Editing Pathophysiology

{{short description|Convergence of pathology with physiology}}
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'''Pathophysiology''' (or '''physiopathology''') is a branch of study, at the intersection of [[pathology]] and [[physiology]], concerning disordered [[biological process|physiological processes]] that cause, result from, or are otherwise associated with a [[disease]] or [[injury]]. Pathology is the medical discipline that describes conditions typically ''observed'' during a [[disease]] state, whereas physiology is the biological discipline that describes processes or mechanisms ''operating'' within an [[organism]]. Pathology describes the abnormal or undesired condition (symptoms of a disease), whereas pathophysiology seeks to explain the functional changes that are occurring within an individual due to a disease or pathologic state.<ref name="urlpathophysiology - definition of pathophysiology by Medical dictionary">{{cite web | url = http://medical-dictionary.thefreedictionary.com/pathophysiology | title = Pathophysiology – Medical dictionary | work = TheFreeDictionary.com | publisher = Farlex, Inc }}</ref>

==Etymology==

The term ''pathophysiology'' comes from the [[Ancient Greek]] πάθος (''pathos'') and φυσιολογία (''phisiologia'').

==History==

===Early Developments===
The origins of pathophysiology as a distinct field date back to the late 18th century. The first known lectures on the subject were delivered by Professor {{interlanguage link|August Friedrich Hecker|de}} at the [[University of Erfurt]] in 1790, and in 1791, he published the first textbook on pathophysiology, ''Grundriss der Physiologia pathologica'',<ref>{{cite book |last1=Hecker |first1=August Friedrich |title=Grundriss der Physiologia pathologica, oder die Lehre von dem Bau, von der Mischung, und von den Verrichtungen des menschlichen Körpers und seiner Theile im widernatürlichen Zustande |date=1791 |volume=I |url=https://books.google.com/books?id=AM5vSxseazMC&pg=PR1 |language=de}}</ref> spanning 770 pages.<ref>{{cite journal |last1=Stoyanov |first1=George S |last2=Naskovska |first2=Galina |last3=Lyutfi |first3=Emran |last4=Kirneva |first4=Rumiana |last5=Bratoeva |first5=Kameliya |title=In Search of the Ninth Discipline: The History of Pathophysiology, with an Emphasis on Pathophysiology in Varna, Bulgaria—Celebrating 100 Years of Pathophysiology in Bulgaria |journal=Cureus |date=2 April 2018 |page=2 |doi=10.7759/cureus.2404 |doi-access=free|pmid=29872585 |pmc=5984271 }}</ref> Hecker also established the first academic journal in the field, ''Magazin für die pathologische Anatomie und Physiologie'', in 1796.<ref name="Churilov_2015">{{cite journal |last1=Churilov |first1=L. P. |date=December 2015 |title=From Physiology of Disease to Systemic Pathobiology: History and Current Trends in Pathophysiology. |url=https://www.psychiatria-danubina.com/UserDocsImages/pdf/dnb_vol27_sup2/dnb_vol27_sup2_550.pdf |journal=Psychiatria Danubina |volume=27 Suppl 2 |pages=550–570 |pmid=26657983 |archive-url=https://web.archive.org/web/20240802174614/https://www.psychiatria-danubina.com/UserDocsImages/pdf/dnb_vol27_sup2/dnb_vol27_sup2_550.pdf |archive-date=August 2, 2024}}</ref> The French physician [[Jean François Fernel]] had earlier suggested in 1542 that a distinct branch of physiology should study the functions of diseased organisms, an idea further developed by {{interlanguage link|Jean Varandal|de}} in 1617, who first coined the term "pathologic physiology" in a medical text.<ref name=Churilov_2015/>

===Nineteenth century===

====Reductionism====

In Germany in the 1830s, [[Johannes Peter Müller|Johannes Müller]] led the establishment of physiology research autonomous from medical research.  In 1843, the [[Berlin Physical Society]] was founded in part to purge biology and medicine of [[vitalism]], and in 1847 [[Hermann von Helmholtz]], who joined the Society in 1845, published the paper "On the conservation of energy", highly influential to reduce physiology's research foundation to physical sciences. In the late 1850s, German [[anatomical pathology|anatomical pathologist]] [[Rudolf Virchow]], a former student of Müller, directed focus to the cell, establishing [[Cytopathology|cytology]] as the focus of physiological research. He also recognized pathophysiology as a distinct discipline, arguing that it should rely on clinical observation and experimentation rather than purely anatomical pathology.<ref name=Churilov_2015/> Virchow’s influence extended to his student [[Julius Cohnheim]], who pioneered [[experimental pathology]] and the usage of [[intravital microscopy]], further advancing the study of pathophysiology.<ref name=Churilov_2015/>

