Cardiac endothelial cells (ECs) are important targets for cardiovascular gene therapy. However, the approach of stably transducing ECs in vivo using different vectors, including adeno-associated ...virus (AAV), remains unexamined. Regarding this unmet need, two AAV libraries from DNA shuffling and random peptide display were simultaneously screened in a transgenic mouse model. Cardiac ECs were isolated by cell sorting for salvage of EC-targeting AAV. Two AAV variants, i.e., EC71 and EC73, enriched in cardiac EC, were further characterized for their tissue tropism. Both of them demonstrated remarkably enhanced transduction of cardiac ECs and reduced infection of liver ECs in comparison to natural AAVs after intravenous injection. Significantly, persistent transgene expression was maintained in mouse cardiac ECs in vivo for at least 4 months. The EC71 vector was selected for delivery of the endothelial nitric oxide synthase (eNOS) gene into cardiac ECs in a mouse model of myocardial infarction. Enhanced eNOS activity was observed in the mouse heart and lung, which was correlated with partially improved cardiac function. Taken together, two AAV capsids were evolved with more efficient transduction in cardiovascular endothelium in vivo, but their endothelial tropism might need to be further optimized for practical application to cardiac gene therapy.
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Liu et al. used a transgenic mouse model for the evolution of adeno-associated virus targeting cardiac endothelial cells. The selected vectors can mediate long-term endothelial transgene expression in mice, which provides a plausible approach for engineering gene therapy vectors targeting rare cell types in vivo.
Prenatal phthalate exposure impairs testicular function and shortens anogenital distance (AGD) in male rodents. We present data from the first study to examine AGD and other genital measurements in ...relation to prenatal phthalate exposure in humans. A standardized measure of AGD was obtained in 134 boys 2-36 months of age. AGD was significantly correlated with penile volume (R = 0.27, p = 0.001) and the proportion of boys with incomplete testicular descent (R = 0.20, p = 0.02). We defined the anogenital index (AGI) as AGD divided by weight at examination AGI = AGD/weight (mm/kg) and calculated the age-adjusted AGI by regression analysis. We examined nine phthalate monoester metabolites, measured in prenatal urine samples, as predictors of age-adjusted AGI in regression and categorical analyses that included all participants with prenatal urine samples (n = 85). Urinary concentrations of four phthalate metabolites monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), and monoisobutyl phthalate (MiBP) were inversely related to AGI. After adjusting for age at examination, p-values for regression coefficients ranged from 0.007 to 0.097. Comparing boys with prenatal MBP concentration in the highest quartile with those in the lowest quartile, the odds ratio for a shorter than expected AGI was 10.2 (95% confidence interval, 2.5 to 42.2). The corresponding odds ratios for MEP, MBzP, and MiBP were 4.7, 3.8, and 9.1, respectively (all p-values < 0.05). We defined a summary phthalate score to quantify joint exposure to these four phthalate metabolites. The age-adjusted AGI decreased significantly with increasing phthalate score (p-value for slope = 0.009). The associations between male genital development and phthalate exposure seen here are consistent with the phthalate-related syndrome of incomplete virilization that has been reported in prenatally exposed rodents. The median concentrations of phthalate metabolites that are associated with short AGI and incomplete testicular descent are below those found in one-quarter of the female population of the United States, based on a nationwide sample. These data support the hypothesis that prenatal phthalate exposure at environmental levels can adversely affect male reproductive development in humans.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In the phase III MPACT trial, nab-paclitaxel plus gemcitabine (nab-P + Gem) demonstrated superior efficacy versus Gem alone for patients with metastatic pancreatic cancer. We sought to examine the ...feasibility of positron emission tomography (PET) and to compare metabolic response rates and associated correlations with efficacy in the MPACT trial.
Patients with previously untreated metastatic adenocarcinoma of the pancreas were randomized 1:1 to receive nab-P + Gem or Gem alone. Treatment continued until disease progression by RECIST or unacceptable toxicity.
