RESUMO
The aryl hydrocarbon receptor is a ligand-activated transcription factor known for mediating the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. TCDD induces nonalcoholic fatty liver disease (NAFLD)-like pathologies including simple steatosis that can progress to steatohepatitis with fibrosis and bile duct proliferation in male mice. Dose-dependent progression of steatosis to steatohepatitis with fibrosis by TCDD has been associated with metabolic reprogramming, including the disruption of amino acid metabolism. Here, we used targeted metabolomic analysis to reveal dose-dependent changes in the level of ten serum and eleven hepatic amino acids in mice upon treatment with TCDD. Bulk RNA-seq and protein analysis showed TCDD repressed CPS1, OTS, ASS1, ASL, and GLUL, all of which are associated with the urea cycle and glutamine biosynthesis. Urea and glutamine are end products of the detoxification and excretion of ammonia, a toxic byproduct of amino acid catabolism. Furthermore, we found that the catalytic activity of OTC, a rate-limiting step in the urea cycle was also dose dependently repressed. These results are consistent with an increase in circulating ammonia. Collectively, the repression of the urea and glutamate-glutamine cycles increased circulating ammonia levels and the toxicity of TCDD.
Assuntos
Amônia , Redes e Vias Metabólicas , Hepatopatia Gordurosa não Alcoólica , Dibenzodioxinas Policloradas , Animais , Masculino , Camundongos , Amônia/sangue , Amônia/metabolismo , Fibrose , Glutamina/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacosRESUMO
Sepsis-associated encephalopathy (SAE) is a significant cause of mortality in patients with sepsis. Despite extensive research, its exact cause remains unclear. Our previous research indicated a relationship between non-hepatic hyperammonemia (NHH) and SAE. This study aimed to investigate the relationship between NHH and SAE and the potential mechanisms causing cognitive impairment. In the in vivo experimental results, there were no significant abnormalities in the livers of mice with moderate cecal ligation and perforation (CLP); however, ammonia levels were elevated in the hippocampal tissue and serum. The ELISA study suggest that fecal microbiota transplantation in CLP mice can reduce ammonia levels. Reduction in ammonia levels improved cognitive dysfunction and neurological impairment in CLP mice through behavioral, neuroimaging, and molecular biology studies. Further studies have shown that ammonia enters the brain to regulate the expression of aquaporins-4 (AQP4) in astrocytes, which may be the mechanism underlying brain dysfunction in CLP mice. The results of the in vitro experiments showed that ammonia up-regulated AQP4 expression in astrocytes, resulting in astrocyte damage. The results of this study suggest that ammonia up-regulates astrocyte AQP4 expression through the gut-brain axis, which may be a potential mechanism for the occurrence of SAE.
Assuntos
Aquaporina 4 , Astrócitos , Eixo Encéfalo-Intestino , Hiperamonemia , Encefalopatia Associada a Sepse , Animais , Camundongos , Aquaporina 4/metabolismo , Aquaporina 4/genética , Aquaporina 4/biossíntese , Astrócitos/metabolismo , Hiperamonemia/metabolismo , Encefalopatia Associada a Sepse/metabolismo , Masculino , Eixo Encéfalo-Intestino/fisiologia , Camundongos Endogâmicos C57BL , Amônia/metabolismo , Amônia/sangue , Encéfalo/metabolismo , Transplante de Microbiota FecalRESUMO
BACKGROUND: Swimming has been used empirically for rehabilitation and conditioning of horses. However, due to challenges imposed by recording physiological parameters in water, the intensity of free swimming effort is unknown. OBJECTIVES: Measure the physiological workload associated with untethered swimming in horses. Five fit Arabian endurance horses were assessed while swimming in a 100 m-long indoor pool. Horses were equipped with a modified ergospirometry facemask to measure oxygen consumption (VÌO2) and ventilatory parameters (inspired/expired volumes, VI, VE; peak inspiratory/expiratory flows, PkVI, PkVE; respiratory frequency, Rf; minute ventilation, VE; inspiratory/expiratory durations and ratios, tI, tE, tI/ttot, tE/ttot); and an underwater electrocardiogram that recorded heart rate (HR). Postexercise venous blood lactate and ammonia concentrations were measured. Data are reported as median (interquartile ranges). RESULTS: Horses showed bradypnea (12 breaths/min (10-16)) for the first 30 s of swimming. VÌO2 during swimming was 43.2 ml/(kg.min) (36.0-56.6). Ventilatory parameters were: VI = 16.7 L (15.3-21.8), VE = 14.7 L (12.4-18.9), PkVI = 47.8 L/s (45.8-56.5), PkVE = 55.8 L/s (38.3-72.5), Rf = 31.4 breaths/min (20.0-33.8), VE = 522.9 L/min (414.7-580.0), tI = 0.5 s (0.5-0.6), tE = 1.2 s (1.1-1.6), tI/ttot = 0.3 (0.2-0.4), tE/ttot = 0.7 (0.6-0.8). Expiratory flow tracings showed marked oscillations that coincided with a vibrating expiratory sound. HR was 178.0 bpm (148.5-182.0), lactate = 1.5 mmol/L (1.0-1.9) and ammonia = 41.0 µmol/L (36.5-43.5). CONCLUSIONS: Free (untethered) swimming represents a submaximal, primarily aerobic exercise in horses. The breathing pattern during swimming is unique, with a relatively longer apneic period at the beginning of the exercise and an inspiratory time less than half that of expiration.
