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1.
South Med J ; 117(7): 379-382, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38959967

RESUMO

OBJECTIVES: Individuals employed in the agricultural industry encounter hazards in their work that could lead to injury or illness. Furthermore, the mental stress of being involved in the agricultural industry could lead to negative health-related outcomes for workers. This study evaluates the causes of deaths among employees in Mississippi's agricultural industry from 2017 to 2021. METHODS: Data are provided by the Mississippi Department of Health. Proportionate mortality ratios (PMRs) are calculated to determine if agricultural industry employees show an elevated mortality in comparison to the general population for any cause of death. RESULTS: Agricultural industry employees show a statistically significant elevated mortality for circulatory disease (PMR 107, 95% confidence interval [CI] 103-110) and coronavirus disease 2019 (PMR 122, 95% CI 111-134). They also show a significant excess mortality for deaths caused by transport accidents (PMR 117, 95% CI 101-136) and exposure to inanimate mechanical forces (PMR 274, 95% CI 183-396). CONCLUSIONS: The causes of death for which agricultural employees show an excess mortality can be explained by the hazards associated with working in the agricultural industry. These findings can be used to create targeted future public health programs for individuals who are employed in agriculture.


Assuntos
Agricultura , COVID-19 , Causas de Morte , Humanos , Mississippi/epidemiologia , Causas de Morte/tendências , COVID-19/mortalidade , Masculino , Feminino , Agricultura/estatística & dados numéricos , Adulto , Pessoa de Meia-Idade , Fazendeiros/estatística & dados numéricos
2.
Sci Rep ; 14(1): 2735, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302540

RESUMO

We analyze the visual perception task that home plate umpires (N = 121) perform calling balls and strikes (N = 3,001,019) in baseball games, focusing on the topics of perceptual learning and bias in decision-making. In the context of perceptual learning, our results show that monitoring, training, and feedback improve skill over time. In addition, we document two other aspects of umpires' improvement that are revealing with respect to the nature of their perceptual expertise. First, we show that biases in umpires' decision-making persist even as their overall accuracy improves. This suggests that bias and accuracy are orthogonal and that reduction of bias in decision-making requires interventions aimed specifically at this goal. Second, we measure a distinct difference in the rate of skill improvement between older and younger umpires. Younger umpires improve more quickly, suggesting that the decision task umpires engage in becomes routinized over time.


Assuntos
Beisebol , Percepção Visual , Visão Ocular , Aprendizagem , Psicofísica , Tomada de Decisões
3.
Nano Lett ; 24(1): 97-103, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38127716

RESUMO

The programmable photonic integrated circuit (PIC) is an enabling technology behind optical interconnects and quantum information processing. Conventionally, the programmability of PICs is driven by the thermo-optic effect, free carrier dispersion, or mechanical tuning. These effects afford either high speed or a large extinction ratio, but all require constant power or bias to maintain the states, which is undesirable for programmability with infrequent switching. Recent progress in programmable PICs based on nonvolatile phase-change materials (PCMs) offers an attractive solution to a truly "set-and-forget" switch that requires zero static energy. Here, we report an essential building block of large-scale programmable PICs─a racetrack resonator with independent control of coupling and phase. We changed the resonance extinction ratio (ER) without perturbing the resonance wavelength, leveraging a programmable unit based on a directional coupler and a low-loss PCM Sb2Se3. The unit is only 33-µm-long and has an operating bandwidth over 50 nm, a low insertion loss (∼0.36 dB), high ER (∼15 dB), and excellent fabrication yield of over 1000 cycles endurance across nine switches. The work is a crucial step toward future large-scale energy-efficient programmable PICs.

