Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy.

Research into the disequilibrium of microglial phenotypes has become an area of intense focus in neurodegenerative disease as a potential mechanism that contributes to chronic neuroinflammation and neuronal loss in Parkinson's disease (PD). There is growing evidence that neuroinflammation accompanies and may promote progression of alpha-synuclein (Asyn)-induced nigral dopaminergic (DA) degeneration. From a therapeutic perspective, development of immunomodulatory strategies that dampen overproduction of pro-inflammatory cytokines from chronically activated immune cells and induce a pro-phagocytic phenotype is expected to promote Asyn removal and protect vulnerable neurons. Cannabinoid receptor-2 (CB2) is highly expressed on activated microglia and peripheral immune cells, is upregulated in the substantia nigra of individuals with PD and in mouse models of nigral degeneration. Furthermore, modulation of CB2 protects against rotenone-induced nigral degeneration; however, CB2 has not been pharmacologically and selectively targeted in an Asyn model of PD. Here, we report that 7 weeks of peripheral administration of CB2 inverse agonist SMM-189 reduced phosphorylated (pSer129) alpha-synuclein in the substantia nigra compared to vehicle treatment. Additionally, SMM-189 delayed Asyn-induced immune cell infiltration into the brain as determined by flow cytometry, increased CD68 protein expression, and elevated wound-healing-immune-mediator gene expression. Additionally, peripheral immune cells increased wound-healing non-classical monocytes and decreased pro-inflammatory classical monocytes. In vitro analysis of RAW264.7 macrophages treated with lipopolysaccharide (LPS) and SMM-189 revealed increased phagocytosis as measured by the uptake of fluorescence of pHrodo E. coli bioparticles. Together, results suggest that targeting CB2 with SMM-189 skews immune cell function toward a phagocytic phenotype and reduces toxic aggregated species of Asyn. Our novel findings demonstrate that CB2 may be a target to modulate inflammatory and immune responses in proteinopathies.

Soluble TNF mediates amyloid-independent, diet-induced alterations to immune and neuronal functions in an Alzheimer's disease mouse model.

Introduction: Increasing evidence indicates that neurodegenerative diseases, including Alzheimer's disease (AD), are a product of gene-by-environment interplay. The immune system is a major contributor mediating these interactions. Signaling between peripheral immune cells and those within the microvasculature and meninges of the central nervous system (CNS), at the blood-brain barrier, and in the gut likely plays an important role in AD. The cytokine tumor necrosis factor (TNF) is elevated in AD patients, regulates brain and gut barrier permeability, and is produced by central and peripheral immune cells. Our group previously reported that soluble TNF (sTNF) modulates cytokine and chemokine cascades that regulate peripheral immune cell traffic to the brain in young 5xFAD female mice, and in separate studies that a diet high in fat and sugar (HFHS) dysregulates signaling pathways that trigger sTNF-dependent immune and metabolic responses that can result in metabolic syndrome, which is a risk factor for AD. We hypothesized that sTNF is a key mediator of peripheral immune cell contributions to gene-by-environment interactions to AD-like pathology, metabolic dysfunction, and diet-induced gut dysbiosis. Methods: Female 5xFAD mice were subjected to HFHS diet for 2 months and then given XPro1595 to inhibit sTNF for the last month or saline vehicle. We quantified immune cell profiles by multi-color flow cytometry on cells isolated from brain and blood; metabolic, immune, and inflammatory mRNA and protein marker biochemical and immunhistological analyses, gut microbiome, and electrophysiology in brain slices were also performed. Results: Here, we show that selective inhibition of sTNF signaling via the biologic XPro1595 modulates the effects of an HFHS diet in 5xFAD mice on peripheral and central immune profiles including CNS-associated CD8+ T cells, the composition of gut microbiota, and long-term potentiation deficits. Discussion: Obesogenic diet induces immune and neuronal dysfunction in 5xFAD mice and sTNF inhibition mitigates its effects. A clinical trial in subjects at risk for AD due to genetic predisposition and underlying inflammation associated with peripheral inflammatory co-morbidities will be needed to investigate the extent to which these findings translate to the clinic.

