Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 58
Filtrar
1.
BMC Med Educ ; 22(1): 547, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35840942

RESUMO

BACKGROUND: Persistent pain is a highly prevalent, global cause of disability. Research suggests that many healthcare professionals are not well equipped to manage pain, and this may be attributable at least in part to undergraduate education. The primary aim of this study was to quantify and compare first and final year nursing, midwifery and allied health professional (NMAHP) students' pain related knowledge and attitudes. The secondary aim was to explore what factors influence students' pain related knowledge and attitudes. METHODS: In this cross-sectional study, 1154 first and final year healthcare students, from 12 universities in five different countries completed the Revised Neurophysiology of Pain Quiz (RNPQ) [knowledge] and the Health Care Providers Pain and Impairment Relationship Scale (HC-PAIRS) [attitudes]. RESULTS: Physiotherapy was the only student group with statistically and clinically improved pain related knowledge [mean difference, 95% CI] (3.4, 3.0 to 3.9, p = 0.01) and attitudes (-17.2, -19.2 to 15.2, p = 0.01) between first and final year. Pain education teaching varied considerably from course to course (0 to 40 h), with greater levels of pain related knowledge and attitudes associated with higher volumes of pain specific teaching. CONCLUSIONS: There was little difference in pain knowledge and attitudes between all first and final year NMAHP students other than physiotherapy. This suggests that for most NMAHP disciplines, undergraduate teaching has little or no impact on students' understanding of pain. There is an urgent need to enhance pain education provision at the undergraduate level in NMAHPs. TRIAL REGISTRATION: The study protocol was prospectively registered at ClinicalTrials.Gov NCT03522857 .


Assuntos
Tocologia , Estudantes de Ciências da Saúde , Estudantes de Enfermagem , Atitude , Estudos Transversais , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Dor , Gravidez , Inquéritos e Questionários
2.
BMC Med Educ ; 22(1): 211, 2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-35351106

RESUMO

BACKGROUND: Persistent pain is a leading cause of disability worldwide yet implementation of clinical guidelines that recommend a biopsychosocial approach remains a challenge in clinical practise. Limited pain understanding amongst clinicians may be partly responsible for this. PURPOSE OF THE STUDY: 1) Qualitatively explore the experience of receiving PSE, understanding of PSE and operationalisation of PSE-related principles in routine clinical practice. 2) Quantitatively explore pain knowledge, attitudes, and behaviours of general practitioners (GPs) and nurse practitioners (NPs) before and after pain science education (PSE). METHODS: An exploratory, single-site, mixed-methods study in north-east England. Fifteen NPs/GPs completed questionnaires and a case-vignette before and after a 70-min face-to-face PSE lecture. Qualitative data were thematically analysed from two focus groups after the intervention. RESULTS: Clinicians' relatively high prior levels of knowledge, attitudes, and behaviour were similar after PSE. Qualitative themes described facilitation of self-reflection on pain management behaviours, and difficulties in operationalising PSE principles in practise including: limited patient rapport; short appointment times; patients' passive and often oppositional biomedical treatment expectations; and clinicians' lack of readily understandable language to communicate with patients. CONCLUSION: The findings highlight the value of PSE perceived by these clinicians who were already favourably inclined towards biopsychosocial pain management. They sought more resources for their personal learning and for communication with patients. Even with such favourable disposition, the practicalities and environment of clinical practice impeded the operationalisation of PSE-related principles. TRIAL REGISTRATION: This study was prospectively registered at ClinicalTrials.Gov ( NCT04587596 ) in October 2020.