5.
iScience ; 26(10): 107946, 2023 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-37854690

RESUMO

Phase Change Materials (PCMs) have demonstrated tremendous potential as a platform for achieving diverse functionalities in active and reconfigurable micro-nanophotonic devices across the electromagnetic spectrum, ranging from terahertz to visible frequencies. This comprehensive roadmap reviews the material and device aspects of PCMs, and their diverse applications in active and reconfigurable micro-nanophotonic devices across the electromagnetic spectrum. It discusses various device configurations and optimization techniques, including deep learning-based metasurface design. The integration of PCMs with Photonic Integrated Circuits and advanced electric-driven PCMs are explored. PCMs hold great promise for multifunctional device development, including applications in non-volatile memory, optical data storage, photonics, energy harvesting, biomedical technology, neuromorphic computing, thermal management, and flexible electronics.

6.
Neurology ; 101(9): e953-e965, 2023 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-37479529

RESUMO

BACKGROUND AND OBJECTIVES: Repeated impacts in high-contact sports such as American football can affect the brain's microstructure, which can be studied using diffusion MRI. Most imaging studies are cross-sectional, do not include low-contact players as controls, or lack advanced tract-specific microstructural metrics. We aimed to investigate longitudinal changes in high-contact collegiate athletes compared with low-contact controls using advanced diffusion MRI and automated fiber quantification. METHODS: We examined brain microstructure in high-contact (football) and low-contact (volleyball) collegiate athletes with up to 4 years of follow-up. Inclusion criteria included university and team enrollment. Exclusion criteria included history of neurosurgery, severe brain injury, and major neurologic or substance abuse disorder. We investigated diffusion metrics along the length of tracts using nested linear mixed-effects models to ascertain the acute and chronic effects of subconcussive and concussive impacts, and associations between diffusion changes with clinical, behavioral, and sports-related measures. RESULTS: Forty-nine football and 24 volleyball players (271 total scans) were included. Football players had significantly divergent trajectories in multiple microstructural metrics and tracts. Longitudinal increases in fractional anisotropy and axonal water fraction, and decreases in radial/mean diffusivity and orientation dispersion index, were present in volleyball but absent in football players (all findings |T-statistic|> 3.5, p value <0.0001). This pattern was present in the callosum forceps minor, superior longitudinal fasciculus, thalamic radiation, and cingulum hippocampus. Longitudinal differences were more prominent and observed in more tracts in concussed football players (n = 24, |T|> 3.6, p < 0.0001). An analysis of immediate postconcussion scans (n = 12) demonstrated a transient localized increase in axial diffusivity and mean/radial kurtosis in the uncinate and cingulum hippocampus (|T| > 3.7, p < 0.0001). Finally, within football players, those with high position-based impact risk demonstrated increased intracellular volume fraction longitudinally (T = 3.6, p < 0.0001). DISCUSSION: The observed longitudinal changes seen in football, and especially concussed athletes, could reveal diminished myelination, altered axonal calibers, or depressed pruning processes leading to a static, nondecreasing axonal dispersion. This prospective longitudinal study demonstrates divergent tract-specific trajectories of brain microstructure, possibly reflecting a concussive and repeated subconcussive impact-related alteration of white matter development in football athletes.


Assuntos
Concussão Encefálica , Futebol Americano , Voleibol , Humanos , Estudos Transversais , Estudos Longitudinais , Estudos Prospectivos , Universidades , Concussão Encefálica/diagnóstico por imagem
7.
Ann Neurol ; 94(3): 457-469, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37306544

