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1.
J Cereb Blood Flow Metab ; 40(2): 298-313, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30398083

RESUMO

Neurovascular coupling (through which local cerebral blood flow changes in response to neural activation are mediated) is impaired in many diseases including diabetes. Current preclinical rodent models of neurovascular coupling rely on invasive surgery and instrumentation, but transgenic zebrafish coupled with advances in imaging techniques allow non-invasive quantification of cerebrovascular anatomy, neural activation, and cerebral vessel haemodynamics. We therefore established a novel non-invasive, non-anaesthetised zebrafish larval model of neurovascular coupling, in which visual stimulus evokes neuronal activation in the optic tectum that is associated with a specific increase in red blood cell speed in tectal blood vessels. We applied this model to the examination of the effect of glucose exposure on cerebrovascular patterning and neurovascular coupling. We found that chronic exposure of zebrafish to glucose impaired tectal blood vessel patterning and neurovascular coupling. The nitric oxide donor sodium nitroprusside rescued all these adverse effects of glucose exposure on cerebrovascular patterning and function. Our results establish the first non-mammalian model of neurovascular coupling, offering the potential to perform more rapid genetic modifications and high-throughput screening than is currently possible using rodents. Furthermore, using this zebrafish model, we reveal a potential strategy to ameliorate the effects of hyperglycemia on cerebrovascular function.

2.
Laryngoscope ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31566749

RESUMO

OBJECTIVE: Oropharyngeal squamous cell carcinoma (OPSCC) incidence is rapidly increasing, as are survival rates, in large part due to the human papillomavirus (HPV). Treatment intensity, however, has remained unchanged, making treatment-related toxicity (i.e., dysphagia) a critical problem for an increasing number of patients. The primary objective of this study was to determine whether pretreatment objective swallowing measures can predict percutaneous fluoroscopic guided gastrostomy tube (PFG) utilization during OPSCC treatment. METHODS: Forty-one newly diagnosed OPSCC patients treated with radiation underwent evaluation of swallow function with modified barium swallow study (MBSS) prior to and at completion of radiation treatment using the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST); a subset of patients were evaluated using the MD Anderson Dysphagia Inventory (MDADI). RESULTS: Patients were male (100%), primarily Caucasian (85.4%) and p16 positive (85.4%) with mean age of 65.7 years. PFG were placed in 70.7% patients (n = 29) and used by 63.4% (n = 26). Pre- and post-treatment DIGEST scores were associated with T-classification (t = -2.9, p = .001, t = -2.7, p = .01) and indicated deteriorating swallow function during treatment (mean change = 0.46 [t = -2.7, p = .01]). DIGEST and MDADI scores were generally not associated with patient PFG utilization. DIGEST and MDADI scores were significantly correlated prior to, but not following completion of treatment. CONCLUSION: Pre-treatment DIGEST and patient reported swallowing outcomes (MDADI) can be useful in identifying patients with unsafe and/or grossly inefficient swallowing function. However, objectively measured swallow function was not associated with PFG utilization. Development of PFG placement algorithms (reactive vs. prophylactic) therefore require additional inputs/metrics. LEVEL OF EVIDENCE: 4 Laryngoscope, 2019.

