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71.
PC Rummel KN Arfelt L Baumann TJ Jenkins S Thiele HR Lüttichau A Johnsen J Pease S Ghosh R Kolbeck MM Rosenkilde 《British journal of pharmacology》2012,167(6):1206-1217
BACKGROUND AND PURPOSE
Here we present a novel series of CCR8 antagonists based on a naphthalene-sulfonamide structure. This structure differs from the predominant pharmacophore for most small-molecule CC-chemokine receptor antagonists, which in fact activate CCR8, suggesting that CCR8 inhibition requires alternative structural probes.EXPERIMENTAL APPROACH
The compounds were tested as inverse agonists and as antagonists against CCL1-induced activity in Gαi signalling and chemotaxis. Furthermore, they were assessed by heterologous competition binding against two radiolabelled receptor ligands: the endogenous agonist CCL1 and the virus-encoded antagonist MC148.KEY RESULTS
All compounds were highly potent inverse agonists with EC50 values from 1.7 to 23 nM. Their potencies as antagonists were more widely spread (EC50 values from 5.9 to 1572 nM). Some compounds were balanced antagonists/inverse agonists whereas others were predominantly inverse agonists with >100-fold lower potency as antagonists. A correspondingly broad range of affinities, which followed the antagonist potencies, was disclosed by competition with [125I]-CCL1 (Ki 3.4–842 nM), whereas the affinities measured against [125I]-MC148 were less widely spread (Ki 0.37–27 nM), and matched the inverse agonist potencies.CONCLUSION AND IMPLICATIONS
Despite highly potent and direct effects as inverse agonists, competition-binding experiments against radiolabelled agonist and tests for antagonism revealed a probe-dependent allosteric effect of these compounds. Thus, minor chemical changes affected the ability to modify chemokine binding and action, and divided the compounds into two groups: predominantly inverse agonists and balanced antagonists/inverse agonists. These studies have important implications for the design of new inverse agonists with or without antagonist properties. 相似文献72.
J Mark FitzGerald Charles KN Chan Martin C Holroyde Louis-Philippe Boulet 《Canadian respiratory journal》2008,15(1):27-32
BACKGROUND:
Oropharyngeal (OP) symptoms are common in asthma patients using inhaled corticosteroids (ICSs) alone and in combination with a long-acting beta2-agonist (LABA). Patterns of medication use, level of asthma control and association with OP symptoms are not often reported in a nonstudy setting.OBJECTIVES:
To determine the prevalence of OP symptoms among adult asthma patients using ICSs alone and an ICS plus a LABA; to investigate the relationships between medication use, asthma control and OP symptoms; and to assess family physicians’ (FPs’) perceptions of the prevalence and management of OP symptoms.METHODS:
A random telephone survey of 1003 asthma patients and 250 FPs treating asthma patients was conducted from February to March 2005 across Canada.RESULTS:
Twenty-four per cent of patients experienced OP symptoms; 67% of them spoke to their FPs about the OP symptoms. Thirty-one per cent of patients who experienced OP symptoms stopped or reduced their dose of medication. OP symptoms were reported by 25% of patients using ICSs and 22% using an ICS plus a LABA. The incidence of OP symptoms was not affected by the choice of inhalation device (metered-dose inhaler versus dry powder inhaler) or the use of a spacer. Fifty-eight per cent of patients had uncontrolled asthma; patients achieving a lower level of general education were more likely to have poor control. Patients with uncontrolled asthma were more likely than those with controlled asthma to report OP symptoms (28% versus 18%, respectively; P<0.05). Eighty-nine per cent of FPs had patients who had reported OP symptoms to them. FPs estimated that 15% of their patients experienced OP symptoms and that compliance to treatment worsened in approximately 20% of them.CONCLUSIONS:
The prevalence of OP symptoms in asthma patients using ICSs and an ICS plus a LABA is significant. OP symptoms were found to be associated with a reduced patient education level, with a likelihood of reducing or stopping medication, and with a less well-controlled asthma patient. While FPs recognized that a significant proportion of their asthma patients experience OP symptoms and that OP symptoms may affect compliance, they underestimated the prevalence of this problem. 相似文献73.
74.
ObjectiveTo evaluate the possible antifilarial effect of ethyl acetate extract of Vitex negundo (Verbenaceae) leaves against Setaria cervi filarial parasite in vitro.MethodsIn vitro screening was done by the method of motility inhibition and MTT reduction assay with concentrations of 0.03 to 1.00 mg/mL for 2 to 24 h incubation periods respectively, for possible antifilarial effect by comparing with control.ResultsIn motility assay, complete inhibition of motility was observed and in MTT reduction assay which gave >50% reduction for concentrations 0.20, 0.50 and 1.00 mg/mL at 10, 6 and 2 h incubation periods respectively in a dose dependent manner (P<0.05). An antifilarial effect imparted by plant extract was found to be a function of their relative concentrations. Inhibitory concentration (IC50) for the plant extract was found to be 0.16 mg/mL.ConclusionsThe present study recorded significant antifilarial effect of Vitex negundo plant extract and contributed toward the development of database for novel drug candidates for lymphatic filariasis. 相似文献
75.
