Evolution of a chronic pain management program in a Northwestern Ontario community: from structural elements to practical application.

BACKGROUND: Chronic pain is a highly prevalent health problem especially in rural regions. There is a dearth of comprehensive pain management programs particularly in rural areas. AIM: The objectives of this paper are to describe the evolution of an interprofessional chronic pain team employing a patient-centered model of care with a biopsychosocial approach, and health services metrics. METHOD: This descriptive case study approach includes an overview of the Chronic Pain Management Program (CPMP) services at St. Joseph Care Group in Thunder Bay, NW Ontario; the process involved in the development of an interprofessional chronic pain team employing a patient-centered model of care with a biopsychosocial approach; and metrics of the program's operations. RESULTS: Established in 1998, CPMP has evolved to become inter-professional, providing consultations and management, with partial funding by the Ontario Ministry of Health and Long term Care that has allowed expansion of services. The CPMP currently provides three distinct program streams as follows: a) Intensive 6-week, four half-days/week, outpatient program that offers an interdisciplinary team approach in groups and individual format; b) PACE-IT (Pain Assessment Collaborative Education Inter-professional Therapy), 8-week long, half-day/ week, interprofessional treatment program, in person; and c) Individual format for one-on-one services for patients not fitting in either the 6-Week or PACE-IT programs. In addition, Additional services provide virtual consultations and didactic videoteleconference sessions on opioid stewardship and pain management to health providers. Health services outcomes, research, and educational opportunities across the Northwestern Ontario Region, challenges and future needs are discussed. CONCLUSION: The CPMP's model of care can serve as a foundation for expert chronic pain care delivery across rural Canada, and as template for similar institutionally-based and publicly funded pain clinics.

Chemokine regulation of the inflammatory response to a low-dose influenza infection in CCR2-/- mice.

Influenza virus infections induce chemokines and cytokines, which regulate the immune response. The chemokine receptor CCR2 plays an important role in macrophage recruitment and in the development of T1 immunity. In the present study, we addressed the role of CCR2 in influenza A virus infection. CCR2 knockout (-/-) mice are protected against influenza A virus infection, despite delayed recruitment of macrophages. We show that low-dose influenza infection of CCR2-/- mice leads to increased neutrophilia between Days 5 and 10 after infection and decreased monocyte/macrophage and CD4(+) T cell recruitment to the lungs between Days 5 and 7 after infection. These changes in leukocyte recruitment did not result from or cause increased viral titers or delayed viral clearance. Neutrophilia in the lungs correlated with increased keratinocyte-derived chemokine (KC) and/or MIP-2 expression in CCR2-/- mice between Days 5 to 10 after infection, although the kinetics of neutrophil recruitment was not altered. MIP-2 mRNA and protein expression was increased three- to fivefold, and KC protein levels were increased two- to threefold in CCR2-/- compared with CCR2 wild-type mice at Day 5 after infection. This preceded the peak neutrophil influx, which occurred 7 days after infection. In vitro studies confirmed that MIP-2 and KC accounted for neutrophil chemotactic activity in the bronchoalveolar lavage. CCR2 deficiency also resulted in increased MIP-1alpha, MIP-1beta, MCP-1, and IFN-inducible protein 10 and decreased RANTES mRNA expression. Furthermore, IL-6 and TNF-alpha cytokine production were elevated after infection. These studies suggest that CCR2 plays a multifactorial role in the development of the immune response to influenza.

Differential requirement for CD28 and CD80/86 pathways of costimulation in the long-term control of murine gammaherpesvirus-68.

The costimulatory molecules CD80 and CD86 (B7-1 and B7-2) are upregulated on mature antigen-presenting cells and interact with positive and negative regulators of CD8 T cell function, CD28 and CD152 (CTLA4) respectively. In this study, we examined the role of CD80 and CD86 in the immune response to murine gammaherpesvirus-68 (MHV-68) using CD80/86-/- mice. As we had previously shown that CD28 (the only known activating receptor for CD80 and 86) is not essential for long-term control of MHV-68, we predicted that CD80 and 86 would also be dispensable for an effective response to this virus. However, surprisingly, we observed that CD80/86-/- mice failed to maintain effective long-term control of MHV-68 and showed viral reactivation in the lungs. We did not observe viral reactivation in mice deficient in either CD80 or CD86 alone, indicating that these molecules play overlapping roles in the long-term control of MHV-68. Antiviral antibody responses were dramatically reduced in CD80/86-/- mice, while CD8 T cell expansion and recruitment to the lungs were not significantly affected. The unexpected disparity in the requirement for CD28 and CD80/86 in the response to MHV-68 suggests that CD28 is not the only positive regulatory receptor for CD80/86.

