Pathophysiology

Last updated
Pathophysiology sample values
BMP/ELECTROLYTES:
Na+ = 140 Cl− = 100 BUN = 20 /
Glu = 150
\
K+ = 4 CO2 = 22 PCr = 1.0
ARTERIAL BLOOD GAS:
HCO3− = 24 p a CO2 = 40 p a O2 = 95 pH = 7.40
ALVEOLAR GAS:
p A CO2 = 36 p A O2 = 105 A-a g = 10
OTHER:
Ca = 9.5 Mg2+ = 2.0 PO4 = 1
CK = 55 BE = −0.36 AG = 16
SERUM OSMOLARITY/RENAL:
PMO = 300 PCO = 295 POG = 5 BUN:Cr = 20
URINALYSIS:
UNa+ = 80 UCl− = 100 UAG = 5 FENa = 0.95
UK+ = 25 USG = 1.01 UCr = 60 UO = 800
PROTEIN/GI/LIVER FUNCTION TESTS:
LDH = 100 TP = 7.6 AST = 25 TBIL = 0.7
ALP = 71 Alb = 4.0 ALT = 40 BC = 0.5
AST/ALT = 0.6 BU = 0.2
AF alb = 3.0 SAAG = 1.0 SOG = 60
CSF:
CSF alb = 30 CSF glu = 60 CSF/S alb = 7.5 CSF/S glu = 0.6

Pathophysiology (or physiopathology) is a branch of study, at the intersection of pathology and physiology, concerning disordered 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. [1]

Contents

Etymology

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

History

Nineteenth century

Reductionism

In Germany in the 1830s, 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 pathologist Rudolf Virchow, a former student of Müller, directed focus to the cell, establishing cytology as the focus of physiological research, while Julius Cohnheim pioneered experimental pathology in medical schools' scientific laboratories.[ citation needed ]

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. [2] 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 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. [3] 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." [3] Koch used bacteriology and the new staining methods with aniline dyes to identify particular microorganisms for each. [3] Germ theory of disease crystallized the concept of cause—presumably identifiable by scientific investigation. [4]

Scientific medicine

The American physician William Welch trained in German pathology from 1876 to 1878, including under Cohnheim, and opened America's first scientific laboratory —a pathology laboratory— at Bellevue Hospital in New York City in 1878. [5] Welch's course drew enrollment from students at other medical schools, which responded by opening their own pathology laboratories. [5] 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. [5] Welch returned to America but moved to Baltimore, eager to overhaul American medicine, while blending Vichow's anatomical pathology, Cohnheim's experimental pathology, and Koch's bacteriology. [6] Hopkins medical school, led by the "Four Horsemen" —Welch, William Osler, Howard Kelly, and William Halsted— opened at last in 1893 as America's first medical school devoted to teaching German scientific medicine, so called. [5]

Twentieth century

Biomedicine

The first biomedical institutes, Pasteur Institute and Berlin Institute for Infectious Diseases, whose first directors were Pasteur and Koch, were founded in 1888 and 1891, respectively. America's first biomedical institute, 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.[ citation needed ]

Molecular paradigm

The 1918 pandemic triggered frenzied search for its cause, although most deaths were via lobar pneumonia, already attributed to pneumococcal invasion. In London, pathologist with the Ministry of Health, Fred Griffith in 1928 reported pneumococcal transformation from virulent to avirulent and between antigenic types —nearly a switch in species— challenging pneumonia's specific causation. [7] [8] The laboratory of Rockefeller Institute's Oswald Avery, America's leading pneumococcal expert, was so troubled by the report that they refused to attempt repetition. [9]

When Avery was away on summer vacation, 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. [9] Having returned, Avery kept a photo of Griffith on his desk while his researchers followed the trail. In 1944, Avery, Colin MacLeod, and Maclyn McCarty reported the transformation factor as DNA, widely doubted amid estimations that something must act with it. [10] At the time of Griffith's report, it was unrecognized that bacteria even had genes. [11]

