Analysing agricultural plant protection product concentrations in groundwater in Germany: Nationwide database with site and compound insights.

Pesticides from agricultural practices are among the most pressing reasons why groundwater sources do not reach the good chemical status standards as required by the European Water Framework directive. Complementary to previous federal pesticide reports, we analysed groundwater-monitoring data from 13 German Länder assembled in a database consisting of 26.192 groundwater measuring sites sampled between 1973 and 2021 of in total 521 parent compounds and metabolites. This study focuses on agricultural plant protection products. The monitored substance spectrum and site density developed over time and differs between Länder. More than 95 % of all samples lie below the respective (multiple) limits of quantification (LOQ). We thus report the frequency of exceedance above concentration thresholds, which allows to compare measurements temporally and spatially. Pesticide detections were found in all aquifer types, land uses and well screen depths. Most detections of higher concentrations were found in agricultural areas, at shallow screen depth in porous aquifers. Karst aquifers showed also a higher percentage of samples in higher concentration classes. Metabolites with high mobility and persistence were found in higher concentration ranges. Herbicides and metabolites thereof dominate the top 20 of pesticides that most frequently exceed 0.1 µg L-1. The ranking for 2010-2019 includes both authorised and banned compounds and their occurrence is discussed in the context of their mobility, persistence and underlying monitoring density. Yearly exceedance frequencies above 0.05, 0.1 µg L-1 and higher thresholds of metazachlor and its esa-metabolite, and national sales data of the parent compound did not show a temporal correlation in subsequent years. This study stresses the need for the harmonisation of heterogeneous pesticide data. Further, a characterisation of the groundwater data used to analyse pesticide occurrence in selected concentration ranges for relevant site factors and compound properties and provides a pesticide ranking based on exceedance frequencies is provided.

"The expert and the patient": a discourse analysis of the house of commons' debates regarding the 2007 Mental Health Act.

BACKGROUND: The Mental Health Act 1983 was amended in 2007. This legislation appears to be predicated on the assumption that an entity of "mental disorder" exists and that people who are designated mentally disordered require medical treatment, administered by force if necessary. AIMS: To explore the ways in which mental disorder is constructed and the possible practical effects of these constructions in the House of Commons' debates regarding the Mental Health Act 2007. METHOD: Verbatim transcripts from the House of Commons debates on the Mental Health Act were studied through a discourse analysis. RESULTS: Two primary discursive constructions were identified: "The Expert" and "The Patient." CONCLUSION: Mental disorder and associated roles, such as "The Expert," were constructed through particular selective rhetoric, which taken together, made particular psychiatric practices and the need for legislation, such as compulsory detention, seem normal, and necessary.

Clinical psychologists' use of transformative models of psychosis.

Some theories (e.g. Jackson's Paradigm Shifting Hypothesis) and many personal accounts suggest that some psychotic crises, whilst distressing, can also be transformative, leading to growth and valued outcomes. However, little is known about the extent to which this idea informs mainstream mental health care. Clinical psychologists are influential advocates of psychosocial approaches more broadly: This study explored their use of transformative models. Twelve U.K. clinical psychologists were interviewed: Transcripts informed a grounded theory. No participants saw psychosis as a purely biological problem where the content of experiences is irrelevant. Two held a "biopsychosocial" model, viewing psychosis as an illness with psychosocial elements. Most either held a continuum view (i.e., schizotypy), in which psychosis proneness was also associated with positive attributes such as creativity or sensitivity, or a "fully psychological" view, seeing experiences as meaningful and/or as adaptive responses to events. Many believed that psychosis can be transformative in a broad sense, that is, lead to "post-traumatic growth." Some went further, believing that it can be a purposeful (e.g., an attempt, albeit painful and sometimes unsuccessful, to solve problems) or even a spiritual phenomenon. Participants' perspectives influenced their therapeutic approach: Those who saw experiences as purposeful were more likely to facilitate direct engagement with them and to support clients to explore potentially transformative aspects. However, this represented an extension of conventional approaches rather than being qualitatively different. More research is needed to clarify how widespread this approach is, to explore its utility, and to establish for whom and when it may be appropriate.

