Chronic inflammatory diseases are associated with accelerated atherosclerosis and increased risk of cardiovascular diseases (CVD). As the pathogenesis of atherosclerosis is increasingly recognized as ...an inflammatory process, similarities between atherosclerosis and systemic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel diseases, lupus, psoriasis, spondyloarthritis and others have become a topic of interest. Endothelial dysfunction represents a key step in the initiation and maintenance of atherosclerosis and may serve as a marker for future risk of cardiovascular events. Patients with chronic inflammatory diseases manifest endothelial dysfunction, often early in the course of the disease. Therefore, mechanisms linking systemic inflammatory diseases and atherosclerosis may be best understood at the level of the endothelium. Multiple factors, including circulating inflammatory cytokines, TNF-α (tumor necrosis factor-α), reactive oxygen species, oxidized LDL (low density lipoprotein), autoantibodies and traditional risk factors directly and indirectly activate endothelial cells, leading to impaired vascular relaxation, increased leukocyte adhesion, increased endothelial permeability and generation of a pro-thrombotic state. Pharmacologic agents directed against TNF-α-mediated inflammation may decrease the risk of endothelial dysfunction and cardiovascular disease in these patients. Understanding the precise mechanisms driving endothelial dysfunction in patients with systemic inflammatory diseases may help elucidate the pathogenesis of atherosclerosis in the general population.
An extensive analysis of dental plaque samples over the years has led to the identification of “red” complex oral bacteria that have a strong association with each other and with disease. ...Consequently, these bacteria have been labeled ‘periopathogens’. Studies with one of these bacteria, Porphyromonas gingivalis, have revealed that it contains several different mechanisms which either impede or modulate periodontal protective mechanisms. In a mouse model of periodontitis, it has been shown that modulation of complement function by P. gingivalis facilitates a significant change in both the amount and composition of the normal oral microbiotia. This altered oral commensal microbiota is responsible for pathologic bone loss in the mouse. Thus, P. gingivalis creates a dysbiosis between the host and dental plaque, and this may represent one mechanism by which periodontitis can be initiated. We have therefore termed P. gingivalis a keystone pathogen.
The epidemiology of osteoporosis Clynes, Michael A; Harvey, Nicholas C; Curtis, Elizabeth M ...
British medical bulletin,
05/2020, Letnik:
133, Številka:
1
Journal Article
Recenzirano
Odprti dostop
With a worldwide ageing population, the importance of the prevention and management of osteoporotic fragility fractures is increasing over time. In this review, we discuss in detail the epidemiology ...of fragility fractures, how this is shaped by pharmacological interventions and how novel screening programmes can reduce the clinical and economic burden of osteoporotic fractures.
PubMed and Google Scholar were searched using various combinations of the keywords 'osteoporosis', 'epidemiology', 'fracture', 'screening', `FRAX' and 'SCOOP'.
The economic burden of osteoporosis-related fracture is significant, costing approximately $17.9 and £4 billion per annum in the USA and UK.
Risk calculators such as the web-based FRAX® algorithm have enabled assessment of an individual's fracture risk using clinical risk factors, with only partial consideration of bone mineral density (BMD).
As with all new interventions, we await the results of long-term use of osteoporosis screening algorithms and how these can be refined and incorporated into clinical practice.
Despite advances in osteoporosis screening, a minority of men and women at high fracture risk worldwide receive treatment. The economic and societal burden caused by osteoporosis is a clear motivation for improving the screening and management of osteoporosis worldwide.
This study examines how the incentives related to ownership structure influence labor cost management decisions in publicly traded and privately held organizations. I document that public banks have ...more elastic labor cost structures than private banks, which suggests that public bank managers prefer greater flexibility to remove labor resources when desired. Consistent with public banks facing greater financial reporting pressures, I find that they reduce labor costs to avoid earnings declines. However, I also find that the use of labor cost reductions to manage required regulatory capital is more pronounced in private banks. Consistent with the explanation that access to the equity markets allows public firms to sell equity in lieu of cutting costs, I find that the use of labor cost reductions to manage capital requirements is concentrated in the subsample of banks with lower equity issuances. These findings suggest that while public ownership induces financial reporting pressure, it may also alleviate regulatory pressure through greater ability to sell equity.
