Pseudoephedrine

Pseudoephedrine (PSE) is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent in higher doses.
It was first characterized in 1889, by the German chemists Ladenburg and Oelschlägel, who used a sample that had been isolated from "Ephedra vulgaris" by the Merck pharmaceutical corporation of Darmstadt, Germany. The salts pseudoephedrine hydrochloride and pseudoephedrine sulfate are found in many over-the-counter preparations, either as a single ingredient or (more commonly) in a fixed-dose combination with one or more additional active ingredients such as antihistamines, guaifenesin, dextromethorphan, paracetamol (acetaminophen) or an NSAID (such as aspirin or ibuprofen).
Medical uses.
Pseudoephedrine is a stimulant, but it is well known for shrinking swollen nasal mucous membranes, so it is often used as a decongestant. It reduces tissue hyperemia, edema, and nasal congestion commonly associated with colds or allergies. Other beneficial effects may include increasing the drainage of sinus secretions, and opening of obstructed Eustachian tubes. The same vasoconstriction action can also result in hypertension, which is a noted side effect of pseudoephedrine.
Pseudoephedrine can be used either as oral or as topical decongestant. However, due to its stimulating qualities, the oral preparation is more likely to cause adverse effects, including urinary retention. According to one study, pseudoephedrine may show effectiveness as an antitussive drug (suppression of cough).
Pseudoephedrine is indicated for the treatment of nasal congestion, sinus congestion and Eustachian tube congestion. Pseudoephedrine is also indicated for vasomotor rhinitis, and as an adjunct to other agents in the optimum treatment of allergic rhinitis, croup, sinusitis, otitis media, and tracheobronchitis.
Pseudoephedrine is also used as a first-line prophylactic for recurrent priapism. Erection is largely a parasympathetic response, so the sympathetic action of pseudoephedrine may serve to relieve this condition. Treatment for urinary incontinence is an off-label use ("unlabeled use") for these medications.
Adverse effects.
Common adverse drug reactions (ADRs) associated with pseudoephedrine therapy include central nervous system stimulation, insomnia, nervousness, excitability, dizziness and anxiety. Infrequent ADRs include tachycardia or palpitations. Rarely, pseudoephedrine therapy may be associated with mydriasis (dilated pupils), hallucinations, arrhythmias, hypertension, seizures and ischemic colitis; as well as severe skin reactions known as recurrent pseudo-scarlatina, systemic contact dermatitis, and nonpigmenting fixed drug eruption. Pseudoephedrine, particularly when combined with other drugs including narcotics, may also play a role in the precipitation of episodes of paranoid psychosis.
It has also been reported that pseudoephedrine, among other sympathomimetic agents, may be associated with the occurrence of stroke.
Precautions and contraindications.
Pseudoephedrine is contraindicated in patients with diabetes mellitus, cardiovascular disease, severe or uncontrolled hypertension, severe coronary artery disease, prostatic hypertrophy, hyperthyroidism, closed angle glaucoma, or by pregnant women. The safety and effectiveness of nasal decongestant use in children is unclear.
Interactions.
Concomitant or recent (previous fourteen days) monoamine oxidase inhibitor use can lead to hypertensive reactions, including hypertensive crises.
The antihypertensive effects of methyldopa, mecamylamine, reserpine and veratrum alkaloids may be reduced by sympathomimetics. Beta-adrenergic antagonists may also interact with sympathomimetics. Increase of ectopic pacemaker activity can occur when pseudoephedrine is used concomitantly with digitalis. Antacids increase the rate of pseudoephedrine absorption, while kaolin decreases it.
Mechanism of action.
Pseudoephedrine is a sympathomimetic amine. Its principal mechanism of action relies on its direct action on the adrenergic receptor system.<ref name="Thomson/Micromedex 2007 2452"></ref> The vasoconstriction that pseudoephedrine produces is believed to be principally an α-adrenergic receptor response.
Pseudoephedrine acts on α- and β2-adrenergic receptors, to cause vasoconstriction and relaxation of smooth muscle in the bronchi, respectively. α-Adrenergic receptors are located on the muscles lining the walls of blood vessels. When these receptors are activated, the muscles contract, causing the blood vessels to constrict (vasoconstriction). The constricted blood vessels now allow less fluid to leave the blood vessels and enter the nose, throat and sinus linings, which results in decreased inflammation of nasal membranes, as well as decreased mucus production. Thus, by constriction of blood vessels, mainly those located in the nasal passages, pseudoephedrine causes a decrease in the symptoms of nasal congestion. Activation of β2-adrenergic receptors produces relaxation of smooth muscle of the bronchi, causing bronchial dilation and in turn decreasing congestion (although not fluid) and difficulty breathing.
Other uses.
There have been reports of off-label uses of pseudoephedrine for its stimulant properties. Long-distance truck drivers and athletes, for example, have reportedly used pseudoephedrine as a stimulant to increase their state of alertness/awareness.
A study has also found that pseudophedrine can reduce milk production in breastfeeding women.
Manufacture of amphetamines.
Its membership in the amphetamine class has made pseudoephedrine a sought-after chemical precursor in the illicit manufacture of methamphetamine and methcathinone. As a result of the increasing regulatory restrictions on the sale and distribution of pseudoephedrine, many pharmaceutical firms have reformulated, or are in the process of reformulating medications to use alternative, but less effective, decongestants, such as phenylephrine.
In the United States, federal laws control the sale of pseudoephedrine-containing products. Many retailers in the US have created corporate policies restricting the sale of pseudoephedrine-containing products. Their policies restrict sales by limiting purchase quantities and requiring a minimum age and government issued photographic identification. These requirements are similar to and sometimes more stringent than existing law. Internationally, pseudoephedrine is listed as a Table I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.
Sports.
Pseudoephedrine was on the IOC's banned substances list until 2004, when the World Anti-Doping Agency (WADA) list replaced the IOC list. Although WADA initially only monitored pseudoephedrine, it is once again on the banned list starting January 1, 2010.
Pseudoephedrine is excreted through urine, and concentration in urine of this drug shows a large inter-individual spread; that is, the same dose can give a vast difference in urine concentration for different individuals. Pseudoephedrine is approved to be taken up to 240 mg per day. In seven healthy male subjects this dose yielded a urine concentration range of 62.8 to 294.4 microgram per milliliter (µg/ml) with mean ± standard deviation 149 ± 72 µg/ml. Thus, normal dosage of 240 mg pseudoephedrine per day can result in urine concentration levels exceeding the limit of 150 µg/ml set by WADA for about half of all users. Furthermore, hydration status does not affect urinary concentration of pseudoephedrine.
Canadian rower Silken Laumann was stripped of her 1995 Pan American Games team gold medal after testing positive for pseudoephedrine.
In February 2000, Elena Berezhnaya and Anton Sikharulidze won gold at the 2000 European Figure Skating Championships but were stripped of their medals after Berezhnaya tested positive. This resulted in a three-month disqualification from the date of the test, and the medal being stripped. She stated that she had taken cold medication approved by a doctor but had failed to inform the ISU as required. The pair missed the World Championships that year as a result of the disqualification.
Romanian gymnast Andreea Răducan was stripped of her gold medal at the 2000 Summer Olympic Games after testing positive. She took two pills given to her by the team coach for a cold. Although she was stripped of the overall gold medal, she kept her other medals, and, unlike in most other doping cases, was not banned from competing again; only the team doctor was banned for a number of years. Ion Ţiriac, the president of the Romanian Olympic Committee, resigned over the scandal.
In the 2010 Winter Olympic Games, the IOC issued a reprimand against the Slovak ice hockey player Lubomir Visnovsky for usage of pseudoephedrine.
In the 2014 Winter Olympic Games Team Sweden and Washington Capitals ice hockey player Nicklas Bäckström was prevented from playing in the final for usage of pseudoephedrine. Bäckström claimed he was using it as allergy medication. In March 2014, the IOC Disciplinary Commission decided that Bäckström would be awarded the silver medal. In January 2015 Bäckström, the IOC, WADA and the IIHF agreed to a settlement in which he accepted a reprimand but was cleared of attempting to enhance his performance.
Detection of use.
Pseudoephedrine may be quantified in blood, plasma, or urine to monitor any possible performance-enhancing use by athletes, confirm a diagnosis of poisoning, or to assist in a medicolegal death investigation. Many commercial immunoassay screening tests directed at the amphetamines cross-react appreciably with pseudoephedrine, but chromatographic techniques can easily distinguish pseudoephedrine from other phenethylamine derivatives. Blood or plasma pseudoephedrine concentrations are typically in the 50–300 µg/l range in persons taking the drug therapeutically, 500–3000 µg/l in people with substance use disorder involving pseudoephedrine, or poisoned patients and 10–70 mg/l in cases of acute fatal overdose.
Chemistry.
Pseudoephedrine is a diastereomer of ephedrine and is readily reduced into methamphetamine or oxidized into methcathinone.
Nomenclatures.
The dextrorotary (+)- or d- enantiomer is (1"S",2"S")-pseudoephedrine, whereas the levorotating (−)- or l- form is (1"R",2"R")-pseudoephedrine.
In the outdated (+)-pseudoephedrine is also referred to as pseudoephedrine and (−)-pseudoephedrine as pseudoephedrine (in the Fisher projection then the phenyl ring is drawn at bottom).
Often the system (with small caps) and the d/l system (with lower-case) are confused. The result is that the dextrorotary d-pseudoephedrine is wrongly named pseudoephedrine and the levorotary l-ephedrine (the diastereomer) wrongly ephedrine.
The IUPAC names of the two enantiomers are (1"S",2"S")- respectively (1"R",2"R")-2-methylamino-1-phenylpropan-1-ol. Synonyms for both are "psi"-ephedrine and "threo"-ephedrine.
Pseudoephedrine is the International Nonproprietary Name of the (+)-form, when used as pharmaceutical substance.
Society and culture.
Brand names.
The following is a list of consumer medicines that either contain pseudoephedrine or have switched to an alternative such as phenylephrine.
Legal status.
Australia.
Illicit diversion of pseudoephedrine in Australia has caused significant changes to the way the products are regulated. , all products containing pseudoephedrine have been rescheduled as either "Pharmacist Only Medicines" (Schedule 3) or "Prescription Only Medicines" (Schedule 4), depending on the amount of pseudoephedrine in the product. A Pharmacist Only Medicine may only be sold to the public if a pharmacist is directly involved in the transaction. These medicines must be kept behind the counter, away from public access.
Pharmacists are also encouraged (and in some states required) to log purchases with the online database Project STOP. This system aims to prevent individuals from purchasing small quantities of pseudoephedrine from many different pharmacies.
