Radiographic Risk Factors for Contralateral Rupture in Dogs with Unilateral Cranial Cruciate Ligament Rupture

Background

Complete cranial cruciate ligament rupture (CR) is a common cause of pelvic limb lameness in dogs. Dogs with unilateral CR often develop contralateral CR over time. Although radiographic signs of contralateral stifle joint osteoarthritis (OA) influence risk of subsequent contralateral CR, this risk has not been studied in detail.

Methodology/Principal Findings

We conducted a retrospective longitudinal cohort study of client-owned dogs with unilateral CR to determine how severity of radiographic stifle synovial effusion and osteophytosis influence risk of contralateral CR over time. Detailed survival analysis was performed for a cohort of 85 dogs after case filtering of an initial sample population of 513 dogs. This population was stratified based on radiographic severity of synovial effusion (graded on a scale of 0, 1, and 2) and severity of osteophytosis (graded on a scale of 0, 1, 2, and 3) of both index and contralateral stifle joints using a reproducible scoring method. Severity of osteophytosis in the index and contralateral stifles was significantly correlated. Rupture of the contralateral cranial cruciate ligament was significantly influenced by radiographic OA in both the index and contralateral stifles at diagnosis. Odds ratio for development of contralateral CR in dogs with severe contralateral radiographic stifle effusion was 13.4 at one year after diagnosis and 11.4 at two years. Odds ratio for development of contralateral CR in dogs with severe contralateral osteophytosis was 9.9 at one year after diagnosis. These odds ratios were associated with decreased time to contralateral CR. Breed, age, body weight, gender, and tibial plateau angle did not significantly influence time to contralateral CR.

Conclusion

Subsequent contralateral CR is significantly influenced by severity of radiographic stifle effusion and osteophytosis in the contralateral stifle, suggesting that synovitis and arthritic joint degeneration are significant factors in the disease mechanism underlying the arthropathy.     

Blood Pressure Associates with Standing Balance in Elderly Outpatients

Objectives

Assessment of the association of blood pressure measurements in supine and standing position after a postural change, as a proxy for blood pressure regulation, with standing balance in a clinically relevant cohort of elderly, is of special interest as blood pressure may be important to identify patients at risk of having impaired standing balance in routine geriatric assessment.

Materials and Methods

In a cross-sectional cohort study, 197 community-dwelling elderly referred to a geriatric outpatient clinic of a middle-sized teaching hospital were included. Blood pressure was measured intermittently (n = 197) and continuously (subsample, n = 58) before and after a controlled postural change from supine to standing position. The ability to maintain standing balance was assessed during ten seconds of side-by-side, semi-tandem and tandem stance, with both eyes open and eyes closed. Self-reported impaired standing balance and history of falls were recorded by questionnaires. Logistic regression analyses were used to examine the association between blood pressure and 1) the ability to maintain standing balance; 2) self-reported impaired standing balance; and 3) history of falls, adjusted for age and sex.

Results

Blood pressure decrease after postural change, measured continuously, was associated with reduced ability to maintain standing balance in semi-tandem stance with eyes closed and with increased self-reported impaired standing balance and falls. Presence of orthostatic hypotension was associated with reduced ability to maintain standing balance in semi-tandem stance with eyes closed for both intermittent and continuous measurements and with increased self-reported impaired standing balance for continuous measurements.

Conclusion

Continuous blood pressure measurements are of additional value to identify patients at risk of having impaired standing balance and may therefore be useful in routine geriatric care.     

Macrophage derived chemokine (CCL22), thymus and activation-regulated chemokine (CCL17), and CCR4 in idiopathic pulmonary fibrosis

Background

Idiopathic pulmonary fibrosis (IPF) is a chronically progressive interstitial lung disease of unknown etiology. Previously, we have demonstrated the selective upregulation of the macrophage-derived chemokine CCL22 and the thymus activation-regulated chemokine CCL17 among chemokines, in a rat model of radiation pneumonitis/pulmonary fibrosis and preliminarily observed an increase in bronchoalveolar (BAL) fluid CCL22 levels of IPF patients.

Methods

We examined the expression of CCR4, a specific receptor for CCL22 and CCL17, in bronchoalveolar lavage (BAL) fluid cells, as well as the levels of CCL22 and CCL17, to elucidate their pathophysiological roles in pulmonary fibrosis. We also studied their immunohistochemical localization.