Altered Response Pattern following AZD5582 Treatment of SIV-Infected, ART-Suppressed Rhesus Macaque Infants.

The "shock and kill" strategy for HIV-1 cure incorporates latency-reversing agents (LRA) in combination with interventions that aid the host immune system in clearing virally reactivated cells. LRAs have not yet been investigated in pediatric clinical or preclinical studies. Here, we evaluated an inhibitor of apoptosis protein (IAP) inhibitor (IAPi), AZD5582, that activates the noncanonical NF-κB (ncNF-κB) signaling pathway to reverse latency. Ten weekly doses of AZD5582 were intravenously administered at 0.1 mg/kg to rhesus macaque (RM) infants orally infected with SIVmac251 at 4 weeks of age and treated with a triple ART regimen for over 1 year. During AZD5582 treatment, on-ART viremia above the limit of detection (LOD, 60 copies/mL) was observed in 5/8 infant RMs starting at 3 days post-dose 4 and peaking at 771 copies/mL. Of the 135 measurements during AZD5582 treatment in these 5 RM infants, only 8 were above the LOD (6%), lower than the 46% we have previously reported in adult RMs. Pharmacokinetic analysis of plasma AZD5582 levels revealed a lower Cmax in treated infants compared to adults (294 ng/mL versus 802 ng/mL). RNA-Sequencing of CD4+ T cells comparing pre- and post-AZD5582 dosing showed many genes that were similarly upregulated in infants and adults, but the expression of key ncNF-κB genes, including NFKB2 and RELB, was significantly higher in adult RMs. Our results suggest that dosing modifications for this latency reversal approach may be necessary to maximize virus reactivation in the pediatric setting for successful "shock and kill" strategies. IMPORTANCE While antiretroviral therapy (ART) has improved HIV-1 disease outcome and reduced transmission, interruption of ART results in rapid viral rebound due to the persistent latent reservoir. Interventions to reduce the viral reservoir are of critical importance, especially for children who must adhere to lifelong ART to prevent disease progression. Here, we used our previously established pediatric nonhuman primate model of oral SIV infection to evaluate AZD5582, identified as a potent latency-reversing agent in adult macaques, in the controlled setting of daily ART. We demonstrated the safety of the IAPi AZD5582 and evaluate the pharmacokinetics and pharmacodynamics of repeated dosing. The response to AZD5582 in macaque infants differed from what we previously showed in adult macaques with weaker latency reversal in infants, likely due to altered pharmacokinetics and less inducibility of infant CD4+ T cells. These data supported the contention that HIV-1 cure strategies for children are best evaluated using pediatric model systems.

Experimental colitis promotes sustained, sex-dependent, T-cell-associated neuroinflammation and parkinsonian neuropathology.

