The prostanoid receptors on human airway smooth muscle cells (HASMC) that augment the release by IL-1beta of granulocyte colony-stimulating factor (G-CSF) have been characterized and the signaling ...pathway elucidated. PCR of HASM cDNA identified products corresponding to EP(2), EP(3), and EP(4) receptor subtypes. These findings were corroborated at the protein level by immunocytochemistry. IL-1beta promoted the elaboration of G-CSF, which was augmented by PGE(2). Cicaprost (IP receptor agonist) was approximately equiactive with PGE(2), whereas PGD(2), PGF(2alpha), and U-46619 (TP receptor agonist) were over 10-fold less potent. Neither SQ 29,548 nor BW A868C (TP and DP(1) receptor antagonists, respectively) attenuated the enhancement of G-CSF release evoking any of the prostanoids studied. With respect to PGE(2), the EP receptor agonists 16,16-dimethyl PGE(2) (nonselective), misoprostol (EP(2)/EP(3) selective), 17-phenyl-omega-trinor PGE(2) (EP(1) selective), ONO-AE1-259, and butaprost (both EP(2) selective) were full agonists at enhancing G-CSF release. AH 6809 (10 microM) and L-161,982 (2 microM), which can be used in HASMC as selective EP(2) and EP(4) receptor antagonists, respectively, failed to displace to the right the PGE(2) concentration-response curve that described the augmented G-CSF release. In contrast, AH 6809 and L-161,982 in combination competitively antagonized PGE(2)-induced G-CSF release. Augmentation of G-CSF release by PGE(2) was mimicked by 8-BrcAMP and abolished in cells infected with an adenovirus vector encoding an inhibitor protein of cAMP-dependent protein kinase (PKA). These data demonstrate that PGE(2) facilitates G-CSF secretion from HASMC through a PKA-dependent mechanism by acting through EP(2) and EP(4) prostanoid receptors and that effective antagonism is realized only when both subtypes are blocked concurrently.
Neutron probe measurements from aluminum access tubes (3.2 m deep) show that conifers and sclerophyllous shrubs deplete water from soil-rock profiles in distinctly different patterns. Measurements ...were taken during two growing seasons (1993 and 1994) in southwestern Oregon (U.S.A.) under 14-year-old stands of Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco), ponderosa pine (Pinus ponderosa Dougl. ex Laws.), Pacific madrone (Arbutus menziesii Pursh), and whiteleaf manzanita (Arctostaphylos viscida Parry) covers. Both conifer species showed very limited abilities to utilize water from bedrock, even during very dry periods. Ericaceous plants, on the other hand, were very efficient in taking water from the deep rock layers, using nearly all available water and removing about twice as much water as conifers of the same age. Patterns of water depletion suggest that the water resources used by these two types of plants overlap considerably, and competition will be very strong in mixed stands. The ability of ericaceous plants to utilize bedrock water that is unavailable to conifers in late summer will enhance their potential for dominance.
Objective
To devise and test a system with which to evaluate abnormalities on muscle biopsy samples obtained from children diagnosed with juvenile dermatomyositis (DM).
Methods
We established an ...International Consensus Group on Juvenile DM Biopsy and carried out 2 phases of consensus process and scoring workshops. Biopsy sections (n = 33) were stained by standard methods. The scoring tool was based on 4 domains of change: inflammatory, vascular, muscle fiber, and connective tissue. Using a Latin square design, biopsy samples were scored by 11 experts for items in each domain, and for a global abnormality measure using a 10‐cm visual analog score (VAS 0–10). The tool's reliability was assessed using an intraclass correlation coefficient (ICC) and scorer agreement (α) by determining variation in scorers' ratings.
Results
There was good agreement in many items of the tool, and several items refined between the meetings improved in reliability and/or agreement. The inflammatory and muscle fiber domains had the highest reliability and agreement. The overall VAS score for abnormality had high agreement and reliability, reaching an ICC of 0.863 at the second consensus meeting.
Conclusion
We propose a provisional scoring system to measure abnormalities on muscle biopsy samples obtained from children with juvenile DM. This system needs to be validated, and then could be used in prospective studies to test which features of muscle pathology are prognostic of disease course or outcome. We suggest that the process we used could be a template for developing similar systems in other forms of myositis.
