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Kakisaka K, Sato T, Wada Y, Abe H, Abe S, Shimodate A, Watanabe T, Sasaki T, Fujiwara Y, Abe T, Suzuki A, Endo K, Yoshida Y, Oikawa T, Sawara K, Miyasaka A, Komaki S, Shimizu A, Ishikawa K, Akasaka M, Kuroda H, Matsumoto T. Dual pathogenic mechanisms in lysinuric protein intolerance: Interplay between hyperammonemia and cellular metabolic dysregulation in astrocyte injury. Mol Genet Metab 2025; 145:109134. [PMID: 40349487 DOI: 10.1016/j.ymgme.2025.109134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 05/02/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND Lysinuric protein intolerance (LPI) is a rare genetic disorder characterized by an inherited defect in cationic amino acid transport caused by pathogenic variants in the SLC7A7 gene. While LPI causes systemic complications, the underlying cellular mechanisms remain poorly understood. This study investigated the cellular characteristics of LPI, focusing on intracellular metabolite profiles and astrocyte response to hyperammonemia. OBJECTIVES To examine intracellular metabolite changes in LPI patients and to evaluate the response of patient-derived astrocytes to ammonia exposure. METHODS Peripheral blood mononuclear cells (PBMCs) from three LPI patients and three healthy controls were analyzed for intracellular metabolite profiles using capillary electrophoresis-fourier transform mass spectrometry. Induced pluripotent stem cells were generated from a patient's PBMCs and differentiated into astrocytes. We evaluated LPI-astrocytes and their response to ammonia treatment by RNA sequencing, gene expression profiling, and cell viability assays. RESULTS Metabolite analysis revealed significant intracellular metabolite imbalances in LPI patients, with increases of 21 metabolites including 11 amino acids. LPI-astrocytes exhibited distinct cellular characteristics regarding altered gene expression and enhanced cell cycle progression. When exposed to ammonia, the astrocytes demonstrated markedly lower cell viability and increased reactive oxygen species (ROS) production compared to control astrocytes. N-acetylcysteine supplementation significantly ameliorated ammonia-induced cytotoxicity. CONCLUSIONS SLC7A7 dysfunction leads to intracellular metabolite disturbances and an increase in vulnerability to ammonia toxicity through ROS production of astrocyte, suggesting hyperammonemia and amino acid deficiencies as potential therapeutic targets in LPI patient care.
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Affiliation(s)
- Keisuke Kakisaka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan.
| | - Takuro Sato
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Yasunori Wada
- Department of Pediatrics, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Hiroaki Abe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Shizuka Abe
- Department of Pediatrics, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Ai Shimodate
- Department of Pediatrics, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Takuya Watanabe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Tokio Sasaki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Yudai Fujiwara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Tamami Abe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Akiko Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Kei Endo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Yuichi Yoshida
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Takayoshi Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Kei Sawara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Akio Miyasaka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Shohei Komaki
- Division of Biomedical Information Analysis, Iwate Medical University, Yahaba, Japan
| | - Atsushi Shimizu
- Division of Biomedical Information Analysis, Iwate Medical University, Yahaba, Japan
| | - Ken Ishikawa
- Department of Pediatrics, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Manami Akasaka
- Department of Pediatrics, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Hidekatsu Kuroda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
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Borrie AE, Pike M, Villeneuve S, Verma N. Severe non-hepatic hyperammonaemic encephalopathy in an immunocompromised adolescent with enterocolitis. BMJ Case Rep 2024; 17:e256225. [PMID: 38901854 PMCID: PMC11191012 DOI: 10.1136/bcr-2023-256225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/26/2024] [Indexed: 06/22/2024] Open
Abstract
Non-hepatic causes of hyperammonaemia are uncommon relative to hepatic aetiologies. An adolescent female was admitted to the hospital with a diagnosis of very severe aplastic anaemia. During her treatment with immunosuppressive therapy, she developed neutropenic enterocolitis, pseudomonal bacteraemia and hyperammonaemia. A combination of intermittent haemodialysis and high-volume continuous veno-venous haemodiafiltration (CVVHDF) was required to manage the hyperammonaemia. Despite a thorough investigation, there were no hepatic, metabolic or genetic aetiologies identified that explained the hyperammonaemia. The hyperammonaemia resolved only after the surgical resection of her inflamed colon, following which she was successfully weaned off from the renal support. This is a novel case report of hyperammonaemia of non-hepatic origin secondary to widespread inflammation of the colon requiring surgical resection in an immunocompromised patient. This case also highlights the role of high-volume CVVHDF in augmenting haemodialysis in the management of severe refractory hyperammonaemia.
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Affiliation(s)
| | - Meghan Pike
- Medicine, Dalhousie Medical School, Halifax, Nova Scotia, Canada
- Pediatric Oncology/Hematology, IWK Health Centre, Halifax, Nova Scotia, Canada
| | - Stephanie Villeneuve
- Medicine, Dalhousie Medical School, Halifax, Nova Scotia, Canada
- Pediatric Oncology/Hematology, IWK Health Centre, Halifax, Nova Scotia, Canada
| | - Neeraj Verma
- Critical Care, Dalhousie University, Halifax, Nova Scotia, Canada
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Moedas MF, Simões RJM, Silva MFB. Mitochondrial targets in hyperammonemia: Addressing urea cycle function to improve drug therapies. Biochem Pharmacol 2024; 222:116034. [PMID: 38307136 DOI: 10.1016/j.bcp.2024.116034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 12/27/2023] [Accepted: 01/25/2024] [Indexed: 02/04/2024]
Abstract
The urea cycle (UC) is a critically important metabolic process for the disposal of nitrogen (ammonia) produced by amino acids catabolism. The impairment of this liver-specific pathway induced either by primary genetic defects or by secondary causes, namely those associated with hepatic disease or drug administration, may result in serious clinical consequences. Urea cycle disorders (UCD) and certain organic acidurias are the major groups of inherited rare diseases manifested with hyperammonemia (HA) with UC dysregulation. Importantly, several commonly prescribed drugs, including antiepileptics in monotherapy or polytherapy from carbamazepine to valproic acid or specific antineoplastic agents such as asparaginase or 5-fluorouracil may be associated with HA by mechanisms not fully elucidated. HA, disclosing an imbalance between ammoniagenesis and ammonia disposal via the UC, can evolve to encephalopathy which may lead to significant morbidity and central nervous system damage. This review will focus on biochemical mechanisms related with HA emphasizing some poorly understood perspectives behind the disruption of the UC and mitochondrial energy metabolism, namely: i) changes in acetyl-CoA or NAD+ levels in subcellular compartments; ii) post-translational modifications of key UC-related enzymes, namely acetylation, potentially affecting their catalytic activity; iii) the mitochondrial sirtuins-mediated role in ureagenesis. Moreover, the main UCD associated with HA will be summarized to highlight the relevance of investigating possible genetic mutations to account for unexpected HA during certain pharmacological therapies. The ammonia-induced effects should be avoided or overcome as part of safer therapeutic strategies to protect patients under treatment with drugs that may be potentially associated with HA.
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Affiliation(s)
- Marco F Moedas
- Research Institute for Medicines-iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Ricardo J M Simões
- Research Institute for Medicines-iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
| | - Margarida F B Silva
- Research Institute for Medicines-iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
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Khokhar M. Non-invasive detection of renal disease biomarkers through breath analysis. J Breath Res 2024; 18:024001. [PMID: 38099568 DOI: 10.1088/1752-7163/ad15fb] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 12/14/2023] [Indexed: 01/06/2024]
Abstract
Breath biomarkers are substances found in exhaled breath that can be used for non-invasive diagnosis and monitoring of medical conditions, including kidney disease. Detection techniques include mass spectrometry (MS), gas chromatography (GC), and electrochemical sensors. Biosensors, such as GC-MS or electronic nose (e-nose) devices, can be used to detect volatile organic compounds (VOCs) in exhaled breath associated with metabolic changes in the body, including the kidneys. E-nose devices could provide an early indication of potential kidney problems through the detection of VOCs associated with kidney dysfunction. This review discusses the sources of breath biomarkers for monitoring renal disease during dialysis and different biosensor approaches for detecting exhaled breath biomarkers. The future of using various types of biosensor-based real-time breathing diagnosis for renal failure is also discussed.
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Affiliation(s)
- Manoj Khokhar
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
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Duff C, Alexander IE, Baruteau J. Gene therapy for urea cycle defects: An update from historical perspectives to future prospects. J Inherit Metab Dis 2024; 47:50-62. [PMID: 37026568 PMCID: PMC10953416 DOI: 10.1002/jimd.12609] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/31/2023] [Accepted: 04/04/2023] [Indexed: 04/08/2023]
Abstract
Urea cycle defects (UCDs) are severe inherited metabolic diseases with high unmet needs which present a permanent risk of hyperammonaemic decompensation and subsequent acute death or neurological sequelae, when treated with conventional dietetic and medical therapies. Liver transplantation is currently the only curative option, but has the potential to be supplanted by highly effective gene therapy interventions without the attendant need for life-long immunosuppression or limitations imposed by donor liver supply. Over the last three decades, pioneering genetic technologies have been explored to circumvent the consequences of UCDs, improve quality of life and long-term outcomes: adenoviral vectors, adeno-associated viral vectors, gene editing, genome integration and non-viral technology with messenger RNA. In this review, we present a summarised view of this historical path, which includes some seminal milestones of the gene therapy's epic. We provide an update about the state of the art of gene therapy technologies for UCDs and the current advantages and pitfalls driving future directions for research and development.
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Affiliation(s)
- Claire Duff
- Genetics and Genomic Medicine Department, Great Ormond Street Institute of Child HealthUniversity College LondonLondonUK
| | - Ian E. Alexander
- Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and HealthThe University of Sydney and Sydney Children's Hospitals NetworkWestmeadNew South WalesAustralia
- Discipline of Child and Adolescent HealthThe University of SydneyWestmeadNew South WalesAustralia
| | - Julien Baruteau
- Genetics and Genomic Medicine Department, Great Ormond Street Institute of Child HealthUniversity College LondonLondonUK
- National Institute of Health Research Great Ormond Street Biomedical Research CentreLondonUK
- Metabolic Medicine DepartmentGreat Ormond Street Hospital for Children NHS Foundation TrustLondonUK
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Sakran N, Parmar C, Pouwels S. Nonhepatic hyperammonemic encephalopathy following bariatric surgery: A systematic review. Obes Res Clin Pract 2023; 17:458-467. [PMID: 38007358 DOI: 10.1016/j.orcp.2023.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 09/18/2023] [Accepted: 11/03/2023] [Indexed: 11/27/2023]
Abstract
BACKGROUND Nonhepatic Hyperammonemic encephalopathy (NHAE) following Bariatric Surgery (BS), mainly Roux-en-Y Gastric Bypass (RYGB) and Biliopancreatic Diversion (BPD) is a potentially devastating condition if not diagnosed and managed promptly. METHODS A literature review was performed using PRISMA guidelines. Eighteen studies and 3 conference abstracts with a total of 33 patients were included in this review. RESULTS Majority (28 patients, 84.8 %) had RYGB. Seven patients (21.2 %) had associated metabolic disorders. 60 % of patients presented with neurological symptoms or signs such as confusion, cognitive and/or psychomotor changes, and decreased reflexes. Two patients presented with status epilepticus. In 30 of the 33 patients an elevated serum ammonia levels was reported (90.9 %). The overall mortality was 39.3 %. CONCLUSION NHAE is a rare condition following bariatric surgery (in particular bypass procedures), carrying a high mortality rate. The signs and symptoms are predominantly neurological and may be mistaken for Wernicke's encephalopathy or other more common neurological conditions. Serum ammonia levels should be checked in those who present with these symptoms and signs. Prompt treatment might be life saving in patients with NHAE.
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Affiliation(s)
- Nasser Sakran
- Department of Surgery, Holy Family Hospital, Nazareth, Israel, and the Azrieli, Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Chetan Parmar
- Department of Surgery, Whittington Health NHS Trust, London, United Kingdom
| | - Sjaak Pouwels
- Department of Intensive Care Medicine, Elisabeth-Tweesteden Hospital, Tilburg, the Netherlands; Department of General, Abdominal Surgery and Coloproctology, Helios St. Elisabeth Klinik, Oberhausen, NRW, Germany; Faculty of Health, Witten/Herdecke University, Witten, Germany.
