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Sample records for acute metabolic acidosis

  1. Metabolic acidosis.

    PubMed

    Lim, Salim

    2007-01-01

    Acute metabolic acidosis is frequently encountered in critically ill patients. Metabolic acidosis can occur as a result of either the accumulation of endogenous acids that consumes bicarbonate (high anion gap metabolic acidosis) or loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic or normal anion gap metabolic acidosis). The cause of high anion gap metabolic acidosis includes lactic acidosis, ketoacidosis, renal failure and intoxication with ethylene glycol, methanol, salicylate and less commonly with pyroglutamic acid (5-oxoproline), propylene glycole or djenkol bean (gjenkolism). The most common causes of hyperchloremic metabolic acidosis are gastrointestinal bicarbonate loss, renal tubular acidosis, drugs-induced hyperkalemia, early renal failure and administration of acids. The appropriate treatment of acute metabolic acidosis, in particular organic form of acidosis such as lactic acidosis, has been very controversial. The only effective treatment for organic acidosis is cessation of acid production via improvement of tissue oxygenation. Treatment of acute organic acidosis with sodium bicarbonate failed to reduce the morbidity and mortality despite improvement in acid-base parameters. Further studies are required to determine the optimal treatment strategies for acute metabolic acidosis.

  2. Metabolic acidosis

    MedlinePlus

    ... diarrhea. Lactic acidosis results from a buildup of lactic acid. It can be caused by: Alcohol Cancer Exercising ... functions) Urine pH Urine ketones or blood ketones Lactic acid test Arterial blood gas analysis Other tests may ...

  3. Characterisation of metabolic acidosis in Kenyan children admitted to hospital for acute non-surgical conditions.

    PubMed

    Sasi, P; English, M; Berkley, J; Lowe, B; Shebe, M; Mwakesi, R; Kokwaro, G

    2006-05-01

    Metabolic acidosis is associated with most severe malaria deaths in African children, and most deaths occur before maximum antimalarial action is achieved. Thus, specific acidosis treatment may reduce mortality. However, the underlying mechanisms remain poorly understood and no specific interventions have been developed. A detailed characterisation of this acidosis is critical in treatment development. We used the traditional and Stewart's approach to characterise acidosis in consecutive paediatric admissions for malaria and other acute non-surgical conditions to Kilifi District Hospital in Kenya. The overall acidosis prevalence was 21%. Gastroenteritis had the highest prevalence (61%). Both the mean albumin-corrected anion gap and the strong ion gap were high (>13 mmol/l and >0 mmol/l, respectively) in malaria, gastroenteritis, lower respiratory tract infection and malnutrition. Presence of salicylate in plasma was not associated with acidosis but was associated with signs of severe illness (odds ratio 2.11, 95% CI 1.1-4.2). In malaria, mean (95% CI) strong ion gap was 15 (14-7) mmol/l, and lactate, creatinine and inorganic phosphorous explained only approximately 40% of the variability in base excess (adjusted R2 = 0.397). Acidosis may be more common than previously recognised amongst paediatric admissions in Africa and is characterised by the presence of currently unidentified strong anions. In malaria, lactate and ketones, but not salicylate, are associated with acidosis. However, unidentified anions may be more important.

  4. Acute renal failure and metabolic acidosis due to oxalic acid intoxication: a case report.

    PubMed

    Yamamoto, Rie; Morita, Seiji; Aoki, Hiromichi; Nakagawa, Yoshihide; Yamamoto, Isotoshi; Inokuchi, Sadaki

    2011-12-20

    Most of the reports of oxalic acid intoxication are in cases of ethylene glycol intoxication. These symptoms are known to be central nerve system manifestations, cardiopulmonary manifestations and acute renal failure. There have been only a few reports of direct oxalic acid intoxication. However, there have been a few recent reports of oxalic acid intoxication due to the ingestion of star fruit and ascorbic acid. We herein report the case of a patient with acute renal failure and metabolic acidosis caused directly by consumption of oxalic acid. During the initial examination by the physician at our hospital, the patient presented with tachypnea, a precordinal burning sensation, nausea and metabolic acidosis. After admission, the patient developed renal failure and anion gap high metabolic acidosis, but did not develop any CNS or cardio-pulmonary manifestations in the clinical course. The patient benefitted symptomatically from hemodialysis.

  5. Successful Treatment of Severe Metabolic Acidosis Due to Acute Aluminum Phosphide Poisoning With Peritoneal Dialysis: a Report of 2 Cases.

    PubMed

    Bashardoust, Bahman; Farzaneh, Esmaeil; Habibzadeh, Afshin; Seyyed Sadeghi, Mir Salim

    2017-03-01

    Aluminum phosphide poisoning is common in our region. It can cause severe metabolic acidosis and persistent hypotension, which lead to cardiogenic shock and subsequently mortality. Oliguric or anuric acute kidney injury is seen in almost all patients with aluminum phosphide poisoning. Renal replacement therapies are recommended in these patients to improve metabolic acidosis and increase the rate of survival. We report 2 cases of severe acute aluminum phosphide poisoning treated successfully with peritoneal dialysis.

  6. Role of the endocrine pancreas in the kalemic response to acute metabolic acidosis in conscious dogs.

    PubMed

    Adrogué, H J; Chap, Z; Ishida, T; Field, J B

    1985-03-01

    Metabolic acidosis due to organic acids infusion fails to elicit hyperkalemia. Although plasma potassium levels may rise, the increase is smaller than in mineral acid acidosis. The mechanisms responsible for the different effects of organic acid acidosis and mineral acid acidosis remain undefined, although dissimilar hormonal responses by the pancreas may explain dissimilar hormonal responses by the pancreas may explain the phenomena. To test this hypothesis, beta-hydroxybutyric acid (7 meq/kg) or hydrochloric acid (3 meq/kg) was infused over 30 min into conscious dogs (n = 12) with chronically implanted catheters in the portal, hepatic, and systemic circulation, and flow probes were placed around the portal vein and hepatic artery. Acid infusion studies in two groups of anesthetized dogs were also done to assess the urinary excretion of potassium (n = 14), and to evaluate the effects of acute suppression of renal electrolyte excretion on plasma potassium and on the release/uptake of potassium in peripheral tissues of the hindleg (n = 17). Ketoacid infusion caused hypokalemia and a significant increase in portal vein plasma insulin, from the basal level of 27 +/- 4 microU/ml to a maximum of 84 +/- 22 microU/ml at 10 min, without changes in glucagon levels. By contrast, mineral acid acidosis of similar severity resulted in hyperkalemia and did not increase portal insulin levels but enhanced portal glucagon concentration from control values of 132 +/- 25 pg/ml to 251 +/- 39 pg/ml at 40 min. A significant decrease in plasma glucose levels due to suppression of hepatic release was observed during ketoacid infusion, while no changes were observed with mineral acid infusion. Plasma flows in the portal vein and hepatic artery remained unchanged from control values in both acid infusion studies. Differences in renal potassium excretion were ruled out as determinants of the disparate kalemic responses to organic acid infusion compared with HCl acidosis. Evaluation of the

  7. Drug-Induced Metabolic Acidosis

    PubMed Central

    Pham, Amy Quynh Trang; Xu, Li Hao Richie; Moe, Orson W.

    2015-01-01

    Metabolic acidosis could emerge from diseases disrupting acid-base equilibrium or from drugs that induce similar derangements. Occurrences are usually accompanied by comorbid conditions of drug-induced metabolic acidosis, and clinical outcomes may range from mild to fatal. It is imperative that clinicians not only are fully aware of the list of drugs that may lead to metabolic acidosis but also understand the underlying pathogenic mechanisms. In this review, we categorized drug-induced metabolic acidosis in terms of pathophysiological mechanisms, as well as individual drugs’ characteristics. PMID:26918138

  8. Topiramate and metabolic acidosis.

    PubMed

    Wilner, A; Raymond, K; Pollard, R

    1999-06-01

    Topiramate (TPM) is a novel antiepileptic medication (AED) with at least three mechanisms of action. A possible fourth mechanism, that of a carbonic anhydrase inhibitor, also may contribute to its antiepileptic properties. We report a patient with intractable epilepsy and normal renal function who developed a normal anion gap metabolic acidosis, which worsened during elective surgery for temporal lobectomy. We believe this side effect of TPM can become clinically significant during surgery, concomitant use of another carbonic anhydrase inhibitor, and potentially with the ketogenic diet.

  9. Acute but not chronic metabolic acidosis potentiates the acetylcholine-induced reduction in blood pressure: an endothelium-dependent effect.

    PubMed

    Celotto, A C; Ferreira, L G; Capellini, V K; Albuquerque, A A S; Rodrigues, A J; Evora, P R B

    2016-02-01

    Metabolic acidosis has profound effects on vascular tone. This study investigated the in vivo effects of acute metabolic acidosis (AMA) and chronic metabolic acidosis (CMA) on hemodynamic parameters and endothelial function. CMA was induced by ad libitum intake of 1% NH4Cl for 7 days, and AMA was induced by a 3-h infusion of 6 M NH4Cl (1 mL/kg, diluted 1:10). Phenylephrine (Phe) and acetylcholine (Ach) dose-response curves were performed by venous infusion with simultaneous venous and arterial blood pressure monitoring. Plasma nitrite/nitrate (NOx) was measured by chemiluminescence. The CMA group had a blood pH of 7.15±0.03, which was associated with reduced bicarbonate (13.8±0.98 mmol/L) and no change in the partial pressure of arterial carbon dioxide (PaCO2). The AMA group had a pH of 7.20±0.01, which was associated with decreases in bicarbonate (10.8±0.54 mmol/L) and PaCO2 (47.8±2.54 to 23.2±0.74 mmHg) and accompanied by hyperventilation. Phe or ACh infusion did not affect arterial or venous blood pressure in the CMA group. However, the ACh infusion decreased the arterial blood pressure (ΔBP: -28.0±2.35 mm Hg [AMA] to -4.5±2.89 mmHg [control]) in the AMA group. Plasma NOx was normal after CMA but increased after AMA (25.3±0.88 to 31.3±0.54 μM). These results indicate that AMA, but not CMA, potentiated the Ach-induced decrease in blood pressure and led to an increase in plasma NOx, reinforcing the effect of pH imbalance on vascular tone and blood pressure control.

  10. Diet-induced metabolic acidosis.

    PubMed

    Adeva, María M; Souto, Gema

    2011-08-01

    The modern Western-type diet is deficient in fruits and vegetables and contains excessive animal products, generating the accumulation of non-metabolizable anions and a lifespan state of overlooked metabolic acidosis, whose magnitude increases progressively with aging due to the physiological decline in kidney function. In response to this state of diet-derived metabolic acidosis, the kidney implements compensating mechanisms aimed to restore the acid-base balance, such as the removal of the non-metabolizable anions, the conservation of citrate, and the enhancement of kidney ammoniagenesis and urinary excretion of ammonium ions. These adaptive processes lower the urine pH and induce an extensive change in urine composition, including hypocitraturia, hypercalciuria, and nitrogen and phosphate wasting. Low urine pH predisposes to uric acid stone formation. Hypocitraturia and hypercalciuria are risk factors for calcium stone disease. Even a very mild degree of metabolic acidosis induces skeletal muscle resistance to the insulin action and dietary acid load may be an important variable in predicting the metabolic abnormalities and the cardiovascular risk of the general population, the overweight and obese persons, and other patient populations including diabetes and chronic kidney failure. High dietary acid load is more likely to result in diabetes and systemic hypertension and may increase the cardiovascular risk. Results of recent observational studies confirm an association between insulin resistance and metabolic acidosis markers, including low serum bicarbonate, high serum anion gap, hypocitraturia, and low urine pH.

