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OBJECTIVES/SPECIFIC AIMS: Treatment of acute myeloid leukemia (AML) is challenging, as apoptosis-resistant AML cells often persist within the bone marrow microenvironment despite chemotherapy. The overall goal of our laboratory is to identify and ultimately target the bone marrow factors that protect AML cells. METHODS/STUDY POPULATION: Using cell cultures, we previously reported that SDF-1 (CXCL12), an abundant bone marrow chemokine, induces apoptosis of isolated CXCR4+ AML cells, including freshly isolated bone marrow-derived AML cells from approximately one-third of AML patients. However, co-culture of AML cells with differentiating osteoblasts protected AML cells from apoptosis. RESULTS/ANTICIPATED RESULTS: Histone deacetylase inhibitors (HDACi) abrogated the ability of osteoblasts to protect AML cells and altered expression of matrix mineralization genes including tissue nonspecific alkaline phosphatase (TNAP). A different drug, cyclosporine A (CSA), similarly inhibited osteoblast-mediated protection of AML cells and reduced TNAP expression. Specifically targeting osteoblast TNAP via siRNA was sufficient to prevent osteoblasts from protecting AML cells in co-cultures. In addition, we are targeting TNAP enzymatically. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results indicate that targeting TNAP may be useful in AML treatment to render the bone marrow microenvironment more hostile to leukemic cell survival.
Little is known about the association of cortical Aβ with depression and anxiety among cognitively normal (CN) elderly persons.
We conducted a cross-sectional study derived from the population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota; involving CN persons aged ≥ 60 years that underwent PiB-PET scans and completed Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI). Cognitive diagnosis was made by an expert consensus panel. Participants were classified as having abnormal (≥1.4; PiB+) or normal PiB-PET (<1.4; PiB−) using a global cortical to cerebellar ratio. Multi-variable logistic regression analyses were performed to calculate odds ratios (OR) and 95% confidence intervals (95% CI) after adjusting for age and sex.
Of 1,038 CN participants (53.1% males), 379 were PiB+. Each one point symptom increase in the BDI (OR = 1.03; 1.00–1.06) and BAI (OR = 1.04; 1.01–1.08) was associated with increased odds of PiB-PET+. The number of participants with BDI > 13 (clinical depression) was greater in the PiB-PET+ than PiB-PET- group but the difference was not significant (OR = 1.42; 0.83–2.43). Similarly, the number of participants with BAI > 10 (clinical anxiety) was greater in the PiB-PET+ than PiB-PET− group but the difference was not significant (OR = 1.77; 0.97–3.22).
As expected, depression and anxiety levels were low in this community-dwelling sample, which likely reduced our statistical power. However, we observed an informative albeit weak association between increased BDI and BAI scores and elevated cortical amyloid deposition. This observation needs to be tested in a longitudinal cohort study.
Potassium titanyl phosphate crystals in both x-cut and z-cut were irradiated with 185 MeV Au ions. The morphology of the resulting ion tracks was investigated using small angle x-ray scattering (SAXS), transmission electron microscopy (TEM), and atomic force microscopy (AFM). SAXS measurements indicate the presence of cylindrical ion tracks with abrupt boundaries and a density contrast of 1 ± 0.5% compared to the surrounding matrix, consistent with amorphous tracks. The track radius depends on the crystalline orientation, with 6.0 ± 0.1 nm measured for ion tracks along the x-axis and 6.3 ± 0.1 nm for those along the z-axis. TEM images in both cross-section and plan-view show amorphous ion tracks with radii comparable to those determined from SAXS analysis. The protruding hillocks covering the sample surface detected by AFM are consistent with a lower density of the amorphous material within the ion tracks compared to the surrounding matrix. Simulations using an inelastic thermal-spike model indicate that differences in the thermal conductivity along the z- and x-axis can partially explain the different track radii along these directions.
