Set phrase

A set phrase (also known as, a phraseme or fixed phrase) is a phrase which parts are fixed in a certain order, even if the phrase could be changed without harming the literal meaning. This is because a set phrase is a culturally accepted phrase. A set phrase does not necessarily have any literal meaning in and of itself. Set phrases may function as idioms (e.g. "red herring") or as words with a unique referent (e.g. "Red Sea"). There is no clear dividing line between a commonly used phrase and a set phrase. It is also not easy to draw a clear distinction between set phrases and compound words.
It is different from a proverb in that it is used as a part of a sentence, and is the standard way of expressing a concept or idea.
In theoretical linguistics, two-word set phrases are said to arise during the generative formation of English nouns.
A certain stricter notion of set phrases, more in line with the concept of a lexical item, provides an important underpinning for the formulation of meaning–text theory.
In other languages.
Fixed expressions occur in other languages, as well, such as:


Suprapineal recess

The suprapineal recess is an anatomical structure in the ventricular system of the brain.
It is located in the posterior part of the third ventricle, overlying the cerebral aqueduct.
In severe cases of hydrocephalus with increased pressure, this structure can dilate causing mass effect on the midbrain resulting in Parinaud's Syndrome with bilateral inward and downward deviation of the eyes.


Ciclazindol

Ciclazindol (WY-23409) is an antidepressant and anorectic drug of the tetracyclic chemical class that was developed in the mid to late 1970s, but was never marketed. It acts as a norepinephrine reuptake inhibitor, and to a lesser extent as a dopamine reuptake inhibitor. Ciclazindol has no effects on the SERT, 5-HT receptors, mACh receptors, or α-adrenergic receptors, and has only weak affinity for the H1 receptor. As suggested by its local anesthetic properties, ciclazindol may also inhibit sodium channels. It is known to block potassium channels as well.


Kalaleng

A kalaleng is a nose flute made from bamboo from the Philippines.
Usually around two feet in length a kalaleng has holes cut in the side, to be stopped by the fingers producing the notes. The player closes one nostril with a bit of cotton, then forces the air from the other into a small hole cut in the end of the tube. This instrument is found mostly in the northern Philippines and is popular with all the native mountain population of the area. It is a usually decorated with etched patterns.
The instrument is popular with men and is often used in courting.


Ventrolateral prefrontal cortex

The ventrolateral prefrontal cortex (VLPFC) is a part of the prefrontal cortex located on the inferior frontal gyrus, bounded superiorly by the inferior frontal sulcus and inferiorly by the lateral sulcus. It is attributed to the anatomical structures of Brodmann's area (BA) 47, 45 and 44 (considered the subregions of the VLPFC – the anterior, mid and posterior subregions).
Specific functional distinctions have been presented between the three Brodmann subregions of the VLPFC. There are also specific functional differences in activity in the right and left VLPFC. Neuroimaging studies employing various cognitive tasks have shown that the right VLPFC region is a critical substrate of control. At present, two prominent theories feature the right VLPFC as a key functional region. From one perspective, the right VLPFC is thought to play a critical role in motor inhibition, where control is engaged to stop or override motor responses. Alternatively, Corbetta and Shulman have advanced the hypothesis that there are two distinct frontoparietal networks involved in spatial attention, with the right VLPFC being a component of a right-lateralized ventral attention network that governs reflexive reorienting. From this perspective, the right lateral PFC, along with a region spanning the right temporoparietal junction (TPJ) and the inferior parietal lobule, are engaged when abrupt onsets occur in the environment, suggesting that these regions are involved in re-orienting attention to perceptual events that occur outside the current focus of attention. Also, the VLPFC is the end point of the ventral pathway (stream) that brings information about the stimuli's characteristics.
Functions.
The whole right VLPFC is active during motor inhibition, having a critical role, meaning when a person is walking and suddenly stops, the VLPFC activates to stop or override the motor activity in the cortex. The right posterior VLPFC (BA 44) is active during the updating of action plans. The right middle VLPFC (BA 45) responds to decision uncertainty (presumably in right-handed individuals).


Turd Blossom

"Turd Blossom" (or Sand Turd) is a Texan United States term for a flower which grows from a pile of cow dung. As Turd Blossom, the term has gained fame in the United States as a nickname that was reportedly assigned by former U.S. President George W. Bush as a term of endearment for his former chief political advisor, Karl Rove.
In July 2005, several newspapers declined to run two "Doonesbury" comic strips portraying Bush addressing Rove by this nickname.


