Myoendothelial feedback in mouse mesenteric resistance arteries is similar between the sexes, dependent on nitric oxide synthase, and independent of TPRV4.

Myoendothelial feedback (MEF), the endothelium-dependent vasodilation following sympathetic vasoconstriction (mediated by smooth muscle to endothelium gap junction communication), has been well studied in resistance arteries of males, but not females. We hypothesized that MEF responses would be similar between the sexes, but different in the relative contribution of the underlying nitric oxide and hyperpolarization mechanisms, given that these mechanisms differ between the sexes in agonist-induced endothelium-dependent dilation. We measured MEF responses (diameter changes) of male and female first- to second-order mouse mesenteric arteries to phenylephrine (10 µM) over 30 min using isolated pressure myography ± blinded inhibition of nitric oxide synthase (NOS) using Nω-nitro-l-arginine methyl ester (l-NAME; 0.1-1.0 mM), hyperpolarization using 35 mM KCl, or transient receptor potential vanilloid 4 (TRPV4) channels using GSK219 (0.1-1.0 µM) or RN-1734 (30 µM). MEF was similar [%dilation (means ± SE): males = 26.7 ± 2.0 and females = 26.1 ± 1.9 at 15 min] and significantly inhibited by l-NAME (1.0 mM) at 15 min [%dilation (means ± SE): males = 8.2 ± 3.3, P < 0.01; females = 6.8 ± 1.9, P < 0.001] and over time (P < 0.01) in both sexes. l-NAME (0.1 mM) + 35 mM KCl nearly eliminated MEF in both sexes (P < 0.001-0.0001). Activation of TRPV4 with GSK101 (0.1-10 µM) induced similar dilation between the sexes. Inhibition of TRPV4, which is reportedly involved in the hyperpolarization mechanism, did not inhibit MEF in either sex. Similar expression of eNOS was found between the sexes with Western blot. Thus, MEF is prominent and similar in murine first- and second-order mesenteric resistance arteries of both sexes, and reliant primarily on NOS and secondarily on hyperpolarization, but not TRPV4.NEW & NOTEWORTHY We found that female mesenteric resistance arteries have similar postconstriction dilatory responses (i.e., myoendothelial feedback) to a sympathetic neurotransmitter analog as male arteries. Both sexes use nitric oxide synthase (NOS) and hyperpolarization, but not TRPV4, in this response. Moreover, the key protein involved in this pathway (eNOS) is similarly expressed in these arteries between the sexes. These similarities are surprising given that agonist-induced endothelium-dependent dilatory mechanisms differ in these arteries between the sexes.

Increased hippocampal blood flow in people at clinical high risk for psychosis and effects of cannabidiol.

BACKGROUND: Hippocampal hyperperfusion has been observed in people at Clinical High Risk for Psychosis (CHR), is associated with adverse longitudinal outcomes and represents a potential treatment target for novel pharmacotherapies. Whether cannabidiol (CBD) has ameliorative effects on hippocampal blood flow (rCBF) in CHR patients remains unknown. METHODS: Using a double-blind, parallel-group design, 33 CHR patients were randomized to a single oral 600 mg dose of CBD or placebo; 19 healthy controls did not receive any drug. Hippocampal rCBF was measured using Arterial Spin Labeling. We examined differences relating to CHR status (controls v. placebo), effects of CBD in CHR (placebo v. CBD) and linear between-group relationships, such that placebo > CBD > controls or controls > CBD > placebo, using a combination of hypothesis-driven and exploratory wholebrain analyses. RESULTS: Placebo-treated patients had significantly higher hippocampal rCBF bilaterally (all pFWE<0.01) compared to healthy controls. There were no suprathreshold effects in the CBD v. placebo contrast. However, we found a significant linear relationship in the right hippocampus (pFWE = 0.035) such that rCBF was highest in the placebo group, lowest in controls and intermediate in the CBD group. Exploratory wholebrain results replicated previous findings of hyperperfusion in the hippocampus, striatum and midbrain in CHR patients, and provided novel evidence of increased rCBF in inferior-temporal and lateral-occipital regions in patients under CBD compared to placebo. CONCLUSIONS: These findings suggest that hippocampal blood flow is elevated in the CHR state and may be partially normalized by a single dose of CBD. CBD therefore merits further investigation as a potential novel treatment for this population.