Assuntos
Frequência Cardíaca , Consumo de Oxigênio , Espirometria , Natação , Animais , Cavalos/fisiologia , Natação/fisiologia , Consumo de Oxigênio/fisiologia , Frequência Cardíaca/fisiologia , Espirometria/veterinária , Masculino , Condicionamento Físico Animal/fisiologia , Ácido Láctico/sangue , Feminino , Amônia/sangueRESUMO
A 64-year-old woman was admitted to our hospital because of severe constipation and was diagnosed with unresectable cStage â £b rectal cancer with multiple lung metastases and liver metastases. Because of obstructive symptoms, a laparoscopic sigmoid colostomy was performed. Because of RAS/BRAF wild type, we started the mFOLFOX6 plus panitumumab (Pmab). Ten days after 10 cycles of chemotherapy, she was admitted because of general fatigue, stoma edema, ascites, and leg edema. She became confused(JCSâ ¢-200). The laboratory results revealed that her serum ammonia level was 293µg/ dL. We diagnosed 5-FU-induced hyperammonemic encephalopathy. Treatment with branched-chain amino acid solutions resulted in improvement of his mental status and serum ammonia level decreased. After that, the chemotherapy was changed to 5-FU 80% FOLFIRI plus bevacizumab, but hyperammonemia recurred. After improvement of hyperammonemia, the patient has been treated for 4 cycles without becoming unconscious after switching to FTD/TPI plus bevacizumab therapy. In this case, muscle weakness due to sarcopenia was considered to be one of the causes. We believe that oral drugs containing FTD/TPI can be used relatively safely without causing hyperammonemia.
Assuntos
Neoplasias Colorretais , Fluoruracila , Hiperamonemia , Feminino , Humanos , Pessoa de Meia-Idade , Amônia/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/cirurgia , Edema/tratamento farmacológico , Fluoruracila/efeitos adversos , Demência Frontotemporal/tratamento farmacológico , Hiperamonemia/induzido quimicamente , Hiperamonemia/tratamento farmacológico , LeucovorinaRESUMO
Hepatic encephalopathy (HE) is a debilitating neurological complication of cirrhosis. By definition, HE is considered a reversible disorder, and therefore HE should resolve following liver transplantation (LT). However, persisting neurological complications are observed in as many as 47% of LT recipients. LT is an invasive surgical procedure accompanied by various perioperative factors such as blood loss and hypotension which could influence outcomes post-LT. We hypothesize that minimal HE (MHE) renders the brain frail and susceptible to hypotension-induced neuronal cell death. Six-week bile duct-ligated (BDL) rats with MHE and respective SHAM-controls were used. Several degrees of hypotension (mean arterial pressure of 30, 60 and 90 mm Hg) were induced via blood withdrawal from the femoral artery and maintained for 120 min. Brains were collected for neuronal cell count and apoptotic analysis. In a separate group, BDL rats were treated for MHE with the ammonia-lowering strategy ornithine phenylacetate (OP; MNK-6105), administered orally (1 g/kg) for 3 weeks before induction of hypotension. Hypotension 30 and 60 mm Hg (not 90 mm Hg) significantly decreased neuronal marker expression (NeuN) and cresyl violet staining in the frontal cortex compared to respective hypotensive SHAM-operated controls as well as non-hypotensive BDL rats. Neuronal degeneration was associated with an increase in cleaved caspase-3, suggesting the mechanism of cell death was apoptotic. OP treatment attenuated hyperammonaemia, improved anxiety and activity, and protected the brain against hypotension-induced neuronal cell death. Our findings demonstrate that rats with chronic liver disease and MHE are more susceptible to hypotension-induced neuronal cell degeneration. This highlights MHE at the time of LT is a risk factor for poor neurological outcome post-transplant and that treating for MHE pre-LT might reduce this risk.
