Publications

Coronary artery ectasia (CAE) is generally diagnosed in patients undergoing arteriography for presumptive atherosclerotic coronary artery disease. CAE is commonly considered as a variant of atherosclerotic disease; however, recent studies suggest that CAE is the result of a systemic vascular disorder. There is increasing evidence that aneurysmal vascular disease is a systemic disorder characterized by enhanced expression of pro-inflammatory cytokines and increased synthesis of enzymes capable of degrading elastin and other components of the vascular wall. Matrix metalloproteinase-2 degrades a number of extracellular substrates, including elastin and has been shown to play a critical role in the development of abdominal aortic aneurysms. This study characterizes the development of CAE in a unique murine transgenic model with cardiac-specific expression of active MMP-2. Transgenic mice were engineered to express an active form of MMP-2 under control of the α-myosin heavy chain promoter. Coronary artery diameters were quantified, along with studies of arterial structure, elastin integrity and vascular expression of the MMP-2 transgene. Latex casts quantified total coronary artery volumes and arterial branching. Mid-ventricular coronary luminal areas were increased in the MMP-2 transgenics, coupled with foci of aneurysmal dilation, ectasia and perivascular fibrosis. There was no evidence for atherogenesis. Coronary vascular elastin integrity was compromised and coupled with inflammatory cell infiltration. Latex casts of the coronary arteries displayed ectasia with fusiform dilatation. The MMP-2 transgenic closely replicates human CAE and supports a critical and initiating role for this enzyme in the pathogenesis of this disorder.

OBJECTIVES

To conduct an evidence-based review of the common medication toxicities and strategies and utility of drug toxicity monitoring among patients with systemic lupus erythematosus (SLE).

METHODS

PubMed and other databases were searched for articles published between the years 1960 and 2010 for keywords referring to medication toxicity or monitoring strategies for 7 drugs commonly used in SLE. All relevant English-language articles were reviewed. Most of the evidence we reviewed comprised studies that addressed the incidence of toxicity-randomized trials that compare different monitoring strategies for these drugs do not exist.

RESULTS

Data to describe the frequency of adverse events and appropriate strategies for screening for these events are scarce. Toxicities do not appear to be substantially more common among patients with SLE compared to other conditions for which these drugs are used.

CONCLUSIONS

Our review demonstrates that the scientific basis for many aspects of drug toxicity monitoring is weak and that most current recommendations are based largely on expert consensus. We present a future research agenda to address these gaps.

BACKGROUND

Several strategies have been proposed to reform physician reimbursement while improving quality of care. Despite much debate, physicians' opinions regarding reimbursement reform proposals have not been objectively assessed.

METHODS

We conducted a national survey of randomly selected physicians between June 25 and October 31, 2009. Physicians rated their support for several reimbursement reform proposals: rewarding quality with financial incentives, bundling payments for episodes of care, shifting payments from procedures to management and counseling services, increasing pay to generalists, and offsetting increased pay to generalists with a reduction in pay for other specialties. Support for the different reform options was compared with physician practice characteristics.

RESULTS

The response rate was 48.5% (n = 1222). Four of 5 physicians (78.4%) indicated that under Medicare, some procedures are compensated too highly and others are compensated at rates insufficient to cover costs. Incentives were the most frequently supported reform option (49.1%), followed by shifting payments (41.6%) and bundling (17.2%). Shifting payments and bundling were more commonly supported by generalists than by other specialists. There was broad support for increasing pay for generalists (79.8%), but a proposal to offset the increase with a 3% reduction in specialist reimbursement was supported by only 39.1% of physicians.

CONCLUSIONS

Physicians are dissatisfied with Medicare reimbursement and show little consensus for major proposals to reform reimbursement. The successful adoption of payment reform proposals may require a better understanding of physicians' concerns and their willingness to make tradeoffs.

OBJECTIVE

To determine whether raltegravir-containing antiretroviral therapy (ART) intensification reduces HIV levels in the gut.

DESIGN

Open-label study in HIV-positive adults on ART with plasma HIV RNA below 40 copies/ml.

METHODS

Seven HIV-positive adults received 12 weeks of ART intensification with raltegravir alone or in combination with efavirenz or darunavir. Gut cells were obtained by upper and lower endoscopy with biopsies from duodenum, ileum, colon, and rectum at baseline and 12 weeks. Study outcomes included plasma HIV RNA, HIV DNA and RNA from peripheral blood mononuclear cells (PBMC) and four gut sites, T-cell subsets, and activation markers.

RESULTS

Intensification produced no consistent decrease in HIV RNA in the plasma, PBMC, duodenum, colon, or rectum. However, five of seven participants had a decrease in unspliced HIV RNA per 10 CD4(+) T cells in the ileum. There was a trend towards decreased T-cell activation in all sites, which was greatest for CD8(+) T cells in the ileum and PBMC, and a trend towards increased CD4(+) T cells in the ileum.

CONCLUSION

Most HIV RNA and DNA in the blood and gut is not the result of ongoing replication that can be impacted by short-term intensification with raltegravir. However, the ileum may support ongoing productive infection in some patients on ART, even if the contribution to plasma RNA is not discernible.

Little is known about electrocardiographic (ECG) characteristics of menopausal women with or at increased risk of coronary heart disease (CHD). Data from 10,101 participants in the Raloxifene Use for The Heart (RUTH) trial were used to correlate baseline ECG abnormalities with clinical characteristics. Baseline characteristics that were statistically significantly associated (p ≤ 0.05) with ECG findings in univariate analyses were used to derive multivariate model selection. Of 59% normal electrocardiograms, 50% were from women with CHD and 69% from women at increased risk of CHD. In the women with CHD, 59% reported a previous myocardial infarction (MI); 43% had a normal electrocardiogram, and 49% had a definite ECG Q-wave MI. Women in the increased-risk group had not reported a previous MI, yet 11% had a definite ECG Q-wave MI. Of women reporting hypertension, 35% had ECG evidence of left ventricular hypertrophy, but 58% did not have an abnormal electrocardiogram. Significantly more women with diabetes in the increased-risk and documented CHD cohorts had abnormal electrocardiograms (p < 0.01 for the 2 cohorts). Percent abnormal electrocardiograms increased with increasing age (55 to 64, 65 to 74, and ≥ 75 years, p < 0.01) in all cohorts. Angina and coronary artery bypass graft surgery, but not percutaneous coronary intervention, predicted an abnormal electrocardiogram. In conclusion, there were high percentages of normal electrocardiograms in the increased-risk and documented CHD groups of RUTH participants, with substantial discrepancy between MI history and ECG MI documentation, and increasing age was the predominant correlate with an abnormal electrocardiogram in all 3 cohorts.

BACKGROUND

The gut is a major reservoir for human immunodeficiency virus (HIV) in patients receiving antiretroviral therapy (ART). We hypothesized that distinct immune environments within the gut may support varying levels of HIV.

METHODS

In 8 HIV-1-positive adults who were receiving ART and had CD4(+) T cell counts of >200 cells/μL and plasma viral loads of <40 copies/mL, levels of HIV and T cell activation were measured in blood samples and endoscopic biopsy specimens from the duodenum, ileum, ascending colon, and rectum.

RESULTS

HIV DNA and RNA levels per CD4(+) T cell were higher in all 4 gut sites compared with those in the blood. HIV DNA levels increased from the duodenum to the rectum, whereas the median HIV RNA level peaked in the ileum. HIV DNA levels correlated positively with T cell activation markers in peripheral blood mononuclear cells (PBMCs) but negatively with T cell activation markers in the gut. Multiply spliced RNA was infrequently detected in gut, and ratios of unspliced RNA to DNA were lower in the colon and rectum than in PBMCs, which reflects paradoxically low HIV transcription, given the higher level of T cell activation in the gut.

CONCLUSIONS

HIV DNA and RNA are both concentrated in the gut, but the inverse relationship between HIV DNA levels and T cell activation in the gut and the paradoxically low levels of HIV expression in the large bowel suggest that different processes drive HIV persistence in the blood and gut.

TRIAL REGISTRATION

ClinicalTrials.gov identifier: NCT00884793 (PLUS1).