Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models

Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer’s disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE₂) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE₂ receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE₂/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.     

Molecular determinants of cetuximab efficacy.

PURPOSE: To investigate whether mRNA expression levels of cyclin D1 (CCND1), cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), interleukin 8 (IL-8), and vascular endothelial growth factor (VEGF), all members of the EGFR signaling pathway, are associated with clinical outcome in patients with EGFR-expressing metastatic colorectal cancer (CRC) treated with cetuximab. PATIENTS AND METHODS: Thirty-nine patients with metastatic CRC, refractory to both irinotecan and oxaliplatin, were enrolled on IMCL-0144 and treated with single-agent cetuximab. The intratumoral mRNA levels of CCND1, Cox-2, EGFR, IL-8, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture microdissection and quantitative real-time polymerase chain reaction. RESULTS: There were 21 women and 18 men with a median age of 64 years (range, 35 to 83 years). Higher gene expression levels of VEGF were associated with resistance to cetuximab (P = .038; Kruskal-Wallis test). The combination of low gene expression levels of Cox-2, EGFR, and IL-8 was significantly associated with overall survival (13.5 v 2.3 months; P = .028; log-rank test). Both findings were independent of skin toxicity that was itself significantly correlated to survival. Patients with a lower mRNA amount of EGFR had a longer overall survival compared with patients that had a higher mRNA amount (7.3 v 2.2 months; P = .09; log-rank test). Patients with lower expression of Cox-2 had a significantly higher rate of grade 2 to 3 skin reactions under cetuximab treatment. CONCLUSION: This pilot study suggests that gene expression levels of Cox-2, EGFR, IL-8, and VEGF in patients with metastatic CRC may be useful markers of clinical outcome in single-agent cetuximab treatment.     

The ability of the SCORE high-risk model to predict 10-year cardiovascular disease mortality in Norway.

AIMS: To evaluate the predictive accuracy of the Systematic Coronary Risk Evaluation (SCORE) project high-risk function in Norway. METHODS AND RESULTS: We included 57 229 individuals screened in 1985-1992 from two population-based surveys in Norway (age groups 40-49, 50-59, and 60-69 years). The data have been linked to the Norwegian Cause of Death Registry. The SCORE high-risk algorithm for the prediction of 10-year cardiovascular disease (CVD) mortality was applied, and the risk factors entered into the model were age, sex, total cholesterol, systolic blood pressure, and smoking (yes/no). The number of expected events estimated by the SCORE model (E) was compared with the observed numbers (O). The SCORE low-risk algorithm was studied for comparison. In men, the observed number of CVD deaths was 718, compared with 1464 estimated by the SCORE high-risk function (O/E ratios 0.53, 0.53 and 0.45, for age groups 40-49, 50-59 and 60-69, respectively). In women, the observed and expected numbers were 226 and 547. The O/E ratios decreased with age (ratios 0.60, 0.45 and 0.37, respectively), i.e. the overestimation increased with age. The low-risk function predicted reasonably well for men (ratios 0.85, 0.92 and 0.79, respectively), whereas an overestimation was found for women aged 50-59 and 60-69 years (ratios 0.69 and 0.56, respectively). CONCLUSION: The SCORE high-risk model overestimated the number of CVD deaths in Norway. Before implementation in clinical practice, proper adjustments to national levels are required.     

Comparative early and midterm results of open juxtarenal and infrarenal aneurysm repair

Background and aims Since the introduction of endovascular aortic aneurysm repair (EVAR) for aortic aneurysms, the number of juxtarenal aortic aneurysms (JRA) has been growing steadily due to selection bias (neck morphology for EVAR). This case-match study compares the perioperative outcome and midterm results of suprarenally clamped JRA with infrarenal aortic aneurysms (AAA). Methods From 1997 to 2004, patients who received open surgery with suprarenal clamping for JRA were included in the study and compared to matched patients with infrarenal clamping (AAA). Measurements analyzed were the in-hospital mortality and morbidity. Midterm results were obtained through clinical investigation and magnetic resonance angiography imaging. Results Thirty-five patients (mean age, 68.4 years; 30 male and 5 female) received suprarenal cross-clamping for JRA. The overall in-hospital mortality for JRA and for the controls (AAA) with elective aortic repair was 4.5% (6.1% JRA; 3% AAA, p = 0.058). The morbidity of JRA was elevated according to the rate of pulmonary complications (p = 0.021) and the need for re-operation (p = 0.019). The mean follow-up time was 2.3 years (range, 8–96 months). At follow-up, 28 patients (80%) from the JRA group and 29 patients from the AAA group (82.9%) were alive. Conclusion Open aortic surgery for JRA with the need for suprarenal cross-clamping shows a slightly elevated in-hospital mortality rate without statistical significance and equal midterm mortality results in comparison with infrarenally clamped aortic aneurysms.     

Cancer-related anemia

Anemia has a high prevalence in patients with cancer. Its frequency and severity depend on tumor type, tumor stage, duration of disease, and treatment status. The etiology of cancer-related anemia is multifactorial and includes myelotoxicity of treatment, bone marrow infiltration, impaired erythropoietin production, blood loss, and the anemia of chronic disease. Anemia affects health-related quality of life (QOL) and may impact on tolerance or even outcome of anticancer therapy. Despite its high prevalence and impact on QOL, anemia is often under-recognized and under-treated. Treatment should correct etiologic factors, whenever possible. Symptomatic treatments are red blood cell transfusions and administration of erythropoietic growth factors. Transfusions result in rapid improvement of anemia-related symptoms but are usually only given to patients with moderate to severe anemia. Administration of epoetins (epoetin alfa, epoetin beta) or darbepoetin alfa increases hemoglobin levels, reduces the need for blood transfusions, and improves QOL in patients with cancer-related anemia. Trials determining the exact association of anemia with both response to chemo(radio)therapy and survival are ongoing. Physicians should be aware of the clinical relevance of and treatment options for anemia in cancer patients.