BACKGROUND: The etiology of sporadic Parkinson's disease (PD) remains uncertain, but genetic, epidemiological, and physiological overlap between PD and inflammatory bowel disease suggests that gut inflammation could promote dysfunction of dopamine-producing neurons in the brain. Mechanisms behind this pathological gut-brain effect and their interactions with sex and with environmental factors are not well understood but may represent targets for therapeutic intervention. METHODS: We sought to identify active inflammatory mechanisms which could potentially contribute to neuroinflammation and neurological disease in colon biopsies and peripheral blood immune cells from PD patients. Then, in mouse models, we assessed whether dextran sodium sulfate-mediated colitis could exert lingering effects on dopaminergic pathways in the brain and whether colitis increased vulnerability to a subsequent exposure to the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We assessed the involvement of inflammatory mechanisms identified in the PD patients in colitis-related neurological dysfunction in male and female mice, utilizing mice lacking the Regulator of G-Protein Signaling 10 (RGS10)-an inhibitor of nuclear factor kappa B (NFκB)-to model enhanced NFκB activity, and mice in which CD8+ T-cells were depleted. RESULTS: High levels of inflammatory markers including CD8B and NFκB p65 were found in colon biopsies from PD patients, and reduced levels of RGS10 were found in immune cells in the blood. Male mice that experienced colitis exhibited sustained reductions in tyrosine hydroxylase but not in dopamine as well as sustained CD8+ T-cell infiltration and elevated Ifng expression in the brain. CD8+ T-cell depletion prevented colitis-associated reductions in dopaminergic markers in males. In both sexes, colitis potentiated the effects of MPTP. RGS10 deficiency increased baseline intestinal inflammation, colitis severity, and neuropathology. CONCLUSIONS: This study identifies peripheral inflammatory mechanisms in PD patients and explores their potential to impact central dopaminergic pathways in mice. Our findings implicate a sex-specific interaction between gastrointestinal inflammation and neurologic vulnerability that could contribute to PD pathogenesis, and they establish the importance of CD8+ T-cells in this process in male mice.

Sequestration and potential release of PFAS from spent engineered sorbents.

Per- and poly-fluoroalkyl substances (PFAS) have contaminated land and water at numerous sites worldwide that now require remediation. The most common approach for treating contaminated water currently relies on removal of PFAS by sorption. The spent sorbents loaded with PFAS can potentially be disposed of at landfills, provided the sorbed contaminants remain sequestered and certain risk criteria are met. Hence, it is essential that remediation sorbents (i) rapidly adsorb a large variety of PFAS under varying water chemistry conditions, and (ii) do not release the adsorbed PFAS in due course. This review aims at establishing the current state of knowledge about the potential release of PFAS that may occur during and after treatment. The scientific literature currently provides data for a very restricted range of long-chain PFAS. Our knowledge of the dynamics of PFAS adsorption processes on engineered sorbents is limited, and even less is known about their desorption processes. The sorption of PFAS can be strongly affected by changes in the solution pH, ionic strength and dissolved organic matter content, and the process is also subject to complex competition mechanisms in the presence of other PFAS as well as organic contaminants and inorganic salts. Several studies suggest that changes in one or several of these factors may trigger the release of PFAS from engineered sorbents. This phenomenon is more likely to occur for PFAS with shorter carbon chain lengths (

Transgenic Mice Expressing Human α-Synuclein in Noradrenergic Neurons Develop Locus Ceruleus Pathology and Nonmotor Features of Parkinson's Disease.

Degeneration of locus ceruleus (LC) neurons and dysregulation of noradrenergic signaling are ubiquitous features of Parkinson's disease (PD). The LC is among the first brain regions affected by α-synuclein (asyn) pathology, yet how asyn affects these neurons remains unclear. LC-derived norepinephrine (NE) can stimulate neuroprotective mechanisms and modulate immune cells, while dysregulation of NE neurotransmission may exacerbate disease progression, particularly nonmotor symptoms, and contribute to the chronic neuroinflammation associated with PD pathology. Although transgenic mice overexpressing asyn have previously been developed, transgene expression is usually driven by pan-neuronal promoters and thus has not been selectively targeted to LC neurons. Here we report a novel transgenic mouse expressing human wild-type asyn under control of the noradrenergic-specific dopamine ß-hydroxylase promoter (DBH-hSNCA). These mice developed oligomeric and conformation-specific asyn in LC neurons, alterations in hippocampal and LC microglial abundance, upregulated GFAP expression, degeneration of LC fibers, decreased striatal DA metabolism, and age-dependent behaviors reminiscent of nonmotor symptoms of PD that were rescued by adrenergic receptor antagonists. These mice provide novel insights into how asyn pathology affects LC neurons and how central noradrenergic dysfunction may contribute to early PD pathophysiology.SIGNIFICANCE STATEMENT ɑ-Synuclein (asyn) pathology and loss of neurons in the locus ceruleus (LC) are two of the most ubiquitous neuropathologic features of Parkinson's disease (PD). Dysregulated norepinephrine (NE) neurotransmission is associated with the nonmotor symptoms of PD, including sleep disturbances, emotional changes such as anxiety and depression, and cognitive decline. Importantly, the loss of central NE may contribute to the chronic inflammation in, and progression of, PD. We have generated a novel transgenic mouse expressing human asyn in LC neurons to investigate how increased asyn expression affects the function of the central noradrenergic transmission and associated behaviors. We report cytotoxic effects of oligomeric and conformation-specific asyn, astrogliosis, LC fiber degeneration, disruptions in striatal dopamine metabolism, and age-dependent alterations in nonmotor behaviors without inclusions.

