Longitudinal Predictors of Pain in Pediatric Sickle Cell Disease.

OBJECTIVE: Despite the identified pathophysiology of vaso-occlusive pain in sickle cell disease (SCD), predictors of pain in youth with SCD remain elusive. In this study, we measured changes in pain frequency, intensity, and interference over 1 year and examined biopsychosocial risk factors (SCD disease severity, age, female, depression, and sleep quality) as possible longitudinal predictors. METHODS: Medical history was obtained from retrospective chart review for 79 children with SCD (ages 2-18 years; 48.1% female; 100% Black/African American; 83.5% SCD, SS genotype). As part of a clinical screening protocol, caregivers (n = 79) and youth 8-18 years (n = 43) completed psychosocial questionnaires approximately 1 year apart (M = 15.52 months, SD = 5.69). Zero-order correlations, paired t-tests, and hierarchical linear models examined longitudinal predictors of pain. The longitudinal bidirectional relationship between pain and sleep was also examined. RESULTS: The rate of severe SCD disease increased from 41.8% to 55.7% across the year, while most hematologic medical parameters remained stable. Increased depression and pain interference at survey 1 significantly predicted increased pain interference at survey 2. Poor sleep quality and increased pain frequency at survey 1 predicted increased pain frequency at survey 2. Finally, increased pain interference at survey 1 predicted poor sleep quality at survey 2. DISCUSSION: History of pain, depression, and sleep quality were longitudinal predictors of pain over 1 year in youth with SCD. Identifying longitudinal predictors of pain may lead to earlier identification of patients with a high-risk SCD pain phenotype and earlier medical, psychological, and behavioral interventions.

Physical Activity and Pain in Youth With Sickle Cell Disease.

Study objectives were to examine the relationships between physical activity, pain, and psychological distress in youth 8 to 17 years of age with sickle cell disease. Participants were 206 youth with sickle cell disease (M = 11.73 years, 54.9% female, 99.5% African American). Caregivers and youth completed a clinical psychosocial screening battery. Results revealed frequent pain (37.6%), moderate median pain intensity, and elevated median pain interference in youth. Lower caregiver-reported physical activity was associated with worse pain outcomes. Increased anxiety was also associated with worse pain outcomes. A better understanding of the relationship between physical activity/inactivity and pain will guide multifactorial treatment interventions.

Mutations in bone marrow-derived stromal stem cells unmask latent malignancy.

Neoplastic epithelia may remain dormant and clinically unapparent in human patients for decades. Multiple risk factors including mutations in tumor cells or the stromal cells may affect the switch from dormancy to malignancy. Gene mutations, including p53 mutations, within the stroma of tumors are associated with a worse clinical prognosis; however, it is not known if these stromal mutations can promote tumors in genetically at-risk tissue. To address this question, Apc(Min/+) and Apc(Min/+) Rag2(-/-) mice, which have a predilection to mammary carcinoma (as well as wild-type (wt) mice), received mesenchymal stem cells (MSC) with mutant p53 (p53MSC) transferred via tail vein injection. In the wt mouse, p53MSC circulated in the periphery and homed to the marrow cavity where they could be recovered up to a year later without apparent effect on the health of the mouse. No mammary tumors were found. However, in mice carrying the Apc(Min/+) mutation, p53MSC homed to mammary tissue and significantly increased the incidence of mammary carcinoma. Tumor necrosis factor (TNF)-alpha-dependent factors elaborated from mesenchymal cells converted quiescent epithelia into clinically apparent disease. The increased cancer phenotype was completely preventable with neutralization of TNF-alpha or by transfer of CD4(+) regulatory T cells from immune competent donors, demonstrating that immune competency to regulate inflammation was sufficient to maintain neoplastic dormancy even in the presence of oncogenic epithelial and stromal mutations. The significant synergy between host immunity and mesenchymal cells identified here may restructure treatments to restore an anticancer microenvironment.

Unifying roles for regulatory T cells and inflammation in cancer.

