Accelerated coronary atherosclerosis not explained by traditional risk factors in 13% of young individuals.

IMPORTANCE: Most individuals who die of sudden cardiac death (SCD) display very advanced lesions of atherosclerosis in their coronary arteries. Thus, we sought to identify and characterize a putative subpopulation of young individuals exhibiting accelerated coronary artery atherosclerosis. OBJECTIVE: Our analysis of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study-which examined 2651 individuals, obtaining quantitative measurements of traditional risk factors for coronary heart disease (CHD)-aimed to identify individuals with advanced coronary artery lesions, and to determine whether risk factors could account for such rapid disease progression, or not. DESIGN: Using the cross-sectional PDAY study data, an exploratory de facto analysis stratified the population by age and observed number of coronary raised lesions and examined these groups via Poisson regression modeling. A separate de novo approach utilized Poisson mixture modeling to generate low- and high-growth groups based on measurements of traditional risk factors, and identified factors contributing to disease progression. PARTICIPANTS: Participants, n = 2651 individuals aged 15-34, who had died of non-cardiac death, were recruited post mortem. Tissues and other samples were harvested for analysis (details in previously published PDAY studies). Main Outcome(s) and Measure(s). Using quantitative measurements of raised coronary lesions and traditional risk factors of CHD, we sought to identify which risk factors account for disease progression. RESULTS: A group of ~13% of the PDAY population exhibits accelerated coronary atherosclerosis despite their young age. Several traditional risk factors were associated with increased odds of inclusion in this subgroup, reflecting current understanding of these markers of disease. However, only age was a significant contributing factor to the observed coronary lesion burden. CONCLUSIONS: While a range of traditional risk factors contribute to an individual's inclusion to the identified subgroup with accelerated atherosclerosis, these factors, with the exceptions of age, are not able to predict an individual's lesion burden. Moreover, unattributed variances in observations indicate the need to study novel risk factors. SHORT SUMMARY: Hypothesis The extent of coronary atherosclerotic disease is limited and homogeneous within youth, and its progression can be accounted for by traditional risk factors in this population. FINDINGS: A subpopulation (~13%) of the Pathobiological Determinants of Atherosclerosis in Youth cohort exhibited accelerated coronary artery atherosclerosis. While several traditional risk factors contribute to an individual's inclusion in this subgroup, these factors, with the exceptions of age, do not predict accurately an individual's lesions burden. Critically, unattributed variances in observations indicate the need for the identification of novel risk factors. MEANING: Screening of the general population at a young age for high-risk group membership could provide opportunity for disease prevention and avoidance of the worse complications such as myocardial infarction and sudden cardiac death later in life.

Cardiometabolic risks and atherosclerotic disease in ApoE knockout mice: Effect of spinal cord injury and Salsalate anti-inflammatory pharmacotherapy.

OBJECTIVE: To test in mice with a double mutation of the ApoE gene (ApoE-/-) whether spinal cord injury (SCI) hastens the native trajectory of, and established component risks for, atherosclerotic disease (AD), and whether Salsalate anti-inflammatory pharmacotherapy attenuates the impact of SCI. METHODS: ApoE-/- mice were anesthetized and underwent a T9 laminectomy. Exposed spinal cords were given a contusion injury (70 k-dynes). Sham animals underwent all surgical procedures, excluding injury. Injured animals were randomized to 2 groups: SCI or SCI+Salsalate [120 mg/Kg/day i.p.]. Mice were serially sacrificed at 20-, 24-, and 28-weeks post-SCI, and body mass was recorded. At sacrifice, heart and aorta were harvested intact, fixed in 10% buffered formalin, cleaned and cut longitudinally for en face preparation. The aortic tree was stained with oil-red-O (ORO). AD lesion histomorphometry was calculated from the proportional area of ORO. Plasma total cholesterol, triglycerides and proatherogenic inflammatory cytokines (PAIC's) were analyzed. RESULTS: AD lesion in the aortic arch progressively increased in ApoE-/-, significant at 24- and 28-weeks. AD in SCI is significantly greater at 24- and 28-weeks compared to time-controlled ApoE-/-. Salsalate treatment attenuates the SCI-induced increase at these time points. Body mass in all SCI groups are significantly reduced compared to time-controlled ApoE-/-. Cholesterol and triglycerides are significantly higher with SCI by 24- and 28-weeks, compared to ApoE-/-, and Salsalate reduces the SCI-induced effect on cholesterol. PAIC's interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1), and chemokine (C-C motif) ligand 5 (CCL-5) are significantly greater with SCI compared to ApoE-/- at varying timepoints. Salsalate confers a marginal reducing effect on PAIC's by 28-weeks compared to SCI. Regression models determine that each PAIC is a significant and positive predictor of lesion. (p's <0.05). CONCLUSIONS: SCI accelerates aortic AD and associated risk factors, and anti-inflammatory treatment may attenuate the impact of SCI on AD outcomes. PAIC's IL-1ß, IL-6, TNFα, MCP-1, and CCL-5 may be effective predictors of AD.

