Manual physical therapy and exercise versus supervised home exercise in the management of patients with inversion ankle sprain: a multicenter randomized clinical trial.

STUDY DESIGN: Randomized clinical trial. OBJECTIVE: To compare the effectiveness of manual therapy and exercise (MTEX) to a home exercise program (HEP) in the management of individuals with an inversion ankle sprain. BACKGROUND: An in-clinic exercise program has been found to yield similar outcomes as an HEP for individuals with an inversion ankle sprain. However, no studies have compared an MTEX approach to an HEP. METHODS: Patients with an inversion ankle sprain completed the Foot and Ankle Ability Measure (FAAM) activities of daily living subscale, the FAAM sports subscale, the Lower Extremity Functional Scale, and the numeric pain rating scale. Patients were randomly assigned to either an MTEX or an HEP treatment group. Outcomes were collected at baseline, 4 weeks, and 6 months. The primary aim (effects of treatment on pain and disability) was examined with a mixed-model analysis of variance. The hypothesis of interest was the 2-way interaction (group by time). RESULTS: Seventy-four patients (mean ± SD age, 35.1 ± 11.0 years; 48.6% female) were randomized into the MTEX group (n = 37) or the HEP group (n = 37). The overall group-by-time interaction for the mixed-model analysis of variance was statistically significant for the FAAM activities of daily living subscale (P<.001), FAAM sports subscale (P<.001), Lower Extremity Functional Scale (P<.001), and pain (P ≤.001). Improvements in all functional outcome measures and pain were significantly greater at both the 4-week and 6-month follow-up periods in favor of the MTEX group. CONCLUSION: The results suggest that an MTEX approach is superior to an HEP in the treatment of inversion ankle sprains. Registered at clinicaltrials.gov (NCT00797368). LEVEL OF EVIDENCE: Therapy, level 1b-.

Triggering receptor expressed on myeloid cells-1 (TREM-1) modulates immune responses to Aspergillus fumigatus during fungal asthma in mice.

Triggering receptor expressed on myeloid cells-1 (TREM-1) expression is increased during pulmonary fungal infection suggesting that this receptor might be involved in anti-fungal immune responses. To address the role of TREM-1 in a murine model of fungal allergic airway disease, A. fumigatus-sensitized CBA/J mice received by intratracheal injection a mixture of live A. fumigatus conidia and one of a control adenovirus vector (Ad70), an adenovirus containing a gene encoding for the extracellular domain of mouse TREM-1 and the F(c) portion of human IgG (AdTREM-1Ig; a soluble inhibitor of TREM-1 function), or an adenovirus containing mouse DAP12 (AdDAP12; DAP12 is an intracellular adaptor protein required for TREM-1 signaling), and examined at various days after challenge. Whole lung TREM-1 levels peaked at day 3 whereas circulating TREM-1 levels peaked at day 30 in this fungal asthma model. AdTREM-1Ig-treated mice exhibited significantly higher airway hyperresponsiveness following methacholine challenge compared with Ad70- and AdDAP12-treated mice. Whole lung analysis of AdTREM-1Ig treated mice revealed markedly higher amounts of fungal material compared with the other groups. ELISA analysis of whole lung and bronchoalveolar lavage samples indicated that several pro-allergic cytokine and chemokines including CCL17 and CCL22 were significantly increased in the AdTREM-1Ig group compared with the other groups. Finally, Pam3Cys and soluble Aspergillus antigens induced TREM-1 transcript expression in macrophages in a TLR2 dependent manner. In conclusion, TREM-1 modulates the immune response directed against A. fumigatus during experimental fungal asthma.

Some factors predict successful short-term outcomes in individuals with shoulder pain receiving cervicothoracic manipulation: a single-arm trial.

