Deficits in basal and evoked striatal dopamine release following alpha-synuclein preformed fibril injection: An in vivo microdialysis study.

Parkinson's disease (PD) is characterized by the accumulation of misfolded alpha-synuclein (α-syn) protein, forming intraneuronal Lewy body (LB) inclusions. The α-syn preformed fibril (PFF) model of PD recapitulates α-syn aggregation, progressive nigrostriatal degeneration and motor dysfunction; however, little is known about the time course of PFF-induced alterations in basal and evoked dopamine (DA). In vivo microdialysis is well suited for identifying small changes in neurotransmitter levels over extended periods. In the present study, adult male Fischer 344 rats received unilateral, intrastriatal injections of either α-syn PFFs or phosphate-buffered saline (PBS). At 4 or 8 months post-injection (p.i.), animals underwent in vivo microdialysis to evaluate basal extracellular striatal DA and metabolite levels, local KCl-evoked striatal DA release and the effects of systemic levodopa (l-DOPA). Post-mortem analysis demonstrated equivalent PFF-induced reductions in tyrosine hydroxylase (TH) immunoreactive nigral neurons (~50%) and striatal TH (~20%) at both time points. Compared with reduction in striatal TH, reduction in striatal dopamine transporter (DAT) was more pronounced and progressed between the 4- and 8-month p.i. intervals (36% âž” 46%). Significant PFF-induced deficits in basal and evoked striatal DA, as well as deficits in motor performance, were not observed until 8 months p.i. Responses to l-DOPA did not differ regardless of PBS or PFF treatment. These results suggest that basal and evoked striatal DA are maintained for several months following PFF injection, with loss of both associated with motor dysfunction. Our studies provide insight into the time course and magnitude of PFF-induced extracellular dopaminergic deficits in the striatum.

Characterizing the relationship between L-DOPA-induced-dyskinesia and psychosis-like behaviors in a bilateral rat model of Parkinson's disease.

Parkinson's disease associated psychosis (PDAP) is a prevalent non-motor symptom (NMS) that significantly erodes patients' and caregivers' quality of life yet remains vastly understudied. One potential source of PDAP in late-stage Parkinson's disease (PD) is the common dopamine (DA) replacement therapy for motor symptoms, Levodopa (L-DOPA). Given the high incidence of L-DOPA-induced dyskinesia (LID) in later phases of PD, this study sought to characterize the relationship between PDAP and LID in a bilateral medial forebrain bundle 6-hydroxydopamine hydrobromide (6-OHDA) lesion rat model. To assess PDAP in this model, prepulse inhibition (PPI), a well-validated assay of sensorimotor gating, was employed. First, we tested whether a bilateral lesion alone or after chronic L-DOPA treatment was sufficient to induce PPI dysfunction. Rats were also monitored for LID development, using the abnormal involuntary movements (AIMs) test, to examine PPI and LID associations. In experiment 2, Vilazodone (VZD), a serotonin transporter (SERT) blocker and 1A receptor (5-HT1A) partial agonist was administered to test its potential efficacy in reducing LID and PPI dysfunction. Once testing was complete, tissue was collected for high performance liquid chromatography (HPLC) to examine the monoamine levels in motor and non-motor circuits. Results indicate that bilateral DA lesions produced motor deficits and that chronic L-DOPA induced moderate AIMs; importantly, rats that developed more severe AIMs were more likely to display sensorimotor gating dysfunction. In addition, VZD treatment dose-dependently reduced L-DOPA-induced AIMs without impairing L-DOPA efficacy, although VZD's effects on PPI were limited. Altogether, this project established the bilateral 6-OHDA lesion model accurately portrayed LID and PDAP-like behaviors, uncovered their potential relationship, and finally, demonstrated the utility of VZD for reducing LID.

Pharmacological targeting of G protein-coupled receptor heteromers.

