Characteristics of the Alternative Phenotype of Microglia/Macrophages and its Modulation in Experimental Gliomas

Microglia (brain resident macrophages) accumulate in malignant gliomas and instead of initiating the anti-tumor response, they switch to a pro-invasive phenotype, support tumor growth, invasion, angiogenesis and immunosuppression by release of cytokines/chemokines and extracellular matrix proteases. Using immunofluorescence and flow cytometry, we demonstrate an early accumulation of activated microglia followed by accumulation of macrophages in experimental murine EGFP-GL261 gliomas. Those cells acquire the alternative phenotype, as evidenced by evaluation of the production of ten pro/anti-inflammatory cytokines and expression profiling of 28 genes in magnetically-sorted CD11b+ cells from tumor tissues. Furthermore, we show that infiltration of implanted gliomas by amoeboid, Iba1-positive cells can be reduced by a systematically injected cyclosporine A (CsA) two or eight days after cell inoculation. The up-regulated levels of IL-10 and GM-CSF, increased expression of genes characteristic for the alternative and pro-invasive phenotype (arg-1, mt1-mmp, cxcl14) in glioma-derived CD11b+ cells as well as enhanced angiogenesis and tumor growth were reduced in CsA-treated mice. Our findings define for the first time kinetics and biochemical characteristics of glioma-infiltrating microglia/macrophages. Inhibition of the alternative activation of tumor-infiltrating macrophages significantly reduced tumor growth. Thus, blockade of microglia/macrophage infiltration and their pro-invasive functions could be a novel therapeutic strategy in malignant gliomas

Fall-related emergency department admission: fall environment and settings and related injury patterns in 6357 patients with special emphasis on the elderly

PRINCIPALS Throughout the world, falls are a major public health problem and a socioeconomic burden. Nevertheless there is little knowledge about how the injury types may be related to the aetiology and setting of the fall, especially in the elderly. We have therefore analysed all patients presenting with a fall to our Emergency Department (ED) over the past five years. METHODS Our retrospective data analysis comprised adult patients admitted to our Emergency Department between January 1, 2006, and December 31, 2010, in relation to a fall. RESULTS Of a total of 6357 patients 78% (n = 4957) patients were younger than 75 years. The main setting for falls was patients home (n = 2239, 35.3%). In contrast to the younger patients, the older population was predominantly female (56.3% versus 38.6%; P < 0.0001). Older patients were more likely to fall at home and suffer from medical conditions (all P < 0.0001). Injuries to the head (P < 0.0001) and to the lower extremity (P < 0.019) occurred predominantly in the older population. Age was the sole predictor for recurrent falls (OR 1.2, P < 0.0001). CONCLUSION Falls at home are the main class of falls for all age groups, particularly in the elderly. Fall prevention strategies must therefore target activities of daily living. Even though falls related to sports mostly take place in the younger cohort, a significant percentage of elderly patients present with falls related to sporting activity. Falls due to medical conditions were most likely to result in mild traumatic brain injury

Fall-Related Emergency Department Admission: Fall Environment and Settings and Related Injury Patterns in 6357 Patients with Special Emphasis on the Elderly

Principals. Throughout the world, falls are a major public health problem and a socioeconomic burden. Nevertheless there is little knowledge about how the injury types may be related to the aetiology and setting of the fall, especially in the elderly. We have therefore analysed all patients presenting with a fall to our Emergency Department (ED) over the past five years. Methods. Our retrospective data analysis comprised adult patients admitted to our Emergency Department between January 1, 2006, and December 31, 2010, in relation to a fall. Results. Of a total of 6357 patients 78% ( = 4957) patients were younger than 75 years. The main setting for falls was patients home ( = 2239, 35.3%). In contrast to the younger patients, the older population was predominantly female (56.3% versus 38.6%; &lt; 0.0001). Older patients were more likely to fall at home and suffer from medical conditions (all &lt; 0.0001). Injuries to the head ( &lt; 0.0001) and to the lower extremity ( &lt; 0.019) occurred predominantly in the older population. Age was the sole predictor for recurrent falls (OR 1.2, &lt; 0.0001). Conclusion. Falls at home are the main class of falls for all age groups, particularly in the elderly. Fall prevention strategies must therefore target activities of daily living. Even though falls related to sports mostly take place in the younger cohort, a significant percentage of elderly patients present with falls related to sporting activity. Falls due to medical conditions were most likely to result in mild traumatic brain injury