RESUMO

OBJECTIVE: Repetitive head trauma is common in high-contact sports. Cerebral blood flow (CBF) can measure changes in brain perfusion that could indicate injury. Longitudinal studies with a control group are necessary to account for interindividual and developmental effects. We investigated whether exposure to head impacts causes longitudinal CBF changes. METHODS: We prospectively studied 63 American football (high-contact cohort) and 34 volleyball (low-contact controls) male collegiate athletes, tracking CBF using 3D pseudocontinuous arterial spin labeling magnetic resonance imaging for up to 4 years. Regional relative CBF (rCBF, normalized to cerebellar CBF) was computed after co-registering to T1-weighted images. A linear mixed effects model assessed the relationship of rCBF to sport, time, and their interaction. Within football players, we modeled rCBF against position-based head impact risk and baseline Standardized Concussion Assessment Tool score. Additionally, we evaluated early (1-5 days) and delayed (3-6 months) post-concussion rCBF changes (in-study concussion). RESULTS: Supratentorial gray matter rCBF declined in football compared with volleyball (sport-time interaction p = 0.012), with a strong effect in the parietal lobe (p = 0.002). Football players with higher position-based impact-risk had lower occipital rCBF over time (interaction p = 0.005), whereas players with lower baseline Standardized Concussion Assessment Tool score (worse performance) had relatively decreased rCBF in the cingulate-insula over time (interaction effect p = 0.007). Both cohorts showed a left-right rCBF asymmetry that decreased over time. Football players with an in-study concussion showed an early increase in occipital lobe rCBF (p = 0.0166). INTERPRETATION: These results suggest head impacts may result in an early increase in rCBF, but cumulatively a long-term decrease in rCBF. ANN NEUROL 2023;94:457-469.


Assuntos
Concussão Encefálica , Futebol Americano , Humanos , Masculino , Concussão Encefálica/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Futebol Americano/lesões , Imageamento por Ressonância Magnética , Circulação Cerebrovascular/fisiologia
8.
Neurotherapeutics ; 18(2): 1039-1063, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33786806

RESUMO

Huntington's disease (HD) is caused by an expansion of the CAG repeat in the huntingtin gene leading to preferential neurodegeneration of the striatum. Disease-modifying treatments are not yet available to HD patients and their development would be facilitated by translatable pharmacodynamic biomarkers. Multi-modal magnetic resonance imaging (MRI) and plasma cytokines have been suggested as disease onset/progression biomarkers, but their ability to detect treatment efficacy is understudied. This study used the R6/2 mouse model of HD to assess if structural neuroimaging and biofluid assays can detect treatment response using as a prototype the small molecule p75NTR ligand LM11A-31, shown previously to reduce HD phenotypes in these mice. LM11A-31 alleviated volume reductions in multiple brain regions, including striatum, of vehicle-treated R6/2 mice relative to wild-types (WTs), as assessed with in vivo MRI. LM11A-31 also normalized changes in diffusion tensor imaging (DTI) metrics and diminished increases in certain plasma cytokine levels, including tumor necrosis factor-alpha and interleukin-6, in R6/2 mice. Finally, R6/2-vehicle mice had increased urinary levels of the p75NTR extracellular domain (ecd), a cleavage product released with pro-apoptotic ligand binding that detects the progression of other neurodegenerative diseases; LM11A-31 reduced this increase. These results are the first to show that urinary p75NTR-ecd levels are elevated in an HD mouse model and can be used to detect therapeutic effects. These data also indicate that multi-modal MRI and plasma cytokine levels may be effective pharmacodynamic biomarkers and that using combinations of these markers would be a viable and powerful option for clinical trials.


Assuntos
Doença de Huntington/diagnóstico por imagem , Doença de Huntington/metabolismo , Isoleucina/análogos & derivados , Morfolinas/metabolismo , Morfolinas/uso terapêutico , Neuroimagem/métodos , Receptores de Fator de Crescimento Neural/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/urina , Estudos Transversais , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Doença de Huntington/tratamento farmacológico , Isoleucina/metabolismo , Isoleucina/farmacologia , Isoleucina/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Morfolinas/farmacologia
9.
Brain Imaging Behav ; 15(2): 576-584, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32720179

RESUMO

Sport-related brain injury is very common, and the potential long-term effects include a wide range of neurological and psychiatric symptoms, and potentially neurodegeneration. Around the globe, researchers are conducting neuroimaging studies on primarily homogenous samples of athletes. However, neuroimaging studies are expensive and time consuming, and thus current findings from studies of sport-related brain injury are often limited by small sample sizes. Further, current studies apply a variety of neuroimaging techniques and analysis tools which limit comparability among studies. The ENIGMA Sports Injury working group aims to provide a platform for data sharing and collaborative data analysis thereby leveraging existing data and expertise. By harmonizing data from a large number of studies from around the globe, we will work towards reproducibility of previously published findings and towards addressing important research questions with regard to diagnosis, prognosis, and efficacy of treatment for sport-related brain injury. Moreover, the ENIGMA Sports Injury working group is committed to providing recommendations for future prospective data acquisition to enhance data quality and scientific rigor.


