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Journal of Neuroinflammation May 2024Sepsis-associated encephalopathy (SAE) is a significant cause of mortality in patients with sepsis. Despite extensive research, its exact cause remains unclear. Our...
Sepsis-associated encephalopathy (SAE) is a significant cause of mortality in patients with sepsis. Despite extensive research, its exact cause remains unclear. Our previous research indicated a relationship between non-hepatic hyperammonemia (NHH) and SAE. This study aimed to investigate the relationship between NHH and SAE and the potential mechanisms causing cognitive impairment. In the in vivo experimental results, there were no significant abnormalities in the livers of mice with moderate cecal ligation and perforation (CLP); however, ammonia levels were elevated in the hippocampal tissue and serum. The ELISA study suggest that fecal microbiota transplantation in CLP mice can reduce ammonia levels. Reduction in ammonia levels improved cognitive dysfunction and neurological impairment in CLP mice through behavioral, neuroimaging, and molecular biology studies. Further studies have shown that ammonia enters the brain to regulate the expression of aquaporins-4 (AQP4) in astrocytes, which may be the mechanism underlying brain dysfunction in CLP mice. The results of the in vitro experiments showed that ammonia up-regulated AQP4 expression in astrocytes, resulting in astrocyte damage. The results of this study suggest that ammonia up-regulates astrocyte AQP4 expression through the gut-brain axis, which may be a potential mechanism for the occurrence of SAE.
Topics: Animals; Mice; Aquaporin 4; Astrocytes; Hyperammonemia; Sepsis-Associated Encephalopathy; Male; Brain-Gut Axis; Mice, Inbred C57BL; Ammonia; Brain; Fecal Microbiota Transplantation
PubMed: 38802927
DOI: 10.1186/s12974-024-03135-2 -
Zhongguo Dang Dai Er Ke Za Zhi =... May 2024Glyceryl phenylbutyrate (GPB) serves as a long-term management medication for Ornithine transcarbamylase deficiency (OTCD), effectively controlling hyperammonemia, but...
Glyceryl phenylbutyrate (GPB) serves as a long-term management medication for Ornithine transcarbamylase deficiency (OTCD), effectively controlling hyperammonemia, but there is a lack of experience in using this medicine in China. This article retrospectively analyzes the case of a child diagnosed with OTCD at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, including a review of related literature. After diagnosis, the patient was treated with GPB, followed by efficacy follow-up and pharmacological monitoring. The 6-year and 6-month-old male patient exhibited poor speech development, disobedience, temper tantrums, and aggressive behavior. Blood ammonia levels peaked at 327 μmol/L; urine organic acid analysis indicated elevated uracil levels; cranial MRI showed extensive abnormal signals in both cerebral hemispheres. Genetic testing revealed mutation in the gene (c.241T>C, p.S81P). Blood ammonia levels were approximately 43, 80, and 56 μmol/L at 1, 2, and 3 months after starting GPB treatment, respectively. During treatment, blood ammonia was well-controlled without drug-related adverse effects. The patient showed improvement in developmental delays, obedience, temperament, and absence of aggressive behavior.
Topics: Humans; Male; Ornithine Carbamoyltransferase Deficiency Disease; Phenylbutyrates; Child; Glycerol
PubMed: 38802913
DOI: 10.7499/j.issn.1008-8830.2310050 -
Nanoscale Advances May 2024High concentrations of ammonia in the human body can occur due to a wide variety of underlying causes such as liver cirrhosis and the symptoms of high ammonia...
High concentrations of ammonia in the human body can occur due to a wide variety of underlying causes such as liver cirrhosis and the symptoms of high ammonia concentrations are diffuse and hard to diagnose. The measurement of blood ammonia levels is an important diagnostic tool but is challenging to perform at the patient's bedside. Here, we present a plasmonic Ag nanoparticle-based ammonia sensor which provides a colorimetric optical readout and does not require specialised equipment. This is achieved using plasmonic Ag/SiO nanoparticles with the sensing mechanism that in the presence of OCl they rapidly degrade reducing their plasmonic extinction and losing their characteristic colour. However, if ammonia is also present in the system, it neutralises the OCl and thus the silver nanoparticles retain their plasmonic colour as can be measured by the naked eye or using a spectrometer. This sensing was further developed to enable measurements with animal serum as well as a implementing a facile "dip-stick" style paper-based sensor.
PubMed: 38752137
DOI: 10.1039/d4na00021h -
Cureus Apr 2024Hepatic encephalopathy is typically seen in advanced liver disease and in patients with a transjugular intrahepatic portosystemic shunt. Common triggers include...