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. [12] In the 1940s, most scientists viewed the cell as a "sack of chemicals" —a membrane containing only loose molecules in chaotic motion— and the only especial cell structures as chromosomes, which bacteria lack as such. [12] Chromosomal DNA was presumed too simple, so genes were sought in 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, 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. [13] Yet the reality of organelles in cells was controversial amid unclear visualization with conventional light microscopy. [12] Around 1940, largely via cancer research at Rockefeller Institute, cell biology emerged as a new discipline filling the vast gap between cytology and biochemistry by applying new technology —ultracentrifuge and electron microscope— to identify and deconstruct cell structures, functions, and mechanisms. [12] The two new sciences interlaced, cell and molecular biology. [12]

Mindful of Griffith and Avery, Joshua Lederberg confirmed bacterial conjugation —reported decades earlier but controversial— and was awarded the 1958 Nobel Prize in Physiology or Medicine. [14] At Cold Spring Harbor Laboratory in Long Island, New York, Delbrück and Salvador Luria led the Phage Group —hosting Watson— discovering details of cell physiology by tracking changes to bacteria upon infection with their viruses, the process transduction. Lederberg led the opening of a genetics department at Stanford University's medical school, and facilitated greater communication between biologists and medical departments. [14]

Disease mechanisms

In the 1950s, researches on rheumatic fever, a complication of 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 immune cells macrophages and that degrade host tissue. [15] In the late 1970s, as president of Memorial Sloan–Kettering Cancer Center, Thomas collaborated with 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. [16] Thomas became for American basic researchers a patron saint. [17]

Examples

Parkinson's disease

The pathophysiology of Parkinson's disease is death of dopaminergic neurons as a result of changes in biological activity in the brain with respect to Parkinson's disease (PD). There are several proposed mechanisms for neuronal 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 bodies, disruption of autophagy, changes in cell metabolism or mitochondrial function, neuroinflammation, and blood–brain barrier (BBB) breakdown resulting in vascular leakiness. [18]

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 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 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 [19]

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 (also known as primary or idiopathic) or secondary. About 90–95% of hypertension is essential hypertension. [20] [21] [22] [23]

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 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, [24] 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. [25] [26]

This field of research had been almost unapproached until the leptin gene was discovered in 1994 by J. M. Friedman's laboratory. [27] 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 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. [28]

See also

Related Research Articles

<span class="mw-page-title-main">Robert Koch</span> German physician and bacteriologist (1843–1910)

Heinrich Hermann Robert Koch was a German physician and microbiologist. As the discoverer of the specific causative agents of deadly infectious diseases including tuberculosis, cholera and anthrax, he is regarded as one of the main founders of modern bacteriology. As such he is popularly nicknamed the father of microbiology, and as the father of medical bacteriology. His discovery of the anthrax bacterium in 1876 is considered as the birth of modern bacteriology. Koch used his discoveries to establish that germs "could cause a specific disease" and directly provided proofs for the germ theory of diseases, therefore creating the scientific basis of public health, saving millions of lives. For his life's work Koch is seen as one of the founders of modern medicine.

<span class="mw-page-title-main">Oswald Avery</span> Canadian-American physician

Oswald Theodore Avery Jr. was a Canadian-American physician and medical researcher. The major part of his career was spent at the Rockefeller Hospital in New York City. Avery was one of the first molecular biologists and a pioneer in immunochemistry, but he is best known for the experiment that isolated DNA as the material of which genes and chromosomes are made.

<span class="mw-page-title-main">Bacteriology</span> Subdiscipline of microbiology that studies bacteria

Bacteriology is the branch and specialty of biology that studies the morphology, ecology, genetics and biochemistry of bacteria as well as many other aspects related to them. This subdivision of microbiology involves the identification, classification, and characterization of bacterial species. Because of the similarity of thinking and working with microorganisms other than bacteria, such as protozoa, fungi, and viruses, there has been a tendency for the field of bacteriology to extend as microbiology. The terms were formerly often used interchangeably. However, bacteriology can be classified as a distinct science.

<span class="mw-page-title-main">Frederick Griffith</span> British bacteriologist

Frederick Griffith (1877–1941) was a British bacteriologist whose focus was the epidemiology and pathology of bacterial pneumonia. In January 1928 he reported what is now known as Griffith's Experiment, the first widely accepted demonstrations of bacterial transformation, whereby a bacterium distinctly changes its form and function.

<span class="mw-page-title-main">Leptin</span> Hormone that inhibits hunger

Leptin, also known as obese protein, is a protein hormone predominantly made by adipocytes. Its primary role is likely to regulate long-term energy balance.

