Monocyte chemotactic protein-3 (MCP3) interacts with multiple leukocyte receptors: binding and signaling of MCP3 through shared as well as unique receptors on monocytes and neutrophils

The diversity of monocyte chemotactic protein (MCP)3 target cell types, as well as the capacity of MCP3 to desensitize leukocyte responses to other CC chemokines, suggested that MCP3 may interact with multiple CC chemokine receptors. The purpose of this study is to establish how MCP3 binds and activates monocytes and neutrophils. We show that human monocytes exhibit high-affinity binding for ¹²⁵I-MCP3 with an estimated Kd of 1–3 nM and about 10000 binding sites/cell. The binding of ¹²⁵I-MCP3 to monocytes was progressively less well competed by CC chemokines macrophage inflammatory protein (MIP)lα (Kd = 5–10 nM), RANTES (Kd = 5–10 nM), MCP1 (monocyte chemoattractant and activating factor, or MCAF) (Kd = 60 nM) and MIP1β (Kd > 100 nM). On the other hand, unlabeled MCP3 displaced the binding of radiolabeled MIP1α, RANTES, MCP1 and MIP1β as effectively as the isologous CC chemokines. In agreement with the binding data, pretreatment of monocytes with MCP3 completely desensitized the calcium flux in response to MIP1α and RANTES. However, MIP1α and RANTES failed to desensitize the response of monocytes to MCP3. MCP3 and MCP1 partially desensitized each other's effects on monocytes. These binding and cross-desensitization results suggest that MCP3 binds and signals through other binding sites in addition to those shared with MIP1α, RANTES and MCP1. The unidirectional competition for MIP1β binding and signaling by MCP3 suggests the existence of an as-yet unidentified site for MCP3 shared with MIP1β. The existence of another unique binding site(s) for MCP3 was further shown by the failure of any of the other CC chemokines to compete effectively for MCP3 binding on neutrophils. MCP3 in our study was also the only human CC chemokine that consistently chemoattracted neutrophils. These results suggest that MCP3 is a ligand that can bind and activate a broad range of target cells through receptors shared by other CC chemokines as well as its own receptor.     

Vitamin D Level and Risk of Community-Acquired Pneumonia and Sepsis

Previous research has reported reduced serum 25-hydroxyvitamin D (25(OH)D) levels is associated with acute infectious illness. The relationship between vitamin D status, measured prior to acute infectious illness, with risk of community-acquired pneumonia (CAP) and sepsis has not been examined. Community-living individuals hospitalized with CAP or sepsis were age-, sex-, race-, and season-matched with controls. ICD-9 codes identified CAP and sepsis; chest radiograph confirmed CAP. Serum 25(OH)D levels were measured up to 15 months prior to hospitalization. Regression models adjusted for diabetes, renal disease, and peripheral vascular disease evaluated the association of 25(OH)D levels with CAP or sepsis risk. A total of 132 CAP patients and controls were 60 ± 17 years, 71% female, and 86% Caucasian. The 25(OH)D levels <37 nmol/L (adjusted odds ratio (OR) 2.57, 95% CI 1.08–6.08) were strongly associated with increased odds of CAP hospitalization. A total of 422 sepsis patients and controls were 65 ± 14 years, 59% female, and 91% Caucasian. The 25(OH)D levels <37 nmol/L (adjusted OR 1.75, 95% CI 1.11–2.77) were associated with increased odds of sepsis hospitalization. Vitamin D status was inversely associated with risk of CAP and sepsis hospitalization in a community-living adult population. Further clinical trials are needed to evaluate whether vitamin D supplementation can reduce risk of infections, including CAP and sepsis.     

Body mass index and acute asthma severity among children presenting to the emergency department

Ginde AA, Santillan AA, Clark S, Camargo CA Jr. Body mass index and acute asthma severity among children presenting to the emergency department.
Pediatr Allergy Immunol 2010: 21: 480–488.
© 2009 John Wiley & Sons A/S To determine the prevalence of obesity among children presenting to the emergency department (ED) with acute asthma, and to examine the relationship between body mass index (BMI) and acute asthma severity in the ED setting. We analyzed data from a multicenter prospective cohort study during 1997–1998; 44 ED in 17 US states and two Canadian provinces enrolled 672 patients, age 5–17, with acute asthma. BMI and Pulmonary Index were collected in the ED. We defined overweight and obesity using age, sex, and race‐specific BMI values from national and international databases. The prevalence of obesity was significantly higher among ED patients with acute asthma as compared with children from the general population (23% vs. 9–15%; p < 0.001). Obese children with acute asthma did not differ from their non‐obese counterparts, by demographic factors or chronic asthma severity (all p > 0.2). Initial Pulmonary Index was the same across underweight, intermediate, and obese groups (3.7 ± 2.4, 3.8 ± 2.2, 3.7 ± 2.3; p = 0.70). Admission status also did not vary across groups (22%, 22% and 23%; p = 0.98). Stratifying the analysis by age group and sex did not change these results. The prevalence of obesity among children presenting to the ED with acute asthma was significantly higher compared with children from the general population. BMI was not associated with markers of chronic and acute asthma severity. The results of this study support a positive association between obesity and asthma, and suggest that asthma exacerbations among obese children are very similar to those experienced by other children.     

