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__NOTOC__
* Mixed Cryoglobulinemia is a combination of both types II and III.
* Mixed CGs is associated with following conditions:
** '''SLE (systemic lupus erythematous)'''
**  '''Sjögren's syndrome,'''
** '''HCV'''
** '''Lymphoproliferative disorders'''
* Al the above mentioned disorders can cause excessive production of B-cell which can further lead to selective expansion of Cryoglobulinemia producing B-cell clones.
* In HCV infected patients the HCV complexes such as HCV-IgG, HCV-lipoprotein cause B-cell hyper-proliferation through the CD81 leading to expansion of specific B-cell clones such as WA idiotype or V(H)1-69.
* HCV particles are often found in such patients' serum CG complexes, but, at the same time, CG development in hepatitis C infection does not directly require the HCV virion or its components [38]. In this sense, CG development may, in fact, reflect a normal, expected response to regulate immune complexes in states of chronic immune activation.
* Among patients with HCV infection, the number of circulating T cells with surface markers compatible with a suppressor phenotype may be a feature that differs between patients with cryoglobulinemic vasculitis and those with asymptomatic CG.
* This was illustrated in a study that compared the percentage of "regulatory" T cells in 69 patients with HCV infection who had symptomatic CG with others with asymptomatic HCV infection [39].
* The mean levels of regulatory T cells were significantly lower in those with symptomatic HCV-associated CG than asymptomatic subjects (2.6 versus 7.4 percent, respectively).
* Whether the diminished proportion of regulatory T cells plays a role in causing vasculitis is uncertain but warrants further exploration.


{{CMG}}; {{AE}} {{FT}}




==Overview==
=== Differentiating uremia from other diseases ===
 
Uremia and uremic encephalopathy must be differentiated from other diseases that cause [[personality changes]], altered level of [[consciousness]] and hand [[tremors]] ([[asterixis]]). The differentials include the following:<nowiki/><ref name="pmid20495225">{{cite journal| author=Meparidze MM, Kodua TE, Lashkhi KS| title=[Speech impairment predisposes to cognitive deterioration in hepatic encephalopathy]. | journal=Georgian Med News | year= 2010 | volume= | issue= 181 | pages= 43-9 | pmid=20495225 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20495225 }} </ref><ref name="pmid25013309">{{cite journal| author=Kattimani S, Bharadwaj B| title=Clinical management of alcohol withdrawal: A systematic review. | journal=Ind Psychiatry J | year= 2013 | volume= 22 | issue= 2 | pages= 100-8 | pmid=25013309 | doi=10.4103/0972-6748.132914 | pmc=4085800 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25013309  }} </ref><ref name="pmid12813481">{{cite journal| author=Roldán J, Frauca C, Dueñas A| title=[Alcohol intoxication]. | journal=An Sist Sanit Navar | year= 2003 | volume= 26 Suppl 1 | issue= | pages= 129-39 | pmid=12813481 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12813481 }} </ref><ref name="pmid21590619">{{cite journal| author=Seifter JL, Samuels MA| title=Uremic encephalopathy and other brain disorders associated with renal failure. | journal=Semin Neurol | year= 2011 | volume= 31 | issue= 2 | pages= 139-43 | pmid=21590619 | doi=10.1055/s-0031-1277984 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21590619  }} </ref><ref name="pmid6864698">{{cite journal| author=Handler CE, Perkin GD| title=Wernicke's encephalopathy. | journal=J R Soc Med | year= 1983 | volume= 76 | issue= 5 | pages= 339-42 | pmid=6864698 | doi= | pmc=1439130 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6864698 }} </ref><ref name="pmid23251840">{{cite journal| author=Kim Y, Kim JW| title=Toxic encephalopathy. | journal=Saf Health Work | year= 2012 | volume= 3 | issue= 4 | pages= 243-56 | pmid=23251840 | doi=10.5491/SHAW.2012.3.4.243 | pmc=3521923 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23251840 }} </ref><ref name="pmid2497395">{{cite journal| author=Hartmann A, Buttinger C, Rommel T, Czernicki Z, Trtinjiak F| title=Alteration of intracranial pressure, cerebral blood flow, autoregulation and carbondioxide-reactivity by hypotensive agents in baboons with intracranial hypertension. | journal=Neurochirurgia (Stuttg) | year= 1989 | volume= 32 | issue= 2 | pages= 37-43 | pmid=2497395 | doi=10.1055/s-2008-1053998 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2497395 }} </ref><ref name="pmid21590622">{{cite journal| author=Kumar N| title=Acute and subacute encephalopathies: deficiency states (nutritional). | journal=Semin Neurol | year= 2011 | volume= 31 | issue= 2 | pages= 169-83 | pmid=21590622 | doi=10.1055/s-0031-1277986 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21590622  }} </ref><ref name="pmid23035103">{{cite journal| author=Chiu GS, Chatterjee D, Darmody PT, Walsh JP, Meling DD, Johnson RW et al.| title=Hypoxia/reoxygenation impairs memory formation via adenosine-dependent activation of caspase 1. | journal=J Neurosci | year= 2012 | volume= 32 | issue= 40 | pages= 13945-55 | pmid=23035103 | doi=10.1523/JNEUROSCI.0704-12.2012 | pmc=3476834 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23035103 }} </ref><ref name="pmid15284663">{{cite journal| author=Peate I| title=An overview of meningitis: signs, symptoms, treatment and support. | journal=Br J Nurs | year= 2004 | volume= 13 | issue= 13 | pages= 796-801 | pmid=15284663 | doi=10.12968/bjon.2004.13.13.13501 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15284663 }} </ref><ref name="pmid25821643">{{cite journal| author=Abdelhafiz AH, Rodríguez-Mañas L, Morley JE, Sinclair AJ| title=Hypoglycemia in older people - a less well recognized risk factor for frailty. | journal=Aging Dis | year= 2015 | volume= 6 | issue= 2 | pages= 156-67 | pmid=25821643 | doi=10.14336/AD.2014.0330 | pmc=4365959 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25821643 }} </ref>
Mesenteric ischemia is a type of intestinal ischemia primarily affecting the small intestine. It is one of the life-threatening gastrointestinal vascular emergencies which requires prompt surgical/medical intervention depending upon the underlying cause.
{|
 