As a result, many pharmacies no longer stock Sudafed, the common brand of pseudoephedrine cold/sinus tablets, opting instead to sell Sudafed PE, a phenylephrine product which has not been proven effective in clinical trials.
Canada.
Health Canada has investigated the risks and benefits of pseudoephedrine and ephedrine/ephedra. Near the end of the study, Health Canada issued a warning on their website stating that those who are under the age of 12, or who have heart disease and may suffer from strokes, should avoid taking pseudoephedrine and ephedrine. Also, they warned that everyone should avoid taking ephedrine or pseudoephrine with other stimulants like caffeine. They also banned all products that contain both ephedrine (or pseudoephedrine) and caffeine.
Products whose only medicinal ingredient is pseudoephedrine must be kept behind the pharmacy counter. Products containing pseudoephedrine along with other medicinal ingredients may be displayed on store shelves but may be sold only in a pharmacy when a pharmacist is present.
Colombia.
The Colombian government prohibited the trade of pseudoephedrine in 2010.
Japan.
Medications that contain more than 10% pseudoephedrine are prohibited under the Stimulants Control Law in Japan.
Mexico.
On November 23, 2007, the use and trade of pseudoephedrine in Mexico was made illicit, as it was argued that it was extremely popular as a precursor in the synthesis of methamphetamine.
Netherlands.
Pseudoephedrine was withdrawn from sale in 1989 due to concerns about adverse cardiac side effects.
New Zealand.
In New Zealand, pseudoephedrine is currently classified as a Class B Part II controlled drug in the Misuse of Drugs Act 1975, making it illegal to supply or possess except on prescription.
Pseudoephedrine, ephedrine, and any product containing these substances, e.g. cold and flu medicines, were first classified in October 2004 as Class C Part III (partially exempted) controlled drugs, due to being the principal ingredient in methamphetamine. New Zealand Customs and police officers continued to make large interceptions of precursor substances believed to be destined for methamphetamine production. On 9 October 2009, Prime Minister John Key announced pseudoephedrine-based cold and flu tablets would become prescription-only drugs and reclassified as a class B2 drug. The law was amended by The Misuse of Drugs Amendment Bill 2010, which passed in August 2011.
Turkey.
In Turkey, medications containing pseudoephedrine are available with prescription only.
United Kingdom.
In the UK, pseudoephedrine is available over the counter under the supervision of a qualified pharmacist, or on prescription. In 2007, the MHRA reacted to concerns over diversion of ephedrine and pseudoephedrine for the illicit manufacture of methamphetamine by introducing voluntary restrictions limiting over the counter sales to one box containing no more than 720 mg of pseudoephedrine in total per transaction. These restrictions became law in April 2008. However no form of ID is required.
United States.
Federal.
The United States Congress has recognized that pseudoephedrine is used in the illegal manufacture of methamphetamine. In 2005, the Committee on Education and the Workforce heard testimony concerning education programs and state legislation designed to curb this illegal practice.
Attempts to control the sale of the drug date back to 1986, when federal officials at the Drug Enforcement Administration (DEA) first drafted legislation, later proposed by Senator Bob Dole, R-KS, that would have placed a number of chemicals used in the manufacture of illicit drugs under the Controlled Substances Act. The bill would have required each transaction involving pseudoephedrine to be reported to the government, and federal approval of all imports and exports. Fearing this would limit legitimate use of the drug, lobbyists from over the counter drug manufacturing associations sought to stop this legislation from moving forward, and were successful in exempting from the regulations all chemicals that had been turned into a legal final product, such as Sudafed.
Prior to the passage of the Combat Methamphetamine Epidemic Act of 2005, sales of the drug became increasingly regulated, as DEA regulators and pharmaceutical companies continued to fight for their respective positions. The DEA continued to make greater progress in their attempts to control pseudoephedrine as methamphetamine production skyrocketed, becoming a serious problem in the western United States. When purity dropped, so did the number of people in rehab and people admitted to emergency rooms with methamphetamine in their systems. However, this reduction in purity was usually short lived, as methamphetamine producers eventually found a way around the new regulations.
Congress passed the "Combat Methamphetamine Epidemic Act of 2005" ("CMEA") as an amendment to the renewal of the USA Patriot Act. Signed into law by president George W. Bush on March 6, 2006, the act amended , concerning the sale of pseudoephedrine-containing products. The law mandated two phases, the first needing to be implemented by April 8, 2006, and the second to be completed by September 30, 2006. The first phase dealt primarily with implementing the new buying restrictions based on amount, while the second phase encompassed the requirements of storage, employee training, and record keeping. Though the law was mainly directed at pseudoephedrine products it also applies to all over-the-counter products containing ephedrine, pseudoephedrine, and phenylpropanolamine, their salts, optical isomers,
and salts of optical isomers.
Pseudoephedrine was defined as a "scheduled listed chemical product" under (45(A)). The act included the following requirements for merchants ("regulated sellers") who sell such products:
In regards to the identification that may be used by an individual buying pseudoephedrine products the following constitute acceptable forms of identification:
The requirements were revised in the Methamphetamine Production Prevention Act of 2008 to require that a regulated seller of scheduled listed chemical products may not sell such a product unless the purchaser:
State.
Most states also have laws regulating pseudoephedrine.
The states of Alabama, Arizona, Arkansas, California, Colorado, Delaware, Florida, Georgia, Hawaii () Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana (), Massachusetts, Michigan, Minnesota, Missouri, Montana, Nebraska, Nevada, New Jersey, North Carolina, Ohio, Oklahoma, Pennsylvania, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia, Washington, West Virginia and Wisconsin have laws requiring pharmacies to sell pseudoephedrine "behind the counter". Though the drug can be purchased without a prescription, states can limit the number of units sold and can collect personal information from purchasers."
The states of Oregon and Mississippi require a prescription for the purchase of products containing pseudoephedrine. The state of Oregon reduced the number of methamphetamine lab seizures from 467 in 2004 (the final full year before implementation of the prescription only law) to a new low of 12 in 2009. However, the decrease in meth lab incidents in Oregon occurred largely before the prescription-only law took effect, according to a NAMSDL report titled "Pseudoephedrine Prescription Laws in Oregon and Mississippi". The report posits that the decline in meth lab incidents in both states may be due to other factors: "Mexican traffickers may have contributed to the decline in meth labs in Mississippi and Oregon (and surrounding states) as they were able to provide ample supply of equal or greater quality meth at competitive prices". Additionally, similar decreases in meth lab incidents were seen in surrounding states, according to the report, and meth-related deaths in Oregon have dramatically risen since 2007. Some municipalities in Missouri have enacted similar ordinances, including Washington, Union, New Haven, Cape Girardeau and Ozark. Certain pharmacies in Terre Haute, Indiana do so as well.
Another approach to controlling the drug on the state level which has been mandated by some state governments to control the purchases of their citizens is the use of electronic tracking systems, which require the electronic submission of specified purchaser information by all retailers who sell pseudoephedrine. 32 states now require the National Precursor Log Exchange (NPLEx) to be used for every pseudoephedrine and ephedrine OTC purchase, and ten of the eleven largest pharmacy chains in the US voluntarily contribute all of their similar transactions to NPLEx. These states have seen dramatic results in reducing the number of methamphetamine laboratory seizures. Prior to implementation of the system in Tennessee in 2005, methamphetamine laboratory seizures totaled 1,497 in 2004, but were reduced to 955 in 2005, and 589 in 2009. Kentucky's program was implemented statewide in 2008, and since statewide implementation, the number of laboratory seizures has significantly decreased. Oklahoma initially experienced success with their tracking system after implementation in 2006, as the number of seizures dropped in that year and again in 2007. However, in 2008, seizures began rising again, and have continued to rise in 2009. However, when Oklahoma adopted NPLEx, their lab seizures also dropped significantly.
NPLEx appears to be successful by requiring the real-time submission of transactions, thereby enabling the relevant laws to be enforced at the point of sale. By creating a multi-state database and the ability to compare all transactions quickly, NPLEx enables pharmacies to deny purchases that would be illegal based on gram limits, age, or even to convicted meth offenders in some states. NPLEx also enforces the federal gram limits across state lines, which was impossible with state-operated systems. Access to the records is by law enforcement agencies only, through an online secure portal.
In popular culture.
In the pilot episode of Breaking Bad, Walter White first synthesizes methamphetamine through the Nagai route, using red phosphorus and iodine to reduce pseudoephedrine.
In the episode "Vitamin D" of Glee, Terri takes a job as the school nurse to stop her husband, Will Schuester, from becoming closer to guidance counsellor Emma Pillsbury (Jayma Mays), but is fired after giving the students performance-enhancing pseudoephedrine tablets.
In her 2013 single , Australian rock musician Courtney Barnett refers to the effects of pseudoephedrine: "Reminds me of the time/When I was really sick and I/Had too much pseudoephedrine and I/Couldn't sleep at night".
In her critically acclaimed 2017 album Melodrama, pop artist Lorde references pseudoephedrine on the song "Writer in the Dark". The lyric reads: "I still feel you, now and then/Slow like pseudoephedrine/When you see me, will you say I've changed?"
Synthesis.
Although pseudoephedrine occurs naturally as an alkaloid in certain plant species (for example, as a constituent of extracts from the "Ephedra" species, also known as "ma huang", in which it occurs together with other isomers of ephedrine), the majority of pseudoephedrine produced for commercial use is derived from yeast fermentation of dextrose in the presence of benzaldehyde. In this process, specialized strains of yeast (typically a variety of "Candida utilis" or "Saccharomyces cerevisiae") are added to large vats containing water, dextrose and the enzyme pyruvate decarboxylase (such as found in beets and other plants). After the yeast has begun fermenting the dextrose, the benzaldehyde is added to the vats, and in this environment the yeast converts the ingredients to the precursor l-phenylacetylcarbinol (L-PAC). L-PAC is then chemically converted to pseudoephedrine via reductive amination.
The bulk of pseudoephedrine is produced by commercial pharmaceutical manufacturers in India and China, where economic and industrial conditions favor its mass production for export.