The enteric pathogen enterohemorrhagic Escherichia coli (EHEC) causes severe diarrhea, but the influence of the gut microbiota on EHEC infection is largely unknown. A predominant member of the ...microbiota, Bacteroides thetaiotaomicron (Bt), is resident at EHEC attachment sites. We show that Bt enhances EHEC virulence gene expression through the transcription factor Cra, which is functionally sensitive to sugar concentrations. This enhanced virulence accompanies increased formation of attaching and effacing (AE) lesions requisite for EHEC colonization. Infection with Citrobacter rodentium, a natural mouse pathogen homologous to EHEC, in Bt-reconstituted mice results in increased gut permeability along with exacerbated host pathology and mortality compared to mice deplete of microflora. Bt modifies the metabolite environment at infection sites, increasing metabolites involved in gluconeogenesis, with stark increases in succinate, which can be sensed by Cra. Our findings suggest that microbiota composition affects disease outcome and may explain links between microbiota composition and disease susceptibility.
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•B. thetaiotaomicron (Bt) enhances EHEC virulence through the Cra transcription factor•Bt regulates EHEC virulence by changing the metabolite landscape within the gut•Bt increases succinate, which can be sensed by Cra to activate virulence genes•C. rodentium disease prognosis and host pathology worsen in the presence of Bt
Host-microbiota interactions influence infection and disease. Curtis et al. demonstrate that the commensal Bacteroides thetaiotaomicron (Bt) enhances virulence gene expression of enterohemorrhagic E. coli and exacerbates Citrobacter rodentium infection. Bt modifies the metabolite environment, increasing metabolites involved in gluconeogenesis, which are sensed through the transcription factor Cra to activate virulence.
The microbiological characteristics of both caries and periodontal disease show significant change from those in health. In both instances, there is evidence of co‐association of different organisms ...into consortia.
Aim
We review and summarize a number of issues pertinent to the community organization and functional activity of the bacterial populations resident on supra‐ and subgingival tooth surface and the influence of these populations on disease.
Methods
A literature review was undertaken with a particular emphasis on recent publications involving high‐throughput, deep sequencing approaches to the analysis of microbial populations and their functional activity.
Results
There is increasing evidence to suggest that both caries and periodontal disease represent dysbiotic states of the oral microbiome. The mode of acquisition of the oral microbial communities may be less passive than previously recognized but once established remains relatively stable within an individual although there are very significant site variations. A repertoire of stable dysbiotic states may occur in both caries and periodontitis involving different microbial community structures with potentially similar functional properties.
Conclusions
The processes which underlie the development and stability of microbial populations in the healthy mouth are fundamental to understanding how these populations are transformed into a dysbiotic state in disease.
Osteoporosis constitutes a major public health problem, through its association with age-related fractures, particularly of the hip, vertebrae, distal forearm and humerus. Substantial geographic ...variation has been noted in the incidence of osteoporotic fractures worldwide, with Western populations (North America, Europe and Oceania), reporting increases in hip fracture throughout the second half of the 20th century, with a stabilisation or decline in the last two decades. In developing populations however, particularly in Asia, the rates of osteoporotic fracture appears to be increasing. The massive global burden consequent to osteoporosis means that fracture risk assessment should be a high priority among health measures considered by policy makers. The WHO operational definition of osteoporosis, based on a measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), has been used globally since the mid-1990s. However, although this definition identifies those at greatest individual risk of fracture, in the population overall a greater total number of fractures occur in individuals with BMD values above the threshold for osteoporosis diagnosis. A number of web-based tools to enable the inclusion of clinical risk factors, with or without BMD, in fracture prediction algorithms have been developed to improve the identification of individuals at high fracture risk, the most commonly used globally being FRAX®. Access to DXA, osteoporosis risk assessment, case finding and treatment varies worldwide, but despite such advances studies indicate that a minority of men and women at high fracture risk receive treatment. Importantly, research is ongoing to demonstrate the clinical efficacy and cost-effectiveness of osteoporosis case finding and risk assessment strategies worldwide. The huge burden caused by osteoporosis related fractures to individuals, healthcare systems and societies should provide a clear impetus for the progression of such approaches.
