Publications

Eosinophil accumulation is a defining feature of the immune response to parasitic worm infection. Tissue-resident cells, such as epithelial cells, are thought to initiate eosinophil recruitment. However, direct recognition of worms by eosinophils has not been explored as a mechanism for amplifying eosinophil accumulation. Here, we report that eosinophils rapidly migrate toward diverse nematode species in three-dimensional culture. These include the mammalian parasite Nippostrongylus brasiliensis and the free-living nematode Caenorhabditis elegans. Surprisingly, collective migration toward worms requires paracrine leukotriene B4 signaling between eosinophils. In contrast, neutrophils show a minimal response to nematodes, yet are able to undergo robust leukotriene-dependent migration toward IgG-coated beads. We further demonstrate that eosinophils accumulate around C. elegans in the lungs of mice. This response is not dependent on bacterial products, CCR3, or complement activation. However, mice deficient in leukotriene signaling show markedly attenuated eosinophil accumulation after injection of C. elegans or N. brasiliensis. Our findings establish that nematode-derived signals can directly induce leukotriene production by eosinophils and that leukotriene signaling is a major contributor to nematode-induced eosinophil accumulation in the lung. The similarity of the eosinophil responses to diverse nematode species suggests that conserved features of nematodes are recognized during parasite infection.

BACKGROUND

Over the past two decades, drug injection-related risk behaviors have been the major drivers of the HIV epidemic in Iran. This study assesses the access of people who injected drugs (PWID) to harm reduction services (needle-exchange programs [NEP] and methadone maintenance treatment [MMT]) in Tehran, Iran in 2007, almost five years after the large-scale implementation of these programs.

METHODS

572 consenting PWID (>18 years old, ever injected in the past month, lived in Tehran or its suburbs) were recruited (24 seeds) into a sero-behavioral survey using respondent-driven sampling method. Participants completed a face-to-face interview about HIV-related risk behaviors and access to harm reduction services. We calculated adjusted population estimates using RDSAT.

RESULTS

Overall, 99.2% of the participants were male, 41.6% aged between 30 and 39 years old, 55.4% lived alone in the past year, 83.2% were ever incarcerated, and 88.8% lived in the southern areas of Tehran. In terms of "awareness" and "use" of services among PWID, 62.8% and 54.8% reported for NEP (respectively) and 19.7% and 9.1% for drug treatment services (respectively). PWID who lived in Northwest and South-central Tehran were more likely to be aware (85.0% and 82.8%, respectively) of one or more services than PWID who lived elsewhere. Similarly, PWID who lived with friends were more likely to be aware of (88.6%) and use (85.9%) services (vs. other living partners). Overall, 11% of the participants were aware of but had not used any harm reduction services.

CONCLUSIONS

Despite a relatively high level of access to NEP among PWID in Tehran, a sizable fraction of the population remains without access to other services five years after their implementation. The use of harm reduction may be affected by certain PWID characteristics (e.g., living partners and geographical location). Ongoing surveillance activities are necessary to track change in access over time.

OBJECTIVE

The management of atrial fibrillation (AF) involves two choices: (1) rate control versus rhythm control, and (2) anticoagulation treatment based upon risk of stroke. The objective of the study was to describe practice patterns in both of these treatment areas in patients with newly diagnosed AF among a commercially insured population.

METHODS

This retrospective administrative claims analysis included patients with ≥2 AF claims between 1 January 2008 and 30 September 2010. Patients with AF claims within a year prior to the index date (i.e., the first AF diagnosis date) were excluded. The primary outcome was the proportion of patients treated with rate control (i.e., beta blockers, calcium channel blockers, digoxin) versus rhythm control (i.e., electrical cardioversion, left atrial catheter ablation [LACA], and/or surgical ablation) and the use of anticoagulants stratified by risk of stroke based on CHADS2 score.

RESULTS

Of 48,814 patients with a diagnosis of AF, 38,502 (78.9%) received treatment. Of those treated, the majority received only pharmacologic treatment (73.4%), of which beta blockers were predominantly used in the initial regimen (66.7%). Antiarrhythmic drugs were used in 23.9% of patients, but within the initial regimen in only 11.7% of patients. Direct current cardioversion occurred in 18.2% of patients, with the majority being either first-line (8.5%) or second-line (9.1%) therapy. LACA was used in only 5.2% of patients and was typically reserved for use after pharmacologic treatment or direct current cardioversion. Of 1924 patients who received LACA, 14.6% received a repeat procedure and 53.4% of the repeat procedures occurred within 6 months of the initial one. A little more than half of all patients (57.0%) received anticoagulant therapy (predominantly warfarin); of those at high risk for stroke, 63.8% with a CHADS2 score ≥2 received anticoagulants.