Glial scar

Glial scar formation (gliosis) is a reactive cellular process involving astrogliosis that occurs after injury to the central nervous system. As with scarring in other organs and tissues, the glial scar is the body's mechanism to protect and begin the healing process in the nervous system.
In the context of neurodegeneration, formation of the glial scar has been shown to have both beneficial and detrimental effects. Particularly, many neuro-developmental inhibitor molecules are secreted by the cells within the scar that prevent complete physical and functional recovery of the central nervous system after injury or disease. On the other hand, absence of the glial scar has been associated with impairments in the repair of the blood brain barrier.
Scar components.
The glial scar is composed of several components briefly discussed below.
Reactive astrocytes.
Reactive astrocytes are the main cellular component of the glial scar. After injury, astrocytes undergo morphological changes, extend their processes, and increase synthesis of glial fibrillary acidic protein (GFAP). GFAP is an important intermediate filament protein that allows the astrocytes to begin synthesizing more cytoskeletal supportive structures and extend pseudopodia. Ultimately, the astrocytes form a dense web of their plasma membrane extensions that fills the empty space generated by the dead or dying neuronal cells (a process called astrogliosis). The heavy proliferation of astrocytes also modifies the extracellular matrix surrounding the damaged region by secreting many molecules including laminin, fibronectin, tenascin C, and proteoglycans. These molecules are important modulators of neuronal outgrowth. Accordingly, their presence after injury contributes to inhibition of regeneration.
Another important caveat of the astrocytic response to CNS injuries is its heterogeneity. Particularly, the response of the astrocytes to the injury varies depending on factors such as the nature of the injury and the microenvironment at the injury location. Further, the reactive astrocytes in the immediate vicinity of the injury increase gene expression, thus compounding the response of other astrocytes and contributing to the heterogeneity. Particularly, astrocytes closest to the lesion generally secrete more inhibitory molecules into the extracellular matrix.
Microglia.
Microglia are the second most prominent cell type present within the glial scar. They are the nervous system analog of immune system macrophages. Microglia rapidly activate near the injury and secrete several cytokines, bioactive lipids, coagulation factors, reactive oxygen intermediates, and neurotrophic factors. The expression of these molecules depends on the location of the microglial cells relative to the injury, with the cells closest to the injury secreting the largest amount of such biologically active molecules.
Endothelial cells and fibroblasts.
The various biologically active molecules secreted by microglia stimulate and recruit endothelial cells and fibroblasts. These cells help stimulate angiogenesis and collagen secretion into the injured area. Ultimately, the amount of capillaries extended into the injured area is twice that of uninjured central nervous system regions.
Basal membrane.
The basal membrane is a histopathological extracellular matrix feature that forms at the center of injury and partially covers the astrocytic processes. It is composed of three layers with the basal lamina as the prominent layer. Molecularly, the basal membrane is created by glycoprotein and proteoglycan protomers. Further, two independent networks are formed within the basal membrane by collagen IV and laminin for structural support. Other molecular components of the basal membrane include fibulin-1, fibronectin, entactin, and heparin sulfate proteoglycan perlecan. Ultimately, the astrocytes attach to the basal membrane, and the complex surrounds the blood vessels and nervous tissue to form the initial wound covering.
Beneficial effects of the scar.
The ultimate function of the glial scar is to reestablish the physical and chemical integrity of the CNS. This is done by generating a barrier across the injured area that seals the nervous/non-nervous tissue boundary. This also allows for the regeneration of the selective barrier to prevent further microbial infections and spread of cellular damage. Moreover, the glial scar stimulates revascularization of blood capillaries to increase the nutritional, trophic, and metabolic support of the nervous tissue.
Detrimental effects of the scar.
The glial scar also prevents neuronal regrowth. Following trauma to the CNS, axons begin to sprout and attempt to extend across the injury site in order to repair the damaged regions. However, the scar prevents axonal extensions via physical and chemical means. Astrocytes form a dense network of gap junctions that generates a physical barrier to axonal regrowth. Further, the astrocytes secrete several growth-inhibitory molecules that chemically prevent axonal extensions. Moreover, the basal membrane component is expected to generate an additional physical and chemical barrier to axonal extensions.
Primary scar molecular inducers.
The formation of the glial scar is a complex process. Several main classes of molecular mediators of gliosis have been identified and are briefly discussed below.
Transforming growth factor β.
Two neuronally-important subclasses of transforming growth factor family of molecules are TGFβ-1 and TGFβ-2 that directly stimulate astrocytes, endothelial cells, and macrophages. TGFβ-1 has been observed to increase immediately after injury to the central nervous system, whereas TGFβ-2 expression occurs more slowly near the injury site. Further, TGFβ-2 has been shown to stimulate growth-inhibitory proteoglycans by astrocytes. Experimental reduction of TGFβ-1 and TGFβ-2 has been shown to partially reduce glial scarring.
Interleukins.
Interleukins are another potential family of scar-inducing cellular messengers. Particularly, interleukin-1, a protein produced by mononuclear phagocytes, helps to initiate the inflammatory response in astrocytes, leading to reactive astrogliosis and the formation of the glial scar.
Cytokines.
The cytokine family of glial scar inducers include interferon-γ (IFNγ) and fibroblast growth factor 2 (FGF2). IFNγ has been shown to induce astrocyte proliferation and increase the extent of glial scarring in injured brain models. Further, FGF2 production increases after injury to the brain and spinal cord. FGF2 has also been shown to increase astrocyte proliferation "in vitro".
Ciliary neurotrophic factor.
Ciliary neurotrophic factor (CNTF) is a cytosolic protein that is not secreted. CNTF has been shown to promote the survival of neuronal cultures "in vitro", and it can also act as a differentiator and trophic factor on glial cells. Further, CNTF has been previously shown to affect the differentiation of glial precursor cells "in vitro"; however, the influence of CNTF in the "in vivo" setting has only recently been determined. Winter "et al." used CNTF over-expressing transgenic mice as well as wildtype controls that had CNTF levels artificially elevated via injection, were subjected to neuronal damage using ZnSO4 (a known neuronal degenerative factor), which was injected intranasally in the olfactory epithelium. The olfactory bulb was then assessed for the expression of GFAP mRNA- a common marker for the glial scar. It was determined that mice with elevated levels of CNTF increased their GFAP mRNA expression two-fold. This data suggests that CNTF may mediate glial scar formation following CNS damage.
Upregulation of nestin intermediate filament protein.
Nestin is an intermediate filament (IF) protein that assists with IF polymerization and macromolecule stability. Intermediate filaments are an integral part of cell motility, a requirement for any large migration or cellular reaction. Nestin is normally present during (CNS) development and reactivates after minor stresses to the nervous system. However, Frisen "et al." determined that nestin is also upregulated during severe stresses such as lesions which involve the formation of the glial scar. Mid-thoracic spinal cord lesions, optic nerve lesions, but not lesions to the sciatic nerve, have shown marked increases in nestin expression within the first 48 hours after trauma. Further, nestin upregulation was shown to last for up to 13 months post-injury. This data suggests that nestin upregulation may be associated with CNS glial scarring.
Suppression of glial scar formation.
Several techniques have been devised to impede scar formation. Such techniques can be combined with other neuroregeneration techniques to help with functional recovery.
Olomoucine.
Olomoucine, a purine derivative, is a cyclin-dependent kinase (CDK) inhibitor. CDK is a cell-cycle promoting protein, which along with other pro-growth proteins is abnormally activated during glial scar formation. Such proteins can increase astrocyte proliferation and can also lead to cell death, thus exacerbating cellular damage at the lesion site. Administration of olomoucine peritoneally has been shown to suppress CDK function. Further, olomoucine has been shown to reduce neuronal cell death, reduce astroglial proliferation (and therefore reduce astrogliosis), and increase GAP-43 expression, a useful protein marker for neurite growth. Moreover, reduced astrocyte proliferation decreases expression of chondroitin sulfate proteoglycans (CSPGs), major extracellular matrix molecules associated with inhibition of neuroregneration after trauma to the CNS.
Recent work has also shown that olomoucine suppresses microglial proliferation within the glial scar. This is particularly important because microglia play an important role in the secondary damage following lesion to the CNS, during the time of scar formation. Microglial cells are activated via various pro-inflammatory cytokines (some discussed above). Rat spinal cord injury models have shown remarkable improvements after the administration of olomoucine. One hour-post administration, olomoucine suppressed microglial proliferation, as well as reduced the tissue edema normally present during the early stages of glial scar formation. Further, 24 hours post-administration, a reduction in concentration of interleukin-1β was observed. Additionally, the administration of olomoucine has also been shown to decrease neuronal cell death.
Inhibition of phosphodiesterase 4 (PDE4).
Phosphodiesterase 4 is a member of the phosphodiesterase family of proteins that cleave phosphodiester bonds. This is an important step in degrading cyclic adenosine monophosphate (cAMP), a major intracellular signaling molecule; conversely, blocking PDE4 will increase cAMP. Increased intracellular cAMP levels in neurons has been previously shown to induce axonal growth. In 2004, Nikulina "et al." showed that administration of "rolipram", a PDE4 inhibitor, can increase cAMP levels in neurons after spinal cord injury. This is partially possible because rolipram is sufficiently small to pass through the blood–brain barrier and immediately begin to catalyze reactions in neurons. 10 day administration of rolipram in spinal cord injured rodents resulted in considerable axonal growth associated with a reduction in glial scarring at 2 weeks post-injury. The mechanism for this reduction in glial scarring is currently unknown, but possible mechanisms include axonal extensions that physically prevent reactive astrocytes from proliferating, as well as chemical signaling events to reduce reactive astrogliosis.
Ribavirin.
Ribavirin is a purine nucleoside analogue that is generally used as an anti-viral medication. However, it has also been shown to decrease the amount of reactive astrocytes. Daily administration for at least five days following brain trauma was shown to significantly decrease the number of reactive astrocytes.
Antisense GFAP retrovirus.
An antisense GFAP retrovirus (PLBskG) to reduce GFAP mRNA expression, has been implemented in suppressing growth and arresting astrocytes in the G1 phase of the cell cycle. However, a main caveat to the clinical application of retroviral use is the non-discriminatory effects of PLBskG on normal as well as injured astrocytes. Further "in vivo" studies are needed to determine the systemic effects of PLBskG administration.
Recombinant monoclonal antibody to transforming growth factor-β2.
As noted in the above section, transforming growth factor-β2 (TGFβ2) is an important glial scar stimulant that directly affects astrocyte proliferation. Logan "et al." developed monoclonal antibodies to TGFβ2, cerebral wounds were generated in rat brains, and the antibodies were administered via the ventricles, daily for 10 days. Subsequent analysis showed a marked reduction in glial scarring. Particularly, extracellular matrix protein deposition (laminin, fibronectin, and chondroitin sulfate proteoglycans) was closer to baseline (levels of protein expression in an uninjured animal). Further, a reduction in astrocytes and microglia, as well as a reduction in inflammation and angiogenesis, were observed.
Recombinant monoclonal antibody to interleukin-6 receptor.
Interleukin-6 (IL-6) is thought to be a molecular mediator of glial scar formation. It has been shown to promote differentiation of neural stem cells into astrocytes. A monoclonal antibody, MR16-1, has been used to target and block the IL-6 receptors in rat spinal cord injury models. In a study by Okada "et al.", mice were intraperitoneally injected with a single dose of MR16-1 immediately after generating a spinal cord injury. Blockade of IL-6 receptors decreased the number of astrocytes present at the spinal cord lesion and this decrease was associated with a reduction in glial scarring.
Glial scar treatment or removal.
Chondroitinase ABC has been shown to degrade glial scars. Degrading the glial scar with chondroitinase has been shown to promote recovery from spinal cord injury, especially when combined with other techniques such as nerve guidance conduits, schwann cell transplants, and peripheral nerve autografts.


Computer to plate

Computer-to-plate (CTP) is an imaging technology used in modern printing processes. In this technology, an image created in a Desktop Publishing (DTP) application is output directly to a printing plate.
This compares with the older technology, computer-to-film (CTF), where the computer file is output onto a photographic film. This film is then used to make a printing plate, in a similar manner to a contact proof in darkroom photography.
Technology.
CTP methods differ according to the construction type of the imagesetter and the light source used to expose the plate surface. In terms of construction type there are three different kinds: internal drum, external drum and flat-bed imagesetters. The two main light sources used to expose the plate are ultraviolet light lamps and laser diodes. The wavelength and energy of the laser diodes depend on the type of plate that is used. This technology is mainly used in newspaper and magazine printing.
Internal drum imagesetters.
In an internal drum image setter the plate is put into a cylinder, while the imaging head moves along the axis of the cylinder to expose the plate. The rotating mirror at the end of the imaging head rotates around its axis to beam the laser on the desired part of the fixed plate. The construction type makes it more difficult to use several lasers at the same time, but just using one laser also has advantages such as uniform beam intensity over the whole plate imaging period.
External drum image setters.
The plate is wrapped around a drum that can rotate around its axis, while the imaging head that projects the image on the plate can move along this axis to focus the laser beam on the surface. The simple construction type makes it possible to arrange multiple image heads next to each other and use them simultaneously. This leads to a decrease of the imaging time needed to expose a whole printing plate.
Flat-bed image setters.
The image is reproduced line by line on a fixed flat printing plate by a laser beam that is deflected by a rotating polygon mirror and then onto the printing plate. Because of the setup the laser beam becomes less accurate at the edges of the printing plate and is therefore mainly smaller formats or production with lower quality expectations.
Comparison with CTP.
Advantages.
CTP has several advantages over conventional platemaking. In CTP, one generation (transfer of film image to the printing plate) is removed from the printing process (eliminating the need for film and related developer chemicals), increasing sharpness and detail. CTP avoids potential losses in quality that may occur during film processing, including scratches in the film, and variations in the exposure. An imagesetter usually has an accuracy rate of ±2%. Plates are produced in less time, are more consistent, and at a lower cost. CTP can also improve registration and image-to-edge repeatability over traditional methods. More recent advancements in CTP plate technology made by companies such as Dupont and PlateCrafters have further widened the gap with analog plates, allowing for very fine vignettes and minimal dot gain on press.
In CTP, the media is registered (held in precise position) in the platesetter during imaging, and does not rely on a separately-aligned pin grid, as is the case with film. Defects due to dust, scratches or other artifacts are minimized.
CTP systems can significantly increase plate production outputs. Platesetters for newspaper production can output up to 300 plates per hour at 1,270 dpi (dots per inch), whilst for commercial applications a CTP system could output 60 B1 plates at 2,400 dpi for higher screen rulings.
Small portrait presses that typically create 1 or 2 color output can use anything from a standard laser printer, for low quality/low volume, up to a higher-end dedicated platesetter for higher quality and volume.
Disadvantages.
CTP is restricted to digital format. CTP productions require that the basis for the printed matter as well as the imposition be digital.
In CTP, if for some reason a plate is damaged, if an error occurs when it's ripped or if something has to be corrected after the plate is exposed, a completely new, imposed plate must be created.