Biochemical, immunological, and in vivo functional characterization of B-domain-deleted factor VIII 总被引:12,自引:4,他引:12
Coagulation factor VIII (FVIII) is a cofactor in the intrinsic pathway of blood coagulation for which deficiency results in the bleeding disorder hemophilia A. FVIII contains a domain structure of A1-A2-B-A3- C1-C2 of which the B domain is dispensable for procoagulant activity in vitro. In this report, we compare the properties of B-domain-deleted FVIII (residues 760 through 1639, designated LA-VIII) to wildtype recombinant FVIII. In transfected Chinese hamster ovary (CHO) cells, LA- VIII was expressed at a 10- to 20-fold greater level compared with wildtype FVIII. The specific activity of purified LA-VIII was indistinguishable from wild-type recombinant FVIII and both exhibited similar thrombin activation coefficients. Wildtype recombinant-derived FVIII and LA-VIII also displayed similar timecourses of thrombin activation and heavy chain cleavage. However, compared with wildtype recombinant-derived FVIII, the light chain of LA-VIII was cleaved fivefold more rapidly by thrombin. Addition of purified von Willebrand factor (vWF) did not alter the kinetics of thrombin cleavage or activation of either wildtype recombinant-derived FVIII or LA-VIII. The immunogenicity of LA-VIII was compared with wildtype FVIII in a novel model of neonatal tolerance induction in mice. The results did not detect any immunologic differences between wildtype FVIII and LA-VIII, suggesting that LA-VIII does not contain significant new epitopes that are absent in wildtype FVIII. LA-VIII was tolerated well on infusion into FVIII-deficient dogs and was able to correct the cuticle bleeding time similar to wildtype recombinant factor VIII. In vivo, LA-VIII was bound to canine vWF and exhibited a half-life similar to wildtype recombinant FVIII. These studies support that B-domain-deleted FVIII may be efficacious in treatment of hemophilia A in humans. 相似文献
76.
77.
Christina Gummesson Isam Atroshi Charlotte Ekdahl Ragnar Johnsson Ewald Ornstein 《Arthritis care & research》2003,49(5):697-702
Objective
To estimate the prevalence of self reported chronic upper extremity pain associated with physical impairment in a general population, and its co‐occurrence with chronic upper extremity numbness or tingling and chronic pain at other locations.Methods
A general health questionnaire was mailed to 3,000 persons (age 25–74 years) who were randomly selected from a general population register.Results
The response rate was 83%. The prevalence of chronic upper extremity pain associated with physical impairment was 20.8% (95% confidence interval [95% CI] 19.2–22.5), and that of co‐occurring numbness or tingling was 6.7% (95% CI 5.7–7.7). Among the responders with chronic upper extremity pain associated with physical impairment, 84% reported more than 1 painful area.Conclusion
Chronic upper extremity pain associated with physical impairment and co‐occurring chronic upper extremity numbness or tingling were common in the general population. The presence of more than 1 location for pain in the upper extremity as well as in other parts of the body was frequent.78.
Factors associated with the development of arm lymphedema following breast cancer treatment: a match pair case-control study 总被引:3,自引:0,他引:3
We examined factors that may influence the development of arm lymphedema following breast cancer treatment including the specific mode of therapy, patient occupation and life style. Medical record data and a questionnaire were used to collect information after surgery concerning such issues as wound seroma, infection, adjuvant treatment, vessel string (phlebitis), body mass index, smoking habits and stress. Occupational workload was assessed after surgery whereas housework, exercise, hobbies and body weight were assessed both before and after surgery. Seventy-one breast cancer treated women with arm lymphedema lasting more than 6 months but less than 2 years were matched to women similarly treated for breast cancer but without arm lymphedema (controls). The matching factors included axillary node status, time after axillary dissection, and age. In the lymphedema group, there was a higher body mass index at time of surgery (p=0.03) as well at time of study (p=0.04). No differences were found in occupational workload (n=38) or housework, but the lymphedema group reduced their spare time activities including exercise after surgery compared with the controls (p<0.01). In conclusion, women treated for breast cancer with axillary node dissection with or without adjuvant radiotherapy could maintain their level of physical activity and occupational workload after treatment without an added risk of developing arm lymphedema. On the other hand, a higher BMI before and after operation increases the lymphedema risk. 相似文献
79.
Summary. The aim of this study was to assess the risk of hepatocellular carcinoma (HCC) and other primary liver cancers (PLC) in the nationwide cohort of hepatitis C virus (HCV) infected patients in Sweden. The basis was the total HCV-cohort notified in 1990–2004, after excluding 3238 people also reported with hepatitis B, the study cohort consisted of 36 126 people contributing an observation time of 246 105 person-years. The most common route of transmission was intravenous drug use (57%). The national Cancer Registry was used for follow-up, and 354 developed PLC (mainly HCC), of whom 234 were eligible for statistical analysis. The PLC incidence in the HCV cohort was compared with the incidence in the general population, and a standardized incidence ratio (SIR) was calculated for six different strata according to estimated duration of infection. The highest relative risk, SIR: 46 (95% CI: 36–56) was found in the stratum 25–30 years with HCV infection and SIR: 40 (95% CI: 31–51) in the stratum 30–35 years with infection. In the entire community-based HCV cohort in Sweden we found a highly increased risk of liver cancer compared to the general population. The highest relative risk was among people who had been infected for more than 25 years. 相似文献
80.
Automated segmentation of visceral and subcutaneous (deep and superficial) adipose tissues in normal and overweight men 下载免费PDF全文
Suresh Anand Sadananthan PhD Bhanu Prakash KN PhD Melvin Khee‐Shing Leow MMed PhD Chin Meng Khoo MBBS Hong Chou MMed Kavita Venkataraman MBBS PhD Eric Y.H. Khoo MBChB Yung Seng Lee MMed PhD Peter D. Gluckman DSc E. Shyong Tai MBChB PhD S. Sendhil Velan PhD 《Journal of magnetic resonance imaging : JMRI》2015,41(4):924-934