BACKGROUND: It has been reported that manipulative therapy directed at the cervical and thoracic spine may improve outcomes in patients with shoulder pain. To date, limited data are available to help physical therapists determine which patients with shoulder pain may experience changes in pain and disability following the application of these interventions. OBJECTIVE: The purpose of this study was to identify prognostic factors from the history and physical examination in individuals with shoulder pain who are likely to experience rapid improvement in pain and disability following cervical and thoracic spine manipulation. DESIGN: This was a prospective single-arm trial. SETTING: This study was conducted in outpatient physical therapy clinics. PARTICIPANTS: The participants were individuals who were seen by physical therapists for a primary complaint of shoulder pain. INTERVENTION AND MEASUREMENTS: Participants underwent a standardized examination and then a series of thrust and nonthrust manipulations directed toward the cervicothoracic spine. Individuals were classified as having achieved a successful outcome at the second and third sessions based on their perceived recovery. Potential prognostic variables were entered into a stepwise logistic regression model to determine the most accurate set of variables for prediction of treatment success. RESULTS: Data for 80 individuals were included in the data analysis, of which 49 had a successful outcome. Five prognostic variables were retained in the final regression model. If 3 of the 5 variables were present, the chance of achieving a successful outcome improved from 61% to 89% (positive likelihood ratio=5.3). LIMITATIONS: A prospective single-arm trial lacking a control group does not allow for inferences to be made regarding cause and effect. The statistical procedures used may result in "overfitting" of the model, which can result in low precision of the prediction accuracy, and the bivariate analysis may have resulted in the rejection of some important variables. CONCLUSIONS: The identified prognostic variables will allow clinicians to make an a priori identification of individuals with shoulder pain who are likely to experience short-term improvement with cervical and thoracic spine manipulation. Future studies are necessary to validate these findings.

Early neuromuscular electrical stimulation to optimize quadriceps muscle function following total knee arthroplasty: a case report.

STUDY DESIGN: Case report. BACKGROUND: Following total knee arthroplasty (TKA), restoration of normal quadriceps muscle function is rare. One month after surgery, quadriceps torque (force) is only 40% of preoperative values and quadriceps activation is only 82% of preoperative levels, despite initiating postoperative rehabilitation the day after surgery. Early application of neuromuscular electrical stimulation (NMES) offers a possible approach to minimize loss of quadriceps torque more effectively than traditional rehabilitation exercises alone. CASE DESCRIPTION: A 65-year-old female underwent a right, cemented TKA. Isometric quadriceps and hamstrings muscle torque were measured preoperatively and at 3, 6, and 12 weeks after TKA. Quadriceps muscle activation was measured using a doublet interpolation technique at the same time points. The patient participated in a traditional TKA rehabilitation program augmented by NMES, which was initiated 48 hours after surgery and continued twice a day for the first 3 weeks, and once daily for 3 additional weeks. OUTCOMES: Preoperatively, the involved quadriceps produced 75% of the torque of the uninvolved side and demonstrated only 72.9% activation. At 3, 6, and 12 weeks after TKA, quadriceps torque was greater than the preoperative values of the involved side by 16%, 29%, and 56%, respectively. Similarly, activation improved to 93.4%, 94.6%, and 93.5% at 3, 6, and 12 weeks after TKA. DISCUSSION: Mitigating quadriceps muscle weakness immediately after TKA using early NMES may improve functional outcomes, because quadriceps weakness has been associated with numerous functional limitations and an increased risk for falls. Despite presenting preoperatively with substantial quadriceps torque and activation deficits, the patient in this case demonstrated improvements in quadriceps function at all the times measured, all of which were superior to those reported in the literature. The patient also made substantial improvements in functional outcomes, including the Knee Injury and Osteoarthritis Outcome Score (KOOS), 6-minute walk test, timed up and go (TUG) test, stair-climbing test, and the SF-36 Physical Component Score. Appropriately controlled clinical trials will be necessary to determine whether such favorable outcomes following TKA are specifically attributable to the addition of NMES to the rehabilitation program.

Intrapulmonary, adenovirus-mediated overexpression of KARAP/DAP12 enhances fungal clearance during invasive aspergillosis.

Herein, we report that the intrapulmonary delivery of an adenovirus vector expressing KARAP/DAP12, an adaptor protein expressed in granulocytes and mononuclear cells, enhanced fungal clearance during experimental invasive pulmonary aspergillosis in neutropenic mice.

Immunosuppressive effects of CCL17 on pulmonary antifungal responses during pulmonary invasive aspergillosis.