  11. Sodium Bicarbonate Therapy in Patients with Metabolic Acidosis

    PubMed Central

    Adeva-Andany, María M.; Fernández-Fernández, Carlos; Mouriño-Bayolo, David; Castro-Quintela, Elvira; Domínguez-Montero, Alberto

    2014-01-01

    Metabolic acidosis occurs when a relative accumulation of plasma anions in excess of cations reduces plasma pH. Replacement of sodium bicarbonate to patients with sodium bicarbonate loss due to diarrhea or renal proximal tubular acidosis is useful, but there is no definite evidence that sodium bicarbonate administration to patients with acute metabolic acidosis, including diabetic ketoacidosis, lactic acidosis, septic shock, intraoperative metabolic acidosis, or cardiac arrest, is beneficial regarding clinical outcomes or mortality rate. Patients with advanced chronic kidney disease usually show metabolic acidosis due to increased unmeasured anions and hyperchloremia. It has been suggested that metabolic acidosis might have a negative impact on progression of kidney dysfunction and that sodium bicarbonate administration might attenuate this effect, but further evaluation is required to validate such a renoprotective strategy. Sodium bicarbonate is the predominant buffer used in dialysis fluids and patients on maintenance dialysis are subjected to a load of sodium bicarbonate during the sessions, suffering a transient metabolic alkalosis of variable severity. Side effects associated with sodium bicarbonate therapy include hypercapnia, hypokalemia, ionized hypocalcemia, and QTc interval prolongation. The potential impact of regular sodium bicarbonate therapy on worsening vascular calcifications in patients with chronic kidney disease has been insufficiently investigated. PMID:25405229

  12. Chronic metabolic acidosis destroys pancreas.

    PubMed

    Melamed, Peter; Melamed, Felix

    2014-11-28

    One primary reason for the current epidemic of digestive disorders might be chronic metabolic acidosis, which is extremely common in the modern population. Chronic metabolic acidosis primarily affects two alkaline digestive glands, the liver, and the pancreas, which produce alkaline bile and pancreatic juice with a large amount of bicarbonate. Even small acidic alterations in the bile and pancreatic juice pH can lead to serious biochemical/biomechanical changes. The pancreatic digestive enzymes require an alkaline milieu for proper function, and lowering the pH disables their activity. It can be the primary cause of indigestion. Acidification of the pancreatic juice decreases its antimicrobial activity, which can lead to intestinal dysbiosis. Lowering the pH of the pancreatic juice can cause premature activation of the proteases inside the pancreas with the potential development of pancreatitis. The acidification of bile causes precipitation of the bile acids, which irritate the entire biliary system and create bile stone formation. Aggressive mixture of the acidic bile and the pancreatic juice can cause erratic contractions of the duodenum's walls and subsequent bile reflux into the stomach and the esophagus. Normal exocrine pancreatic function is the core of proper digestion. Currently, there is no effective and safe treatment for enhancing the exocrine pancreatic function. Restoring normal acid-base homeostasis can be a useful tool for pathophysiological therapeutic approaches for various gastrointestinal disorders. There is strong research and practical evidence that restoring the HCO3(-) capacity in the blood can improve digestion.

  13. [Severe metabolic acidosis in an alcoholic].

    PubMed

    Sonne, Morten Egede; Rudolph, Søren Finnemann; Pott, Frank Christian

    2008-09-29

    Severe metabolic acidosis is associated with poor prognosis. We present a patient with profound alcohol and starvation-related combined lactic and keto acidosis (lactate = 29 mM; pH = 6.83) who made a good recovery following 18 hours of intensive care therapy. A brief summary of the proposed mechanism by which these metabolic derangements develop is presented.

  14. Bilateral putaminal necrosis in a comatose patient with metabolic acidosis

    PubMed Central

    Kumar, Sudhir; Reddy, Chenna Rajesh; Prabhakar, Subhashini

    2016-01-01

    We present a case of acute-onset coma in a young woman, associated with metabolic acidosis, respiratory distress, and hypotension. Magnetic resonance imaging of the brain done on day 2 of admission showed features of bilateral putaminal necrosis. History of methanol ingestion, though not forthcoming at admission, was confirmed later after the patient regained consciousness. A final diagnosis of methyl alcohol toxicity resulting in severe metabolic acidosis, coma, and bilateral blindness was made. This case is reported to emphasize the point that the finding of bilateral putaminal necrosis in a patient with coma and metabolic acidosis is virtually diagnostic of methyl alcohol toxicity even in the absence of any positive history. PMID:28149036

  15. Metabolic acidosis during parenteral nutrition: Pathophysiological mechanisms

    PubMed Central

    Dounousi, Evangelia; Zikou, Xanthi; Koulouras, Vasilis; Katopodis, Kostas

    2015-01-01

    Total parenteral nutrition (TPN) is associated with metabolic complications including metabolic acidosis (MA), one of the main disorders of acid-base balance. The main causes involved in the appearance of MA during TPN administration are the metabolism of cationic amino acids and amino acids containing sulfuric acid (exogenous addition), the titratable acidity of the infused parenteral solution, the addition of acidificant agents (hydrochloric acid, acetic acid), thiamine deficiency, disruption of carbohydrate and lipid metabolic pathways and D-fructose administration. Moreover, hypophosphatemia that appears during TPN therapy contributes significantly to the maintenance of MA. This review describes in a comprehensive way the pathophysiological mechanisms involved in the appearance of MA induced by intravenous administration of TPN products most commonly used in critically ill-patients. PMID:25983433

  16. Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress

    PubMed Central

    2013-01-01

    Background A variety of oncogenic and environmental factors alter tumor metabolism to serve the distinct cellular biosynthetic and bioenergetic needs present during oncogenesis. Extracellular acidosis is a common microenvironmental stress in solid tumors, but little is known about its metabolic influence, particularly when present in the absence of hypoxia. In order to characterize the extent of tumor cell metabolic adaptations to acidosis, we employed stable isotope tracers to examine how acidosis impacts glucose, glutamine, and palmitate metabolism in breast cancer cells exposed to extracellular acidosis. Results Acidosis increased both glutaminolysis and fatty acid β-oxidation, which contribute metabolic intermediates to drive the tricarboxylic acid cycle (TCA cycle) and ATP generation. Acidosis also led to a decoupling of glutaminolysis and novel glutathione (GSH) synthesis by repressing GCLC/GCLM expression. We further found that acidosis redirects glucose away from lactate production and towards the oxidative branch of the pentose phosphate pathway (PPP). These changes all serve to increase nicotinamide adenine dinucleotide phosphate (NADPH) production and counter the increase in reactive oxygen species (ROS) present under acidosis. The reduced novel GSH synthesis under acidosis may explain the increased demand for NADPH to recycle existing pools of GSH. Interestingly, acidosis also disconnected novel ribose synthesis from the oxidative PPP, seemingly to reroute PPP metabolites to the TCA cycle. Finally, we found that acidosis activates p53, which contributes to both the enhanced PPP and increased glutaminolysis, at least in part, through the induction of G6PD and GLS2 genes. Conclusions Acidosis alters the cellular metabolism of several major metabolites, which induces a significant degree of metabolic inflexibility. Cells exposed to acidosis largely rely upon mitochondrial metabolism for energy generation to the extent that metabolic intermediates are

  17. Acute isoniazid intoxication: an uncommon cause of convulsion, coma and acidosis.

    PubMed

    Uzman, Sinan; Uludağ Yanaral, Tümay; Toptaş, Mehmet; Koç, Alparslan; Taş, Aytül; Bican, Gülşen

    2013-01-01

    Despite the widespread use, suicidal ingestion of isoniazid is a rare condition in Turkey. We reported a case of acute isoniazid intoxication associated with alcohol intake presenting with convulsion, coma and metabolic acidosis. The patient was treated successfully with intravenous pyridoxine administration. Early recognation and appropriate treatment in the intensive care unit is very important to prevent mortality in patients with acute isoniazid toxicity.

  18. Acidosis

    MedlinePlus

    ... Respiratory acidosis develops when there is too much carbon dioxide (an acid) in the body. This type ... when the body is unable to remove enough carbon dioxide through breathing. Other names for respiratory acidosis ...

  19. Intractable metabolic acidosis in a patient with colovesical fistula.

    PubMed

    Pillinger, Toby; Abdelrahman, Mohamed; Jones, Gregory; D'Souza, Francis

    2012-11-23

    A 58-year-old female presented with urosepsis and faecaluria secondary to a colovesical fistula of diverticular aetiology. A plan was made for surgical repair of the fistula. Preoperatively the patient developed a hyperchloraemic metabolic acidosis, with hyperkalaemia and hyponatraemia. Renal function was normal, and a short synachten test ruled out Addison's disease. Postoperatively her acid-base physiology normalised in the absence of medical management, demonstrating that surgical intervention was responsible for resolution of the patient's metabolic acidosis. The mechanisms by which colovesical pathophysiology causes hyperchloraemic metabolic acidosis are discussed. Although diverticular disease is the most common cause of colovesical fistulae, this is the first report of such fistulae causing metabolic acidosis.

  20. Enterolobium contortisiliquum is a cause of acute ruminal acidosis in sheep.

    PubMed

    Pupin, Rayane C; Leal, Paula V; Lima, Stephanie C; Melo, Gleice Kelli A; Pott, Arnildo; Araújo, Marcelo A; Barros, Claudio S L; Lemos, Ricardo A A

    2017-02-01

    The ingestion of pods of Enterolobium contortisiliquum is associated with digestive disturbances, photosensitivity and abortion in domestic ruminants. This experiment was designed to test the hypothesis that digestive disturbances in this toxicosis are really caused by acute ruminal acidosis. Three sheep fed large doses (10-15 g/kg/body weight [bw]) of E. contortisiliquum pods developed ruminal acidosis and were treated with sodium bicarbonate to try to control this metabolic disturbance, thus providing additional evidence of the involvement of ruminal acidosis in the pathogenesis of toxicosis. Two of the sheep died, and one recovered after treatment. In the two sheep that developed severe signs of ruminal acidosis, the values of blood lactate were 18 mg/dL and 196.88 mg/dL, indicating metabolic acidosis as the cause of death. Additionally, four sheep developed elevated serum levels of aspartate aminotransferase and gamma glutamyl transferase, indicating that the pods had hepatotoxic effects. Necropsy findings included the accentuation of the hepatic lobular pattern and multiple focally extensive red areas in the rumen mucosa and on the surface of the liver. Repeated ingestion of small doses induced tolerance but did not induce cumulative effects. Histopathologically, the epithelial mucosa of the rumen and reticulum exhibited swollen and vacuolated epithelia with intraepithelial pustules. Focal ulceration of the mucosa was also observed. Multifocal vacuolar degeneration of hepatocytes and scattered individual hepatocellular necrosis were evident in the liver. We concluded that the main clinical manifestation of intoxication by E. contortisiliquum pods in sheep was acute ruminal lactic acidosis and metabolic acidosis. Ingestion of repeated sublethal doses could stimulate proliferation of the ruminal fauna that degrades the sugar present in the pods, and thereby prevent the occurrence of ruminal acidosis. The plant is also hepatotoxic, and no abortions were

  1. Citric acid ingestion: a life-threatening cause of metabolic acidosis.

    PubMed

    DeMars, C S; Hollister, K; Tomassoni, A; Himmelfarb, J; Halperin, M L

    2001-11-01

    We present a case that illustrates the acute (<6 hours) metabolic and hemodynamic effects of the ingestion of a massive oral citric acid load. The principal findings included metabolic acidosis accompanied by an increase in the plasma anion gap that was not caused by L -lactic acidosis, hyperkalemia, and the abrupt onset of hypotension. A unique feature was a dramatic clinical improvement when ionized calcium was infused. The case illustrates the importance of considering the properties of the conjugate base (anion) of the added acid because, in this instance, the citrate anion had a unique and life-threatening consequence (lower ionized calcium level) that was rapidly reversible.

  2. Ethylene glycol induces hyperoxaluria without metabolic acidosis in rats.

    PubMed

    Green, Mike L; Hatch, Marguerite; Freel, Robert W

    2005-09-01

    Ethylene glycol (EG) consumption is commonly employed as an experimental regimen to induce hyperoxaluria in animal models of calcium oxalate nephrolithiasis. This approach has, however, been criticized because EG overdose induces metabolic acidosis in humans. We tested the hypothesis that EG consumption (0.75% in drinking water for 4 wk) induces metabolic acidosis by comparing arterial blood gases, serum electrolytes, and urinary chemistries in five groups of Sprague-Dawley rats: normal controls (CON), those made hyperoxaluric (HYP) with EG administration, unilaterally nephrectomized controls (UNI), unilaterally nephrectomized rats fed EG (HRF), and a metabolic acidosis (MA) reference group imbibing sweetened drinking water (5% sucrose) containing 0.28 M NH4Cl. Arterial pH, plasma bicarbonate concentrations, anion gap, urinary pH, and the excretion of titratable acid, ammonium, phosphate, citrate, and calcium in HYP rats were not significantly different from CON rats, indicating that metabolic acidosis did not develop in HYP rats with two kidneys. Unilateral nephrectomy alone (UNI group) did not significantly affect arterial pH, plasma bicarbonate, anion gap, or urinary pH compared with CON rats; however, HRF rats exhibited some signs of a nascent acidosis in having an elevated anion gap, higher phosphate excretion, lower urinary pH, and an increase in titratable acid. Frank metabolic acidosis was observed in the MA rats: decreased arterial pH and plasma HCO3(-) concentration with lower urinary pH and citrate excretion with elevated excretion of ammonium, phosphate and, hence, titratable acid. We conclude that metabolic acidosis does not develop in conventional EG treatments but may ensue with renal insufficiency resulting from an oxalate load.

  3. Molecular and pathophysiologic mechanisms of hyperkalemic metabolic acidosis.

    PubMed

    DuBose, T D

    2000-01-01

    In summary, hyperkalemia may have a dramatic impact on ammonium production and excretion. Chronic hyperkalemia decreases ammonium production in the proximal tubule and whole kidney, inhibits absorption of NH4+ in the mTALH, reduces medullary interstitial concentrations of NH4+ and NH3, and decreases entry of NH4+ and NH3 into the medullary collecting duct. The potential for development of a hyperchloremic metabolic acidosis is greatly augmented when renal insufficiency with associated reduction in functional renal mass coexists with the hyperkalemia, or in the presence of aldosterone deficiency or resistance. Such a cascade of events helps to explain, in part, the hyperchloremic metabolic acidosis and reduction in net acid excretion characteristic of several experimental models of hyperkalemic-hyperchloremic metabolic acidosis including: obstructive nephropathy, selective aldosterone deficiency, and chronic amiloride administration (7.9).

