Increased red cell distribution width (RDW), a marker of anisocytosis, has been associated with adverse outcomes in multiple settings. Whether RDW is predictive of mortality in patients with peripheral artery disease (PAD) is unknown. We studied 13,039 consecutive outpatients (age 69.5 ±12.0 years, 60.9% men, 97.6% white) with PAD identified by non-invasive lower-extremity arterial testing at Mayo Clinic from 1/97 to 12/07, with follow-up through 9/09. We defined PAD as low (≤0.9) or high (≥1.4) ankle-brachial index (ABI). Cardiovascular risk factors and comorbidities were ascertained using electronic medical record (EMR)-based algorithms. RDW was obtained from the complete blood count drawn around the time of arterial evaluation. Mortality was ascertained using the Mayo EMR and Accurint® database. The association of RDW with all-cause mortality was analyzed by multivariable Cox proportional hazards regression. During a median follow-up of 5.5 years, 4039 (31.0 %) deaths occurred (28.7% in low and 38.9% in high ABI subsets). After adjustment for age, sex, cardiovascular risk factors and comorbidities, patients in the highest quartile of RDW (>14.5%) had 66% greater risk of mortality compared to the lowest quartile (<12.8%) (P<0.0001); a 1% increment in RDW was associated with 10% greater risk of all-cause mortality (hazard ratio, 1.10, 95% confidence interval [CI], 1.08 to 1.12, P<0.0001). The adjusted hazard ratio was similar in the low (1.10, 1.08-1.12) and high (1.09, 1.06-1.12) ABI subsets. In conclusion, RDW, a routinely available measure, is an independent prognostic marker in patients with PAD.

Background Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann–Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug. Methods We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease. Results With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P = 0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P = 0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%). Conclusions Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. (Funded by the National Institutes of Health and others.)

BackgroundLipocalin-2 is a novel adipokine with connection to insulin resistance. In this study, we aimed to investigate the association of serum lipocalin-2 with glucose metabolism and other metabolic phenotype in a large-scale Chinese population.MethodsWe evaluated serum lipocalin-2 in a cross-sectional sample of 2519 Chinese aged from 50 to 82 year in a Shanghai downtown district by ELISA. Glucose, insulin, lipid profile, inflammatory markers, and adipokines were also measured.ResultsSerum lipocalin-2 was significantly higher in subjects with isolated impaired fasting glucose, isolated impaired glucose tolerance, combined impaired fasting glucose/impaired glucose tolerance and newly-diagnosed type 2 diabetes than in those with normal glucose regulation. Lipocalin-2 elevation was clearly associated with a higher risk for impaired glucose regulation (OR 1.30 for each 10 ng/ml increase in serum lipocalin-2, 95% CI 1.23-1.62, p = 0.009) after adjustment of age, gender, smoking, alcohol drinking, family history of diabetes, serum CRP, serum adiponectin, serum CXCL5, HOMA-IR, BMI, and waist/hip ratio. The OR for participants with impaired glucose regulation and type 2 diabetes was 1.31 (95% CI 1.21-1.69, p < 0.001).ConclusionsOur findings suggest that elevated serum lipocalin-2 is closely and independently associated with impaired glucose regulation and type 2 diabetes.

Returning to work can be challenging for burn survivors. Approximately 28% never return to any form of employment, resulting in lower health-related quality of life. Open communication has been identified as a facilitator for return to work (RTW). To ease the RTW process and promote communication with coworkers and employers a knowledge translation (KT) intervention was developed for burn survivors. Following its implementation, the impact on the RTW process was evaluated. This study was a cross-sectional, mixed methods study where burn survivors included in the KT intervention were compared with a control group. Control group participants were selectively invited so that the two groups’ mean age, sex, and percent total body surface area burned were similar. Semistructured interviews gathered information about their RTW process and outcomes. Qualitative data were analyzed through thematic analysis and quantitative data were summarized and compared using Mann–Whitney tests. Overall, both groups were satisfied with their RTW process. Participants from the control group identified more barriers related to support received, particularly at work, and reported more psychological symptoms such as posttraumatic stress disorder, self-consciousness, and discomfort with questions. Many participants from the KT group indicated the KT intervention gave them tools and information to provide others with a better understanding of their lived experience. It is possible that the KT intervention facilitated more open communication by empowering burn survivors to explain their situation on their own, thus reducing the prevalence of social and psychological barriers by allowing them to self-advocate for more support.

Objective The aim of this study was to investigate whether remedial hydration (RH) reduces the incidence of contrast-induced nephropathy (CIN) and short-term adverse events in ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). Methods A total of 216 consecutive STEMI patients were prospectively and randomly assigned into two groups: 108 patients in the RH group and 108 patients in the no RH (control) group. The serum creatinine (SCr) and creatinine clearance (CCr) levels were measured on admission and at 24, 48 and 72 hours after primary PCI. The rates of CIN and short-term adverse events were analyzed for each group. After surgery, the patients were categorized into four groups according to the Mehran risk score: low (! 5, n =98), moderate (6-10, n=56), high (11-15, n=40) or very high (" 16, n=22). Results The incidence of CIN in the RH group was lower than that observed in the control group (22/108; 20.4% vs. 38/108; 35.2%, p<0.05). The subgroup analysis showed that the rate of CIN was lower in the moderate (6/29; 20.7% vs. 13/30; 43.3%, p<0.10) and significantly lower in both the high (5/21; 23.8% vs. 10/18; 55.6%, p<0.05) and very high score groups (3/12; 25.0% vs. 8/12; 66.7%, p<0.05) among the RH patients compared to the controls. At 24, 48 and 72 hours after PCI, the patients in the RH group exhibited lower SCr levels and higher CCr levels than the patients in the control group (both p<0.05). A lower incidence of in-hospital clinical events was also observed in the RH group. Conclusion Remedial hydration decreases the occurrence of CIN and improves the short-term prognosis of STEMI patients undergoing primary PCI.

