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The objective was to evaluate whether physician feedback accompanied by an action checklist improved diabetes care process measures. Eighty-three physicians in an academic general medicine clinic were provided a single feedback report on the most recent date and result of diabetes care measures (glycosylated hemoglobin [A1c], urine microalbumin, serum creatinine, lipid levels, retinal examination) as well as recent diabetes medication refills with calculated dosing and adherence on 789 patients. An educational session regarding the feedback and adherence information was provided. The physicians were asked to complete a checklist accompanying the feedback on each of their patients, indicating requested actions with respect to follow-up, testing, and counseling. The physicians completed 82% of patient checklists, requesting actions consistent with patient needs on the basis of the feedback. Of the physicians, 93% felt the patient information and intervention format to be useful. The odds of urine microalbumin testing, serum creatinine, lipid profile, A1c, and retinal examination increased in the 6 months after the feedback. The increase was sustained at 1 year only for microalbumin and retinal exams. There was no significant change in refill adherence for the group overall after the feedback, although adherence did improve among patients of physicians attending the educational session. No significant change was noted in lipid or A1c levels during the study period. In conclusion, a simple physician feedback tool with action checklist can be both helpful and popular for improving rates of diabetes care guideline adherence. More complex interventions are likely required to improve diabetes outcomes. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness of a lifestyle intervention (LI) in reducing work loss and disability days., Methods: One year randomized controlled trial of health plan members (n = 147) with type 2 diabetes and obesity. Members were randomized to modest-cost LI or usual care (UC). Outcomes were group differences in cumulative days either missed at work or with disability using Mann-Whitney U-tests and Poisson regression models., Results: LI reduced the risk of workdays lost by 64.3% (P

Cell migration is essential to cancer invasion and metastasis and is spatially and temporally integrated through transcriptionally dependent and independent mechanisms. As cell migration is studied in vitro, it is important to identify genes that both drive cell migration and are biologically relevant in promoting invasion and metastasis in patients with cancer. Here, gene expression profiling and a high-throughput cell migration system answers this question in human bladder cancer. In vitro migration rates of 40 microarray-profiled human bladder cancer cell lines were measured by radial migration assay. Genes whose expression was either directly or inversely associated with cell migration rate were identified and subsequently evaluated for their association with cancer stage in 61 patients. This analysis identified genes known to be associated with cell invasion such as versican, and novel ones, including metallothionein 1E (MT1E) and nicotinamide N-methyltransferase (NNMT), whose expression correlated positively with cancer cell migration and tumor stage. Using loss of function analysis, we show that MT1E and NNMT are necessary for cancer cell migration. These studies provide a general approach to identify the clinically relevant genes in cancer cell migration and mechanistically implicate two novel genes in this process in human bladder cancer.

Biomedical data useful for data mining are often distributed across multiple databases. These databases may be aggregated using several techniques to create single data sets that may be mined using standard approaches; however, separate databases may, in their design or data representation, capture information that is analytically useful and that is lost on integration. Recent techniques for mining multiple databases simultaneously but separately may preserve and leverage the unique perspectives within each database. This article presents an example, "dual mining," in which concurrent analysis of a target database with a related knowledge base can improve the identification of association patterns in the target most likely to be of interest for further analysis.

