Autoimmunity can result from the interplay between genetic background and effects of environmental and/or occupational exposure to hazardous materials. Several compounds, including silica dust, have ...been linked with systemic autoimmunity and systemic autoimmune diseases, based on epidemiological evidence. For asbestos, a strong link with systemic autoimmune diseases does not yet exist, however, several studies have documented features of autoimmunity following asbestos exposure. Even so, human studies are limited in their ability to identify and examine isolated exposures, making it difficult to demonstrate causation or to assess pathogenic mechanisms. Therefore, this systematic review examines the existing animal evidence regarding autoimmunity and exposure to silicates (silica and asbestos).
PubMed and EMBASE were systematically searched for peer-reviewed studies examining systemic autoimmune disease-related outcomes after silicate exposure in rodents. Literature databases were searched up to September 2021 for studies written in English and where the full text was available. Search strings were established based on a PECO (Population, Exposure, Comparator, Outcome) format. After title, abstract, and full-text screening, thirty-four studies were identified for further analysis. Quality assessment through ToxR tool and qualitative analysis of the results was performed.
Although there was significant heterogeneity in the included studies in terms of exposure protocol and genetic background of the rodent models used, it was noted that both genetic background and exposure to silicates (crystalline) silica and asbestos are highly relevant to the development of (sub-) clinical systemic autoimmune disease.
Parallels were observed between the findings from the animal (this review) and human (epidemiological) studies, arguing that experimental animal models are valuable tools for examining exacerbation or development of autoimmune disease after silicate exposure. However, genetic background and synergism between exposures should be considered in future studies.
Background Sensitization to food antigen can occur through cutaneous exposure. Objective We sought to test the hypothesis that epicutaneous sensitization with food antigen predisposes to IgE-mediated ...anaphylaxis on oral allergen challenge. Methods BALB/c mice were epicutaneously sensitized by repeated application of ovalbumin (OVA) to tape-stripped skin over 7 weeks or orally immunized with OVA and cholera toxin (CT) weekly for 8 weeks and then orally challenged with OVA. Body temperature was monitored, and serum mouse mast cell protease 1 levels were determined after challenge. Tissue mast cell (MC) counts were examined by using chloroacetate esterase staining. Levels of serum OVA-specific IgE and IgG1 antibodies and cytokines in supernatants of OVA-stimulated splenocytes were measured by means of ELISA. Serum IL-4 levels were measured by using an in vivo cytokine capture assay. Results Epicutaneously sensitized mice exhibited expansion of connective tissue MCs in the jejunum, increased serum IL-4 levels, and systemic anaphylaxis after oral challenge, as evidenced by decreased body temperature and increased serum mouse mast cell protease 1 levels. Intestinal MC expansion and anaphylaxis were IgE dependent because they did not occur in epicutaneously sensitized IgE−/− mice. Mice orally immunized with OVA plus CT did not have increased serum IL-4 levels, expanded intestinal MCs, or anaphylaxis after oral challenge, despite OVA-specific IgE levels and splenocyte cytokine production in response to OVA stimulation, which were comparable with those of epicutaneously sensitized mice. Conclusion Epicutaneously sensitized mice, but not mice orally immunized with antigen plus CT, have expansion of intestinal MCs and IgE-mediated anaphylaxis after single oral antigen challenge. IgE is necessary but not sufficient for food anaphylaxis, and MC expansion in the gut can play an important role in the development of anaphylaxis.
Here we have identified 'triple D' (3d), a recessive N-ethyl-N-nitrosourea-induced mutation and phenotype in which no signaling occurs via the intracellular Toll-like receptors 3, 7 and 9 (sensors ...for double-stranded RNA, single-stranded RNA and unmethylated DNA, respectively). The 3d mutation also prevented cross-presentation and diminished major histocompatibility complex class II presentation of exogenous antigen; it also caused hypersusceptibility to infection by mouse cytomegalovirus and other microbes. By positional identification, we found 3d to be a missense allele of Unc93b1, which encodes the 12-membrane-spanning protein UNC-93B, a highly conserved molecule found in the endoplasmic reticulum with multiple paralogs in mammals. Innate responses to nucleic acids and exogenous antigen presentation, which both initiate in endosomes, thus seem to depend on an endoplasmic reticulum-resident protein, which suggests communication between these organellar systems.