Oxytocin attenuates atherosclerosis and adipose tissue inflammation in socially isolated ApoE-/- mice.

OBJECTIVE: To determine the effect of exogenous oxytocin (OT) administration on inflammation and atherosclerosis in socially isolated apoE(-/-) mice. Hyperlipidemic animals housed in isolated or stressful social environments display more extensive atherosclerosis than those in an affiliative social environment. The neurohypophyseal peptide OT may be involved in both affiliative social behavior and cardiovascular homeostasis, suggesting a role in mediating the benefits of positive social interactions on atherosclerosis. METHODS: A total of 43, 12-week-old, apoE(-/-) mice were surgically implanted with osmotic minipumps containing OT (n = 23) or vehicle (n = 20). Blood samples were taken at baseline and after 6 weeks and 12 weeks of treatment. After 12 weeks of treatment, animals were killed, and samples of adipose tissue were dissected from a subset of OT-treated (n = 12) and vehicle-treated (n = 12) animals and incubated in culture media for 6 hours. Media samples were analyzed for interleukin (IL)-6 concentration corrected by sample dry weight. Aortas were dissected, formalin-fixed, and stained with oil-red O for en face quantification of lesion area. t tests were used to compare group means on measures of percent lesion area and IL-6 concentrations. RESULTS: There were no group differences in plasma lipids. Adipose tissue samples taken from OT-treated animals secreted significantly less IL-6 over 6 hours (p < .01). OT-treated animals displayed significantly less atherosclerosis in the thoracic aorta (p < .05). CONCLUSIONS: These results indicate that peripheral OT administration can inhibit atherosclerotic lesion development and adipose tissue inflammation, suggesting a potential role for this neuropeptide in mediating the benefits of stable group housing on atherosclerosis.

CLMI: the cone location and magnitude index.

PURPOSE: To develop an index for the detection of keratoconic patterns in corneal topography maps from multiple devices. METHODS: For development, an existing Keratron (EyeQuip) topographic dataset, consisting of 78 scans from the right eyes of 78 healthy subjects and 25 scans from the right eyes of 25 subjects with clinically diagnosed keratoconus, was retrospectively analyzed. The Cone Location and Magnitude Index (CLMI) was calculated on the available axial and tangential curvature data. Stepwise logistic regression analysis was performed to determine the best predictor(s) for the detection of keratoconus. A sensitivity and specificity analysis was performed by using the best predictor of keratoconus. Percent probability of keratoconus was defined as the optimal probability threshold for the detection of disease. For validation, CLMI was calculated retrospectively on a second distinct dataset, acquired on a different topographer, the TMS-1. The validation dataset consisted of 2 scans from 24 eyes of 12 healthy subjects with no ocular history and 4 scans from 21 eyes of 14 subjects with clinically diagnosed keratoconus. Probability of keratoconus was calculated for the validation set from the equation determined from the development dataset. RESULTS: The strongest significant sole predictor in the stepwise logistic regression was aCLMI, which is CLMI calculated from axial data. Sensitivity and specificity for aCLMI on the development dataset were 92% and 100%, respectively. A complete separation of normals and keratoconics with 100% specificity and 100% sensitivity was achieved by using the validation set. CONCLUSIONS: CLMI provides a robust index that can detect the presence or absence of a keratoconic pattern in corneal topography maps from 2 devices.