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Landerl A, Covaliova I, Ganter CC, Mancini S, David S, Andermatt R. Older Adult Woman in a Coma After Acute Laryngitis. Chest 2023; 164:e65-e69. [PMID: 37689475 DOI: 10.1016/j.chest.2023.04.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 04/12/2023] [Accepted: 04/25/2023] [Indexed: 09/11/2023] Open
Abstract
CASE PRESENTATION A 72-year-old woman with a history of adenocarcinoma of the lung, for which she was receiving tyrosine kinase inhibitor therapy with osimertinib, was admitted to the ED because of clinical deterioration with extreme fatigue and fever. She was already receiving antibiotic therapy initiated by her general practitioner because of symptoms of an upper respiratory tract infection. She was febrile (38.5 °C) with normal laboratory values except for leukocytosis and elevated C-reactive protein. She was hospitalized because of profound general malaise. On the basis of the physician's working hypothesis of severe viral laryngitis, the antibiotic therapy was stopped, and only supportive measures were taken. Over the next 3 days, her condition deteriorated, and she developed respiratory symptoms with a right-sided pleural effusion demonstrated by ultrasound examination. Over time, the patient became increasingly confused and drowsy. There was preserved urinary output and a stable glomerular filtration rate of 57 mL/min. Further on, bilirubin levels as well as coagulation were normal, indicating the absence of any relevant underlying chronic liver condition. Clinically, there were no signs of meningitis. No sedative medications that would explain her confusion were given except for low-dose opioid analgesics. On day 4 after hospitalization, she was transferred to the shock room for immediate stabilization and diagnostics because of profound encephalopathy and increasing oxygen requirements.
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Affiliation(s)
- Alexander Landerl
- Institute of Intensive Care Medicine, University Hospital Zurich, Zurich, Switzerland
| | - Irina Covaliova
- Institute of Intensive Care Medicine, University Hospital Zurich, Zurich, Switzerland
| | | | - Stefano Mancini
- Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland
| | - Sascha David
- Institute of Intensive Care Medicine, University Hospital Zurich, Zurich, Switzerland.
| | - Rea Andermatt
- Institute of Intensive Care Medicine, University Hospital Zurich, Zurich, Switzerland
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[Expert consensus on the diagnosis and treatment of neonatal hyperammonemia]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2023; 25:437-447. [PMID: 37272168 PMCID: PMC10247199 DOI: 10.7499/j.issn.1008-8830.2302140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 04/07/2023] [Indexed: 06/06/2023]
Abstract
Neonatal hyperammonemia is a disorder of ammonia metabolism that occurs in the neonatal period. It is a clinical syndrome characterized by abnormal accumulation of ammonia in the blood and dysfunction of the central nervous system. Due to its low incidence and lack of specificity in clinical manifestations, it is easy to cause misdiagnosis and missed diagnosis. In order to further standardize the diagnosis and treatment of neonatal hyperammonemia, the Youth Commission, Subspecialty Group of Neonatology, Society of Pediatrics, Chinese Medical Association formulated the expert consensus based on clinical evidence in China and overseas and combined with clinical practice experience,and put forward 18 recommendations for the diagnosis and treatment of neonatal hyperaminemia.
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Ni B, Qin M, Zhao J, Guo Q. A glance at transient hyperammonemia of the newborn: Pathophysiology, diagnosis, and treatment: A review. Medicine (Baltimore) 2022; 101:e31796. [PMID: 36482558 PMCID: PMC9726343 DOI: 10.1097/md.0000000000031796] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hyperammonemia is the excessive accumulation of ammonia in the blood, and is usually defined as a plasma level above 100 µmol/L in neonates or above 50 µmol/L in term infants, children, and adolescents. Patients with hyperammonemia usually experience life-threatening neuropsychiatric symptoms, especially newborns. It is routinely caused by inherited metabolic diseases and also by acquired disorders, such as liver failure, portosystemic shunting, gastrointestinal hemorrhage, ureterosigmoidostomy, renal tubular acidosis, hypoxic ischemic encephalopathy, infections with urea-metabolizing organisms, and some drugs. Transient hyperammonemia of the newborn (THAN) is a special type of hyperammonemia acknowledged in the field of metabolic disease as an inwell-defined or well-understood entity, which can be diagnosed only after the exclusion of genetic and acquired causes of hyperammonemia. Although the prognosis for THAN is good, timely identification and treatment are essential. Currently, THAN is underdiagnosed and much less is mentioned for early diagnosis and vigorous treatment. Herein, we present common themes that emerge from the pathogenesis, diagnosis, and management of THAN, based on current evidence. When a newborn presents with sepsis, intracranial hemorrhage, or asphyxia that cannot explain coma and seizures, doctors should always keep this disease in mind.
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Affiliation(s)
- Beibei Ni
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Miao Qin
- Department of Neonatology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jun Zhao
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qie Guo
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, China
- * Correspondence: Qie Guo, Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, Shandong 266003, China (e-mail: )
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Abdelghffar EAR, El-Nashar HAS, Fayez S, Obaid WA, Eldahshan OA. Ameliorative effect of oregano (Origanum vulgare) versus silymarin in experimentally induced hepatic encephalopathy. Sci Rep 2022; 12:17854. [PMID: 36284120 PMCID: PMC9596437 DOI: 10.1038/s41598-022-20412-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 09/13/2022] [Indexed: 01/20/2023] Open
Abstract
Hepatic encephalopathy (HE) is a deterioration of brain function in patients suffering from chronic liver disease, cirrhosis as a result of elevated blood ammonia and the production of pseudo-neurotransmitters. Herein, we investigated the chemical composition of hexane extract from Origanum vulgare (O. vulgare) leaves as well as its possible protective effects against thioacetamide (TAA)-induced HE in rats. GC-MS analysis of the extract revealed tentative identification of twenty-five compounds (82.93%), predominated by cholesten-3-one (27.30%), followed by γ-tocopherol (13.52%), α-tocopherol (5.01%), β-amyrin (5.24%) and α-amyrin (4.89%). Albino rats were distributed into seven groups (n = 7). G1 served as negative control; G2 and G3 served as controls treated with O. vulgare (100 and 200 mg/kg/p.o b.w, respectively); G4 served as TAA-positive control group (100 mg/kg/day/i.p., three alternative days per week for six weeks); G5, G6, and G7 served as TAA -induced HE rat model that received O. vulgare 100, O. vulgare 200, and silymarin (100 mg/kg of SILY, as standard drug), respectively. TAA showed depressive and anxiety-like behaviors in forced swimming test (FST) and reduction of cognitive score in elevated plus-maze test (EPMT) as well as impairment of locomotor and exploratory activities in open-field test (OFT). TAA caused a significant decline in body weight gain; however, the relative liver weight and brain water content were statistically increased. TAA-intoxicated rats showed significant increase of serum biomarker enzymes, proinflammatory cytokines, blood ammonia levels, brain serotonin, acetyl cholinesterase and cellular lipid peroxidation with significant decrease of brain dopamine, norepinephrine, antioxidant status. The hepatoprotective/neuro-protective activities of O. vulgare was found to be comparable with that of SILY in HE rats model. Where, treatment of TAA-intoxicated rats with O. vulgare attenuated anxiety, depressive-related behaviors, and reduced the biochemical changes in HE-induced by TAA. Therefore, O. vulgare could be an excellent hepato-/neuroprotective against hepatic injury and HE via improving the oxidative/inflammatory status through its antioxidant and neuro-modulatory properties and its effect is equal to that of SILY.
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Affiliation(s)
- Eman A. R. Abdelghffar
- grid.7269.a0000 0004 0621 1570Department of Zoology, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Heba A. S. El-Nashar
- grid.7269.a0000 0004 0621 1570Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Cairo, Egypt ,grid.7269.a0000 0004 0621 1570Centre of Drug Discovery Research and Development, Ain Shams University, Cairo, Egypt
| | - Shaimaa Fayez
- grid.7269.a0000 0004 0621 1570Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Cairo, Egypt ,grid.7269.a0000 0004 0621 1570Centre of Drug Discovery Research and Development, Ain Shams University, Cairo, Egypt
| | - Wael A. Obaid
- grid.412892.40000 0004 1754 9358Department of Biology, College of Science, Taibah University, Al-Madīnah Al-Munawarah, Saudi Arabia
| | - Omayma A. Eldahshan
- grid.7269.a0000 0004 0621 1570Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Cairo, Egypt ,grid.7269.a0000 0004 0621 1570Centre of Drug Discovery Research and Development, Ain Shams University, Cairo, Egypt
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Fátima Lopes F, Sitta A, de Moura Coelho D, Schmitt Ribas G, Lamberty Faverzani J, Gomes Dos Reis B, Wajner M, Vargas CR. Clinical findings of patients with hyperammonemia affected by urea cycle disorders with hepatic encephalopathy. Int J Dev Neurosci 2022; 82:772-788. [PMID: 36129623 DOI: 10.1002/jdn.10229] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/21/2022] [Accepted: 09/15/2022] [Indexed: 11/10/2022] Open
Abstract
Urea Cycle Disorders (UCD) are a group of genetic diseases caused by deficiencies in the enzymes and transporters involved in the urea cycle. The impairment of the cycle results in ammonia accumulation, leading to neurological dysfunctions and poor outcomes to affected patients. The aim of this study is to investigate and describe UCD patients principal clinical and biochemical presentations to support professionals on urgent diagnosis and quick management, aiming better outcomes for patients. We explored medical records of thirty patients diagnosed in a referral center from Brazil to delineate UCD clinical and biochemical profile. Patients demonstrated a range of signs and symptoms, such as altered levels of consciousness, acute encephalopathy, seizures, progressive loss of appetite, vomiting, coma, and respiratory distress, in most cases combined with high levels of ammonia, which is an immediate biomarker, leading to an UCD suspicion. The most prevalent UCD detected were ornithine transcarbamylase deficiency (11), followed by citrullinemia type I (10), hyperargininemia (5), carbamoyl phosphate synthase 1 deficiency (2) and argininosuccinic aciduria (2). Clinical symptoms were highly severe, being the majority developmental and neurological disabilities, with 20% of death rate. Laboratory analysis revealed high levels of ammonia (mean ± SD: 860 ± 470 μmol/L; reference value: ≤ 80 μmol/L), hypoglycemia, metabolic acidosis, and high excretion of orotic acid in the urine (except in CPS1 deficiency). We emphasize the need of urgent identification of UCD clinical and biochemical conditions, and immediate measurement of ammonia, to enable the correct diagnosis and increase the chances of patients survival, minimizing neurological and psychomotor damage caused by hepatic encephalopathy.
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Affiliation(s)
- Franciele Fátima Lopes
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Angela Sitta
- Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | | | | | - Jéssica Lamberty Faverzani
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Bianca Gomes Dos Reis
- Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Moacir Wajner
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Carmen Regla Vargas
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
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12
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Abstract
PURPOSE OF REVIEW Hyperammonemia syndrome is an increasingly recognized and often fatal condition that occurs in immunosuppressed individuals, most commonly lung transplant recipients. Growing evidence suggests hyperammonemia syndrome is associated with systemic infections caused by urease-producing organisms, namely Ureaplasma spp., an organism unable to grow with routine culturing techniques. This review will summarize the epidemiology and clinical manifestations of hyperammonemia syndrome, as well as diagnostic and management strategies once hyperammonemia syndrome is suspected. RECENT FINDINGS Hyperammonemia syndrome is being described in increasing frequency in the solid organ transplant population. Morbidity and mortality, even with treatment, is high once hyperammonemia syndrome occurs. Surveillance studies indicate the prevalence of lung donor colonization with Ureaplasma spp. is high, suggesting screening and treatment may be of benefit. Antibiotic resistance is common, and rapid diagnostics can facilitate appropriate antimicrobial therapy in the peri-transplant period. SUMMARY Hyperammonemia syndrome is most commonly seen in lung transplant recipients and has a high mortality rate once it occurs. Screening for Ureaplasma spp. should be considered in all lung transplant donors.
