Association of C2, a derivative of the radial artery pressure waveform, with new onset of type 2 diabetes mellitus: the MESA study.

BackgroundAlthough microvascular dysfunction is known to result from diabetes, it might also lead to diabetes. Lower values of C2, a derivative of the radial artery pressure waveform, indicate microvascular dysfunction and predict hypertension and cardiovascular disease (CVD). We studied the association of C2 with incident diabetes in subjects free of overt CVD.MethodsAmong multi-ethnic participants (n = 5214), aged 45-84 years with no diabetes, C2 was derived from the radial artery pressure waveform. Incident diabetes (N = 651) was diagnosed as new fasting glucose ≥ 126 mg/dL or antidiabetic medicine over ~ 10 years. The relative incidence density (RID) for incident diabetes per standard deviation (SD) of C2 was studied during ~ 10 years follow-up using four levels of adjustment.ResultsMean C2 at baseline was 4.58 ± 2.85 mL/mmHg × 100. The RID for incident diabetes per SD of C2 was 0.90 (95% CI 0.82-0.99, P = 0.03). After adjustment for demographics plus body size, the corresponding RID was 0.81 (95% CI 0.73-0.89, P < 0.0001); body mass index (BMI) was the dominant covariate here. After adjustment for demographics plus cardiovascular risk factors, the RID was 0.98 (95% CI 0.89, 1.07, P = 0.63). After adjustment for all the parameters in the previous models, the RID was 0.87 (95% CI 0.78, 0.96, P = 0.006).ConclusionsIn a multi-ethnic sample free of overt CVD and diabetes at baseline, C2 predicted incident diabetes after adjustment for demographics, BMI and CVD risk factors. Differences in arterial blood pressure wave morphology may indicate a long-term risk trajectory for diabetes, independently of body size and the classical risk factors

Racial/ethnic heterogeneity in associations of blood pressure and incident cardiovascular disease by functional status in a prospective cohort: the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVES:Research has demonstrated that the association between high blood pressure and outcomes is attenuated among older adults with functional limitations, compared with healthier elders. However, it is not known whether these patterns vary by racial/ethnic group. We evaluated race/ethnicity-specific patterns of effect modification in the association between blood pressure and incident cardiovascular disease (CVD) by functional status. SETTING:We used data from the Multi-Ethnic Study of Atherosclerosis (2002-2004, with an average of 8.8 years of follow-up for incident CVD). We assessed effect modification of systolic blood pressure and cardiovascular outcomes by self-reported physical limitations and by age. PARTICIPANTS:The study included 6117 participants (aged 46 to 87; 40% white, 27% black, 22% Hispanic and 12% Chinese) who did not have CVD at the second study examination (when self-reported physical limitations were assessed). OUTCOME MEASURES:Incident CVD was defined as an incident myocardial infarction, coronary revascularisation, resuscitated cardiac arrest, angina, stroke (fatal or non-fatal) or death from CVD. RESULTS:We observed weaker associations between systolic blood pressure (SBP) and CVD among white adults with physical limitations (incident rate ratio (IRR) per 10 mm Hg higher SBP: 1.09 (95% CI 0.99 to 1.20)) than those without physical limitations (IRR 1.29 (1.19, 1.40); P value for interaction <0.01). We found a similar pattern among black adults. Poor precision among the estimates for Hispanic or Chinese participants limited the findings in these groups. The attenuated associations were consistent across both multiplicative and additive scales, though physical limitations showed clearer patterns than age on an additive scale. CONCLUSION:Attenuated associations between high blood pressure and incident CVD were observed for blacks and whites with poor function, though small sample sizes remain a limitation for identifying differences among Hispanic or Chinese participants. Identifying the characteristics that distinguish those in whom higher SBP is associated with less risk of morbidity or mortality may inform our understanding of the consequences of hypertension among older adults

Association Between APOL1 Genotypes and Risk of Cardiovascular Disease in MESA (Multi-Ethnic Study of Atherosclerosis).