Human arachnoid granulations Part I: a technique for quantifying area and distribution on the superior surface of the cerebral cortex.

BACKGROUND: The arachnoid granulations (AGs) are herniations of the arachnoid membrane into the dural venous sinuses on the surface of the brain. Previous morphological studies of AGs have been limited in scope and only one has mentioned surface area measurements. The purpose of this study was to investigate the topographic distribution of AGs on the superior surface of the cerebral cortex. METHODS: En face images were taken of the superior surface of 35 formalin-fixed human brains. AGs were manually identified using Adobe Photoshop, with a pixel location containing an AG defined as 'positive'. A set of 25 standard fiducial points was marked on each hemisphere for a total of 50 points on each image. The points were connected on each hemisphere to create a segmented image. A standard template was created for each hemisphere by calculating the average position of the 25 fiducial points from all brains. Each segmented image was mapped to the standard template using a linear transformation. A topographic distribution map was produced by calculating the proportion of AG positive images at each pixel in the standard template. The AG surface area was calculated for each hemisphere and for the total brain superior surface. To adjust for different brain sizes, the proportional involvement of AGs was calculated by dividing the AG area by the total area. RESULTS: The total brain average surface area of AGs was 78.53 +/- 13.13 mm2 (n = 35) and average AG proportional involvement was 57.71 x 10(-4) +/- 7.65 x 10(-4). Regression analysis confirmed the reproducibility of AG identification between independent researchers with r2 = 0.97. The surface AGs were localized in the parasagittal planes that coincide with the region of the lateral lacunae. CONCLUSION: The data obtained on the spatial distribution and en face surface area of AGs will be used in an in vitro model of CSF outflow. With an increase in the number of samples, this analysis technique can be used to study the relationship between AG surface area and variables such as age, race and gender.

Integrated Colony Imaging, Analysis, and Selection Device for Regenerative Medicine.

Stem and progenitor cells derived from human tissues are being developed as cell sources for cell-based assays and therapies. However, tissue-derived stem and progenitor cells are heterogeneous. Differences in observed clones of stem cells likely reflect important aspects of the underlying state of the source cells, as well as future potency for cell therapies. This paper describes a colony analysis and picking device that provides quantitative analysis of heterogeneous cell populations and precise tools for cell picking for research or biomanufacturing applications. We describe an integrated robotic system that enables image acquisition and automated image analysis to be coupled with rapid automated selection of individual colonies in adherent cell cultures. Other automated systems have demonstrated feasibility with picking from semisolid media or off feeder layers. We demonstrate the capability to pick adherent bone-derived stem cells from tissue culture plastic. Cells are efficiently picked from a target site and transferred to a recipient well plate. Cells demonstrate viability and adherence and maintain biologic potential for surface markers CD73 and CD90 based on phase contrast and fluorescence imaging 6 days after transfer. Methods developed here can be applied to the study of other stem cell types and automated culture of cells.

Aortic rhythmic wrinkling in youth: the PDAY study.

Transverse, white-streak 'wrinkles' in the aorta were first described as Querlinien (cross lines) or Wellenlinien (wave lines) in the German literature in the early 20th century. These rhythmic structures were previously thought to be artifacts of stretching and shrinkage of the aorta. Not until the 1970s was it proposed that the areas of rhythmic wrinkling (RW) might be part of the process of atherosclerosis. We analyzed 2,650 aortas from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study for prevalence, extent, and topographical distribution of these areas of RW. Furthermore, we investigated the possible relationship of RW to atherosclerotic sudanophilic stained 'fatty streaks' and elevated intimal lesions called 'raised lesions' (RL). This study provides evidence that (1) the prevalence of RW is fairly high in the aorta and occurs in a specific distribution in both the thoracic and abdominal aorta; (2) RW seems to precede the development of RL, with RL occurring in the same topographical areas as RW; and (3) RW may be associated with the subsequent development of advanced atherosclerosis, particularly raised lesions.

Elevated serum C-reactive protein levels and advanced atherosclerosis in youth.