Terfluranol

Terfluranol (INN, BAN) (developmental code name BX-428) is a synthetic, nonsteroidal estrogen of the stilbestrol group related to diethylstilbestrol that was developed for the treatment of breast cancer but was never marketed. It was described in the medical literature in 1974.


Ocular dominance column

Ocular dominance columns are stripes of neurons in the visual cortex of certain mammals (including humans) that respond preferentially to input from one eye or the other. The columns span multiple cortical layers, and are laid out in a striped pattern across the surface of the striate cortex (V1). The stripes lie perpendicular to the orientation columns.
Ocular dominance columns were important in early studies of cortical plasticity, as it was found that monocular deprivation causes the columns to degrade, with the non-deprived eye assuming control of more of the cortical cells.
It is believed that ocular dominance columns must be important in binocular vision. Surprisingly, however, many squirrel monkeys either lack or partially lack ocular dominance columns, which would not be expected if they are useful. This has led some to question whether they serve a purpose, or are just a byproduct of development.
History.
Discovery.
Ocular dominance columns were discovered in the 1960s by Hubel and Wiesel as part of their Nobel prize winning work on the structure of the visual cortex in cats. Ocular dominance columns have since been found in many animals, such as ferrets, macaques, and humans. Notably, they are also absent in many animals with binocular vision, such as rats.
Structure.
Ocular dominance columns are stripe shaped regions of the primary visual cortex that lie perpendicular to the orientation columns, as can be seen in the accompanying figure. Different species have somewhat different morphologies and levels of organization. For example, humans, cats, ferrets, and macaques all have fairly well defined columns, while squirrel monkeys have quite variable columns. There is even variation in expression in individuals of the same species and in different parts of the cortex of the same individual.
The columns are by input from the lateral geniculate nucleus (LGN) into cortical layer 4 and have mostly reciprocal projections to many other parts of the visual cortex.
Relation to other features of V1.
The ocular dominance columns cover the primary (striate) visual cortex, with the exception of monocular regions of the cortical map corresponding to peripheral vision and the blind spot. If the columns corresponding to one eye were colored, a pattern similar to that shown in the accompanying figure would be visible when looking at the surface of the cortex. However, the same region of cortex could also be colored by the direction of edge that it responds to, resulting in the orientation columns, which are laid out in a characteristic pinwheel shape. Similarly, there are columns in the cortex that have high levels of the protein cytochrome oxidase. These are called cytochrome oxidase "blobs" because of their scattered blob-like appearance.
All three types of column are present in the visual cortex of humans and macaques, among other animals. In macaques, it was found that both blobs and pinwheel centers tend to lie in the center of ocular dominance columns, but no particular relation has been found between pinwheel centers and blobs. In humans, the layout of the columns is similar; however, humans have somewhat variable column expression with at least one subject having disordered columns similar to those commonly found in squirrel monkeys.
Most early models of the columns supposed that there were discrete "modules" or "hypercolumns" tiling the cortex, consisting of a repeating unit containing a full set of orientation and ocular dominance columns. While such units can be constructed, the map of columns is so distorted that there is no repeating structure and no clear boundaries between modules. Additionally, practically every combination of having or not having orientation, dominance, and cytochrome oxidase columns has been observed in one species or another. Further confusing the issue, squirrel monkeys don't always express columns, and even when they do the cytochrome oxidase blobs are not in register with the ocular dominance columns.
Development.
Formation.
There is no consensus yet as to how ocular dominance columns are initially developed. One possibility is that they develop through Hebbian learning triggered by spontaneous activity coming from retinal waves in the eyes of the developing fetus, or from the LGN. Another possibility is that axonal guidance cues may guide the formation, or a combination of mechanisms may be at work. It is known that ocular dominance columns develop before birth, which indicates that if an activity dependent mechanism is involved it must work based on intrinsic activity rather than being sensory experience dependent. It is known that spontaneous waves of activity in the retina occur before birth and that these waves are crucial for eye specific segregation of inputs to the LGN by correlating the activity of nearby neurons. Similarly, the correlated activation for the retinal waves may direct development of the ocular dominance columns, which receive input from the LGN. Similar spontaneous activity in the cortex may also play a role. In any case, it has been shown that disrupting the retinal waves at least alters the pattern of ocular dominance columns.
Plasticity.
Sensitive periods.
Although the ocular dominance columns are formed before birth, there is a period after birth—formerly called a "critical period" and now called a "sensitive period"—when the ocular dominance columns may be modified by activity dependent plasticity. This plasticity is so strong that if the signals from both eyes are blocked the ocular dominance columns will completely . Similarly, if one eye is closed ("monocular deprivation"), removed("enucleation"), or silenced during the sensitive period, the size of the columns corresponding to the removed eye shrink dramatically.
Models.
Many models have been proposed to explain the development and plasticity of the ocular dominance columns. In general these models can be split into two categories, those that posit formation via chemotaxis and those that posit a Hebbian activity dependent mechanism. Generally, chemotaxis models assume activity independent formation via the action of axon guidance molecules, with the structures only later being refined by activity, but there are now known to be activity dependent and activity modifying guidance molecules.
Modified Hebbian learning.
One major model of the formation of the stripes seen in ocular dominance columns is that they form by Hebbian competition between axon terminals.
The ocular dominance columns look like Turing patterns, which can be formed by modified Hebbian mechanisms. In a normal Hebbian model, if two neurons are connected to a neuron and fire together, they increase the strength of the synapses, "moving" the axon terminals closer together. The model must be modified to incorporate incoming activity that is locally excitatory and long range inhibitory, because if this is not done then the column width will only be dependent on the width of the axonal arbor, and also segregation will often fail in the presence of inter eye correlation. This basic model has since been extended to be more physiologically plausible with the addition of long term potentiation and depression, synaptic normalization, neurotrophin release, reuptake, and spike-timing-dependent plasticity.
Chemotaxis.
Chemotactic models posit the existence of axon guidance molecules that direct the initial formation of the ocular dominance columns. These molecules would guide the axons as they develop based on markers specific to the axons from each eye. All chemotactic models must take into account the activity dependent effects demonstrated in later development, but they have been called for because several pieces of evidence make entirely activity dependent formation unlikely. First, it has been shown that the ocular dominance columns in squirrel monkeys have mirror symmetry across the cortex. This is very unlikely to occur by activity dependent means because it implies a correlation between the nasal retina of one eye and the temporal retina of the other, which has not been observed. Furthermore, work in achiasmatic Belgian sheepdogs has shown that columns can form between the projections from the temporal and nasal retina of the same eye, clearly suggesting a nasal-temporal labeling, rather than contralateral vs. ipsilateral, which would be much easier to explain with activity dependent mechanisms. Despite this, a molecular label that directs the formation of the ocular dominance columns has never been found.
Function.
It has long been believed that ocular dominance columns play some role in binocular vision. Another candidate function for ocular dominance columns (and for columns in general) is the minimization of connection lengths and processing time, which could be evolutionarily important. It has even been suggested that the ocular dominance columns serve no function.


Far point

In visual perception, the far point is the farthest point at which an object can be placed (along the optical axis of the eye) for its image to be focused on the retina within the eye's accommodation. It is sometimes described as the farthest point from the eye at which images are clear. The other limit of eye's accommodation is the near point.
For an unaccommodated emmetropic eye, the far point is at infinity, but for the sake of practicality, infinity is considered to be because the accommodation change from 6 m to infinity is negligible. See visual acuity or Snellen chart for details about 6/6 (m) or 20/20 (ft) vision.
For an unaccommodated myopic eye, the far point is closer than 6 m. It depends upon the refractive error of the person's eye.
For an unaccommodated hypermetropic eye, incident light must be converging before entering the eye so as to focus on the retina. In this case (the hypermetropic eye) the focus point is behind the retina in virtual space, rather than on the retina screen.
Sometimes far point is given in diopters, the inverse of the distance in meters (see Simple myopia). For example, an individual who can see clearly out to 50 cm would have a far point of formula_1.
Vision correction.
A corrective lens can be used to correct myopia by imaging an object at infinity onto a virtual image at the patient's far point. According to the thin lens formula the required optical power is
formula_2,
where is the distance to the patient's far point. is negative, because a diverging lens is required.
This calculation can be improved by taking into account the distance between the spectacle lens and the human eye, which is usually about 1.5 cm:
formula_3.
For example, if a person has , then the optical power needed is where one diopter is the reciprocal of one meter.


Middle cardiac nerve

The middle cardiac nerve ("great cardiac nerve"), the largest of the three cardiac nerves, arises from the middle cervical ganglion, or from the trunk between the middle and inferior ganglia.
On the right side it descends behind the common carotid artery, and at the root of the neck runs either in front of or behind the subclavian artery; it then descends on the trachea, receives a few filaments from the recurrent nerve, and joins the right half of the deep part of the cardiac plexus.
In the neck, it communicates with the superior cardiac and recurrent nerves.
On the left side, the middle cardiac nerve enters the chest between the left carotid and subclavian arteries, and joins the left half of the deep part of the cardiac plexus.


Prevertebral plexus

A prevertebral plexus is a nerve plexus which branches from a prevertebral ganglion.


Meat Curtains


Inferior longitudinal fasciculus

The inferior longitudinal fasciculus (ILF) is traditionally considered one of the major occipitotemporal association tracts. It is the white matter backbone of the ventral visual stream. It connects the ventral surface of the anterior temporal lobe and the extrastriate cortex of the occipital lobe, running along the lateral and inferior wall of the lateral ventricle.
The existence of this fasciculus and its anatomical description have been the subject of several mutually conflicting studies. Some authors denied its existence because of the unclear results obtained in non-human brains.
Using diffusion tensor imaging (DTI), several authors have confirmed the presence of this constant longitudinal pathway in humans.
Some other studies of the ILF based on Klingler's dissection method (a type of white matter blunt dissection, providing reliable data on the anatomy of major fibre bundles and, in some cases, additional tractography not only confirmed the classical descriptions of the direct connection between occipital and temporal regions but also sought to detail the subcomponents of this association tract.
Four branches were consistently identified: a fusiform branch connecting the fusiform gyrus to the anterior temporal regions; a dorsolateral occipital branch connecting the superior, middle and inferior occipital gyri to the anterior temporal regions; a lingual branch connecting the lingual gyrus to the anterior part of the middle temporal gyrus; and a minor cuneal branch connecting the cuneus to the anterior mesial temporal gyri.
Functions of the ILF.
Summarising studies from healthy individuals, intraoperative and lesional findings, this white matter bundle supports functions linked to the ventral visual stream such as object recognition and face perception, Likewise, disorders linked to this white matter tract are disorders with perturbed visual perception such as associative visual agnosia, prosopagnosia, visual amnesia, visual hypo-emotionality; but also some forms of autism spectrum disorders, schizophrenia and alexia.
ILF supports brain functions concerning the visual modality, including object, face and place processing, reading, lexical and semantic processing, emotion processing, and visual memory. Based on these recent findings ILF can be described as a multi-functional white matter pathway involved in visually guided behavior (See Herbet et al. for review).


