Hypervirulent
(hvKp) is an emerging pathogen of increasing concern due to its ability to cause serious organ and life-threatening infections in healthy individuals and its increasing acquisition of ...antimicrobial resistance determinants. Identification of hvKp is critical for patient care and epidemiologic and research studies. Five genotypic markers on the hvKp-specific virulence plasmid can accurately differentiate hvKp from the less virulent classical
(cKp) strain, but it is unclear whether the possession of fewer markers accurately predicts the hvKp pathotype. Likewise, the effect, if any, of various antimicrobial resistance factors on the pathogenic potential of hvKp has been incompletely explored. The
infection model is often used to assess virulence, but this tool has not been validated. Therefore, levels of lethality of defined hvKp and cKp strain cohorts were compared in
and outbred mouse models. The murine model, but not the
model, accurately differentiated hvKp from cKp strains. Therefore, isolates in which the pathogenic potential is ambiguous due to an incomplete hvKp biomarker profile, an incomplete pLVPK-like hvKp-specific virulence plasmid, antimicrobial resistance that could decrease biofitness, and/or the lack of a characteristic clinical presentation should be validated in an outbred murine model. These data will assist in determining the minimal genomic content needed for full expression of the hypervirulence phenotype. This information, in turn, is critical for the development of the pragmatic point-of-care testing requisite for patient care and for the performance of epidemiologic and research studies going forward.
Hypervirulent
(hvKp) is of increasing concern because it can infect individuals in community and health care settings and because such infections are becoming difficult to treat. Identification of hvKp is important for patient care and to track its global spread. The genetic definition of hvKp, which can be used for its identification and the development of diagnostic tests, has not been optimized. Determination of possession of 4 of 5 genes that are present on the hvKp-specific virulence plasmid is highly accurate for identifying hvKp. However, an ongoing issue is whether strains that possess only some of these markers are still hypervirulent. The
model and, less commonly, the murine infection model have been used to assess the virulence of these ambiguously identifiable strains. This report demonstrates that the murine model but not the
model accurately identifies suspected hvKp strains. This information is critical for the development of diagnostics for patient care and for future research studies.
No clinical trials have compared osteoporosis drugs with incident fractures as the primary outcome. We compared the anti-fracture efficacy of teriparatide with risedronate in patients with severe ...osteoporosis.
In this double-blind, double-dummy trial, we enrolled post-menopausal women with at least two moderate or one severe vertebral fracture and a bone mineral density T score of less than or equal to −1·50. Participants were randomly assigned to receive 20 μg of teriparatide once daily plus oral weekly placebo or 35 mg of oral risedronate once weekly plus daily injections of placebo for 24 months. The primary outcome was new radiographic vertebral fractures. Secondary, gated outcomes included new and worsened radiographic vertebral fractures, clinical fractures (a composite of non-vertebral and symptomatic vertebral), and non-vertebral fractures. This study is registered with ClinicalTrials.gov (NCT01709110) and EudraCT (2012-000123-41).
We enrolled 680 patients in each group. At 24 months, new vertebral fractures occurred in 28 (5·4%) of 680 patients in the teriparatide group and 64 (12·0%) of 680 patients in the risedronate group (risk ratio 0·44, 95% CI 0·29–0·68; p<0·0001). Clinical fractures occurred in 30 (4·8%) of 680 patients in the teriparatide group compared with 61 (9·8%) of 680 in the risedronate group (hazard ratio 0·48, 95% CI 0·32–0·74; p=0·0009). Non-vertebral fragility fractures occurred in 25 (4·0%) patients in the teriparatide group and 38 (6·1%) in the risedronate group (hazard ratio 0·66; 95% CI 0·39–1·10; p=0·10).
Among post-menopausal women with severe osteoporosis, the risk of new vertebral and clinical fractures is significantly lower in patients receiving teriparatide than in those receiving risedronate.
Lilly.
