SUMMARY / RELATED TOPICS

Acetylcholine

Acetylcholine is an organic chemical that functions in the brain and body of many types of animals as a neurotransmitter—a chemical message released by nerve cells to send signals to other cells, such as neurons, muscle cells and gland cells. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic. Substances that interfere with acetylcholine activity are called anticholinergics. Acetylcholine is the neurotransmitter used at the neuromuscular junction—in other words, it is the chemical that motor neurons of the nervous system release in order to activate muscles; this property means that drugs that affect cholinergic systems can have dangerous effects ranging from paralysis to convulsions. Acetylcholine is a neurotransmitter in the autonomic nervous system, both as an internal transmitter for the sympathetic nervous system and as the final product released by the parasympathetic nervous system.

Acetylcholine is the primary neurotransmitter of the parasympathetic nervous systems. In the brain, acetylcholine functions as a neurotransmitter and as a neuromodulator; the brain contains a number of cholinergic areas, each with distinct functions. Acetylcholine, has been traced in cells of non-neural origins and microbes. Enzymes related to its synthesis and cellular uptake have been traced back to early origins of unicellular eukaryotes; the protist pathogen Acanthamoeba spp. has shown the presence of ACh, which provides growth and proliferative signals via a membrane located M1-muscarinic receptor homolog. Because of its muscle-activating function, but because of its functions in the autonomic nervous system and brain, many important drugs exert their effects by altering cholinergic transmission. Numerous venoms and toxins produced by plants and bacteria, as well as chemical nerve agents such as Sarin, cause harm by inactivating or hyperactivating muscles via their influences on the neuromuscular junction.

Drugs that act on muscarinic acetylcholine receptors, such as atropine, can be poisonous in large quantities, but in smaller doses they are used to treat certain heart conditions and eye problems. Scopolamine, which acts on muscarinic receptors in the brain, can cause delirium and amnesia; the addictive qualities of nicotine are derived from its effects on nicotinic acetylcholine receptors in the brain. Acetylcholine is a choline molecule, acetylated at the oxygen atom; because of the presence of a polar, charged ammonium group, acetylcholine does not penetrate lipid membranes. Because of this, when the drug is introduced externally, it remains in the extracellular space and does not pass through the blood–brain barrier. A synonym of this drug is miochol. Acetylcholine is synthesized in certain neurons by the enzyme choline acetyltransferase from the compounds choline and acetyl-CoA. Cholinergic neurons are capable of producing ACh. An example of a central cholinergic area is the nucleus basalis of Meynert in the basal forebrain.

The enzyme acetylcholinesterase converts acetylcholine into the inactive metabolites choline and acetate. This enzyme is abundant in the synaptic cleft, its role in clearing free acetylcholine from the synapse is essential for proper muscle function. Certain neurotoxins work by inhibiting acetylcholinesterase, thus leading to excess acetylcholine at the neuromuscular junction, causing paralysis of the muscles needed for breathing and stopping the beating of the heart. Acetylcholine functions in both the central nervous system and the peripheral nervous system. In the CNS, cholinergic projections from the basal forebrain to the cerebral cortex and hippocampus support the cognitive functions of those target areas. In the PNS, acetylcholine activates muscles and is a major neurotransmitter in the autonomic nervous system. Like many other biologically active substances, acetylcholine exerts its effects by binding to and activating receptors located on the surface of cells. There are two main classes of acetylcholine receptor and muscarinic.

They are named for chemicals that can selectively activate each type of receptor without activating the other: muscarine is a compound found in the mushroom Amanita muscaria. Nicotinic acetylcholine receptors are ligand-gated ion channels permeable to sodium and calcium ions. In other words, they are ion channels embedded in cell membranes, capable of switching from a closed to an open state when acetylcholine binds to them. Nicotinic receptors come in two main types, known as neuronal-type; the muscle-type can be selectively blocked by the neuronal-type by hexamethonium. The main location of muscle-type receptors is on muscle cells. Neuronal-type receptors are located in autonomic ganglia, in the central nervous system. Muscarinic acetylcholine receptors have a more complex mechanism, affect target cells over a longer time frame. In mammals, five subtypes of muscarinic receptors have been identified, labeled M1 through M5. All of them function as G protein-coupled receptors, meaning that they exert their effects via a second messenger system.