OBJECTIVE: To determine the associations among serum C-reactive protein (CRP) concentration, age, sex, risk factors for coronary heart disease (CHD), and atherosclerosis in young people. METHODS AND RESULTS: In 1244 subjects 15 to 34 years of age, we measured gross atherosclerotic lesions in the right coronary artery (RCA) and abdominal aorta (AA) and American Heart Association (AHA) lesion grade in the left anterior descending (LAD) coronary artery; serum CRP, lipoprotein cholesterol, and thiocyanate (for smoking) concentrations; intimal thickness of renal arteries (for hypertension); glycohemoglobin (for hyperglycemia); and body mass index (for obesity). Serum CRP levels increased with age, were higher in women than in men, and were positively related to obesity and hyperglycemia. Serum CRP > or =10 mg/L was associated with more extensive gross raised lesions in the RCA after age 25 and in the AA after age 30. Serum CRP > or =3 was associated with a greater prevalence of AHA grade 5 lesions in the proximal LAD coronary artery after age 25. The associations of CRP with lesions were independent of the traditional CHD risk factors. CONCLUSIONS: Serum CRP level is independently associated with advanced atherosclerosis in young persons.

Obesity accelerates the progression of coronary atherosclerosis in young men.

BACKGROUND: Obesity is a risk factor for adult coronary heart disease and is increasing in prevalence among youths as well as adults. Results regarding the association of obesity with atherosclerosis are conflicting, particularly when analyses account for other risk factors. METHODS AND RESULTS: The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study collected arteries, blood, and other tissue from approximately 3000 persons aged 15 to 34 years dying of external causes and autopsied in forensic laboratories. We measured gross atherosclerotic lesions in the right coronary artery (RCA), American Heart Association (AHA) lesion grade in the left anterior descending coronary artery (LAD), serum lipid concentrations, serum thiocyanate (for smoking), intimal thickness of renal arteries (for hypertension), glycohemoglobin (for hyperglycemia), and adiposity by body mass index (BMI) and thickness of the panniculus adiposus. BMI in young men was associated with both fatty streaks and raised lesions in the RCA and with AHA grade and stenosis in the LAD. The effect of obesity (BMI>30 kg/m(2)) on RCA raised lesions was greater in young men with a thick panniculus adiposus. Obesity was associated with non-HDL and HDL (inversely) cholesterol concentrations, smoking (inversely), hypertension, and glycohemoglobin concentration, and these variables accounted for approximately 15% of the effect of obesity on coronary atherosclerosis in young men. BMI was not associated with coronary atherosclerosis in young women although there was trend among those with a thick panniculus adiposus. CONCLUSIONS: Obesity is associated with accelerated coronary atherosclerosis in adolescent and young adult men. These observations support the current emphasis on controlling obesity to prevent adult coronary heart disease.

Overexpression of soluble fas attenuates transplant arteriosclerosis in rat aortic allografts.

BACKGROUND: The killing of vascular cells by activated macrophages is an important step in the process of destabilization of the arterial wall. The death receptor Fas is implicated in vascular cell death. Hence, we extended our studies in a rat aortic allograft model, using adenovirus-mediated overexpression of soluble Fas (sFas) to block Fas binding to Fas ligand (Fas-L). The contribution of Fas to vascular cell injury and consequent transplant arteriosclerosis was investigated. METHODS AND RESULTS: Activated monocytes in the presence of macrophage colony-stimulating factor induce endothelial cell apoptosis in vitro, which was significantly inhibited by adenovirus-mediated sFas overexpression. Next, donor rat abdominal aortas were either untreated or transduced with adenoviruses encoding (1) rat soluble Fas (Ad3rsFas), (2) no insert (Ad3Null), and (3) beta-galactosidase (Ad3nBg). A total of 175 aortic grafts were harvested 2 to 90 days after transplantation. Vascular cell apoptosis and CD45+ cell infiltration were significantly reduced in Ad3rsFas-transduced aortas, as compared with control allografts. Moreover, the control allografts developed marked intimal thickening, whereas Ad3rsFas-transduced allografts had significantly less neointima until the 90-day time point. CONCLUSIONS: sFas overexpression protects the integrity of the vessel wall from immune injury and attenuates transplant arteriosclerosis.