Assuntos
Clínicos Gerais , Manejo da Dor , Atenção à Saúde , Clínicos Gerais/psicologia , Humanos , Dor , Manejo da Dor/métodos , Atenção Primária à Saúde
3.
Eur J Neurosci ; 55(3): 746-761, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34964525

RESUMO

Navigating through our environment raises challenges for perception by generating salient background visual motion and eliciting prominent eye movements to stabilise the retinal image. It remains unclear if exogenous spatial attentional orienting is possible during background motion and the eye movements it causes and whether this compromises the underlying neural processing. To test this, we combined exogenous orienting, visual scene motion, and electroencephalography (EEG). A total of 26 participants viewed a background of moving black and grey bars (optokinetic stimulation). We tested for effects of non-spatially predictive peripheral cueing on visual motion discrimination of a target dot, presented either at the same (valid) or opposite (invalid) location as the preceding cue. Valid cueing decreased reaction times not only when participants kept their gaze fixed on a central point (fixation blocks) but also even when there was no fixation point, so that participants performed intensive, repetitive tracking eye movements (eye movement blocks). Overall, manual response reaction times were slower during eye movements. Cueing also produced reliable effects on neural activity on either block, including within the first 120 ms of neural processing of the target. The key pattern with larger event-related potential (ERP) amplitudes on invalid versus valid trials showed that the neural substrate of exogenous cueing was highly similar during eye movements or fixation. Exogenous peripheral cueing and its neural correlates are robust against distraction from the moving visual scene, important for perceptual cognition during navigation.


Assuntos
Atenção , Sinais (Psicologia) , Atenção/fisiologia , Movimentos Oculares , Fixação Ocular , Humanos , Estimulação Luminosa , Tempo de Reação/fisiologia , Percepção Visual/fisiologia
4.
Biochem Biophys Res Commun ; 580: 107-112, 2021 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-34638028

RESUMO

Peroxynitrite is a reactive intermediate formed in vivo through uncatalysed reaction of superoxide and nitric oxide radicals. Despite significant interest in detecting peroxynitrite in vivo and understanding its production, little attention has been given to the evolutionary origins of peroxynitrite signalling. Herein we focus on two enzymes that are key to the biosynthesis of superoxide and nitric oxide, NADPH oxidase 5 (NOX5) and endothelial nitric oxide synthase (eNOS), respectively. Multiple sequence alignments of both enzymes including homologues from all domains of life, coupled with a phylogenetic analysis of NOX5, suggest eNOS and NOX5 are present in animals as the result of horizontal gene transfer from ancestral cyanobacteria to ancestral eukaryotes. Therefore, biochemical studies from other laboratories on a NOX5 homologue in Cylindrospermum stagnale and an eNOS homologue in Synechococcus sp. PCC 7335 are likely to be of relevance to human NOX5 and eNOS and to the production of superoxide, nitric oxide and peroxynitrite in humans.


Assuntos
Ácido Peroxinitroso/metabolismo , Transdução de Sinais , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Cianobactérias/genética , Cianobactérias/metabolismo , Evolução Molecular , Humanos , NADPH Oxidase 5/genética , NADPH Oxidase 5/metabolismo , Óxido Nítrico/genética , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Ácido Peroxinitroso/genética , Filogenia , Superóxidos/metabolismo
5.
Neuropsychologia ; 162: 108054, 2021 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-34626619

RESUMO

Mentalizing is the powerful cognitive ability to understand others. By attributing mental states to others, we become able to explain and predict their behavior. The right temporoparietal junction (rTPJ) plays a key role in processing models of mental states. Yet, a different line of research suggests that the rTPJ is crucially involved in attentional control, prompting debates on its cognitive function. In this pre-registered neuro-navigated event-related TMS study, we tested for the rTPJ's specificity in mentalizing and attentional control. We interfered with its activity in a recently developed spatial cueing paradigm in which another's mental states were apparently task-relevant, allowing direct comparison of TMS effects on attention and mentalizing. We contrasted effects with a nearby control TMS site. Our confirmatory analysis showed no evidence for an involvement of the rTPJ in mentalizing or attentional control, presumably due to an observed large inter-individual variability of TMS effects on context and validity. To follow up this finding, we conducted exploratory analyses which revealed that rTPJ TMS had an influence on both attentional control and mentalizing. TMS effects on attention and mentalizing co-varied across participants: participants responding most to rTPJ TMS on mentalizing were also those for whom rTPJ TMS increased the attentional effect the most. This provides further evidence against total absolute segregation between mentalizing and attention within the rTPJ. Rather, our results suggest a common cognitive mechanism in both domains for which the rTPJ is necessary, paving the way for future research to cross-validate and extend these findings.