Hepatic encephalopathy is typically seen in advanced liver disease and in patients with a transjugular intrahepatic portosystemic shunt. Common triggers include infections, gastrointestinal bleeding, electrolyte disturbances, dehydration, and drug/toxin use such as benzodiazepines and alcohol. In rare instances, other metabolic abnormalities such as hypothyroidism may also exacerbate hyperammonemia in patients with underlying liver disease due to hypothyroidism-induced myopathy, which increases urea production and decreases clearance through reduced glutamine synthetase activity. We present the case of a 60-year-old female who presented with markedly elevated thyroid stimulating hormone, reduced free thyroxine, and elevated serum ammonia levels. Although lactulose and rifaximin were initially started, her symptoms did not clinically improve until the underlying cause of her hyperammonemia was treated. Levothyroxine was initiated, and she reported rapid clinical improvement in her symptoms. Hyperammonemia carries a 40% mortality rate, and therefore clinicians need to be aware of this rare but intricate relationship between advanced liver disease and hypothyroidism for the prompt diagnosis and management of this condition.
PubMed: 38721206
DOI: 10.7759/cureus.57861 -
Frontiers in Psychiatry 2024Acquired hepatocerebral degeneration (AHD) is a neurological condition associated with cerebral manganese (Mn) accumulation caused by portosystemic shunts (PSS), usually...
INTRODUCTION
Acquired hepatocerebral degeneration (AHD) is a neurological condition associated with cerebral manganese (Mn) accumulation caused by portosystemic shunts (PSS), usually because of advanced liver disease. AHD is diagnosed by the identification of T1-weighted brain magnetic resonance imaging (MRI) hyperintensities coupled with the presence of PSS and neurological symptoms. Clinical presentations primarily involve motor dysfunction and cognitive impairment. As a result of the frequently concurrent hepatic encephalopathy, the psychiatric symptoms of AHD alone remain unclear. This report is the first documentation of unique psychiatric symptoms of AHD due to a congenital PSS (CPSS) and suggests the efficacy of shunt embolization in achieving sustained remission of psychiatric symptoms in such cases.
METHODS
A 57-year-old Japanese woman presented with recurrent severe depression, pain, and somatosensory hallucinations, along with fluctuating motor dysfunction, including parkinsonism, and cognitive impairments. Psychiatric interventions, including antidepressants, antipsychotics or electroconvulsive therapy, had limited efficacy or did not prevent relapse.
RESULTS
T1-weighted MRI showed bilateral hyperintensity in the globus pallidus. No history of Mn exposure or metabolic abnormalities, including copper, was identified. Furthermore, no evidence of liver dysfunction or hyperammonemia was found. Eventually, a gastrorenal shunt was observed on contrast-enhanced abdominal computed tomography. The diagnosis of AHD due to CPSS was made based on the clinical manifestations and abnormal imaging findings. Shunt embolization was performed, which prevented the relapse of psychiatric symptoms and substantially reduced the T1-weighted MRI hyperintensities.
CONCLUSIONS
This case highlights the potential involvement of AHD in adult-onset psychiatric symptoms, even in the absence of liver disease. Furthermore, this case underscores the efficacy of shunt embolization in treating the psychiatric symptoms of AHD due to CPSS.
PubMed: 38716114
DOI: 10.3389/fpsyt.2024.1402695 -
Journal of Intensive Medicine Apr 2024Hepatic encephalopathy (HE) is highly prevalent in patients with liver diseases. The pathophysiology of HE is centered on the synergic role of hyperammonemia and...
BACKGROUND
Hepatic encephalopathy (HE) is highly prevalent in patients with liver diseases. The pathophysiology of HE is centered on the synergic role of hyperammonemia and systemic inflammation. However, some data suggest altered functioning of the blood-brain barrier (BBB). Assessing BBB function is challenging in clinical practice and at the bedside. Protein-S-100 Beta (PS100-Beta) could be a useful peripheral marker of BBB permeability in HE. This study aimed to assess plasmatic PS100-Beta levels in a prospective cohort of patients admitted to the intensive care unit (ICU) with decompensated cirrhosis with and without overt HE.
METHODS
We retrospectively evaluated a prospective cohort of cirrhotic patients admitted to the ICU from October 2013 to September 2015 that had an available plasmatic PS100-Beta measurement. Patients with previous neurological impairment or limitation of intensive or resuscitative measures were excluded. Overt HE was defined as West-Haven grades 2 to 4. The patients were compared to a control cohort of outpatient clinic cirrhotic and non-cirrhotic patients explored for isolated elevation of liver enzymes. After ICU discharge, the patients were followed for at least 3 months for the occurrence of overt HE. Adverse outcomes (liver transplantation or death) were collected. The ability of PS100-Beta - in combination with other factors - to predict overt HE was evaluated in a multivariate analysis using logistic regression. Likelihood ratios were used to determine the effects and calculate odds ratios (OR). Survival analysis was performed by using the Kaplan-Meier method and survival between groups was compared using a Log-rank test.