  4. Molecular and pathophysiologic mechanisms of hyperkalemic metabolic acidosis.

    PubMed Central

    DuBose, T. D.

    2000-01-01

    In summary, hyperkalemia may have a dramatic impact on ammonium production and excretion. Chronic hyperkalemia decreases ammonium production in the proximal tubule and whole kidney, inhibits absorption of NH4+ in the mTALH, reduces medullary interstitial concentrations of NH4+ and NH3, and decreases entry of NH4+ and NH3 into the medullary collecting duct. The potential for development of a hyperchloremic metabolic acidosis is greatly augmented when renal insufficiency with associated reduction in functional renal mass coexists with the hyperkalemia, or in the presence of aldosterone deficiency or resistance. Such a cascade of events helps to explain, in part, the hyperchloremic metabolic acidosis and reduction in net acid excretion characteristic of several experimental models of hyperkalemic-hyperchloremic metabolic acidosis including: obstructive nephropathy, selective aldosterone deficiency, and chronic amiloride administration (7.9). PMID:10881337

  5. Ionized alkaline water: new strategy for management of metabolic acidosis in experimental animals.

    PubMed

    Abol-Enein, Hassan; Gheith, Osama A; Barakat, Nashwa; Nour, Eman; Sharaf, Abd-Elhameed

    2009-06-01

    Metabolic acidosis can occur as a result of either the accumulation of endogenous acids or loss of bicarbonate from the gastrointestinal tract or the kidney, which represent common causes of metabolic acidosis. The appropriate treatment of acute metabolic acidosis has been very controversial. Ionized alkaline water was not evaluated in such groups of patients in spite of its safety and reported benefits. So, we aimed to assess its efficacy in the management of metabolic acidosis in animal models. Two models of metabolic acidosis were created in dogs and rats. The first model of renal failure was induced by ligation of both ureters; and the second model was induced by urinary diversion to gut (gastrointestinal bicarbonate loss model). Both models were subjected to ionized alkaline water (orally and by hemodialysis). Dogs with renal failure were assigned to two groups according to the type of dialysate utilized during hemodialysis sessions, the first was utilizing alkaline water and the second was utilizing conventional water. Another two groups of animals with urinary diversion were arranged to receive oral alkaline water and tap water. In renal failure animal models, acid-base parameters improved significantly after hemodialysis with ionized alkaline water compared with the conventional water treated with reverse osmosis (RO). Similar results were observed in urinary diversion models as there was significant improvement of both the partial pressure of carbon dioxide and serum bicarbonate (P = 0.007 and 0.001 respectively) after utilizing alkaline water orally. Alkaline ionized water can be considered as a major safe strategy in the management of metabolic acidosis secondary to renal failure or dialysis or urinary diversion. Human studies are indicated in the near future to confirm this issue in humans.

  6. Starvation Ketoacidosis as a Cause of Unexplained Metabolic Acidosis in the Perioperative Period

    PubMed Central

    Mostert, Monique; Bonavia, Anthony

    2016-01-01

    Patient: Female, 24 Final Diagnosis: Starvation ketoacidosis Symptoms: None Medication: — Clinical Procedure: Lumbar laminectomy Specialty: Orthopedics and Traumatology Objective: Unusual clinical course Background: Besides providing anesthesia for surgery, the anesthesiologist’s role is to optimize the patient for surgery and for post-surgical recovery. This involves timely identification and treatment of medical comorbidities and abnormal laboratory values that could complicate the patient’s perioperative course. There are several potential causes of anion and non-anion gap metabolic acidosis in surgical patients, most of which could profoundly affect a patient’s surgical outcome. Thus, the presence of an acute acid-base disturbance requires a thorough workup, the results of which will influence the patient’s anesthetic management. Case Report: An otherwise-healthy 24-year-old female presented for elective spine surgery and was found to have metabolic acidosis, hypotension, and polyuria intraoperatively. Common causes of acute metabolic acidosis were investigated and systematically ruled out, including lactic acidosis, diabetic ketoacidosis, drug-induced ketoacidosis, ingestion of toxic alcohols (e.g., methanol, ethylene glycol), uremia, and acute renal failure. Laboratory workup was remarkable only for elevated serum and urinary ketone levels, believed to be secondary to starvation ketoacidosis. Due to the patient’s unexplained acid-base disturbance, she was kept intubated postoperatively to allow for further workup and management. Conclusions: Starvation ketoacidosis is not widely recognized as a perioperative entity, and it is not well described in the medical literature. Lack of anesthesiologist awareness about this disorder may complicate the differential diagnosis for acute intraoperative metabolic acidosis and lead to a prolonged postoperative stay and an increase in hospital costs. The short- and long-term implications of perioperative

  7. Unmeasured anions in metabolic acidosis: unravelling the mystery.

    PubMed

    Forni, Lui G; McKinnon, William; Hilton, Philip J

    2006-01-01

    In the critically ill, metabolic acidosis is a common observation and, in clinical practice, the cause of this derangement is often multi-factorial. Various measures are often employed to try and characterise the aetiology of metabolic acidosis, the most popular of which is the anion gap. The purpose of the anion gap can be perceived as a means by which the physician is alerted to the presence of unmeasured anions in plasma that contribute to the observed acidosis. In many cases, the causative ion may be easily identified, such as lactate, but often the causative ion(s) remain unidentified, even after exclusion of the 'classic' causes. We describe here the various attempts in the literature that have been made to address this observation and highlight recent studies that reveal potential sources of such hitherto unmeasured anions.

  8. Approach to the Treatment of Chronic Metabolic Acidosis in CKD.

    PubMed

    Raphael, Kalani L

    2016-04-01

    Chronic metabolic acidosis is not uncommon in patients with chronic kidney disease (CKD). Clinical practice guidelines suggest that clinicians administer alkali to maintain serum bicarbonate level at a minimum of 22 mEq/L to prevent the effects of acidosis on bone demineralization and protein catabolism. Small interventional studies support the notion that correcting acidosis slows CKD progression as well. Furthermore, alkaline therapy in persons with CKD and normal bicarbonate levels may also preserve kidney function. Observational studies suggest that targeting a serum bicarbonate level near 28 mEq/L may improve clinical outcomes above and beyond targeting a value ≥ 22 mEq/L, yet values > 26 mEq/L have been reported to be associated with incident heart failure and mortality in the CRIC (Chronic Renal Insufficiency Cohort) Study. Furthermore, correcting acidosis may provoke vascular calcification. This teaching case discusses several uncertainties regarding the management of acidosis in CKD, such as when to initiate alkali treatment, potential side effects of alkali, and the optimum serum bicarbonate level based on current evidence in CKD. Suggestions regarding the maximum sodium bicarbonate dose to administer to patients with CKD to achieve the target serum bicarbonate concentration are offered.

  9. Mild metabolic acidosis impairs the β-adrenergic response in isolated human failing myocardium

    PubMed Central

    2012-01-01

    Introduction Pronounced extracellular acidosis reduces both cardiac contractility and the β-adrenergic response. In the past, this was shown in some studies using animal models. However, few data exist regarding how the human end-stage failing myocardium, in which compensatory mechanisms are exhausted, reacts to acute mild metabolic acidosis. The aim of this study was to investigate the effect of mild metabolic acidosis on contractility and the β-adrenergic response of isolated trabeculae from human end-stage failing hearts. Methods Intact isometrically twitching trabeculae isolated from patients with end-stage heart failure were exposed to mild metabolic acidosis (pH 7.20). Trabeculae were stimulated at increasing frequencies and finally exposed to increasing concentrations of isoproterenol (0 to 1 × 10-6 M). Results A mild metabolic acidosis caused a depression in twitch-force amplitude of 26% (12.1 ± 1.9 to 9.0 ± 1.5 mN/mm2; n = 12; P < 0.01) as compared with pH 7.40. Force-frequency relation measurements yielded no further significant differences of twitch force. At the maximal isoproterenol concentration, the force amplitude was comparable in each of the two groups (pH 7.40 versus pH 7.20). However, the half-maximal effective concentration (EC50) was significantly increased in the acidosis group, with an EC50 of 5.834 × 10-8 M (confidence interval (CI), 3.48 × 10-8 to 9.779 × 10-8; n = 9), compared with the control group, which had an EC50 of 1.056 × 10-8 M (CI, 2.626 × 10-9 to 4.243 × 10-8; n = 10; P < 0.05), indicating an impaired β-adrenergic force response. Conclusions Our data show that mild metabolic acidosis reduces cardiac contractility and significantly impairs the β-adrenergic force response in human failing myocardium. Thus, our results could contribute to the still-controversial discussion about the therapy regimen of acidosis in patients with critical heart failure. PMID:22889236

  10. Thyroid hormones changes in infants and children with metabolic acidosis.

    PubMed

    Tahirović, H F

    1991-10-01

    The influence of the acidotic state on the thyroxine (T4) peripheral metabolism was studied in two different forms of metabolic acidosis, ie infantile diarrhea and diabetic ketoacidosis. The serum concentrations of T4, free T4 (FT4), triiodothyronine (T3), reverse T3 (rT3), thyrotropin (TSH) and thyroxine-binding globulin (TBG) were measured and compared to healthy control groups. Lower T4 and T3 and higher rT3 serum concentrations were found in both tested groups of patients in relation to the control groups. In infants with severe metabolic acidosis FT4 values were lower than those observed in the control group. In addition, serum TBG levels were lower in diabetic patients as compared to control subjects. Despite the reduced serum T3 and T4 concentrations in both groups of patients, TSH concentrations, were within the normal range. Therefore, we concluded that acidosis caused either by diarrhea (not so far described) or by diabetes mellitus (well documented up to now) affects the thyroid hormones metabolism in a similar way, at least as far as the thyroid hormones blood levels are concerned.

  11. Metabolic Acidosis in a Pediatric Patient Receiving Topiramate

    PubMed Central

    Malik, Razia; Iacoune, John

    2003-01-01

    Topiramate is an anticonvulsant that is labeled for the management of several seizure types in children >2 years of age. With the exception of cognitive dysfunction, nephrolithiasis, weight loss, and paresthesia, adverse effects in children are similar to other those noted with other anticonvulsants. We describe a 33-month-old child with complex partial seizures and secondary generalization who received topiramate 45 mg orally twice daily (6.2 mg/kg/d) for approximately 4 weeks before admission. He developed asymptomatic metabolic acidosis that was evidenced by a decrease in HCO3−, which was unresponsive to treatment with sodium bicarbonate. The child was weaned off topiramate and the metabolic acidosis resolved 48 hours after its discontinuation. PMID:23118685

  12. Proximal renal tubular acidosis

    MedlinePlus

    ... References Krapf R, Seldin DW, Alpern RJ. Clinical syndromes of metabolic acidosis. In: Alpern RJ, Caplan M, Moe OW, ... 529. Read More Distal renal tubular acidosis Fanconi syndrome Low potassium level Metabolic acidosis Osteomalacia Respiratory acidosis Rickets Review Date 10/ ...

  13. Krebs cycle anions in metabolic acidosis.

    PubMed

    Bowling, Francis G; Morgan, Thomas J

    2005-10-05

    For many years it has been apparent from estimates of the anion gap and the strong ion gap that anions of unknown identity can be generated in sepsis and shock states. Evidence is emerging that at least some of these are intermediates of the citric acid cycle. The exact source of this disturbance remains unclear, because a great many metabolic blocks and bottlenecks can disturb the anaplerotic and cataplerotic pathways that enter and leave the cycle. These mechanisms require clarification with the use of tools such as gas chromatography-mass spectrometry.

  14. High Anion Gap Metabolic Acidosis after a Suicide Attempt with Cyanide: The Rebirth of Cyanide Poisoning.

    PubMed

    Hsiao, Po-Jen; Chang, Che-Fu; Chiu, Chih-Chien; Chan, Jenq-Shyong; Chiang, Wen-Fang; Wu, Chia-Chao; Lin, Shih-Hua; Chen, Jin-Shuen

    2015-01-01

    A 33-year-old woman was admitted to our emergency department in a state of unconsciousness after attempting suicide with unknown substances. Severe metabolic acidosis (pH: 6.81), with a high anion gap (36.2) and high lactate level (20.2 mmol/L), was observed. After four hours of intensive medical treatment, the patient regained consciousness, with a return of the arterial pH to 7.42. Finally, cyanide intoxication was diagnosed based on the detection of a serum cyanide level of 3.5 mg/L. The presence of a high anion gap associated with severe lactic acidosis is a clue for making a rapid differential diagnosis of acute cyanide intoxication. Providing intensive and immediate supportive management is also crucial, even in cases without obtainable specific antidotes.

  15. [Metformin-associated lactic acidosis and acute kidney injury].

