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51.
van Halm VP Nurmohamed MT Twisk JW Dijkmans BA Voskuyl AE 《Arthritis research & therapy》2006,8(5):R151-6
Rheumatoid arthritis (RA) is characterized by inflammation and an increased risk for cardiovascular disease (CVD). This study
investigates possible associations between CVD and the use of conventional disease-modifying antirheumatic drugs (DMARDs)
in RA. Using a case control design, 613 RA patients (5,649 patient-years) were studied, 72 with CVD and 541 without CVD. Data
on RA, CVD and drug treatment were evaluated from time of RA diagnosis up to the first cardiovascular event or the end of
the follow-up period. The dataset was categorized according to DMARD use: sulfasalazine (SSZ), hydroxychloroquine (HCQ) or
methotrexate (MTX). Odds ratios (ORs) for CVD, corrected for age, gender, smoking and RA duration, were calculated per DMARD
group. Patients who never used SSZ, HCQ or MTX were used as a reference group. MTX treatment was associated with a significant
CVD risk reduction, with ORs (95% CI): 'MTX only', 0.16 (0.04 to 0.66); 'MTX and SSZ ever', 0.20 (0.08 to 0.51); and 'MTX,
SSZ and HCQ ever', 0.20 (0.08 to 0.54). The risk reductions remained significant after additional correction for the presence
of rheumatoid factor and erosions. After correction for hypertension, diabetes and hypercholesterolemia, 'MTX or SSZ ever'
and 'MTX, SSZ and HCQ ever' showed significant CVD risk reduction. Rheumatoid factor positivity and erosions both increased
CVD risk, with ORs of 2.04 (1.02 to 4.07) and 2.36 (0.92 to 6.08), respectively. MTX and, to a lesser extent, SSZ were associated
with significantly lower CVD risk compared to RA patients who never used SSZ, HCQ or MTX. We hypothesize that DMARD use, in
particular MTX use, results in powerful suppression of inflammation, thereby reducing the development of atherosclerosis and
subsequently clinically overt CVD. 相似文献
52.
Zificsak CA Theroff JP Aimone LD Albom MS Angeles TS Brown RA Galinis D Grobelny JV Herbertz T Husten J Kocsis LS LoSardo C Miknyoczki SJ Murthy S Rolon-Steele D Underiner TL Wells-Knecht KJ Worrell CS Zeigler KS Dorsey BD 《Bioorganic & medicinal chemistry letters》2011,21(2):660-663
Elaboration of the SAR around a series of 2,4-diaminopyrimidines led to a number of c-Met inhibitors in which kinase selectivity was modulated by substituents appended on the C4-aminobenzamide ring and the nature of the C2-aminoaryl ring. Further lead optimization of the C2-aminoaryl group led to benzoxazepine analogs whose pharmaceutical properties were modulated by the nature of the substituent on the benzoxazepine nitrogen. Tumor stasis (with partial regressions) were observed when an orally bioavailable analog was evaluated in a GTL-16 tumor xenograft mouse model. Subsequent PK/PD studies suggested that a metabolite contributed to the overall in vivo response. 相似文献
53.
J. Jeffry Howbert Edward E. Patterson S. Matt Stead Ben Brinkmann Vincent Vasoli Daniel Crepeau Charles H. Vite Beverly Sturges Vanessa Ruedebusch Jaideep Mavoori Kent Leyde W. Douglas Sheffield Brian Litt Gregory A. Worrell 《PloS one》2014,9(1)
Seizure forecasting has the potential to create new therapeutic strategies for epilepsy, such as providing patient warnings and delivering preemptive therapy. Progress on seizure forecasting, however, has been hindered by lack of sufficient data to rigorously evaluate the hypothesis that seizures are preceded by physiological changes, and are not simply random events. We investigated seizure forecasting in three dogs with naturally occurring focal epilepsy implanted with a device recording continuous intracranial EEG (iEEG). The iEEG spectral power in six frequency bands: delta (0.1–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), beta (12–30 Hz), low-gamma (30–70 Hz), and high-gamma (70–180 Hz), were used as features. Logistic regression classifiers were trained to discriminate labeled pre-ictal and inter-ictal data segments using combinations of the band spectral power features. Performance was assessed on separate test data sets via 10-fold cross-validation. A total of 125 spontaneous seizures were detected in continuous iEEG recordings spanning 6.5 to 15 months from 3 dogs. When considering all seizures, the seizure forecasting algorithm performed significantly better than a Poisson-model chance predictor constrained to have the same time in warning for all 3 dogs over a range of total warning times. Seizure clusters were observed in all 3 dogs, and when the effect of seizure clusters was decreased by considering the subset of seizures separated by at least 4 hours, the forecasting performance remained better than chance for a subset of algorithm parameters. These results demonstrate that seizures in canine epilepsy are not randomly occurring events, and highlight the feasibility of long-term seizure forecasting using iEEG monitoring. 相似文献
54.