RESULTS
A total of 194 ICU patients and 207 outpatients were included in the study. Increased levels of plasmatic PS100-Beta were detected in the ICU decompensated cirrhotic patients compared with the outpatients ([0.15±0.01] mg/L [0.08±0] mg/L, <0.001). ICU patients with overt HE had higher levels of PS100-Beta ([0.19±0.03] mg/L) compared with the ICU patients without overt HE ([0.13±0.01] mg/L) (=0.003). PS100-Beta levels did not differ in outpatients with F 0-3 compared to F 4 fibrosis (0.670). PS100-Beta values were correlated with Child-Pugh score (0.001), Model for End-Stage Liver Disease (MELD) score (0.004), C-reactive protein (0.001), ammonemia (0.001), and chronic liver failure consortium (CLIF-C) organ failure (0.001) and CLIF-C acute-on-chronic (0.038) scores, but not with leukocytes (0.053), procalcitonin (PCT) (0.107), or the lymphocyte-to-neutrophil ratio in ICU patients (0.522). In a multivariate model including age, ammonemia, PS100-Beta, PCT, MELD, presence of transjugular portosystemic shunt, and sodium level, the diagnostic performance was 0.765 for the diagnosis of overt HE. Patients with a PS100-Beta level <0.12 mg/L had a better overall survival (0.019) and a better survival without liver transplantation (0.013).
CONCLUSIONS
Serum levels of PS100-Beta are elevated in ICU patients with decompensated cirrhosis, and even more so in those displaying overt HE, and the levels are correlated with outcome. This suggests an increase in the permeability of the BBB in these patients.
PubMed: 38681783
DOI: 10.1016/j.jointm.2023.08.006 -
International Journal of Molecular... Apr 2024There are two paralogs of glutamate dehydrogenase (GDH) in humans encoded by the and genes as a result of a recent retroposition during the evolution of primates. The... (Review)
Review
There are two paralogs of glutamate dehydrogenase (GDH) in humans encoded by the and genes as a result of a recent retroposition during the evolution of primates. The two human GDHs possess significantly different regulation by allosteric ligands, which is not fully characterized at the structural level. Recent advances in identification of the GDH ligand binding sites provide a deeper perspective on the significance of the accumulated substitutions within the two GDH paralogs. In this review, we describe the evolution of GLUD1 and GLUD2 after the duplication event in primates using the accumulated sequencing and structural data. A new gibbon sequence questions the indispensability of ancestral R496S and G509A mutations for GLUD2 irresponsiveness to GTP, providing an alternative with potentially similar regulatory features. The data of both and evolution not only confirm substitutions enhancing GLUD2 mitochondrial targeting, but also reveal a conserved mutation in ape GLUD1 mitochondrial targeting sequence that likely reduces its transport to mitochondria. Moreover, the information of GDH interactors, posttranslational modification and subcellular localization are provided for better understanding of the GDH mutations. Medically significant point mutations causing deregulation of GDH are considered from the structural and regulatory point of view.
Topics: Animals; Humans; Evolution, Molecular; Glutamate Dehydrogenase; Ligands; Mutation; Primates; Protein Processing, Post-Translational
PubMed: 38673928
DOI: 10.3390/ijms25084341 -
Biological Research Apr 2024Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with mild cognitive impairment and motor incoordination. Rats with chronic hyperammonemia...
BACKGROUND
Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with mild cognitive impairment and motor incoordination. Rats with chronic hyperammonemia reproduce these alterations. Motor incoordination in hyperammonemic rats is due to increased GABAergic neurotransmission in cerebellum, induced by neuroinflammation, which enhances TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway activation. The initial events by which hyperammonemia triggers activation of this pathway remain unclear. MHE in cirrhotic patients is triggered by a shift in inflammation with increased IL-17. The aims of this work were: (1) assess if hyperammonemia increases IL-17 content and membrane expression of its receptor in cerebellum of hyperammonemic rats; (2) identify the cell types in which IL-17 receptor is expressed and IL-17 increases in hyperammonemia; (3) assess if blocking IL-17 signaling with anti-IL-17 ex-vivo reverses activation of glia and of the TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway.
RESULTS
IL-17 levels and membrane expression of the IL-17 receptor are increased in cerebellum of rats with hyperammonemia and MHE, leading to increased activation of IL-17 receptor in microglia, which triggers activation of STAT3 and NF-kB, increasing IL-17 and TNFα levels, respectively. TNFα released from microglia activates TNFR1 in Purkinje neurons, leading to activation of NF-kB and increased IL-17 and TNFα also in these cells. Enhanced TNFR1 activation also enhances activation of the TNFR1-S1PR2-CCL2-BDNF-TrkB pathway which mediates microglia and astrocytes activation.
CONCLUSIONS
All these steps are triggered by enhanced activation of IL-17 receptor in microglia and are prevented by ex-vivo treatment with anti-IL-17. IL-17 and IL-17 receptor in microglia would be therapeutic targets to treat neurological impairment in patients with MHE.
Topics: Animals; Hyperammonemia; Microglia; Cerebellum; Male; Rats; Receptors, Interleukin-17; Rats, Wistar; Neuroinflammatory Diseases; Interleukin-17; Hepatic Encephalopathy; Signal Transduction; Disease Models, Animal
PubMed: 38671534
DOI: 10.1186/s40659-024-00504-2