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This study aimed to investigate the ability of disulphide-less crotamine (dLCr) to complex DNA and to evaluate whether the DNA–dLCr complex is capable of improving transfection in bovine embryos. Three experiments were performed to: (i) evaluate the formation and stability of the DNA–dLCr complex; (ii) assess the dLCr embryotoxicity by exposure of bovine embryos to dLCr; and (iii) assess the efficiency of bovine embryo transfection after microinjection of the DNA–dLCr complex or green fluorescent protein (GFP) plasmid alone (control). DNA complexation by dLCr after 30 min of incubation at 1:100 and 1:50 proportions presented higher efficiency (P < 0.05) than the two controls: native crotamine (NCr) 1:10 and lipofectamine. There was no difference between DNA–dLCr 1:25 and the controls. The DNA–dLCr complexation was evaluated at different proportions and times. In all, at least half of maximum complexation was achieved within the initial 30 min. No embryotoxicity of dLCr was verified after exposure of in vitro fertilized embryos to different concentrations of the peptide. The effectiveness of dLCr to improve exogenous gene expression was evaluated by microinjection of the DNA–dLCr complex into in vitro fertilized zygotes, followed by verification of both embryo development and GFP expression. From embryos microinjected with DNA only, 4.6% and 2.8% expressed the GFP transgene at day 5 and day 7, respectively. The DNA–dLCr complex did not increase the number of GFP-positive embryos. In conclusion, dLCr forms a complex with DNA and its application in in vitro culture is possible. However, the dLCr peptide sequence should be redesigned to improve GFP expression.
Background: Hereditary transthyretin-mediated (hATTR) amyloidosis a hereditary, multi-systemic and life-threatening disease resulting in neuropathy and cardiomyopathy. In the APOLLO study, patisiran, an investigational RNAi therapeutic targeting hepatic TTR production resulted in significant improvement in neuropathy and QoL compared to placebo and was generally well tolerated. Methods: APOLLO, a Phase 3 study of patisiran vs. placebo (NCT01960348) prespecified a cardiac subpopulation (n=126 of 225 total) that included patients with baseline left ventricular (LV) wall thickness ≥ 13mm and no medical history of aortic valve disease or hypertension. Cardiac measures included structure and function by electrocardiography, changes in NT-proBNP and 10-MWT gait speed. Results: At 18 months, patisiran treatment resulted in a mean reduction in LV wall thickness of 1 mm (p=0.017) compared to baseline, which was associated with significant improvements relative to placebo in LV end diastolic volume (+8.31 mL, p=0.036), global longitudinal strain (-1.37%, p=0.015) and NT-proBNP (55% reduction, p=7.7 x 10-8) (Figure 1). Gait speed was also improved relative to placebo (+0.35 m/sec, p=7.4 x 10-9). Rate of death or hospitalization was lower with patisiran. mNIS+7 results in the cardiac subpopulation will also be presented. Conclusions: These data suggest patisiran has the potential to halt or reverse cardiac manifestations of hATTR amyloidosis.
To assess the safety of, and subsequent allergy documentation associated with, an antimicrobial stewardship intervention consisting of test-dose challenge procedures prompted by an electronic guideline for hospitalized patients with reported β-lactam allergies.
Retrospective cohort study.
Large healthcare system consisting of 2 academic and 3 community acute-care hospitals between April 2016 and December 2017.
We evaluated β-lactam antibiotic test-dose outcomes, including adverse drug reactions (ADRs), hypersensitivity reactions (HSRs), and electronic health record (EHR) allergy record updates. HSR predictors were examined using a multivariable logistic regression model. Modification of the EHR allergy record after test doses considered relevant allergy entries added, deleted, and/or specified.