Sorption behaviour of per- and polyfluoroalkyl substances (PFASs) as affected by the properties of coastal estuarine sediments.

The sorption of three perfluoroalkyl substances (PFASs), namely perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and perfluorohexane sulfonic acid (PFHxS), was determined in 19 coastal sediments. There are currently limited data on the sorption behaviour of these chemicals in marine or estuarine sediments and the properties controlling their sorption have not been well established. The median average PFOS Kd value (30.4 L/kg) was >8 times that for PFOA (3.3 L/kg) and PFHxS (2.8 L/kg). Highly significant (P < .001) linear relationships were found between values for sorption coefficients (Kd) for all three chemicals (PFOS, PFOA and PFHxS) to the estuarine sediments and organic carbon (OC) content with r2 values ranging from 0.87 to 0.91. The nature of the constituents of OC was determined by nuclear magnetic resonance (NMR) for a subset (10) of the sediments to assess whether the strong relationship between sorption and OC was due solely to an increasing amount of OC or to particular OC fractions. The NMR analysis could not provide strong evidence for one OC fraction type explaining the variation in sorption of the three PFASs. Further investigation using partial least squares of the whole spectra also did not show any particular OC components could explain the Kd variation. This data suggests that variation in sorption in these sediments was primarily due to the varying OC content and not its chemistry.

Molecular Signatures of Neuroinflammation Induced by αSynuclein Aggregates in Microglial Cells.

Alpha-synuclein (αSynAgg) are pathological hallmarks of Parkinson's disease (PD) and other synucleinopathies that induce microglial activation and immune-mediated neurotoxicity, but the molecular mechanisms of αSynAgg-induced immune activation are poorly defined. We performed quantitative proteomics by mass spectrometry coupled with PCR, immunohistochemical and functional validations studies to define the molecular characteristics of alpha synuclein mediated microglial activation. In mouse microglia, αSynAgg induced robust pro-inflammatory activation (increased expression of 864 genes including Irg1, Ifit1, and Pyhin) and increased nuclear proteins involved in RNA synthesis, splicing, and anti-viral defense mechanisms. Conversely, αSynAgg decreased expression several proteins (including Cdc123, Sod1, and Grn), which were predominantly cytosolic and involved in metabolic, proteasomal and lysosomal mechanisms. Pathway analyses and confirmatory in vitro studies suggested that αSynAgg partly mediates its effects via Stat3 activation. As predicted by our proteomic findings, we verified that αSynAgg induces mitochondrial dysfunction in microglia. Twenty-six proteins differentially expressed by αSynAgg were also identified as PD risk genes in genome-wide association studies (upregulated: Brd2, Clk1, Siglec1; down-regulated: Memo1, Arhgap18, Fyn, and Pgrn/Grn). We validated progranulin (PGRN) as a lysosomal PD-associated protein that is downregulated by αSynAgg in microglia in-vivo and is expressed by microglia in post-mortem PD brain, congruent with our in vitro findings. Conclusion: Together, proteomics approach both reveals novel molecular insights into αSyn-mediated neuroinflammation in PD and other synucleinopathies.

Organic waste from sugar mills as a potential soil ameliorant to minimise herbicide runoff to the Great Barrier Reef.