Patients diagnosed with locally advanced esophageal cancer are often treated with neoadjuvant chemoradiotherapy followed by surgery. This study explored whether detection of circulating tumor DNA ...(ctDNA) in plasma can be used to predict residual disease during treatment. Diagnostic tissue biopsies from patients with esophageal cancer receiving neoadjuvant chemoradiotherapy and surgery were analyzed for tumor-specific mutations. These tumor-informed mutations were used to measure the presence of ctDNA in serially collected plasma samples using hybrid capture-based sequencing. Plasma samples were obtained before chemoradiotherapy, and prior to surgery. The association between ctDNA detection and progression-free and overall survival was measured. Before chemoradiotherapy, ctDNA was detected in 56% (44/78) of patients and detection was associated with tumor stage and volume (p = 0.05, Fisher exact and p = 0.02, Mann-Whitney, respectively). After chemoradiotherapy, ctDNA was detected in 10% (8/78) of patients. This preoperative detection of ctDNA was independently associated with recurrent disease (hazard ratio 2.8, 95% confidence interval 1.1–6.8, p = 0.03, multivariable Cox-regression) and worse overall survival (hazard ratio 2.9, 95% confidence interval 1.2–7.1, p = 0.02, multivariable Cox-regression).Ultradeep sequencing-based detection of ctDNA in preoperative plasma of patients with locally advanced esophageal cancer may help to assess which patients have a high risk of recurrence after neoadjuvant chemoradiotherapy and surgery.
Estimation of HIV Incidence in the United States Hall, H. Irene; Song, Ruiguang; Rhodes, Philip ...
JAMA : the journal of the American Medical Association,
08/2008, Letnik:
300, Številka:
5
Journal Article
Recenzirano
Odprti dostop
CONTEXT Incidence of human immunodeficiency virus (HIV) in the United States has not been directly measured. New assays that differentiate recent vs long-standing HIV infections allow improved ...estimation of HIV incidence. OBJECTIVE To estimate HIV incidence in the United States. DESIGN, SETTING, AND PATIENTS Remnant diagnostic serum specimens from patients 13 years or older and newly diagnosed with HIV during 2006 in 22 states were tested with the BED HIV-1 capture enzyme immunoassay to classify infections as recent or long-standing. Information on HIV cases was reported to the Centers for Disease Control and Prevention through June 2007. Incidence of HIV in the 22 states during 2006 was estimated using a statistical approach with adjustment for testing frequency and extrapolated to the United States. Results were corroborated with back-calculation of HIV incidence for 1977-2006 based on HIV diagnoses from 40 states and AIDS incidence from 50 states and the District of Columbia. MAIN OUTCOME MEASURE Estimated HIV incidence. RESULTS An estimated 39 400 persons were diagnosed with HIV in 2006 in the 22 states. Of 6864 diagnostic specimens tested using the BED assay, 2133 (31%) were classified as recent infections. Based on extrapolations from these data, the estimated number of new infections for the United States in 2006 was 56 300 (95% confidence interval CI, 48 200-64 500); the estimated incidence rate was 22.8 per 100 000 population (95% CI, 19.5-26.1). Forty-five percent of infections were among black individuals and 53% among men who have sex with men. The back-calculation (n = 1.230 million HIV/AIDS cases reported by the end of 2006) yielded an estimate of 55 400 (95% CI, 50 000-60 800) new infections per year for 2003-2006 and indicated that HIV incidence increased in the mid-1990s, then slightly declined after 1999 and has been stable thereafter. CONCLUSIONS This study provides the first direct estimates of HIV incidence in the United States using laboratory technologies previously implemented only in clinic-based settings. New HIV infections in the United States remain concentrated among men who have sex with men and among black individuals.
This study assessed the effectiveness of a school‐based intervention in reducing adolescents’ sugar‐sweetened beverage (SSB) consumption and percentage of energy from SSBs. Secondary outcomes were ...SSB consumption within school, average daily energy intake, and body mass index z‐scores.
