The influence of the optical properties on the determination of capillary diameters.

Various clinically applicable scores and indices are available to help identify the state of a microcirculatory disorder in a patient. Several of these methods, however, leave room for interpretation and only provide clues for diagnosis. Thus, a measurement method that allows a reliable detection of impending or manifest circulatory malfunctions would be of great value. In this context, the optical and non-invasive method of shifted position-diffuse reflectance imaging (SP-DRI) was developed. It allows to determine the capillary diameter and thus to assess the state of the microcirculation. The aim of the present study is to investigate how the quantification of capillary diameters by SP-DRI behaves in different individuals, i.e. for a wide range of optical properties. For this, within Monte-Carlo simulations all optical properties (seven skin layers, hemoglobin) were randomly varied following a Gaussian distribution. An important finding from the present investigation is that SP-DRI works when the optical properties are chosen randomly. Furthermore, it is shown that appropriate data analysis allows calibration-free absolute quantification of the capillary diameter across individuals using SP-DRI. This underpins the potential of SP-DRI to serve as an early alert system for the onset of microcirculatory associated diseases.

Type 1 diabetes and hearing loss: Audiometric assessment and measurement of circulating levels of soluble receptor for advanced glycation end products.

BACKGROUND: We examined the hearing function in adults with and without type 1 diabetes (T1D) to investigate whether an association exists between hearing loss and duration of diabetes, haemoglobin A1C level, diabetes complications and levels of select serum and urinary biomarkers. METHODS: We measured pure tone audiometry (PTA) thresholds; serum levels of C-reactive protein (CRP), vascular endothelial growth factor (VEGF), soluble receptors for advanced glycation end-product (sRAGE); and urinary isoprostane in 30 adults with T1D (age 43.8 ± 11.4 years). We also measured PTA thresholds in 11 adults without diabetes (age 53 ± 5.5 years). RESULTS: 63.3% of adults with T1D had high-frequency hearing loss. Among adults with T1D, those with hearing loss were older (48.2 vs 36.2 years old, P < .01), had a longer duration of diabetes (30.7 vs 21.2 years, P = .02), a greater prevalence of peripheral neuropathy (57.9 vs 9.1%, P = .02) and significantly lower median levels of sRAGE (1054.27 vs 1306.83 pg/mL, P = .03) compared to those with normal hearing. Adults with T1D between the ages of 40 and 60 years old, who had diabetes for ≥35 years, had significantly higher PTA thresholds at both 500and 8000 Hz than age-matched adults without diabetes. CONCLUSIONS: A significant proportion of adults with T1D have high-frequency hearing loss before age of 60 that is positively associated with age, duration of diabetes and presence of peripheral neuropathy. Our results are in support of previous studies suggesting a potential protective role of sRAGE against AGE toxicity and diabetes complications.

High predictive ability of glycated hemoglobin on comparison with oxidative stress markers in assessment of chronic vascular complications in type 2 diabetes mellitus.

OBJECTIVE: To validate the diagnostic utility of oxidative stress markers along with glycated hemoglobin (HbA1c ) in the assessment of chronic vascular complications in type 2 diabetes mellitus (DM). METHODS: Ischemia modified albumin (IMA), advanced oxidation protein products (AOPP) and malondialdehyde (MDA) were measured in 100 type 2 DM (without complications n = 50, with complications n = 50) and healthy controls (n = 50). Diagnostic potential was evaluated by receiver operating characteristic analysis and their relationships to risk variables were analyzed. RESULTS: MDA, IMA and AOPP were significantly increased in diabetics, both with and without complications. Oxidative stress parameters correlated with fasting blood glucose and HbA1c (independent predictors). Duration of diabetes was an independent predictor for AOPP and MDA. The association of IMA with diabetes duration was lost on multiple regression analysis. Area under the curve, sensitivity and specificity for MDA were 0.795, 84%, 66%; for AOPP, they were 0.762, 82%, 56%; for IMA, they were 0.611, 60%, 52%; and for HbA1c, they were 0.848, 90%, 70%, respectively. CONCLUSION: MDA and AOPP could be considered better than IMA in the evaluation of diabetes progression, but MDA is more useful as a diagnostic indicator to detect vascular complications. HbA1c measurement is of greater value than the oxidative stress markers in the prediction of vascular complications.