We studied sorption potential for a range of herbicides using eleven waste materials (mill muds) containing organic matter (47.6 to 65.1%) produced by sugar mills and applied as soil conditioners by farmers. Sorption/desorption behaviour of five herbicides commonly used in sugarcane production (imazapic, atrazine, hexazinone, diuron and metribuzin) was studied on these mill muds, as is and after adding these to three soils at different rates (5-25%, dry weight basis). All mill muds had significant sorption capacity, especially for diuron, atrazine and metribuzin which was 6 to 26 times higher than the soil with 3.5% organic carbon (OC). Generally, sorption of the five herbicides assessed in all mill muds followed the order diuron > atrazine = metribuzin > hexazinone = imazapic. Eight out of 11 mill muds had similar sorption capacity for any given herbicides. Amending soils with selected mill muds significantly enhanced their sorption efficiency, depending on the rate of application especially in soil with low OC. Generally, application of mill muds at 5% w/w or 40 tons/ha increased sorption of studied herbicides by 2 to 10 folds. Soil amendment with mill muds also reduced the rate and extent of desorption of herbicides- especially mobile herbicides like metribuzin. Nearly 79% release of metribuzin was observed after three desorption steps in amended soil (at 5% w/w), whereas in unamended soil, 100% of metribuzin was released during first desorption step. The study demonstrates that wastes produced by sugar mills may have recycling use in enhancing the retention of mobile herbicides in soils with low OC content.

Sorption behaviour of per- and polyfluoroalkyl substances (PFASs) in tropical soils.

The sorption behaviour of three perfluoroalkyl substances (PFASs), namely perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and perfluorohexane sulfonic acid (PFHxS), was determined on 28 tropical soils. Tropical soils are often highly weathered, richer in sesquioxides than temperate soils and may contain variable charge minerals. There are little data on sorption of PFASs in tropical soils. The highest Kd values were found for PFOS with mean values ranging from 0 to 31.6 L/kg. The Kd values for PFOA and PFHxS ranged from 0 to 4.9 L/kg and from 0 to 5.6 L/kg, respectively. While these values are in the range of literature sorption data, the average Kd values for PFOS and PFOA from the literature were 3.7 times and 3.6 times higher, respectively, than those measured in this study. Stepwise regression analysis did explain some of the variance, but with different explanatory variables for the different PFASs. The main soil properties explaining sorption for PFOS and PFOA were oxalate-extractable Al and pH, and for PFHxS was pH.

The role of surface charge and pH changes in tropical soils on sorption behaviour of per- and polyfluoroalkyl substances (PFASs).

This study investigated the effect of surface charge on the sorption of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and perfluorohexane sulfonic acid (PFHxS) onto 7 tropical soils as a function of pH. The net surface charge became less negative with decreasing pH (from 7.5 to 3.5) in all soils. The rate of change in net surface charge varied from -0.6 to -2.8 (cmol/kg)/pH unit. The effect on sorption behaviour of PFASs was variable among soils. For two soils, the average sorption increased 54- and 45-fold for PFOS, 33- and 9-fold for PFOA, and 39- and 400-fold for PFHxS, across the pH range 7.5 to 3.5. Sorption in another sandier soil showed negligible change with decreasing pH. Sorption in the other soils did not change significantly until the pH decreased to approximately 5.5. The soils with high contents of sesquioxides (Fe and Al oxides) showed the most marked increase in sorption with decreasing pH. This study demonstrated that in addition to hydrophobic interactions with OC and other processes, electrostatic interactions are also important in the sorption process for these chemicals in soils. In acidic, variably charged tropical soils there is the possibility that any PFOS, PFOA or PFHxS sorbed to the soils may become desorbed if management practices (e.g. liming) raised soil pH.

A critical analysis of published data to discern the role of soil and sediment properties in determining sorption of per and polyfluoroalkyl substances (PFASs).