We identified 1,046 test-doses: 809 (77%) to cephalosporins, 148 (14%) to penicillins, and 89 (9%) to carbapenems. Overall, 78 patients (7.5%; 95% confidence interval [CI], 5.9%–9.2%) had signs or symptoms of an ADR, and 40 (3.8%; 95% CI, 2.8%–5.2%) had confirmed HSRs. Most HSRs occurred at the second (ie, full-dose) step (68%) and required no treatment beyond drug discontinuation (58%); 3 HSR patients were treated with intramuscular epinephrine. Reported cephalosporin allergy history was associated with an increased odds of HSR (odds ratio [OR], 2.96; 95% CI, 1.34–6.58). Allergies were updated for 474 patients (45%), with records specified (82%), deleted (16%), and added (8%).
This antimicrobial stewardship intervention using β-lactam test-dose procedures was safe. Overall, 3.8% of patients with β-lactam allergy histories had an HSR; cephalosporin allergy histories conferred a 3-fold increased risk. Encouraging EHR documentation might improve this safe, effective, and practical acute-care antibiotic stewardship tool.
Lung surfactant (LS), a thin layer of phospholipids and proteins inside the alveolus of the lung is the first biological barrier to inhaled nanoparticles (NPs). LS stabilizes and protects the alveolus during its continuous compression and expansion by fine-tuning the surface tension at the air-water interface. Previous modelling studies have reported the biophysical function of LS monolayer and its role, but many open questions regarding the consequences and interactions of airborne nano-sized particles with LS monolayer remain. In spite of gold nanoparticles (AuNPs) having a paramount role in biomedical applications, the understanding of the interactions between bare AuNPs (as pollutants) and LS monolayer components still unresolved. Continuous inhalation of NPs increases the possibility of lung ageing, reducing the normal lung functioning and promoting lung malfunction, and may induce serious lung diseases such as asthma, lung cancer, acute respiratory distress syndrome, and more. Different medical studies have shown that AuNPs can disrupt the routine lung functions of gold miners and promote respiratory diseases. In this work, coarse-grained molecular dynamics simulations are performed to gain an understanding of the interactions between bare AuNPs and LS monolayer components at the nanoscale. Different surface tensions of the monolayer are used to mimic the biological process of breathing (inhalation and exhalation). It is found that the NP affects the structure and packing of the lipids by disordering lipid tails. Overall, the analysed results suggest that bare AuNPs impede the normal biophysical function of the lung, a finding that has beneficial consequences to the potential development of treatments of various respiratory diseases.
GravityCam is a new concept of ground-based imaging instrument capable of delivering significantly sharper images from the ground than is normally possible without adaptive optics. Advances in optical and near-infrared imaging technologies allow images to be acquired at high speed without significant noise penalty. Aligning these images before they are combined can yield a 2.5–3-fold improvement in image resolution. By using arrays of such detectors, survey fields may be as wide as the telescope optics allows. Consequently, GravityCam enables both wide-field high-resolution imaging and high-speed photometry. We describe the instrument and detail its application to provide demographics of planets and satellites down to Lunar mass (or even below) across the Milky Way. GravityCam is also suited to improve the quality of weak shear studies of dark matter distribution in distant clusters of galaxies and multiwavelength follow-ups of background sources that are strongly lensed by galaxy clusters. The photometric data arising from an extensive microlensing survey will also be useful for asteroseismology studies, while GravityCam can be used to monitor fast multiwavelength flaring in accreting compact objects and promises to generate a unique data set on the population of the Kuiper belt and possibly the Oort cloud.
The skull base is a highly complex anatomical region that provides passage for important nerves and vessels as they course into and out of the cranial cavity. Key to the management of pathology in this region is a thorough understanding of the anatomy, with its variations, and the relationship of various neurovascular structures to the pathology in question. Targeted high-resolution magnetic resonance imaging on high field strength magnets can enable the skull base surgeon to understand this intricate relationship and deal with the pathology from a position of relative advantage.
With the help of case studies, this paper illustrates the application of specialised magnetic resonance techniques to study pathology of the orbital apex in particular.