BACKGROUND:APOL1 genetic variants confer an increased risk for kidney disease. Their associations with cardiovascular disease (CVD) are less certain. We aimed to compare the prevalence of subclinical CVD and incidence of atherosclerotic CVD and heart failure by APOL1 genotypes among self-identified black participants of MESA (Multi-Ethnic Study of Atherosclerosis). METHODS AND RESULTS:Cross-sectional associations of APOL1 genotypes (high-risk=2 alleles; low-risk=0 or 1 allele) with coronary artery calcification, carotid-intimal media thickness, and left ventricular mass were evaluated using logistic and linear regression. Longitudinal associations of APOL1 genotypes with incident myocardial infarction, stroke, coronary heart disease, and congestive heart failure were examined using Cox regression. We adjusted for African ancestry, age, and sex. We also evaluated whether hypertension or kidney function markers explained the observed associations. Among 1746 participants with APOL1 genotyping (mean age 62 years, 55% women, mean cystatin C-based estimated glomerular filtration rate 89 mL/min per 1.73 m2, 12% with albuminuria), 12% had the high-risk genotypes. We found no difference in prevalence or severity of coronary artery calcification, carotid-intimal media thickness, or left ventricular mass by APOL1 genotypes. The APOL1 high-risk group was 82% more likely to develop incident heart failure compared with the low-risk group (95% confidence interval, 1.01-3.28). Adjusting for hypertension (hazard ratio, 1.80; 95% confidence interval, 1.00-3.24) but not markers of kidney function (hazard ratio, 1.86; 95% confidence interval, 1.03-3.35) slightly attenuated this association. The APOL1 high-risk genotypes were not significantly associated with other clinical CVD outcomes. CONCLUSIONS:Among blacks without baseline CVD, the APOL1 high-risk variants may be associated with increased risk for incident heart failure but not subclinical CVD or incident clinical atherosclerotic CVD

Urinary Tubular Injury Biomarkers Are Associated With ESRD and Death in the REGARDS Study.

IntroductionUrinary neutrophil gelatinase-associated lipocalin (uNGAL) and urinary kidney injury molecule-1 (uKIM-1) are established markers of subclinical acute kidney injury. In persons with reduced estimated glomerular filtration rate (eGFR) and albuminuria who are at high risk for end-stage renal disease (ESRD) and death, the associations of these urinary markers with incident ESRD or death is an area of active investigation.MethodsAmong 1472 black and white participants from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study with eGFR ≤60 ml/min per 1.73 m2 (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] cystatin, 2012) and albumin-to-creatinine ratio (ACR) ≥30 mg/g, we evaluated the associations of baseline uNGAL and uKIM-1 with progression to ESRD and all-cause death. Cox models were sequentially adjusted for urinary creatinine, traditional risk factors, C-reactive protein, ACR, and eGFR.ResultsThere were 257 ESRD events and 819 deaths over a median follow-up of 5.7 and 6.5 years, respectively. In demographic adjusted models, higher levels of uNGAL were associated with increased risk of ESRD and death, but these associations were attenuated in fully adjusted models including baseline eGFR for both ESRD (hazard ratio [HR] = 1.06 per doubling, 95% confidence interval [CI] 0.98-1.14) and death (HR = 1.04, 95% CI = 1.00-1.08). Higher levels of uKIM-1 were associated with increased risk of ESRD and death in demographic-adjusted models, and although attenuated in fully adjusted models, remained statistically significant for both ESRD (HR = 1.24 per doubling, 95% CI = 1.08-1.42) and death (HR = 1.10, 95% CI =1.03-1.19).ConclusionIn this cohort of high-risk patients with baseline eGFR ≤60 ml/min per 1.73 m2 and albuminuria, renal tubular injury is associated with higher mortality and progression to ESRD. Further studies are necessary to investigate the mechanism underlying this increased risk

Microemulsions for colorectal cancer treatments: general considerations and formulation of methotrexate

