes associated with NIT resistance (nfsA, nfsB, ribE, oqxA, and oqxB) among 100 clinical Enterobacteriaceae suggested that a combination of oqxB, nfsB, ribE, and oqxA is ideal for NIT resistance prediction. In addition, four Escherichia coli NIT-resistant mutants were in vitro generated by exposing an NIT-susceptible E. coli to varying concentrations of NIT. The in vitro selected NIT resistant mutants (NI2, NI3, NI4 and NI5) were found to have mutations resulting in frameshifts, premature/lost stop codons or failed amplification of nfsA and/or nfsB genes. The in vitro selected NI5 and the transductant colonies with reconstructed NI5 genotype exhibited reduced fitness compared to their parent strain NS30, while growth of a resistant clinical isolate (NR42) was found to be unaffected in the absence of NIT. These results emphasize the importance of strict adherence to prescribed antibiotic treatment regimens and dosage duration. If left unchecked, these resistant bacteria may thrive at sub-therapeutic concentrations of NIT and spread in the community.Aurantio-obtusin (AO) is a major anthraquinone (AQ) compound derived from Cassiae semen (CS). Although pharmacological studies have shown that the CS extracts can serve as effective agents in preclinical and clinical practice, AQ-induced hepatotoxicity in humans has attracted widespread attention. To explore whether AO induces hepatotoxicity and its underlying mechanisms, we exposed larval zebrafish and mice to AO. We found that AO delayed yolk sac absorption, and increased liver area and inflammation in the larval zebrafish. This inflammation was manifested as an increase in liver neutrophils and the up-regulated mRNA expression of interleukin-6 (Il-6) and tumor necrosis factor-α (Tnf-α) in the larval zebrafish. Furthermore, a pharmacokinetics study showed that AO was quickly absorbed into the blood and rapidly metabolized in the mice. Of note, AO induced hepatotoxicity in a gender-dependent manner, characterized by liver dysfunction, increased hepatocyte necrosis with inflammatory infiltration, and up-regulated mRNAs of Il-6, Tnf-α and monocyte chemotactic protein 1(Mcp1) in the female mice after 28-day oral administration. It also highlighted that AO triggered NOD-like receptor protein (NLRP) signaling in the female mice, as evidenced by the increased NLRP3, Caspase-1, pro-IL-1β, IL-1β and IL-18. Finally, we found that AO led to a significant increase in potassium calcium-activated channel, subfamily N, member 4 (KCNN4) and reactive oxygen species (ROS) levels, along with decreased nuclear factor kappa B, p65 (NF-κB p65), in the female mouse livers. selleck chemical In conclusion, AO induced hepatotoxicity by activating NLRP3 inflammasome signaling, at least in part, through increased KCNN4 and ROS production, and NF-κB inhibition.

Questions remain about whether moderately hypofractionated whole breast irradiation is appropriate for patients with triple-negative breast cancer.

Using a prospective database of a multicenter, collaborative quality improvement consortium, we identified patients with node-negative, triple-negative breast cancer who received whole breast irradiation with either moderate hypofractionation or conventional fractionation. Using inverse probability of treatment weighting (IPTW), we compared outcomes using the product-limit estimation method of Kaplan and Meier with Cox regression models estimating the hazard ratio for time-to-event endpoints between groups.