Background: Receiving extraneous articles in response to a query submitted to MEDLINE/PubMed is common. When submitting a multi-word query (which is the majority of queries submitted), the presence of all query words within each article may be a necessary condition for retrieving relevant articles, but not sufficient. Ideally a relationship between the query words in the article is also required. We propose that if two words occur within an article, the probability that a relation between them is explained is higher when the words occur within adjacent sentences versus remote sentences. Therefore, sentence-level concurrence can be used as a surrogate for existence of the relationship between the words. In order to avoid the irrelevant articles, one solution would be to increase the search specificity. Another solution is to estimate a relevance score to sort the retrieved articles. However among the >30 retrieval services available for MEDLINE, only a few estimate a relevance score, and none detects and incorporates the relation between the query words as part of the relevance score., Results: We have developed "Relemed", a search engine for MEDLINE. Relemed increases specificity and precision of retrieval by searching for query words within sentences rather than the whole article. It uses sentence-level concurrence as a statistical surrogate for the existence of relationship between the words. It also estimates a relevance score and sorts the results on this basis, thus shifting irrelevant articles lower down the list. In two case studies, we demonstrate that the most relevant articles appear at the top of the Relemed results, while this is not necessarily the case with a PubMed search. We have also shown that a Relemed search includes not only all the articles retrieved by PubMed, but potentially additional relevant articles, due to the extended 'automatic term mapping' and text-word searching features implemented in Relemed., Conclusion: By using sentence-level matching, Relemed can deliver higher specificity, thus eliminating more false-positive articles. By introducing an appropriate relevance metric, the most relevant articles on which the user wishes to focus are listed first. Relemed also shrinks the displayed text, and hence the time spent scanning the articles.

Context: Despite multiple attempts to document and quantify the danger of venous thromboembolism (VTE) following prolonged travel, there is still uncertainty about the magnitude of risk and what can be done to lower it., Objectives: To review the methodologic strength of the literature, estimate the risk of travel-related VTE, evaluate the efficacy of preventive treatments, and develop evidence-based recommendations for practice., Data Sources: Studies identified from MEDLINE from 1966 through December 2005, supplemented by a review of the Cochrane Central Registry of Controlled Trials, the Database of Abstracts of Reviews of Effects, and relevant bibliographies., Study Selection: We included all clinical studies that either reported primary data concerning travel as a risk factor for VTE or tested preventive measures for travel-related VTE., Data Extraction and Analysis: Two reviewers reviewed each study independently to assess inclusion criteria, classify research design, and rate methodologic features. The effect of methodologic differences, VTE risk, and travel duration on VTE rate was evaluated using a logistic regression model., Data Synthesis: Twenty-four published reports, totaling 25 studies, met inclusion criteria (6 case-control studies, 10 cohort studies, and 9 randomized controlled trials). Method of screening for VTE [screening ultrasound compared to usual clinical care, odds ratio (OR) 390], outcome measure [all VTE compared to pulmonary embolism (PE) only, OR 21], duration of travel (<6 hours compared to 6-8 hours, OR 0.011), and clinical risk ("higher" risk travelers compared to "lower," OR 3.6) were significantly related to VTE rate. Clinical VTE after prolonged travel is rare [27 PE per million flights diagnosed through usual clinical care, 0.05% symptomatic deep venous thrombosis (DVT) diagnosed through screening ultrasounds], but asymptomatic thrombi of uncertain clinical significance are more common. Graduated compression stockings prevented travel-related VTE (P < 0.05 in 4 of 6 studies), aspirin did not, and low-molecular-weight heparin (LMWH) showed a trend toward efficacy in one study., Conclusions: All travelers, regardless of VTE risk, should avoid dehydration and frequently exercise leg muscles. Travelers on a flight of less than 6 hours and those with no known risk factors for VTE, regardless of the duration of the flight, do not need DVT prophylaxis. Travelers with 1 or more risk factors for VTE should consider graduated compression stockings and/or LMWH for flights longer than 6 hours.

Clinical repositories containing large amounts of biological, clinical, and administrative data are increasingly becoming available as health care systems integrate patient information for research and utilization objectives. To investigate the potential value of searching these databases for novel insights, we applied a new data mining approach, HealthMiner, to a large cohort of 667,000 inpatient and outpatient digital records from an academic medical system. HealthMiner approaches knowledge discovery using three unsupervised methods: CliniMiner, Predictive Analysis, and Pattern Discovery. The initial results from this study suggest that these approaches have the potential to expand research capabilities through identification of potentially novel clinical disease associations.

