Patients with Epstein Barr virus-positive lymphomas have decreased CD4(+) T-cell responses to the viral nuclear antigen 1

Epstein Barr virus (EBV) causes lymphomas in immune competent and, at increased frequencies, in immune compromised patients. In the presence of an intact immune system, EBV-associated lymphomas express in most cases only 3 or fewer EBV antigens at the protein level, always including the nuclear antigen 1 of EBV (EBNA1). EBNA1 is a prominent target for EBV-specific CD4(+) T cell and humoral immune responses in healthy EBV carriers. Here we demonstrate that patients with EBV-associated lymphomas, primarily Hodgkin's lymphoma, lack detectable EBNA1-specific CD4(+) T-cell responses and have slightly altered EBNA1-specific antibody titers at diagnosis. In contrast, the majority of EBV-negative lymphoma patients had detectable IFN-gamma expression and proliferation by CD4(+) T cells in response to EBNA1, and carry EBNA1-specific immunoglobulins at levels similar to healthy virus carriers. Other EBV antigens, which were not present in the tumors, were recognized in less EBV positive, than negative lymphoma patients, but detectable responses reached similar CD8(+) T cell frequencies in both cohorts. Patients with EBV-positive and -negative lymphomas did not differ in T-cell responses in influenza-specific CD4(+) T cell proliferation and in antibody titers against tetanus toxoid. These data suggest a selective loss of EBNA1-specific immune control in EBV-associated lymphoma patients, which should be targeted for immunotherapy of these malignancies.     

Evidence for a pathophysiological role of cysteinyl leukotrienes in classical Hodgkin lymphoma

Classical Hodgkin lymphoma (cHL) is characterized histologically by a minority of malignant Hodgkin Reed-Sternberg cells surrounded by abundant inflammatory cells, generally believed to be of major importance in the pathophysiology of the disease. Here, we present data that link inflammatory cell-derived arachidonic acid metabolites, the cysteinyl leukotrienes (CysLT), to the pathogenesis of cHL. Two HL cell lines, L1236 and KMH2, were shown to express functional CysLT(1) receptors, responding with a robust calcium signal upon leukotriene (LT) D(4) challenge. LTD(4) stimulated protein release of tumor necrosis factor-alpha, interleukin-6 and -8 by L1236 cells and interleukin-8 by KMH2 cells. Importantly, all these LTD(4)-induced effects were blocked by the CysLT(1) receptor-specific antagonist zafirlukast. Immunohistochemical studies of cHL biopsies and microarray analysis of microdissected cells revealed that the CysLT(1) receptor is expressed also by primary Hodgkin Reed-Sternberg cells. As these cells are surrounded by CysLT-producing eosinophils, macrophages and mast cells, our results suggest the CysLTs as mediators in the pathogenesis of cHL, contributing to the aberrant cytokine network of this lymphoma.     

Docosahexaenoic acid stimulates non-amyloidogenic APP processing resulting in reduced Abeta levels in cellular models of Alzheimer's disease

Epidemiological studies suggest that a high intake of polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), is associated with a reduced risk of Alzheimer's disease. Here, we examined the effects of DHA on amyloid precursor protein (APP) processing in cellular models of Alzheimer's disease by analysing levels of different APP fragments, including amyloid-beta (Abeta). DHA administration stimulated non-amyloidogenic APP processing and reduced levels of Abeta, providing a mechanism for the reported beneficial effects of DHA in vivo. However, an increased level of APP intracellular domain was also observed, highlighting the need to increase our knowledge about the relevance of this fragment in Alzheimer's disease pathogenesis. In conclusion, our results suggest that the proposed protective role of DHA in Alzheimer's disease pathogenesis might be mediated by altered APP processing and Abeta production.     

Maternal smoking during pregnancy and intellectual performance in young adult Swedish male offspring

Lundberg F, Cnattingius S, D'Onofrio B, Altman D, Lambe M, Hultman C, Iliadou A. Maternal smoking during pregnancy and intellectual performance in young adult Swedish male offspring. Paediatric and Perinatal Epidemiology 2010; 24: 79–87.
Smoking during pregnancy has been linked to an increased risk of several adverse birth outcomes. Associations with deficits in cognitive development have also been suggested. It is unclear whether these associations are due to genetic and/or environmental confounding. In a population-based Swedish cohort study on 205 777 singleton males born to Nordic mothers between 1983 and 1988, we examined the association between maternal smoking during pregnancy and the risk of poor intellectual performance in young adult male offspring.
In the cohort analyses, the risk of poor intellectual performance was increased in sons of smoking mothers compared with sons of non-smokers. Stratifying for maternal smoking habits across two pregnancies, there was an increased risk of poor intellectual performance for both sons if the mother was only smoking in the first pregnancy, but in neither son if the mother was only smoking in the second pregnancy. The effect of smoking during pregnancy on intellectual performance was not present when the association was evaluated within sibling pairs. Thus, the association between prenatal smoking exposure and offspring risk of low intellectual performance appears to be completely confounded by familial (genetic and early environmental) factors.     

Expanding the genotype–phenotype spectrum in hereditary colorectal cancer by gene panel testing

Hereditary syndromes causing colorectal cancer include both polyposis and non-polyposis syndromes. Overlapping phenotypes between the syndromes have been recognized and this make targeted molecular testing for single genes less favorable, instead there is a gaining interest for multi-gene panel-based approaches detecting both SNVs, indels and CNVs in the same assay. We applied a panel including 19 CRC susceptibility genes to 91 individuals of six phenotypic subgroups. Targeted NGS-based sequencing of the whole gene regions including introns of the 19 genes was used. The individuals had a family history of CRC or had a phenotype consistent with a known CRC syndrome. The purpose of the study was to demonstrate the diagnostic difficulties linked to genotype-phenotype diversity and the benefits of using a gene panel. Pathogenicity classification was carried out on 46 detected variants. In total we detected sixteen pathogenic or likely pathogenic variants and 30 variants of unknown clinical significance. Four of the pathogenic or likely pathogenic variants were found in BMPR1A in patients with unexplained familial adenomatous polyposis or atypical adenomatous polyposis, which extends the genotype-phenotype spectrum for this gene. Nine patients had more than one variant remaining after the filtration, including three with truncating mutations in BMPR1A, PMS2 and AXIN2. CNVs were found in three patients, in upstream regions of SMAD4, MSH3 and CTNNB1, and one additional individual harbored a 24.2 kb duplication in CDH1 intron1.     

Variability of inotropic and chronotropic response during dobutamine stress echocardiography and possible implications for diagnostic accuracy

Chronotropic and inotropic response patterns were assessed during dobutamine stress echocardiography. Three heart rate response patterns were noted: nonresponders (48% of patients), slow responders (30% of patients), and fast responders (21% of patients). There was no relation between heart rate and contractile response.