125-606: Leonardo's Horse (also known as the Sforza Horse or the Gran Cavallo ("Great Horse") ) is a project for a bronze sculpture that was commissioned from Leonardo da Vinci in 1482 by the Duke of Milan Ludovico il Moro , but never completed. It was intended to be the largest equestrian statue in the world, a monument to the duke's father Francesco Sforza . Leonardo did extensive preparatory work for it but produced only
250-601: A Vinča culture site in Pločnik ( Serbia ), and believed to have been smelted from a natural tin-copper ore, stannite . Other early examples date to the late 4th millennium BC in Egypt , Susa (Iran) and some ancient sites in China, Luristan (Iran), Tepe Sialk (Iran), Mundigak (Afghanistan), and Mesopotamia (Iraq). Tin bronze was superior to arsenic bronze in that the alloying process could be more easily controlled, and
375-481: A 20% change in the slope of the ALSFRS-R as being clinically meaningful, which is the most common threshold used to determine whether a new treatment is working in clinical trials. Difficulties with chewing and swallowing make eating very difficult ( dysphagia ) and increase the risk of choking or of aspirating food into the lungs. In later stages of the disorder, aspiration pneumonia can develop, and maintaining
500-492: A bulbar onset have a worse prognosis than limb-onset ALS; a population-based study found that bulbar-onset ALS patients had a median survival of 2.0 years and a 10-year survival rate of 3%, while limb-onset ALS patients had a median survival of 2.6 years and a 10-year survival rate of 13%. Those with respiratory-onset ALS had a shorter median survival of 1.4 years and 0% survival at 10 years. While astrophysicist Stephen Hawking lived for 55 more years following his diagnosis, his
625-472: A common disease spectrum (ALS–FTD) because of genetic, clinical, and pathological similarities. Genetically, repeat expansions in the C9orf72 gene account for about 40% of genetic ALS and 25% of genetic FTD. Cognitive and behavioral issues are associated with poorer prognosis as they may reduce adherence to medical advice, and deficits in empathy and social cognition which may increase caregiver burden. It
750-524: A copper oxide (eventually becoming copper carbonate) layer is formed, the underlying metal is protected from further corrosion . This can be seen on statues from the Hellenistic period. If copper chlorides are formed, a corrosion-mode called " bronze disease " will eventually completely destroy it. Bronze, or bronze-like alloys and mixtures, were used for coins over a longer period. Bronze was especially suitable for use in boat and ship fittings prior to
875-430: A definitive diagnosis of PLS cannot be made until several years have passed. PLS has a better prognosis than classical ALS, as it progresses slower, results in less functional decline, does not affect the ability to breathe, and causes less severe weight loss than classical ALS. Progressive muscular atrophy (PMA) is another subtype that accounts for about 5% of the overall ALS category and affects lower motor neurons in
1000-444: A disease, ALS itself can be classified in a few different ways: by which part of the motor neurons are affected; by the parts of the body first affected; whether it is genetic; and the age at which it started. Each individual diagnosed with the condition will sit at a unique place at the intersection of these complex and overlapping subtypes, which presents a challenge to diagnosis, understanding, and prognosis. ALS can be classified by
1125-403: A genetic cause, often linked to a family history of the disease , and these are known as familial ALS (hereditary). About half of these genetic cases are due to disease-causing variants in one of four specific genes . The diagnosis is based on a person's signs and symptoms , with testing conducted to rule out other potential causes. There is no known cure for ALS. The goal of treatment
1250-424: A healthy weight can become a significant problem that may require the insertion of a feeding tube. As the diaphragm and intercostal muscles of the rib cage that support breathing weaken, measures of lung function such as vital capacity and inspiratory pressure diminish. In respiratory-onset ALS, this may occur before significant limb weakness is apparent. Individuals affected by the disorder may ultimately lose
1375-482: A large clay model, which was later destroyed. About five centuries later, Leonardo's surviving designs were used as the basis for sculptures intended to bring the project to fruition. An equestrian monument was commissioned of Leonardo da Vinci in 1482 by Duke of Milan Ludovico il Moro . It was intended to be the largest equestrian statue in the world, a monument to the duke's father Francesco Sforza . Seventy tons of bronze were collected by Ludovico for casting
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#17327731997441500-665: A major influence on the development of cultures. In Europe, a major source of tin was the British deposits of ore in Cornwall , which were traded as far as Phoenicia in the eastern Mediterranean . In many parts of the world, large hoards of bronze artifacts are found, suggesting that bronze also represented a store of value and an indicator of social status. In Europe, large hoards of bronze tools, typically socketed axes (illustrated above), are found, which mostly show no signs of wear. With Chinese ritual bronzes , which are documented in
1625-467: A number of ALS genes that encode for RNA-binding proteins. The first to be discovered was TDP-43 protein, a nuclear protein that aggregates in the cytoplasm of motor neurons in almost all cases of ALS; however, mutations in TARDBP , the gene that codes for TDP-43, are a rare cause of ALS. FUS codes for FUS, another RNA-binding protein with a similar function to TDP-43, which can cause ALS when mutated. It
1750-510: A physician suspects the person may have a myopathy rather than ALS, a muscle biopsy may be performed. A number of infectious diseases can sometimes cause ALS-like symptoms, including human immunodeficiency virus ( HIV ), human T-lymphotropic virus (HTLV), Lyme disease , and syphilis . Neurological disorders such as multiple sclerosis, post-polio syndrome , multifocal motor neuropathy , CIDP , spinal muscular atrophy , and spinal and bulbar muscular atrophy can also mimic certain aspects of
1875-464: A predominantly upper motor neuron phenotype. Emotional lability is a symptom in which patients cry, smile, yawn, or laugh, either in the absence of emotional stimuli, or when they are feeling the opposite emotion to that being expressed; it is experienced by about half of ALS patients and is more common in those with bulbar-onset ALS. While relatively benign relative to other symptoms, it can cause increased stigma and social isolation as people around
2000-550: A project to re-create the unfinished sculpture in his home town, Allentown, Pennsylvania , and founded the nonprofit organization Leonardo da Vinci's Horse, Inc. (LDVHI) to support the project. His efforts to grow the organization to finance the project proved a difficult task that required more than 15 years. Dent's projected cost for the horse came to nearly US$ 2.5 million. He had a domed studio/workshop constructed in Allentown within which he personally began to conceptualize
2125-463: A rapid worsening of symptoms. Sudden death or acute respiratory distress are uncommon. Access to palliative care is recommended from an early stage to explore options, ensure psychosocial support for the patient and caregivers, and to discuss advance healthcare directives . As with cancer staging , ALS has staging systems numbered between 1 and 4 that are used for research purposes in clinical trials. Two very similar staging systems emerged around
2250-551: A sharper edge longer. Bronze was still used during the Iron Age, and has continued in use for many purposes to the modern day. There are many different bronze alloys, but typically modern bronze is 88% copper and 12% tin. Alpha bronze consists of the alpha solid solution of tin in copper. Alpha bronze alloys of 4–5% tin are used to make coins, springs, turbines and blades. Historical "bronzes" are highly variable in composition, as most metalworkers probably used whatever scrap
2375-525: A similar time, the King's staging system and Milano-Torino (MiToS) functional staging. 2B: Involvement of the second region 4B: Need for non-invasive ventilation 4B: 30.3 months Providing individual patients with a precise prognosis is not currently possible, though research is underway to provide statistical models on the basis of prognostic factors including age at onset, progression rate, site of onset, and presence of frontotemporal dementia . Those with
2500-436: A single region for at least a year; they progress more slowly than classical ALS and are associated with longer survival. These regional variants of ALS can only be considered as a diagnosis should the initial symptoms fail to spread to other spinal cord regions for an extended period of time (at least 12 months). Flail arm syndrome is characterized by lower motor neuron damage affecting the arm muscles, typically starting with
2625-573: A small percentage of people have a much slower progression, on average people with ALS lose about 1 ALSFRS-R point per month. Brief periods of stabilization ("plateaus") and even small reversals in ALSFRS-R score are not uncommon, due to the fact the tool is subjective, can be affected by medication, and different forms of compensation for changes in function. However, it is rare (<1%) for these improvements to be large (i.e. greater than 4 ALSFRS-R points) or sustained (i.e. greater than 12 months). A survey-based study among clinicians showed that they rated
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#17327731997442750-477: A smaller family, older generations dying earlier of causes other than ALS, genetic non-paternity , and uncertainty over whether certain neuropsychiatric conditions (e.g. frontotemporal dementia , other forms of dementia , suicide, psychosis, schizophrenia ) should be considered significant when determining a family history. There have been calls in the research community to routinely counsel and test all diagnosed ALS patients for familial ALS, particularly as there
2875-498: A treatise on horse anatomy. Another treatise, titled Of Weight , included detailed plans for casting the statue, which would have been done in separate hollow pieces and featured iron braces for internal support. By November 1493, a full-size clay model of the horse (without its rider) was exhibited at one of the Sforzas' weddings, gaining Leonardo significant fame. In a 20 December 1493 note by Leonardo, he stated his readiness to begin
3000-416: Is a better conductor of heat and electricity than most steels. The cost of copper-base alloys is generally higher than that of steels but lower than that of nickel -base alloys. Bronzes are typically ductile alloys, considerably less brittle than cast iron. Copper and its alloys have a huge variety of uses that reflect their versatile physical, mechanical, and chemical properties . Some common examples are
3125-408: Is a symptom experienced by most people with ALS caused by reduced mobility. Symptoms of lower motor neuron degeneration include muscle weakness and atrophy, muscle cramps, and fleeting twitches of muscles that can be seen under the skin ( fasciculations ). Although the initial site of symptoms and subsequent rate of disability progression vary from person to person, the initially affected body region
3250-493: Is an alloy consisting primarily of copper , commonly with about 12–12.5% tin and often with the addition of other metals (including aluminium , manganese , nickel , or zinc ) and sometimes non-metals, such as phosphorus , or metalloids , such as arsenic or silicon . These additions produce a range of alloys that may be harder than copper alone, or have other useful properties, such as strength , ductility , or machinability . The archaeological period in which bronze
3375-418: Is in modern times. Because historical artworks were often made of brasses (copper and zinc) and bronzes of different metallic compositions, modern museum and scholarly descriptions of older artworks increasingly use the generalized term "copper alloy" instead of the names of individual alloys. This is done (at least in part) to prevent database searches from failing merely because of errors or disagreements in
3500-527: Is likely that 'nehoshet' refers to copper and its alloys with tin, now called bronze. In the King James Version, there is no use of the word 'bronze' and 'nehoshet' was translated as 'brass'. Modern translations use 'bronze'. Bronze (nehoshet) was used widely in the Tabernacle for items such as the bronze altar (Exodus Ch.27), bronze laver (Exodus Ch.30), utensils, and mirror (Exodus Ch.38). It
3625-575: Is more likely to be genetic in origin than adult-onset ALS; the most common genes associated with juvenile ALS are FUS , ALS2 , and SETX . Although most people with juvenile ALS live longer than those with adult-onset ALS, some of them have specific mutations in FUS and SOD1 that are associated with a poor prognosis. Late onset (after age 65) is generally associated with a more rapid functional decline and shorter survival. The disorder causes muscle weakness, atrophy , and muscle spasms throughout
3750-657: Is not known what causes sporadic ALS, hence it is described as an idiopathic disease . Though its exact cause is unknown, genetic and environmental factors are thought to be of roughly equal importance. The genetic factors are better understood than the environmental factors; no specific environmental factor has been definitively shown to cause ALS. A multi-step liability threshold model for ALS proposes that cellular damage accumulates over time due to genetic factors present at birth and exposure to environmental risks throughout life. ALS can strike at any age, but its likelihood increases with age. Most people who develop ALS are between
3875-631: Is now a licensed gene therapy ( tofersen ) specifically targeted to carriers of SOD-1 ALS. A shortage of genetic counselors and limited clinical capacity to see such at-risk individuals makes this challenging in practice, as does the unequal access to genetic testing around the world. More than 40 genes have been associated with ALS, of which four account for nearly half of familial cases, and around 5% of sporadic cases: C9orf72 (40% of familial cases, 7% sporadic), SOD1 (12% of familial cases, 1–2% sporadic), FUS (4% of familial cases, 1% sporadic), and TARDBP (4% of familial cases, 1% sporadic), with
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4000-412: Is often feasible, albeit slow, and needs may change over time. Despite these challenges, many people in an advanced state of disease report satisfactory wellbeing and quality of life. Although respiratory support using non-invasive ventilation can ease problems with breathing and prolong survival, it does not affect the progression rate of ALS. Most people with ALS die between two and four years after
4125-532: Is often marked by walking with a " dropped foot " that drags gently on the ground. If the arms are affected first, they may experience difficulty with tasks requiring manual dexterity, such as buttoning a shirt, writing, or turning a key in a lock. In bulbar-onset ALS, the first symptoms are difficulty speaking or swallowing. Speech may become slurred, nasal in character, or quieter. There may be difficulty with swallowing and loss of tongue mobility. A smaller proportion of people experience "respiratory-onset" ALS, where
4250-495: Is respiratory-onset, in which the initial symptoms are difficulty breathing ( dyspnea ) upon exertion, at rest, or while lying flat ( orthopnea ). Primary lateral sclerosis (PLS) is a subtype of the overall ALS category which accounts for about 5% of all cases and only affects the upper motor neurons in the arms, legs, and bulbar region. However, more than 75% of people with apparent PLS go on to later develop lower motor neuron signs within four years of symptom onset, meaning that
4375-450: Is the main transporter that removes glutamate from the synapse; this leads to increased synaptic glutamate levels and excitotoxicity. Riluzole , a drug that modestly prolongs survival in ALS, inhibits glutamate release from pre-synaptic neurons; however, it is unclear if this mechanism is responsible for its therapeutic effect. No single test can provide a definite diagnosis of ALS. Instead,
4500-473: Is the most common form of the motor neuron diseases . ALS often presents in its early stages with gradual muscle stiffness , twitches , weakness , and wasting . Motor neuron loss typically continues until the abilities to eat, speak, move, and, lastly, breathe are all lost. While only 15% of people with ALS also fully develop frontotemporal dementia , an estimated 50% face at least some minor difficulties with thinking and behavior . Depending on which of
4625-424: Is thought that misfolded mutant SOD1 can cause misfolding and aggregation of wild-type SOD1 in neighboring neurons in a prion-like manner. Other protein degradation genes that can cause ALS when mutated include VCP , OPTN , TBK1 , and SQSTM1 . Three genes implicated in ALS that are important for maintaining the cytoskeleton and for axonal transport include DCTN1 , PFN1 , and TUBA4A . There are
4750-403: Is thought that mutations in TARDBP and FUS increase the binding affinity of the low-complexity domain, causing their respective proteins to aggregate in the cytoplasm. Once these mutant RNA-binding proteins are misfolded and aggregated, they may be able to misfold normal proteins both within and between cells in a prion-like manner. This also leads to decreased levels of RNA-binding protein in
4875-429: Is thought to account for 10–15% of cases overall and can include monogenic , oligogenic , and polygenic modes of inheritance. There is considerable variation among clinicians on how to approach genetic testing in ALS, and only about half discuss the possibility of genetic inheritance with their patients, particularly if there is no discernible family history of the disease. In the past, genetic counseling and testing
5000-496: Is to slow the disease progression, and improve symptoms. FDA approved treatments that slow the progression of ALS include riluzole and edaravone. Non-invasive ventilation may result in both improved quality, and length of life. Mechanical ventilation can prolong survival but does not stop disease progression. A feeding tube may help maintain weight and nutrition. Death is usually caused by respiratory failure. The disease can affect people of any age, but usually starts around
5125-453: Is used to make hammers , mallets , wrenches and other durable tools to be used in explosive atmospheres or in the presence of flammable vapors. Bronze is used to make bronze wool for woodworking applications where steel wool would discolor oak . Phosphor bronze is used for ships' propellers, musical instruments, and electrical contacts. Bearings are often made of bronze for its friction properties. It can be impregnated with oil to make
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5250-541: Is used to make the tone rings of many professional model banjos . The tone ring is a heavy (usually 3 lb; 1.4 kg) folded or arched metal ring attached to a thick wood rim, over which a skin, or most often, a plastic membrane (or head) is stretched – it is the bell bronze that gives the banjo a crisp powerful lower register and clear bell-like treble register. Bronze has also been used in coins; most "copper" coins are actually bronze, with about 4 percent tin and 1 percent zinc. As with coins, bronze has been used in
5375-431: Is usually the most affected over time, and symptoms usually spread to a neighbouring body region. For example, symptoms starting in one arm usually spread next to either the opposite arm or to the leg on the same side. Bulbar-onset patients most typically get their next symptoms in their arms rather than legs, arm-onset patients typically spreads to the legs before the bulbar region, and leg-onset patients typically spread to
5500-486: The ALS Functional Rating Scale - Revised (ALSFRS-R), a 12-item instrument survey administered as a clinical interview or self-reported questionnaire that produces a score between 48 (normal function) and 0 (severe disability). The ALSFRS-R is the most frequently used outcome measure in clinical trials and is used by doctors to track disease progression. Though the degree of variability is high and
5625-560: The Etruscans were making bronze mirrors in the sixth century BC, and Greek and Roman mirrors followed the same pattern. Although other materials such as speculum metal had come into use, and Western glass mirrors had largely taken over, bronze mirrors were still being made in Japan and elsewhere in the eighteenth century, and are still made on a small scale in Kerala , India. Bronze is
5750-571: The Golden Age , when men lived among the gods; the Silver age , where youth lasted a hundred years; and the Bronze Age , the era of heroes. It was first adopted for a sports event at the 1904 Summer Olympics . At the 1896 event, silver was awarded to winners and bronze to runners-up, while at 1900 other prizes were given rather than medals. Bronze is the normal material for the related form of
5875-756: The Kingdom of Benin ; in Europe, Grecian bronzes typically of figures from Greek mythology ; in east Asia , Chinese ritual bronzes of the Shang and Zhou dynasty —more often ceremonial vessels but including some figurine examples. Bronze continues into modern times as one of the materials of choice for monumental statuary. Tiffany Glass Studios, made famous by Louis C. Tiffany commonly referred to his product as favrile glass or " Tiffany glass ," and used bronze in their artisan work for his Tiffany lamps . The largest and most ornate bronze fountain known to be cast in