Background: Data mining can be utilized to automate analysis of substantial amounts of data produced in many organizations. However, data mining produces large numbers of rules and patterns, many of which are not useful. Existing methods for pruning uninteresting patterns have only begun to automate the knowledge acquisition step (which is required for subjective measures of interestingness), hence leaving a serious bottleneck. In this paper we propose a method for automatically acquiring knowledge to shorten the pattern list by locating the novel and interesting ones., Methods: The dual-mining method is based on automatically comparing the strength of patterns mined from a database with the strength of equivalent patterns mined from a relevant knowledgebase. When these two estimates of pattern strength do not match, a high "surprise score" is assigned to the pattern, identifying the pattern as potentially interesting. The surprise score captures the degree of novelty or interestingness of the mined pattern. In addition, we show how to compute p values for each surprise score, thus filtering out noise and attaching statistical significance., Results: We have implemented the dual-mining method using scripts written in Perl and R. We applied the method to a large patient database and a biomedical literature citation knowledgebase. The system estimated association scores for 50,000 patterns, composed of disease entities and lab results, by querying the database and the knowledgebase. It then computed the surprise scores by comparing the pairs of association scores. Finally, the system estimated statistical significance of the scores., Conclusion: The dual-mining method eliminates more than 90% of patterns with strong associations, thus identifying them as uninteresting. We found that the pruning of patterns using the surprise score matched the biomedical evidence in the 100 cases that were examined by hand. The method automates the acquisition of knowledge, thus reducing dependence on the knowledge elicited from human expert, which is usually a rate-limiting step.

Expression profiling by DNA microarray analysis has provided insights into molecular alterations that underpin cancer progression and metastasis. Although differential expression of microarray-defined probes can be related to numerical or structural chromosomal alterations, it is unclear if such changes are also clustered in distinct chromosomes or genomic regions and whether chromosomal alterations always reflect changes in gene expression. Here we apply the dChip algorithm and a novel technique to test the hypothesis that expression changes occurring as a function of tumor progression and metastasis are nonrandomly distributed. Expression profiling of a human xenograft model of lung metastasis phenotype indicates that chromosomes 2, 11, and 20 contain higher percentages of differentially expressed genes (P < .05). Furthermore, we show that a number of differentially expressed probes mapped to chromosome 17q, defining the existence of an expression "hot spot" corresponding to an area of gain determined by comparative genomic hybridization (CGH). Interestingly, other areas of gains detected by CGH were not associated with expression hot spots. In summary, we show that gene expression changes during bladder cancer lung metastasis occur nonrandomly in specific chromosomes and intrachromosomal locations.

Background: Most studies on predictors of mortality for patients with congestive heart failure (CHF) have described predictors that are either difficult to measure in routine practice or are only modestly sensitive and specific. Having observed 3 patients whose body temperature decreased shortly before death, we hypothesized that hypothermia may predict inhospital mortality., Methods: The medical records of 291 patients with a primary discharge diagnosis of CHF were selected from 423 admissions to Memorial Hermann Hospital, Houston, Tex, 1998, after excluding patients with comorbidities that confound body temperature, deaths for causes other than progressive pump failure, and readmissions except the last. Three groups were defined on the basis of admission body temperature (T adm): hypothermia groups T adm (95.5 degrees F-96.5 degrees F) and T adm < 95.5 degrees F, and reference group T adm > or = 96.6 degrees F. Several other known CHF risk factors were studied for confounding, and adjusted hazard ratios were calculated using Cox regression., Results: Of the 291 patients (mean age 73 years, 47% men), 17 (6%) had hypothermia on admission. Mean hospital stay was 5 days. Of the 17 (6%) patients who died of pump failure, 5 had been hypothermic on admission. Hypothermia was significantly associated with survival, and after adjusting for New York Heart Association functional class, hazard ratio for T adm < 95.5 degrees F was 4.46 (95% confidence interval 1.38-14.3) (P trend = .0283)., Conclusions: Hypothermia predicted inhospital death in these patients with CHF. If confirmed by future studies, this finding could prove useful, because temperature can be measured continuously, rapidly, and inexpensively, in or out of the hospital.