The fine anatomical detail provided gives surgeons the ability to design an endonasal endoscopic procedure appropriate to the anatomy of the pathology.
Stalagmites and stalactites, as observed within natural caves, may develop inside geological repositories during constructional and post-operational periods. It is therefore important to understand actinide sorption within such materials. Towards this, experimental studies were carried out with 233U, 238Np (VI), 238Np (IV), 239Pu and 241Am radiotracers using natural speleothem samples collected from the Dharamjali cave of the Kumaon Lesser Himalayas, India. Petrological/mineralogical studies showed that natural speleothems have three general domains: (1) columnar calcite; (2) microcrystalline calcite; and (3) botryoidal aragonite – each with ferruginous materials. Results showed that all domains of speleothems can take up >99% actinides, irrespective of valence state and pH (1–6 range) of the solution. However, distribution coefficients were found to be at a maximum in aragonite for most of the actinides. Such data are very important for long-term performance and safety assessments of the deep geological repositories planned for the disposal of high-level nuclear wastes.
Scarce data exist on the relationship between diabetes and extrapulmonary tuberculosis (EPTB). We evaluated whether diabetes impacts site of TB and risk of death in patients with EPTB. We evaluated a cohort of TB cases from the state of Georgia between 2009 and 2012. Patients aged ⩾16 years were classified by diabetes status according to medical records. Site of EPTB was determined by culture and/or state TB classification. Death was defined by all-cause mortality. Of 1325 eligible reported TB cases, 369 (27·8%) had any EPTB including 258 (19·5%) with only EPTB and 111 (8·4%) with pulmonary TB and EPTB. Of all TB cases, 158 had diabetes (11·9%). In multivariable analysis, the odds of any EPTB was similar in patients with and without diabetes [adjusted odds ratio 1·04, 95% confidence interval (CI) 0·70–1·56]. The risk of death was 23·8% in patients with EPTB and diabetes vs. 9·8% in those with no diabetes (P < 0·01); after adjusting for covariates the difference was not significant (aRR 1·19, 95% CI 0·54–2·63). Diabetes was common in patients with EPTB and risk of death was high. Improved understanding of the relationship between diabetes and EPTB is critical to determine the extent that diabetes affects TB diagnosis and clinical management.
A multidisciplinary team approach is required for the preservation of voice and appropriate management of glottic cancer. This study aimed to investigate the outcomes of surgically treated glottic cancers of all stages. All aspects of surgical management, such as laser cordectomy, partial laryngectomy, total laryngectomy with voice prosthesis, and salvage laryngectomy, conducted at a single tertiary care institute in India, were reviewed.
A retrospective analysis of hospital records was performed for 192 glottic cancer patients who were surgically treated between 2003 and 2007.
Patients with tumour stages 1 or 2 glottic cancer treated with laser cordectomy had a local control rate of 85 per cent and five-year survival rate of 98.6 per cent. The findings suggest that the number of partial laryngectomies performed for stage 3 tumours is declining. Patients with a tumour stage 3 lesion with a fixed hemilarynx or a tumour stage 4 lesion, treated with total laryngectomy, were found to have a five-year survival rate of 61.6 per cent. Nodal status was significantly associated with five-year survival rate.
Surgery offers a viable five-year survival rate in glottic cancer patients.
