Pharmacodynamic evaluation of meropenem,cefepime, or aztreonam combined with a novel β-lactamase inhibitor,nacubactam, against carbapenem-resistant and/or carbapenemase-producing Klebsiella pneumoniae and Escherichia coli using a murine thigh-infection model

BackgroundCarbapenem-resistant Enterobacterales (CRE) and carbapenemase-producing Enterobacterales (CPE) are difficult to treat and are a serious public health threat. Nacubactam (NAC) is a novel non-β-lactam diazabicyclooctane β-lactamase inhibitor with in vitro activity against some Enterobacterales expressing classes of β-lactamases.MethodsThe antimicrobial efficacy of meropenem (MEM), cefepime (FEP), and aztreonam (ATM), each in combination with NAC, were assessed in vitro and in vivo against Klebsiella pneumoniae and Escherichia coli. Ten isolates, including CRE and/or CPE with β-lactamase genes, were used in this study. The relationship between phenotype and in vivo efficacy was assessed in a murine neutropenic thigh-infection model. Efficacy was determined by the change in bacterial quantity.ResultsThe results of the in vitro study showed the minimum inhibitory concentrations of the combination of NAC with either MEM, FEP, or ATM in a 1:1 ratio were 2 to >128-fold lower than those of MEM, FEP, or ATM alone against CRE+ isolates. In addition, combinations of β-lactams and NAC administered in the murine thigh-infection model showed greater efficacy against CRE+/CPE+, CRE+/CPE-, and CRE-/CPE+ isolates harboring various β-lactamase genes (IMP-1, IMP-6, KPC, DHA-1, or OXA-48) compared with MEM, FEP, ATM, and NAC alone.ConclusionMEM, FEP, or ATM in combination with NAC showed potent in vivo antimicrobial activity in a murine thigh-infection model caused by K. pneumoniae and E. coli, including CRE and/or CPE isolates. These findings indicate that these combinations of β-lactams and NAC are potential candidates for the treatment of CRE and/or CPE infections.     

A fly, Drosophila melanogaster, forms 11-cis 3-hydroxyretinal in the dark

All-trans and 11-cis 3-hydroxyretinals were synthesized and the presence of these substances in the head of Drosophila melanogaster was shown by using high performance liquid chromatography. Even when the head extract was prepared in the dark from the flies reared successively in the dark, both of the 3-hydroxyretinal isomers were detected. In the culture medium, they were not present. D. melanogaster must have an 11-cis 3-hydroxyretinal forming-system that does not need light.     

Tumor necrosis factor alpha-gene therapy for an established murine melanoma using RGD (Arg-Gly-Asp) fiber-mutant adenovirus vectors.

Although adenovirus vectors (Ad) provide high-level transduction efficacy to many cell types, extremely high doses of Ad are required for sufficient gene transduction into several tumors, including melanoma. Here, we demonstrated that the expression of coxsackie-adenovirus receptor, a primitive Ad-receptor, was very low in murine and human melanoma cells. We also found that fiber-mutant Ad containing the Arg-Gly-Asp (RGD) sequence in the fiber knob remarkably augmented gene transduction efficacy in melanoma cells by targeting alpha(v)-integrins. In addition, intratumoral injection of RGD fiber-mutant Ad containing the tumor necrosis factor alpha gene (Ad-RGD-TNFalpha) revealed dramatic anti-tumor efficacy through hemolytic necrosis in an established murine B16 BL6 melanoma model. Ad-RGD-TNFalpha required one-tenth the dosage of Ad-TNFalpha to induce an equal therapeutic effect. These results suggest that alpha(v)-integrin-targeted Ad will be a very powerful tool for the advancement of melanoma gene therapy.     