The importance of chronic low-grade inflammation in the pathology of numerous age-related chronic conditions is now clear. An unresolved inflammatory response is likely to be involved from the early stages of disease development. The present position paper is the most recent in a series produced by the International Life Sciences Institute's European Branch (ILSI Europe). It is co-authored by the speakers from a 2013 workshop led by the Obesity and Diabetes Task Force entitled ‘Low-grade inflammation, a high-grade challenge: biomarkers and modulation by dietary strategies’. The latest research in the areas of acute and chronic inflammation and cardiometabolic, gut and cognitive health is presented along with the cellular and molecular mechanisms underlying inflammation–health/disease associations. The evidence relating diet composition and early-life nutrition to inflammatory status is reviewed. Human epidemiological and intervention data are thus far heavily reliant on the measurement of inflammatory markers in the circulation, and in particular cytokines in the fasting state, which are recognised as an insensitive and highly variable index of tissue inflammation. Potential novel kinetic and integrated approaches to capture inflammatory status in humans are discussed. Such approaches are likely to provide a more discriminating means of quantifying inflammation–health/disease associations, and the ability of diet to positively modulate inflammation and provide the much needed evidence to develop research portfolios that will inform new product development and associated health claims.
The National Healthcare Safety Network surgical site infections risk models for hip (HPRO) and knee (KPRO) replacement are intended for case-mix adjustment when reporting surgical site infection rates across institutions, but they are not validated in external data sets
To evaluate the validity of HPRO and KPRO risk models and improvement in risk prediction with inclusion of information on morbid obesity and diabetes mellitus.
Retrospective cohort study.
A single-center cohort of 21,941 hip and knee replacement procedures performed between 2002 and 2009.
Discriminative ability was assessed using the concordance statistic (C statistic). Calibration was assessed using the Hosmer-Lemeshow goodness-of-fit tests.
The discrimination of HPRO was good, with a C statistic of 0.695 for surgical site infections and 0.749 for prosthetic joint infections. The discrimination of KPRO was worse than that of HPRO, with a C statistic of 0.592 for surgical site infections and 0.675 for prosthetic joint infections. Adding morbid obesity and diabetes mellitus to the HPRO and KPRO risk models modestly improved discrimination. There was no significant evidence of miscalibration based on the Hosmer-Lemeshow tests, but calibration of HPRO models appeared to be better than that of the KPRO models.
HPRO performed better than the KPRO in predicting surgical site infections after hip and knee replacements. Both fared well in predicting prosthetic joint infections.
Infect Control Hosp Epidemiol 2014;35(11):1323–1329
Soil microbial community structure and activity are linked to plant communities. Weeds may alter their soil environment, selecting for specific rhizosphere microbial communities. Rhizosphere modification occurs for many crop and horticultural plants. However, impacts of weeds in agroecosystems on soil biology and ecology have received less attention because effective weed management practices were developed to minimize their impacts on crop production. The recent development of herbicide resistance (HR) in several economically important weeds leading to widespread infestations in crop fields treated with a single herbicide has prompted a re-evaluation of the effects of weed growth on soil biology and ecology. The objective of this article is to review the potential impacts of herbicide-resistant weeds on soil biological and ecological properties based on reports for crops, weeds, and invasive plants. Persistent weed infestations likely establish extensive root systems and release various plant metabolites through root exudation. Many exudates are selective for specific soil microbial groups mediating biochemical and nutrient acquisition processes. Exudates may stimulate development of microbial groups beneficial to weed but detrimental to crop growth or beneficial to both. Changes in symbiotic and associative microbial interactions occur, especially for arbuscular mycorrhizal fungi (AMF) that are important in plant uptake of nutrients and water, and protecting from phytopathogens. Mechanisms used by weeds to disrupt symbioses in crops are not clearly described. Many herbicide-resistant weeds including Amaranthus and Chenopodium do not support AMF symbioses, potentially reducing AMF propagule density and establishment with crop plants. Herbicides applied to control HR weeds may compound effects of weeds on soil microorganisms. Systemic herbicides released through weed roots may select microbial groups that mediate detrimental processes such as nutrient immobilization or serve as opportunistic pathogens. Understanding complex interactions of weeds with soil microorganisms under extensive infestations is important in developing effective management of herbicide-resistant weeds.
