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21.
Turner SC Carroll WA White TK Gopalakrishnan M Coghlan MJ Shieh CC Zhang XF Parihar AS Buckner SA Milicic I Sullivan JP 《Bioorganic & medicinal chemistry letters》2003,13(12):2003-2007
2-Amino-4-azaindoles have been identified as a structurally novel class of BK(Ca) channel openers. Their synthesis from 2-chloro-3-nitropyridine is described together with their in vitro properties assessed by 86Rb(+) efflux and whole-cell patch-clamp assays using HEK293 cells stably transfected with the BK(Ca) alpha subunit. In vitro functional characterization of BK(Ca) channel opening activity was also assessed by measurement of relaxation of smooth muscle tissue strips obtained from Landrace pig bladders. The preliminary SAR data indicate the importance of steric bulk around the 2-amino substituent. 相似文献
22.
Logging and hunting are two key direct threats to the survival of wildlife in the tropics, and also disrupt important ecosystem processes. We investigated the impacts of these two factors on the different stages of the seed dispersal cycle, including abundance of plants and their dispersers and dispersal of seeds and recruitment, in a tropical forest in north-east India. We focused on hornbills, which are important seed dispersers in these forests, and their food tree species. We compared abundances of hornbill food tree species in a site with high logging and hunting pressures (heavily disturbed) with a site that had no logging and relatively low levels of hunting (less disturbed) to understand logging impacts on hornbill food tree abundance. We compared hornbill abundances across these two sites. We, then, compared the scatter-dispersed seed arrival of five large-seeded tree species and the recruitment of four of those species. Abundances of hornbill food trees that are preferentially targeted by logging were two times higher in the less disturbed site as compared to the heavily disturbed site while that of hornbills was 22 times higher. The arrival of scatter-dispersed seeds was seven times higher in the less disturbed site. Abundances of recruits of two tree species were significantly higher in the less disturbed site. For another species, abundances of younger recruits were significantly lower while that of older recruits were higher in the heavily disturbed site. Our findings suggest that logging reduces food plant abundance for an important frugivore-seed disperser group, while hunting diminishes disperser abundances, with an associated reduction in seed arrival and altered recruitment of animal-dispersed tree species in the disturbed site. Based on our results, we present a conceptual model depicting the relationships and pathways between vertebrate-dispersed trees, their dispersers, and the impacts of hunting and logging on these pathways. 相似文献
23.
Background
Outpatient parenteral antimicrobial therapy (OPAT) is accepted as safe and effective for medically stable patients to complete intravenous (IV) antibiotics in an outpatient setting. Since, however, uninsured patients in the United States generally cannot afford OPAT, safety-net hospitals are often burdened with long hospitalizations purely to infuse antibiotics, occupying beds that could be used for patients requiring more intensive services. OPAT is generally delivered in one of four settings: infusion centers, nursing homes, at home with skilled nursing assistance, or at home with self-administered therapy. The first three—termed healthcare-administered OPAT (H-OPAT)—are most commonly used in the United States by patients with insurance funding. The fourth—self-administered OPAT (S-OPAT)—is relatively uncommon, with the few published studies having been conducted in the United Kingdom. With multidisciplinary planning, we established an S-OPAT clinic in 2009 to shift care of selected uninsured patients safely to self-administration of their IV antibiotics at home. We undertook this study to determine whether the low-income mostly non-English-speaking patients in our S-OPAT program could administer their own IV antimicrobials at home with outcomes as good as, or better than, those receiving H-OPAT.Methods and Findings
Parkland Hospital is a safety-net hospital serving Dallas County, Texas. From 1 January 2009 to 14 October 2013, all uninsured patients meeting criteria were enrolled in S-OPAT, while insured patients were discharged to H-OPAT settings. The S-OPAT patients were trained through multilingual instruction to self-administer IV antimicrobials by gravity, tested for competency before discharge, and thereafter followed at designated intervals in the S-OPAT outpatient clinic for IV access care, laboratory monitoring, and physician follow-up. The primary outcome was 30-d all-cause readmission, and the secondary outcome was 1-y all-cause mortality. The study was adequately powered for readmission but not for mortality. Clinical, sociodemographic, and outcome data were collected from the Parkland Hospital electronic medical records and the US census, constituting a historical prospective cohort study. We used multivariable logistic regression to develop a propensity score predicting S-OPAT versus H-OPAT group membership from covariates. We then estimated the effect of S-OPAT versus H-OPAT on the two outcomes using multivariable proportional hazards regression, controlling for selection bias and confounding with the propensity score and covariates.Of the 1,168 patients discharged to receive OPAT, 944 (81%) were managed in the S-OPAT program and 224 (19%) by H-OPAT services. In multivariable proportional hazards regression models controlling for confounding and selection bias, the 30-d readmission rate was 47% lower in the S-OPAT group (adjusted hazard ratio [aHR], 0.53; 95% CI 0.35–0.81; p = 0.003), and the 1-y mortality rate did not differ significantly between the groups (aHR, 0.86; 95% CI 0.37–2.00; p = 0.73). The S-OPAT program shifted a median 26 d of inpatient infusion per patient to the outpatient setting, avoiding 27,666 inpatient days. The main limitation of this observational study—the potential bias from the difference in healthcare funding status of the groups—was addressed by propensity score modeling.Conclusions
S-OPAT was associated with similar or better clinical outcomes than H-OPAT. S-OPAT may be an acceptable model of treatment for uninsured, medically stable patients to complete extended courses of IV antimicrobials at home. 相似文献24.
25.