Gene expression profiles by microarray analysis during matrigel-induced tube formation in a human extravillous trophoblast cell line: comparison with endothelial cells

Endovascular differentiation of extravillous cytotrophoblasts (EVT) during placentogenesis induces remodeling of spiral arteries that increases blood flow toward the intravillous space and is required for maintaining pregnancy. To address the molecular mechanisms involved in this differentiation, we investigated the gene expression profile during matrigel-induced tube formation in TCL1 cells, a human immortalized EVT cell line, and HUV-EC-C, human umbilical vessel endothelial cells, and compared their profiles. The numbers of genes that showed significant up-regulation (>3-fold expression at both 3 and 6h, and/or >5-fold expression at either 3 or 6h) during tube formation and significant down-regulation (0.33-fold expression at both 3 and 6h, and/or less than 0.2-fold expression at either 3 or 6h), were 969 and 659 in TCL1, respectively. In HUV-EC-C, the numbers of genes that showed significant up-regulation and down-regulation were 86 and 65, respectively. Only 73 of 1628 genes that showed significant expression changes in TCL1 were common with HUV-EC-C. The genes showing significant expression change specifically in TCL1 were associated with cellular, metabolisms, proliferation, anti-apoptosis, proteolysis adhesion, and some known to be involved in EVT differentiation or related to angiogenesis. The gene expression profile in EVT during tube formation is very different from that of endothelial cells. Further investigations based on the current data may help to elucidate mechanisms of normal and abnormal placentogenesis.     

Urinary cadmium excretion is correlated with calcaneal bone mass in Japanese women living in an urban area

Nine hundred eight women aged 40-88 years living in a non-Cd-polluted area in Japan were analyzed for urinary cadmium (Cd), N-acetyl-beta-D-glucosaminidase (NAG) activity, beta(2)-microglobulin (B2MG) concentration, and for the stiffness index (STIFF) of calcaneal bone using an ultrasound method. The urinary Cd in the subjects, with a mean and range of 2.87 and 0.25-11.4 microg/g creatinine, respectively, showed a significant correlation with NAG but not with B2MG. STIFF was significantly inversely correlated with urinary Cd, and the association remained significant after adjusting for age, body weight, and menstrual status, suggesting a significant effect of Cd on the bone loss in these subjects without signs of Cd-induced kidney damage. A two-fold increase in urinary Cd was accompanied by a decrease in STIFF corresponding to a 1.7-year rise in age. These results emphasize the need for reassessment of the significance of Cd exposure in the general Japanese population.     

Association between maternal gestational diabetes mellitus and high‐sensitivity C‐reactive protein levels in 8‐year‐old children: The Yamanashi Adjunct Study of the Japan Environment and Children’s Study (JECS)

Gestational diabetes mellitus (GDM) is one of the most common pregnancy‐related complications; it is associated with adverse pregnancy outcomes and metabolic disorders in offspring, consistent with the concept of the developmental origins of health and disease. This cohort study of women without diabetes (n = 761), who were part of the Yamanashi Adjunct Study of the Japan Environment and Children’s Study, aimed to explore the associations between maternal GDM and their offspring’s level of high‐sensitivity C‐reactive protein (hsCRP), a biomarker of inflammatory and cardiovascular diseases. We analyzed the associations between GDM and the offspring’s hsCRP levels using a multiple logistic regression model. A mother with GDM significantly increased the risk for high hsCRP level by 4.07‐fold (≥2.0 mg/L) in the child. As such, maternal GDM was significantly associated with increased serum hsCRP levels in 8‐year‐old children.     

Size-Controllable Synthesis of Monodisperse Magnetite Microparticles Leading to Magnetically Tunable Colloidal Crystals

Colloidal crystals (CCs) are periodic arrays of monodisperse microparticles. Such CCs are very attractive as they can be potentially applicable as versatile photonic devices such as reflective displays, sensors, lasers, and so forth. In this article, we describe a promising methodology for synthesizing monodisperse magnetite microparticles whose diameters are controllable in the range of 100–200 nm only by adjusting the base concentration of the reaction solution. Moreover, monodisperse magnetite microparticles in aqueous suspensions spontaneously form the CC structures under an external magnetic field, leading to the appearance of Bragg reflection colors. The reflection peak can be blue-shifted from 730 nm to 570 nm by the increase in the external magnetic field from 28 mT to 220 mT. Moreover, the reflection properties of CCs in suspension depend on the microparticle concentration in suspension and the diameter of the magnetite microparticles. Both fine-control of microparticle diameter and investigation of magneto-optical properties of CCs would contribute to the technological developments in full-color reflective displays and sensors by utilizing these monodisperse magnetite microparticles.