Results

BAL fluid CCL22 and CCL17 levels were significantly higher in patients with IPF than those with collagen vascular diseases and healthy volunteers, and there was a significant correlation between the levels of CCL22 and CCL17 in patients with IPF. CCL22 levels in the BAL fluid did not correlate with the total cell numbers, alveolar lymphocytes, or macrophages in BAL fluid. However, the CCL22 levels significantly correlated with the numbers of CCR4-expressing alveolar macrophages. By immunohistochemical and immunofluorescence analysis, localization of CCL22 and CCR4 to CD68-positive alveolar macrophages as well as that of CCL17 to hyperplastic epithelial cells were shown. Clinically, CCL22 BAL fluid levels inversely correlated with DLco/VA values in IPF patients.

Conclusion

We speculated that locally overexpressed CCL22 may induce lung dysfunction through recruitment and activation of CCR4-positive alveolar macrophages.     

The Homeostatic Chemokine CCL21 Predicts Mortality in Aortic Stenosis Patients and Modulates Left Ventricular Remodeling

Background

CCL21 acting through CCR7, is termed a homeostatic chemokine. Based on its role in concerting immunological responses and its proposed involvement in tissue remodeling, we hypothesized that this chemokine could play a role in myocardial remodeling during left ventricular (LV) pressure overload.

Methods and Results

Our main findings were: (i) Serum levels of CCL21 were markedly raised in patients with symptomatic aortic stenosis (AS, n = 136) as compared with healthy controls (n = 20). (ii) A CCL21 level in the highest tertile was independently associated with all-cause mortality in these patients. (iii) Immunostaining suggested the presence of CCR7 on macrophages, endothelial cells and fibroblasts within calcified human aortic valves. (iv). Mice exposed to LV pressure overload showed enhanced myocardial expression of CCL21 and CCR7 mRNA, and increased CCL21 protein levels. (v) CCR7^−/− mice subjected to three weeks of LV pressure overload had similar heart weights compared to wild type mice, but increased LV dilatation and reduced wall thickness.

Conclusions

Our studies, combining experiments in clinical and experimental LV pressure overload, suggest that CCL21/CCR7 interactions might be involved in the response to pressure overload secondary to AS.     

Age-related and obstacle height-related differences in movements while stepping over obstacles

Background

This study aims to examine age-related and obstacle height-related differences in movements while stepping over obstacles.

Methods

The participants included 16 elderly and nine young women. Obstacles that were either 5 or 20 cm high were positioned at the center of a 4-m walking path. The participants were instructed to walk along the path as quickly as possible. The participants’ movements were analyzed using a three-dimensional motion analysis system that recorded their movements as they walked and stepped over the obstacles.

Results and conclusions

Seven joint angles and the distances between the ground and six markers were examined in the initial contact and swing instants of the leading and trailing limbs. In the initial contact instant, the elderly women prepared for stepping with a lower toe height than the young women when stepping over the 20-cm obstacle. Trunk rotation was greater in the young women than in the elderly women. In the swing instant, the elderly women showed greater ankle dorsiflexion and hip adduction angles for the leading limb when stepping over the 20-cm obstacle. They moved the trailing limb with increased ankle dorsiflexion, knee flexion, hip flexion, and foot inversion to ensure that they did not touch the obstacle as they stepped over it. These movement patterns are characteristic of elderly individuals who cannot easily lift their lower limbs because of decreased lower-limb strength.     

Comparison of Invasive Blood Pressure Measurements from the Caudal Ventral Artery and the Femoral Artery in Male Adult SD and Wistar Rats

Background and Purpose

Studies have suggested that the caudal ventral artery is a potential site for continuous arterial blood pressure monitoring in rats. However, the agreement of mean arterial pressure values between the femoral artery and the caudal ventral artery has not been investigated. This study was performed to identify whether the caudal ventral artery could be safely used for continuous blood pressure monitoring as an alternative site to the femoral artery.

Methods

Rats were randomized into four groups: Sprague Dawley rats under normothermia; Wistar rats under normothermia; Sprague Dawley rats under hypothermia; Wistar rats under hypothermia. Each rat underwent simultaneous monitoring of blood pressure using femoral artery and caudal ventral artery catheterization during a stable hemodynamic state and three periods of acute severe hemodynamic changes. The effects of rat strain, rectal temperature, experimental time course and hemodynamic factors on pressure gradients, the concordance of mean arterial pressure values between the femoral artery and the caudal ventral artery, and the rates of distal ischemia after surgery were determined.