|- style="background: #4479BA; color: #FFFFFF; text-align: center;"
It can be divided into occlusive/non-occlusive, arterial or venous, localized/generalized and superficial or transmural.<ref name="pmid24160929">{{cite journal| author=Corcos O, Nuzzo A| title=Gastro-intestinal vascular emergencies. | journal=Best Pract Res Clin Gastroenterol | year= 2013 | volume= 27 | issue= 5 | pages= 709-25 | pmid=24160929 | doi=10.1016/j.bpg.2013.08.006 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24160929 }} </ref>
! rowspan="2" |Diseases
 
! colspan="3" |History and Symptoms
==Overview==
! colspan="4" |Physical Examination
The anatomy and physiology of the small intestine plays a vital role in the develpoment of mesenteric ischemia. Intestinal muscosa has a high metabolic rate and accordingly a high blood flow requirement. The majority of blood supply of the intestine comes from the superior mesenteric artery, with a collateral blood supply from superior and inferior pancreaticoduodenal arteries (branches of the celiac artery) as well as the inferior mesenteric artery. The splanchnic circulation (arteries supplying the viscera) receives 15-35% of the cardiac output, making it sensitive to the effects of decreased perfusion. Mesenteric ischemia occurs when intestinal blood supply is compromised by more than 50% of the original blood flow. This can lead to disrutpion of mucosal barrier, allowing the release of bacterial toxins (present in the intestinal lumen) and vasoactive mediators which ultimately lead to complete necrosis (cell death) of the intestinal mucosa. This can further progress to  depression in myocardial activity, sepsis, multiorgan failure, and without prompt intervention, even death.<ref name="pmid9146713">{{cite journal| author=Rosenblum JD, Boyle CM, Schwartz LB| title=The mesenteric circulation. Anatomy and physiology. | journal=Surg Clin North Am | year= 1997 | volume= 77 | issue= 2 | pages= 289-306 | pmid=9146713 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9146713 }} </ref>
! colspan="3" |Laboratory Findings
 
|- style="background: #4479BA; color: #FFFFFF; text-align: center;"
==Pathophysiology==
!Personality changes
 
!Altered level of consciousness
=== '''Pathogenesis''' ===
!Hand tremors (asterixis)
Three major factors contributing towards the develpoment of mesenteric ischemia are:
!Slurred speech
 
!Writing disturbances
(a) Mesenteric vascular anatomy and physiology
!Voice monotonous
 
!Impaired '''memory'''
(b) Collateral circulation
!Elevated blood ammonia
 
!Hyponatremia
(c) Factors regulating the mesenteric blood flow
!hypokalemia
 
'''(a) Mesenteric vascular anatomy and physiology:'''
 
The arterial supply of the intestine originates from three major arteries:<ref name="pmid11759648">{{cite journal| author=Kumar S, Sarr MG, Kamath PS| title=Mesenteric venous thrombosis. | journal=N Engl J Med | year= 2001 | volume= 345 | issue= 23 | pages= 1683-8 | pmid=11759648 | doi=10.1056/NEJMra010076 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11759648 }} </ref><ref name="pmid19491858">{{cite journal| author=Ha C, Magowan S, Accortt NA, Chen J, Stone CD| title=Risk of arterial thrombotic events in inflammatory bowel disease. | journal=Am J Gastroenterol | year= 2009 | volume= 104 | issue= 6 | pages= 1445-51 | pmid=19491858 | doi=10.1038/ajg.2009.81 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19491858 }} </ref><ref name="pmid6101568">{{cite journal| author=Granger DN, Richardson PD, Kvietys PR, Mortillaro NA| title=Intestinal blood flow. | journal=Gastroenterology | year= 1980 | volume= 78 | issue= 4 | pages= 837-63 | pmid=6101568 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6101568 }} </ref>
* Superior mesenteric artery (SMA)
** Supplies the small intestine, proximal and mid colon upto the splenic flexure.
* Inferior mesenteric artery (IMA)
** Supplies hind gut starting from the splenic flexure to the rectum.
* Celiac artery (CA)
** Supplies the foregut, hepatobiliary system and spleen.
 