Widespread usage of per- and polyfluoroalkyl substances (PFASs) has caused major environmental contamination globally. The hydrophilic and hydrophobic properties of PFASs affect the sorption behaviour and suggest organic carbon may not be the only factor affecting sorption. We reviewed the quality of all data published in peer-reviewed literature on sorption of PFASs to critically evaluate the role organic carbon (OC) and other properties have in sorption of PFASs in soils or sediments. The largest data sets available were for perfluorooctanoic acid (PFOA, n = 147) and perfluorooctane sulfonic acid (PFOS, n = 178), and these analyses showed very weak correlations between sorption coefficient (Kd) and OC alone (R2 = 0.05-0.07). When only laboratory-derived Kd values of PFASs and OC were analysed, the R2 values increased for PFOA (R2 = 0.24, n = 42), PFOS (R2 = 0.38, n = 69), perfluorononanoic acid (PFNA, R2 = 0.77 n = 12), and perfluorodecanoic acid (PFDA, R2 = 0.78, n = 13). However, the relationships were heavily skewed by one or two high OC values. Similarly there was no significant relationship between Kd values and pH for PFOS (R2 = 0.06) and PFOA (R2 = 0.07), across a range of environmental pH values. Our analyses showed sorption behaviour of a range of PFASs could not be explained by a single soil or sediment property. Multiple regression models better explained the sorption behaviour of a number of PFASs. Regressions of OC and pH together explained a significant proportion of the variation in Kd values for 9 out of 14 PFASs and 8 of these regressions had ≥10 data points. This review highlighted that at least OC, pH and clay content are properties having significant effect on sorption. There is a clear need for more data and studies with thorough characterisation of soils or sediments to better understand their role in PFASs sorption. Current assessments based on OC alone are likely to be erroneous.

Field evaluation of two risk indicators for predicting likelihood of pesticide transport to surface water from two orchards.

Two pesticide risk indicators, Pesticide Impact Rating Index (PIRI) and Environmental Potential Risk Indicator for Pesticides (EPRIP), were used to determine the likelihood of off-site transport to surface water of pesticides used in a cherry (Prunus avium cultivars) and an apple (Malus domestica cultivars) orchard. The predictions of off-site transport of some of the pesticides were verified against actual pesticide concentrations in surface water continuously monitored over two years. To our knowledge, only one other study in the published literature has attempted this. Of the chemicals monitored there was good agreement between the predictions and the field measurements from the apple orchard, but less so for the cherry orchard. In both risk indicators the attenuation factor based on the width of the buffer strip over-estimated the effectiveness of the buffer strip. There was good agreement between the EPRIP and PIRI risk assessment except for ethephon which EPRIP rated a higher risk than PIRI and dithianon which EPRIP rated a lower risk than PIRI. A strong correlation was found between the field observations and the EPRIP predicted environmental concentrations for the majority of cases. This study showed that even simple risk indicators (e.g. PIRI and EPRIP) can be good predictors for a first tier risk assessment of pesticide transport to neighbouring water bodies.

Comparative environmental impact assessment of herbicides used on genetically modified and non-genetically modified herbicide-tolerant canola crops using two risk indicators.