Medullary pyramids (brainstem)

The medullary pyramids are paired white matter structures of the brainstem's medulla oblongata that contain motor fibers of the corticospinal and corticobulbar tracts – known together as the pyramidal tracts. The lower limit of the pyramids is marked when the fibers cross (decussate).
Structure.
The ventral portion of the medulla oblongata contains the medullary pyramids. These two ridge-like structures travel along the length of the medulla oblongata and are bordered medially by the anterior median fissure. They each have an anterolateral sulcus along their lateral borders, where the hypoglossal nerve emerges from. Also at the side of each pyramid there is a pronounced bulge known as an olive. Fibers of the posterior column, which transmit sensory and proprioceptive information, are located behind the pyramids on the medulla oblongata.
The medullary pyramids contain motor fibers that are known as the corticobulbar and corticospinal tracts. The corticospinal tracts are on the anterior surface of the pyramids. These tracts transport motor signals that originated in the precentral gyrus and travelled through the internal capsule to the medulla oblongata and pyramids. Extrapyramidal tracts are those motor tracts that do not traverse the medullary pyramids.
At the pyramids' most caudal end, the corticospinal axons decussate (or cross over) the midline and continue down the spinal cord on the contralateral side. The fibers that decussated will go down the lateral corticospinal tract while the fibers that did not decussate will travel down the anterior corticospinal tract. Nearly 90 percent of the fibers decussate and travel down the lateral corticospinal tract while the other 10 percent travels down the anterior corticospinal tract.
Decussation.
The two pyramids contain the motor fibers that pass from the brain to the medulla oblongata and spinal cord. These are the corticobulbar and corticospinal fibers that make up the pyramidal tracts.
About 90% of these fibers leave the pyramids in successive bundles and decussate (cross over) in the anterior median fissure of the medulla oblongata as the "pyramidal decussation" or "motor decussation". Having crossed over at the middle line, they pass down in the posterior part of the lateral funiculus as the lateral corticospinal tract. The other 10% of the fibers stay uncrossed in the anterior corticospinal tract. The pyramidal decussation marks the border between the spinal cord and the medulla oblongata.
Function.
The medullary pyramids contain the motor fibers of the pyramidal tracts – the corticospinal and corticobulbar tracts.
Clinical significance.
Whiplash as a result of a car accident can lead to brainstem injuries that affect the pyramids at the medulla oblongata. These pyramid injuries are usually a result of a dislocation at the occiput or spinal level C1. Injuries to the pyramids of the medulla oblongata can also be caused by the quick hyperextension of the neck (cervical region of the spine). Hyperextension of the neck can pull and tear the pyramids, leading to a variety of symptoms such as weakness in all four limbs, difficulty swallowing, and difficulty speaking. A bilateral infarction in the pyramids of the medulla can result in motor quadriplegia. This is rare, however, as there have only been four cases of this reported.
References.
Saladin, Kenneth (2012). Anatomy & Physiology: The Unity of Form and Function, Sixth Edition. New York: McGraw-Hill.


Subcommissural organ

The subcommissural organ (SCO) is one of the circumventricular organs of the brain. It is a small glandular structure that is located in the posterior region of the third ventricle, near the entrance of the cerebral aqueduct. The name of the SCO comes from its location beneath the posterior commissure, a bundle of nerve fibers interconnecting parts of the two hemispheres of the brain. The SCO is one of the first differentiated brain structures to develop. Although it is evolutionarily an ancient structure that is present throughout the chordate phylum, its arrangement varies somewhat among species. Functions of the SCO are unknown; some evidence indicates it may participate in clearance of certain compounds from the cerebrospinal fluid, and possibly in morphogenetic mechanisms, such as development of the posterior commissure.
Structure.
Cells of the subcommissural organ, which are specialized in the secretion of glycoproteins (see below), are arranged into two layers: a superficial layer called the ependyma and an underlying layer called the hypendyma. The ependyma consists of long, columnar cells that release their secretions into the ventricular cerebrospinal fluid. The hypendyma (which is most prominent in mammals) is characterized by numerous capillaries and glial cells. Hypendymal cells and ependymal cells both are secretory in nature; their processes project to local blood vessels and also to the subarachnoidal space.
The ependymal cell bodies present a clear zonation that is especially marked in certain species: 1) In the perinuclear region, large and dilated cisternae of the rough endoplasmic reticulum (RER) are the most distinctive ultrastructural feature of virtually all species; 2) the intermediate region consists mainly of RER and Golgi apparatus; 3) the subapical region is relatively narrow, and includes microtubules, mitochondria and smooth endoplasmic reticulum; and 4) the apical region comprises a large protrusion into the ventricle. There are no neuronal cell bodies within the subcommissural organ, although the specialized cells receive some innervation from outside neurons.
Function.
Ependymal cells secrete high molecular mass glycoproteins into the cerebrospinal fluid, in which the bulk of them condense to form a filamentous structure named Reissner’s fiber. The subcommissural organ/Reissner’s fiber complex is thought to be involved in the reabsorption and circulation of the cerebrospinal fluid, and with functions related to electrolyte and water balance.
One of the proteins secreted by the subcommissural organ, and which is present in Reissner’s fiber, is spondin. SCO-spondin is a “giant” (5000 amino acids) glycoprotein (thrombospondin superfamily) found in Vertebrata. This glycoprotein shares molecular domains with axonal pathfinding molecules. The ependymal cells and the SCO–spondin secretion are thought to play a role in homeostasis.
The ependymal cells of the SCO are also involved in the production of brain transthyretin, a protein involved in the transport of thyroid hormones in blood.
Some studies indicate the presence of both tyrosine-hydroxylase-immunoreactive nerve fibers and dopamine receptors in the SCO ependyma. In addition, there is evidence suggesting that the SCO activity in adult animals may be regulated by serotonin.
All capillaries in the central nervous system with a functional blood-brain barrier express glucose transporters (GLUT1). These transporters are generally absent in leaky barrier structures. The circumventricular organs that are known to have leaky barrier capillaries were stained by fibronectin antibodies but not by GLUT1 antibodies. The subcommissural organ appears to be unique in that it shows neither GLUT1 nor capillary.
Reissner's fiber.
Reissner's fiber is also thought to be important in morphogenetic neuronal processes, being involved in neuronal survival, aggregation and neurite extension. In vitro studies demonstrated that the presence of RF, in conjunction with glial cells, is essential to the survival of neuronal cells. The studies seem to point that the RF might bind some of the growth factors produced by glial cells and transport them to the neurons. On the process of neuronal aggregation, RF seems to serve as a control factor in direct cell-to-cell communication, favoring neuronal aggregation when the density of neurons is low and preventing this aggregation when the density gets higher. Although the mechanism behind this is not well understood, it is known to be linked to the different domains in SCO-spondin that are related to coagulation factors and TSRs, as referred above. Furthermore, the RF as a part on the neurite extension, promoting neurite outgrowth from both spinal and cortical neurons, in cell cultures, which may also be connected to the TSR domains of SCO-spondin.
SCO-spondin, a glycoprotein of the SCO/RF complex.
The primary structure of the major constituent of bovine RF, SCO-spondin, has been fully established as a large N-glycosylated protein (450 kDa). Many lines of evidence denote that SCO-spondin plays a role in CNS development. This molecule belongs to a protein superfamily exhibiting conserved motifs of the thrombospondin type 1 repeat. Proteins of this family are strongly expressed during mammalian CNS development, being involved in mechanisms of cellular adhesion and axonal pathfinding (a process by which neurons send out axons to reach the correct targets during neural development).
Numerous investigations have been directed towards the identification and characterization of the secretory compounds of the SCO, clarifying partially its function. Immunoblot analyses of bovine SCO using antibodies against RF glycoproteins allowed the identification of high molecular weight glycoproteins of 540, 450, 320 and 190 kDa.
The 540 and the 320 kDa compounds would correspond to precursor forms.
Multidomain organization.
The main SCO-spondin isoform consists of multiple domains. This multidomain organization is a special feature of the Chordate Phylum, and there is a high degree of conservation in the amino acids composition in mammals. The complete sequence and modular organization of SCO-spondin was first characterized in Bos taurus.
The structure of this protein is unique as it presents a mosaic arrangement of these domains along the backbone.
The putative function of SCO-spondin in neuronal differentiation is discussed regarding these features and homologies with other developmental molecules of the central nervous system exhibiting TSR domains, and involved in axonal guidance. Peptides corresponding to SCO-spondin TSR domains strongly increased adhesivity and neuritic outgrouth of cortical neurons and induced disaggregation of spinal cord neurons. Therefore, it is a candidate to interfere with neuronal development and/or axonal guidance during ontogenesis of the central nervous system in the modulation of side-to-side and side-to-substratum interactions, and also in promoting neurite outgrowth.
The identification of conserved domains including Emilin (EMI), von Willebrand factor D (vWD) low-density lipoprotein receptor type A repeats (LDLrA) domains, SCO repeats (SCORs), 26 thrombospondin type 1 repeats (TSRs), a coagulation factor 5/8 type C (FA5-8C) or discoidin motif and a C-terminal cystin knot (CTCK) domain provides a wider insight into the putative function of this protein. Similar types of arrangement was encountered in zonadhesins and immunoglobulin G (IgG) FC binding fragment which may account for SCO-spondin functional aspect on promoting cell-to-substratum adhesivity.
The presence of low-density lipoprotein receptor type A (LDLrA) domains repeated ten times in the consensus sequence could provide a hint as to the function of SCORs, since LDLrA are known to interact with proteases or protease inhibitors. There may be a functional link between LDLrAs and SCORs, which could both be involved in the regulation of either protease activation or protease inhibition. The motifs coagulation factor 5/8 type C or discoidin and thrombospondin type 1 repeat (TSR) present in SCO-spondin consensus were initially described in blood proteins, where they were shown to play a role in coagulation or platelet aggregation. SCO-spondin and F-spondin share a similar pattern of expression in the floor plate, flexural organ and subcommissural organ and could have a redundant activity. The biological function of F-spondin and SCO-spondin on the deflection of commissural axons in the neural tube was assessed respectively by experiments of gain and loss of function and by analyses of mutants with defective floor plate. F-spondin and SCO-spondin were both shown to promote neurite outgrowth of various neuronal cell populations, in cell culture.
SCO-spondin may interfere with several biological events during early ontogenetical development of the CNS. Nevertheless, SCO-spondin is also present during the adult life, and similarly to thrombospondins, which act on various biological systems, i.e., neuronal differentiation, angiogenesis and platelet aggregation.
Development.
SCO.
Despite being a much conserved structure throughout evolution, there are some differences on the SCO from different mammals. It is the first secretory structure to differentiate and remains fully developed and functional during the life of almost every vertebrate, excluding bats, anthropoid apes and humans. More specifically, in humans, the SCO development has a regressive nature. It reaches its apex development in fetus from 3 to 5 month old, functioning as a fully active secretory structure of the brain during this time span, and extending from the pineal recess over the posterior commissure to the mesocoelic recess. It is composed by a characteristic high columnar epithelium, which is not found in the adult SCO. Following this maxed developed state, the SCO starts regressing and in children from 3 to 4 years old it already has a vestigial character, being reduced to islet like structures on the adult. Although the remaining cells can possess some secretory material the SCO is truly vestigial in both structure and secretory function, in adults.
SCO-spondin.
As part of the embryonic cerebrospinal fluid (eCSF), SCO-spondin is of the uttermost importance in the development of the neuronal system, being a key protein in the balancing of differentiation and proliferation of the neuroepithelium. It starts being secreted by the diencephalic floor plate in the first embryonic stages playing an important part in the development and differentiation of structures such as the pineal gland. In particular, the SCO-spondin appears to have a major role on the growth of the posterior commissure (PC), which was proved when mutants lacking SCO, and hence having no SCO-spondin, were unable to form a functional PC. On early stages of development the axonal growth is stimulated, being inhibited afterwards. A steep gradient of spondin expression in the neuroepithelium signals the need for different processes to take place, favoring the fasciculation on the cephalic region and the incorporation of new neurons on the caudal region. As such, the lower concentrations of SCO-spondin in the caudal region favor the axonal outgrowth and incorporation of new axons on the posterior commissure and the higher concentrations in the cephalic region promotes the interactions between the neighboring axons. In conjugation with the secretion of SCO-spondin, the midline positioning of the SCO assumes a great importance on the axon guidance process. This positioning facilitates the signaling of the turning points for the axons, through the spreading of spondin.
In addition to the functions in axon guidance and related growth of the posterior commissure, the SCO-spondin also appears to have a role on the adhesion of the trophoblast to the uterine walls.
There is a slightly different SCO-spondin produced in the trophoblast, most likely due to alternative splicing. This spondin may recognize the classic protein on the uterine wall, facilitating the adhesion.
Clinical significance.
Hydrocephalus.
Given that the subcommissural organ is not highly permeable and does not possess fenestrated capillaries like other subventricular organs, it has emerged as a major site of congenital hydrocephalus. It is suggested that this is related to immunological blockage of SCO secretions and Sylvian's aqueduct malformation and obliteration or turbulent cerebrospinal fluid flow due to the absence of Reissner's fibers. There is evidence that in transgenic mice the overexpression of Sox3 in the dorsal midline of the diencephalon in a dose-dependent manner and that the conditional inactivation of presenilin-1 or the lack of huntingtin in wnt cell lineages leads to congenital hydrocephalus, which highlights the role of these proteins mediating the relation between the SCO and the condition (see also: Wnt signaling pathway for more information). A more recent study using HTx rats reinforced the idea that the abnormal and dysfunction of the SCO precedes the development of the hydrocephalus.
Other disease.
It is reported that in spontaneously hypertensive rats there is a relation between SCO and hypertension due to changing in its secretor activity and protein composition.
History.
In 1860, Ernst Reissner, anatomist at the University of Dorpat, published a monograph on the microscopic structure of the spinal cord of "Petromyzon fluviatilis". He described a string of 1.5 μm in diameter characterized by its high refringence, its extremely regular shape, and its lying free within the central canal. In 1866, Karl Kutschin confirmed Reissner’s observations and named the fibrous structure Reissner’s fiber.
Edinger (1892) described, in sharks, what later was known as “the subcommissural organ”. Studnicka (1900), called attention to uncommonly tall ependymal cells covering the posterior comissure of "P. fluviatilis". Sargent, also in 1900, establishes the basis of what is presently regarded as the subcomissural organ – Reissner fiber complex. Finally, in 1910, Dendy and Nicholls introduce the term “subcommissural organ” to describe this brain gland.
The rich vascularization of the SCO was first reported by Pesonen (1940). In 1958, Helmut Hofer postulated that this organ, despite its structural and functional differences from other circumventricular organs, is a highly secretory component of the circumventricular organ system.