Assuntos
Traumatismos em Atletas , Concussão Encefálica , Lesões Encefálicas , Traumatismos em Atletas/diagnóstico por imagem , Concussão Encefálica/diagnóstico por imagem , Concussão Encefálica/epidemiologia , Concussão Encefálica/etiologia , Humanos , Imageamento por Ressonância Magnética , Reprodutibilidade dos Testes
10.
Neuroimage ; 217: 116864, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32360690

RESUMO

Collegiate football athletes are subject to repeated head impacts. The purpose of this study was to determine whether this exposure can lead to changes in brain structure. This prospective cohort study was conducted with up to 4 years of follow-up on 63 football (high-impact) and 34 volleyball (control) male collegiate athletes with a total of 315 MRI scans (after exclusions: football n â€‹= â€‹50, volleyball n â€‹= â€‹24, total scans â€‹= â€‹273) using high-resolution structural imaging. Volumetric and cortical thickness estimates were derived using FreeSurfer 5.3's longitudinal pipeline. A linear mixed-effects model assessed the effect of group (football vs. volleyball), time from baseline MRI, and the interaction between group and time. We confirmed an expected developmental decrement in cortical thickness and volume in our cohort (p â€‹< â€‹.001). Superimposed on this, total cortical gray matter volume (p â€‹= â€‹.03) and cortical thickness within the left hemisphere (p â€‹= â€‹.04) showed a group by time interaction, indicating less age-related volume reduction and thinning in football compared to volleyball athletes. At the regional level, sport by time interactions on thickness and volume were identified in the left orbitofrontal (p â€‹= â€‹.001), superior temporal (p â€‹= â€‹.001), and postcentral regions (p â€‹< â€‹.001). Additional cortical thickness interactions were found in the left temporal pole (p â€‹= â€‹.003) and cuneus (p â€‹= â€‹.005). At the regional level, we also found main effects of sport in football athletes characterized by reduced volume in the right hippocampus (p â€‹= â€‹.003), right superior parietal cortical gray (p â€‹< â€‹.001) and white matter (p â€‹< â€‹.001), and increased volume of the left pallidum (p â€‹= â€‹.002). Within football, cortical thickness was higher with greater years of prior play (left hemisphere p â€‹= â€‹.013, right hemisphere p â€‹= â€‹.005), and any history of concussion was associated with less cortical thinning (left hemisphere p â€‹= â€‹.010, right hemisphere p â€‹= â€‹.011). Additionally, both position-associated concussion risk (p â€‹= â€‹.002) and SCAT scores (p â€‹= â€‹.023) were associated with less of the expected volume decrement of deep gray structures. This prospective longitudinal study comparing football and volleyball athletes shows divergent age-related trajectories of cortical thinning, possibly reflecting an impact-related alteration of normal cortical development. This warrants future research into the underlying mechanisms of impacts to the head on cortical maturation.