Assuntos
Mentalização , Teoria da Mente , Atenção , Humanos , Lobo Parietal , Lobo Temporal
6.
Neuropsychologia ; 161: 107995, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34425143

RESUMO

It is unclear how the brain reaches the correct balance between temporal and spatial processing necessary to perceive motion across space. Here, we tested whether visual motion area V5/MT + plays a causal role in Ternus illusion. Ternus displays can be perceived as showing either group motion or element motion and are empirically useful for dissociating temporal and spatial grouping across visual fields. Online single-pulse TMS was applied to observers during the presentation of Ternus displays, either within or across hemifields, over left V5/MT + or, respectively, a control site in the left somatosensory cortex, or an additional 'Sham' control condition. In the cross-hemifields condition, observers perceived more element motion with TMS over left V5/MT + than in either control condition. By contrast, in the within-hemifield condition, observers reported more group motion after left V5/MT + TMS. Our findings demonstrate a causal role of left V5/MT+ in the spatio-temporal grouping of Ternus apparent motion, and in maintaining the balance of spatio-temporal processing both within and across individual hemifields.


Assuntos
Percepção de Movimento , Córtex Visual , Humanos , Movimento (Física) , Estimulação Magnética Transcraniana , Campos Visuais
7.
Neuroscience ; 470: 37-51, 2021 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-34273415

RESUMO

As we move through our environment, our visual system is presented with optic flow, a potentially important cue for perception, navigation and postural control. How does the brain anticipate the optic flow that arises as a consequence of our own movement? Converging evidence suggests that stimuli are processed differently by the brain if occurring as a consequence of self-initiated actions, compared to when externally generated. However, this has mainly been demonstrated with auditory stimuli. It is not clear how this occurs with optic flow. We measured behavioural, neurophysiological and head motion responses of 29 healthy participants to radially expanding, vection-inducing optic flow stimuli, simulating forward transitional motion, which were either initiated by the participant's own button-press ("self-initiated flow") or by the computer ("passive flow"). Self-initiation led to a prominent and left-lateralized inhibition of the flow-evoked posterior event-related alpha desynchronization (ERD), and a stabilisation of postural responses. Neither effect was present in control button-press-only trials, without optic flow. Additionally, self-initiation also produced a large event-related potential (ERP) negativity between 130-170 ms after optic flow onset. Furthermore, participants' visual induced motion sickness (VIMS) and vection intensity ratings correlated positively across the group - although many participants felt vection in the absence of any VIMS, none reported the opposite combination. Finally, we found that the simple act of making a button press leads to a detectable head movement even when using a chin rest. Taken together, our results indicate that the visual system is capable of predicting optic flow when self-initiated, to affect behaviour.


Assuntos
Percepção de Movimento , Enjoo devido ao Movimento , Fluxo Óptico , Potenciais Evocados , Humanos , Estimulação Luminosa , Equilíbrio Postural
8.
Health Serv Res ; 56(6): 1271-1280, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33754333

RESUMO

OBJECTIVE: To assess the impact of interventions for improving the management of chronic obstructive pulmonary disease (COPD), specifically increased use of pulmonary rehabilitation (PR) on patient outcomes and cost-benefit analysis. DATA SOURCES: We used the national Hospital Episode Statistics (HES) datasets in England, local data and experts from the hospital setting, National Prices and National Tariffs, reports and the literature around the effectiveness of PR programs. STUDY DESIGN: The COPD pathway was modeled using discrete event simulation (DES) to capture the patient pathway to an adequate level of detail as well as randomness in the real world. DES was further enhanced by the integration of a health economic model to calculate the net benefit and cost of treating COPD patients based on key sets of interventions. DATA COLLECTION/EXTRACTION METHODS: A total of 150 input parameters and 75 distributions were established to power the model using the HES dataset, outpatient activity data from the hospital and community services, and the literature. PRINCIPAL FINDINGS: The simulation model showed that increasing referral to PR (by 10%, 20%, or 30%) would be cost-effective (with a benefit-cost ratio of 5.81, 5.95, and 5.91, respectively) by having a positive impact on patient outcomes and operational metrics. Number of deaths, admissions, and bed days decreased (ie, by 3.56 patients, 4.90 admissions, and 137.31 bed days for a 30% increase in PR referrals) as well as quality of life increased (ie, by 5.53 QALY among 1540 patients for the 30% increase). CONCLUSIONS: No operational model, either statistical or simulation, has previously been developed to capture the COPD patient pathway within a hospital setting. To date, no model has investigated the impact of PR on COPD services, such as operations, key performance, patient outcomes, and cost-benefit analysis. The study will support policies around extending availability of PR as a major intervention.