Results

There was a significant difference in the rate of distal ischemia between femoral and caudal ventral arteries after catheterization (25% vs 5%, P<0.05). The overall mean gradient and the mean gradient under a steady hemodynamic state were 4.9±3.7 mm Hg and 5.5±2.5 mm Hg, respectively. The limits of agreement (bias±1.96 SD) were (−2.5 mm Hg, 12.3 mm Hg) and (-0.5 mm Hg, 10.5 mm Hg), respectively. Although the concordance decreased during the first 30 sec of each period of severe hemodynamic changes, the degree of agreement was acceptable regardless of the effects of rat strain and rectal temperature.

Conclusions

Based on the degree of agreement and the safety of catheterization, the caudal ventral artery may be a preferred site for continuous arterial blood pressure monitoring without acute severe hemodynamic changes.     

Impaired Limb Shortening following Stroke: What’s in a Name?

Background

Difficulty advancing the paretic limb during the swing phase of gait is a prominent manifestation of walking dysfunction following stroke. This clinically observable sign, frequently referred to as ‘foot drop’, ostensibly results from dorsiflexor weakness.

Objective

Here we investigated the extent to which hip, knee, and ankle motions contribute to impaired paretic limb advancement. We hypothesized that neither: 1) minimal toe clearance and maximal limb shortening during swing nor, 2) the pattern of multiple joint contributions to toe clearance and limb shortening would differ between post-stroke and non-disabled control groups.

Methods

We studied 16 individuals post-stroke during overground walking at self-selected speed and nine non-disabled controls who walked at matched speeds using 3D motion analysis.

Results

No differences were detected with respect to the ankle dorsiflexion contribution to toe clearance post-stroke. Rather, hip flexion had a greater relative influence, while the knee flexion influence on producing toe clearance was reduced.

Conclusions

Similarity in the ankle dorsiflexion, but differences in the hip and knee, contributions to toe clearance between groups argues strongly against dorsiflexion dysfunction as the fundamental impairment of limb advancement post-stroke. Marked reversal in the roles of hip and knee flexion indicates disruption of inter-joint coordination, which most likely results from impairment of the dynamic contribution to knee flexion by the gastrocnemius muscle in preparation for swing. These findings suggest the need to reconsider the notion of foot drop in persons post-stroke. Redirecting the focus of rehabilitation and restoration of hemiparetic walking dysfunction appropriately, towards contributory neuromechanical impairments, will improve outcomes and reduce disability.     

Blockade of T Cell Contact-Activation of Human Monocytes by High-Density Lipoproteins Reveals a New Pattern of Cytokine and Inflammatory Genes

Background

Cellular contact with stimulated T cells is a potent inducer of cytokine production in human monocytes and is likely to play a substantial part in chronic/sterile inflammatory diseases. High-density lipoproteins (HDL) specifically inhibit the production of pro-inflammatory cytokines induced by T cell contact.

Methodology/Principal Findings

To further elucidate the pro-inflammatory functions of cellular contact with stimulated T cells and its inhibition by HDL, we carried out multiplex and microarray analyses. Multiplex analysis of monocyte supernatant revealed that 12 out of 27 cytokines were induced upon contact with stimulated T cells, which cytokines included IL-1Ra, G-CSF, GM-CSF, IFNγ, CCL2, CCL5, TNF, IL-1β, IL-6, IL-8, CCL3, and CCL4, but only the latter six were inhibited by HDL. Microarray analysis showed that 437 out of 54,675 probe sets were enhanced in monocytes activated by contact with stimulated T cells, 164 probe sets (i.e., 38%) being inhibited by HDL. These results were validated by qPCR. Interestingly, the cytokines induced by T cell contact in monocytes comprised IL-1β, IL-6 but not IL-12, suggesting that this mechanism might favor Th17 polarization, which emphasizes the relevance of this mechanism to chronic inflammatory diseases and highlights the contrast with acute inflammatory conditions that usually involve lipopolysaccharides (LPS). In addition, the expression of miR-155 and production of prostaglandin E₂—both involved in inflammatory response—were triggered by T cell contact and inhibited in the presence of HDL.