Immunosuppression overcomes insulin- and vector-specific immune responses that limit efficacy of AAV2/8-mediated insulin gene therapy in NOD mice.

We report the restoration of euglycaemia in chemically induced diabetic C57BL/6 mice and spontaneously diabetic Non Obese Diabetic (NOD) mice by intravenous systemic administration of a single-stranded adeno-associated virus (ssAAV2/8) codon optimised (co) vector encoding furin cleavable human proinsulin under a liver-specific promoter. There were no immunological barriers to efficacy of insulin gene therapy in chemically induced C57BL/6 mice, which enjoyed long-lasting correction of hyperglycaemia after therapy, up to 250 days. Euglycaemia was also restored in spontaneously diabetic NOD mice, although these mice required a 7-10-fold higher dose of vector to achieve similar efficacy as the C57BL/6 mice and the immunodeficient NODscid mice. We detected CD8+ T cell reactivity to insulin and mild inflammatory infiltration in the livers of gene therapy recipient NOD mice, neither of which were observed in the treated C57BL/6 mice. Efficacy of the gene therapy in NOD mice was partially improved by targeting the immune system with anti-CD4 antibody treatment, while transfer of NOD mouse AAV2/8-reactive serum to recipients prevented successful restoration of euglycaemia in AAV2/8-HLP-hINSco-treated NODscid mice. Our data indicate that both immune cells and antibodies form a barrier to successful restoration of euglycaemia in autoimmune diabetic recipient mice with insulin gene therapy, but that this barrier can be overcome by increasing the dose of vector and by suppressing immune responses.

Harnessing CD8(+) regulatory T cells: therapy for type 1 diabetes?

In this issue of Immunity, Tsai et al. (2010) demonstrate that low-avidity autoantigen-specific regulatory CD8(+) T cells can reverse ongoing autoimmune disease and provide insight into the mechanism by which this is achieved.

Trabecular Bone Score at the Distal Femur and Proximal Tibia in Individuals With Spinal Cord Injury.

Rapid declines in bone mineral density (BMD) at the knee after spinal cord injury (SCI) are associated with an increased risk of fracture. Evaluation of bone quality using the trabecular bone score (TBS) may provide a complimentary measure to BMD assessment to examine bone health and fracture risk after SCI. The purpose of this study was to assess bone mineral density (BMD) and trabecular bone score (TBS) at the knee in individuals with and without SCI. Nine individuals with complete SCI (mean time since SCI 2.9 ± 3.8 yr) and 9 non-SCI controls received dual-energy X-ray absorptiometry scans of the right knee using the lumbar spine protocol. BMD and TBS were quantified at epiphyseal, metaphyseal, diaphyseal, and total bone regions of the distal femur and proximal tibia. Individuals with SCI illustrated significantly lower total BMD at the distal femur (23%; p = 0.029) and proximal tibia (19%; p = 0.02) when compared with non-SCI controls. Despite these marked differences in BMD from both locations, significant differences in total TBS were observed at the distal femur only (6%; p = 0.023). The observed differences in total BMD and TBS could be attributed to reductions in epiphyseal rather than metaphyseal or diaphysis measurements. The relationship between TBS and duration of SCI was well explained by a logarithmic trend at the distal femoral epiphysis (r2 = 0.54, p = 0.025). The logarithmic trend would predict that after 3 yr of SCI, TBS would be approximately 6% lower than the non-SCI controls. Further evaluation is needed to determine if TBS measures at the knee provide important information about bone quality that is not captured by traditional BMD.

Metabolomics and Lipidomics Study of Mouse Models of Type 1 Diabetes Highlights Divergent Metabolism in Purine and Tryptophan Metabolism Prior to Disease Onset.