6000-426: The intercostal muscles that support breathing are affected first. Over time, people experience increasing difficulty moving, swallowing ( dysphagia ), and speaking or forming words ( dysarthria ). Symptoms of upper motor neuron involvement include tight and stiff muscles ( spasticity ) and exaggerated reflexes ( hyperreflexia ), including an overactive gag reflex. While the disease does not cause pain directly, pain
6125-468: The lower motor neurons in the spinal cord. Primary lateral sclerosis (PLS) involves degeneration of only the upper motor neurons, and progressive muscular atrophy (PMA) involves only the lower motor neurons. There is debate over whether PLS and PMA are separate diseases or simply variants of ALS. Classical ALS accounts for about 70% of all cases of ALS and can be subdivided into where symptoms first appear as these are usually focussed to one region of
6250-432: The neuromuscular junction , such as myasthenia gravis (MG) and Lambert–Eaton myasthenic syndrome , may also mimic ALS, although this rarely presents diagnostic difficulty over time. Benign fasciculation syndrome and cramp fasciculation syndrome may also, occasionally, mimic some of the early symptoms of ALS. Nonetheless, the absence of other neurological features that develop inexorably with ALS means that, over time,
6375-545: The pathogenesis of ALS. It is still not fully understood why neurons die in ALS, but this neurodegeneration is thought to involve many different cellular and molecular processes. The genes known to be involved in ALS can be grouped into three general categories based on their normal function: protein degradation, the cytoskeleton , and RNA processing. Mutant SOD1 protein forms intracellular aggregations that inhibit protein degradation. Cytoplasmic aggregations of wild-type (normal) SOD1 protein are common in sporadic ALS. It
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#17327731997446500-550: The plaquette , normally a rectangular work of art with a scene in relief , for a collectors' market. Bronze is also associated with eighth wedding anniversaries. There are over 125 references to bronze ('nehoshet'), which appears to be the Hebrew word used for copper and any of its alloys. However, the Old Testament era Hebrews are not thought to have had the capability to manufacture zinc (needed to make brass) and so it
6625-682: The 12th-century Romanesque Baptismal font at St Bartholomew's Church, Liège is sometimes described as bronze and sometimes as brass . In the Bronze Age, two forms of bronze were commonly used: "classic bronze", about 10% tin, was used in casting; and "mild bronze", about 6% tin, was hammered from ingots to make sheets. Bladed weapons were mostly cast from classic bronze, while helmets and armor were hammered from mild bronze. Modern commercial bronze (90% copper and 10% zinc) and architectural bronze (57% copper, 3% lead , 40% zinc) are more properly regarded as brass alloys because they contain zinc as
6750-640: The Institute and Museum of the History of Science in Florence, Italy. It is made of steel frame with special resin coated fibreglass, to make it look like bronze. It is made of six pieces and can be transported and re-assembled. It has been on display at various locations during exhibitions on Leonardo. Some of the venues have been; 45°28′51″N 9°07′47″E / 45.48083°N 9.12972°E / 45.48083; 9.12972 Bronze Bronze
6875-418: The ability to initiate and control all voluntary movement, known as locked-in syndrome . Bladder and bowel function are usually spared, meaning urinary and fecal incontinence are uncommon, although trouble getting to a toilet can lead to difficulties. The extraocular muscles responsible for eye movement are usually spared, meaning the use of eye tracking technology to support augmentative communication
7000-420: The above personality traits might underlie lifestyle choices which are in turn risk factors for ALS. Upon examination at autopsy, features of the disease that can be seen with the naked eye include skeletal muscle atrophy , motor cortex atrophy, sclerosis of the corticospinal and corticobulbar tracts , thinning of the hypoglossal nerves (which control the tongue), and thinning of the anterior roots of
7125-405: The aforementioned symptoms develops first, ALS is classified as limb-onset (begins with weakness in the arms or legs) or bulbar-onset (begins with difficulty in speaking or swallowing ). Most cases of ALS (about 90–95%) have no known cause , and are known as sporadic ALS . However, both genetic and environmental factors are believed to be involved. The remaining 5–10% of cases have
7250-471: The age of 60. The average survival from onset to death is two to four years, though this can vary, and about 10% of those affected survive longer than ten years. Descriptions of the disease date back to at least 1824 by Charles Bell . In 1869, the connection between the symptoms and the underlying neurological problems was first described by French neurologist Jean-Martin Charcot , who in 1874 began using
7375-425: The age of onset. While the peak age of onset is 58 to 63 for sporadic ALS and 47 to 52 for genetic ALS, about 10% of all cases of ALS begin before age 45 ("young-onset" ALS), and about 1% of all cases begin before age 25 ("juvenile" ALS). People who develop young-onset ALS are more likely to be male, less likely to have bulbar onset of symptoms, and more likely to have a slower progression of the disease. Juvenile ALS
7500-512: The ages of 40 and 70, with an average age of 55 at the time of diagnosis. ALS is 20% more common in men than women, but this difference in sex distribution is no longer present in patients with onset after age 70. While they appear identical clinically and pathologically, ALS can be classified as being either familial or sporadic, depending on whether there is a known family history of the disease and/or whether an ALS-associated genetic mutation has been identified via genetic testing. Familial ALS
7625-482: The arms rather than the bulbar region. Over time, regardless of where symptoms began, most people eventually lose the ability to walk or use their hands and arms independently. Less consistently, they may lose the ability to speak and to swallow food. It is the eventual development of weakness of the respiratory muscles, with the loss of ability to cough and to breathe without support, that is ultimately life-shortening in ALS. The rate of progression can be measured using
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#17327731997447750-497: The arms, legs, and bulbar region. While PMA is associated with longer survival on average than classical ALS, it is still progressive over time, eventually leading to respiratory failure and death. As with PLS developing into classical ALS, PMA can also develop into classical ALS over time if the lower motor neuron involvement progresses to include upper motor neurons, in which case the diagnosis might be changed to classic ALS. Isolated variants of ALS have symptoms that are limited to
7875-452: The barrel. It is still widely used today for springs, bearings, bushings, automobile transmission pilot bearings, and similar fittings, and is particularly common in the bearings of small electric motors . Phosphor bronze is particularly suited to precision-grade bearings and springs. It is also used in guitar and piano strings. Unlike steel, bronze struck against a hard surface will not generate sparks, so it (along with beryllium copper )