Ranitidine bismuth citrate

Ranitidine bismuth citrate - drug, which has antisecretory and bactericidal action.
Group affiliation: H2-histamine receptor blocker.
Shape.
Physical.
Pills. The film-coated tablet contains ranitidine bismuth citrate 400 mg; in a blister 14 pcs., in a box 1, 2 or 4 blisters.
Chemical.
N- / 2 - /// 5 - / (Dimethylamino) methyl / -2-furanyl / methyl / thio / ethyl / -N'-methyl-2-nitro-1,1-ethenediamine bismuth citrate.
Pharmacological properties.
Antiulcer, which is mediated by two active ingredients. Ranitidine - a blocker of H2-histamine receptors, suppresses basal and stimulated, day and night gastric acid secretion, reducing both the volume of its secretion and the concentration hydrochloric acid and pepsin are secreted. Bismuth citrate " in vitro " has a bactericidal effect on Helicobacter pylori, a protective effect on the gastric mucosa.
Indications.
Stomach ulcer and duodenal ulcer, including those associated with Helicobacter pylori (in combination with amoxicillin or clarithromycin ohm).
Prospects for repurposing.
Ranitidine bismuth citrate may also be effective against coronavirus and SARS-CoV-2, since it exhibits low cytotoxicity and is able to protect cells from infection with the SARS-CoV-2 virus, with a selectivity index of several times higher than that of remdesivir a. This is due to the fact that it inhibits the activity required for viral replication helicase Nsp13 SARS-CoV-2 due to irreversible displacement of zinc (II) ions from enzyme and bismuth ions ( III)
Contraindications.
Hypersensitivity, acute porphyria, chronic renal failure (CC less than 25 ml / min), childhood (up to 14 years), pregnancy, lactation.
Side effects.
From the digestive system: gastralgia, diarrhea or constipation, increased activity of "hepatic" transaminases, hepatitis (hepatocellular, cholestatic or mixed, with or without jaundice, usually reversible), acute pancreatitis. From the side of the cardiovascular system: decrease BP, bradycardia, AV block, chest pain, asystole (with injection). On the part of the hematopoietic organs: anemia, leukopenia, thrombocytopenia, agranulocytosis, pancytopenia, aplasia bone marrow. From the nervous system and sensory organs: headache, dizziness, depression, hallucinations, in severe and elderly patients - impaired visual perception (associated with a violation of accommodation); violation of taste; tremor, confusion. From the side of the musculoskeletal system: arthralgia, myalgia. Allergic reactions: pruritus, urticaria, angioedema, bronchospasm, anaphylactic shock, anaphylactoid reactions. Others: gynecomastia in men.
Overdose. Symptoms: neuro- and nephrotoxicity. Treatment: gastric lavage, symptomatic therapy. Ranitidine and bismuth can be removed from the bloodstream by hemodialysis a.
Method of administration and dosage.
Inside, regardless of food intake, 2 times a day (morning and evening). In the treatment and prevention of benign gastric and duodenal ulcers, as well as for the eradication of Helicobacter pylori and the relief of concomitant symptoms of dyspepsia, the following combination therapy regimens are used. Within 7 days - 3 drugs: Scheme 1. 2 times a day - ranitidine bismuth citrate 400 mg, clarithromycin 500 mg, metronidazole 400 mg or amoxicillin 1 g. Scheme 2. 2 times a day - ranitidine bismuth citrate 400 mg, clarithromycin 250 mg, metronidazole 400 or 500 mg or tinidazole 500 mg. Scheme 3. Ranitidine bismuth citrate 400 mg 2 times a day, metronidazole 500 mg 3 times a day, tetracycline 500 mg 4 times a day. Scheme 4. 2 times a day - ranitidine bismuth citrate 400 mg, tinidazole 500 mg, amoxicillin 1 g. Within 14 days - 2 drugs: Scheme 5. Ranitidine bismuth citrate 400 mg 2 times a day and clarithromycin 500 mg 2 or 3 times a day. Scheme 6. Ranitidine bismuth citrate 400 mg 2 times a day and amoxicillin 500 mg 4 times a day. To stimulate regeneration processes in ulcerative diseases of the stomach and duodenal ulcer - 800 mg / day (for 2 doses) for 28 days. For the treatment of duodenal ulcers - 800 mg / day (for 2 doses) for 4 weeks (can be extended up to 8 weeks if necessary); with a stomach ulcer - 8 weeks.
Special instructions.
Before starting therapy, the possibility of gastric ulcer malignancy is excluded, since ranitidine bismuth citrate can mask the symptoms of carcinoma of the stomach. Patients with mild or moderate renal impairment with CC of at least 50 ml / min do not require dose adjustment. In elderly patients with CC more than 25 ml / min, the dose is not changed. Dose changes in liver failure are not required, since ranitidine and bismuth are excreted mainly by the kidneys. H 2 -histamine receptor blockers should be taken 2 hours after taking itraconazole a or ketoconazole a to avoid a significant decrease in their absorption. H 2 -histamine receptor blockers can counteract the effects of pentagastrin a and histamine a on gastric acid-forming function, so use H 2 blockers within 24 hours prior to the test -histamine receptors are not recommended. H 2 -histamine receptor blockers can suppress the cutaneous reaction to histamine, thus resulting in to false negative results (it is recommended to discontinue the use of H 2 -histamine receptor blockers before performing diagnostic skin tests to detect an immediate allergic skin reaction). As with the use of other medicines containing bismuth, darkening of feces and blackening of the tongue are possible. The drug is taken with food or regardless of food intake.
Interaction.
Clarithromycin increases the absorption of ranitidine. The concentration of clarithromycin in plasma does not change when combined with ranitidine bismuth citrate. With the simultaneous administration of ranitidine bismuth citrate with antacids, the absorption of bismuth does not change. Medicines that depress the bone marrow increase the risk of neutropenia. Reduces the absorption of itraconazole and ketoconazole due to an increase in pH in the gastrointestinal tract.


Pentafluranol

Pentafluranol (INN, BAN) (developmental code name BX-430) is a synthetic, nonsteroidal estrogen of the stilbestrol group related to diethylstilbestrol that was developed for the treatment of benign prostatic hyperplasia never marketed. It was described in the medical literature in 1974.


Bexlosteride

Bexlosteride is a potent and noncompetitive inhibitor of the enzyme 5α-reductase related to finasteride and dutasteride. It is selective for the type I isoform of the enzyme. It advanced to Phase III clinical trials, but development was halted at that stage, and it was never marketed.


Fenethazine

Fenethazine (INN) (brand names Anergen, Contralergial, Ethysine, Etisine, Lisergan, Lysergan; former developmental code names RP-3015, SC-1627, WY-1143), or phenethazine, is a first-generation antihistamine of the phenothiazine group. Promethazine, and subsequently chlorpromazine, were derived from fenethazine. Fenethazine, in turn, was derived from phenbenzamine.


Thoracic spinal nerve 5

The thoracic spinal nerve 5 (T5) is a spinal nerve of the thoracic segment.
It originates from the spinal column from below the thoracic vertebra 5 (T5).


Nepadutant

Nepadutant (INN) (code name MEN-11420) is a glycosylated bicyclic cyclohexapeptide drug which acts as a highly selective NK2 receptor antagonist. It was developed by the Menarini Group and investigated for the treatment of functional gastrointestinal disorders and asthma but was never marketed.