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Affiliation(s)
- Scott C Roberts
- Division of Infectious Diseases, Yale University School of Medicine, New Haven, Connecticut
| | - Waleed Malik
- Division of Infectious Diseases, Yale University School of Medicine, New Haven, Connecticut
| | - Michael G Ison
- Divisions of Infectious Diseases and Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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13
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Calvo-López A, Rebollo-Calderon B, Ormazábal A, Artuch R, Rosell-Ferrer J, Alonso-Chamarro J, Puyol M. Biomedical point-of-care microanalyzer for potentiometric determination of ammonium ion in plasma and whole blood. Anal Chim Acta 2022; 1205:339782. [DOI: 10.1016/j.aca.2022.339782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 03/24/2022] [Accepted: 03/26/2022] [Indexed: 11/01/2022]
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14
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Sulaiman RA, Alali A, Hosaini S, Hussein M, Pasha F, Albogami M, Aamir Sheikh A, AlSayed M, Al-Owain M. Emergency management of critically ill adult patients with inherited metabolic disorders. Am J Emerg Med 2022; 55:138-142. [DOI: 10.1016/j.ajem.2022.02.053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 02/09/2022] [Accepted: 02/24/2022] [Indexed: 10/18/2022] Open
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15
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Kim JH, Jeon H, Lee SS, Heo IR, Choi JW, Kim HJ, Cha RR, Lee JM, Kim HJ. Impact of non-hepatic hyperammonemia on mortality in intensive care unit patients: a retrospective cohort study. Korean J Intern Med 2021; 36:1347-1355. [PMID: 34256430 PMCID: PMC8588975 DOI: 10.3904/kjim.2021.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 04/26/2021] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND/AIMS The effect of hyperammonemia on the mortality in patients with liver cirrhosis is well documented. However, little is known about the impact of hyperammonemia on mortality among intensive care unit patients without hepatic disease. We aimed to investigate factors associated with non-hepatic hyperammonemia among intensive care unit patients and to evaluate the factors related to the 7- and 90-day mortality. METHODS Between February 2016 and February 2020, 948 patients without hepatic disease who had 972 episodes of admission to the intensive care unit were retrospectively enrolled and classified as hyperammonemia grades 0 (≤ 80 µg/dL; 585 [60.2%]), 1 (≤ 160 µg/dL; 291 [29.9%]), 2 (≤ 240 µg/dL; 55 [5.7%]), and 3 (> 240 µg/dL; 41 [4.2%]). Factors associated with hyperammonemia and the 7- and 90-day mortality were evaluated by multivariate logistic regression analysis and Cox regression analysis, respectively. Kaplan-Meier survival curves for the 7- and 90-day mortality were constructed. RESULTS The independent risk factors for hyperammonemia were male sex (odds ratio, 1.517), age (0.984/year), acute brain failure (2.467), acute kidney injury (1.437), prothrombin time-international normalized ratio (2.272/unit), and albumin (0.694/g/dL). The 90-day mortality rate in the entire cohort was 24.3% and gradually increased with increasing hyperammonemia grade at admission (17.9%, 28.2%, 43.6%, and 61.0% in patients with grades 0, 1, 2, and 3, respectively). Additionally, non-hepatic hyperammonemia was an independent predictor of the 90- day mortality in intensive care unit patients. CONCLUSION Non-hepatic hyperammonemia is common (39.8%) and associated with the 90-day mortality among intensive care unit patients.
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Affiliation(s)
- Jae Heon Kim
- Department of Internal Medicine, Gyeongsang National University Hospital, Jinju,
Korea
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon,
Korea
| | - Hankyu Jeon
- Department of Internal Medicine, Gyeongsang National University Hospital, Jinju,
Korea
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon,
Korea
| | - Sang Soo Lee
- Department of Internal Medicine, Gyeongsang National University Hospital, Jinju,
Korea
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon,
Korea
- Institute of Health Sciences, Gyeongsang National University, Jinju,
Korea
| | - I Re Heo
- Department of Internal Medicine, Gyeongsang National University Hospital, Jinju,
Korea
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon,
Korea
| | - Jung Woo Choi
- Department of Internal Medicine, Gyeongsang National University Hospital, Jinju,
Korea
| | - Hee Jin Kim
- Department of Internal Medicine, Gyeongsang National University Hospital, Jinju,
Korea
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon,
Korea
- Institute of Health Sciences, Gyeongsang National University, Jinju,
Korea
| | - Ra Ri Cha
- Department of Internal Medicine, Gyeongsang National University Hospital, Jinju,
Korea
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon,
Korea
- Institute of Health Sciences, Gyeongsang National University, Jinju,
Korea
| | - Jae Min Lee
- Department of Internal Medicine, Gyeongsang National University Hospital, Jinju,
Korea
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon,
Korea
- Institute of Health Sciences, Gyeongsang National University, Jinju,
Korea
| | - Hyun Jin Kim
- Department of Internal Medicine, Gyeongsang National University Hospital, Jinju,
Korea
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon,
Korea
- Institute of Health Sciences, Gyeongsang National University, Jinju,
Korea
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16
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Effect of Uncaria rhynchophylla against Thioacetamide-Induced Acute Liver Injury in Rat. Can J Gastroenterol Hepatol 2021; 2021:5581816. [PMID: 34557455 PMCID: PMC8455208 DOI: 10.1155/2021/5581816] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 08/26/2021] [Indexed: 12/17/2022] Open
Abstract
Both oxidative stress (OS) and inflammation are two fundamental pathological processes of acute liver injury (ALI). The current work is to investigate the effect and possible mechanism of Uncaria rhynchophylla (UR) on thioacetamide- (TAA-) induced ALI in rats. UR (100 and 200 mg/kg) was orally administrated with TAA (200 mg/kg of bodyweight, intraperitoneal injection) for 3 consecutive days. ALI was confirmed using histological examination and the factors associated with OS and liver function activity measured in serum. Moreover, expressions of inflammation and collagen-related proteins were measured by the Western blot analysis. Myeloperoxidase (MPO), which mediates OS in the ALI control group, was manifested by a significant rise compared with the normal group. UR significantly reduced AST, ALT, and ammonia levels in serum. The nuclear factor-κB (NF-κB) activation induced by TAA led to increase both inflammatory mediators and cytokines. Whereas, UR administration remarkably suppressed such an overexpression. UR supplementation improved matrix metalloproteinases (MMPs) such as MMP-1, -2, and -8. In contrast, tissue inhibitors of metalloproteinases- (TIMP-) 1 level increased significantly by UR treatment. In addition, the histopathological analysis showed that the liver tissue lesions were improved obviously by UR treatment. UR may ameliorate the effects of TAA-induced ALI in rats by suppressing both OS through MPO activation and proinflammatory factors through NF-κB activation. In conclusion, UR exhibited a potent hepatoprotective effect on ALI through the suppression of OS.
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17
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The Cerebral Effect of Ammonia in Brain Aging: Blood-Brain Barrier Breakdown, Mitochondrial Dysfunction, and Neuroinflammation. J Clin Med 2021; 10:jcm10132773. [PMID: 34202669 PMCID: PMC8268635 DOI: 10.3390/jcm10132773] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 06/23/2021] [Accepted: 06/23/2021] [Indexed: 12/14/2022] Open
Abstract
Aging occurs along with multiple pathological problems in various organs. The aged brain, especially, shows a reduction in brain mass, neuronal cell death, energy dysregulation, and memory loss. Brain aging is influenced by altered metabolites both in the systemic blood circulation and the central nervous system (CNS). High levels of ammonia, a natural by-product produced in the body, have been reported as contributing to inflammatory responses, energy metabolism, and synaptic function, leading to memory function in CNS. Ammonia levels in the brain also increase as a consequence of the aging process, ultimately leading to neuropathological problems in the CNS. Although many researchers have demonstrated that the level of ammonia in the body alters with age and results in diverse pathological alterations, the definitive relationship between ammonia and the aged brain is not yet clear. Thus, we review the current body of evidence related to the roles of ammonia in the aged brain. On the basis of this, we hypothesize that the modulation of ammonia level in the CNS may be a critical clinical point to attenuate neuropathological alterations associated with aging.
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18
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Tantengco OAG, De Jesus FCC, Gampoy EFS, Ornos EDB, Vidal MS, Abad CLR. Hyperammonemia syndrome associated with Ureaplasma spp. Infections in immunocompromised patients and transplant recipients: A systematic review and meta-analysis. Clin Transplant 2021; 35:e14334. [PMID: 33948993 DOI: 10.1111/ctr.14334] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/15/2021] [Accepted: 04/26/2021] [Indexed: 01/09/2023]
Abstract
BACKGROUND Hyperammonemia syndrome (HS) is reported to occur in patients with Ureaplasma spp. infections. We performed a systematic review and meta-analysis of studies reporting HS in patients with Ureaplasma spp. infection. METHODS We searched several databases (CINAHL, OVID, ProQuest, and Scopus) from inception to January 2021. We described case reports and series, and performed a meta-analysis for all cohort studies. The pooled risk ratio (RR) for the association between HS and Ureaplasma spp. infections was derived using a random-effects model. RESULTS The systematic review yielded 18 studies. HS was reported in 53 patients with Ureaplasma spp. infections. The most common clinical manifestations were neurologic. Meta-analysis showed a higher incidence of HS (41.67%) and peak ammonia concentration among Ureaplasma spp.-infected lung transplant recipients compared with Ureaplasma spp.-negative recipients (2.84%). The risk of HS was significantly increased in Ureaplasma spp.-infected recipients compared with Ureaplasma spp.-negative recipients (RR: 14.64; CI: 2.85-75.24). Mortality from Ureaplasma-associated HS was 27.27% compared with 5.24% in those with HS from other causes. CONCLUSIONS The risk of developing HS is higher among Ureaplasma-infected patients compared with uninfected patients. Lung transplant recipients appear to be disproportionally affected, and HS should be suspected in those who present with neurologic symptoms.
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Affiliation(s)
| | | | | | - Eric David B Ornos
- College of Medicine, University of the Philippines Manila, Manila, Philippines
| | - Manuel S Vidal
- College of Medicine, University of the Philippines Manila, Manila, Philippines
| | - Cybele Lara R Abad
- College of Medicine, University of the Philippines Manila, Manila, Philippines.,Division of Infectious Diseases, Department of Medicine, Philippine General Hospital, University of the Philippines Manila, Manila, Philippines
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19
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Burma JS, Copeland P, Macaulay A, Khatra O, Wright AD, Smirl JD. Dynamic cerebral autoregulation across the cardiac cycle during 8 hr of recovery from acute exercise. Physiol Rep 2021; 8:e14367. [PMID: 32163235 PMCID: PMC7066871 DOI: 10.14814/phy2.14367] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 12/28/2019] [Accepted: 12/30/2019] [Indexed: 01/02/2023] Open
Abstract
Current protocols examining cerebral autoregulation (CA) parameters require participants to refrain from exercise for 12–24 hr, however there is sparse objective evidence examining the recovery trajectory of these measures following exercise across the cardiac cycle (diastole, mean, and systole). Therefore, this study sought to determine the duration acute exercise impacts CA and the within‐day reproducibility of these measures. Nine participants performed squat–stand maneuvers at 0.05 and 0.10 Hz at baseline before three interventions: 45‐min moderate‐continuous exercise (at 50% heart‐rate reserve), 30‐min high‐intensity intervals (ten, 1‐min at 85% heart‐rate reserve), and a control day (30‐min quiet rest). Squat–stands were repeated at hours zero, one, two, four, six, and eight after each condition. Transcranial doppler ultrasound of the middle cerebral artery (MCA) and the posterior cerebral artery (PCA) was used to characterize CA parameters across the cardiac cycle. At baseline, the systolic CA parameters were different than mean and diastolic components (ps < 0.015), however following both exercise protocols in both frequencies this disappeared until hour four within the MCA (ps > 0.079). In the PCA, phase values were affected only following high‐intensity intervals until hour four (ps > 0.055). Normalized gain in all cardiac cycle domains remained different following both exercise protocols (ps < 0.005) and across the control day (p < .050). All systolic differences returned by hour six across all measures (ps < 0.034). Future CA studies may use squat–stand maneuvers to assess the cerebral pressure–flow relationship 6 hr after exercise. Finally, CA measures under this paradigm appear to have negligible within‐day variation, allowing for reproducible interpretations to be drawn.