Conclusions/Significance

These results leave no doubt as to the pro-inflammatory nature of T cell contact-activation of human monocytes and the anti-inflammatory functions of HDL.     

CCL3L1 copy number variation and susceptibility to HIV-1 infection: a meta-analysis

Background

Although several studies have investigated whether CCL3L1 copy number variation (CNV) influences the risk of HIV-1 infection, there are still no clear conclusions. Therefore, we performed a meta-analysis using two models to generate a more robust estimate of the association between CCL3L1 CNV and susceptibility to HIV-1 infection.

Methods

We divided the cases and controls into two parts as individuals with CCL3L1 gene copy number (GCN) above the population specific median copy number (PMN) and individuals with CCL3L1 GCN below PMN, respectively. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were given for the main analysis. We also conducted stratified analyses by ethnicity, age group and sample size. Relevant literatures were searched through PubMed and ISI Web of Knowledge up to March 2010.

Results

In total, 9 studies with 2434 cases and 4029 controls were included. ORs for the main analysis were 1.35 (95% CI, 1.02–1.78, model: GCN ≤ PMN Vs. GCN > PMN) and 1.70 (95% CI, 1.30–2.23, model: GCN < PMN Vs. GCN ≥ PMN), respectively. Either in stratified analysis, statistically significant results can be detected in some subgroups.

Conclusions

Our analyses indicate that CCL3L1 CNV is associated with susceptibility to HIV-1 infection. A lower copy number is associated with an increased risk of HIV-1 infection, while a higher copy number is associated with reduced risk for acquiring HIV-1.     

The Relationships between Foot Arch Volumes and Dynamic Plantar Pressure during Midstance of Walking in Preschool Children

Objectives

The purpose of this study was to examine the correlation between the foot arch volume measured from static positions and the plantar pressure distribution during walking.

Methods

A total of 27 children, two to six years of age, were included in this study. Measurements of static foot posture were obtained, including navicular height and foot arch volume in sitting and standing positions. Plantar pressure, force and contact areas under ten different regions of the foot were obtained during walking.

Results

The foot arch index was correlated (r = 0.32) with the pressure difference under the midfoot during the foot flat phase. The navicular heights and foot arch volumes in sitting and standing positions were correlated with the mean forces and pressures under the first (r = −0.296∼−0.355) and second metatarsals (r = −0.335∼−0.504) and midfoot (r = −0.331∼−0.496) during the stance phase of walking. The contact areas under the foot were correlated with the foot arch parameters, except for the area under the midfoot.

Conclusions

The foot arch index measured in a static position could be a functional index to predict the dynamic foot functions when walking. The foot arch is a factor which will influence the pressure distribution under the foot. Children with a lower foot arch demonstrated higher mean pressure and force under the medial forefoot and midfoot, and lower contact areas under the foot, except for the midfoot region. Therefore, children with flatfoot may shift their body weight to a more medial foot position when walking, and could be at a higher risk of soft tissue injury in this area.     

Differential Dermal Expression of CCL17 and CCL18 in Tuberculoid and Lepromatous Leprosy

Background

Leprosy is characterized by polar clinical, histologic and immunological presentations. Previous immunologic studies of leprosy polarity were limited by the repertoire of cytokines known at the time.

Methodology

We used a candidate gene approach to measure mRNA levels in skin biopsies from leprosy lesions. mRNA from 24 chemokines and cytokines, and 6 immune cell type markers were measured from 85 Nepalese leprosy subjects. Selected findings were confirmed with immunohistochemistry.

Principal Results

Expression of three soluble mediators (CCL18, CCL17 and IL-10) and one macrophage cell type marker (CD14) was significantly elevated in lepromatous (CCL18, IL-10 and CD14) or tuberculoid (CCL17) lesions. Higher CCL18 protein expression by immunohistochemistry and a trend in increased serum CCL18 in lepromatous lesions was observed. No cytokines were associated with erythema nodosum leprosum or Type I reversal reaction following multiple comparison correction. Hierarchical clustering suggested that CCL18 was correlated with cell markers CD209 and CD14, while neither CCL17 nor CCL18 were highly correlated with classical TH1 and TH2 cytokines.

