Transcriptional Profiling of Human Brain Endothelial Cells Reveals Key Properties Crucial for Predictive In Vitro Blood-Brain Barrier Models

Brain microvascular endothelial cells (BEC) constitute the blood-brain barrier (BBB) which forms a dynamic interface between the blood and the central nervous system (CNS). This highly specialized interface restricts paracellular diffusion of fluids and solutes including chemicals, toxins and drugs from entering the brain. In this study we compared the transcriptome profiles of the human immortalized brain endothelial cell line hCMEC/D3 and human primary BEC. We identified transcriptional differences in immune response genes which are directly related to the immortalization procedure of the hCMEC/D3 cells. Interestingly, astrocytic co-culturing reduced cell adhesion and migration molecules in both BECs, which possibly could be related to regulation of immune surveillance of the CNS controlled by astrocytic cells within the neurovascular unit. By matching the transcriptome data from these two cell lines with published transcriptional data from freshly isolated mouse BECs, we discovered striking differences that could explain some of the limitations of using cultured BECs to study BBB properties. Key protein classes such as tight junction proteins, transporters and cell surface receptors show differing expression profiles. For example, the claudin-5, occludin and JAM2 expression is dramatically reduced in the two human BEC lines, which likely explains their low transcellular electric resistance and paracellular leakiness. In addition, the human BEC lines express low levels of unique brain endothelial transporters such as Glut1 and Pgp. Cell surface receptors such as LRP1, RAGE and the insulin receptor that are involved in receptor-mediated transport are also expressed at very low levels. Taken together, these data illustrate that BECs lose their unique protein expression pattern outside of their native environment and display a more generic endothelial cell phenotype. A collection of key genes that seems to be highly regulated by the local surroundings of BEC within the neurovascular unit are presented and discussed

Quantitative Analysis of the Exercise Tolerance Test for Determining the Severity of Coronary Artery Disease.

Results were compiled from the literature on the use of the exercise tolerance test to identify patients with severe coronary artery disease. Pooled estimates of sensitivity and specificity were derived for the ability of the exercise tolerance test to identify three-vessel or left main coronary artery disease. There was great variability among the studies examined in the estimated sensitivity and specificity of a given criterion for severe coronary artery disease. This variability could not be explained by reported variations in study design. The findings suggest that the accuracy of the exercise tolerance test and other tests cannot be properly interpreted without much greater detail presented in the literature on patient selection and test administration

The Inexact Use of Fisher\u27s Exact Test in Six Major Medical Journals.

We reviewed the use of Fisher\u27s Exact Test in 71 articles published between 1983 and 1987 in six medical journals. Thirty-three of 56 selected articles did not specify use of a one- or two-tailed test, and 12 (36%) of these actually used the one-tailed test. Five (42%) of these 12 articles contained at least one table in which the standard significance level of P less than .05 was no longer met when a two-tailed analysis was run instead. Eleven (65%) of 17 articles with a statistical consultant compared with 10 (28%) of 36 articles without a consultant specified use of a one- or two-sided test. The use of Fisher\u27s Exact Test without specification as a one- or two-tailed version may misrepresent the statistical significance of data. A uniform specification statement should be required for all manuscripts to correct such potential errors in interpretation

A Measure of Mortality Risk for Elderly Patients With Acute Myocardial Infarction.

The objective of this study was to derive and validate a simple scoring system that predicts risk of short-term mortality in elderly patients hospitalized with acute myocardial infarction (AMI) and to compare this derived score with the MedisGroups admission severity score. A myocardial infarction severity score (MISS) was derived from a database of clinical information abstracted using MedisGroups and follow-up information on 30-day mortality status. The MISS was validated and compared with the MedisGroups Admission Severity Groups (ASGs) in a separate database. The derivation set included 2,037 Medicare patients 65 years old or older with confirmed AMI who were randomly selected from patients discharged from hospitals in seven states during 1985. The validation set consisted of 6,323 patients from the 1988 MedisGroups comparative database who were at least 65 years of age and had confirmed AMI. Multivariate logistic regression analysis found a set of nine abnormal patient characteristics that independently predict 30-day mortality. There was good agreement between mortality rates predicted by the logistic model and observed mortality rates in the validation population. This regression model was then simplified to an additive score where eight of the characteristics were weighted as one point and one characteristic was weighted as two points. The MISS is the sum of the points for each patient. In the validation dataset, the 1,373 patients with the lowest MISS scores had a mortality rate of 4.6% and the 400 patients with the highest MISS scores had a mortality rate of 64%.(ABSTRACT TRUNCATED AT 250 WORDS

Research Collaboration

The complexity and cost of cardiovascular medical care dictate research to deliver high quality and cost-conscious cardiovascular care. This goal is aided by modeling medical decision making. To be useful, the modeling must be based on real data so that the results can serve as a guide to actual practice. It is suggested that a registry of randomized clinical trials and larger data bases in cardiovascular disease and health care delivery be established. The registry would be a resource for those desiring to model decision making. The registry would contain key words allowing retrieval by modelers accessing the registry and would contain contact information for consideration of possible collaborative work. The initiation of such a registry should contain plans for its evaluation to determine whether the registry itself is a cost-effective tool to encourage the needed research

Association Between Postoperative Complications and Clinical Cancer Outcomes

ABSTRACT Introduction. The treatment for a majority of solid organ tumors is surgical resection; 10-20 % of patients suffer a perioperative complication. Perioperative complications may contribute to cancer recurrence. This study examined the relationship between postoperative complications and risk-adjusted patient overall survival. Methods. Data from 2003 to 2009 were linked from our clinical cancer registry, the National Surgery Quality Improvement Project (NSQIP), and medical records. Patients who had tumor extirpation for cure were included. The NSQIP was used to identify complications. Patients with a complication were matched to patients without a complication. v 2 tests and Cox proportional hazard regression models were used. Results. A total of 415 patients were included for survival analysis. The hazard ratio (HR) for mortality associated with having a complication was 2.17. The HR for mortality after 200 days postoperatively was 2.47. Infectious complications were associated with the highest association with increased mortality (HR = 3.56). Noninfectious complications were not associated with an increased risk of mortality. Conclusions. This study investigated the relationship of surgical infectious complications in cancer patients with long-term survival for patients who had a number of different types of cancer. After taking into account the site, histology, and stage of the cancer, we found that patients with infectious complications had earlier death. The primary treatment for the majority of solid organ tumors remains surgical tumor extirpation. The complex nature of these surgeries leads to a high rate of perioperative complications, occurring in 5-30 % of all cases