The present study investigated the effects of crotamine, a cell-penetrating peptide from rattlesnake venom, at different exposure times and concentrations, on both developmental competence and gene expression (ATP1A1, AQP3, GLUT1 and GLUT3) of in vitro fertilized (IVF) bovine embryos. In Experiment 1, presumptive zygotes were exposed to 0.1 μM crotamine for 6, 12 or 24 h and control groups (vehicle and IVF) were included. In Experiment 2, presumptive zygotes were exposed to 0 (vehicle), 0.1, 1 and 10 μM crotamine for 24 h. Additionally, to visualize crotamine uptake, embryos were exposed to rhodamine B-labelled crotamine and subjected to confocal microscopy. In Experiment 1, no difference (P > 0.05) was observed among different exposure times and control groups for cleavage and blastocyst rates and total cells number per blastocyst. Within each exposure time, mRNA levels were similar (P > 0.05) in embryos cultured with or without crotamine. In Experiment 2, concentrations as high as 10 μM crotamine did not affect (P > 0.05) the blastocyst rate. Crotamine at 0.1 and 10 μM did not alter mRNA levels when compared with the control (P > 0.05). Remarkably, only 1 μM crotamine decreased both ATP1A1 and AQP3 expression levels relative to the control group (P < 0.05). Also, it was possible to visualize the intracellular localization of crotamine. These results indicate that crotamine can translocate intact IVF bovine embryos and its application in the culture medium is possible at concentrations from 0.1–10 μM for 6–24 h.
To explore the treatment outcomes of patients treated with re-irradiation for recurrent or second primary head and neck cancer.
An analysis was performed of 79 head and neck cancer patients who underwent re-irradiation for second primaries or recurrent disease from January 1999 to December 2011.
Median time from previous radiation to re-irradiation for second primary or recurrence was 53.6 months (range, 2.7–454.7 months). Median age at diagnosis of first primary was 54 years. Median re-irradiation dose was 45 Gy (range, 45–60 Gy). Acute grade 3 or worse toxicity was seen in 30 per cent of patients. Median progression-free survival for recurrent disease was 15.0 months (95 per cent confidence interval, 8.33–21.66). The following factors had a statistically significant, positive impact on progression-free survival: patient age of less than 50 years (median progression-free survival was 29.43, vs 13.9 months for those aged 50 years or older; p = 0.004) and disease-free interval of 2 years or more (median progression-free survival was 51.66, vs 13.9 months for those with less than 2 years disease-free interval).
Re-irradiation of second primaries or recurrences of head and neck cancers with moderate radiation doses yields acceptable progression-free survival and morbidity rates.
We present a strong correlation between 12μm mid-IR and intrinsic X-ray (2–10 keV) luminosities of local Seyferts. This work is based on new diffraction-limited mid-IR observations with the 8-m Very Large Telescope (VLT), resulting in the least-contaminated core fluxes of 42 Seyferts to date.
The relative immunogenicity in mice of whole influenza virus, and virus split with different disrupting agents, was compared. Using the single radial immunodiffusion test to estimate the haemagglutinin antigen concentration in different virus preparations, it was found that, in general, split virus preparations induced substantially lower titres of HI antibody in mice than whole virus after one or two injections of the antigen.
Jointed goatgrass is an important weed of wheat in the United States and other parts of the world. Under field conditions, wheat and jointed goatgrass can hybridize and produce backcross derivatives, a situation that may allow gene flow between these two species. In order to gain a better understanding of the factors governing gene flow, a study to characterize patterns of mating between these two species was undertaken. Chloroplast and nuclear microsatellite markers were used to evaluate the parentage of 413 first-generation backcross (BC1) seeds obtained from 127 wheat–jointed goatgrass F1 hybrids, produced naturally under field conditions. Of the 127 hybrids evaluated, 109 (85.8%) had jointed goatgrass as the female parent, whereas the remaining 18 F1 plants (14.2%) had wheat as the female parent. Of the 413 BC1 plants analyzed, 358 (86.7%) had wheat and 24 (5.8%) had jointed goatgrass as the male backcross parent. The male parentage of 31 BC1 (7.5%) plants could not be determined. Under natural field conditions, wheat was the prevalent pollen donor for the production of hybrids and first-generation backcross derivatives. However, hybrids and backcrosses with jointed goatgrass as the male parent also were observed. Thus, the establishment and persistence of a zone of hybridization between these species would result in the development of jointed goatgrass carrying wheat genes.