The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable, and mutations have been described in syndromatic cases.
To conduct a meta-analysis ...of genome-wide association studies to identify common genetic variants influencing ERP.
We ascertained ERP on the basis of electrocardiograms in 3 large community-based cohorts from Europe and the United States: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed genome-wide association studies in participants with and without ERP by logistic regression assuming an additive genetic model and meta-analyzed individual cohort results. We then sought to strengthen support for findings that reached P ≤ 1 × 10(-5) in independent individuals by direct genotyping or in-silico analysis of genome-wide data. We meta-analyzed the results from both stages.
Of 7482 individuals in the discovery stage, 452 showed ERP (ERP positive: mean age 46.9 ± 8.9 years, 30.3% women; ERP negative: 47.5 ± 9.4 years, 54.2% women). After meta-analysis, 8 single nucleotide polymorphisms reached P ≤ 1 × 10(-5): The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36-0.61; P = 6.9 × 10(-9)). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95% confidence interval 1.25-1.69; P = 8.5 × 10(-7)). In the replication step (7151 individuals), none of the 8 variants replicated, and combined meta-analysis results failed to reach genome-wide significance.
In a genome-wide association study, we were not able to reliably identify genetic variants predisposing to ERP, presumably due to insufficient statistical power and phenotype heterogeneity. The reported heritability of ERP warrants continued investigation in larger well-phenotyped populations.
Since 2‘-fluoro-5-methyl-β-l-arabinofuranosyluracil (l-FMAU) has been shown to be a potent anti-HBV agent in vitro, it was of interest to study the structure−activity relationships of related ...nucleosides. Thus, a series of 1-(2-deoxy-2-fluoro-β-l-arabinofuranosyl)pyrimidine nucleosides have been synthesized and evaluated for antiviral activity against HBV in 2.2.15 cells. For this study, l-ribose was initially used as the starting material. Due to the commercial cost of l-ribose, we have developed an efficient procedure for the preparation of l-ribose derivative 6. Starting from l-xylose, 6 was obtained in an excellent total yield (70%) through the pyridinium dichromate oxidation of the 3-OH group followed by stereoselective reduction with NaBH4. It was further converted to the 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-l-arabinofuranose (10), which was then condensed with various 5-substituted pyrimidine bases to give the nucleosides. Among the compounds synthesized, the lead compound, l-FMAU (13), exhibited the most potent anti-HBV activity (EC50 0.1 μM). None of the other uracil derivatives showed significant anti-HBV activity up to 10 μM. Among the cytosine analogues, the cytosine (27) and 5-iodocytosine (35) derivatives showed moderately potent anti-HBV activity (EC50 1.4 and 5 μM, respectively). The cytotoxicity of these nucleoside analogues has also been assessed in 2.2.15 cells as well as CEM cells. None of these compounds displayed any toxicity up to 200 μM in 2.2.15 cells. Thus, compound 13 (l-FMAU), 27, and 35 showed a selectivity of over 2000, 140, and 40, respectively.
Anger Proneness, Gender, and the Risk of Heart Failure Kucharska-Newton, Anna M., PhD, MPH; Williams, Janice E., PhD, MPH; Chang, Patricia P., MD, MPH ...
Journal of cardiac failure,
12/2014, Volume:
20, Issue:
12
Journal Article
Peer reviewed
Open access
Abstract Background Evidence regarding the association of anger proneness with incidence of heart failure is lacking. Methods and Results Anger proneness was ascertained among 13,171 black and white ...participants of the Atherosclerosis Risk in Communities (ARIC) study cohort with the use of the Spielberger Trait Anger Scale. Incident heart failure events, defined as occurrence of ICD-9-CM code 428.x, were ascertained from participants' medical records during follow-up in the years 1990–2010. Relative hazard of heart failure across categories of trait anger was estimated with the use of Cox proportional hazard models. Study participants (mean age 56.9 SD 5.7 years) experienced 1,985 incident HF events during 18.5 (SD 4.9) years of follow-up. Incidence of HF was greater among those with high, as compared to those with low or moderate trait anger, with higher incidence observed for men than for women. The relative hazard of incident HF was modestly high among those with high trait anger, compared with those with low or moderate trait anger (age-adjusted hazard ratio for men: 1.44 (95% confidence interval CI 1.23–1.69). Adjustment for comorbidities and depressive symptoms attenuated the estimated age-adjusted relative hazard in men to 1.26 (95% CI 1.00–1.60). Conclusions Assessment of anger proneness may be necessary in successful prevention and clinical management of heart failure, especially in men.