Gene expression phenotypes of atherosclerosis.

OBJECTIVE: Fulfilling the promise of personalized medicine by developing individualized diagnostic and therapeutic strategies for atherosclerosis will depend on a detailed understanding of the genes and gene variants that contribute to disease susceptibility and progression. To that end, our group has developed a nonbiased approach congruent with the multigenic concept of complex diseases by identifying gene expression patterns highly associated with disease states in human target tissues. METHODS AND RESULTS: We have analyzed a collection of human aorta samples with varying degrees of atherosclerosis to identify gene expression patterns that predict a disease state or potential susceptibility. We find gene expression signatures that relate to each of these disease measures and are reliable and robust in predicting the classification for new samples with >93% in each analysis. The genes that provide the predictive power include many previously suspected to play a role in atherosclerosis and additional genes without prior association with atherosclerosis. CONCLUSIONS: Hence, we are reporting a novel method for generating a molecular phenotype of disease and then identifying genes whose discriminatory capability strongly implicates their potential roles in human atherosclerosis.

Prediction of flap response.

PURPOSE: To find predictors of the induced biomechanical and optical effects of lamellar flap creation on the cornea. SETTING: Optimed Eye and Laser Clinic, Pretoria, South Africa, and the Department of Ophthalmology and Biomedical Engineering Center, The Ohio State University, Columbus, Ohio, and Bausch & Lomb Vision Research Laboratory, Rochester, New York, USA. METHODS: This prospective study monitored the refractive, wavefront aberration, and corneal topographic changes in 29 eyes of 15 patients for 3 months after the creation of a corneal lamellar flap. The main outcome measures for statistical analysis were refraction, total corneal thickness, residual corneal bed thickness, horizontal white-to-white corneal diameter, horizontal flap diameter, topography data, and wavefront data. RESULTS: Statistically significant changes were seen in the autorefraction mode. Wavefront data showed significant change in 4 Zernike modes-90/180-degree astigmatism, vertical coma, horizontal coma, and spherical aberration. The topography data indicated the corneal biomechanical response was significantly predicted by stromal bed thickness in the early follow-up period and by total corneal pachymetry and flap diameter in a 2-parameter statistical model in the late follow-up period. CONCLUSIONS: Uncomplicated lamellar flap creation is responsible for systematic changes in corneal topography and induction of higher-order optical aberrations. Predictors of this response include stromal bed thickness, flap diameter, and total corneal pachymetry.

Quantitative descriptors of corneal topography that influence soft toric contact lens fitting.

PURPOSE: Empirical soft toric contact lens fitting based on manifest refraction and keratometry often presents unanticipated fitting and power errors upon initial lens dispensing. However, corneal topography may provide features that influence soft toric lens performance, flexure, and back vertex power in situ, which may assist in improved fitting guidelines. In this study, quantitative topographic descriptors were generated and analyzed as potential variables in predicting soft toric fitting success. METHODS: One hundred five eyes of 54 patients were empirically fit with back surface toric, prism ballasted, soft contact lenses after videokeratography was performed with the EyeSys 2000 (v. 4.0) or Humphrey Atlas (v. A6) instrument. Custom software was written to generate 54 separate quantitative descriptors of shape and astigmatism from the raw data files. A logistic regression was used to determine which variables significantly contributed to a successful or failed fit. RESULTS: Two types of empirical fitting failures were identified: loose fit (n = 15) and power errors (n = 17). The following variables were associated with a fitting failure: flat simulated keratometry (SimKf2b) within the central 3 mm zone, steep simulated keratometry (SimKs2b) within the central 3 mm zone, a difference between central and peripheral flat meridian axis (DIFFAXIS), and a difference between central and peripheral astigmatism (DIFFASTIG). For fitting failures caused by power errors, a larger steep SimKs2b (p< 0.01) and smaller DIFFAXIS (p< 0.05) were associated with a failed fit. For failures caused by physical fit of a selected base curve, a smaller DIFFAXIS (p< 0.05), larger steep SimKs2b (p< 0.05), and larger DIFFASTIG (p< 0.01) were associated with a failed fit. CONCLUSIONS: Novel quantitative descriptors of corneal shape and toricity derived from topography are associated with empirical soft toric contact lens fitting failures. Future algorithms or recommendations for improved soft toric lens selection may be derived from such indices to develop a predictive model for successful soft toric lens fitting using corneal topography data.