    PubMed

    Greco, Paolo; Regolisti, Giuseppe; Antoniotti, Riccardo; Maccari, Caterina; Parenti, Elisabetta; Corrado, Silvia; Fiaccadori, Enrico

    2016-01-01

    Metformin is recommended as the treatment of choice in patients with type 2 diabetes mellitus because of its efficacy, general tolerability and low cost. Recent guidelines have extended the use of metformin to patients with Chronic Kidney Disease (CKD) up to stage III. However, in the recent literature, cases of MALA (metformin-associated lactic acidosis) are increasingly reported. MALA is the most dangerous side effect of the drug, with an incidence rate of 2-9 cases per 100000 person-years of exposure. We report on two patients with accidental metformin overdose, severe lactic acidosis and acute kidney injury. In both cases, the usual dose of metformin was inappropriate with respect to the level of kidney dysfunction (CKD stage III). As both patients met the criteria for renal replacement therapy in metformin poisoning, they were treated effectively with sustained low-efficiency dialysis until normalization of serum lactate and bicarbonate values. Clinical status and kidney function improved and both patients could be discharged from the hospital.

  16. Metabolic acidosis mimicking diabetic ketoacidosis after use of calorie-free mineral water.

    PubMed

    Dahl, Gry T; Woldseth, Berit; Lindemann, Rolf

    2012-09-01

    A previously healthy boy was admitted with fever, tachycardia, dyspnea, and was vomiting. A blood test showed a severe metabolic acidosis with pH 7.08 and an anion gap of 36 mmol/L. His urine had an odor of acetone. The serum glucose was 5.6 mmol/L, and no glucosuria was found. Diabetic ketoacidosis could therefore be eliminated. Lactate level was normal. Tests for the most common metabolic diseases were negative. Because of herpes stomatitis, the boy had lost appetite and only been drinking Diet Coke and water the last days. Diet Coke or Coca-Cola Light is sweetened with a blend containing cyclamates, aspartame, and acesulfame potassium, all free of calories. The etiology of the metabolic acidosis appeared to be a catabolic situation exaggerated by fasting with no intake of calories. The elevated anion gap was due to a severe starvation ketoacidosis, mimicking a diabetic ketoacidosis. Pediatricians should recommend carbohydrate/calorie-containing fluids for rehydration of children with acute fever, diarrhea, or illness.

  17. Lactate versus non-lactate metabolic acidosis: a retrospective outcome evaluation of critically ill patients

    PubMed Central

    Gunnerson, Kyle J; Saul, Melissa; He, Shui; Kellum, John A

    2006-01-01

    Introduction Acid–base abnormalities are common in the intensive care unit (ICU). Differences in outcome exist between respiratory and metabolic acidosis in similar pH ranges. Some forms of metabolic acidosis (for example, lactate) seem to have worse outcomes than others (for example, chloride). The relative incidence of each type of disorder is unknown. We therefore designed this study to determine the nature and clinical significance of metabolic acidosis in critically ill patients. Methods An observational, cohort study of critically ill patients was performed in a tertiary care hospital. Critically ill patients were selected on the clinical suspicion of the presence of lactic acidosis. The inpatient mortality of the entire group was 14%, with a length of stay in hospital of 12 days and a length of stay in the ICU of 5.8 days. Results We reviewed records of 9,799 patients admitted to the ICUs at our institution between 1 January 2001 and 30 June 2002. We selected a cohort in which clinicians caring for patients ordered a measurement of arterial lactate level. We excluded patients in which any necessary variable required to characterize an acid–base disorder was absent. A total of 851 patients (9% of ICU admissions) met our criteria. Of these, 548 patients (64%) had a metabolic acidosis (standard base excess < -2 mEq/l) and these patients had a 45% mortality, compared with 25% for those with no metabolic acidosis (p < 0.001). We then subclassified metabolic acidosis cases on the basis of the predominant anion present (lactate, chloride, or all other anions). The mortality rate was highest for lactic acidosis (56%); for strong ion gap (SIG) acidosis it was 39% and for hyperchloremic acidosis 29% (p < 0.001). A stepwise logistic regression model identified serum lactate, SIG, phosphate, and age as independent predictors of mortality. Conclusion In critically ill patients in which a measurement of lactate level was ordered, lactate and SIG were strong

  18. Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism.

    PubMed Central

    May, R C; Kelly, R A; Mitch, W E

    1986-01-01

    Metabolic acidosis is associated with enhanced renal ammonia-genesis which is regulated, in part, by glucocorticoids. The interaction between glucocorticoids and chronic metabolic acidosis on nitrogen utilization and muscle protein metabolism is unknown. In rats pair-fed by gavage, we found that chronic acidosis stunted growth and caused a 43% increase in urinary nitrogen and an 87% increase in urinary corticosterone. Net protein degradation in incubated epitrochlearis muscles from chronically acidotic rats was stimulated at all concentrations of insulin from 0 to 10(4) microU/ml. This effect of acidosis persisted despite supplementation of the media with amino acids with or without insulin, indomethacin, and inhibitors of lysosomal thiol cathepsins. Acidosis did not change protein synthesis; hence, the increase in net protein degradation was caused by stimulation of proteolysis. Acidosis did not increase glutamine production in muscle. The protein catabolic effect of acidosis required glucocorticoids; protein degradation was stimulated in muscle of acidotic, adrenalectomized rats only if they were treated with dexamethasone. Moreover, when nonacidotic animals were given 3 micrograms/100 g of body weight dexamethasone twice a day, muscle protein degradation was increased if the muscles were simply incubated in acidified media. We conclude that chronic metabolic acidosis depresses nitrogen utilization and increases glucocorticoid production. The combination of increased glucocorticoids and acidosis stimulates muscle proteolysis but does not affect protein synthesis. These changes in muscle protein metabolism may play a role in the defense against acidosis by providing amino acid nitrogen to support the glutamine production necessary for renal ammoniagenesis. PMID:3511100

  19. Treatment of Metformin Intoxication Complicated by Lactic Acidosis and Acute Kidney Injury: The Role of Prolonged Intermittent Hemodialysis.

    PubMed

    Regolisti, Giuseppe; Antoniotti, Riccardo; Fani, Filippo; Greco, Paolo; Fiaccadori, Enrico

    2017-02-17

    Metformin intoxication with lactic acidosis, a potentially lethal condition, may develop in diabetic patients when the drug dose is inappropriate and/or its clearance is reduced. Diagnosis and therapy may be delayed due to nonspecific symptoms at presentation, with severe anion gap metabolic acidosis and elevated serum creatinine values being the most prominent laboratory findings. Confirmation requires measurement of serum metformin by high-performance liquid chromatography-tandem mass spectrometry, but this technique is available only at specialized institutions and cannot be relied on as a guide to immediate treatment. Thus, based on strong clinical suspicion, renal replacement therapy must be started promptly to achieve efficient drug clearance and correct the metabolic acidosis. However, because metformin accumulates in the intracellular compartment with prolonged treatment, a rebound in serum concentrations due to redistribution is expected at the end of dialysis. We report a case of metformin intoxication, severe lactic acidosis, and acute kidney injury in a diabetic patient with pre-existing chronic kidney disease stage 3, treated effectively with sustained low-efficiency dialysis. We discuss the pathophysiology, differential diagnosis, and treatment options and highlight specific pharmacokinetic issues that should be considered in selecting the appropriate modality of renal replacement therapy.

  20. Hyperchloremic Metabolic Acidosis Following Total Gut Irrigation with Normal Saline in Pediatric Patients: A Rare Occurrence

    PubMed Central

    Bala, Indu; Dwivedi, Deepak; Jain, Divya; Mahajan, Jai Kumar

    2017-01-01

    Use of 0.9% sodium chloride for total gut irrigation (TGI) through nasogastric route is an effective method of bowel preparation in children undergoing colorectal surgeries. TGI with normal saline (NS) can result in nausea, vomiting, abdominal distension, and mild electrolyte imbalance; however, hyperchloremic metabolic acidosis has not been documented. We report two cases of hyperchloremic metabolic acidosis in children posted for colorectal surgery following TGI with NS who were successfully managed. PMID:28197054

  1. Citrate metabolism in blood transfusions and its relationship due to metabolic alkalosis and respiratory acidosis

    PubMed Central

    Li, Kai; Xu, Yuan

    2015-01-01

    Metabolic alkalosis commonly results from excessive hydrochloric acid (HCl), potassium (K+) and water (H2O) loss from the stomach or through the urine. The plasma anion gap increases in non-hypoproteinemic metabolic alkalosis due to an increased negative charge equivalent on albumin and the free ionized calcium (Ca++) content of plasma decreases. The mean citrate load in all patients was 8740±7027 mg from 6937±6603 mL of transfused blood products. The citrate load was significantly higher in patients with alkalosis (9164±4870 vs. 7809±3967, P < 0.05). The estimated mean total citrate administered via blood and blood products was calculated as 43.2±34.19 mg/kilogram/day. In non-massive and frequent blood transfusions, the elevated carbon dioxide output has been shown to occur. Due to citrate metabolism causes intracellular acidosis. As a result of intracellular acidosis compensation, decompensated metabolic alkalosis + respiratory acidosis and electrolyte imbalance may develop, blood transfusions may result in certain complications. PMID:26131288

  2. Effect of acidosis on skeletal muscle metabolism with and without propranolol.

    PubMed

    Barclay, J K; Graham, T E; Wolfe, B R; Van Dijk, J; Wilson, B A

    1990-07-01

    Does the stimulatory effect of circulating catecholamines counteract the inhibitory effect of acidosis on skeletal muscle metabolism? To investigate this possibility, we studied gastrocnemii in dogs breathing either air (n = 10) or 4% carbon dioxide in air (n = 10) at rest and during contractions. In five dogs from each group, we infused propranolol into the arterial supply of the right and left muscles for 40 min. After 30 min of infusion, the left muscle was stimulated at 3 Hz for 10 min. During the 10th min of contractions, we removed and froze both muscles in liquid nitrogen. Oxygen uptake and blood flow to the left muscle prior to or during stimulation was not affected by acidosis either with or without propranolol. Glycogen concentration in resting muscle was unaffected by acidosis with or without propranolol. There was an acidosis related decrease of approximately 50% in the glycolytic intermediates (glucose 6-phosphate, fructose 1,6-diphosphate, alpha-glycerol phosphate, and dihydroxyacetone phosphate) in unstimulated muscles without beta-blockade. At rest, acidosis decreased muscle lactate by 50% with and 64% without propranolol, but lactate release was decreased only with acidosis without propranolol (1.4-0.1 mumols/kg.s). Acidosis without propranolol had no effect on the changes in glycogen concentration or the change in the concentration of glycolytic intermediates resulting from contractions. In beta-blocked muscle, the difference between stimulated and unstimulated concentrations of glycogen and glycolytic intermediates including lactate was 20-50% smaller with acidosis. Thus, with beta-blockade, the acidotic effects at rest disappeared and an inhibition of the metabolic adjustment to contractions appeared, indicating that circulating catecholamines do modify some metabolic effects of acidosis.

  3. Clinical significance of the fractional excretion of anions in metabolic acidosis.

    PubMed

    Kim, H Y; Han, J S; Jeon, U S; Joo, K W; Earm, J H; Ahn, C; Kim, S; Lee, J S; Kim, G H

    2001-06-01

    The fractional excretion of anions has been proposed as a new index for the differential diagnosis of metabolic acidosis, identifying the properties of the conjugate base by examining the renal handling of the anion. Here, we investigated clinical significance of the fractional excretion of anions in pathophysiologic diagnosis of metabolic acidosis by measuring urine ammonium (NH4+) excretion, the ratio of A plasma anion gap/delta plasma HCO3- concentration (deltaAG/deltaHCO3-), and fractional excretion of anions in three different groups of metabolic acidosis: acid overproduction (8 patients with lactic acidosis, 8 with diabetic ketoacidosis, 3 with hippuric acidosis following glue sniffing), acid underexcretion (10 patients with chronic renal failure) and normal controls (10 normal volunteers who underwent 3-day NH4Cl loading). As expected, urine NH4+ excretion was higher in overproduction acidosis than in acid-loaded normal controls (88.1 +/- 12.3 vs. 54.0 +/- 3.7 mmol/day, p < 0.05), and it was lower in chronic renal failure than in acid-loaded normal controls (12.8 +/- 1.7 vs. 54.0 +/- 3.7 mmol/day, p < 0.05). The fractional excretion of anions had no difference between overproduction acidosis and chronic renal failure (41.2 +/- 42.8% vs. 41.0 +/- 8.1%). However, the fractional excretion of anions showed significant differences between the subgroups in acid overproduction (lactic acidosis, 4.7 +/- 0.3%; diabetic ketoacidosis, 45.8 +/- 3.1%; hippuric acidosis, 126.0 +/- 14.4%; p < 0.05). The ratio of plasma deltaAG/deltaHCO3- also exhibited significant differences between the subgroups in acid overproduction (lactic acidosis, 1.5 +/- 0.1; diabetic ketoacidosis, 1.0 +/- 0.1; hippuric acidosis, 0.3 +/- 0.1; p < 0.05). There was an inverse linear correlation between the fractional excretion of anions and the ratio of plasma deltaAG/deltaHCO3- (r2 =-0.89, p < 0.05). In conclusion, determination of the fractional excretion of anions may provide a useful clue to the