<span class="mw-page-title-main">Adipose tissue</span> Loose connective tissue composed mostly by adipocytes

Adipose tissue is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells such as adipose tissue macrophages. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body.

<span class="mw-page-title-main">Joshua Lederberg</span> American molecular biologist (1925–2008)

Joshua Lederberg, ForMemRS was an American molecular biologist known for his work in microbial genetics, artificial intelligence, and the United States space program. He was 33 years old when he won the 1958 Nobel Prize in Physiology or Medicine for discovering that bacteria can mate and exchange genes. He shared the prize with Edward Tatum and George Beadle, who won for their work with genetics.

<i>Streptococcus pneumoniae</i> Species of bacterium

Streptococcus pneumoniae, or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic member of the genus Streptococcus. S. pneumoniae cells are usually found in pairs (diplococci) and do not form spores and are non motile. As a significant human pathogenic bacterium S. pneumoniae was recognized as a major cause of pneumonia in the late 19th century, and is the subject of many humoral immunity studies.

<span class="mw-page-title-main">Rockefeller University</span> Biomedical research university in New York City, US

The Rockefeller University is a private biomedical research and graduate-only university in New York City, New York. It focuses primarily on the biological and medical sciences and provides doctoral and postdoctoral education. It is classified as a "Special Focus – Research Institution". Rockefeller is the oldest biomedical research institute in the United States.

<span class="mw-page-title-main">Maclyn McCarty</span> Biology research scientist, focused on DNA

Maclyn McCarty was an American geneticist, a research scientist described in 2005 as "the last surviving member of a Manhattan scientific team that overturned medical dogma in the 1940s and became the first to demonstrate that genes were made of DNA." He had worked at Rockefeller University "for more than 60 years." 1994 marked 50 years since this work's release.

Martin Henry Dawson was a Canadian researcher who made important contributions in the fields of infectious diseases.

<span class="mw-page-title-main">Alphonse Dochez</span>

Alphonse Raymond Dochez was an American physician and microbiologist. His research focused on infectious diseases, including scarlet fever, the common cold, and pneumococcal pneumonia. Dochez is credited with developing the first effective treatment for scarlet fever. His work also established viruses as the cause of the common cold.

<span class="mw-page-title-main">Jeffrey M. Friedman</span>

Jeffrey M. Friedman is a molecular geneticist at New York City's Rockefeller University and an Investigator of the Howard Hughes Medical Institute. His discovery of the hormone leptin and its role in regulating body weight has had a major role in the area of human obesity. Friedman is a physician scientist studying the genetic mechanisms that regulate body weight. His research on various aspects of obesity received national attention in late 1994, when it was announced that he and his colleagues had isolated the mouse ob gene and its human homologue. They subsequently found that injections of the encoded protein, leptin, decreases body weight of mice by reducing food intake and increasing energy expenditure. Current research is aimed at understanding the genetic basis of obesity in human and the mechanisms by which leptin transmits its weight-reducing signal.

<span class="mw-page-title-main">Leptin receptor</span> Type I cytokine receptor

Leptin receptor, also known as LEP-R or OB-R, is a type I cytokine receptor, a protein that in humans is encoded by the LEPR gene. LEP-R functions as a receptor for the fat cell-specific hormone leptin. LEP-R has also been designated as CD295. Its location is the cell membrane, and it has extracellular, trans-membrane and intracellular sections.

<span class="mw-page-title-main">Avery–MacLeod–McCarty experiment</span> 1944 microbiology experiment

The Avery–MacLeod–McCarty experiment was an experimental demonstration by Oswald Avery, Colin MacLeod, and Maclyn McCarty that, in 1944, reported that DNA is the substance that causes bacterial transformation, in an era when it had been widely believed that it was proteins that served the function of carrying genetic information. It was the culmination of research in the 1930s and early 20th century at the Rockefeller Institute for Medical Research to purify and characterize the "transforming principle" responsible for the transformation phenomenon first described in Griffith's experiment of 1928: killed Streptococcus pneumoniae of the virulent strain type III-S, when injected along with living but non-virulent type II-R pneumococci, resulted in a deadly infection of type III-S pneumococci. In their paper "Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types: Induction of Transformation by a Desoxyribonucleic Acid Fraction Isolated from Pneumococcus Type III", published in the February 1944 issue of the Journal of Experimental Medicine, Avery and his colleagues suggest that DNA, rather than protein as widely believed at the time, may be the hereditary material of bacteria, and could be analogous to genes and/or viruses in higher organisms.