A main rationale for the role of G protein-coupled receptor (GPCR) heteromers as targets for drug development is the putative ability of selective ligands for specific GPCRs to change their pharmacological properties upon GPCR heteromerization. The present study provides a proof of concept for this rationale by demonstrating that heteromerization of dopamine D1 and D3 receptors (D1R and D3R) influences the pharmacological properties of three structurally similar selective dopamine D3R ligands, the phenylpiperazine derivatives PG01042, PG01037 and VK4-116. By using D1R-D3R heteromer-disrupting peptides, it could be demonstrated that the three D3R ligands display different D1R-D3R heteromer-dependent pharmacological properties: PG01042, acting as G protein-biased agonist, counteracted D1R-mediated signaling in the D1R-D3R heteromer; PG01037, acting as a D3R antagonist cross-antagonized D1R-mediated signaling in the D1R-D3R heteromer; and VK4-116 specifically acted as a ß-arrestin-biased agonist in the D1R-D3R heteromer. Molecular dynamics simulations predicted potential molecular mechanisms mediating these qualitatively different pharmacological properties of the selective D3R ligands that are dependent on D1R-D3R heteromerization. The results of in vitro experiments were paralleled by qualitatively different pharmacological properties of the D3R ligands in vivo. The results supported the involvement of D1R-D3R heteromers in the locomotor activation by D1R agonists in reserpinized mice and L-DOPA-induced dyskinesia in rats, highlighting the D1R-D3R heteromer as a main pharmacological target for L-DOPA-induced dyskinesia in Parkinson's disease. More generally, the present study implies that when suspecting its pathogenetic role, a GPCR heteromer, and not its individual GPCR units, should be considered as main target for drug development.

Effects of pedunculopontine nucleus cholinergic lesion on gait and dyskinesia in hemiparkinsonian rats.

Pedunculopontine nucleus (PPN) cholinergic neurons are implicated in freezing of gait in Parkinson's disease (PD) and motor stereotypy in normal animals, but the causal role of these neurons on specific gait parameters and treatment-induced dyskinesia remains speculative. Therefore, we examined whether selective cholinergic lesion of the rostral PPN affects PD motor and gait deficits, L-DOPA-induced dyskinesia and motor improvement, and DA-agonist-induced dyskinesia. Sprague-Dawley rats were assigned to one unilaterally lesioned group: Sham lesion, PPN cholinergic lesion with diphtheria urotensin II fusion toxin, medial forebrain bundle dopamine lesion with 6-hydroxydopamine, or dual acetylcholine and dopamine lesion. We used gait analysis and forepaw adjusting steps to examine PD gait and motor deficits. Forepaw adjusting steps were also used to assess motor improvement with L-DOPA treatment. The abnormal involuntary movements scale measured L-DOPA and dopamine D1- and D2-receptor agonist-induced dyskinesia. Lesions, verified via tyrosine hydroxylase and choline acetyltransferase immunohistochemistry reduced an average of 95% of nigral dopamine neurons and 80% of PPN cholinergic neurons, respectively. Rats receiving acetylcholine and dual lesion demonstrated enhanced freezing, and acetylcholine lesioned rats exhibited increased print area and stand index. Dopamine and dual lesion produced similar forepaw adjusting steps task on and off L-DOPA. Relative to DA lesioned rats, dual lesioned rats displayed reduced L-DOPA and DA agonist-induced dyskinesia at specific time points. Our results indicate that PPN cholinergic neurons affect gait parameters related to postural stability. Therefore, therapeutically targeting PPN cholinergic neurons could reduce intractable postural instability in PD without affecting motor benefits or side effects of L-DOPA treatment.

Genetic basis of susceptibility to low-dose paraquat and variation between the sexes in Drosophila melanogaster.