  4. Endocrine and metabolic emergencies in children: hypocalcemia, hypoglycemia, adrenal insufficiency, and metabolic acidosis including diabetic ketoacidosis

    PubMed Central

    2015-01-01

    It is important to fast diagnosis and management of the pediatric patients of the endocrine metabolic emergencies because the signs and symptoms of these disorders are nonspecific. Delayed diagnosis and treatment may lead to serious consequences of the pediatric patients, for example, cerebral dysfunction leading to coma or death of the patients with hypoglycemia, hypocalcemia, adrenal insufficiency, or diabetic ketoacidosis. The index of suspicion of the endocrine metabolic emergencies should be preceded prior to the starting nonspecific treatment. Importantly, proper diagnosis depends on the collection of blood and urine specimen before nonspecific therapy (intravenous hydration, electrolytes, glucose or calcium injection). At the same time, the taking of precise history and searching for pathognomonic physical findings should be performed. This review was described for fast diagnosis and proper management of hypoglycemic emergencies, hypocalcemia, adrenal insufficiency, and metabolic acidosis including diabetic ketoacidosis. PMID:26817004

  5. Autophagic Clearance of Mitochondria in the Kidney Copes with Metabolic Acidosis

    PubMed Central

    Namba, Tomoko; Takabatake, Yoshitsugu; Kimura, Tomonori; Takahashi, Atsushi; Yamamoto, Takeshi; Matsuda, Jun; Kitamura, Harumi; Niimura, Fumio; Matsusaka, Taiji; Iwatani, Hirotsugu; Matsui, Isao; Kaimori, Junya; Kioka, Hidetaka; Rakugi, Hiromi

    2014-01-01

    Metabolic acidosis, a common complication of CKD, causes mitochondrial stress by undefined mechanisms. Selective autophagy of impaired mitochondria, called mitophagy, contributes toward maintaining cellular homeostasis in various settings. We hypothesized that mitophagy is involved in proximal tubular cell adaptations to chronic metabolic acidosis. In transgenic mice expressing green fluorescent protein–tagged microtubule-associated protein 1 light chain 3 (GFP-LC3), NH4Cl loading increased the number of GFP puncta exclusively in the proximal tubule. In vitro, culture in acidic medium produced similar results in proximal tubular cell lines stably expressing GFP-LC3 and facilitated the degradation of SQSTM1/p62 in wild-type cells, indicating enhanced autophagic flux. Upon acid loading, proximal tubule–specific autophagy-deficient (Atg5-deficient) mice displayed significantly reduced ammonium production and severe metabolic acidosis compared with wild-type mice. In vitro and in vivo, acid loading caused Atg5-deficient proximal tubular cells to exhibit reduced mitochondrial respiratory chain activity, reduced mitochondrial membrane potential, and fragmented morphology with marked swelling in mitochondria. GFP-LC3–tagged autophagosomes colocalized with ubiquitinated mitochondria in proximal tubular cells cultured in acidic medium, suggesting that metabolic acidosis induces mitophagy. Furthermore, restoration of Atg5-intact nuclei in Atg5-deficient proximal tubular cells increased mitochondrial membrane potential and ammoniagenesis. In conclusion, metabolic acidosis induces autophagy in proximal tubular cells, which is indispensable for maintaining proper mitochondrial functions including ammoniagenesis, and thus for adapted urinary acid excretion. Our results provide a rationale for the beneficial effect of alkali supplementation in CKD, a condition in which autophagy may be reduced, and suggest a new therapeutic option for acidosis by modulating autophagy. PMID

  6. Aluminum phosphide poisoning: effect of correction of severe metabolic acidosis on patient outcome.

    PubMed

    Jaiswal, S; Verma, R K; Tewari, N

    2009-01-01

    Forty patients of aluminum phosphide poisoning who were admitted to the ICU of Sir Sunder Lal Hospital, Banaras Hindu University, were studied. Restlessness, excessive thirst, shock, arrhythmias, tachypnoea, and severe metabolic acidosis were the common clinical findings. Only repeated and full correction with intravenous sodium bicarbonate was able to cope up with the severity and rapidity of acidosis. There was no significant change in blood pressure, pulse rate, and respiratory rate after full correction but gradually pulse and systolic blood pressure settled after ionotropic support in the survivors. There was significant improvement from 30.36% in the case when only half correction was done, as has been the common practice, to 57.5%, when full correction of metabolic acidosis was done.

  7. Grocery store baking soda. A source of sodium bicarbonate in the management of chronic metabolic acidosis.

    PubMed

    Booth, B E; Gates, J; Morris, R C

    1984-02-01

    Oral sodium bicarbonate is used to treat metabolic acidosis in patients with renal tubular acidosis. Since infants and young children are unable to swallow tablets, those affected must ingest sodium bicarbonate in a powder or liquid form. Pharmacy-weighed sodium bicarbonate is expensive and inconvenient to obtain; some pharmacists are reluctant to provide it. We determined that the sodium bicarbonate contained in 8-oz boxes of Arm and Hammer Baking Soda was sufficiently constant in weight that, dissolved in water to a given volume, it yielded a quantitatively acceptable therapeutic solution of sodium bicarbonate at a cost of approximately 3 percent of that of pharmacy-weighed sodium bicarbonate. Grocery store baking soda can be a safe, economical, and convenient source of sodium bicarbonate for the treatment of chronic metabolic acidosis in infants and young children.

  8. [Gastric emptying and metabolic acidosis. III. Study of gastric retention of a sodium citrate solution using an experimental model of metabolic acidosis in rats].

    PubMed

    Baracat, E C; Collares, E F

    1992-01-01

    The gastric emptying of sodium citrate solution 0.25 mEq/ml was studied in rats with metabolic acidosis induced by orogastric infusion of 0.5 M ammonium chloride solution. Two control groups were used: one infused with 0.5 M sodium chloride and the other with water. The 3 solutions content was 2 ml/100 g weight of the animal. Six hours after the infusion, there was a moderate metabolic acidosis in the group with ammonium citrate. This 6 hour interval marked the beginning of the gastric emptying study. The test meal (sodium citrate 0.25 mEq/ml) was utilized containing 6 mg% red fenol as a marker. The gastric emptying of sodium citrate was studied at 5, 10, 20 and 30 minutes after the infusion, and the results showed no differences between the 3 groups. The data suggest that the duodenal receptors to pH were more effective do determine the pattern of gastric response than the acidosis.

  9. Propylene Glycol Poisoning From Excess Whiskey Ingestion: A Case of High Osmolal Gap Metabolic Acidosis.

    PubMed

    Cunningham, Courtney A; Ku, Kevin; Sue, Gloria R

    2015-01-01

    In this report, we describe a case of high anion gap metabolic acidosis with a significant osmolal gap attributed to the ingestion of liquor containing propylene glycol. Recently, several reports have characterized severe lactic acidosis occurring in the setting of iatrogenic unintentional overdosing of medications that use propylene glycol as a diluent, including lorazepam and diazepam. To date, no studies have explored potential effects of excess propylene glycol in the setting of alcohol intoxication. Our patient endorsed drinking large volumes of cinnamon flavored whiskey, which was likely Fireball Cinnamon Whisky. To our knowledge, this is the first case of propylene glycol toxicity from an intentional ingestion of liquor containing propylene glycol.

  10. Severe lactic acidosis and acute pancreatitis associated with cimetidine in a patient with type 2 diabetes mellitus taking metformin.

    PubMed

    Seo, Ji Ho; Lee, Da Young; Hong, Chang Woo; Lee, In Hee; Ahn, Ki Sung; Kang, Gun Woo

    2013-01-01

    An 82-year-old woman with type 2 diabetes mellitus, hypertension, and unstable angina presented with severe lactic acidosis and acute kidney injury (AKI) accompanied by acute pancreatitis. Her medical history revealed that she had taken cimetidine for two weeks while taking other medications, including metformin. Continuous veno-venous hemodiafiltration (CVVHDF) was initiated under diagnosis of lactic acidosis due to metformin and AKI caused by cimetidine-induced acute pancreatitis. In three days of CVVHDF, the levels of serum biochemical markers of lactic acidosis and AKI improved and the patient's urine output reached over 1 L/day. The pancreatitis improved over time.

  11. Proximal tubule-specific glutamine synthetase deletion alters basal and acidosis-stimulated ammonia metabolism.

    PubMed

    Lee, Hyun-Wook; Osis, Gunars; Handlogten, Mary E; Lamers, Wouter H; Chaudhry, Farrukh A; Verlander, Jill W; Weiner, I David

    2016-06-01

    Glutamine synthetase (GS) catalyzes the recycling of NH4 (+) with glutamate to form glutamine. GS is highly expressed in the renal proximal tubule (PT), suggesting ammonia recycling via GS could decrease net ammoniagenesis and thereby limit ammonia available for net acid excretion. The purpose of the present study was to determine the role of PT GS in ammonia metabolism under basal conditions and during metabolic acidosis. We generated mice with PT-specific GS deletion (PT-GS-KO) using Cre-loxP techniques. Under basal conditions, PT-GS-KO increased urinary ammonia excretion significantly. Increased ammonia excretion occurred despite decreased expression of key proteins involved in renal ammonia generation. After the induction of metabolic acidosis, the ability to increase ammonia excretion was impaired significantly by PT-GS-KO. The blunted increase in ammonia excretion occurred despite greater expression of multiple components of ammonia generation, including SN1 (Slc38a3), phosphate-dependent glutaminase, phosphoenolpyruvate carboxykinase, and Na(+)-coupled electrogenic bicarbonate cotransporter. We conclude that 1) GS-mediated ammonia recycling in the PT contributes to both basal and acidosis-stimulated ammonia metabolism and 2) adaptive changes in other proteins involved in ammonia metabolism occur in response to PT-GS-KO and cause an underestimation of the role of PT GS expression.

  12. Branched-chain amino acid metabolism in rat muscle: abnormal regulation in acidosis

    SciTech Connect

    May, R.C.; Hara, Y.; Kelly, R.A.; Block, K.P.; Buse, M.G.; Mitch, W.E.

    1987-06-01

    Branched-chain amino acid (BCAA) metabolism is frequently abnormal in pathological conditions accompanied by chronic metabolic acidosis. To study how metabolic acidosis affects BCAA metabolism in muscle, rats were gavage fed a 14% protein diet with or without 4 mmol NH/sub 4/Cl x 100 g body wt/sup -1/ x day/sup -1/. Epitrochlearis muscles were incubated with L-(1-/sup 14/C)-valine and L-(1-/sup 14/C)leucine, and rates of decarboxylation, net transamination, and incorporation into muscle protein were measured. Plasma and muscle BCAA levels were lower in acidotic rats. Rates of valine and leucine decarboxylation and net transamination were higher in muscles from acidotic rats; these differences were associated with a 79% increase in the total activity of branched-chain ..cap alpha..-keto acid dehydrogenase and a 146% increase in the activated form of the enzyme. They conclude that acidosis affects the regulation of BCAA metabolism by enhancing flux through the transaminase and by directly stimulating oxidative catabolism through activation of branched-chain ..cap alpha..-keto acid dehydrogenase.

