HDL Cholesterol Is Not Associated with Lower Mortality in Patients with Kidney Dysfunction

In the general population, HDL cholesterol (HDL-C) is associated with reduced cardiovascular events. However, recent experimental data suggest that the vascular effects of HDL can be heterogeneous. We examined the association of HDL-C with all-cause and cardiovascular mortality in the Ludwigshafen Risk and Cardiovascular Health study comprising 3307 patients undergoing coronary angiography. Patients were followed for a median of 9.9 years. Estimated GFR (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration eGFR creatinine-cystatin C (eGFRcreat-cys) equation. The effect of increasing HDL-C serum levels was assessed using Cox proportional hazard models. In participants with normal kidney function (eGFR>90 ml/min per 1.73 m(2)), higher HDL-C was associated with reduced risk of all-cause and cardiovascular mortality and coronary artery disease severity (hazard ratio [HR], 0.51, 95% confidence interval [95% CI], 0.26-0.92 [P=0.03]; HR, 0.30, 95% CI, 0.13-0.73 [P=0.01]). Conversely, in patients with mild (eGFR=60-89 ml/min per 1.73 m(2)) and more advanced reduced kidney function (eGFR<60 ml/min per 1.73 m(2)), higher HDL-C did not associate with lower risk for mortality (eGFR=60-89 ml/min per 1.73 m(2): HR, 0.68, 95% CI, 0.45-1.04 [P=0.07]; HR, 0.84, 95% CI, 0.50-1.40 [P=0.50]; eGFR<60 ml/min per 1.73 m(2): HR, 1.18, 95% CI, 0.60-1.81 [P=0.88]; HR, 0.82, 95% CI, 0.40-1.69 [P=0.60]). Moreover, Cox regression analyses revealed interaction between HDL-C and eGFR in predicting all-cause and cardiovascular mortality (P=0.04 and P=0.02, respectively). We confirmed a lack of association between higher HDL-C and lower mortality in an independent cohort of patients with definite CKD (P=0.63). In summary, higher HDL-C levels did not associate with reduced mortality risk and coronary artery disease severity in patients with reduced kidney function. Indeed, abnormal HDL function might confound the outcome of HDL-targeted therapies in these patients.

Effects of chronic renal disease on the transport of vitamin A in plasma and urine of dogs

OBJECTIVE To determine plasma and urine concentrations of retinol, retinyl esters, retinol-binding protein (RBP), and Tamm-Horsfall protein (THP) in dogs with chronic renal disease (CRD). ANIMALS 17 dogs with naturally developing CRD and 21 healthy control dogs. PROCEDURE A diagnosis of CRD was established on the basis of clinical signs, plasma concentrations of creatinine and urea, and results of urinalysis. Concentrations of retinol and retinyl esters were measured by use of reverse-phase high-performance liquid chromatography. Concentrations of RBP and THP were measured by use of sensitive ELISA systems. RESULTS Dogs with CRD had higher plasma concentrations of retinol, which were not paralleled by differences in plasma concentrations of RBP. Calculated ratio of urinary total vitamin A (sum of concentrations of retinol and retinyl esters to creatinine concentration) and ratio of the concentration of urinary retinyl esters to creatinine concentration did not differ between groups. However, we detected a significantly higher retinol-to-creatinine ratio in the urine of dogs with CRD, which was paralleled by a higher urinary RBP-to-creatinine ratio. Thus, in dogs with CRD, the estimated fractional clearance of total vitamin A, retinol, and RBP was increased. Furthermore, dogs with CRD had a reduced urinary THP-to-creatinine ratio. CONCLUSIONS AND CLINICAL RELEVANCE Results of this study documented that CRD affects the concentrations of retinol in plasma and urine of dogs. Analysis of the data indicates that measurement of urinary RBP and urinary THP concentrations provides valuable information that can be helpful in follow-up monitoring of dogs with CRD.

Discovery of a highly potent anti-inflammatory epoxyisoprostane-derived lactone.

Epoxyisoprostanes EI (1) and EC (2) are effective inhibitors of the secretion of proinflammatory cytokines IL-6 and IL-12. In detailed studies toward the investigation of the molecular mode of action of these structures, a highly potent lactone (3) derived from 1 was identified. The known isoprostanoids 1 and 2 are most likely precursors of 3, the product of facile intramolecular reaction between the epoxide with the carboxylic acid in 2.

