Background-Inflammation is implicated in atherogenesis and plaque disruption. Toll-like receptor 2 (TLR-2) and TLR-4, a human homologue of drosophila Toll, play an important role in the innate and inflammatory signaling responses to microbial agents. To investigate a potential role of these receptors in atherosclerosis, we assessed the expression of TLR-2 and TLR-4 in murine and human atherosclerotic plaques. Methods and Results-Aortic root lesions of high-fat diet-fed apoE-deficient mice (nϭ5) and human coronary atherosclerotic plaques (nϭ9) obtained at autopsy were examined for TLR-4 and TLR-2 expression by immunohistochemistry. Aortic atherosclerotic lesions in all apoE-deficient mice expressed TLR-4, whereas aortic tissue obtained from control C57BL/6J mice showed no TLR-4 expression. All 5 lipid-rich human plaques expressed TRL-4, whereas the 4 fibrous plaques and 4 normal human arteries showed no or minimal expression. Serial sections and double immunostaining showed TLR-4 colocalizing with macrophages both in murine atherosclerotic lesions and at the shoulder region of human coronary artery plaques. In contrast to TLR-4, none of the plaques expressed TLR-2. Furthermore, basal TLR-4 mRNA expression by human monocyte-derived macrophages was upregulated by ox-LDL in vitro. A potential role for infection in the development of atherosclerosis has been considered for several decades, but interest in this topic has recently reemerged because of several recent observations. Accumulating evidence has implicated specific infectious agents, including Chlamydia pneumoniae, in the progression and/or destabilization of atherosclerosis. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] Recent studies suggest that chlamydia lipopolysaccharide (LPS) induces foam-cell formation, whereas its heat-shock protein (chlamydia HSP60) induces oxidative modification of LDL. 5,18 Chlamydia HSP60 has been implicated in the induction of deleterious immune responses in human chlamydial infection and has been found to colocalize with infiltrating macrophages in the atheroma lesions. 19 Collectively, these data support a potential role for C pneumoniae in the development and progression of atherosclerosis and suggest that this organism may indeed play an active role in atheroma development. Available data, however, also underscore the current lack of a complete understanding of the molecular mechanisms that link C pneumoniae infection to innate immunity and trigger the signals for enhanced inflammation and atherogenesis. Conclusions-OurLPS, a major component of the outer surface of Gramnegative bacteria, activates the proinflammatory transcription factor nuclear factor (NF)-B in endothelial cells and macrophages. 20,21 Recently, human Toll-like receptor-4 (TLR-4), a human homologue of drosophila Toll, has been identified as Currently, more than 10 human TLRs have been identified, and at least 10 human homologues of drosophila Toll have been sequenced. Whereas TLR-4 is used by enteric Gramnegative bacteria and LPS, TLR-2 is use...

Background Successful therapy for ependymoma includes aggressive surgical intervention and radiation therapy administered using methods which minimize the risk of side effects. We extended this treatment approach to include children under the age of 3 years. Methods Between July 1997 and 2007, 153 pediatric patients (median age 2·9 years, range 0·9–22·9 years) with localized ependymoma received conformal radiation therapy after definitive surgery. Doses of 59·4 (n=131) or 54·0 Gy (n=22) were prescribed to a 10mm clinical target volume margin surrounding the post-operative residual tumor and/or tumor bed. The patients had the following characteristics: anaplastic ependymoma (n=85), infratentorial location (n=122), prior chemotherapy (n=35) and extent of resection (gross-total=125, near-total=17, subtotal=11). Disease control, patterns of failure and complications were recorded for patients followed through 10 years. Findings With a median follow-up of 5·3 years (range 0·4 to 10·4 years), death was recorded in 23 patients and tumor progression in 36, including local (n=14), distant (n=15) and combined failure (n=7). Tumor grade predicted overall (OS) and event-free (EFS) survival and distant failure. Extent of resection predicted OS, EFS and local failure. Race predicted OS. The 7 year local control, event-free and overall survival were 83·7% (95% CI: 73·9–93·5%), 69·1% (95% CI: 56·9–81·3%) and 81·0% (95% CI: 71·0–91·0%), respectively. The cumulative incidence of local and distance failure were 16·3% (95% CI: 9·6–23·0%) and 11·48% (95% CI: 5·9–17·1%), respectively. Considering only those patients treated with immediate post-operative CRT (without delay or chemotherapy) the 7 year OS, EFS and CI of local and distant failure were 85·0% (95% CI: 74·2–95·8%), 76·9% (95% CI: 63·4–90·4%), 12·59% (95% CI: 5·1–20·1%)and 8·56% (95% CI: 2·8–14·3%), respectively. The incidence of secondary malignant brain tumor at 7 years was 2·3% (95% CI: 0–5·6%) and brainstem necrosis 1·6% (95% CI: 0–4·0%). Interpretation This study provides new disease control benchmarks and a unifying approach for the treatment of ependymoma that should include surgery with the aim of gross-total resection and conformal, high-dose, post-operative irradiation even for the youngest children. Future trials might consider treatment stratification based on gender and age as female patients are more likely to be long-term survivors and younger patients have higher rates of failure.

