Publications

Activation induces extensive changes in the gene expression program of naive CD4(+) T cells, promoting their differentiation into helper T cells that coordinate immune responses. MicroRNAs (miRNAs) play a critical role in this process, and miRNA expression also changes dramatically during T cell differentiation. Quantitative analyses revealed that T cell activation induces global posttranscriptional miRNA down-regulation in vitro and in vivo. Argonaute (Ago) proteins, the core effector proteins of the miRNA-induced silencing complex (miRISC), were also posttranscriptionally down-regulated during T cell activation. Ago2 was inducibly ubiquitinated in activated T cells and its down-regulation was inhibited by the proteasome inhibitor MG132. Therefore, activation-induced miRNA down-regulation likely occurs at the level of miRISC turnover. Measurements of miRNA-processing intermediates uncovered an additional layer of activation-induced, miRNA-specific transcriptional regulation. Thus, transcriptional and posttranscriptional mechanisms cooperate to rapidly reprogram the miRNA repertoire in differentiating T cells. Altering Ago2 expression in T cells revealed that Ago proteins are limiting factors that determine miRNA abundance. Naive T cells with reduced Ago2 and miRNA expression differentiated more readily into cytokine-producing helper T cells, suggesting that activation-induced miRNA down-regulation promotes acquisition of helper T cell effector functions by relaxing the repression of genes that direct T cell differentiation.

We have previously shown, in the rat, that neuropathic and inflammatory events produce a neuroplastic change in nociceptor function whereby a subsequent exposure to a proinflammatory mediator (e.g. prostaglandin E2 ; PGE2 ) produces markedly prolonged mechanical hyperalgesia. While the initial approximately 30 min of this prolonged PGE2 hyperalgesia remains PKA-dependent, it subsequently switches to become dependent on protein kinase C epsilon (PKCε). In this study we tested the hypothesis that the delayed onset, PKCε-mediated, component of PGE2 hyperalgesia is generated by the active release of a nucleotide from the peripheral terminal of the primed nociceptor and this nucleotide is then metabolized to produce adenosine, which acts on a Gi-coupled A1 adenosine receptor on the nociceptor to generate PKCε-dependent hyperalgesia. We report that inhibitors of ATP-binding cassette transporters, of ecto-5'-phosphodiesterase and ecto-5'nucleotidase (enzymes involved in the metabolism of cyclic nucleotides to adenosine) and of A1 adenosine receptors each eliminated the late, but not the early, phase of PGE2 -induced hyperalgesia in primed animals. A second model of chronic pain induced by transient attenuation of G-protein-coupled receptor kinase 2, in which the prolongation of PGE2 hyperalgesia is not PKCε-dependent, was not attenuated by inhibitors of any of these mechanisms. Based on these results we propose a contribution of an autocrine mechanism, in the peripheral terminal of the nociceptor, in the hyperalgesic priming model of chronic pain.

OBJECTIVES

To examine the effect of the relationship between literacy and other individual-level factors on having an advance directive (AD).

DESIGN

Face-to-face structured interview.

SETTING

Participants were recruited from an academic general internal medicine clinic and one of four federally qualified health centers in Chicago.

PARTICIPANTS

Seven hundred eighty-four adults aged 55 to 74.

MEASUREMENTS

Assessment of participant literacy, sociodemographic factors, and having an AD for medical care.

RESULTS

One-eighth (12.4%) of participants with low literacy, 26.6% of those with marginal literacy, and 49.5% of those with adequate literacy reported having an AD (P < .001). In multivariable analyses, literacy and race were independently associated with less likelihood of having an AD. Specifically, participants with limited literacy (risk ratio (RR) = 0.45, 95% confidence interval (CI) = 0.22-0.95) and African Americans (RR = 0.64, 95% CI = 0.47-0.88) were less likely to have an AD. Exploratory analyses showed that there was not a significant interaction between the effect of literacy and race.

CONCLUSION

Limited literacy and African-American race were significant risk factors for not having an AD in this cohort of older adults. Literacy and race probably represent two separate but important causal pathways that need to be understood to improve how the healthcare system ascertains and protects individuals' advance care preferences.

There is huge variation in the evaluation, diagnosis, and treatment of patients with morphea (localized scleroderma). In part, this variability results from the lack of validated methods to assess severity and outcomes with a consequent lack of adequate therapeutic trials. Evaluation is also hindered by lack of information regarding the impact of morphea on patients. Recent studies are addressing this gap in knowledge and include: development of clinical outcome measures, validation of imaging studies, publication of consensus treatment plans, and increased understanding of the impact of morphea on patients and parents. The purpose of this review is to summarize the results of these studies and to synthesize the information into a rational approach to the diagnosis and assessment of patients with morphea.

BACKGROUND

The development of tools to monitor the right ventricle in pulmonary arterial hypertension (PAH) is of clinical importance. PAH is associated with pathologic expression of the transcription factor hypoxia-inducible factor (HIF)-1α, which induces glycolytic metabolism and mobilization of proangiogenic progenitor (CD34(+)CD133(+)) cells. We hypothesized that PAH cardiac myocytes have a HIF-related switch to glycolytic metabolism that can be detected with fasting 2-deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography (FDG-PET) and that glucose uptake is informative for cardiac function.

METHODS

Six healthy control subjects and 14 patients with PAH underwent fasting FDG-PET and echocardiogram. Blood CD34(+)CD133(+) cells and erythropoietin were measured as indicators of HIF activation. Twelve subjects in the PAH cohort underwent repeat studies 1 year later to determine if changes in FDG uptake were related to changes in echocardiographic parameters or to measures of HIF activation.

MEASUREMENTS AND RESULTS

FDG uptake in the right ventricle was higher in patients with PAH than in healthy control subjects and correlated with echocardiographic measures of cardiac dysfunction and circulating CD34(+)CD133(+) cells but not erythropoietin. Among patients with PAH, FDG uptake was lower in those receiving β-adrenergic receptor blockers. Changes in FDG uptake over time were related to changes in echocardiographic parameters and CD34(+)CD133(+) cell numbers. Immunohistochemistry of explanted PAH hearts of patients undergoing transplantation revealed that HIF-1α was present in myocyte nuclei but was weakly detectable in control hearts.

CONCLUSIONS

PAH hearts have pathologic glycolytic metabolism that is quantitatively related to cardiac dysfunction over time, suggesting that metabolic imaging may be useful in therapeutic monitoring of patients.