Publications

People with depression and other mental illness comprise a growing proportion of individuals living with HIV in the United States; at the same time, the prevalence of HIV among mentally ill individuals is at least seven times higher than in the general population. Individuals with mental illness are particularly vulnerable to infection with HIV because of several factors, including the higher prevalence of poverty, homelessness, high-risk sexual activities, drug abuse, sexual abuse, and social marginalization found in this population. Nevertheless, mentally ill individuals are often not screened for HIV and may not be appropriately targeted in current HIV prevention efforts. Moreover, despite widespread access to antiretroviral treatment in the United States, HIV outcomes among mentally ill individuals continue to be poor. This disparity can be explained by several interrelated factors, including lower rates of highly active antiretroviral therapy (HAART) utilization, lower rates of adherence to HAART, and immunologic changes associated with mental illness itself. We need to improve our design of prevention, screening, and treatment programs to better reach individuals with comorbid HIV and mental illness.

The melanocortin-4 receptor (MC4R), a centrally expressed G protein-coupled receptor (GPCR), is essential for the maintenance of long-term energy balance in humans. Mutations in MC4R are the most common genetic cause of obesity. Since activation of this receptor leads to a decrease in food intake, MC4R is also a major therapeutic target for the treatment of obesity. Control of MC4R activity in vivo is modulated by the opposing effects of the anorexigenic agonist alpha-melanocyte-stimulating hormone (alpha-MSH) and the orexigenic antagonist agouti-related protein (AGRP). In addition, experiments in vitro have demonstrated that the human MC4R has an intrinsic constitutive activity on which AGRP also acts as an inverse agonist. The physiological role of this constitutive activity in the control of energy balance as well as the domain of the protein implicated in its maintenance are unknown. By systematically studying functional defects in naturally occurring MC4R mutations from obese patients, we defined a cluster of N-terminal mutations that selectively impair the constitutive activity of the receptor. Further characterization of this domain demonstrated that it functions as a tethered intramolecular ligand that maintains the constitutive activity of MC4R and may provide novel avenues for the design of drugs targeting this receptor. Our results also suggest that the tonic satiety signal provided by the constitutive activity of MC4R may be required for maintaining long-term energy homeostasis in humans.

The five integrins that contain the alphav subunit are widely expressed and their expression is tightly regulated. However, most tissues in mice lacking the alphav subunit, and thus deficient in all five integrins, develop normally, suggesting that nearly all of the critical steps in development and cellular differentiation can occur in the absence of these integrins. Studies over the past few years have identified highly specialized roles for specific alphav integrins in preventing inappropriate vascular growth and in control of vascular permeability. Two members of this family, alphavbeta6 and alphavbeta8, play novel roles in activating latent complexes of the growth factor TGFbeta (transforming growth factor beta). Studies in mice lacking the beta6 subunit have identified unexpected roles for alphavbeta6-mediated TGFbeta activation in models of pulmonary and renal fibrosis, acute lung injury and pulmonary emphysema.

BACKGROUND

Factors affecting health-related quality of life (HRQOL) in adult rhinitis have not been well described.

OBJECTIVE

To understand how symptom severity, physical functioning, psychological distress, and perceived control of disease relate to HRQOL in a population-based sample of adults with rhinitis.

METHODS

We conducted telephone interviews in 109 adults with rhinitis recruited via random digit dialing. We assessed HRQOL by using the Rhinosinusitis Disability Index, physical functioning by using the physical component score of the Short Form-12, and psychological distress by using the Center for Epidemiologic Studies Depression Scale. To evaluate the role of patient-perceived control of disease in rhinitis, we developed a new 8-item instrument, the Perceived Control of Rhinitis Questionnaire.

RESULTS

Lower HRQOL correlated with greater symptom severity ( r=0.57), poorer physical functioning ( r=-0.41), greater psychological distress ( r=0.44), and less perceived control ( r=-0.53). In a multivariate model, symptom severity ( P < .001), psychological distress ( P <.001), and perceived control ( P <.001) were all independent predictors of HRQOL. Adding functional and psychosocial measures to a base model with demographics and disease severity explained an additional 26% of variance in HRQOL.