Douglas L. Coleman was a scientist and professor emeritus at the Jackson Laboratory, in Bar Harbor, Maine. His work predicted that there exists a hormone that can cause mice to feel full, and that a mutation in the gene encoding this hormone can lead to obesity. The gene and corresponding hormone were discovered about 20 years later by Jeffrey M. Friedman, Rudolph Leibel, and their research teams at Rockefeller University, which Friedman named leptin.

The French Louis Pasteur (1822–1895) and German Robert Koch (1843–1910) are the two greatest figures in medical microbiology and in establishing acceptance of the germ theory of disease. In 1882, fueled by national rivalry and a language barrier, the tension between Pasteur and the younger Koch erupted into an acute conflict.

<span class="mw-page-title-main">Stephen R. Bloom</span>

Sir Stephen Robert Bloom FRS is a British Professor of Medicine at Imperial College London where he leads the Diabetes, Endocrinology and Metabolism division.

Comparative medicine is a distinct discipline of experimental medicine that uses animal models of human and animal disease in translational and biomedical research. In other words, it relates and leverages biological similarities and differences among species to better understand the mechanism of human and animal disease. It has also been defined as a study of similarities and differences between human and veterinary medicine including the critical role veterinarians, animal resource centers, and Institutional Animal Care and Use Committees play in facilitating and ensuring humane and reproducible lab animal care and use. The discipline has been instrumental in many of humanity's most important medical advances.

<span class="mw-page-title-main">Pathophysiology of obesity</span> Physiological processes in obese people

Pathophysiology of obesity is the study of disordered physiological processes that cause, result from, or are otherwise associated with obesity. A number of possible pathophysiological mechanisms have been identified which may contribute in the development and maintenance of obesity.