Greenhouse and laboratory experiments were conducted on common waterhemp and soil collected from 131 soybean fields in Missouri that contained late-season common waterhemp escapes. The objectives of these experiments were to determine the effects of soil sterilization on glyphosate-resistant (GR) and -susceptible (GS) common waterhemp survival, to determine the effects of soil sterilization and glyphosate treatment on infection of GR and GS common waterhemp biotypes by Fusarium spp., and to determine the soil microbial abundance and diversity in soils collected from soybean fields with differences in common waterhemp biotypes and herbicide and crop rotation histories. Common waterhemp biotypes were treated with 1.7 kg glyphosate ae ha−1 or left untreated once plants reached approximately 15 cm in height. Common waterhemp survival was visually assessed at 21 d after glyphosate treatment (21 DAT). To determine Fusarium infection frequency, a single intact common waterhemp root was harvested from each treatment at 0, 3, 7, 14, and 21 DAT and surface sterilized, and 10 to 15–mm common waterhemp root sections were plated on Komada culture medium. After 14 d incubation, fungal colonies were selected from colonized roots and maintained on potato dextrose agar medium amended with antibiotics before identification. Speciation of Fusarium isolates was conducted through microscopic examination of fungal characters and confirmed by sequencing and analysis of ribosomal DNA. Soil samples from 131 different collections were subjected to phospholipid fatty acid (PLFA) analysis and were conducted utilizing gas chromatography to determine the soil microbial community abundance and structure. Common waterhemp plants grown in sterile soils had the highest common waterhemp survival, regardless of biotype. After treatment with glyphosate, survival of GS common waterhemp grown in nonsterile soil was only 29% 21 DAT, whereas survival of GS common waterhemp grown in nonsterile soil was only 10%. Similarly, GR common waterhemp survival was reduced from 83 to 61% following treatment with glyphosate when grown in nonsterile compared to sterile soil. Fusarium spp. were recovered from only 12% of the assayed roots (223 treatments with Fusarium out of a total 1,920 treatments). The greatest occurrence of Fusarium root infection in both GR and GS common waterhemp occurred in nonsterile soils following a glyphosate treatment. Few differences in total PLFA were observed in field soil collected from locations with either GR or GS common waterhemp, and regardless of herbicide or crop history. This research supports previous findings that plant species are more sensitive to glyphosate in nonsterile than sterile soils and indicates glyphosate may predispose plants to soil-borne phytopathogens. This research also suggests that continuous use of glyphosate does not significantly affect soil microbial abundance or diversity.
It has been postulated that aging is the consequence of an accelerated accumulation of somatic DNA mutations and that subsequent errors in the primary structure of proteins ultimately reach levels sufficient to affect organismal functions. The technical limitations of detecting somatic changes and the lack of insight about the minimum level of erroneous proteins to cause an error catastrophe hampered any firm conclusions on these theories. In this study, we sequenced the whole genome of DNA in whole blood of two pairs of monozygotic (MZ) twins, 40 and 100 years old, by two independent next-generation sequencing (NGS) platforms (Illumina and Complete Genomics). Potentially discordant single-base substitutions supported by both platforms were validated extensively by Sanger, Roche 454, and Ion Torrent sequencing. We demonstrate that the genomes of the two twin pairs are germ-line identical between co-twins, and that the genomes of the 100-year-old MZ twins are discerned by eight confirmed somatic single-base substitutions, five of which are within introns. Putative somatic variation between the 40-year-old twins was not confirmed in the validation phase. We conclude from this systematic effort that by using two independent NGS platforms, somatic single nucleotide substitutions can be detected, and that a century of life did not result in a large number of detectable somatic mutations in blood. The low number of somatic variants observed by using two NGS platforms might provide a framework for detecting disease-related somatic variants in phenotypically discordant MZ twins.
Ecologically based farming conserves and improves the soil resource and protects environmental quality by using organic or natural resources without the application of synthetic chemicals. Soil quality assessment indicates the ability of management systems to optimize soil productivity and to maintain its structural and biological integrity. Our objective was to evaluate the effect of ecologically based management on biochemical characteristics of soil [soil quality indicators (SQI)] as an assessment of soil quality. The study was conducted on an ecologically based farming enterprise established on gently sloping soils of Sharpsburg silt loam (fine montmorillonitic, mesic Typic Argiudolls) in Clay County, Missouri, which was previously under conventional corn and soybean production. The transition to organic farming began in 1995, which included a primary management strategy to restore soil organic matter consisting of the establishment of native prairie plants and the application of composted vegetative residues and litter from horse and laying hen operations. Soils were collected at 0–10cm depths from sites under organic production (orchard and vegetable), managed prairie/pasture and from adjacent unmanaged fields during 2003–2008 for soil quality assessment. Soil organic carbon (SOC) and water-stable soil aggregates were considerably increased by up to 60 and 72%, respectively, in organic production sites compared with tilled cropland by the fifth year of assessment. Organically managed systems and restored prairie sites significantly increased (P<0.05) soil enzyme activities compared with unmanaged grass and tilled cropland. For example, dehydrogenase and glucosaminidase activities increased by 60 and 73%, respectively, under organic vegetables compared with tilled cropland. Soil enzyme activities were significantly correlated with SOC content (r values up to 0.90, P<0.001). The results of the soil quality assessment suggest that ecologically based management successfully restored biological activity of silt loam soils previously under intensive conventional agriculture. The system practiced at the study sites illustrates how resources internal to the farm (i.e., composts) can be used to manage soil productivity.
The electroretinographic response to L- and M-cone isolating stimuli was measured at different luminance levels to study the effect of retinal illuminance on amplitude and phase, and how this may influence estimates of L:M ratios in the retina. It was found that the amplitude of L- and M-cone driven responses increases differently with increasing retinal illuminance: L-cone responses increase more quickly than those of M-cones. The L:M ratio does not change strongly with retinal illuminance. The phase of both L- and M-cone driven responses advances with increasing retinal illuminance. There is considerable interindividual variability in the phase difference between the two, but generally M-cone driven responses are phase advanced.
The nondestructive neutron depth profiling (NDP) technique has been used to measure the boron (10B) distributions in GaAs, CdTe, Hg0.7 Cd0.3 Te, and Hg0.85 Mn0.15Te after multiple energy ion implants. The NDP results are found to be in good agreement with the theoretical ion ranges obtained from Monte Carlo computer simulations. Only minor changes in the boron profiles were seen for the chosen annealing conditions.
Broadband dielectric spectroscopy (10−2 Hz – 109 Hz) is employed to study the molecular dynamics of the glassforming liquid salol (phenyl salicylate) being contained in (dielectric inactive) porous glasses with pore sizes of about 2.5 nm, 5.0 nm and 7.5 nm. Besides the bulk relaxation (I) of salol, two further dielectric loss processes are observed due to the geometrical constraint of the inner surfaces of the pores: the “interfacial relaxation” (II) and a Maxwell-Wagner polarization (III). The “interfacial relaxation” is assigned to the restricted dynamics of the molecules close to the inner surface of the pores. It shows a strong pore-size dependence for pores < 5 nm both in relaxation rate and dielectric strength.
Broadband dielectric spectroscopy (10−2 Hz - 109Hz) is employed to study the molecular dynamics of low-molecular-weight glassforming liquids being confined to nanopores. For the H-bond forming liquid propylene glycol being confined to (uncoated and silanized) nanopores (pore size: 2.5 nm, 5.0 nm and 7.5 nm) a molecular dynamics is observed which is comparable to that of the bulk liquid. Due to surface effects in uncoated nanopores the relaxation time distribution is broadened on the long term side and the mean relaxation rate is decreased by about half a decade. This effect can be counterbalanced by lubricating the inner surfaces of the pores resulting in a relaxation rate which is slightly faster compared to the bulk liquid. For the H-bonded liquid ethylene glycol (EG) embedded in zeolites of different pore size and topology one observes a sharp transition from a single-molecule dynamics to that of a liquid depending on the coordination number of the confined molecules. While EG in silicalite (showing a single molecule relaxation) has four neighboring molecules, EG in zeolite beta or AIPO4-5 has a coordination number of five and behaves like a bulk liquid.
Diffusion processes in typical metals are slow at room temperature but there are many applications for which very long-term use is envisaged and stability needs to be assured over a timescale of 10, 000 years, where even slow processes can be important. It is common to perform accelerated tests at higher temperatures and extrapolate the necessary information from the measurements so obtained. We have tested the validity of this type of extrapolation for room-temperature, grain boundary diffusion in the copper-silver system, by measuring low-temperature diffusion profiles in antique samples of Sheffield plate.