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Affiliation(s)
- Joel S Burma
- Concussion Research Laboratory, Faculty of Health and Exercise Science, University of British Columbia, Kelowna, BC, Canada.,Sport Injury Prevention Research Center, Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada.,Human Performance Laboratory, Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada.,Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Paige Copeland
- Concussion Research Laboratory, Faculty of Health and Exercise Science, University of British Columbia, Kelowna, BC, Canada
| | - Alannah Macaulay
- Concussion Research Laboratory, Faculty of Health and Exercise Science, University of British Columbia, Kelowna, BC, Canada
| | - Omeet Khatra
- Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Alexander D Wright
- Concussion Research Laboratory, Faculty of Health and Exercise Science, University of British Columbia, Kelowna, BC, Canada.,MD/PhD Program, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.,Experimental Medicine Program, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.,Southern Medical Program, University of British Columbia, Kelowna, BC, Canada
| | - Jonathan D Smirl
- Concussion Research Laboratory, Faculty of Health and Exercise Science, University of British Columbia, Kelowna, BC, Canada.,Sport Injury Prevention Research Center, Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada.,Human Performance Laboratory, Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada.,Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.,Southern Medical Program, University of British Columbia, Kelowna, BC, Canada.,Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.,Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada
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20
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Li J, Li R, Gao Y, Jin X, Zhang J, Ren J, Hou Y, Wang X, Wang G. Increasing serum ammonia level is a risk factor for the prognosis of critically ill patients: A multicenter retrospective cohort study. J Crit Care 2020; 62:218-222. [PMID: 33429115 DOI: 10.1016/j.jcrc.2020.12.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 12/15/2020] [Accepted: 12/27/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE To assess the association between serum ammonia level upon admission during the initial intensive care unit (ICU) stay and mortality. MATERIALS AND METHODS This retrospective cohort study included 2703 adult patients in eICU Collaborative Research Database. The ICU mortality within ammonia deciles were assessed. Logistic regression analyses were performed to analyze the relationship between ammonia and mortality. RESULTS We defined three ammonia categories: <47, 47-111, and ≥111 μg/dL, corresponding to low, intermediate, and high ICU mortality. Increased ammonia was significantly associated with increased ICU mortality (per 10 μg/dL increase: odds ratio, 1.070 [95% confidence intervals, 1.05-1.09]; intermediate vs. low: 1.90 [1.41-2.56]; high vs. low: 4.38 [2.99-6.41]) and in-hospital mortality (1.06 [1.04-1.08]; 1.45 [1.13-1.87]; 3.41 [2.43-4.79]). Adding ammonia to the Acute Physiology and Chronic Health Evaluation (APACHE) IV score improved the area under the curve from 0.826 to 0.839 (P < 0.001) and from 0.806 to 0.813 (P = 0.001) for ICU and in-hospital mortality, respectively. Interaction and subgroup analyses demonstrated consistent results in patients with different APACHE IV scores, with or without hepatic diseases. CONCLUSIONS Elevated serum ammonia level in critically ill patients upon admission was an early risk factor for higher ICU and in-hospital mortality.
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Affiliation(s)
- Jiamei Li
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ruohan Li
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ya Gao
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xuting Jin
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jingjing Zhang
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jiajia Ren
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yanli Hou
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaochuang Wang
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Gang Wang
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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21
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Khoshnejad M, Dia Y, Patel A, Xu Z, Zhu X, Yun K, Wojtak K, Qureshi R, Humeau L, Muthumani K, Weiner DB. DNA-Encoded Glutamine Synthetase Enzyme as Ammonia-Lowering Therapeutic for Hyperammonemia. Nucleic Acid Ther 2020; 30:379-391. [PMID: 32907467 DOI: 10.1089/nat.2020.0886] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Hyperammonemia is a dangerous life-threatening metabolic complication characterized by markedly elevated ammonia levels that can lead to irreversible brain damage if not carefully monitored. Current pharmacological treatment strategies available for hyperammonemia patients are suboptimal and associated with major side effects. In this study, we focus on developing and evaluating the in vivo delivery of novel DNA-encoded glutamine synthetase (GS) enzymes for the treatment of hyperammonemia. Direct in vivo delivered DNA-encoded GS enzyme was evaluated in ammonium acetate-induced hyperammonemia and thioacetamide-induced acute liver injury (ALI) models in C57BL/6 mice. In ammonium acetate-induced hyperammonemia model, we achieved a 30.5% decrease in blood ammonia levels 15 min postadministration of ammonium acetate, with DNA-encoded GS-treated group. Significant increase in survival was observed in ALI model with the treated mice. A comparison of the secreted versus intracellular DNA-encoded GS enzyme demonstrated similar increases in survival in the ALI model, with 40% mortality in the secreted enzymes and 30% mortality in the intracellular enzymes, as compared with 90% mortality in the control group. Direct in vivo delivery of DNA-encoded GS demonstrated important ammonia-lowering potential. These results provide the initial steps toward development of delivered DNA as a potential new approach to ammonia-lowering therapeutics.
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Affiliation(s)
- Makan Khoshnejad
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Yaya Dia
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Ami Patel
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Ziyang Xu
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA.,Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Xizhou Zhu
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Kun Yun
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Krzysztof Wojtak
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA.,Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rehman Qureshi
- Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Laurent Humeau
- Inovio Pharmaceuticals, Inc., Plymouth Meeting, Pennsylvania, USA
| | - Kar Muthumani
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - David B Weiner
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA
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22
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Afifi NA, Ramadan A, Erian EY, Sedik AA, Amin MM, Hassan A, Saleh DO. Synergistic effect of aminoguanidine and l-carnosine against thioacetamide-induced hepatic encephalopathy in rats: behavioral, biochemical, and ultrastructural evidence. Can J Physiol Pharmacol 2020; 99:332-347. [PMID: 32721224 DOI: 10.1139/cjpp-2020-0212] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatic encephalopathy depicts the cluster of neurological alterations that occur during acute or chronic hepatic injury. Hyperammonemia, inflammatory injury, and oxidative stress are the main predisposing factors for the direct and indirect changes in cerebral metabolism causing encephalopathy. The aim of this study was to evaluate the possible synergistic effect between aminoguanidine (AG; 100 mg/kg, p.o.) and l-carnosine (CAR; 200 mg/kg, p.o.) on hepatic encephalopathy that was induced by thioacetamide (TAA; 100 mg/kg, i.p.) administered three times weekly for six weeks. Behavioral changes, biochemical parameters, histopathological analysis, and immunohistochemical and ultrastructural studies were conducted 24 h after the last treatment. Combining AG with CAR improved TAA-induced locomotor impairment and motor incoordination evidenced by reduced locomotor activity and decline in motor skill performance, as well as ameliorated cognitive deficits. Moreover, both drugs restored the levels of serum hepatic enzymes and serum and brain levels of ammonia. In addition, the combination significantly modulated hepatic and brain oxidative stress biomarkers, inflammatory cytokines, and cleaved caspase-3 expression. Furthermore, they succeeded in activating nuclear erythroid 2-related factor 2 (Nrf2) expression and heme oxygenase-1 (HO-1) activity and ameliorating markers of hepatic encephalopathy, including hepatic necrosis and brain astrocyte swelling. This study shows that combining AG with CAR exerted a new intervention for hepatic and brain damage in hepatic encephalopathy due to their complementary antioxidant, anti-inflammatory effects and hypoammonemic effects via Nrf2/HO-1 activation and NO inhibition.
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Affiliation(s)
- Nehal A Afifi
- Pharmacology Department, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt
| | - A Ramadan
- Pharmacology Department, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt
| | - Emad Y Erian
- Pharmacology Department, Medical Division, National Research Centre, Cairo, Egypt
| | - Ahmed A Sedik
- Pharmacology Department, Medical Division, National Research Centre, Cairo, Egypt
| | - Mohamed M Amin
- Pharmacology Department, Medical Division, National Research Centre, Cairo, Egypt
| | - Azza Hassan
- Pathology Department, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt
| | - Dalia O Saleh
- Pharmacology Department, Medical Division, National Research Centre, Cairo, Egypt
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23
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Instant activation of TRP channels by NH 4 + promotes neuronal bursting and glutamate spikes in CA1 neurons. Curr Res Physiol 2020; 3:20-29. [PMID: 34746817 PMCID: PMC8562246 DOI: 10.1016/j.crphys.2020.05.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 05/11/2020] [Accepted: 05/24/2020] [Indexed: 11/22/2022] Open
Abstract
Ammonia ( NH 4 + ) is a by-product of cell metabolism and may elicit subcellular effects with specific physiological responses. Chronic effects have been implicated in several neurological diseases and attributed to persistent elevation in blood ammonia levels transferred to the brain. In previous studies the activities of neurons and astrocytes have been examined at ammonia concentrations an order of magnitude higher than measured in the blood. The effects developed within several minutes. Here we focused upon acute responses of neurons to ammonia and whether they may occur at much lower doses. To this end, we combined patch-clamp in CA1 neurons with glutamate imaging in hippocampal slices. Particular attention was paid to the Rett syndrome that has been originally attributed to hyperammonemia. We compared the responses in the wild-type (WT) and model Rett mice (MECP2-null, RTT) to ammonia doses from 0.3 mM on. In both preparations NH 4 + promptly depolarized neurons and increased the ambient glutamate. The bursting activity emerged in WT and it was augmented in RTT. Searching for subcellular mechanisms we examined possible modulation of ion channels by ammonia. We did not find any changes in HCN- and Ca2+ currents, which substantially contribute to the bursting activity. The non-selective cation channels were markedly potentiated by ammonia. ASIC channels had a major contribution to the augmentation of neuronal activity by ammonia. Interestingly, their general blocker amiloride (100 μM) moderately excited CA1 cells akin to NH 4 + . In its presence subsequent ammonia effects were markedly compromised. Blockade of TRPC1 channels partially occluded NH 4 + effects. ASIC and TRPC1 blockers decreased the amplitude of excitatory postsynaptic currents (EPSC) and neuronal bursts, congruent with a postsynaptic location of the channels. Inhibition of TRPV1 channels potentiated the responses to NH 4 + . EPSC amplitudes did not change, but the frequency decreased, indicating presynaptic effects. All extracellular NH 4 + actions were observed at concentrations as low as 0.3 mM and the neurons reacted immediately after ammonia arrived the slice. We propose that a brief augmentation of neuronal activity by NH 4 + may occur either spontaneously during arousal or induced by inhalation of smelling salts.
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24
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Hussein KH, Park KM, Yu L, Kwak HH, Woo HM. Decellularized hepatic extracellular matrix hydrogel attenuates hepatic stellate cell activation and liver fibrosis. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 116:111160. [PMID: 32806289 DOI: 10.1016/j.msec.2020.111160] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 05/31/2020] [Accepted: 06/03/2020] [Indexed: 12/21/2022]
Abstract
Liver fibrosis results from excessive accumulation of extracellular matrix (ECM) proteins that distort the hepatic architecture. Progression of liver fibrosis results in cirrhosis and liver failure, and often, liver transplantation is required. The decellularized liver tissue contains different components that mimic the natural hepatic environment. We hypothesized that a decellularized liver hydrogel can be used to replace the necrotic hepatocytes and damaged ECM. Therefore, our aim in this study is to develop a therapy for treating liver fibrosis. Mice livers were decellularized and processed to form a hepatic hydrogel. We evaluated the biocompatibility and bioactivity of the hydrogel. The ability of the hydrogel to enhance the migration of hepatocytes and endothelial cells was investigated. Human hepatic stellate cell line (LX-2) activated by transforming growth factor-β1 (TGF-β1) was used as in vitro model for fibrogenesis. Then, the hydrogel was injected into the liver parenchyma of mice after the induction of liver fibrosis using thioacetamide. The resulting hydrogel maintained a complex composition, which included glycosaminoglycans, collagen, elastin, and growth factors. Hepatocytes and endothelial cells were shown to migrate toward the hydrogel in vitro. Liver hydrogel improved TGF-β1-induced LX-2 cells activation via blocking the TGF-β1/Smad pathway. The matrix was delivered successfully in vivo and enhanced the reduction of fibrosis and recovery to a nearly normal structure. In conclusion, we have demonstrated that the liver hydrogel can be utilized as an injectable biomaterial for liver tissue engineering in order to reduce the degree of fibrosis.
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Affiliation(s)
- Kamal H Hussein
- Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea; Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea; Department of Animal Surgery, College of Veterinary Medicine, Assiut University, Assiut 71515, Egypt
| | - Kyung-Mee Park
- College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Lina Yu
- Stem Cell institute, College of Veterinary Medicine & Institute of Veterinary Science, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Ho-Hyun Kwak
- Stem Cell institute, College of Veterinary Medicine & Institute of Veterinary Science, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea.
| | - Heung-Myong Woo
- Stem Cell institute, College of Veterinary Medicine & Institute of Veterinary Science, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea.
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Lee MC, Hsu YJ, Ho HH, Hsieh SH, Kuo YW, Sung HC, Huang CC. Lactobacillus salivarius Subspecies salicinius SA-03 is a New Probiotic Capable of Enhancing Exercise Performance and Decreasing Fatigue. Microorganisms 2020; 8:microorganisms8040545. [PMID: 32283729 PMCID: PMC7232535 DOI: 10.3390/microorganisms8040545] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 03/23/2020] [Accepted: 04/07/2020] [Indexed: 12/12/2022] Open
Abstract
Probiotics are increasingly being used as a nutritional supplement by athletes to improve exercise performance and reduce post-exercise fatigue. Lactobacillus salivarius is a natural flora in the gastrointestinal tract of humans and animals. Lactobacillus salivarius subspecies salicinius (SA-03) is an isolate from the 2008 Olympic women’s 48 kg weightlifting gold medalist’s gut microbiota. In this study, we investigated its beneficial effects on physical fitness. Male ICR mice were divided into four groups (n = 10 per group) and orally administered with SA-03 for 4 weeks at 0, 2.05 × 109, 4.10 × 109, or 1.03 × 1010 CFU/kg/day. Results showed that 4 weeks of SA-03 supplementation significantly improved muscle strength and endurance performance, increased hepatic and muscular glycogen storage, and decreased lactate, blood urea nitrogen (BUN), ammonia, and creatine kinase (CK) levels after exercise. These observations suggest that SA-03 could be used as a nutritional supplement to enhance exercise performance and reduce.