Toxicant resistance is a complex trait, affected both by genetics and the environment. Like most complex traits, it can exhibit sexual dimorphism, yet sex is often overlooked as a factor in studies of toxicant resistance. Paraquat, one such toxicant, is a commonly used herbicide and is known to produce mitochondrial oxidative stress, decrease dopaminergic neurons and dopamine (DA) levels, and decrease motor ability. While the main effects of paraquat are well-characterized, less is known about the naturally occurring variation in paraquat susceptibility. The purpose of this study was to map the genes contributing to low-dose paraquat susceptibility in Drosophila melanogaster, and to determine if susceptibility differs between the sexes. One hundred of the Drosophila Genetic Reference Panel (DGRP) lines were scored for susceptibility via climbing ability and used in a genome-wide association study (GWAS). Variation in seventeen genes in females and thirty-five genes in males associated with paraquat susceptibility. Only two candidate genes overlapped between the sexes despite a significant positive correlation between male and female susceptibilities. Many associated polymorphisms had significant interactions with sex, with most having conditionally neutral effects. Conditional neutrality between the sexes probably stems from sex-biased expression which may result from partial resolution of sexual conflict. Candidate genes were verified with RNAi knockdowns, gene expression analyses, and DA quantification. Several of these genes are novel associations with paraquat susceptibility. This research highlights the importance of assessing both sexes when studying toxicant susceptibility.

The branched-chain amino acids valine and leucine have differential effects on hepatic lipid metabolism.

Dairy intake, as a source of branched-chain amino acids (BCAA), has been linked to a lower incidence of type-2-diabetes and increased circulating odd-chain fatty acids (OCFA). To understand this connection, we aimed to investigate differences in BCAA metabolism of leucine and valine, a possible source of OCFA, and their role in hepatic metabolism. Male mice were fed a high-fat diet supplemented with leucine and valine for 1 week and phenotypically characterized with a focus on lipid metabolism. Mouse primary hepatocytes were treated with the BCAA or a Pparα activator WY-14643 to systematically examine direct hepatic effects and their mechanisms. Here, we show that only valine supplementation was able to increase hepatic and circulating OCFA levels via two pathways; a PPARα-dependent induction of α-oxidation and an increased supply of propionyl-CoA for de novo lipogenesis. Meanwhile, we were able to confirm leucine-mediated effects on the inhibition of food intake and transport of fatty acids, as well as induction of S6 ribosomal protein phosphorylation. Taken together, these data illustrate differential roles of the BCAA in lipid metabolism and provide preliminary evidence that exclusively valine contributes to the endogenous formation of OCFA which is important for a better understanding of these metabolites in metabolic health.

The running shoe comfort assessment tool (RUN-CAT): Development and evaluation of a new multi-item assessment tool for evaluating the comfort of running footwear.

Comfort is important for running shoe prescription in athletes to enhance performance and potentially decrease injury risk. A three-stage process was used to develop a new running footwear comfort assessment tool (RUN-CAT): (i) a survey of 282 runners to identify meaningful items of comfort, (ii-a) field testing of 100 runners who assessed the comfort of different shoes, (ii-b) item reduction using bootstrap aggregation and weightings using multiple regressions to identify a final set of items, and (iii) defining test-retest reliability, standard error of measurement (SEM), minimal detectable difference (MDD90) and minimal important difference (MID) values for the final tool. Of the 19 initial items, after item reduction, four were included in the final tool: heel cushioning, shoe stability, forefoot cushioning and forefoot flexibility. Reliability of the overall comfort score was good to excellent (within-day ICC 0.88, between-day 0.70) with all four components displaying good reliability (ICC >0.70). The SEM of the comfort score was 2.8 points and the MDD90 was 6.5 mm. Subject nominated MID values ranged from 9.3 to 9.9 mm. The RUN-CAT demonstrates excellent reliability, acceptable measurement error and can discriminate between footwear models. Clinicians and researchers can incorporate the RUN-CAT to optimise running shoe comfort in athletes.

The effect of foot orthoses and insoles on running economy and performance in distance runners: A systematic review and meta-analysis.

Foot orthoses and insoles are prescribed to runners, however their impact on running economy and performance is uncertain. The aim of this systematic review and meta-analysis was to determine the effect of foot orthoses and insoles on running economy and performance in distance runners. Seven electronic databases were searched from inception until June 2018. Eligible studies investigated the effect of foot orthoses or insoles on running economy (using indirect calorimetry) or running performance. Standardised mean differences (SMDs) were computed and meta-analyses were conducted using random effects models. Methodological quality was assessed using the Quality Index. Nine studies met the criteria and were included: five studies investigated the effect of foot orthoses on running economy and four investigated insoles. Foot orthoses were associated with small negative effects on running economy compared to no orthoses (SMD 0.42 [95% CI 0.17,0.72] p = 0.007). Shock absorbing insoles were also associated with negative effects on running economy, but an imprecise estimate (SMD 0.26 [95% CI -0.33,0.84] p = 0.83). Quality Index scores ranged from 4 to 15 out of 17. Foot orthoses and shock absorbing insoles may adversely affect running economy in distance runners. Future research should consider their potential effects on running performance.