Canola (Brassica napus L.) is the third largest field crop in Australia by area sown. Genetically modified (GM) and non-GM canola varieties released or being developed in Australia include Clearfield® (imidazolinone tolerant), TT (triazine tolerant), InVigor® (glufosinate-ammonium tolerant), Roundup Ready® - RR® (glyphosate tolerant) and Hyola® RT® (tolerant to both glyphosate and triazine). We used two risk assessment approaches - the Environmental Impact Quotient (EIQ) and the Pesticide Impact Rating Index (PIRI) - to compare the environmental risks associated with herbicides used in the canola varieties (GM and non-GM) that are currently grown or may be grown in the future. Risk assessments found that from an environmental impact viewpoint a number of herbicides used in the production of TT canola showed high relative risk in terms of mobility and ecotoxicity of herbicides. The EIQ field use rating values for atrazine and simazine in particular were high compared with those for glyphosate and trifluralin. Imazapic and imazapyr, which are only used in Clearfield® canola, had extremely low EIQ field use rating values, likely reflecting the very low application rates used for these chemicals (0.02 to 0.04kg/ha) compared with those used for atrazine and simazine (1.2 to 1.5kg/ha). The PIRI assessment showed that irrespective of the canola variety grown, trifluralin posed a high toxicity risk to fish (Rainbow trout, Oncorhynchus mykiss), algae and Daphnia sp. While the replacement of trifluralin with propyzamide had little effect on the mobility score, it greatly decreased the ecotoxicity score to fish, algae and Daphnia sp. due to the lower LC50 values for propyzamide compared with trifluralin. This study has shown that based on likelihood of off-site transport of herbicides in surface water and potential toxicity to non-target organisms, the GM canola varieties have no advantage over non-herbicide tolerant (non HT) or Clearfield® canola.

Age-related changes in regulator of G-protein signaling (RGS)-10 expression in peripheral and central immune cells may influence the risk for age-related degeneration.

Inflammation in the aging brain increases risk for neurodegenerative disease. In humans, the regulator of G-protein signaling-10 (RGS10) locus has been associated with age-related maculopathy. Chronic peripheral administration of lipopolysaccharide in the RGS10-null mice induces nigral dopaminergic (DA) degeneration, suggesting that RGS10 modulates neuroimmune interactions and may influence susceptibility to neurodegeneration. Because age is the strongest risk factor for neurodegenerative disease, we assessed whether RGS10 expression changes with age and whether aged RGS10-null mice have altered immune cell profiles. Loss of RGS10 in aged mice does not alter the regulation of nigral DA neurons but does alter B-cell, monocyte, microglial, and CD4+ T-cell populations and inflammatory cytokine levels in the cerebrospinal fluid. These results suggest that loss of RGS10 is associated with an age-dependent dysregulation of peripheral and central immune cells rather than dysregulation of DA neuron function.

Banded applications are highly effective in minimising herbicide migration from furrow-irrigated sugar cane.

Runoff from farm fields is a common source of herbicide residues in surface waters in many agricultural industries around the world. In Queensland, Australia, the runoff of PSII inhibitor herbicides (in particular diuron and atrazine) is a major concern due to their potential impact on the Great Barrier Reef. This study compared the conventional practice of broadcast application of herbicides in sugarcane production across the whole field with the banded application of particular herbicides onto raised beds only using a shielded sprayer. This study found that the application of two moderately soluble herbicides, diuron and atrazine, to only the raised beds decreased the average total load of both herbicides moving off-site by >90% compared with the conventional treatment. This was despite the area being covered with the herbicides by the banded application being only 60% less than with the conventional treatment. The average total amount of atrazine in drainage water was 7.5% of the active ingredient applied in the conventional treatment compared with 1.8% of the active ingredient applied in the banded application treatment. Similarly, the average total amount of diuron in drainage water was 4.6% of that applied in the conventional treatment compared with 0.9% of that applied in the banded application treatment. This study demonstrates that the application of diuron and atrazine to raised beds only is a highly effective way of minimising migration of these herbicides in drainage water from furrow irrigated sugarcane.

Sorption of pesticides by a mineral sand mining by-product, neutralised used acid (NUA).