Assuntos
Simulação por Computador , Análise Custo-Benefício , Tomada de Decisões , Modelos Econômicos , Doença Pulmonar Obstrutiva Crônica/reabilitação , Inglaterra , Hospitalização , Humanos , Avaliação de Resultados da Assistência ao Paciente
9.
Brain Stimul ; 13(6): 1689-1696, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33035723

RESUMO

BACKGROUND: Recent evidence suggests that the dorsal medial frontal cortex (dMFC) may make an important contribution to perceptual decision-making, and not only to motor control. OBJECTIVE/HYPOTHESIS: By fitting psychometric functions to behavioural data after TMS we tested whether the dMFC is critical specifically for the precision and/or bias of perceptual judgements. Additionally we aimed to disentangle potential roles of the dMFC in dealing with perceptual versus response switching. METHODS: A subjective visual vertical task (SVV) was used in which participants weight visual (and other, e.g., vestibular) information to establish whether a line is oriented vertically. To ensure a high perceptual demand (putatively necessary to demonstrate a dMFC involvement) SVV lines were presented inside pop-out targets within a visual search array. Distinct features of perceptual performance were analysed before as compared to following theta-burst TMS stimulation of the dMFC, a control site, or no stimulation, in three groups, each of 20 healthy participants. RESULTS: dMFC stimulation improved the precision of verticality judgments. Moreover, dMFC stimulation improved accuracy, selectively when response switches occurred with perceptual repeats. CONCLUSION: These findings point to a causal role of the dMFC in establishing the precision of perceptual decision making, demonstrably dissociable from an additional role in motor control in attentionally demanding contexts.


Assuntos
Tomada de Decisões/fisiologia , Lobo Frontal/fisiologia , Ritmo Teta/fisiologia , Estimulação Magnética Transcraniana/métodos , Percepção Visual/fisiologia , Adulto , Atenção/fisiologia , Feminino , Humanos , Masculino , Estimulação Luminosa/métodos , Tempo de Reação/fisiologia , Adulto Jovem
10.
J Mol Evol ; 88(8-9): 662-673, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32979052

RESUMO

Eukaryogenesis, the origin of the eukaryotes, is still poorly understood. Herein, we show how a detailed all-kingdom phylogenetic analysis overlaid with a map of key biochemical features can provide valuable clues. The photolyase/cryptochrome family of proteins are well known to repair DNA in response to potentially harmful effects of sunlight and to entrain circadian rhythms. Phylogenetic analysis of photolyase/cryptochrome protein sequences from a wide range of prokaryotes and eukaryotes points to a number of horizontal gene transfer events between ancestral bacteria and ancestral eukaryotes. Previous experimental research has characterised patterns of tryptophan residues in these proteins that are important for photoreception, specifically a tryptophan dyad, a canonical tryptophan triad, an alternative tryptophan triad, a tryptophan tetrad and an alternative tetrad. Our results suggest that the spread of the different triad and tetrad motifs across the kingdoms of life accompanied the putative horizontal gene transfers and is consistent with multiple bacterial contributions to eukaryogenesis.