  13. Uncoventional Views on Certain Aspects of Toxin-Induced Metabolic Acidosis

    PubMed Central

    2010-01-01

    This discussion will highlight the following 9 specific points that related to metabolic acidosis caused by various toxins. The current recommendation suggests that alcohol dehydrogenase inhibitor fomepizole is preferred to ethanol in treatment of methanol and ethylene glycol poisoning, but analysis of the enzyme kinetics indicates that ethanol is a better alternative. In the presence of a modest increase in serum osmolal gap (<30 mOsm/L), the starting dose of ethanol should be far less than the usual recommended dose. One can take advantage of the high vapor pressure of methanol in the treatment of methanol poisoning when hemodialysis is not readily available. Profuse sweating with increased water ingestion can be highly effective in reducing methanol levels. Impaired production of ammonia by the proximal tubule of the kidney plays a major role in the development of metabolic acidosis in pyroglutamic acidosis. Glycine, not oxalate, is the main final end product of ethylene glycol metabolism. Metabolism of ethylene glycol to oxalate, albeit important clinically, represents less than 1% of ethylene glycol disposal. Urine osmolal gap would be useful in the diagnosis of ethylene glycol poisoning, but not in methanol poisoning. Hemodialysis is important in the treatment of methanol poisoning and ethylene glycol poisoning with renal impairment, with or without fomepizole or ethanol treatment. Severe leucocytosis is a highly sensitive indicator of ethylene glycol poisoning. Uncoupling of oxidative phosphorylation by salicylate can explain most of the manifestations of salicylate poisoning. PMID:21468195

  14. Electrolyte Imbalances and Nephrocalcinosis in Acute Phosphate Poisoning on Chronic Type 1 Renal Tubular Acidosis due to Sjögren's Syndrome

    PubMed Central

    Cho, Sung-Gun; Han, Sang-Woong; Kim, Ho-Jung

    2013-01-01

    Although renal calcium crystal deposits (nephrocalcinosis) may occur in acute phosphate poisoning as well as type 1 renal tubular acidosis (RTA), hyperphosphatemic hypocalcemia is common in the former while normocalcemic hypokalemia is typical in the latter. Here, as a unique coexistence of these two seperated clinical entities, we report a 30-yr-old woman presenting with carpal spasm related to hypocalcemia (ionized calcium of 1.90 mM/L) due to acute phosphate poisoning after oral sodium phosphate bowel preparation, which resolved rapidly after calcium gluconate intravenously. Subsequently, type 1 RTA due to Sjögren's syndrome was unveiled by sustained hypokalemia (3.3 to 3.4 mEq/L), persistent alkaline urine pH (> 6.0) despite metabolic acidosis, and medullary nephrocalcinosis. Through this case report, the differential points of nephrocalcinosis and electrolyte imbalances between them are discussed, and focused more on diagnostic tests and managements of type 1 RTA. PMID:23400265

  15. Metabolic acidosis status and mortality in patients on the end stage of renal disease

    PubMed Central

    2016-01-01

    Abstract Background and Objectives Uncorrected metabolic acidosis leads to higher death risk in dialysis patients. We observed the relationship between metabolic acidosis status and mortality rate in patients on renal replacement therapy during a median follow up time of 60 months. Methods We studied 76 patients on an on-line hemodiafiltration. The dialysis adequacy was defined by Kt/V for urea. The Framingham risk score (FRS) points were used to determine the 10-year risk for coronary heart disease. We examined the impact of high or low serum bicarbonate concentrations on mortality rate and on 10-year risk for coronary heart disease via the Kaplan-Meier method. Cox’s model was used to evaluate a combination of prognostic variables, such as dialysis adequacy defined by Kt/V for urea, age and serum bicarbonate concentrations. Results We divided the enrolled patients in three groups according to serum bicarbonate concentrations (< 20 mmol/L, 20-22 mmol/L and > 22 mmol/L). Kaplan-Meier survival curve for the impact of serum bicarbonate concentrations on overall mortality was found significant (log-rank = 7.8, P = 0.02). The prevalence of serum bicarbonate less or more than 20 mmol/L on high FRS (> 20%) by Kaplan-Meier curve was also found significant (log-rank = 4.9, P = 0.02). Cox’s model revealed the significant predictive effect of serum bicarbonate on overall mortality (P = 0.006, OR = 1.5, 95% CI = 1.12-1.98) in combination to Kt/V for urea and age. Conclusion Uncorrected severe metabolic acidosis, defined by serum bicarbonate concentrations less than 20 mmol/L, is associated with a 10-year risk for coronary heart disease more than 20% and high overall mortality in patients on renal replacement therapy. PMID:28191541

  16. Coma, metabolic acidosis, and methemoglobinemia in a patient with acetaminophen toxicity.

    PubMed

    Kanji, Hussein D; Mithani, Shazma; Boucher, Paul; Dias, Valerian C; Yarema, Mark C

    2013-01-01

    We present a case of early coma, metabolic acidosis and methemoglobinemia after substantial acetaminophen toxicity in the absence of hepatic failure. A 77-year-old female presented to the emergency department with a decreased level of consciousness. She was found unresponsive by a family member in her bed, and was reported to be acting normally when she was last seen eight hours earlier. Laboratory results on arrival were: pH 7.19, sodium 139 mmol/L, chloride 106 mmol/L, potassium 3.3 mmol/L, CO2 8 mmol/L, and an anion gap of 25. Both venous lactate (10.2 mmol/L) and methemoglobin (9.4 %) were elevated. The patient's acetaminophen concentration was markedly elevated at 7138 µmol/L (1078 µg/ml). Hepatic enzymes and coagulation tests were normal [alanine transaminase (ALT) 8 U/L, international normalized ratio (INR) 1.0]. Intravenous N-acetylcysteine (NAC) was initiated at a dose of 150 mg/kg over 15 minutes, followed by 50 mg/kg over the next four hours, followed by 100 mg/kg over the next 16 hours. Twenty-four hours after admission, the anion gap metabolic acidosis had resolved, and the methemoglobin was 2.1%. Aminotransferases peaked at 44 U/L and INR peaked at 1.9. A urine 5-oxoproline assay performed five days after admission was negative, suggesting no evidence of a 5-oxoprolinase deficiency. We describe the pathophysiology and discuss the literature on acetaminophen-induced coma and metabolic acidosis in the absence of hepatic injury; and propose mechanisms for associated methemoglobinemia. 

  17. The deleterious effect of metabolic acidosis on nutritional status of hemodialysis patients.

    PubMed

    Soleymanian, Tayebeh; Ghods, Ahad

    2011-11-01

    One of the main causes of protein-energy malnutrition in patients on maintenance hemodialysis (MHD) is metabolic acidosis. The aim of this study was to evaluate the effect of metabolic acidosis on nutritional status in a group of MHD patients with adequately delivered dialysis treatment. Of 165 eligible anuric MHD outpatients with Kt/V ≥ 1 and no underlying inflammatory diseases, 47 subjects were enrolled. In order to evaluate the effect of different parameters on serum albumin, we measured the pre-dialysis serum albumin, blood pH, serum bicarbonate (HCO 3‾ ), Kt/V, normalized protein catabolic rate (nPCR) and body mass index (BMI) in these patients. The mean age of the study patients was 55 ± 13.8 years; there were 22 females and six diabetics. The average Kt/V was 1.22 ± 0.16, pH was 7.40 ± 0.15, serum HCO 3‾ was 23.18 ± 2.38 mEq/L, serum albumin was 4.03 ± 0.56 g/dL, nPCR was 1.00 ± 0.16 g/kg/day, post-dialysis body weight was 58.50 ± 11.50 kg and BMI was 23.47 ± 2.70 kg/m 2 . There was a statistically significant direct correlation between serum albumin and BMI (r = 0.415, P = 0.004), and between serum albumin and serum HCO 3 (r = 0.341, P = 0.019). On multiple regression analysis, the predictors of serum albumin were serum HCO3‾ and BMI (direct effect) and nPCR (inverse effect). In 17 patients on MHD with serum HCO3‾ <22 mEq/L, there was a significant inverse correlation between HCO 3 and nPCR (r = 0.492, P = 0.045), and these patients had significantly lower serum albumin compared with patients with serum HCO3‾ >22 mEq/L (P = 0.046). These data demonstrate that patients on MHD with metabolic acidosis had a lower serum albumin concentration despite adequate dialysis treatment. The inverse effect of nPCR on serum albumin concentration in acidotic MHD patients may be due to hypercatabolism in the setting of metabolic acidosis, leading to deleterious effects on the nutritional status of patients on MHD.

  18. Lanthanum carbonate versus sevelamer hydrochloride: improvement of metabolic acidosis and hyperkalemia in hemodialysis patients.

    PubMed

    Filiopoulos, Vassilis; Koutis, Ioannis; Trompouki, Sofia; Hadjiyannakos, Dimitrios; Lazarou, Dimitrios; Vlassopoulos, Dimosthenis

    2011-02-01

    Sevelamer hydrochloride (SH) has been reported to aggravate metabolic acidosis and hyperkalemia. This study was performed to evaluate acid-base status and serum potassium changes after replacing SH with lanthanum carbonate (LC) in hemodialysis patients. SH was prescribed for 24 weeks in 14 stable hemodialysis patients and replaced by LC in a similar treatment schedule. Laboratory tests, including indices of acid-base status, nutrition, bone/mineral metabolism, and dialysis adequacy, were performed monthly during the study. Dialysate bicarbonate, potassium and calcium concentrations remained constant. Serum bicarbonate and pH rose, and serum potassium dropped significantly under LC. Alkaline phosphatase also decreased significantly under LC. No significant differences were observed in the other studied parameters between the two treatment periods. Control of serum phosphate was similar under both phosphate-binders and no differences were observed in calcium, Ca × P product, CRP, or lipid levels. Dialysis adequacy was constantly kept within K/DOQI target-range. Although full compliance to treatment was reported, three patients on LC complained of gastrointestinal upset and/or a metallic taste, and four had difficulty chewing the LC tablet. LC improves metabolic acidosis and hyperkalemia in hemodialysis patients previously under SH. Although both medications are well-tolerated, the gastrointestinal side-effects appear to occur more frequently with LC; a fact that, together with difficulties in chewing the tablet, may result in decreased compliance.

  19. Mechanism of potassium depletion during chronic metabolic acidosis in the rat

    SciTech Connect

    Scandling, J.D.; Ornt, D.B.

    1987-01-01

    Pair-fed rats on a normal K diet were given either 1.5% NH/sub 4/Cl or water for 4 days. The acid-fed animals developed metabolic acidosis, negative K balance, and K depletion. Urinary Na excretion and urinary flow were not different between the groups beyond the first day. After the 4 days, isolated kidneys from animals in each of these groups were perfused at normal pH and bicarbonate concentrations. Urinary K excretion was similar between the groups despite the potassium depletion in the acid-fed animals. In contrast, isolated kidneys from animals with comparable K depletion induced by dietary K restriction readily conserved K. Sodium excretion and urinary flow were similar among the three groups of isolated kidneys. Plasma aldosterone concentrations were greater in the acid-fed rats after the 4 days of NH/sub 4/Cl ingestion than in the control animals. Adrenalectomized rats were treated with either normal (4 ..mu..g/day) or high (22 ..mu..g/day) aldosterone replacement while ingesting NH/sub 4/Cl for 4 days. Only in the presence of high aldosterone replacement did the acid-fed adrenalectomized animals develop K depletion. The authors conclude that chronic metabolic acidosis stimulates aldosterone secretion, and that aldosterone maintains the inappropriately high urinary potassium excretion and K depletion seen in this acid-base disorder.

  20. Effects of acute hypoxia/acidosis on intracellular pH in differentiating neural progenitor cells.

    PubMed

    Nordström, Tommy; Jansson, Linda C; Louhivuori, Lauri M; Akerman, Karl E O

    2012-06-21

    The response of differentiating mouse neural progenitor cells, migrating out from neurospheres, to conditions simulating ischemia (hypoxia and extracellular or intracellular acidosis) was studied. We show here, by using BCECF and single cell imaging to monitor intracellular pH (pH(i)), that two main populations can be distinguished by exposing migrating neural progenitor cells to low extracellular pH or by performing an acidifying ammonium prepulse. The cells dominating at the periphery of the neurosphere culture, which were positive for neuron specific markers MAP-2, calbindin and NeuN had lower initial resting pH(i) and could also easily be further acidified by lowering the extracellular pH. Moreover, in this population, a more profound acidification was seen when the cells were acidified using the ammonium prepulse technique. However, when the cell population was exposed to depolarizing potassium concentrations no alterations in pH(i) took place in this population. In contrast, depolarization caused an increase in pH(i) (by 0.5 pH units) in the cell population closer to the neurosphere body, which region was positive for the radial cell marker (GLAST). This cell population, having higher resting pH(i) (pH 6.9-7.1) also responded to acute hypoxia. During hypoxic treatment the resting pH(i) decreased by 0.1 pH units and recovered rapidly after reoxygenation. Our results show that migrating neural progenitor cells are highly sensitive to extracellular acidosis and that irreversible damage becomes evident at pH 6.2. Moreover, our results show that a response to acidosis clearly distinguishes two individual cell populations probably representing neuronal and radial cells.

  1. Insulin sensitivity of muscle protein metabolism is altered in patients with chronic kidney disease and metabolic acidosis

    PubMed Central

    Garibotto, Giacomo; Sofia, Antonella; Russo, Rodolfo; Paoletti, Ernesto; Bonanni, Alice; Parodi, Emanuele L; Viazzi, Francesca; Verzola, Daniela

    2015-01-01

    An emergent hypothesis is that a resistance to the anabolic drive by insulin may contribute to loss of strength and muscle mass in patients with chronic kidney disease (CKD). We tested whether insulin resistance extends to protein metabolism using the forearm perfusion method with arterial insulin infusion in 7 patients with CKD and metabolic acidosis (bicarbonate 19 mmol/l) and 7 control individuals. Forearm glucose balance and protein turnover (2H-phenylalanine kinetics) were measured basally and in response to insulin infused at different rates for 2 h to increase local forearm plasma insulin concentration by approximately 20 and 50 μU/ml. In response to insulin, forearm glucose uptake was significantly increased to a lesser extent (−40%) in patients with CKD than controls. In addition, whereas in the controls net muscle protein balance and protein degradation were decreased by both insulin infusion rates, in patients with CKD net protein balance and protein degradation were sensitive to the high (0.035 mU/kg per min) but not the low (0.01 mU/kg per min) insulin infusion. Besides blunting muscle glucose uptake, CKD and acidosis interfere with the normal suppression of protein degradation in response to a moderate rise in plasma insulin. Thus, alteration of protein metabolism by insulin may lead to changes in body tissue composition which may become clinically evident in conditions characterized by low insulinemia. PMID:26308671

  2. Survival from profound metabolic acidosis due to hypovolaemic shock. A world record?

    PubMed

    Di Rollo, Nicola; Caesar, David; Ferenbach, David A; Dunn, Mark J G

    2013-01-30

    This case describes the unexpected survival of an adult man who presented to the emergency department with hypovolaemic shock secondary to a splenic haemorrhage. Before surgery he had a pH 6.527, base excess (BE) -34.2 mmol/l and lactate 15.6 mmol/l. He underwent a splenectomy after which his condition stabilised. He was managed in the intensive care unit postoperatively where he required organ support including renal replacement therapy but was subsequently discharged home with no neurological or renal deficit. Although there are case reports of patients surviving such profound metabolic acidosis these have mainly been cases of near drowning or toxic alcohol ingestion. To the best of our knowledge this is the first reported case of survival after a pH of 6.5 secondary to hypovolaemic shock.