3.
Dis Model Mech ; 12(9)2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31481433

RESUMO

Diabetes is associated with dysfunction of the neurovascular unit, although the mechanisms of this are incompletely understood and currently no treatment exists to prevent these negative effects. We previously found that the nitric oxide (NO) donor sodium nitroprusside (SNP) prevents the detrimental effect of glucose on neurovascular coupling in zebrafish. We therefore sought to establish the wider effects of glucose exposure on both the neurovascular unit and on behaviour in zebrafish, and the ability of SNP to prevent these. We incubated 4-days post-fertilisation (dpf) zebrafish embryos in 20 mM glucose or mannitol for 5 days until 9 dpf, with or without 0.1 mM SNP co-treatment for 24 h (8-9 dpf), and quantified vascular NO reactivity, vascular mural cell number, expression of a klf2a reporter, glial fibrillary acidic protein (GFAP) and transient receptor potential cation channel subfamily V member 4 (TRPV4), as well as spontaneous neuronal activation at 9 dpf, all in the optic tectum. We also assessed the effect on light/dark preference and locomotory characteristics during free-swimming studies. We find that glucose exposure significantly reduced NO reactivity, klf2a reporter expression, vascular mural cell number and TRPV4 expression, while significantly increasing spontaneous neuronal activation and GFAP expression (all in the optic tectum). Furthermore, when we examined larval behaviour, we found that glucose exposure significantly altered light/dark preference and high and low speed locomotion while in light. Co-treatment with SNP reversed all these molecular and behavioural effects of glucose exposure. Our findings comprehensively describe the negative effects of glucose exposure on the vascular anatomy, molecular phenotype and function of the optic tectum, and on whole-organism behaviour. We also show that SNP or other NO donors may represent a therapeutic strategy to ameliorate the complications of diabetes on the neurovascular unit.This article has an associated First Person interview with the first author of the paper.

4.
EMBO Rep ; 20(8): e47047, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31379129

RESUMO

We identify a novel endothelial membrane behaviour in transgenic zebrafish. Cerebral blood vessels extrude large transient spherical structures that persist for an average of 23 min before regressing into the parent vessel. We term these structures "kugeln", after the German for sphere. Kugeln are only observed arising from the cerebral vessels and are present as late as 28 days post fertilization. Kugeln do not communicate with the vessel lumen and can form in the absence of blood flow. They contain little or no cytoplasm, but the majority are highly positive for nitric oxide reactivity. Kugeln do not interact with brain lymphatic endothelial cells (BLECs) and can form in their absence, nor do they perform a scavenging role or interact with macrophages. Inhibition of actin polymerization, Myosin II, or Notch signalling reduces kugel formation, while inhibition of VEGF or Wnt dysregulation (either inhibition or activation) increases kugel formation. Kugeln represent a novel Notch-dependent NO-containing endothelial organelle restricted to the cerebral vessels, of currently unknown function.

5.
Semin Oncol Nurs ; 35(4): 337-341, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31248677

RESUMO

OBJECTIVES: To describe caregiving and relationship challenges in cancer and the state of the science of dyadic interventions that target survivors and caregivers. DATA SOURCES: Narrative review. CONCLUSION: Viewing the survivor-caregiver dyad as the unit of care may improve multiple aspects of survivor and caregiver quality of life. However, several questions remain regarding how, why, and for whom dyadic interventions are effective. IMPLICATIONS FOR NURSING PRACTICE: Nurses should consider survivor, caregiver, and relationship needs when formulating supportive care protocols. Screening for survivor distress and extending distress screening to caregivers is an important first step in providing comprehensive psychosocial care.

6.
Nat Commun ; 10(1): 732, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760708

RESUMO

Angiogenesis requires co-ordination of multiple signalling inputs to regulate the behaviour of endothelial cells (ECs) as they form vascular networks. Vascular endothelial growth factor (VEGF) is essential for angiogenesis and induces downstream signalling pathways including increased cytosolic calcium levels. Here we show that transmembrane protein 33 (tmem33), which has no known function in multicellular organisms, is essential to mediate effects of VEGF in both zebrafish and human ECs. We find that tmem33 localises to the endoplasmic reticulum in zebrafish ECs and is required for cytosolic calcium oscillations in response to Vegfa. tmem33-mediated endothelial calcium oscillations are critical for formation of endothelial tip cell filopodia and EC migration. Global or endothelial-cell-specific knockdown of tmem33 impairs multiple downstream effects of VEGF including ERK phosphorylation, Notch signalling and embryonic vascular development. These studies reveal a hitherto unsuspected role for tmem33 and calcium oscillations in the regulation of vascular development.