Oxytocin administration attenuates atherosclerosis and inflammation in Watanabe Heritable Hyperlipidemic rabbits.

Oxytocin (OT) is a neurohypophyseal peptide traditionally associated with female reproductive functioning, and more recently with prosocial behavior. OT and its receptor are also expressed in the heart and vascular tissue and play a role in cardiovascular homeostasis. In vitro, it has been demonstrated that OT decreases NADPH-dependent superoxide production and pro-inflammatory cytokine release from vascular endothelial cells and macrophages, suggesting that OT may attenuate pathophysiological processes involved with atherosclerotic lesion formation. The present study sought to determine the effect of chronic exogenous OT administration on inflammation and atherosclerosis in an animal model of dyslipidemia and atherosclerosis, the Watanabe Heritable Hyperlipidemic (WHHL) rabbit. Twenty-two, 3-month-old WHHLs were surgically implanted with osmotic mini-pumps containing OT (n=11) or vehicle (n=11), and then were individually housed for the entire study. Blood and 24-h urine samples were taken at baseline and after 8 (midpoint) and 16 (endpoint) weeks of treatment. At endpoint, the aortas and visceral fat samples were dissected and stored for analyses. There were no group differences in body weight, serum lipids, plasma/urinary measures of oxidative stress, plasma cortisol or urinary catecholamines over the 16-week treatment. OT-treated animals exhibited significantly lower plasma C-reactive protein levels at midpoint and endpoint and developed significantly less atherosclerosis in the thoracic aorta relative to vehicle control animals at endpoint (p<0.05). Cytokine gene expression from visceral adipose tissue samples suggested that there was a decrease in adipose tissue inflammation in the OT-treated group compared to the vehicle control group, however these differences were not statistically significant. These results suggest that chronic peripheral OT administration can inhibit inflammation and atherosclerotic lesion development.

Voluntary running suppresses proinflammatory cytokines and bone marrow endothelial progenitor cell levels in apolipoprotein-E-deficient mice.

Long-term exercise is associated with reduced atherosclerotic burden, inflammation, and enhanced endothelial progenitor cell (EPC) levels in mice. Infusion of progenitor cells in mice decreases atherosclerosis and suppresses inflammation. The aim of this study was to determine whether exercise-induced enhancement of EPCs is associated with reduced atherosclerosis and inflammation. To study this, 20-week old ApoE(-/-) mice with advanced atherosclerotic lesions (n = 12/group) were randomized to voluntary running or no running for 8 weeks. Exercise led to a potent suppression of elevated circulating proinflammatory cytokines without significant reduction of atherosclerotic lesions. When repeated in ApoE(-/-) mice with early atherosclerotic disease, exercise led to a 62% (p = 0.017) reduction in lesion thickness (intima-to-media ratio) at the aortic root. Interestingly, BM-EPC levels were significantly elevated under proinflammatory conditions seen in ApoE(-/-) mice and decreased in response to exercise, independent of the degree of atherosclerosis. Under early atherosclerotic conditions, long-term exercise reduces atherosclerotic plaque burden and is associated with reduced systemic inflammation. Elevated BM-EPCs seen in atherosclerotic conditions may be a marker of generalized vascular inflammation or injury, and decrease in response to exercise, along with other markers of inflammation.

Associations of arterial tissue lipids with coronary heart disease risk factors in young people.