====Germ theory====
By 1863, motivated by [[Louis Pasteur]]'s report on fermentation to [[butyric acid]], fellow Frenchman [[Casimir Davaine]] identified a microorganism as the crucial causal agent of the cattle disease [[anthrax]], but its routinely vanishing from blood left other scientists inferring it a mere byproduct of [[putrefaction]].<ref>{{cite journal | author = Théodoridès J | title = Casimir Davaine (1812-1882): A precursor of Pasteur | journal = Medical History | volume = 10 | issue = 2 | pages = 155–65 | year = 1966 | pmid = 5325873 | pmc = 1033586 | doi = 10.1017/S0025727300010942 }}</ref>  In 1876, upon [[Ferdinand Cohn]]'s report of a tiny spore stage of a bacterial species, the fellow German [[Robert Koch]] isolated Davaine's ''bacterides'' in [[pure culture]] —a pivotal step that would establish [[bacteriology]] as a distinct discipline— identified a spore stage, applied [[Jakob Henle]]'s postulates, and confirmed Davaine's conclusion, a major feat for [[experimental pathology]]. Pasteur and colleagues followed up with [[ecology|ecological]] investigations confirming its role in the natural environment via spores in soil.

Also, as to [[sepsis]], Davaine had injected rabbits with a highly diluted, tiny amount of putrid blood, duplicated disease, and used the term ''ferment of putrefaction'', but it was unclear whether this referred as did Pasteur's term ''ferment'' to a microorganism or, as it did for many others, to a chemical.<ref name=Bulloch143-148>Bulloch, William, [https://books.google.com/books/about/The_history_of_bacteriology.html?id=TQgZAAAAMAAJ ''The History of Bacteriology''] (Oxford: Oxford University Press, 1938 & 1960 / New York: Dover Publications, 1979), p 143–144, 147-148</ref>  In 1878, Koch published ''Aetiology of Traumatic Infective Diseases'', unlike any previous work, where in 80 pages Koch, as noted by a historian, "was able to show, in a manner practically conclusive, that a number of diseases, differing clinically, anatomically, and in [[aetiology]], can be produced experimentally by the injection of putrid materials into animals."<ref name=Bulloch143-148/>  Koch used bacteriology and the new staining methods with [[aniline dye]]s to identify particular microorganisms for each.<ref name=Bulloch143-148/> [[Germ theory of disease]] crystallized the concept of cause—presumably identifiable by scientific investigation.<ref>{{cite journal | author = Carter KC | title = Germ theory, hysteria, and Freud's early work in psychopathology | journal = Medical History | volume = 24 | issue = 3 | pages = 259–74 | year = 1980 | pmid = 6997653 | pmc = 1082654 | doi = 10.1017/S002572730004031X }}</ref>

====Scientific medicine====

The American physician [[William Henry Welch|William Welch]] trained in German pathology from 1876 to 1878, including under [[Julius Cohnheim|Cohnheim]], and opened America's first scientific laboratory —a pathology laboratory— at [[Bellevue Hospital]] in New York City in 1878.<ref name=Silverman>{{cite journal | author = Silverman BD | title = William Henry Welch (1850-1934): The road to Johns Hopkins | journal = Proceedings | volume = 24 | issue = 3 | pages = 236–42 | year = 2011 | pmid = 21738298 | pmc = 3124910 | doi=10.1080/08998280.2011.11928722}}</ref>  Welch's course drew enrollment from students at other medical schools, which responded by opening their own pathology laboratories.<ref name=Silverman/>  Once appointed by [[Daniel Coit Gilman]], upon advice by [[John Shaw Billings]], as founding dean of the medical school of the newly forming [[Johns Hopkins University]] that Gilman, as its first president, was planning, Welch traveled again to Germany for training in Koch's bacteriology in 1883.<ref name=Silverman/>  Welch returned to America but moved to Baltimore, eager to overhaul American medicine, while blending Virchow's anatomical pathology, Cohnheim's experimental pathology, and Koch's bacteriology.<ref name=Benson>{{cite journal | author = Benson KR | title = Welch, Sedgwick, and the Hopkins model of hygiene | journal = The Yale Journal of Biology and Medicine | volume = 72 | issue = 5 | pages = 313–20 | year = 1999 | pmid = 11049162 | pmc = 2579023 }}</ref>  Hopkins medical school, led by the "Four Horsemen" —Welch, [[William Osler]], [[Howard A. Kelly|Howard Kelly]], and [[William Stewart Halsted|William Halsted]]— opened at last in 1893 as America's first medical school devoted to teaching German scientific medicine, so called.<ref name=Silverman/>