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Affiliation(s)
- Mon-Chien Lee
- Graduate Institute of Sports Science, National Taiwan Sport University, No. 250, Wenhua 1st Rd., Guishan District, Taoyuan City 33301, Taiwan; (M.-C.L.); (Y.-J.H.)
| | - Yi-Ju Hsu
- Graduate Institute of Sports Science, National Taiwan Sport University, No. 250, Wenhua 1st Rd., Guishan District, Taoyuan City 33301, Taiwan; (M.-C.L.); (Y.-J.H.)
| | - Hsieh-Hsun Ho
- Glac Biotech Co. Ltd., Tainan City 74442, Taiwan; (H.-H.H.); (S.-H.H.); (Y.-W.K.)
| | - Shih-Hung Hsieh
- Glac Biotech Co. Ltd., Tainan City 74442, Taiwan; (H.-H.H.); (S.-H.H.); (Y.-W.K.)
| | - Yi-Wei Kuo
- Glac Biotech Co. Ltd., Tainan City 74442, Taiwan; (H.-H.H.); (S.-H.H.); (Y.-W.K.)
| | - Hsin-Ching Sung
- Aesthetic Medical Center, Department of Dermatology, Chang Gung Memorial Hospital, Taoyuan 33301, Taiwan
- Department of Anatomy, College of Medicine, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Township, Taoyuan City, Taoyuan 33301, Taiwan
- Correspondence: (H.-C.S.); (C.-C.H.); Tel.: +886-3-211-8800 (ext. 5977) (H.-C.S.); +886-3-328-3201 (ext. 2409) (C.-C.H.)
| | - Chi-Chang Huang
- Graduate Institute of Sports Science, National Taiwan Sport University, No. 250, Wenhua 1st Rd., Guishan District, Taoyuan City 33301, Taiwan; (M.-C.L.); (Y.-J.H.)
- Correspondence: (H.-C.S.); (C.-C.H.); Tel.: +886-3-211-8800 (ext. 5977) (H.-C.S.); +886-3-328-3201 (ext. 2409) (C.-C.H.)
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Zhou Z, Chen X, Sheng H, Shen X, Sun X, Yan Y, Wang J, Yuan Q. Engineering probiotics as living diagnostics and therapeutics for improving human health. Microb Cell Fact 2020; 19:56. [PMID: 32131831 PMCID: PMC7055047 DOI: 10.1186/s12934-020-01318-z] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 02/26/2020] [Indexed: 02/08/2023] Open
Abstract
The gut microbiota that inhabit our gastrointestinal tract are well known to play an important role in maintaining human health in many aspects, including facilitating the digestion and absorption of nutrients, protecting against pathogens and regulating immune system. Gut microbiota dysbiosis is associated with a lot of diseases, such as inflammatory bowel disease, allergy, obesity, cardiovascular and neurodegenerative diseases and cancers. With the increasing knowledge of the microbiome, utilization of probiotic bacteria in modulating gut microbiota to prevent and treat a large number of disorders and diseases has gained much interest. In recent years, aided by the continuous development of tools and techniques, engineering probiotic microbes with desired characteristics and functionalities to benefit human health has made significant progress. In this paper, we summarize the recent advances in design and construction of probiotics as living diagnostics and therapeutics for probing and treating a series of diseases including metabolic disorders, inflammation and pathogenic bacteria infections. We also discuss the current challenges and future perspectives in expanding the application of probiotics for disease treatment and detection. We intend to provide insights and ideas for engineering of probiotics to better serve disease therapy and human health.
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Affiliation(s)
- Zhao Zhou
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, 15# Beisanhuan East Road, Chaoyang District, Beijing, 100029, China
| | - Xin Chen
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, 15# Beisanhuan East Road, Chaoyang District, Beijing, 100029, China
| | - Huakang Sheng
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, 15# Beisanhuan East Road, Chaoyang District, Beijing, 100029, China
| | - Xiaolin Shen
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, 15# Beisanhuan East Road, Chaoyang District, Beijing, 100029, China
| | - Xinxiao Sun
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, 15# Beisanhuan East Road, Chaoyang District, Beijing, 100029, China
| | - Yajun Yan
- College of Engineering, The University of Georgia, Athens, GA, 30602, USA
| | - Jia Wang
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, 15# Beisanhuan East Road, Chaoyang District, Beijing, 100029, China.
| | - Qipeng Yuan
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, 15# Beisanhuan East Road, Chaoyang District, Beijing, 100029, China.
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The Efficacy of Lactulose for the Treatment of Hyperammonemic Encephalopathy Due to Severe Heart Failure. Diagnostics (Basel) 2020; 10:diagnostics10020070. [PMID: 32012742 PMCID: PMC7168910 DOI: 10.3390/diagnostics10020070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 01/23/2020] [Accepted: 01/26/2020] [Indexed: 11/29/2022] Open
Abstract
Hyperammonemic encephalopathy secondary to heart failure is rare and there had been little reports about effective treatment. Organ hypoperfusion or congestion by heart failure may lead to various organ dysfunctions, and liver and intestinal circulatory impairment might cause ammonia metabolic failure. Here, we report on the case of a patient with hyperammonemic encephalopathy that was secondary to heart failure, which was effectively treated by lactulose.
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Abstract
Oxidative stress is an important contributor to the pathophysiology of sickle cell disease. The pathways involved are complex and interlinked. L-glutamine is an amino acid with myriad roles in the body, including the synthesis of antioxidants, such as reduced glutathione and the cofactors NAD(H) and NADP(H), as well as nitric oxide—so it has therapeutic potential as an antioxidant. However, the relative impact of L-glutamine on the redox environment in red blood cells in sickle cell disease is not fully understood, and there are few therapeutic trials in sickle cell disease. Following the FDA approval of L-glutamine for sickle cell disease, more research is still needed to understand its clinical effects and role in therapy.
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Affiliation(s)
- Alina Sadaf
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Charles T Quinn
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
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Abstract
RATIONALE Adult hyperammonemia is most often the result of hepatic dysfunction. Hyperammonemia in the setting of normal hepatic function is a much less common phenomenon and has usually been associated with medications and certain disease states. Here, we present an unusual case of severe hyperammonemia caused physiologically by intense muscle activity in a patient lacking any evidence of liver disease. PATIENT CONCERNS A 36-year-old woman was brought to the emergency department for a suicide attempt after being found covered in Lysol and Clorox germicidal bleach. She was noted to be in a state of violent psychosis with extreme agitation and had to be sedated and intubated for airway protection. DIAGNOSIS AND INTERVENTIONS Initial labs revealed hyperammonemia, lactic acidosis, and anion gap metabolic acidosis. Aminotransferases, bilirubin, and creatine kinase (CK) were normal. Renal function, prothrombin time, activated partial thromboplastin time, and international normalized ratio were also unremarkable and remained so at 24 hours. Ethyl alcohol, acetaminophen, salicylate, and valproic acid were all undetectable in blood. She received 2 doses of lactulose overnight, with a subsequent bowel movement. Next day, her mentation, serum ammonia level, and lactic acid level were back to normal, and she was extubated. Aminotransferases and CK levels were elevated but improved with supportive care. A detailed history and relevant biochemical investigations were unremarkable for any other etiology of hyperammonemia including the common inborn errors of metabolism (IEM). The combination of clinical findings of extreme skeletal muscle activity along with hyperammonemia and lactic acidosis, and subsequently rhabdomyolysis in the setting of unremarkable history and otherwise normal hepatic function strongly suggest the myokinetic origin of hyperammonemia in the patient. OUTCOME The patient recovered well with supportive care and was discharged on day 5. LESSONS This unique case illustrates the important role of skeletal muscle in the human metabolism of ammonia. In our discussion, we also elucidate the underlying pathophysiology, with the objective of improving clinician understanding of various differential diagnoses.
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Affiliation(s)
| | - Haneesh Jasuja
- Materials and Nanotechnology Program, North Dakota State University, Fargo, ND
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Baruteau J, Diez-Fernandez C, Lerner S, Ranucci G, Gissen P, Dionisi-Vici C, Nagamani S, Erez A, Häberle J. Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects. J Inherit Metab Dis 2019; 42:1147-1161. [PMID: 30723942 DOI: 10.1002/jimd.12047] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 12/20/2018] [Indexed: 12/30/2022]
Abstract
The first patients affected by argininosuccinic aciduria (ASA) were reported 60 years ago. The clinical presentation was initially described as similar to other urea cycle defects, but increasing evidence has shown overtime an atypical systemic phenotype with a paradoxical observation, that is, a higher rate of neurological complications contrasting with a lower rate of hyperammonaemic episodes. The disappointing long-term clinical outcomes of many of the patients have challenged the current standard of care and therapeutic strategy, which aims to normalize plasma ammonia and arginine levels. Interrogations have raised about the benefit of newborn screening or liver transplantation on the neurological phenotype. Over the last decade, novel discoveries enabled by the generation of new transgenic argininosuccinate lyase (ASL)-deficient mouse models have been achieved, such as, a better understanding of ASL and its close interaction with nitric oxide metabolism, ASL physiological role outside the liver, and the pathophysiological role of oxidative/nitrosative stress or excessive arginine treatment. Here, we present a collaborative review, which highlights these recent discoveries and novel emerging concepts about ASL role in human physiology, ASA clinical phenotype and geographic prevalence, limits of current standard of care and newborn screening, pathophysiology of the disease, and emerging novel therapies. We propose recommendations for monitoring of ASA patients. Ongoing research aims to better understand the underlying pathogenic mechanisms of the systemic disease to design novel therapies.
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Affiliation(s)
- Julien Baruteau
- UCL Great Ormond Street Institute of Child Health, NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK
- Metabolic Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Carmen Diez-Fernandez
- Division of Metabolism and Children Research Centre (CRC), University Children's Hospital, Zurich, Switzerland
| | - Shaul Lerner
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israël
| | - Giusy Ranucci
- Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Paul Gissen
- UCL Great Ormond Street Institute of Child Health, NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK
- Metabolic Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Carlo Dionisi-Vici
- Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Sandesh Nagamani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Ayelet Erez
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israël
| | - Johannes Häberle
- Division of Metabolism and Children Research Centre (CRC), University Children's Hospital, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology (ZIHP) and Neuroscience Center Zurich (ZNZ), Zurich, Switzerland
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Hendrikx L, Brandts H, van Borren M, de Boer H. Recurrent Hyperammonemia During Enteral Tube Feeding for Severe Protein Malnutrition After Bariatric Surgery. Obes Surg 2019; 29:4127-4130. [DOI: 10.1007/s11695-019-04231-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Nonfatal Hyperammonemic Encephalopathy as a Late Complication of Roux-en-Y Gastric Bypass. Case Rep Gastrointest Med 2019; 2019:9031087. [PMID: 31355019 PMCID: PMC6632496 DOI: 10.1155/2019/9031087] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Accepted: 06/11/2019] [Indexed: 11/17/2022] Open
Abstract
Roux-en-Y gastric bypass (RYGB) is the most common weight loss procedure performed in the US. Gastric bypass–related hyperammonemia (GaBHA) is a potentially fatal entity, characterized by encephalopathy associated with hyperammonemia and various nutritional deficiencies, which can present at variable time intervals after RYGB. Twenty-five cases of hyperammonemic encephalopathy after bariatric surgery have been previously reported in the literature. We describe the case of a 48-year-old Hispanic woman with no prior history of liver disease, presenting with nonfatal hyperammonemic encephalopathy as a late postoperative complication 20 years after undergoing a RYGB. Hyperammonemic encephalopathy in the absence of known hepatic dysfunction presents a diagnostic dilemma. An early diagnosis and intervention are crucial to decrease morbidity and mortality.