[ASSESSMENT OF SPECIFIC PHARMACOLOGIC ACTIVITY OF UNIFUSOL ON ENDOTHELIUM DYSFUNCTION MODEL INDUCED BY N-NITRO-L-ARGININE METHYL ETHER.]

Specific pharmacologic activity of sodium-L-arginine succinate (unifusol) was studied on endothelium dysfunction model (EDM) in rats. EDM was induced by daily administration of N-nitro-L-arginine methyl ether (L-NAME). The effectiveness of experimental therapy with unifusol was assessed by changes in the arterial pressure level, duration of endothelium-dependent and -independent vasodilation, and the blood concentration of endothelial dysfunction markers including VEGF, NO, endothelin-I and the number of desquamated endotheliocytes. Administration of unifusol favors correction of blood vessel endothelium state manifested by normalization of its functional activity and reduction of the apoptosis of endotheliocytes. In addition, the obtained results unambiguously confirm considerable vasodilating and antihypertensive effects of unifusol.

Update in preoperative risk assessment in vascular surgery patients.

Multiple clinical factors and now serum biomarkers may aid with risk stratification in vascular surgical patients. Herein, we review and update the clinical risk models, biomarker data, and currently used noninvasive cardiac stress tests. We also review the most recent American Heart Association guideline changes, and suggest a pathway for risk stratification.

Causal inference algorithms can be useful in life course epidemiology.

OBJECTIVES: Life course epidemiology attempts to unravel causal relationships between variables observed over time. Causal relationships can be represented as directed acyclic graphs. This article explains the theoretical concepts of the search algorithms used for finding such representations, discusses various types of such algorithms, and exemplifies their use in the context of obesity and insulin resistance. STUDY DESIGN AND SETTING: We investigated possible causal relations between gender, birth weight, waist circumference, and blood glucose level of 4,081 adult participants of the Prevention of REnal and Vascular ENd-stage Disease study. The latter two variables were measured at three time points at intervals of about 3 years. RESULTS: We present the resulting causal graphs, estimate parameters of the corresponding structural equation models, and discuss usefulness and limitations of this methodology. CONCLUSION: As an exploratory method, causal graphs and the associated theory can help construct possible causal models underlying observational data. In this way, the causal search algorithms provide a valuable statistical tool for life course epidemiological research.

LDL cholesterol targets--how low to go?

PURPOSE OF REVIEW: Lowering LDL cholesterol (LDL-C) reduces vascular risk. Current guidelines recommend initiating statin therapy in patients with a yearly coronary heart disease risk of around 1.5-2%, and most clinicians prescribe standard statin regimens (e.g. 40 mg simvastatin daily). However, there is some uncertainty about whether patients at somewhat lower vascular risk should receive lipid-lowering therapy and also how intensive statin treatment should be. RECENT FINDINGS: Lowering LDL-C by around 1 mmol/l reduces vascular mortality and major morbidity by about one-fifth, and more recent randomized trials comparing intensive versus standard statin regimens confirm that a further LDL-C reduction of 0.5 mmol/l results in an additional 15% reduction in the risk of a major vascular event. Furthermore, statin therapy significantly reduces vascular mortality and morbidity in patients with less than 1% annual risk of a major vascular event. In general, statins are safe and well tolerated, but 80 mg simvastatin is associated with an unacceptably high risk of statin-induced myopathy. SUMMARY: Lipid-lowering therapy with statins is cost-effective for a wider range of patients than currently recommended. Intensive statin therapy is associated with larger reductions in vascular risk, and lower LDL-C targets (particularly for higher-risk individuals) should help reduce vascular mortality and major vascular morbidity substantially.

Global variation in the prevalence of elevated cholesterol in outpatients with established vascular disease or 3 cardiovascular risk factors according to national indices of economic development and health system performance.