Hippocampal formation

The hippocampal formation is a compound structure in the medial temporal lobe of the brain. There is no consensus concerning which brain regions are encompassed by the term, with some authors defining it as the dentate gyrus, the hippocampus proper and the subiculum; and others including also the presubiculum, parasubiculum, and entorhinal cortex. The hippocampal formation is thought to play a role in memory, spatial navigation and control of attention. The neural layout and pathways within the hippocampal formation are very similar in all mammals.
History and function.
During the nineteenth and early twentieth centuries, based largely on the observation that, between species, the size of the olfactory bulb varies with the size of the parahippocampal gyrus, the hippocampal formation was thought to be part of the olfactory system.
In 1937 Papez theorized that a circuit including the hippocampal formation constitutes the neural substrate of emotional behavior, and Klüver and Bucy reported that, in monkeys, surgical removal of the hippocampal formation and the amygdaloid complex has a profound effect on emotional responses. As a consequence of these publications, the idea that the hippocampal formation is entirely dedicated to olfaction began to recede.
In an influential 1947 review, Alf Brodal pointed out that mammal species thought to have no sense of smell nevertheless have fully intact hippocampal formations, that removal of the hippocampal formation did not affect the ability of dogs to perform tasks dependent on olfaction, and that no fibers were actually known that carry information directly from the olfactory bulb to any part of the hippocampal formation. Though massive direct input from the olfactory bulb to the entorhinal cortex has subsequently been found, the current view is that the hippocampal formation is not an integral part of the olfactory system.
In 1900, the Russian neurologist Vladimir Bekhterev described two patients with a significant memory deficit who, on autopsy, were found to have softening of hippocampal and adjacent cortical tissue; and, in 1957, Scoville and Milner reported memory loss in a series of patients subsequent to their removal of the patients' medial temporal lobes. Thanks to these observations and a great deal of subsequent research, it is now broadly accepted that the hippocampal formation plays a role in some aspects of memory.
EEG evidence from 1938 to the present, stimulation evidence from the 1950s, and modern imaging techniques together suggest a role for some part of the hippocampal formation (in concert with the anterior cingulate cortex) in the control of attention.
In 1971, John O'Keefe and his student Jonathan Dostrovsky discovered place cells, neurons in the rat hippocampus whose activity relates to the animal's location within its environment. Despite skepticism from other investigators, O'Keefe and his co-workers, including Lynn Nadel, continued to investigate this question, in a line of work that eventually led to their very influential 1978 book "The Hippocampus as a Cognitive Map". In addition to place cells, three further classes of spatial cell have since been identified in the hippocampal formation: head direction cells, grid cells, and boundary cells. As with the memory theory, there is now almost universal agreement that the hippocampal formation plays an important role in spatial coding, but the details are widely debated.


6-Nitroquipazine

6-Nitroquipazine (developmental code name DU-24,565) is a potent and selective serotonin reuptake inhibitor used in scientific research.
6-Nitroquipazine has been found to inhibit melanogenesis "in-vitro", suggesting that it can be used for skin whitening.


Transverse cervical nerve

The transverse cervical nerve (superficial cervical or cutaneous cervical) arises from the second and third spinal nerves, turns around the posterior border of the sternocleidomastoideus about its middle, and, passing obliquely forward beneath the external jugular vein to the anterior border of the muscle, it perforates the deep cervical fascia, and divides beneath the Platysma into ascending and descending branches, which are distributed to the antero-lateral parts of the neck. It provides cutaneous innervation to this area.
During dissection, the sternocleidomastoid (SCM) is the landmark. The transverse cervical nerves will pass horizontally directly over the SCM from Erb's point.


Jamshed Ansari

Jamshed Ansari () (31 December 1942 in Saharanpur – 24 August 2005 in Karachi) was a Pakistani film, television and radio actor. He is remembered for his numerous performances on both radio and television including Safdar in Hamid Mian Kay Haan and Hasnat Bhai on Uncle Urfi.
Background.
Born in Saharanpur, United Provinces, British India (now in UP, India) on 31 December 1942, to the family of a business tycoon, Zamir Hasan Ansari. Dubai Islamic Bank is the brainchild of Jamshed's older brother Tamiz. Ansari migrated with his family to Pakistan in 1948. Ansari was married and had three children, one son and two daughters.
Career.
Radio.
Ansari is remembered for his role as Safdar in Pakistan Radio's longest running programme, "Hamid Mian Kay Haan" (In Hamid Mian's house).
Television.
Ansari made his debut in 1968 with Lahore Centre's drama, "Jharokay." His first drama from Karachi Centre was Agha Nasir's "" ("The horse eats grass").
Death.
Ansari died of a brain tumour on 24 August 2005. Funeral prayers were held at Baitul Mukarram Mosque, Gulshan-e-Iqbal, Karachi followed by burial at Khurshidpura Graveyard in Hub, Balochistan.
Awards.
He was awarded 55 national and 2 international awards.


