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{{Brucellosis}}
== Overview ==
''[[Brucella|Brucellosis]]'' is a [[zoonotic]] disease, [[humans]] could be infected by eating undercook meat or raw [[Dairy product|dairy]] products, inhalation of the [[bacteria]] and direct contact of bacteria with [[skin]] [[wounds]] or [[Mucous membranes|mucous membranes.]] Following transmission, [[white blood cells]] phagocyte the pathogen and transports it via hematologic or [[Lymphatic system|lymphatic route]] to different organs, specially to those of the [[reticuloendothelial system]].
 
== Pathophysiology ==
''[[Brucella|Brucellosis]]'' is a [[zoonotic]] disease, [[humans]] could be infected by eating undercook meat or raw [[Dairy product|dairy]] products, inhalation of the [[bacteria]] and direct contact of bacteria with [[skin]] [[wounds]] or [[Mucous membranes|mucous membranes.]] Following transmission, [[white blood cells]] phagocyte the pathogen and transports it via hematologic or [[Lymphatic system|lymphatic route]] to different organs specially to those of the [[reticuloendothelial system]]. [[Endotoxic]] [[lipopolysaccharide]] LPS, plays an important role in: survival of bacteria inside [[Monocytic|monocytic cel]]<nowiki/>l, supressing [[Lysosome|phagosome-lysosome fusion]] and internalizing bacteria into [[endoplasmic reticulum]]. The pathophysiology of Brucellosis can be described in the following steps:<ref name="pmid15930423">{{cite journal| author=Pappas G, Akritidis N, Bosilkovski M, Tsianos E| title=Brucellosis. | journal=N Engl J Med | year= 2005 | volume= 352 | issue= 22 | pages= 2325-36 | pmid=15930423 | doi=10.1056/NEJMra050570 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15930423  }}</ref><ref name=":0">{{Cite web|url=https://www.cdc.gov/brucellosis/transmission/index.html|title=CDC|date=|access-date=|website=|publisher=|last=|first=}}</ref><ref name="pmid8698508">{{cite journal| author=Zhan Y, Liu Z, Cheers C| title=Tumor necrosis factor alpha and interleukin-12 contribute to resistance to the intracellular bacterium Brucella abortus by different mechanisms. | journal=Infect Immun | year= 1996 | volume= 64 | issue= 7 | pages= 2782-6 | pmid=8698508 | doi= | pmc=174139 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8698508  }} </ref><ref name="pmid1574477">{{cite journal| author=Larralde de Luna M, Raspa ML, Ibargoyen J| title=Oral-facial-digital type 1 syndrome of Papillon-Léage and Psaume. | journal=Pediatr Dermatol | year= 1992 | volume= 9 | issue= 1 | pages= 52-6 | pmid=1574477 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1574477  }} </ref><ref name="pmid2915152">{{cite journal| author=Gazapo E, Gonzalez Lahoz J, Subiza JL, Baquero M, Gil J, de la Concha EG| title=Changes in IgM and IgG antibody concentrations in brucellosis over time: importance for diagnosis and follow-up. | journal=J Infect Dis | year= 1989 | volume= 159 | issue= 2 | pages= 219-25 | pmid=2915152 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2915152  }} </ref><ref name="pmid10858243">{{cite journal| author=Arenas GN, Staskevich AS, Aballay A, Mayorga LS| title=Intracellular trafficking of Brucella abortus in J774 macrophages. | journal=Infect Immun | year= 2000 | volume= 68 | issue= 7 | pages= 4255-63 | pmid=10858243 | doi= | pmc=101738 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10858243  }} </ref><ref name="pmid12414154">{{cite journal| author=Boschiroli ML, Ouahrani-Bettache S, Foulongne V, Michaux-Charachon S, Bourg G, Allardet-Servent A et al.| title=Type IV secretion and Brucella virulence. | journal=Vet Microbiol | year= 2002 | volume= 90 | issue= 1-4 | pages= 341-8 | pmid=12414154 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12414154  }} </ref><ref name="pmid15694858">{{cite journal| author=Lapaque N, Moriyon I, Moreno E, Gorvel JP| title=Brucella lipopolysaccharide acts as a virulence factor. | journal=Curr Opin Microbiol | year= 2005 | volume= 8 | issue= 1 | pages= 60-6 | pmid=15694858 | doi=10.1016/j.mib.2004.12.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15694858  }} </ref><ref name="pmid12414174">{{cite journal| author=DelVecchio VG, Kapatral V, Elzer P, Patra G, Mujer CV| title=The genome of Brucella melitensis. | journal=Vet Microbiol | year= 2002 | volume= 90 | issue= 1-4 | pages= 587-92 | pmid=12414174 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12414174  }} </ref><ref name="pmid11782541">{{cite journal| author=Moreno E, Moriyon I| title=Brucella melitensis: a nasty bug with hidden credentials for virulence. | journal=Proc Natl Acad Sci U S A | year= 2002 | volume= 99 | issue= 1 | pages= 1-3 | pmid=11782541 | doi=10.1073/pnas.022622699 | pmc=117501 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11782541  }} </ref><ref name="pmid12414149">{{cite journal| author=Gorvel JP, Moreno E| title=Brucella intracellular life: from invasion to intracellular replication. | journal=Vet Microbiol | year= 2002 | volume= 90 | issue= 1-4 | pages= 281-97 | pmid=12414149 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12414149  }} </ref><ref name="pmid12525425">{{cite journal| author=Ko J, Splitter GA| title=Molecular host-pathogen interaction in brucellosis: current understanding and future approaches to vaccine development for mice and humans. | journal=Clin Microbiol Rev | year= 2003 | volume= 16 | issue= 1 | pages= 65-78 | pmid=12525425 | doi= | pmc=145300 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12525425  }} </ref><ref name="pmid12414158">{{cite journal| author=Dornand J, Gross A, Lafont V, Liautard J, Oliaro J, Liautard JP| title=The innate immune response against Brucella in humans. | journal=Vet Microbiol | year= 2002 | volume= 90 | issue= 1-4 | pages= 383-94 | pmid=12414158 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12414158  }} </ref>
 
