Publications

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.

OBJECTIVE

A substantial minority of HIV-positive individuals have comorbid affective or substance use disorders, which can interfere with effective medical management. The present study examined the associations among affect regulation, substance use, non-adherence to anti-retroviral therapy (ART), and immune status in a diverse sample of HIV-positive persons.

METHODS

A total of 858 HIV-positive participants self-reporting risk of transmitting HIV were enrolled in a randomized behavioral prevention trial and provided baseline blood samples to measure T-helper (CD4+) counts and HIV viral load.

RESULTS

Among individuals on ART, regular stimulant users had a five-fold (0.70 log10) higher HIV viral load than those who denied regular stimulant use. The association between regular stimulant use and elevated HIV viral load remained after accounting for demographics, differences in CD4+ counts, and polysubstance use. In the final model, 1 unit increase in affect regulation (decreased severity of depressive symptoms as well as enhanced positive states of mind) was associated with a 23% decrease in the likelihood of reporting regular stimulant use and 15% decrease in the likelihood of being classified as nonadherent to ART. Regular stimulant users, in turn, were more than twice as likely to be nonadherent to ART. Even after accounting for the effects of nonadherence and CD4+ counts, regular stimulant use was independently associated with 50% higher HIV viral load.

CONCLUSIONS

Increased mental health treatment as well as more intensive referrals to substance abuse treatment or 12-step self-help groups may be crucial to assist stimulant users with more effectively managing treatment for HIV/AIDS.

OBJECTIVE

To determine whether an advance directive redesigned to meet most adults' literacy needs (fifth grade reading level with graphics) was more useful for advance care planning than a standard form (>12th grade level).

METHODS

We enrolled 205 English and Spanish-speaking patients, aged >/=50 years from an urban, general medicine clinic. We randomized participants to review either form. Main outcomes included acceptability and usefulness in advance care planning. Participants then reviewed the alternate form; we assessed form preference and six-month completion rates.

RESULTS

Forty percent of enrolled participants had limited literacy. Compared to the standard form, the redesigned form was rated higher for acceptability and usefulness in care planning, P

CONCLUSIONS

The redesigned advance directive was rated more acceptable and useful for advance care planning and was preferred over a standard form. It also resulted in higher six-month completion rates.

PRACTICE IMPLICATIONS

An advance directive redesigned to meet most adults' literacy needs may better enable patients to engage in advance care planning.

PURPOSE

SNS-032, (formerly BMS-387032) is a potent and selective inhibitor of cyclin-dependent kinases (CDK) 2, 7 and 9. The primary objective of the study was to establish the maximum tolerated dose (MTD), the maximum administered dose (MAD), dose limiting toxicity (DLT), and the recommended phase 2 dose for SNS-032 when administered as a weekly 1-h infusion. The secondary objective was to assess the safety and tolerability of SNS-032 and to evaluate its bioavailability as an oral solution.

METHODS

Patients with metastatic solid tumors or refractory lymphoma were treated with a starting dose of 4 mg/m2 intravenously administered over 1-h with a cycle defined as 3 weekly doses of SNS-032 every 21 days. Three patient cohorts were utilized in the dose-escalation schema. Pharmacokinetic studies were performed. For the 13 and 16 mg/m2 dose cohorts, the first dose of cycle 2 was given as an oral solution to estimate the oral bioavailability of the drug in humans.

RESULTS

A total of 21 patients were enrolled. Twenty treated patients received a total of 39 cycles of treatment. The most common treatment-related adverse events occurring with greater than 20% incidence were fatigue (25%) and nausea (20%). Following intravenous administration, plasma concentrations declined in a biphasic manner, resulting in mean terminal half-lives between 5 and 10 hours. The mean Cmax and AUC0-inf increased nearly linearly with dose, ranging from 0.067 to 0.287 microg/ml and 0.103 to 0.553 microg h/ml, respectively. The CL and Vss remained unchanged with increasing dose levels, averaging 38 l/h/m2 and 212 l/m2, respectively. Average oral bioavailability was 19% (range: 4-33%). Three (15%) patients experienced a best response of stable disease. Study enrollment was terminated during dose-escalation due to a change in the development strategy for the study drug.

CONCLUSIONS

SNS-032 administered as a weekly 1-h infusion was well tolerated, although study enrollment was terminated during dose-escalation and the MTD of SNS-032 administered intravenously on days 1, 8, and 15 of each treatment cycle was not reached. Tumor progression or stable disease was determined to be the best response in all evaluable patients. At the dose levels tested, the oral bioavailability of SNS-032 ranged from 4-33%. The data suggest that oral administration of SNS-032 may be feasible, though the tolerability and bioavailability of the oral formulation would have to be formally assessed.