The sample included 538 patients treated at 18 centers in one state in the United States, of whom 307 received conventionally fractionated whole breast irradiation and 231 received moderately hypofractionated whole breast irradiation. The median follow-up time was 5.0 years (95% CI 4.77-5.15). The 5-year IPTW estimates for FFLR were 93.6% (95% CI 87.8%-96th triple-negative, node-negative breast cancer treated with whole breast irradiation reveals no differences by dose fractionation. This adds evidence to support the use of moderate hypofractionation in patients with triple-negative disease.Kiwi (Actinidia chinensis) plants are severely destroyed by canker disease which is caused by the bacterium Pseudomonas syringae pv. actinidiae (Psa). This program tries to find anti-Psa agents among secondary metabolites of endophytic fungi from kiwi plant itself. The chemical investigation on one kiwi endophytic fungi, Fusarium tricinctum, resulted in the isolation of nine new imidazole alkaloids, fusaritricines A-I (1-9) together with seven known analogues (10-16). The structures of new compounds were established by extensive spectroscopic methods. Compounds 2, 3, 9, and 13 showed good antibacterial activity against Psa with MIC values between 25 and 50 μg/mL. It is suggested that imidazole alkaloids should be potential anti-Psa agents.The essential oil from Vladimiriae Radix (VEO) is a medicinal natural product with anti-ulcer activity. A novel gastroretentive drug delivery system was developed by preparing the hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex incorporated into chitosan nanoparticles (V-CD/NPs), to improve the bioavailability of VEO and its protective effect on gastric mucosa. The optimum preparation process of V-CD/NPs was obtained by Plackett-Burman and Box-Behnken response surface methodology. The resulting V-CD/NPs gained a suitable positive potential and small particle size, and showed stability in simulated gastric fluid, whose morphology and in vitro drug release profiles had a pH-sensitivity. Besides, V-CD/NPs was proved to strongly bind with mucin, and in vivo imaging revealed that it could be retained in the stomach for more than 8 h. The results of drug concentration in gastric tissues showed that the sequential loading of inclusion complex/nanoparticles promoted the local absorption of VEO in gastric tissues, which was favorable to reach the effective therapeutic concentration in the lesioned mucosa area. In comparison to VEO and V-CD, the callback effect of V-CD/NPs on 1L-1β, 1L-6, TNF-α, NF-κB, MDA and SOD was comparable to cimetidine, and V-CD/NPs outperformed in gastric mucosal protection. Therefore, the gastroretentive drug delivery system developed in our study effectively enhanced the anti-ulcer activity of VEO, which could be a promising strategy for the prevention and treatment of the acute gastric mucosal injury.Highly porous nanoscale metal-organic frameworks (nanoMOFs) attract growing interest as drug nanocarriers. However, engineering "stealth" nanoMOFs with poly(ethylene glycol) (PEG) coatings remains a main challenge. Here we address the goal of coating nanoMOFs with biodegradable shells using novel cyclodextrin (CD)-based oligomers with a bulky structure to avoid their penetration inside the open nanoMOF porosity. The PEG chains were grafted by click chemistry onto the CDs which were further crosslinked by citric acid. Advantageously, the oligomers' free citrate units allowed their spontaneous anchoring onto the nanoMOFs by complexation with the iron sites in the top layers. Up to 31 wt% oligomers could be firmly attached by simple incubation with the nanoMOFs in an aqueous medium. Moreover, the anticancer drug doxorubicin (DOX) was successfully entrapped in the core-shell nanoMOFs with loadings up to 41 wt%. High resolution STEM (HR-STEM) showed that the organized crystalline structures were preserved. Remarkably, at the highest loadings, DOX was poorly released out of the nanoMOFs at pH 7.4 ( less then 2% in 2 days). In contrast, around 80% of DOX was released out at pH 4.5 of artificial lysosomal fluid in 24 h. Confocal microscopy investigations showed that the DOX-loaded nanoMOFs penetrated inside Hela cancer cell together with their PEG shells. There, they released the DOX cargo which further diffused inside the nucleus to eradicate the cancer cells.Lecithin-linker microemulsions have been previously proposed as a platform for designing a fully dilutable self-microemulsifying drug delivery system (SMEDDS). This SMEDDS formulation, composed of ethyl caprate (oil), lecithin (Le), glycerol monooleate (lipophilic linker, LL) and polyglycerol caprylate (hydrophilic linker, HL), produced a ternary phase diagram (TPD) that had a fully dilutable path suitable for oral drug delivery. However, introducing ibuprofen as an active pharmaceutical ingredient (API) resulted in TPD phase boundaries that eliminated the fully dilutable path. The purpose of this work was to understand the origin of the changes in the TPD, use that understanding to restore the fully dilutable path with an ibuprofen-loaded SMEDDS, and finally to evaluate the absorption of ibuprofen in vivo. The effect of ibuprofen on the HLD (hydrophilic-lipophilic difference, interpreted as normalized net interfacial curvature) of the system was evaluated via a polar oil model, showing that ibuprofen played a surfactant-like role, having a characteristic curvature (Cc) value of +5 (highly hydrophobic). The net-average curvature (NAC) framework used the HLD calculated with Le, LL, HL and ibuprofen Cc to generate TPDs in ibuprofen lecithin-linker systems. The HLD-NAC simulations show that restoring full dilutability required a highly hydrophilic linker (HL-) with a Cc of -5 or more negative. The fully dilutable path was restored after introducing a hexaglycerol caprylate as HL- (Cc = -6). Plasma concentration profiles obtained with this ibuprofen-loaded SMEDDS showed a more than three-fold increase in the area under the curve (AUC) of rat plasma concentration profiles compared to the same 25 mg/kg ibuprofen dose in suspension.Evidence has emerged about the use of visual-related training as an intervention to improve mobility that could implicate fall prevention in the older population. The objective of this systematic review was to investigate whether visual-related interventions are effective in improving balance and walking ability in healthy older adults. An electronic database search was conducted using Pubmed, Embase, CINAHL Plus, Web of Science, PsycINFO, and SportDiscus. Seventeen studies out of a total of 3297 studies were identified in this review that met the inclusion criteria of (1) adopting a longitudinal design with at least one control comparison group, (2) targeting healthy older adults (age 60 or above), (3) primary focus targeting visual element, and (4) the primary outcome(s) were measures indicating walking and/or balance ability. Our results indicated that visual-related training generally led to improvements in balance and walking ability in healthy older adults. It seems necessary that visual-related training should at least involve mobility-related movement component(s), or form a part of a multi-component training to achieve a beneficial effect on balance and walking. The effectiveness and feasibility of these visual-related training in clinical practice for rehabilitation has been discussed and needs to be investigated in future studies. (197/200).Estuaries are subject to intense human use globally, with impacts from multiple stressors, such as metal contaminants. A key challenge is extending beyond traditional monitoring approaches to understand effects to biota and system function. To explore the metabolic effects of complex metal contaminants to sediment dwelling (benthic) fauna, we apply a multiple-lines-of-evidence approach, coupling environmental monitoring, benthic sampling, total metals analysis and targeted metabolomics. We characterise metabolic signatures of metal exposure in three benthic invertebrate taxa, which differed in distribution across sites and severity of metal exposure sipunculid (very high), amphipod (high), maldanid polychaete (moderate). We observed sediment and tissue metal loads far exceeding sediment guidelines where toxicity-related adverse effects may be expected, for metals including, As, Cd, Pb, Zn and Hg. Change in site- and taxa-specific metabolite profiles was highly correlated with natural environmental drivers (sediment total organic carbon and water temperature).