PET scans were carried out on the first 257 patients enrolled at PET-equipped centers (PET cohort). Most patients (252 of 257) had ≥2 PET-avid lesions, and median maximum standardized uptake values at baseline were 4.6 and 4.5 in the nab-P + Gem and Gem-alone arms, respectively. In a pooled treatment arm analysis, a metabolic response by PET (best response at any time during study) was associated with longer overall survival (OS) (median 11.3 versus 6.9 months; HR, 0.56; P < 0.001). Efficacy results within each treatment arm appeared better for patients with a metabolic response. The metabolic response rate (best response and week 8 response) was higher for nab-P + Gem (best response: 72% versus 53%, P = 0.002; week 8: 67% versus 51%; P = 0.014). Efficacy in the PET cohort was greater for nab-P + Gem versus Gem alone, including for OS (median 10.5 versus 8.4 months; hazard ratio HR, 0.71; P = 0.009) and ORR by RECIST (31% versus 11%; P < 0.001).
Pancreatic lesions were PET avid at baseline, and the rate of metabolic response was significantly higher for nab-P + Gem versus Gem alone at week 8 and for best response during study. Having a metabolic response was associated with longer survival, and more patients experienced a metabolic response than a RECIST-defined response.
NCT00844649.
CONTEXT Respiratory syncytial virus (RSV) causes more lower respiratory tract
infections, often manifested as bronchiolitis, among young children than any
other pathogen. Few national estimates exist ...of the hospitalizations attributable
to RSV, and recent advances in prophylaxis warrant an update of these estimates. OBJECTIVES To describe rates of bronchiolitis-associated hospitalizations and to
estimate current hospitalizations associated with RSV infection. DESIGN AND SETTING Descriptive analysis of US National Hospital Discharge Survey data from
1980 through 1996. PARTICIPANTS Children younger than 5 years who were hospitalized in short-stay, nonfederal
hospitals for bronchiolitis. MAIN OUTCOME MEASURE Bronchiolitis-associated hospitalization rates by age and year. RESULTS During the 17-year study period, an estimated 1.65 million hospitalizations
for bronchiolitis occurred among children younger than 5 years, accounting
for 7.0 million inpatient days. Fifty-seven percent of these hospitalizations
occurred among children younger than 6 months and 81% among those younger
than 1 year. Among children younger than 1 year, annual bronchiolitis hospitalization
rates increased 2.4-fold, from 12.9 per 1000 in 1980 to 31.2 per 1000 in 1996.
During 1988-1996, infant hospitalization rates for bronchiolitis increased
significantly (P for trend <.001), while hospitalization
rates for lower respiratory tract diseases excluding bronchiolitis did not
vary significantly (P for trend = .20). The proportion
of hospitalizations for lower respiratory tract illnesses among children younger
than 1 year associated with bronchiolitis increased from 22.2% in 1980 to
47.4% in 1996; among total hospitalizations, this proportion increased from
5.4% to 16.4%. Averaging bronchiolitis hospitalizations during 1994-1996 and
assuming that RSV was the etiologic agent in 50% to 80% of November through
April hospitalizations, an estimated 51,240 to 81,985 annual bronchiolitis
hospitalizations among children younger than 1 year were related to RSV infection. CONCLUSIONS During 1980-1996, rates of hospitalization of infants with bronchiolitis
increased substantially, as did the proportion of total and lower respiratory
tract hospitalizations associated with bronchiolitis. Annual bronchiolitis
hospitalizations associated with RSV infection among infants may be greater
than previous estimates for RSV bronchiolitis and pneumonia hospitalizations
combined.
To determine the most accurate and reproducible semi-automated greyscale thresholding technique for quantifying late gadolinium enhancement (LGE) in cardiovascular magnetic resonance imaging (CMRI), ...by using positron-emission tomography (PET) as the reference standard in patients with coronary artery chronic total occlusion (CTO).
LGE in CMRI, single-photon-emission computed tomography (SPECT), and PET were performed within 1 week in each of 63 patients with known CTO. The presence and quantity of LGE were determined with greyscale thresholds of 2, 4, 5, 6, and 8 standard deviations (SDs) above the mean signal intensity for normal remote myocardium and full width at half maximum (FWHM). The infarcted myocardium was delineated by PET.