===Twentieth century===

====Biomedicine====

The first biomedical institutes, [[Pasteur Institute]] and [[Robert Koch Institute|Berlin Institute for Infectious Diseases]], whose first directors were [[Louis Pasteur|Pasteur]] and [[Robert Koch|Koch]], were founded in 1888 and 1891, respectively. America's first biomedical institute, [[The Rockefeller University|The Rockefeller Institute for Medical Research]], was founded in 1901 with Welch, nicknamed "dean of American medicine", as its scientific director, who appointed his former Hopkins student [[Simon Flexner]] as director of pathology and bacteriology laboratories.  By way of [[World War I]] and [[World War II]], Rockefeller Institute became the globe's leader in biomedical research.{{cn|date=June 2022}}

====Molecular paradigm====

The [[1918 pandemic]] triggered frenzied search for its cause, although most deaths were via [[lobar pneumonia]], already attributed to [[pneumococcus|pneumococcal]] invasion.  In London, pathologist with the Ministry of Health, [[Fred Griffith]] in 1928 reported pneumococcal [[bacterial transformation|transformation]] from virulent to avirulent and between antigenic types —nearly a switch in species— challenging pneumonia's specific causation.<ref>"In the bacteriology of the 1920s, the conversion of the R to the S form could be regarded as an adaptation to the environment. However, the transformation of Type I to Type II was the equivalent of the transformation of one species into another, a phenomenon never before observed.  Avery was initially skeptical of Griffith's findings and for some time refused to accept the validity of his claims, believing that they were the result of inadequate experimental controls. Avery's research on therapeutic sera led him to conclude that pneumococcal types were fixed and that specific therapeutic agents could thus be developed to combat the various types. A transformation from type to type [[in vivo]] presented a disturbing clinical picture, as well as a challenge to the theoretical formulations of contemporary bacteriology" [Oswald T Avery Collection, [http://profiles.nlm.nih.gov/ps/retrieve/Narrative/CC/p-nid/38 "Shifting focus: Early work on bacterial transformation, 1928-1940"], ''Profiles in Science'', US National Library of Medicine, Web: 24 Jan 2013].</ref><ref>[[René Dubos|Dubos, René J]], [http://profiles.nlm.nih.gov/ps/access/CCAAOG.ocr ''Oswald T Avery: His Life and Scientific Achievements''] (New York: Rockefeller University Press, 1976), pp 133, 135-136</ref> The laboratory of Rockefeller Institute's [[Oswald T. Avery|Oswald Avery]], America's leading pneumococcal expert, was so troubled by the report that they refused to attempt repetition.<ref name=Dubos>Dubos, René, [http://profiles.nlm.nih.gov/ps/retrieve/ResourceMetadata/CCAAOA "Memories of working in Oswald Avery's laboratory"], Symposium Celebrating the Thirty-Fifth Anniversary of the Publication of "Studies on the chemical nature of the substance inducing transformation of pneumococcal types", 2 Feb 1979</ref>

When Avery was away on summer vacation, [[Martin Henry Dawson|Martin Dawson]], British-Canadian, convinced that anything from England must be correct, repeated Griffith's results, then achieved transformation ''[[in vitro]]'', too, opening it to precise investigation.<ref name=Dubos/> Having returned, Avery kept a photo of Griffith on his desk while his researchers followed the trail.  In 1944, Avery, [[Colin Munro MacLeod|Colin MacLeod]], and [[Maclyn McCarty]] reported the transformation factor as [[DNA]], widely doubted amid estimations that something must act with it.<ref>{{cite journal | author = Lederberg J | year = 1956 | title = Notes on the biological interpretation of Fred Griffith's finding | url = http://profiles.nlm.nih.gov/ps/retrieve/ResourceMetadata/CCAAQX | journal = American Scientist | volume = 44 | issue = 3| pages = 268–269 }}</ref>  At the time of Griffith's report, it was unrecognized that bacteria even had genes.<ref>{{cite journal | author = Lacks SA | title = Rambling and scrambling in bacterial transformation—a historical and personal memoir | journal = J Bacteriol | volume = 185 | issue = 1 | pages = 1–6 | date = Jan 2003 | pmid = 12486033 | doi = 10.1128/jb.185.1.1-6.2003 | pmc=141969}}</ref>