What Is the Incidence of Intracranial Bleeding in Patients with Mild Traumatic Brain Injury? A Retrospective Study in 3088 Canadian CT Head Rule Patients

Objective. Only limited data exists in terms of the incidence of intracranial bleeding (ICB) in patients with mild traumatic brain injury (MTBI). Methods. We retrospectively identified 3088 patients (mean age 41 range (7–99) years) presenting with isolated MTBI and GCS 14-15 at our Emergency Department who had undergone cranial CT (CCT) between 2002 and 2011. Indication for CCT was according to the “Canadian CT head rules.” Patients with ICB were either submitted for neurosurgical treatment or kept under surveillance for at least 24 hours. Pearson’s correlation coefficient was used to correlate the incidence of ICB with age, gender, or intake of coumarins, platelet aggregation inhibitors, or heparins. Results. 149 patients (4.8%) had ICB on CCT. No patient with ICB died or deteriorated neurologically. The incidence of ICB increased with age and intake of anticoagulants without clinically relevant correlation (R=0.11; P<0.001; R=-0.06; P<0.001). Conclusion. Our data show an incidence of 4.8% for ICB after MTBI. However, neurological deterioration after MTBI seems to be rare, and the need for neurosurgical intervention is only required in selected cases. The general need for CCT in patients after MTBI is therefore questionable, and clinical surveillance may be sufficient when CCT is not available

Analysis of interleukin (IL)-8 expression in human astrocytomas: Associations with IL-6, cyclooxygenase-2, vascular endothelial growth factor, and microvessel morphometry

Malignant astrocytomas are highly vascular neoplasms with potent angiogenic activity. The present study aimed to investigate peripheral and local expression of interleukin (IL)-8 in astrocytomas with possible associations to IL-6, cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) expression, and microvessel morphometry. IL-6- and IL-8-secreting peripheral blood monocytes (PBMCs) were evaluated in 17 glioblastoma (WHO grade IV), 5 anaplastic astrocytoma (WHO grade III), and 6 diffuse astrocytoma patients (WHO grade II), in parallel with 23 healthy controls using enzyme-linked immunosorbent spot (ELISPOT) assay. The IL-8 expression was assessed immunohistochemically in patients&apos; tumor tissue sections and correlated with the expression of COX-2, VEGF, IL-6, and microvessel morphometry (assessed using CD34 antibody). Eighteen cases were also stained for CD31 and used as an additional vessel marker to validate our results regarding microvessel morphometry. IL-6 and IL-8 were highly secreted in the PBMCs of glioma patients compared with controls (p = 0.0001, p &lt; 0.0001, respectively), with a positive correlation between IL-8 expression and secretion levels (p = 0.001). IL-8 immunoreactivity was detected in malignant cells or macrophages in perivascular areas and in pseudopalisading cells around necrosis and was positively correlated with histological grade (p = 0.0175) and tumor necrosis (p = 0.0793). IL-6 and IL-8 expression levels were positively correlated (p = 0.0036) and associated with COX-2 and VEGF expression (IL-6: p = 0.0133, p = 0.065; IL-8: p = 0.0139, p = 0.0101), but not with microvessel morphometry, by either CD31 or CD34. The coordinate expression and topographical relationship of IL-6, IL-8, COX-2, and VEGF in the same tumor areas (e.g., perinecrotic areas) attest to their intimate liaison in terms of cancer-induced angiogenesis, which is probably secondary to the induction of multiple interdependent molecular pathways. Moreover, our study seems to be the first attempt to link IL-8 expression by tumor cells with histological grade, implicating its potent role in gliomagenesis. © 2009 American Society for Histocompatibility and Immunogenetics