FTY720 and two novel butterfly derivatives exert a general anti-inflammatory potential by reducing immune cell adhesion to endothelial cells through activation of S1P3 and phosphoinositide 3-kinase

Sphingosine-1-phosphate (S1P) is a key lipid regulator of a variety of cellular responses including cell proliferation and survival, cell migration, and inflammatory reactions. Here, we investigated the effect of S1P receptor activation on immune cell adhesion to endothelial cells under inflammatory conditions. We show that S1P reduces both tumor necrosis factor (TNF)-α- and lipopolysaccharide (LPS)-stimulated adhesion of Jurkat and U937 cells to an endothelial monolayer. The reducing effect of S1P was reversed by the S1P1+3 antagonist VPC23019 but not by the S1P1 antagonist W146. Additionally, knockdown of S1P3, but not S1P1, by short hairpin RNA (shRNA) abolished the reducing effect of S1P, suggesting the involvement of S1P3. A suppression of immune cell adhesion was also seen with the immunomodulatory drug FTY720 and two novel butterfly derivatives ST-968 and ST-1071. On the molecular level, S1P and all FTY720 derivatives reduced the mRNA expression of LPS- and TNF-α-induced adhesion molecules including ICAM-1, VCAM-1, E-selectin, and CD44 which was reversed by the PI3K inhibitor LY294002, but not by the MEK inhibitor U0126.In summary, our data demonstrate a novel molecular mechanism by which S1P, FTY720, and two novel butterfly derivatives acted anti-inflammatory that is by suppressing gene transcription of various endothelial adhesion molecules and thereby preventing adhesion of immune cells to endothelial cells and subsequent extravasation.

Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis.

BACKGROUND Non-steroidal anti-inflammatory drugs (NSAIDs) are the backbone of osteoarthritis pain management. We aimed to assess the effectiveness of different preparations and doses of NSAIDs on osteoarthritis pain in a network meta-analysis. METHODS For this network meta-analysis, we considered randomised trials comparing any of the following interventions: NSAIDs, paracetamol, or placebo, for the treatment of osteoarthritis pain. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and the reference lists of relevant articles for trials published between Jan 1, 1980, and Feb 24, 2015, with at least 100 patients per group. The prespecified primary and secondary outcomes were pain and physical function, and were extracted in duplicate for up to seven timepoints after the start of treatment. We used an extension of multivariable Bayesian random effects models for mixed multiple treatment comparisons with a random effect at the level of trials. For the primary analysis, a random walk of first order was used to account for multiple follow-up outcome data within a trial. Preparations that used different total daily dose were considered separately in the analysis. To assess a potential dose-response relation, we used preparation-specific covariates assuming linearity on log relative dose. FINDINGS We identified 8973 manuscripts from our search, of which 74 randomised trials with a total of 58 556 patients were included in this analysis. 23 nodes concerning seven different NSAIDs or paracetamol with specific daily dose of administration or placebo were considered. All preparations, irrespective of dose, improved point estimates of pain symptoms when compared with placebo. For six interventions (diclofenac 150 mg/day, etoricoxib 30 mg/day, 60 mg/day, and 90 mg/day, and rofecoxib 25 mg/day and 50 mg/day), the probability that the difference to placebo is at or below a prespecified minimum clinically important effect for pain reduction (effect size [ES] -0·37) was at least 95%. Among maximally approved daily doses, diclofenac 150 mg/day (ES -0·57, 95% credibility interval [CrI] -0·69 to -0·46) and etoricoxib 60 mg/day (ES -0·58, -0·73 to -0·43) had the highest probability to be the best intervention, both with 100% probability to reach the minimum clinically important difference. Treatment effects increased as drug dose increased, but corresponding tests for a linear dose effect were significant only for celecoxib (p=0·030), diclofenac (p=0·031), and naproxen (p=0·026). We found no evidence that treatment effects varied over the duration of treatment. Model fit was good, and between-trial heterogeneity and inconsistency were low in all analyses. All trials were deemed to have a low risk of bias for blinding of patients. Effect estimates did not change in sensitivity analyses with two additional statistical models and accounting for methodological quality criteria in meta-regression analysis. INTERPRETATION On the basis of the available data, we see no role for single-agent paracetamol for the treatment of patients with osteoarthritis irrespective of dose. We provide sound evidence that diclofenac 150 mg/day is the most effective NSAID available at present, in terms of improving both pain and function. Nevertheless, in view of the safety profile of these drugs, physicians need to consider our results together with all known safety information when selecting the preparation and dose for individual patients. FUNDING Swiss National Science Foundation (grant number 405340-104762) and Arco Foundation, Switzerland.

Temporal variations of dyspnea, fatigue, and lung function in chronic lung disease

Background. Research investigating symptom management in patients with chronic obstructive pulmonary disease (COPD) largely has been undertaken assuming the homeostatic construct, without regard to potential roles of circadian rhythms. Temporal relations among dyspnea, fatigue, peak expiratory flow rate (PEFR) and objective measures of activity/rest have not been reported in COPD. ^ Objectives. The specific aims of this study were to (1) explore the 24-hour patterns of dyspnea, fatigue, and PEFR in subjects with COPD; (2) examine the relations among dyspnea, fatigue, and PEFR in COPD; and (3) examine the relations among objective measures of activity/rest and dyspnea, fatigue, and PEFR in COPD. ^ Methods. The repeated-measures design involved 10 subjects with COPD who self-assessed dyspnea and fatigue by 100 mm visual analog scales, and PEFR by peak flow meter in their home 5 times a day for 8 days. Activity/rest was measured by wrist actigraphy. Single and population mean cosinor analyses and correlations were computed for dyspnea, fatigue, and PEFR; correlations were done among these variables and activity/rest. ^ Results. Circadian rhythms were documented by single cosinor analysis in 40% of the subjects for dyspnea, 60% for fatigue, and 60% for PEFR. The population cosinor analysis of PEFR yielded a significant rhythm (p < .05). The 8-day 24-hour means of dyspnea and fatigue was moderately correlated (r = .48, p < .01). Dyspnea and PEFR, and fatigue and PEFR, were weakly correlated in a negative way (r = −.11, p < .05 and r = −.15, p < .01 respectively). Weak to moderate correlations (r = .12–.34, p < .05) were demonstrated between PEFR and mean activity level measured up to 4 hours before PEFR measurement. ^ Conclusions. The findings suggest that (1) the dyspnea and fatigue experienced by COPD patients are moderately related, (2) there is a weak to modest positive relation between PEFR and activity levels, and (3) temporal variation in lung function may not affect the dyspnea and fatigue experienced by patients with COPD. Further research, examining the relations among dyspnea, fatigue, PEFR, and activity/rest is needed. Replication of this study is suggested with a larger sample size. ^