Kavita Venkataraman Luor Shyuan Maudrene Tan Dianne Carrol Tan Bautista Konstadina Griva Yasmin Laura Marie Zuniga Mohamed Amir Yung Seng Lee Jeannette Lee E. Shyong Tai Eric Yin Hao Khoo Hwee Lin Wee 《PloS one》2015,10(9)
Background
Emotional distress is an important dimension in diabetes, and several instruments have been developed to measure this aspect. The Problem Areas in Diabetes (PAID) scale is one such instrument which has demonstrated validity and reliability in Western populations, but its psychometric properties in Asian populations have not been examined.Methods
This was a secondary analysis of data from patients with Type 2 diabetes mellitus recruited through convenience sampling from a diabetes specialist outpatient clinic in Singapore. The following psychometric properties were assessed: Construct validity through confirmatory factor analysis (CFA) and Rasch analysis, concurrent validity through correlation with related scales (Kessler Psychological Distress Scale, Diabetes Health Profile—psychological distress, Audit of Diabetes Dependent Quality of Life), reliability through assessment of internal consistency and floor and ceiling effects, and sensitivity by estimating effect sizes for known clinical and social functioning groups.Results
203 patients with mean age of 45±12 years were analysed. None of the previously published model structures achieved a good fit on CFA. On Rasch analysis, four items showed poor fit and were removed. The abridged 16-item PAID mapped to a single latent trait, with a high degree of internal consistency (Cronbach ɑ 0.95), but significant floor effect (24.6% scoring at floor). Both 20-item and 16-item PAID scores were moderately correlated with scores of related scales, and sensitive to differences in clinical and social functioning groups, with large effect sizes for glycemic control and diabetes related complications, nephropathy and neuropathy.Conclusion
The abridged 16-item PAID measures a single latent trait of emotional distress due to diabetes whereas the 20-item PAID appears to measures more than one latent trait. However, both the 16-item and 20-item PAID versions are valid, reliable and sensitive for use among Singaporean patients with diabetes. 相似文献26.
27.
Reto Guler Suraj P. Parihar Suzana Savvi Erin Logan Anita Schwegmann Sugata Roy Natalie E. Nieuwenhuizen Mumin Ozturk Sebastian Schmeier Harukazu Suzuki Frank Brombacher 《PloS one》2015,10(3)
Classical activation of macrophages (caMph or M1) is crucial for host protection against Mycobacterium tuberculosis (Mtb) infection. Evidence suggests that IL-4/IL-13 alternatively activated macrophages (aaMph or M2) are exploited by Mtb to divert microbicidal functions of caMph. To define the functions of M2 macrophages during tuberculosis (TB), we infected mice deficient for IL-4 receptor α on macrophages (LysMcreIL-4Rα-/lox) with Mtb. We show that absence of IL-4Rα on macrophages does not play a major role during infection with Mtb H37Rv, or the clinical Beijing strain HN878. This was demonstrated by similar mortality, bacterial burden, histopathology and T cell proliferation between infected wild-type (WT) and LysMcreIL-4Rα-/lox mice. Interestingly, we observed no differences in the lung expression of inducible nitric oxide synthase (iNOS) and Arginase 1 (Arg1), well-established markers for M1/M2 macrophages among the Mtb-infected groups. Kinetic expression studies of IL-4/IL-13 activated bone marrow-derived macrophages (BMDM) infected with HN878, followed by gene set enrichment analysis, revealed that the MyD88 and IL-6, IL-10, G-CSF pathways are significantly enriched, but not the IL-4Rα driven pathway. Together, these results suggest that IL-4Rα-macrophages do not play a central role in TB disease progression. 相似文献
28.
Reshu Saxena Sudipti Gupta Kavita Singh Kalyan Mitra Anil Kumar Tripathi Raj Kamal Tripathi 《PloS one》2015,10(4)
Nef is an accessory viral protein that promotes HIV-1 replication, facilitating alterations in cellular pathways via multiple protein-protein interactions. The advent of proteomics has expanded the focus on better identification of novel molecular pathways regulating disease progression. In this study, nef was sequenced from randomly selected patients, however, sequence variability identified did not elicited any specific mutation that could have segregated HIV-1 patients in different stages of disease progression. To explore the difference in Nef functionality based on sequence variability we used proteomics approach. Proteomic profiling was done to compare the effect of Nef variants in host cell protein expression. 2DGE in control and Nef transfected SupT1 cells demonstrated several differentially expressed proteins. Fourteen protein spots were detected with more than 1.5 fold difference. Significant down regulation was seen in six unique protein spots in the Nef treated cells. Proteins were identified as Cyclophilin A, EIF5A-1 isoform B, Rho GDI 1 isoform a, VDAC1, OTUB1 and α-enolase isoform 1 (ENO1) through LC-MS/MS. The differential expression of the 6 proteins was analyzed by Real time PCR, Western blotting and Immunofluorescence studies with two Nef variants (RP14 and RP01) in SupT1 cells. There was contrasting difference between the effect of these Nef variants upon the expression of these six proteins. Downregulation of α-enolase (ENO1), VDAC1 and OTUB1 was more significant by Nef RP01 whereas Cyclophilin A and RhoGDI were found to be more downregulated by Nef RP14. This difference in Nef variants upon host protein expression was also studied through a site directed mutant of Nef RP01 (55AAAAAAA61) and the effect was found to be reversed. Deciphering the role of these proteins mediated by Nef variants will open a new avenue of research in understanding Nef mediated pathogenesis. Overall study determines modulation of cellular protein expression in T cells by HIV-1 Nef variants. 相似文献
29.
30.
Arti Parihar Mordhwaj S. Parihar Rafal Nazarewicz Pedram Ghafourifar 《Biochimica et Biophysica Acta (BBA)/General Subjects》2010