Geraldine AC Lim Erica G Jewell Xi Li Timothy A Erwin Christopher Love Jacqueline Batley German Spangenberg David Edwards 《BMC plant biology》2007,7(1):40
Background
Molecular genetic maps provide a means to link heritable traits with underlying genome sequence variation. Several genetic maps have been constructed for Brassica species, yet to date, there has been no simple means to compare this information or to associate mapped traits with the genome sequence of the related model plant, Arabidopsis. 相似文献55.
AC Martin IA Laing G Zhang S Brennan K Winfield PD Sly SM Stick J Goldblatt PN LeSouef 《Respiratory research》2005,6(1):1-4
Early acquisition of Pseudomonas aeruginosa is associated with a poorer prognosis in patients with cystic fibrosis. We investigated whether polymorphisms in CD14, the lipopolysaccharide receptor, increase the risk of early infection. Forty-five children with cystic fibrosis were investigated with annual bronchoalveolar lavage (BAL) and plasma sCD14 levels. Plasma sCD14 levels were significantly lower in children from whom P.aeruginosa was subsequently isolated (492.75 μg/ml vs. 1339.43 μg/ml, p = 0.018). Those with the CD14 -159CC genotype had a significantly increased risk of early infection with P.aeruginosa suggesting that CD14 C-159T plays a role in determining the risk of early infection with P.aeruginosa. 相似文献
56.
Jo Moore Stephen AC Hawkins Anthony R Austin Timm Konold Robert B Green Ian W Blamire Ian Dexter Michael J Stack Melanie J Chaplin Jan PM Langeveld Marion M Simmons Yvonne I Spencer Paul R Webb Michael Dawson Gerald AH Wells 《BMC research notes》2011,4(1):1-13
Background
Escherichia coli O157:H7 is the most common serovar of enterohemorrhagic E. coli associated with serious human disease outbreaks. Cattle are the main reservoir with E. coli O157:H7 inducing hemorrhagic enteritis in persistent shedding beef cattle, however little is known about how this pathogen affects cattle health. Jejunal Hemorrhage Syndrome (JHS) has unclear etiology but the pathology is similar to that described for E. coli O157:H7 challenged beef cattle suggestive that E. coli O157:H7 could be involved. There are no effective treatments for JHS however new approaches to managing pathogen issues in livestock using prebiotics and probiotics are gaining support. The first objective of the current study was to characterize pathogen colonization in hemorrhaged jejunum of dairy cattle during natural JHS outbreaks. The second objective was to confirm the association of mycotoxigenic fungi in feeds with the development of JHS and also to identify the presence of potential mycotoxins. The third objective was to determine the impact of a prebiotic, Celmanax?, or probiotic, Dairyman's Choice? paste, on the cytotoxicity associated with feed extracts in vitro. The fourth objective was to determine the impact of a prebiotic or a probiotic on E. coli O157:H7 colonization of mucosal explants and a bovine colonic cell line in vitro. The final objective was to determine if prebiotic and probiotic feed additives could modify the symptoms that preceded JHS losses and the development of new JHS cases.Findings
Dairy cattle developed JHS after consuming feed containing several types of mycotoxigenic fungi including Fusarium culmorum, F. poae, F. verticillioides, F. sporotrichioides, Aspergillus flavus, Penicillium roqueforti, P. crustosum, P. paneum and P. citrinum. Mixtures of Shiga toxin - producing Escherichia coli (STEC) colonized the mucosa in the hemorrhaged tissues of the cattle and no other pathogen was identified. The STECs expressed Stx1 and Stx2, but more significantly, Stxs were also present in the blood clot blocking the jejunum. Mycotoxin analysis of the corn crop confirmed the presence of fumonisin, NIV, ZEAR, DON, 15-ADON, 3-ADON, NEO, DAS, HT-2 and T-2. Feed extracts were toxic to enterocytes and 0.1% Celmanax? removed the cytotoxicity in vitro. There was no effect of Dairyman's Choice? paste on feed-extract activity in vitro. Fumonisin, T-2, ZEAR and DON were toxic to bovine cells and 0.1% Celmanax? removed the cytotoxicity in vitro. Celmanax? also directly decreased E. coli O157:H7 colonization of mucosal explants and a colonic cell line in a dose-dependent manner. There was no effect of Dairyman's Choice? paste on E. coli O157:H7 colonization in vitro. The inclusion of the prebiotic and probiotic in the feed was associated with a decline in disease.Conclusion
The current study confirmed an association between mycotoxigenic fungi in the feed and the development of JHS in cattle. This association was further expanded to include mycotoxins in the feed and mixtures of STECs colonizing the severely hemorrhaged tissues. Future studies should examine the extent of involvement of the different STEC in the infection process. The prebiotic, Celmanax?, acted as an anti-adhesive for STEC colonization and a mycotoxin binder in vitro. Future studies should determine the extent of involvement of the prebiotic in altering disease. 相似文献57.