Background: Neuropsychiatric symptoms (NPS) affect almost all patients with dementia and are a major focus of study and treatment. Accurate assessment of NPS through valid, sensitive and reliable measures is crucial. Although current NPS measures have many strengths, they also have some limitations (e.g. acquisition of data is limited to informants or caregivers as respondents, limited depth of items specific to moderate dementia). Therefore, we developed a revised version of the NPI, known as the NPI-C. The NPI-C includes expanded domains and items, and a clinician-rating methodology. This study evaluated the reliability and convergent validity of the NPI-C at ten international sites (seven languages).
Methods: Face validity for 78 new items was obtained through a Delphi panel. A total of 128 dyads (caregivers/patients) from three severity categories of dementia (mild = 58, moderate = 49, severe = 21) were interviewed separately by two trained raters using two rating methods: the original NPI interview and a clinician-rated method. Rater 1 also administered four additional, established measures: the Apathy Evaluation Scale, the Brief Psychiatric Rating Scale, the Cohen-Mansfield Agitation Index, and the Cornell Scale for Depression in Dementia. Intraclass correlations were used to determine inter-rater reliability. Pearson correlations between the four relevant NPI-C domains and their corresponding outside measures were used for convergent validity.
Results: Inter-rater reliability was strong for most items. Convergent validity was moderate (apathy and agitation) to strong (hallucinations and delusions; agitation and aberrant vocalization; and depression) for clinician ratings in NPI-C domains.
Conclusion: Overall, the NPI-C shows promise as a versatile tool which can accurately measure NPS and which uses a uniform scale system to facilitate data comparisons across studies.
There is growing interest in estimating rates of evolutionary change, motivated by the ongoing environmental change (Gingerich 2001; Stockwell et al. 2003; Carroll et al. 2007). Particular concerns have been raised about forest trees, which are thought to be less able to adapt to these rapid changes due to their long generation time (Reich & Oleksyn 2008). Other authors have suggested that large standing genetic variation in trees may enable rapid adaptive responses, at a pace matching that of ongoing climate change (Kremer 2007; Aitken et al. 2008). An elegant approach to get some insights on the evolutionary responses to global warming is to reconstruct past genetic changes and processes that occurred during the postglacial periods, when temperatures were steadily increasing (Petit et al. 2008). The timing and direction of spread of wind-pollinated trees following the last ice age can be reconstructed from their pollen remains in sediments (e.g., Cheddadi et al. 2005). Palynological data have now been compared to phylogeographic approaches based on range-wide surveys of genetic fingerprints of maternally inherited organelle genomes (Petit et al. 2002b for oaks, Magri et al. 2006 for beech, Cheddadi et al. 2006 for Scots pine). This combination has elucidated genetic and demographic processes associated with tree responses to environmental change. A second approach for predicting adaptive responses to environmental changes is based on theory and simulations (Bürger & Lynch 1995; Bürger & Krall 2004; Sato & Waxman 2008). These studies have been limited so far to single populations and have focused on the amount of environmental change that a population can tolerate, given its genetic and demographic properties.
To identify patients undergoing arteriography to verify vascular complications of tonsillectomy, with an emphasis on pseudoaneurysm.
Patients and methods:
We undertook a retrospective analysis of the case records of 8837 patients who had undergone tonsillectomy between 1988 and 2004 at our institution, together with a review of expert reports written for professional boards and civil courts as well as personal experiences or communication. We also conducted a literature review using the PubMed database.
We identified seven cases with vascular abnormalities. In addition, we identified three cases of pseudoaneurysm formation, involving two children and one adult patient, with bleeding 21, 36 and 58 days after tonsillectomy. Successful management included embolisation (two patients) and revision surgery (one patient).
Post-tonsillectomy pseudoaneurysm formation is extremely rare and unrestricted by age. Correct diagnosis depends largely on a high index of clinical suspicion. Delayed and repeated episodes of gushing haemorrhage with spontaneous cessation appear to be a significant clinical marker. Immediate arteriography, with simultaneous embolisation, is highly recommended. The lingual artery is the most commonly involved vessel.