Assuntos
Amônia/metabolismo , Ductos Biliares , Hipotensão/patologia , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Amônia/sangue , Animais , Antígenos Nucleares/metabolismo , Ansiedade/psicologia , Apoptose , Comportamento Animal , Caspase 3/metabolismo , Circulação Cerebrovascular/efeitos dos fármacos , Modelos Animais de Doenças , Encefalopatia Hepática/patologia , Hiperamonemia , Ligadura , Masculino , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/psicologia , Ornitina/análogos & derivados , Ornitina/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
Our study provides novel findings of experimental hypokalemia reducing urea cycle functionality and thereby severely increasing plasma ammonia. This is pathophysiologically interesting because plasma ammonia increases during hypokalemia by a hitherto unknown mechanism, which may be particular important in relation to the unexplained link between hypokalemia and hepatic encephalopathy. Potassium deficiency decreases gene expression, protein synthesis, and growth. The urea cycle maintains body nitrogen homeostasis including removal of toxic ammonia. Hyperammonemia is an obligatory trait of liver failure, increasing the risk for hepatic encephalopathy, and hypokalemia is reported to increase ammonia. We aimed to clarify the effects of experimental hypokalemia on the in vivo capacity of the urea cycle, on the genes of the enzymes involved, and on ammonia concentrations. Female Wistar rats were fed a potassium-free diet for 13 days. Half of the rats were then potassium repleted. Both groups were compared with pair- and free-fed controls. The following were measured: in vivo capacity of urea-nitrogen synthesis (CUNS); gene expression (mRNA) of urea cycle enzymes; plasma potassium, sodium, and ammonia; intracellular potassium, sodium, and magnesium in liver, kidney, and muscle tissues; and liver sodium/potassium pumps. Liver histology was assessed. The diet induced hypokalemia of 1.9 ± 0.4 mmol/L. Compared with pair-fed controls, the in vivo CUNS was reduced by 34% (P < 0.01), gene expression of argininosuccinate synthetase 1 (ASS1) was decreased by 33% (P < 0.05), and plasma ammonia concentrations were eightfold elevated (P < 0.001). Kidney and muscle tissue potassium contents were markedly decreased but unchanged in liver tissue. Protein expressions of liver sodium/potassium pumps were unchanged. Repletion of potassium reverted all the changes. Hypokalemia decreased the capacity for urea synthesis via gene effects. The intervention led to marked hyperammonemia, quantitatively explainable by the compromised urea cycle. Our findings motivate clinical studies of patients with liver disease.
Assuntos
Amônia/sangue , Hiperamonemia/etiologia , Hipopotassemia/etiologia , Deficiência de Potássio/complicações , Potássio/sangue , Ureia/sangue , Animais , Modelos Animais de Doenças , Feminino , Regulação Enzimológica da Expressão Gênica , Hiperamonemia/sangue , Hiperamonemia/genética , Hipopotassemia/sangue , Hipopotassemia/genética , Rim/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Deficiência de Potássio/sangue , Potássio na Dieta/administração & dosagem , Potássio na Dieta/metabolismo , Ratos WistarRESUMO
BACKGROUND/AIMS: Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age. METHODS: This was an open-label study in UCD patients aged 0 - 2 months, consisting of an initiation/transition period (1 - 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter. RESULTS: All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported. CONCLUSIONS: This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.
Assuntos
Glicerol/análogos & derivados , Hiperamonemia/tratamento farmacológico , Fenilbutiratos/administração & dosagem , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Idade de Início , Amônia/sangue , Pré-Escolar , Feminino , Glicerol/administração & dosagem , Humanos , Hiperamonemia/sangue , Hiperamonemia/patologia , Lactente , Recém-Nascido , Masculino , Pediatria , Fenilacetatos/administração & dosagem , Diálise Renal , Distúrbios Congênitos do Ciclo da Ureia/sangue , Distúrbios Congênitos do Ciclo da Ureia/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/patologiaRESUMO
Ornithine transcarbamylase deficiency (OTCD) is a metabolic and genetic disease caused by dysfunction of the hepatocytic urea cycle. To develop new drugs or therapies for OTCD, it is ideal to use models that are more closely related to human metabolism and pathology. Primary human hepatocytes (HHs) isolated from two patients (a 6-month-old boy and a 5-year-old girl) and a healthy donor were transplanted into host mice (hemi-, hetero-OTCD mice, and control mice, respectively). HHs were isolated from these mice and used for serial transplantation into the next host mouse or for in vitro experiments. Histological, biochemical, and enzyme activity analyses were performed. Cultured HHs were treated with ammonium chloride or therapeutic drugs. Replacement rates exceeded 80% after serial transplantation in both OTCD mice. These highly humanized OTCD mice showed characteristics similar to OTCD patients that included increased blood ammonia levels and urine orotic acid levels enhanced by allopurinol. Hemi-OTCD mice showed defects in OTC expression and significantly low enzymatic activities, while hetero-OTCD mice showed residual OTC expression and activities. A reduction in ammonium metabolism was observed in cultured HHs from OTCD mice, and treatment with the therapeutic drug reduced the ammonia levels in the culture medium. In conclusion, we established in vivo OTC mouse models with hemi- and hetero-patient HHs. HHs isolated from the mice were useful as an in vitro model of OTCD. These OTC models could be a source of valuable patient-derived hepatocytes that would enable large scale and reproducible experiments using the same donor.
