Broncho-alveolar Lavage Matrix Metalloproteases as a Sensitive Measure of Bronchiolitis Obliterans

Bronchiolitis obliterans (BO) is a survival-limiting factor in lung transplantation. There are no common BO markers in use. Since BO is associated with extracellular matrix remodeling, we asked whether matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs) could serve as BO markers. In 72 lung transplant patients (34 BO syndrome (BOS) 0, 15 BOS 0-p, and 23 BOS 1) serum and broncho-alveolar lavage (BAL) MMP and TIMP levels were examined by ELISA. The BAL cell counts were additionally analyzed. The serum MMP-2, MMP-8, MMP-9 and TIMP-2 levels were not different in all groups. In contrast, the BAL MMP-8, -9 and TIMP-1 levels were significantly elevated in BOS 0-p (p = 0.003; p = 0.007; p = 0.0003, respectively) and BOS 1 (p = 0.003; p = 0.001; p = 0.0004, respectively) as compared to BOS 0 patients. The BAL MMP-8, -9 and TIMP-1 levels were significant predictors of BOS 0-p (p = 0.01; p = 0.01; p = 0.01, respectively) and BOS-1 (p = 0.007; p = 0.01; p = 0.006, respectively) in receiver operating characteristic analysis. Except for BAL macrophages that were significantly decreased in BOS 0-p versus BOS 0 patients; other cell counts were not different between the groups. BAL MMP-8, -9 and TIMP-1 might be useful markers to detect BO in lung transplant patients.     

Colon cancer cell-derived tumor necrosis factor-alpha mediates the tumor growth-promoting response in macrophages by up-regulating the colony-stimulating factor-1 pathway

The interplay between malignant and stromal cells is essential in tumorigenesis. We have previously shown that colony-stimulating factor (CSF)-1, matrix metalloprotease (MMP)-2, and vascular endothelial growth factor (VEGF)-A production by stromal cells is enhanced by CSF-1-negative SW620 colon cancer cells. In the present study, the mechanisms by which colon cancer cells up-regulate host factors to promote tumorigenesis were investigated. Profiling of tumor cell cytokine expression in SW620 tumor xenografts in nude mice showed increased human tumor necrosis factor (TNF)-alpha mRNA expression with tumor growth. Incubation of macrophages with small interfering (si) RNAs directed against TNF-alpha or TNF-alpha-depleted SW620 cell conditioned medium versus SW620 cell conditioned medium failed to support mouse macrophage proliferation, migration, and expression of CSF-1, VEGF-A, and MMP-2 mRNAs. Consistent with these results, human TNF-alpha gene silencing decreased mouse macrophage TNF-alpha, CSF-1, MMP-2, and VEGF-A mRNA expression in macrophages cocultured with human cancer cells. In addition, inhibition of human TNF-alpha or mouse CSF-1 expression by siRNA reduced tumor growth in SW620 tumor xenografts in mice. These results suggest that colon cancer cell-derived TNF-alpha stimulates TNF-alpha and CSF-1 production by macrophages, and that CSF-1, in turn, induces macrophage VEGF-A and MMP-2 in an autocrine manner. Thus, interrupting tumor cell-macrophage communication by targeting TNF-alpha may provide an alternative therapeutic approach for the treatment of colon cancer.     

Stromal cell‐derived CSF‐1 blockade prolongs xenograft survival of CSF‐1‐negative neuroblastoma

The molecular mechanisms of tumor–host interactions that render neuroblastoma (NB) cells highly invasive are unclear. Cancer cells upregulate host stromal cell colony‐stimulating factor‐1 (CSF‐1) production to recruit tumor‐associated macrophages (TAMs) and accelerate tumor growth by affecting extracellular matrix remodeling and angiogenesis. By coculturing NB with stromal cells in vitro, we showed the importance of host CSF‐1 expression for macrophage recruitment to NB cells. To examine this interaction in NB in vivo, mice bearing human CSF‐1‐expressing SK‐N‐AS and CSF‐1‐negative SK‐N‐DZ NB xenografts were treated with intratumoral injections of small interfering RNAs directed against mouse CSF‐1. Significant suppression of both SK‐N‐AS and SK‐N‐DZ NB growth by these treatments was associated with decreased TAM infiltration, matrix metalloprotease (MMP)‐12 levels and angiogenesis compared to controls, while expression of tissue inhibitors of MMPs increased following mouse CSF‐1 blockade. Furthermore, Tie‐2‐positive and ‐negative TAMs recruited by host CSF‐1 were identified in NB tumor tissue by confocal microscopy and flow cytometry. However, host‐CSF‐1 blockade prolonged survival only in CSF‐1‐negative SK‐N‐DZ NB. These studies demonstrated that increased CSF‐1 production by host cells enhances TAM recruitment and NB growth and that the CSF‐1 phenotype of NB tumor cells adversely affects survival.     

Comparison of neurological clinical manifestation in patients with hemorrhagic and ischemic stroke

BACKGROUND: Cerebrovascular accident (CVA) is the third leading cause of death and disability in developed countries. Anyone suspected of having a stroke should be taken immediately to a medical facility for diagnosis and treatment. The symptoms that follow a stroke aren't significant and depend on the area of the brain that has been affected and the amount of tissue damaged. Parameters for predicting long-term outcome in such patients have not been clearly delineated, therefore the aim of this study was to investigate this possibility and to test a system that might practicably be used routinely to aid management and predict outcomes of individual stroke patients.     

A new modality for the estimation of corrected flow time via electrocardiography as an alternative to Doppler ultrasonography

Background

Evaluation of corrected flow time (FTc) via ultrasonography is one of the suggested modalities for the assessment of intravascular volume status. This study aimed to compare the results of FTc of carotid artery measured via ultrasonography, as a measure of mechanical outcome of the cardiac cycle, with the results of FTc estimation from a new modified formula via electrocardiography (ECG), as a measure of electrical function of the cardiac cycle.

Methods

Healthy volunteers were evaluated before and after a passive leg raising (PLR) maneuver. FTc was measured concurrently before and after PLR via a modified method from ECG and via ultrasonography of the carotid artery.

Results

A total number of 98 healthy volunteers (51 women and 47 men) with a mean age of 30.69 ± 6.28 years were included. There was a significant correlation between FTc measured by ultrasonography and estimated by ECG both before PLR and after PLR (r = .878, p < .0001 and r = .797, p < .0001, respectively). Changes in FTc were slightly higher in measurements by ultrasonography compared to estimations by ECG (22.33 ± 17.15 ms^0.5 vs. 15.86 ± 14.25 ms^0.5, p = .001).

Conclusion

Estimation of FTc via ECG is potentially an effective and feasible method for the assessment of volume status at the clinical settings. Further investigations should determine the significance of differences that may be observed between ultrasonography and ECG in patients with either dehydration or volume overload and in the need of real‐time volume status assessment.