Cannabidiol attenuates insular activity during motivational salience processing in patients with early psychosis.

BACKGROUND: The mechanisms underlying the antipsychotic potential of cannabidiol (CBD) remain unclear but growing evidence indicates that dysfunction in the insula, a key brain region involved in the processing of motivationally salient stimuli, may have a role in the pathophysiology of psychosis. Here, we investigate whether the antipsychotic mechanisms of CBD are underpinned by their effects on insular activation, known to be involved in salience processing. METHODS: A within-subject, crossover, double-blind, placebo-controlled investigation of 19 healthy controls and 15 participants with early psychosis was conducted. Administration of a single dose of CBD was compared with placebo in psychosis participants while performing the monetary incentive delay task, an fMRI paradigm. Anticipation of reward and loss were used to contrast motivationally salient stimuli against a neutral control condition. RESULTS: No group differences in brain activation between psychosis patients compared with healthy controls were observed. Attenuation of insula activation was observed following CBD, compared to placebo. Sensitivity analyses controlling for current cannabis use history did not affect the main results. CONCLUSION: Our findings are in accordance with existing evidence suggesting that CBD modulates brain regions involved in salience processing. Whether such effects underlie the putative antipsychotic effects of CBD remains to be investigated.

Coffee intake and trace element blood concentrations in association with renal cell cancer among smokers.

PURPOSE: To determine whether higher coffee intake may reduce the risk of renal cell cancer (RCC) associated with lead (Pb) and other heavy metals with known renal toxicity. METHODS: We conducted a nested case-control study of male smokers (136 RCC cases and 304 controls) within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Cases diagnosed with RCC at 5 or more years following cohort enrollment were matched to controls on age (± 7 years) and whole blood draw date (± 30 days). Conditional logistic regression (using two-sided tests) was used to test for main effects and additive models of effect modification. RESULTS: After a mean follow-up of 16.3 years, coffee consumption was not significantly associated with renal cell cancer risk, when adjusting for blood concentrations of Cd, Hg, and Pb and RCC risk factors (age, smoking, BMI, and systolic blood pressure) (p-trend, 0.134). The association with above median blood Pb and RCC (HR = 1.69, 95% CI 1.06, 2.85) appeared to be modified by coffee consumption, such that RCC risk among individuals with both increased coffee intake and higher blood lead concentration were more than threefold higher RCC risk (HR = 3.40, 95% CI 1.62, 7.13; p-trend, 0.003). CONCLUSION: Contrary to our initial hypothesis, this study suggests that heavy coffee consumption may increase the previously identified association between higher circulating lead (Pb) concentrations and increased RCC risk. Improved assessment of exposure, including potential trace element contaminants in coffee, is needed.

An Eclectic Cast of Cellular Actors Orchestrates Innate Immune Responses in the Mechanisms Driving Obesity and Metabolic Perturbation.