Assuntos
Hepatócitos/transplante , Doença da Deficiência de Ornitina Carbomoiltransferase/terapia , Ornitina Carbamoiltransferase/genética , Amônia/sangue , Animais , Pré-Escolar , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Hepatócitos/química , Hepatócitos/citologia , Humanos , Lactente , Masculino , Camundongos , Doença da Deficiência de Ornitina Carbomoiltransferase/genética , Ácido Orótico/urinaRESUMO
Urea cycle disorders (UCDs) are inherited metabolic disorders with impaired nitrogen detoxification caused by defects in urea cycle enzymes. They often manifest with hyperammonemic attacks resulting in significant morbidity or death. We performed a nationwide questionnaire-based study between January 2000 and March 2018 to document all UCDs in Japan, including diagnoses, treatments, and outcomes. A total of 229 patients with UCDs were enrolled in this study: 73 males and 53 females with ornithine transcarbamylase deficiency (OTCD), 33 patients with carbamoylphosphate synthetase 1 deficiency, 48 with argininosuccinate synthetase deficiency, 14 with argininosuccinate lyase deficiency, and 8 with arginase deficiency. Survival rates at 20 years of age of male and female patients with late-onset OTCD were 100% and 97.7%, respectively. Blood ammonia levels and time of onset had a significant impact on the neurodevelopmental outcome (P < .001 and P = .028, respectively). Hemodialysis and liver transplantation did not prevent poor neurodevelopmental outcomes. While treatment including medication, hemodialysis, and liver transplantation may aid in decreasing blood ammonia and/or preventing severe hyperammonemia, a blood ammonia level ≥ 360 µmol/L was found to be a significant indicator for a poor neurodevelopmental outcome. In conclusion, although current therapy for UCDs has advanced and helped saving lives, patients with blood ammonia levels ≥ 360 µmol/L at onset often have impaired neurodevelopmental outcomes. Novel neuroprotective measures should therefore be developed to achieve better neurodevelopmental outcomes in these patients.
Assuntos
Hiperamonemia/prevenção & controle , Transtornos do Neurodesenvolvimento/etiologia , Distúrbios Congênitos do Ciclo da Ureia/fisiopatologia , Distúrbios Congênitos do Ciclo da Ureia/terapia , Adolescente , Adulto , Amônia/sangue , Criança , Pré-Escolar , Feminino , Humanos , Hiperamonemia/etiologia , Japão/epidemiologia , Transplante de Fígado , Masculino , Diálise Renal , Taxa de Sobrevida , Distúrbios Congênitos do Ciclo da Ureia/sangue , Distúrbios Congênitos do Ciclo da Ureia/epidemiologia , Adulto JovemRESUMO
INTRODUCTION: Hyperammonemia is a life-threatening condition. However, clearance of ammonia via extracorporeal treatment has not been systematically evaluated. METHODS: We searched EMBASE and MEDLINE databases. We included all publications reporting ammonia clearance by extracorporeal treatment in adult and pediatric patients with clearance estimated by direct dialysate ammonia measurement or calculated by formula. Two reviewers screened and extracted data independently. RESULTS: We found 1,770 articles with 312 appropriate for assessment and 28 studies meeting eligibility criteria. Most of the studies were case reports. Hyperammonemia was typically secondary to inborn errors of metabolisms in children and to liver failure in adult patients. Ammonia clearance was most commonly reported during continuous renal replacement therapy (CRRT) and appeared to vary markedly from <5 mL/min/m2 to >250 mL/min/m2. When measured during intermittent hemodialysis (IHD), clearance was highest and correlated with blood flow rate (R2 = 0.853; p < 0.001). When measured during CRRT, ammonia clearance could be substantial and correlated with effluent flow rate (EFR; R2 = 0.584; p < 0.001). Neither correlated with ammonia reduction. Peritoneal dialysis (PD) achieved minimal clearance, and other extracorporeal techniques were rarely studied. CONCLUSIONS: Extracorporeal ammonia clearance varies widely with sometimes implausible values. Treatment modality, blood flow, and EFR, however, appear to affect such clearance with IHD achieving the highest values, PD achieving minimal values, and CRRT achieving substantial values especially at high EFRs. The role of other techniques remains unclear. These findings can help inform practice and future studies.
