Publications

Lymphocytes integrate Ag and cytokine receptor signals to make cell fate decisions. Using a specific reporter of TCR signaling that is insensitive to cytokine signaling, Nur77-eGFP, we identify a sharp, minimal threshold of cumulative TCR signaling required for proliferation in CD4 and CD8 T cells that is independent of both Ag concentration and affinity. Unexpectedly, IL-2 reduces this threshold in CD8 but not CD4 T cells, suggesting that integration of multiple mitogenic inputs may alter the minimal requirement for TCR signaling in CD8 T cells. Neither naive CD4 nor naive CD8 T cells are responsive to low doses of IL-2. We show that activated CD8 T cells become responsive to low doses of IL-2 more quickly than CD4 T cells, and propose that this relative delay in turn accounts for the differential effects of IL-2 on the minimal TCR signaling threshold for proliferation in these populations. In contrast to Nur77-eGFP, c-Myc protein expression integrates mitogenic signals downstream of both IL-2 and the TCR, yet marks an invariant minimal threshold of cumulative mitogenic stimulation required for cell division. Our work provides a conceptual framework for understanding the regulation of clonal expansion of CD8 T cells by subthreshold TCR signaling in the context of mitogenic IL-2 signals, thereby rendering CD8 T cells exquisitely dependent upon environmental cues. Conversely, CD4 T cell proliferation requires an invariant minimal intensity of TCR signaling that is not modulated by IL-2, thereby restricting responses to low-affinity or low-abundance self-antigens even in the context of an inflammatory milieu.

PURPOSE

To compare remote myocardium native T in patients with chronic myocardial infarction (MI) and controls without MI and to elucidate the relationship of infarct size and native T in the remote myocardium for the prediction of left ventricular (LV) systolic dysfunction after MI.

MATERIALS AND METHODS

A total of 41 chronic MI (18 anterior MI) patients and 15 age-matched volunteers with normal LV systolic function and no history of MI underwent cardiac magnetic resonance imaging (MRI) at 1.5T. Native T map was performed using a slice interleaved T mapping and late gadolinium enhancement (LGE) imaging. Cine MR was acquired to assess LV function and mass.

RESULTS

The remote myocardium native T time was significantly elevated in patients with prior MI, compared to controls, for both anterior MI and nonanterior MI (anterior MI: 1099 ± 30, nonanterior MI: 1097 ± 39, controls: 1068 ± 25 msec, P < 0.05). Remote myocardium native T moderately correlated with LV volume, mass index, and ejection fraction (r = 0.38, 0.50, -0.49, respectively, all P < 0.05). LGE infarct size had a moderate correlation with reduced LV ejection fraction (r = -0.33, P < 0.05), but there was no significant association between native T and infarct size. Native T time in the remote myocardium was independently associated with reduced LV ejection fraction, after adjusting for age, gender, infarct size, and comorbidity (β = -0.34, P = 0.03).

CONCLUSION

In chronic MI, the severity of LV systolic dysfunction after MI is independently associated with native T in the remote myocardium. Diffuse myocardial fibrosis in the remote myocardium may play an important pathophysiological role of post-MI LV dysfunction.

LEVEL OF EVIDENCE

1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1073-1081.

OBJECTIVES

To examine 6-month change in life-space mobility as a predictor of subsequent 6-month mortality in community-dwelling older adults.

DESIGN

Prospective cohort study.

SETTING

Community-dwelling older adults from five Alabama counties in the University of Alabama at Birmingham (UAB) Study of Aging.

PARTICIPANTS

A random sample of 1,000 Medicare beneficiaries, stratified according to sex, race, and rural or urban residence, recruited between November 1999 and February 2001, followed by a telephone interview every 6 months for the subsequent 8.5 years.

MEASUREMENTS

Mortality data were determined from informant contacts and confirmed using the National Death Index and Social Security Death Index. Life-space was measured at each interview using the UAB Life-Space Assessment, a validated instrument for assessing community mobility. Eleven thousand eight hundred seventeen 6-month life-space change scores were calculated over 8.5 years of follow-up. Generalized linear mixed models were used to test predictors of mortality at subsequent 6-month intervals.

RESULTS

Three hundred fifty-four deaths occurred within 6 months of two sequential life-space assessments. Controlling for age, sex, race, rural or urban residence, and comorbidity, life-space score and life-space decline over the preceding 6-month interval predicted mortality. A 10-point decrease in life-space resulted in a 72% increase in odds of dying over the subsequent 6 months (odds ratio = 1.723, P < .001).

CONCLUSIONS

Life-space score at the beginning of a 6-month interval and change in life-space over 6 months were each associated with significant differences in subsequent 6-month mortality. Life-space assessment may assist clinicians in identifying older adults at risk of short-term mortality.

OBJECTIVES

To describe the association between restricted life-space and characteristics of community-dwelling adults hospitalized for congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD), to estimate the effect of hospitalization on postdischarge mobility, and to determine whether baseline restricted life-space predicts hospital readmission.

DESIGN

Observational.

SETTING

Urban academic hospital that serves as a safety net for urban and rural populations with low resources and serves central and northern Alabama.

PARTICIPANTS

Individuals with CHF or COPD hospitalized from home (N = 478).

MEASUREMENTS

The Life-Space Assessment (LSA) measures mobility by asking about movement in situations ranging from within one's dwelling to beyond one's town. LSA scores below 60 correspond to "restricted life-space." Baseline LSA scores before admission were measured during an index hospitalization; follow-up LSA scores were determined over the telephone at 90 days. Participant characteristics were examined according to baseline restricted life-space using the chi-square test and Student's t-test. Each characteristic's association with restricted life-space was estimated uisng logistic regression.

RESULTS

Of the participants, 372 (77.8%) were classified as having baseline restricted life-space. Baseline restricted life-space was associated with older age (odds ratio (OR) = 1.29 per decade, 95% confidence interval (CI) = 1.17-1.42, P = .001), female sex (OR = 2.69, 95% CI = 1.69-4.29, P < .001), African-American race (OR = 1.55, 95% CI = 1.00-2.41, P = .05), and having inadequate financial resources (OR = 2.03, 95% CI = 1.22-3.38, P = .006). In the baseline unrestricted life-space group, 49.5% (n = 49) had restricted life-space at 90-day follow-up. Baseline restricted life-space was associated with greater odds of 90-day hospital readmission (unadjusted OR = 1.64, 95% CI = 1.00-2.70, P = .05; adjusted OR = 1.72, 95% CI = 1.04-2.85, P = .03).

CONCLUSION

Baseline restricted life-space was associated with greater risk of hospital readmission within 90 days after hospital discharge. These findings suggest a need to customize the management of individuals hospitalized with CHF or COPD based on baseline life-space level.

Latent infection with human cytomegalovirus (CMV) is common. Functional immunity effectively contains such latent infections; however, CMV reactivation may cause significant complications in patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). In spite of the universal implementation of post-transplant screening for CMV viremia and the institution of pre-emptive antiviral management, CMV disease still occurs in a small portion of patients. Moreover, interactions between CMV and the immune system have significant implications for the incidence of graft-versus-host disease, the recurrence of malignancy, and non-relapse mortality following alloHCT, even in the era of pre-emptive antiviral management. CMV serostatus thus remains an important consideration for patients undergoing alloHCT. We review the clinical impact of CMV in the setting of alloHCT, interactions between CMV serostatus, viral reactivation, and transplant outcomes, as well as current and evolving strategies for prevention and treatment of CMV-related complications that may have significant impact for alloHCT recipients.