* The venous system parallels the arterial branches and drains into the portal venous system.
* The mesenteric circulation recevies approximately 25% of the resting and 35% of the postprandial cardiac output.
* Mucosal and submucosal layers of the intestine receive 70% of the mesenteric blood flow, with the rest supplying the muscularis and serosal layers.
'''Commonly affected arteries:'''
* Embolus can typically lodge into points of normal anatomic narrowing.  
* This makes [[superior mesenteric artery]] the most vulnerable site because of its relatively larger diameter (more blood flow) and low take off angle (more likely to  from the aorta.
*The majority of emboli lodge 3-10cm distal to the origin of [[superior mesenteric artery]], classically sparing the proximal jejunum and colon.
'''(b) Collateral circulation:'''
 
The role of collateral circulation in the development of mesenteric ischemia is as follows:<ref name="pmid9146714">{{cite journal| author=McKinsey JF, Gewertz BL| title=Acute mesenteric ischemia. | journal=Surg Clin North Am | year= 1997 | volume= 77 | issue= 2 | pages= 307-18 | pmid=9146714 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9146714 }} </ref><ref name="pmid21326561">{{cite journal| author=Walker TG| title=Mesenteric vasculature and collateral pathways. | journal=Semin Intervent Radiol | year= 2009 | volume= 26 | issue= 3 | pages= 167-74 | pmid=21326561 | doi=10.1055/s-0029-1225663 | pmc=3036491 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21326561 }} </ref><ref name="pmid3554567">{{cite journal| author=Fisher DF, Fry WJ| title=Collateral mesenteric circulation. | journal=Surg Gynecol Obstet | year= 1987 | volume= 164 | issue= 5 | pages= 487-92 | pmid=3554567 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3554567 }} </ref>
* Intestines receive collateral blood supply at all levels from the superior and inferior pancreaticoduodenal arteries, branches of the celiac artery, which provides protection from ischemia.
* These arteries can compensate for 75% reduction in mesenteric blood flow for upto 12 hours, without substanial injury.
 
*  An extensive collateral circulation protects the intestines from transient periods of inadequate perfusion. However, prolonged reduction in splanchnic blood flow leads to vasoconstriction in the affected vascular bed, and eventually reduces collateral blood flow.  
 
* The SMA and IMA communicate via the marginal artery of Drummond and the meandering mesenteric artery.
 
* Collateralization between the IMA and systemic circulation occurs in the rectum as the superior rectal (hemorrhoidal) vessels merge with the middle rectal vessels from the internal iliac arteries.
* The areas lacking this collateralization are prone towards ischemia.
'''(c) Factors regulating the mesenteric blood flow:'''
 
Physiologically mesenteric circulation is affected by:<ref name="pmid10052599">{{cite journal| author=Hansen MB, Dresner LS, Wait RB| title=Profile of neurohumoral agents on mesenteric and intestinal blood flow in health and disease. | journal=Physiol Res | year= 1998 | volume= 47 | issue= 5 | pages= 307-27 | pmid=10052599 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10052599  }} </ref><ref name="pmid8370303">{{cite journal| author=Schoenberg MH, Beger HG| title=Reperfusion injury after intestinal ischemia. | journal=Crit Care Med | year= 1993 | volume= 21 | issue= 9 | pages= 1376-86 | pmid=8370303 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8370303  }} </ref>
* Intrinsic regulatory system that includes metabolic and myogenic factors.
* Extrinsic regulatory system that includes neural and humoral factors.
'''Intrinsic regulation:'''
* Metabolic factors: 
** Reduction in blood supply to the mesentery causes adaptive changes in the splanchnic circulation. 
** A discrepancy between tissue oxyegn demand and supply raises the concentration of local metabolites such as hydrogen, potassium, carbon dioxide, and adenosine, resulting in vasodilation and hyperemia.
 
* Myogenic factors:
** Myogenic theory suggests that arteriolar tension receptors act to regulate vascular resistance in accordance with the transmural pressure.
** An acute decrease in perfusion pressure is compensated for by a reduction in arteriolar wall tension, thereby maintaining splanchnic blood flow.
'''Extrinsic regulation:'''
* Neural component:
** The extrinsic neural component of splanchnic circulatory regulation comprises the alpha-activated vasoconstrictor fibers.
** Intense activation of vasoconstrictor fibers through alpha-adrenergic stimulation results in vasoconstriction of small vessels and a decrease in mesenteric blood flow.
** After periods of prolonged alpha-adrenergic vasoconstriction, blood flow increases, presumably through β-adrenergic stimulation, which acts as a protective response.
** Although numerous types of neural stimulation (e.g. vagal, cholinergic, histaminergic, and sympathetic) can affect the blood supply of the gut, the adrenergic limb of the autonomic nervous system is the predominant neural influence on splanchnic circulation.
 