Assuntos
Amônia/isolamento & purificação , Estado Terminal/terapia , Hiperamonemia/terapia , Terapia de Substituição Renal/métodos , Amônia/sangue , Terapia de Substituição Renal Contínua/métodos , Humanos , Hiperamonemia/sangue , Diálise Peritoneal/métodos , Diálise Renal/métodosRESUMO
PURPOSE: Amanita phalloides poisoning with high mortality is rare but serious. The aim of this study is to identify the risk indicators of death in patients with Amanita phalloides poisoning and a good score tool to predict prognosis. METHODS: In this respective study (1/2009-12/2018), the patients (n = 105) with Amanita phalloides poisoning from two hospitals of China Medical University who met the inclusion/exclusion criteria were included. The laboratory markers and the clinical scoring systems including Child-Turcotte-Pugh (CTP), Sequential organ failure assessment (SOFA), Liver injury and Failure evaluation (LiFe), Chronic liver failure-organ failure score system (CLIF-OF), King's College criteria (KCH criteria), Model for end-stage liver disease (MELD) and Platelet-bilirubin-albumin (PALBI) within 24 h of admission to the two hospitals were analyzed and area under the curve (AUC) analyses were also performed regarding the prediction of death. RESULTS: The data analysis indicated that high international normalized ratio (INR) (>3.6, AUC = 0.941) and plasma ammonia (>95.1 µmol/L, AUC = 0.805) were closely associated with mortality after multivariate logistic regression. CLIF-OF (>9) within 24 h with really good diagnostic accuracy (>90%) significantly outperformed the other scores in predicting mortality. CONCLUSION: CLIF-OF (>9) within 24 h of admission is considered as a satisfactory and practical tool to predict a poor outcome of Amanita phalloides poisoning.
Assuntos
Amanita , Doença Hepática Terminal/fisiopatologia , Intoxicação Alimentar por Cogumelos/mortalidade , Escores de Disfunção Orgânica , Amônia/sangue , Área Sob a Curva , China , Doença Hepática Terminal/etiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de RiscoRESUMO
PURPOSE: To reduce the need for invasive and expensive measures of human biomarkers, sweat is becoming increasingly popular in use as an alternative to blood. Therefore, the (in)dependency of blood and sweat composition has to be explored. METHODS: In an environmental chamber (33 °C, 65% relative humidity; RH), 12 participants completed three subsequent 20-min cycling stages to elicit three different local sweat rates (LSR) while aiming to limit changes in blood composition: at 60% of their maximum heart rate (HRmax), 70% HRmax and 80% HRmax, with 5 min of seated-rest in between. Sweat was collected from the arm and back during each stage and post-exercise. Blood was drawn from a superficial antecubital vein in the middle of each stage. Concentrations of sodium, chloride, potassium, ammonia, lactate and glucose were determined in blood plasma and sweat. RESULTS: With increasing exercise intensity, LSR, sweat sodium, chloride and glucose concentrations increased (P ≤ 0.026), while simultaneously limited changes in blood composition were elicited for these components (P ≥ 0.093). Sweat potassium, lactate and ammonia concentrations decreased (P ≤ 0.006), while blood potassium decreased (P = 0.003), and blood ammonia and lactate concentrations increased with higher exercise intensities (P = 0.005; P = 0.007, respectively). The vast majority of correlations between blood and sweat parameters were non-significant (P > 0.05), with few exceptions. CONCLUSION: The data suggest that sweat composition is at least partly independent of blood composition. This has important consequences when targeting sweat as non-invasive alternative for blood measurements.
Assuntos
Amônia/metabolismo , Cloretos/metabolismo , Exercício Físico/fisiologia , Glucose/metabolismo , Ácido Láctico/metabolismo , Potássio/metabolismo , Sódio/metabolismo , Suor/metabolismo , Adulto , Amônia/sangue , Cloretos/sangue , Feminino , Humanos , Ácido Láctico/sangue , Masculino , Potássio/sangue , Sódio/sangueRESUMO
Ammonia is both a respiratory gas and a toxicant in teleost fish. Hyperventilation is a well-known response to elevations of both external and internal ammonia levels. Branchial neuroepithelial cells (NECs) are thought to serve as internal sensors of plasma ammonia (peripheral chemoreceptors), but little is known about other possible ammonia-sensors. Here, we investigated whether trout possess external sensors and/or internal central chemoreceptors for ammonia. For external sensors, we analyzed the time course of ventilatory changes at the start of exposure to high environmental ammonia (HEA, 1 mM). Hyperventilation developed gradually over 20 min, suggesting that it was a response to internal ammonia elevation. We also directly perfused ammonia solutions (0.01-1 mM) to the external surfaces of the first gill arches. Immediate hypoventilation occurred. For central chemoreceptors, we injected ammonia solutions (0.5-1.0 mM) directly onto the surface of the hindbrain of anesthetized trout. Immediate hyperventilation occurred. This is the first evidence of central chemoreception in teleost fish. We conclude that trout possess both external ammonia sensors, and dual internal ammonia sensors (perhaps for redundancy), but their roles differ. External sensors cause short term hypoventilation, which would help limit toxic waterborne ammonia uptake. When fish cannot avoid HEA, the diffusion of waterborne ammonia into the blood will stimulate both peripheral (NECs) and central (brain) chemoreceptors, resulting in hyperventilation. This hyperventilation will be beneficial in increasing ammonia excretion via the Rh metabolon system in the gills not only after HEA exposure, but also after endogenous ammonia loading from feeding or exercise.