Circadian Clock Proteins and Immunity Curtis, Anne M.; Bellet, Marina M.; Sassone-Corsi, Paolo ...
Immunity,
02/2014, Letnik:
40, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Immune parameters change with time of day and disruption of circadian rhythms has been linked to inflammatory pathologies. A circadian-clock-controlled immune system might allow an organism to ...anticipate daily changes in activity and feeding and the associated risk of infection or tissue damage to the host. Responses to bacteria have been shown to vary depending on time of infection, with mice being more at risk of sepsis when challenged ahead of their activity phase. Studies highlight the extent to which the molecular clock, most notably the core clock proteins BMAL1, CLOCK, and REV-ERBα, control fundamental aspects of the immune response. Examples include the BMAL1:CLOCK heterodimer regulating toll-like receptor 9 (TLR9) expression and repressing expression of the inflammatory monocyte chemokine ligand (CCL2) as well as REV-ERBα suppressing the induction of interleukin-6. Understanding the daily rhythm of the immune system could have implications for vaccinations and how we manage infectious and inflammatory diseases.
A cell line representative of human high-grade serous ovarian cancer (HGSOC) should not only resemble its tumour of origin at the molecular level, but also demonstrate functional utility in ...pre-clinical investigations. Here, we report the integrated proteomic analysis of 26 ovarian cancer cell lines, HGSOC tumours, immortalized ovarian surface epithelial cells and fallopian tube epithelial cells via a single-run mass spectrometric workflow. The in-depth quantification of >10,000 proteins results in three distinct cell line categories: epithelial (group I), clear cell (group II) and mesenchymal (group III). We identify a 67-protein cell line signature, which separates our entire proteomic data set, as well as a confirmatory publicly available CPTAC/TCGA tumour proteome data set, into a predominantly epithelial and mesenchymal HGSOC tumour cluster. This proteomics-based epithelial/mesenchymal stratification of cell lines and human tumours indicates a possible origin of HGSOC either from the fallopian tube or from the ovarian surface epithelium.
The evolution of volatile compounds was explored in grape berries at fortnightly intervals from fruit-set to late ripening to identify when biosynthetic pathways may be targeted for enhancement of ...grape and wine aroma. Stepwise linear discriminant analysis (SLDA) fully recognized patterns in berry physiological developmental stages with most of the variance (>99.0%) explained. The preveraison berry developmental stage was identified as a transition stage for volatile compound biosynthesis when most compounds were potentially sequestered to nonvolatile conjugates and berries lost their potential to synthesize esters and terpenes. Terpenes (predominantly eucalyptol, β-caryophyllene, and α-humulene) characterized early berry development, whereas benzene derivatives (2-phenylethanol and 2-phenylethanal) appeared toward late ripening. Furthermore, C6 volatile compounds changed from acetate esters to aldehydes and finally to alcohols during early, middle, and late berry developmental stages, respectively. The dominance of alcohols in the late stages of berry development, preceded by aldehydes, offers an opportunity for alcohols to aldehydes ratios to be used in the prediction of harvest timing for enhanced grape and wine aroma. The evolution of volatile compounds during berry development suggests a greater dependency on enzyme activity and specificity than extent of fatty acid unsaturation. The dependence of the stage of berry development on the accumulation of the products of alcohol dehydrogenase (ADH), alcohol acetyl transferase (AAT), and enal isomerase enzyme activity from the lipoxygenase pathway raises possibilities for the manipulation of aroma profiles in grapes and wines.
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