* Humoral component:
** Numerous endogenous and exogenous humoral factors affect the splanchnic circulation.
** Norepinephrine and high doses of epinephrine produce intense vasoconstriction by stimulating the adrenergic receptors.
** Other pharmacologic compounds that decrease splanchnic blood flow include:
*** Vasopressin
*** Phenylephrine
*** Digoxin
** Low-dose dopamine causes splanchnic vasodilation, whereas higher doses lead to vasoconstriction by stimulating alpha adrenergic receptors.
** Exogenous agents that increase mesenteric blood flow include:
*** Papaverine
*** Adenosine
*** Dobutamine
*** Fenoldopam
*** Sodium nitroprusside
** In addition, numerous natural neurotransmitters can serve as splanchnic vasodilators, including acetylcholine, histamine, nitric oxide, leukotrienes, thromboxane analogues, glucagon, and a couple of gastrointestinal hormones.
 
==Regulatory system==
{| class="wikitable"
! colspan="2" |Factors regulating mesenteric blood flow
|-
| colspan="2" |                                                            '''Extrinsic reguatory system'''
|-
|-
| colspan="2" |                                                '''Humoral (endogenous and exogenous)'''
|'''Hepatic encephalopathy'''
| ++
| ++
| ++
|<nowiki>++</nowiki>
|<nowiki>++</nowiki>
|<nowiki>++</nowiki>
|<nowiki>++</nowiki>
|<nowiki>++</nowiki>
|<nowiki>++</nowiki>
|<nowiki>++</nowiki>
|-
|-
|Decrease blood flow
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Alcohol intoxication]]'''
|Increase blood flow
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | ++
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -/+
|-
|-
|
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Alcohol withdrawal]]'''
* Epinephrine (high dose)
| style="background: #F5F5F5; padding: 5px;" | +
* Norepinephrine (moderate to high dose)
| style="background: #F5F5F5; padding: 5px;" | +
* Dopamine (high dose)
| style="background: #F5F5F5; padding: 5px;" | -
* Phenylephrine
| style="background: #F5F5F5; padding: 5px;" | ++
* Vasopressin
| style="background: #F5F5F5; padding: 5px;" | +
* Angiotensin
| style="background: #F5F5F5; padding: 5px;" | -
|  
| style="background: #F5F5F5; padding: 5px;" | +
Digoxin
| style="background: #F5F5F5; padding: 5px;" | -
|
| style="background: #F5F5F5; padding: 5px;" | -/+
* Epinephrine (low dose)
| style="background: #F5F5F5; padding: 5px;" | -/+
* Norepinephrine (low dose)
* Dopamine (low dose)
* Dobutamine
* Sodium nitroprusside
* Papaverine
* Nitric oxide
* Acetylcholine
* Histamine
|-
|-
| colspan="2" |                                                                               '''Neural component'''
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Uremia]]'''
| style="background: #F5F5F5; padding: 5px;" | ++
| style="background: #F5F5F5; padding: 5px;" | ++
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" |
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | ++
| style="background: #F5F5F5; padding: 5px;" |[[Hyperkalemia]]
|-
|-
|
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Wernicke encephalopathy]]'''
* Alpha-adrenergic receptors
| style="background: #F5F5F5; padding: 5px;" | +
* Dopamenergic receptors
| style="background: #F5F5F5; padding: 5px;" | +
|
| style="background: #F5F5F5; padding: 5px;" | -/+
* Beta-adrenergic receptors
| style="background: #F5F5F5; padding: 5px;" | +
|}
| style="background: #F5F5F5; padding: 5px;" | +
'''Areas prone to ischemia:'''
| style="background: #F5F5F5; padding: 5px;" | +
 
| style="background: #F5F5F5; padding: 5px;" | ++
{| class="wikitable"
| style="background: #F5F5F5; padding: 5px;" | -
!Areas prone to ischemia
| style="background: #F5F5F5; padding: 5px;" | -
! colspan="3" |Blood supply
| style="background: #F5F5F5; padding: 5px;" | -
|-
|-
|
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Toxic encephalopathy]] from drugs'''
* Splenic flexure
| style="background: #F5F5F5; padding: 5px;" | +
| colspan="3" |End arteries of superior mesenteric artery
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -/+
|-
|-
|
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''Altered [[intracranial pressure]]'''
* Rectosigmoid junction
| style="background: #F5F5F5; padding: 5px;" | +
| colspan="3" |End arteries of inferior mesenteric artery
| style="background: #F5F5F5; padding: 5px;" | -/+
|}
| style="background: #F5F5F5; padding: 5px;" | -
* The watershed areas that lack collateralization are as follows:
| style="background: #F5F5F5; padding: 5px;" | -/+
 
| style="background: #F5F5F5; padding: 5px;" | -/+
* Splenic flexure
| style="background: #F5F5F5; padding: 5px;" | -
** Supplied by the end arteries of SMA with no collateral circulation.
| style="background: #F5F5F5; padding: 5px;" | -/+
* Rectosigmoid junction
| style="background: #F5F5F5; padding: 5px;" | -
Supplied by the end arteries of IMA with no collateral circulation.
| style="background: #F5F5F5; padding: 5px;" | -
 
| style="background: #F5F5F5; padding: 5px;" | -
'''Mechanism of ischemia:'''  
 