Crystalline SnO2/reduced graphene oxide (RGO) nanocomposites were synthesized by a one-pot microwave-assisted non-aqueous sol–gel method, in which partially reduction of the graphene oxide and ...nanoparticle formation occurs simultaneously. Composite samples with different SnO2 loadings on the RGO were prepared and characterized by TEM, XRD, TGA-DSC and FT-IR. Chemoresistive devices, consisting of a thick layer of the samples synthesized on alumina substrates provided with Pt interdigitated electrodes, were fabricated and their electrical and NO2 sensing characteristics investigated. The results obtained have shown the possibility of a fine tuning of the sensing characteristics of the devices fabricated by simply controlling the amount of metal oxide nanoparticles loaded onto the reduced graphene oxide sheets. This was explained on the basis of the critical role played by the n-SnO2/p-RGO heterojunction formed on the composite materials.
Hypervirulent (hypermucoviscous) Klebsiella pneumoniae (hvKP) strains are an emerging variant of "classical" K. pneumoniae (cKP) that cause organ and life-threatening infection in healthy ...individuals. An understanding of hvKP-specific virulence mechanisms that enabled evolution from cKP is limited. Observations by our group and previously published molecular epidemiologic data led us to hypothesize that hvKP strains produced more siderophores than cKP strains and that this trait enhanced hvKP virulence. Quantitative analysis of 12 hvKP strains in iron-poor minimal medium or human ascites fluid showed a significant and distinguishing 6- to 10-fold increase in siderophore production compared to that for 14 cKP strains. Surprisingly, high-pressure liquid chromatography (HPLC)-mass spectrometry and characterization of the hvKP strains hvKP1, A1142, and A1365 and their isogenic aerobactin-deficient (ΔiucA) derivatives established that aerobactin accounted for the overwhelming majority of increased siderophore production and that this was not due to gene copy number. Further, aerobactin was the primary factor in conditioned medium that enhanced the growth/survival of hvKP1 in human ascites fluid. Importantly the ex vivo growth/survival of hvKP1 ΔiucA was significantly less than that of hvKP1 in human ascites fluid, and the survival of outbred CD1 mice challenged subcutaneously or intraperitoneally with hvKP1 was significantly less than that of mice challenged with hvKP1 ΔiucA. The lowest subcutaneous and intraperitoneal challenge inocula of 3 × 10(2) and 3.2 × 10(1) CFU, respectively, resulted in 100% mortality, demonstrating the virulence of hvKP1 and its ability to cause infection at a low dose. These data strongly support that aerobactin accounts for increased siderophore production in hvKP compared to cKP (a potential defining trait) and is an important virulence factor.
The achievement of a strong and stable bond between composite resin and dentin remains a challenge in restorative dentistry. Over the past two decades, dental materials have been substantially ...improved, with better handling and bonding characteristics. However, little attention has been paid to the contribution of collagen structure/stability to bond strength. We hypothesized that the induction of cross-linking in dentin collagen improves dentin collagen stability and bond strength. This study investigated the effects of glutaraldehyde-and grape seed extract-induced cross-linking on the dentin bond strengths of sound and caries-affected dentin, and on the stability of dentin collagen. Our results demonstrated that the application of chemical cross-linking agents to etched dentin prior to bonding procedures significantly enhanced the dentin bond strengths of caries-affected and sound dentin. Glutaraldehyde and grape seed extract significantly increased dentin collagen stability in sound and caries-affected dentin, likely via distinct mechanisms.
The use of ceramic coatings to improve mechanical, chemical, and biological properties of a large variety of materials including polymers and metals has often produced technologically attractive as ...well as problematic surfaces to study, because of their complicate morphology compared to smooth surfaces obtained, for example, by atomistic processes. In this work we deposited thin films of zirconia by a new generation pulsed electron deposition system named Ionized Jet Deposition onto four materials, different from each other by structure and surface texture, and applied methods of fractal geometry to investigate their microstructure and roughening mechanism at different thickness values. Our findings show that the film growth does not follow any known class of universality, but is strongly influenced by non-local effects inherent to deposition technique. In this context, we show that deposition onto rough materials is dominated by a strong memory effect that leads to uniform surface coverages that microscopically retain the shape of the substrate. This circumstance is potentially useful for deposition of conformal coatings in view of applications of such plasma-based deposition technique to cases of technological interest.