The escalating problem of obesity and its multiple metabolic and cardiovascular complications threatens the health and longevity of humans throughout the world. The cause of obesity and one of its chief complications, insulin resistance, involves the participation of multiple distinct organs and cell types. From the brain to the periphery, cell-intrinsic and intercellular networks converge to stimulate and propagate increases in body mass and adiposity, as well as disturbances of insulin sensitivity. This review focuses on the roles of the cadre of innate immune cells, both those that are resident in metabolic organs and those that are recruited into these organs in response to cues elicited by stressors such as overnutrition and reduced physical activity. Beyond the typical cast of innate immune characters invoked in the mechanisms of metabolic perturbation in these settings, such as neutrophils and monocytes/macrophages, these actors are joined by bone marrow-derived cells, such as eosinophils and mast cells and the intriguing innate lymphoid cells, which are present in the circulation and in metabolic organ depots. Upon high-fat feeding or reduced physical activity, phenotypic modulation of the cast of plastic innate immune cells ensues, leading to the production of mediators that affect inflammation, lipid handling, and metabolic signaling. Furthermore, their consequent interactions with adaptive immune cells, including myriad T-cell and B-cell subsets, compound these complexities. Notably, many of these innate immune cell-elicited signals in overnutrition may be modulated by weight loss, such as that induced by bariatric surgery. Recently, exciting insights into the biology and pathobiology of these cell type-specific niches are being uncovered by state-of-the-art techniques such as single-cell RNA-sequencing. This review considers the evolution of this field of research on innate immunity in obesity and metabolic perturbation, as well as future directions.

Altered relationship between cortisol response to social stress and mediotemporal function during fear processing in people at clinical high risk for psychosis: a preliminary report.

Evidence suggests that people at Clinical High Risk for Psychosis (CHR) have a blunted cortisol response to stress and altered mediotemporal activation during fear processing, which may be neuroendocrine-neuronal signatures of maladaptive threat responses. However, whether these facets are associated with each other and how this relationship is affected by cannabidiol treatment is unknown. We examined the relationship between cortisol response to social stress and mediotemporal function during fear processing in healthy people and in CHR patients. In exploratory analyses, we investigated whether treatment with cannabidiol in CHR individuals could normalise any putative alterations in cortisol-mediotemporal coupling. 33 CHR patients were randomised to 600 mg cannabidiol or placebo treatment. Healthy controls (n = 19) did not receive any drug. Mediotemporal function was assessed using a fearful face-processing functional magnetic resonance imaging paradigm. Serum cortisol and anxiety were measured immediately following the Trier Social Stress Test. The relationship between cortisol and mediotemporal blood-oxygen-level-dependent haemodynamic response was investigated using linear regression. In healthy controls, there was a significant negative relationship between cortisol and parahippocampal activation (p = 0.023), such that the higher the cortisol levels induced by social stress, the lower the parahippocampal activation (greater deactivation) during fear processing. This relationship differed significantly between the control and placebo groups (p = 0.033), but not between the placebo and cannabidiol groups (p = 0.67). Our preliminary findings suggest that the parahippocampal response to fear processing may be associated with the neuroendocrine (cortisol) response to experimentally induced social stress, and that this relationship may be altered in patients at clinical high risk for psychosis.

Normalization of mediotemporal and prefrontal activity, and mediotemporal-striatal connectivity, may underlie antipsychotic effects of cannabidiol in psychosis.

BACKGROUND: Recent evidence suggests that cannabidiol (CBD), a non-intoxicating ingredient present in cannabis extract, has an antipsychotic effect in people with established psychosis. However, the effect of CBD on the neurocognitive mechanisms underlying psychosis is unknown. METHODS: Patients with established psychosis on standard antipsychotic treatment were studied on separate days at least one week apart, to investigate the effects of a single dose of orally administered CBD (600 mg) compared to a matched placebo (PLB), using a double-blind, randomized, PLB-controlled, repeated-measures, within-subject cross-over design. Three hours after taking the study drug participants were scanned using a block design functional magnetic resonance imaging (fMRI) paradigm, while performing a verbal paired associate learning task. Fifteen psychosis patients completed both study days, 13 completed both scanning sessions. Nineteen healthy controls (HC) were also scanned using the same fMRI paradigm under identical conditions, but without any drug administration. Effects of CBD on brain activation measured using the blood oxygen level-dependent hemodynamic response fMRI signal were studied in the mediotemporal, prefrontal, and striatal regions of interest. RESULTS: Compared to HC, psychosis patients under PLB had altered prefrontal activation during verbal encoding, as well as altered mediotemporal and prefrontal activation and greater mediotemporal-striatal functional connectivity during verbal recall. CBD attenuated dysfunction in these regions such that activation under its influence was intermediate between the PLB condition and HC. CBD also attenuated hippocampal-striatal functional connectivity and caused trend-level symptom reduction in psychosis patients. CONCLUSIONS: This suggests that normalization of mediotemporal and prefrontal dysfunction and mediotemporal-striatal functional connectivity may underlie the antipsychotic effects of CBD.