The sequence of events that take place in the small intestine subsequent to decreased blood flow:
 
{{Family tree/start}}
{{familytree | boxstyle= text-align: Center; | | | |B01| | | | |B01= Ischemic insult
| boxstyle_B02= text-align: Center;  
| boxstyle_B03= text-align: left;  
}}
{{Family tree | | | | |!| | | | | }}
{{familytree | boxstyle= text-align: Center; | | | |B01| | | | |B01= Decreased delivery of oxygen and nutrients
| boxstyle_B02= text-align: Center;  
| boxstyle_B03= text-align: left;  
}}
{{Family tree | | | | |!| | | | | }}
{{familytree | boxstyle= text-align: Center; | | | |B01| | | | |B01= Disruption in cellular metabolism
| boxstyle_B02= text-align: Center;  
| boxstyle_B03= text-align: left;
}}
{{Family tree | | | | |!| | | | | }}
{{familytree | boxstyle= text-align: Center; | | | |B01| | | | |B01= Tissue injury due to hypoxia and reperfusion
}}
{{Family tree | | | | |!| | | | | }}
{{familytree | boxstyle= text-align: Center; | | | |B01| | | | |B01= Full thickness necrosis of the bowel
}}
{{Family tree | | | | |!| | | | | }}
{{familytree | boxstyle= text-align: Center; | | | |B01| | | | |B01= Perforation of the bowel wall
}}
 
{{Family tree/end}}
* Mesenteric ischemia occurs when the blood supply to mesentery is reduced leading to disruption of cellular metabolism owing to oxygen and nutrient deficiency.
* In the first 4 hours following ischemia, necrosis of the mucosal villi occurs.
* Persistent ischemia for more than 6 hours results in transmural, mural or mucosal infarction, ultimately leading to bowel perforation.
* Prolonged ischemia leads to progressive vasoconstriction of the mesenetric vessels which raises the pressure in them resulting in lowering the collateral flow.
* This is followed by vasodilation, trying to restore blood flow to the area of ischemic insult which causes reperfusion injury.
* Reperfusion injury causes release of oxygen free radicals, toxic byproducts of ischemic injury and neutrophil activation.
 The pathophysiology of mesenteric ischemia can be explained on the basis of etiology:<ref name="pmid25689121">{{cite journal| author=Acosta S| title=Mesenteric ischemia. | journal=Curr Opin Crit Care | year= 2015 | volume= 21 | issue= 2 | pages= 171-8 | pmid=25689121 | doi=10.1097/MCC.0000000000000189 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25689121  }} </ref><ref name="pmid15729076">{{cite journal| author=Acosta S, Ogren M, Sternby NH, Bergqvist D, Björck M| title=Clinical implications for the management of acute thromboembolic occlusion of the superior mesenteric artery: autopsy findings in 213 patients. | journal=Ann Surg | year= 2005 | volume= 241 | issue= 3 | pages= 516-22 | pmid=15729076 | doi= | pmc=1356992 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15729076  }} </ref>
*'''Acute mesenteric arterial embolism''': Attributes to 50% cases of mesenteric ischemia.
*Mesenteric embolus can oringinate from the left atrium, associated with cardiac arrythmias such as atrial fibrillation.
*Recent myocardial infarction resulting in segmental wall motion abnormality leading to poor ejaction fraction and embolus formation.
*[[Infective endocarditis]]: vegetations on the cardiac valves resulting in turbulence in blood flow predisposing to formation of emboli into the blood stream.
*'''Acute mesenteric arterial thrombosis''':
*25% cases of mesenteric ischemia result from mesenteric arterial thrombosis.
*Most likely due to underlying atherosclerosis(plaque formation) leading to stenosis.
*An underlying plaque(fatty streak) in the superior mesenteric artery leads to critical stenosis over the years forming collaterals.
*It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
*[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
*Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
*[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
*The progression to [disease name] usually involves the [molecular pathway].
*The pathophysiology of [disease/malignancy] depends on the histological subtype.
 
==Genetics==
*[Disease name] is transmitted in [mode of genetic transmission] pattern.
*Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
*The development of [disease name] is the result of multiple genetic mutations.
==Associated Conditions==
 
==Gross Pathology==
*Gross pathology shows following changes:
**Early stage of ischemia: Intestinal wall in congested.
**Late stage of ischemia: Edematous, friable and hemorrhagic bowel wall.
 