To determine causes of visual impairment in children at the Low Vision Service of the Ophthalmic Clinic at the University of São Paulo and at the Brazilian Association for the Visually Impaired ...People (Laramara), located in São Paulo, Brazil.
This study evaluated 3,210 visually impaired children (49% female, 51% male; average age, 5.9 years). Visual impairment was present in 57% (visually impaired group) and 43% presented another associated disability (multiple disability group).
The main causes of visual impairment in the visually impaired group were toxoplasmic macular retinochoroiditis (20.7%), retinal dystrophies (12.2%), retinopathy of prematurity (11.8%), ocular malformation (11.6%), congenital glaucoma (10.8%), optic atrophy (9.7%), and congenital cataracts (7.1%). The main causes of visual impairment in the multiple disability group were optic atrophy (37.7%), cortical visual impairment (19.7%), toxoplasmic macular retinochoroiditis (8.6%), retinopathy of prematurity (7.6%), ocular malformation (6.8%), congenital cataracts (6.1%), and degenerative disorders of the retina and macula (4.8%). The retina was the most frequently affected anatomic site in the visually impaired group (49.2%) and the optic nerve in the multiple disability group (39%).
Primary, secondary, and tertiary prevention efforts for childhood blindness and visual rehabilitation must be considered in Latin America.
Species-specific polymerase chain reaction (PCR) primers have been designed to identify the causative agent of columnaris disease,
Flavobacterium columnare. The 16S rRNA gene sequences of
F. ...columnare (eight sequences representing the different genotypes of the species) and related species (18 sequences) were aligned and compared to choose specific regions that are unique to
F. columnare and do not have significant intraspecies variability. The species-specific regions in the 16S rRNA gene were used to design a pair of species-specific PCR primers, ColF and ColR. The PCR technique produced a specific amplicon of about 675 base pairs (bp) in 27 isolates of
F. columnare and there was no amplification in the closely related species. The specificity of the amplified product was confirmed by digesting with
HhaI. The PCR primers did not produce a 675
bp product with
F. columnare ATCC43622 strain. This ATCC43622 strain was characterized by biochemical and ribotyping methods and renamed
Flavobacterium johnsoniae. The American Type Culture Collection has confirmed these findings and made the change.
Pathogenic bacteria were isolated from 90% of patients with acute otitis media. This higher-than-expected rate of positive cultures was probably related to the meticulous bacteriologic techniques ...used.
Abstract Physical activity during and after cancer treatment has beneficial effects on a number of physical and psychosocial outcomes. This paper aims to discuss the existing physical activity ...guidelines for cancer survivors and to describe future research directions to optimize prescriptions. Studies on physical activity during and after cancer treatment were searched in PubMed, Clinicaltrials.gov, Australian New Zealand Clinical Trials Registry, and Dutch Trial registry. Physical activity guidelines for cancer survivors suggest that physical activity should be an integral and continuous part of care for all cancer survivors. However, the development of these guidelines has been limited by the research conducted. To be able to develop more specific guidelines, future studies should focus on identifying clinical, personal, physical, psychosocial, and intervention moderators explaining ‘for whom’ or ‘under what circumstances’ interventions work. Further, more insight into the working mechanisms of exercise interventions on health outcomes in cancer survivors is needed to improve the efficacy and efficiency of interventions. Finally, existing programs should embrace interests and preferences of patients to facilitate optimal uptake of interventions. In conclusion, current physical activity guidelines for cancer survivors are generic, and research is needed to develop more personalized physical activity guidelines.
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