Aims Heart failure is associated with decreased myocardial fatty acid oxidation capacity and has been likened to energy starvation. Increased fatty acid availability results in an induction of genes ...promoting fatty acid oxidation. The aim of the present study was to investigate possible mechanisms by which high fat feeding improved mitochondrial and contractile function in heart failure. Methods and results Male Wistar rats underwent coronary artery ligation (HF) or sham surgery and were immediately fed either a normal (14% kcal fat) (SHAM, HF) or high-fat diet (60% kcal saturated fat) (SHAM+FAT, HF+FAT) for 8 weeks. Mitochondrial respiration and gene expression and enzyme activities of fatty acid-regulated mitochondrial genes and proteins were assessed. Subsarcolemmal (SSM) and interfibrillar mitochondria were isolated from the left ventricle. State 3 respiration using lipid substrates octanoylcarnitine and palmitoylcarnitine increased in the SSM of HF+FAT compared with SHAM+FAT and HF, respectively (242 ± 21, 246 ± 21 vs. 183 ± 8, 181 ± 6 and 193 ± 17, 185 ± 16 nAO min−1 mg−1). Despite decreased medium-chain acyl-CoA dehydrogenase (MCAD) mRNA in HF and HF+FAT, MCAD protein was not altered, and MCAD activity increased in HF+FAT (HF, 65.1 ± 2.7 vs. HF+FAT, 81.5 ± 5.4 nmoles min−1 mg−1). Activities of short- and long-chain acyl-CoA dehydrogenase also were elevated and correlated to increased state 3 respiration. This was associated with an improvement in myocardial contractility as assessed by left ventricular +dP/dt max. Conclusion Administration of a high-fat diet increased state 3 respiration and acyl-CoA dehydrogenase activities, but did not normalize mRNA or protein levels of acyl-CoA dehydrogenases in coronary artery ligation-induced heart failure rats.
BACKGROUND.: Obesity is a significant problem among children undergoing renal transplantation. We sought to describe changes in adiposity (reflected by percent difference from the median body mass ...index BMI for height-age and sex BMI%) after pediatric renal transplantation and to identify risk factors for greater gains in adiposity within 12 months of transplantation and for persistence of these gains at 48 months. The changes in height-for-age were also examined. METHODS.: By using the North American Pediatric Renal Trials and Collaborative Studies registry, we performed a retrospective cohort study of children (age 2-18 years.) transplanted between 1995 and 2006, and followed up to January 2007. Multivariable linear regression was used to identify risk factors for greater gains in adiposity and height. RESULTS.: BMI was recorded at baseline in 4326 children, and collected every 6 months. Median BMI% increased by 11.37 units within 6 months; no substantial changes were seen thereafter. The pattern of change in BMI% was similar regardless of BMI% at transplant. Age 6 to 12 years at transplant, more remote transplant, female sex, black race, Hispanic ethnicity, and lower baseline BMI% were associated with significantly greater gains in adiposity both within 12 months and persisting 48 months posttransplant. Compared with daily use, no corticosteroid use at 6 and 48 months were associated with smaller increases in BMI% within the first 12 months and at 48 months, respectively. CONCLUSIONS.: The majority of children experienced early increases in BMI%, which persisted up to 4 years. Increases in BMI% were similar regardless of BMI% at baseline.
Some natural health products (NHPs) affect drug metabolism enzymes and transport proteins, potentially affecting the safety and efficacy of the drug or other NHPs. This study was undertaken to ...characterize the effect of uva-ursi (
Arctostaphylos uva-ursi
) on cytochrome P450 isozyme (3A4, 3A5, 3A7, 2C19, and 19)-mediated metabolism and P-glycoprotein (P-gp) transport. Three bulk and 2 capsulated uva-ursi samples were obtained from commercial outlets. The capsules were batched, and herbal samples were ground to a common consistency. Aqueous and methanol extracts were freshly prepared. Cytochrome P450 isozyme-mediated metabolism was determined by using in vitro bioassays. P-gp transport function was determined by using a rhodamine 123 (Rh123) uptake test in human (THP-1) monocytes and human Caco-2 cells. All products were analyzed by HPLC for arbutin, gallic acid, myricitrin, and isoquercetin. A large variation was observed in the biomarkers found between the bulk and capsulated samples. Our data indicate that both the aqueous and methanol extracts of all 5 uva-ursi products showed high cytochrome P450 isozyme inhibition, with the exception of the methanol extracts against cytochromes P3A4 and P19, which had low to moderate activity. The aqueous extracts of uva-ursi showed an inhibitory effect on Rh123 efflux by P-gp at 1 h and an inductive effect at 18 h for both cell lines. Our results show that the uva-ursi herbal products tested here have pharmacological properties, including the potential capacity to affect drug safety and efficacy. Further studies are warranted against a wider range of cytochrome P450 isozymes and to determine whether these effects are clinically significant.