Irene EM Bultink D?rte Hamann Marc A Seelen Margreet H Hart Ben AC Dijkmans Mohamed R Daha Alexandre E Voskuyl 《Arthritis research & therapy》2007,8(6):R183
Infection imposes a serious burden on patients with systemic lupus erythematosus (SLE). The increased infection rate in SLE
patients has been attributed in part to defects of immune defence. Recently, the lectin pathway of complement activation has
also been suggested to play a role in the occurrence of infections in SLE. In previous studies, SLE patients homozygous for
mannose-binding lectin (MBL) variant alleles were at an increased risk of acquiring serious infections in comparison with
patients who were heterozygous or homozygous for the normal allele. This association suggests a correlation between functional
MBL level and occurrence of infections in SLE patients. We therefore investigated the biological activity of MBL and its relationship
with the occurrence of infections in patients with SLE. Demographic and clinical data were collected in 103 patients with
SLE. Functional MBL serum levels and MBL-induced C4 deposition were measured by enzyme-linked immunosorbent assay using mannan
as coat and an MBL- or C4b-specific monoclonal antibody. The complete MBL-dependent pathway activity was determined by using
an assay that measures the complete MBL pathway activity in serum, starting with binding of MBL to mannan, and was detected
with a specific monoclonal antibody against C5b-9. Charts were systematically reviewed to obtain information on documented
infections since diagnosis of SLE. Major infections were defined as infections requiring hospital admission and intravenous
administration of antibiotics. In total, 115 infections since diagnosis of lupus, including 42 major infections, were documented
in the 103 SLE patients (mean age 41 ± 13 years, mean disease duration 7 ± 4 years). The percentage of SLE patients with severe
MBL deficiency was similar to that in 100 healthy controls: 13% versus 14%, respectively. Although deposition of C4 to mannan
and MBL pathway activity were reduced in 21% and 43% of 103 SLE patients, respectively, neither functional MBL serum levels
nor MBL pathway activity was associated with infections or major infections in regression analyses. In conclusion, SLE patients
frequently suffer from infections, but deficiency of functional MBL does not confer additional risk. 相似文献
58.
A covariotide model explains apparent phylogenetic structure of oxygenic photosynthetic lineages 总被引:4,自引:13,他引:4
Lockhart PJ; Steel MA; Barbrook AC; Huson DH; Charleston MA; Howe CJ 《Molecular biology and evolution》1998,15(9):1183-1188
The aims of the work were (1) to develop statistical tests to identify
whether substitution takes place under a covariotide model in sequences
used for phylogenetic inference and (2) to determine the influence of
covariotide substitution on phylogenetic trees inferred for photosynthetic
and other organisms. (Covariotide and covarion models are ones in which
sites that are variable in some parts of the underlying tree are invariable
in others and vice versa.) Two tests were developed. The first was a
contingency test, and the second was an inequality test comparing the
expected number of variable sites in two groups with the observed number.
Application of these tests to 16S rDNA and tufA sequences from a range of
nonphotosynthetic prokaryotes and oxygenic photosynthetic prokaryotes and
eukaryotes suggests the occurrence of a covariotide mechanism. The degree
of support for partitioning of taxa in reconstructed trees involving these
organisms was determined in the presence or absence of sites showing
particular substitution patterns. This analysis showed that the support for
splits between (1) photosynthetic eukaryotes and prokaryotes and (2)
photosynthetic and nonphotosynthetic organisms could be accounted for by
patterns arising from covariotide substitution. We show that the additional
problem of compositional bias in sequence data needs to be considered in
the context of patterns of covariotide/covarion substitution. We argue that
while covariotide or covarion substitution may give rise to
phylogenetically informative patterns in sequence data, this may not always
be so.
相似文献
59.
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