Publications

Increased osteoclastic bone resorption leads to periarticular erosions and systemic osteoporosis in RA patients. Although a great deal is known about how osteoclasts differentiate from precursors and resorb bone, the identity of an osteoclast precursor (OCP) population in vivo and its regulatory role in RA remains elusive. Here, we report the identification of a CD11b(-/lo)Ly6C(hi) BM population with OCP activity in vitro and in vivo. These cells, which can be distinguished from previously characterized precursors in the myeloid lineage, display features of both M1 and M2 monocytes and expand in inflammatory arthritis models. Surprisingly, in one mouse model of RA (adoptive transfer of SKG arthritis), cotransfer of OCP with SKG CD4+ T cells diminished inflammatory arthritis. Similar to monocytic myeloid-derived suppressor cells (M-MDSCs), OCPs suppressed CD4+ and CD8+ T cell proliferation in vitro through the production of NO. This study identifies a BM myeloid precursor population with osteoclastic and T cell-suppressive activity that is expanded in inflammatory arthritis. Therapeutic strategies that prevent the development of OCPs into mature bone-resorbing cells could simultaneously prevent bone resorption and generate an antiinflammatory milieu in the RA joint.

By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations.

Understanding the metabolic, transporter, and genetic influences on the disposition of drugs used in chemotherapy is critical to individualization of drug therapy. Recognition of the importance of transporter-enzyme interplay, in which genetic variants of drug uptake transporters can change drug metabolism when the enzymes are unchanged, is an important advance in predicting appropriate drug dosage regimens for the individual patient.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening inflammatory disorder characterized by uncontrolled proliferation and activation of histiocytes with phagocytosis of normal hematopoietic cells. A 41-year-old woman, 19 weeks pregnant with twins, and a history of Still's disease, presented with rash, fever, and headache. Laboratory studies revealed transaminitis, hyperbilirubinemia, and eventually severe neutropenia as well as elevations in ferritin, lactate dehydrogenase, and C-reactive protein. A bone marrow biopsy confirmed HLH. She declined standard HLH-treatment but responded well to high-dose corticosteroids. Her blood counts remained stable following corticosteroid taper, and she delivered healthy twin girls at 30-week gestation. Few cases of HLH during pregnancy have been reported. In some cases, the condition has proved fatal. Therefore recognizing signs and symptoms of HLH is essential to avoid treatment delay. In our case, high-dose corticosteroids alone were a safe and effective therapy for the mother and fetuses resulting in long-term disease control.

BACKGROUND

Contraceptives are among the most commonly prescribed medications used by women of reproductive age, but little is known about women's information-seeking behavior after receiving prescriptions for medication.

STUDY DESIGN

All reproductive-age women who visited one of four primary care clinics in Western Pennsylvania between October 2008 and April 2010 were invited to complete a follow-up survey after their visit which included questions regarding medications prescribed, information-seeking after their visit and their perceptions of the quality of the information they found.

RESULTS

Of the 218 women prescribed contraceptives, 49% sought additional information after their visit. In models adjusted for sociodemographic and reproductive characteristics of the respondents, women who received a contraceptive prescription were twice as likely to seek additional information about their medication as women who received noncontraceptive prescriptions [odds ratio (OR)=2.06, 95% confidence interval (CI) 1.47-2.90]. Women who received a contraceptive prescription were more likely to seek information from the Internet (OR=1.84, 95% CI 1.26-2.70) and from the package insert (OR=1.55, 95% CI 1.02-2.36) than women who received noncontraceptive prescriptions.

CONCLUSIONS

Women frequently sought additional information on contraceptive prescriptions. Efforts are needed to increase the quantity and improve the quality of contraceptive counseling provided by primary care providers and the quality of the information provided by package inserts and the Internet.

BACKGROUND

While cigarette consumption in the USA continues to decline, promotion for and consumption of smokeless tobacco (SLT) is growing. However, little research has explored what product features are driving SLT growth, despite awareness that product-level factors may be important in SLT use. This study analyses national sales data to better understand the impact of product features on SLT sales.

METHODS

Data on sales of SLT in US convenience stores from 2005 to 2011 were obtained from Nielsen Research Company. Each listed product was coded for attributes such as type, brand, flavouring and form to calculate their respective total sales, market share and contribution to overall SLT growth.

RESULTS

Sales of moist snuff products (including snus) increased by 65.6% between 2005 and 2011. Sales of pouched and flavoured forms of moist snuff increased by 333.8% and 72.1%, respectively, and contributed to 28% and 59.4% of the total growth in the moist snuff category, respectively. Value/discount brands accounted for 42% of moist snuff sales in 2011 among the top 10 selling brands, largely driven by Grizzly. After 2 years on the national market, Camel Snus was also one of the top 10 selling moist snuff brands.

CONCLUSIONS

Sales of moist snuff, both overall and for particular styles, are increasing. Growing pouch use may be attributed to new SLT users, which may include cigarette smokers using them as starter SLT products. Increased sales of flavoured and discounted snuff raise concerns about use and appeal to youth. Continued surveillance of SLT sales trends is warranted.