Encephalopathy

Encephalopathy (; from "brain" + πάθος "suffering") means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of overall brain dysfunction; this syndrome has many possible organic and inorganic causes.
Signs and symptoms.
The hallmark of encephalopathy is an altered mental state or delirium. Characteristic of the altered mental state is impairment of the cognition, attention, orientation, sleep–wake cycle and consciousness. An altered state of consciousness may range from failure of selective attention to drowsiness. Hypervigilance may be present; with or without: cognitive deficits, headache, epileptic seizures, myoclonus (involuntary twitching of a muscle or group of muscles) or asterixis ("flapping tremor" of the hand when wrist is extended).
Depending on the type and severity of encephalopathy, common neurological symptoms are loss of cognitive function, subtle personality changes, and an inability to concentrate. Other neurological signs may include dysarthria, hypomimia, problems with movements (they can be clumsy or slow), ataxia, tremor. Other neurological signs may include involuntary grasping and sucking motions, nystagmus (rapid, involuntary eye movement), jactitation (restlessness while in bed), and respiratory abnormalities such as Cheyne-Stokes respiration (cyclic waxing and waning of tidal volume), apneustic respirations and post-hypercapnic apnea. Focal neurological deficits are less common.
Wernicke encephalopathy can co-occur with Korsakoff alcoholic syndrome, characterized by amnestic-confabulatory syndrome: retrograde amnesia, anterograde amnesia, confabulations (invented memories), poor recall and disorientation.
Anti-NMDA receptor encephalitis is the most common autoimmune encephalitis. It can cause paranoid and grandiose delusions, agitation, hallucinations (visual and auditory), bizarre behavior, fear, short-term memory loss, and confusion.
HIV encephalopathy can lead to dementia.
Types.
There are many types of encephalopathy. Some examples include:
Toxicity from chemotherapy.
Chemotherapy medication, for example, fludarabine can cause a
permanent severe global encephalopathy. Ifosfamide can cause
a severe encephalopathy (but it can be reversible with stopping use of the drug and starting the use of methylene blue). Bevacizumab and other anti–vascular endothelial growth factor medication can cause posterior reversible encephalopathy syndrome.
Toxicity from Psychotropic Medications.
All therapeutic interventions are double-edged swords with benefits and adverse effects, and pharmacotherapy is not an exception. Shortly after the introduction of conventional antipsychotic drugs into clinical practice, relatively rare but serious complications with hyperthermia, muscle rigidity, autonomic instability, and disturbed mental status were recognized to develop in some patients treated with antipsychotics. This type of encephalopathy induced by the use of antipsychotics was referred to as neuroleptic malignant syndrome (NMS), and almost all physicians prescribing antipsychotics are nowadays aware of this adverse phenomenon. Another well-known type of encephalopathy associated with psychotropic drug therapy is serotonin toxicity (ST) or serotonin syndrome (SS), which is characterized by autonomic and neuromuscular symptoms and altered mental status. In contrast with the idiosyncratic nature of NMS, ST is a spectrum pathophysiological state assumed to derive from excess serotonergic neural transmission caused by serotonin-related psychotropic agents. In these two decades, pharmacotherapy with psychotropic drugs for mentally ill patients has been dramatically changed, and classical prototypal antipsychotics and antidepressants have been replaced with atypical antipsychotics and selective serotonin reuptake inhibitors (SSRIs), respectively. These newly developed psychotropic drugs are generally safer and more tolerable than older drugs. However, atypical antipsychotics are not free of the risk of development of NMS, and the explosive prevalence of SSRIs prescribed not only for depression but also for a number of psychiatric diagnoses such as anxiety, eating, impulse-control, and personality disorders may increase the incidence of ST. Therefore, these two pathological states still remain as major adverse effects of psychotropic drugs involving altered functioning of the central nervous system (CNS), to which all clinicians prescribing psychoactive drugs should pay attention. The popularity of SSRIs also increased the case reports of patients suffering from discontinuation syndrome, which sometimes includes CNS symptoms like anxiety and irritability. In this chapter, the author provides a comprehensive overview of the above- mentioned adverse effects affecting the CNS function associated with psychotropic pharmacotherapy. In addition, several other pathological conditions potentially causing encephalopathic symptoms in psychiatric patients treated with psychotropic drugs, e.g., hyponatremia, valproate-induced hyperammonemia, transient splenial lesion of the corpus callosum, and so on, are also described.
Diagnosis.
Blood tests, cerebrospinal fluid examination by lumbar puncture (also known as spinal tap), brain imaging studies, electroencephalography (EEG), and similar diagnostic studies may be used to differentiate the various causes of encephalopathy.
Diagnosis is frequently clinical. That is, no set of tests give the diagnosis, but the entire presentation of the illness with nonspecific test results informs the experienced clinician of the diagnosis.
Treatment.
Treatment varies according to the type and severity of the encephalopathy. Anticonvulsants may be prescribed to reduce or halt any seizures. Changes to diet and nutritional supplements may help some people. In severe cases, dialysis or organ replacement surgery may be needed.
Sympathomimetic drugs can increase motivation, cognition, motor performance and alertness in persons with encephalopathy caused by brain injury, chronic infections, strokes, brain tumors.
When the encephalopathy is caused by untreated celiac disease or non-celiac gluten sensitivity, the gluten-free diet stops the progression of brain damage and improves the headaches.
Prognosis.
Treating the underlying cause of the disorder may improve or reverse symptoms. However, in some cases, the encephalopathy may cause permanent structural changes and irreversible damage to the brain. These permanent deficits can be considered a form of stable dementia. Some encephalopathies can be fatal.
Terminology.
Encephalopathy is a difficult term because it can be used to denote either a disease or finding (i.e., an observable sign in a person).
When referring to a finding, encephalopathy refers to permanent (or degenerative) brain injury, or a reversible one. It can be due to direct injury to the brain, or illness remote from the brain. The individual findings that cause a clinician to refer to a person as having encephalopathy include intellectual disability, irritability, agitation, delirium, confusion, somnolence, stupor, coma and psychosis. As such, describing a person as having a clinical picture of encephalopathy is not a very specific description.
When referring to a disease, encephalopathy refers to a wide variety of brain disorders with very different etiologies, prognoses and implications. For example, prion diseases, all of which cause transmissible spongiform encephalopathies, are invariably fatal, but other encephalopathies are reversible and can have a number of causes including nutritional deficiencies and toxins.
References.
Encephalopathy Associated with Psychotropic Drug Therapy
Yuji Odagaki
Department of Psychiatry, Faculty of Medicine, Saitama Medical University Department of Psychiatry, Moro Hospital Japan.
https://cdn.intechopen.com/pdfs/35738/InTech-Encephalopathy_associated_with_psychotropic_drug_therapy.pdf#:~:text=encephalopathy%20induced%20by%20the%20use%20of%20antipsychotics%20was,therapy%20is%20serotonin%20toxicity%20%28ST%29%20or%20serotonin%20syndrome


Propriospinal tracts

Propriospinal tracts are collections of nerve fibers ascending, descending, crossed and uncrossed, that interconnect various levels of the spinal cord. They are located in the white columns of the spinal cord where the columns meet the spinal central gray. Shorter fibers are located closer and longer fibers farther from the gray. The tracts include the ventral propriospinal tract, the lateral propriospinal tract and the dorsal propriospinal tract. Some authors include the semilunar tract in this category. A few other fibers intrinsic to the cord run in the dorsolateral fasciculus of the spinal cord and the septomarginal tract.