The first genetics, [[Mendelian genetics]], began at 1900, yet inheritance of Mendelian traits was localized to [[chromosomes]] by 1903, thus [[chromosomal genetics]]. [[Biochemistry]] emerged in the same decade.<ref name=Bechtel>Bechtel, William, [https://books.google.com/books/about/Discovering_Cell_Mechanisms.html?id=WrEquK3hoDwC ''Discovering Cell Mechanisms: The Creation of Modern Cell Biology''] (New York: Cambridge University Press, 2005)</ref> In the 1940s, most scientists viewed the cell as a "sack of chemicals" —a membrane containing only loose molecules in [[Brownian motion|chaotic motion]]— and the only especial cell structures as chromosomes, which bacteria lack as such.<ref name=Bechtel/>  Chromosomal DNA was presumed too simple, so genes were sought in [[histones|chromosomal proteins]].  Yet in 1953, American biologist [[James Watson]], British physicist [[Francis Crick]], and British chemist [[Rosalind Franklin]] inferred DNA's molecular structure —a [[double helix]]— and conjectured it to spell a code.  In the early 1960s, [[Francis Crick|Crick]] helped crack a [[genetic code]] in [[DNA]], thus establishing [[molecular genetics]].

In the late 1930s, [[Rockefeller Foundation]] had spearheaded and funded the [[molecular biology]] [[research program]] —seeking fundamental explanation of organisms and life— led largely by physicist [[Max Delbrück]] at [[Caltech]] and [[Vanderbilt University]].<ref>Kay, Lily, [https://books.google.com/books?id=vEHeNI2a8OEC ''Molecular Vision of Life: Caltech, the Rockefeller Foundation, and the Rise of the New Biology''] (New York: Oxford University Press, 1993)</ref>  Yet the reality of [[organelles]] in cells was controversial amid unclear visualization with conventional [[light microscopy]].<ref name=Bechtel/>  Around 1940, largely via cancer research at Rockefeller Institute, [[cell biology]] emerged as a new discipline filling the vast gap between [[Cytopathology|cytology]] and [[biochemistry]] by applying new technology —[[ultracentrifuge]] and [[electron microscope]]— to identify and deconstruct cell structures, functions, and mechanisms.<ref name=Bechtel/>  The two new sciences interlaced, ''cell and molecular biology''.<ref name=Bechtel/>

Mindful of [[Fred Griffith|Griffith]] and [[Oswald T. Avery|Avery]], [[Joshua Lederberg]] confirmed [[bacterial conjugation]] —reported decades earlier but controversial— and was awarded the 1958 [[Nobel Prize in Physiology or Medicine]].<ref name=IOM2009>{{cite book |author=[[Institute of Medicine]] Forum on Microbial Threats |title=Microbial Evolution and Co-Adaptation: A Tribute to the Life and Scientific Legacies of Joshua Lederberg: Workshop Summary |location=Washington DC |publisher=National Academies Press |year=2009 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK45705 |chapter=The Life and Legacies of Joshua Lederberg |isbn=978-0-309-13121-6}}</ref>   At [[Cold Spring Harbor Laboratory]] in Long Island, New York, [[Max Delbrück|Delbrück]] and [[Salvador Luria]] led the [[Phage Group]] —hosting [[James Watson|Watson]]— discovering details of cell physiology by tracking changes to bacteria upon infection with [[bacteriophage|their viruses]], the process [[transduction (genetics)|transduction]].  Lederberg led the opening of a genetics department at [[Stanford University]]'s medical school, and facilitated greater communication between biologists and medical departments.<ref name=IOM2009/>