Objective: To test the hypothesis that the continuous infusion of papaverine-containing solutions in peripheral arterial catheters would decrease the catheter failure rate and increase the functional duration of the catheter in neonates., Study Design: In a prospective, randomized, placebo-controlled, masked trial, 82 catheters were placed in 70 neonates in the papaverine group and 98 catheters were placed in 71 neonates in the placebo group., Results: The catheters in the papaverine group remained functional for a significantly longer duration than those in the placebo group. The median (25th%, 75th%) time before catheter failure was 16.6 (9.5, 24.3) days in the papaverine group and 12 days (6.1, 18.2) in the placebo group ( P = .023; Cox proportional hazards model). There was no significant difference in the incidence of intraventricular hemorrhage (IVH) between groups, and there was no evidence of hepatic toxicity., Conclusions: The continuous infusion of papaverine-containing fluids prolongs the patency of peripheral arterial catheters in neonates. In this small number of infants, we found no difference in the incidence of IVH or hepatic toxicity.

Background: Consider a meta-analysis where a 'head-to-head' comparison of diagnostic tests for a disease of interest is intended. Assume there are two or more tests available for the disease, where each test has been studied in one or more papers. Some of the papers may have studied more than one test, hence the results are not independent. Also the collection of tests studied may change from one paper to the other, hence incomplete matched groups., Methods: We propose a model, the proportional odds ratio (POR) model, which makes no assumptions about the shape of ORp, a baseline function capturing the way OR changes across papers. The POR model does not assume homogeneity of ORs, but merely specifies a relationship between the ORs of the two tests. One may expand the domain of the POR model to cover dependent studies, multiple outcomes, multiple thresholds, multi-category or continuous tests, and individual-level data., Results: In the paper we demonstrate how to formulate the model for a few real examples, and how to use widely available or popular statistical software (like SAS, R or S-Plus, and Stata) to fit the models, and estimate the discrimination accuracy of tests. Furthermore, we provide code for converting ORs into other measures of test performance like predictive values, post-test probabilities, and likelihood ratios, under mild conditions. Also we provide code to convert numerical results into graphical ones, like forest plots, heterogeneous ROC curves, and post test probability difference graphs., Conclusions: The flexibility of POR model, coupled with ease with which it can be estimated in familiar software, suits the daily practice of meta-analysis and improves clinical decision-making.

Background: The use of D-dimer assays as a rule-out test for deep venous thrombosis (DVT) is controversial. To clarify this issue we performed a systematic review of the relevant literature., Methods: We identified eligible studies, using MEDLINE entries from February 1995 through October 2003, supplemented by a review of bibliographies of relevant articles. Studies reporting accuracy evaluations comparing D-dimer test results with lower extremity ultrasound or venography in symptomatic patients with suspected acute DVT were selected for review. Two reviewers critically appraised each study independently according to previously established methodologic standards for diagnostic test research. Those studies judged to be of highest quality were designated Level 1., Results: The 23 Level 1 studies reported data on 21 different D-dimer assays. There was wide variation in assay sensitivity, specificity, and negative predictive values, and major differences in methodology of reviewed studies. A multivariate analysis of assay performance, controlling for sample size, DVT prevalence, reference standard, and patient mix, found few differences among the assays in effect on test performance as measured by diagnostic odds ratio. Increasing prevalence of DVT was associated with poorer test performance (P = 0.01), whereas the choice of venography as the reference standard was associated with better test performance (P <0.005)., Conclusions: Explanations for the wide variation in assay performance include differences in biochemical and technical characteristics of the assays, heterogeneity and small size of patient groups, and bias introduced by choice of reference standards. Assay sensitivity and negative predictive value were frequently <90%, uncharacteristic of a good rule-out test. General use of D-dimer assays as a stand-alone test for the diagnosis of DVT is not supported by the literature.

