scholarly journals P11.62 Brain distribution models to select polymer-delivered drugs for the intra-cavity treatment of malignant glioma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii58-iii58
Author(s):  
J Rowlinson ◽  
P McCrorie ◽  
S Smith ◽  
D Barrett ◽  
D Kim ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Brain Homogenate ◽  
Systemic Toxicity ◽  
The Body ◽  
Whole Body ◽  
Label Free ◽  
In Vivo Models ◽  
Franz Cell ◽  
Diffusion Rates ◽  
The Brain

Abstract BACKGROUND Conventional oral or intravenous chemotherapy distributes drugs to the whole body whereby systemic toxicity to healthy parts of the body (e.g. bone marrow failure) limits the maximum dose that can be achieved in the brain. This presents a particular concern for CNS tumours where the blood-brain-barrier (BBB) restricts drug influx from the circulation. The ability to deliver chemotherapy locally at the tumour site offers the opportunity to target residual cancer cells post-surgery whilst minimising systemic toxicity. We have developed a poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) polymer matrix that forms a porous paste at room temperature when mixed with chemotherapy-containing saline, solidifying only at body temperature, with close apposition to the irregular surgical cavity. It is important that we can observe whether the drugs released from PLGA/PEG can penetrate brain parenchyma beyond the surgical resection margin at therapeutic doses. Currently the only way to measure the distribution of drugs in the body is to inject radioactive drugs into an animal. We aim to establish drug distribution parameters using label-free mass spectrometry imaging methods, prior to selection of drug formulations for clinically-relevant in vivo models. Drugs that penetrate the brain the furthest will be identified as good candidates for localised brain cancer drug delivery using PLGA/PEG paste. MATERIAL AND METHODS Diffusion rates were measured by examining the proportion of olaparib, dasatnib, carboplatin, etoposide, paclitaxel and gemcitabine at 2mg/ml concentration, which passes through 1mm slices of rat brain tissue within Franz cell chambers over a 6 hour period. The spatio-temporal distribution of label-free olaparib and dasatinib within mouse brain homogenate was quantitatively measured using innovative 3D OrbiSIMS, a hybrid time-of-flight / OrbitrapTM secondary ion mass spectrometer. RESULTS Within the Franz cell model, carboplatin and gemcitabine showed the highest diffusion rate diffusion at 16.4 and 6.53 µg/cm2/h respectively whereas olaparib, etoposide and paclitaxel were relatively poorly diffused at 1.87, 3.82 and 2.27 µg/cm2/h respectively. The minimum threshold of OrbiSIMS detection for label-free olaparib and dasatinib ions was 0.025 mg/ml and 0.2 mg/ml respectively throughout brain homogenate. CONCLUSION This study demonstrates different diffusion rates through brain tissue, between label-free chemotherapy drugs of distinct chemistries, with highest diffusion rates observed for carboplatin and gemcitabine. We also demonstrate label-free detection of olaparib and dasatinib using the innovative 3D OrbiSIMS method. These models will facilitate the rapid identification of agents most amenable for localised biomaterial-based chemotherapy delivery with high brain penetrance.

scholarly journals EXPERIMENTS ON THE SURVIVAL OF THE FEBRILE HERPETIC AND ALLIED VIRUSES IN VITRO

1924 ◽  
Vol 39 (4) ◽  
pp. 533-542 ◽  
Author(s):  
James E. McCartney
Keyword(s):  
Brain Tissue ◽  
Secondary Infection ◽  
The Body ◽  
Herpes Viruses ◽  
Encephalitis Lethargica ◽  
Aerobic Conditions ◽  
Maximum Period ◽  
Suitable Technique ◽  
The Brain