8000-458: The basis for sculptures intended to bring the project to fruition. Charles C. Dent , an amateur artist and flying enthusiast since his youth, strove to become a pioneering United Airlines pilot by profession as well as a dedicated art collector. In 1977, he read in the September issue of National Geographic its feature article on the history of Leonardo's horse and statue. Dent then began
8125-508: The battle of David and Goliath in I Samuel 17:5-6;38 (also see II Chron. 12:10). Lou Gehrig%27s disease Amyotrophic lateral sclerosis ( ALS ), also known as motor neurone disease ( MND ) or Lou Gehrig's disease ( LGD ) in the United States, is a rare, terminal neurodegenerative disorder that results in the progressive loss of both upper and lower motor neurons that normally control voluntary muscle contraction. ALS
8250-542: The beginning of the Second Italian War ; it was afterward destroyed by cycles of rains and subsequent freezes. In 1511, Leonardo undertook an equestrian monument as a tomb for Gian Giacomo Trivulzio , for which he again designed a rearing pose and supporting victim—but this was never modelled due to a confederation of Swiss, Spanish, and Venetian forces driving the French from Milan. In 1640, Pietro Tacca built
8375-465: The body at initial presentation before later spread. Limb-onset ALS (also known as spinal-onset) and bulbar-onset ALS. Limb-onset ALS begins with weakness in the hands, arms, feet, and/or legs and accounts for about two-thirds of all classical ALS cases. Bulbar-onset ALS begins with weakness in the muscles of speech, chewing, and swallowing and accounts for about 25% of classical ALS cases. A rarer type of classical ALS affecting around 3% of patients
8500-420: The body due to the degeneration of the upper motor and lower motor neurons. Sensory nerves and the autonomic nervous system are generally unaffected, meaning the majority of people with ALS maintain hearing , sight , touch , smell , and taste . The start of ALS may be so subtle that the symptoms are overlooked. The earliest symptoms of ALS are muscle weakness or muscle atrophy, typically on one side of
8625-499: The body. Other presenting symptoms include trouble swallowing or breathing, cramping, or stiffness of affected muscles; muscle weakness affecting an arm or a leg; or slurred and nasal speech. The parts of the body affected by early symptoms of ALS depend on which motor neurons in the body are damaged first. In limb-onset ALS, the first symptoms are in the arms or the legs. If the legs are affected first, people may experience awkwardness, tripping, or stumbling when walking or running; this
8750-401: The brain to muscle, causes different types of symptoms. Damage to the upper motor neuron typically causes spasticity including stiffness and increased tendon reflexes , and/or clonus , while damage to the lower motor neuron typically causes weakness , muscle atrophy , and fasciculations . Classical, or classic ALS, involves degeneration to both the upper motor neurons in the brain and
8875-494: The casting process, but in November 1494, Ludovico gave the bronze to his father-in-law Ercole d'Este to be used to forge cannons to defend the city from the invasion of Charles VIII . Leonardo's rival Michelangelo encountered him at some point in Florence, and insulted him by implying that he was unable to perform the casting. The clay model was used as an archery target by French soldiers when they invaded Milan in 1499 at
9000-477: The company contracted by LDVHI to cast the horse, had suggested bringing Nina Akamu , an experienced animal sculptor, on board to improve upon the Dent-Herrick horse. After several months. Nina Akamu determined that the original model could not be salvaged and concluded that a completely new sculpture needed to be executed. Leonardo had made numerous small sketches of horses to help illustrate his notes about
9125-412: The complex procedures for molding and casting the sculpture. But his notes were far from systematic, and none of the sketches points to the final position of the horse, with no single definitive drawing of the statue. Akamu researched multiple information sources to gain insight into the original sculptor's intentions. She studied both Leonardo's notes and drawings of the horse and those of other projects he
9250-466: The condition, but as of 2023 are not in general medical use. Because symptoms of ALS can be similar to those of a wide variety of other, more treatable diseases or disorders, appropriate tests must be conducted to exclude the possibility of other conditions. One of these tests is electromyography (EMG), a special recording technique that detects electrical activity in muscles. Certain EMG findings can support
9375-448: The cytoplasm of motor neurons. In about 97% of people with ALS, the main component of the inclusion bodies is TDP-43 protein; however, in those with SOD1 or FUS mutations, the main component of the inclusion bodies is SOD1 protein or FUS protein, respectively. Prion -like propagation of misfolded proteins from cell to cell may explain why ALS starts in one area and spreads to others. The glymphatic system may also be involved in
9500-424: The diagnosis of ALS is primarily made based on a physician's clinical assessment after ruling out other diseases. Physicians often obtain the person's full medical history and conduct neurologic examinations at regular intervals to assess whether signs and symptoms such as muscle weakness, muscle atrophy , hyperreflexia , Babinski's sign , and spasticity are worsening. A number of biomarkers are being studied for
9625-487: The diagnosis of ALS. Another common test measures nerve conduction velocity (NCV). Specific abnormalities in the NCV results may suggest, for example, that the person has a form of peripheral neuropathy (damage to peripheral nerves) or myopathy (muscle disease) rather than ALS. While a magnetic resonance imaging (MRI) is often normal in people with early-stage ALS, it can reveal evidence of other problems that may be causing
9750-424: The diagnosis. Around 50% of people with ALS die within 30 months of their symptoms beginning, about 20% live between five and ten years, and about 10% survive for 10 years or longer. The most common cause of death among people with ALS is respiratory failure , often accelerated by pneumonia . Most ALS patients die at home after a period of worsening difficulty breathing, a decline in their nutritional status, or
9875-426: The disease and should be considered. ALS must be differentiated from the "ALS mimic syndromes", which are unrelated disorders that may have a similar presentation and clinical features to ALS or its variants. Because the prognosis of ALS and closely related subtypes of motor neuron disease are generally poor, neurologists may carry out investigations to evaluate and exclude other diagnostic possibilities. Disorders of
10000-466: The excitatory neurotransmitter glutamate , is a mechanism thought to be common to all forms of ALS. Motor neurons are more sensitive to excitotoxicity than other types of neurons because they have a lower calcium-buffering capacity and a type of glutamate receptor (the AMPA receptor ) that is more permeable to calcium. In ALS, there are decreased levels of excitatory amino acid transporter 2 ( EAAT2 ), which
10125-473: The first equestrian monument featuring a (freestanding) rearing horse and King Philip IV of Spain , for which Galileo Galilei helped compute gravitational solutions—similar to Leonardo's—to deal with its offset weight. Étienne Maurice Falconet 's Bronze Horseman accomplishes a similar feat, although neither reach the physical scale of Leonardo's design. About five centuries after the original project failed, Leonardo's surviving design materials were used as
10250-507: The former United States Ambassador to Italy, and his wife, Joan, The Vinci horse inspired a sister city relationship between Vinci, Italy, and Allentown, Pennsylvania. A plaza in Vinci also was named in the memory of Charles C. Dent. A 12-foot (3.6 m) replica was placed in Charles C. Dent's hometown of Allentown , Pa. in the Charles C. Dent Memorial Garden at The Baum School of Art , where it
10375-545: The high electrical conductivity of pure copper, low-friction properties of bearing bronze (bronze that has a high lead content— 6–8%), resonant qualities of bell bronze (20% tin, 80% copper), and resistance to corrosion by seawater of several bronze alloys. The melting point of bronze varies depending on the ratio of the alloy components and is about 950 °C (1,742 °F). Bronze is usually nonmagnetic, but certain alloys containing iron or nickel may have magnetic properties. Typically bronze oxidizes only superficially; once
10500-699: The highest form of sculpture in Ancient Greek art , though survivals are few, as bronze was a valuable material in short supply in the Late Antique and medieval periods. Many of the most famous Greek bronze sculptures are known through Roman copies in marble, which were more likely to survive. In India, bronze sculptures from the Kushana ( Chausa hoard ) and Gupta periods ( Brahma from Mirpur-Khas , Akota Hoard, Sultanganj Buddha ) and later periods ( Hansi Hoard) have been found. Indian Hindu artisans from
10625-484: The inscriptions they carry and from other sources, the case is clear. These were made in enormous quantities for elite burials, and also used by the living for ritual offerings. Though bronze is generally harder than wrought iron , with Vickers hardness of 60–258 vs. 30–80, the Bronze Age gave way to the Iron Age after a serious disruption of the tin trade: the population migrations of around 1200–1100 BC reduced
10750-878: The likelihood of a very rare condition by a small amount. For instance an individual's lifetime risk of developing ALS might go from "1 in 400" without an exposure to between "1 in 300" and "1 in 200" if they were exposed to heavy metals. A range of other exposures have weaker evidence supporting them and include participation in professional sports , having a lower body mass index , lower educational attainment , manual occupations, military service, exposure to Beta-N-methylamino-L-alanin (BMAA), and viral infections. Although some personality traits, such as openness , agreeableness and conscientiousness appear remarkably common among patients with ALS, it remains open whether personality can increase susceptibility to ALS directly. Instead, genetic factors giving rise to personality might simultaneously predispose people to developing ALS, or
10875-824: The main alloying ingredient. They are commonly used in architectural applications. Plastic bronze contains a significant quantity of lead, which makes for improved plasticity, and was possibly used by the ancient Greeks in ship construction. Silicon bronze has a composition of Si: 2.80–3.80%, Mn: 0.50–1.30%, Fe: 0.80% max., Zn: 1.50% max., Pb: 0.05% max., Cu: balance. Other bronze alloys include aluminium bronze , phosphor bronze , manganese bronze, bell metal , arsenical bronze , speculum metal , bismuth bronze , and cymbal alloys . Copper-based alloys have lower melting points than steel or iron and are more readily produced from their constituent metals. They are generally about 10 percent denser than steel, although alloys using aluminum or silicon may be slightly less dense. Bronze
11000-462: The manufacture of various types of medals for centuries, and " bronze medals " are known in contemporary times for being awarded for third place in sporting competitions and other events. The term is now often used for third place even when no actual bronze medal is awarded. The usage in part arose from the trio of gold , silver and bronze to represent the first three Ages of Man in Greek mythology:
11125-673: The massive bronze doors to the United States Supreme Court Building in Washington, DC. Before it became possible to produce glass with acceptably flat surfaces, bronze was a standard material for mirrors. Bronze was used for this purpose in many parts of the world, probably based on independent discoveries. Bronze mirrors survive from the Egyptian Middle Kingdom (2040–1750 BC), and China from at least c. 550 BC . In Europe,
11250-650: The naming of historic copper alloys. The word bronze (1730–1740) is borrowed from Middle French bronze (1511), itself borrowed from Italian bronzo ' bell metal, brass ' (13th century, transcribed in Medieval Latin as bronzium ) from either: The discovery of bronze enabled people to create metal objects that were harder and more durable than previously possible. Bronze tools , weapons , armor , and building materials such as decorative tiles were harder and more durable than their stone and copper (" Chalcolithic ") predecessors. Initially, bronze
11375-735: The nucleus, translation of the RNA into toxic dipeptide repeat proteins in the cytoplasm, and decreased levels of the normal C9orf72 protein. Mitochondrial bioenergetic dysfunction leading to dysfunctional motor neuron axonal homeostasis (reduced axonal length and fast axonal transport of mitochondrial cargo) has been shown to occur in C9orf72 -ALS using human induced pluripotent stem cell (iPSC) technologies coupled with CRISPR/Cas9 gene-editing, and human post-mortem spinal cord tissue examination. Excitotoxicity , or nerve cell death caused by high levels of intracellular calcium due to excessive stimulation by
11500-705: The nucleus, which may mean that their target RNA transcripts do not undergo normal processing. Other RNA metabolism genes associated with ALS include ANG , SETX , and MATR3 . C9orf72 is the most commonly mutated gene in ALS and causes motor neuron death through a number of mechanisms. The pathogenic mutation is a hexanucleotide repeat expansion (a series of six nucleotides repeated over and over); people with up to 30 repeats are considered normal, while people with hundreds or thousands of repeats can have familial ALS, frontotemporal dementia, or sometimes sporadic ALS. The three mechanisms of disease associated with these C9orf72 repeats are deposition of RNA transcripts in
11625-456: The patient struggle to react appropriately to what can be frequent and inappropriate outbursts in public. In addition to mild changes in cognition that may only emerge during neuropsychological testing, around 10–15% of individuals have signs of frontotemporal dementia (FTD). Repeating phrases or gestures , apathy, and loss of inhibition are the most frequently reported behavioral features of ALS. ALS and FTD are now considered to be part of
11750-581: The period of the Chola empire in Tamil Nadu used bronze to create intricate statues via the lost-wax casting method with ornate detailing depicting the deities of Hinduism . The art form survives to this day, with many silpis, craftsmen, working in the areas of Swamimalai and Chennai . In antiquity other cultures also produced works of high art using bronze. For example: in Africa, the bronze heads of
11875-424: The preferred metal for bells in the form of a high tin bronze alloy known as bell metal , which is typically about 23% tin. Nearly all professional cymbals are made from bronze, which gives a desirable balance of durability and timbre . Several types of bronze are used, commonly B20 bronze , which is roughly 20% tin, 80% copper, with traces of silver, or the tougher B8 bronze made from 8% tin and 92% copper. As
12000-452: The proprietary Oilite and similar material for bearings. Aluminum bronze is hard and wear-resistant, and is used for bearings and machine tool ways. The Doehler Die Casting Co. of Toledo, Ohio were known for the production of Brastil , a high tensile corrosion resistant bronze alloy. The Seagram Building on New York City 's Park Avenue is the "iconic glass box sheathed in bronze, designed by Mies van der Rohe ." The Seagram Building
12125-503: The re-creation and initial modelling of the sculpture. In 1988, he enlisted sculptor/painter Garth Herrick to begin part-time work on the horse. When Charles Dent died of Lou Gehrig's disease on December 25, 1994 he left his private art collection to LDVHI, the sale of which brought more than $ 1 million to the fund. The LDVHI Board acted on its promise to Dent to complete Dent’s vision. By 1997, Tallix Art Foundry, in Beacon, New York ,
12250-454: The ready availability of silicon bronze brazing rod, which allows color-matched repair of defects in castings. Aluminum is also used for the structural metal aluminum bronze. Bronze parts are tough and typically used for bearings , clips, electrical connectors and springs . Bronze also has low friction against dissimilar metals, making it important for cannons prior to modern tolerancing , where iron cannonballs would otherwise stick in
12375-908: The remaining genes mostly accounting for fewer than 1% of either familial or sporadic cases. ALS genes identified to date explain the cause of about 70% of familial ALS and about 15% of sporadic ALS. Overall, first-degree relatives of an individual with ALS have a ~1% risk of developing ALS themselves. The multi-step hypothesis suggests the disease is caused by some interaction between an individual's genetic risk factors and their cumulative lifetime of exposures to environmental factors, termed their exposome . The most consistent lifetime exposures associated with developing ALS (other than genetic mutations) include heavy metals (e.g. lead and mercury ), chemicals (e.g. pesticides and solvents ), electric shock , physical injury (including head injury ), and smoking (in men more than women). Overall these effects are small, with each exposure in isolation only increasing
12500-690: The resulting alloy was stronger and easier to cast. Also, unlike those of arsenic , metallic tin and the fumes from tin refining are not toxic . Tin became the major non-copper ingredient of bronze in the late 3rd millennium BC. Ores of copper and the far rarer tin are not often found together (exceptions include Cornwall in the United Kingdom, one ancient site in Thailand and one in Iran), so serious bronze work has always involved trade with other regions. Tin sources and trade in ancient times had
12625-478: The shipping of tin around the Mediterranean and from Britain, limiting supplies and raising prices. As the art of working in iron improved, iron became cheaper and improved in quality. As later cultures advanced from hand- wrought iron to machine- forged iron (typically made with trip hammers powered by water), blacksmiths also learned how to make steel . Steel is stronger and harder than bronze and holds
12750-448: The spinal cord. The defining feature of ALS is the death of both upper motor neurons (located in the motor cortex of the brain) and lower motor neurons (located in the brainstem and spinal cord). In ALS with frontotemporal dementia, neurons throughout the frontal and temporal lobes of the brain die as well. The pathological hallmark of ALS is the presence of inclusion bodies (abnormal aggregations of protein) known as Bunina bodies in
12875-438: The statue, which approached 8 metres (26 ft) in height, dwarfing earlier horse monuments by Donatello and by Leonardo's former master , Verrocchio . Leonardo initially planned a more dynamic design than those of his predecessors, initially including a fallen soldier to support the rearing horse, but at some point acquiesced to a more traditional walking horse. In preparation for the work, Leonardo studied horses, and wrote
13000-405: The symptoms, such as a spinal cord tumor, multiple sclerosis , a herniated disc in the neck, syringomyelia , or cervical spondylosis . Based on the person's symptoms and findings from the examination and from these tests, the physician may order tests on blood and urine samples to eliminate the possibility of other diseases, as well as routine laboratory tests. In some cases, for example, if
13125-419: The term amyotrophic lateral sclerosis . ALS is a motor neuron disease , which is a group of neurological disorders that selectively affect motor neurons , the cells that control voluntary muscles of the body. Other motor neuron diseases include primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), progressive bulbar palsy , pseudobulbar palsy , and monomelic amyotrophy (MMA). As
13250-469: The tin content in a bell or cymbal rises, the timbre drops. Bronze is also used for the windings of steel and nylon strings of various stringed instruments such as the double bass , piano, harpsichord , and guitar. Bronze strings are commonly reserved on pianoforte for the lower pitch tones, as they possess a superior sustain quality to that of high-tensile steel. Bronzes of various metallurgical properties are widely used in struck idiophones around
13375-404: The types of motor neurons that are affected. To successfully control any voluntary muscle in the body, a signal must be sent from the motor cortex in the brain down the upper motor neuron as it travels down the spinal cord. There, it connects via a synapse to the lower motor neuron which connects to the muscle itself. Damage to either the upper or lower motor neuron, as it makes its way from
13500-439: The unusual and desirable property of expanding slightly just before they set, thus filling the finest details of a mould. Then, as the bronze cools, it shrinks a little, making it easier to separate from the mould. The Assyrian king Sennacherib (704–681 BC) claims to have been the first to cast monumental bronze statues (of up to 30 tonnes) using two-part moulds instead of the lost-wax method . Bronze statues were regarded as
13625-509: The upper arms symmetrically and progressing downwards to the hands. Flail leg syndrome is characterized by lower motor neuron damage leading to asymmetrical weakness and wasting in the legs starting around the feet. Isolated bulbar palsy is characterized by upper or lower motor neuron damage in the bulbar region (in the absence of limb symptoms for at least 20 months), leading to gradual onset of difficulty with speech ( dysarthria ) and swallowing ( dysphagia ). ALS can also be classified based on
13750-419: The wide employment of stainless steel owing to its combination of toughness and resistance to salt water corrosion. Bronze is still commonly used in ship propellers and submerged bearings. In the 20th century, silicon was introduced as the primary alloying element, creating an alloy with wide application in industry and the major form used in contemporary statuary . Sculptors may prefer silicon bronze because of
13875-657: The world was by the Roman Bronze Works and General Bronze Corporation in 1952. The material used for the fountain, known as statuary bronze, is a quaternary alloy made of copper, zinc, tin, and lead, and traditionally golden brown in color. This was made for the Andrew W. Mellon Memorial Fountain in Federal Triangle in Washington, DC. Another example of the massive, ornate design projects of bronze, and attributed to General Bronze/Roman Bronze Works were
14000-710: The world, notably bells, singing bowls, gongs , cymbals, and other idiophones from Asia. Examples include Tibetan singing bowls , temple bells of many sizes and shapes, Javanese gamelan , and other bronze musical instruments . The earliest bronze archeological finds in Indonesia date from 1–2 BC, including flat plates probably suspended and struck by a wooden or bone mallet. Ancient bronze drums from Thailand and Vietnam date back 2,000 years. Bronze bells from Thailand and Cambodia date back to 3600 BC. Some companies are now making saxophones from phosphor bronze (3.5 to 10% tin and up to 1% phosphorus content). Bell bronze/B20
14125-507: Was an unusual case. Cognitive impairment or behavioral dysfunction is present in 30–50% of individuals with ALS, and can appear more frequently in later stages of the disease. Language dysfunction , executive dysfunction , and troubles with social cognition and verbal memory are the most commonly reported cognitive symptoms in ALS. Cognitive impairment is found more frequently in patients with C9orf72 gene repeat expansions, bulbar onset, bulbar symptoms, family history of ALS, and/or
14250-641: Was commissioned by philanthropist Frederik Meijer and was placed at the Frederik Meijer Gardens and Sculpture Park , a botanical garden and sculpture park in Grand Rapids, Michigan on October 7, 1999. A 2.5-metre (8 ft) bronze version of the sculpture stands in Leonardo's birthplace, Vinci, Tuscany , Italy, where it was dedicated on November 17, 2001. Made possible with gifts from several benefactors, including Peter F. Secchia ,
14375-788: Was dedicated on October 4, 2002. The Da Vinci Science Center – the organization that is shaped by the merger of LDVHI and what was then known as the Discovery Center of Science and Technology – displays a three-foot (1 m) replica of The Horse in its main lobby, which was dedicated when the science center opened its current location on October 30, 2005. The Da Vinci Science Center's sculpture also has appeared on loan at Discovery Times Square in New York City, New York, and at The Franklin Institute in Philadelphia, Pennsylvania. An eight-foot-tall (2.5 m) replica of The Horse
14500-525: Was made out of copper and arsenic or from naturally or artificially mixed ores of those metals, forming arsenic bronze . The earliest known arsenic-copper-alloy artifacts come from a Yahya Culture (Period V 3800-3400 BCE) site, at Tal-i-Iblis on the Iranian plateau , and were smelted from native arsenical copper and copper-arsenides, such as algodonite and domeykite . The earliest tin-copper-alloy artifact has been dated to c. 4650 BC , in
14625-474: Was mentioned in the account of Moses holding up a bronze snake on a pole in Numbers Ch.21. In First Kings, it is mentioned that Hiram was very skilled in working with bronze, and he made many furnishings for Solomon's Temple including pillars, capitals, stands, wheels, bowls, and plates, some of which were highly decorative (see I Kings 7:13-47). Bronze was also widely used as battle armor and helmet, as in
14750-424: Was not only the most expensive building of its time — $ 36 million — but it was the first building in the world with floor-to-ceiling glass walls. Mies van der Rohe achieved the crisp edges that were custom-made with specific detailing by General Bronze and "even the screws that hold in the fixed glass-plate windows were made of brass." Bronze is widely used for casting bronze sculptures . Common bronze alloys have
14875-481: Was on hand; the metal of the 12th-century English Gloucester Candlestick is bronze containing a mixture of copper, zinc, tin, lead, nickel, iron, antimony, arsenic and an unusually large amount of silver – between 22.5% in the base and 5.76% in the pan below the candle. The proportions of this mixture suggest that the candlestick was made from a hoard of old coins. The 13th-century Benin Bronzes are in fact brass, and
15000-501: Was only offered to those with obviously familial ALS. But it is increasingly recognized that cases of sporadic ALS may also be due to disease-causing de novo mutations in SOD1 , or C9orf72 , an incomplete family history, or incomplete penetrance , meaning that a patient's ancestors carried the gene but did not express the disease in their lifetimes. The lack of positive family history may be caused by lack of historical records, having
15125-542: Was placed at the Hippodrome of San Siro in Milan, and unveiled on September 10, 1999. The Da Vinci Science Center in Allentown, Pennsylvania, holds the rights to Leonardo da Vinci's Horse as a result of its 2003 merger with LDVHI. Additional renderings of The Horse of different sizes are displayed in the United States and Italy. The second full-size cast of Nina Akamu's design became known as The American Horse, which
15250-777: Was placed in Sheridan , Wyoming, where it was dedicated on August 20, 2014. The Wyoming Horse was commissioned by the Wyoming Community Foundation on behalf of the Sheridan Public Arts Committee. Another 24-foot-high recreation (7.3 m) of the Sforza horse , based on different design interpretation, was manufactured by the Opera Laboratori Fiorentini S.p.A. , in collaboration with Polo Museale Fiorentino and
15375-593: Was the first time that an entire building was sheathed in bronze. The General Bronze Corporation fabricated 3,200,000 pounds (1,600 tons) of bronze at its plant in Garden City, New York . The Seagram Building is a 38-story, 516-foot bronze-and- topaz -tinted glass building. The building looks like a "squarish 38-story tower clad in a restrained curtain wall of metal and glass." "Bronze was selected because of its color, both before and after aging, its corrosion resistance, and its extrusion properties. In 1958, it
15500-468: Was the hardest metal in widespread use is known as the Bronze Age . The beginning of the Bronze Age in western Eurasia and India is conventionally dated to the mid-4th millennium BC (~3500 BC), and to the early 2nd millennium BC in China; elsewhere it gradually spread across regions. The Bronze Age was followed by the Iron Age starting about 1300 BC and reaching most of Eurasia by about 500 BC, although bronze continued to be much more widely used than it
15625-520: Was working on. She reviewed his thoughts on anatomy, painting, sculpture, and natural phenomena. Her research expanded to include the teachers who had influenced Leonardo. Akamu also studied Iberian horse breeds, such as the Andulasian , which were favored by the Sforza stables in the late 15th century. Two full-size casts were made of Akamu's 24-foot (7.3 m) design. The primary cast – The Horse –
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