This study investigated the sorption-desorption behaviour of four pesticides by a by-product from mineral sand mining, commonly referred to as neutralised used acid (NUA). In batch studies the average amount of pesticide removed after 6h was 69% for atrazine, 89% for diuron, 61% for 2,4-D and 83% for chlorpyrifos. The lower sorption of 2,4-D to NUA compared with the other pesticides studied is most likely to be due to the high pH of the solutions (7.8 to 8.8) which would have resulted in 2,4-D being predominantly in an anionic form. The presence of other pesticides only significantly decreased the amount of 2,4-D sorbed from 59% to 34% when present in a mixture. Little (2 to 17%) diuron, chlorpyrifos, atrazine or 2,4-D were found to desorb from the NUA. The presence of nitrate or phosphate had minimal effect on the amount of diuron or atrazine sorbed to the NUA. However, all phosphate and nitrate treatments significantly (P<0.05) decreased the amount of 2,4-D sorbed (<50%) compared with when 2,4-D was present alone (65%). This study has shown that NUA has potential to be used as a sorbent for pesticides.

Spatial distribution of diuron sorption affinity as affected by soil, terrain and management practices in an intensively managed apple orchard.

We investigated how the sorption affinity of diuron (3'-(3,4-dichlorophenyl)-1,1-dimenthyl-urea), a moderately hydrophobic herbicide, is affected by soil properties, topography and management practices in an intensively managed orchard system. Soil-landscape analysis was carried out in an apple orchard which had a strong texture contrast soil and a landform with relief difference of 50 m. Diuron sorption (K(d)) affinity was successfully predicted (R(2)=0.79; p<0.001) using a mid-infrared - partial least squares model and calibrated against measured data using a conventional batch sorption technique. Soil and terrain properties explained 75% of the variance of diuron K(d) with TOC, pH(w), slope and WI as key variables. Mean diuron K(d) values were also significantly different (p<0.05) between alley and tree line and between the different management zones. Soil in the tree line generally had lower sorption capacity for diuron than soil in the alleys. Younger stands, which were found to have lower TOC than in the older stands, also had lower diuron K(d) values. In intensively managed orchards, sorption affinity of pesticides to soils was not only affected by soil properties and terrain attributes but also by management regime.

Psychiatric patients' views on why their involuntary hospitalisation was right or wrong: a qualitative study.

PURPOSE: To explore involuntary patients' retrospective views on why their hospitalisation was right or wrong. METHODS: Involuntary patients were recruited from 22 hospitals in England and interviewed in-depth. The study drew on grounded theory and thematic analysis. RESULTS: Most of the patients felt mentally unwell before admission and out of control during their treatment. Despite these common experiences, three groups of patients with distinct views on their involuntary hospitalisation were identified: those who believed that it was right, those who thought it was wrong and those with ambivalent views. Those with retrospectively positive views believed that hospitalisation ensured that they received treatment, averted further harm and offered them the opportunity to recover in a safe place. They felt that coercion was necessary, as they could not recognise that they needed help when acutely unwell. Those who believed that involuntary admission was wrong thought that their problems could have been managed through less coercive interventions, and experienced hospitalisation as an unjust infringement of their autonomy, posing a permanent threat to their independence. Patients with ambivalent views believed that they needed acute treatment and that hospitalisation averted further harm. Nonetheless, they thought that their problems might have been managed through less coercive community interventions or a shorter voluntary hospitalisation. CONCLUSIONS: The study illustrates why some patients view their involuntary hospitalisation positively, whereas others believe it was wrong. This knowledge could inform the development of interventions to improve patients' views and treatment experiences.

A comparison of participant information elicited by service user and non-service user researchers.

OBJECTIVE: The study examined whether data collected by researchers who were service users differed from data collected by non-service user researchers in a study that measured perceived coercion. METHODS: Over two years, 548 inpatients in England were interviewed during their first week of compulsory admission to a psychiatric bed at three regional mental health provider settings. Each site had one service user researcher and one nonuser researcher. The dependent variables were two measures of perceived coercion. Service users disclosed their status, including past hospitalization, to 93 of the 242 (38%) patients they interviewed. RESULTS: No differences were found on either variable between the three researcher categories (nondisclosed user, disclosed user, and nonuser researcher). An interaction with site was noted, and possible interpretations of this finding are discussed. CONCLUSIONS: Further research is needed to determine the conditions under which service user researchers obtain information that differs from that obtained by nonuser researchers.