Assuntos
Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/lesões , Futebol Americano/lesões , Adolescente , Adulto , Atletas , Encéfalo/diagnóstico por imagem , Concussão Encefálica/diagnóstico por imagem , Estudos de Coortes , Lateralidade Funcional , Substância Cinzenta/diagnóstico por imagem , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Estudos Prospectivos , Voleibol/lesões , Adulto Jovem
11.
J Neurotrauma ; 36(19): 2762-2773, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31044639

RESUMO

Collegiate football athletes are subject to repeated traumatic brain injuriesthat may cause brain injury. The hippocampus is composed of several distinct subfields with possible differential susceptibility to injury. The aim of this study is to determine whether there are longitudinal changes in hippocampal subfield volume in collegiate football. A prospective cohort study was conducted over a 5-year period tracking 63 football and 34 volleyball male collegiate athletes. Athletes underwent high-resolution structural magnetic resonance imaging, and automated segmentation provided hippocampal subfield volumes. At baseline, football (n = 59) athletes demonstrated a smaller subiculum volume than volleyball (n = 32) athletes (-67.77 mm3; p = 0.012). A regression analysis performed within football athletes similarly demonstrated a smaller subiculum volume among those at increased concussion risk based on athlete position (p = 0.001). For the longitudinal analysis, a linear mixed-effects model assessed the interaction between sport and time, revealing a significant decrease in cornu ammonis area 1 (CA1) volume in football (n = 36) athletes without an in-study concussion compared to volleyball (n = 23) athletes (volume difference per year = -35.22 mm3; p = 0.005). This decrease in CA1 volume over time was significant when football athletes were examined in isolation from volleyball athletes (p = 0.011). Thus, this prospective, longitudinal study showed a decrease in CA1 volume over time in football athletes, in addition to baseline differences that were identified in the downstream subiculum. Hippocampal changes may be important to study in high-contact sports.


Assuntos
Concussão Encefálica/diagnóstico por imagem , Futebol Americano , Hipocampo/diagnóstico por imagem , Atletas , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Neuroimagem , Tamanho do Órgão/fisiologia , Estudantes , Universidades , Voleibol
12.
Accid Anal Prev ; 127: 186-197, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30897524

RESUMO

Past research has shown that winter precipitation is an important environmental factor that increases the frequency of motor vehicle collisions that cause personal injury and property damage. Questions remain about the magnitude of winter storm effects on collision occurrence, changes in risk over time, and the role of driver behaviour in conjunction with other factors (e.g., winter maintenance by road authorities) as it affects exposure and sensitivity to hazardous conditions. In response, a matched-pair, retrospective cohort method was used to estimate injury and non-injury collision risks for a mid-sized urban community based on a new definition of winter storm events that, relative to previous studies, captures a greater portion of time during which drivers respond to hazardous weather and road surface conditions. Winter storm definition criteria were applied to weather radar imagery and traditional surface station observations in a unique manner to classify and characterize a set of 196 variable-length storm events in terms of precipitation type and amount, visibility, temperature profile, presence of government-issued warnings, location, and temporal factors. Injury and non-injury collisions increased by 66 and 137 percent, respectively, during winter storms relative to dry weather conditions. Although these increases were higher than findings from similar studies of winter precipitation events conducted over the same timeframe (i.e., 2002-2016), they were found to have declined by a statistically significant amount over the course of the study period and disproportionately to collisions in general. Understanding why this is occurring, and then attributing improvements to specific winter road safety interventions and behavioural adjustments, is a key focus for future research and for informing future risk-mitigating investments.


Assuntos
Acidentes de Trânsito/estatística & dados numéricos , Estações do Ano , Tempo (Meteorologia) , Humanos , Ontário/epidemiologia , Estudos Retrospectivos , Medição de Risco , Temperatura , Ferimentos e Lesões/epidemiologia
14.
Netw Neurosci ; 2(2): 200-217, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30215033

RESUMO

In children with attention deficit hyperactivity disorder (ADHD) difficulty maintaining task focus may relate to the coordinated, negatively correlated activity between brain networks that support the initiation and maintenance of task sets (task positive networks) and networks that mediate internally directed processes (i.e., the default mode network). Here, resting-state functional connectivity MRI between these networks was examined in ADHD, across development, and in relation to attention. Children with ADHD had reduced negative connectivity between task positive and task negative networks (p = 0.002). Connectivity continues to become more negative between these networks throughout development (7-15 years of age) in children with ADHD (p = 0.005). Regardless of group status, females had increased negative connectivity (p = 0.003). In regards to attentional performance, the ADHD group had poorer signal detection (d') on the continuous performance task (CPT) (p < 0.0001), more so on easy than difficult d' trials (p < 0.0001). The reduced negative connectivity in children with ADHD also relates to their attention, where increased negative connectivity is related to better performance on the d' measure of the CPT (p = 0.008). These results highlight and further strengthen prior reports underscoring the role of segregated system integrity in ADHD.