Patrick Cargill

Patrick Cargill (3 June 191823 May 1996) was an English actor remembered for his lead role in the British television sitcom "Father, Dear Father".
Career.
Cargill was born to middle-class parents living in Bexhill-on-Sea, Sussex. After education at Haileybury College, he made his debut in the Bexhill Amateur Theatrical Society. However, he was aiming for a military career and was selected for training at the Royal Military Academy at Sandhurst. Cargill became a commissioned officer in the British Indian Army.
The stage.
After the Second World War ended, Cargill returned to Britain to focus on a stage career, and joined Anthony Hawtrey's company at Buxton, Croydon and later the Embassy Theatre at Swiss Cottage in London. He became a supporting player in John Counsell's repertory at Windsor alongside Brenda Bruce and Beryl Reid and scored a huge hit in the revue "The World's the Limit", which was seen by the Queen and 26 of her guests one evening. He made his first West End appearance in 1953 in Ian Carmichael's revue "High Spirits" at the London Hippodrome. He also co-wrote the stage play "Ring for Catty", with Jack Beale. The second of the "Carry On" films, "Carry On Nurse", produced in 1959, was based on this play as was the 1962 film "Twice Round the Daffodils".
After a number of other West End roles he was cast as Bernard in "Boeing Boeing" at the Apollo Theatre in 1962. The farce, which was ideal for Cargill, drew the attention of major producers led to him starring in "Say Who You Are" at Her Majesty's Theatre in 1965 and directing "Not Now Darling" by Ray Cooney and John Chapman at the Strand Theatre in 1968.
Television.
Cargill first came to TV notice when playing "Sergeant Cuff" in the 1959 series "The Moonstone".
In 1960, Cargill played Gestapo agent Herr Grosnitz in the BBC TV series "The Long Way Home". He also performed on several occasions with Tony Hancock, twice in Hancock's final BBC television series, including a role as the doctor who clashes with him in the well-known episode "The Blood Donor" (1961). In 1961–62 he featured as the regular character Miguel Garetta in all 26 episodes of the British spy series "Top Secret", and in 1962 he played Herr Straffen in "The Last Man Out", a TV series by Shaun Sutton, followed two years later by a major part of an episode of "The Avengers" TV series. In 1967, he appeared in two episodes of "The Prisoner" as an unusually cruel and brutal Number Two in "Hammer Into Anvil", and as a colleague from Number Six's pre-Village days in "Many Happy Returns".
Cargill starred in three television series of Feydeau farces, adapted by Ned Sherrin and Caryl Brahms and entitled "Ooh! La La!" (1968–1973), which were shown on BBC 2. These vignette Feydeau farces were originally intended to provide variety for Parisian audiences who were used to more than one production during an evening's entertainment. The third and final series showcased Feydeau's longer pieces. Brahms and Sherrin turned six of their adaptations into book form, and published it as "Ooh! La-La!" in 1973, with a dedication: "To Patrick Cargill – First among Farceurs"".
In 1968, Cargill starred in "Father, Dear Father" on ITV (written specifically for him) as Patrick Glover, a thriller writer and an inept father of two teenage daughters, played by Natasha Pyne (Anna) and Ann Holloway (Karen). The show ran until 1973 and was produced and directed by William G. Stewart.
Many performers who had worked before with the actor featured in an entertainment special called "Patrick, Dear Patrick, An Evening with Patrick Cargill and His Guests" (1972). Cargill was a friend of Patrick Macnee from their early acting days, and Macnee returned from California to make a guest appearance on the show. It included both Patricks singing "Mad Dogs and Englishmen". Cargill's companion, Vernon Page, recounts that at the time of casting Cargill wanted to sing this duet with Sir Noël Coward and even visited him at the hotel in London where he was staying in an attempt to persuade him to appear, but Coward was either unwilling or unable to agree to the request and he died 15 months later. This one-off special production by Thames Television also guest-starred Beryl Reid, with whom Cargill sang the duet "I Remember It Well" by Alan Jay Lerner and Frederick Loewe (from "Gigi"). Cargill added a new response to the line "We drank champagne" (Cargill's line): "You gave me Coke, you drank the wine yourself, you soak!" (Reid's riposte).
In 1976, Cargill returned to the TV screens with "The Many Wives of Patrick", playing a middle-aged playboy and antiques dealer, Patrick Woodford, who is trying to divorce his sixth wife in order to remarry his first. This series showcased many prominent stars such as Patrick Macnee and Dawn Addams. The 1980s was something of a revival for Cargill's natural talent at farce. He co-starred in "Key for Two" with Moira Lister at the Vaudeville Theatre and then at the Old Vic Theatre in William Douglas-Home's "After the Ball is Over". In 1986, he starred with Frankie Howerd in "A Funny Thing Happened on the Way to the Forum" at the Chichester Festival Theatre, in which he played the part of Senex.
In his final years, Cargill was seen in "Captain Beaky" at the Playhouse in 1990 and after that he toured in Derek Nimmo's British Airways Playhouse. He also played Neville Chamberlain in the 1990 British Sitcom "Heil Honey I'm Home", which was cancelled after one episode. For the centenary staging of "Charley's Aunt" in 1992, Cargill played the part of the dreaded Spettigue.
Films.
His film appearances included "An Alligator Named Daisy" and "Expresso Bongo"; two of the "Carry On" films: "Carry On Regardless" and "Carry On Jack"; "Help!" (1965) starring The Beatles, "The Magic Christian" (1969) with Peter Sellers and Ringo Starr and Charlie Chaplin's "A Countess from Hong Kong", in which he played the part of the butler, Hudson.
Music.
A lesser known detail of Cargill's showbusiness career is the handful of recordings that he made in the 1960s and 1970s. The first was an album called "Father, Dear Father" (1969) in which Cargill sang a medley of songs. The female voice on the album was not Noel Dyson (Nanny) but that of June Hunt, a friend of Cargill.
He followed this with three singles. One called "Father, Dear Father Christmas" and another called "Thinking Young" and the final single called "Father, Dear Father." None of these recordings were commercially successful.
Cargill appeared as Sir Joseph Porter in "H.M.S. Pinafore" at the Queen Elizabeth Hall in August 1983.
Personal life.
From the mid-1960s Cargill lived at Sheen Gate Gardens, Richmond on Thames. He spent his time 'resting' at Spring Cottage, his country retreat situated in Warren Lane, near , East Sussex.
Cargill's private life was little known and his homosexuality was not public for decades. For many years, Cargill's companion was Vernon Page, an eccentric landscape gardener, poet and lampoon songwriter, until he married in 1984 with Cargill's blessing. Cargill was a private man, who did not relish his celebrity status, though he was always kind to fans who approached him. He would shun the awards ceremonies in favour of a quiet evening at home playing mahjong. He never made any public acknowledgment of his private life as he felt that to confirm his homosexuality would damage his professional image. Notwithstanding his reluctance to "come out" in this respect, Cargill was happy in his private life and his wit when not in the spotlight reflected that. Once, whilst lunching with Ray Cooney, the theatrical impresario, Cargill observed, when a particularly handsome waiter mistakenly removed his soup spoon, "Aah, look Ray, the dish has run away with the spoon." In the later years of his life, Cargill lived in Henley-on-Thames with his last companion, James Camille Markowski.
The love of his life was his Bentley, a black and dark green model of which only six were ever made. Cargill also had a Mini and often told a story about driving through Barnes one day and on seeing one of the other five Bentley Drop-Heads at the traffic lights, waved furiously at the driver, only to realise that he was driving his Mini that day. In the mid-1980s he changed the Bentley for a Rolls Royce.
Cargill's many pets included a monkey, a parrot and a castrated ram. His favourites were Ra, a cross-border collie, and Charles, a cat that lived at Spring Cottage.
Death.
At the time of his death at the age of 77, Cargill was suffering from a brain tumour and was being nursed in a hospice in Richmond on Thames, London. In 1995, the year before he died, Cargill had been struck by a car in Australia; though he was only slightly injured, this accident led to false reports that the cause of his death was a hit-and-run accident.


County nicknames

County nicknames are used as a shortened version of a full county name.


The Magic Bullet (Angel)

"The Magic Bullet" is episode 19 of season 4 in the television show "Angel". Written and directed by Jeffrey Bell, it was originally broadcast on April 16, 2003 on the WB network. While Jasmine settles in at the hotel with her followers for a mysterious gathering, Fred is forced to flee Los Angeles while the rest of the gang hunt her down, with assistance from most of the populace, who are also under Jasmine's enchantment. Fred learns that Jasmine's blood is the key to seeing her for what she really is and plots to free Angel and the gang from Jasmine's influence.
Plot.
Thanks to the events of "Shiny Happy People," everyone in L.A. is happy and cheerful. The first scene opens with the Beach Boys’ “Wouldn't It Be Nice?” playing behind a montage of harmonious street scenes of pedestrians and drivers in the city, until Fred runs into a car at an intersection and the music stops. She’s pursued by Wesley and Gunn, but Fred eludes them by hiding out in a sewer under a shopping center. Back at the Hyperion, Lorne has to turn away people who have come to the hotel to see Jasmine. She makes time to talk to many of them, and Angel asks how Jasmine always knows exactly what to say to people. She tells him that she looks into their hearts, though sometimes what they need is right on their faces. She tells a man in Spanish that his mustache "provides [him] great strength and dignity." Wesley and Gunn return with the news that Fred escaped. Connor wants to kill her and bring her back, but Wesley reminds him that Jasmine wants her alive.
In the lobby, Jasmine invites a couple of people to go upstairs with her. Fred goes to the Magic Bullet Bookstore, which she apparently visited three days earlier to read up on mass hypnosis. Now she's looking for information on mind control. The shopkeeper, Ted (Patrick Fischler), says that he used to be obsessed with mind control, and though he still believes in it, he just doesn't worry about it anymore because of Jasmine. The shopkeeper pulls out a gun (as well as a yoyo and a book called "Making Mind Control Work for You") and says that he thinks Fred is trying to get the government to learn about Jasmine's love. Connor and Angel try to track Fred through the sewers; Angel learns that Connor has been tracking people since he was a kid. Holtz would tie him to a tree and then run away, expecting Connor to free himself and find Holtz. Angel is shocked that Holtz abandoned Connor like that, but Connor considers it good, since he learned to track. Angel and Connor both suddenly close their eyes, receiving a message that Jasmine wants them back at the Hyperion.
Jasmine explains that everyone is connected by love, and she wants to test that connection to see if they can find Fred. Everyone holds hands as Jasmine tells them to picture Fred and concentrate on finding her. Fred checks into a motel, where people around her start looking at her. Fred takes off running, passing a man who is fueling his car. Another car hits his car, which sets off a fire. The guy from the car gets out and, in flames, walks to Fred and tells her not to be afraid. Jasmine's hand starts smoking and burning as she takes the physical damage of the man; she adds that she saw Fred, and now that all of the Jasmaniacs know what she looks like, she can't hide anywhere. Fred walks by the side of a highway and falls down a hill while trying to run from an SUV. She takes refuge in a cave where a short demon is also holed up. The creature assures Fred that he is vegetarian and won't hurt her; it doesn't seem to matter, since Fred makes sure he knows that she can handle herself. Back at the Hyperion, Lorne gives the "hourly Jasmine report," then announces that he has a surprise - open mic night.
A montage follows of various odes to Jasmine, including Lorne singing "Freddie's Dead" and Angel and Connor singing a revised version of "Mandy". The demon in the cave reveals that he's hiding out because of "those freakin’ Jasminites and their demon jihad", but then he uncovers a bunch of human hands, revealing himself to be carnivorous, and attacks Fred, who is injured but fights back with an axe. Fred returns to the Magic Bullet Bookstore, luring a crowd of people outside. The shopkeeper tells Fred that she's famous now, and that he's not supposed to hurt her.
Jasmine arrives with Angel and Connor and, in exchange for the shopkeeper's help, tells him that Lee Harvey Oswald worked alone in assassinating JFK. Fred says that she's sorry, and Jasmine accepts the apology, but it turns out that Fred is talking to Angel. She raises the shopkeeper's handgun, aims at Jasmine, and fires. The bullet goes through Jasmine and then into Angel's shoulder. Angel vamps out and attacks Fred, grabbing the gun and pointing it at her jaw. Crying, Fred tells him to look at Jasmine. He does, seeing the same decaying, maggot-infested flesh that Fred saw earlier. Jasmine realizes that it was her blood that released Fred and Angel and tells Connor that Angel is infected. Fred shoots Jasmine several more times before Connor stops her. Angel runs out with Fred and Jasmine keeps Connor from following them. Jasmine sees how much blood she's lost and tells the shopkeeper to burn the store down. In the hotel office, Jasmine explains that they've lost Angel to Fred: "by being loving to Fred, I opened the door to her hate. By trying to save Fred, I lost Angel. It won't happen again. We must eradicate their hate."
Fred explains that Jasmine's blood breaks the spell - she got it in her system when she washed Jasmine's shirt, and Angel got it after the bullet passed through Jasmine. Fred decides that they need to get more of Jasmine's blood so that they can break the spell for the others. They hear people coming, and Fred kisses Angel to throw the people off, but they do have to run. Later they sneak not-so-stealthily into Cordelia’s room, where she’s still comatose. Angel apologizes to Cordelia, then starts to cut her arm with a knife. She grabs his wrist and he panics, thinking that she’s awake. Fred has to tell him that people in comas sometimes move or do things that don’t mean they’re waking up. Meanwhile, Jasmine tells Connor to keep guard in the hallway as she goes into her room with her chosen guests. She tells them to strip, and as they do, she heals her gunshot wounds. Connor stands guard outside Jasmine’s room; inside, green light shines. In the next act, the green light disappears from Jasmine’s room. Connor asks her where the people went, and Jasmine replies, "I ate them." "Cool," Connor says.
Angel and Fred succeed in "infecting" Lorne with Cordelia's blood to break the spell. Lorne lures Wesley and Gunn upstairs, grabs a baseball bat, and knocks them out so that Fred can administer the cure. When they come to, Wesley brings Connor in, and the others hold him down for the cure. After Connor calms down, Angel tells him they had to make him see the truth. "You understand why we’re here?" Angel asks. Connor nods and goes to the door. He throws it open and yells, "They’re here! Come quick!"
Production.
This was Jeffrey Bell's first experience as a director. "What's the word?" Bell says when asked how it felt to direct. "Terrifying."
Cultural references.
The title of the bookstore and the episode itself is a reference to the Single Bullet Theory of the John F. Kennedy assassination. Jasmine confirms the theory when she tells the shopkeeper that "Oswald acted alone", thus implying that a single bullet struck two people, moments before the same thing happens to her.


