High-sensitivity cardiac troponin I (cTnI) assays hold promise in detecting the transition from hypertrophy to heart failure in aortic stenosis. We sought to investigate the mechanism for troponin ...release in patients with aortic stenosis and whether plasma cTnI concentrations are associated with long-term outcome.
Plasma cTnI concentrations were measured in two patient cohorts using a high-sensitivity assay. First, in the Mechanism Cohort, 122 patients with aortic stenosis (median age 71, 67% male, aortic valve area 1.0 ± 0.4 cm(2)) underwent cardiovascular magnetic resonance and echocardiography to assess left ventricular (LV) myocardial mass, function, and fibrosis. The indexed LV mass and measures of replacement fibrosis (late gadolinium enhancement) were associated with cTnI concentrations independent of age, sex, coronary artery disease, aortic stenosis severity, and diastolic function. In the separate Outcome Cohort, 131 patients originally recruited into the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact of REgression (SALTIRE) study, had long-term follow-up for the occurrence of aortic valve replacement (AVR) and cardiovascular deaths. Over a median follow-up of 10.6 years (1178 patient-years), 24 patients died from a cardiovascular cause and 60 patients had an AVR. Plasma cTnI concentrations were associated with AVR or cardiovascular death HR 1.77 (95% CI, 1.22 to 2.55) independent of age, sex, systolic ejection fraction, and aortic stenosis severity.
In patients with aortic stenosis, plasma cTnI concentration is associated with advanced hypertrophy and replacement myocardial fibrosis as well as AVR or cardiovascular death.
Two experiments (Exp.) were conducted to evaluate effects of a lysophospholipid-based bio-emulsifier (LPL) on growth performance, nutrient digestibility and energy utilization of broilers as well as ...the return on investment (ROI). In Exp. 1, 392 chicks were housed in battery cages in a completely randomized design with 8 treatments and 7 replicates of 7 birds each from d 0 to 21 posthatch. In Exp. 2, 1,400 chicks were allocated in floor pens and fed the same 8 treatments, with 7 replicates and 25 birds each from d 0 to 43 posthatch. Treatments consisted of 6 degummed soybean oil-based diets: positive control (PC1); PC1 formulated with 500 g/ton LPL (PC1+LPL on top); PC1 formulated with 60 kcal LPL matrix (PC1+LPL60); PC1 formulated with 100 kcal LPL matrix (PC1+LPL100); and two negative controls NC-60 and NC-100 with reductions of 60 and 100 kcal/kg ME, respectively. Two other diets were formulated with acid soybean oil: positive control (PC2) and PC2 formulated with 60 kcal LPL matrix (PC2+LPL60). In Exp. 1, performance was evaluated from d 0 to 21, ME and ileal digestibility of DM, CP and energy were determined on d 21. In Exp. 2, growth performance was evaluated from d 0 to 42, and on d 43 carcass and abdominal fat yields were calculated. There were no effects of soybean oil sources in any parameter. Inclusion of LPL increased (P < 0.05) BW gain and ileal digestibility of DM, fat and CP. Broilers fed the PC1+LPL on top diet had increased (P < 0.05) performance, ileal digestibility and energy utilization as well as decreased abdominal fat compared to NC-60 or NC-100. The use of LPL on top had a ROI of 8:1 vs. PC1, considering the gains in revenue of the slaughtered broilers in relation to the investment with LPL in feed. In conclusion, a lysophospholipid-based bio-emulsifier increased performance, digestibility and return on investment of broilers fed standard or reformulated diets.
Abstract The loss of bone mineral in NASA astronauts during spaceflight has been investigated throughout the more than 40 years of space travel. Consequently, it is a medical requirement at NASA ...Johnson Space Center (JSC) that changes in bone mass be monitored in crew members by measuring bone mineral density (BMD), with dual-energy X-ray absorptiometry (DXA) before and after flight, of astronauts who serve on long-duration missions (4–6 months). We evaluated this repository of medical data to track whether there is recovery of bone mineral that was lost during spaceflight. Our analysis was supplemented by BMD data from cosmonauts (by convention, a space traveler formally employed by the Russia Aviation and Space Agency or by the previous Soviet Union) who had also flown on long-duration missions. Data from a total of 45 individual crew members – a small number of whom flew on more than one mission – were used in this analysis. Changes in BMD (between 56 different sets of pre- and postflight measurements) were plotted as a function of time (days after landing). Plotted BMD changes were fitted to an exponential mathematical function that estimated: (i) BMD change on landing day (day 0) and (ii) the number of days after landing when 50% of the lost bone would be recovered (“50% recovery time”) in the lumbar spine, trochanter, pelvis, femoral neck and calcaneus. In sum, averaged losses of bone mineral after long-duration spaceflight ranged between 2% and 9% across all sites with our recovery model predicting a 50% restoration of bone loss for all sites to be within 9 months.