Assuntos
Amônia/sangue , Encéfalo/fisiologia , Brânquias/metabolismo , Oncorhynchus mykiss/fisiologia , Oxigênio/metabolismo , Amônia/química , Animais , Transporte Biológico , Encéfalo/metabolismo , Sistema Nervoso Central/fisiologia , Meio Ambiente , Hiperventilação , Células Neuroepiteliais/metabolismo , Fenômenos Fisiológicos Respiratórios , ÁguaRESUMO
Acute or chronic liver injury is closely related to hyperammonemia, which will result in oxidative stress and damage to nerve cells, and these factors are vital to the development of anxiety and depression. In this study, the effect of Nootkatone (NKT) on the anxiety- and depression-like behavioral changes in mice induced by liver injury was investigated. Liver injury was induced by D-galactosamine (D-GalN; 350 mg/kg) three times a week for 4 weeks. NKT (5 mg/kg or 10 mg/kg) was given as co-treatment daily for 4 weeks. NKT (5 mg/kg) co-treatment remarkably ameliorates D-GalN-induced anxiety- and depression-like behaviors as evident from the results of sucrose preference test, forced swimming test, tail suspension test, and novelty suppressed feeding test. Results showed that NKT could induce an elevation in serum alanine transaminase and aspartate transaminase level, alleviate the oxidative stress induced by hyperammonemia through activating Keap1/Nrf2/HO-1 antioxidant pathways, decrease the expression of inducible nitric oxide synthase and NOX2 in hippocampus and prefrontal cortex, enhance the vitality of superoxide dismutase, catalase, and glutathione levels in serum, liver, and brain, and significantly reduce the generation of malondialdehyde. At the same time, NKT also reduces the level of ammonia in serum and brain and upgrades the activity of glutamine synthetase in the hippocampus and prefrontal cortex. Taken together, the present results suggested that NKT has a significant antidepressant effect through modulation of oxidative stress induced by D-GalN administration.
Assuntos
Antidepressivos/farmacologia , Ansiedade/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Depressão/prevenção & controle , Galactosamina/toxicidade , Hiperamonemia/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sesquiterpenos Policíclicos/farmacologia , Amônia/sangue , Amônia/toxicidade , Animais , Antioxidantes/metabolismo , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/psicologia , Hiperamonemia/psicologia , Lipopolissacarídeos/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Células PC12 , RatosRESUMO
INTRODUCTION: Ammonia levels are used to assess hepatic encephalopathy, but their levels are highly variable in clinical practice. METHODS: We studied factors associated with variation in ammonia values in cirrhotic patients without previous hepatic encephalopathy and healthy volunteers (HVs). RESULTS: Ammonia increased by 12% and 18% at 1 and 2 hour, respectively, after a protein meal in 64 cirrhotic patients (P < 0.001). In 237 HVs, ammonia levels varied significantly between sites (P < 0.0001). New site-specific ammonia upper limits based on HV levels using a strict analysis protocol differed from routinely used values. Correlation between paired fresh samples was high (r = 0.83) but modest between fresh and frozen samples (r = 0.62). DISCUSSION: Sample handling, processing, and protein intake impact ammonia levels across sites.
Assuntos
Amônia/sangue , Ensaios Clínicos como Assunto , Encefalopatia Hepática/sangue , Cirrose Hepática/sangue , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Progressão da Doença , Feminino , Voluntários Saudáveis , Encefalopatia Hepática/diagnóstico , Encefalopatia Hepática/etiologia , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto JovemRESUMO
PURPOSE: We aimed to identify prognostic factors for survival and long-term intellectual and developmental outcome in neonatal patients with early-onset urea cycle disorders (UCD) experiencing hyperammonaemic coma. METHODS: We retrospectively analysed ammonia (NH3) and glutamine levels, electroencephalogram and brain images obtained during neonatal coma of UCD patients born between 1995 and 2011 and managed at a single centre and correlated them to survival and intellectual and developmental outcome. RESULTS: We included 38 neonates suffering from deficiencies of argininosuccinate synthetase (ASSD, N = 12), ornithine transcarbamylase (OTCD, N = 10), carbamoylphosphate synthetase 1 (CPSD, N = 7), argininosuccinate lyase (ASLD, N = 7), N-acetylglutamate synthase (NAGS, N = 1) or arginase (ARGD, N = 1). Symptoms occurred earlier in mitochondrial than in cytosolic UCD. Sixty-eight percent of patients survived, with a mean (standard deviation-SD) follow-up of 10.4 (5.3) years. Mortality was mostly observed in OTCD (N = 7/10) and CPSD (N = 4/7) patients. Plasma NH3 level during the neonatal period, expressed as area under the curve, but not glutamine level was associated with mortality (p = .044 and p = .610). 62.1% of the patients had normal intellectual and developmental outcome. Intellectual and developmental outcome tended to correlate with UCD subtype (p = .052). No difference in plasma NH3 or glutamine level during the neonatal period among developmental outcomes was identified. EEG severity was linked to UCD subtypes (p = .004), ammonia levels (p = .037), duration of coma (p = .043), and mortality during the neonatal period (p = .020). Status epilepticus was recorded in 6 patients, 3 of whom died neonatally, 1 developed a severe intellectual disability while the 2 last patients had a normal development. CONCLUSION: UCD subtypes differed by survival rate, intellectual and developmental outcome and EEG features in the neonatal period. Hyperammonaemia expressed as area under the curve was associated with survival but not with intellectual and developmental outcome whereas glutamine was not associated with one of these outcomes. Prognostic value of video-EEG monitoring and the association between status epilepticus and mortality should be assessed in neonatal hyperammonaemic coma in further studies.
