How Did They Do This
On the first day, the patient received a small dose of chemotherapy that was slowly infused into her bloodstream through a drip IV in her arm.
She was then taken to an MRI Suite where she was prepped for the focused ultrasound procedure. A head frame was screwed to her skull and she laid down on the MRI bed where the head frame was connected to a helmet that is part of Insightecs Exablate Neuro System.
A number of standard MRI scans were initially done to help the researchers locate positions and plans of where they needed to go.
The researchers administered microscopic bubbles into the patient’s bloodstream through an IV. The microbubbles are smaller than red blood cells and pass harmlessly through the circulation. Once ready, the researchers used state-of-the-art MRI-guided focused low-intensity ultrasound to target blood vessels in the BBB area near the tumour.
The Microplastic Menace: Plummeting Fertility
As if this new news isnt bad enough, its already well known that microplastics are carriers of toxic xenoestrogens, industrial chemicals that have disastrous gender-bending effects.
These chemicals are believed to be one of the principal causes of a calamitous decline in fertility that could bring about the end of human reproduction as we know it.
Were about 40 years behind global warming, in terms of awareness, she says yet the threat to human survival is just as great as, if not greater than, our concerns about greenhouse gas emissions.
According to Swans projections from the available data, by 2045 the sperm count of the median man will reach zero meaning that one half of all men will have no sperm at all, and the other half will have an amount that is barely more than zero. Functionally, all men will be infertile.
The implications should be obvious: no sperm, no babies. Such a scenario has already been dubbed Spermageddon.
But its not just xenoestrogens that are responsible for the precipitous decline in male fertility were witnessing. Swan also points to a variety of other factors that seem to be at work, including the use of contraceptives, obesity, smoking and cultural shifts, a rather vague term which would deserve further explanation.
At home we may be inhaling 100 times the amount of microplasticsscientists previously thought: shock research
Only time will tell if we have the good sense, and the courage, to do so.
Apicobasal Polarity Of Bbb Endothelium
The apicobasal polarity of the BBB endothelium is more remarkable than those in other organs in terms of polarized distributions of lipids, glycoproteins, receptors, and transporters between apical and basal membranes . It is initiated during angiogenesis by the partitioning defective protein complex, including PAR3, PAR6, and CDC42, and is tightly regulated by VEGF and Wnt signaling pathways . PAR3 interaction with VE-cadherin and JAM proteins triggers the reorganization of intercellular junction proteins including ZO1, claudin-5, and CD99, resulting in the formation of TJs on the apical side of AJs, thereby limiting paracellular flow . On the other hand, lumen formation and expansion are achieved by redistribution of surface receptors including CD34 and glycoproteins such as podocalyxin, and reorganization of cytoskeleton networks that requires 1-integrin, non-muscle myosin II, activation of RhoA pathway, and F-actin formation . Brain endothelial cells also express the Crumbs protein complex that stabilizes the intercellular junctions .
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Immune Cell Movement Across The Bbb
The CNS is considered as an immune-privileged site as a result of the low infiltration of neutrophils into the brain compared to other tissues and the strictly regulated immune cell-BBB interaction. Under normal physiological conditions, mononuclear cells enter the brain during embryonic development and become resident immunologically competent microglia . They penetrate by process of diapedesis directly through the cytoplasm of the endothelial cells and not via a paracellular route involving re-arrangement and opening of the tight junctional complexes as had been previously suggested . However, in inflammatory pathological conditions, the TJs between endothelial cells may be disrupted. This is the result of cytokines and other pro-inflammatory agents. Furthermore, mononuclear leukocytes, monocytes, and macrophages can enter the CNS via transcellular and paracellular routes and play roles complementary to those of the resident microglia . In some cases, these immune cells may transform into a microglial phenotype .
Other studies indicated that the transmigration of CD4+ and CD8+ T cells across the CNS autoimmunity could be controlled through additional cell adhesion molecules such as melanoma cell adhesion molecule and activated leukocyte cell adhesion molecule .
Regulation Of The Bbb By Astrocytes
The persistence of a functional BBB throughout adulthood is maintained and regulated by numerous factors unique to the microniche of the neurovascular unit . AstrocyteBBBEC interactions are known to regulate EC morphology, angiogenesis, and to influence the phenotype of the barrier under physiological and pathological conditions .
Astrocytes are known to produce factors that modulate endothelial functioning during development and adulthood. One of these pathways is the Hedgehog signaling cascade known to be involved in embryonic morphogenesis, neuronal guidance, and angiogenesis. Astrocytes secrete Sonic Hh , and BBB ECs express the Hh receptor Patched-1, the signal transducer Smoothened , as well as transcription factors of the Gli family. Interestingly, transendothelial electrical resistance and permeability experiments showed that activation of the Hh pathway induced expression of junctional proteins and promoted a BBB phenotype. In addition, mice genetically engineered to lose the signal transducer Smo on ECs had a significant increase in BBB permeability that correlated with a decrease in junctional protein expression and disturbed BMs , supporting the concept that the Hh pathway has a significant influence on BBB function.