With the increase in incidence of type 1 diabetes (T1DM), there is an urgent need to understand the early molecular and metabolic alterations that accompany the autoimmune disease. This is not least because in murine models early intervention can prevent the development of disease. We have applied a liquid chromatography (LC-) and gas chromatography (GC-) mass spectrometry (MS) metabolomics and lipidomics analysis of blood plasma and pancreas tissue to follow the progression of disease in three models related to autoimmune diabetes: the nonobese diabetic (NOD) mouse, susceptible to the development of autoimmune diabetes, and the NOD-E (transgenic NOD mice that express the I-E heterodimer of the major histocompatibility complex II) and NOD-severe combined immunodeficiency (SCID) mouse strains, two models protected from the development of diabetes. All three analyses highlighted the metabolic differences between the NOD-SCID mouse and the other two strains, regardless of diabetic status indicating that NOD-SCID mice are poor controls for metabolic changes in NOD mice. By comparing NOD and NOD-E mice, we show the development of T1DM in NOD mice is associated with changes in lipid, purine, and tryptophan metabolism, including an increase in kynurenic acid and a decrease in lysophospholipids, metabolites previously associated with inflammation.

Opposing effects on the cell cycle of T lymphocytes by Fbxo7 via Cdk6 and p27.

G1 phase cell cycle proteins, such as cyclin-dependent kinase 6 (Cdk6) and its activating partners, the D-type cyclins, are important regulators of T-cell development and function. An F-box protein, called F-box only protein 7 (Fbxo7), acts as a cell cycle regulator by enhancing cyclin D-Cdk6 complex formation and stabilising levels of p27, a cyclin-dependent kinase inhibitor. We generated a murine model of reduced Fbxo7 expression to test its physiological role in multiple tissues and found that these mice displayed a pronounced thymic hypoplasia. Further analysis revealed that Fbxo7 differentially affected proliferation and apoptosis of thymocytes at various stages of differentiation in the thymus and also mature T-cell function and proliferation in the periphery. Paradoxically, Fbxo7-deficient immature thymocytes failed to undergo expansion in the thymus due to a lack of Cdk6 activity, while mature T cells showed enhanced proliferative capacity upon T-cell receptor engagement due to reduced p27 levels. Our studies reveal differential cell cycle regulation by Fbxo7 at different stages in T-cell development.

Assessment of Bone Mineral Density at the Distal Femur and the Proximal Tibia by Dual-Energy X-ray Absorptiometry in Individuals With Spinal Cord Injury: Precision of Protocol and Relation to Injury Duration.

Spinal cord injury (SCI) is characterized by marked bone loss at the knee, and there is a need for established dual-energy X-ray absorptiometry (DXA) protocols to examine bone mineral density (BMD) at this location to track therapeutic progress and to monitor fracture risk. The purpose of this study was to quantify the precision and reliability of a DXA protocol for BMD assessment at the distal femur and the proximal tibia in individuals with SCI. The protocol was subsequently used to investigate the relationship between BMD and duration of SCI. Nine individuals with complete SCI and 9 able-bodied controls underwent 3 repeat DXA scans in accordance with the short-term precision methodology recommended by the International Society of Clinical Densitometry. The DXA protocol demonstrated a high degree of precision with the root-mean-square standard deviation ranging from 0.004 to 0.052 g/cm2 and the root-mean-square coefficient of variation ranging from 0.6% to 4.4%, depending on the bone, the region of interest, and the rater. All measurements of intra- and inter-rater reliability were excellent with an intraclass correlation of ≥0.950. The relationship between the BMD and the duration of SCI was well described by a logarithmic trend (r2 = 0.68-0.92). Depending on the region of interest, the logarithmic trends would predict that, after 3 yr of SCI, BMD at the knee would be 43%-19% lower than that in the able-bodied reference group. We believe the DXA protocol has the level of precision and reliability required for short-term assessments of BMD at the distal femur and the proximal tibia in people with SCI. However, further work is required to determine the degree to which this protocol may be used to assess longitudinal changes in BMD after SCI to examine clinical interventions and to monitor fracture risk.

Failure of the Anti-Inflammatory Parasitic Worm Product ES-62 to Provide Protection in Mouse Models of Type I Diabetes, Multiple Sclerosis, and Inflammatory Bowel Disease.