Conclusions

Our findings suggest that CCL17 and CCL18 dermal expression is associated with leprosy polarity.     

Analysis of the Stress and Displacement Distribution of Inferior Tibiofibular Syndesmosis Injuries Repaired with Screw Fixation: A Finite Element Study

Background

Studies of syndesmosis injuries have concentrated on cadaver models. However, they are unable to obtain exact data regarding the stress and displacement distribution of various tissues, and it is difficult to compare models. We investigated the biomechanical effects of inferior tibiofibular syndesmosis injuries (ITSIs) and screw fixation on the ankle using the finite element (FE) method.

Methodology/Principal Findings

A three-dimensional model of a healthy ankle complex was developed using computed tomography (CT) images. We established models of an ITSI and of screw fixation at the plane 2.5 cm above and parallel to the tibiotalar joint surface of the injured syndesmosis. Simulated loads were applied under three conditions: neutral position with single-foot standing and internal and external rotation of the ankle. ITSI reduced contact forces between the talus and fibula, helped periarticular ankle ligaments withstand more load-resisting movement, and increased the magnitude of displacement at the lower extreme of the tibia and fibula. ITSI fixation with a syndesmotic screw reduced contact forces in all joints, decreased the magnitude of displacement at the lower extreme of the tibia and fibula, and increased crural interosseous membrane stress.

Conclusions/significance

Severe syndesmosis injuries cause stress and displacement distribution of the ankle to change multidirectional ankle instability and should be treated by internal fixation. Though the transverse syndesmotic screw effectively stabilizes syndesmotic diastasis, it also changes stress distribution around the ankle and decreases the joint''s range of motion (ROM). Therefore, fixation should not be performed for a long period of time because it is not physiologically suitable for the ankle joint.     

Involvement of CCR6/CCL20/IL-17 axis in NSCLC disease progression

Objectives

Autocrine and paracrine chemokine/chemokine receptor-based interactions promote non-small-cell-lung-cancer (NSCLC) carcinogenesis. CCL20/CCR6 interactions are involved in prostatic and colonic malignancy pathogenesis. The expression and function of CCL20/CCR6 and its related Th-17 type immune response in NSCLC is not yet defined. We sought to characterize the role of the CCL20/CCR6/IL-17 axis in NSCLC tumor growth.

Methods

A specialized histopathologist blindly assessed CCL20/CCR6 expression levels in 49 tissue samples of NSCLC patients operated in our department. Results were correlated to disease progression. Colony assays, ERK signaling and chemokine production were measured to assess cancer cell responsiveness to CCL20 and IL-17 stimulation.

Results

CCL20 was highly expressed in the majority (38/49, 77.5%) of tumor samples. Only a minority of samples (8/49, 16.5%) showed high CCR6 expression. High CCR6 expression was associated with a shorter disease-free survival (P = 0.008) and conferred a disease stage-independent 4.87-fold increased risk for disease recurrence (P = 0.0076, CI 95% 1.52–15.563). Cancerous cell colony-forming capacity was increased by CCL20 stimulation; this effect was dependent in part on ERK phosphorylation and signaling. IL-17 expression was detected in NSCLC; IL-17 potentiated the production of CCL20 by cancerous cells.

Conclusion

Our findings suggest that the CCL20/CCR6 axis promotes NSCLC disease progression. CCR6 is identified as a potential new prognostic marker and the CCL20/CCR6/IL-17 axis as a potential new therapeutic target. Larger scale studies are required to consolidate these observations.     

Hemolytic Streptococcus May Exacerbate Kidney Damage in IgA Nephropathy through CCL20 Response to the Effect of Th17 Cells

Background

The exacerbation of IgA nephropathy (IgAN) is related to respiratory tract infection with hemolytic streptococcus (HS), but the mechanism is unknown. In this study we investigated the role of chemokine ligand 20 (CCL20) in response to the effect of T helper 17 (Th17) cells in the pathogenesis of IgAN associated with HS.