==Microscopic Pathology==
*On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
 
==References==
{{Reflist|2}}
 
{{WH}}
{{WS}}
[[Category: (name of the system)]]
==Risk Factors==
===Common Risk Factors===
The following conditions pose a signifiacnt risk towards the development of mesenteric ischemia either by interrupting the blood flow through the artery or vein supplying the small intestine (e.g.thromboemboli) or by reducing the blood supply (e.g. vasoconstriction). Also, there are certain life-style related risk factors which predominantly cause mesenteric ischemia in the older age group. <ref name="pmid10917470">{{cite journal| author=Fitzgerald T, Kim D, Karakozis S, Alam H, Provido H, Kirkpatrick J| title=Visceral ischemia after cardiopulmonary bypass. | journal=Am Surg | year= 2000 | volume= 66 | issue= 7 | pages= 623-6 | pmid=10917470 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10917470  }} </ref><ref name="pmid9746774">{{cite journal| author=Martinelli I, Mannucci PM, De Stefano V, Taioli E, Rossi V, Crosti F et al.| title=Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. | journal=Blood | year= 1998 | volume= 92 | issue= 7 | pages= 2353-8 | pmid=9746774 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9746774  }} </ref><ref name="pmid16476108">{{cite journal| author=Acosta S, Ogren M, Sternby NH, Bergqvist D, Björck M| title=Fatal nonocclusive mesenteric ischaemia: population-based incidence and risk factors. | journal=J Intern Med | year= 2006 | volume= 259 | issue= 3 | pages= 305-13 | pmid=16476108 | doi=10.1111/j.1365-2796.2006.01613.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16476108  }} </ref>
{| class="wikitable"
!Risk factors
!
!
|-
|-
| rowspan="13" |Occlusive
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''Intoxication by chemical agents'''
| rowspan="7" |Embolic
| style="background: #F5F5F5; padding: 5px;" | -/+
|[[Atrial fibrillation]]
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -/+
|-
|-
|[[Cardiac arrhythmia]]
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Malnutrition]]'''
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -/+
|-
|-
|[[Valvular heart disease]]
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Hypoxic brain injury]]'''
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
|-
|-
|[[Infective endocarditis]]
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Meningitis]] and [[encephalitis]]'''
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | +
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -/+
| style="background: #F5F5F5; padding: 5px;" | -
|-
|-
|Recent [[myocardial infarction]]
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Hypoglycemia]]'''
|-
| style="background: #F5F5F5; padding: 5px;" | -/+
|[[Ventricular aneurysm]]
| style="background: #F5F5F5; padding: 5px;" | -/+
|-
| style="background: #F5F5F5; padding: 5px;" | -
|Aortic atherosclerosis
| style="background: #F5F5F5; padding: 5px;" | -/+
|-
| style="background: #F5F5F5; padding: 5px;" | -/+
| rowspan="6" |Thrombotic
| style="background: #F5F5F5; padding: 5px;" | -
|Advanced age
| style="background: #F5F5F5; padding: 5px;" | -
|-
| style="background: #F5F5F5; padding: 5px;" | -
|Low cardiac output states
| style="background: #F5F5F5; padding: 5px;" | -/+
|-
| style="background: #F5F5F5; padding: 5px;" | -/+
|[[Peripheral arterial disease]]
|-
|Traumatic injury
|-
|Inherited thrombophilia-
* [[Factor V Leiden mutation|Factor V Leidin mutation]]
* [[Prothrombin G20210A mutation]]
* [[Protein S deficiency]]
 
* [[Antithrombin III deficiency]]
* [[Activated protein C resistance]]
* Anti-phospholipid syndrome
* [[Myeloproliferative neoplasm|Myeloproliferative disorders(JAK2 V617F) mutation.]]
|-
|Acquired thrombophilia- malignancy, oral contraceptives intake.
|-
| colspan="2" rowspan="6" |Non-occlusive
|Heart failure
|-
|[[Aortic insufficiency]]
|-
|[[Septic shock]]
|-
|Vasoconstrictive drugs:
* [[Digoxin]]
* [[Alpha-adrenergic agonist|Alpha-adrenergic agonists]]
|-
|Cocaine abuse or ergot poisoning
|-
|[[Hemodialysis]]
|-
| colspan="2" |Other causes
|Lifestyle related risk factors:
* High cholesterol levels
* History of smoking
* Immobility
 