•Ionized Jet Deposition is used to deposit zirconia thin films.•The growth onto four different substrates is investigated by fractal methods.•Shadowing effect is dominant upon the film growth.•The growth onto “rough” substrates is reminiscent of their pristine corrugation.
The etiology of bisphosphonate-related osteonecrosis of the jaw is unknown but was initially postulated to be mediated by bisphosphonate accumulation within the jaws, resulting in avascular necrosis. ...Bisphosphonates may not be the primary cause. Actinomyces are an underrecognized agent in pathogenesis, and timely actinomycosis-specific treatment may improve outcome.
The hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER) play key roles in the conversion of energy derived from renewable energy sources into chemical energy. Efficient, robust, ...and inexpensive electrocatalysts are necessary for driving these reactions at high rates at low overpotentials and minimize energetic losses. Recently, electrocatalysts derived from hybrid metal phosphonate compounds have shown high activity for the HER or OER. We review here the utilization of metal phosphonate coordination networks and metal-organic frameworks as precursors/templates for transition-metal phosphides, phosphates, or oxyhydroxides generated in situ in alkaline solutions, and their electrocatalytic performance in HER or OER.
In the last years a large number of weather driven extreme events has occurred worldwide with unprecedented socio-economic impacts and are expected to increase, in both frequency and intensity, under ...future global-warming conditions. In this context early identification and predictability of such events are paramount as they mostly affect several socio-economic activities. Despite the effort in monitoring and evaluation of these extreme events, a quantitative assessment of their interaction is still a challenge. We propose to analyze if the occurrence of extremely hot days/nights in the summer is preceded by drought events in spring and early summer throughout the Mediterranean area. This was investigated by correlating the number of hot days and nights in the regions hottest months with a drought indicator on the prior months. Drought characterization was performed using both the Standardized Precipitation Evaporation Index (SPEI) and the Standardized Precipitation Index (SPI) for the 3-, 6- and 9-months time scales, considering the period 1980-2014 with a spatial resolution of 0.5°. The number of hot days and nights per month (NHD and NHN, respectively) is determined for the same period and spatial resolution. Results show that the most frequent hottest months for the Mediterranean region occur in July and August. Most regions exhibit statistically significant negative correlations, i.e. high (low) NHD/NHN following negative (positive) SPEI/SPI values, and thus a potential for NHD/NHN early warning. This analysis allowed to identify the Iberian Peninsula, northern Italy, northern Africa and the Balkans as the main hotspots of predictability of extreme hot temperatures in the summer preceded by the occurrence of drought events in the spring or early summer.
In liver the mitochondrial sirtuin, SIRT5, controls ammonia detoxification by regulating CPS1, the first enzyme of the urea cycle. However, while SIRT5 is ubiquitously expressed, urea cycle and CPS1 ...are only present in the liver and, to a minor extent, in the kidney. To address the possibility that SIRT5 is involved in ammonia production also in nonliver cells, clones of human breast cancer cell lines MDA-MB-231 and mouse myoblast C2C12, overexpressing or silenced for SIRT5 were produced. Our results show that ammonia production increased in SIRT5-silenced and decreased in SIRT5-overexpressing cells. We also obtained the same ammonia increase when using a new specific inhibitor of SIRT5 called MC3482. SIRT5 regulates ammonia production by controlling glutamine metabolism. In fact, in the mitochondria, glutamine is transformed in glutamate by the enzyme glutaminase, a reaction producing ammonia. We found that SIRT5 and glutaminase coimmunoprecipitated and that SIRT5 inhibition resulted in an increased succinylation of glutaminase. We next determined that autophagy and mitophagy were increased by ammonia by measuring autophagic proteolysis of long-lived proteins, increase of autophagy markers MAP1LC3B, GABARAP, and GABARAPL2, mitophagy markers BNIP3 and the PINK1-PARK2 system as well as mitochondrial morphology and dynamics. We observed that autophagy and mitophagy increased in SIRT5-silenced cells and in WT cells treated with MC3482 and decreased in SIRT5-overexpressing cells. Moreover, glutaminase inhibition or glutamine withdrawal completely prevented autophagy. In conclusion we propose that the role of SIRT5 in nonliver cells is to regulate ammonia production and ammonia-induced autophagy by regulating glutamine metabolism.
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