====Disease mechanisms====

In the 1950s, researches on [[rheumatic fever]], a complication of [[streptococcus|streptococcal]] infections, revealed it was mediated by the host's own immune response, stirring investigation by pathologist [[Lewis Thomas]] that led to identification of enzymes released by the [[innate immunity|innate immune]] cells [[macrophages]] and that degrade host tissue.<ref>{{cite journal |vauthors=Sauerwald A, Hoesche C, Oschwald R, Kilimann MW | title = Lewis Thomas and droopy rabbit ears | journal = Journal of Experimental Medicine | volume = 204 | issue = 12 | pages = 2777 | year = 2007 | pmc = 2118519 | doi = 10.1084/jem.20412fta }}</ref>  In the late 1970s, as president of [[Memorial Sloan–Kettering Cancer Center]], Thomas collaborated with [[Joshua Lederberg|Lederberg]], soon to become president of [[Rockefeller University]], to redirect the funding focus of the US [[National Institutes of Health]] toward basic research into the mechanisms operating during disease processes, which at the time medical scientists were all but wholly ignorant of, as biologists had scarcely taken interest in disease mechanisms.<ref>Letter: Lewis Thomas (MSKCC) to Joshua Lederberg (Stanford Univ), 7 Aug 1978, [http://profiles.nlm.nih.gov/ps/access/BBARNX.pdf p 1]</ref>   Thomas became for American [[basic research]]ers a [[patron saint]].<ref>{{cite journal | author = Weissmann G | title = Planning science (a generation after Lewis Thomas) | journal = Journal of Clinical Investigation | volume = 116 | issue = 6 | pages = 1463 | year = 2006 | pmid = 16648878 | pmc = 1449953 | doi = 10.1172/JCI28895 }}</ref>

==Examples==

===Parkinson's disease===

The [[pathophysiology of Parkinson's disease]] is [[apoptosis|death]] of [[dopamine|dopaminergic]] [[neuron]]s as a result of changes in biological activity in the brain with respect to [[Parkinson's disease]] (PD). There are several proposed mechanisms for [[neuron]]al [[apoptosis|death]] in PD; however, not all of them are well understood. Five proposed major mechanisms for neuronal death in Parkinson's Disease include protein aggregation in [[Lewy Body|Lewy bodies]], disruption of [[autophagy]], changes in cell metabolism or [[mitochondria]]l function, [[neuroinflammation]], and [[blood–brain barrier]] (BBB) breakdown resulting in vascular leakiness.<ref>{{cite journal | author = Tansey M. G., Goldberg M. S. | year = 2010 | title = Neuroinflammation in Parkinson's disease: Its role in neuronal death and implications for therapeutic intervention | journal = Neurobiology of Disease | volume = 37 | issue = 3| pages = 510–518 | doi = 10.1016/j.nbd.2009.11.004 | pmc = 2823829 | pmid=19913097}}</ref>

===Heart failure===

The [[pathophysiology of heart failure]] is a reduction in the efficiency of the heart muscle, through damage or overloading. As such, it can be caused by a wide number of conditions, including myocardial infarction (in which the heart muscle is [[ischemia|starved of oxygen]] and dies), hypertension (which increases the force of contraction needed to pump blood) and [[amyloidosis]] (in which misfolded proteins are deposited in the heart muscle, causing it to stiffen). Over time these increases in workload will produce changes to the heart itself.

===Multiple sclerosis===

The [[pathophysiology of multiple sclerosis]] is that of an [[inflammatory demyelinating diseases of the CNS|inflammatory demyelinating disease of the CNS]] in which activated immune cells invade the central nervous system and cause inflammation, neurodegeneration and tissue damage. The underlying condition that produces this behaviour is currently unknown. Current research in neuropathology, neuroimmunology, neurobiology, and neuroimaging, together with clinical neurology provide support for the notion that MS is not a single disease but rather a spectrum<ref>{{Cite journal |doi= 10.1097/WCO.0000000000000324 |pmid= 27070218 |title= Shifting paradigms in multiple sclerosis |journal= Current Opinion in Neurology |volume= 29 |issue= 3 |pages= 354–361 |year= 2016 |last1= Golan |first1= Daniel |last2= Staun-Ram |first2= Elsebeth |last3= Miller |first3= Ariel|s2cid= 20562972 }}</ref>

===Hypertension===

The [[pathophysiology of hypertension]] is that of a chronic disease characterized by elevation of [[blood pressure]]. Hypertension can be classified by cause as either [[Essential hypertension|essential]] (also known as primary or [[idiopathy|idiopathic]]) or [[secondary hypertension|secondary]]. About 90–95% of hypertension is essential hypertension.<ref name="pmid10645931">{{cite journal |vauthors=Carretero OA, Oparil S |title=Essential hypertension. Part I: definition and etiology |journal=[[Circulation (journal)|Circulation]] |volume=101 |issue=3 |pages=329–35 |date=January 2000 |pmid=10645931 |doi=10.1161/01.CIR.101.3.329|doi-access=free }}</ref><ref name="pmid14597461">{{cite journal |vauthors=Oparil S, Zaman MA, Calhoun DA |title=Pathogenesis of hypertension |journal=[[Ann. Intern. Med.]] |volume=139 |issue=9 |pages=761–76 |date=November 2003 |pmid=14597461 |doi=10.7326/0003-4819-139-9-200311040-00011|s2cid=32785528 }}</ref><ref name="isbn0-7216-0240-1">{{cite book |author1=Hall, John E. |author2=Guyton, Arthur C. |title=Textbook of medical physiology |url=https://archive.org/details/textbookmedicalp00acgu |url-access=limited |publisher=Elsevier Saunders |location=St. Louis, Mo |year=2006 |page=[https://archive.org/details/textbookmedicalp00acgu/page/n262 228] |isbn=0-7216-0240-1 }}</ref><ref name="urlHypertension: eMedicine Nephrology">{{cite web |url=http://emedicine.medscape.com/article/241381-overview |title=Hypertension: eMedicine Nephrology |access-date=2009-06-05 }}</ref>

