Publications

NO is critical to immunity, but its role in the development of the immune system is unknown. In this study, we show that S-nitrosoglutathione reductase (GSNOR), a protein key to the control of protein S-nitrosylation, is important for the development of lymphocytes. Genetic deletion of GSNOR in mice results in significant decrease in both T and B lymphocytes in the periphery. In thymus, GSNOR deficiency causes excessive protein S-nitrosylation, increases apoptosis, and reduces the number of CD4 single-positive thymocytes. Lymphopenia and increase in S-nitrosylation and apoptosis in GSNOR-deficient mice are largely abolished by genetic deletion of inducible NO synthase. Furthermore, the protection of lymphocyte development by GSNOR is apparently intrinsic to hematopoietic cells. Thus, GSNOR, likely through regulation of S-nitrosylation and apoptosis, physiologically plays a protective role in the development of the immune system.

Innate immune recognition of the bacterial cell wall constituent peptidoglycan by the cytosolic nucleotide-binding oligomerization domain 2 (Nod2) receptor has a pivotal role in the maintenance of intestinal mucosal homeostasis. Whereas peptidoglycan cleavage by gut-derived lysozyme preserves the recognition motif, the N-acetylmuramoyl-L-alanine amidase activity of the peptidoglycan recognition protein 2 (PGLYRP-2) destroys the Nod2-detected muramyl dipeptide structure. PGLYRP-2 green fluorescent protein (GFP) reporter and wild-type mice were studied by flow cytometry and quantitative RT-PCR to identify Pglyrp-2 expression in cells of the intestinal mucosa and reveal a potential regulatory function on epithelial peptidoglycan recognition. CD3(+)/CD11c(+) T lymphocytes revealed significant Pglyrp-2 expression, whereas epithelial cells and intestinal myeloid cells were negative. The mucosal Pglyrp-2-expressing lymphocyte population demonstrated a mixed T-cell receptor (TCR) αβ or γδ phenotype with predominant CD8α and less so CD8β expression, as well as significant staining for the activation markers B220 and CD69, presenting a typical intraepithelial lymphocyte phenotype. Importantly, exposure of peptidoglycan to PGLYRP-2 significantly reduced Nod2/Rip2-mediated epithelial activation. Also, moderate but significant alterations of the intestinal microbiota composition were noted in Pglyrp-2-deficient animals. PGLYRP-2 might thus have a significant role in regulation of the enteric host-microbe homeostasis.

Rfv3 is an autosomal dominant gene that influences the recovery of resistant mice from Friend retrovirus (FV) infection by limiting viremia and promoting a more potent neutralizing antibody response. We previously reported that Rfv3 is encoded by Apobec3, an innate retrovirus restriction factor. However, it was recently suggested that the Rfv3 susceptible phenotype of high viremia at 28 days postinfection (dpi) was more dominantly controlled by the B-cell-activating factor receptor (BAFF-R), a gene that is linked to but located outside the genetically mapped region containing Rfv3. Although one prototypical Rfv3 susceptible mouse strain, A/WySn, indeed contains a dysfunctional BAFF-R, two other Rfv3 susceptible strains, BALB/c and A.BY, express functional BAFF-R genes, determined on the basis of genotyping and B-cell immunophenotyping. Furthermore, transcomplementation studies in (C57BL/6 [B6] × BALB/c)F(1) and (B6 × A.BY)F(1) mice revealed that the B6 Apobec3 gene significantly influences recovery from FV viremia, cellular infection, and disease at 28 dpi. Finally, the Rfv3 phenotypes of prototypic B6, A.BY, A/WySn, and BALB/c mouse strains correlate with reported Apobec3 mRNA expression levels. Overall, these findings argue against the generality of BAFF-R polymorphisms as a dominant mechanism to explain the Rfv3 recovery phenotype and further strengthen the evidence that Apobec3 encodes Rfv3.

OBJECTIVES

To conduct an evidence-based review of the common medication toxicities and strategies and utility of drug toxicity monitoring among patients with systemic lupus erythematosus (SLE).

METHODS

PubMed and other databases were searched for articles published between the years 1960 and 2010 for keywords referring to medication toxicity or monitoring strategies for 7 drugs commonly used in SLE. All relevant English-language articles were reviewed. Most of the evidence we reviewed comprised studies that addressed the incidence of toxicity-randomized trials that compare different monitoring strategies for these drugs do not exist.

RESULTS

Data to describe the frequency of adverse events and appropriate strategies for screening for these events are scarce. Toxicities do not appear to be substantially more common among patients with SLE compared to other conditions for which these drugs are used.

CONCLUSIONS

Our review demonstrates that the scientific basis for many aspects of drug toxicity monitoring is weak and that most current recommendations are based largely on expert consensus. We present a future research agenda to address these gaps.

OBJECTIVE

Older adults receiving Medicare home health services who experience undernutrition may be at increased risk of experiencing adverse outcomes. We sought to identify the association between baseline nutritional status and subsequent health service utilization and mortality over a 1-year period in older adults receiving Medicare home health services.

DESIGN

This was a longitudinal study using questionnaires and anthropometric measures designed to assess nutritional status (Mini-Nutritional Assessment) at baseline and health services utilization and mortality status at 6-month and 1-year follow-ups.

SETTING

Participants were evaluated in their homes.

PARTICIPANTS

A total of 198 older adults who were receiving Medicare home health services.

RESULTS

Based on Mini-Nutritional Assessment, 12.0% of patients were malnourished, 51.0% were at risk for malnourishment, and 36.9% had normal nutritional status. Based on body mass index, 8.1% of participants were underweight, 37.9% were normal weight, 25.3% were overweight, and 28.8% were obese. Using multivariate binary logistic regression analyses, participants who were malnourished or at risk for malnourishment were more likely to experience subsequent hospitalization, emergency room visit, home health aide use, and mortality for the entire sample and hospitalization and nursing home stay for overweight and obese participants.

CONCLUSIONS

Experiencing undernutrition at the time of receipt of Medicare home health services was associated with increased health services utilization and mortality for the entire sample, and with increased health services utilization only for the overweight and obese subsample. Opportunities exist to address risk of undernutrition in patients receiving home health services, including those who are overweight or obese, to prevent subsequent adverse health outcomes.

BACKGROUND

Several strategies have been proposed to reform physician reimbursement while improving quality of care. Despite much debate, physicians' opinions regarding reimbursement reform proposals have not been objectively assessed.

METHODS

We conducted a national survey of randomly selected physicians between June 25 and October 31, 2009. Physicians rated their support for several reimbursement reform proposals: rewarding quality with financial incentives, bundling payments for episodes of care, shifting payments from procedures to management and counseling services, increasing pay to generalists, and offsetting increased pay to generalists with a reduction in pay for other specialties. Support for the different reform options was compared with physician practice characteristics.

RESULTS

The response rate was 48.5% (n = 1222). Four of 5 physicians (78.4%) indicated that under Medicare, some procedures are compensated too highly and others are compensated at rates insufficient to cover costs. Incentives were the most frequently supported reform option (49.1%), followed by shifting payments (41.6%) and bundling (17.2%). Shifting payments and bundling were more commonly supported by generalists than by other specialists. There was broad support for increasing pay for generalists (79.8%), but a proposal to offset the increase with a 3% reduction in specialist reimbursement was supported by only 39.1% of physicians.

CONCLUSIONS

Physicians are dissatisfied with Medicare reimbursement and show little consensus for major proposals to reform reimbursement. The successful adoption of payment reform proposals may require a better understanding of physicians' concerns and their willingness to make tradeoffs.