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.

Lifting the lid on impact and peer review.

Brain and Neuroscience Advances has grown in tandem with the British Neuroscience Association's campaign to build Credibility in Neuroscience, which encourages actions and initiatives aimed at improving reproducibility, reliability and openness. This commitment to credibility impacts not only what the Journal publishes, but also how it operates. With that in mind, the Editorial Board sought the views of the neuroscience community on the peer review process, and on how they should respond to the Journal Impact Factor that will be assigned to Brain and Neuroscience Advances. In this editorial, we present the results of a survey of neuroscience researchers conducted in the autumn of 2020 and discuss the broader implications of our findings for the Journal and the neuroscience community.

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.

Autoimmune encephalomyelitis in NOD mice is not initially a progressive multiple sclerosis model.

OBJECTIVE: Despite progress in treating relapsing multiple sclerosis (MS), effective inhibition of nonrelapsing progressive MS is an urgent, unmet, clinical need. Animal models of MS, such as experimental autoimmune encephalomyelitis (EAE), provide valuable tools to examine the mechanisms contributing to disease and may be important for developing rational therapeutic approaches for treatment of progressive MS. It has been suggested that myelin oligodendrocyte glycoprotein (MOG) peptide residues 35-55 (MOG35-55 )-induced EAE in nonobese diabetic (NOD) mice resembles secondary progressive MS. The objective was to determine whether the published data merits such claims. METHODS: Induction and monitoring of EAE in NOD mice and literature review. RESULTS: It is evident that the NOD mouse model lacks validity as a progressive MS model as the individual course seems to be an asynchronous, relapsing-remitting neurodegenerative disease, characterized by increasingly poor recovery from relapse. The seemingly progressive course seen in group means of clinical score is an artifact of data handling and interpretation. INTERPRETATION: Although MOG35-55 -induced EAE in NOD mice may provide some clues about approaches to block neurodegeneration associated with the inflammatory penumbra as lesions form, it should not be used to justify trials in people with nonactive, progressive MS. This adds further support to the view that drug studies in animals should universally adopt transparent raw data deposition as part of the publication process, such that claims can adequately be interrogated. This transparency is important if animal-based science is to remain a credible part of translational research in MS.

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.

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.

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.

Non-Invasive Multiphoton Imaging of Islets Transplanted Into the Pinna of the NOD Mouse Ear Reveals the Immediate Effect of Anti-CD3 Treatment in Autoimmune Diabetes.

We present a novel and readily accessible method facilitating cellular time-resolved imaging of transplanted pancreatic islets. Grafting of islets to the mouse ear pinna allows non-invasive, in vivo longitudinal imaging of events in the islets and enables improved acquisition of experimental data and use of fewer experimental animals than is possible using invasive techniques, as the same mouse can be assessed for the presence of islet infiltrating cells before and after immune intervention. We have applied this method to investigating therapeutic protection of beta cells through the well-established use of anti-CD3 injection, and have acquired unprecedented data on the nature and rapidity of the effect on the islet infiltrating T cells. We demonstrate that infusion of anti-CD3 antibody leads to immediate effects on islet infiltrating T cells in islet grafts in the pinna of the ear, and causes them to increase their speed and displacement within 20 min of infusion. This technique overcomes several technical challenges associated with intravital imaging of pancreatic immune responses and facilitates routine study of beta islet cell development, differentiation, and function in health and disease.

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.

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.

Regulation of type 1 diabetes development and B-cell activation in nonobese diabetic mice by early life exposure to a diabetogenic environment.

Microbes, including viruses, influence type 1 diabetes (T1D) development, but many such influences remain undefined. Previous work on underlying immune mechanisms has focussed on cytokines and T cells. Here, we compared two nonobese diabetic (NOD) mouse colonies, NODlow and NODhigh, differing markedly in their cumulative T1D incidence (22% vs. 90% by 30 weeks in females). NODhigh mice harbored more complex intestinal microbiota, including several pathobionts; both colonies harbored segmented filamentous bacteria (SFB), thought to suppress T1D. Young NODhigh females had increased B-cell activation in their mesenteric lymph nodes. These phenotypes were transmissible. Co-housing of NODlow with NODhigh mice after weaning did not change T1D development, but T1D incidence was increased in female offspring of co-housed NODlow mice, which were exposed to the NODhigh environment both before and after weaning. These offspring also acquired microbiota and B-cell activation approaching those of NODhigh mice. In NODlow females, the low rate of T1D was unaffected by cyclophosphamide but increased by PD-L1 blockade. Thus, environmental exposures that are innocuous later in life may promote T1D progression if acquired early during immune development, possibly by altering B-cell activation and/or PD-L1 function. Moreover, T1D suppression in NOD mice by SFB may depend on the presence of other microbial influences. The complexity of microbial immune regulation revealed in this murine model may also be relevant to the environmental regulation of human T1D.

Hyperglycaemia does not affect antigen-specific activation and cytolytic killing by CD8+ T cells in vivo.

Metabolism is of central importance for T cell survival and differentiation. It is well known that T cells cannot function in the absence of glucose, but it is less clear how they respond to excessive levels of glucose. In the present study, we investigated how increasing levels of glucose affect T-cell-mediated immune responses. We examined the effects of increased levels of glucose on CD8+ T-cell behaviour in vitro by assessing activation and cytokine production, as well as oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and intracellular signalling. In addition, we assessed in vivo proliferation, cytokine production and cytolytic activity of cells in chemically induced diabetic C57BL/6 mice. Elevated levels of glucose in in vitro cultures had modest effects on proliferation and cytokine production, while in vivo hyperglycaemia had no effect on CD8+ T-cell proliferation, interferon γ (IFNγ) production or cytolytic killing.