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Cudré-Cung HP, Remacle N, do Vale-Pereira S, Gonzalez M, Henry H, Ivanisevic J, Schmiesing J, Mühlhausen C, Braissant O, Ballhausen D. Ammonium accumulation and chemokine decrease in culture media of Gcdh -/- 3D reaggregated brain cell cultures. Mol Genet Metab 2019; 126:416-428. [PMID: 30686684 DOI: 10.1016/j.ymgme.2019.01.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 01/15/2019] [Accepted: 01/15/2019] [Indexed: 01/05/2023]
Abstract
Glutaric Aciduria type I (GA-I) is caused by mutations in the GCDH gene. Its deficiency results in accumulation of the key metabolites glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in body tissues and fluids. Present knowledge on the neuropathogenesis of GA-I suggests that GA and 3-OHGA have toxic properties on the developing brain. We analyzed morphological and biochemical features of 3D brain cell aggregates issued from Gcdh-/- mice at two different developmental stages, day-in-vitro (DIV) 8 and 14, corresponding to the neonatal period and early childhood. We also induced a metabolic stress by exposing the aggregates to 10 mM l-lysine (Lys). Significant amounts of GA and 3-OHGA were detected in Gcdh-/- aggregates and their culture media. Ammonium was significantly increased in culture media of Gcdh-/- aggregates at the early developmental stage. Concentrations of GA, 3-OHGA and ammonium increased significantly after exposure to Lys. Gcdh-/- aggregates manifested morphological alterations of all brain cell types at DIV 8 while at DIV 14 they were only visible after exposure to Lys. Several chemokine levels were significantly decreased in culture media of Gcdh-/- aggregates at DIV 14 and after exposure to Lys at DIV 8. This new in vitro model for brain damage in GA-I mimics well in vivo conditions. As seen previously in WT aggregates exposed to 3-OHGA, we confirmed a significant ammonium production by immature Gcdh-/- brain cells. We described for the first time a decrease of chemokines in Gcdh-/- culture media which might contribute to brain cell injury in GA-I.
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Affiliation(s)
- Hong-Phuc Cudré-Cung
- Pediatric Metabolic Disease Unit, Department of Pediatrics, Lausanne University Hospital, Chemin de Mont-Paisible 18, 1011 Lausanne, Switzerland.
| | - Noémie Remacle
- Pediatric Metabolic Disease Unit, Department of Pediatrics, Lausanne University Hospital, Chemin de Mont-Paisible 18, 1011 Lausanne, Switzerland.
| | - Sonia do Vale-Pereira
- Pediatric Metabolic Disease Unit, Department of Pediatrics, Lausanne University Hospital, Chemin de Mont-Paisible 18, 1011 Lausanne, Switzerland
| | - Mary Gonzalez
- Pediatric Metabolic Disease Unit, Department of Pediatrics, Lausanne University Hospital, Chemin de Mont-Paisible 18, 1011 Lausanne, Switzerland.
| | - Hugues Henry
- Service of Clinical Chemistry, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne, Switzerland
| | - Julijana Ivanisevic
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 19, 1005 Lausanne, Switzerland.
| | - Jessica Schmiesing
- Department of Biochemistry, University Medical Center Hamburg-Eppendorf, University Children's Hospital, Martinistrasse 52, 20246 Hamburg, Germany.
| | - Chris Mühlhausen
- Department of Biochemistry, University Medical Center Hamburg-Eppendorf, University Children's Hospital, Martinistrasse 52, 20246 Hamburg, Germany.
| | - Olivier Braissant
- Service of Clinical Chemistry, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne, Switzerland.
| | - Diana Ballhausen
- Pediatric Metabolic Disease Unit, Department of Pediatrics, Lausanne University Hospital, Chemin de Mont-Paisible 18, 1011 Lausanne, Switzerland.
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Intravenous and Oral Hyperammonemia Management. CURRENT EMERGENCY AND HOSPITAL MEDICINE REPORTS 2018. [DOI: 10.1007/s40138-018-0174-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Sakusic A, Sabov M, McCambridge AJ, Rabinstein AA, Singh TD, Mukesh K, Kashani KB, Cook D, Gajic O. Features of Adult Hyperammonemia Not Due to Liver Failure in the ICU. Crit Care Med 2018; 46:e897-e903. [PMID: 29985210 PMCID: PMC6095817 DOI: 10.1097/ccm.0000000000003278] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To evaluate the epidemiology of hyperammonemia unrelated to liver failure in the critical care setting. DESIGN Retrospective case series. SETTING Critically ill patients admitted to ICUs at Mayo Clinic, Rochester, MN (medical ICU, two mixed medical-surgical ICUs, coronary care unit, or the cardiosurgical ICU) between July 1, 2004, and October 31, 2015. PATIENTS Adult critically ill patients with hyperammonemia not related to acute or chronic liver failure. We excluded patients with diagnosis of moderate or severe liver disease, hyperbilirubinemia, and patients who denied the use of their medical records. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Of 3,908 ICU patients with hyperammonemia, 167 (4.5%) had no evidence of acute or chronic liver failure. One-hundred one patients (60.5%) were male with median age of 65.7 years (interquartile range, 50-74.5 yr) and median serum ammonia level of 68 µg/dL (interquartile range, 58-87 µg/dL). Acute encephalopathy was present in 119 patients (71%). Predisposing conditions included malnutrition 27 (16%), gastric bypass six (3.6%), total parenteral nutrition four (2.4%); exposure to valproic acid 17 (10%); status epilepticus 11 (6.6%), high tumour burden 19 (11.3%), and renal failure 82 (49.1%). Urea cycle defects were diagnosed in seven patients (4.1%). Hospital mortality was high (30%), and median ammonia level was higher among the nonsurvivors (74 vs 67 µg/dL; p = 0.05). Deaths were more likely in hyperammonemic patients who were older (p = 0.016), had greater illness severity (higher Acute Physiology and Chronic Health Evaluation III score, p < 0.01), malignancy (p < 0.01), and solid organ transplantation (p = 0.04), whereas seizure disorder was more common in survivors (p = 0.02). After adjustment, serum ammonia level was not associated with increased mortality. CONCLUSIONS Hyperammonemia occurs in a substantial minority of critically ill patients without liver failure. These patients have a poor prognosis, although ammonia level per se is not independently associated with mortality. Serum ammonia should be measured when risk factors are present, such as nutritional deficiencies and protein refeeding, treatment with valproic acid, high tumour burden, and known or suspected urea cycle abnormalities.
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Affiliation(s)
- Amra Sakusic
- Departments of Internal Medicine and Pulmonary Medicine, University Clinical Centre Tuzla, Bosnia and Herzegovina; Medical Faculty, University of Tuzla
- Multidisciplinary Epidemiology and Translational Research in Intensive Care, Emergency and Perioperative Medicine (METRIC), Mayo Clinic, Rochester, MN, USA
| | - Moldovan Sabov
- Multidisciplinary Epidemiology and Translational Research in Intensive Care, Emergency and Perioperative Medicine (METRIC), Mayo Clinic, Rochester, MN, USA
| | - Amanda J McCambridge
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
| | | | | | - Kumar Mukesh
- Montefiore Medical Center, North Division (Wakefield), New York
| | | | - David Cook
- Intensive Care Unit, Princess Alexandra Hospital, Brisbane, Australia
| | - Ognjen Gajic
- Multidisciplinary Epidemiology and Translational Research in Intensive Care, Emergency and Perioperative Medicine (METRIC), Mayo Clinic, Rochester, MN, USA
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
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Singh P, Chung HJ, Lee IA, D'Souza R, Kim HJ, Hong ST. Elucidation of the anti-hyperammonemic mechanism of Lactobacillus amylovorus JBD401 by comparative genomic analysis. BMC Genomics 2018; 19:292. [PMID: 29695242 PMCID: PMC5918772 DOI: 10.1186/s12864-018-4672-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 04/13/2018] [Indexed: 12/15/2022] Open
Abstract
Background Recent experimental evidence showed that lactobacilli could be used as potential therapeutic agents for hyperammonemia. However, lack of understanding on how lactobacilli reduce blood ammonia levels limits application of lactobacilli to treat hyperammonemia. Results We report the finished and annotated genome sequence of L. amylovorus JBD401 (GenBank accession no. CP012389). L. amylovorus JBD401 reducing blood ammonia levels dramatically was identified by high-throughput screening of several thousand probiotic strains both within and across Lactobacillus species in vitro. Administration of L. amylovorus JBD401 to hyperammonemia-induced mice reduced the blood ammonia levels of the mice to the normal range. Genome sequencing showed that L. amylovorus JBD401 had a circular chromosome of 1,946,267 bp with an average GC content of 38.13%. Comparative analysis of the L. amylovorus JBD401 genome with L. acidophilus and L. amylovorus strains showed that L. amylovorus JBD401 possessed genes for ammonia assimilation into various amino acids and polyamines Interestingly, the genome of L. amylovorus JBD401 contained unusually large number of various pseudogenes suggesting an active stage of evolution. Conclusions L. amylovorus JBD401 has genes for assimilation of free ammonia into various amino acids and polyamines which results in removal of free ammonia in intestinal lumen to reduce the blood ammonia levels in the host. This work explains the mechanism of how probiotics reduce blood ammonia levels. Electronic supplementary material The online version of this article (10.1186/s12864-018-4672-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Parul Singh
- Department of Biomedical Sciences and Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Chonbuk, 54907, South Korea
| | - Hea-Jong Chung
- Department of Biomedical Sciences and Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Chonbuk, 54907, South Korea
| | - In-Ah Lee
- Present address: Department of Chemistry, Gunsan National University, Gunsan, Chonbuk, 51450, South Korea
| | - Roshan D'Souza
- Department of Biomedical Sciences and Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Chonbuk, 54907, South Korea
| | - Hyeon-Jin Kim
- JINIS BDRD institute, JINIS Biopharmaceuticals Co., 913 Gwahak-Ro, Bongdong, Wanju, Chonbuk, 55321, South Korea
| | - Seong-Tshool Hong
- Department of Biomedical Sciences and Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Chonbuk, 54907, South Korea.
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The Pharmabiotic Approach to Treat Hyperammonemia. Nutrients 2018; 10:nu10020140. [PMID: 29382084 PMCID: PMC5852716 DOI: 10.3390/nu10020140] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 01/22/2018] [Accepted: 01/26/2018] [Indexed: 12/12/2022] Open
Abstract
Ammonia is constantly produced as a metabolic waste from amino acid catabolism in mammals. Ammonia, the toxic waste metabolite, is resolved in the liver where the urea cycle converts free ammonia to urea. Liver malfunctions cause hyperammonemia that leads to central nervous system (CNS) dysfunctions, such as brain edema, convulsions, and coma. The current treatments for hyperammonemia, such as antibiotics or lactulose, are designed to decrease the intestinal production of ammonia and/or its absorption into the body and are not effective, besides being often accompanied by side effects. In recent years, increasing evidence has shown that modifications of the gut microbiota could be used to treat hyperammonemia. Considering the role of the gut microbiota and the physiological characteristics of the intestine, the removal of ammonia from the intestine by modulating the gut microbiota would be an ideal approach to treat hyperammonemia. In this review, we discuss the significance of hyperammonemia and its related diseases and the efficacy of the current management methods for hyperammonemia to understand the mechanism of ammonia transport in the human body. The possibility to use the gut microbiota as pharmabiotics to treat hyperammonemia and its related diseases is also explored.
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Lanz B, Rackayova V, Braissant O, Cudalbu C. MRS studies of neuroenergetics and glutamate/glutamine exchange in rats: Extensions to hyperammonemic models. Anal Biochem 2017; 529:245-269. [DOI: 10.1016/j.ab.2016.11.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Revised: 11/16/2016] [Accepted: 11/30/2016] [Indexed: 01/27/2023]
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Mostafa RE, Salama AAA, Abdel-Rahman RF, Ogaly HA. Hepato- and neuro-protective influences of biopropolis on thioacetamide-induced acute hepatic encephalopathy in rats. Can J Physiol Pharmacol 2016; 95:539-547. [PMID: 28177688 DOI: 10.1139/cjpp-2016-0433] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that ultimately occurs as a complication of acute or chronic liver failure; accompanied by hyperammonemia. This study aimed to evaluate the potential of biopropolis as a hepato- and neuro-protective agent using thioacetamide (TAA)-induced acute HE in rats as a model. Sixty Wistar rats were divided into 5 groups: Group 1 (normal control) received only saline and paraffin oil. Group 2 (hepatotoxic control) received TAA (300 mg/kg, once). Groups 3, 4, and 5 received TAA followed by vitamin E (100 mg/kg) and biopropolis (100 and 200 mg/kg), respectively, daily for 30 days. Evidences of HE were clearly detected in TAA-hepatotoxic group including significant elevation in the serum level of ammonia, liver functions, increased oxidative stress in liver and brain, apoptotic DNA fragmentation and overexpression of iNOS gene in brain tissue. The findings for groups administered biopropolis, highlighted its efficacy as a hepato- and neuro-protectant through improving the liver functions, oxidative status and DNA fragmentation as well as suppressing the brain expression of iNOS gene. In conclusion, biopropolis, at a dose of 200 mg/kg per day protected against TAA-induced HE through its antioxidant and antiapoptotic influence; therefore, it can be used as a protective natural product.