CONCLUSIONS

Although disease severity is an important factor in HRQOL, psychosocial factors, such as perceived control of disease, explain a substantial amount of the variability in HRQOL among adults with rhinitis.

In HIV-1-infected subjects, the magnitude of HIV-1 viral load in cerebrospinal fluid (CSF) correlates with the CSF white cell count. To determine whether HIV-1-producing T cells appear in CSF and whether their percentage and number correlate with viral load in CSF, we developed a flow cytometric assay that detects HIV-1-producing T cells by identifying intracellular p24 HIV-1 antigen. We found that most CSF T cells were not HIV-1 producing, even when cell-free viral load in CSF was high. Most activated T cells in CSF were also not HIV-1 producing, but the activated CD38+ CD4 T-cell fraction in CSF was independently associated with the fraction of HIV-1-producing T cells in CSF. We conclude that HIV-1-producing T cells appear in CSF and that their percentage and number correlate with cell-free viral load in CSF, even though the CSF total white cell count remains the best predictor for CSF viral load. In HIV-1 infection, CSF white cell counts seem to contain a large number of uninfected cells. White cell counts and viral load in CSF may result from systemic inflammation and immune activation.

A novel intracoronary microsyringe system (MicroSyringe) was developed for regulated drug injection into the adventitial space. In this report, the feasibility, safety, and distribution pattern of vascular treatment with this modality were tested in 17 swine by delivering Oregon green-labeled paclitaxel (OGP) and tacrolimus. Coronaries were harvested 0.5-96 hr postinjection and analyzed for drug by fluorescence histochemistry (OGP) and liquid chromatography-mass spectrometry (tacrolimus). Histopathological analysis was subsequently performed. The microsyringe deliveries were performed safely in all cases. In the OGP-injected group, within 2 hr postprocedure there was intense staining of the adventitia, media, and endothelium around the injection site, and by 23 hr staining extended distally by 27.5 mm. With tacrolimus, similar longitudinal drug distribution was seen; furthermore, by 48 hr there was detectable drug over 40 mm proximal and distal to the injection site. Significant levels of tacrolimus were detectable in coronaries at 96 hr. Percutaneous adventitial delivery is safe, feasible, and provides consistent dosing for complete treatment of a vascular territory.

An analytic assay based on automated sample preparation and liquid chromatography (LC) coupled with electrospray mass spectrometry (ESI-MS) was developed for the quantification of 6 protease inhibitors (PIs) and 3 nonnucleoside reverse transcriptase inhibitors (NNRTIs). The 6 PIs, amprenavir, indinavir, ritonavir, lopinavir, nelfinavir, and saquinavir, as well as the three NNRTIs, nevirapine, efavirenz, and delavirdine, require a succinct analysis technique for therapeutic drug monitoring in HIV/AIDS patients. After protein precipitation, samples were loaded on a C8, 10 x 4-mm extraction column, washed, and, after activation of the column-switching valve, backflushed onto the 30 x 2.1 mm C8 analytic column. [M+H] ions were detected in the selected ion mode. A nonlinear fit (y(-1) = a + b/x, all r2 > 0.999) for amprenavir, indinavir, ritonavir, lopinavir, nelfinavir, and saquinavir and a linear fit (y = ax + b, all r2 > 0.999) for nevirapine, efavirenz, and delavirdine led to best regression. Absolute recoveries were as follows: PIs > 81%; NNRTIs > 76%. Interday and intraday precision were <12.5% for the PIs and <11.7% for the NNRTIs. Interday and intraday accuracy were <12.2% for the PIs and <14.9% for the NNRTIs. Limits of quantification were 20, 40, 50, 40, 40, 20, and 100 microg/L for amprenavir, indinavir, ritonavir, lopinavir, nelfinavir, saquinavir, and the NNRTIs, respectively. The assay allows fast analysis of patient samples for therapeutic drug monitoring (TDM) and has successfully been used for TDM and pharmacokinetic drug-drug interactions studies.