Validity and Reliability of the Rear Foot Elevated Split Squat 5 Repetition Maximum to Determine Unilateral Leg Strength Symmetry.

Helme, M, Bishop, C, Emmonds, S, and Low, C. Validity and reliability of the rear foot elevated split squat 5 repetition maximum to determine unilateral leg strength symmetry. J Strength Cond Res 33(12): 3269-3275, 2019-The purpose of this study was to examine the validity and reliability of the rear foot elevated split squat (RFESS) 5 repetition maximum (5RM) test as a field method for measuring unilateral leg strength symmetry. As a validated method of testing symmetry, the RFESS 5RM may be used by strength and conditioning coaches and sports medicine staff to measure the presence of imbalances with minimal equipment and time. Twenty-six subjects (age = 23.8 ± 4.6 years, mass = 88.1 ± 10.7 kg, and height = 1.79 ± 0.1 m) with a minimum 2 years of strength and conditioning experience were recruited. After a familiarization session, subjects performed an incremental 5RM protocol on both legs, on 2 occasions where 3D motion and force data were collected. Moderate reliability of bar load symmetry was found between test and retest conditions correlation (intraclass coefficient = 0.73, 0.33-0.91) with no proportional bias between sessions. Validation of the exercise was analyzed using a correlation between asymmetries in mean set vertical ground reaction forces (vGRF) of the lead foot during the concentric phase, with bar load. When all maximal trials, from both test conditions, were analyzed, a most likely large positive correlation (0.57, 0.30-0.76) was found for mean set concentric lead foot vGRF. When a threshold level of load symmetry (96.54-103.46%) was applied, a most likely large positive correlation (r = 0.59, 0.14-0.84) between symmetry in lead foot vGRF was found in subjects who exceeded this limit. Conversely, analysis of subjects within the threshold produced unclear correlations. Findings of this study suggest the RFESS is a valid and reliable measure of unilateral leg strength symmetry. Practitioners are recommended to use this exercise to investigate the strength symmetry of athletes, but are guided to note that a threshold level of symmetry (96.54-103.46%) may be required to have been exceeded to indicate a true difference in vGRF production.

Diverse serotonin actions of vilazodone reduce l-3,4-dihidroxyphenylalanine-induced dyskinesia in hemi-parkinsonian rats.

BACKGROUND: The serotonergic system is a well-established modulator of l-dopa-induced dyskinesia. To date, targeting serotonin transporters or serotonin receptor subtype 1A (5-HT1A ) reduces l-dopa-induced dyskinesia in animal models; however, these strategies have failed to translate clinically. Ideally, a compound acting at both known antidyskinetic sites could optimize serotonin-mediated approaches. Vilazodone is a selective serotonin reuptake inhibitor and a partial 5-HT1A agonist approved by the U.S. Food and Drug Administration, situating Vilazodone in a unique position to reduce l-dopa-induced dyskinesia without compromising l-dopa-mediated motor improvements. OBJECTIVES: The goal of the present study was to characterize Vilazodone's effects on l-dopa-induced behaviors, neurochemistry and gene expression in unilateral 6-hydroxydopamine-lesioned hemi-parkinsonian rats. METHODS: In experiments 1 and 2, l-dopa-naïve and l-dopa-primed animals were coadministered Vilazodone and l-dopa daily for 3 weeks to model subchronic use, and behavioral, neurochemical, and messenger RNA (mRNA) expression changes were measured. In experiment 3, dyskinetic behavior was assessed following 5-HT1A or serotonin receptor subtype 1B blockade prior to Vilazodone-l-dopa coadministration. RESULTS: Vilazodone significantly suppressed developing and established l-dopa-induced dyskinesia without compromising the promotor effects of l-dopa therapy. In the dopamine-depleted striatum, Vilazodone-l-dopa cotreatment increased dopamine content, suggesting a normalization of dopamine kinetics in dyskinetic brain, and reduced l-dopa-induced c-Fos and preprodynorphin mRNA overexpression, indicative of attenuated dopamine D1 receptor-mediated direct pathway overactivity. Only 5-HT1A antagonism partially attenuated Vilazodone's antidyskinetic efficacy, suggesting both serotonin transporter-dependent effects and 5-HT1A receptors in Vilazodone's actions. CONCLUSIONS: Our findings show Vilazodone has a serotonin-dependent effect on rodent l-dopa-induced dyskinesia and implicate the potential for repositioning Vilazodone against l-dopa-induced dyskinesia development and expression in Parkinson's disease patients. © 2018 International Parkinson and Movement Disorder Society.