=== Transmission===
According to CDC, humans are generally infected with Brucellosis in one of the following three ways:<ref name="pmid15930423" /><ref>{{Cite web|url=CDC|title=https://www.cdc.gov/brucellosis/transmission/index.html|last=|first=|date=|website=|publisher=|access-date=}}</ref>
{| class="wikitable"
! colspan="2" |ROUTE OF TRANSMISSION
|-
|[[Gastrointestinal]]
|
Eating undercooked meat or consuming [[Unpasteurized milk|unpasteurized]]/raw dairy products
|-
|[[Inhalation]]
|
[[Breathing]] in the [[bacteria]] that cause brucellosis (inhalation)
|-
|[[Cutaneous]]
|
[[Bacteria]] entering the body through skin [[wounds]] or [[mucous membranes]]
|-
|Other modes of transmission
|
*Person-to-person spread of [[brucellosis]] is extremely rare.
*Infected mothers who are breast-feeding may transmit the infection to their infants.
*Sexual transmission has been rarely reported.
*While uncommon, [[transmission]] may also occur via [[Transplantation|tissue transplantation]] or [[blood transfusions]].
|}
 
=== '''Incubation''' ===
[[Incubation period]] of brucellosis varies from one to four weeks. But occasionally, it may be as long as several months. 
 
=== '''Dissemination''' ===
Following transmission, brucellae is ingested by [[macrophages]] and [[Polymorphonuclear cells|polymorphonuclea]]<nowiki/>r cells. On ingestion, they replicate [[Intracellular|intracellularly]] inside the lysed cells and disseminate systemically. 
 
===Seeding===
* On [[transmission]], [[bacteria]] is actively [[phagocytosed]]  by neurophilic [[granulocytes]] and [[monocytes]].
 
*On entry into the body, [[Brucella|brucellae]] multiply in the [[Neutrophil|neutrophilic]] [[granulocytes]] and [[monocytes]], initially in [[lymph nodes]], which is followed by systemic hematogenous spread resulting in multiple localizing [[infection]]
 
===Immune response===
Brucellosis elicits both [[Humoral immunity|humoral]] and [[Cell-mediated immunity|cell-mediated]] [[immune]] responses:<ref name="pmid15930423" /><ref name=":0" /><ref name="pmid8698508" /><ref name="pmid1574477" /><ref name="pmid2915152" /><ref name="pmid10858243" /><ref name="pmid12414154" /><ref name="pmid15694858" /><ref name="pmid12414174" /><ref name="pmid27672085">{{cite journal| author=Khan M, Harms JS, Marim FM, Armon L, Hall CL, Liu YP et al.| title=The Bacterial Second Messenger Cyclic di-GMP Regulates Brucella Pathogenesis and Leads to Altered Host Immune Response. | journal=Infect Immun | year= 2016 | volume= 84 | issue= 12 | pages= 3458-3470 | pmid=27672085 | doi=10.1128/IAI.00531-16 | pmc=5116723 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27672085  }}</ref><ref name="pmid159304233">{{cite journal| author=Pappas G, Akritidis N, Bosilkovski M, Tsianos E| title=Brucellosis. | journal=N Engl J Med | year= 2005 | volume= 352 | issue= 22 | pages= 2325-36 | pmid=15930423 | doi=10.1056/NEJMra050570 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15930423  }}</ref>
====Humoral immune response====
* [[Humoral immune system|Humoral]] response has a limited role in protecting host from [[Brucellosis|Brucellae]].
* On activation, [[Chronic lymphocytic leukemia|B-cell]] produce [[IgM]] class [[antibody]], which is followed by [[IgG]] antibodies .
* [[Antibodies]] promote clearance of extracellular [[bacteria]] and facilitate [[phagocytosis]] of the Brucellae.
 
====Cell mediates immune response====
*Tumor necrosis factor α ([[TNF-α]]) produces on activation of [[cell mediated immunity]], stimulates [[T lymphocytes]] and [[macrophages]], which help in eliminating intracellular [[brucellae]]. Virulent brucellae tend to suppress the activity of tumor necrosis factor α (TNF-α) and  [[IFN|IFN-gamma]].
*[[Cytokines]] such as [[Interleukin 12|interleukin (IL) 12]] promote production of Interferon γ ([[Interferon|IFN-γ]]) responses. IFN-γ, which drives [[TH1]]-type responses and stimulates [[macrophage]] activation. [[Cytokines]], which include , [[IL-6]], [[IL-4]]<nowiki/>and [[IL-10]], down-regulate the protective response.
 
==Pathogenesis==
The pathogenesis of brucellosis is complex and not fully understood:<ref name="pmid15930423" /><ref name=":0" /><ref name="pmid8698508" /><ref name="pmid1574477" /><ref name="pmid2915152" /><ref name="pmid10858243" /><ref name="pmid12414154" /><ref name="pmid15694858" /><ref name="pmid12414174" /><ref>Barquero-Calvo E, Chaves-Olarte E, Weiss DS, et al. Brucella abortus uses a stealthy strategy to avoid activation of the innate immune system during the onset of infection. PLoS One 2007; 2:e631.</ref><ref>Gorvel JP, Moreno E. Brucella intracellular life: from invasion to intracellular replication. Vet Microbiol 2002; 90:281.</ref><ref name="pmid159304234">{{cite journal| author=Pappas G, Akritidis N, Bosilkovski M, Tsianos E| title=Brucellosis. | journal=N Engl J Med | year= 2005 | volume= 352 | issue= 22 | pages= 2325-36 | pmid=15930423 | doi=10.1056/NEJMra050570 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15930423  }}</ref>
 
By avoiding [[innate immunity]], [[Brucella infection|brucella]] survive with in [[Monocytic|monocytic cells]].
*Endotoxic [[lipopolysaccharide]] (LPS), plays a key role in survival of bacteria inside [[monocytic]] cell.
*[[LPS]] helps in survival of the [[bacteria]] inside the [[monocytic]] cell, by suppressing [[phagosome]]–[[lysosome]] fusion, internalizing bacteria into [[endoplasmic reticulum]] and inhibiting [[apoptosis]] of [[infected]] cell.
*Type IV secretion system (VirB) and  type III secretion system, that regulates [[intracellular]] survival and trafficking has been identified, although type 3 not yet confirmed. Secretion system plays an important role in [[intracellular]] transport of the bacteria acid-stable [[proteins]] produced by brucella, facilitates the survival in [[phagosomes]]
*Cu-Zn [[superoxide dismutase]], produced by brucellae, gives them resistance from [[reactive oxygen]] intermediates.
*Two component BvrS/BvrR system, codes for [[histidine]] [[kinase]] [[sensor]]. Histidine kinase sensor plays an important role in controlling the expression of [[molecular]] determinants which are necessary for cell invasion.<ref name="pmid159304232">{{cite journal| author=Pappas G, Akritidis N, Bosilkovski M, Tsianos E| title=Brucellosis. | journal=N Engl J Med | year= 2005 | volume= 352 | issue= 22 | pages= 2325-36 | pmid=15930423 | doi=10.1056/NEJMra050570 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15930423  }}</ref>
*[[Hemolysin|Hemolysins]] help the [[bacteria]] to be realeased from a [[cell]] and induce cell [[necrosis]].
==Genetics==
There is no known genetic association to Brucellosis.
 