Glia

Glia, also called glial cells or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form myelin in the peripheral nervous system, and provide support and protection for neurons. In the central nervous system, glial cells include oligodendrocytes, astrocytes, ependymal cells, and microglia, and in the peripheral nervous system glial cells include Schwann cells and satellite cells. They have four main functions: (1) to surround neurons and hold them in place; (2) to supply nutrients and oxygen to neurons; (3) to insulate one neuron from another; (4) to destroy pathogens and remove dead neurons. They also play a role in neurotransmission and synaptic connections,<ref name="doi:10.1111/j.1742-4658.2008.06515.x"></ref> and in physiological processes like breathing.<ref name="doi:10.1126/science.1190721"></ref> While glia were thought to outnumber neurons by a ratio of 10:1, recent studies using newer methods and reappraisal of historical quantitative evidence suggests an overall ratio of less than 1:1, with substantial variation between different brain tissues.
Glial cells have far more cellular diversity and functions than neurons, and glial cells can respond to and manipulate neurotransmission in many ways. Additionally, they can affect both the preservation and consolidation of memories.
Glia were discovered in 1856, by the pathologist Rudolf Virchow in his search for a "connective tissue" in the brain. The term derives from Greek γλία and γλοία "glue" ( or ), and suggests the original impression that they were the glue of the nervous system.
Types.
Macroglia.
Derived from ectodermal tissue.
Microglia.
Microglia are specialized macrophages capable of phagocytosis that protect neurons of the central nervous system. They are derived from the earliest wave of mononuclear cells that originate in yolk sac blood islands early in development, and colonize the brain shortly after the neural precursors begin to differentiate.
These cells are found in all regions of the brain and spinal cord. Microglial cells are small relative to macroglial cells, with changing shapes and oblong nuclei. They are mobile within the brain and multiply when the brain is damaged. In the healthy central nervous system, microglia processes constantly sample all aspects of their environment (neurons, macroglia and blood vessels). In a healthy brain, microglia direct the immune response to brain damage and play an important role in the inflammation that accompanies the damage. Many diseases and disorders are associated with deficient microglia, such as Alzheimer's disease, Parkinson's disease, and ALS.
Other.
Pituicytes from the posterior pituitary are glial cells with characteristics in common to astrocytes. Tanycytes in the median eminence of the hypothalamus are a type of ependymal cell that descend from radial glia and line the base of the third ventricle. "Drosophila melanogaster," the fruit fly, contains numerous glial types that are functionally similar to mammalian glia but are nonetheless classified differently.
Total number.
In general, neuroglial cells are smaller than neurons. There are approximately 85 billion glia cells in the human brain, about the same number as neurons. Glial cells make up about half the total volume of the brain and spinal cord. The glia to neuron-ratio varies from one part of the brain to another. The glia to neuron-ratio in the cerebral cortex is 3.72 (60.84 billion glia (72%); 16.34 billion neurons), while that of the cerebellum is only 0.23 (16.04 billion glia; 69.03 billion neurons). The ratio in the cerebral cortex gray matter is 1.48, with 3.76 for the gray and white matter combined. The ratio of the basal ganglia, diencephalon and brainstem combined is 11.35.
The total number of glia cells in the human brain is distributed into the different types with oligodendrocytes being the most frequent (45–75%), followed by astrocytes (19–40%) and microglia (about 10% or less).
Development.
Most glia are derived from ectodermal tissue of the developing embryo, in particular the neural tube and crest. The exception is microglia, which are derived from hemopoietic stem cells. In the adult, microglia are largely a self-renewing population and are distinct from macrophages and monocytes, which infiltrate an injured and diseased CNS.
In the central nervous system, glia develop from the ventricular zone of the neural tube. These glia include the oligodendrocytes, ependymal cells, and astrocytes. In the peripheral nervous system, glia derive from the neural crest. These PNS glia include Schwann cells in nerves and satellite glial cells in ganglia.
Capacity to divide.
Glia retains the ability to undergo cell divisions in adulthood, whereas most neurons cannot. The view is based on the general inability of the mature nervous system to replace neurons after an injury, such as a stroke or trauma, where very often there is a substantial proliferation of glia, or gliosis, near or at the site of damage. However, detailed studies have found no evidence that 'mature' glia, such as astrocytes or oligodendrocytes, retain mitotic capacity. Only the resident oligodendrocyte precursor cells seem to keep this ability once the nervous system matures.
Glial cells are known to be capable of mitosis. By contrast, scientific understanding of whether neurons are permanently post-mitotic, or capable of mitosis, is still developing. In the past, glia had been considered to lack certain features of neurons. For example, glial cells were not believed to have chemical synapses or to release transmitters. They were considered to be the passive bystanders of neural transmission. However, recent studies have shown this to not be entirely true.
Functions.
Some glial cells function primarily as the physical support for neurons. Others provide nutrients to neurons and regulate the extracellular fluid of the brain, especially surrounding neurons and their synapses. During early embryogenesis, glial cells direct the migration of neurons and produce molecules that modify the growth of axons and dendrites. Some glial cells display regional diversity in the CNS and their functions may vary between the CNS regions.
Neuron repair and development.
Glia are crucial in the development of the nervous system and in processes such as synaptic plasticity and synaptogenesis. Glia have a role in the regulation of repair of neurons after injury. In the central nervous system (CNS), glia suppress repair. Glial cells known as astrocytes enlarge and proliferate to form a scar and produce inhibitory molecules that inhibit regrowth of a damaged or severed axon. In the peripheral nervous system (PNS), glial cells known as Schwann cells (or also as neuri-lemmocytes) promote repair. After axonal injury, Schwann cells regress to an earlier developmental state to encourage regrowth of the axon. This difference between the CNS and the PNS, raises hopes for the regeneration of nervous tissue in the CNS. For example, a spinal cord may be able to be repaired following injury or severance.
Myelin sheath creation.
Oligodendrocytes are found in the CNS and resemble an octopus: they have bulbous cell bodies with up to fifteen arm-like processes. Each process reaches out to an axon and spirals around it, creating a myelin sheath. The myelin sheath insulates the nerve fiber from the extracellular fluid and speeds up signal conduction along the nerve fiber. In the peripheral nervous system, Schwann cells are responsible for myelin production. These cells envelop nerve fibers of the PNS by winding repeatedly around them. This process creates a myelin sheath, which not only aids in conductivity but also assists in the regeneration of damaged fibers.
Neurotransmission.
Astrocytes are crucial participants in the tripartite synapse. They have several crucial functions, including clearance of neurotransmitters from within the synaptic cleft, which aids in distinguishing between separate action potentials and prevents toxic build-up of certain neurotransmitters such as glutamate, which would otherwise lead to excitotoxicity. Furthermore, astrocytes release gliotransmitters such as glutamate, ATP, and D-serine in response to stimulation.
Clinical significance.
While glial cells in the PNS frequently assist in regeneration of lost neural functioning, loss of neurons in the CNS does not result in a similar reaction from neuroglia. In the CNS, regrowth will only happen if the trauma was mild, and not severe. When severe trauma presents itself, the survival of the remaining neurons becomes the optimal solution. However, some studies investigating the role of glial cells in Alzheimer's disease are beginning to contradict the usefulness of this feature, and even claim it can "exacerbate" the disease. In addition to impacting the potential repair of neurons in Alzheimer's disease, scarring and inflammation from glial cells have been further implicated in the degeneration of neurons caused by amyotrophic lateral sclerosis.
In addition to neurodegenerative diseases, a wide range of harmful exposure, such as hypoxia, or physical trauma, can lead to the end result of physical damage to the CNS. Generally, when damage occurs to the CNS, glial cells cause apoptosis among the surrounding cellular bodies. Then, there is a large amount of microglial activity, which results in inflammation, and finally, there is a heavy release of growth inhibiting molecules.
History.
Although glial cells and neurons were probably first observed at the same time in the early 19th century, unlike neurons whose morphological and physiological properties were directly observable for the first investigators of the nervous system, glial cells had been considered to be merely “glue” that held neurons together until the mid-20th century.
Glia were first described in 1856 by the pathologist Rudolf Virchow in a comment to his 1846 publication on connective tissue. A more detailed description of glial cells was provided in the 1858 book 'Cellular Pathology' by the same author.
When markers for different types of cells were analyzed, Albert Einstein's brain was discovered to contain significantly more glia than normal brains in the left angular gyrus, an area thought to be responsible for mathematical processing and language. However, out of the total of 28 statistical comparisons between Einstein's brain and the control brains, finding one statistically significant result is not surprising and the claim that Einstein's brain is different, is not scientific (c.f. Multiple comparisons problem).
Not only does the ratio of glia to neurons increase through evolution, but so does the size of the glia. Astroglial cells in human brains have a volume 27 times greater than in mouse brains.
These important scientific findings may begin to shift the neuron-specific perspective into a more holistic view of the brain which encompasses the glial cells as well. For the majority of the twentieth century, scientists had disregarded glial cells as mere physical scaffolds for neurons. Recent publications have proposed that the number of glial cells in the brain is correlated with the intelligence of a species.