Role of CXCR3 in the immune response to murine gammaherpesvirus 68.

The chemokine IP-10 (CXCL10) and its cellular receptor CXCR3 are upregulated in the lung during murine gammaherpesvirus 68 (MHV-68) infection. In order to determine the role of the CXCR3 chemokine receptor in the immune response to MHV-68, CXCR3-/- mice were infected with the virus. CXCR3-/- mice showed delayed clearance of replicating MHV-68 from the lungs. This correlated with delayed T-cell recruitment to the lungs and reduced cytolytic activity prior to viral clearance. Splenomegaly and the numbers of latently infected cells per spleen were transiently increased. However, CXCR3-/- mice showed normal virus-specific antibody titers and effective long-term control of MHV-68 infection.

Protein kinase C theta is not essential for T-cell-mediated clearance of murine gammaherpesvirus 68.

Murine gammaherpesvirus 68 (MHV-68) is a naturally occurring rodent pathogen with significant homology to human pathogens Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. T cells are essential for primary clearance of MHV-68 and survival of mice following intranasal infection. Previous reports have suggested that protein kinase C theta (PKCtheta) is essential for T-cell activation and cytokine production in vitro. To determine the role of this molecule in vivo during the immune response to a viral infection, PKCtheta-/- mice were infected with MHV-68. Despite the essential role of T cells in viral clearance, PKCtheta-/- mice survived infection, cleared lytic virus, and maintained effective long-term control of latency. CD8 T-cell expansion, trafficking to the lung, and cytotoxic activity were similar in PKCtheta+/+ and PKCtheta-/- mice, whereas antiviral antibody and T-helper cell cytokine production were significantly lower in PKCtheta-/- mice than in PKCtheta+/+ mice. These studies demonstrate a differential requirement for PKCtheta in the immune response to MHV-68 and show that PKCtheta is not essential for the T-cell activation events leading to viral clearance.

Chemokine expression during the development and resolution of a pulmonary leukocyte response to influenza A virus infection in mice.

Influenza A virus replicates in the respiratory epithelium and induces an inflammatory infiltrate comprised of mononuclear cells and neutrophils. To understand the development of the cell-mediated immune response to influenza and how leukocyte trafficking to sites of inflammation is regulated, we examined the chemokine expression pattern in lung tissue from A/PR/8/34-infected C57BL/6 mice using an RNase protection assay. Monocyte chemoattractant protein 1, macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, MIP-3alpha, regulated on activation, normal T expressed and secreted (RANTES), MIP-2, and interferon-inducible protein 10 (IP-10) mRNA expression was up-regulated between days 5 and 15 after infection, consistent with a role for these chemokines in leukocyte recruitment to the lung. Low levels of expression were detected for the CC chemokine receptors (CCR)2 and CCR5, whereas CXC chemokine receptor (CXCR)3 was significantly up-regulated by day 10 after infection, coinciding with peak inflammatory cell infiltration in the airways. As RANTES, IP-10, and their receptors were up-regulated during influenza virus infection, we investigated leukocyte recruitment and viral clearance in mice deficient in RANTES or CXCR3, the receptor for IP-10. Leukocyte recruitment and viral replication in influenza-infected RANTES knockout(-/-) mice were similar to that in control mice, showing that RANTES is not essential for the immune response to influenza infection. Similarly, leukocyte recruitment and viral replication in CXCR3-/- mice were identical to control mice, except at day 8 postinfection, where fewer lymphocytes, neutrophils, and eosinophils were detected in the bronchoalveolar lavage of CXCR3-/- mice. These studies suggest that although the chemokines detected may play a role in regulating leukocyte trafficking to the lung during influenza infection, some may be functionally redundant.