Methods

Thirty mice were randomly divided into five groups: control mice (control), IgAN mice (IgAN), HS-infected IgAN mice (HS-IgAN), CCL20-treated IgAN mice (CCL20-IgAN), and CCL20-treated HS infected IgAN mice (CCL20-HS-IgAN). IgAN mice were induced with lipopolysaccharide, carbon tetrachloride and bovine serum albumin. Then the mice were sensitized with CCL20 antibody and infected with alpha-hemolytic streptococcus (α-HS) isolated from tonsils in sequence. Urine Albumin-Creatinine ratio and sediments were measured. The pathological changes in kidney and lung tissues were observed under microscopy. Th17 cells and regulatory T cells (Tregs) in kidneys were tested by flow cytometry. CCL20, IL-17A, IL-6 and IL-21 in the kidneys were detected by ELISA.

Results

The IgAN mice had albuminuria and microscopic hematuria, renal mesangial proliferation, IgA deposition, high electron dense deposition in glomerular mesangial region, decreased frequency of Tregs, increased frequency of Th17 and Th17-Treg ratio. Furthermore, Th17-related cytokines CCL20, IL-17A, IL-6 and IL-21 were all increased in the kidneys of IgAN mice. Compared with IgAN mice, the manifestations in HS-IgAN mice were more severe, but alleviated in CCL20-treated groups.

Conclusion

α-HS may exacerbate kidney damage in IgAN through CCL20 response to the effect of Th17 cells.     

Early phase resolution of mucosal eosinophilic inflammation in allergic rhinitis

Background

It is widely assumed that apoptosis of eosinophils is a central component of resolution of allergic airway disease. However, this has not been demonstrated in human allergic airways in vivo. Based on animal in vivo observations we hypothesised that steroid-induced resolution of human airway eosinophilic inflammation involves inhibition of CCL5 (RANTES), a CC-chemokine regulating eosinophil and lymphocyte traffic, and elimination of eosinophils without evident occurrence of apoptotic eosinophils in the diseased tissue.

Objective

To determine mucosal eosinophilia, apoptotic eosinophils, general cell apoptosis and cell proliferation, and expression of CCL5 and CCL11 (eotaxin) in human allergic airway tissues in vivo at resolution of established symptomatic eosinophilic inflammation.

Methods

Twenty-one patients with intermittent (birch and/or grass) allergic rhinitis received daily nasal allergen challenges for two seven days'' periods separated by more than two weeks washout. Five days into these "artificial pollen seasons", nasal treatment with budesonide was instituted and continued for six days in a double blinded, randomized, placebo-controlled, and crossover design. This report is a parallel group comparison of nasal biopsy histochemistry data obtained on the final day of the second treatment period.

Results

Treatments were instituted when clinical rhinitis symptoms had been established. Compared to placebo, budesonide reduced tissue eosinophilia, and subepithelial more than epithelial eosinophilia. Steroid treatment also attenuated tissue expression of CCL5, but CCL11 was not reduced. General tissue cell apoptosis and epithelial cell proliferation were reduced by budesonide. However, apoptotic eosinophils were not detected in any biopsies, irrespective of treatment.

Conclusions

Inhibition of CCL5-dependent recruitment of cells to diseased airway tissue, and reduced cell proliferation, reduced general cell apoptosis, but not increased eosinophil apoptosis, are involved in early phase steroid-induced resolution of human allergic rhinitis.     

Assessment of Prosthesis Alignment after Revision Total Knee Arthroplasty Using EOS 2D and 3D Imaging: A Reliability Study

Introduction

A new low-dose X-ray device, called EOS, has been introduced for determining lower-limb alignment in 2D and 3D. Reliability has not yet been assessed when using EOS on lower limbs containing a knee prosthesis. Therefore purpose of this study was to determine intraobserver and interobserver reliability of EOS 2D and 3D knee prosthesis alignment measurements after revision total knee arthroplasty (rTKA).

Methods

Forty anteroposterior and lateral images of 37 rTKA patients were included. Two observers independently performed measurements on these images twice. Varus/valgus angles were measured in 2D (VV2D) and 3D (VV3D). Intraclass correlation coefficients and the Bland and Altman method were used to determine reliability. T-tests were used to test potential differences.

Results

Intraobserver and interobserver reliability were excellent for VV2D and VV3D. No significant difference or bias between the first and second measurements or the two observers was found. A significant mean and absolute difference of respectively 1.00° and 1.61° existed between 2D and 3D measurements.

Conclusions

EOS provides reliable varus/valgus measurements in 2D and 3D for the alignment of the knee joint with a knee prosthesis. However, significant differences exist between varus/valgus measurements in 2D and 3D.     