Axon guidance

Axon guidance (also called axon pathfinding) is a subfield of neural development concerning the process by which neurons send out axons to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they manage to find their way so accurately is an area of ongoing research.
Axon growth takes place from a region called the growth cone and reaching the axon target is accomplished with relatively few guidance molecules. Growth cone receptors respond to the guidance cues.
Mechanisms.
Growing axons have a highly motile structure at the growing tip called the growth cone, which "sniffs out" the extracellular activities in the environment for signals that instruct the axon which direction to grow. These signals, called guidance cues, can be fixed in place or diffusible; they can attract or repel axons. Growth cones contain receptors that recognize these guidance cues and interpret the signal into a chemotropic response. The general theoretical framework is that when a growth cone "senses" a guidance cue, the receptors activate various signaling molecules in the growth cone that eventually affect the cytoskeleton. If the growth cone senses a gradient of guidance cue, the intracellular signaling in the growth cone happens asymmetrically, so that cytoskeletal changes happen asymmetrically and the growth cone turns toward or away from the guidance cue.
A combination of genetic and biochemical methods (see below) has led to the discovery of several important classes of axon guidance molecules and their receptors:
In addition, many other classes of extracellular molecules are used by growth cones to navigate properly:
Integration of information in axon guidance.
Growing axons rely on a variety of guidance cues in deciding upon a growth pathway. The growth cones of extending axons process these cues in an intricate system of signal interpretation and integration, in order to ensure appropriate guidance. These cues can be functionally subdivided into:
Given the abundance of these different guidance cues it was previously believed that growth cones integrate various information by simply summing the gradient of cues, in different valences, at a given point in time, to making a decision on the direction of growth. However, studies in vertebrate nervous systems of ventral midline crossing axons, has shown that modulatory cues play a crucial part in tuning axon responses to other cues, suggesting that the process of axon guidance is nonlinear. For example, commissural axons are attracted by Netrin and repelled by Slit. However, as axons approach the midline, the repellent action of Slit is suppressed by Robo-3/Rig-1 receptor. Once the axons cross the midline, activation of Robo by Slit silences Netrin-mediated attraction, and the axons are repelled by Slit.
Cellular strategies of nerve tract formation.
Pioneer axons.
The formation of a nerve tract follows several basic rules. In both invertebrate and vertebrate nervous systems initial nerve tracts are formed by the pioneer axons of pioneer neurons. These axons follow a reproducible pathway, stop at intermediate targets, and branch axons at certain choice points, in the process of targeting their final destination. This principle is illustrated by CNS extending axons of sensory neurons in insects.
During the process of limb development, proximal neurons are the first to form axonal bundles while growing towards the CNS. In later stages of limb growth, axons from more distal neurons fasciculate with these pioneer axons. Deletion of pioneer neurons disrupts the extension of later axons, destined to innervate the CNS. At the same time, it is worth noting that in most cases pioneer neurons do not contain unique characteristics and their role in axon guidance can be substituted by other neurons. For instance, in Xenopus retinotectal connection systems, the pioneer axons of retinal ganglion cells originate from the dorsal part of the eye. However, if the dorsal half of the eye is replaced by less mature dorsal part, ventral neurons can replace the pioneer pathway of the dorsal cells, after some delay. Studies in zebrafish retina showed that inhibiting neural differentiation of early retinal progenitors prevents axons from exiting the eye. The same study demonstrated aberrant growth trajectories in secondary neurons, following the growth of pioneer neurons missing a guidance receptor. Thus, while the extent of guidance provided by pioneer axons is under debate and may vary from system to system, the pioneer pathways clearly provide the follower projections with guidance cues and enhance their ability to navigate to target.
Role of glia.
The first extending axons in a pathway interact closely with immature glia cells. In the forming corpus callosum of vertebrates, primitive glia cells first migrate to the ependymal zones of hemispheres and the dorsal septum wall to form a transient structure that the pioneer axons of the callosal fibers use to extend. The signaling between glia and neurons in the developing nervous system is reciprocal. For instance, in the fly visual system, axons of photoreceptors require glia to exit the eye stalk whereas glia cells rely on signals from neurons to migrate back along axons.
Guideposts.
The growing axons also rely on transient neuronal structures such as guidepost cells, during pathfinding. In the mouse visual system, proper optic chiasm formation depends on a V-shaped structure of transient neurons that intersect with specialized radial glia at the midline of the chiasm. The chiasm axons grow along and around this structure but do not invade it. Another example is the subplate in the developing cerebral cortex that consists of transient neuronal layer under the subventricular zone and serves as a guidepost for axons entering permanent cortical layers. The subplate is similar to the chiasmatic neurons in that these cell groups disappear (or transit into other cell types) as the brain matures. These findings indicate that transitory cell populations can serve an important guidance role even though they have no function in the mature nervous system.
Studying axon guidance.
The earliest descriptions of the axonal growth cone were made by the Spanish neurobiologist Santiago Ramón y Cajal in the late 19th century. However, understanding the molecular and cellular biology of axon guidance would not begin until decades later. In the last thirty years or so, scientists have used various methods to work out how axons find their way. Much of the early work in axon guidance was done in the grasshopper, where individual motor neurons were identified and their pathways characterized. In genetic model organisms like mice, zebrafish, nematodes, and fruit flies, scientists can generate mutations and see whether and how they cause axons to make errors in navigation. In vitro experiments can be useful for direct manipulation of growing axons. A popular method is to grow neurons in culture and expose growth cones to purified guidance cues to see whether these cause the growing axons to turn. These types of experiments have often been done using traditional embryological non-genetic model organisms, such as the chicken and African clawed frog. Embryos of these species are easy to obtain and, unlike mammals, develop externally and are easily accessible to experimental manipulation.
Axon guidance model systems.
Several types of axon pathways have been extensively studied in model systems to further understand the mechanisms of axon guidance. Perhaps the two most prominent of these are commissures and topographic maps. Commissures are sites where axons cross the midline from one side of the nervous system to the other. Topographic maps are systems in which groups of neurons in one tissue project their axons to another tissue in an organized arrangement such that spatial relationships are maintained; i.e. adjacent neurons will innervate adjacent regions of the target tissue.
Commissure formation: attraction and repulsion.
As described above, axonal guidance cues are often categorized as "attractive" or "repulsive." This is a simplification, as different axons will respond to a given cue differently. Furthermore, the same axonal growth cone can alter its responses to a given cue based on timing, previous experience with the same or other cues, and the context in which the cue is found. These issues are exemplified during the development of commissures. The bilateral symmetry of the nervous system means that axons will encounter the same cues on either side of the midline. Before crossing (ipsilaterally), the growth cone must navigate toward and be attracted to the midline. However, after crossing (contralaterally), the same growth cone must become repelled or lose attraction to the midline and reinterpret the environment to locate the correct target tissue.
Two experimental systems have had particularly strong impacts on understanding how midline axon guidance is regulated:
The ventral nerve cord of "Drosophila".
The use of powerful genetic tools in "Drosophila" led to the identification of a key class of axon guidance cues, the Slits, and their receptors, the Robos (short for Roundabout). The ventral nerve cord looks like a ladder, with three longitudinal axon bundles (fascicles) connected by the commissures, the "rungs" of the ladder. There are two commissures, anterior and posterior, within each segment of the embryo.
The currently accepted model is that Slit, produced by midline cells, repels axons from the midline via Robo receptors. Ipsilaterally projecting (non-crossing) axons always have Robo receptors on their surface, while commissural axons have very little or no Robo on their surface, allowing them to be attracted to the midline by Netrins and, probably, other as-yet unidentified cues. After crossing, however, Robo receptors are strongly upregulated on the axon, which allows Robo-mediated repulsion to overcome attraction to the midline. This dynamic regulation of Robo is at least in part accomplished by a molecule called Comm (short for Commissureless), which prevents Robo from reaching the cell surface and targeting it for destruction.
The spinal cord of mice and chickens.
In the spinal cord of vertebrates, commissural neurons from the dorsal regions project downward toward the ventral floor plate. Ipsilateral axons turn before reaching the floor plate to grow longitudinally, while commissural axons cross the midline and make their longitudinal turn on the contralateral side. Strikingly, Netrins, Slits, and Robos all play similar functional roles in this system as well. One outstanding mystery was the apparent lack of any "comm" gene in vertebrates. It now seems that at least some of Comm's functions are performed by a modified form of Robo called Robo3 (or Rig1).
The spinal cord system was the first to demonstrate explicitly the altered responsiveness of growth cones to cues after exposure to the midline. Explanted neurons grown in culture would respond to exogenously supplied Slit according to whether or not they had contacted floor plate tissue.
Topographic maps: gradients for guidance.
As described above, topographic maps occur when spatial relationships are maintained between neuronal populations and their target fields in another tissue. This is a major feature of nervous system organization, particular in sensory systems. The neurobiologist Roger Sperry proposed a prescient model for topographic mapping mediated by what he called molecular "tags." The relative amounts of these tags would vary in gradients across both tissues. We now think of these tags as ligands (cues) and their axonal receptors. Perhaps the best understood class of tags are the Ephrin ligands and their receptors, the Ephs.
In the simplest type of mapping model, we could imagine a gradient of Eph receptor expression level in a field of neurons, such as the retina, with the anterior cells expressing very low levels and cells in the posterior expressing the highest levels of the receptor. Meanwhile, in the target of the retinal cells (the optic tectum), Ephrin ligands are organized in a similar gradient: high posterior to low anterior. Retinal axons enter the anterior tectum and proceed posteriorly. Because, in general, Eph-bearing axons are repelled by Ephrins, axons will become more and more reluctant to proceed the further they advance toward the posterior tectum. However, the degree to which they are repelled is set by their own particular level of Eph expression, which is set by the position of the neuronal cell body in the retina. Thus, axons from the anterior retina, expressing the lowest level of Ephs, can project to the posterior tectum, even though this is where Ephrins are highly expressed. Posterior retinal cells express high Eph level, and their axons will stop more anteriorly in the tectum.
The retinotectal projection of chickens, frogs and fish.
The large size and accessibility of the chicken embryo has made it a favorite model organism for embryologists. Researchers used the chick to biochemically purify components from the tectum that showed specific activity against retinal axons in culture. This led to the identification of Ephs and Ephrins as Sperry's hypothesized "tags."
The retinotectal projection has also been studied in "Xenopus" and zebrafish. Zebrafish is a potentially powerful system because genetic screens like those performed in invertebrates can be done relatively simply and cheaply. In 1996, large scale screens were conducted in zebrafish, including screens for retinal axon guidance and mapping. Many of the mutants have yet to be characterized.
Cell biology.
Genetics and biochemistry have identified a large set of molecules that affect axon guidance. How all of these pieces fit together is less understood. Most axon guidance receptors activate signal transduction cascades that ultimately lead to reorganization of the cytoskeleton and adhesive properties of the growth cone, which together underlie the motility of all cells. This has been well documented in mammalian cortical neurons. However, this raises the question of how the same cues can result in a spectrum of response from different growth cones. It may be that different receptors activate attraction or repulsion in response to a single cue. Another possibility is the receptor complexes act as "coincidence detectors" to modify responses to one cue in the presence of another. Similar signaling "cross-talk" could occur intracellularly, downstream of receptors on the cell surface.
In fact, commissural axon growth responses have been shown to be attracted, repressed, or silenced in the presence of Netrin activated DCC receptor. This variable activity is dependent on Robo or UNC-5 receptor expression at growth cones. Such that Slit activated Robo receptor, causes a silencing of Netrin’s attractive potential through the DCC receptor. While growth cones expressing UNC-5 receptor, respond in a repulsive manner to Netrin-DCC activation. These events occur as consequence of cytoplasmic interactions between the Netrin activated DCC receptor and Robo or UNC-5 receptor, which ultimately alters DCC’s cytoplasmic signaling. Thus, the picture that emerges is that growth cone advancement is highly complex and subject to plasticity from guidance cues, receptor expression, receptor interactions, and the subsequent signaling mechanisms that influence cytoskeleton remodeling.
Growth cone translation in guided axons.
The ability for axons to navigate and adjust responses to various extracellular cues, at long distances from the cell body, has prompted investigators to look at the intrinsic properties of growth cones. Recent studies reveal that guidance cues can influence spatiotemporal changes in axons by modulating the local translation and degradation of proteins in growth cones. Furthermore, this activity seems to occur independent of distal nuclear gene expression. In fact, in retinal ganglion cells (RGCs) with soma severed axons, growth cones continue to track and innervate the tectum of Xenopus embryos.
To accommodate this activity, growth cones are believed to pool mRNAs that code for receptors and intracellular signaling proteins involved in cytoskeleton remodeling. In Xenopus retinotectal projection systems, the expression of these proteins has been shown to be influenced by guidance cues and the subsequent activation of local translation machinery. The attractive cue Netrin-1, stimulates mRNA transport and influence synthesis of β-Actin in filopodia of growth cones, to restructure and steer RGC growth cones in the direction of Netrin secretion. While the repulsive cue, Slit, is suggested to stimulate the translation of Cofilin (an actin depolymerizing factor) in growth cones, leading to axon repulsion. In addition, severed commissural axons in chicks, display the capability of translating and expressing Eph-A2 receptor during midline crossing. As a result, studies suggest that local protein expression is a convenient mechanism to explain the rapid, dynamic, and autonomous nature of growth cone advancement in response to guidance molecules.
The axon growth hypothesis and the consensus connectome dynamics.
Contemporary diffusion-weighted MRI techniques may also uncover the macroscopical process of axonal development. The connectome, or the braingraph, can be constructed from diffusion MRI data: the vertices of the graph correspond to anatomically labelled brain areas, and two such vertices, say "u" and "v", are connected by an edge if the tractography phase of the data processing finds an axonal fiber that connects the two areas, corresponding to "u" and "v". Numerous braingraphs, computed from the Human Connectome Project can be downloaded from the http://braingraph.org site. The Consensus Connectome Dynamics (CCD) is a remarkable phenomenon that was discovered by continuously decreasing the minimum confidence-parameter at the graphical interface of the Budapest Reference Connectome Server. The Budapest Reference Connectome Server depicts the cerebral connections of n=418 subjects with a frequency-parameter k: For any k=1,2...,n one can view the graph of the edges that are present in at least k connectomes. If parameter k is decreased one-by-one from k=n through k=1 then more and more edges appear in the graph, since the inclusion condition is relaxed. The surprising observation is that the appearance of the edges is far from random: it resembles a growing, complex structure, like a tree or a shrub (visualized on .
It is hypothesized in that the growing structure copies the axonal development of the human brain: the earliest developing connections (axonal fibers) are common in most of the subjects, and the subsequently developing connections have larger and larger variance, because their variances are accumulated in the process of axonal development.
Genetic association.
Axon guidance is genetically associated with other characteristics or features. For example, enrichment analyses of different signaling pathways led to the discovery of a genetic association with intracranial volume.


