Publications

High-affinity antibodies are critical for host protection and underlie successful vaccines. The generation of such antibodies requires T cell-dependent help, which mediates germinal center reactions in which mutation and selection of B cells occurs. Using an interleukin 4-reporter system, we show here that CD4(+) follicular helper T cells constituted essentially all of the cytokine-secreting T cells in lymph nodes and were functionally distinct from T cells secreting the same cytokine in peripheral tissues. Follicular helper T cells with different cytokine profiles could be isolated as conjugates with B cells undergoing cytokine-specific immunoglobulin class switching with evidence of somatic hypermutation. Our findings support a model in which B cells compete for cytokines produced by follicular helper T cells that shape the affinity and isotype of the antibody response.

OBJECTIVE

The authors sought to evaluate the association of self-efficacy with objective measures of cardiac function, subsequent hospitalization for heart failure (HF), and all-cause mortality.

DESIGN

Observational cohort of ambulatory patients with stable CHD. The authors measured self-efficacy using a published, validated, 5-item summative scale, the Sullivan Self-Efficacy to Maintain Function Scale. The authors also performed a cardiac assessment, including an exercise treadmill test with stress echocardiography.

MAIN OUTCOME MEASURES

Hospitalizations for HF, as determined by blinded review of medical records, and all-cause mortality, with adjustment for demographics, medical history, medication use, depressive symptoms, and social support.

RESULTS

Of the 1,024 predominately male, older CHD patients, 1013 (99%) were available for follow-up, 124 (12%) were hospitalized for HF, and 235 (23%) died during 4.3 years of follow-up. Mean cardiac self-efficacy score was 9.7 (SD 4.5, range 0-20), corresponding to responses between "not at all confident" and "somewhat confident" for ability to maintain function. Lower self-efficacy predicted subsequent HF hospitalization (OR per SD decrease = 1.4, p = .0006), and all-cause mortality (OR per SD decrease = 1.4, p < .0001). After adjustment, the association of cardiac self-efficacy with both HF hospitalization and mortality was explained by worse baseline cardiac function.

CONCLUSION

Among patients with CHD, self-efficacy was a reasonable proxy for predicting HF hospitalizations. The increased risk of HF associated with lower baseline self-efficacy was explained by worse cardiac function. These findings indicate that measuring cardiac self-efficacy provides a rapid and potentially useful assessment of cardiac function among outpatients with CHD.

BACKGROUND

Improved control efforts are reducing the burden of malaria in Africa but may result in decreased antimalarial immunity.

METHODS

A cohort of 129 children aged 1-10 years in Kampala, Uganda, were treated with amodiaquine plus sulfadoxine-pyrimethamine for 396 episodes of uncomplicated malaria over a 29-month period as part of a longitudinal clinical trial.

RESULTS

The risk of treatment failure increased over the course of the study from 5% to 21% (hazard ratio [HR], 2.4 per year [95% confidence interval {CI}, 1.3-4.3]). Parasite genetic polymorphisms were associated with an increased risk of failure, but their prevalence did not change over time. Three markers of antimalarial immunity were associated with a decreased risk of treatment failure: increased age (HR, 0.5 per 5-year increase [95% CI, 0.2-1.2]), living in an area of higher malaria incidence (HR, 0.26 [95% CI, 0.11-0.64]), and recent asymptomatic parasitemia (HR, 0.06 [95% CI, 0.01-0.36]). In multivariate analysis, adjustment for recent asymptomatic parasitemia, but not parasite polymorphisms, removed the association between calendar time and the risk of treatment failure (HR, 1.5 per year [95% CI, 0.7-3.4]), suggesting that worsening treatment efficacy was best explained by decreasing host immunity.

CONCLUSION

Declining immunity in our study population appeared to be the primary factor underlying decreased efficacy of amodiaquine plus sulfadoxine-pyrimethamine. With improved malaria-control efforts, decreasing immunity may unmask resistance to partially efficacious drugs.

Reciprocal regulation of tyrosine phosphorylation by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) is central to normal immune cell function. Disruption of the equilibrium between PTK and PTP activity can result in immunodeficiency, autoimmunity, or malignancy. Src family kinases (SFKs) play a central role in both immune cell function and disease due to their proximal position in numerous signal transduction cascades including those emanating from integrin, T and B-cell antigen receptors, Fc, growth factor, and cytokine receptors. Given that tight regulation of SFKs activity is critical for appropriate responses to stimulation of these various signaling pathways, it is perhaps not surprising that multiple PTPs are involved in their regulation. Here, we focus on the role of three phosphatases, CD45, CD148, and LYP/PEP, which are critical regulators of SFKs in hematopoietic cells. We review our current understanding of their structures, expression, functions in different hematopoietic cell subsets, regulation, and putative roles in disease. Finally, we discuss remaining questions that must be addressed if we are to have a clearer understanding of the coordinated regulation of tyrosine phosphorylation and signaling networks in hematopoietic cells and how they could potentially be manipulated therapeutically in disease.

Trastuzumab is a targeted therapy for human EGF receptor-2 (HER2)-positive breast cancer. The effectiveness and cost-effectiveness of trastuzumab hinges not only on its clinical efficacy in responding patients, but on the ability to accurately identify appropriate therapeutic candidates. We sought to systematically review the cost-effectiveness of trastuzumab with a focus on the impact of the test(s) used for HER2 diagnosis. Our review included 17 economic evaluations or health technology assessments of trastuzumab therapy or HER2 testing. Trastuzumab was considered cost-effective in all early-stage disease studies, while one author concluded that trastuzumab was not cost-effective for metastatic disease. Only two papers considered the joint effects of test accuracy and sequencing with trastuzumab therapy. These demonstrated that trastuzumab cost-effectiveness is sensitive to HER2-test properties.

BACKGROUND

Home health and hospice services can constitute important elements in the continuum of care for older adults diagnosed with cancer. The Balanced Budget Act (BBA) of 1997 included provisions affecting those services.

OBJECTIVES

The first objective of this study is to assess the effect of the BBA of 1997 on home health and hospice service utilization in older cancer patients. The second objective is to estimate the effect of the BBA of 1997 on costs associated specifically with home health and hospice services and on total costs of care. The final objective is to evaluate the effect of the BBA of 1997 on mortality in these patients.

RESEARCH DESIGN

Longitudinal analysis using the Surveillance, Epidemiology, and End Results-Medicare Database, covering a service area that includes 26% of the US population.

PARTICIPANTS

Community-dwelling Medicare beneficiaries 65 years of age and older.

MEASURES

Utilization rates of home health and hospice services; costs associated with those services, and total costs of care; and mortality.

RESULTS

Home health utilization rates dropped substantially and hospice utilization rates increased after the BBA. Medicare costs for home health services declined as did total Medicare costs but hospice costs increased. There was no discernable effect on mortality rates.

CONCLUSIONS

The BBA was successful in containing the costs of home health services and resulted in savings in overall costs of care for older cancer patients. Reduction in utilization of home health services did not seem to negatively affect outcomes. The BBA may have contributed to the trend of increasing use of hospice care.

Staphylococcus aureus is the most abundant cause of bacterial infections in the United States. As such, the pathogen has devised means to circumvent destruction by the innate immune system. Neutrophils are a critical component of innate immunity and the primary cellular defense against S aureus infections. This article reviews human neutrophil function in the context of S aureus virulence mechanisms and provides an overview of community-associated methicillin-resistant S aureus pathogenicity.