Serotonergic targets for the treatment of L-DOPA-induced dyskinesia.

Dopamine (DA) replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) continues to be the gold-standard treatment for Parkinson's disease (PD). Despite clear symptomatic benefit, long-term L-DOPA use often results in the development of L-DOPA-induced dyskinesia (LID), significantly reducing quality of life and increasing costs for PD patients and their caregivers. Accumulated research has demonstrated that several pre- and post-synaptic mechanisms contribute to LID development and expression. In particular, raphe-striatal hyperinnervation and unregulated DA release from 5-HT terminals is postulated to play a central role in LID manifestation. As such, manipulation of the 5-HT system has garnered considerable attention. Both pre-clinical and clinical research has supported the potential of modulating the 5-HT system for LID prevention and treatment. This review discusses the rationale for continued investigation of several potential anti-dyskinetic strategies including 5-HT stimulation of 5-HT1A and 5-HT1B receptors and blockade of 5-HT2A receptors and SERT. We present the latest findings from experimental and clinical investigations evaluating these 5-HT targets with the goal of identifying those with translational promise and the challenges associated with each.

Predictors of the Biomechanical Effects of Customized Foot Orthoses in Adults With Flat-Arched Feet.

OBJECTIVE: To determine the potential presence and characteristics of biomechanical responders to customized foot orthoses during walking in adults with flat-arched feet. DESIGN: Experimental, repeated-measures. SETTING: University clinic and laboratory. PARTICIPANTS: Eighteen symptom-free adults with flat-arched feet. INTERVENTIONS: Customized foot orthoses. MAIN OUTCOME MEASURES: In-shoe foot biomechanics were measured during walking with and without customized foot orthoses using 3D analysis. Selected kinematic and kinetic variables during baseline walking were compared between subgroups who displayed reductions in calcaneal eversion with foot orthoses to those with no change or increases. RESULTS: Biomechanical responders displayed significantly greater peak calcaneal eversion (+2.2 degrees, P = 0.009). Time to peak calcaneal eversion (-11%, P = 0.006), peak dorsiflexion of the hallux (-6 degrees, P = 0.001), and medial-lateral excursion of the center of pressure during loading response were all reduced in the responder subgroup (-2 mm, P ≤ 0.001). Variables significantly different between subgroups were moderately associated with the response to foot orthoses (canonical correlation = 0.687, effect size = 0.47, P = 0.063). CONCLUSIONS: Individuals with increased dynamic foot pronation were more likely to show a favorable biomechanical response to customized foot orthoses, providing preliminary evidence to support the stratified use of foot orthoses to optimize their effectiveness.

Disaggregating asthma: Big investigation versus big data.