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Affiliation(s)
- Rasha E Mostafa
- a Pharmacology Department, National Research Centre, Giza, Egypt
| | - Abeer A A Salama
- a Pharmacology Department, National Research Centre, Giza, Egypt
| | | | - Hanan A Ogaly
- b Chemistry Department, Faculty of Science, King Khalid University, Saudi Arabia.,c Biochemistry Department, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
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Weiss N, Barbier Saint Hilaire P, Colsch B, Isnard F, Attala S, Schaefer A, Amador MDM, Rudler M, Lamari F, Sedel F, Thabut D, Junot C. Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy. J Hepatol 2016; 65:1120-1130. [PMID: 27520878 DOI: 10.1016/j.jhep.2016.07.046] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Revised: 07/11/2016] [Accepted: 07/22/2016] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS Hepatic encephalopathy (HE) is a neurological complication observed in patients with liver disease and/or porto-systemic shunt. The proportion of cirrhotic patients developing overt HE is about 20%, and 60-80% of cirrhotic patients exhibit mild cognitive impairment potentially related to minimal HE. However, the pathophysiological mechanisms of HE remain poorly understood. In this context, metabolomics was used to highlight dysfunction of metabolic pathways in cerebrospinal fluid (CSF) samples of patients suffering from HE. METHODS CSF samples were collected in 27 control patients without any proven neurological disease and 14 patients with symptoms of HE. Plasma samples were obtained from control patients, and from cirrhotic patients with and without HE. Metabolomic analysis was performed using liquid chromatography coupled to high-resolution mass spectrometry. RESULTS Concentrations of 73 CSF metabolites, including amino acids, acylcarnitines, bile acids and nucleosides, were altered in HE patients. Accumulation of acetylated compounds, which could be due to a defect of the Krebs cycle in HE patients, is reported for the first time. Furthermore, analysis of plasma samples showed that concentrations of metabolites involved in ammonia, amino-acid and energy metabolism are specifically and significantly increased in CSF samples of HE patients. Lastly, several drugs were detected in CSF samples and could partially explain worsening of neurological symptoms for some patients. CONCLUSION By enabling the simultaneous monitoring of a large set of metabolites in HE patients, CSF metabolomics highlighted alterations of metabolic pathways linked to energy metabolism that were not observed in plasma samples. LAY SUMMARY CSF metabolomics provides a global picture of altered metabolic pathways in CSF samples of HE patients and highlights alterations of metabolic pathways linked to energy metabolism that are not observed in plasma samples.
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Affiliation(s)
- Nicolas Weiss
- Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, Groupement Hospitalier Pitié-Salpêtrière-Charles Foix, Paris, France; Unité de réanimation neurologique, Fédération de neurologie 1, pôle des maladies du système nerveux, Groupement Hospitalier Pitié-Salpêtrière-Charles Foix, Assistance Publique - Hôpitaux de Paris et Institut de neurosciences translationnelles IHU-A-ICM, Paris, France
| | - Pierre Barbier Saint Hilaire
- CEA, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etude du Métabolisme des Médicaments, MetaboHUB-Paris, Université Paris Saclay, 91191 Gif-sur-Yvette cedex, France
| | - Benoit Colsch
- CEA, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etude du Métabolisme des Médicaments, MetaboHUB-Paris, Université Paris Saclay, 91191 Gif-sur-Yvette cedex, France
| | - Foucauld Isnard
- CEA, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etude du Métabolisme des Médicaments, MetaboHUB-Paris, Université Paris Saclay, 91191 Gif-sur-Yvette cedex, France
| | - Suleiman Attala
- CEA, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etude du Métabolisme des Médicaments, MetaboHUB-Paris, Université Paris Saclay, 91191 Gif-sur-Yvette cedex, France
| | - Augustin Schaefer
- Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, Groupement Hospitalier Pitié-Salpêtrière-Charles Foix, Paris, France
| | - Maria Del Mar Amador
- Neurometabolic Unit and University Pierre and Marie Curie, Paris, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, 83 Boulevard de l'Hôpital, 75013 Paris, France
| | - Marika Rudler
- Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, Groupement Hospitalier Pitié-Salpêtrière-Charles Foix, Paris, France; Unité de Soins Intensifs d'Hépato-gastroentérologie, Groupement Hospitalier Pitié-Salpêtrière-Charles Foix, Assistance Publique - Hôpitaux de Paris et Université Pierre et Marie Curie Paris 6, Paris, France
| | - Foudil Lamari
- Department of Metabolic Biochemistry, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, 83 Boulevard de l'Hôpital, 75013 Paris, France
| | - Frédéric Sedel
- Medday Pharmaceuticals, ICM-Brain and Spine Institute-iPEPS, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, 83 Boulevard de l'Hôpital, 75013 Paris, France
| | - Dominique Thabut
- Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, Groupement Hospitalier Pitié-Salpêtrière-Charles Foix, Paris, France; Unité de Soins Intensifs d'Hépato-gastroentérologie, Groupement Hospitalier Pitié-Salpêtrière-Charles Foix, Assistance Publique - Hôpitaux de Paris et Université Pierre et Marie Curie Paris 6, Paris, France
| | - Christophe Junot
- CEA, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etude du Métabolisme des Médicaments, MetaboHUB-Paris, Université Paris Saclay, 91191 Gif-sur-Yvette cedex, France.
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Barkovich E, Robinson C, Gropman A. Brain biomarkers and neuroimaging to diagnose urea cycle disorders and assess prognosis. Expert Opin Orphan Drugs 2016. [DOI: 10.1080/21678707.2016.1242407] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Cudré-Cung HP, Zavadakova P, do Vale-Pereira S, Remacle N, Henry H, Ivanisevic J, Tavel D, Braissant O, Ballhausen D. Ammonium accumulation is a primary effect of 2-methylcitrate exposure in an in vitro model for brain damage in methylmalonic aciduria. Mol Genet Metab 2016; 119:57-67. [PMID: 27599447 DOI: 10.1016/j.ymgme.2016.07.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 07/27/2016] [Accepted: 07/27/2016] [Indexed: 01/09/2023]
Abstract
Using 3D organotypic rat brain cell cultures in aggregates we recently identified 2-methylcitrate (2-MCA) as the main toxic metabolite for developing brain cells in methylmalonic aciduria. Exposure to 2-MCA triggered morphological changes and apoptosis of brain cells. This was accompanied by increased ammonium and decreased glutamine levels. However, the sequence and causal relationship between these phenomena remained unclear. To understand the sequence and time course of pathogenic events, we exposed 3D rat brain cell aggregates to different concentrations of 2-MCA (0.1, 0.33 and 1.0mM) from day in vitro (DIV) 11 to 14. Aggregates were harvested at different time points from DIV 12 to 19. We compared the effects of a single dose of 1mM 2-MCA administered on DIV 11 to the effects of repeated doses of 1mM 2-MCA. Pan-caspase inhibitors Z-VAD FMK or Q-VD-OPh were used to block apoptosis. Ammonium accumulation in the culture medium started within few hours after the first 2-MCA exposure. Morphological changes of the developing brain cells were already visible after 17h. The highest rate of cleaved caspase-3 was observed after 72h. A dose-response relationship was observed for all effects. Surprisingly, a single dose of 1mM 2-MCA was sufficient to induce all of the biochemical and morphological changes in this model. 2-MCA-induced ammonium accumulation and morphological changes were not prevented by concomitant treatment of the cultures with pan-caspase inhibitors Z-VAD FMK or Q-VD-OPh: ammonium increased rapidly after a single 1mM 2-MCA administration even after apoptosis blockade. We conclude that following exposure to 2-MCA, ammonium production in brain cell cultures is an early phenomenon, preceding cell degeneration and apoptosis, and may actually be the cause of the other changes observed. The fact that a single dose of 1mM 2-MCA is sufficient to induce deleterious effects over several days highlights the potential damaging effects of even short-lasting metabolic decompensations in children affected by methylmalonic aciduria.
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Affiliation(s)
| | - Petra Zavadakova
- Center of Molecular Diseases, Lausanne University Hospital, Switzerland
| | | | - Noémie Remacle
- Center of Molecular Diseases, Lausanne University Hospital, Switzerland
| | - Hugues Henry
- Biomedicine, Innovation & Development, Lausanne University Hospital, Switzerland
| | - Julijana Ivanisevic
- Metabolomics Research Platform, Faculty of Biology and Medicine, University of Lausanne, Switzerland
| | - Denise Tavel
- Department of Physiology, Lausanne University, Switzerland
| | | | - Diana Ballhausen
- Center of Molecular Diseases, Lausanne University Hospital, Switzerland.
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Neurotoxicity of Ammonia. Neurochem Res 2016; 42:713-720. [PMID: 27465396 DOI: 10.1007/s11064-016-2014-x] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 07/15/2016] [Accepted: 07/21/2016] [Indexed: 12/25/2022]
Abstract
Abnormal liver function has dramatic effects on brain functions. Hyperammonemia interferes profoundly with brain metabolism, astrocyte volume regulation, and in particular mitochondrial functions. Gene expression in the brain and excitatory and inhibitory neurotransmission circuits are also affected. Experiments with a number of pertinent animal models have revealed several potential mechanisms which could underlie the pathological phenomena occurring in hepatic encephalopathy.
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Frea S, Bovolo V, Pidello S, Canavosio FG, Botta M, Bergerone S, Gaita F. Clinical and prognostic role of ammonia in advanced decompensated heart failure. The cardio-abdominal syndrome? Int J Cardiol 2015; 195:53-60. [PMID: 26022800 DOI: 10.1016/j.ijcard.2015.05.061] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 04/29/2015] [Accepted: 05/08/2015] [Indexed: 01/03/2023]
Abstract
BACKGROUND Advanced heart failure is associated with end-organ damage. Recent literature suggested an intriguing crosstalk between failing heart, abdomen and kidneys. Venous ammonia, as a by-product of the gut, could be a marker of abdominal injury in heart failure patients. The aim of the study was to investigate the clinical and prognostic role of ammonia in patients with advanced decompensated heart failure (ADHF). METHODS & RESULTS 90 patients admitted with ADHF were prospectively studied. The prognostic role of ammonia at admission was evaluated. Primary end-points were: a composite of cardiac death, urgent heart transplantation and mechanical circulatory support at 3 months and need for renal replacement therapies (RRT). In the study cohort (age 59.0 ± 12.0 years, FE 21.6 ± 9.0%, INTERMACS profile 3.7 ± 0.9, creatinine 1.71 ± 0.95 mg/dl) 27 patients (30%) underwent the cardiac composite endpoint, while 9 patients (10%) needed RRT. At ROC curve analysis ammonia ≥ 130 μg/dl (abdominal damage) showed the best diagnostic accuracy. At multivariate analysis abdominal damage predicted the cardiac composite endpoint. Abdominal damage further increased risk among patient with cold profile at admission (HR 2.7, 95% CI 1.1-7.0, p = 0.046). At multivariate analysis abdominal damage also predicted need for RRT (OR 10.8, 95% CI 1.5-75.8, p = 0.017). The combined use of estimated right atrial pressure and ammonia showed the highest diagnostic accuracy and a very high specificity in prediction of need for RRT. CONCLUSION In a selected population admitted for ADHF ammonia, as a marker of abdominal derangement, predicted adverse cardiac events and need for RRT.