Activities of CD4(+) regulatory (T(REG)) cells restore immune homeostasis during chronic inflammatory disorders. Roles for T(REG) cells in inflammation-associated cancers, however, are paradoxical. It is widely believed that T(REG) function in cancer mainly to suppress protective anticancer responses. However, we demonstrate here that T(REG) cells also function to reduce cancer risk throughout the body by efficiently downregulating inflammation arising from the gastrointestinal (GI) tract. Building on a "hygiene hypothesis" model in which GI infections lead to changes in T(REG) that reduce immune-mediated diseases, here we show that gut bacteria-triggered T(REG) may function to inhibit cancer even in extraintestinal sites. Ability of bacteria-stimulated T(REG) to suppress cancer depends on interleukin (IL)-10, which serves to maintain immune homeostasis within bowel and support a protective antiinflammatory T(REG) phenotype. However, under proinflammatory conditions, T(REG) may fail to provide antiinflammatory protection and instead contribute to a T helper (Th)-17-driven procarcinogenic process; a cancer state that is reversible by downregulation of inflammation. Consequently, hygienic individuals with a weakened IL-10 and T(REG)-mediated inhibitory loop are highly susceptible to the carcinogenic consequences of elevated IL-6 and IL-17 and show more frequent inflammation-associated cancers. Taken together, these data unify seemingly divergent disease processes such as autoimmunity and cancer and help explain the paradox of T(REG) and inflammation in cancer. Enhancing protective T(REG) functions may promote healthful longevity and significantly reduce risk of cancer.

CD4+ lymphocytes modulate prostate cancer progression in mice.

Chronic inflammation contributes to the development of prostate cancer in humans. Here, we show that male Apc(Min/+) mice also develop prostate carcinoma with increasing age, mimicking that seen in humans in their 5th or 6th decade of life. Proinflammatory cytokines were significantly linked with cancer and increasing age in our mouse model; however, prostate and bowel tissues lacked evidence of inflammatory cell infiltrates other than mast cells. Lymphocytes protected against cancer, and protection from prostate cancer resided in antiinflammatory CD4(+)CD25(+) regulatory (T(REG)) cells that downregulated inflammatory cytokines. Supplementation with syngeneic T(REG) cells collected from wild-type mice reduced the levels of interleukin (IL)-6 (p < 0.05) and IL-9 (p < 0.001) and lowered prostate cancer risk (p < 0.05). Depletion of CD25(+) cells in 2-month-old animals increased the expression of IL-6 (p < 0.005) within prostate and increased the frequency of high-grade prostatic intraepithelial neoplasia (p < 0.05) and microinvasive prostatic carcinoma (p < 0.05) in dorsolateral prostate. Depletion of CD25(+) cells in young animals also increased the frequency of intestinal cancer in Min mice. Taken together, chronically elevated proinflammatory cytokines promoted carcinoma in Apc(Min/+) mice. T(REG) lymphocytes downregulated inflammation-associated carcinogenic processes and contributed to immune and epithelial homeostasis.

c-Rel is essential for the development of innate and T cell-induced colitis.

Inflammatory bowel disease is a chronic inflammatory response of the gastrointestinal tract mediated in part by an aberrant response to intestinal microflora. Expression of IL-23 subunits p40 and p19 within cells of the innate immune system plays a central role in the development of lower bowel inflammation in response inflammatory challenge. The NF-kappaB subunit c-Rel can regulate expression of IL-12/23 subunits suggesting that it could have a critical role in mediating the development of chronic inflammation within the lower bowel. In this study, we have analyzed the role of c-Rel within the innate immune system in the development of lower bowel inflammation, in two well-studied models of murine colitis. We have found that the absence of c-Rel significantly impaired the ability of Helicobacter hepaticus to induce colitis upon infection of RAG-2-deficient mice, and ameliorated the ability of CD4(+)CD45RB(high) T cells to induce disease upon adoptive transfer into RAG-deficient mice. The absence of c-Rel interfered with the expression of IL-12/23 subunits both in cultured primary macrophages and within the colon. Thus, c-Rel plays a critical role in regulating the innate inflammatory response to microflora within the lower bowel, likely through its ability to modulate expression of IL-12/23 family members.