Objective: Current methods for meta-analysis of diagnostic tests do not allow utilizing all the information from papers in which several tests have been studied on the same patient sample. We demonstrate how to combine several studies of diagnostic tests, where each study reports on more than one test and some tests (but not necessarily all of them) are shared with other papers selected for the meta-analysis. We adopt statistical methodology for repeated measurements for the purpose of meta-analysis of diagnostic tests., Study Design and Setting: The method allows for missing values of some tests for some papers, takes into account different sample sizes of papers, adjusts for background and confounding factors including test-specific covariates and paper-specific covariates, and accounts for correlations of the repeated measurements within each paper. It does not need individual-level data, although it can be modified to use them, and uses the two-by-two table of test results vs. gold standard., Results: The results are translated from diagnostic odds ratios (DOR) to more clinically useful measures such as predictive values, post-test probabilities, and likelihood ratios. Models to capture between-study variation are introduced. The fit and influence of specific studies on the regression can be evaluated. Furthermore, model-based tests for homogeneity of DORs across papers are presented., Conclusion: The use of this new method is illustrated using a recent meta-analysis of the D-dimer test for the diagnosis of deep venous thrombosis.

Developed by the Virginia Bioinformatics Consortium (VBC), GeneX Va is an open source, freeware database and bioinformatics analysis software for archiving and analyzing Affymetrix GeneChip data. It provides an integrated framework for management, documentation, and analysis of microarray experiments and data to support a range of users, from individual research laboratories to institutional microarray facilities. GeneX Va also provides web-based access to a PostgreSQL relational database system with a comprehensive security system. Data can be extracted from the database and delivered to interactive or scriptable statistical analysis protocols. The security system allows each investigator to manage their own array data and analysis output files and also provides custom access privileges for other users, groups, and internal/external collaborators. The analysis interface uses "Analysis Trees," an innovative user interface that allows researchers to interactively create a tree-structured flow chart of analysis routines. The latest GeneX Va software is available from and can be freely downloaded at the Sourceforge web site http://va-genex.sourceforge.net. To allow researchers to access the database and analysis capabilities of the GeneX Va system, microarray data from many VBC GeneChip experiments have been deposited into a public section of the GeneX Va system at the University of Virginia. The VBC GeneX Va sites, which include documentation, are at http://genes.med.virginia.edu/ of the University of Virginia and at http://genex.csbc.vcu.edu/ of the Virginia Commonwealth University.

Objectives: To examine the use of hospital and related medical care services of a novel managed care program using nurse practitioners (NPs) and directed specifically at long-stay nursing home residents., Design: Quasi-experimental posttest design with two control groups to minimize selection bias., Setting: Nursing homes., Participants: Evercare enrollees in five sites were compared with two sets of controls: nursing home residents in the same nursing homes who did not enroll in Evercare (control-in) and residents of nursing homes that did not participate in Evercare (control-out)., Measurements: Utilization data from Medicare and United Healthcare (the parent corporation for Evercare) were obtained for slightly more than 2 years. Patterns of use were assessed by calculating the monthly use rate for each group and aggregating to form annual rates. Usages addressed included hospital admissions and days, emergency room visits, therapy services, mental health services, and podiatry. Adjustments were made to correct for age, race, and sex. Because the groups differed in terms of the rate of cognitive impairment, the analysis was stratified on this variable., Results: The incidence of hospitalizations was twice as high in control residents as in Evercare residents (4.63 and 4.67 per 100 enrollees per month vs 2.43 in the 15 months after census, P<.001). This difference corresponded to Evercare's use of intensive service days. The same pattern held for preventable hospitalizations (0.80 and 0.86 vs 0.28, P<.001). The pattern held when residents were stratified by cognitive status. On average, using a NP is estimated to save about $103,000 a year in hospital costs per NP., Conclusion: The use of active primary care provided by NPs may have prevented the occurrence of some hospitalizable events, but its major effect was allowing cases to be managed more cost-effectively.