Assuntos
Criptocromos , Desoxirribodipirimidina Fotoliase , Evolução Molecular , Fotorreceptores Microbianos/genética , Filogenia , Sequência de Aminoácidos , Criptocromos/genética , Desoxirribodipirimidina Fotoliase/genética , Transferência Genética Horizontal , Triptofano
11.
Eur J Neurosci ; 51(7): 1657-1675, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31408562

RESUMO

Self-motion perception is a key aspect of higher vestibular processing, suggested to rely upon hemispheric lateralization and alpha-band oscillations. The first aim of this study was to test for any lateralization in the EEG alpha band during the illusory sense of self-movement (vection) induced by large optic flow stimuli. Visual stimuli flickered at alpha frequency (approx. 10 Hz) in order to produce steady state visually evoked potentials (SSVEPs), a robust EEG measure which allows probing the frequency-specific response of the cortex. The first main result was that differential lateralization of the alpha SSVEP response was found during vection compared with a matched random motion control condition, supporting the idea of lateralization of visual-vestibular function. Additionally, this effect was frequency-specific, not evident with lower frequency SSVEPs. The second aim of this study was to test for a causal role of the right hemisphere in producing this lateralization effect and to explore the possibility of selectively modulating the SSVEP response. Transcranial alternating current stimulation (tACS) was applied over the right hemisphere simultaneously with SSVEP recording, using a novel artefact removal strategy for combined tACS-EEG. The second main result was that tACS enhanced SSVEP amplitudes, and the effect of tACS was not confined to the right hemisphere. Subsequent control experiments showed the effect of tACS requires the flicker frequency and tACS frequency to be closely matched and tACS to be of sufficient intensity. Combined tACS-SSVEPs are a promising method for future investigation into the role of neural oscillations and for optimizing tACS.


Assuntos
Potenciais Evocados Visuais , Ilusões , Estimulação Transcraniana por Corrente Contínua , Córtex Cerebral , Eletroencefalografia , Humanos
12.
J Neurosci Methods ; 332: 108540, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31809763

RESUMO

BACKGROUND: The ability to record brain activity in humans during movement, and in real world environments, is an important step towards understanding cognition. Electroencephalography (EEG) is well suited to mobile applications but suffers from the problem of artefacts introduced into the signal during movement. Steady state visually evoked potentials (SSVEPs) give an excellent signal-to-noise ratio and averaging a sufficient number of trials will eventually remove any noise not phase locked to the visual flicker. NEW METHOD: Here we present a method for producing SSVEPs of real world environments using modified LCD shutter glasses, which are commonly used for 3D TV, by adapting the glass to flicker at neurophysiologically relevant frequencies (alpha band). Participants viewed a room whilst standing and walking. Either the left or right side of the room was illuminated, to test if it is possible to recover the resulting SSVEPs when walking, as well as to probe the effect of walking on neural activity. Additionally, by using a signal generator to produce "simulated SSVEPs" on the scalp we can demonstrate that this method is able to accurately recover evoked neural responses during walking. RESULTS: The amplitude of SSVEPs over right parietal cortex was reduced by walking. Furthermore, the waveform and phase of the SSVEPs is highly preserved between walking and standing, but was sensitive to whether the left or right side of the room was illuminated. CONCLUSIONS: This method allows probing neural responses during natural movements within real environments, potentially at a wide range of frequencies.


Assuntos
Eletroencefalografia , Potenciais Evocados Visuais , Artefatos , Cognição , Humanos , Estimulação Luminosa
13.
J Neurophysiol ; 123(2): 571-586, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31875488

RESUMO

The right frontal eye field (rFEF) is associated with visual perception and eye movements. rFEF is activated during optokinetic nystagmus (OKN), a reflex that moves the eye in response to visual motion (optokinetic stimulation, OKS). It remains unclear whether rFEF plays causal perceptual and/or oculomotor roles during OKS and OKN. To test this, participants viewed a leftward-moving visual scene of vertical bars and judged whether a flashed dot was moving. Single pulses of transcranial magnetic stimulation (TMS) were applied to rFEF on half of trials. In half of blocks, to explore oculomotor control, participants performed an OKN in response to the OKS. rFEF TMS, during OKN, made participants more accurate on trials when the dot was still, and it slowed eye movements. In separate blocks, participants fixated during OKS. This not only controlled for eye movements but also allowed the use of EEG to explore the FEF's role in visual motion discrimination. In these blocks, by contrast, leftward dot motion discrimination was impaired, associated with a disruption of the frontal-posterior balance in alpha-band oscillations. None of these effects occurred in a control site (M1) experiment. These results demonstrate multiple related yet dissociable causal roles of the right FEF during optokinetic stimulation.NEW & NOTEWORTHY This study demonstrates causal roles of the right frontal eye field (FEF) in motion discrimination and eye movement control during visual scene motion: previous work had only examined other stimuli and eye movements such as saccades. Using combined transcranial magnetic stimulation and EEG and a novel optokinetic stimulation motion-discrimination task, we find evidence for multiple related yet dissociable causal roles within the FEF: perceptual processing during optokinetic stimulation, generation of the optokinetic nystagmus, and the maintenance of alpha oscillations.