Objective Compare survival of patients with poorly compressible arteries (PCA) to those with a normal ankle-brachial index (ABI) and those with peripheral arterial disease (PAD). Background Limited data are available regarding survival in patients with PCA identified in the clinical setting by non-invasive lower extremity arterial evaluation. Methods We conducted a historical cohort study of consecutive patients who underwent outpatient, non-invasive lower extremity arterial evaluation at Mayo Clinic, Rochester, Minnesota, from January 1998 through December 2007, and were followed for a mean duration of 5.8±3.1 years. An ABI 1.00-1.30 was considered normal, PAD was defined as a resting or post-exercise ABI ≤0.90, and PCA defined as an ABI ≥1.4 and/or an ankle systolic blood pressure >255 mm Hg. Patients were followed for all-cause mortality through 09/30/2009. Results Of 16,493 individuals (mean age ± standard deviation = 67.8±13.0 years, 59% male); 29% had normal ABI, 54% had PAD, and 17% had PCA. During follow-up (mean duration = 5.8±3.1 years), 4365 patients (26%) died. The percent alive at the end of the study period was 88%, 70%, and 60% for normal ABI, PAD, and PCA respectively. After adjustment for age, sex, cardiovascular risk factors, comorbid conditions, and medication use, the hazard ratios (confidence interval) of death associated with PCA were 2.0 (1.8-2.2) and 1.3 (1.2-1.4) compared to normal ABI and PAD groups, respectively. Conclusions Patients identified by non-invasive vascular testing to have poorly compressible leg arteries have poor survival, worse than those with a normal ABI or those with PAD.

Several novel circulating adipokines are associated with insulin resistance and inflammation. Little information exists in NAFLD about three recently recognized adipokines lipocalin-2, cathepsin S and chemerin. To assess the relationship between serum lipocalin-2, cathepsin S and chemerin levels and the development of non-alcoholic fatty liver in Chinese subjects, we measured serum lipocalin-2, cathepsin S and chemerin levels in 903 Chinese subjects by ELISA. Among the study population, 436 patients are with B-mode ultrasound-proven NAFLD and 467 controls. Levels of lipocalin-2, but not cathepsin S and chemerin, were significantly elevated in NAFLD versus control [lipocalin-2, 89.67 ± 4.47 vs. 68.70 ± 3.65 ng/mL (p < 0.001)]. After stepwise linear regression analysis adjusting for potential cofounders, further revealed that serum lipocalcin-2 was an independent predictor of NAFLD in whole cohort (standardized β = 0.114, t = 2.347, p = 0.02). Lipocalin-2 levels correlated with insulin resistance (homeostasis model assessment of insulin resistance) and inflammation (CRP) in whole cohorts and NAFLD, whereas cathepsin S and chemerin only correlated positively with insulin resistance and inflammation in whole cohorts. Our results indicated that circulating lipocalin-2, produced by adipocytes, are elevated and may contribute to the development of NAFLD. Serum lipocalin-2, which correlates with inflammation and insulin resistance, may have a direct pathogenic link to disease progression.

Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury (AKI), but detailed pathogenesis and effectual remedy remain elusive. Here, we tested the hypothesis that contrast media (CM) impaired mitochondrial quality control (MQC) in tubules, including mitochondrial fragmentation and mitophagy, induced systemic inflammation, and intestinal injury. Since we previously demonstrated that the natural antioxidant 2,3,5,6-tetramethylpyrazine (TMP) can be a protectant against CIN, we moreover investigated the involved renoprotective mechanisms of TMP. In a well-established CIN rat model, renal functions, urinary AKI biomarkers, and renal reactive oxygen species (ROS) production were measured. Mitochondrial damage and mitophagy were detected by transmission electron microscopy (TEM) and western blot. The abundance of Drp1 and Mfn2 by western blot and immunohistochemistry (IHC) was used to evaluate mitochondrial fragmentation. TUNEL staining, TEM, and the abundance of cleaved-caspase 3 and procaspase 9 were used to assay apoptosis. We demonstrated that increased mitophagy, mitochondrial fragmentation, ROS generation, autophagy, and apoptosis occurred in renal tubular cells. These phenomena were accompanied by renal dysfunction and an increased excretion of urinary AKI biomarkers. Meanwhile, CM exposure resulted in concurrent small intestinal injury and villous capillary endothelial apoptosis. The abundance of the inflammatory cytokines CCL2 and CCR2 markedly increased in the renal tubules of CIN rats, accompanied by increased concentrations of IL-6 and TNF-α in the kidneys and the serum. Interestingly, TMP efficiently prevented CM-induced kidney injury in vivo by reversing these pathological processes. Mechanistically, TMP inhibited the CM-induced activation of the CCL2/CCR2 pathway, ameliorated renal oxidative stress and aberrant mitochondrial dynamics, and modulated mitophagy in tubular cells. In summary, this study demonstrated novel pathological mechanisms of CIN, that is, impairing MQC, inducing CCL2/CCR2-mediated inflammation and small intestinal injury, and provided novel renoprotective mechanisms of TMP; thus, TMP may be a promising therapeutic agent for CIN.