Clinicopathologic and Molecular Characterization of Anorectal Neuroendocrine Carcinomas Reveals Human Papillomavirus, p53, and c-Myc as Alternative Mechanisms of Carcinogenesis.

Poorly differentiated neuroendocrine carcinomas (NECs) are rare malignant neoplasms with aggressive behavior. The diagnosis remains challenging due to ever-changing terminologies and morphologic overlaps with other disease entities. Herein, we seek to better define anorectal NECs by high-risk human papillomavirus (HPV) status and molecular profiling. Fourteen cases, including 3 men and 11 women with a median age of 63 years, were included. High-risk HPV RNA in situ hybridization was diffusely positive (+) in 7 cases, focal rarely positive (+/-) in 2 cases, and completely negative (-) in 5 cases. By morphology, all HPV(-) NECs were large-cell type, 3 mixed with a tubular adenoma/dysplasia or invasive adenocarcinoma. HPV-related (+ or +/-) NECs were mostly small-cell type, 3 mixed with squamous dysplasia and/or squamous cell carcinoma. Immunohistochemically, all NECs were positive for at least 2 neuroendocrine markers. The HPV(-) NECs were also positive for CDX2, whereas all HPV-related NECs were negative or only focally positive for CDX2, p40, and p63. Overexpression of p53 was found in 3 HPV(-) and 2 HPV(+/-) NECs but not in any HPV(+) NECs. Molecular analysis revealed MYC gene amplification in 4 cases: 2 HPV(-), 1 HPV(+/-), and 1 HPV(+). This was confirmed by fluorescence in situ hybridization in all but 1 HPV(-) NEC, which showed polysomy 8 but no true MYC amplification. Interestingly, only 2 of the 4 MYC amplification-bearing cases, both p53 normal/wild-type, expressed c-Myc protein by immunohistochemistry. The other 2 cases, both p53 overexpressed, did not show c-Myc expression despite true MYC amplification. Our study demonstrates that anorectal NECs arise in HPV-dependent or -independent pathways, with heterogeneous expression of other lineage markers and different molecular signatures. Expressions of p53 and c-Myc proteins appear to be mutually exclusive regardless of HPV status, likely mediating alternative mechanisms of NEC carcinogenesis.

Transfer Learning Approach to Vascular Permeability Changes in Brain Metastasis Post-Whole-Brain Radiotherapy.

The purpose of this study is to further validate the utility of our previously developed CNN in an alternative small animal model of BM through transfer learning. Unlike the glioma model, the BM mouse model develops multifocal intracranial metastases, including both contrast enhancing and non-enhancing lesions on DCE MRI, thus serving as an excellent brain tumor model to study tumor vascular permeability. Here, we conducted transfer learning by transferring the previously trained GBM CNN to DCE MRI datasets of BM mice. The CNN was re-trained to learn about the relationship between BM DCE images and target permeability maps extracted from the Extended Tofts Model (ETM). The transferred network was found to accurately predict BM permeability and presented with excellent spatial correlation with the target ETM PK maps. The CNN model was further tested in another cohort of BM mice treated with WBRT to assess vascular permeability changes induced via radiotherapy. The CNN detected significantly increased permeability parameter Ktrans in WBRT-treated tumors (p < 0.01), which was in good agreement with the target ETM PK maps. In conclusion, the proposed CNN can serve as an efficient and accurate tool for characterizing vascular permeability and treatment responses in small animal brain tumor models.

Aerosolized immunotherapeutic nanoparticle inhalation potentiates PD-L1 blockade for locally advanced lung cancer.

Despite therapeutic advancements, the prognosis of locally advanced non-small cell lung cancer (LANSCLC), which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes, remains poor. The emergence of immunotherapy with immune checkpoint blockade (ICB) is transforming cancer treatment. However, only a fraction of lung cancer patients benefit from ICB. Significant clinical evidence suggests that the proinflammatory tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression correlate positively with response to the PD-1/PD-L1 blockade. We report here a liposomal nanoparticle loaded with cyclic dinucleotide and aerosolized (AeroNP-CDN) for inhalation delivery to deep-seated lung tumors and target CDN to activate stimulators of interferon (IFN) genes in macrophages and dendritic cells (DCs). Using a mouse model that recapitulates the clinical LANSCLC, we show that AeroNP-CDN efficiently mitigates the immunosuppressive TME by reprogramming tumor-associated macrophage from the M2 to M1 phenotype, activating DCs for effective tumor antigen presentation and increasing tumor-infiltrating CD8+ T cells for adaptive anticancer immunity. Intriguingly, activation of interferons by AeroNP-CDN also led to increased PD-L1 expression in lung tumors, which, however, set a stage for response to anti-PD-L1 treatment. Indeed, anti-PD-L1 antibody-mediated blockade of IFNs-induced immune inhibitory PD-1/PD-L1 signaling further prolonged the survival of the LANSCLC-bearing mice. Importantly, AeroNP-CDN alone or combination immunotherapy was safe without local or systemic immunotoxicity. In conclusion, this study demonstrates a potential nano-immunotherapy strategy for LANSCLC, and mechanistic insights into the evolution of adaptive immune resistance provide a rational combination immunotherapy to overcome it.

The impact of the COVID-19 pandemic on antibiotic consumption and prevalence of pathogens in primary and secondary healthcare settings in Northern Ireland.

AIM: To evaluate the impact of the COVID-19 pandemic on the patterns of antimicrobial use and the incidence of pathogens in primary and secondary healthcare settings in Northern Ireland. METHODS: Data were collected on antibiotic use and Gram-positive and Gram-negative pathogens from primary and secondary healthcare settings in Northern Ireland for the period before (January 2015-March 2020) and during (April 2020-December 2021) the pandemic. Time series intervention analysis methods were utilized. RESULTS: In the hospital setting, the mean total hospital antibiotic consumption during the pandemic was 1864.5 defined daily doses (DDDs) per 1000 occupied-bed days (OBD), showing no significant change from pre-pandemic (P = .7365). During the pandemic, the use of second-generation cephalosporins, third-generation cephalosporins, co-amoxiclav and levofloxacin increased, there was a decrease in the percentage use of the hospital Access group (P = .0083) and an increase in the percentage use of Watch group (P = .0040), and the number of hospital Klebsiella oxytoca and methicillin-susceptible Staphylococcus aureus cases increased. In primary care, the mean total antibiotic consumption during the COVID-19 pandemic was 20.53 DDDs per 1000 inhabitants per day (DID), compared to 25.56 DID before the COVID-19 pandemic (P = .0071). During the pandemic, there was a decrease in the use of several antibiotic classes, an increase in the percentage use of the Reserve group (P = .0032) and an increase in the number of community-onset Pseudomonas aeruginosa cases. CONCLUSION: This study provides details of both changes in antibiotic consumption and the prevalence of infections in hospitals and primary care before and during the COVID-19 pandemic that emphasize the importance of antimicrobial stewardship in pandemic situations.

Dietary inclusion of nitrite-containing frankfurter exacerbates colorectal cancer pathology and alters metabolism in APCmin mice.

Colorectal cancer (CRC) is the second most prevelant malignancy in Europe and diet is an important modifiable risk factor. Processed meat consumption, including meats with preservative salts such as sodium nitrite, have been implicated in CRC pathogenesis. This study investigated how the CRC pathology and metabolic status of adenomatous polyposis coli (APC) multiple intestinal neoplasia (min) mice was perturbed following 8 weeks of pork meat consumption. Dietary inclusions (15%) of either nitrite-free pork, nitrite-free sausage, or nitrite-containing sausage (frankfurter) were compared against a parallel control group (100% chow). Comprehensive studies investigated: gastrointestinal tract histology (tumours), aberrant crypt foci (ACF), mucin deplin foci (MDF), lipid peroxidation (urine and serum), faecal microbiota, and serum metabolomics (599 metabolites). After 8 weeks mice consuming the frankfurter diet had 53% more (P = 0.014) gastrointestinal tumours than control, although ACF and MDF did not differ. Urine and serum lipid peroxidation markers were 59% (P = 0.001) and 108% (P = 0.001) higher, respectively in the frankfurter group. Gut dysbiosis was evident in these mice with comparably fewer Bacteriodes and more Firmicutes. Fasting serum levels of trimethylamine N-oxide (TMAO) and numerous triglycerides were elevated. Various serum phosphotidylcholine species were decreased. These results demonstrate that nitrite-containing sausages may exaccerbate the development of CRC pathology in APCMin mice to a greater extent than nitrite-free sausages, and this is associated with greater lipid peroxidation, wide-ranging metabolic alternation and gut dysbiosis.

Community transmission of monkeypox in the United Kingdom, April to May 2022.

Between 7 and 25 May, 86 monkeypox cases were confirmed in the United Kingdom (UK). Only one case is known to have travelled to a monkeypox virus (MPXV) endemic country. Seventy-nine cases with information were male and 66 reported being gay, bisexual, or other men who have sex with men. This is the first reported sustained MPXV transmission in the UK, with human-to-human transmission through close contacts, including in sexual networks. Improving case ascertainment and onward-transmission preventive measures are ongoing.

Effectiveness of a co-designed technology package on perceptions of safety in community-dwelling older adults.

OBJECTIVES: Increasing numbers of older people are living longer, often alone, in their own homes. Services and products that enable older people to remain safely in their own homes are required. The My Smart Home project recruited 30 community-dwelling people aged 65+ to co-design a package of technology to address their individual goals for safety and security at home. The technology package, up to the value of $4000, included installation of health monitoring, communication and entertainment devices, and security alarms, with 6 hours of technology coaching. METHODS: Participants completed the Personal Wellbeing Index (PWI), the Australian Quality of Life-8 Dimensions (AQoL-8D) and the Canadian Occupational Performance Measure (COPM) at baseline, and after 4 weeks' use of the technology package. Semi-structured interviews were also used to qualitatively understand the challenges, enablers and outcomes of the project with respect to safety and security in the home. RESULTS: Significant improvements in PWI (p < 0.01), AQoL-8D (p < 0.001) and COPM for goal performance (p < 0.001) and goal satisfaction (p < 0.001) were reported. Participants also reported feeling safer and more secure in their own homes. Common barriers to adoption of technology, cost, integration with already-owned technology and lack of confidence were overcome with this technology and coaching package. CONCLUSIONS: An individualised package of technology, with coaching, that supports older people to realise their personal goals with technology resulted in improved well-being, quality of life and sense of safety and security in community-dwelling older people. Ultimately, this should support a longer and better quality of life at home.

Deep learning quantification of vascular pharmacokinetic parameters in mouse brain tumor models.

BACKGROUND: Dynamic contrast-enhanced (DCE) MRI is widely used to assess vascular perfusion and permeability in cancer. In small animal applications, conventional modeling of pharmacokinetic (PK) parameters from DCE MRI images is complex and time consuming. This study is aimed at developing a deep learning approach to fully automate the generation of kinetic parameter maps, Ktrans (volume transfer coefficient) and Vp (blood plasma volume ratio), as a potential surrogate to conventional PK modeling in mouse brain tumor models based on DCE MRI. METHODS: Using a 7T MRI, DCE MRI was conducted in U87 glioma xenografts growing orthotopically in nude mice. Vascular permeability Ktrans and Vp maps were generated using the classical Tofts model as well as the extended-Tofts model. These vascular permeability maps were then processed as target images to a twenty-four layer convolutional neural network (CNN). The CNN was trained on T1-weighted DCE images as source images and designed with parallel dual pathways to capture multiscale features. Furthermore, we performed a transfer study of this glioma trained CNN on a breast cancer brain metastasis (BCBM) mouse model to assess the potential of the network for alternative brain tumors. RESULTS: Our data showed a good match for both Ktrans and Vp maps generated between the target PK parameter maps and the respective CNN maps for gliomas. Pixel-by-pixel analysis revealed intratumoral heterogeneous permeability, which was consistent between the CNN and PK models. The utility of the deep learning approach was further demonstrated in the transfer study of BCBM. CONCLUSIONS: Because of its rapid and accurate estimation of vascular PK parameters directly from the DCE dynamic images without complex mathematical modeling, the deep learning approach can serve as an efficient tool to assess tumor vascular permeability to facilitate small animal brain tumor research.

Intrapleural nano-immunotherapy promotes innate and adaptive immune responses to enhance anti-PD-L1 therapy for malignant pleural effusion.

Malignant pleural effusion (MPE) is indicative of terminal malignancy with a uniformly fatal prognosis. Often, two distinct compartments of tumour microenvironment, the effusion and disseminated pleural tumours, co-exist in the pleural cavity, presenting a major challenge for therapeutic interventions and drug delivery. Clinical evidence suggests that MPE comprises abundant tumour-associated myeloid cells with the tumour-promoting phenotype, impairing antitumour immunity. Here we developed a liposomal nanoparticle loaded with cyclic dinucleotide (LNP-CDN) for targeted activation of stimulators of interferon genes signalling in macrophages and dendritic cells and showed that, on intrapleural administration, they induce drastic changes in the transcriptional landscape in MPE, mitigating the immune cold MPE in both effusion and pleural tumours. Moreover, combination immunotherapy with blockade of programmed death ligand 1 potently reduced MPE volume and inhibited tumour growth not only in the pleural cavity but also in the lung parenchyma, conferring significantly prolonged survival of MPE-bearing mice. Furthermore, the LNP-CDN-induced immunological effects were also observed with clinical MPE samples, suggesting the potential of intrapleural LNP-CDN for clinical MPE immunotherapy.

Cook Like A Boss: An effective co-created multidisciplinary approach to improving children's cooking competence.

Cooking interventions are emphasised as promising methods for changing children's food-related preferences, attitudes and behaviours. However, criticisms remain, including relatively weak intervention designs; lack of validated tools, and limited underpinning theory. Therefore, this research aimed to assess the effectiveness of a theory-driven co-created children's cooking intervention with underpinning rationale for the content, using a validated measure. 'Cook Like A Boss' was a one week, controlled cooking camp style intervention. Thirty two children aged 10-12 years participated. The intervention was developed using the Cook-Ed model for planning, implementing and evaluating cooking programs and was underpinned by Social Learning theory and Experiential Learning theory. The intervention content was developed in a co-creation process with the research team, a chef and the children. The underlying developmental skills required for the recipes were assessed to ensure they were age-appropriate. Children completed pre and post measurements including perceived cooking competence. Process evaluations were also gathered. There was a significant increase in perceived cooking competence after the intervention (P < 0.05) and a significant difference between the intervention and control group (P < 0.001). Additionally, process evaluations found the intervention to have high fidelity and dose received and that it was received extremely positively. The 'Cook Like A Boss' children's cooking camp was an effective multidisciplinary co-created intervention with a vulnerable group, e.g. children, guided by a model and underpinned by theory. The content was developed to ensure it was age-appropriate and achievable for the children. This approach could act as a template for future children's cooking interventions.

Evaluating the Residual Nitrite Concentrations of Bacon in the United Kingdom.

The preservative sodium nitrite is added to processed meat with the intention of preventing the growth of Clostridium botulinum, but this also influences product flavour and colour. The World Health Organisation has declared nitrites to be 'probably carcinogenic'. Use is permitted by the European Union but its addition is limited to 100 mg/kg in all processed meat, except bacon, which is limited to 175 mg/kg. At present, there is no independent peer-reviewed literature assessing the residual nitrite levels in bacon in the United Kingdom. Furthermore, this is the largest study of residual nitrite concentrations in bacon that has ever been conducted. A total of 89 different commercially available bacon samples were collected, and analysed using flow injection analysis to determine their residual nitrite content. The mean residual nitrite concentration for all bacon samples was 10.80 mg/kg. Residual nitrite levels did not differ between smoked and unsmoked bacon. Middle cut bacon (26.00 mg/kg) had significantly higher residual nitrite concentrations than back bacon (8.87 mg/kg; p = 0.027), and medallion bacon (4.47 mg/kg; p = 0.008). This study shows that there is large variation in the mean residual nitrite levels of bacon sold in the UK and all the reported values are within current regulatory limits. Despite this, it appears that many manufacturers could decrease the amount that they are currently using in their products.

An inhalable nanoparticulate STING agonist synergizes with radiotherapy to confer long-term control of lung metastases.

Mounting evidence suggests that the tumor microenvironment is profoundly immunosuppressive. Thus, mitigating tumor immunosuppression is crucial for inducing sustained antitumor immunity. Whereas previous studies involved intratumoral injection, we report here an inhalable nanoparticle-immunotherapy system targeting pulmonary antigen presenting cells (APCs) to enhance anticancer immunity against lung metastases. Inhalation of phosphatidylserine coated liposome loaded with STING agonist cyclic guanosine monophosphate-adenosine monophosphate (NP-cGAMP) in mouse models of lung metastases enables rapid distribution of NP-cGAMP to both lungs and subsequent uptake by APCs without causing immunopathology. NP-cGAMP designed for enhanced cytosolic release of cGAMP stimulates STING signaling and type I interferons production in APCs, resulting in the pro-inflammatory tumor microenvironment in multifocal lung metastases. Furthermore, fractionated radiation delivered to one tumor-bearing lung synergizes with inhaled NP-cGAMP, eliciting systemic anticancer immunity, controlling metastases in both lungs, and conferring long-term survival in mice with lung metastases and with repeated tumor challenge.

A Review of the In Vivo Evidence Investigating the Role of Nitrite Exposure from Processed Meat Consumption in the Development of Colorectal Cancer.

The World Cancer Research Fund (WCRF) 2007 stated that the consumption of processed meat is a convincing cause of colorectal cancer (CRC), and therefore, the public should avoid it entirely. Sodium nitrite has emerged as a putative candidate responsible for the CRC-inducing effects of processed meats. Sodium nitrite is purported to prevent the growth of Clostridium botulinum and other food-spoiling bacteria, but recent, contradictory peer-reviewed evidence has emerged, leading to media reports questioning the necessity of nitrite addition. To date, eleven preclinical studies have investigated the effect of consuming nitrite/nitrite-containing meat on the development of CRC, but the results do not provide an overall consensus. A sizable number of human clinical studies have investigated the relationship between processed meat consumption and CRC risk with widely varying results. The unique approach of the present literature review was to include analysis that limited the human studies to those involving only nitrite-containing meat. The majority of these studies reported that nitrite-containing processed meat was associated with increased CRC risk. Nitrite consumption can lead to the formation of N-nitroso compounds (NOC), some of which are carcinogenic. Therefore, this focused perspective based on the current body of evidence links the consumption of meat containing nitrites and CRC risk.

MRI evaluation of the effects of whole brain radiotherapy on breast cancer brain metastasis.

PURPOSE: To assess early changes in brain metastasis in response to whole brain radiotherapy (WBRT) by longitudinal Magnetic Resonance Imaging (MRI). MATERIALS AND METHODS: Using a 7T system, MRI examinations of brain metastases in a breast cancer MDA-MD231-Br mouse model were conducted before and 24 hours after 3 daily fractionations of 4 Gy WBRT. Besides anatomic MRI, diffusion-weighted (DW) MRI and dynamic contrast-enhanced (DCE) MRI were applied to study cytotoxic effect and blood-tumor-barrier (BTB) permeability change, respectively. RESULTS: Before treatment, high-resolution T2-weighted images revealed hyperintense multifocal lesions, many of which (∼50%) were not enhanced on T1-weighted contrast images, indicating intact BTB in the brain metastases. While no difference in the number of new lesions was observed, WBRT-treated tumors were significantly smaller than sham controls (p < .05). DW MRI detected significant increase in apparent diffusion coefficient (ADC) in WBRT tumors (p < .05), which correlated with elevated caspase 3 staining of apoptotic cells. Many lesions remained non-enhanced post WBRT. However, quantitative DCE MRI analysis showed significantly higher permeability parameter, Ktrans, in WBRT than the sham group (p < .05), despite marked spatial heterogeneity. CONCLUSIONS: MRI allowed non-invasive assessments of WBRT induced changes in BTB permeability, which may provide useful information for potential combination treatment.

Associations of maternal immune response with MeHg exposure at 28 weeks' gestation in the Seychelles Child Development Study.

PROBLEM: Maternal methylmercury (MeHg) exposure may be associated with immune response during pregnancy. METHOD OF STUDY: In the high fish-eating Seychelles Child Development Study Nutrition Cohort 2, we examined the association between maternal MeHg, polyunsaturated fatty acids (PUFA), and immune markers (Th1:Th2; TNF-α, IL-1ß, IFN-γ, IL-2, IL-4, IL-5, IL-10, MCP-1, TARC, sFlt-1, VEGF-D, CRP and IL-6) at 28 weeks' gestation. Linear regression examined associations between MeHg exposure and immune markers with and without adjustment for PUFA. RESULTS: In all models, as MeHg concentrations increased, the Th1:Th2 ratio, total Th1 and individual Th1 (IL-1ß, IL-2, TNF-α) concentrations decreased. MeHg was not associated with total Th2 cytokines but was associated with a decrease in IL-4 and IL-10. MeHg was positively associated with TARC and VEGF-D and negatively associated with CRP. There was a significant interaction between MeHg and the n-6:n-3 ratio, with MeHg associated with a larger decrease in Th1:Th2 at higher n-6:n-3 PUFA ratios. The n-3 PUFA were associated with lower CRP, IL-4 and higher IFN-γ. The n-6 PUFA were associated with higher IL-1ß, IL-2, TNF-α, IL-4, IL-10, CRP and IL-6. CONCLUSION: Maternal MeHg was associated with markers of immune function at 28 weeks' gestation. A significant interaction between MeHg and the n-6:n-3 ratio on the Th1:Th2 ratio suggests that the n-3 PUFA may mitigate any immunosuppressive associations of MeHg. The n-3 and n-6 PUFA were associated with suppressive and stimulatory immune responses, respectively. Overall, the associations were of small magnitude, and further research is required to determine the clinical significance.

Inflammatory response following in vitro exposure to methylmercury with and without n-3 long chain polyunsaturated fatty acids in peripheral blood mononuclear cells from systemic lupus erythematosus patients compared to healthy controls.

Methylmercury (MeHg) is a proposed environmental stimulus in systemic lupus erythematosus (SLE). Humans are primarily exposed to MeHg through fish consumption. Fish are also important sources of n-3 long chain polyunsaturated fatty acids (n-3 LCPUFA). This in vitro study investigated the inflammatory response of isolated peripheral blood mononuclear cells (PBMCs), when exposed to either MeHg alone or with added n-3 LCPUFA, from SLE patients (N = 12) compared to healthy sex matched controls (N = 12). The PBMCs were isolated and exposed to 200 nM of MeHg for 24 h with or without pre-exposure to eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) at a concentration of 100 µM each. Supernatants were analyzed for the inflammatory markers. Following exposure to MeHg, mean TNF-α concentrations were significantly higher in SLE patients (2226.01 ±â€¯348.98pg/ml) compared to controls (701.40 ±â€¯680.65 pg/ml) (P = .008). Pre-exposure of cells with MeHg and EPA resulted in a significantly higher concentration of IL-8 in supernatants from SLE patients (2137.83 ±â€¯1559.01 pg/ml) compared to that of the controls (879.26 ±â€¯979.49 pg/ml) (P = .030). EPA and DHA attenuated the pro-inflammatory inducing effects of MeHg in SLE and control cells. In summary, exposure to MeHg stimulated a higher TNF-α response in SLE patients compared with healthy controls; nevertheless the presence of n-3 LCPUFA reduced the overall inflammatory response, albeit to a lesser degree in SLE patients.

Making room for interactivity: using the cloud-based audience response system Nearpod to enhance engagement in lectures.

Active and collaborative learning provides distinct advantages for students in higher education, yet can often be hampered by the barrier of large class sizes. Solutions that combine a 'bring your own device culture' with cloud-based technologies may facilitate a more interactive learning experience. In this pilot study, we describe the use of one such technology, Nearpod, to enhance interactivity in lectures delivered to pharmacy and bioscience students at Ulster University. Existing material in PowerPoint or Keynote format is uploaded to the instructor area of Nearpod, interactive elements are added, and the lecture is then broadcasted via the internet to student devices. The lecturer may choose to share polling responses or examples of submissions from the drawing tool or open-ended questions, thereby providing instant feedback on learning. Students commented favourably on the interactivity and engagement afforded by Nearpod. Most students were happy to use their own electronic devices (smartphones, tablets and laptops) for such activities with a minority expressing concern over problems with connecting to the institutional Wi-Fi. Nearpod and similar products represent a new class of feature-rich audience response systems that have potential to transform learning even in large classes.

Mercury as an environmental stimulus in the development of autoimmunity - A systematic review.

Autoimmune diseases result from an interplay of genetic predisposition and factors which stimulate the onset of disease. Mercury (Hg), a well-established toxicant, is an environmental factor reported to be linked with autoimmunity. Hg exists in several chemical forms and is encountered by humans in dental amalgams, certain vaccines, occupational exposure, atmospheric pollution and seafood. Several studies have investigated the effect of the various forms of Hg, including elemental (Hg0), inorganic (iHg) and organic mercury (oHg) and their association with autoimmunity. In vitro studies using peripheral blood mononuclear cells (PBMC) from healthy participants have shown that methylmercury (MeHg) causes cell death at lower concentrations than iHg albeit exposure to iHg results in a more enhanced pro-inflammatory profile in comparison to MeHg. In vivo research utilising murine models susceptible to the development of metal-induced autoimmunity report that exposure to iHg results in a lupus-like syndrome, whilst mice exposed to MeHg develop autoimmunity without the formation of immune complexes. Furthermore, lower concentrations of IgE are detected in MeHg-treated animals in comparison with those treated with iHg. It appears that, oHg has a negative impact on animal models with existing autoimmunity. The research conducted on humans in this area is diverse in study design and the results are conflicting. There is currently no evidence to implicate a role for Hg0 exposure from dental amalgams in the development or perpetuation of autoimmune disease, apart from some suggestion of individual sensitivity. Several studies have consistently shown a positive correlation between iHg exposure and serum autoantibody concentrations in gold miners, although the clinical impact of iHg remains unknown. Furthermore, a limited number of studies have reported individuals with autoimmune disease have higher concentrations of blood Hg compared to healthy controls. In summary, it appears that iHg perpetuates markers of autoimmunity to a greater extent than oHg, albeit the impact on clinical outcomes in humans is yet to be elucidated.

The effect of consuming Palmaria palmata-enriched bread on inflammatory markers, antioxidant status, lipid profile and thyroid function in a randomised placebo-controlled intervention trial in healthy adults.

PURPOSE: Palmaria palmata (P. Palmata) is reported to contain anti-inflammatory and antioxidant compounds albeit no study has investigated these effects in humans. METHODS: A randomised parallel placebo-controlled human intervention study was carried out to investigate the effect of consuming P. Palmata (5 g/day) incorporated into a bread on serum markers of inflammation [C-reactive protein (CRP); cytokine analysis] with secondary analysis investigating changes in lipids (cholesterol, triglycerides), thyroid function [thyroid-stimulating hormone (TSH)] and antioxidant status ferric reducing antioxidant power. ANCOVA with baseline values as covariates, controlling for age, BMI, sex and smoking status, was used to compare differences between treatment groups over time . In vitro studies investigated the inflammatory activity of P. Palmata extracts (hot water, cold water and ethanol extract), protein extracts and associated protein hydrolysates using a Caco-2 inflammation cell model. RESULTS: Consumption of P. Palmata-enriched bread significantly increased serum CRP (+16.1 %, P = 0.011), triglycerides (+31.9 %, P = 0.001) and TSH (+17.2 %, P = 0.017) when compared to the control group. In vitro evaluation of P. palmata extracts and protein hydrolysates identified a significant induction of IL-8 secretion by Caco-2 cells, and the hot water P. palmata extract was shown to increase adipocyte glycerol release (P < 0.05). CONCLUSION: Evidence from this human study suggests that P. palmata stimulates inflammation, increases serum triglycerides and alters thyroid function; however, these changes are not likely to impact health as changes remained within the normal clinical range. The data from the in vitro study provided indications that IL-8 may contribute to the apparent immunostimulation noted in the human study.

Mercury in Hair Is Inversely Related to Disease Associated Damage in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease, and environmental factors are proposed to exacerbate existing symptoms. One such environmental factor is mercury. The aim of this study was to investigate the relationship between exposure to mercury (Hg) and disease activity and disease associated damage in Total Hg concentrations in hair and urine were measured in 52 SLE patients. Dental amalgams were quantified. Disease activity was assessed using three indexes including the British Isles Lupus Assessment Group Index (BILAG). Disease associated damage was measured using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology SLICC/ACR Damage Index. Pearson's correlation identified a significant negative correlation between hair Hg and BILAG (r = -0.323, p = 0.029) and SLICC/ACR (r = -0.377, p = 0.038). Multiple regression analysis identified hair Hg as a significant predictor of disease associated damage as determined by SLICC/ACR (ß = -0.366, 95% confidence interval (CI): -1.769, -0.155 p = 0.019). Urinary Hg was not related to disease activity or damage. Fish consumption is the primary route of MeHg exposure in humans and the inverse association of hair Hg with disease activity observed here might be explained by the anti-inflammatory effects of n-3 long chain polyunsaturated fatty acids also found in fish.