Assuntos
Argininossuccinato Sintase/metabolismo , Carbamoil-Fosfato Sintase (Amônia)/metabolismo , Deficiências do Desenvolvimento/epidemiologia , Mortalidade Infantil/tendências , Deficiência Intelectual/epidemiologia , Ornitina Carbamoiltransferase/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/mortalidade , Idade de Início , Amônia/sangue , Deficiências do Desenvolvimento/enzimologia , Deficiências do Desenvolvimento/patologia , Feminino , França/epidemiologia , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/enzimologia , Deficiência Intelectual/patologia , Masculino , Estudos Retrospectivos , Distúrbios Congênitos do Ciclo da Ureia/enzimologia , Distúrbios Congênitos do Ciclo da Ureia/patologiaRESUMO
Ammonia is thought to be central to the pathogenesis of hepatic encephalopathy (HE), but its prognostic role in patients with cirrhosis and acute decompensation is unknown. The aims of this study were to determine the relationship between ammonia levels and severity of HE and its association with organ dysfunction and short-term mortality. We identified 498 patients from two institutions as part of prospective observational studies in patients with cirrhosis. Plasma ammonia levels were measured on admission and Chronic Liver Failure-Sequential Organ Failure Assessment criteria were used to determine the presence of organ failures. The 28-day patient survival was determined. Receiver operating characteristic analysis was used to identify the cutoff points for ammonia values, and multivariable analysis was performed using the Cox proportional hazard regression model. The 28-day mortality was 43.4%. Plasma ammonia correlated with severity of HE (P < 0.001), was significantly higher in nonsurvivors (93 [73-121] versus 67 [55-89] µmol/L, P < 0.001), and was an independent predictor of 28-day mortality (hazard ratio, 1.009, P < 0.001). An ammonia level of 79.5 µmol/L had sensitivity of 68.1% and specificity of 67.4% for predicting 28-day mortality. An ammonia level of ≥79.5 µmol/L was associated with a higher frequency of organ failures (liver [P = 0.004], coagulation [P < 0.001], kidney [P = 0.004], and respiratory [P < 0.001]). Lack of improvement in baseline ammonia at day 5 was associated with high mortality (70.6%). Conclusion: Ammonia level correlates with not only the severity of HE but also the failure of other organs and is an independent risk factor for mortality; lack of improvement in ammonia level is associated with high risk of death, making it an important biomarker and a therapeutic target.
Assuntos
Amônia/sangue , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Falência Hepática Aguda/sangue , Adulto , Biomarcadores/sangue , Biópsia por Agulha , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Hospitais Universitários , Humanos , Imuno-Histoquímica , Índia , Estimativa de Kaplan-Meier , Cirrose Hepática/mortalidade , Falência Hepática Aguda/mortalidade , Falência Hepática Aguda/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Medição de Risco , Papel (figurativo) , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Análise de Sobrevida , Reino UnidoRESUMO
OBJECTIVE: Dravet syndrome (DS) is a rare cause of severe and pharmacoresistant epileptic encephalopathy. Stiripentol (STP) has a significant therapeutic benefit in the pediatric DS population. However, STP effects on adult patients have not been well studied. In our adult STP-naive DS patient population, STP initiation was associated with encephalopathy, despite decreases in valproate and clobazam dosage. Here we explored the cause and treatment of encephalopathic manifestations associated with STP in adults. METHODS: Twenty-eight patients with a confirmed clinical and genetic diagnosis of DS who attended the Adult Epilepsy Genetics Clinic were identified retrospectively. Patients who declined or discontinued STP after fewer than 3 months of use, patients who were deceased before starting STP or seizure-free when the genetic diagnosis was confirmed, and those who started STP before leaving the pediatric system (<18 years) were excluded. Levels of ammonia, carnitine, and other anti-epileptic drugs (AEDs) were observed for patients receiving STP. Patients with high ammonia levels who received carnitine supplementation were reevaluated. They were also offered an increased dosage of stiripentol if treatment with carnitine improved the encephalopathy. RESULTS: We observed hyperammonemic encephalopathy in 77% of patients treated with STP. In seven of nine patients, we observed a rate of improvement in ammonia levels of 35% (95% confidence interval [CI] 21%-49%) at a mean carnitine dose of 991 ± 286 mg/d (range 660-1320 mg/d). Five patients whose ammonia levels normalized were also offered an increase in STP dose and they were able to tolerate higher doses with improvement in side effects. Despite such adjustments, the mean maximum stiripentol dose reached was 14.89 ± 8.72 mg/kg/d, which is lower than what is typically recommended in children (50 mg/kg/d). SIGNIFICANCE: We report hyperammonemia in adult STP-naive patients who were on valproate and clobazam, despite dose reduction of the latter drugs. We also report that treatment with carnitine improved hyperammonemia, allowing the continuation of STP.