OBJECTIVE: To examine the associations of the coronary heart disease (CHD) risk factors with lipid composition of arterial tissue in 397 autopsied subjects 15-34 years of age from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. METHODS AND RESULTS: We measured esterified cholesterol, free cholesterol, and phospholipid in the left circumflex coronary artery and two segments of the abdominal aorta, one of which is more susceptible to advanced atherosclerosis than the other, and also measured the major CHD risk factors. Non-HDL cholesterol concentration was positively associated, and HDL cholesterol concentration was negatively associated, with tissue lipids in the left circumflex coronary artery and the abdominal aorta. Hypertension was positively associated with tissue lipids in both arteries. Hyperglycemia was associated with tissue lipids in the left circumflex coronary artery and smoking with lipids in the abdominal aorta. PDAY risk scores summarize the effects of the CHD risk factors on advanced atherosclerosis. These risk scores, computed from the mutable risk factors, were associated with tissue lipids in the left circumflex coronary artery and both segments of the abdominal aorta. CONCLUSIONS: The CHD risk factors are associated with lipids in arterial tissue just as they are associated with gross and microscopic lesions. These results support the proposal that early control of risk factors is likely to prevent or delay progression of atherosclerosis and prevent or delay the onset of CHD.

Application of physicochemically modified silicon substrates as reverse-phase protein microarrays.

Physicochemically modified silicon substrates can provide a high quality alternative to nitrocellulose-coated glass slides for use in reverse-phase protein microarrays. Enhancement of protein microarray sensitivities is an important goal, especially because molecular targets within patient tissues exist in low abundance. The ideal array substrate has a high protein binding affinity and low intrinsic background signal. Silicon, which has low intrinsic autofluorescence, is being explored as a potential microarray surface. In a previous paper ( Nijdam , A. J. ; Cheng , M. M.-C. ; Fedele , R. ; Geho , D. H. ; Herrmann , P. ; Killian , K. ; Espina , V. ; Petricoin , E. F. ; Liotta , L. A. ; Ferrari , M. Physicochemically Modified Silicon as Substrate for Protein Microarrays . Biomaterials 2007 , 28 , 550 - 558 ), it is shown that physicochemical modification of silicon substrates increases the binding of protein to silicon to a level comparable with that of nitrocellulose. Here, we apply such substrates in a reverse-phase protein microarray setting in two model systems.

Simulation of machine-specific topographic indices for use across platforms.

PURPOSE: The objective of this project is to simulate the current published topographic indices used for the detection and evaluation of keratoconus to allow their application to maps acquired from multiple topographic machines. METHODS: A retrospective analysis was performed on 21 eyes of 14 previously diagnosed keratoconus patients from a single practice using a Tomey TMS-1, an Alcon EyeMap, and a Keratron Topographer. Maps that could not be processed or that contained processing errors were excluded from analysis. Topographic indices native to each of the three devices were recorded from each map. Software was written in ANSI standard C to simulate the indices based on the published formulas and/or descriptions to extend the functionality of The Ohio State University Corneal Topography Tool (OSUCTT), a software package designed to accept the input from many corneal topographic devices and provide consistent display and analysis. Twenty indices were simulated. Linear regression analysis was performed between each simulated index and the corresponding native index. A cross-platform comparison using regression analysis was also performed. RESULTS: All simulated indices were significantly correlated with the corresponding native indices (p < 0.01), with a mean R of 0.84, ranging from 0.42 to 0.99. Cross-platform comparisons were nonsignificant for specific indices and devices. CONCLUSION: Topographic indices native to three devices were successfully simulated. Cross-platform comparisons may be limited for specific indices.

Molecular evidence for arterial repair in atherosclerosis.

Atherosclerosis is a chronic inflammatory process and progresses through characteristic morphologic stages. We have shown previously that chronically injecting bone-marrow-derived vascular progenitor cells can effect arterial repair. This repair capacity depends on the age of the injected marrow cells, suggesting a progressive decline in progenitor cell function. We hypothesized that the progression of atherosclerosis coincides with the deteriorating repair capacity of the bone marrow. Here, we ascribe patterns of gene expression that accurately and reproducibly identify specific disease states in murine atherosclerosis. We then use these expression patterns to determine the point in the disease process at which the repair of arteries by competent bone marrow cells ceases to be efficient. We show that the loss of the molecular signature for competent repair is concurrent with the initiation of atherosclerotic lesions. This work provides a previously unreported comprehensive molecular data set using broad-based analysis that links the loss of successful repair with the progression of a chronic illness.