CCL5 and CCR5 interaction promotes cell motility in human osteosarcoma

Background

Osteosarcoma is characterized by a high malignant and metastatic potential. CCL5 (previously called RANTES) was originally recognized as a product of activated T cells, and plays a crucial role in the migration and metastasis of human cancer cells. It has been reported that the effect of CCL5 is mediated via CCR receptors. However, the effect of CCL5 on migration activity and integrin expression in human osteosarcoma cells is mostly unknown.

Methodology/Principal Findings

Here we found that CCL5 increased the migration and expression of αvβ3 integrin in human osteosarcoma cells. Stimulation of cells with CCL5 increased CCR5 but not CCR1 and CCR3 expression. CCR5 mAb, inhibitor, and siRNA reduced the CCL5-enhanced the migration and integrin up-regulation of osteosarcoma cells. Activations of MEK, ERK, and NF-κB pathways after CCL5 treatment were demonstrated, and CCL5-induced expression of integrin and migration activity was inhibited by the specific inhibitor and mutant of MEK, ERK, and NF-κB cascades. In addition, over-expression of CCL5 shRNA inhibited the migratory ability and integrin expression in osteosarcoma cells.

Conclusions/Significance

CCL5 and CCR5 interaction acts through MEK, ERK, which in turn activates NF-κB, resulting in the activations of αvβ3 integrin and contributing the migration of human osteosarcoma cells.     

Increased levels of soluble interleukin-6 receptor and CCL3 in COPD sputum

Background

COPD patients have increased numbers of macrophages and neutrophils in the lungs. Interleukin-6 (IL-6) trans-signaling via its soluble receptor sIL-6R, governs the influx of innate immune cells to inflammatory foci through regulation of the chemokine CCL3. We hypothesized that there would be enhanced levels of IL-6, sIL-6R and CCL3 in COPD sputum.

Methods

59 COPD patients, 15 HNS and 15 S underwent sputum induction and processing with phosphate buffered saline to obtain supernatants for IL-6, sIL-6R and CCL3 analysis. Cytoslides were produced for differential cell counting and immunocytochemistry (COPD; n = 3) to determine cell type surface expression of the CCL3 receptors CCR5 and CCR1.

Results

COPD patients expressed higher levels (p < 0.05) of sIL-6R and CCL3 compared to controls (sIL-6R medians pg/ml: COPD 166.4 vs S 101.1 vs HNS 96.4; CCL3 medians pg/ml: COPD 117.9 vs S 0 vs HNS 2.7). COPD sIL-6R levels were significantly correlated with sputum neutrophil (r = 0.5, p < 0.0001) and macrophage (r = 0.3, p = 0.01) counts. Immunocytochemical analysis revealed that CCR5 and CCR1 were exclusively expressed on airway macrophages.

Conclusion

Enhanced airway generation of sIL-6R may promote IL-6 trans-signaling in COPD. Associated upregulation of CCL3 may facilitate the recruitment of macrophages into the airways by ligation of CCR1 and CCR5.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0103-4) contains supplementary material, which is available to authorized users.     

CCL2 Accelerates Microglia-Mediated Aβ Oligomer Formation and Progression of Neurocognitive Dysfunction

Background

The linkages between neuroinflammation and Alzheimer''s disease (AD) pathogenesis are well established. What is not, however, is how specific immune pathways and proteins affect the disease. To this end, we previously demonstrated that transgenic over-expression of CCL2 enhanced microgliosis and induced diffuse amyloid plaque deposition in Tg2576 mice. This rodent model of AD expresses a Swedish β-amyloid (Aβ) precursor protein mutant.

Methodology/Principal Findings

We now report that CCL2 transgene expression accelerates deficits in spatial and working memory and hippocampal synaptic transmission in β-amyloid precursor protein (APP) mice as early as 2–3 months of age. This is followed by increased numbers of microglia that are seen surrounding Aβ oligomers. CCL2 does not suppress Aβ degradation. Rather, CCL2 and tumor necrosis factor-α directly facilitated Aβ uptake, intracellular Aβ oligomerization, and protein secretion.

Conclusions/Significance

We posit that CCL2 facilitates Aβ oligomer formation in microglia and propose that such events accelerate memory dysfunction by affecting Aβ seeding in the brain.