Six secondary schools located in New South Wales, Australia were recruited to participate in a six‐month pilot randomised controlled trial (1:1). The intervention included components targeting the school nutrition environment, curricula and community. Outcomes were collected via online surveys, observations, anthropometric measurements and project records. Between‐group differences were assessed via linear mixed models.
At the six‐month intervention endpoint (n=862) there were no statistically significant differences between students in intervention or control schools for mean daily intake of SSBs (8.55mL; CI −26.77, 43.87; p=0.63), percentage daily energy from SSBs (0.12% kJ; CI −0.55, 0.80; p=0.72), or for secondary outcomes. Acceptability of the school‐based strategies were high, however intervention fidelity varied across schools.
While acceptable, improving fidelity of implementation and increasing the duration or intensity of the intervention may be required to reduce SSB intake.
Engaging parents and education stakeholders in the development phase to co‐design interventions may prove beneficial in improving intervention fidelity and enhance behavioural outcomes.
Internationally, governments have implemented school-based nutrition policies to restrict the availability of unhealthy foods from sale. The aim of the trial was to assess the effectiveness of a ...multi-strategic intervention to increase implementation of a state-wide healthy canteen policy. The impact of the intervention on the energy, total fat, and sodium of children's canteen purchases and on schools' canteen revenue was also assessed.
Australian primary schools with a canteen were randomised to receive a 12-14-month, multi-strategic intervention or to a no intervention control group. The intervention sought to increase implementation of a state-wide healthy canteen policy which required schools to remove unhealthy items (classified as 'red' or 'banned') from regular sale and encouraged schools to 'fill the menu' with healthy items (classified as 'green'). The intervention strategies included allocation of a support officer to assist with policy implementation, engagement of school principals and parent committees, consensus processes with canteen managers, training, provision of tools and resources, academic detailing, performance feedback, recognition and marketing initiatives. Data were collected at baseline (April to September, 2013) and at completion of the implementation period (November, 2014 to April, 2015).
Seventy schools participated in the trial. Relative to control, at follow-up, intervention schools were significantly more likely to have menus without 'red' or 'banned' items (RR = 21.11; 95% CI 3.30 to 147.28; p ≤ 0.01) and to have at least 50% of menu items classified as 'green' (RR = 3.06; 95% CI 1.64 to 5.68; p ≤ 0.01). At follow-up, student purchases from intervention school canteens were significantly lower in total fat (difference = -1.51 g; 95% CI -2.84 to -0.18; p = 0.028) compared to controls, but not in energy (difference = -132.32 kJ; 95% CI -280.99 to 16.34; p = 0.080) or sodium (difference = -46.81 mg; 95% CI -96.97 to 3.35; p = 0.067). Canteen revenue did not differ significantly between groups.
Poor implementation of evidence-based school nutrition policies is a problem experienced by governments internationally, and one with significant implications for public health. The study makes an important contribution to the limited experimental evidence regarding strategies to improve implementation of school nutrition policies and suggests that, with multi-strategic support, implementation of healthy canteen policies can be achieved in most schools.
Australian New Zealand Clinical Trials Registry ( ACTRN12613000311752 ).
Rationale
: Asthma is characterized by increases in airway resistance, pulmonary remodeling, and lung inflammation. The cytokine transforming growth factor (TGF)-β has been shown to have a central ...role in asthma pathogenesis and in mouse models of allergic airway disease.
Objectives
: To determine the contribution of TGF-β to airway hyperresponsiveness (AHR), we examined the time course, source, and isoform specificity of TGF-β production in an
in vivo
mouse asthma model. To then elucidate the function of TGF-β in AHR, inflammation, and pulmonary fibrosis, we examined the effects of blocking TGF-β signaling with neutralizing antibody.
Methods
: Mice were sensitized and challenged with ovalbumin (OVA) to establish allergic airway disease. TGF-β activity was neutralized by intranasal administration of monoclonal antibody.
Measurements and Main Results
: TGF-β1 protein levels were increased in OVA-challenged lungs versus naive controls, and airway epithelial cells were shown to be a likely source of TGF-β1. In addition, TGF-β1 levels were elevated in OVA-exposed IL-5–null mice, which fail to recruit eosinophils into the airways. Neutralization of TGF-β1 with specific antibody had no significant effect on airway inflammation and eosinophilia, although anti–TGF-β1 antibody enhanced OVA-induced AHR and suppressed pulmonary fibrosis.