These studies fail to confirm the statements previously made that microorganisms of the class of the globoid bodies of poliomyelitis may be cultivated in the Smith-Noguchi medium from the so called virus of encephalitis lethargica. They show equally that the herpes virus does not multiply in this medium. The experiments indicate, moreover, that the medium is unfavorable to the survival of the virus, while ordinary broth under aerobic conditions is more favorable for maintaining the activity of both the encephalitic and the herpes viruses. Probably no multiplication of either takes place in the latter medium but merely a survival, and for a maximum period of 6 days in the broth itself, and 12 days in the fragment of brain tissue immersed in the broth. Finally, it has been shown that with a suitable technique the viruses can be passed from the brain of one rabbit to that of another through a long series without contamination with cocci or other common bacterial forms. Hence we regard all reports of the finding of ordinary bacteria in the brain of cases of epidemic or lethargic encephalitis as instances of mixed or secondary infection arising during life, or examples of postmortem invasion of the body, or of faulty technique at the autopsy.

scholarly journals Perception of the dynamic visual vertical during sinusoidal linear motion

2017 ◽  
Vol 118 (4) ◽  
pp. 2499-2506 ◽  
Author(s):  
A. Pomante ◽  
L. P. J. Selen ◽  
W. P. Medendorp
Keyword(s):  
Vestibular System ◽  
Spatial Orientation ◽  
Linear Acceleration ◽  
The Body ◽  
Body Motion ◽  
Whole Body ◽  
Linear Motion ◽  
Modeling Framework ◽  
Visual Vertical ◽  
The Brain

The vestibular system provides information for spatial orientation. However, this information is ambiguous: because the otoliths sense the gravitoinertial force, they cannot distinguish gravitational and inertial components. As a consequence, prolonged linear acceleration of the head can be interpreted as tilt, referred to as the somatogravic effect. Previous modeling work suggests that the brain disambiguates the otolith signal according to the rules of Bayesian inference, combining noisy canal cues with the a priori assumption that prolonged linear accelerations are unlikely. Within this modeling framework the noise of the vestibular signals affects the dynamic characteristics of the tilt percept during linear whole-body motion. To test this prediction, we devised a novel paradigm to psychometrically characterize the dynamic visual vertical—as a proxy for the tilt percept—during passive sinusoidal linear motion along the interaural axis (0.33 Hz motion frequency, 1.75 m/s2peak acceleration, 80 cm displacement). While subjects ( n=10) kept fixation on a central body-fixed light, a line was briefly flashed (5 ms) at different phases of the motion, the orientation of which had to be judged relative to gravity. Consistent with the model’s prediction, subjects showed a phase-dependent modulation of the dynamic visual vertical, with a subject-specific phase shift with respect to the imposed acceleration signal. The magnitude of this modulation was smaller than predicted, suggesting a contribution of nonvestibular signals to the dynamic visual vertical. Despite their dampening effect, our findings may point to a link between the noise components in the vestibular system and the characteristics of dynamic visual vertical.NEW & NOTEWORTHY A fundamental question in neuroscience is how the brain processes vestibular signals to infer the orientation of the body and objects in space. We show that, under sinusoidal linear motion, systematic error patterns appear in the disambiguation of linear acceleration and spatial orientation. We discuss the dynamics of these illusory percepts in terms of a dynamic Bayesian model that combines uncertainty in the vestibular signals with priors based on the natural statistics of head motion.

scholarly journals The Kidney Clock Contributes to Timekeeping by the Master Circadian Clock

2019 ◽  
Vol 20 (11) ◽  
pp. 2765 ◽  
Author(s):  
Jihwan Myung ◽  
Mei-Yi Wu ◽  
Chun-Ya Lee ◽  
Amalia Ridla Rahim ◽  
Vuong Hung Truong ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Sleep Disturbances ◽  
The Body ◽  
Circadian Clocks ◽  
Whole Body ◽  
The Hierarchical Structure ◽  
Body Level ◽  
The Brain ◽  
Master Clock

The kidney harbors one of the strongest circadian clocks in the body. Kidney failure has long been known to cause circadian sleep disturbances. Using an adenine-induced model of chronic kidney disease (CKD) in mice, we probe the possibility that such sleep disturbances originate from aberrant circadian rhythms in kidney. Under the CKD condition, mice developed unstable behavioral circadian rhythms. When observed in isolation in vitro, the pacing of the master clock, the suprachiasmatic nucleus (SCN), remained uncompromised, while the kidney clock became a less robust circadian oscillator with a longer period. We find this analogous to the silencing of a strong slave clock in the brain, the choroid plexus, which alters the pacing of the SCN. We propose that the kidney also contributes to overall circadian timekeeping at the whole-body level, through bottom-up feedback in the hierarchical structure of the mammalian circadian clocks.