== Microscopic Pathology ==
[[File:Brucellosis histopathology.png|center|thumb|673x673px|Brucella spp. are poorly staining, small gram-negative coccobacilli (0.5-0.7 x 0.6-1.5 µm), and are seen mostly as single cells and appearing like “fine sand”.- By Photo Credit:Content Providers(s): CDC/Courtesy of Larry Stauffer, Oregon State Public Health Laboratory - This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #1901.Note: Not all PHIL images are public domain; be sure to check copyright status and credit authors and content providers.English | Slovenščina | +/−, Public Domain, https://commons.wikimedia.org/w/index.php?curid=723156]]
[[File:Brucella granuloma with necrosis.png|center|thumb|705x705px|Histopathology of guinea pig liver in experimental Brucella suis infection. Granuloma with necrosis. - Public Domain, https://commons.wikimedia.org/w/index.php?curid=2255655]]
 
==Reference==
{{reflist|2}}
<references />
 
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Latest revision as of 20:45, 29 July 2020


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Danitza LukacVishal Devarkonda, M.B.B.S[2]

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Overview

Brucellosis is a zoonotic disease, humans could be infected by eating undercook meat or raw dairy products, inhalation of the bacteria and direct contact of bacteria with skin wounds or mucous membranes. Following transmission, white blood cells phagocyte the pathogen and transports it via hematologic or lymphatic route to different organs, specially to those of the reticuloendothelial system.

Pathophysiology

Brucellosis is a zoonotic disease, humans could be infected by eating undercook meat or raw dairy products, inhalation of the bacteria and direct contact of bacteria with skin wounds or mucous membranes. Following transmission, white blood cells phagocyte the pathogen and transports it via hematologic or lymphatic route to different organs specially to those of the reticuloendothelial system. Endotoxic lipopolysaccharide LPS, plays an important role in: survival of bacteria inside monocytic cell, supressing phagosome-lysosome fusion and internalizing bacteria into endoplasmic reticulum. The pathophysiology of Brucellosis can be described in the following steps:[1][2][3][4][5][6][7][8][9][10][11][12][13]

Transmission

According to CDC, humans are generally infected with Brucellosis in one of the following three ways:[1][14]

ROUTE OF TRANSMISSION
Gastrointestinal

Eating undercooked meat or consuming unpasteurized/raw dairy products

Inhalation

Breathing in the bacteria that cause brucellosis (inhalation)

Cutaneous

Bacteria entering the body through skin wounds or mucous membranes

Other modes of transmission

Incubation

Incubation period of brucellosis varies from one to four weeks. But occasionally, it may be as long as several months. 

Dissemination

Following transmission, brucellae is ingested by macrophages and polymorphonuclear cells. On ingestion, they replicate intracellularly inside the lysed cells and disseminate systemically. 

Seeding

Immune response

Brucellosis elicits both humoral and cell-mediated immune responses:[1][2][3][4][5][6][7][8][9][15][16]

Humoral immune response

Cell mediates immune response

Pathogenesis

The pathogenesis of brucellosis is complex and not fully understood:[1][2][3][4][5][6][7][8][9][17][18][19]

By avoiding innate immunity, brucella survive with in monocytic cells.

Genetics

There is no known genetic association to Brucellosis.

Microscopic Pathology

+/−, Public Domain, https://commons.wikimedia.org/w/index.php?curid=723156
Histopathology of guinea pig liver in experimental Brucella suis infection. Granuloma with necrosis. - Public Domain, https://commons.wikimedia.org/w/index.php?curid=2255655

Reference

  1. ↑ 1.0 1.1 1.2 1.3 Pappas G, Akritidis N, Bosilkovski M, Tsianos E (2005). "Brucellosis". N Engl J Med. 352 (22): 2325–36. doi:10.1056/NEJMra050570. PMID 15930423.
  2. ↑ 2.0 2.1 2.2 "CDC".
  3. ↑ 3.0 3.1 3.2 Zhan Y, Liu Z, Cheers C (1996). "Tumor necrosis factor alpha and interleukin-12 contribute to resistance to the intracellular bacterium Brucella abortus by different mechanisms". Infect Immun. 64 (7): 2782–6. PMC 174139. PMID 8698508.
  4. ↑ 4.0 4.1 4.2 Larralde de Luna M, Raspa ML, Ibargoyen J (1992). "Oral-facial-digital type 1 syndrome of Papillon-Léage and Psaume". Pediatr Dermatol. 9 (1): 52–6. PMID 1574477.
  5. ↑ 5.0 5.1 5.2 Gazapo E, Gonzalez Lahoz J, Subiza JL, Baquero M, Gil J, de la Concha EG (1989). "Changes in IgM and IgG antibody concentrations in brucellosis over time: importance for diagnosis and follow-up". J Infect Dis. 159 (2): 219–25. PMID 2915152.
  6. ↑ 6.0 6.1 6.2 Arenas GN, Staskevich AS, Aballay A, Mayorga LS (2000). "Intracellular trafficking of Brucella abortus in J774 macrophages". Infect Immun. 68 (7): 4255–63. PMC 101738. PMID 10858243.
  7. ↑ 7.0 7.1 7.2 Boschiroli ML, Ouahrani-Bettache S, Foulongne V, Michaux-Charachon S, Bourg G, Allardet-Servent A; et al. (2002). "Type IV secretion and Brucella virulence". Vet Microbiol. 90 (1–4): 341–8. PMID 12414154.
  8. ↑ 8.0 8.1 8.2 Lapaque N, Moriyon I, Moreno E, Gorvel JP (2005). "Brucella lipopolysaccharide acts as a virulence factor". Curr Opin Microbiol. 8 (1): 60–6. doi:10.1016/j.mib.2004.12.003. PMID 15694858.
  9. ↑ 9.0 9.1 9.2 DelVecchio VG, Kapatral V, Elzer P, Patra G, Mujer CV (2002). "The genome of Brucella melitensis". Vet Microbiol. 90 (1–4): 587–92. PMID 12414174.
  10. ↑ Moreno E, Moriyon I (2002). "Brucella melitensis: a nasty bug with hidden credentials for virulence". Proc Natl Acad Sci U S A. 99 (1): 1–3. doi:10.1073/pnas.022622699. PMC 117501. PMID 11782541.
  11. ↑ Gorvel JP, Moreno E (2002). "Brucella intracellular life: from invasion to intracellular replication". Vet Microbiol. 90 (1–4): 281–97. PMID 12414149.
  12. ↑ Ko J, Splitter GA (2003). "Molecular host-pathogen interaction in brucellosis: current understanding and future approaches to vaccine development for mice and humans". Clin Microbiol Rev. 16 (1): 65–78. PMC 145300. PMID 12525425.
  13. ↑ Dornand J, Gross A, Lafont V, Liautard J, Oliaro J, Liautard JP (2002). "The innate immune response against Brucella in humans". Vet Microbiol. 90 (1–4): 383–94. PMID 12414158.
  14. ↑ [CDC "https://www.cdc.gov/brucellosis/transmission/index.html"] Check |url= value (help). External link in |title= (help)
  15. ↑ Khan M, Harms JS, Marim FM, Armon L, Hall CL, Liu YP; et al. (2016). "The Bacterial Second Messenger Cyclic di-GMP Regulates Brucella Pathogenesis and Leads to Altered Host Immune Response" Check |url= value (help). Infect Immun. 84 (12): 3458–3470. doi:10.1128/IAI.00531-16. PMC 5116723. PMID 27672085.
  16. ↑ Pappas G, Akritidis N, Bosilkovski M, Tsianos E (2005). "Brucellosis". N Engl J Med. 352 (22): 2325–36. doi:10.1056/NEJMra050570. PMID 15930423.
  17. ↑ Barquero-Calvo E, Chaves-Olarte E, Weiss DS, et al. Brucella abortus uses a stealthy strategy to avoid activation of the innate immune system during the onset of infection. PLoS One 2007; 2:e631.
  18. ↑ Gorvel JP, Moreno E. Brucella intracellular life: from invasion to intracellular replication. Vet Microbiol 2002; 90:281.
  19. ↑ Pappas G, Akritidis N, Bosilkovski M, Tsianos E (2005). "Brucellosis". N Engl J Med. 352 (22): 2325–36. doi:10.1056/NEJMra050570. PMID 15930423.
  20. ↑ Pappas G, Akritidis N, Bosilkovski M, Tsianos E (2005). "Brucellosis" Check |url= value (help). N Engl J Med. 352 (22): 2325–36. doi:10.1056/NEJMra050570. PMID 15930423.
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