Sixty-three patients and 1,008 segments were analysed. Based on patient analysis, with PET as the reference standard, the 5 SD method yielded the strongest correlation (r=0.85, p<0.0001) compared with the 2 SDs (r=0.42), 4 SDs (r=0.73), 6 SDs (r=0.81), 8 SDs (r=0.71), and FWHM (r=0.69; p<0.001 for all comparisons). The 5 SDs threshold quantification showed high interobserver and intra-observer agreement (intraclass correlation coefficient ICC=0.90, p<0.0001; ICC=0.93, p<0.0001, respectively).
Semi-automated LGE CMRI greyscale thresholding with 5 SDs above the mean signal intensity for normal remote myocardium yields the strongest correlation to the extent of LGE identified using PET and is highly reproducible in patients with CTO.
•LGE CMR with 5 SDs yields the strongest correlation with PET in CTO.•LGE CMR with 5 SDs is highly reproducible in patients with CTO.•LGE CMR with 5 SDs should be considered for quantifying LGE in patients with CTO.
We report on the coherent optical excitation of electron spin polarization in the ground state of charged GaAs quantum dots via an intermediate charged exciton (trion) state. Coherent optical fields ...are used for the creation and detection of the Raman spin coherence between the spin ground states of the charged quantum dot. The measured spin decoherence time, which is likely limited by the nature of the spin ensemble, approaches 10 ns at zero field. We also show that the Raman spin coherence in the quantum beats is caused not only by the usual stimulated Raman interaction but also by simultaneous spontaneous radiative decay of either excited trion state to a coherent combination of the two spin states.
Magnetic nanoparticles of nickel ferrite (NiFe
2O
4) have been synthesized by co-precipitation route using stable ferric and nickel salts with sodium hydroxide as the precipitating agent and oleic ...acid as the surfactant. X-ray diffraction (XRD) and transmission electron microscope (TEM) analyses confirmed the formation of single-phase nickel ferrite nanoparticles in the range 8–28
nm depending upon the annealing temperature of the samples during the synthesis. The size of the particles (
d) was observed to be increasing linearly with annealing temperature of the sample while the coercivity with particle size goes through a maximum, peaking at ∼11
nm and then decreases for larger particles. Typical blocking effects were observed below ∼225
K for all the prepared samples. The superparamagnetic blocking temperature (
T
B
) was found to be increasing with increasing particle size that has been attributed to the increased effective anisotropy energy of the nanoparticles. The saturation moment of all the samples was found much below the bulk value of nickel ferrite that has been attributed to the disordered surface spins or dead/inert layer in these nanoparticles.
Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women ...to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
A mechanistic model was developed to examine how natural ventilation influences residential indoor exposure to semivolatile organic compounds (SVOCs) via inhalation, dermal sorption, and dust ...ingestion. The effect of ventilation on indoor particle mass concentration and mass transfer at source/sink surfaces, and the enhancing effect of particles on mass transfer at source/sink surfaces are included. When air exchange rate increases from 0.6/h to 1.8/h, the steady‐state SVOC (gas‐phase plus particle phase with log KOA varying from 9 to 13) concentration in the idealized model decreases by about 60%. In contrast, for the same change in ventilation, the simulated indoor formaldehyde (representing volatile organic compounds) gas‐phase concentration decreases by about 70%. The effect of ventilation on exposure via each pathway has a relatively insignificant association with the KOA of the SVOCs: a change of KOA from 109 to 1013 results in a change of only 2–30%. Sensitivity analysis identifies the deposition rate of PM2.5 as a primary factor influencing the relationship between ventilation and exposure for SVOCs with log KOA = 13. The relationship between ventilation rate and air speed near surfaces needs to be further substantiated.
Abstract
In order to improve the equalization control efficiency of the battery charge equalization system, this paper applies the double closed-loop controller to the battery charge automatic ...equalization system. First, the overall block diagram of the hardware circuit of the charging system is designed, and the switching control of charging and discharging is completed by using TMS320F2812 chip. Secondly, the optimal charging current is calculated according to Mars law. Then, a double closed-loop controller is introduced to balance the battery charge, and the charge balance equation is constructed and solved. Finally, the adjusted parameters are obtained to realize the automatic charging equalization control. The experimental results show that the equalization control time of this method is always within 25s, which indicates that its charge equalization control effect is good.
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