[Abstract] Microemulsions combine the advantages of emulsions with those of nanocarriers, overcoming the stability problems of the former and providing facile scalable systems with compartments adequate for high drug loadings. Recently, microemulsions are gaining attention in the formulation of anticancer drugs not only for topical treatment, but also for systemic delivery as well as for the development of theranostic systems. The aim of this paper is two-fold. First, an updated review about general features, preparation, characterization and pharmaceutical applications, with a special focus on colorectal cancer, is provided. Second, a case study of formulation of methotrexate in microemulsions is presented. Various essential oils (menthol, trans-anethole, α-tocopherol) and surfactants (TPGS-l000, Maxemul 6112, Noigen RN-20) were investigated for the preparation of o/w microemulsions for the delivery of methotrexate, and the ability of methotrexate-loaded microemulsions to inhibit cancer cell growth was then evaluated. Disregarding the surfactants used, menthol and trans-anethole led to cytotoxic microemulsions, whereas α-tocopherol based-formulations induced cell proliferation. These findings highlight the role that the oily component may play in the efficacy and safety of the microemulsions.México. Consejo Nacional de Ciencia y Tecnologia; No. CB-2011/ 168472Ministerio de Economia y Competitividad; SAF2014-52632-RRed Gallega de Investigación sobre Cáncer Colorrectal; R2014/03

Blood Pressure in Older Adults: the Importance of Frailty

The importance of high blood pressure (BP) and the effect of BP lowering in older adults remain controversial due to the mixed evidence in this population. Frailty status may resolve the apparently conflicting findings and identify subpopulations who share common risk. Emerging evidence demonstrates that low BP is associated with poor outcomes in older frail adults or those with poor functional status. In contrast, in non-frail older adults, low BP appears beneficial. Frail older adults may be at increased risk of hypotension, serious fall injuries, and polypharmacy. Additionally, peripheral BP may not be the best prognostic measure in this population. The majority of clinical practice guidelines give little recommendation for frail older adults, which is likely due to their systematic underrepresentation in randomized controlled trials. Future studies need to consider modifications to safely include frail older adults, and guidelines should consider inclusion of evidence beyond randomized controlled trials.This article is part of the Topical Collection on Resistant Hypertension. This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Springer and can be found at: http://www.springer.com/medicine/internal/journal/11906Keywords: Antihypertensive medications, Cognitive function, Aged, Physical function, Falls, Frailt

Cardiovascular Risk Score, Cognitive Decline, and Dementia in Older Mexican Americans: The Role of Sex and Education

Background: The purpose of this study was to examine the associations of cardiovascular disease (CVD) risk with cognitive decline and incidence of dementia and cognitive impairment but not dementia (CIND) and the role of education as a modifier of these effects. Methods and Results: One thousand one hundred sixteen Mexican American elderly were followed annually in the Sacramento Area Latino Study on Aging. Our sex‐specific 10‐year CVD risk score included baseline age, systolic blood pressure, total cholesterol, high‐density lipoprotein, smoking, body mass index, and diabetes. From adjusted linear mixed models, errors on the Modified Mini–Mental State Exam (3MSE) were annually 0.41% lower for women at the 25th percentile of CVD risk, 0.11% higher at the 50th percentile, and 0.83% higher at the 75th percentile (P value of CVDrisk×time <0.01). In men, 3MSE errors were annually 1.76% lower at the 25th percentile of CVD risk, 0.96% lower at the 50th percentile, and 0.12% higher at the 75th percentile (P value of CVDrisk×time <0.01). From adjusted linear mixed models, the annual decrease in the Spanish and English Verbal Learning Test score was 0.09 points for women at the 25th percentile of CVD risk, 0.10 points at the 50th percentile, and 0.12 points at the 75th percentile (P value of CVDrisk×time=0.02). From adjusted Cox models in women, compared with having <6 years of education, having 12+ years of education was associated with a 76% lower hazard of dementia/CIND (95% CI, 0.08 to 0.71) at the 25th percentile of CVD risk and with a 45% lower hazard (95% CI, 0.28 to 1.07) at the 75th percentile (P value of CVDrisk×education=0.05). Conclusions: CVD risk score may provide a useful tool for identifying individuals at risk for cognitive decline and dementia