Assuntos
Amônia , Anticonvulsivantes/efeitos adversos , Carnitina/administração & dosagem , Dioxolanos/efeitos adversos , Epilepsias Mioclônicas/tratamento farmacológico , Hiperamonemia/induzido quimicamente , Adulto , Amônia/sangue , Anticonvulsivantes/administração & dosagem , Estudos de Coortes , Dioxolanos/administração & dosagem , Epilepsias Mioclônicas/sangue , Feminino , Humanos , Hiperamonemia/sangue , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: Little is known about normative ammonia concentrations in extremely low birthweight (ELBW) babies and whether these vary with birth characteristics. We aimed to determine ammonia concentrations in ELBW babies in the first week after birth and relationships with neonatal characteristics and protein intake. METHODS: Arterial blood samples for the measurement of plasma ammonia concentration were collected within 7 days of birth from ProVIDe trial participants in six New Zealand neonatal intensive care units. RESULTS: Three hundred and twenty-two babies were included. Median (range) gestational age was 25.7 (22.7-31.6) weeks. Median (interquartile range (IQR)) ammonia concentration was 102 (80-131) µg/dL. There were no statistically significant associations between ammonia concentrations and birthweight or sex. Ammonia concentrations were weakly correlated with mean total (Spearman's rs = 0.11, P = 0.047) and intravenous (rs = 0.13, P = 0.02) protein intake from birth, gestational age at birth (rs = -0.13, P = 0.02) and postnatal age (rs = -0.13, P = 0.02). CONCLUSIONS: Plasma ammonia concentrations in ELBW babies are similar to those of larger and more mature babies and only weakly correlated with protein intake. Currently, recommended thresholds for investigation of hyperammonaemia are appropriate for ELBW babies. Protein intake should not be limited by concerns about potential hyperammonaemia.
Assuntos
Amônia/sangue , Peso ao Nascer , Interpretação Estatística de Dados , Feminino , Idade Gestacional , Humanos , Hiperamonemia/sangue , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Terapia Intensiva Neonatal , Masculino , Nova Zelândia , Resultado do TratamentoRESUMO
Adult-onset noncirrhotic hyperammonemia (NCH) is poorly understood and has a high morbidity and mortality. To elucidate the etiology and management of NCH, we performed a retrospective analysis of 23 adults (median age 51) with NCH treated between 2014 and 2020 at two academic medical centers. Hyperammonemia was diagnosed in all cases during the evaluation of altered mental status, with 22% presenting with seizures. Peak ammonia levels were >200 µmol/L in 70% of cases. Defects in ammonia metabolism were assessed using urea cycle biochemical testing, germline genetic testing, and testing for urease-producing infectious agents. Ammonia metabolism defects in these cases appear attributable to four major sources: (a) infection with urease-producing organism (n = 5); (b) previously undiagnosed inborn errors of metabolism (IEMs) (n = 4); (c) clinical exposures causing acquired urea cycle dysfunction (n = 6); and (d) unexplained acquired urea cycle dysfunction (uaUCD) (n = 8), as evidenced by biochemical signatures of urea cycle dysfunction without a genetic or clinical exposure. Severe protein malnutrition appeared to be a reversible risk factor for uaUCD. Overall, 13% of our cohort died prior to resolution of hyperammonemia, 26% died after hyperammonemia resolution, 57% survived after having reversible neurological changes, and 4% survived with irreversible neurological changes. Renal replacement therapy for ammonia clearance was often utilized for patients with an ammonia level above 250 µmol/L and patients were frequently empirically treated with antibiotics targeting urea-splitting organisms. Our study demonstrates that acquired urea cycle dysfunction, IEMs and urease-producing infections are major sources of adult-onset NCH and highlights successful management strategies for adult-onset NCH.