15.
J Neurosci ; 38(25): 5774-5787, 2018 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-29789379

RESUMO

Cognition and behavior depend on synchronized intrinsic brain activity that is organized into functional networks across the brain. Research has investigated how anatomical connectivity both shapes and is shaped by these networks, but not how anatomical connectivity interacts with intra-areal molecular properties to drive functional connectivity. Here, we present a novel linear model to explain functional connectivity by integrating systematically obtained measurements of axonal connectivity, gene expression, and resting-state functional connectivity MRI in the mouse brain. The model suggests that functional connectivity arises from both anatomical links and inter-areal similarities in gene expression. By estimating these effects, we identify anatomical modules in which correlated gene expression and anatomical connectivity support functional connectivity. Along with providing evidence that not all genes equally contribute to functional connectivity, this research establishes new insights regarding the biological underpinnings of coordinated brain activity measured by BOLD fMRI.SIGNIFICANCE STATEMENT Efforts at characterizing the functional connectome with fMRI have risen exponentially over the last decade. Yet despite this rise, the biological underpinnings of these functional measurements are still primarily unknown. The current report begins to fill this void by investigating the molecular underpinnings of the functional connectome through an integration of systematically obtained structural information and gene expression data throughout the rodent brain. We find that both white matter connectivity and similarity in regional gene expression relate to resting-state functional connectivity. The current report furthers our understanding of the biological underpinnings of the functional connectome and provides a linear model that can be used to streamline preclinical animal studies of disease.


Assuntos
Encéfalo/fisiologia , Conectoma , Expressão Gênica/fisiologia , Modelos Neurológicos , Rede Nervosa/fisiologia , Animais , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL
16.
Behav Brain Res ; 308: 14-23, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27050322

RESUMO

Domoic acid (DA) is a toxin produced by marine algae and known primarily for its role in isolated outbreaks of Amnestic Shellfish Poisoning and for the damage it inflicts on marine mammals, particularly California sea lions. Lethal effects of DA are often preceded by seizures and coma. Exposure to DA during development can result in subtle and highly persistent effects on brain development and include behavioral changes that resemble diagnostic features of schizophrenia and anomalies in social behavior we believe are relevant to autism spectrum disorder (ASD). To more fully examine this hypothesis, we chose to examine adolescent mice exposed in utero to DA for endpoints relevant to ASD, specifically changes in social behavior and network structure, the latter measured by resting state functional connectivity (rs-fcMRI). We found that male offspring exposed in utero to DA expressed reproducible declines in social interaction and atypical patterns of functional connectivity in the anterior cingulate, a region of the default mode network that is critical for social functioning. We also found disruptions in global topology in regions involved in the processing of reward, social, and sensory experiences. Finally, we found that DA exposed males expressed a pattern of local over-connectivity. These anomalies in brain connectivity bear resemblance to connectivity patterns in ASD and help validate DA-exposed mice as a model of this mental disability.