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DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A strategy to reduce the physical aging in PIM-1 membranes by incorporating novel functionalized graphene oxide (GO) fillers is reported. PIM-1 was covalently attached both to as-synthesized GO and ...to GO reacted with (3-aminopropyl)triethoxysilane (APTS-GO), leading to homogeneous dispersion of the nanofillers in the mixed matrix membranes (MMMs). It was found that the aging rate decreases with increasing content of (PIM-1)-functionalized GO, as evidenced by the smaller decrease in gas permeability over time. The best performance was achieved by a membrane containing 10 wt% of (PIM-1)-functionalized APTS-GO. This membrane maintains 85% of the initial CO2 permeability after 150 days (drop of only 310 Barrer), which represents about nine-fold less CO2 permeability drop as compared to pure PIM-1.
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•PIM-1 membranes containing GO-based fillers were prepared.•GO was functionalized with PIM-1 to improve the dispersion of the 2D filler in the polymer matrix.•PIM-1 was synthesized on silane-functionalized GO and used for the preparation of MMMs.•CO2/CH4 separation performance for pure PIM-1 and MMMs was assessed over 150 days.•Physical aging in the MMMs decreases as the amount of filler increases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A novel approach to improve the initial performance as well as to prevent physical aging of superglassy high free volume polymer PIM-1 is reported. Bis(phenyl)fluorene-based polymer of intrinsic ...microporosity (Cardo-PIM-1) was used at different loadings in PIM-1 to fabricate thin film composite (TFC) membranes and freestanding membranes. The gas performances of both TFCs and thick freestanding membranes exhibited similar trends; higher CO2 permeance and higher CO2/CH4 selectivity at relatively low loadings (≤5 wt %). TFCs containing 5 wt % Cardo-PIM-1 achieved a CO2 permeance of (12600 ± 866 GPU), which corresponds to about a threefold increase as compared to the pristine TFC-PIM-1 membranes (2850 ± 254 GPU) and higher CO2/CH4 selectivity (14.6 ± 1.3) as compared to pure PIM-1 (10 ± 3). With regards to physical aging, PIM-1 TFC membranes experienced a 96 % reduction in CO2 permeance after 1 year. However, for the TFCs containing 5 wt % cardo the reduction was considerably lower (59%) and all took place at an initial stage of up to 37 days, remaining at a good and stable CO2 permeance of c.a. 5000 GPU for the remaining testing period of up to one year.