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If Found Effective Who Will This Approach Help
Breaching this barrier opens up a new frontier in treating the brain. The success of this research opens up the potential for delivering drug therapies to parts of the brain protected by the BBB, including researching treatments for patients with various kinds of brain tumours, Alzheimers disease, and some psychiatric conditions.
Implications Of This Research And Information About The Trial
While this breakthrough opens up potential in the future for delivering drug therapies to parts of the brain protected by the blood brain barrier , please note that the patients in this clinical trial will not benefit from this procedure .
These research participants will undergo needed surgery to remove much of their brain tumour the next day. Therefore any chemotherapy that did potentially get through to the brain tumour will also be removed.
The point of this trial is to test for the feasibility, safety and proof of concept of using MR-guided focused ultrasound to temporarily open the BBB to get chemotherapy across into the brain tumour directly.
This case was the first of up to 10 participants in this study all of the participants will be those who are already scheduled for traditional neurosurgery to remove parts of their brain tumour.
Enrolment is currently limited to Canadian residents only, due to the inpatient surgical procedure.
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Associated Conditions And Problems
The blood-brain barrier is usually effective at keeping foreign or toxic substances out of your central nervous system. Most of the time this is a good thing, but it can pose a problem when developing new drugs for the nervous system. For example, one of the major challenges in treating brain tumors is that it can be difficult to make a medication capable of getting across the blood-brain barrier to reach the cancer. Because of this problem, researchers are developing medicine to try to bypass the blood-brain barrier.
The blood-brain barrier can sometimes also be broken down by injuries and infections. Research shows that strokes and traumatic brain injury can damage the endothelial tissue and cause the blood-brain barrier to open. Researchers have also found that those with early signs of cognitive impairment have a breakdown of the blood-brain barrier. The findings could help to lead to early diagnostic tests for Alzheimers disease and other conditions that cause cognitive impairment.
Insulin Signaling Within Cells Of The Blood
There is not a cell type in the CNS that we are aware of that does not express the insulin receptor. In mice, the expression of the insulin receptor gene is most abundant in endothelial cells, about two times greater than astrocytes, with neurons falling in close behind in terms of RNA expression levels1 . This same expression pattern was not observed in samples from human tissue . Instead, expression of the insulin receptor is more evenly distributed between the cell types. Insulin interacts with receptors on neurons and glial cells , endothelial cells , and pericytes to elicit various physiological effects, some of which are highlighted in Figure 1. The insulin receptor exists in two isoforms, an A and B form, due to differences in splicing of the subunit, resulting in different binding affinities to insulin and insulin-like growth factor . However, until recently, the ability to detect these two isoforms by immunological methods in vivo in different cell types has been a challenge. With the advances in single cell RNA sequencing and a novel in situ RT-PCR/FISH assay , we expect a growth in the knowledge of expression pattern of these isoforms and alterations in human disease within specific cell types and regional variations. The insulin receptor can also form heterodimers with the IGF-1 receptor and can have varying post-translational modifications leading to further diversity of insulin action .
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What Is A Blood
It is composed of high-density cells restricting passage of substances from the bloodstream much more than does the endothelial cells in capillaries elsewhere in the body. The brain presents a unique challenge for medical treatment: it is locked away behind an impenetrable layer of tightly packed cells. Although the blood-brain barrier prevents harmful chemicals and bacteria from reaching our control center, it also blocks roughly 95 percent of medicine delivered orally or intravenously. As a result, doctors who treat patients with neurodegenerative diseases, such as Parkinsons, often have to inject drugs directly into the brain, an invasive approach that requires drilling into the skull.
Endothelial cells line the inside of every blood vessel in the body. They form a one-cell-thick later called the endothelium, which is also found on the inner walls of the heart chambers and lymphatic vessels, which carry excess blood plasma around the body. The BBB is a layer of endothelial cells that selectively allow entry of molecules needed for brain function, such as amino acids, oxygen, glucose, and water, while keeping others out.
In the future, this approach could be used to treat a range of neurological diseases.
The ability to deliver genes to the brain without invasive methods will be extremely useful as a research tool. It has tremendous potential in the clinic as well, says Anthony Zador, a neuroscientist who studies brain wiring at Cold Spring Harbor Laboratory.
Capillary Structure And Function In The Body
Capillaries are the smallest blood vessels in the body, connecting the smallest arteries to the smallest veins. These vessels are often referred to as the “microcirculation.”
Only two layers of cells thick, the purpose of capillaries is to play the central role in the circulation, delivering oxygen in the blood to the tissues, and picking up carbon dioxide to be eliminated. They are also the place where nutrients are delivered to feed all of the cells of the body.
There are three primary types of capillariescontinuous, fenestrated, and discontinuous or sinusoidal that are found in different regions of the body, and specialized capillaries in the brain make up the blood-brain barrier.
Tests that evaluate the capillaries are important in assessing people medically, and there are several medical conditions associated with these vessels.