BACKGROUND: Elevated serum cholesterol accounts for a considerable proportion of cardiovascular disease worldwide. An understanding of the relationship between country-level economic and health system factors and elevated cholesterol may provide insight for prioritization of cardiovascular prevention programs. METHODS AND RESULTS: Using hierarchical models, we examined the relationship between elevated total cholesterol (>200 mg/dL) in 53 570 outpatients from 36 countries, and tertiles of several country-level indices: (1) gross national income, (2) total expenditure on health as percentage of gross domestic product, (3) government expenditure on health as percentage of total expenditure on health, (4) out-of-pocket expenditures as percentage of private expenditure on health, and the World Health Organization indices of (5) Health System Achievement and (6) Performance/Efficiency. Overall, 38% of outpatients had total cholesterol >200 mg/dL (>5.18 mmol/L), and 9.3% of the total variability in elevated cholesterol was at the country level; this proportion was higher for patients with (12.1%) versus without (7.4%) history of hyperlipidemia. Among patients with history of hyperlipidemia, countries in the highest tertile of gross national income or World Health Organization Health System Achievement had lower odds of elevated cholesterol than lower tertiles (P<0.001, for both). Countries in the highest tertile of out-of-pocket health expenditures had higher odds of elevated cholesterol than those in the lowest tertile (P<0.001). No significant associations were found for patients without history of hyperlipidemia. CONCLUSIONS: Global variations in the prevalence of elevated cholesterol among patients with history of hyperlipidemia are associated with country-level economic development and health system indices. These results support the need for strengthening efforts toward effective cardiovascular disease prevention and control and may provide insight for health policy setting at the national level.

Cost-effectiveness of statin therapy for vascular event prevention in adults with elevated C-reactive protein: implications of JUPITER.

OBJECTIVES: High-sensitivity C-reactive protein (hs-CRP) has been explored for use in predicting cardiovascular risk. The recent Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study found that statin therapy reduced cardiovascular events in those with low-density lipoprotein (LDL) cholesterol levels below current treatment thresholds (≤130 mg/dL, 3.4 = mmol/L), but with elevated hs-CRP levels (≥2.0 mg/L). This study examines the cost-effectiveness of statin treatment for individuals with elevated hs-CRP but normal LDL cholesterol. METHODS: A Markov decision-analytic model was conducted from the U.S. societal perspective. Data from JUPITER were used to estimate rates of myocardial infarction, angina and stroke. Statin costs were based on generic simvastatin 80 mg, equipotent to the rosuvastatin 20 mg dose used in JUPITER. Primary prevention was the focus and secondary prevention was not modeled explicitly. Quality-adjusted life-years (QALYs) were calculated using nationally representative preference-based utility weights. One-way sensitivity analyses and multivariate probabilistic sensitivity analysis were used to explore uncertainty in model parameters as well as estimate the likelihood of cost-effectiveness when all event rates, costs and utilities were drawn randomly from distributions reflecting uncertainty. RESULTS: Statin therapy cost $10,889/QALY for vascular event prevention in this population. Results were sensitive to the cost of statin treatment. Based on 10,000 simulations, statin therapy was cost-effective in 99.5% of simulations, using a willingness-to-pay threshold of $20,000/QALY, and 100% of simulations using a threshold of $50,000/QALY. CONCLUSIONS: Treatment with statins in patients with elevated hs-CRP but normal cholesterol appears to be cost-effective. Limitations of this study include the assumption that an equipotent dose of simvastatin resulted in the same risk reduction as rosuvastatin. Further, post-event states simulated the average experience of a patient. Continued statin use, subsequent events and/or heart failure were not explicitly modeled.

Selective thromboxane inhibition after vascular protectant AGI-1067: results of assessment of lipoprotein profiles (ALPS) biomarkers in vitro and in vivo substudy.