Conclusions
: These data show that TGF-β1 is the main TGF-β isoform produced after OVA challenge, with a likely cellular source being the airway epithelium. The effects of blocking TGF-β1 signaling had differential effects on AHR, fibrosis, and inflammation. While TGF-β neutralization may be beneficial to abrogating airway remodeling, it may be detrimental to lung function by increasing AHR.
Inhalation of airborne particulate matter, such as silica and diesel exhaust particles, poses serious long-term respiratory and systemic health risks. Silica exposure can lead to silicosis and ...systemic autoimmune diseases, while DEP exposure is linked to asthma and cancer. Combined exposure to silica and DEP, common in mining, may have more severe effects. This study investigates the separate and combined effects of occupational-level silica and ambient-level DEP on lung injury, inflammation, and autoantibody formation in two genetically distinct mouse strains, thereby aiming at understanding the interplay between genetic susceptibility, particulate exposure, and disease outcomes. Silica and diesel exhaust particles were administered to mice via oropharyngeal aspiration. Assessments of lung injury and host response included in vivo lung micro-computed tomography, lung function tests, bronchoalveolar lavage fluid analysis including inflammatory cytokines and antinuclear antibodies, and histopathology with particle colocalization.
The findings highlight the distinct effects of silica and diesel exhaust particles (DEP) on lung injury, inflammation, and autoantibody formation in C57BL/6J and NOD/ShiLtJ mice. Silica exposure elicited a well-established inflammatory response marked by inflammatory infiltrates, release of cytokines, and chemokines, alongside mild fibrosis, indicated by collagen deposition in the lungs of both C57BL/6J and NOD/ShilLtJ mice. Notably, these strains exhibited divergent responses in terms of respiratory function and lung volumes, as assessed through micro-computed tomography. Additionally, silica exposure induced airway hyperreactivity and elevated antinuclear antibody levels in bronchoalveolar lavage fluid, particularly prominent in NOD/ShiLtJ mice. Moreover, antinuclear antibodies correlated with extent of lung inflammation in NOD/ShiLTJ mice. Lung tissue analysis revealed DEP loaded macrophages and co-localization of silica and DEP particles. However, aside from contributing to airway hyperreactivity specifically in NOD/ShiLtJ mice, the ambient-level DEP did not significantly amplify the effects induced by silica. There was no evidence of synergistic or additive interaction between these specific doses of silica and DEP in inducing lung damage or inflammation in either of the mouse strains.
Mouse strain variations exerted a substantial influence on the development of silica induced lung alterations. Furthermore, the additional impact of ambient-level DEP on these silica-induced effects was minimal.
Issue addressed: School-based nutrition policies can have a positive effect on the school food environment. The primary aim of this study was to assess the primary school adherence to a mandatory ...state-wide healthy canteen policy 12 months after an effective multi-strategic implementation intervention concluded.
Methods: Primary schools were randomised to (a) a 12-14 months multi-strategic intervention or (b) no-intervention (control). The intervention aimed to improve implementation of a state-wide canteen policy by encouraging schools to remove unhealthy food and beverages (classified as ''red'' or ''banned'') from canteen menus and replace with healthy items (classified as ''green''). No implementation support was provided to either group by the research team between the 12 and 24 months data collection period.
Results: Seventy schools participated, of which 56 schools were assessed at 24-month follow-up. Intervention schools were less likely to have a menu which contained ''red/banned'' items at 24-month follow-up (RR = 2.28; 95% CI: 1.18-4.40; P = 0.01). Intervention schools, however, were not more likely than controls to have a menu which contained >50% ''green'' items at 24-month follow-up (RR = 1.29; 95% CI: 0.98-1.70; P = 0.10). Intervention schools were more likely to adhere to both policy components (no red/banned items and >50% green items on the menu) than control schools (RR = 2.61; 95% CI: 1.29-5.29; P = 0.006). Among intervention schools that were fully adherent to the policy following implementation support (12-month post baseline), all were also adherent at the 24-month follow-up.
Conclusion: The intervention was effective in achieving long-term school adherence to a state-wide canteen policy at 24-month follow-up.
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