Publications

Mast cells make and secrete an abundance of peptidases, which are stored in such large amounts in granules that they comprise a high fraction of all cellular protein. Perhaps no other immune cell is so generously endowed with peptidases. For many years after the main peptidases were first described, they were best known as markers of degranulation, for they are released locally in response to mast cell stimulation and can be distributed systemically and detected in blood. The principal peptidases are tryptases, chymases, carboxypeptidase A3, and dipeptidylpeptidase I (cathepsin C). Numerous studies suggest that these enzymes are important and even critical for host defense and homeostasis. Endogenous and allergen or pathogen-associated targets have been identified. Belying the narrow notion of peptidases as proinflammatory, several of the peptidases limit inflammation and toxicity of endogenous peptides and venoms. The peptidases are interdependent, so that absence or inactivity of one enzyme can alter levels and activity of others. Mammalian mast cell peptidases--chymases and tryptases especially--vary remarkably in number, expression, biophysical properties, and specificity, perhaps because they hyper-evolved under pressure from the very pathogens they help to repel. Tryptase and chymase involvement in some pathologies stimulated development of therapeutic inhibitors for use in asthma, lung fibrosis, pulmonary hypertension, ulcerative colitis, and cardiovascular diseases. While animal studies support the potential for mast cell peptidase inhibitors to mitigate certain diseases, other studies, as in mice lacking selected peptidases, predict roles in defense against bacteria and parasites and that systemic inactivation may impair host defense.

BACKGROUND

Both disability and depression are common in COPD, but limited information is available on the time-ordered relationship between increases in disability and depression onset.

METHODS

Subjects were members of a longitudinal cohort with self-reported physician-diagnosed COPD, emphysema, or chronic bronchitis. Data were collected through three annual structured telephone interviews (T1, T2, and T3). Depression was defined as a score >/= 4 on the Geriatric Depression Scale Short Form (S-GDS). Disability was measured with the Valued Life Activities (VLA) scale; three disability scores were calculated: percent of VLAs unable to perform, percent of VLAs affected (unable to perform or with some degree of difficulty), and mean VLA difficulty rating. Disability increases were defined as a 0.5 SD increase in disability score between T1 and T2. Multiple logistic regression analyses estimated the risk of T3 depression following a T1 to T2 disability increase for the total cohort and then excluding individuals who met the depression criterion at T1 or T2.

RESULTS

Approximately 30% of subjects met the depression criterion each year. Eight percent to 19% experienced a T1 to T2 disability increase, depending on the disability measure. Including all cohort members and controlling for baseline S-GDS scores, T1 to T2 increases in disability yielded a significantly elevated risk of T3 depression (% affected odds ratio [OR] =3.6; 95% CI, [1.7, 7.7]; % unable OR = 6.1 [17, 21.8]; mean difficulty OR= 3.6 [1.7, 8.0]). Omitting individuals depressed at T1 or T2 yielded even stronger risk estimates for % unable (OR = 13.4 [2.0, 91.4]) and mean difficulty (OR = 3.9 [1.3, 11.8]).

CONCLUSIONS

Increases in VLA disability are strongly predictive of the onset of depression.

OBJECTIVE

To compare the efficacy and safety of mycophenolate mofetil (MMF) and intravenous cyclophosphamide (IVC) as induction treatment for lupus nephritis (LN), by race, ethnicity and geographical region.

METHODS

A total of 370 patients with active Class III-V LN received MMF (target dose 3.0 g/day) or IVC (0.5-1.0 g/m(2)/month), plus tapered prednisone, for 24 weeks. Renal function, global disease activity, immunological complement (C3 and C4) and anti-dsDNA levels are the outcomes that were assessed in this study.