BACKGROUND: Oxidative stress play an important role triggering platelet/endothelial activation. AGI-1067 is a novel, phenolic antioxidant, and vascular protectant which dose-dependently inhibits PEA biomarkers in vitro. Whether treatment with AGI-1067 alters platelets in vivo is not known. We serially assessed release of established PEA biomarkers in subjects treated with AGI-1067 versus placebo in the frame of Assessment of Lipoprotein Profiles Randomized Trial (ALPS). METHODS: Healthy subjects (18-65 years) with multiple risk factors for coronary artery disease were randomized 1:1 to receive 300 mg AGI-1067 (n = 112) or matching placebo (n = 117) daily for 12 weeks. Anticoagulants, aspirin, NSAIDS, and COX inhibitors were not permitted in this study. Plasma samples were collected at baseline, and at week 12 after randomization. Platelet factor 4 (PF4), beta-thromboglobulin (betaTG), P-selectin, thromboxane (TxB2), and prostacyclin (6-keto-PGF1a) were measured by ELISA. RESULTS: Treatment with AGI-1067 was associated with a highly significant reduction of TxB2 release (P < 0.0001) when compared to the placebo. There were no differences in PF4, betaTG, P-selectin, and 6-keto-PGF1a between and within groups. AGI-1067 also inhibits TxB2 release from calcium ionophore (A23187)-stimulated human platelets with the IC50 equals 1 microM; but does not interfere with 6-keto-PGF1alpha release in either A23187-, or TXA2-stimulated human aortic endothelial cells. CONCLUSION: AGI-1067 selectively reduces TxB(2 )production from stimulated platelets, and diminishes plasma TxB2 levels in ALPS participants. These data support earlier in vitro, and pilot ex vivo experiments suggesting antiplatelet properties of AGI-1067. Lack of 6-keto-PGF1a down regulation may represent an attractive advantage of AGI-1067 over currently available antiplatelet regimens.

[Vascular risk factors in healthy population in the repeated screening examinations]. / A vascularis kockázati tényezok alakulása az egészséges lakosság körében megismételt szurovizsgálatban.

UNLABELLED: An epidemiological study on vascular risk factors have been repeated two times in a two years interval in a cohort of 4511 healthy subjects. The participants in this study were volunteer members of Dimenzio Health Insurance. METHODS: Data on life style, family history of vascular diseases have been documented. Detailed physical examination including neurological examination and structured questionnaire on stress and related problems, blood glucose, and cholesterol level, carotid Doppler ultrasound and ECG examinations made complete this screening program. RESULTS: Blood pressure, total cholesterol, glucose level increased steadily and significantly by age. Significant differences between male and female groups have been noted in favor of females in all age groups. In subjects having positive family history of vascular diseases, all the blood pressure, cholesterol and glucose level were significantly higher as in the sex and age matched subjects with negative family history. Comparing the dataset of two consecutive screening periods, the average value of blood pressure of different age groups did not increase, even decreased in the older age groups. Smoking habit is also decreased. Interestingly enough the cholesterol level increased significantly in all age groups by the time of second examination. CONCLUSION: Stressful life has been reported mostly by females. The frequency of stress increased significantly by the two years lapsed between the two data collections. Parallel with the stress frequency consumption of antidepressants and anxiolytics increased significantly. The average blood pressure of subjects with stressful life was significantly higher compared to subjects without stress. This cohort study is the first in this country in which we used repeatedly a screening program for identifying high risk subjects, or high risk age groups in a healthy population. Data subtracted from this study could support a prevention strategy.

Assessment of inflammatory markers and endothelial function.

PURPOSE OF REVIEW: To describe the background and assessment of inflammatory markers and endothelial function in atherosclerosis. RECENT FINDINGS: Recent observations have related several inflammation markers, including cytokines and chemokines, soluble adhesion molecules, and acute-phase reactants, to the pathophysiology of atherosclerosis. Chronic inflammatory states such as rheumatoid arthritis and systemic lupus erythematosus have been identified as independent risk factors for early atherosclerosis. The role of endothelial function in atherosclerosis has been elucidated by clinical studies that have demonstrated that the status of vascular endothelium may modify the effects of risk factors on the development of atherosclerosis. These observations support the response-to-injury theory of atherosclerosis that emphasizes the role of endothelium in atherosclerosis. SUMMARY: Inflammation and endothelial function play significant roles in the pathogenesis of atherosclerosis. Elevations in certain inflammatory mediators as well as evidence of endothelial dysfunction are related to increased risk of future cardiovascular morbidity. The value of measuring inflammatory markers and endothelial function in clinical practice remains to be defined.

Circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in metabolic bone disease assessment.

CONTEXT: The discovery of the receptor activator for nuclear factor kappaB (RANK) ligand (RANKL)/RANK signaling pathway has marked a major advance in our understanding of the mechanisms controlling osteoclastogenesis. RANKL, expressed by preosteoblasts and stromal cells, binds to RANK, expressed by cells of the osteoclast lineage, inducing a signaling cascade leading to the differentiation and fusion of osteoclast precursor cells and stimulating the activity of the mature osteoclast. The effects of RANKL are counteracted by osteoprotegerin (OPG), a soluble neutralizing decoy receptor. EVIDENCE: This paper reviews the literature surrounding the use of circulating OPG and soluble RANKL (sRANKL) measurements and assesses their potential as markers of bone disease. Original clinical and basic research articles and reviews were identified using a Pubmed search strategy (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) and cover the time period up until January 2005. Search terms osteoprotegerin, OPG, RANK, RANKL, and RANK ligand were used alone and in combination with bone, osteoporosis, and disease. EVIDENCE SYNTHESIS: Assays for detecting OPG and sRANKL in the circulation in humans have been developed, and differences in the circulating concentrations of OPG and sRANKL have been observed in different disease states. There are, however, some inconsistencies in study outcome. These may relate to differences in study design, methodology, and other unknown factors influencing the variability of these measurements. CONCLUSIONS: The clinical utility of serum OPG and sRANKL measurements as markers of disease activity requires additional investigation. In particular, rigorous testing of assays and identification of the sources of measurement variability are required.

Homocysteinemia: new information about an old risk factor for vascular disease.

OBJECTIVE: To determine the importance of homocysteinemia as a risk factor for atherosclerotic vascular disease. DESIGN: Literature review of published studies homocysteine as risk factor for atherosclerotic vascular disease. METHODS: MEDLINE search from 1969 to 1998 using homocysteine and vascular disease as search terms, from which 13 articles were selected for review. RESULTS: Homocysteine is a sulfur containing amino acid derivative formed during methionine metabolism. Inherited deficiencies of cystathionine B synthase or MTHF reductase result in markedly elevated plasma homocysteine levels and homocystinuria. Although rare, hereditary homocystinuria results in a variety of life threatening vascular complications occurring at a young age. Lesser degrees of homocysteinemia may result from vitamin B12, folate and pyridoxine deficiencies as well as a recently described mutation of the MTHF reductase gene. Homocysteinemia from these causes has been shown to increase the risk of coronary artery disease, peripheral artery disease, stroke, and venous thrombosis. Postulated mechanisms for this association are discussed. CONCLUSION: Homocysteinemia is a risk factor for premature vascular disease. The strength of this association is similar to that due to hyperlipidemia and tobacco use. Although vitamin supplementation with folic acid, B12, and B6 is able to reduce homocysteine levels in many persons, proof of the effectiveness of vitamin treatment in preventing or halting the progression of vascular disease is not yet available.

Hyperhomocysteinemia: detection, risk assessment, and treatment.

Homocysteine is formed by the demethylation of methionine in the course of its normal metabolism. Hyperhomocysteinemia is an independent risk factor for vascular disease. It develops most commonly from folate deficiency, genetic abnormalities, and chronic renal failure. Current models favor direct angiotoxicity involving endothelial and vascular smooth muscle cells, and impaired thrombolysis. Folic acid reduces hyperhomocysteinemia and thus provides an opportunity for risk-factor modification.

Flow cytometry assessment of leukocyte functions in vascular pathologies.

Intravascular activation of leukocytes has been shown to be involved in a wide range of different and apparently unrelated clinical situations, such as systemic inflammatory response syndrome, ischemia/reperfusion, disseminated intravascular coagulation, atherosclerosis... All of them involve to different degrees many steps of the inflammation process, with leukocyte accumulation and release of toxic species. Haemostasis, leukocyte functions and their cross-talk are summarized in this paper, as well as the most popular methods used for studying leukocyte functions in vascular pathologies. The strengths and present limitations of flow cytometry are analyzed in comparison with the biochemical and functional approaches.