Adolescent-onset heavy cannabis use associated with significantly reduced glial but not neuronal markers and glutamate levels in the hippocampus.

Cannabis use has been associated with adverse mental health outcomes, the neurochemical underpinnings of which are poorly understood. Although preclinical evidence suggests glutamatergic dysfunction following cannabis exposure in several brain regions including the hippocampus, evidence from human studies have been inconsistent. We investigated the effect of persistent cannabis use on the brain levels of N-acetyl aspartate (NAA) and myoinositol, the metabolite markers of neurons and glia, the site of the main central cannabinoid CB1 receptor, and the levels of glutamate, the neurotransmitter directly affected by CB1 modulation. We investigated cannabis users (CUs) who started using during adolescence, the period of greatest vulnerability to cannabis effects and focused on the hippocampus, where type 1 cannabinoid receptors (CBR1) are expressed in high density and have been linked to altered glutamatergic neurotransmission. Twenty-two adolescent-onset CUs and 21 nonusing controls (NU), completed proton magnetic resonance spectroscopy, to measure hippocampal metabolite concentrations. Glutamate, NAA, and myoinositol levels were compared between CU and NU using separate analyses of covariance. CU had significantly lower myoinositol but not glutamate or NAA levels in the hippocampus compared with NU. Myoinositol levels in CU positively correlated with glutamate levels, whereas this association was absent in NU. Altered myoinositol levels may be a marker of glia dysfunction and is consistent with experimental preclinical evidence that cannabinoid-induced glial dysfunction may underlie cannabinoid-induced memory impairments. Future studies using appropriate imaging techniques such as positron emission tomography should investigate whether glial dysfunction associated with cannabis use underlies hippocampal dysfunction and memory impairment in CUs.

Shear Stress Attenuates Inward Remodeling in Cultured Mouse Thoracodorsal Arteries in an eNOS-Dependent, but Not Hemodynamic Manner, and Increases Cx37 Expression.

BACKGROUND: Arteries chronically constricted in culture remodel to smaller diameters. Conversely, elevated luminal shear stress (SS) promotes outward remodeling of arteries in vivo and prevents inward remodeling in culture in a nitric oxide synthase (NOS)-dependent manner. OBJECTIVES: To determine whether SS-induced prevention of inward remodeling in cultured arteries is specifically eNOS-dependent and requires dilation, and whether SS alters the expression of eNOS and other genes potentially involved in remodeling. METHODS: Female mouse thoracodorsal arteries were cannulated, pressurized to 80 mm Hg, and cultured for 2 days with low SS (<7 dyn/cm2), high SS (≥15 dyn/cm2), high SS + L-NAME (NOS inhibitor, 10-4 M), or high SS in arteries from eNOS-/- mice. In separate arteries cultured 1 day with low or high SS, eNOS and connexin (Cx) 37, Cx40, and Cx43 mRNA were assessed with real-time PCR. RESULTS: High SS caused little change in passive diameters after culture (-4.7 ± 2.0%), which was less than low SS (-18.9 ± 1.4%; p < 0.0001), high SS eNOS-/- (-18.0 ± 1.5; p < 0.001), or high SS + L-NAME (-12.0 ± 0.6%; nonsignificant) despite similar constriction during culture. Cx37 mRNA expression was increased (p < 0.05) with high SS, but other gene levels were not different. CONCLUSIONS: eNOS is involved in SS-induced prevention of inward remodeling in cultured small arteries. This effect does not require NO-mediated dilation. SS increased Cx37.