Parasitic helminths and their isolated secreted products show promise as novel treatments for allergic and autoimmune conditions in humans. Foremost amongst the secreted products is ES-62, a glycoprotein derived from Acanthocheilonema viteae, a filarial nematode parasite of gerbils, which is anti-inflammatory by virtue of covalently-attached phosphorylcholine (PC) moieties. ES-62 has been found to protect against disease in mouse models of rheumatoid arthritis, systemic lupus erythematosus, and airway hyper-responsiveness. Furthermore, novel PC-based synthetic small molecule analogues (SMAs) of ES-62 have recently been demonstrated to show similar anti-inflammatory properties to the parent molecule. In spite of these successes, we now show that ES-62 and its SMAs are unable to provide protection in mouse models of certain autoimmune conditions where other helminth species or their secreted products can prevent disease development, namely type I diabetes, multiple sclerosis and inflammatory bowel disease. We speculate on the reasons underlying ES-62's failures in these conditions and how the negative data generated may help us to further understand ES-62's mechanism of action.

Anti-CD3 treatment up-regulates programmed cell death protein-1 expression on activated effector T cells and severely impairs their inflammatory capacity.

T cells play a key role in the pathogenesis of type 1 diabetes, and targeting the CD3 component of the T-cell receptor complex provides one therapeutic approach. Anti-CD3 treatment can reverse overt disease in spontaneously diabetic non-obese diabetic mice, an effect proposed to, at least in part, be caused by a selective depletion of pathogenic cells. We have used a transfer model to further investigate the effects of anti-CD3 treatment on green fluorescent protein (GFP)+ islet-specific effector T cells in vivo. The GFP expression allowed us to isolate the known effectors at different time-points during treatment to assess cell presence in various organs as well as gene expression and cytokine production. We find, in this model, that anti-CD3 treatment does not preferentially deplete the transferred effector cells, but instead inhibits their metabolic function and their production of interferon-γ. Programmed cell death protein 1 (PD-1) expression was up-regulated on the effector cells from anti-CD3-treated mice, and diabetes induced through anti-PD-L1 antibody could only be reversed with anti-CD3 antibody if the anti-CD3 treatment lasted beyond the point when the anti-PD-L1 antibody was washed out of the system. This suggests that PD-1/PD-L1 interaction plays an important role in the anti-CD3 antibody mediated protection. Our data demonstrate an additional mechanism by which anti-CD3 therapy can reverse diabetogenesis.

They're NICE and Neat, but Are They Useful? A Grounded Theory of Clinical Psychologists' Beliefs About and Use of NICE Guidelines.

Guidelines are ubiquitous but inconsistently used in UK mental health services. Clinical psychologists are often influential in guideline development and implementation, but opinion within the profession is divided. This study utilized grounded theory methodology to examine clinical psychologists' beliefs about and use of NICE guidelines. Eleven clinical psychologists working in the NHS were interviewed. The overall emerging theme was; NICE guidelines are considered to have benefits but to be fraught with dangers. Participants were concerned that guidelines can create an unhelpful illusion of neatness. They managed the tension between the helpful and unhelpful aspects of guidelines by relating to them in a flexible manner. The participants reported drawing on specialist skills such as idiosyncratic formulation and integration. However, due to the pressures and dominant discourses within services they tended to practice in ways that prevent these skills from being recognized. This led to fears that their professional identity was threatened, which impacted upon perceptions of the guidelines. To our knowledge, the theoretical framework presented in this paper is the first that attempts to explain why NICE guidelines are not consistently utilized in UK mental health services. The current need for services to demonstrate 'NICE compliance' may be leading to a perverse incentive for clinical psychologists in particular to do one thing but say another and for specialist skills to be obscured. If borne out by future studies, this represents a threat to continued quality improvement and also to the profession. Copyright © 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Guidelines have many benefits, but the current pressure for services to be 'NICE compliant' may be having unintended negative as well as positive effects. Lack of implementation may be partly the result of active choice by clinicians concerned to use the full range of professional skills and to offer flexibility and choice to service users. The current context is creating a perverse incentive for clinicians to say one thing but do another. This is problematic for services and a potential threat to the profession of clinical psychology.

Immune mechanisms in type 1 diabetes.

There are three prerequisites for development of the autoimmune disease type 1 diabetes (T1D). First, ß cell-reactive T cells need to be activated; second, the response needs to be proinflammatory; and finally, immune regulation of autoreactive responses must fail. Here, we describe our current understanding of the cell types and immune mechanisms involved in each of these steps leading to T1D. Novel findings regarding ß cell involvement in its own destruction, the importance of the microbiota for instruction of the immune system, and recent data from studies in T1D patients are discussed. In addition, we summarise therapeutic approaches to T1D, and how these relate to the immune mechanisms involved in disease development.