Endoplasmic reticulum stress inhibition protects steatotic and non-steatotic livers in partial hepatectomy under ischemia-reperfusion

During partial hepatectomy, ischemia-reperfusion (I/R) is commonly applied in clinical practice to reduce blood flow. Steatotic livers show impaired regenerative response and reduced tolerance to hepatic injury. We examined the effects of tauroursodeoxycholic acid (TUDCA) and 4-phenyl butyric acid (PBA) in steatotic and non-steatotic livers during partial hepatectomy under I/R (PH + I/R). Their effects on the induction of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress were also evaluated. We report that PBA, and especially TUDCA, reduced inflammation, apoptosis and necrosis, and improved liver regeneration in both liver types. Both compounds, especially TUDCA, protected both liver types against ER damage, as they reduced the activation of two of the three pathways of UPR (namely inositol-requiring enzyme and PKR-like ER kinase) and their target molecules caspase 12, c-Jun N-terminal kinase and C/EBP homologous protein-10. Only TUDCA, possibly mediated by extracellular signal-regulated kinase upregulation, inactivated glycogen synthase kinase-3β. This is turn, inactivated mitochondrial voltage-dependent anion channel, reduced cytochrome c release from the mitochondria and caspase 9 activation and protected both liver types against mitochondrial damage. These findings indicate that chemical chaperones, especially TUDCA, could protect steatotic and non-steatotic livers against injury and regeneration failure after PH + I/R. © 2010 Macmillan Publishers Limited.This work was supported by the Ministerio de Educación y Ciencia (project grant SAF 2005-00385; project grant manager BFU2009-07410) (Madrid, Spain) and the Ministerio de Sanidad y Consumo (project grant PIO60021) (Madrid, Spain). Centro de Investigaciones Biomédicas Esther Koplowitz, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas is supported by the Instituto de Salud Carlos III (Spain).Peer Reviewe

Association of C2, a derivative of the radial artery pressure waveform, with new onset of type 2 diabetes mellitus: the MESA study

Background Although microvascular dysfunction is known to result from diabetes, it might also lead to diabetes. Lower values of C2, a derivative of the radial artery pressure waveform, indicate microvascular dysfunction and predict hypertension and cardiovascular disease (CVD). We studied the association of C2 with incident diabetes in subjects free of overt CVD. Methods Among multi-ethnic participants (n = 5214), aged 45–84 years with no diabetes, C2 was derived from the radial artery pressure waveform. Incident diabetes (N = 651) was diagnosed as new fasting glucose ≥ 126 mg/dL or antidiabetic medicine over ~ 10 years. The relative incidence density (RID) for incident diabetes per standard deviation (SD) of C2 was studied during ~ 10 years follow-up using four levels of adjustment. Results Mean C2 at baseline was 4.58 ± 2.85 mL/mmHg × 100. The RID for incident diabetes per SD of C2 was 0.90 (95% CI 0.82–0.99, P = 0.03). After adjustment for demographics plus body size, the corresponding RID was 0.81 (95% CI 0.73–0.89, P < 0.0001); body mass index (BMI) was the dominant covariate here. After adjustment for demographics plus cardiovascular risk factors, the RID was 0.98 (95% CI 0.89, 1.07, P = 0.63). After adjustment for all the parameters in the previous models, the RID was 0.87 (95% CI 0.78, 0.96, P = 0.006). Conclusions In a multi-ethnic sample free of overt CVD and diabetes at baseline, C2 predicted incident diabetes after adjustment for demographics, BMI and CVD risk factors. Differences in arterial blood pressure wave morphology may indicate a long-term risk trajectory for diabetes, independently of body size and the classical risk factors