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Models To Study The Bbb
In vitro models of the BBB have proven very effective to study the transport of endogenous macromolecules like fatty acids across the BMEC. They have also been used extensively in pharmaceutical research to study the passage of therapeutic molecules across the BMEC . Several studies have shown that the BMEC lose many of their special properties when removed from their natural environment and show dedifferentiation behaviour. Thus, one potential limitation of in vitro BBB models is that the BMEC may not behave as site-specific specialized endothelial cells in vitro, but rather as common peripheral endothelial cells . In spite of this shortcoming, several successful in vitro models of the BBB have been described . Many of these have used human, bovine, and porcine or rat endothelial cells:
Organic Anion Transporting Polypeptide
Organic anion transporting polypeptides are members of the solute carrier organic anion transporter family . The OATPs accommodate the transport of a wide variety of amphipathic solutes, including bile salts, anionic peptides, steroid conjugates, thyroid hormones and an increasing number of pharmaceutical drugs and xenobiotics . Members of the OATP family, of which there are currently 11 known to be expressed in humans , share a great deal of amino acid sequence identity and transport solutes in a sodium independent manner .
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Bbb Permeation Prediction Methods
The widely used in silico prediction of the BBB permeability is an inexpensive, less time consuming, and high throughput screening method for novel compounds in the drug discovery process. Although this method is based on several molecular descriptors or physicochemical characteristics of the molecule, it has its strengths and weaknesses.6265 These computational models are typically based on the previous in vivo and in vitro experimental data. Therefore, for the predictive power of estimations, the selection of datasets is a critical component. The assumption of passive diffusion of a compound as a major route of transport through the BBB is the base for the in silico predictions that do not consider various BBB transport pathways, e.g., nanoparticle-based transport/carrier-mediated, receptor-mediated, and active efflux or influx transport methods.66 Recently, cerebrospinal fluid penetration is also considered in in silico model while analyzing the brain penetration of the molecule.67
Table 3 In-silico models and their parameters used for predicting drug penetrability
B Traversing Bbb For Cns Drug Delivery
Traversing BBB remains a major challenge for neurotherapeutics. Strategies have been developed to breach the barrier, including 1) direct opening of the BBB with intravenous bolus injection of hypertonic sugar solution or focused ultrasound scanning with microbubbles 2) encapsulation in nanoparticles made from biocompatible and/or biodegradable polymers and liposomes that can penetrate the BBB 3) utilizing CMT systems for better penetrability of drug analogs 4) engineering therapeutic peptides, oligonucleotides , and monoclonal antibodies that target RMT systems at the BBB , or specific transport system such as system L amino acid transporter in case of anti-CD98hc/BACE1 antibodies and 5) viral vector-mediated gene delivery to CNS .
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Molecular Components Of The Tight Junctions
The tight junctions consist of both membrane proteins as well as cytoplasmic proteins . The integral membrane proteins are Claudins, Occludin and Junctional adhesion molecules . There are also several cytoplasmic accessory proteins that form a plaque and function as adapter proteins to link the membrane proteins to the actin cytoskeleton of the cell . These include Zonula occludens proteins , Cingulin, AF-6, 7H6 antigen and Symplekin. These tight junctional complexes are not static structures but rather very dynamic entities that can bend without breaking, thereby maintaining structural integrity .
Schematic representation of proteins that are involved in the formation of the tight junction and adherens junctions in brain microvessel endothelial cells.
Other Diseases: In Vitro And Computational Models
Several other neurological diseases are known to predominantly affect the BBB . Although not discussed extensively in this review, these include neurodegenerative disorders such as Parkinson’s and Huntington’s diseases, as well as epilepsy and mental disorders such as schizophrenia, clinical depression, and anxiety disorder. In vivo animal models, although useful to understand the genetic and phenotypic profiles of these diseases, often fail in their translation to meaningful clinical results. Yet, the use of in vitro platforms to recapitulate these pathologies remains limited. Lim et al. designed a 2D in vitro model of Huntington’s disease by using patient iPSC-derived endothelial cells. They uncovered BBB deficits in terms of angiogenic signaling, transcytosis protein expression, and overall barrier permeability. Similar models that recapitulate other neurological diseases are necessary to bridge the gap between in vivo models and clinical outcomes.
Gene And Protein Expression
Bioinformatics is a field of study that includes the creation and advancement of databases, and computational and statistical techniques, that can be used in studies of the human brain, particularly in the areas of gene and protein expression. Bioinformatics and studies in genomics, and functional genomics, generated the need for DNA annotation, a transcriptome technology, identifying genes, their locations and functions.GeneCards is a major database.
As of 2017, just under 20,000 protein-coding genes are seen to be expressed in the human, and some 400 of these genes are brain-specific. The data that has been provided on gene expression in the brain has fuelled further research into a number of disorders. The long term use of alcohol for example, has shown altered gene expression in the brain, and cell-type specific changes that may relate to alcohol use disorder. These changes have been noted in the synaptictranscriptome in the prefrontal cortex, and are seen as a factor causing the drive to alcohol dependence, and also to other substance abuses.