Assuntos
Ácido Caínico/análogos & derivados , Vias Neurais/diagnóstico por imagem , Neurotoxinas/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Transtornos do Comportamento Social/induzido quimicamente , Fatores Etários , Animais , Animais Recém-Nascidos , Mapeamento Encefálico , Feminino , Processamento de Imagem Assistida por Computador , Ácido Caínico/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Oxigênio/sangue , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/diagnóstico por imagem , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Descanso , Recompensa , Comportamento Social , Transtornos do Comportamento Social/diagnóstico por imagem , Vocalização Animal/efeitos dos fármacos
17.
Vet Parasitol ; 222: 3-11, 2016 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-26961590

RESUMO

The novel isoxazoline ectoparasiticide, sarolaner, was identified during a lead optimization program for an orally-active compound with efficacy against fleas and ticks on dogs. The aim of the discovery program was to identify a novel isoxazoline specifically for use in companion animals, beginning with de novo synthesis in the Zoetis research laboratories. The sarolaner molecule has unique structural features important for its potency and pharmacokinetic (PK) properties, including spiroazetidine and sulfone moieties. The flea and tick activity resides in the chirally pure S-enantiomer, which was purified to alleviate potential off-target effects from the inactive enantiomer. The mechanism of action was established in electrophysiology assays using CHO-K1 cell lines stably expressing cat flea (Ctenocephalides felis) RDL (resistance-to-dieldrin) genes for assessment of GABA-gated chloride channel (GABACls) pharmacology. As expected, sarolaner inhibited GABA-elicited currents at both susceptible (CfRDL-A285) and resistant (CfRDL-S285) flea GABACls with similar potency. Initial whole organism screening was conducted in vitro using a blood feeding assay against C. felis. Compounds which demonstrated robust activity in the flea feed assay were subsequently tested in an in vitro ingestion assay against the soft tick, Ornithodoros turicata. Efficacious compounds which were confirmed safe in rodents at doses up to 30mg/kg were progressed to safety, PK and efficacy studies in dogs. In vitro sarolaner demonstrated an LC80 of 0.3µg/mL against C. felis and an LC100 of 0.003µg/mL against O. turicata. In a head-to-head comparative in vitro assay with both afoxolaner and fluralaner, sarolaner demonstrated superior flea and tick potency. In exploratory safety studies in dogs, sarolaner demonstrated safety in dogs≥8 weeks of age upon repeated monthly dosing at up to 20mg/kg. Sarolaner was rapidly and well absorbed following oral dosing. Time to maximum plasma concentration occurred within the first day post-dose. Bioavailability for sarolaner was calculated at >85% and the compound was highly protein bound (>99.9%). The half-life for sarolaner was calculated at 11-12 days. Sarolaner plasma concentrations indicated dose proportionality over the range 1.25-5mg/kg, and these same doses provided robust efficacy (>99%) for ≥35days against both fleas (C. felis) and multiple species of ticks (Rhipicephalus sanguineus, Ixodes ricinus and Dermacentor reticulatus) after oral administration to dogs. As a result of these exploratory investigations, sarolaner was progressed for development as an oral monthly dose for treatment and control of fleas and ticks on dogs.


Assuntos
Doenças do Cão/prevenção & controle , Ectoparasitoses/veterinária , Isoxazóis , Administração Oral , Animais , Cães , Ectoparasitoses/prevenção & controle , Meia-Vida , Inseticidas/farmacocinética , Inseticidas/farmacologia , Inseticidas/normas , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Isoxazóis/normas , Sifonápteros/efeitos dos fármacos , Carrapatos/efeitos dos fármacos
18.
Proc Natl Acad Sci U S A ; 111(52): 18745-50, 2014 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-25512496

RESUMO

Noninvasive functional imaging holds great promise for serving as a translational bridge between human and animal models of various neurological and psychiatric disorders. However, despite a depth of knowledge of the cellular and molecular underpinnings of atypical processes in mouse models, little is known about the large-scale functional architecture measured by functional brain imaging, limiting translation to human conditions. Here, we provide a robust processing pipeline to generate high-resolution, whole-brain resting-state functional connectivity MRI (rs-fcMRI) images in the mouse. Using a mesoscale structural connectome (i.e., an anterograde tracer mapping of axonal projections across the mouse CNS), we show that rs-fcMRI in the mouse has strong structural underpinnings, validating our procedures. We next directly show that large-scale network properties previously identified in primates are present in rodents, although they differ in several ways. Last, we examine the existence of the so-called default mode network (DMN)--a distributed functional brain system identified in primates as being highly important for social cognition and overall brain function and atypically functionally connected across a multitude of disorders. We show the presence of a potential DMN in the mouse brain both structurally and functionally. Together, these studies confirm the presence of basic network properties and functional networks of high translational importance in structural and functional systems in the mouse brain. This work clears the way for an important bridge measurement between human and rodent models, enabling us to make stronger conclusions about how regionally specific cellular and molecular manipulations in mice relate back to humans.


Assuntos
Axônios/patologia , Conectoma , Imageamento por Ressonância Magnética , Rede Nervosa , Doenças do Sistema Nervoso , Transtornos Psicóticos , Animais , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/fisiopatologia , Transtornos Psicóticos/patologia , Transtornos Psicóticos/fisiopatologia
19.
PLoS One ; 9(11): e111048, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25386919

RESUMO

A better characterization of how an individual's brain is functionally organized will likely bring dramatic advances to many fields of study. Here we show a model-based approach toward characterizing resting state functional connectivity MRI (rs-fcMRI) that is capable of identifying a so-called "connectotype", or functional fingerprint in individual participants. The approach rests on a simple linear model that proposes the activity of a given brain region can be described by the weighted sum of its functional neighboring regions. The resulting coefficients correspond to a personalized model-based connectivity matrix that is capable of predicting the timeseries of each subject. Importantly, the model itself is subject specific and has the ability to predict an individual at a later date using a limited number of non-sequential frames. While we show that there is a significant amount of shared variance between models across subjects, the model's ability to discriminate an individual is driven by unique connections in higher order control regions in frontal and parietal cortices. Furthermore, we show that the connectotype is present in non-human primates as well, highlighting the translational potential of the approach.


Assuntos
Conectoma/métodos , Lobo Frontal/fisiologia , Rede Nervosa/fisiologia , Vias Neurais/fisiologia , Lobo Parietal/fisiologia , Adulto , Algoritmos , Animais , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Macaca fascicularis , Imageamento por Ressonância Magnética , Masculino , Modelos Teóricos , Adulto Jovem
20.
J Neurosci ; 34(16): 5552-63, 2014 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-24741045

RESUMO

Resting state functional connectivity MRI (rs-fcMRI) may provide a powerful and noninvasive "bridge" for comparing brain function between patients and experimental animal models; however, the relationship between human and macaque rs-fcMRI remains poorly understood. Here, using a novel surface deformation process for species comparisons in the same anatomical space (Van Essen, 2004, 2005), we found high correspondence, but also unique hub topology, between human and macaque functional connectomes. The global functional connectivity match between species was moderate to strong (r = 0.41) and increased when considering the top 15% strongest connections (r = 0.54). Analysis of the match between functional connectivity and the underlying anatomical connectivity, derived from a previous retrograde tracer study done in macaques (Markov et al., 2012), showed impressive structure-function correspondence in both the macaque and human. When examining the strongest structural connections, we found a 70-80% match between structural and functional connectivity matrices in both species. Finally, we compare species on two widely used metrics for studying hub topology: degree and betweenness centrality. The data showed topological agreement across the species, with nodes of the posterior cingulate showing high degree and betweenness centrality. In contrast, nodes in medial frontal and parietal cortices were identified as having high degree and betweenness in the human as opposed to the macaque. Our results provide: (1) a thorough examination and validation for a surface-based interspecies deformation process, (2) a strong theoretical foundation for making interspecies comparisons of rs-fcMRI, and (3) a unique look at topological distinctions between the species.


Assuntos
Encéfalo/anatomia & histologia , Encéfalo/fisiologia , Conectoma , Vias Neurais/anatomia & histologia , Adulto , Animais , Encéfalo/irrigação sanguínea , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Macaca mulatta , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/irrigação sanguínea , Oxigênio/sangue , Curva ROC , Análise de Regressão , Especificidade da Espécie , Adulto Jovem
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