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Affiliation(s)
- Simone Frea
- Cardiovascular and Thoracic Department, Division of Cardiology, Città della Salute e della Scienza University Hospital of Torino, Italy
| | - Virginia Bovolo
- Cardiovascular and Thoracic Department, Division of Cardiology, Città della Salute e della Scienza University Hospital of Torino, Italy
| | - Stefano Pidello
- Cardiovascular and Thoracic Department, Division of Cardiology, Città della Salute e della Scienza University Hospital of Torino, Italy.
| | - Federico G Canavosio
- Cardiovascular and Thoracic Department, Division of Cardiology, Città della Salute e della Scienza University Hospital of Torino, Italy
| | - Michela Botta
- Cardiovascular and Thoracic Department, Division of Cardiology, Città della Salute e della Scienza University Hospital of Torino, Italy
| | - Serena Bergerone
- Cardiovascular and Thoracic Department, Division of Cardiology, Città della Salute e della Scienza University Hospital of Torino, Italy
| | - Fiorenzo Gaita
- Cardiovascular and Thoracic Department, Division of Cardiology, Città della Salute e della Scienza University Hospital of Torino, Italy
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Tapper EB, Jiang ZG, Patwardhan VR. Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy. Mayo Clin Proc 2015; 90:646-58. [PMID: 25865476 DOI: 10.1016/j.mayocp.2015.03.003] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Revised: 02/27/2015] [Accepted: 03/03/2015] [Indexed: 12/12/2022]
Abstract
Hepatic encephalopathy (HE) is one of the most important complications of cirrhosis and portal hypertension. Although the etiology is incompletely understood, it has been linked to ammonia directly and indirectly. Our goal is to review for the clinician the mechanisms behind hyperammonemia and the pathogenesis of HE to explain the rationale for its therapy. We reviewed articles collected through a search of MEDLINE/PubMed, Cochrane Database of Systematic Reviews, and Google Scholar between October 1, 1948, and December 8, 2014, and by a manual search of citations within retrieved articles. Search terms included hepatic encephalopathy, ammonia hypothesis, brain and ammonia, liver failure and ammonia, acute-on-chronic liver failure and ammonia, cirrhosis and ammonia, portosytemic shunt, ammonia and lactulose, rifaximin, zinc, and nutrition. Ammonia homeostatsis is a multiorgan process involving the liver, brain, kidneys, and muscle as well as the gastrointestinal tract. Indeed, hyperammonemia may be the first clue to poor functional reserves, malnutrition, and impending multiorgan dysfunction. Furthermore, the neuropathology of ammonia is critically linked to states of systemic inflammation and endotoxemia. Given the complex interplay among ammonia, inflammation, and other factors, ammonia levels have questionable utility in the staging of HE. The use of nonabsorbable disaccharides, antibiotics, and probiotics reduces gut ammoniagenesis and, in the case of antibiotics and probiotics, systemic inflammation. Nutritional support preserves urea cycle function and prevents wasting of skeletal muscle, a significant site of ammonia metabolism. Correction of hypokalemia, hypovolemia, and acidosis further assists in the reduction of ammonia production in the kidney. Finally, early and aggressive treatment of infection, avoidance of sedatives, and modification of portosystemic shunts are also helpful in reducing the neurocognitive effects of hyperammonemia. Refining the ammonia hypothesis to account for these other factors instructs a solid foundation for the effective treatment and prevention of hepatic encephalopathy.
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Affiliation(s)
- Elliot B Tapper
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA.
| | - Z Gordon Jiang
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA
| | - Vilas R Patwardhan
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA
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Pathophysiology, diagnosis, and management of hepatic encephalopathy. Inflammopharmacology 2014; 22:319-26. [DOI: 10.1007/s10787-014-0217-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 09/19/2014] [Indexed: 12/23/2022]
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Singh S, Suresh S, McClave SA, Cave M. Treating Every Needle in the Haystack. JPEN J Parenter Enteral Nutr 2014; 39:977-85. [DOI: 10.1177/0148607114546900] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 07/20/2014] [Indexed: 12/16/2022]
Affiliation(s)
- Sanjeev Singh
- Department of General Internal Medicine, Palliative Medicine and Medical Education, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
| | - Swetha Suresh
- Department of General Internal Medicine, Palliative Medicine and Medical Education, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
- Department Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky
| | - Stephen A. McClave
- Department of General Internal Medicine, Palliative Medicine and Medical Education, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
| | - Matt Cave
- Department of General Internal Medicine, Palliative Medicine and Medical Education, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
- Department of Pharmacology & Toxicology, University of Louisville, Louisville, Kentucky
- Robley Rex Louisville VAMC, Louisville, Kentucky
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Pacheco-Colón I, Fricke S, VanMeter J, Gropman AL. Advances in urea cycle neuroimaging: Proceedings from the 4th International Symposium on urea cycle disorders, Barcelona, Spain, September 2013. Mol Genet Metab 2014; 113:118-26. [PMID: 25066103 PMCID: PMC4177962 DOI: 10.1016/j.ymgme.2014.05.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2014] [Accepted: 05/10/2014] [Indexed: 11/20/2022]
Abstract
Our previous imaging research performed as part of a Urea Cycle Rare Disorders Consortium (UCRDC) grant, has identified specific biomarkers of neurologic injury in ornithine transcarbamylase deficiency, OTCD. While characterization of mutations can be achieved in most cases, this information does not necessarily predict the severity of the underlying neurological syndrome. The biochemical consequences of any mutation may be modified additionally by a large number of factors, including contributions of other enzymes and transport systems that mediate flux through the urea cycle, diet and other environmental factors. These factors likely vary from one patient to another, and they give rise to heterogeneity of clinical severity. Affected cognitive domains include non-verbal learning, fine motor processing, reaction time, visual memory, attention, and executive function. Deficits in these capacities may be seen in symptomatic patients, as well as asymptomatic carriers with normal IQ and correlate with variances in brain structure and function in these patients. Using neuroimaging we can identify biomarkers that reflect the downstream impact of UCDs on cognition. This manuscript is a summary of the presentation from the 4th International Consortium on urea cycle disorders held in, Barcelona, Spain, September 2, 2014.
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Affiliation(s)
| | - Stanley Fricke
- Children's National Medical, USA; George Washington University, USA
| | - John VanMeter
- Center for Functional and Molecular Imaging, Georgetown University, USA
| | - Andrea L Gropman
- Center for Functional and Molecular Imaging, Georgetown University, USA; Children's National Medical, USA; George Washington University, USA.
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Bergmann KR, McCabe J, Smith TR, Guillaume DJ, Sarafoglou K, Gupta S. Late-onset ornithine transcarbamylase deficiency: treatment and outcome of hyperammonemic crisis. Pediatrics 2014; 133:e1072-6. [PMID: 24616362 DOI: 10.1542/peds.2013-1324] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Hyperammonemic crises in ornithine transcarbamylase deficiency (OTC) can be associated with devastating cerebral edema resulting in severe long-term neurologic impairment and death. We present an 8-year-old boy who had late-onset OTC deficiency in which early and aggressive management of hyperammonemia and associated cerebral edema, including therapeutic hypothermia and barbiturate-induced coma, resulted in favorable neurologic outcome. Our patient presented with vomiting and altered mental status, and was found to have a significantly elevated serum ammonia level of 1561 μmol/L. Hyperammonemia was managed with hemodialysis, 10% sodium phenylacetate, 10% sodium benzoate, L-arginine, intravenous 10% dextrose, intralipids, and protein restriction. He developed significant cerebral edema with intracranial pressures >20 mm Hg, requiring treatment with 3% saline and mannitol. Despite this treatment our patient continued to have elevated intracranial pressures, which were treated aggressively with non-conventional modalities including therapeutic hypothermia, barbiturate-induced coma, and external ventricular drainage. This therapy resulted in stabilization of hyperammonemia and resolution of cerebral edema. Molecular testing later revealed a hemizygous mutation within the OTC gene. Neuropsychological testing 1 year after discharge showed normal intelligence with no visual-motor deficits, minor deficits in working memory and processing speed, and slightly below average processing speed and executive functioning.
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50
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Rüegger CM, Lindner M, Ballhausen D, Baumgartner MR, Beblo S, Das A, Gautschi M, Glahn EM, Grünert SC, Hennermann J, Hochuli M, Huemer M, Karall D, Kölker S, Lachmann RH, Lotz-Havla A, Möslinger D, Nuoffer JM, Plecko B, Rutsch F, Santer R, Spiekerkoetter U, Staufner C, Stricker T, Wijburg FA, Williams M, Burgard P, Häberle J. Cross-sectional observational study of 208 patients with non-classical urea cycle disorders. J Inherit Metab Dis 2014; 37:21-30. [PMID: 23780642 PMCID: PMC3889631 DOI: 10.1007/s10545-013-9624-0] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Revised: 05/13/2013] [Accepted: 05/23/2013] [Indexed: 12/30/2022]
Abstract
Urea cycle disorders (UCDs) are inherited disorders of ammonia detoxification often regarded as mainly of relevance to pediatricians. Based on an increasing number of case studies it has become obvious that a significant number of UCD patients are affected by their disease in a non-classical way: presenting outside the newborn period, following a mild course, presenting with unusual clinical features, or asymptomatic patients with only biochemical signs of a UCD. These patients are surviving into adolescence and adulthood, rendering this group of diseases clinically relevant to adult physicians as well as pediatricians. In preparation for an international workshop we collected data on all patients with non-classical UCDs treated by the participants in 20 European metabolic centres. Information was collected on a cohort of 208 patients 50% of which were ≥ 16 years old. The largest subgroup (121 patients) had X-linked ornithine transcarbamylase deficiency (OTCD) of whom 83 were female and 29% of these were asymptomatic. In index patients, there was a mean delay from first symptoms to diagnosis of 1.6 years. Cognitive impairment was present in 36% of all patients including female OTCD patients (in 31%) and those 41 patients identified presymptomatically following positive newborn screening (in 12%). In conclusion, UCD patients with non-classical clinical presentations require the interest and care of adult physicians and have a high risk of neurological complications. To improve the outcome of UCDs, a greater awareness by health professionals of the importance of hyperammonemia and UCDs, and ultimately avoidance of the still long delay to correctly diagnose the patients, is crucial.
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Affiliation(s)
- Corinne M. Rüegger
- Division of Metabolism, University Children’s Hospital, Steinwiesstr. 75, 8032 Zurich, Switzerland
- Children’s Research Center, Zurich, Switzerland
| | - Martin Lindner
- Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Diana Ballhausen
- Inborn Errors of Metabolism, Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, 1011 Lausanne, Switzerland
| | - Matthias R. Baumgartner
- Division of Metabolism, University Children’s Hospital, Steinwiesstr. 75, 8032 Zurich, Switzerland
- Children’s Research Center, Zurich, Switzerland
| | - Skadi Beblo
- University Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany
| | - Anibh Das
- Department of Paediatrics, Hannover Medical School, Carl Neuberg Str. 1, D-30625 Hannover, Germany
| | - Matthias Gautschi
- University Children’s Hospital, Paediatric Endocrinology, Diabetes and Metabolism, University of Bern, Bern, Switzerland
| | - Esther M. Glahn
- Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Sarah C. Grünert
- Department of Pediatrics and Adolescent Medicine, University Children’s Hospital Freiburg, Freiburg, Germany
| | - Julia Hennermann
- Department of Pediatric Endocrinology, Gastroenterology and Metabolic Diseases, Charité Universitätsmedizin, Berlin, Germany
| | - Michel Hochuli
- Department of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, CH-8091 Zurich, Switzerland
| | - Martina Huemer
- Department of Pediatrics, Landeskrankenhaus Bregenz, Carl Pedenz Str. 2, 6900 Bregenz, Austria
| | - Daniela Karall
- Clinic of Pediatrics I, Division Metabolic Inherited Disorders, Medical University Innsbruck, Innsbruck, Austria
| | - Stefan Kölker
- Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Robin H. Lachmann
- National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG UK
| | - Amelie Lotz-Havla
- Department of Inborn Errors of Metabolism, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, 80337 Germany
| | - Dorothea Möslinger
- Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, Waehringerguertel 18-20, 1090 Vienna, Austria
| | - Jean-Marc Nuoffer
- University Children’s Hospital, Paediatric Endocrinology, Diabetes and Metabolism, University of Bern, Bern, Switzerland
- University Institute of Clinical Chemistry, University Bern, Bern, Switzerland
| | - Barbara Plecko
- Children’s Research Center, Zurich, Switzerland
- Department of Pediatrics, University Hospital Graz, Auenbruggerplatz 30, A-8036 Graz, Austria
- Division of Neuropediatrics, University Children’s Hospital, Zurich, Switzerland
| | - Frank Rutsch
- Department of General Pediatrics, Münster University Children’s Hospital, Münster, Germany
| | - René Santer
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
| | - Ute Spiekerkoetter
- Department of Pediatrics and Adolescent Medicine, University Children’s Hospital Freiburg, Freiburg, Germany
- Department of General Pediatrics and Neonatology, University Children’s Hospital Duesseldorf, Duesseldorf, Germany
| | - Christian Staufner
- Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Tamar Stricker
- Division of Metabolism, University Children’s Hospital, Steinwiesstr. 75, 8032 Zurich, Switzerland
- Children’s Research Center, Zurich, Switzerland
| | - Frits A. Wijburg
- Department of Pediatrics, Academic Medical Centre, Amsterdam, The Netherlands
| | - Monique Williams
- Department of Pediatrics, Erasmus Medical Center, Sophia Children’s Hospital Rotterdam, Rotterdam, The Netherlands
| | - Peter Burgard
- Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Johannes Häberle
- Division of Metabolism, University Children’s Hospital, Steinwiesstr. 75, 8032 Zurich, Switzerland
- Children’s Research Center, Zurich, Switzerland
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