References

  1. ↑ "Pathophysiology – Medical dictionary". TheFreeDictionary.com. Farlex, Inc.
  2. ↑ Théodoridès J (1966). "Casimir Davaine (1812-1882): A precursor of Pasteur". Medical History. 10 (2): 155–65. doi:10.1017/S0025727300010942. PMC   1033586 . PMID   5325873.
  3. 1 2 3 Bulloch, William, The History of Bacteriology (Oxford: Oxford University Press, 1938 & 1960 / New York: Dover Publications, 1979), p 143–144, 147-148
  4. ↑ Carter KC (1980). "Germ theory, hysteria, and Freud's early work in psychopathology". Medical History. 24 (3): 259–74. doi:10.1017/S002572730004031X. PMC   1082654 . PMID   6997653.
  5. 1 2 3 4 Silverman BD (2011). "William Henry Welch (1850-1934): The road to Johns Hopkins". Proceedings. 24 (3): 236–42. doi:10.1080/08998280.2011.11928722. PMC   3124910 . PMID   21738298.
  6. ↑ Benson KR (1999). "Welch, Sedgwick, and the Hopkins model of hygiene". The Yale Journal of Biology and Medicine. 72 (5): 313–20. PMC   2579023 . PMID   11049162.
  7. ↑ "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, "Shifting focus: Early work on bacterial transformation, 1928-1940", Profiles in Science, US National Library of Medicine, Web: 24 Jan 2013].
  8. ↑ Dubos, René J, Oswald T Avery: His Life and Scientific Achievements (New York: Rockefeller University Press, 1976), pp 133, 135-136
  9. 1 2 Dubos, René, "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
  10. ↑ Lederberg J (1956). "Notes on the biological interpretation of Fred Griffith's finding". American Scientist. 44 (3): 268–269.
  11. ↑ Lacks SA (Jan 2003). "Rambling and scrambling in bacterial transformation—a historical and personal memoir". J Bacteriol. 185 (1): 1–6. doi:10.1128/jb.185.1.1-6.2003. PMC   141969 . PMID   12486033.
  12. 1 2 3 4 5 Bechtel, William, Discovering Cell Mechanisms: The Creation of Modern Cell Biology (New York: Cambridge University Press, 2005)
  13. ↑ Kay, Lily, Molecular Vision of Life: Caltech, the Rockefeller Foundation, and the Rise of the New Biology (New York: Oxford University Press, 1993)
  14. 1 2 Institute of Medicine Forum on Microbial Threats (2009). "The Life and Legacies of Joshua Lederberg". Microbial Evolution and Co-Adaptation: A Tribute to the Life and Scientific Legacies of Joshua Lederberg: Workshop Summary. Washington DC: National Academies Press. ISBN   978-0-309-13121-6.
  15. ↑ Sauerwald A, Hoesche C, Oschwald R, Kilimann MW (2007). "Lewis Thomas and droopy rabbit ears". Journal of Experimental Medicine. 204 (12): 2777. doi:10.1084/jem.20412fta. PMC   2118519 .
  16. ↑ Letter: Lewis Thomas (MSKCC) to Joshua Lederberg (Stanford Univ), 7 Aug 1978, p 1
  17. ↑ Weissmann G (2006). "Planning science (a generation after Lewis Thomas)". Journal of Clinical Investigation. 116 (6): 1463. doi:10.1172/JCI28895. PMC   1449953 . PMID   16648878.
  18. ↑ Tansey M. G., Goldberg M. S. (2010). "Neuroinflammation in Parkinson's disease: Its role in neuronal death and implications for therapeutic intervention". Neurobiology of Disease. 37 (3): 510–518. doi:10.1016/j.nbd.2009.11.004. PMC   2823829 . PMID   19913097.
  19. ↑ Golan, Daniel; Staun-Ram, Elsebeth; Miller, Ariel (2016). "Shifting paradigms in multiple sclerosis". Current Opinion in Neurology. 29 (3): 354–361. doi:10.1097/WCO.0000000000000324. PMID   27070218. S2CID   20562972.
  20. ↑ Carretero OA, Oparil S (January 2000). "Essential hypertension. Part I: definition and etiology". Circulation . 101 (3): 329–35. doi: 10.1161/01.CIR.101.3.329 . PMID   10645931 . Retrieved 2009-06-05.
  21. ↑ Oparil S, Zaman MA, Calhoun DA (November 2003). "Pathogenesis of hypertension". Ann. Intern. Med. 139 (9): 761–76. doi:10.7326/0003-4819-139-9-200311040-00011. PMID   14597461. S2CID   32785528.
  22. ↑ Hall, John E.; Guyton, Arthur C. (2006). Textbook of medical physiology . St. Louis, Mo: Elsevier Saunders. p.  228. ISBN   0-7216-0240-1.
  23. ↑ "Hypertension: eMedicine Nephrology" . Retrieved 2009-06-05.
  24. ↑ Doitsh, G; Greene, WC (2016). "Dissecting How CD4 T Cells Are Lost During HIV Infection". Cell Host Microbe. 19 (3): 280–91. doi:10.1016/j.chom.2016.02.012. PMC   4835240 . PMID   26962940.
  25. ↑ Flier JS (2004). "Obesity wars: Molecular progress confronts an expanding epidemic". Cell (Review). 116 (2): 337–50. doi: 10.1016/S0092-8674(03)01081-X . PMID   14744442.
  26. ↑ Rodriguez-Muñoz, A.; Motahari-Rad, H.; Martin-Chaves, L.; Benitez-Porres, J.; Rodriguez-Capitan, J.; Gonzalez-Jimenez, A.; Insenser, M.; Tinahones, F.J.; Murri, M. (2024). "A Systematic Review of Proteomics in Obesity: Unpacking the Molecular Puzzle". Current Obesity Reports. doi: 10.1007/s13679-024-00561-4 . PMC   11306592 . PMID   38703299.
  27. ↑ Zhang, Y; Proenca, R; Maffei, M; Barone, M; Leopold, L; Friedman, JM (Dec 1, 1994). "Positional cloning of the mouse obese gene and its human homologue". Nature (Research Support). 372 (6505): 425–32. Bibcode:1994Natur.372..425Z. doi:10.1038/372425a0. PMID   7984236. S2CID   4359725.
  28. ↑ Considine, RV; Considine, EL; Williams, CJ; Nyce, MR; Magosin, SA; Bauer, TL; Rosato, EL; Colberg, J; Caro, JF (Jun 1995). "Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity". The Journal of Clinical Investigation (Research Support). 95 (6): 2986–8. doi:10.1172/jci118007. PMC   295988 . PMID   7769141.
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