Forces applied during manual therapy to patients with low back pain

BACKGROUND: To date, there is little information available regarding the forces used during mobilization treatment of patients with low back pain (LBP). OBJECTIVE: This study measured such forces and investigated whether the force characteristics could be predicted on the basis of physical therapist and patient characteristics. SUBJECTS: Ten physical therapists applied a central posteroanterior (PA) mobilization treatment to 80 patients with LBP, providing data on treatment of 123 lumbar levels. METHODS: Physical therapists were required to treat their patients while the patients lay on an instrumented couch. This couch has been shown to be highly accurate in its measurement of force in 3 directions (error <2%) and has demonstrated high test-retest reliability (ICC [2, 1], 99% CI = 0.99-1.00). The forces applied by the physical therapists were recorded over a 10-second period. Data on the characteristics of the physical therapists and patients were collected by means of questionnaires. RESULTS: The force used by physical therapists related not only to patient characteristics but also to physical therapist characteristics. Interestingly, current pain intensity and nature of symptoms did not affect the forces used. The overall patterns of the force characteristics were generally consistent with previous studies performed in asymptomatic subjects. However, the magnitude of the force applied and the frequency of each grade used in the present study are relatively higher than in earlier studies. CONCLUSION: These preliminary data provide some useful quantitative information about the forces used during mobilization treatment of patients with LBP. Also, the force characteristics described here may provide useful data for both teaching and research in manual therapy.     

Progression of mouse mammary tumors: MCP-1-TNFalpha cross-regulatory pathway and clonal expression of promalignancy and antimalignancy factors

The progression of breast cancer is affected by multiple cellular and microenvironmental components. The monocyte chemoattractant MCP-1, IL-6 and matrix metalloproteinases (MMP) were suggested to promote, each on its own, breast cancer progression. We recently demonstrated that the high-tumorigenicity phenotype of the DA3 and CSML murine mammary adenocarcinoma cells is correlated with a high expression of MCP-1, IL-6 and MMP. This raised the possibility that common intrinsic tumor-derived factors regulate the concordant expression of these 3 components. The aim of the present study was to gain insight into the mode by which the secretion of MCP-1, IL-6 and MMP from murine mammary adenocarcinoma cells is regulated. This was investigated in cellular clones established from a highly malignant variant of the DA3 tumor (DA3-high). We also determined the secretion of the antimalignancy chemokine IP-10 from these cells. The results indicate that the secretion levels of IL-6, MMP and IP-10 varied between the clones. In contrast, all the clones secreted uniformly high levels of MCP-1, suggesting that MCP-1 constitutes an important feature of the malignancy phenotype of mammary carcinoma. In most of the clones, elevated levels of 1 of the 3 promalignancy factors did not correlate with a high expression of the other 2 factors and vice versa. These findings indicate that the 3 promalignancy factors are not coregulated by a common intrinsic tumor-derived factor. Rather, these results suggest that the individual capacities of the different clones to secrete these factors are summed up in the high-malignancy DA3 parental tumor population, which secretes relatively high levels of MCP-1, IL-6 and MMP as compared to DA3 cells expressing a low-malignancy phenotype. In contrast to the lack of coordinated intrinsic regulation of MCP-1, IL-6 and MMP, it was found that recombinant TNFalpha, a product of tumor-associated macrophages contributing to breast cancer progression, upregulated the secretion of MCP-1, IL-6 and MMP from all the clones. These results suggest a key role for this microenvironmental, monocyte-derived cytokine in the coordinated regulation of these 3 molecules. Furthermore, additional results demonstrated that monocytic cell-derived TNFalpha upregulated MCP-1 secretion from the tumor cells and that MCP-1 in turn promoted the secretion of TNFalpha from monocytic cells. This may result in a positive feedback loop, whereby the tumor cells and the monocytic cells at tumor site promote each other's ability to express and secrete promalignancy factors. We next attempted to assess the contribution of the promalignancy factors MCP-1, IL-6 and MMP and of the antimalignancy factor IP-10 to mammary adenocarcinoma progression. To this end, a preliminary formula was developed in which the net balance between secretion levels of the promalignancy factors and that of the antimalignancy IP-10 chemokine from different clones was related to their in vivo tumorigenicity profile. This formula suggests that a balance between the secretion levels of these factors plays an important role in determining the malignancy phenotype of mammary carcinomas. In all, our findings demonstrate that the mammary tumor cell population is composed of a heterogeneous assortment of clones whose individual characteristics are averaged in the whole population. The malignancy potential of such tumors is thus determined, inter alia, by a combinatorial effect of several promalignancy and antimalignancy factors secreted from each of the clones comprising these tumors. Our results also suggest that the expression of such factors is determined by several nonmutually exclusive regulatory mechanisms.     

The angiogenic factors CXCL8 and VEGF in breast cancer: regulation by an array of pro-malignancy factors

The regulation of secretion of the angiogenic factors CXCL8 and Vascular Endothelial Growth Factors (VEGF) was determined in breast tumor cells and in monocytic cells (as host cells that contribute to breast cancer). CXCL8 secretion, and partly the secretion of VEGF, were up-regulated in monocytic cells, but not in breast tumor cells, by the CC chemokines CCL5 and CCL2. EGF potently up-regulated CXCL8 secretion by breast tumor cells, and its effect was promoted by a consecutive treatment of the cells by estrogen and progesterone. These findings provide evidence for a complex set of pro-malignancy factors that may control the expression of angiogenic mediators at breast tumor sites.     

Efficacy of turmeric (curcumin) in pain and postoperative fatigue after laparoscopic cholecystectomy: a double-blind, randomized placebo-controlled study

Objective  

Better patient-reported outcomes (PROs) of laparoscopic cholecystectomy (LC) are premised upon PROs such as postoperative pain and fatigue. These PROs are indices of convalescence and return to normal activity. Curcumin (turmeric) is used in India for traumatic pain and fatigue for its anti-inflammatory/antioxidant and tissue modulation/healing properties. We studied the effect of curcumin on pain and postoperative fatigue in patients of LC.