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•Thin film composite (TFC) membranes of PIM-1 containing Cardo-PIM-1 were fabricated.•Gas transport properties for freshly prepared TFCs and aged ones were assessed.•Physical aging was prevented to a larger extent for TFCs containing 5 wt % cardo.•Reduction in gas permeance for TFCs with Cardo-PIM-1 took place up to 37 days.•A stable value of c.a. 5000 GPU was reached remaining constant for up to a year.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases in which autoimmune pathology is suspected to promote chronic muscle inflammation and weakness. We have performed ...low to high resolution genotyping to characterize the allelic profiles of HLA-A, -B, -Cw, -DRB1, and -DQA1 loci in a large population of North American Caucasian patients with IIM representing the major clinicopathologic groups (n = 571). We confirmed that alleles of the 8.1 ancestral haplotype were important risk markers for the development of IIM, and a random forests classification analysis suggested that within this haplotype, HLA-B*0801, DRB1*0301 and/ or closely linked genes are the principal HLA risk factors. In addition, we identified several novel HLA factors associated distinctly with 1 or more clinicopathologic groups of IIM. The DQA1*0201 allele and associated peptide-binding motif (KLPLFHRL) were exclusive protective factors for the CD8+ T cell-mediated IIM forms of polymyositis (PM) and inclusion body myositis (IBM) (pc < 0.005). In contrast, HLA-A*68 alleles were significant risk factors for dermatomyositis (DM) (pc = 0.0021), a distinct clinical group thought to involve a humorally mediated immunopathology. While the DQA1*0301 allele was detected as a possible risk factor for IIM, PM, and DM patients (p < 0.05), DQA1*03 alleles were protective factors for IBM (pc = 0.0002). Myositis associated with malignancies was the most distinctive group of IIM wherein HLA Class I alleles were the only identifiable susceptibility factors and a shared HLA-Cw peptide-binding motif (AGSHTLQWM) conferred significant risk (pc = 0.019). Together, these data suggest that HLA susceptibility markers distinguish different myositis phenotypes with divergent pathogenetic mechanisms. These variations in associated HLA polymorphisms may reflect responses to unique environmental triggers resulting in the tissue pathospecificity and distinct clinicopathologic syndromes of the IIM.
Polyfluorenes with pendant alkoxysilyl groups have been used to prepare inorganic-organic composite nanoparticles (diameter = 80-220 nm) in which the conjugated polymer is dispersed within a silica ...matrix. Preparation of these nanoparticles is achieved by simultaneous nanoprecipitation of the conjugated polymer and hydrolysis/crosslinking of the alkoxysilyl groups under basic conditions. The composition of the nanocomposites is controlled by addition of an alkoxysilane monomer, tetramethylorthosilicate. The hybrid nanoparticles form highly stable dispersions in water and buffer (pH 9.2). The size of the nanoparticles can be tuned by varying the amount of the alkoxysilane monomer added during the nanoprecipitation process. Increasing the relative amount of alkoxysilane monomer also increases the proportion of polyfluorene chains that adopt the higher energy beta -phase conformation within the resultant nanoparticles. Nanoparticles with the highest silica content were found to have increased photoluminescence quantum yields. This work provides a controllable method for optimisation of the photophysical properties of light-emitting conjugated polymer nanoparticles viaa simple aqueous processing technique.
causes diarrheal diseases mediated in part by the secreted toxins TcdA and TcdB.
produces flagella that also contribute to motility and bacterial adherence to intestinal cells during infection. ...Flagellum expression and toxin gene expression are linked via the flagellar alternative sigma factor, SigD. Recently, we identified a flagellar switch upstream of the early flagellar biosynthesis operon that mediates phase variation of both flagellum and toxin production in
strain R20291. However, we were unable to detect flagellar switch inversion in
strain 630, a ribotype 012 strain commonly used in research labs, suggesting that the strain is phase locked. To determine whether a phase-locked flagellar switch is limited to 630 or present more broadly in ribotype 012 strains, we assessed the frequency and phenotypic outcomes of flagellar switch inversion in multiple
ribotype 012 isolates. The laboratory-adapted strain JIR8094, a derivative of strain 630, and six clinical and environmental isolates were all found to be phase-off, nonmotile, and attenuated for toxin production. We isolated low-frequency motile derivatives of JIR8094 with partial recovery of motility and toxin production and found that additional changes in JIR8094 impact these processes. The clinical and environmental isolates varied considerably in the frequency by which flagellar phase-on derivatives arose, and these derivatives showed fully restored motility and toxin production. Taken together, these results demonstrate heterogeneity in flagellar and toxin phase variation among
ribotype 012 strains and perhaps other ribotypes, which could impact disease progression and diagnosis.
produces flagella that enhance bacterial motility and secretes toxins that promote diarrheal disease symptoms. Previously, we found that production of flagella and toxins is coregulated via a flippable DNA element termed the flagellar switch, which mediates the phase-variable production of these factors. Here, we evaluate multiple isolates of
ribotype 012 strains and find them to be primarily flagellar phase off (
-off state). Some, but not all, of these isolates showed the ability to switch between
-on and -off states. These findings suggest heterogeneity in the ability of
ribotype 012 strains to phase-vary flagellum and toxin production, which may broadly apply to pathogenic
.
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