Aspergillus fumigatus-sensitized CCR4-deficient (CCR4-/-) mice exhibit an accelerated clearance of conidia during fungal asthma. In the present study, we examined the roles of CCL17 and CCL22, two CCR4 ligands, during pulmonary invasive aspergillosis in neutropenic mice. Kaplan-Meier survival curve analysis revealed that wild-type C57BL/6 (CCR4+/+) mice were significantly protected from the lethal effects of Aspergillus compared with their wild-type controls following systemic neutralization with anti-CCL17 but not anti-CCL22 antibodies. Systemic neutralization of CCL17 significantly increased whole-lung CCL2 levels. Mouse survival and histological analysis revealed that the receptor mediating the deleterious effects of CCL17 was CCR4 since mice genetically deficit in CCR4 (CCR4-/-) did not develop invasive aspergillosis. Enzyme-linked immunosorbent assay analysis of whole-lung samples at day 2 after conidial challenge in neutrophil-depleted CCR4-/- and CCR4+/+ mice revealed that whole-lung IL-12 levels were significantly increased in the CCR4-/- group compared with the wild-type group. Also at day 2 after conidial challenge, significantly greater numbers of CD11c+ F4/80+ and CD11c+/CD86+ but fewer CD3/NK1.1+ cells were present in the lungs of CCR4-/- mice compared with their wild-type counterparts. Thus, CCL17-CCR4 interactions dramatically impair the pulmonary antifungal response against A. fumigatus in neutropenic mice.

Approaches to evaluation of fibrogenic pathways in surgical lung biopsy specimens.

Idiopathic interstitial pneumonias (IIPs) are a heterogeneous group of pulmonary fibrotic disorders consisting of several clinicopathologic entities with differing histopathologic patterns, clinical course, response to therapy, and prognosis. It is now recognized that accurate diagnosis is required in IIP, particularly in distinguishing various clinicopathologic entities of this disease from usual interstitial pneumonia, the most common histological pattern in IIP. Although no longer considered the "gold standard" for diagnosis, surgical lung biopsies (SLBs) have provided clinicians and researchers with important clues as to the identity of soluble mediators that may account for the subtype differences in IIP. Given that the expression of chemokine ligands and chemokine receptors appear to be markedly altered during the development of pulmonary fibrosis in IIP , we have focused on the characterization of these mediators in IIP and non-IIP SLBs and in primary human fibroblast lines grown from these biopsies. Herein, we describe laboratory techniques routinely employed to detect these important profibrotic factors and their corresponding receptors in SLBs and in primary human fibroblast lines.

The therapeutic potential in targeting CCR5 and CXCR4 receptors in infectious and allergic pulmonary disease.

Targeting chemokines and chemokine receptors in various acute and chronic pulmonary diseases remains a vibrant area of basic and clinical research despite major hurdles including cross-species barriers, toxicity, and redundancy. In this review, we draw upon our basic research with a murine model in which innate and acquired immunity are linked in the development and maintenance of chronic asthma due to Aspergillus fumigatus. Using intact and genetically altered mice, studies have also been undertaken to elucidate safe and effective therapeutic strategies that interrupt the initiation and amplification of inflammatory and immune events that follow the intrapulmonary introduction of Aspergillus into A. fumigatus-sensitized mice. These events include resident immune cell activation, immune and inflammatory cell recruitment to the airways, changes in lung physiology, and profound changes in the architecture of the airway due to the activation of lung resident cells. The expression of 2 major chemokine receptors, namely, CC chemokine receptor (CCR) 5 and CXC chemokine receptor (CXCR) 4, has been identified and their roles in innate and acquired immune events during fungal asthma have been explored. CCR5 and CXCR4 are best known for their roles in human immunodeficiency virus-1 (HIV-1) infection, but both are attractive targets in the context of overt inflammatory and remodeling responses in the lung. This avenue of research is markedly enhanced by the existence of numerous small molecule antagonists that are available to selectively target these receptors.

Therapeutic targeting of CCR1 attenuates established chronic fungal asthma in mice.

CC chemokine receptor 1 (CCR1) represents a promising target in chronic airway inflammation and remodeling due to fungus-associated allergic asthma. The present study addressed the therapeutic effect of a nonpeptide CCR1 antagonist, BX-471, in a model of chronic fungal asthma induced by Aspergillus fumigatus conidia. BX-471 treatment of isolated macrophages inhibited CCL22 and TNF-alpha and promoted IL-10 release. BX-471 also increased toll like receptor-9 (TLR9) and decreased TLR2 and TLR6 expression in these cells. When administered daily by intraperitoneal injection, from days 15 to 30 after the initiation of chronic fungal asthma, BX-471 (3, 10, or 30 mg kg(-1)) dose-dependently reduced airway inflammation, hyper-responsiveness, and remodeling at day 30 after conidia challenge. The maximal therapeutic effect was observed at the 10 mg kg(-1) dose. In summary, the therapeutic administration of BX-471 significantly attenuated experimental fungal asthma via its effects on both innate and adaptive immune processes.

CCR1 and CC chemokine ligand 5 interactions exacerbate innate immune responses during sepsis.