Non-Endoplasmic Reticulum-Based Calr (Calreticulin) Can Coordinate Heterocellular Calcium Signaling and Vascular Function.

OBJECTIVE: In resistance arteries, endothelial cell (EC) extensions can make contact with smooth muscle cells, forming myoendothelial junction at holes in the internal elastic lamina (HIEL). At these HIEL, calcium signaling is tightly regulated. Because Calr (calreticulin) can buffer ≈50% of endoplasmic reticulum calcium and is expressed throughout IEL holes in small arteries, the only place where myoendothelial junctions form, we investigated the effect of EC-specific Calr deletion on calcium signaling and vascular function. APPROACH AND RESULTS: We found Calr expressed in nearly every IEL hole in third-order mesenteric arteries, but not other ER markers. Because of this, we generated an EC-specific, tamoxifen inducible, Calr knockout mouse (EC Calr Δ/Δ). Using this mouse, we tested third-order mesenteric arteries for changes in calcium events at HIEL and vascular reactivity after application of CCh (carbachol) or PE (phenylephrine). We found that arteries from EC Calr Δ/Δ mice stimulated with CCh had unchanged activity of calcium signals and vasodilation; however, the same arteries were unable to increase calcium events at HIEL in response to PE. This resulted in significantly increased vasoconstriction to PE, presumably because of inhibited negative feedback. In line with these observations, the EC Calr Δ/Δ had increased blood pressure. Comparison of ER calcium in arteries and use of an ER-specific GCaMP indicator in vitro revealed no observable difference in ER calcium with Calr knockout. Using selective detergent permeabilization of the artery and inhibition of Calr translocation, we found that the observed Calr at HIEL may not be within the ER. CONCLUSIONS: Our data suggest that Calr specifically at HIEL may act in a non-ER dependent manner to regulate arteriolar heterocellular communication and blood pressure.

Ancestry-Adjusted Vitamin D Metabolite Concentrations in Association With Cytochrome P450 3A Polymorphisms.

We investigated the association between genetic polymorphisms in cytochrome P450 (CYP2R1, CYP24A1, and the CYP3A family) with nonsummer plasma concentrations of vitamin D metabolites (25-hydroxyvitamin D3 (25(OH)D3) and proportion 24,25-dihydroxyvitamin D3 (24,25(OH)2D3)) among healthy individuals of sub-Saharan African and European ancestry, matched on age (within 5 years; n = 188 in each ancestral group), in central suburban Pennsylvania (2006-2009). Vitamin D metabolites were measured using high-performance liquid chromatography with tandem mass spectrometry. Paired multiple regression and adjusted least-squares mean analyses were used to test for associations between genotype and log-transformed metabolite concentrations, adjusted for age, sex, proportion of West-African genetic ancestry, body mass index, oral contraceptive (OC) use, tanning bed use, vitamin D intake, days from summer solstice, time of day of blood draw, and isoforms of the vitamin D receptor (VDR) and vitamin D binding protein. Polymorphisms in CYP2R1, CYP3A43, vitamin D binding protein, and genetic ancestry proportion remained associated with plasma 25(OH)D3 after adjustment. Only CYP3A43 and VDR polymorphisms were associated with proportion 24,25(OH)2D3. Magnitudes of association with 25(OH)D3 were similar for CYP3A43, tanning bed use, and OC use. Significant least-squares mean interactions (CYP2R1/OC use (P = 0.030) and CYP3A43/VDR (P = 0.013)) were identified. A CYP3A43 genotype, previously implicated in cancer, is strongly associated with biomarkers of vitamin D metabolism. Interactive associations should be further investigated.

The Neural Substrate of Reward Anticipation in Health: A Meta-Analysis of fMRI Findings in the Monetary Incentive Delay Task.