* Recent surgery
Less common risk factors:
* Fibromuscular dysplasia
* Beta receptor blocking agents
* Hepatitis
|}
*Common risk factors in the development of mesenteric ischemia include:
**'''Occlusive causes'''
***'''Embolic causes''':<ref name="pmid10917470">{{cite journal| author=Fitzgerald T, Kim D, Karakozis S, Alam H, Provido H, Kirkpatrick J| title=Visceral ischemia after cardiopulmonary bypass. | journal=Am Surg | year= 2000 | volume= 66 | issue= 7 | pages= 623-6 | pmid=10917470 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10917470  }} </ref>
***Atrial fibrillation
***Cardiac arrhythmias
***Valvular heart diseases
***Infective endocarditis
***Recent myocardial infarction
***Ventricular aneurysm
***Aortic atherosclerosis 
***Aortic aneurysm
**'''Thrombotic causes''':<ref name="pmid9746774">{{cite journal| author=Martinelli I, Mannucci PM, De Stefano V, Taioli E, Rossi V, Crosti F et al.| title=Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. | journal=Blood | year= 1998 | volume= 92 | issue= 7 | pages= 2353-8 | pmid=9746774 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9746774  }} </ref>
***Advanced age
***Low cardiac output states
***Traumatic injury
***Peripheral artery disease
*'''Non-occlusive causes:'''<ref name="pmid16476108">{{cite journal| author=Acosta S, Ogren M, Sternby NH, Bergqvist D, Björck M| title=Fatal nonocclusive mesenteric ischaemia: population-based incidence and risk factors. | journal=J Intern Med | year= 2006 | volume= 259 | issue= 3 | pages= 305-13 | pmid=16476108 | doi=10.1111/j.1365-2796.2006.01613.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16476108  }} </ref>
**[[Heart failure]]
**[[Aortic insufficiency]]
**[[Septic shock]]
**Vasoconstrictive drugs(e.g. [[Digoxin]], [[Alpha-adrenergic agonist|alpha-adrenergic agonists)]]
 
**[[Cocaine abuse]] or ergot poisoning
 
**[[Hemodialysis]]
 
===Less Common Risk Factors===
*Less common risk factors in the development of mesenteric ischemia include:
**Fibromuscular dysplasia
**Hepatitis
**Beta recpetor blocking agents
**Polyarteritis nodosa
 
===Causes===
Narrowing of the arteries that supply blood to the intestine causes mesenteric ischemia. The arteries that supply blood to the intestines run directly from the aorta. Mesenteric ischemia is often seen in people who have hardening of the arteries in other parts of the body (for example, those with coronary artery disease or peripheral vascular disease). The condition is more common in smokers and in patients with high blood pressure or blood cholesterol. Mesenteric ischemia may also be caused by an embolus that suddenly blocks one of the mesenteric arteries. The emboli usually come from the heart or aorta. These clots are more commonly seen in patients with arrhythmias, such as atrial fibrillation. They can be broadly classified into four categories:<ref name="pmid2194948">{{cite journal| author=Reinus JF, Brandt LJ, Boley SJ| title=Ischemic diseases of the bowel. | journal=Gastroenterol Clin North Am | year= 1990 | volume= 19 | issue= 2 | pages= 319-43 | pmid=2194948 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2194948  }} </ref>
*[[Arterial thrombosis]]
*[[Arterial embolism]]
*[[Venous thrombosis]]
*[[Non-occlusive ischemia]]
 
{| class="wikitable"
! colspan="4" |Classification based on etiology
|-
!Etiology
!Cause
!Incidence
!Examples
|-
! rowspan="3" |Occlusive causes
|Aterial embolism
|50-70%
|
* Superior mesenteric artery obstruction (most common cause)
* [[Arrhythmia]]
* [[Myocardial infarction]]
* [[Infective endocarditis]]
* [[Valvular heart disease|Valvular heart diseases]]
* [[Ventricular aneurysm|Ventricular aneurysms]]
* History of embolic events
* Recent [[angiography]]
|-
|Arterial thrombosis
|15-25%
|
* Atherosclerosis
* Advanced age
* Prlonged hypotension
* [[Hypercoagulability|Hypercoagulabilty]] states
* [[Peripheral arterial disease]]
* Traumatic injury
|-
|Venous thrombosis
|5%
|
* Right-sided heart failure
* Previous deep venous thrombosis (20-40% risk)
* Primary clotting disorder
* Pancreatitis
* Polycythemia
* Sickle cell anemia
* Recent abdominal surgery or infection
|-
|Non-Occlusive causes
|Non-occlusive ischemia
|20-30%
|
* Low cardiac output states(most commom cause)
* Hypovolemia
* Vasoconstrictive drugs (Digoxin, alpha-adrernergic agonists)
* Septic schock
* Aortic insufficiency
* Cocaine abuse or ergot poisoning
|}
|}
==References==
{{Reflist|2}}
{{WH}}
{{WS}}
[[Category: (name of the system)]]
==References==
<references />

Latest revision as of 19:56, 1 June 2018

  • Mixed Cryoglobulinemia is a combination of both types II and III.
  • Mixed CGs is associated with following conditions:
    • SLE (systemic lupus erythematous)
    • Sjögren's syndrome,
    • HCV
    • Lymphoproliferative disorders
  • Al the above mentioned disorders can cause excessive production of B-cell which can further lead to selective expansion of Cryoglobulinemia producing B-cell clones.
  • In HCV infected patients the HCV complexes such as HCV-IgG, HCV-lipoprotein cause B-cell hyper-proliferation through the CD81 leading to expansion of specific B-cell clones such as WA idiotype or V(H)1-69.
  • HCV particles are often found in such patients' serum CG complexes, but, at the same time, CG development in hepatitis C infection does not directly require the HCV virion or its components [38]. In this sense, CG development may, in fact, reflect a normal, expected response to regulate immune complexes in states of chronic immune activation.
  • Among patients with HCV infection, the number of circulating T cells with surface markers compatible with a suppressor phenotype may be a feature that differs between patients with cryoglobulinemic vasculitis and those with asymptomatic CG.
  • This was illustrated in a study that compared the percentage of "regulatory" T cells in 69 patients with HCV infection who had symptomatic CG with others with asymptomatic HCV infection [39].
  • The mean levels of regulatory T cells were significantly lower in those with symptomatic HCV-associated CG than asymptomatic subjects (2.6 versus 7.4 percent, respectively).
  • Whether the diminished proportion of regulatory T cells plays a role in causing vasculitis is uncertain but warrants further exploration.