We are facing a major challenge in bridging the gap between identifying subtypes of asthma to understand causal mechanisms and translating this knowledge into personalized prevention and management strategies. In recent years, "big data" has been sold as a panacea for generating hypotheses and driving new frontiers of health care; the idea that the data must and will speak for themselves is fast becoming a new dogma. One of the dangers of ready accessibility of health care data and computational tools for data analysis is that the process of data mining can become uncoupled from the scientific process of clinical interpretation, understanding the provenance of the data, and external validation. Although advances in computational methods can be valuable for using unexpected structure in data to generate hypotheses, there remains a need for testing hypotheses and interpreting results with scientific rigor. We argue for combining data- and hypothesis-driven methods in a careful synergy, and the importance of carefully characterized birth and patient cohorts with genetic, phenotypic, biological, and molecular data in this process cannot be overemphasized. The main challenge on the road ahead is to harness bigger health care data in ways that produce meaningful clinical interpretation and to translate this into better diagnoses and properly personalized prevention and treatment plans. There is a pressing need for cross-disciplinary research with an integrative approach to data science, whereby basic scientists, clinicians, data analysts, and epidemiologists work together to understand the heterogeneity of asthma.

The Role of Primary Motor Cortex (M1) Glutamate and GABA Signaling in l-DOPA-Induced Dyskinesia in Parkinsonian Rats.

UNLABELLED: Long-term treatment of Parkinson's disease with l-DOPA almost always leads to the development of involuntary movements termed l-DOPA-induced dyskinesia. Whereas hyperdopaminergic signaling in the basal ganglia is thought to cause dyskinesia, alterations in primary motor cortex (M1) activity are also prominent during dyskinesia, suggesting that the cortex may represent a therapeutic target. The present study used the rat unilateral 6-hydroxydopamine lesion model of Parkinson's disease to characterize in vivo changes in GABA and glutamate neurotransmission within M1 and determine their contribution to behavioral output. 6-Hydroxydopamine lesion led to parkinsonian motor impairment that was partially reversed by l-DOPA. Among sham-lesioned rats, l-DOPA did not change glutamate or GABA efflux. Likewise, 6-hydroxydopamine lesion did not impact GABA or glutamate among rats chronically treated with saline. However, we observed an interaction of lesion and treatment whereby, among lesioned rats, l-DOPA given acutely (1 d) or chronically (14-16 d) reduced glutamate efflux and enhanced GABA efflux. Site-specific microinjections into M1 demonstrated that l-DOPA-induced dyskinesia was reduced by M1 infusion of a D1 antagonist, an AMPA antagonist, or a GABAA agonist. Overall, the present study demonstrates that l-DOPA-induced dyskinesia is associated with increased M1 inhibition and that exogenously enhancing M1 inhibition may attenuate dyskinesia, findings that are in agreement with functional imaging and transcranial magnetic stimulation studies in human Parkinson's disease patients. Together, our study suggests that increasing M1 inhibitory tone is an endogenous compensatory response designed to limit dyskinesia severity and that potentiating this response is a viable therapeutic strategy. SIGNIFICANCE STATEMENT: Most Parkinson's disease patients will receive l-DOPA and eventually develop hyperkinetic involuntary movements termed dyskinesia. Such symptoms can be as debilitating as the disease itself. Although dyskinesia is associated with dynamic changes in primary motor cortex physiology, to date, there are no published studies investigating in vivo neurotransmitter release in M1 during dyskinesia. In parkinsonian rats, l-DOPA administration reduced M1 glutamate efflux and enhanced GABA efflux, coincident with the emergence of dyskinetic behaviors. Dyskinesia could be reduced by local M1 modulation of D1, AMPA, and GABAA receptors, providing preclinical support for the notion that exogenously blunting M1 signaling (pharmacologically or with cortical stimulation) is a therapeutic approach to the treatment of debilitating dyskinesias.

Ceftriaxone reduces L-dopa-induced dyskinesia severity in 6-hydroxydopamine parkinson's disease model.