Assuntos
Sinalização do Cálcio , Células Endoteliais/metabolismo , Proteínas de Membrana/metabolismo , Neovascularização Fisiológica , Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Vasos Sanguíneos/embriologia , Vasos Sanguíneos/metabolismo , Embrião não Mamífero/irrigação sanguínea , Embrião não Mamífero/embriologia , Embrião não Mamífero/metabolismo , Retículo Endoplasmático/metabolismo , MAP Quinases Reguladas por Sinal Extracelular , Técnicas de Silenciamento de Genes , Humanos , Proteínas de Membrana/genética , Fosforilação , Peixe-Zebra
7.
Cancer ; 125(7): 1176-1184, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30521075

RESUMO

BACKGROUND: Patients with head and neck cancer (HNC) experience significant physical and psychological morbidity during radiotherapy (RT) that contributes to treatment interruptions and a poor quality of life. Although spouses/partners can help by encouraging patient self-management (eg, self-care) during RT, they often experience high psychological distress rates, lack basic health care knowledge and skills, and report increased marital conflict regarding patient self-management. The current pilot study examined the feasibility and acceptability of a 6-session telephone-based intervention called Spouses coping with the Head And neck Radiation Experience (SHARE), which teaches self-management, communication, and coping skills to patients with HNC and their spouses. The treatment effects of SHARE compared with usual medical care (UMC) in controlling patient physical symptoms and improving patient/spouse psychological and marital functioning also were examined. METHODS: Thirty patients who initiated RT and their spouses (60 participants; 40% of whom were racial/ethnic minorities) were randomized to SHARE or UMC, and preintervention and postintervention assessments were completed. RESULTS: Solid recruitment (70%) and low attrition rates (7%) demonstrated feasibility. Strong program evaluations and homework completion rates (72%) supported acceptability. Significant treatment effects (medium in magnitude) were observed for SHARE compared with UMC with regard to HNC-specific physical symptom burden (Cohen's d, -0.89) and symptom interference (Cohen's d, -0.86). Medium to large effects favoring SHARE also were found for patient and spouse depressive symptoms (Cohen's d, -0.84) and cancer-specific distress (Cohen's d, -1.05). CONCLUSIONS: The findings of the current study support the feasibility, acceptability, and preliminary efficacy of SHARE. They also suggest that programs that empower HNC couples with the necessary skills to coordinate care and manage the challenges of RT together hold great promise for controlling a patient's physical symptoms and improving the psychological functioning of both partners.


Assuntos
Conflito Familiar , Neoplasias de Cabeça e Pescoço/reabilitação , Qualidade de Vida , Autogestão/métodos , Cônjuges , Adaptação Psicológica , Adulto , Idoso , Quimiorradioterapia , Terapia Combinada , Estudos de Viabilidade , Feminino , Neoplasias de Cabeça e Pescoço/psicologia , Neoplasias de Cabeça e Pescoço/terapia , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Projetos Piloto , Radioterapia , Procedimentos Cirúrgicos Operatórios , Telefone , Adulto Jovem
8.
Geriatrics (Basel) ; 3(4)2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31011125

RESUMO

Evidence suggests that community dwelling older adults (CDOA) are at risk for dysphagia (swallowing difficulties). Dysphagia is often unidentified until related morbidities like under nutrition or pneumonia occur. These cases of unidentified dysphagia, prior to any clinical intervention, may be termed 'pre-clinical dysphagia'. Identifying pre-clinical dysphagia is challenged by the lack of validated tools appropriate for CDOA. This study addresses preliminary development of a novel patient reported outcome (PRO) screening tool for pre-clinical dysphagia. Initially, 34 questions were developed from literature review and expert opinion. Following pilot testing (n = 53), the questionnaire was revised and tested on 335 additional CDOA. Face validity, content validity, item analysis, reliability (internal consistency), and construct validity (exploratory factor analysis) measures were completed. Psychometric validation resulted in a 17-question PRO tool. Construct analysis identified a three-factor model that explained 67.345% of the variance. Emergent factors represented swallowing effort, physical function, and cognitive function. The results revealed strong construct validity and internal consistency (Cronbach's α = 0.90). A novel, simple PRO incorporating multiple function domains associated with aging demonstrated strong preliminary psychometric properties. This tool is more comprehensive and aging-focused than existing dysphagia screening tools. Inclusion of multiple domains may be key in early identification of pre-clinical dysphagia.