The M1, M3, M5 subtypes are Gq-coupled. Their effect on target cells is excitatory; the M2 and M4 subtypes are Gi/Go-coupled. Their effect on target cells is inhibito

Drugs for Neglected Diseases Initiative

The Drugs for Neglected Diseases initiative is a collaborative, patients’ needs-driven, non-profit drug research and development organization, developing new treatments for neglected diseases, notably leishmaniasis, sleeping sickness, Chagas disease, filarial diseases, paediatric HIV, hepatitis C. DNDi's malaria activities were transferred to Medicines for Malaria Venture in 2015. Led by Executive Director Bernard Pécoul, DNDi is headquartered in Geneva, with offices in Brazil, the Democratic Republic of Congo, Japan, Malaysia, South Africa, an affiliate in the United States. Despite the major progress achieved in medicine during the past 50 years, many tropical diseases affecting the poorest are still neglected. More than a billion people – more than a seventh of the world’s population – are infected with one of the 20 diseases listed by the World Health Organization as neglected tropical diseases. Although neglected tropical diseases can be fatal, there is a lack of modern and effective medications to treat these illnesses.

Evidence of the lack of new drugs for diseases that cause high mortality and morbidity among people living in poor areas has been published in the scientific literature. One publication reported that only 1.1% of new drugs were approved for neglected diseases over a period of 25 years despite the fact that these diseases represented 11.4% of the global burden. Another indicated that this trend remained the same between 2000 and 2011 with only 1.2% of the new chemical entities brought to market indicated for neglected diseases. DNDi was created in 2003 to develop new treatments for neglected diseases; the organization was set up by key research and health institutions, notably from the public sector in neglected-disease-endemic countries - the Oswaldo Cruz Foundation from Brazil, the Indian Council of Medical Research, the Kenya Medical Research Institute, the Ministry of Health of Malaysia and France’s Pasteur Institute, with seed funding from Médecins Sans Frontières' 1999 Nobel Peace Prize.

The WHO Special Programme for Research and Training in Tropical Diseases acts as a permanent observer to the initiative. As people suffering from neglected diseases do not represent a lucrative market for pharmaceutical companies, incentives to invest in research and development are lacking for these diseases. Alternatives to profit-driven drug development emerged in the early 2000's to meet the needs of these neglected patients. Product development partnerships called public-private partnerships aim to implement and accelerate research and development into health tools for diseases that are neglected, by enabling new collaborations between private industry and the public sector. Examples of PDPs include the International AIDS Vaccine Initiative, MMV, the Global Alliance for TB Drug Development, DNDi. PDPs act as ‘conductors of a virtual orchestra’, leveraging partners’ specific assets and expertise to implement projects at all stages of the R&D process, integrating capabilities from academia.

To overcome the lack of commercial research into drug development, PDPs can apply “delinkage” principles that aim to separate the cost of research and development from the price of products. This allows the incentive for investing in a particular disease to be independent of the price at which any developed products will be sold. To date, DNDi has delivered eight new treatments and built a large drug pipeline for neglected diseases with both improvements on existing drugs and new chemical entities. Treatments delivered to date: Launched in 2007, this antimalarial product is a fixed-dose combination of artesunate/amodiaquine; the result of a partnership between DNDi and French pharmaceutical company Sanofi, ASAQ, produced in Morocco, is affordable, is administered in a simple regimen, meets the latest WHO guidelines for malaria treatment in Africa and was granted "pre-qualified" status in 2008. Although developed without a patent, ASAQ is included in the WHO Model List of Essential Medicines and Essential Medicines List for Children, is registered in 32 African countries, Ecuador, in Colombia, more than 437 million treatments have been distributed.

A technology transfer agreement has been signed with industrial partner Zenufa in Tanzania in order to provide an additional source of ASAQ. ASAQ was handed over to the MMV Access and Product Management Team in May 2015; the second antimalarial treatment developed by DNDi is a fixed-dose combination of artesunate and mefloquine launched in 2008. It was developed by an international collaboration within the FACT Project Consortium, it has a simple and adapted regimen, a three-year shelf-ife and a high compliance rate. ASMQ is produced in Brazil by Farmanguinhos/Fiocruz and thanks to a South–South technology transfer, it is now produced by Cipla; the latter was granted "pre-qualified" status by the WHO in 2012 and included on the WHO Model List of Essential Medicines and Essential Medicines List for Children in 2013. By 2015 it was registered in Brazil, Malaysia, Tanzania, Niger, Burkina Faso and Cambodia. By the end of 2015 more than one million treatments had been distributed. ASMQ was handed over to the MMV Access and Product Management Team in May 2015.