Assuntos
Ritmo alfa/fisiologia , Movimentos Oculares/fisiologia , Lobo Frontal/fisiologia , Percepção de Movimento/fisiologia , Nistagmo Optocinético/fisiologia , Adulto , Discriminação Psicológica/fisiologia , Feminino , Humanos , Masculino , Estimulação Luminosa , Percepção Espacial/fisiologia , Estimulação Magnética Transcraniana , Adulto Jovem
14.
Neuropsychologia ; 127: 113-122, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30831119

RESUMO

The intraparietal sulcus within the dorsal right posterior parietal cortex is associated with spatial orientation and attention in relation to egocentric reference frames, such as left or right hemifield. It remains unclear whether it plays a causal role in the human in the roll plane (i.e. when visual stimuli are tilted clockwise or anticlockwise) which this is an important aspect of egocentric visual processing with clinical relevance in vestibular disorders. The subjective visual vertical (SVV) task measures the deviation between an individual's subjective vertical perception and the veridical vertical, involves the integration of visual, and vestibular information, and relies on a distributed network of multisensory regions that shows right lateralization and inter-areal inhibition. This study used combined TMS-EEG to investigate the role of the human dorsal parietal cortex in verticality perception using the SVV task in darkness. Participants were sorted according to their baseline bias at this task i.e. those with either a slight counterclockwise versus clockwise bias when judging a line to be truly vertical. Right parietal TMS facilitated verticality perception, reducing the difference between groups. ERPs suggested that the behavioral TMS effect occurred through normalizing individual SVV biases, evident frontally and late in the trial, and which was abolished after right parietal TMS. Effects were site and task specific, shown with a homologous left hemisphere control, and a landmark task performed on the same stimuli. These results support a right lateralization of visual-vestibular cognition and a distinct representation of the roll plane for egocentric processing in dorsal parietal cortex.


Assuntos
Potenciais Evocados/fisiologia , Lobo Parietal/fisiologia , Estimulação Magnética Transcraniana/métodos , Percepção Visual/fisiologia , Adulto , Eletroencefalografia , Feminino , Lateralidade Funcional/fisiologia , Humanos , Masculino , Tempo de Reação/fisiologia , Percepção Espacial/fisiologia , Dimensão Vertical
15.
Eur J Drug Metab Pharmacokinet ; 44(4): 557-565, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30628010

RESUMO

BACKGROUND AND OBJECTIVES: A clinical trial was conducted to measure and analyse the pharmacokinetic parameters of a lipid formulation of risperidone, VAL401. The VAL401 formulation is designed to repurpose risperidone from an antipsychotic to an adenocarcinoma treatment, with the lipid formulation altering the cellular uptake of risperidone, thus enabling anticancer biology to be exhibited in preclinical testing. METHODS: This first human trial of VAL401 measured the concentrations of risperidone and its primary metabolite, 9-hydroxyrisperidone, in the blood of patients after treatment with a single 2-mg dose of VAL401. RESULTS: The trial provided information on differences in the pharmacokinetic profile of risperidone in VAL401 that may be caused by the formulation and/or the nature of the cancer patient population. VAL401 provided the following key pharmacokinetic parameters for the risperidone plasma concentration after a single 2-mg dose of VAL401, with results normalised to a dosage of 1 mg for comparison with literature values: Tmax, 2 h; Cmax, 8 ng/ml; half-life, 3.5 h; area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), 58.2 ng h2/mL. CONCLUSIONS: Further comparisons of the pharmacokinetic parameters of risperidone and 9-hydroxyrisperidone in plasma of patients administered VAL401 and the corresponding parameters obtained from published data for conventionally formulated risperidone provide evidence for altered biological processing of VAL401 as compared to risperidone. The absolute values obtained provide support for future studies of VAL401 as a cancer treatment, as the Cmax demonstrates sufficient exposure to reach the concentrations seen during preclinical anticancer testing, yet the overall exposure to the active moiety supports the use of the safety and tolerability data from conventional risperidone during future clinical trials.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Lipídeos/farmacocinética , Risperidona/farmacocinética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adulto , Idoso , Antipsicóticos/farmacocinética , Área Sob a Curva , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Química Farmacêutica/métodos , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Palmitato de Paliperidona/farmacocinética , Equivalência Terapêutica
16.
Biochem Biophys Res Commun ; 510(1): 27-34, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30660368

