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31.
C C Schwartz Z R Vlahcevic L G Halloran D H Gregory J B Meek L Swell 《Gastroenterology》1975,69(6):1379-1382
A bile fistula patient was administered intravenously a constant infusion of [3H]mevalonic acid for 4 hrs, and then after 2 weeks he was given a pulse of [3H]mevalonic acid. Bile and blood were collected at frequent intervals. The specific activity-time course curves did not show a precursor-product relationship between biliary cholesterol, plasma free cholesterol and bile acids. Both the constant infusion and pulse labeling data indicated that the bile acid precursor had a more rapid rate of turnover than plasma or biliary cholesterol; the biliary cholesterol precursor turned over more rapidly than plasma cholesterol. The data suggest the presence of multiple hepatic cholesterol precursor compartments. Bile acids may be derived predominantly from newly synthesized cholesterol in man. 相似文献
32.
R L Meek N Eriksen E P Benditt 《Proceedings of the National Academy of Sciences of the United States of America》1992,89(17):7949-7952
The serum amyloid A (SAA) proteins make up a multigene family of apolipoproteins associated with high density lipoproteins. They are of ancient origin; the finding of a highly homologous protein in mammals and ducks indicates that SAAs have been in existence for at least 300 million years. The interspecies similarity among the SAAs makes the mouse, in which they have been most thoroughly studied, a reasonable model to use for defining the function(s) of this family of proteins in humans. Originally it was observed that the SAA proteins were made in the liver and represented a set of proteins belonging to acute-phase reactants. SAA3 is a unique member of the SAA multigene family in mice in that its mRNA is also expressed in extrahepatic tissues by a variety of cell types, mainly macrophages and adipocytes. To date, nothing has been reported regarding the fate or function of the SAA3 translation product. To identify the SAA3 protein, we developed SAA3-specific antibodies by immunizing rabbits against a portion of SAA3 protein synthesized in a bacterial fusion protein expression system. Electroimmunoblot analysis of serum and lipoprotein fractions of it showed SAA3 to be associated with high density lipoproteins of mice treated with lipopolysaccharide. Furthermore, a continuous mouse macrophage cell line (J-774.1), when exposed to lipopolysaccharide, expressed SAA3 mRNA in a dose-dependent manner and secreted SAA3 protein. The expression and secretion of SAA3 by macrophages stimulated with lipopolysaccharide suggest a role for this SAA in local responses to injury and inflammation. 相似文献
33.
Katharina Hopp Andrea G. Cogal Eric J. Bergstralh Barbara M. Seide Julie B. Olson Alicia M. Meek John C. Lieske Dawn S. Milliner Peter C. Harris 《Journal of the American Society of Nephrology : JASN》2015,26(10):2559-2570
Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial. 相似文献
34.
Shashikant Srivastava Jotam Pasipanodya Carleton M. Sherman Claudia Meek Richard Leff Tawanda Gumbo 《Antimicrobial agents and chemotherapy》2015,59(4):2273-2279
Mycobacterium kansasii is the second most common mycobacterial cause of lung disease. Standard treatment consists of rifampin, isoniazid, and ethambutol for at least 12 months after negative sputum. Thus, shorter-duration therapies are needed. Moxifloxacin has good MICs for M. kansasii. However, good preclinical models to identify optimal doses currently are lacking. We developed a novel hollow fiber system model of intracellular M. kansasii infection. We indexed the efficacy of the standard combination regimen, which was a kill rate of −0.08 ± 0.05 log10 CFU/ml/day (r2 = 0.99). We next performed moxifloxacin dose-effect and dose-scheduling studies at a half-life of 11.1 ± 6.47 h. Some systems also were treated with the efflux pump inhibitor reserpine. The highest moxifloxacin exposure, as well as lower exposures plus reserpine, sterilized the cultures by day 7. This suggests that efflux pump-mediated tolerance at low ratios of the area under the concentration-time curve from 0 to 24 h (AUC0–24) to MICs is an early bacterial defense mechanism but is overcome by higher exposures. The highest rate of moxifloxacin monotherapy sterilization was −0.82 ± 0.15 log10 CFU/ml/day (r2 = 0.97). The moxifloxacin exposure associated with 80% of maximal kill (EC80) was an AUC0–24/MIC of 317 (the non-protein-bound moxifloxacin AUC0–24/MIC was 158.5). We performed Monte Carlo simulations of 10,000 patients in order to identify the moxifloxacin dose that would achieve or exceed the EC80. The simulations revealed an optimal moxifloxacin dose of 800 mg a day. The MIC susceptibility breakpoint at this dose was 0.25 mg/liter. Thus, moxifloxacin, at high enough doses, is suitable to study in patients for the potential to add rapid sterilization to the standard regimen. 相似文献
35.
37.
Autumn R. Meek Gordon A. Simms Donald F. Weaver 《Journal of psychiatry & neuroscience : JPN》2013,38(4):269-275
Background
Alzheimer disease is a neurodegenerative disorder that progresses with marked interindividual clinical variability. We postulate the existence of endogenous molecules within the human brain exerting an antiaggregant activity that will prevent/slow Alzheimer disease progression.Methods
We performed in silico studies to determine if the small endogenous molecules L-phosphoserine (L-PS) and 3-hydroxyanthranilic acid (3-HAA) could bind to the target region of β-amyloid responsible for protein misfolding. In vitro assays measured the antiaggregation effect of these molecules at varying concentrations.Results
In silico studies demonstrated that L-PS and 3-HAA, both endogenous brain molecules, were capable of binding to the histidine13–histidine–glutamine–lysine16 (HHQK) region of β-amyloid involved in misfolding: these interactions were energetically favoured. The in vitro assays showed that both L-PS and 3-HAA were capable of inhibiting β-amyloid aggregation in a dose-dependent manner, with 3-HAA being more potent than L-PS.Limitations
Studies were performed in silico and in vitro but not in vivo.Conclusion
We successfully identified 2 endogenous brain molecules, L-PS and 3-HAA, that were capable of binding to the region of β-amyloid that leads to protein misfolding and neurotoxicity. Both L-PS and 3-HAA were able to inhibit β-amyloid aggregation in varying concentrations; levels of these compounds in the brain may impact their effectiveness in slowing/preventing β-amyloid aggregation. 相似文献38.
39.
40.
Garg S Chaves SS Pérez A D'Mello T Gershman K Meek J Yousey-Hindes K Arnold KE Farley MM Tengelsen L Ryan P Sharangpani R Lynfield R Morin C Baumbach J Hancock EB Zansky S Bennett NM Fowler B Bradley K Thomas A Cooper T Schaffner W Boulton R Finelli L Fry AM 《Clinical infectious diseases》2012,55(3):e18-e21
Influenza antiviral treatment is recommended for all persons hospitalized with influenza virus infection. During the 2010-2011 influenza season, antiviral treatment of children and adults hospitalized with laboratory-confirmed influenza declined significantly compared with treatment during the 2009 pandemic (children, 56% vs 77%; adults, 77% vs 82%; both P < .01). 相似文献