Objectives: We hypothesized that combining functional assessment to perfusion enhances the ability of electrocardiographic gating Tc-99m sestamibi single photon emission computed tomography (gated SPECT) myocardial perfusion imaging (MPI) to detect defects in multiple vascular territories in patients with severe three-vessel coronary artery disease (3VD)., Background: In patients with 3VD, perfusion defects in multiple vascular territories may not always be evident due to globally reduced perfusion., Methods: Gated SPECT MPIs were interpreted sequentially with perfusion first, followed by combined perfusion/function, in 143 patients with angiographic 3VD and a control group of 112 non-3VD patients. All patients underwent coronary arteriography within one month of MPI., Results: In 3VD patients, combined perfusion/function analysis yielded significantly greater numbers of abnormal segments/patient (6.2 +/- 4.7 vs. 4.1 +/- 2.8, p < 0.001) and more defects in multiple vascular territories (60% vs. 46%, p < 0.05) than perfusion alone. In the control group, there were no differences between the combined perfusion/function and perfusion alone interpretations. Multivariate analysis of 15 different clinical, stress, and scintigraphic variables in all patients revealed age (p < 0.0001) and number of abnormal vascular territories by combined perfusion/function (p < 0.0001) to be the most powerful predictors of 3VD. Addition of functional data to clinical, stress, and perfusion yielded a significant increase in the predictive value of 3VD (global chi-square: 131.7 vs. 89.8, p < 0.00001). Specificity of combined perfusion/function analysis was not lower than perfusion alone (72% vs. 69%, p = NS). CONCLUSIONS; Adjunctive assessment of function with perfusion by gated SPECT MPI enhances the detection of defects in multiple vascular territories in patients with severe 3VD, without adversely affecting its specificity.

We have developed an intravascular thermography basket catheter to measure the temperature of the vessel wall to locate foci of inflammation. Our 3 Fr thermography basket catheter is a thermocouple-based catheter made of a nitinol expandable and externally controllable basket system loaded with nine small and flexible built-in thermosensors. It is equipped with real-time data acquisition software with a thermal resolution of 0.0001 degrees C and a sampling rate of 20 readings per second. In 10 inbred cholesterol-fed dogs with femoral (but not carotid) atherosclerosis, we found foci of warmth on the surface of atherosclerotic but not disease-free regions (P < 0.05). Marked temperature heterogeneity was also observed in the aortas of atherosclerotic Watanabe rabbits but not in normal rabbits. The catheters showed satisfactory accuracy, reproducibility, and safety. If confirmed in further studies, it has the potential to be utilized in detection of vulnerable plaques., (Copyright 2003 Wiley-Liss, Inc.)

Background: Angiographic predictors of plaque progression are weak and few: length, irregular surface, turbulence, low shear, and (in some studies) eccentricity and calcification. Having noted plaques that briefly retained dye after angiography, we interpreted these as plaques with a fissured surface or neovascularization and hypothesized that progression would be predicted by "plaque blush.", Methods: Plaques (<50% diameter stenosis) in 68 pairs of angiograms, 5.6 +/- 4.8 months apart, were reviewed by 2 blinded observers. The presence of plaque blush, calcification, clot (mobile defect), eccentricity, and a branch point location were compared between progressing (> or =20% stenosis increase) and nonprogressing plaques., Results: Sixteen lesions in 15 patients progressed from 29% +/- 13% to 68% +/- 14% over a period of 8.1 +/- 7.9 months. Patients with and without progression were similar in sex, age, congestive heart disease risk factors, medications, interval between angiograms, clinical presentation, and initial stenosis severity. By logistic regression, plaque blush (BL) (P =.002), calcification (CA) (P =.024), and a branch (BR) point location (P =.001) predicted plaque progression. The odds ratio for plaque progression (ORp) was calculated as ORp = e(2.5 x BL + 1.8 x CA + 2.6 x BR). Using an ORp of 1/3, the model has 81% sensitivity and 77% specificity. A second analysis in which each progressive lesion was compared with proximal and distal lesions and with one in a different coronary artery yielded similar results., Conclusions: In mild to moderate coronary stenoses, studied retrospectively, plaque blush (a new sign) and a branch point location were strong predictors of plaque progression, whereas calcification was a weak predictor of progression.

