Publications

Initiation of an adaptive cellular immune response depends on intimate interactions with APCs and naive T lymphocytes. We previously reported that activation of naive Mycobacterium tuberculosis-specific CD4+ T cells depends on dendritic cell (DC) transport of live bacteria from the lungs to the mediastinal lymph node (MDLN). Because the migratory paths of DCs are largely governed by the chemokine receptor CCR7, which is expressed on DCs upon maturation by proinflammatory stimuli, we examined the quantitative contribution of CCR7-dependent DC migration in the context of tuberculosis. We found that early trafficking of DCs from the lungs to the MDLN depended on CCR7-mediated signaling, but alternative mechanism(s) are used later in infection. Impaired migration of DCs in CCR7(-/-) mice resulted in delayed dissemination of bacteria to MDLN and spleen and in delayed kinetics of activation of adoptively transferred Ag85B-specific CD4+ T cells. Furthermore, in contrast to control mice, we found that naive Ag85B-specific CD4+ T cells are activated to proliferate in the lungs of CCR7(-/-) mice and, when infected with higher doses of bacteria, resistance to M. tuberculosis infection in CCR7(-/-) mice is compromised compared with wild-type mice.

Upstream transcription factor 1 (USF1) has been associated with familial combined hyperlipidemia, the metabolic syndrome, and related conditions, but the mechanisms involved are unknown. In this study, we report validation of Usf1 as a causal gene of cholesterol homeostasis, insulin sensitivity and body composition in mouse models using several complementary approaches and identify associated pathways and gene expression network modules. Over-expression of human USF1 in both transgenic mice and mice with transient liver-specific over-expression influenced metabolic trait phenotypes, including obesity, total cholesterol level, LDL/VLDL cholesterol and glucose/insulin ratio. Additional analyses of trait and hepatic gene expression data from an F2 population derived from C57BL/6J and C3H/HeJ strains in which there is a naturally occurring variation in Usf1 expression supported a causal role for Usf1 for relevant metabolic traits. Gene network and pathway analyses of the liver gene expression signatures in the F2 population and the hepatic over-expression model suggested the involvement of Usf1 in immune responses and metabolism, including an Igfbp2-centered module. In all three mouse model settings, notable sex specificity was observed, consistent with human studies showing differences in association with USF1 gene polymorphisms between sexes.

RATIONALE

The response characteristics of the 6 minute walk test (6MWT) in studies of idiopathic pulmonary fibrosis (IPF) are only poorly understood, and the change in walk distance that constitutes the minimum important difference (MID) over time is unknown.

OBJECTIVES

To examine changes over time in distance walked (ie, 6MWD) during the 6MWT and to estimate the change in distance that constitutes the MID in patients with IPF.

METHODS

Data from a recently completed trial that included subjects with IPF who completed the 6MWT, Saint George's Respiratory Questionnaire (SGRQ) and forced vital capacity (FVC) at 6 and 12 months were used to examine longitudinal changes in 6MWD. Both anchor- and distribution-based approaches as well as linear regression analyses were used to determine the MID for 6MWD. The SGRQ Total score and FVC were used as clinical anchors.

MAIN RESULTS

Among 123 subjects alive and able to complete the 6MWT at both follow-up time points, 6MWD did not change significantly over time (378.1 m at baseline vs 376.8 m at 6 months vs 361.3 m at 12 months, p=0.5). The point estimate for the 6MWD MID was 28 m with a range of 10.8-58.5 m.

CONCLUSION

In a group of patients with IPF with moderate physiological impairment, for those alive and able to complete a 6MWT, 6MWD does not change over 12 months. At the population level, the MID for 6MWD appears to be approximately 28 m. Further investigation using other anchors and derivation methods is required to refine estimates of the MID for 6MWD in this patient population.

OBJECTIVE

The literature on psychosocial job factors and musculoskeletal pain is inconclusive in part due to insufficient control for confounding by biomechanical factors. The aim of this study was to investigate prospectively the independent effects of effort-reward imbalance (ERI) at work on regional musculoskeletal pain of the neck and upper extremities of call center operators after controlling for (i) duration of computer use both at work and at home, (ii) ergonomic workstation design, (iii) physical activities during leisure time, and (iv) other individual worker characteristics.

METHODS

This was a one-year prospective study among 165 call center operators who participated in a randomized ergonomic intervention trial that has been described previously. Over an approximate four-week period, we measured ERI and 28 potential confounders via a questionnaire at baseline. Regional upper-body pain and computer use was measured by weekly surveys for up to 12 months following the implementation of ergonomic interventions. Regional pain change scores were calculated as the difference between average weekly pain scores pre- and post intervention.

RESULTS

A significant relationship was found between high average ERI ratios and one-year increases in right upper-extremity pain after adjustment for pre-intervention regional mean pain score, current and past physical workload, ergonomic workstation design, and anthropometric, sociodemographic, and behavioral risk factors. No significant associations were found with change in neck-shoulder or left upper-extremity pain.

CONCLUSIONS

This study suggests that ERI predicts regional upper-extremity pain in -computer operators working >or=20 hours per week. Control for physical workload and ergonomic workstation design was essential for identifying ERI as a risk factor.