The monetary incentive delay task breaks down reward processing into discrete stages for fMRI analysis. Here we look at anticipation of monetary gain and loss contrasted with neutral anticipation. We meta-analysed data from 15 original whole-brain group maps (n = 346) and report extensive areas of relative activation and deactivation throughout the whole brain. For both anticipation of gain and loss we report robust activation of the striatum, activation of key nodes of the putative salience network, including anterior cingulate and anterior insula, and more complex patterns of activation and deactivation in the central executive and default networks. On between-group comparison, we found significantly greater relative deactivation in the left inferior frontal gyrus associated with incentive valence. This meta-analysis provides a robust whole-brain map of a reward anticipation network in the healthy human brain.

Correction to: The Neural Substrate of Reward Anticipation in Health: A Meta-Analysis of fMRI Findings in the Monetary Incentive Delay Task.

The members of MTAC were removed from the author group and full list are shown in the Acknowledgements section. Also, members "Roee, A" and "Van Amselvoort, T" should be "Admon, R" and "Van Amelsvoort, T", respectively. The original article has been corrected.

Human Striatal Response to Reward Anticipation Linked to Hippocampal Glutamate Levels.

Background: Dysfunctional reward processing is associated with a number of psychiatric disorders, such as addiction and schizophrenia. It is thought that reward is regulated mainly by dopamine transmission in the ventral striatum. Contemporary animal models suggest that striatal dopamine concentrations and associated behaviors are related to glutamatergic functioning in the ventral hippocampus. However, in humans the association between reward-related ventral striatal response and hippocampal glutamate levels is unclear. Methods: Nineteen healthy participants were studied using proton magnetic resonance spectroscopy to measure hippocampal glutamate levels, and functional magnetic resonance imaging to assess striatal activation and functional connectivity during performance of a monetary incentive delay task. Results: We found that ventral striatal activation related to reward processing was correlated with hippocampal glutamate levels. In addition, context-dependent functional coupling was demonstrated between the ventral striatum and both the lingual gyrus and hippocampus during reward anticipation. Elevated hippocampal glutamate levels were inversely related to context-dependent functional connectivity between the ventral striatum and the anterior hippocampus while anticipating reward. Conclusions: These findings indicate that human striatal responses to reward are influenced by hippocampal glutamate levels. This may be relevant for psychiatric disorders associated with abnormal reward processing such as addiction and schizophrenia.

Increased myoendothelial feedback is associated with increased connexin37 and IK1 channel expression in mesenteric arteries of diet-induced hyperhomocysteinemic mice.

OBJECTIVE: Previously, we found that diet-induced HHcy in mice caused decreased eNOS expression and signaling in mesenteric arteries, but greatly enhanced non-NOS, non-prostacyclin-dependent vasodilation, which involves MEJ communication. To further assess whether HHcy enhances MEJ communication, this study examined endothelium-dependent attenuation of phenylephrine-induced vasoconstriction (myoendothelial feedback) and key molecules involved. METHODS: Myoendothelial feedback was examined in isolated mouse mesenteric arteries, after 6-weeks diet-induced HHcy, using pressure myography. Gap junction (Cx37, Cx40, Cx43), NOS (eNOS, nNOS, iNOS), and potassium channel (IK1) protein expression were measured with immunoblots, and connexin mRNAs with real-time PCR. Contribution of nNOS + iNOS to vasomotor responses was assessed using the drug TRIM. RESULTS: Myoendothelial feedback was significantly (P < .05) enhanced in HHcy arteries compared to control, coincident with significantly greater Cx37 and IK1 protein and Cx37 mRNA. Cx43 protein, but not mRNA, was significantly less in HHcy, and Cx40 was not different. eNOS protein was significantly less in HHcy. nNOS and iNOS were not different. TRIM had little effect on vasomotor function. CONCLUSIONS: Diet-induced HHcy enhanced myoendothelial feedback, and increased Cx37 and IK1 expression may contribute. nNOS or iNOS did not upregulate to compensate for decreased eNOS, and they had little involvement in vasomotor function.

For whom the cells pull: Hydrogel and micropost devices for measuring traction forces.

While performing several functions, adherent cells deform their surrounding substrate via stable adhesions that connect the intracellular cytoskeleton to the extracellular matrix. The traction forces that deform the substrate are studied in mechanotrasduction because they are affected by the mechanics of the extracellular milieu. We review the development and application of two methods widely used to measure traction forces generated by cells on 2D substrates: (i) traction force microscopy with polyacrylamide hydrogels and (ii) calculation of traction forces with arrays of deformable microposts. Measuring forces with these methods relies on measuring substrate displacements and converting them into forces. We describe approaches to determine force from displacements and elaborate on the necessary experimental conditions for this type of analysis. We emphasize device fabrication, mechanical calibration of substrates and covalent attachment of extracellular matrix proteins to substrates as key features in the design of experiments to measure cell traction forces with polyacrylamide hydrogels or microposts. We also report the challenges and achievements in integrating these methods with platforms for the mechanical stimulation of adherent cells. The approaches described here will enable new studies to understand cell mechanical outputs as a function of mechanical inputs and advance the understanding of mechanotransduction mechanisms.

Commonness and rarity in the marine biosphere.

Explaining patterns of commonness and rarity is fundamental for understanding and managing biodiversity. Consequently, a key test of biodiversity theory has been how well ecological models reproduce empirical distributions of species abundances. However, ecological models with very different assumptions can predict similar species abundance distributions, whereas models with similar assumptions may generate very different predictions. This complicates inferring processes driving community structure from model fits to data. Here, we use an approximation that captures common features of "neutral" biodiversity models--which assume ecological equivalence of species--to test whether neutrality is consistent with patterns of commonness and rarity in the marine biosphere. We do this by analyzing 1,185 species abundance distributions from 14 marine ecosystems ranging from intertidal habitats to abyssal depths, and from the tropics to polar regions. Neutrality performs substantially worse than a classical nonneutral alternative: empirical data consistently show greater heterogeneity of species abundances than expected under neutrality. Poor performance of neutral theory is driven by its consistent inability to capture the dominance of the communities' most-abundant species. Previous tests showing poor performance of a neutral model for a particular system often have been followed by controversy about whether an alternative formulation of neutral theory could explain the data after all. However, our approach focuses on common features of neutral models, revealing discrepancies with a broad range of empirical abundance distributions. These findings highlight the need for biodiversity theory in which ecological differences among species, such as niche differences and demographic trade-offs, play a central role.

Metal-contaminated potato crops and potential human health risk in Bolivian mining highlands.

This study assessed metals in irrigation water, soil and potato crops impacted by mining discharges, as well as potential human health risk in the high desert near the historic mining center of Potosí, Bolivia. Metal concentrations were compared with international concentration limit guidelines. In addition, an ingested average daily dose and minimum risk level were used to determine the hazard quotient from potato consumption for adults and children. Irrigation water maximum concentrations of Cd, Pb and Zn in mining-impacted sites were elevated 20- to 1100-fold above international concentration limit guidelines. Agricultural soils contained total metal concentrations of As, Cd, Pb and Zn that exceeded concentration limits in agricultural soil guidelines by 22-, 9-, 3- and 12-fold, respectively. Potato tubers in mining-impacted sites had maximum concentrations of As, Cd, Pb and Zn that exceeded concentration limits in commercially sold vegetables by 9-, 10-, 16- and fourfold, respectively. Using conservative assumptions, hazard quotients (HQ) for potatoes alone were elevated for As, Cd and Pb among children (range 1.1-71.8), in nearly all of the mining-impacted areas; and for As and Cd among adults (range 1.2-34.2) in nearly all of the mining-impacted areas. Only one mining-impacted area had a Pb adult HQ for potatoes above 1 for adults. Toxic trace elements in a major regional dietary staple may be a greater concern than previously appreciated. Considering the multitude of other metal exposure routes in this region, it is likely that total HQ values for these metals may be substantially higher than our estimates.

Cannabis use and treatment resistance in first episode psychosis: a natural language processing study.

BACKGROUND: Cannabis is frequently used among individuals with first episode psychosis and is associated with poor clinical outcomes. However, little is known about the effect of cannabis use on the response to antipsychotic medications and how use could affect outcomes. Using natural language processing on clinical data from a large electronic case register, we sought to investigate whether resistance to antipsychotic treatment mediated poor clinical outcomes associated with cannabis use. METHODS: Data were obtained from 2026 people with first episode psychosis in south London, UK. Cannabis use documented in free text clinical records was identified with natural language processing. Data for age, sex, ethnicity, marital status, psychotic disorder diagnosis, subsequent hospital admission, and number of unique antipsychotic medications prescribed were obtained using the Clinical Record Interactive Search instrument. The association of these variables with cannabis use was analysed with multivariable regression and mediation analysis. FINDINGS: 939 people (46·3%) with first episode psychosis were using cannabis at first presentation. Cannabis use was most strongly associated with being 16-25 years old, male, and single, and was also associated with an increase in number of hospital admissions (incidence rate ratio 1·50, 95% CI 1·25-1·80), compulsory hospital admission (odds ratio 1·55, 1·16-2·08), and number of days spent in hospital (ß coefficient 35·1 days, 12·1-58·1) over 5 years' follow-up. An increase in number of unique antipsychotic medications mediated an increase in number of hospital admissions (natural indirect effect 1·11, 1·04-1·17; total effect 1·41, 1·22-1·64), compulsory hospital admission (1·27, 1·10-1·45; 1·71, 1·05-2·78), and number of days spent in hospital (16·1, 6·7-25·5; 19·9, 2·5-37·3). INTERPRETATION: We showed that a substantial number of people with first episode psychosis used cannabis and that its use was associated with increased likelihood of hospital admission and number of days spent in hospital. These associations were partly mediated by an increase in number of unique antipsychotic medications prescribed. These findings suggest that cannabis might reduce response to conventional antipsychotic treatment and highlight the importance of strategies to reduce its use. FUNDING: National Institute for Health Research, UK Medical Research Council.

High C-Reactive Protein Is Associated with Poor Sleep Quality Independent of Nocturnal Symptoms in Patients with Inflammatory Bowel Disease.

BACKGROUND: Sleep disruption is common in inflammatory bowel diseases (IBD). However, studies demonstrating a similar prevalence in irritable bowel syndrome suggest that nighttime disruption due to diarrhea and abdominal pain may be key drivers of poor sleep quality. Whether inflammation is associated with poor sleep independently has not been examined previously. METHODS: This single-center study included subjects with IBD recruited to an ongoing prospective registry who completed a questionnaire assessing sleep quality and mood. Inflammatory marker levels [C-reactive protein (CRP), erythrocyte sedimentation rate] and clinical disease activity including nighttime disruption on the day of enrollment were obtained from the medical record. Logistic regression models were used to identify predictors of sleep quality. RESULTS: The study included 131 subjects (72 women) with a median age of IBD diagnosis of 25 years. Twenty-three subjects (19 %) had a high C-reactive protein level (≥8 mg/dL). Poor sleep was more common in those with high CRP levels than with normal values (70 vs. 39 %, p = 0.009). This association remained significant on multivariate analysis [Odds ratio (OR) 4.12, 95 % confidence interval (CI) 1.38-12.29]. Adjusting for the presence of nighttime disruption did not significant alter this association (OR 3.16, 95 % CI 1.01-9.90). High CRP correlated with poor sleep even in patients not experiencing nocturnal symptoms (n = 101, OR 4.89, 95 % CI 1.24-19.36). CONCLUSION: High CRP is associated with poor sleep quality in IBD independent of the presence of nighttime disruptions, suggesting that a relationship exists between circulating inflammatory markers and sleep.