===HIV/AIDS===

The [[pathophysiology of HIV/AIDS]] involves, upon acquisition of the virus, that the virus replicates inside and kills [[T helper cells]], which are required for almost all [[adaptive immune system|adaptive immune responses]]. There is an initial period of [[influenza-like illness]], and then a latent, asymptomatic phase. When the [[CD4]] lymphocyte count falls below 200 cells/ml of blood, the HIV host has progressed to AIDS,<ref>{{cite journal | pmid = 26962940 | doi=10.1016/j.chom.2016.02.012 | pmc=4835240 | volume=19 | title=Dissecting How CD4 T Cells Are Lost During HIV Infection | journal=Cell Host Microbe | pages=280–91 | last1 = Doitsh | first1 = G | last2 = Greene | first2 = WC | year=2016| issue=3 }}</ref> a condition characterized by deficiency in [[cell-mediated immunity]] and the resulting increased susceptibility to [[opportunistic infections]] and certain forms of [[cancer]].

===Spider bites===

The [[pathophysiology of spider bites]] is due to the effect of its [[venom]]. A spider envenomation occurs whenever a spider injects [[venom]] into the skin. Not all spider bites inject venom – a dry bite, and the amount of venom injected can vary based on the type of spider and the circumstances of the encounter. The mechanical injury from a spider bite is not a serious concern for humans.

===Obesity===

The [[pathophysiology of obesity]] involves many possible pathophysiological mechanisms involved in its development and maintenance.<ref name="flier">{{cite journal | author = Flier JS | title = Obesity wars: Molecular progress confronts an expanding epidemic | journal = Cell | volume = 116 | issue = 2 | pages = 337–50 | year = 2004 | pmid = 14744442 | doi = 10.1016/S0092-8674(03)01081-X | type = Review | doi-access = free }}</ref><ref name="murri">{{cite journal
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This field of research had been almost unapproached until the [[leptin]] gene was discovered in 1994 by J. M. Friedman's laboratory.<ref>{{cite journal|last1=Zhang|first1=Y|last2=Proenca|first2=R|last3=Maffei|first3=M|last4=Barone|first4=M|last5=Leopold|first5=L|last6=Friedman|first6=JM|title=Positional cloning of the mouse obese gene and its human homologue.|journal=Nature|date=Dec 1, 1994|volume=372|issue=6505|pages=425–32|doi=10.1038/372425a0|pmid=7984236|bibcode=1994Natur.372..425Z|s2cid=4359725|type=Research Support}}</ref> These investigators postulated that leptin was a satiety factor. In the ob/ob mouse, mutations in the [[leptin]] gene resulted in the obese phenotype opening the possibility of leptin therapy for human obesity. However, soon thereafter [[Jose F. Caro|J. F. Caro's]] laboratory could not detect any mutations in the leptin gene in humans with obesity. On the contrary [[Leptin]] expression was increased proposing the possibility of Leptin-resistance in human obesity.<ref>{{cite journal|last1=Considine|first1=RV|last2=Considine|first2=EL|last3=Williams|first3=CJ|last4=Nyce|first4=MR|last5=Magosin|first5=SA|last6=Bauer|first6=TL|last7=Rosato|first7=EL|last8=Colberg|first8=J|last9=Caro|first9=JF <!--exactly 9 authors--> |title=Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity.|journal=The Journal of Clinical Investigation|date=Jun 1995|volume=95|issue=6|pages=2986–8|pmid=7769141|doi=10.1172/jci118007|pmc=295988|type=Research Support}}</ref>

==See also==
* [[Pathogenesis]]

==References==
{{reflist|2}}

{{Authority control}}

[[Category:Pathophysiology| ]]
[[Category:Pathology]]
[[Category:Physiology]]