The reported transmission of avian H9N2 influenza viruses to humans and the isolation of these viruses from Hong Kong poultry markets lend urgency to studies of their ecology and pathogenicity. We found that H9N2 viruses from North America differ from those of Asia. The North American viruses, which infect primarily domestic turkeys, replicated poorly in inoculated chickens. Phylogenetic analysis of the hemagglutinin and nucleoprotein genes indicated that the Asian H9N2 influenza viruses could be divided into three sublineages. Initial biological characterization of at least one virus from each lineage was done in animals. Early isolates of one lineage (A/Chicken/Beijing/1/94, H9N2) caused as high as 80% mortality rates in inoculated chickens, whereas all other strains were nonpathogenic. Sequence analysis showed that some isolates, including the pathogenic isolate, had one additional basic amino acid (A-R/K-S-S-R-) at the hemagglutinin cleavage site. Later isolates of the same lineage (A/Chicken/Hong Kong/G9/97, H9N2) that contains the PB1 and PB2 genes similar to Hong Kong/97 H5N1 viruses replicated in chickens, ducks, mice, and pigs but were pathogenic only in mice. A/Quail/Hong Kong/G1/97 (H9N2), from a second lineage that possesses the replicative complex similar to Hong Kong/97 H5N1 virus, replicated in chickens and ducks without producing disease signs, was pathogenic in mice, and spread to the brain without adaptation. Examples of the third Asian H9N2 sublineage (A/Chicken/Korea/323/96, Duck/Hong Kong/Y439/97) replicated in chickens, ducks, and mice without producing disease signs. The available evidence supports the notion of differences in pathogenicity of H9N2 viruses in the different lineages and suggests that viruses possessing genome segments similar to 1997 H5N1-like viruses are potentially pathogenic in mammals.

A B S T R A C T PurposeWe conducted a prospective trial to evaluate late effects in pediatric patients with low-grade glioma (LGG) treated with conformal radiation therapy (CRT). Patients and MethodsBetween August 1997 and August 2006, 78 pediatric patients with LGG (mean age, 9.7 years; standard deviation, Ϯ4.4 years) received 54 Gy of CRT with a 10-mm clinical target volume margin. Tumor locations were diencephalon (n ϭ 58), cerebral hemisphere (n ϭ 3), and cerebellum (n ϭ 17). Baseline and serial evaluations were performed to identify deficits in cognition, endocrine function, and hearing. Deficits were correlated with clinical factors and radiation dose within specific normal tissue volumes. ResultsCognitive effects of CRT through 5 years after CRT correlated with patient age, neurofibromatosis type 1 status, tumor location and volume, extent of resection, and radiation dose. The effect of age exceeded that of radiation dose; patients younger than 5 years experienced the greatest decline in cognition. Before CRT, growth hormone (GH) secretion abnormality was diagnosed in 24% of tested patients, and 12% had precocious puberty. The 10-year cumulative incidence of GH replacement was 48.9%; of thyroid hormone replacement, 64.0%; of glucocorticoid replacement, 19.2%; and of gonadotropin-releasing hormone analog therapy, 34.2%. The mean Ϯ standard errors of the cumulative incidence of hearing loss at 10 years did not exceed 5.7% Ϯ 3.3% at any frequency. ConclusionTo our knowledge, this is the largest series of prospectively followed children with LGG to undergo irradiation. Adverse effects are limited and predictable for most patients; however, this study provides additional evidence that CRT should be delayed for young patients and identifies the potential benefits of reducing radiation dose to normal brain.