RESUMO

Retinoic acid signalling is generally considered to be of animal origin. Recently, retinoic acid has been identified in cyanobacteria, yet no mechanism for its production has been identified. Here, we characterise for the first time a cyanobacterial aldehyde dehydrogenase that produces retinoic acid in vitro. Our computational studies suggest that the cyanobacterial aldehyde dehydrogenase resembles an ancestor of both eukaryotic aldehyde dehydrogenase 1 and aldehyde dehydrogenase 2. The Chlorogloeopsis fritschii aldehyde dehydrogenase described here may find applications in synthetic production of retinoic acid as well as contributing to our understanding of retinoid synthesis in cyanobacteria.


Assuntos
Aldeído Desidrogenase/metabolismo , Cianobactérias/enzimologia , Tretinoína/metabolismo , Cianobactérias/metabolismo , Evolução Molecular , Filogenia
17.
J Cogn Neurosci ; 31(3): 442-452, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30457915

RESUMO

This study investigates the causal contribution of the left frontopolar cortex (FPC) to the processing of violated expectations from learned target-distractor spatial contingencies during visual search. The experiment consisted of two phases: learning and test. Participants searched for targets presented either among repeated or nonrepeated target-distractor configurations. Prior research showed that repeated encounters of identically arranged displays lead to memory about these arrays, which then can come to guide search (contextual cueing effect). The crucial manipulation was a change of the target location, in a nevertheless constant distractor layout, at the transition from learning to test. In addition to this change, we applied repetitive transcranial magnetic stimulation (rTMS) over the left lateral FPC, over a posterior control site, or no rTMS at all (baseline; between-group manipulation) to see how FPC rTMS influences the ability of observers to adapt context-based memories acquired in the training phase. The learning phase showed expedited search in repeated relative to nonrepeated displays, with this context-based facilitation being comparable across all experimental groups. For the test phase, the recovery of cueing was critically dependent on the stimulation site: Although there was evidence of context adaptation toward the end of the experiment in the occipital and no-rTMS conditions, observers with FPC rTMS showed no evidence of relearning at all after target location changes. This finding shows that FPC plays an important role in the regulation of prediction errors in statistical context learning, thus contributing to an update of the spatial target-distractor contingencies after target position changes in learned spatial arrays.


Assuntos
Atenção/fisiologia , Lobo Frontal/fisiologia , Memória/fisiologia , Percepção Visual/fisiologia , Adulto , Feminino , Humanos , Aprendizagem/fisiologia , Masculino , Estimulação Luminosa , Tempo de Reação/fisiologia , Aprendizagem Espacial/fisiologia , Estimulação Magnética Transcraniana
18.
Neuroimage ; 171: 222-233, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29307607