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St. Rumbold's Cathedral

St. Rumbold's Cathedral is the Belgian metropolitan archiepiscopal cathedral in Mechelen, dedicated to Saint Rumbold, Christian missionary and martyr who had founded an abbey nearby, his remains are rumoured to be buried inside the cathedral. State-of-the-art examination of the relics honoured as Saint Rumbold's and kept in a shrine in the retro-choir, showed a life span of about 40 years and a death date between 580 and 655, while tradition had claimed 775 AD. Construction of the church itself started shortly after 1200, it was consecrated in 1312, when part had become usable. From 1324 onwards the flying buttresses and revised choir structure acquired characteristics that would distinguish Brabantine Gothic from French Gothic. After the city fire of 1342, the Master Mason Jean d'Oisy managed repairs and continued this second phase, which by the time of his death in 1375 formed the prototype for that High Gothic style, his successors finished the vaults of the nave by 1437, those of the choir by 1451.

During the final phase of 1452-1520, the tower was erected, financed by pilgrims and by its proprietor, the City. Designed to reach 600 Mechlinian feet or about 167 metres, higher than any church tower would attain, the heavy St. Rumbold's tower was built on what had once been wetlands, though with foundations only three metres deep its site appears to have been well-chosen. After a few years, in 1454, its chief architect Andries I Keldermans constructed the Saint Livinus' Monster Tower in Zierikzee, where leaning or sagging of the tower could wreck the church; this concern led to separate edifices, a solution applied in Mechelen. At both places, in the early 16th century the upper part of the tower was abandoned, not for technical but for financial reasons. St-Rumbold's should have been topped by a 77-metre spire but only seven metres of this were built, hence the unusual shape. A deliberately weak connection closed the gap between tower and church upon finishing the construction; the church has functioned as a cathedral since 1559.

In the 18th century, each capital's surrounding ornament of sculpted cabbage leaves, an inspiration for numerous Brabantine Gothic churches, was replaced with a double ring of crops. In 2005, after engineers had figured out the support capacity of ground and tower, there was talk of completing the entire spire from the original drawings; the flat-topped silhouette of the cathedral's tower is recognizable and dominates the surroundings. For centuries it held the city documents, served as a watchtower, could sound the fire alarm. Despite its characteristic incompleteness, this World Heritage monument is 97.28 metres high and its 514 steps are mounted by thousands of tourists every year, following the footsteps of Louis XV, King Albert I, King Baudouin with queen Fabiola in 1981. Of the original carillon's set of 49 bells, which are still in working order, each has its own name; some of the most notable are Salvator. Thirty-nine steps above this instrument, there is a second complete carillon on which concerts are played during the summer months.

The total weight of both these carillons is over 80 tonnes and there are 98 bells in all. Many of the region's cities have a nickname for their populace; the Mechlinians are said to have had ancestors running up their great Tower and passing on buckets of water to extinguish a blazing fire behind the perpendicular windows, where it turned out to be mere moonlight through sprightly clouds, hence are called Maneblussers. The main entrance, underneath the tower, leads into the nave of the cathedral. Apart from small heraldic shields dating from the Thirty Knights of the Golden Fleece chapter meetings presided in the church by young Philip the Handsome while his Burgundian inheritance was still under guardianship of his father, few original movables survive. Forty preciously decorated Gothic altars and all other furniture disappeared during the religious troubles of 1566-1585. Though the cathedral was spared in the 1566 Iconoclasm, Mechelen was sacked in the 1572 three-days Spanish Fury by slaughtering troops under command of Alva's son Fadrique, suffered the English Fury of pillaging by rampant mercenaries in the service of the States General in 1580.

The interior features a Baroque high altar and choir by Lucas Faydherbe, as well as paintings by Anthony van Dyck, sculptures by Lucas Faydherbe, Michiel Vervoort, stained-glass windows, including one depicting —though with a white face— the Black Madonna painting in the church. In 2010, prior to the construction of an underground car park by Saint Rumbold's north side, 4,165 skeletons were unearthed during archeological excavations of the cemetery. St. Rumbold's was the venue for the 2008 wedding of Count Rodolphe de Limburg Stirum to Archduchess Marie-Christine of Austria, daughter of Princess Marie-Astrid of Luxembourg. In 1985, on his 65th birthday, Pope John Paul II celebrated a mass at St. Rumbold's. Jo Haazen the City's carillon player, heard him state: "Your tower is not complete." Flor Peeters, cathedral organist between 1923–1986 Brussels Cathedral site "MECHELEN: Saint-Rumbold's Tower". Trabel: Belgium Travel Network, Belgium. Retrieved 28 July 2011. "Mechelen Stad met een gezicht, een toren, z'n beiaard, z'n slechtvalken, een kathedraal sitem