Purpose: To assess changes in various functional and satisfaction measures between older persons enrolled in Minnesota Senior Health Options (MSHO), a managed care program for older persons eligible for both Medicare and Medicaid., Design and Methods: We used two sets of matched controls for MSHO enrollees and their families and matched controls living in the community and in nursing homes: Persons in the same county who were eligible to enroll but did not enroll in MSHO and persons in other metropolitan areas where MSHO is not available. For the community sample, we used questionnaires to measure functional status (activities of daily living), pain, unmet care needs, satisfaction, and caregiver burden. Approximately 2 years after the first survey, we resurveyed respondents who lived in the community at the time of the first survey. For the nursing home residents, we used annual assessments to calculate case mix to compare changes in functional levels over time., Results: There were few significant differences in change over time between the MSHO sample and the two control groups. Out-of-area controls showed greater increases in pain but in-area controls showed less interference from pain. Compared with out-of-area controls, MSHO clients showed greater increase in homemaker use, meals on wheels, and outpatient rehabilitation. Compared with in-area controls, they showed more use of meals on wheels and less help from family with household tasks. There were few differences in satisfaction, but the MSHO families showed significantly lower burden than controls on five items., Implications: The analyses show only modest evidence of benefit from MSHO compared with the two control groups. The model represented by MSHO does not appear to generate substantial differences in outcomes across function, satisfaction, and caregiver burden.

Background: The role of infection in the development and complications of atherosclerosis has been the focus of much attention. We reported previously that influenza vaccination was associated with reduced risk of recurrent myocardial infarction. Here, we report the effect of influenza A virus on the apolipoprotein E-deficient (apoE(-/-)) mouse, an animal model of atherosclerosis., Methods and Results: Twenty-four apoE(-/-) mice >24 months old were injected with 1 LD(50) (lethal dose 50) of influenza A virus. Ten wild-type C57BL/6 infected mice and 11 noninfected age-matched apoE(-/-) mice served as controls. Multiple aortic sections were studied histologically 3, 5, and 10 days later. The infected mice showed markedly increased intimal cellularity compared with the noninfected apoE(-/-) mice. No aortic abnormalities were seen in infected wild-type mice. Ten infected apoE(-/-) mice had a significant subendothelial infiltrate composed of a heterogeneous group of cells that stained positively for smooth muscle cell actin, F4/80 (macrophages), and CD3 (T lymphocytes). One case of subocclusive platelet and fibrin-rich thrombus was seen., Conclusions: This study shows that influenza infection promotes inflammation, smooth muscle cell proliferation, and fibrin deposition in atherosclerotic plaques.

Background: Atherosclerotic plaques are heterogeneous with respect to inflammation, calcification, vascularity, oxygen, and temperature. We hypothesized that they also vary in pH and measured pH in living human carotid endarterectomized atherosclerotic plaques (CEA), Watanabe heritable hyperlipidemic (WHHL) rabbit aortas and human umbilical arteries (HUA)., Methods and Results: We measured pH of CEA of 48 patients, nine WHHL rabbit aortas and 11 HUA specimens (as controls) using a glass type microelectrode mounted on a micromanipulator in a 37 degrees C incubator. We also used single emission and also dual emission fluorescence ratio imaging microscopy employing pH-sensitive probes to confirm pH heterogeneity. Mean pH measured at 415 points of CEA was 7.55+/-0.32; at 275 points of WHHL rabbit aortas it was 7.40+/-0.43; and in 233 points of HUA it was 7.24+/-0.1. In CEA, pH of yellow (lipid-rich) areas was significantly lower than pH in calcified areas (7.15+/-0.01 vs. 7.73+/-0.01, P<0.0001). The coefficients of variation (heterogeneity) of pH in CEA, WHHL rabbit aortas, and HUA were 0.038+/-0.010, 0.039+/-0.007, and 0.009+/-0.003, respectively (P=0.0001). Fluorescence microscopic imaging confirmed pH heterogeneity in both humans and rabbits but not in HUA. In a variance components analysis 82% of the heterogeneity was due to the within-plaque variation and 2% was attributable to between-plaque variation., Conclusions: Our findings support the hypothesis of pH heterogeneity in plaques, and suggest a possible role for detecting low pH in the detection of plaque vulnerability. The source of pH heterogeneity particularly acidic pH, its impact on the stability of plaques and its potential clinical utility in locating vulnerable plaques remain to be evaluated.