High Energy Neutrinos from Quasars

We review and clarify the assumptions of our basic model for neutrino production in the cores of quasars, as well as those modifications to the model subsequently made by other workers. We also present a revised estimate of the neutrino background flux and spectrum obtained using more recent empirical studies of quasars and their evolution. We compare our results with other thoeretical calculations and experimental upper limits on the AGN neutrino background flux. We also estimate possible neutrino fluxes from the jets of blazars detected recently by the EGRET experiment on the Compton Gamma Ray Observatory. We discuss the theoretical implications of these estimates.Comment: 14 pg., ps file (includes figures), To be published in Space Science Review

Characterization of NF-κB reporter U937 cells and their application for the detection of inflammatory immune-complexes

Our study tested the hypothesis that immunoglobulins differ in their ability to activate the nuclear factor-κB pathway mediated cellular responses. These responses are modulated by several properties of the immune complex, including the ratio of antibody isotypes binding to antigen. Immunoassays allow the measurement of antigen specific antibodies belonging to distinct immunoglobulin classes and subclasses but not the net biological effect of the combination of these antibodies. We set out to develop a biosensor that is suitable for the detection and characterization of antigen specific serum antibodies. We genetically modified the monocytoid U937 cell line carrying Fc receptors with a plasmid encoding NF-κB promoter-driven GFP. This clone, U937-NF-κB, was characterized with respect to FcR expression and response to solid-phase immunoglobulins. Human IgG3, IgG4 and IgG1 induced GFP production in a time- and dose-dependent manner, in this order of efficacy, while IgG2 triggered no activation at the concentrations tested. IgA elicited no response alone but showed significant synergism with IgG3 and IgG4. We confirmed the importance of activation via FcγRI by direct stimulation with monoclonal antibody and by competition assays. We used citrullinated peptides and serum from rheumatoid arthritis patients to generate immune complexes and to study the activation of U937-NF-κB, observing again a synergistic effect between IgG and IgA. Our results show that immunoglobulins have distinct pro-inflammatory potential, and that U937-NF-κB is suitable for the estimation of biological effects of immune-complexes, offering insight into monocyte activation and pathogenesis of antibody mediated diseases

Pregnancy postponement and childlessness leads to chronic hypervascularity of the breasts and cancer risk

Epidemiologists have established that women with small families, and particularly nulliparae, are prone to develop breast cancer later in life. We report that physiological mammary hypervascularity may be an intermediate reason against the background that breast-core vascularity is normal in pregnancy but pathological in the vascularisation of cancer. We examined breast ‘core’ vascularity in nulliparae during their potential reproductive life and in parous women after their last birth but before their menopause. Fifty clinically normal pre-menopausal non-pregnant women (100 breasts) were studied daily for one ‘luteal positive’ menstrual cycle. Their parity history varied from zero to five babies. Under controlled domestic conditions each wore a special electronic thermometric bra to automatically record breast ‘core’ temperature changes as a measure of mammary tissue blood flow. In the nulliparae there was a rise of breast vascularity throughout reproductive life. In the parous women, a year or so after each birth, breast vascularity was reset at a lower level than before the pregnancy; thereafter, as in nulliparae, there was progressive increase in mammary vascularity until the menopause

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

Association of p53 codon 72 polymorphism with advanced lung cancer: the Arg allele is preferentially retained in tumours arising in Arg/Pro germline heterozygotes

The association of p53 codon 72 polymorphism with cancer has been investigated by several scientific groups with controversial results. In the present study, we examined the genotypic frequency of this polymorphism in 54 patients with advanced lung cancer and 99 normal controls from the geographical region of Greece. Sputum and bronchial washing samples from each patient were assayed for the presence of human papillomavirus. Codon 72 heterozygous (Arg/Pro) patients were also analysed for loss of heterozygosity at the TP53 locus, in order to determine the lost p53 allele (Arg or Pro). p53 Arg/Arg genotype was significantly increased in lung cancer patients compared to normal controls (50% vs 24.2%, P<0.002). Human papillomavirus was detected only in two patients (3.7%). Loss of heterozygosity at the TP53 locus was found in 14 out of 27 Arg/Pro patients (51.85%). The Pro allele was lost in 11 cases (78.6%), while the Arg allele was lost in three (21.4%). Our results suggest that p53 codon 72 Arg homozygosity is associated with advanced lung cancer, and that the Arg allele is preferentially retained in patients heterozygous for this polymorphism. On the other hand, human papillomavirus infection does not seem to play an important role in lung carcinogenesis

Cutaneous lesions of the external ear

Skin diseases on the external aspect of the ear are seen in a variety of medical disciplines. Dermatologists, othorhinolaryngologists, general practitioners, general and plastic surgeons are regularly consulted regarding cutaneous lesions on the ear

Systematic review of the effects of the intestinal microbiota on selected nutrients and non-nutrients

The systematic review demonstrates that the IM plays a major role in the breakdown and transformation of the dietary substrates examined. However, recent human data are limited with the exception of data from studies examining fibres and polyphenols. Results observed in relation with dietary substrates were not always consistent or coherent across studies and methodological limitations and differences in IM analyses made comparisons difficult. Moreover, non-digestible components likely to reach the colon are often not well defined or characterised in studies making comparisons between studies difficult if not impossible. Going forward, further rigorously controlled randomised human trials with well-defined dietary substrates and utilizing omic-based technologies to characterise and measure the IM and their functional activities will advance the field. Current evidence suggests that more detailed knowledge of the metabolic activities and interactions of the IM hold considerable promise in relation with host health

A Two-Locus Model of the Evolution of Insecticide Resistance to Inform and Optimise Public Health Insecticide Deployment Strategies

We develop a flexible, two-locus model for the spread of insecticide resistance applicable to mosquito species that transmit human diseases such as malaria. The model allows differential exposure of males and females, allows them to encounter high or low concentrations of insecticide, and allows selection pressures and dominance values to differ depending on the concentration of insecticide encountered. We demonstrate its application by investigating the relative merits of sequential use of insecticides versus their deployment as a mixture to minimise the spread of resistance. We recover previously published results as subsets of this model and conduct a sensitivity analysis over an extensive parameter space to identify what circumstances favour mixtures over sequences. Both strategies lasted more than 500 mosquito generations (or about 40 years) in 24% of runs, while in those runs where resistance had spread to high levels by 500 generations, 56% favoured sequential use and 44% favoured mixtures. Mixtures are favoured when insecticide effectiveness (their ability to kill homozygous susceptible mosquitoes) is high and exposure (the proportion of mosquitoes that encounter the insecticide) is low. If insecticides do not reliably kill homozygous sensitive genotypes, it is likely that sequential deployment will be a more robust strategy. Resistance to an insecticide always spreads slower if that insecticide is used in a mixture although this may be insufficient to outperform sequential use: for example, a mixture may last 5 years while the two insecticides deployed individually may last 3 and 4 years giving an overall ‘lifespan’ of 7 years for sequential use. We emphasise that this paper is primarily about designing and implementing a flexible modelling strategy to investigate the spread of insecticide resistance in vector populations and demonstrate how our model can identify vector control strategies most likely to minimise the spread of insecticide resistance

Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival