Acceleration of Autoimmunity by Organochlorine Pesticides in (NZB × NZW)F(1) Mice

Systemic lupus erythematosus (SLE) is an autoimmune disorder that affects women more frequently than men. In the (NZB × NZW)F(1) mouse, a murine SLE model, the presence or absence of estrogen markedly influences the rate of progression of disease. Three organochlorine pesticides with estrogenic effects were administered chronically to ovariectomized female (NZB × NZW)F(1) mice, and we measured the time to development of renal disease, the principal clinical manifestation of lupus in this model. Treatment with chlordecone, methoxychlor, or o,p′-dichlorodiphenyl-trichloroethane (o,p′-DDT) significantly decreased the time to onset of renal impairment, as did treatment with 17β-estradiol used as a positive control. In an expanded study of chlordecone, we found a dose-related early appearance of elevated anti–double-strand DNA autoantibody titers that corresponded with subsequent development of glomerulonephritis. Immunohistofluorescence confirmed early deposition of immune complexes in kidneys of mice treated with chlordecone. These observations are consistent with an effect of these organochlorine pesticides to accelerate the natural course of SLE in the (NZB × NZW)F(1) mouse. Although we originally hypothesized that the effect on progression of autoimmunity was due to estrogenic properties of the pesticides, autoimmune effects and estrogenicity, assessed through measurement of uterine hypertrophy, were not well correlated. This may indicate that uterine hypertrophy is a poor indicator of comparative estrogenic effects of organochlorine pesticides on the immune system, or that the pesticides are influencing autoimmunity through a mode of action unrelated to their estrogenicity

Applied Interventions in the Prevention and Treatment of Obesity Through the Research of Professor Jane Wardle

Purpose of Review Obesity presents a challenge for practitioners, policy makers, researchers and for those with obesity themselves. This review focuses on psychological approaches to its management and prevention in children and adults. Recent Findings Through exploring the work of the late Professor Jane Wardle, we look at the earliest behavioural treatment approaches and how psychological theory has been used to develop more contemporary approaches, for example incorporating genetic feedback and habit formation theory into interventions. We also explore how Jane has challenged thinking about the causal pathways of obesity in relation to eating behaviour. Beyond academic work, Jane was an advocate of developing interventions which had real-world applications. Summary Therefore, we discuss how she not only developed new interventions but also made these widely available and the charity that she established

Alterations of renal phenotype and gene expression profiles due to protein overload in NOD-related mouse strains

BACKGROUND: Despite multiple causes, Chronic Kidney Disease is commonly associated with proteinuria. A previous study on Non Obese Diabetic mice (NOD), which spontaneously develop type 1 diabetes, described histological and gene expression changes incurred by diabetes in the kidney. Because proteinuria is coincident to diabetes, the effects of proteinuria are difficult to distinguish from those of other factors such as hyperglycemia. Proteinuria can nevertheless be induced in mice by peritoneal injection of Bovine Serum Albumin (BSA). To gain more information on the specific effects of proteinuria, this study addresses renal changes in diabetes resistant NOD-related mouse strains (NON and NOD.B10) that were made to develop proteinuria by BSA overload. METHODS: Proteinuria was induced by protein overload on NON and NOD.B10 mouse strains and histology and microarray technology were used to follow the kidney response. The effects of proteinuria were assessed and subsequently compared to changes that were observed in a prior study on NOD diabetic nephropathy. RESULTS: Overload treatment significantly modified the renal phenotype and out of 5760 clones screened, 21 and 7 kidney transcripts were respectively altered in the NON and NOD.B10. Upregulated transcripts encoded signal transduction genes, as well as markers for inflammation (Calmodulin kinase beta). Down-regulated transcripts included FKBP52 which was also down-regulated in diabetic NOD kidney. Comparison of transcripts altered by proteinuria to those altered by diabetes identified mannosidase 2 alpha 1 as being more specifically induced by proteinuria. CONCLUSION: By simulating a component of diabetes, and looking at the global response on mice resistant to the disease, by virtue of a small genetic difference, we were able to identify key factors in disease progression. This suggests the power of this approach in unraveling multifactorial disease processes

Analysis of Marker-Defined HNSCC Subpopulations Reveals a Dynamic Regulation of Tumor Initiating Properties

Head and neck squamous carcinoma (HNSCC) tumors carry dismal long-term prognosis and the role of tumor initiating cells (TICs) in this cancer is unclear. We investigated in HNSCC xenografts whether specific tumor subpopulations contributed to tumor growth. We used a CFSE-based label retentions assay, CD49f (α6-integrin) surface levels and aldehyde dehydrogenase (ALDH) activity to profile HNSCC subpopulations. The tumorigenic potential of marker-positive and -negative subpopulations was tested in nude (Balb/c nu/nu) and NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice and chicken embryo chorioallantoic membrane (CAM) assays. Here we identified in HEp3, SQ20b and FaDu HNSCC xenografts a subpopulation of G0/G1-arrested slow-cycling CD49fhigh/ALDH1A1high/H3K4/K27me3low subpopulation (CD49f+) of tumor cells. A strikingly similar CD49fhigh/H3K27me3low subpopulation is also present in primary human HNSCC tumors and metastases. While only sorted CD49fhigh/ALDHhigh, label retaining cells (LRC) proliferated immediately in vivo, with time the CD49flow/ALDHlow, non-LRC (NLRC) tumor cell subpopulations were also able to regain tumorigenic capacity; this was linked to restoration of CD49fhigh/ALDHhigh, label retaining cells. In addition, CD49f is required for HEp3 cell tumorigenicity and to maintain low levels of H3K4/K27me3. CD49f+ cells also displayed reduced expression of the histone-lysine N-methyltransferase EZH2 and ERK1/2phosphorylation. This suggests that although transiently quiescent, their unique chromatin structure is poised for rapid transcriptional activation. CD49f− cells can “reprogram” and also achieve this state eventually. We propose that in HNSCC tumors, epigenetic mechanisms likely driven by CD49f signaling dynamically regulate HNSCC xenograft phenotypic heterogeneity. This allows multiple tumor cell subpopulations to drive tumor growth suggesting that their dynamic nature renders them a “moving target” and their eradication might require more persistent strategies

Development and validation of the Self-Regulation of Eating Behaviour Questionnaire for adults

Background Eating self-regulatory capacity can help individuals to cope with the obesogenic environment and achieve, as well as maintain, a healthy weight and diet. At present, there is no comprehensive, reliable and valid questionnaire for assessing this capacity and measuring change in response to self-regulation interventions in adults. This paper reports the development of the Self-regulation of Eating Behaviour Questionnaire (SREBQ) for use in UK adults, and presents evidence for its reliability and construct validity. The development of the SREBQ involved generation of an item pool, followed by two pilot studies (Samples 1 and 2) and a test of the questionnaire’s underlying factor structure (Sample 3). The final version of the SREBQ was then assessed for reliability and construct validity (Sample 4). Results Development of the SREBQ resulted in a 5-item questionnaire. The face validity was satisfactory, as assessed by the pilot studies. The factor structure analysis (Sample 3) suggested that it has a single underlying factor, which was confirmed in a second sample (Sample 4). The SREBQ had strong construct validity, showing a positive correlation with general measures of self-regulation. It was also positively correlated with motivation and behavioural automaticity, and negatively correlated with food responsiveness and emotional over-eating (p < 0.001). It showed good discriminant validity, as it was only weakly associated with satiety responsiveness, food fussiness and slowness in eating. Conclusions The SREBQ is a reliable and valid measure for assessment of eating self-regulatory capacity in the general UK adult population