RESULTS

MMF was not superior to IVC as induction treatment (primary objective). There were important pre-specified interactions between treatment and race (P = 0.047) and treatment and region (P = 0.069) (primary endpoint). MMF and IVC response rates were similar for Asians (53.2 vs 63.9%; P = 0.24) and Whites (56.0 vs 54.2%; P = 0.83), but differed in the combined Other and Black group (60.4 vs 38.5%; P = 0.03). Fewer patients in the Black (40 vs 53.9%; P = 0.39) and Hispanic (38.8 vs 60.9%; P = 0.011) groups responded to IVC. Latin American patients had lower response to IVC (32 vs 60.7%; P = 0.003). Baseline disease characteristics were not predictive of response. The incidence of adverse events (AEs) was similar across groups. Serious AEs were slightly more prevalent among Asians.

CONCLUSIONS

MMF and IVC have similar efficacy overall to short-term induction therapy for LN. However, race, ethnicity and geographical region may affect treatment response; more Black and Hispanic patients responded to MMF than IVC. As these factors are inter-related, it is difficult to draw firm conclusions about their importance.

BACKGROUND

Patients with HIV have increased risk for cardiovascular disease, but the underlying mechanisms remain unknown. The purpose of this study was to determine the prevalence of echocardiographic abnormalities among asymptomatic HIV-infected individuals compared with HIV-uninfected individuals. Methods/Results- We performed echocardiography in 196 HIV-infected adults and 52 controls. Left ventricular ejection fraction, left ventricular mass indexed to the body surface area, and diastolic function were assessed according to American Society of Echocardiography standards. Left ventricular mass index was higher in HIV-infected patients (77.2 g/m(2) in patients with HIV versus 66.5 g/m(2) in controls, P<0.0001). Left ventricular ejection fraction was similar in both groups. Eight (4%) of the patients with HIV had evidence of left ventricular systolic dysfunction (defined as an EF <50%) versus none of the controls; 97 (50%) had mild diastolic dysfunction compared with 29% of the HIV-uninfected subjects (P=0.008). After adjustment for hypertension and race, HIV-infected participants had a mean 8 g/m(2) larger left ventricular mass index compared with controls (P=0.001). Higher left ventricular mass index was independently associated with lower nadir CD4 T-cell count, suggesting that immunodeficiency may play a role in this process. After adjustment for age and traditional risk factors, patients with HIV had a 2.4 greater odds of having diastolic dysfunction as compared with controls (P=0.019).

CONCLUSIONS

HIV-infected patients had a higher prevalence of diastolic dysfunction and higher left ventricular mass index compared with controls. These differences were not readily explained by differences in traditional risk factors and were independently associated with HIV infection. These results suggest that contemporary asymptomatic patients with HIV manifest mild functional and morphological cardiac abnormalities, which are independently associated with HIV infection.

BACKGROUND

While spouse correlations have been documented for numerous traits, no prior studies have assessed assortative mating for genetic ancestry in admixed populations.

RESULTS

Using 104 ancestry informative markers, we examined spouse correlations in genetic ancestry for Mexican spouse pairs recruited from Mexico City and the San Francisco Bay Area, and Puerto Rican spouse pairs recruited from Puerto Rico and New York City. In the Mexican pairs, we found strong spouse correlations for European and Native American ancestry, but no correlation in African ancestry. In the Puerto Rican pairs, we found significant spouse correlations for African ancestry and European ancestry but not Native American ancestry. Correlations were not attributable to variation in socioeconomic status or geographic heterogeneity. Past evidence of spouse correlation was also seen in the strong evidence of linkage disequilibrium between unlinked markers, which was accounted for in regression analysis by ancestral allele frequency difference at the pair of markers (European versus Native American for Mexicans, European versus African for Puerto Ricans). We also observed an excess of homozygosity at individual markers within the spouses, but this provided weaker evidence, as expected, of spouse correlation. Ancestry variance is predicted to decline in each generation, but less so under assortative mating. We used the current observed variances of ancestry to infer even stronger patterns of spouse ancestry correlation in previous generations.

CONCLUSIONS

Assortative mating related to genetic ancestry persists in Latino populations to the current day, and has impacted on the genomic structure in these populations.