The metastable solid solubility extension of CoO in ZnO (wurtzite) was investigated in precursor-derived powders as well as in thin films grown on sapphire substrates by pulsed laser deposition. A maximum solubility of 30% Co2+ in ZnO was achieved in the powders. Transmission electron microscopy (TEM) of the films revealed them to have grown epitaxially and retained up to nearly 40% CoO in solid solution, but some Co2+ precipitated as rock-salt. The temperature dependence of the metastable solubility limit in the ZnO–CoO system was assessed and is discussed in terms of the relevant thermodynamic factors. The magnetic properties of n-type conductive Zn0.79Co0.2Al0.01Ofilms were studied, yielding evidence of a ferromagnetic phase with a TC of 25 K and a second, magnetically ordered, phase with positive exchange and arguably a TC of ∼250 K. Connections between the properties and microstructural observations in high resolution TEM are proposed.
Al2O3–Y2O3 powders were synthesized in the range of 25–55% Y2O3 by reverse coprecipitation of nitrate solutions. All starting powders were amorphous and formed primary yttrium aluminum garnet (YAG) upon crystallization. X-ray diffraction detected only garnet in compositions of 30–40% Y2O3 after heat treatment at 1250 °C. Compositions of 45–55% Y2O3 established a metastable YAG + Y4Al2O9 microstructure. The YAG phase field was metastably extended away from its stoichiometry, as indicated by a systematic increase in lattice parameter with Y2O3 content. Although some Al2O3 enrichment was achieved, YAG appears to tolerate greater off-stoichiometry on the Y2O3-rich side. Possible defect structures accommodating the solubility extension were examined. Phase selection results indicate that compositional inhomogeneity is not the only reason behind the appearance of hexagonal YAlO3, which is frequently reported during YAG synthesis.
The metastable-to-equilibrium phase evolution over a wide range of compositions in the TiO2-YO3/2-ZrO2 system was investigated. The competing phases are all derivatives of the fluorite structure and compositions within the fluorite and pyrochlore fields exhibit technologically interesting ionic and mixed ionic-electronic conductivity. Powders of various compositions were synthesized by precursor routes, pyrolyzed and subsequently heat-treated in a stepwise manner at progressively higher temperatures to explore the sequence of phase evolution. Extended solid solutions with amorphous, fluorite and ordered pyrochlore structures were produced over significant composition ranges within the ternary. The study also sheds new light on the correct form of the phase equilibria at 1300°C.
In this work, an attempt is made to gain a better understanding of the breakage of low-viscosity drops in turbulent flows by determining the dynamics of deformation of an inviscid drop in response to a pressure variation acting on the drop surface. Known scaling relationships between wavenumbers and frequencies, and between pressure fluctuations and velocity fluctuations in the inertial subrange are used in characterizing the pressure fluctuation. The existence of a maximum stable drop diameter dmax follows once scaling laws of turbulent flow are used to correlate the magnitude of the disruptive forces with the duration for which they act.
Two undetermined dimensionless quantities, both of order unity, appear in the equations of continuity, motion, and the boundary conditions in terms of pressure fluctuations applied on the surface. One is a constant of proportionality relating root-mean-square values of pressure and velocity differences between two points separated by a distance l. The other is a Weber number based on turbulent stresses acting on the drop and the resisting stresses in the drop due to interfacial tension. The former is set equal to 1, and the latter is determined by studying the interaction of a drop of diameter equal to dmax with a pressure fluctuation of length scale equal to the drop diameter. The model is then used to study the breakage of drops of diameter greater than dmax and those with densities different from that of the suspending fluid.
It is found that, at least during breakage of a drop of diameter greater than dmax by interaction with a fluctuation of equal length scale, a satellite drop is always formed between two larger drops. When very large drops are broken by smaller-length-scale fluctuations, highly deformed shapes are produced suggesting the possibility of further fragmentation due to instabilities. The model predicts that as the dispersed-phase density increases, dmax decreases.