Publications

Solid organ transplantation in human immunodeficiency virus (HIV)-infected individuals requiring concomitant use of immunosuppressants (IS) (e.g. cyclosporine [CsA], sirolimus [SrL], tacrolimus [FK]) and antiretrovirals (ARVs) (e.g. protease inhibitors [PIs] and/or nonnucleoside reverse transcriptase inhibitors [NNRTIs]) is complicated by significant drug interactions. To assist in appropriate clinical management, we describe the pharmacokinetics and dosing modifications in 35 patients (20 kidney, 13 liver and two kidney-liver HIV-infected subjects with end-stage kidney or liver disease), on both IS and NNRTIs, PIs, and combined NNRTIs + PIs, in studies done at weeks 2-4 and/or 12 weeks after transplantation or after a change in IS or ARV drug regimen (n = 97 studies). CsA, SrL and FK concentrations were measured in whole blood by LC/MS. HIV-infected transplant recipients using PIs with IS had marked increases in CsA, FK or SrL trough levels compared to those on NNRTIs alone or to patients not on ARVs, necessitating either a reduction in dose or an increase in dosing interval. Subjects on efavirenz (EFV) and CsA required much higher doses of CsA than those using any other ARV. Changes in antiretroviral therapy should be carefully managed to avoid insufficient immunosuppression or toxicity due to drug interactions.

Chemotaxis (i.e., directed migration) of hepatic stellate cells to areas of inflammation is a requisite event in the liver's response to injury. Previous studies of signaling pathways that regulate stellate cell migration suggest a key role for focal adhesions, but the exact function of these protein complexes in motility remains unclear. Focal adhesions attach a cell to its substrate and therefore must be regulated in a highly coordinated manner during migration. To test the hypothesis that focal adhesion turnover is an essential early event for chemotaxis in stellate cells, we employed a live-cell imaging technique in which chemotaxis was induced by locally stimulating the tips of rat stellate cell protrusions with platelet-derived growth factor-BB (PDGF). Focal adhesions were visualized with an antibody directed against vinculin, a structural component of the focal adhesion complex. PDGF triggered rapid disassembly of adhesions within 6.25 min, subsequent reassembly by 12.5 min, and continued adhesion assembly in concert with the spreading protrusion until the completion of chemotaxis. Blockade of adhesion disassembly by growing cells on fibronectin or treatment with nocodazole prevented a chemotactic response to PDGF. Augmentation of adhesion disassembly with ML-7 enhanced the chemotactic response to PDGF. These data suggest that focal adhesion disassembly is an essential early event in stellate cell chemotaxis in response to PDGF.

BACKGROUND

Some HIV protease inhibitors (PIs) have been shown to induce insulin resistance in vitro but the degree to which specific PIs affect insulin sensitivity in humans is less well understood.

METHODS

In two separate double-blind, randomized, cross-over studies, we assessed the effects of a single dose of ritonavir (800 mg) and amprenavir (1200 mg) on insulin sensitivity (euglycemic hyperglycemic clamp) in healthy normal volunteers.

RESULTS

Ritonavir decreased insulin sensitivity (-15%; P = 0.008 versus placebo) and non-oxidative glucose disposal (-30%; P = 0.0004), whereas neither were affected by amprenavir administration.

CONCLUSION

Compared to previously performed studies of identical design using single doses of indinavir and lopinavir/ritonavir, a hierarchy of insulin resistance was observed with the greatest effect seen with indinavir followed by ritonavir and lopinavir/ritonavir, with little effect of amprenavir.

Human epidermis elaborates two small cationic, highly hydrophobic antimicrobial peptides (AMP), beta-defensin 2 (hBD2), and the carboxypeptide cleavage product of human cathelicidin (hCAP18), LL-37, which are co-packaged along with lipids within epidermal lamellar bodies (LBs) before their secretion. Because of their colocalization, we hypothesized that AMP and barrier lipid production could be coregulated by altered permeability barrier requirements. mRNA and immunostainable protein levels for mBD3 and cathelin-related antimicrobial peptide (CRAMP) (murine homologues of hBD2 and LL-37, respectively) increase 1-8 hours after acute permeability barrier disruption and normalize by 24 hours, kinetics that mirror the lipid metabolic response to permeability barrier disruption. Artificial permeability barrier restoration, which inhibits the lipid-synthetic response leading to barrier recovery, blocks the increase in AMP mRNA/protein expression, further evidence that AMP expression is linked to permeability barrier function. Conversely, LB-derived AMPs are also important for permeability barrier homeostasis. Despite an apparent increase in mBD3 protein, CRAMP-/- mice delayed permeability barrier recovery, attributable to defective LB contents and abnormalities in the structure of the lamellar membranes that regulate permeability barrier function. These studies demonstrate that (1) the permeability and antimicrobial barriers are coordinately regulated by permeability barrier requirements and (2) CRAMP is required for permeability barrier homeostasis.

BACKGROUND

Frozen-section analysis (FS) of the sentinel lymph node (SLN) is performed to avoid reoperation for axillary lymph node dissection (ALND), but it can miss micrometastatic disease, is labor intensive for the pathologist, and does not alter the number of breast-conservation therapy (BCT) patients needing reoperation for positive margins. The purpose of this study was to determine if eliminating FS would change reoperation rates in BCT patients.

STUDY DESIGN

Between January 2004 and December 2005, 1,218 patients had simultaneous BCT and SLN biopsy for invasive breast cancer. FS of the SLN was used selectively at the surgeon's discretion. Clinical and pathologic data were collected.

RESULTS

Overall, 542 of 1,218 (44%) patients had positive margins. FS of the SLN was performed in 931 of 1,218 (76%) patients. In those having FS, the SLN positivity rate was 33% (306 of 931). FS identified the positive SLN in 170 of 306 (56%) patients with positive nodes, allowing for immediate ALND. But 101 of these 170 patients had positive lumpectomy margins; and FS of the SLN saved 69 of 931 (7%) patients a second operation. Of patients not having FS, 48 of 287 (17%) had a positive SLN on final pathology. Only 18 of 48 (those seen on routine hematoxylin and eosin) might have been seen on FS, potentially sparing reoperation. Half of patients not having FS required reexcision for positive margins. FS would have spared reoperation for only 8 of 287 (3%) patients in this group. Overall, of 354 of 1,218 patients with SLN metastases, 170 had immediate ALND and 98 had delayed ALND. Of those having delayed ALND, 68 of 98 also had positive margins.

CONCLUSIONS

Among patients having BCT with SLN biopsy, FS identified the positive SLN in 56% of patients with positive SLNs, allowing immediate ALND, and was false negative in 44%. Margin status remains a frequent indication for reoperation in BCT; routine FS analysis of the SLN ultimately saves only a minority of patients a second operation.

OBJECTIVE

To determine if depression associated with low heart rate variability (HRV) in patients post myocardial infarction (MI), but not in patients with stable coronary heart disease (CHD), may be the result of differential associations of somatic and cognitive depressive symptoms with HRV.

METHODS

To examine the association of somatic and cognitive depressive symptoms with 24-hour HRV, we performed a cross-sectional study of 863 outpatients with stable CHD. The severity of somatic and cognitive depressive symptoms was determined using factor analysis of items of the Patient Health Questionnaire (PHQ-9). Time-domain (SDNN, SDANN) and frequency-domain (VLF, LF, HF, WBF) indices of HRV were derived using ambulatory monitoring.

RESULTS

Unadjusted analyses revealed that somatic symptom scores were significantly associated with HRV (r = -.09 for SDNN; r = -.08 for SDANN; r = -.08 for LnVLF; r = -.08 for LnLF; r = -.10 for LnHF; r = -.08 for LnWBF). After adjustment for demographic variables, comorbidities, and lifestyle factors, somatic symptom scores were no longer associated with lower HRV, with the possible exception of LnWBF (r = -.06). Cognitive depressive symptom scores were not associated with HRV using either unadjusted or adjusted analyses.

CONCLUSIONS

We found that somatic depressive symptoms were associated with lower HRV, although cognitive depressive symptoms were not. The inverse association of somatic symptoms with HRV was largely explained by differences in comorbidities and lifestyle factors. These results suggest that individual symptoms of depression may have differential associations with HRV.