Continuous flash suppression

Continuous flash suppression (CFS) is an adapted version of the original flash suppression method, first reported in 2004 (https://jov.arvojournals.org/article.aspx?articleid=2131303). In CFS, the first eye is presented with a static stimulus, such as a schematic face, while the second eye is presented with a series of rapidly changing stimuli. The result is the static stimulus becomes consciously repressed by the stimuli presented in the second eye. A variant of CFS to suppress a dynamic stimulus is also reported
CFS not only successfully suppresses images, but it strengthens the depth and duration of suppression compared to previous methods, such as flash suppression and binocular rivalry. CFS has the highest magnitude of suppression and allows researchers to increase the suppression time of an image tenfold. Using this method, subjects may report an image presented in their visual field as being invisible for over three minutes. CFS has the longest suppression time compared to other methods. CFS opens the door to studying preconscious processing mechanisms involved in visual perception.
Applications.
CFS can be used to measure the salience of an image. Using this application, CFS can assist in determining if emotionally salient faces have a shorter suppression time compared to neutral faces. Significant differences have been shown in suppression duration depending on the images being suppressed. This illustrates how CFS can be used to more accurately measure the varying strength and perceptual influence of individual visual stimuli.
Continuous flash suppression is a useful method for psychologists and neuroscientists interested in studying the mechanisms of conscious and nonconscious visual processing. Whereas other visual illusions that render otherwise salient images invisible have their own shortcomings and advantages, continuous flash suppression has a number of advantages for wiping images from conscious vision. It can erase an image presented at the fovea (which usually is much more resistant to perceptual suppression, unlike, for example, crowding), in every trial (unlike binocular rivalry), for a longer duration (>1 sec, unlike backward masking), with an excellent control of timing (unlike binocular rivalry). It has been widely exploited to tackle the scope and limits of unconscious processing.
Methodology.
Tsuchiya and Koch (2006) argue that CFS is not simply a stronger form of binocular rivalry, but is actually a continuous form of flash suppression. The succession of multiple flashes that give CFS its increased suppression capabilities. The duration of stimulus suppression is chiefly dependent on the flash rate of the stimulus. Studies conclude that a series of five stimuli flashes in CFS achieve the full depth of suppression. A unique feature of CFS is its immunity to adaptation. Because the stimulus is flashed repeatedly, CFS prevents the subject from achieving actual conscious awareness of the stimulus.
Mondrian patterns.
"Mondrian patterns" are typically used when conducting CFS experiments. Each pattern is generally flashed for 0.1 seconds before being replaced by a different Mondrian image. The typical Mondrian pattern used in CFS is composed of many varied black/grey/white or sometimes multi-colored squares. These Mondrian-scenes act as the suppressors of the probe stimulus. The name comes from Piet Mondrian, an artist who was famous for his use of vertical and horizontal lines.