Publications

At the temperature of its flea vector (approximately 20-30 degrees C), the causative agent of plague, Yersinia pestis, expresses a profile of genes distinct from those expressed in a mammalian host (37 degrees C). When dendritic cells (DC) are exposed to Y. pestis grown at 26 degrees C (Y. pestis-26 degrees), they secrete copious amounts of IL-12p40 homodimer (IL-12(p40)(2)). In contrast, when DCs are exposed to Y. pestis grown at 37 degrees C (Y. pestis-37 degrees), they transcribe very little IL-12p40, which is secreted as IL-12p40 monomer (IL-12p40). Y. pestis-26 degrees also induces migration of DCs to the homeostatic chemokine CCL19, whereas Y. pestis-37 degrees does not; migratory DCs are positive for IL-12p40 transcription and secrete mostly IL-12(p40)(2); DCs lacking IL-12p40 do not migrate. Expression of acyltransferase LpxL from Escherichia coli in Y. pestis-37 degrees results in the production of a hexa-acylated lipid A, also seen in Y. pestis-26 degrees, rather than tetra-acylated lipid A normally seen in Y. pestis-37 degrees. The LpxL-expressing Y. pestis-37 degrees promotes DC IL-12(p40)(2) production and induction of DC migration. In addition, absence of TLR4 ablates production of IL-12(p40)(2) in DC exposed to Y. pestis-26 degrees. The data demonstrate the molecular pathway by which Y. pestis evades induction of early DC activation as measured by migration and IL-12(p40)(2) production.

The Src family kinase Fyn is expressed in T cells and has been shown to phosphorylate proteins involved in TCR signaling, cytoskeletal reorganization, and IL-4 production. Fyn-deficient mice have greatly decreased numbers of NKT cells and have thymocytes and T cells with compromised responses following Ab crosslinking of their TCRs. Herein we have addressed the role of Fyn in peptide/MHC class II-induced CD4(+) T cell responses. In Fyn-deficient mice, CD4(+) T cells expressing the DO11.10 TCR transgene developed normally, and the number and phenotype of naive and regulatory DO11.10(+)CD4(+) T cells in the periphery were comparable with their wild-type counterparts. Conjugation with chicken OVA peptide 323-339-loaded APCs, and the subsequent proliferation in vitro or in vivo of DO11.10(+) Fyn-deficient CD4(+) T cells, was virtually indistinguishable from the response of DO11.10(+) wild-type CD4(+) T cells. Proliferation of Fyn-deficient T cells was not more dependent on costimulation through CD28. Additionally, we have found that differentiation, in vitro or in vivo, of transgenic CD4(+) Fyn-deficient T cells into IL-4-secreting effector cells was unimpaired, and under certain conditions DO11.10(+) Fyn-deficient CD4(+) T cells were more potent cytokine-producing cells than DO11.10(+) wild-type CD4(+) T cells. These data demonstrate that ablation of Fyn expression does not alter most Ag-driven CD4(+) T cell responses, with the exception of cytokine production, which under some circumstances is enhanced in Fyn-deficient CD4(+) T cells.

INTRODUCTION

Although recent case reports and one small single-year observational study report a substantially increased rate of perforation with the St. Jude Riata series defibrillator lead, these results have not been externally validated.

METHODS AND RESULTS

From 2004 to 2007, 593 implantable cardioverter-defibrillator (ICD) implants were performed by six faculty and 13 fellows at four University of California, San Francisco, CA, USA and affiliate hospitals. An electronic medical records system was systematically searched to identify clinically significant cases of ICD lead dislodgment or perforation. Of 307 (56%) St. Jude leads (all Riata series 6.3- and 7.3-French leads), 188 (29%) Medtronic leads (including 99 Sprint Fidelis 6.6 French leads), and 98 (15%) Guidant/Boston Scientific leads, there were three perforations in 593 cases (0.51%). One perforation occurred with a Medtronic Sprint Fidelis 6949 lead (0.53%), and two with a St. Jude Riata 1581 lead (0.65%). There were no statistically significant differences in perforation or dislodgement rates between manufacturers or lead models (p = NS for all). In both cases of perforation with the St. Jude Riata leads, the lead tip perforated through the pericardium into the pleural space.

CONCLUSIONS

In our 4-year series of ICD implants, perforation and dislodgement rates were low, similar across all lead makes and models, and well below published and accepted complication rates. Our findings contradict previously-reported higher rates of perforation with the Riata lead. Registry and product performance reports should also classify complications by severity and outcome to provide a more complete assessment of product safety.

Human immunodeficiency virus (HIV-1) can rapidly evolve due to selection pressures exerted by HIV-specific immune responses, antiviral agents, and to allow the virus to establish infection in different compartments in the body. Statistical models applied to HIV-1 sequence data can help to elucidate the nature of these selection pressures through comparisons of non-synonymous (or amino acid changing) and synonymous (or amino acid preserving) substitution rates. These models also need to take into account the non-independence of sequences due to their shared evolutionary history. We review how we have developed these methods and have applied them to characterize the evolution of HIV-1 in vivo. To illustrate our methods, we present an analysis of compartment-specific evolution of HIV-1 env in blood and cerebrospinal fluid and of site-to-site variation in the gag gene of subtype C HIV-1.

CONTEXT

Guidelines call for documenting ischemia in patients with stable coronary artery disease prior to elective percutaneous coronary intervention (PCI).

OBJECTIVE

To determine the frequency and predictors of stress testing prior to elective PCI in a Medicare population.

DESIGN, SETTING, AND PATIENTS

Retrospective, observational cohort study using claims data from a 20% random sample of 2004 Medicare fee-for-service beneficiaries aged 65 years or older who had an elective PCI (N = 23 887).

MAIN OUTCOME MEASURES

Percentage of patients who underwent stress testing within 90 days prior to elective PCI; variation in stress testing prior to PCI across 306 hospital referral regions; patient, physician, and hospital characteristics that predicted the appropriate use of stress testing prior to elective PCI.

RESULTS

In the United States, 44.5% (n = 10 629) of patients underwent stress testing within the 90 days prior to elective PCI. There was wide regional variation among the hospital referral regions with stress test rates ranging from 22.1% to 70.6% (national mean, 44.5%; interquartile range, 39.0%-50.9%). Female sex (adjusted odds ratio [AOR], 0.91; 95% confidence interval [CI], 0.86-0.97), age of 85 years or older (AOR, 0.83; 95% CI, 0.72-0.95), a history of congestive heart failure (AOR, 0.85; 95% CI, 0.79-0.92), and prior cardiac catheterization (AOR, 0.45; 95% CI, 0.38-0.54) were associated with a decreased likelihood of prior stress testing. A history of chest pain (AOR, 1.28; 95% CI, 1.09-1.54) and black race (AOR, 1.26; 95% CI, 1.09-1.46) increased the likelihood of stress testing prior to PCI. Patients treated by physicians performing 150 or more PCIs per year were less likely to have stress testing prior to PCI (AOR, 0.84; 95% CI, 0.77-0.93). No hospital characteristics were associated with receipt of stress testing.

CONCLUSION

The majority of Medicare patients with stable coronary artery disease do not have documentation of ischemia by noninvasive testing prior to elective PCI.

We performed a longitudinal analysis of 502 unique methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates originating from San Francisco jail inmates between 2000 and 2007. Strain USA300, first encountered in 2001, accounted for 82.1% (412/502) of MRSA infections. Non-USA300 MRSA strains were rarely found after 2005 (one isolate in 2006, three in 2007).