scholarly journals Transformation of vestibular signals for the decisions of hand choice during whole body motion

2019 ◽  
Vol 121 (6) ◽  
pp. 2392-2400 ◽  
Author(s):  
Romy S. Bakker ◽  
Luc P. J. Selen ◽  
W. Pieter Medendorp
Keyword(s):  
Reference Frame ◽  
Early Stage ◽  
Hand Preference ◽  
The Body ◽  
Body Motion ◽  
Whole Body ◽  
Head Orientation ◽  
Inertial Acceleration ◽  
Reach Planning ◽  
The Brain

In daily life, we frequently reach toward objects while our body is in motion. We have recently shown that body accelerations influence the decision of which hand to use for the reach, possibly by modulating the body-centered computations of the expected reach costs. However, head orientation relative to the body was not manipulated, and hence it remains unclear whether vestibular signals contribute in their head-based sensory frame or in a transformed body-centered reference frame to these cost calculations. To test this, subjects performed a preferential reaching task to targets at various directions while they were sinusoidally translated along the lateral body axis, with their head either aligned with the body (straight ahead) or rotated 18° to the left. As a measure of hand preference, we determined the target direction that resulted in equiprobable right/left-hand choices. Results show that head orientation affects this balanced target angle when the body is stationary but does not further modulate hand preference when the body is in motion. Furthermore, reaction and movement times were larger for reaches to the balanced target angle, resembling a competitive selection process, and were modulated by head orientation when the body was stationary. During body translation, reaction and movement times depended on the phase of the motion, but this phase-dependent modulation had no interaction with head orientation. We conclude that the brain transforms vestibular signals to body-centered coordinates at the early stage of reach planning, when the decision of hand choice is computed. NEW & NOTEWORTHY The brain takes inertial acceleration into account in computing the anticipated biomechanical costs that guide hand selection during whole body motion. Whereas these costs are defined in a body-centered, muscle-based reference frame, the otoliths detect the inertial acceleration in head-centered coordinates. By systematically manipulating head position relative to the body, we show that the brain transforms otolith signals into body-centered coordinates at an early stage of reach planning, i.e., before the decision of hand choice is computed.

Spect imaging of the serotonin transporter using a novel ligand - 123-I mZIENT - in human subjects - a dosimetry and biodisortribution study

2011 ◽  
Vol 26 (S2) ◽  
pp. 935-935
Author(s):  
R. Krishnadas ◽  
A. Nicol ◽  
S. Champion ◽  
S. Pimlott ◽  
J. Stehouwer ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Gamma Camera ◽  
Human Subjects ◽  
The Body ◽  
Whole Body ◽  
Body Images ◽  
Promising Agent ◽  
Regional Brain ◽  
The Brain ◽  
Spect Images

Levels of serotonin in the body are regulated by the serotonin transporters (SERT), which are predominantly located on the presynaptic terminals of serotonin-containing neurons. Alterations in the density of SERT have been implicated in the pathophysiology of many neuropsychiatric disorders.AimTo evaluate 123-I mZIENT (2(S)-[(S)-2b-carbomethoxy-3b-[3′-((Z)-2-iodoethenyl)phenyl]nortropane), a novel radiopharmaceutical for imaging SERT. The bio-distribution of the radiopharmaceutical in humans was investigated and dosimetry performed.MethodsThe study includes three healthy volunteers and three patients receiving SSRIs. Whole body images obtained on a gamma camera at 10 minutes, 1, 2, 3, 6, 24 and 48 hours post administration. Dosimetry was performed. ROIs were drawn over the brain, heart, kidneys, liver, lungs, salivary glands, spleen, thyroid and intestines. Blood was sampled at 5, 15, & 30 minutes and 1, 2, 3, 6, 24 and 48 hours post administration. Urine was collected at 1, 2, 3, 4, 6, 24 and 48 hours. Brain SPECT images were obtained using a neuroSPECT scanner at 4 hours, evaluated visually and analysed using ROI analysis.ResultsHigh quality SPECT images can be obtained after 100–150 MBq 123-ImZEINT. Regional brain uptake was observed in midbrain and basal ganglia in healthy volunteers, consistent with the known distribution of SERT. Biodistribution images demonstrated highest uptake in the lungs, brain, liver and intestines. The effective dose was within range of other commonly used ligands and is acceptable for clinical imaging.Conclusion123-ImZIENT is a promising agent for imaging SERT in humans with acceptable dosimetry.

