Clinical studies have been carried out for detailed measurements of the build-up and clearance of engineered gold nanoshell in the tissues of dosed mice. These optically tunable nanoshells are under ...consideration for a new therapy for tumors. The proposed therapy would involve the injection of the nanoshells and their preferential accumulation in tumor sites. This will be followed by irradiation with a monochromatic near infrared laser, which will induce cellular hyperthermia, thereby eradicating the tumor. Neutron activation analysis has been used for the detection and quantitation of gold, and therefore, the nanoshells, in dosing materials, blood, bones and other tissues as well as tumors at varioius sacrifice times following dosing. Feasibility studies have shown instrumental neutron activation analysis to be uniquely suited for detection of the gold nanoshells over a wide dynamic range. This allows for the study of high concentrations of gold in tissues which scavenge the shells from the blood (liver, spleen, kidney) as well as for much lower concentrations in those which do not (muscle, brain). In particular, the tissues from animals sacrificed after the longest post dose delay (28 days) and the control animals required experimental optimization to ensure the lowest possible determination limits. The mass of gold in the tissue samples ranged from our determination limit (about 70 pg) to a few micrograms.
Abstract Dysregulation of Ca2+ signaling following oxidative stress is an important pathophysiological mechanism of many chronic neurodegenerative disorders, including Alzheimer's disease, ...age-related macular degeneration, glaucomatous and diabetic retinopathies. However, the underlying mechanisms of disturbed intracellular Ca2+ signaling remain largely unknown. We here describe a novel mechanism for increased intracellular Ca2+ release following oxidative stress in a neuronal cell line. Using an experimental approach that included quantitative polymerase chain reaction, quantitative immunoblotting, microfluorimetry and the optical imaging of intracellular Ca2+ release, we show that sub-lethal tert-butyl hydroperoxide-mediated oxidative stress result in a selective up-regulation of type-2 inositol-1,4,5,-trisphophate receptors. This oxidative stress mediated change was detected both at the transcriptional and translational level and functionally resulted in increased Ca2+ release into the nucleoplasm from the membranes of the nuclear envelope at a given receptor-specific stimulus. Our data describe a novel source of Ca2+ dysregulation induced by oxidative stress with potential relevance for differential subcellular Ca2+ signaling specifically within the nucleus and the development of novel neuroprotective strategies in neurodegenerative disorders.
is the most common cause of seafood-borne illness reported in the United States. The draft genomes of 132 North American clinical and oyster
isolates were sequenced to investigate their phylogenetic ...and biogeographic relationships. The majority of oyster isolate sequence types (STs) were from a single harvest location; however, four were identified from multiple locations. There was population structure along the Gulf and Atlantic Coasts of North America, with what seemed to be a hub of genetic variability along the Gulf Coast, with some of the same STs occurring along the Atlantic Coast and one shared between the coastal waters of the Gulf and those of Washington State. Phylogenetic analyses found nine well-supported clades. Two clades were composed of isolates from both clinical and oyster sources. Four were composed of isolates entirely from clinical sources, and three were entirely from oyster sources. Each single-source clade consisted of one ST. Some human isolates lack
,
, and some type III secretion system (T3SS) genes, which are established virulence genes of
Thus, these genes are not essential for pathogenicity. However, isolates in the monophyletic groups from clinical sources were enriched in several categories of genes compared to those from monophyletic groups of oyster isolates. These functional categories include cell signaling, transport, and metabolism. The identification of genes in these functional categories provides a basis for future in-depth pathogenicity investigations of
is the most common cause of seafood-borne illness reported in the United States and is frequently associated with shellfish consumption. This study contributes to our knowledge of the biogeography and functional genomics of this species around North America. STs shared between the Gulf Coast and the Atlantic seaboard as well as Pacific waters suggest possible transport via oceanic currents or large shipping vessels. STs frequently isolated from humans but rarely, if ever, isolated from the environment are likely more competitive in the human gut than other STs. This could be due to additional functional capabilities in areas such as cell signaling, transport, and metabolism, which may give these isolates an advantage in novel nutrient-replete environments such as the human gut.
Background
The use of cardiac biomarkers to assist in the diagnosis of occult and symptomatic hypertrophic cardiomyopathy (HCM) in cats has been established. There is limited data describing their ...prognostic utility in cats with HCM.