Background. The efficacy of bacille Calmette-Guérin (BCG) may be enhanced by heterologous vaccination strategies that boost the BCG-primed immune response. One leading booster vaccine, MVA85A (where ...“MVA” denotes “modified vaccinia virus Ankara”), has shown promising safety and immunogenicity in human trials performed in the United Kingdom. We investigated the safety and immunogenicity of MVA85A in mycobacteria-exposed—but Mycobacterium tuberculosis-uninfected—healthy adults from a region of South Africa where TB is endemic. Methods. Twenty-four adults were vaccinated with MVA85A. All subjects were monitored for 1 year for adverse events and for immunological assessment. Results. MVA85A vaccination was well tolerated and induced potent T cell responses, as measured by interferon (IFN)-γ enzyme-linked immunospot assay, which exceeded prevaccination responses up to 364 days after vaccination. BCG-specific CD4+ T cells boosted by MVA85A were comprised of multiple populations expressing combinations of IFN-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and IL-17, as measured by polychromatic flow cytometry. IFN-γ-expressing and polyfunctional IFN-γ+TNF-α+IL-2+ CD4+ T cells were boosted during the peak BCG-specific response, which occurred 7 days after vaccination. Conclusion. The excellent safety profile and quantitative and qualitative immunogenicity data strongly support further trials assessing the efficacy of MVA85A as a boosting vaccine in countries where TB is endemic. Trial registration. ClinicalTrials.gov identifier: NCT00460590.
We present a catalog of 9017 X-ray sources identified in Chandra observations of a 2°X 08 field around the Galactic center. This enlarges the number of known X-ray sources in the region by a factor ...of 2.5. The catalog incorporates all of the ACIS-I observations as of 2007 August, which total 2.25 Ms of exposure. At the distance to the Galactic center (8 kpc), we are sensitive to sources with luminosities of 4 X 1032 erg s-1 (0.5-8.0 keV; 90% confidence) over an area of 1 deg2, and up to an order of magnitude more sensitive in the deepest exposure (1.0 Ms) around Sgr A*. The positions of 60% of our sources are accurate to <1 '' (95% confidence), and 20% have positions accurate to <05. We search for variable sources, and find that 3% exhibit flux variations within an observation, and 10% exhibit variations from observation-to-observation. We also find one source, CXOUGC J174622.7 - 285218, with a periodic 1745 s signal (1.4% chance probability), which is probably a magnetically accreting cataclysmic variable. We compare the spatial distribution of X-ray sources to a model for the stellar distribution, and find 2.8s evidence for excesses in the numbers of X-ray sources in the region of recent star formation encompassed by the Arches, Quintuplet, and Galactic center star clusters. These excess sources are also seen in the luminosity distribution of the X-ray sources, which is flatter near the Arches and Quintuplet than elsewhere in the field. These excess point sources, along with a similar longitudinal asymmetry in the distribution of diffuse iron emission that has been reported by other authors, probably have their origin in the young stars that are prominent at l 01.
BACKGROUND:Chronic kidney disease (CKD) increases cardiovascular risk. Underlying mechanisms, however, remain obscure. The uremic toxin indoxyl sulfate is an independent cardiovascular risk factor in ...CKD. We explored the potential impact of indoxyl sulfate on proinflammatory activation of macrophages and its underlying mechanisms.
METHODS:We examined in vitro the effects of clinically relevant concentrations of indoxyl sulfate on proinflammatory responses of macrophages and the roles of organic anion transporters and organic anion transporting polypeptides (OATPs). A systems approach, involving unbiased global proteomics, bioinformatics, and network analysis, then explored potential key pathways. To address the role of Delta-like 4 (Dll4) in indoxyl sulfate–induced macrophage activation and atherogenesis in CKD in vivo, we used 5/6 nephrectomy and Dll4 antibody in low-density lipoprotein receptor–deficient (Ldlr-/-) mice. To further determine the relative contribution of OATP2B1 or Dll4 to proinflammatory activation of macrophages and atherogenesis in vivo, we used siRNA delivered by macrophage-targeted lipid nanoparticles in mice.
