scholarly journals The association of the kynurenine pathway of tryptophan metabolism with acute brain dysfunction during critical illness*

2012 ◽  
Vol 40 (3) ◽  
pp. 835-841 ◽  
Author(s):  
Jessica R. Adams Wilson ◽  
Alessandro Morandi ◽  
Timothy D. Girard ◽  
Jennifer L. Thompson ◽  
Chad S. Boomershine ◽  
...  
2015 ◽  
Vol 115 (5) ◽  
pp. 794-795 ◽  
Author(s):  
C.G. Hughes ◽  
N.E. Brummel ◽  
T.D. Girard ◽  
A.J. Graves ◽  
E.W. Ely ◽  
...  

2013 ◽  
Vol 118 (3) ◽  
pp. 631-639 ◽  
Author(s):  
Christopher G. Hughes ◽  
Alessandro Morandi ◽  
Timothy D. Girard ◽  
Bernhard Riedel ◽  
Jennifer L. Thompson ◽  
...  

2014 ◽  
Vol 58 (2) ◽  
pp. 66
Author(s):  
Christopher G. Hughes ◽  
Alessandro Morandi ◽  
Timothy D. Girard ◽  
Bernhard Riedel ◽  
Jennifer L. Thompson ◽  
...  

2019 ◽  
Vol 3 (s1) ◽  
pp. 37-37
Author(s):  
Jo Ellen Wilson ◽  
Sarasota Mihalko ◽  
Stephan Heckers ◽  
Pratik P. Pandharipande ◽  
Timothy D. Girard ◽  
...  

OBJECTIVES/SPECIFIC AIMS: Delirium, a form of acute brain dysfunction, characterized by changes in attention and alertness, is a known independent predictor of mortality in the Intensive Care Unit (ICU). We sought to understand whether catatonia, a more recently recognized form of acute brain dysfunction, is associated with increased 30-day mortality in critically ill older adults. METHODS/STUDY POPULATION: We prospectively enrolled critically ill patients at a single institution who were on a ventilator or in shock and evaluated them daily for delirium using the Confusion Assessment for the ICU and for catatonia using the Bush Francis Catatonia Rating Scale. Coma, was defined as a Richmond Agitation Scale score of −4 or −5. We used the Cox Proportional Hazards model predicting 30-day mortality after adjusting for delirium, coma and catatonia status. RESULTS/ANTICIPATED RESULTS: We enrolled 335 medical, surgical or trauma critically ill patients with 1103 matched delirium and catatonia assessments. Median age was 58 years (IQR: 48 - 67). Main indications for admission to the ICU included: airway disease or protection (32%; N=100) or sepsis and/or shock (25%; N=79. In the unadjusted analysis, regardless of the presence of catatonia, non-delirious individuals have the highest median survival times, while delirious patients have the lowest median survival time. Comparing the absence and presence of catatonia, the presence of catatonia worsens survival (Figure 1). In a time-dependent Cox model, comparing non-delirious individuals, holding catatonia status constant, delirious individuals have 1.72 times the hazards of death (IQR: 1.321, 2.231) while those with coma have 5.48 times the hazards of death (IQR: 4.298, 6.984). For DSM-5 catatonia scores, a 1-unit increase in the score is associated with 1.18 times the hazards of in-hospital mortality. Comparing two individuals with the same delirium status, an individual with a DSM-5 catatonia score of 0 (no catatonia) will have 1.178 times the hazard of death (IQR: 1.086, 1.278), while an individual with a score of 3 catatonia items (catatonia) present will have 1.63 times the hazard of death. DISCUSSION/SIGNIFICANCE OF IMPACT: Non-delirious individuals have the highest median survival times, while those who are comatose have the lowest median survival times after a critical illness, holding catatonia status constant. Comparing the absence and presence of catatonia, the presence of catatonia seems to worsen survival. Those individual who are both comatose and catatonic have the lowest median survival time.


2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A493-A493
Author(s):  
Laiba Jamshed ◽  
Genevieve A Perono ◽  
Shanza Jamshed ◽  
Kim Ann Cheung ◽  
Philippe J Thomas ◽  
...  

Abstract Introduction: Serotonin produced in the periphery has been shown to affect glucose and lipid homeostasis. The availability of the amino acid tryptophan, the precursor of serotonin, affects serotonin availability. In addition, the metabolism of tryptophan via the kynurenine pathway produces physiologically active metabolites which have been shown to be altered under conditions of increased adiposity and dysglycemia. There is now evidence demonstrating some environmental xenobiotics, known to affect glucose and lipid homeostasis, can also alter serotonin production and key components of the kynurenine pathway. Recent evidence suggests that exposure to compounds present in petroleum and wastewaters from oil and gas extraction sites can impact endocrine signaling and result in aberrant lipid accumulation and altered glycemic control. However, whether any of these changes can be causally ascribed to altered serotonin synthesis/signaling or tryptophan metabolism remains unknown. The goal of this study was to determine the effects of exposure to naphthenic acid (NA), a key toxicant found in wastewater from bitumen (thick crude oil present in oil sands deposits) extraction on the enzymes involved in tryptophan metabolism and serotonin production. Methods: McA-RH7777 rat hepatoma cells, were exposed to a technical NA mixture for 48 hours at concentrations within the reported range of NA found in wastewaters from oil extraction. We assessed mRNA expression for key rate-limiting enzymes involved in tryptophan metabolism that lead to either serotonin [Tph1] and/or kynurenine [Ido2 and Tdo2] production, as well as downstream enzymes in the kynurenine pathway [Afmid, Kyat1, Aadat, Kyat3, Kmo, Haao, Acmsd, Qprt]. We also examined the effects of NA on prostaglandin synthesis [Ptgs1, Ptgs2, Ptges] and signalling [Ptger2, Ptger4] as prostaglandins have been shown to be induced by serotonin and are linked to hepatic fat accumulation. Results: NA treatment significantly increased Tph1 and Ido2 expression; this occurred in association with a significant increase in the expression of the inducible prostaglandin synthase Ptgs2 (COX-2), prostaglandin E synthase Ptges, and prostaglandin receptors Ptger2 and Ptger4. Acmsd was the only downstream enzyme in the kynurenine pathway that was significantly altered by NA treatment. Conclusion: These results provide proof-of-concept that compounds associated with oil sands extraction have the potential to perturb key components of serotonin synthesis (Tph1) and tryptophan metabolism (Ido2, Acmsd). Furthermore, we found that the increase in Tph1 expression paralleled expression of Ptgs2. As increased prostaglandin production has been reported in association with nonalcoholic steatohepatitis, these data provide a potential mechanism by which exposure to NA and other petroleum-based compounds may increase the risk of metabolic disease.


Author(s):  
Christopher W. Seymour ◽  
Renee E. Torres ◽  
Pratik P. Pandharipande ◽  
Tyler Koestner ◽  
Leonard D. Hudson ◽  
...  

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