Exceptional Hyperthyroidism and a Role for both Major Histocompatibility Class I and Class II Genes in a Murine Model of Graves' Disease

Autoimmune hyperthyroidism, Graves' disease, can be induced by immunizing susceptible strains of mice with adenovirus encoding the human thyrotropin receptor (TSHR) or its A-subunit. Studies in two small families of recombinant inbred strains showed that susceptibility to developing TSHR antibodies (measured by TSH binding inhibition, TBI) was linked to the MHC region whereas genes on different chromosomes contributed to hyperthyroidism. We have now investigated TSHR antibody production and hyperthyroidism induced by TSHR A-subunit adenovirus immunization of a larger family of strains (26 of the AXB and BXA strains). Analysis of the combined AXB and BXA families provided unexpected insight into several aspects of Graves' disease. First, extreme thyroid hyperplasia and hyperthyroidism in one remarkable strain, BXA13, reflected an inability to generate non-functional TSHR antibodies measured by ELISA. Although neutral TSHR antibodies have been detected in Graves' sera, pathogenic, functional TSHR antibodies in Graves' patients are undetectable by ELISA. Therefore, this strain immunized with A-subunit-adenovirus that generates only functional TSHR antibodies may provide an improved model for studies of induced Graves' disease. Second, our combined analysis of linkage data from this and previous work strengthens the evidence that gene variants in the immunoglobulin heavy chain V region contribute to generating thyroid stimulating antibodies. Third, a broad region that encompasses the MHC region on mouse chomosome 17 is linked to the development of TSHR antibodies (measured by TBI). Most importantly, unlike other strains, TBI linkage in the AXB and BXA families to MHC class I and class II genes provides an explanation for the unresolved class I/class II difference in humans

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Potential immunosuppressive effects of Escherichia coli O157:H7 experimental infection on the bovine host

Background: Enterohaemorrhagic Escherichia coli (EHEC), like E. coli O157:H7 are frequently detected in bovine faecal samples at slaughter. Cattle do not show clinical symptoms upon infection, but for humans the consequences after consuming contaminated beef can be severe. The immune response against EHEC in cattle cannot always clear the infection as persistent colonization and shedding in infected animals over a period of months often occurs. In previous infection trials, we observed a primary immune response after infection which was unable to protect cattle from reinfection. These results may reflect a suppression of certain immune pathways, making cattle more prone to persistent colonization after re-infection. To test this, RNA-Seq was used for transcriptome analysis of recto-anal junction tissue and ileal Peyer's patches in nine Holstein-Friesian calves in response to a primary and secondary Escherichia coli O157: H7 infection with the Shiga toxin (Stx) negative NCTC12900 strain. Non-infected calves served as controls. Results: In tissue of the recto-anal junction, only 15 genes were found to be significantly affected by a first infection compared to 1159 genes in the ileal Peyer's patches. Whereas, re-infection significantly changed the expression of 10 and 17 genes in the recto-anal junction tissue and the Peyer's patches, respectively. A significant downregulation of 69 immunostimulatory genes and a significant upregulation of seven immune suppressing genes was observed. Conclusions: Although the recto-anal junction is a major site of colonization, this area does not seem to be modulated upon infection to the same extent as ileal Peyer's patches as the changes in gene expression were remarkably higher in the ileal Peyer's patches than in the recto-anal junction during a primary but not a secondary infection. We can conclude that the main effect on the transcriptome was immunosuppression by E. coli O157: H7 (Stx(-)) due to an upregulation of immune suppressive effects (7/12 genes) or a downregulation of immunostimulatory effects (69/94 genes) in the ileal Peyer's patches. These data might indicate that a primary infection promotes a re-infection with EHEC by suppressing the immune function

Meditation and cognitive ageing: The role of mindfulness meditation in building cognitive reserve

Mindfulness-related meditation practices engage various cognitive skills including the ability to focus and sustain attention, which in itself requires several interacting attentional sub-functions. There is increasing behavioural and neuroscientific evidence that mindfulness meditation improves these functions and associated neural processes. More so than other cognitive training programmes, the effects of meditation appear to generalise to other cognitive tasks, thus demonstrating far transfer effects. As these attentional functions have been linked to age-related cognitive decline, there is growing interest in the question whether meditation can slow-down or even prevent such decline. The cognitive reserve hypothesis builds on evidence that various lifestyle factors can lead to better cognitive performance in older age than would be predicted by the existing degree of brain pathology. We argue that mindfulness meditation, as a combination of brain network and brain state training, may increase cognitive reserve capacity and may mitigate age-related declines in cognitive functions. We consider available direct and indirect evidence from the perspective of cognitive reserve theory. The limited available evidence suggests that MM may enhance cognitive reserve capacity directly through the repeated activation of attentional functions and of the multiple demand system and indirectly through the improvement of physiological mechanisms associated with stress and immune function. The article concludes with outlining research strategies for addressing underlying empirical questions in more substantial ways

Labour Productivity Measures from the ABS: 1998 to 2009

AbstractThis article compares micro and macro measures of productivity. Detailed industry-level productivity estimates are key to understanding how the aggregate economy is driven by the performance of particular sectors, and also how certain sectors perform relative to others. A detailed focus is all the more important in the aftermath of the UK's deepest recession since the 1930s. This article aims to aid the analysis of the economy over the recession and comment on which specific industries saw the biggest changes. The article updates the work of Long (2010) by adding two additional years of data from the Annual Business Survey (ABS), 2008 and 2009.

Influence of anatomical location on CT numbers in cone beam computed tomography

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Objective. To assess the influence of anatomical location on computed tomography (CT) numbers in mid and full field of view (FOV) cone beam computed tomography (CBCT) scans. Study Design. Polypropylene tubes with varying concentrations of dipotassium hydrogen phosphate (K2HPO4) solutions (50 1200 mg/mL) were imaged within the incisor, premolar, and molar dental sockets of a human skull phantom. CBCT scans were acquired using the NewTom 3G and NewTom 5G units. The CT numbers of the K2HPO4 phantoms were measured, and the relationship between CT numbers and K2HPO4 concentration was examined. The measured CT numbers of the K2HPO4 phantoms were compared between anatomical sites. Results. At all six anatomical locations, there was a strong linear relationship between CT numbers and K2HPO4 concentration (R-2 > 0.93). However, the absolute CT numbers varied considerably with the anatomical location. Conclusion. The relationship between CT numbers and object density is not uniform through the dental arch on CBCT scans. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:558 564)1154558564Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CNPq [201237/2010 5