KEY LIMITATIONS

It is a retrospective analysis using administrative claims data from a commercially insured population only. Identification of the first episode of AF may be inaccurate, and we cannot differentiate between paroxysmal and persistent AF.

CONCLUSIONS

Debate continues regarding whether the preferred management of most patients with AF is through rate control or restoration of normal sinus rhythm. Our retrospective study found that treatments to restore normal heart rhythm, including LACA, which could be considered aggressive initial treatment, were typically reserved as second- or third-line alternatives. Initial standard of care for the majority patients was beta blockers. Though use of anticoagulation may be higher than other observational studies, opportunities exist to increase treatment in high risk patients.

Occlusive vasculopathy with intimal hyperplasia and plexogenic arteriopathy are severe histopathological changes characteristic of pulmonary arterial hypertension (PAH). Although a phenotypic switch in pulmonary endothelial cells (ECs) has been suggested to play a critical role in the formation of occlusive lesions, the pathobiology of this process is poorly understood. The goal of this study was to identify novel molecular mechanisms associated with EC dysfunction and PAH-associated bone morphogenetic protein receptor 2 (BMPR2) deficiency during PAH pathogenesis. A bioinfomatics approach, patient samples, and in vitro experiments were used. By combining a metaanalysis of human idiopathic PAH (iPAH)-associated gene-expression microarrays and a unique gene expression-profiling technique in rat endothelium, our bioinformatics approach revealed a PAH-associated dysregulation of genes involving chromatin organization, DNA metabolism, and repair. Our hypothesis that altered DNA repair and loss of genomic stability play a role in PAH was supported by in vitro assays where pulmonary ECs from patients with iPAH and BMPR2-deficient ECs were highly susceptible to DNA damage. Furthermore, we showed that BMPR2 expression is tightly linked to DNA damage control because excessive DNA damage leads to rapid down-regulation of BMPR2 expression. Moreover, we identified breast cancer 1 (BRCA1) as a novel target for BMPR2 signaling and a novel modulator of pulmonary EC homeostasis. We show here that BMPR2 signaling plays a critical role in the regulation of genomic integrity in pulmonary ECs via genes such as BRCA1. We propose that iPAH-associated EC dysfunction and genomic instability are mediated through BMPR2 deficiency-associated loss of DNA damage control.

There is significant evidence that Th2 (T helper 2)-mediated inflammation supports the pathogenesis of both human and experimental animal models of pulmonary hypertension (PH). A key immune regulator is vascular endothelial growth factor (VEGF), which is produced by Th2 inflammation and can itself contribute to Th2 pulmonary responses. In this study, we interrogated the role of VEGF signaling in a murine model of schistosomiasis-induced PH with a phenotype of significant intrapulmonary Th2 inflammation, vascular remodeling, and elevated right ventricular pressures. We found that VEGF receptor blockade partially suppressed the levels of the Th2 inflammatory cytokines interleukin (IL)-4 and IL-13 in both the lung and the liver after Schistosoma mansoni exposure and suppressed pulmonary vascular remodeling. These findings suggest that VEGF positively contributes to schistosomiasis-induced vascular inflammation and remodeling, and they also provide evidence for a VEGF-dependent signaling pathway necessary for pulmonary vascular remodeling and inflammation in this model.

Previous studies have demonstrated the utility of fluorescence in situ hybridization (FISH) as an ancillary method in the diagnostic workup of histopathologically ambiguous melanocytic neoplasms. A combination of probes targeting 3 loci on chromosome 6 and 1 on 11q has been reported to distinguish unequivocal melanomas and nevi with a sensitivity and specificity of 87% and 96%, respectively. However, information on how FISH should be integrated into routine clinical testing is limited. We report our experience of FISH testing of 804 ambiguous melanocytic lesions performed as part of routine workup at University of California, San Francisco. The main category (47% of all cases) for which FISH testing was requested was Spitz tumors. Other categories included the distinction of possible melanoma from combined nevi (9%), acral or mucosal nevi (9%), Clark/dysplastic nevi (7%), and blue or deep penetrating nevi (6%) and to assess the possibility of nevoid melanoma (4%). Of the ambiguous tumors successfully tested, 88% received a more definitive benign or malignant final diagnosis. Of the 630 cases that tested negative by FISH, the final diagnosis was benign in 489 (78%) cases, ambiguous in 91 cases (14%), and malignant in 50 cases (8%). A positive FISH result was observed in 124 cases, with a final diagnosis of melanoma in 117 (94%). One (1%) FISH-positive case had an equivocal final diagnosis, and 6 (5%) were interpreted, despite the positive FISH result, as melanocytic nevi. We conclude that FISH testing can help reduce the number of equivocal diagnoses in ambiguous melanocytic neoplasms, in particular if FISH testing is positive, and discuss the challenges and limitations of FISH in clinical practice.