Faculty Bibliography

Tumor necrosis factor- (TNF-) alpha is a proinflammatory proatherogenic cytokine. Infliximab, an anti-TNF-alpha monoclonal antibody, is effective in treating rheumatoid arthritis. However, its impact on cardiovascular burden and lipid transport is unclear. The present study investigates the effect of TNF-alpha and infliximab on reverse cholesterol transport (RCT) proteins. Uptake of modified lipoproteins by macrophages in the vasculature leads to atherogenic foam cell formation. RCT is mediated by proteins including ATP binding cassette transporters A1 (ABCA1), G1 (ABCG1), liver X receptor- (LXR-) alpha, and 27-hydroxylase. RCT counteracts lipid overload by ridding cells of excess cholesterol. THP-1 human monocytes were incubated with either TNF-alpha alone or TNF-alpha with infliximab. Expression of proteins involved in cholesterol efflux was analyzed. TNF-alpha significantly reduced both ABCA1 and LXR-alpha mRNA (to 68.5 +/- 1.59%, P < 0.05, and 41.2 +/- 0.25%, P < 0.01, versus control set as 100%, resp.). Infliximab nullified the TNF-alpha effect. Results were confirmed by Western blot. Infliximab abolished the increase in foam cells induced by TNF-alpha. TNF-alpha treatment significantly reduces ABCA1 and LXR-alpha expression in monocytes, thus bringing about a proatherogenic state. The anti-TNF drug infliximab, commonly used in rheumatology, restored RCT proteins. This is the first report of an atheroprotective effect of infliximab on RCT in monocytes.

Immunologic derangements in rheumatoid arthritis (RA) patients likely contribute to premature atherosclerotic cardiovascular disease (CVD). Traditional CVD risk factors do not reliably identify at-risk RA patients, probably because disease-associated mechanisms are not taken into account. The purpose of this study was to determine whether plasma from subjects with RA exhibits atheroma-promoting properties leading to disruption of cholesterol homeostasis in human monocytes/macrophages. Twenty-one healthy controls (HC) and 22 RA patients were enrolled in an IRB approved study at Winthrop University Hospital. Naive THP-1 macrophages were exposed to plasma from each HC and RA patient. Following incubation, RNA and protein were isolated. QRT-PCR and Western blotting techniques were then used to measure expression of proteins responsible for cholesterol efflux (ATP binding cassette transporter (ABC)A1, ABCG1, 27-hydroxylase) and cholesterol uptake (CD36, ScR-A1, lectin oxidized low density lipoprotein receptor (LOX)-1, CXCL16). To confirm the pro-atherogenic effects of RA plasma on macrophages, foam cell formation was quantified. Results showed that RA plasma downregulates cholesterol efflux proteins and upregulates scavenger receptors CD36, LOX1 and CXCL16. These pro-atherogenic changes in gene expression in the presence of RA plasma are associated with augmented lipid accumulation and foam cell formation by THP-1 macrophages. RA plasma induces macrophage cholesterol overload. Demonstration of disrupted cholesterol homeostasis mediated by RA plasma provides further evidence of the involvement of the immune system in atherogenesis. Our data suggest that chronic exposure to RA plasma adversely affects the capacity of monocytes/macrophages in the arterial wall to metabolize cholesterol and maintain lipid homeostasis, thereby contributing to the development of premature atherosclerosis.

OBJECTIVE: The greater New York metropolitan area includes 8 medical schools. Their alumni association (AA) presidents formed a council 6 years ago, meeting 3 times a year to share ideas and identify best practices to solve mutual problems challenging students and alumni. METHODS: A survey of the 8 medical AAs was conducted; all responded, and the results constitute the data in this report. RESULTS: Mean AA membership was 2509 or 33% of mean alumni populations (7489). Two AAs conferred membership at graduation; hence, 100% of alumni were AA members. Omitting these 2 AAs reduced mean participation to 1722 or 23%. Alumni association support staff averaged 3.8 persons (range, 1-7 persons). The 2 most frequently cited AA challenges were membership and fund-raising. All AAs had annual or biennial reunions and considered the reunion to be a major commitment of resources. Despite this commitment, mean reunion attendance was only 242 alumni (range, 40-500 alumni) or 7.3% of alumni in anniversary years (5-year intervals). The mean number of alumni who contributed annually to their alma mater through its AA was 1936 alumni (range, 500-3500 alumni), or 26% (range, 5%-47%). Medical AAs reported mean assets of $2,755,000 (range, $6475-$11,000,000). The mean AA budget was $298,750, of which 65% (range, 13%-100%) was devoted to "medical student support". The most frequently cited student activities were "career night" (100%), "white coat ceremonies" (63%), medical equipment (stethoscopes, etc, 50%), and alumni host programs (38%). Eleven additional medical student activities received financial support from the 8 AAs in varying proportions. CONCLUSIONS: Each AA in the Greater Metropolitan Medical Alumni Council has derived significant benefit from the application of best practices to its individual problem set. In particular, a nascent AA developed significant momentum in its formation and development by its participation in the Greater Metropolitan Medical Alumni Council. Additionally, these data provide a foundation for the development of best practices within medical school AA for optimizing support of student programs and alumni participation. Stronger AAs will translate into enhanced support of educational programs for medical students. We urge formation of similar medical AA organizations in other metropolitan areas.