scholarly journals Sociality and Interaction Envelope Organize Visual Action Representations

2019 ◽  
Author(s):  
Leyla Tarhan ◽  
Talia Konkle
Keyword(s):  
Visual Cortex ◽  
Large Scale ◽  
Functional Neuroimaging ◽  
Action Observation ◽  
The Body ◽  
Whole Body ◽  
Action Perception ◽  
Social Content ◽  
Wide Range ◽  
The Brain

Humans observe a wide range of actions in their surroundings. How is the visual cortex organized to process this diverse input? Using functional neuroimaging, we measured brain responses while participants viewed short videos of everyday actions, then probed the structure in these responses using voxel-wise encoding modeling. Responses were well fit by feature spaces that capture the body parts involved in an action and the action’s targets (i.e. whether the action was directed at an object, another person, the actor, and space). Clustering analyses revealed five large-scale networks that summarized the voxel tuning: one related to social aspects of an action, and four related to the scale of the interaction envelope, ranging from fine-scale manipulations directed at objects, to large-scale whole-body movements directed at distant locations. We propose that these networks reveal the major representational joints in how actions are processed by visual regions of the brain.Significance StatementHow does the brain perceive other people’s actions? Prior work has established that much of the visual cortex is active when observing others’ actions. However, this activity reflects a wide range of processes, from identifying a movement’s direction to recognizing its social content. We investigated how these diverse processes are organized within the visual cortex. We found that five networks respond during action observation: one that is involved in processing actions’ social content, and four that are involved in processing agent-object interactions and the scale of the effect that these actions have on the world (its “interaction envelope”). Based on these findings, we propose that sociality and interaction envelope size are two of the major features that organize action perception in the visual cortex.

Computer-Aided Analysis of Transient and Steady State Temperature Distribution in Human Brain During Selective Cooling of Head Surface and Rewarming for Head Injury Patients

2002 ◽  
Author(s):  
Liang Zhu ◽  
Chenguang Diao
Keyword(s):  
Steady State ◽  
Temperature Distribution ◽  
Brain Temperature ◽  
The Body ◽  
Whole Body ◽  
Surface Cooling ◽  
Steady State Temperature ◽  
Head Surface ◽  
The Brain ◽  
Transient And Steady State

In recent years, mild or moderate hypothermia during which brain temperature is reduced to 30–35°C has been proposed for clinical use as an adjunct for achieving protection from cerebral ischemia and traumatic brain injury. There are two approaches for achieving a reduction in brain temperature. One is via systemic hypothermia where the whole body is cooled. This approach may produce deleterious systemic complications and require intensive monitoring. Another approach is called selective brain cooling (SBC) in which the brain is selectively cooled while the rest of the body is kept at normal temperature. Clinically feasible SBC protocols include head hood or helmet with water or chemical cooling, head immersion in iced water, nasophyaryngeal cooling after tracheal intubation, and intro-carotid flushing. Simply packing ice or wearing cooling helmet is easy to implement. Previous theoretical study [Zhu and Diao, 2001] suggests that it is feasible to achieve mild hypothermia via head surface cooling. However, most physicians believe that it takes a much longer time to reduce the brain temperature using head surface cooling. In this study, a three-dimensional theoretical model is developed to study the transient and steady state temperature distribution in the brain during SBC. The effect of regionally varying local blood perfusion rate in the brain tissue on the temporal and spatial temperature gradient is examined. Other factors including the brain size and the thermal contact resistance between the cooling medium and the head scalp are evaluated in the simulation.