Sucrose intolerance

Sucrose intolerance or genetic sucrase-isomaltase deficiency (GSID) is the condition in which sucrase-isomaltase, an enzyme needed for proper metabolism of sucrose (sugar) and starch (e.g., grains), is not produced or the enzyme produced is either partially functional or non-functional in the small intestine. All GSID patients lack fully functional sucrase, while the isomaltase activity can vary from minimal functionality to almost normal activity. The presence of residual isomaltase activity may explain why some GSID patients are better able to tolerate starch in their diet than others with GSID.
Cause.
Sucrose intolerance can be caused by genetic mutations in which both parents must contain this gene for the child to carry the disease (so-called primary sucrose intolerance). Sucrose intolerance can also be caused by irritable bowel syndrome, aging, or small intestine disease (secondary sucrose intolerance). There are specific tests used to help determine if a person has sucrose intolerance. The most accurate test is the enzyme activity determination, which is done by biopsying the small intestine. This test is a diagnostic for GSID. Other tests which can aid in the diagnosis of GSID but which are not truly diagnostic for the disease are the sucrose breath test, and a genetic test which tests for the absence of certain genes which are thought to be responsible for GSID.
Sucrose (also called "saccharose") is a disaccharide and is a two-sugar chain composed of glucose and fructose which are bonded together. A more familiar name is table, beet, or cane sugar. It was believed that most cases of sucrose intolerance were due to an autosomal recessive, genetic, metabolic disease. Based on new data patients with heterozygous and compound heterozygous genotypes can have symptom presentation as well. GSID involves deficiency in the enzyme sucrase-isomaltase, which breaks the bond between the glucose and fructose molecules. When disaccharides are consumed, they must be broken down into monosaccharides by enzymes in the intestines before they can be absorbed. Monosaccharides, or single sugar units, are absorbed directly into the blood.
A deficiency of sucrase may result in malabsorption of sugar, which can lead to potentially serious symptoms. Since sucrase-isomaltase is involved in the digestion of starches, some GSID patients may not be able to absorb starches as well. It is important for those with sucrose intolerance to minimize sucrose consumption as much as possible. Dietary supplements or medications may be taken as a substitute for the missing enzyme or to introduce healthy bacteria into the immune system.
Diagnosis.
Chronic gastrointestinal symptoms that are fairly common but difficult to diagnose may be caused by congenital sucrase-isomaltase deficiency (CSID). CSID is an inherited condition characterized by a dysfunctional digestive enzyme.
The purpose of the digestive enzyme, sucrase-isomaltase, is to break down the compound sugars sucrose (table sugar) and starch sugars so they will be small enough to be absorbed from the gastrointestinal tract.
In addition to CSID, a primary gastrointestinal disorder such as a gastrointestinal infection, celiac disease or Crohn’s disease, can transiently suppress the digestive function of sucrase-isomaltase, causing an acquired form of sucrase-isomaltase deficiency (SID). Once the underlying disorder is treated and resolved, the symptoms of SID usually go away.
A deficiency or absence of sucrase-isomaltase function is likely to cause chronic gastrointestinal symptoms whenever a person eats food containing sucrose or starch sugars, which are very common in carbohydrates. In fact, the sucrase-isomaltase enzyme is responsible for the digestion of all foods containing sucrose and approximately 60% to 80% of all foods containing starch sugars. When sucrose or starch sugars are not absorbed from the gastrointestinal tract, they travel to the large intestine (colon) where two things happen:
The timing of gastrointestinal symptoms associated with CSID is distinctive. CSID symptoms are frequent, daily events; they are lifelong, and they are postprandial (occurring after eating food). These symptoms can range from mild to severe and include chronic, watery, acidic diarrhea; intestinal gas and bloating; nausea; and abdominal pain.
Infants may not show symptoms of CSID until they begin to eat sucrose- and starch-containing foods such as juices, solid foods, and medications sweetened with sucrose. Chronic, watery diarrhea and failure to thrive are the most common symptoms in infants and toddlers. Other symptoms include abdominal distention, gassiness, colic, irritability, excoriated buttocks, severe diaper rash due to acidic diarrhea, indigestion, and vomiting.
Adults with CSID are usually lean, with a low body-mass index and an aversion to eating carbohydrates and “sweets.” Because CSID is an inherited condition, patients with CSID often have close relatives who also experience chronic diarrhea.
Determining the cause of chronic gastrointestinal symptoms may take a long time because the symptoms can be common to many gastrointestinal conditions. One diagnostic method, considered the gold standard for diagnosing CSID, measures the level of activity of four intestinal enzymes that digest compound sugars, also called disaccharides. The four disaccharides digested in the small intestine are lactose, sucrose, maltose, and isomaltose.
This diagnostic method, called a disaccharidase assay, is conducted on tissue samples taken from the small intestine during an endoscopic procedure, also called an upper GI (gastrointestinal) examination. If the level of sucrase activity is below the level considered necessary for normal sucrase function, the patient will be diagnosed with CSID.
Noninvasive diagnostic methods include two breath tests, which can be useful screening tools but are not specific enough for a confirmed diagnosis of CSID.
The first of these is the hydrogen/methane breath test, which measures the amount of hydrogen and methane gases a person exhales after consuming sugary water. The exhaled breath is collected in sealed test tubes at 30-minute intervals over a three-hour period after drinking the sugary water. If a person has CSID and there are little or no working sucrase-isomaltase enzymes in the intestines, greater than normal levels of hydrogen and/or methane are generated and exhaled in the breath. However, there may be other reasons why the person is exhaling excess hydrogen and/or methane gas, such as an overgrowth of bacteria in the small intestine, called small intestinal bacterial overgrowth (SIBO).
The second breath test is called the carbon-13 (13C) breath test. Carbon-13 is a stable isotope of carbon that occurs naturally in sucrose, making it possible to track a person’s ability to digest and absorb sucrose by measuring the amount of 13CO2 exhaled after drinking a sugar-water solution. In this breath test, the exhaled breath is collected in sealed test tubes at 30-minute intervals over a 90-minute period after drinking the sugar-water solution. If the cumulative amount of 13CO2 exhaled is below the normal level that occurs when sucrose is digested by sucrase, the person may have CSID and the person should undergo further examination by their doctor.
The findings from a 13C-breath test are believed to be more definitive for CSID than the hydrogen/methane breath test although neither test is validated to provide, by themselves, a diagnosis for CSID. In both breath tests, the consumption of sugar may cause severe gastrointestinal symptoms in those who have CSID. For this reason, these breath tests should be conducted under the supervision of a healthcare professional.
A relatively new, noninvasive test that shows promise is a genetic test for the gene SI, which codes for the enzyme sucrase-isomaltase. This test requires a swab of tissue from the inside of the cheek. So far, 37 aberrant variations of the SI gene have been found in patients who have been diagnosed with CSID.
A positive genetic test for one or more of the 37 SI gene variations known to cause CSID can help confirm a diagnosis of CSID. However, a negative genetic test cannot rule out a diagnosis of CSID. There are more than 2,000 different variations of the SI gene, and many of these variations have not yet been investigated for their ability to cause CSID. Therefore, a negative genetic test only means that the person does not carry one of the 37 SI gene variations that are known to be associated with CSID, but they may have an SI gene variation that has not yet been identified as one that can cause CSID.
While the breath tests and genetic test have not been validated to be diagnostic for CSID, they may become important tests that help in identifying patients with CSID. As with all diagnoses, a diagnosis of CSID depends on combining a doctor’s clinical findings with results from objective tests. A physical examination, medical history, and other secondary tests, such as stool pH test for acidic stool, can aid in the diagnosis of CSID.
If it is clinically inappropriate or difficult to perform a biopsy or if a CSID diagnosis is in doubt, a physician may suggest a two-week therapeutic trial with an enzyme replacement. If the patient shows a reduction of symptoms it is considered diagnostic for CSID.
Treatment.
The two ways to manage the gastrointestinal symptoms associated with CSID are:
Diet modification.
The level of ability to digest sucrose or starch sugars is unique to each person who is living with CSID and depends on many factors, including the following:
For these reasons, a restriction diet needs to be specific for each patient who has CSID. Before making any changes to the diet, it is important for a patient to speak with a healthcare provider, especially if the patient is underweight or not gaining weight as would be expected.
It is also advised that the patient work with a registered dietitian or nutritionist who can help identify the foods that can be tolerated and those that cannot be tolerated. A registered dietitian or nutritionist can also help the patient plan a diet that will meet the nutritional needs for normal growth and development. Vitamins, minerals, and additional supplements may be needed to meet all nutritional needs.
Epidemiology.
The highest prevalence rates are seen in the Inuit populations of Greenland (5–10%), Alaska (3–7%) and Canada (about 3%). European descent prevalence ranges from 0.2% to 0.05%. There is a lower prevalence reported in African Americans and Hispanics compared to Caucasians.


Rivoglitazone

Rivoglitazone (INN) is a thiazolidinedione derivative undergoing research for use in the treatment of type 2 diabetes.
It is being developed by Daiichi Sankyo.


Spinal fracture

A spinal fracture, also called a vertebral fracture or a broken back, is a fracture affecting the vertebrae of the spinal column. Most types of spinal fracture confer a significant risk of spinal cord injury. After the immediate trauma, there is a risk of spinal cord injury (or worsening of an already injured spine) if the fracture is "unstable", that is, likely to change alignment without internal or external fixation.
Cervical fracture.
A medical history and physical examination can be sufficient in clearing the cervical spine. Notable clinical prediction rules to determine which patients need medical imaging are Canadian C-spine rule and the National Emergency X-Radiography Utilization Study (NEXUS).
The AO Foundation has developed a descriptive system for cervical fractures, the "AOSpine subaxial cervical spine fracture classification system".
The indication to surgically stabilize a cervical fracture can be estimated from the "Subaxial Injury Classification" (SLIC).
Thoracolumbar fracture.
Vertebral fractures of the thoracic vertebrae, lumbar vertebrae or sacrum are usually associated with major trauma and can cause spinal cord injury that results in a neurological deficit.
Thoracolumbar injury classification and severity score.
The thoracolumbar injury classification and severity score (TLICS) is a scoring system to determine the need to surgically treat a spinal fracture of thoracic or lumbar vertebrae. The score is the sum of three values, each being the score of the most fitting alternative in three categories:
Injury type
Posterior ligamentous complex
Neurology
A TLICS score of less than 4 indicates non-operative treatment, a score of 4 indicates that the injury may be treated operatively or non-operatively, while a score of more than 4 means that the injury is usually considered for operative management.
AOSpine Thoracolumbar Injury Classification System.
AOSpine Thoracolumbar Injury Classification System (ATLICS) is the most recent classification scheme for thoracolumbar injuries. ATLICS is broadly based on the TLICS system and has sufficient reliability irrespective of the experience of the observer. ATLICS is primarily focused on fracture morphology, and has two additional sections addressing the neurological grading and clinical modifiers:


Reticulotegmental nucleus

The reticulotegmental nucleus, tegmental pontine reticular nucleus (or pontine reticular nucleus of the tegmentum) is an area within the floor of the midbrain. This area is known to affect the cerebellum with its axonal projections.
These afferent connections have been proven to project not only ipsilaterally, but also to decussate and project to the contralateral side of the vermis.
It has also been shown that the projections from the pontine tegmentum to the cerebellar lobes are only crossed fibers.
The reticulotegmental nucleus also receives efferent axons from the cerebellum.
This nucleus is known for its large number of multipolar cells and its particularly reticular structure.
The reticulotegmental nucleus is topographically related to pontine nuclei (non-reticular), being just dorsal to them.
The reticulotegmental nucleus has been known to mediate eye movements, otherwise known as saccadic movement. This makes sense concerning their connections, as it would require a nucleus that receives and projects to the cerebellum to mediate that kind of complex circuitry. Furthermore, in terms of behavior, one does not "think" about saccadic movements when scanning a room, as the saccadic movements are not directly controlled by the cortex.
The pontine nuclei are the most traditionally studied mostly because it is easy to see which nuclei degrade when the cerebellum is amputated.
The neurons of the lateral reticular formation are very important for reflexes and the mediation of posture. It has been shown in cats that electrical stimulation of the reticular formation can make a standing cat lie down. Also, stimulation of the cat in an alternative spot can make a lying cat stand.


Vasomotor center

The vasomotor center (VMC) is a portion of the medulla oblongata. Together with the cardiovascular center and respiratory center, it regulates blood pressure. It also has a more minor role in other homeostatic processes. Upon increase in carbon dioxide level at central chemoreceptors, it stimulates the sympathetic system to constrict vessels. This is opposite to carbon dioxide in tissues causing vasodilatation, especially in the brain. Cranial nerves IX (glossopharyngeal nerve) and X (vagus nerve) both feed into the vasomotor centre and are themselves involved in the regulation of blood pressure.
Structure.
The vasomotor center is a collection of integrating neurons in the medulla oblongata of the middle brain stem. The term "vasomotor center" is not truly accurate, since this function relies not on a single brain structure ("center") but rather represents a network of interacting neurons.
Afferent fibres.
The vasomotor center integrates nerve impulses from many places via the solitary nucleus:
Efferent fibres.
The vasomotor center gives off sympathetic fibres through the spinal cord and sympathetic ganglia, which reach vascular smooth muscle.
Function.
The vasomotor center changes vascular smooth muscle tone. This changes local and systemic blood pressure.
A drop in blood pressure leads to increased sympathetic tone from the vasomotor center. This acts to raise blood pressure.
Clinical significance.
Methyldopa acts on the vasomotor center, leading to selective stimulation of α2-adrenergic receptor. Guanfacine also causes the same stimulation. This reduces sympathetic tone to vascular smooth muscle. This reduces heart rate and vascular resistance.
Digoxin increases vagal tone from the vasomotor centre, which decreases pulse.
G-series nerve agents have their most potent effect in the vasomotor center. Unlike other parts of the body, where continued stimulation of acetylcholine receptors leads to recoverable paralysis, overstimulation of the vasomotor center is often causes a fatal rise in blood pressure.
History.
The localization of vasomotor center was determined by Filipp Ovsyannikov in 1871.


Neural fold

The neural fold is a structure that arises during neurulation in the embryonic development of both birds and mammals among other organisms. This structure is associated with primary neurulation, meaning that it forms by the coming together of tissue layers, rather than a clustering, and subsequent hollowing out, of individual cells (known as secondary neurulation). In humans, the neural folds are responsible for the formation of the anterior end of the neural tube. The neural folds are derived from the neural plate, a preliminary structure consisting of elongated ectoderm cells. The folds give rise to neural crest cells, as well as bringing about the formation of the neural tube.
Development.
In the embryo, the formation of the neural folds originates from the area where the neural plate and the surrounding ectoderm converge. This region of the embryo is formed after gastrulation, and consists of epithelial tissue. Here, the epithelial cells elongate by means of microtubule polymerization, increasing their height. The thumbnail below shows this process, as well as the subsequent formation of the neural crest cells and the neural tube, which arise from the joining of the neural folds.
Folding.
The formation of the neural fold is initiated by the release of calcium from within the cells. The released calcium interacts with proteins that can modify the actin filaments in the outer epithelial tissue, or ectoderm, in order to induce the dynamic cell movements necessary to create the fold. These cells are held together by cadherins (specifically E and N-cadherin), types of intercellular binding protein. When the cells at the peaks of the neural folds come in proximity with each other, it is the affinity for similar cadherin molecules (N-cadherins) that allows these cells to bind to each other. Thus, when the neural tube precursor cells begin expressing N-cadherin in the place of E-cadherin, this causes the neural tube to form and separate from the ectoderm and settle inside the embryo. When the cells fail to associate in a manner that is not part of the normal course of development, severe diseases can occur.
Process overview.
The process of folding begins when the cells in the central region of the neural plate, the medial hinge point cells, bind to the notochord beneath them. This creates a central anchoring point for the process of folding to occur, and subsequently creates the neural groove. As the neural folds continue to extend, dorsolateral hinge points form, allowing the folds to curve into a tube-like structure. When the peaks of the folds (known as the neural crest regions) touch, they merge and involute, creating the neural tube beneath the newly formed epidermal layer.
Mechanism.
The molecular mechanism behind this process lies in the expression and repression of bone morphogenetic proteins (BMPs). BMPs are a wide family of proteins that perform many functions throughout the growing embryo, including stimulating the growth of cartilage and bone. In order to allow for the growth of precursor neural tissues, as opposed to precursor bone or cartilage tissues, BMP expression is decreased in the neural plate, specifically along the medial line, where the neural groove will soon form.
The proteins produced from the genes "Noggin" and "Chordin" inhibit these BMPs, and subsequently allow neural commitment genes, like "SOX", to be expressed. These genes encode transcription factors, which alter the genomic expression of these cells, furthering them along the path of neural cell commitment.
This process of BMP inhibition allows for the anchoring of the medial hinge point cells, providing the neural folds with the foundation necessary for folding and closure to occur. "Noggin" and "Chordin" have other roles in the neurulation process, including stimulating the neural crest cells to emigrate from the newly formed neural tube.
The "Sonic hedgehog" gene also plays a role in attenuating BMP expression, forming the medial hinge point while inhibiting the formation of the dorsolateral hinge points, and in ensuring the proper closure of the neural folds.
The prechordal plate, notochord, and non-neural ectoderm are believed to be important inducer tissues which release these chemical signals, in order to trigger neural plate folding.
The final adhesion of the converging neural folds is due to several different types of intercellular binding proteins. Cadherins and their CAM receptor molecules, for example, are present in two types in the neural precursor tissue: E-cadherin keeps the cells of the neural plate and surrounding ectoderm adhered to each other, while N-cadherin does the same for the cells of the neural fold. Only cells expressing the same kind of cadherin can bind to each other; since the peaks of the neural folds both express N-cadherin, they are able to merge into a continuous sheet of cells. Likewise, it is this diminished affinity between cells expressing different types of cadherin that allows the neural tube precursor cells to separate from the ectoderm, forming the neural tube on the interior of the embryo and the true epidermis on the exterior.
Another set of molecules involved with the merging of the neural folds are the ephrin molecules and their Eph receptors, which adhere in a similar manner to the cadherin molecules discussed above.
Derivative structures.
The merging of the neural folds gives rise to many structures including: the neural tube (the precursor to the central nervous system), neural crest cells(which give rise to a variety of diverse mesenchymal cells), and to the true epidermal layer. The neural fold is an extremely important structure in that this mechanism is needed to produce these diverse kinds of cells in the right places.
Clinical significance.
There are many potential diseases that can arise from the improper adhesion or merging of the neural folds. During folding, the openings that are formed at the cranial and caudal regions are termed the cranial and caudal neuropores. If the caudal neuropore fails to close, a condition called spina bifida can occur, in which the bottom of the spinal cord remains exposed. Often this condition can be detected during prenatal examinations and be treated before birth, though in more severe cases the individual may cope with the condition for the rest of his or her life. Depending on the severity and the affected area, individuals can experience a variety of symptoms, including a varying motor function and mobility, bladder control, and/or sexual function.
If the failure is instead in the cranial neuropore, anencephaly occurs. In this condition, the brain tissue is directly exposed to the amniotic fluid, and is subsequently degraded.
If the entire neural tube fails to close, the condition is referred to as craniorachischisis.


Histamine H2 receptor

H2 receptors are positively coupled to adenylate cyclase via Gs. It is a potent stimulant of cAMP production, which leads to activation of protein kinase A. PKA functions to phosphorylate certain proteins, affecting their activity. The drug betazole is an example of a histamine H2 receptor agonist.
Function.
Histamine is a ubiquitous messenger molecule released from mast cells, enterochromaffin-like cells, and neurons. Its various actions are mediated by histamine receptors H1, H2, H3 and H4. The histamine receptor H2 belongs to the rhodopsin-like family of G protein-coupled receptors. It is an integral membrane protein and stimulates gastric acid secretion. It also regulates gastrointestinal motility and intestinal secretion and is thought to be involved in regulating cell growth and differentiation.
Tissue distribution.
Histamine H2 receptors are expressed in the following tissues:
Physiological responses.
Activation of the H2 receptor results in the following physiological responses:


Ciglitazone

Ciglitazone (INN) is a thiazolidinedione. Developed by Takeda Pharmaceuticals in the early 1980s, it is considered the prototypical compound for the thiazolidinedione class.
Ciglitazone was never used as a medication, but it sparked interest in the effects of thiazolidinediones. Several analogues were later developed, some of which—such as pioglitazone and troglitazone—made it to the market.
Ciglitazone significantly decreases VEGF production by human granulosa cells in an in vitro study, and may potentially be used in ovarian hyperstimulation syndrome.
Ciglitazone is a potent and selective PPARγ ligand. It binds to the PPARγ ligand-binding domain with an EC50 of 3.0 μM. Ciglitazone is active in vivo as an anti-hyperglycemic agent in the ob/ob murine model. Inhibits HUVEC differentiation and angiogenesis and also stimulates adipogenesis and decreases osteoblastogenesis in human mesenchymal stem cells.


5-HT5A receptor

5-Hydroxytryptamine (serotonin) receptor 5A, also known as HTR5A, is a protein that in humans is encoded by the "HTR5A" gene. Agonists and antagonists for 5-HT receptors, as well as serotonin uptake inhibitors, present promnesic (memory-promoting) and/or anti-amnesic effects under different conditions, and 5-HT receptors are also associated with neural changes.
Function.
The gene described in this record is a member of 5-hydroxytryptamine receptor family and encodes a multi-pass membrane protein that functions as a receptor for 5-hydroxytryptamine and couples to G proteins, negatively influencing cAMP levels via Gi and Go. This protein has been shown to function in part through the regulation of intracellular Ca2+ mobilization. The 5-HT5A receptor has been shown to be functional in a native expression system.
Rodents have been shown to possess two functional 5-HT5 receptor subtypes, 5-HT5A and 5-HT5B, however while humans possess a gene coding for the 5-HT5B subtype, its coding sequence is interrupted by stop codons, making the gene non-functional, and so only the 5-HT5A subtype is expressed in human brain.
It also appears to serve as a presynaptic serotonin autoreceptor.
Clinical significance.
The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been implicated in a wide range of psychiatric conditions and also has vasoconstrictive and vasodilatory effects.
Selective Ligands.
Few highly selective ligands are commercially available for the 5-HT5A receptor. When selective activation of this receptor is desired in scientific research, the non-selective serotonin receptor agonist 5-Carboxamidotryptamine can be used in conjunction with selective antagonists for its other targets (principally 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT7). Research in this area is ongoing.


Parabutoxin

Parabutoxin (PBTx) is a Shaker-related voltage-gated K+ channel (Kvα1) inhibitor purified from different "Parabuthus" scorpion species found in southern Africa. It occurs in different forms: parabutoxin 1 (PBTx1), parabutoxin 2 (PBTx2), parabutoxin 3 (PBTx3) and parabutoxin (PBTx10). The different variants have different affinities towards Kvα1 channels.
Sources.
Four different acidic peptides (PBTx1, PBTx2, PBTx3 and PBTx10) have been isolated and cloned from the venoms of three different "Parabuthus" scorpion species found in southern Africa. PBTx1 and PBTx3 were extracted from the venom of "P. transvaalicus", PBTx2 from "P. villosus" and PBTx10 has been purified from "P. granulatus".
Chemistry.
Scorpion toxins that target potassium channels have been classified into three K+ Toxin (KT) subfamilies α-KTx, β-KTx, and γ-KTx peptides. The α-KTx subfamilies are the best-studied toxins and are usually small basic “short chain toxins”. PBTx1, PBTx2 and PBTx10 structurally belong to an unusually acidic α-KTx short chain scorpion toxins subfamily and are classified as KTx11, α-KTx11.1 (PBTx1), α-KTx11.2 (PBTx2) and α-KTx11.3 (PBTx10).
PBTx1, PBTx2 and PBTx10 toxins have extremely low pI values of 3.82 (PBTx1 and PBTx2) and 3.88 (PBTx10). The toxins are 36-37 amino acids in length and have six aligned cysteine residues. Usually, binding sites of Kvα1-blocking toxins (Kv1.1, Kv1.2, Kv1.3) include a lysine and a hydrophobic residue, but PBTx1, PBTx2 and PBTx10 lack the crucial pore-plugging lysine and have either Val (PBTx1, PBTx2) or Ala (PBTx10) as a substitute.
PBTx3 is the tenth member of subfamily 1 (α-KTx1.10) of K+ channel-blocking peptides. The framework of PBTx3 is homologous to most other α-KTx scorpion toxins. PBTx3 has a mass of 4274 Da and consists of 37 amino acid residues with a well-conserved three-dimensional structure, stabilized by three disulphide bridges.
Target.
Parabutoxins block Shaker-related voltage-gated potassium channels members 1,2 and 3 (Kv1.1, Kv1.2 and Kv1.3 channels). These channels have different functions that include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction and cell volume. PBTxs have a weak affinity towards Kvα1 channels. The dissociation constants (Kd) for Kv1.1, Kv1.2 and Kv1.3 channels are, respectively, 21.1 μM, 1.0 μM and 0.8 μM in the case of PBTx1 and 79 μM, 500 nM and 500 nM for PBTx3.
Mode of action.
Most of the α-KTxs have a positively charged lysine residue, which blocks the pore of the Kvα1 channels, and a hydrophobic residue (mostly Phe or Tyr), which seems crucial in blocking the Kvα1 channels. PBTx1, PBTx2, PBTx3 and PBTx10 lack the hydrophobic residue and PBTx1, PBTx2 and PBTx10 also lack the lysine. The missing of these residues may explain their low affinity towards the Kvα1 channels. A PBTx3 mutant containing the hydrophobic residue indeed had an affinity that was up to 100 times higher than the wild-type PBTx3. A PBTx1 mutant containing the lysine residue had an affinity for the Kvα1 channels in the nanomolar range. The place of interaction between the toxin and the Kvα1 channel is most probably the P region between the fifth and sixth transmembrane segments. Experiments with a recombinant PBTx show a concentration dependency that suggests that the channel is blocked by a single peptide. The blockade is voltage-independent, which suggests that the toxin does not affect the gating characteristics.


Uniform k-CFA


MMAI

5-Methoxy-6-methyl-2-aminoindane (MMAI) is a drug developed in the 1990s by a team led by David E. Nichols at Purdue University. It acts as a non-neurotoxic and highly selective serotonin releasing agent (SSRA) and produces entactogen effects in humans. It has been sold as a designer drug and research chemical online since 2010.
MMAI has been shown to relieve stress-induced depression in rats more robustly than sertraline, and as a result it has been suggested that SSRAs like MMAI and 4-MTA could be developed as novel antidepressants with a faster onset of therapeutic action and superior efficacy to current antidepressants such as the selective serotonin reuptake inhibitors (SSRIs).


Coranto

Corantos were early informational broadsheets, precursors to newspapers. Beginning around the 14th century, a system developed where letters of news and philosophical discussion would be sent to a central collecting point to be bundled and sent around to the various correspondents. The banking house of Fugger had an organized system of collecting and routing these letters, which often could be seen by outsiders. This system would not die until the 18th century. The term "newspaper" was not coined till 1670. Prior to this, a welter of terms were used to describe this genre, including "paper", "newsbook", "pamphlet", "broadsheet", and "coranto".


Sodium channel blocker

Sodium channel blockers are drugs which impair the conduction of sodium ions (Na+) through sodium channels.
Extracellular.
The following naturally-produced substances block sodium channels by binding to and occluding the extracellular pore opening of the channel:
Intracellular.
Drugs which block sodium channels by blocking from the intracellular side of the channel include:
Antiarrhythmic.
Sodium channel blockers are used in the treatment of cardiac arrhythmia. They are classified as "Type I" in the Vaughan Williams classification.
Class I antiarrhythmic agents interfere with the (Na+) channel.
Class I agents are grouped by their effect on the Na+ channel, and by their effect on cardiac action potentials.
Class I agents are called Membrane Stabilizing Agents. 'Stabilizing' refers to the decrease of excitogenicity of the plasma membrane affected by these agents. A few class II agents, propranolol for example, also have a membrane stabilizing effect.
Class Ia agents.
Class Ia agents block the fast sodium channel, which depresses the phase 0 depolarization (i.e. reduces Vmax), which prolongs the action potential duration by slowing conduction.
Agents in this class also cause decreased conductivity and increased refractoriness.
Indications for Class Ia agents are supraventricular tachycardia, ventricular tachycardia, symptomatic ventricular premature beats, and prevention of ventricular fibrillation.
Procainamide can be used to treat atrial fibrillation in the setting of Wolff-Parkinson-White syndrome, and to treat wide complex hemodynamically stable tachycardias. Oral procainamide is no longer being manufactured in the US, but intravenous formulations are still available.
While procainamide and quinidine may be used in the conversion of atrial fibrillation to normal sinus rhythm, they should only be used in conjunction with an AV node blocking agent such as digoxin or verapamil, or a beta blocker), because procainamide and quinidine can increase the conduction through the AV node and may cause 1:1 conduction of atrial fibrillation, causing an increase in the ventricular rate.
Class Ia agents include quinidine, procainamide and disopyramide.
Class Ib agents.
Class Ib antiarrhythmic agents are sodium channel blockers. They have fast onset and offset kinetics, meaning that they have little or no effect at slower heart rates, and more effects at faster heart rates. Class Ib agents shorten the action potential duration and reduce refractoriness. These agents will decrease Vmax in partially depolarized cells with fast response action potentials. They either do not change the action potential duration, or they may decrease the action potential duration. Class Ib drugs tend to be more specific for voltage gated Na channels than Ia. Lidocaine in particular is highly frequency dependent, in that it has more activity with increasing heart rates. This is because lidocaine selectively blocks Na channels in their open and inactive states and has little binding capability in the resting state.
Class Ib agents are indicated for the treatment of ventricular tachycardia and symptomatic premature ventricular beats, and prevention of ventricular fibrillation.
Class Ib agents include lidocaine, mexiletine, tocainide, and phenytoin.
Class Ic agents.
Class Ic antiarrhythmic agents markedly depress the phase 0 depolarization (decreasing Vmax). They decrease conductivity, but have a minimal effect on the action potential duration. Of the sodium channel blocking antiarrhythmic agents (the class I antiarrhythmic agents), the class Ic agents have the most potent sodium channel blocking effects.
Class Ic agents are indicated for supraventricular arrhythmias (i.e. atrial fibrillation) and as a last line treatment for refractory life-threatening ventricular tachycardia or ventricular fibrillation. These agents are potentially pro-arrhythmic, especially in settings of structural heart disease (e.g. post-myocardial infarction), and are contraindicated in such settings.
Class Ic agents include encainide, flecainide, moricizine, and propafenone. Encainide is not available in the United States.
Other uses.
Sodium channel blockers are also used as local anesthetics and anticonvulsants.
Sodium channel blockers have been proposed for use in the treatment of cystic fibrosis, but current evidence is mixed.
It has been suggested that the analgesic effects of some antidepressants may be mediated in part via sodium channel blockade.
Voltage-dependent sodium channel blockers are used as insecticides, comprising Insecticide Resistance Action Committee (IRAC) mechanism of action group 22. these are two, indoxacarb (22A, the oxadiazines) and metaflumizone (22B, the semicarbazones).
Future prospects.
Selective blockers of Nav1.7 and Nav1.8 voltage-gated sodium channels, such as CNV1014802 and Funapide, are being investigated as novel analgesics.