RESUMO

Inhibitory control is an important executive function that is necessary to suppress premature actions and to block interference from irrelevant stimuli. Current experimental studies and models highlight proactive and reactive mechanisms and claim several cortical and subcortical structures to be involved in response inhibition. However, the involved structures, network mechanisms and the behavioral relevance of the underlying neural activity remain debated. We report cortical EEG and invasive subthalamic local field potential recordings from a fully implanted sensing neurostimulator in Parkinson's patients during a stimulus- and response conflict task with and without deep brain stimulation (DBS). DBS made reaction times faster overall while leaving the effects of conflict intact: this lack of any effect on conflict may have been inherent to our task encouraging a high level of proactive inhibition. Drift diffusion modelling hints that DBS influences decision thresholds and drift rates are modulated by stimulus conflict. Both cortical EEG and subthalamic (STN) LFP oscillations reflected reaction times (RT). With these results, we provide a different interpretation of previously conflict-related oscillations in the STN and suggest that the STN implements a general task-specific decision threshold. The timecourse and topography of subthalamic-cortical oscillatory connectivity suggest the involvement of motor, frontal midline and posterior regions in a larger network with complementary functionality, oscillatory mechanisms and structures. While beta oscillations are functionally associated with motor cortical-subthalamic connectivity, low frequency oscillations reveal a subthalamic-frontal-posterior network. With our results, we suggest that proactive as well as reactive mechanisms and structures are involved in implementing a task-related dynamic inhibitory signal. We propose that motor and executive control networks with complementary oscillatory mechanisms are tonically active, react to stimuli and release inhibition at the response when uncertainty is resolved and return to their default state afterwards.


Assuntos
Conflito Psicológico , Tomada de Decisões/fisiologia , Função Executiva/fisiologia , Inibição Psicológica , Idoso , Estimulação Encefálica Profunda , Eletroencefalografia , Feminino , Humanos , Masculino , Doença de Parkinson/fisiopatologia , Núcleo Subtalâmico/fisiologia
19.
J Neurol ; 264(Suppl 1): 45-47, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28293724

RESUMO

Visually induced vection is the illusory sensation of self-motion caused by visual stimuli (such as a dot cloud) that emulate what is seen when an agent moves through space. The sufficient stimulus parameters to generate vection are unknown, but elucidating this is of interest in the study of higher (cognitive) neurological disorders where the relationship between visual and vestibular processing is disturbed. Here, we selectively eliminate that radial motion angle from vection displays and show that vection is still present, although weaker than during normal optic flow, and that vection strength was strikingly variable across individuals.


Assuntos
Cognição/fisiologia , Ilusões/fisiologia , Percepção de Movimento/fisiologia , Doenças Vestibulares/fisiopatologia , Adulto , Feminino , Humanos , Masculino , Fluxo Óptico , Adulto Jovem
20.
Cancer Lett ; 393: 16-21, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28188816

RESUMO

Drug reprofiling is emerging as an effective paradigm for discovery of cancer treatments. Herein, an antipsychotic drug is immobilised using the Magic Tag® chemical genomics tool and screened against a T7 bacteriophage displayed library of polypeptides from Drosophila melanogaster, as a whole genome model, to uncover an interaction with a section of 17-ß-HSD10, a proposed prostate cancer target. A computational study and enzyme inhibition assay with full length human 17-ß-HSD10 identifies risperidone as a drug reprofiling candidate. When formulated with rumenic acid, risperidone slows proliferation of PC3 prostate cancer cells in vitro and retards PC3 prostate cancer tumour growth in vivo in xenografts in mice, presenting an opportunity to reprofile risperidone as a cancer treatment.


Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , 3-Hidroxiacil-CoA Desidrogenases/antagonistas & inibidores , Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Antipsicóticos/farmacologia , Drosophila melanogaster/efeitos dos fármacos , Reposicionamento de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Genômica/métodos , Neoplasias da Próstata/tratamento farmacológico , Risperidona/farmacologia , 17-Hidroxiesteroide Desidrogenases/química , 17-Hidroxiesteroide Desidrogenases/genética , 17-Hidroxiesteroide Desidrogenases/metabolismo , 3-Hidroxiacil-CoA Desidrogenases/química , 3-Hidroxiacil-CoA Desidrogenases/genética , 3-Hidroxiacil-CoA Desidrogenases/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Animais , Antineoplásicos/química , Antipsicóticos/química , Bacteriófago T7/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Drosophila melanogaster/enzimologia , Drosophila melanogaster/genética , Composição de Medicamentos , Inibidores Enzimáticos/química , Biblioteca Gênica , Humanos , Ácidos Linoleicos Conjugados/química , Masculino , Camundongos Nus , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Conformação Proteica , Risperidona/química , Relação Estrutura-Atividade , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA