Psychology Wiki

Assessment | Biopsychology | Comparative | Cognitive | Developmental | Language | Individual differences | Personality | Philosophy | Social |
Methods | Statistics | Clinical | Educational | Industrial | Professional items | World psychology |

Other fields of psychology: AI · Computer · Consulting · Consumer · Engineering · Environmental · Forensic · Military · Sport · Transpersonal · Index


This article is in need of attention from a psychologist/academic expert on the subject.
Please help recruit one, or improve this page yourself if you are qualified.
This banner appears on articles that are weak and whose contents should be approached with academic caution.
This article needs rewriting to enhance its relevance to psychologists..
Please help to improve this page yourself if you can..


File:Baker.jpg

Space monkey "Baker" rode a Jupiter IRBM into space in 1959.

Landmarks for animals in space
1947: First animal in space
1949: First monkey in space
1951: First dogs in space
1957: First animal in orbit
1968: First animal in deep space
2007: First animal survives exposure to space

Animals in space originally only served to test the survivability of spaceflight, before manned space missions were attempted. Later, animals were also flown to investigate various biological processes and the effects microgravity and space flight might have on them. Six national space programs have flown animals into space: the Soviet Union, the United States, France, China, Japan and Iran.

Background[]

Animals had been used in aeronautic exploration since 1783 when the Montgolfier brothers sent a sheep, a duck and a rooster aloft in a hot air balloon (the duck serving as the experimental control). The limited supply of captured German V-2 rockets led to the U.S. use of high-altitude balloon launches carrying fruit flies, mice, hamsters, guinea pigs, cats, dogs, frogs, goldfish and monkeys to heights of up to Template:Convert/ftTemplate:Convert/test/A.[1] These high-altitude balloon flights from 1947-1960 tested radiation exposure, physiological response, life support and recovery systems. The U.S. high-altitude manned balloon flights occurred in the same time frame, one of which also carried fruit flies.

1940s[]

File:Albert II V2 launch.jpg

V2 launch No. 47 carried the monkey Albert II into space.

The first animals sent into space were fruit flies aboard a U.S.-launched V-2 rocket on February 20, 1947.[1][2][3][4] The purpose of the experiment was to explore the effects of radiation exposure at high altitudes. The rocket reached 68 miles (109 km) in 3 minutes and 10 seconds, past both the U.S. 50-mile and the international 100 km definitions of the edge of space. The Blossom capsule was ejected and successfully deployed its parachute. The fruit flies were recovered alive. Other V2 missions carried biological samples, including moss.

Albert II, a Rhesus Monkey, became the first monkey in space on June 14, 1949, in a U.S.-launched V2, after the failure of the original Albert's mission on ascent. Albert I reached only 30–39 miles (48–63 km) altitude; Albert II reached about 83 miles (134 km). Albert II died on impact after a parachute failure. Numerous monkeys of several species were flown by the U.S. in the 1950s and 1960s. Monkeys were implanted with sensors to measure vital signs, and many were under anesthesia during launch. The death rate among monkeys at this stage was very high: about two-thirds of monkeys launched in 1940s and 1950s died on missions or soon after landing.

1950s[]

File:Animals In Rocket Flight.ogv

'Animals In Rocket Flight', a 1953 US air-force film

On August 31, 1950, the U.S. launched a mouse into space (137 km) aboard a V2 (the Albert V flight, which, unlike the Albert I-IV flights, did not have a monkey), but the rocket disintegrated because the parachute system failed.[5] The U.S. launched several other mice in the 1950s.

On July 22, 1951, the Soviet Union launched the R-1 IIIA-1 flight, carrying the dogs Tsygan (Russian: Цыган

, "Gypsy") and Dezik (Russian: Дезик

) into space, but not into orbit.[6] These two dogs were the first living higher organisms successfully recovered from a spaceflight.[6] Both space dogs survived the flight, although one would die on a subsequent flight. The U.S. launched mice aboard spacecraft later that year; however, they failed to reach the altitude for true spaceflight.

On November 3, 1957, the second-ever orbiting spacecraft carried the first animal into orbit, the dog Laika, launched aboard the Soviet Sputnik 2 spacecraft (nicknamed 'Muttnik' in the West). Laika died during the flight, as was intended because the technology to return from orbit had not yet been developed. At least 10 other dogs were launched into orbit and numerous others on sub-orbital flights before the historic date of April 12, 1961, when Yuri Gagarin became the first human in space.

On December 13, 1958, a Jupiter IRBM, AM-13, was launched from Cape Canaveral, Florida, with a United States Navy-trained South American squirrel monkey named Gordo on board. The nose cone recovery parachute failed to operate and Gordo was lost. Telemetry data sent back during the flight showed that the monkey survived the 10G of launch, 8 minutes of weightlessness and 40G of reentry at 10,000 miles per hour. The nose cone sank Template:Convert/nmiTemplate:Convert/test/A downrange from Cape Canaveral and was not recovered.

Monkeys Able and Baker became the first monkeys to survive spaceflight after their 1959 flight. On May 28, 1959, aboard Jupiter IRBM AM-18, were a 7-pound (3.18 kg) American-born rhesus monkey, Able, and an 11 ounce (310 g) squirrel monkey from Peru, Baker. The monkeys rode in the nose cone of the missile to an altitude of 360 miles (579 km) and a distance of 1,700 miles (2,735 km) down the Atlantic Missile Range from Cape Canaveral, Florida. They withstood forces 38 times the normal pull of gravity and were weightless for about 9 minutes. A top speed of 10,000 mph (16,000 km/h) was reached during their 16 minute flight. The monkeys survived the flight in good condition. Able died four days after the flight from a reaction to anesthesia, while undergoing surgery to remove an infected medical electrode. Baker lived until November 29, 1984, at the US Space and Rocket Center in Huntsville, Alabama.

On July 2, 1959, a launch of a Soviet R2 rocket, which reached Template:Convert/kmTemplate:Convert/test/A, carried two space dogs and Marfusa, the first rabbit to go into space.[1]

A September 19, 1959 launch, Jupiter AM-23, carried 2 frogs along with 12 mice but the rocket was destroyed during launch.[1]

1960s[]

File:Ham Retreival GPN-2000-001004.jpg

The famous hand shake welcome. After his flight on the Mercury Redstone rocket, chimpanzee Ham is greeted by the commander of the recovery ship, USS Donner (LSD-20).

On August 19, 1960 Russia launched Sputnik 5 (also known as Korabl-Sputnik 2) which carried the dogs Belka and Strelka. It was the first spacecraft to carry animals into orbit and return them alive.[7] One of Strelka's pups, Pushinka, bred and born after her mission, was given as a present to Caroline Kennedy by Nikita Khrushchev in 1961, and many descendants are known to exist.

The USA sent 3 black mice Sally, Amy and Moe 1,000 km up and 8,000 km distance from Cape Canaveral on 13 Oct 1960 using an Atlas D 71D launch vehicle. The mice were retrieved from the nosecone near Ascension Island and were said to be in good condition.[8]

On January 31, 1961, Ham the Chimp was launched in a Mercury capsule aboard a Redstone rocket. His mission was Mercury-Redstone 2. The chimp had been trained to pull levers to receive rewards of banana pellets and avoid electric shocks.[9] His flight demonstrated the ability to perform tasks during spaceflight. A little over 3 months later the United States sent Alan Shepard into space. Enos the chimp became the first chimpanzee in orbit on November 29, 1961, in another Mercury capsule, an Atlas rocket, Mercury-Atlas 5.

The Soviet Union in the Vostok 3A flights of March 1961 launched mice and, for the first time, guinea pigs[10] and frogs.

France flew the first rat (Hector) into space on February 22, 1961. Two more rats were flown in October 1962.[11]

France planned to launch Felix the astronaut cat into space on October 18, 1963, but Felix escaped so they chose another cat, Félicette. The cat had electrodes implanted into her head to measure neural impulses. Félicette was recovered alive, but, due to an accident, the next cat in space was not. The final French animal launches were of two monkeys in March 1967.

China launched mice and rats in 1964 and 1965, and two dogs in 1966.

During the Voskhod program, two Russian space dogs, Veterok (Ветерок, Little Wind) and Ugolyok (Уголёк, Blackie), were launched on February 22, 1966, on board Cosmos 110 and spent 22 days in orbit before landing on March 16. This spaceflight of record-breaking duration was not surpassed by humans until Skylab 2 in 1974 and still stands as the longest space flight by dogs.

The United States launched Biosatellite I in 1966 and Biosatellite I/II in 1967 with fruit flies, parasitic wasps, flour beetles and frog eggs, along with bacteria, amoebae, plants and fungi.[12]

On April 11, 1967, Argentina also launched the rat Belisario, atop an Orion II rocket[citation needed], from Cordoba military range, which was recovered successfully. This flight was followed by a series of subsequent flights using rats.[13] It is unclear if any Argentinean biological flights passed the 100 km limit of space.

The first tortoise in space was launched September 14, 1968 by the Soviet Union. The Horsfield's tortoise was sent on a circumlunar voyage along with wine flies, meal worms and other biological specimens. These were the first animals in deep space. The capsule was recovered at sea on September 21.

The United States launched the monkey Bonny, a macaque, in 1969 on the first multi-day primate mission; it was one of four U.S. monkey missions in the 1960s.

In total in the 1950s and 1960s, the Soviet Union launched missions with passenger slots for at least 57 dogs. The actual number of dogs in space is smaller, because some dogs flew more than once.

On December 23, 1969, as part of the 'Operación Navidad' (Operation Christmas), Argentina launched Juan (a cai monkey, native of Argentina's Misiones Province) using a Canopus II rocket.[14] It ascended 82 kilometers[15] and then was recovered successfully. Later, on the February 1, 1970 the experience was repeated with a female monkey of the same species using a X-1 Panther rocket. It reached a lower altitude than its predecessor, 20 kilometers,[16] and it was lost after the capsule's parachute failed.

1970s[]

File:Spacweb.jpg

First spider web built in space

Two bullfrogs were launched on a one-way mission on the Orbiting Frog Otolith satellite on November 9, 1970, to better understand space motion sickness.

Apollo 16 on April 16, 1972 carried nematodes, and Apollo 17, launched on December 7, 1972 carried five pocket mice, although one died on the circumlunar trip. Skylab 3 carried pocket mice and the first fish in space (a mummichog), and the first spiders in space (Garden Spiders named Arabella and Anita). Mummichog were also flown by the U.S. on the Apollo-Soyuz joint mission, launched July 15, 1975.

The Soviets flew several Bion program missions which consisted of satellites with biological cargoes. On these launches they flew tortoises, rats, and mummichog. On Soyuz 20, launched November 17, 1975, tortoises set the duration record for an animal in space when they spent 90.5 days in space. Salyut 5 on June 22, 1976, carried tortoises and a fish (a zebra danio).

1980s[]

The Soviet Union sent eight monkeys into space in the 1980s on Bion flights. In 1985, the U.S. sent two squirrel monkeys aboard Spacelab 3 on the space shuttle with 24 male albino rats and stick insect eggs. Bion flights also flew zebra danio, fruit flies, rats, stick insect eggs and the first newts in space.

Bion 7 (1985) had 10 newts (Pleurodeles waltl) on board. The newts had part of their front limbs amputated to study the rate of regeneration in space, knowledge to understand human recovery from space injuries.

After an experiment was lost in the Challenger disaster, chicken embryos (fertilized eggs) were sent into space in an experiment on STS-29 in 1989. The experiment was designed for a student contest.

1990s[]

Four monkeys flew aboard the last Bion flights of the Soviet Union as well as frogs and fruit flies. The Foton program flights carried dormant brine shrimp (Artemia franciscana), newts, fruit flies, and sand desert beetles (Trigonoscelis gigas).[17][18]

File:Space newt.jpg

Astronaut Donald Thomas examines a newt on the Space Shuttle

China launched guinea pigs in 1990.[19]

Toyohiro Akiyama, a Japanese journalist carried Japanese tree frogs with him during his trip to the Mir space station in December 1990. Other biological experiments aboard Mir involved quail eggs.

Japan launched its first animals, a species of newt, into space on March 18, 1995 aboard the Space Flyer Unit.

During the 1990s the U.S. carried crickets, mice, rats, frogs, newts, fruit flies, snails, carp, medaka, oyster toadfish, sea urchins, swordtail fish, gypsy moth eggs, stick insect eggs, brine shrimp (Artemia salina), quail eggs, and jellyfish aboard Space Shuttles.

2000s[]

The last flight of Columbia in 2003 carried silkworms, Garden Orb spiders, carpenter bees, harvester ants, and Japanese killifish (medaka). Nematodes (C. elegans) from one experiment were found still alive in the debris after the Space Shuttle Columbia disaster.[20]

C. elegans are also part of experiments aboard the International Space Station as well as research using quail eggs.

Earlier shuttle missions included grade school, junior high and high school projects; some of these included ants, stick insect eggs and brine shrimp cysts. Other science missions included gypsy moth eggs.

On July 12, 2006, Bigelow Aerospace launched their Genesis I inflatable space module, containing many small items such as toys and simple experiments chosen by company employees that would be observed via camera. These items included insects, perhaps making it the first private flight to launch animals into space. Included were Madagascar hissing cockroaches and Mexican jumping beans — seeds containing live larvae of the moth Cydia deshaisiana.[21] On June 28, 2007, Bigelow launched Genesis II, a near-twin to Genesis I. This spacecraft also carried the Madagascar hissing cockroaches and added South African flat rock scorpions (Hadogenes troglodytes) and seed-harvester ants (Pogonomyrmex californicus).[22]

In September, 2007, during the European Space Agency's FOTON-M3 mission, tardigrades, also known as water-bears, were able to survive 10 days of exposure to open-space with only their natural protection.[23][24]

In November 2009, STS-129 took painted lady and monarch butterfly larva into space for a school experiment as well as thousands of C. elegans roundworms for long-term weight loss studies.

2010s[]

On February 3, 2010, on the 31st anniversary of its revolution, Iran became the latest country to launch animals into space. The animals (a mouse, two turtles and some worms) were launched on top of the Kavoshgar 3 rocket and returned alive to Earth.[25][26][27]

In May 2011, the last flight of Endeavour (STS-134) carried two golden orb spiders, named Gladys and Esmerelda, as well as a fruit fly colony as their food source in order to study the effects of microgravity on spiders' behavior.[28]

In November 2011, the Living Interplanetary Flight Experiment on the Fobos-Grunt mission planned to carry tardigrades to Mars and back; however, the mission failed to leave Earth orbit.

In October 2012, 32 medaka fish were delivered to the International Space Station by Soyuz TMA-06M for the new Aquatic Habitat in the Kibo module.

On January 28, 2013, AFP and Sky News reported that Iran sent a monkey in a "Pishgam" rocket to a height of Template:Convert/miTemplate:Convert/test/A and retrieved "shipment".[29][30] The Iranian media gave no details on the timing or location of the launch.[31]

See also[]

  • Bioastronautics
  • Model organism
  • Soviet space dogs
  • Monkeys in space
  • Organisms at high altitude
  • Timeline of Solar System exploration

References[]

  1. 1.0 1.1 1.2 1.3 Beischer, DE; Fregly, AR (1962). Animals and man in space. A chronology and annotated bibliography through the year 1960.. US Naval School of Aviation Medicine ONR TR ACR-64 (AD0272581).
  2. UPPER AIR ROCKET SUMMARY V-2 NO. 20
  3. The Beginnings of Research in Space Biology at the Air Force Missile Development Center, 1946-1952. History of Research in Space Biology and Biodynamics. NASA. URL accessed on 2008-01-31.
  4. V-2 Firing Tables. White Sands Missile Range. URL accessed on 2008-01-31.
  5. http://www.toptenz.net/top-10-animals-astronauts-in-space.php
  6. 6.0 6.1 Siddiqi, p.95
  7. Dogs, Space Online Today, 2004
  8. astronautix.com. URL accessed on 7 dec 2011.
  9. Swenson Jr., Loyd S., James M. Grimwood and Charles C. Alexander (1989). MR-2: Ham Paves the Way. This New Ocean: A History of Project Mercury. NASA. URL accessed on 2008-01-31.
  10. Gray, Tara (1998). Animals in Space. NASA History Division. URL accessed on 2008-01-31.
  11. France, Encyclopedia Astronautica, 1997-2008
  12. Chris Dubbs and Colin Burgess, Animals In Space: From Research Rockets to the Space Shuttle, 2007.
  13. ARGENTINA Y LA CONQUISTA DEL ESPACIO
  14. http://www.unc.edu.ar/seccion/dossier/2009/diciembre/unc_dossier_de_prensa_19-12-2009.pdf
  15. http://www.hoylauniversidad.unc.edu.ar/especiales/mono-juan
  16. http://tiempo.infonews.com/notas/sueno-espacial-argentino-del-mono-juan-al-gauchito
  17. SHRIMP-2; Effects of cosmic radiation and space vacuum on the viability and development of the primitive crustacean Artemia franciscana (part 2), A. Hernandorena, R. Marco, G. Reitz, R. Facius, 1997
  18. Biological clocks of beetles: reactions of free-running circadian rhythms to spaceflight conditions (BEETLE 2), W. Rietveld, A.M. Alpatov, 1997
  19. Timeline: China's space quest. CNN. URL accessed on 2008-01-31.
  20. includeonly>Brown, Irene. "Shuttle worms found alive", United Press International, 2003-04-30. Retrieved on 2008-01-31.
  21. includeonly>Antczak, John. "NLV firm launches Genesis II", Las Vegas Review-Journal, 2007-06-27. Retrieved on 2007-06-30.
  22. includeonly>Chen, Maijinn. "Life in a Box", BigelowAerospace.com. Retrieved on 2007-08-10.
  23. includeonly>"'Water Bears' are first animal to survive vacuum of space", newscientist.com. Retrieved on 2008-09-10.
  24. includeonly>"'Water Bears' Able To Survive Exposure To Vacuum Of Space", sciencedaily.com. Retrieved on 2008-09-10.
  25. includeonly>"Tehran Times", Tehran Times Political Desk, Tehran Times, February 4, 2010. Retrieved on 5 February 2010.
  26. http://wvgazette.com/News/RickSteelhammer/201002060199
  27. includeonly>"'Iran sends mouse, worms, turtles into space", MSNBC. Retrieved on 2010-03-02.
  28. includeonly>"'Venomous Spiders Spin Weightless Webs in Space'", Mike Wall. Retrieved on 2011-05-29.
  29. Gizmodo: Iran Just Sent a Monkey Into Space, Jamie Condliffe, 28 January 2013
  30. Sky News: Iran Space Monkey: Primate 'Sent Into Orbit', 28 January 2013
  31. includeonly>"Iran sends monkey into space", 3 News NZ, January 29, 2013.



Further reading[]

  • Apanasenko, Z. I., Kusnetsova, M. A., Meizerov, E. S., & Serova, L. V. (1982). Conditioned reflexes of albino rats during a cosmic flight: Zhurnal Vysshei Nervnoi Deyatel'nosti Vol 32(2) Mar-Apr 1982, 263-268.
  • Apanasenko, Z. I., Kusnetsova, M. A., Meizerov, E. S., & Serova, L. V. (1983). On the state of processes of internal inhibition in rats during the flight on board the "Cosmos-1129" bio-satellite: Zhurnal Vysshei Nervnoi Deyatel'nosti Vol 33(1) 1983, 26-31.
  • Apanasenko, Z. I., Kuznetsova, M. A., & Korotkova, V. Y. (1986). Behavioral reactions of animals exposed to space flight effects during prenatal development: Kosmicheskaya Biologiya i Aviakosmicheskaya Meditsina Vol 20(4) Jul-Aug 1986, 55-60.
  • Apanasenko, Z. I., Kuznetsova, M. A., Meizerov, E. S., & Serova, L. V. (1983). Conditioned reflexes in white rats during space flight: Neuroscience and Behavioral Physiology Vol 13(4) Jul-Aug 1983, 283-288.
  • Graille, C., Shlyck, G., Buser, P., Kozlovskaia, I., & Rougeul-Buser, A. (1998). In-flight electrocorticograms compared to ground controls in behaving monkeys: Differences in attentional states? : Brain Research Reviews Vol 28(1-2) Nov 1998, 52-60.
  • Gurieva, T. S., Dadasheva, O. A., Meleshko, G. I., Soloviev, A. Y., & et al. (1993). The reaction of adult quails to the spaceflight environment: Aviakosmicheskaya i Ecologicheskaya Meditsina Vol 27(5-6) Sep-Dec 1993, 71-73.
  • Hyde, T. M., Wu, L.-c., Krasnov, I. B., Sigworth, S. K., & et al. (1992). Quantitative autoradiographic analysis of muscarinic cholinergic and GABA-sub(A ) (benzodiazepine) receptors in the forebrain of rats flown on the Soviet Biosatellite COSMOS 2044: Brain Research Vol 593(2) Oct 1992, 291-294.
  • Kaplansky, A. S., Durnova, G. N., Hinds, W., & Vorobyova, V. N. (1996). Experimental morphological investigation of stress-inducing effects of microgravity in rats flown aboard SLS-2: Aviakosmicheskaya i Ecologicheskaya Meditsina Vol 30(2) 1996, 16-20.
  • Krotov, V. P., Sandler, G., & Anes, A. E. (1997). Effect of microgravity on the indices of hemodynamics in primates during postural tests: Aviakosmicheskaya i Ecologicheskaya Meditsina Vol 31(2) 1997, 14-20.
  • Kurkina, L. M., & Tigranyan, R. A. (1982). The content of nitrogen compounds in the large hemispheres and cerebellum of rats flown on board Cosmos-1129: Kosmicheskaya Biologiya i Aviakosmicheskaya Meditsina Vol 16(3) May-Jun 1982, 68-70.
  • Livshits, N. N., Kuznetsova, M. A., Apanasenko, Z. I., & Meizerov, E. S. (1982). Preservation and recovery of food-procuring skill of rats in a maze after space flight on the "Kosmos-782" biosatellite: Neuroscience and Behavioral Physiology Vol 12(3) May-Jun 1982, 193-198.
  • Mori, S., Mitarai, G., Takabayashi, A., Usui, S., Sakakibara, M., Nagatomo, M., et al. (1996). Evidence of sensory conflict and recovery in carp exposed to prolonged weightlessness: Aviation, Space, and Environmental Medicine Vol 67(3) Mar 1996, 256-261.
  • Nemeth, S., & Tigranyan, R. A. (1983). Effect of Cosmos-1129 flight on enzyme activity in the rat liver: Kosmicheskaya Biologiya i Aviakosmicheskaya Meditsina Vol 17(4) 1983, 33-37.
  • Popova, I. A., & Grigoriev, A. I. (1992). Space flight metabolic effects: the results of biochemical rat experiments onboard Cosmos biosatellites: Aviakosmicheskaya i Ecologicheskaya Meditsina Vol 26(5-6) Sep-Dec 1992, 4-10.
  • Recktenwald, M. R., Hodgson, J. A., Roy, R. R., Riazanski, S., McCall, G. E., Kozlovskaya, I., et al. (1999). Effects of spaceflight on rhesus quadrupedal locomotion after return to 1G: Journal of Neurophysiology Vol 81(5) May 1999, 2451-2463.
  • Rohles, F. H. (1992). Orbital bar pressing: A historical note on Skinner and the chimpanzees in space: American Psychologist Vol 47(11) Nov 1992, 1531-1533.
  • Rohles, F. H. (1993). Orbital bar pressing: A historical note on Skinner and the chimpanzees in apace: Aviation, Space, and Environmental Medicine Vol 64(6) Jun 1993, 567-569.
  • Ronca, A., Fritzsch, B., Bruce, L. L., & Alberts, J. R. (2008). Orbital spaceflight during pregnancy shapes function of mammalian vestibular system: Behavioral Neuroscience Vol 122(1) Feb 2008, 224-232.
  • Zhu, X., & Desiderio, D. M. (1994). Effects of space flight stress on proopiomelanocortin, proenkephalin A, and tachykinin neuropeptidergic systems in the rat posterior pituitary: Life Sciences Vol 55(5) 1994, 347-350.
  • McDowell, Jonathan The History of Spaceflight: Nonhuman astronauts. The History of Spaceflight. URL accessed on 2008-01-31.
  • L. W. Fraser and E. H. Siegler, High Altitude Research Using the V-2 Rocket, March 1946-April 1947 (Johns Hopkins University, Bumblebee Series Report No. 8, July 1948), p. 90.
  • Kenneth W. Gatland, Development of the Guided Missile (London and New York, 1952), p. 188
  • Capt. David G. Simons, Use of V-2 Rocket to Convey Primate to Upper Atmosphere (Wright-Patterson Air Force Base, AF Technical Report 5821, May 1949), p. 1.
  • Lloyd Mallan, Men, Rockets, and Space Rats (New York, 1955), pp. 84–93.
  • Henry, James P.; et al. (1952), "Animal Studies of the Subgravity State during Rocket Flight", Journal of Aviation Medicine 23: 421–432