RESULTS:We found that indoxyl sulfate–induced proinflammatory macrophage activation is mediated by its uptake through transporters, including OATP2B1, encoded by the SLCO2B1 gene. The global proteomics identified potential mechanisms, including Notch signaling and the ubiquitin-proteasome pathway, that mediate indoxyl sulfate-triggered proinflammatory macrophage activation. We chose the Notch pathway as an example of key candidates for validation of our target discovery platform and for further mechanistic studies. As predicted computationally, indoxyl sulfate triggered Notch signaling, which was preceded by the rapid induction of Dll4 protein. Dll4 induction may result from inhibition of the ubiquitin-proteasome pathway, via the deubiquitinating enzyme USP5. In mice, macrophage-targeted OATP2B1/Slco2b1 silencing and Dll4 antibody inhibited proinflammatory activation of peritoneal macrophages induced by indoxyl sulfate. In low-density lipoprotein receptor–deficient mice, Dll4 antibody abolished atherosclerotic lesion development accelerated in Ldlr-/- mice. Moreover, coadministration of indoxyl sulfate and OATP2B1/Slco2b1 or Dll4 siRNA encapsulated in macrophage-targeted lipid nanoparticles in Ldlr-/- mice suppressed lesion development.
CONCLUSIONS:These results suggest that novel crosstalk between OATP2B1 and Dll4-Notch signaling in macrophages mediates indoxyl sulfate–induced vascular inflammation in CKD.
Inflammation following acute myocardial infarction (MI) has detrimental effects on reperfusion, myocardial remodelling, and ventricular function. Magnetic resonance imaging using ultrasmall ...superparamagnetic particles of iron oxide can detect cellular inflammation in tissues, and we therefore explored their role in acute MI in humans.
Sixteen patients with acute ST-segment elevation MI were recruited to undergo 3 sequential magnetic resonance scans within 5 days of admission at baseline, 24 and 48 hours following no infusion (controls; n=6) or intravenous infusion of ultrasmall superparamagnetic particles of iron oxide (n=10; 4 mg/kg). T2*-weighted multigradient-echo sequences were acquired and R2* values were calculated for specific regions of interest. In the control group, R2* values remained constant in all tissues across all scans with excellent repeatability (bias of -0.208 s(-1), coefficient of repeatability of 26.96 s(-1); intraclass coefficient 0.989). Consistent with uptake by the reticuloendothelial system, R2* value increased in the liver (84±49.5 to 319±70.0 s(-1); P<0.001) but was unchanged in skeletal muscle (54±8.4 to 67.0±9.5 s(-1); P>0.05) 24 hours after administration of ultrasmall superparamagnetic particles of iron oxide. In the myocardial infarct, R2* value increased from 41.0±12.0 s(-1) (baseline) to 155±45.0 s(-1) (P<0.001) and 124±35.0 s(-1) (P<0.05) at 24 and 48 hours, respectively. A similar but lower magnitude response was seen in the remote myocardium, where it increased from 39±3.2 s(-1) (baseline) to 80±14.9 s(-1) (P<0.001) and 67.0±15.7 s(-1) (P<0.05) at 24 and 48 hours, respectively.
Following acute MI, uptake of ultrasmall superparamagnetic particles of iron oxide occurs with the infarcted and remote myocardium. This technique holds major promise as a potential method for assessing cellular myocardial inflammation and left ventricular remodelling, which may have a range of applications in patients with MI and other inflammatory cardiac conditions.