A worm's eye view of the immune system: consequences for evolution of human autoimmune disease.

Humans and the many parasites that we can host have co-evolved over millions of years. This has been compared to an arms race in which the immune armoury of the human has evolved to deal with potential pathogens and the pathogen has evolved strategies to evade, and in some cases use, the immune system of the human host. Recently, there have been marked changes in the exposure of individuals in the developed world to both microorganisms and metazoan parasites, so the immune stimuli such organisms provide no longer have a role in our lives. As we discuss here, this is a marked perturbation, and the absence of the associated immunomodulation might have led to the increased emergence of autoimmune diseases.

Butyrophilin Btn2a2 inhibits TCR activation and phosphatidylinositol 3-kinase/Akt pathway signaling and induces Foxp3 expression in T lymphocytes.

The butyrophilin-related protein Btn2a2 was upregulated on murine APC including CD19(+) B cells, CD11b(+)F4/80(+) peritoneal macrophages, and CD11c(+) bone marrow-derived dendritic cells after activation with LPS or Pam3CysK4, suggesting a role in modulation of T lymphocytes. Consistent with this, binding of mouse Btn2a2-Fc to CD3(+) primary mouse T cells stimulated with anti-CD3 and anti-CD28 reduced the number of proliferating cells and entry of cells into the cell cycle. Binding of Btn2a2-Fc to anti-CD3-stimulated T cells inhibited CD3ε, Zap70, and subsequent Erk1/2 activation. It also interfered with activation of the regulatory subunit of PI3K, p85, and activation of Akt in T cells stimulated with both anti-CD3 and anti-CD28. Inhibition of Akt activation by Btn2a2-Fc was, in contrast to inhibition by programmed death ligand-1-Fc, not overcome by anti-CD28 costimulation. Using Foxp3-GFP-transgenic, naive T cells, Btn2a2-Fc induced de novo expression of Foxp3 in a dose-dependent manner, and Btn2a2-Fc-induced CD4(+)CD25(+)Foxp3(+) T cells had inhibitory properties. The data indicate an important physiological role for Btn2a2 in inhibiting T cell activation and inducing Foxp3(+) regulatory T cells.

Accelerated turnover of MHC class II molecules in nonobese diabetic mice is developmentally and environmentally regulated in vivo and dispensable for autoimmunity.

The H2-A(g7) (A(g7)) MHC class II (MHCII) allele is required for type 1 diabetes (T1D) in NOD mice. A(g7) not only has a unique peptide-binding profile, it was reported to exhibit biochemical defects, including accelerated protein turnover. Such defects were proposed to impair Ag presentation and, thus, self-tolerance. Here, we report measurements of MHCII protein synthesis and turnover in vivo. NOD mice and BALB/c controls were labeled continuously with heavy water, and splenic B cells and dendritic cells were isolated. MHCII molecules were immunoprecipitated and digested with trypsin. Digests were analyzed by liquid chromatography/mass spectrometry to quantify the fraction of newly synthesized MHCII molecules and, thus, turnover. MHCII turnover was faster in dendritic cells than in B cells, varying slightly between mouse strains. Some A(g7) molecules exhibited accelerated turnover in B cells from young, but not older, prediabetic female NOD mice. This acceleration was not detected in a second NOD colony with a high incidence of T1D. Turnover rates of A(g7) and H2-A(d) were indistinguishable in (NOD × BALB/c) F1 mice. In conclusion, accelerated MHCII turnover may occur in NOD mice, but it reflects environmental and developmental regulation, rather than a structural deficit of the A(g7) allele. Moreover, this phenotype wanes before the onset of overt T1D and is dispensable for the development of autoimmune diabetes. Our observations highlight the importance of in vivo studies in understanding the role of protein turnover in genotype/phenotype relationships and offer a novel approach for addressing this fundamental research challenge.

Infectious triggers protect from autoimmunity.

While some infectious agents have been linked to onset of autoimmune disease there is also other evidence suggesting that certain infectious agents might inhibit autoimmune pathology. This review focuses on the ways in which infectious agents or their products might intervene in an autoimmune response.