CCR1 has previously been shown to play important roles in leukocyte trafficking, pathogen clearance, and the type 1/type 2 cytokine balance, although very little is known about its role in the host response during sepsis. In a cecal ligation and puncture model of septic peritonitis, CCR1-deficient (CCR1(-/-)) mice were significantly protected from the lethal effects of sepsis when compared with wild-type (WT) controls. The peritoneal and systemic cytokine profile in CCR1(-/-) mice was characterized by a robust, but short-lived and regulated antibacterial response. CCR1 expression was not required for leukocyte recruitment, suggesting critical differences extant in the activation of WT and CCR1(-/-) resident or recruited peritoneal cells during sepsis. Peritoneal macrophages isolated from naive CCR1(-/-) mice clearly demonstrated enhanced cytokine/chemokine generation and antibacterial responses compared with similarly treated WT macrophages. CCR1 and CCL5 interactions markedly altered the inflammatory response in vivo and in vitro. Administration of CCL5 increased sepsis-induced lethality in WT mice, whereas neutralization of CCL5 improved survival. CCL5 acted in a CCR1-dependent manner to augment production of IFN-gamma and MIP-2 to damaging levels. These data illustrate that the interaction between CCR1 and CCL5 modulates the innate immune response during sepsis, and both represent potential targets for therapeutic intervention.

Enhanced monocyte chemoattractant protein-3/CC chemokine ligand-7 in usual interstitial pneumonia.

Chemokines are increased and may exert effects on both inflammatory and remodeling events in idiopathic pulmonary pneumonia (IIP). Accordingly, we examined the concomitant expression of inflammatory CC chemotactic cytokines or chemokines and their corresponding receptors in surgical lung biopsies obtained at the time of disease diagnosis and pulmonary fibroblasts grown from these biopsies. By gene array analysis, upper and lower lobe biopsies and primary fibroblast lines from patients with usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia, and respiratory bronchiolitis-interstitial lung disease, but not patients without IIP, exhibited CCL7 gene expression. TAQMAN, immunohistochemical, and ELISA analyses confirmed that CCL7 was expressed at significantly higher levels in UIP lung biopsies compared with biopsies from patients with nonspecific interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, and from patients without IIP. Higher levels of CCL7 were present in cultures of IIP fibroblasts compared with non-IIP fibroblasts, and CCL5, a CCR5 agonist, significantly increased the synthesis of CCL7 by UIP fibroblasts. Together, these data suggest that CCL7 is highly expressed in biopsies and pulmonary fibroblast lines obtained from patients with UIP relative to patients with other IIP and patients without IIP, and that this CC chemokine may have a major role in the progression of fibrosis in this IIP patient group.

Human pulmonary fibroblasts exhibit altered interleukin-4 and interleukin-13 receptor subunit expression in idiopathic interstitial pneumonia.

Abnormal proliferation of pulmonary fibroblasts is a prominent feature of chronic pulmonary fibrotic diseases such as idiopathic interstitial pneumonia (IIP), but it is not presently clear how this proliferative response by lung fibroblasts can be therapeutically modulated. In the present study, we examined whether it was possible to selectively target primary human pulmonary fibroblasts grown out of surgical lung biopsies (SLBs) from IIP patients based on their expression of interleukin-4 receptor (IL-4R) and IL-13R subunits. Pulmonary fibroblast lines cultured from patients with the severest form of IIP, namely usual interstitial pneumonia, exhibited the greatest gene and protein expression of IL-4Ralpha, IL-13Ralpha1, and IL-13Ralpha2 compared with primary pulmonary fibroblast lines grown from other IIP SLBs and normal SLBs. When exposed to increasing concentrations of a chimeric protein comprised of human IL-13 and a truncated version of Pseudomonas exotoxin (IL13-PE), the proliferation of primary usual interstitial pneumonia fibroblasts was inhibited to a much greater extent compared with fibroblast lines from nonspecific interstitial pneumonia and respiratory bronchiolitis/interstitial lung disease patient groups. Fibroblasts from normal patients exhibited minimal susceptibility to the cytotoxic effect of IL13-PE. IL13-PE-mediated targeting of IIP fibroblasts was dependent on their expression of IL-4Ralpha and IL-13Ralpha2. Thus, these data suggest that the abnormal proliferative properties of human lung fibroblasts from certain IIP patient groups can be modulated in a manner that is dependent on the IL-4 and IL-13 receptor subunit expression by these cells.