CONTEXT African American adolescent girls are at high risk for human immunodeficiency
virus (HIV) infection, but interventions specifically designed for this population
have not reduced HIV risk ...behaviors. OBJECTIVE To evaluate the efficacy of an intervention to reduce sexual risk behaviors,
sexually transmitted diseases (STDs), and pregnancy and enhance mediators
of HIV-preventive behaviors. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial of 522 sexually experienced African American
girls aged 14 to 18 years screened from December 1996 through April 1999 at
4 community health agencies. Participants completed a self-administered questionnaire
and an interview, demonstrated condom application skills, and provided specimens
for STD testing. Outcome assessments were made at 6- and 12-month follow-up. INTERVENTION All participants received four 4-hour group sessions. The intervention
emphasized ethnic and gender pride, HIV knowledge, communication, condom use
skills, and healthy relationships. The comparison condition emphasized exercise
and nutrition. MAIN OUTCOME MEASURES The primary outcome measure was consistent condom use, defined as condom
use during every episode of vaginal intercourse; other outcome measures were
sexual behaviors, observed condom application skills, incident STD infection,
self-reported pregnancy, and mediators of HIV-preventive behaviors. RESULTS Relative to the comparison condition, participants in the intervention
reported using condoms more consistently in the 30 days preceding the 6-month
assessment (unadjusted analysis, intervention, 75.3% vs comparison, 58.2%)
and the 12-month assessment (unadjusted analysis, intervention, 73.3% vs comparison,
56.5%) and over the entire 12-month period (adjusted odds ratio, 2.01; 95%
confidence interval CI, 1.28-3.17; P = .003). Participants
in the intervention reported using condoms more consistently in the 6 months
preceding the 6-month assessment (unadjusted analysis, intervention, 61.3%
vs comparison, 42.6%), at the 12-month assessment (unadjusted analysis, intervention,
58.1% vs comparison, 45.3%), and over the entire 12-month period (adjusted
odds ratio, 2.30; 95% CI, 1.51-3.50; P<.001).
Using generalized estimating equation analyses over the 12-month follow-up,
adolescents in the intervention were more likely to use a condom at last intercourse,
less likely to have a new vaginal sex partner in the past 30 days, and more
likely to apply condoms to sex partners and had better condom application
skills, a higher percentage of condom-protected sex acts, fewer unprotected
vaginal sex acts, and higher scores on measures of mediators. Promising effects
were also observed for chlamydia infections and self-reported pregnancy. CONCLUSION Interventions for African American adolescent girls that are gender-tailored
and culturally congruent can enhance HIV-preventive behaviors, skills, and
mediators and may reduce pregnancy and chlamydia infection.
CONTEXT TGFBR1*6A is a common polymorphism of the type
I transforming growth factor β receptor (TGFBR1).
Epidemiological studies suggest that TGFBR1*6A may
act as a tumor susceptibility allele. How ...TGFBR1*6A
contributes to cancer development is largely unknown. OBJECTIVES To determine whether TGFBR1*6A is somatically
acquired by primary tumors and metastases during cancer development and whether
the 3–amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor
or part of the signal sequence and to investigate TGFBR1*6A signaling in cancer cells. DESIGN, SETTING, AND PATIENTS Tumor and germline tissues from 531 patients with a diagnosis of head
and neck, colorectal, or breast cancer recruited from 3 centers in the United
States and from 1 center in Spain from June 1, 1994, through June 30, 2004.
In vitro translation assays, MCF-7 breast cancer cells stably transfected
with TGFBR1*6A, TGFBR1, or the vector alone, DLD-1
colorectal cancer cells that endogenously carry TGFBR1*6A, and SW48 colorectal cancer cells that do not carry TGFBR1*6A. MAIN OUTCOME MEASURES TGFBR1*6A somatic acquisition in cancer. Determination
of the amino terminus of the mature TGFBR1*6A and TGFBR1 receptors. Determination
of TGF-β–dependent cell proliferation. RESULTS TGFBR1*6A was somatically acquired in 13 of
44 (29.5%) colorectal cancer metastases, in 4 of 157 (2.5%) of colorectal
tumors, in 4 of 226 (1.8%) head and neck primary tumors, and in none of the
104 patients with breast cancer. TGFBR1*6A somatic
acquisition is not associated with loss of heterozygosity, microsatellite
instability, or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A
are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A may switch TGF-β growth inhibitory signals
into growth stimulatory signals in MCF-7 breast cancer cells and in DLD-1
colorectal cancer cells. CONCLUSIONS TGFBR1*6A is somatically acquired in 29.5%
of liver metastases from colorectal cancer and may bestow cancer cells with
a growth advantage in the presence of TGF-β. The functional consequences
of this conversion appear to be mediated by the TGFBR1*6A signal sequence
rather than by the mature receptor. The results highlight a new facet of TGF-β
signaling in cancer and suggest that TGFBR1*6A may
represent a potential therapeutic target in cancer.
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