Spirituality of Thai Buddhists with chronic cardiovascular disease

Background. Advances in medical technology contribute to the survival rate of a growing number of persons with chronic illnesses. Individuals with chronic cardiovascular disease (chronic CVD) are among other chronically ill persons who add to the need for healthcare services. They need to cope and live with the chronic conditions and find a new balance to make sense of their lives. Thai Buddhists with chronic CVD may use their religious resources to cope with their illnesses because religious beliefs are reflected in patterns of living. The aims of the study were to: (a) explore how Thai Buddhists with chronic CVD construct the spiritual aspects of the illness experience, (b) explore how Thai Buddhists with chronic CVD may use their spiritual/religious resources as a means of coping with the illness, and (c) explore the impacts of spiritual/religious beliefs and/or practices on the daily lives of Thai Buddhists with chronic CVD. ^ Methods. Ethnography was employed and data were collected from December 1, 2007 to May 31, 2008 using in-depth interviews with 20 participants. Field notes were also recorded. ^ Findings. Three categories emerged from the study data: set of spiritual and biomedical beliefs and practices, integrated meanings, and positive consequences of the integration of spiritual and biomedical beliefs and practices. ^ Conclusions. The findings of the study suggest the importance of understanding and integrating spiritual needs into care of patients with chronic CVD. The findings revealed that the participants constructed ideas of their illness and meanings for living and coping with the illness, and integrated spiritual and biomedical beliefs and practices, resulting in positive outcomes. Further research could test interventions which facilitate such coping; for example, using reflective thinking and group support. Other studies might explore how age affects Buddhist views of the illness. ^

The role of chronic irritation and inflammation in tumor promotion in CD-1 mice by petroleum middle distillates

An initiation-promotion bioassay in CD-1 mice was used to examine the role of chronic irritation and inflammation in tumor promotion by petroleum middle distillates. A representative hydrodesulfurized middle distillate (API 81-07) was selected as the test article. Test groups (54 mice per group) were initiated once with 50 ug of 7,12-dimethylbenzanthracene (DMBA). Promotion with API 81-07 consisted of twice weekly treatments for 25 weeks with either 25 ul, 50 ul, 50 ul + daily treatment with 15 ug dexamethasone, 50 ul + post-application washings, and 100 ul. Three mice from each group were sacrificed at 21 day intervals (24 total per group). The skin from interim sacrificed (IS) mice was examined histopathologically for tumor, acanthosis, hyperkeratosis, pseudo-epitheliomatous hyperplasia, epidermal crusting, and subacute inflammation. In-life observations included examination of all mice for erythema and edema for 8 weeks following the first promotion treatment. Tumor incident at study termination was as follows: 25 ul (45%), 50 ul (43%), 50 ul + dexamethasone (0%), 50 ul + washing (70%), and 100 ul (81%). An overall correlation of $>$0.90 between tumor incidence and group means for acanthosis and hyperkeratosis was observed in IS mice at all intervals. Correlations of $<$0.75 were observed for other group mean histopathological parameters and tumor incidence. The overall correlation of group mean erythema and edema with tumor incident was $>$0.90. The results of this study support the hypothesis that induction of a lasting, albeit mild, hyperplasia is an essential, but not sufficient requirement, for tumor promotion. Furthermore, subacute inflammation does not appear to be a significant factor in tumor promotion by petroleum middle distillates. However, inflammation may be a factor in tumor progression. ^

Structure of a soluble secreted chemokine inhibitor vCCI (p35) from cowpox virus

Most poxviruses, including variola, the causative agent of smallpox, express a secreted protein of 35 kDa, vCCI, which binds CC-chemokines with high affinity. This viral protein competes with the host cellular CC-chemokine receptors (CCRs), reducing inflammation and interfering with the host immune response. Such proteins or derivatives may have therapeutic uses as anti-inflammatory agents. We have determined the crystal structure to 1.85-Å resolution of vCCI from cowpox virus, the prototype of this poxvirus virulence factor. The molecule is a β-sandwich of topology not previously described. A patch of conserved residues on the exposed face of a β-sheet that is strongly negatively charged might have a role in binding of CC-chemokines, which are positively charged.