Hypothesis
Circulating concentrations of N‐terminal B‐type natriuretic peptide (NTproBNP) and cardiac troponin I (cTnI) predict cardiac death in cats with HCM.
Animals
Forty‐one cats diagnosed with HCM at a veterinary teaching hospital, between February 2010 and May 2011.
Methods
Prospective investigational study. Plasma samples were collected from cats diagnosed with HCM and concentrations of NTproBNP and cTnI were analyzed at a commercial laboratory. Echocardiographic measurements from the day of blood sampling were recorded. Long‐term outcome data were obtained. Associations with time to cardiac death were analyzed using Cox proportional hazards models.
Results
When controlling for the presence/absence of heart failure and echocardiographic measures of left atrial size and function, cTnI > 0.7 ng/mL was independently associated with time to cardiac death. In univariable analysis, NTproBNP > 250 pmol/L was associated with cardiac death (P = .023), but this did not remain significant (P = .951) when controlling for the effect of clinical signs or left atrial size/function.
Conclusions and Clinical Importance
Plasma concentration of cTnI (cutoff >0.7 ng/mL) is a predictor of cardiac death in cats with HCM that is independent of the presence of heart failure or left atrial dilatation.
We present light curves and periods of 53 candidates for short period eclipsing binary stars identified by SuperWASP. These include 48 newly identified objects with periods <2 × 104 s (~0.23 d), as ...well as the shortest period binary known with main sequence components (GSC2314–0530 = 1SWASP J022050.85 + 332047.6) and four other previously known W UMa stars (although the previously reported periods for two of these four are shown to be incorrect). The period distribution of main sequence contact binaries shows a sharp cut-off at a lower limit of around 0.22 d, but until now, very few systems were known close to this limit. These new candidates will therefore be important for understanding the evolution of low mass stars and to allow investigation of the cause of the period cut-off.
T-cell responses against highly conserved influenza antigens have been previously associated with protection. However, these immune responses are poorly maintained following recovery from influenza ...infection and are not boosted by inactivated influenza vaccines. We have previously demonstrated the safety and immunogenicity of two viral vectored vaccines, modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAdOx1 expressing conserved influenza virus antigens, nucleoprotein (NP) and matrix protein-1 (M1). We now report on the safety and long-term immunogenicity of multiple combination regimes of these vaccines in young and older adults.
We conducted a Phase I open-label, randomized, multi-center study in 49 subjects aged 18–46years and 24 subjects aged 50years or over. Following vaccination, adverse events were recorded and the kinetics of the T cell response determined at multiple time points for up to 18months.
Both vaccines were well tolerated. A two dose heterologous vaccination regimen significantly increased the magnitude of pre-existing T-cell responses to NP and M1 after both doses in young and older adults. The fold-increase and peak immune responses after a single MVA-NP+M1 vaccination was significantly higher compared to ChAdOx1 NP+M1. In a mixed regression model, T-cell responses over 18months were significantly higher following the two dose vaccination regimen of MVA/ChAdOx1 NP+M1.
A two dose heterologous vaccination regimen of MVA/ChAdOx1 NP+M1 was safe and immunogenic in young and older adults, offering a promising vaccination strategy for inducing long-term broadly cross-reactive protection against influenza A.
Medical Research Council UK, NIHR BMRC Oxford.
•Heterologous prime-boost vaccination regimens of MVA/ChAdOx1 NP+M1 are safe and immunogenic in young and older adults•All MVA/ChAdOx1 NP+M1 regimens tested significantly increased cross-reactive T-cells•Responses were durable and were maintained 18 months after vaccination•The fold-increase after a single MVA-NP+M1 vaccination was significantly higher compared to ChAdOx1 NP+M1
Current seasonal influenza vaccines induce antibody responses to external glycoproteins, which are highly susceptible to the accumulation of mutations within antigenic sites, allowing escape from serological immunity conferred by prior infection or vaccination. In this phase I clinical study, we present the results of using two replication-deficient viral vectors expressing conserved influenza A antigens in four different vaccination regimens, administered at intervals of either 8weeks or one year. We found that vaccination was safe and boosted T cell responses to influenza antigens substantially, with a further increase after the second vaccination, both in young and older adults.
We report a new test of quantum electrodynamics (QED) for the w (1s2p(1)P(1)→1s(2)(1)S(0)) x-ray resonance line transition energy in heliumlike titanium. This measurement is one of few sensitive to ...two-electron QED contributions. Systematic errors such as Doppler shifts are minimized in our experiment by trapping and stripping Ti atoms in an electron beam ion trap and by applying absolute wavelength standards to calibrate the dispersion function of a curved-crystal spectrometer. We also report a more general systematic discrepancy between QED theory and experiment for the w transition energy in heliumlike ions for Z>20. When all of the data available in the literature for Z=16-92 are taken into account, the divergence is seen to grow as approximately Z(3) with a statistical significance on the coefficient that rises to the level of 5 standard deviations. Our result for titanium alone, 4749.85(7) eV for the w line, deviates from the most recent ab initio prediction by 3 times our experimental uncertainty and by more than 10 times the currently estimated uncertainty in the theoretical prediction.
Anterior mitral valve leaflet (AMVL) elongation is a recognised feature of hypertrophic cardiomyopathy (HCM). However, whether AMVL elongation precedes left ventricular hypertrophy in cats is ...currently unknown. The aim of this study was to explore the risk of developing an HCM phenotype in cats with an elongated AMVL.
This was a retrospective longitudinal study. Cats at the baseline were grouped based on whether or not they developed an HCM phenotype at follow-up. AMVL length and left atrial and left ventricular dimensions were measured from two-dimensional images.
The median follow-up period of the study population was 5.4 years (25th and 75th quartile, 2.7–6.7 years). During this time, 17 cats (30.9%) developed an HCM phenotype. At the baseline, cats that subsequently developed an HCM phenotype had greater AMVL length (9.4 mm 25th and 75th quartile, 9.0–10.6 mm vs. 8.5 mm 25th and 75th quartile, 7.6–9.1 mm, P < 0.0001) and maximal left ventricular wall thickness (4.5 mm 25th and 75th quartile, 4.1–4.7 mm vs. 4.0 mm 25th and 75th quartile, 3.7–4.6 mm, P = 0.007) than those that did not. Multiple logistic regression analysis confirmed that both baseline variables were independent predictors for development of an HCM phenotype.
The AMVL length was greater in cats that subsequently developed left ventricular hypertrophy. Further studies investigating the clinical application of AMVL in the natural history of feline HCM are warranted.
Background
Left ventricular (LV) systolic dysfunction is associated with increased risk of death in cats with hypertrophic cardiomyopathy (HCM). Mitral and tricuspid annular plane systolic excursion ...(MAPSE and TAPSE, respectively) are measures of longitudinal systolic function and are reduced in human patients with HCM.
Hypotheses
Cats with HCM have lower MAPSE and TAPSE compared to control cats; lower MAPSE and TAPSE are associated with the presence of congestive heart failure (CHF) and reduced survival time.
Animals
64 cats with HCM and 27 healthy cats. Forty‐five cats with HCM were not showing clinical signs, and 19 had CHF.
Methods
Retrospective study. Anatomic M‐mode from the left apical 4‐chamber view was used to record MAPSE from the free wall (MAPSE FW) and septum (MAPSE IVS) and TAPSE.
Results
Compared to controls, cats with HCM had lower MAPSE IVS (controls 5.2 4.6–5.6 mm, asymptomatic HCM 4.7 4.1–5.2 mm, HCM with CHF 2.6 2.5–3.2 mm, P < .001), MAPSE FW (controls 5.9 5.3–6.2 mm, asymptomatic HCM 4.7 4.1–5.1 mm, HCM with CHF 2.8 2.4–3.2 mm) and TAPSE (controls 8.6 7.4–10.2 mm, asymptomatic HCM 7.2 6.3–8.2 mm, HCM with CHF 4.6 4.1–5.4 mm), with the lowest in the CHF group. Univariate survival analysis showed a shorter survival in cats displaying lower MAPSE IVS, MAPSE FW, and TAPSE.
Conclusions and Clinical Importance
MAPSE and TAPSE were lower in cats with HCM than in control cats and were lowest in CHF, suggesting that systolic longitudinal dysfunction is present in cats with HCM. MAPSE and TAPSE have potential prognostic significance.
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