BACKGROUND: Increased extracellular glutamate may contribute to l-dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after l-dopa treatment. Therapeutic strategies targeting postsynaptic glutamate receptors to mitigate dyskinesia may have limited success because of significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset. Initiation of a ceftriaxone regimen at the time of nigrostriatal lesion can attenuate tyrosine hydroxylase loss in conjunction with increased glutamate uptake and glutamate transporter GLT-1 expression in a rat 6-hydroxydopamine model. In this article, we examined if a ceftriaxone regimen initiated 1 week after nigrostriatal lesion, but prior to l-dopa, could reduce l-dopa-induced dyskinesia in an established dyskinesia model. METHODS: Ceftriaxone (200 mg/kg, intraperitoneal, once daily, 7 consecutive days) was initiated 7 days post-6-hydroxydopamine lesion (days 7-13) and continued every other week (days 21-27, 35-39) until the end of the study (day 39 postlesion, 20 days of l-dopa). RESULTS: Ceftriaxone significantly reduced abnormal involuntary movements at 5 time points examined during chronic l-dopa treatment. Partial recovery of motor impairment from nigrostriatal lesion by l-dopa was unaffected by ceftriaxone. The ceftriaxone-treated l-dopa group had significantly increased striatal GLT-1 expression and glutamate uptake. Striatal tyrosine hydroxylase loss in this group was not significantly different when compared with the l-dopa alone group. CONCLUSIONS: Initiation of ceftriaxone after nigrostriatal lesion, but prior to and during l-dopa, may reduce dyskinesia severity without affecting l-dopa efficacy or the reduction of striatal tyrosine hydroxylase loss. © 2017 International Parkinson and Movement Disorder Society.

Bicollinear Antiferromagnetic Order, Monoclinic Distortion, and Reversed Resistivity Anisotropy in FeTe as a Result of Spin-Lattice Coupling.

The bicollinear antiferromagnetic order experimentally observed in FeTe is shown to be stabilized by the coupling g[over ˜]_{12} between monoclinic lattice distortions and the spin-nematic order parameter with B_{2g} symmetry, within a three-orbital spin-fermion model studied with Monte Carlo techniques. A finite but small value of g[over ˜]_{12} is required, with a concomitant lattice distortion compatible with experiments, and a tetragonal-monoclinic transition strongly first order. Remarkably, the bicollinear state found here displays a planar resistivity with the "reversed" puzzling anisotropy discovered in transport experiments. Orthorhombic distortions are also incorporated, and phase diagrams interpolating between pnictides and chalcogenides are presented. We conclude that the spin-lattice coupling we introduce is sufficient to explain the challenging properties of FeTe.

Patterns of IgE responses to multiple allergen components and clinical symptoms at age 11 years.

BACKGROUND: The relationship between sensitization to allergens and disease is complex. OBJECTIVE: We sought to identify patterns of response to a broad range of allergen components and investigate associations with asthma, eczema, and hay fever. METHODS: Serum specific IgE levels to 112 allergen components were measured by using a multiplex array (Immuno Solid-phase Allergen Chip) in a population-based birth cohort. Latent variable modeling was used to identify underlying patterns of component-specific IgE responses; these patterns were then related to asthma, eczema, and hay fever. RESULTS: Two hundred twenty-one of 461 children had IgE to 1 or more components. Seventy-one of the 112 components were recognized by 3 or more children. By using latent variable modeling, 61 allergen components clustered into 3 component groups (CG1, CG2, and CG3); protein families within each CG were exclusive to that group. CG1 comprised 27 components from 8 plant protein families. CG2 comprised 7 components of mite allergens from 3 protein families. CG3 included 27 components of plant, animal, and fungal origin from 12 protein families. Each CG included components from different biological sources with structural homology and also nonhomologous proteins arising from the same biological source. Sensitization to CG3 was most strongly associated with asthma (odds ratio [OR], 8.20; 95% CI, 3.49-19.24; P < .001) and lower FEV1 (P < .001). Sensitization to CG1 was associated with hay fever (OR, 12.79; 95% CI, 6.84-23.90; P < .001). Sensitization to CG2 was associated with both asthma (OR, 3.60; 95% CI, 2.05-6.29) and hay fever (OR, 2.52; 95% CI, 1.38-4.61). CONCLUSIONS: Latent variable modeling with a large number of allergen components identified 3 patterns of IgE responses, each including different protein families. In 11-year-old children the pattern of response to components of multiple allergens appeared to be associated with current asthma and hay fever but not eczema.

Effects of the beta-adrenergic receptor antagonist Propranolol on dyskinesia and L-DOPA-induced striatal DA efflux in the hemi-parkinsonian rat.

Dopamine (DA) replacement therapy with L-DOPA continues to be the primary treatment of Parkinson's disease; however, long-term therapy is accompanied by L-DOPA-induced dyskinesias (LID). Several experimental and clinical studies have established that Propranolol, a ß-adrenergic receptor antagonist, reduces LID without affecting L-DOPA's efficacy. However, the exact mechanisms underlying these effects remain to be elucidated. The aim of this study was to evaluate the anti-dyskinetic profile of Propranolol against a panel of DA replacement strategies, as well as elucidate the underlying neurochemical mechanisms. Results indicated that Propranolol, in a dose-dependent manner, reduced LID, without affecting motor performance. Propranolol failed to alter dyskinesia produced by the D1 receptor agonist, SKF81297 (0.08 mg/kg, sc), or the D2 receptor agonist, Quinpirole (0.05 mg/kg, sc). These findings suggested a pre-synaptic mechanism for Propranolol's anti-dyskinetic effects, possibly through modulating L-DOPA-mediated DA efflux. To evaluate this possibility, microdialysis studies were carried out in the DA-lesioned striatum of dyskinetic rats and results indicated that co-administration of Propranolol (20 mg/kg, ip) was able to attenuate L-DOPA- (6 mg/kg, sc) induced DA efflux. Therefore, Propranolol's anti-dyskinetic properties appear to be mediated via attenuation of L-DOPA-induced extraphysiological efflux of DA.

The Study Team for Early Life Asthma Research (STELAR) consortium 'Asthma e-lab': team science bringing data, methods and investigators together.

We created Asthma e-Lab, a secure web-based research environment to support consistent recording, description and sharing of data, computational/statistical methods and emerging findings across the five UK birth cohorts. The e-Lab serves as a data repository for our unified dataset and provides the computational resources and a scientific social network to support collaborative research. All activities are transparent, and emerging findings are shared via the e-Lab, linked to explanations of analytical methods, thus enabling knowledge transfer. eLab facilitates the iterative interdisciplinary dialogue between clinicians, statisticians, computer scientists, mathematicians, geneticists and basic scientists, capturing collective thought behind the interpretations of findings.

Trajectories of lung function during childhood.

RATIONALE: Developmental patterns of lung function during childhood may have major implications for our understanding of the pathogenesis of respiratory disease throughout life. OBJECTIVES: To explore longitudinal trajectories of lung function during childhood and factors associated with lung function decline. METHODS: In a population-based birth cohort, specific airway resistance (sRaw) was assessed at age 3 (n = 560), 5 (n = 829), 8 (n = 786), and 11 years (n = 644). Based on prospective data (questionnaires, skin tests, IgE), children were assigned to wheeze phenotypes (no wheezing, transient, late-onset, and persistent) and atopy phenotypes (no atopy, dust mite, non-dust mite, multiple early, and multiple late). We used longitudinal linear mixed models to determine predictors of change in sRaw over time. MEASUREMENTS AND MAIN RESULTS: Contrary to the assumption that sRaw is independent of age and sex, boys had higher sRaw than girls (mean difference, 0.080; 95% confidence interval [CI], 0.049-0.111; P < 0.001) and a higher rate of increase over time. For girls, sRaw increased by 0.017 kPa ⋅ s(-1) per year (95% CI, 0.011-0.023). In boys this increase was significantly greater (P = 0.012; mean between-sex difference, 0.011 kPa ⋅ s(-1); 95% CI, 0.003-0.019). Children with persistent wheeze (but not other wheeze phenotypes) had a significantly greater rate of deterioration in sRaw over time compared with never wheezers (P = 0.009). Similarly, children with multiple early, but not other atopy phenotypes had significantly poorer lung function than those without atopy (mean difference, 0.116 kPa ⋅ s(-1); 95% CI, 0.065-0.168; P < 0.001). sRaw increased progressively with the increasing number of asthma exacerbations. CONCLUSIONS: Children with persistent wheeze, frequent asthma exacerbations, and multiple early atopy have diminished lung function throughout childhood, and are at risk of a progressive loss of lung function from age 3 to 11 years. These effects are more marked in boys.