Dance in the Body, the Mind, and the Brain

2017 ◽  
pp. 40-56
Author(s):  
Bettina Bläsing
Keyword(s):  
Brain Activity ◽  
Relevant Literature ◽  
Emotional Reactions ◽  
The Body ◽  
Whole Body ◽  
Action Perception ◽  
Dance Training ◽  
Positive Feelings ◽  
Social Communicative ◽  
The Brain

This chapter is based on the view that dancing can promote positive feelings and energy. Even watching others dancing—on stage, in a movie, or in a club—can improve feelings of wellbeing. With reference to relevant literature, it explores how the brain links action with perception, and how technical challenges are resolved in investigating brain activity in dance observers. Early studies using neuroimaging techniques are discussed, and comparisons are drawn with recent studies in neuroaesthetics. Findings from these studies suggest that brain scientists can learn from dancers and dance spectators about action–perception coupling and the integration of movement, cognition, and emotion. Conclusions are drawn regarding how dancing, and dance viewing, stimulates the parts of our brains that are involved in whole-body motor action as well as social, communicative, and creative tasks, and can elicit positive emotional reactions, contributing to wellbeing. Implications are discussed for choreography, dance training, education, and rehabilitation.

scholarly journals Cell Type Specific Expression of Toll-Like Receptors in Human Brains and Implications in Alzheimer’s Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Henriette R. Frederiksen ◽  
Henriette Haukedal ◽  
Kristine Freude
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cellular Response ◽  
The Body ◽  
Cellular Damage ◽  
Whole Body ◽  
Toll Like Receptors ◽  
Cell Type ◽  
Cell Type Specific ◽  
The Brain

Toll-like receptors mediate important cellular immune responses upon activation via various pathogenic stimuli such as bacterial or viral components. The activation and subsequent secretion of cytokines and proinflammatory factors occurs in the whole body including the brain. The subsequent inflammatory response is crucial for the immune system to clear the pathogen(s) from the body via the innate and adaptive immune response. Within the brain, astrocytes, neurons, microglia, and oligodendrocytes all bear unique compositions of Toll-like receptors. Besides pathogens, cellular damage and abnormally folded protein aggregates, such as tau and Amyloid beta peptides, have been shown to activate Toll-like receptors in neurodegenerative diseases such as Alzheimer’s disease. This review provides an overview of the different cell type-specific Toll-like receptors of the human brain, their activation mode, and subsequent cellular response, as well as their activation in Alzheimer’s disease. Finally, we critically evaluate the therapeutic potential of targeting Toll-like receptors for treatment of Alzheimer’s disease as well as discussing the limitation of mouse models in understanding Toll-like receptor function in general and in Alzheimer’s disease.

scholarly journals Label-free imaging of neurotransmitters in live brain tissue by multi-photon ultraviolet microscopy

2018 ◽  
Vol 2 (4) ◽  
Author(s):  
Barun Kumar Maity ◽  
Sudipta Maiti
Keyword(s):  
Brain Tissue ◽  
Label Free ◽  
Monoamine Neurotransmitters ◽  
Chemical Labeling ◽  
Direct Excitation ◽  
Recent Developments ◽  
Direct Fluorescence ◽  
Difficult Challenge ◽  
Small Biomolecules ◽  
The Brain

Visualizing small biomolecules in living cells remains a difficult challenge. Neurotransmitters provide one of the most frustrating examples of this difficulty, as our understanding of signaling in the brain critically depends on our ability to follow the neurotransmitter traffic. Last two decades have seen considerable progress in probing some of the neurotransmitters, e.g. by using false neurotransmitter mimics, chemical labeling techniques, or direct fluorescence imaging. Direct imaging harnesses the weak UV fluorescence of monoamines, which are some of the most important neurotransmitters controlling mood, memory, appetite, and learning. Here we describe the progress in imaging of these molecules using the least toxic direct excitation route found so far, namely multi-photon (MP) imaging. MP imaging of serotonin, and more recently that of dopamine, has allowed researchers to determine the location of the vesicles, follow their intracellular dynamics, probe their content, and monitor their release. Recent developments have even allowed ratiometric quantitation of the vesicular content. This review shows that MP ultraviolet (MP-UV) microscopy is an effective but underutilized method for imaging monoamine neurotransmitters in neurones and brain tissue.

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