Differentiating uremia from other diseases

Uremia and uremic encephalopathy must be differentiated from other diseases that cause personality changes, altered level of consciousness and hand tremors (asterixis). The differentials include the following:[1][2][3][4][5][6][7][8][9][10][11]

Diseases History and Symptoms Physical Examination Laboratory Findings
Personality changes Altered level of consciousness Hand tremors (asterixis) Slurred speech Writing disturbances Voice monotonous Impaired memory Elevated blood ammonia Hyponatremia hypokalemia
Hepatic encephalopathy ++ ++ ++ ++ ++ ++ ++ ++ ++ ++
Alcohol intoxication + + -/+ ++ + - + - -/+ -/+
Alcohol withdrawal + + - ++ + - + - -/+ -/+
Uremia ++ ++ + -/+ -/+ -/+ - ++ Hyperkalemia
Wernicke encephalopathy + + -/+ + + + ++ - - -
Toxic encephalopathy from drugs + + -/+ -/+ + -/+ + + -/+ -/+
Altered intracranial pressure + -/+ - -/+ -/+ - -/+ - - -
Intoxication by chemical agents -/+ -/+ -/+ -/+ -/+ - - - -/+ -/+
Malnutrition -/+ - - - -/+ - -/+ - -/+ -/+
Hypoxic brain injury - -/+ - -/+ -/+ -/+ -/+ - - -
Meningitis and encephalitis -/+ -/+ - -/+ + - - - -/+ -
Hypoglycemia -/+ -/+ - -/+ -/+ - - - -/+ -/+
  1. Meparidze MM, Kodua TE, Lashkhi KS (2010). "[Speech impairment predisposes to cognitive deterioration in hepatic encephalopathy]". Georgian Med News (181): 43–9. PMID 20495225.
  2. Kattimani S, Bharadwaj B (2013). "Clinical management of alcohol withdrawal: A systematic review". Ind Psychiatry J. 22 (2): 100–8. doi:10.4103/0972-6748.132914. PMC 4085800. PMID 25013309.
  3. Roldán J, Frauca C, Dueñas A (2003). "[Alcohol intoxication]". An Sist Sanit Navar. 26 Suppl 1: 129–39. PMID 12813481.
  4. Seifter JL, Samuels MA (2011). "Uremic encephalopathy and other brain disorders associated with renal failure". Semin Neurol. 31 (2): 139–43. doi:10.1055/s-0031-1277984. PMID 21590619.
  5. Handler CE, Perkin GD (1983). "Wernicke's encephalopathy". J R Soc Med. 76 (5): 339–42. PMC 1439130. PMID 6864698.
  6. Kim Y, Kim JW (2012). "Toxic encephalopathy". Saf Health Work. 3 (4): 243–56. doi:10.5491/SHAW.2012.3.4.243. PMC 3521923. PMID 23251840.
  7. Hartmann A, Buttinger C, Rommel T, Czernicki Z, Trtinjiak F (1989). "Alteration of intracranial pressure, cerebral blood flow, autoregulation and carbondioxide-reactivity by hypotensive agents in baboons with intracranial hypertension". Neurochirurgia (Stuttg). 32 (2): 37–43. doi:10.1055/s-2008-1053998. PMID 2497395.
  8. Kumar N (2011). "Acute and subacute encephalopathies: deficiency states (nutritional)". Semin Neurol. 31 (2): 169–83. doi:10.1055/s-0031-1277986. PMID 21590622.
  9. Chiu GS, Chatterjee D, Darmody PT, Walsh JP, Meling DD, Johnson RW; et al. (2012). "Hypoxia/reoxygenation impairs memory formation via adenosine-dependent activation of caspase 1". J Neurosci. 32 (40): 13945–55. doi:10.1523/JNEUROSCI.0704-12.2012. PMC 3476834. PMID 23035103.
  10. Peate I (2004). "An overview of meningitis: signs, symptoms, treatment and support". Br J Nurs. 13 (13): 796–801. doi:10.12968/bjon.2004.13.13.13501. PMID 15284663.
  11. Abdelhafiz AH, Rodríguez-Mañas L, Morley JE, Sinclair AJ (2015). "Hypoglycemia in older people - a less well recognized risk factor for frailty". Aging Dis. 6 (2): 156–67. doi:10.14336/AD.2014.0330. PMC 4365959. PMID 25821643.