9.
Artigo em Inglês | MEDLINE | ID: mdl-26955326

RESUMO

Cerebral vascular dynamics are generally thought to be controlled by neural activity in a unidirectional fashion. However, both computational modeling and experimental evidence point to the feedback effects of vascular dynamics on neural activity. Vascular feedback in the form of glucose and oxygen controls neuronal ATP, either directly or via the agency of astrocytes, which in turn modulates neural firing. Recently, a detailed model of the neuron-astrocyte-vessel system has shown how vasomotion can modulate neural firing. Similarly, arguing from known cerebrovascular physiology, an approach known as "hemoneural hypothesis" postulates functional modulation of neural activity by vascular feedback. To instantiate this perspective, we present a computational model in which a network of "vascular units" supplies energy to a neural network. The complex dynamics of the vascular network, modeled by a network of oscillators, turns neurons ON and OFF randomly. The informational consequence of such dynamics is explored in the context of an auto-encoder network. In the proposed model, each vascular unit supplies energy to a subset of hidden neurons of an autoencoder network, which constitutes its "projective field." Neurons that receive adequate energy in a given trial have reduced threshold, and thus are prone to fire. Dynamics of the vascular network are governed by changes in the reconstruction error of the auto-encoder network, interpreted as the neuronal demand. Vascular feedback causes random inactivation of a subset of hidden neurons in every trial. We observe that, under conditions of desynchronized vascular dynamics, the output reconstruction error is low and the feature vectors learnt are sparse and independent. Our earlier modeling study highlighted the link between desynchronized vascular dynamics and efficient energy delivery in skeletal muscle. We now show that desynchronized vascular dynamics leads to efficient training in an auto-encoder neural network.


Assuntos
Simulação por Computador , Modelos Neurológicos , Neurônios/fisiologia , Acoplamento Neurovascular/fisiologia , Animais , Humanos , Dinâmica não Linear , Sistema Vasomotor/fisiologia
10.
Front Neurol ; 7: 24, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27014179

RESUMO

The motivation of developing simple minimal models for neuro-glio-vascular (NGV) system arises from a recent modeling study elucidating the bidirectional information flow within the NGV system having 89 dynamic equations (1). While this was one of the first attempts at formulating a comprehensive model for neuro-glio-vascular system, it poses severe restrictions in scaling up to network levels. On the contrary, low--dimensional models are convenient devices in simulating large networks that also provide an intuitive understanding of the complex interactions occurring within the NGV system. The key idea underlying the proposed models is to describe the glio-vascular system as a lumped system, which takes neural firing rate as input and returns an "energy" variable (analogous to ATP) as output. To this end, we present two models: biophysical neuro-energy (Model 1 with five variables), comprising KATP channel activity governed by neuronal ATP dynamics, and the dynamic threshold (Model 2 with three variables), depicting the dependence of neural firing threshold on the ATP dynamics. Both the models show different firing regimes, such as continuous spiking, phasic, and tonic bursting depending on the ATP production coefficient, ɛp, and external current. We then demonstrate that in a network comprising such energy-dependent neuron units, ɛp could modulate the local field potential (LFP) frequency and amplitude. Interestingly, low-frequency LFP dominates under low ɛp conditions, which is thought to be reminiscent of seizure-like activity observed in epilepsy. The proposed "neuron-energy" unit may be implemented in building models of NGV networks to simulate data obtained from multimodal neuroimaging systems, such as functional near infrared spectroscopy coupled to electroencephalogram and functional magnetic resonance imaging coupled to electroencephalogram. Such models could also provide a theoretical basis for devising optimal neurorehabilitation strategies, such as non-invasive brain stimulation for stroke patients.

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