  3. Equivalent metabolic acidosis with four colloids and saline on ex vivo haemodilution.

    PubMed

    Morgan, T J; Vellaichamy, M; Cowley, D M; Weier, S L; Venkatesh, B; Jones, M A

    2009-05-01

    Colloid infusions can cause metabolic acidosis. Mechanisms and relative severity with different colloids are incompletely understood. We compared haemodilution acid-base effects of 4% albumin, 3.5% polygeline, 4% succinylated gelatin (all weak acid colloids, strong ion difference 12 mEq/l, 17.6 mEq/l and 34 mEq/l respectively), 6% hetastarch (non-weak acid colloid, strong ion difference zero) and 0.9% saline (crystalloid, strong ion difference zero). Gelatin weak acid properties were tracked via the strong ion gap. Four-step ex vivo dilutions of pre-oxygenated human venous blood were performed to a final [Hb] near 50% baseline. With each fluid, base excess fell to approximately -13 mEq/l. Base excess/[Hb] relationships across dilution were linear and direct (R2 > or = 0.96), slopes and intercepts closely resembling saline. Baseline strong ion gap was -0.3 (2.1) mEq/l. Post-dilution increases occurred in three groups: small with saline, hetastarch and albumin (to 3.5 (02) mEq/l, 4.3 (0.3) mEq/l, 3.3 (1.4) mEq/l respectively), intermediate with polygeline (to 12.2 (0.9) mEq/l) and greatest with succinylated gelatin (to 20.8 (1.4) mEq/l). We conclude that, despite colloid weak acid activity ranging from zero (hydroxyethyl starch) to greater than that of albumin with both gelatin preparations, ex vivo dilution causes a metabolic acidosis of identical severity to saline in each case. This uniformity reflects modifications to the albumin and gelatin saline vehicles, in part aimed at pH correction. By proportionally increasing the strong ion difference, these modifications counter deviations from pure saline effects caused by colloid weak acid activity. Extrapolation in vivo requires further investigation.

  4. The use of chloride-sodium ratio in the evaluation of metabolic acidosis in critically ill neonates.

    PubMed

    Kurt, Abdullah; Ecevit, Ayşe; Ozkiraz, Servet; Ince, Deniz Anuk; Akcan, Abdullah Baris; Tarcan, Aylin

    2012-06-01

    Acid-base disturbances have been usually evaluated with the traditional Henderson-Hasselbach method and Stewart's physiochemical approach by quantifying anions of tissue acids (TA). It is hypothesized that an increase in tissue acids during metabolic acidosis would cause a compensatory decrease in the plasma chloride (Cl) relative to sodium (Cl-Na ratio) in order to preserve electroneutral balance. Therefore, we aimed to investigate the use of Cl-Na ratio as a bedside tool to evaluate the identifying raised TA in neonates as an alternative to complex calculations of Stewart's physiochemical approach. This retrospective study was conducted between January 2008 and December 2009. Infants were included in the study when blood gas analysis reveals a metabolic acidosis; pH <7.25 and sHCO(3) concentration was <22 mEq/L. The Cl-Na ratio, sodium-chloride difference (Diff(NaCl)), anion gap (AG), albumin-corrected AG (AG(corr)), strong ion difference (SID), unmeasured anions (UMA), and TA were calculated at each episode of metabolic acidosis. A total of 105 metabolic acidosis episodes occurred in 59 infants during follow-up. Hypochloremic metabolic acidosis occurred in 17 (16%) of samples, and all had increased TA. The dominant component of TA was UMA rather than lactate. There was a negative correlation between the Cl-Na ratio and SID, AG(corr), UMA, and TA. Also, there was a positive correlation between Diff(NaCl) and SID, AG(corr), UMA, and TA. Base deficit and actual bicarbonate performed poorly in identifying the TA. In conclusion, our study suggested that Diff(NaCl) and Cl-Na ratio are simple and fast, and may be an alternative method to complex Stewart's physiochemical approach in identifying raised UMA and TA in critically ill neonates.

  5. Proteomic profiling and pathway analysis of the response of rat renal proximal convoluted tubules to metabolic acidosis.

    PubMed

    Schauer, Kevin L; Freund, Dana M; Prenni, Jessica E; Curthoys, Norman P

    2013-09-01

    Metabolic acidosis is a relatively common pathological condition that is defined as a decrease in blood pH and bicarbonate concentration. The renal proximal convoluted tubule responds to this condition by increasing the extraction of plasma glutamine and activating ammoniagenesis and gluconeogenesis. The combined processes increase the excretion of acid and produce bicarbonate ions that are added to the blood to partially restore acid-base homeostasis. Only a few cytosolic proteins, such as phosphoenolpyruvate carboxykinase, have been determined to play a role in the renal response to metabolic acidosis. Therefore, further analysis was performed to better characterize the response of the cytosolic proteome. Proximal convoluted tubule cells were isolated from rat kidney cortex at various times after onset of acidosis and fractionated to separate the soluble cytosolic proteins from the remainder of the cellular components. The cytosolic proteins were analyzed using two-dimensional liquid chromatography and tandem mass spectrometry (MS/MS). Spectral counting along with average MS/MS total ion current were used to quantify temporal changes in relative protein abundance. In all, 461 proteins were confidently identified, of which 24 exhibited statistically significant changes in abundance. To validate these techniques, several of the observed abundance changes were confirmed by Western blotting. Data from the cytosolic fractions were then combined with previous proteomic data, and pathway analyses were performed to identify the primary pathways that are activated or inhibited in the proximal convoluted tubule during the onset of metabolic acidosis.

  6. Long-term management of sevelamer hydrochloride-induced metabolic acidosis aggravation and hyperkalemia in hemodialysis patients.

    PubMed

    Sonikian, Macroui; Metaxaki, Polyxeni; Iliopoulos, Anastasios; Marioli, Stamatia; Vlassopoulos, Dimosthenis

    2006-01-01

    Sevelamer hydrochloride use in hemodialysis patients is complicated by metabolic acidosis aggravation and hyperkalemia. Rare reports about a short-term correction of this complication have been published. The current authors investigated the long-term correction of metabolic acidosis and hyperkalemia in sevelamer hydrochloride-treated patients at doses adequate to achieve serum phosphate levels within K/DOQI recommendations. The authors followed 20 hemodialysis patients for 24 months in an open-label prospective study. The dialysate bicarbonate concentration was increased stepwise to a maximum 40 mEq/L and adjusted to reach patient serum bicarbonate levels of 22 mEq/L, according to K/DOQI recommendations. Laboratory results for serum bicarbonate, potassium, calcium, phosphate, albumin, alkaline phosphatase, iPTH, cholesterol (HDL-LDL), triglycerides, Kt/V, systolic-diastolic arterial pressure were recorded. Sevelamer hydrochloride-induced metabolic acidosis aggravation and hyperkalemia in hemodialysis patients were corrected, on the long-term, by an increase in dialysate bicarbonate concentration. Further improvement in bone biochemistry was noted with this adequate acidosis correction and parallel sevelamer hydrochloride administration, in sufficiently large doses to achieve K/DOQI phosphate recommendations.

  7. Metabolic acidosis aggravation and hyperkaliemia in hemodialysis patients treated by sevelamer hydrochloride.

    PubMed

    Sonikian, Macroui A; Pani, Ioanna T; Iliopoulos, Anastasios N; Koutala, Kaliopi G; Marioli, Stamatia I; Vlassopoulos, Dimosthenis A

    2005-01-01

    Reports on acid-base side effects of sevelamer hydrochloride (SH), a new aluminum (Al)- and calcium (Ca)-free phosphate binder are rare and conflicting. In a retrospective analysis, we evaluated SH impact on metabolic acidosis and serum potassium (K) in hemodialysis (HD) patients. Two groups of stable HD patients were studied. Group A included 17 patients, M/F=15/2, 64 (42-80) years old, dialyzed since 130 (34-253) months, under SH for 24 months. Group B serving as controls was made of 7 patients, M/F=4/3, 67 (48-91) years old, dialyzed since 67 (27-174) months, under CaCO3 and/or Al(OH)3 as phosphate binders also for 24 months. Bicarbonate (BIC), K, Ca, phosphorus (P), Ca x P, alkaline phosphatase (ALP), and intact parathyroid hormone (iPTH) were recorded before (MO) and at the end (M24) of 24-month SH or CaCO3-Al(OH)3 treatment in group A and B patients. In group A, BIC fell from 20.02 +/- 1.43 to 17.89 +/- 2.30 mEq/ L, P=.002; and K rose from 5.45 +/- 0.51 to 5.75 +/- 0.49 mEq/L, P=0.02. In group B, BIC (19.8 +/- 3.03 to 19.0 +/- 3.3 mEq/L) and K (5.01 +/- 0.8 to 4.9 +/- 1.1 mEq/L) had nonsignificant changes. In group A, iPTH rose from 132.82 +/- 124.08 to 326.89 +/- 283.91 pg/mL, P=.0008; P fell from 5.92 +/- 1.48 to 4.9 +/- 1.01, P=.02; and Ca x P decreased from 52.04 +/- 9.7 to 45.58 +/- 10.42 mg2/dL2, P=.04. In group B, changes in iPTH from 240.71 +/- 174.7 to 318.57 +/- 260.2 pg/mL, P from 4.9 +/- 0.5 to 4.8 +/- 1.3 mg/dL, and CaxP product from 44.3 +/- 6.6 to 44 +/- 11.2 mg2/dL2 were nonsignificant. The changes observed in Ca and ALP in both groups were nonsignificant. Correlations in group A between metabolic acidosis (BIC) and SH doses, or iPTH and BIC, Ca, or P changes, were also found to be nonsignificant. Long-term use of SH, effectively controlling serum P levels and Ca x P values, is associated with acidosis aggravation and hyperkaliemia. Worsening of secondary hyperparathyroidism, also noted, needs to be confirmed and could be related to Ca/Al salt

  8. Respiration of Chemodenervated Goats in Acute Metabolic Acidosis,

    DTIC Science & Technology

    1983-08-02

    changed after CBx. Cerebral vasodilation in response to hypercapnia and hypoxia was found to be reduced in anesthetized animals after CBx (Ponte and Purves ...M.J. Purves (1974). The role of the carotid body chemo- receptors and carotid sinus baroreceptors in the control of cerebral blood vessels. J

  9. Hypokalemic quadriparesis and rhabdomyolysis as a rare presentation of distal renal tubular acidosis

    PubMed Central

    Ahmad Bhat, Manzoor; Ahmad Laway, Bashir; Mustafa, Farhat; Shafi Kuchay, Mohammad; Mubarik, Idrees; Ahmad Palla, Nazir

    2014-01-01

    Distal renal tubular acidosis is a syndrome of abnormal urine acidification and is characterized by hyperchloremic metabolic acidosis, hypokalemia, hypercalciurea, nephrocalcinosis and nephrolithiasis. Despite the presence of persistent hypokalemia, acute muscular paralysis is rarely encountered in males. Here, we will report an eighteen year old male patient who presented with flaccid quadriparesis and was subsequently found to have rhabdomyolysis, severe short stature, skeletal deformities and primary distal renal tubular acidosis. PMID:25250276

  10. [Metformin- related lactic acidosis].

    PubMed

    Manes, Massimo; Pellu, Valentina; Caputo, Donatella; Molino, Andrea; Paternoster, Giuseppe; Gabrielli, Danila; Nebiolo, Pier Eugenio

    2014-01-01

    Lactic acidosis metformin-related is a potentially fatal complication. Reviews show a stable prevalence of this phenomenon, but nephrological experience is required since it is frequently involved in therapeutic management. Here we report the cases of two old patients with severe lactic acidosis and acute renal failure treated with hemodiafiltration.

  11. Nitazoxanide induces in vitro metabolic acidosis in Taenia crassiceps cysticerci.

    PubMed

    Isac, Eliana; de A Picanço, Guaraciara; da Costa, Tatiane L; de Lima, Nayana F; de S M M Alves, Daniella; Fraga, Carolina M; de S Lino Junior, Ruy; Vinaud, Marina C

    2016-12-01

    Nitazoxanide (NTZ) is a broad-spectrum anti-parasitic drug used against a wide variety of protozoans and helminthes. Albendazole, its active metabolite albendazole sulfoxide (ABZSO), is one of the drugs of choice to treat both intestinal and tissue helminth and protozoan infections. However little is known regarding their impact on the metabolism of parasites. The aim of this study was to compare the in vitro effect of NTZ and ABZSO in the glycolysis of Taenia crassiceps cysticerci. The cysticerci were treated with 1.2; 0.6; 0.3 or 0.15 μg/mL of NTZ or ABZSO. Chromatographic and spectrophotometric analyses were performed in the culture medium and in the cysticerci extract. Regarding the glucose concentrations was possible to observe two responses: impair of the uptake and gluconeogenesis. The pyruvate concentrations were increased in the ABZSO treated group. Lactate concentrations were increased in the culture medium of NTZ treated groups. Therefore it was possible to infer that the metabolic acidosis was greater in the group treated with NTZ than in the ABZSO treated group indicating that this is one of the modes of action used by this drug to induce the parasite death.

  12. Oxidative response of neutrophils to platelet-activating factor is altered during acute ruminal acidosis induced by oligofructose in heifers

    PubMed Central

    Concha, Claudia; Carretta, María Daniella; Alarcón, Pablo; Conejeros, Ivan; Gallardo, Diego; Hidalgo, Alejandra Isabel; Tadich, Nestor; Cáceres, Dante Daniel; Hidalgo, María Angélica

    2014-01-01

    Reactive oxygen species (ROS) production is one of the main mechanisms used to kill microbes during innate immune response. D-lactic acid, which is augmented during acute ruminal acidosis, reduces platelet activating factor (PAF)-induced ROS production and L-selectin shedding in bovine neutrophils in vitro. This study was conducted to investigate whether acute ruminal acidosis induced by acute oligofructose overload in heifers interferes with ROS production and L-selectin shedding in blood neutrophils. Blood neutrophils and plasma were obtained by jugular venipuncture, while ruminal samples were collected using rumenocentesis. Lactic acid from plasma and ruminal samples was measured by HPLC. PAF-induced ROS production and L-selectin shedding were measured in vitro in bovine neutrophils by a luminol chemiluminescence assay and flow cytometry, respectively. A significant increase in ruminal and plasma lactic acid was recorded in these animals. Specifically, a decrease in PAF-induced ROS production was observed 8 h after oligofructose overload, and this was sustained until 48 h post oligofructose overload. A reduction in PAF-induced L-selectin shedding was observed at 16 h and 32 h post oligofructose overload. Overall, the results indicated that neutrophil PAF responses were altered in heifers with ruminal acidosis, suggesting a potential dysfunction of the innate immune response. PMID:25013355

  13. Oxidative response of neutrophils to platelet-activating factor is altered during acute ruminal acidosis induced by oligofructose in heifers.

    PubMed

    Concha, Claudia; Carretta, María Daniella; Alarcón, Pablo; Conejeros, Ivan; Gallardo, Diego; Hidalgo, Alejandra Isabel; Tadich, Nestor; Cáceres, Dante Daniel; Hidalgo, María Angélica; Burgos, Rafael Agustín

    2014-01-01

    Reactive oxygen species (ROS) production is one of the main mechanisms used to kill microbes during innate immune response. D-lactic acid, which is augmented during acute ruminal acidosis, reduces platelet activating factor (PAF)-induced ROS production and L-selectin shedding in bovine neutrophils in vitro. This study was conducted to investigate whether acute ruminal acidosis induced by acute oligofructose overload in heifers interferes with ROS production and L-selectin shedding in blood neutrophils. Blood neutrophils and plasma were obtained by jugular venipuncture, while ruminal samples were collected using rumenocentesis. Lactic acid from plasma and ruminal samples was measured by HPLC. PAF-induced ROS production and L-selectin shedding were measured in vitro in bovine neutrophils by a luminol chemiluminescence assay and flow cytometry, respectively. A significant increase in ruminal and plasma lactic acid was recorded in these animals. Specifically, a decrease in PAF-induced ROS production was observed 8 h after oligofructose overload, and this was sustained until 48 h post oligofructose overload. A reduction in PAF-induced L-selectin shedding was observed at 16 h and 32 h post oligofructose overload. Overall, the results indicated that neutrophil PAF responses were altered in heifers with ruminal acidosis, suggesting a potential dysfunction of the innate immune response.

  14. The effect of metabolic acidosis on the synthesis and turnover of rat renal phosphate-dependent glutaminase.

    PubMed Central

    Tong, J; Harrison, G; Curthoys, N P

    1986-01-01

    Regulation of the mitochondrial phosphate-dependent glutaminase activity is an essential component in the control of renal ammoniagenesis. Alterations in acid-base balance significantly affect the amount of the glutaminase that is present in rat kidney, but not in brain or small intestine. The relative rates of glutaminase synthesis were determined by comparing the amount of [35S]methionine incorporated into specific immunoprecipitates with that incorporated into total protein. In a normal animal, the rate of glutaminase synthesis constitutes 0.04% of the total protein synthesis. After 7 days of metabolic acidosis, the renal glutaminase activity is increased to a value that is 5-fold greater than normal. During onset of acidosis, the relative rate of synthesis increases more rapidly than the appearance of increased glutaminase activity. The increased rate of synthesis reaches a plateau within 5 days at a value that is 5.3-fold greater than normal. Recovery from chronic acidosis causes a rapid decrease in the relative rate of glutaminase synthesis, but a gradual decrease in glutaminase activity. The former returns to normal within 2 days, whereas the latter requires 11 days. The apparent half-time for glutaminase degradation was found to be 5.1 days and 4.7 days for normal and acidotic rats respectively. These results indicate that the increase in renal glutaminase activity associated with metabolic acidosis is due primarily to an increase in its rate of synthesis. From the decrease in activity that occurs upon recovery from acidosis, the true half-life for the glutaminase was estimated to be 3 days. Images Fig. 3. PMID:3954723

  15. Phosphate binders and metabolic acidosis in patients undergoing maintenance hemodialysis—sevelamer hydrochloride, calcium carbonate, and bixalomer.

    PubMed

    Sanai, Toru; Tada, Hideo; Ono, Takashi; Fukumitsu, Toma

    2015-01-01

    The serum bicarbonate (HCO3(-)) levels are decreased in chronic hemodialysis (HD) patients treated with sevelamer hydrochloride (SH). We assessed the effects of bixalomer on the chronic metabolic acidosis in these patients. We examined 12 of the 122 consecutive Japanese patients with end-stage renal disease on HD, who orally ingested a dose of SH (≥2250 mg), and an arterial blood gas analysis and biochemical analysis were performed before HD. Patients whose serum HCO3(-) levels were under 18 mmol/L were changed from SH to the same dose of bixalomer. A total of 12 patients were treated with a large amount of SH. Metabolic acidosis (a serum HCO3(-) level under 18 mmol/L) was found in eight patients. These patients were also treated with or without small dose of calcium carbonate (1.2 ± 1.1 g). The dose of SH was changed to that of bixalomer. After 1 month, the serum HCO3(-) levels increased from 16.3 ± 1.4 to 19.6 ± 1.7 mmol/L (P < 0.05). Metabolic acidosis was not observed in four patients (serum HCO3(-) level: 20.3 ± 0.7 mmol/L) likely because they were taking 3 g of calcium carbonate with SH. In the present study, the development of chronic metabolic acidosis was induced by HCl containing phosphate binders, such as SH, and partially ameliorated by calcium carbonate, then subsequently improved after changing the treatment to bixalomer.

  16. Monitoring of metformin-induced lactic acidosis in a diabetic patient with acute kidney failure and effect of hemodialysis.

    PubMed

    Laforest, Claire; Saint-Marcoux, Franck; Amiel, Jean-Bernard; Pichon, Nicolas; Merle, Louis

    2013-02-01

    Metformin associated lactic acidosis (MALA) is a serious complication occurring especially in elderly patients given high doses of the drug. We report a non-fatal case of MALA with pronounced acidosis (pH 6.76, lactate 30.81 mmol/l) and high metformin concentrations (127 mg/l) in a patient who had developed acute renal failure after undergoing an operation. Multiple measurements of biological parameters and metformin blood concentrations showed the effectiveness of repeated hemodialysis sessions on metformin elimination. Cases previously reported with such a severe MALA were associated with a high mortality rate. We show that close monitoring in an intensive care unit together with prompt and repeated dialysis sessions can lead to a favorable outcome.

  17. Effects of sodium hydroxide treatment of dried distillers' grains on digestibility, ruminal metabolism, and metabolic acidosis of feedlot steers.

    PubMed

    Freitas, T B; Relling, A E; Pedreira, M S; Santana Junior, H A; Felix, T L

    2016-02-01

    The objectives were to determine the optimum inclusion of NaOH necessary to buffer the acidity of dried distillers' grains with solubles (DDGS) and its effects on digestibility, ruminal metabolism, and metabolic acidosis in feedlot steers. Rumen cannulated Angus-crossed steers were blocked by BW (small: 555 ± 42 kg initial BW, = 4; large: 703 ± 85 kg initial BW, = 4) over four 21-d periods in a replicated 4 × 4 Latin square design. Steers were assigned to 1 of 4 dietary treatments: 1) 50% untreated DDGS, 2) 50% DDGS treated with 0.5% (DM basis) sodium hydroxide (NaOH), 3) 50% DDGS treated with 1.0% (DM basis) NaOH, and 4) 50% DDGS treated with 1.5% (DM basis) NaOH. The remainder of the diets, on a DM basis, was composed of 20% corn silage, 20% dry-rolled corn, and 10% supplement. Ruminal pH was not affected by treatments ( = 0.56) or by a treatment × time interaction ( = 0.15). In situ NDF and ruminal DM disappearance did not differ ( ≥ 0.49 and ≥ 0.47, respectively) among treatments. Similar to in situ results, apparent total tract DM and NDF digestibility were not affected ( ≥ 0.33 and ≥ 0.21, respectively) by increasing NaOH inclusion in the diets. Urinary pH increased (linear, < 0.01) with increasing NaOH concentration in the diet. Blood pH was not affected ( ≥ 0.20), and blood total CO and partial pressure of CO were similar ( ≥ 0.56 and ≥ 0.17, respectively) as NaOH increased in the diet. Increasing NaOH in the diet did not affect ( ≥ 0.21) ruminal concentrations of total VFA. There were no linear ( = 0.20) or quadratic ( = 0.20) effects of treatment on ruminal acetate concentrations, nor was there a treatment × time interaction ( = 0.22) for acetate. Furthermore, there were no effects ( ≥ 0.90) of NaOH inclusion on ruminal propionate concentration. However, there was a quadratic response ( = 0.01) of ruminal butyrate concentrations as NaOH inclusion increased in the diet; ruminal butyrate concentrations were greatest with the 0.5 and 1

  18. Differential effects of acidosis, high potassium concentrations, and metabolic inhibition on noradrenaline release and its presynaptic muscarinic regulation.

    PubMed

    Haunstetter, Armin; Schulze Icking, Babette; Backs, Johannes; Krüger, Carsten; Haass, Markus

    2002-03-01

    It was the aim of the present study to characterize the effect of single components of ischaemia, such as inhibition of aerobic and anaerobic energy production by combined anoxic and glucose-free perfusion (metabolic inhibition), high extracellular potassium concentrations (hyperkalaemia), and acidosis, on (1). the stimulated release of noradrenaline from the in situ perfused guinea-pig heart and (2). its presynaptic modulation by the muscarinic agonist carbachol. The release of endogenous noradrenaline from efferent cardiac sympathetic nerve endings was induced by electrical stimulation of the left stellate ganglion (1 min, 5 V, 12 Hz) and quantified in the coronary venous effluent by high-performance liquid chromatography. Under control conditions, two consecutive electrical stimulations (S1, S2) elicited a similar noradrenaline overflow (S2/S1: 0.98 plus minus 0.05). After 10 min of global myocardial ischaemia overflow of endogenous noradrenaline was significantly reduced (S2/S1: 0.18 plus minus 0.03; P< 0.05). When studied separately, metabolic inhibition, hyperkalaemia (16 mM), and acidosis (pH 6.0) each markedly attenuated stimulated noradrenaline overflow (S2/S1: 0.65 plus minus 0.05, 0.43 plus minus 0.14, and 0.37 plus minus 0.09, respectively; P< 0.05). The muscarinic agonist carbachol (10 microM) inhibited stimulated noradrenaline release under normoxic conditions (S2/S1: 0.41 plus minus 0.07; P< 0.05). However, after 10 min of global myocardial ischaemia the inhibitory effect of carbachol on noradrenaline overflow was completely lost. Single components of ischaemia had a differential effect on presynaptic muscarinic modulation. Whereas hyperkalaemia (8-16 mM) did not affect muscarinic inhibition of noradrenaline release, carbachol lost its inhibitory effect during acidosis and metabolic inhibition. In conclusion, hyperkalaemia, metabolic inhibition, and severe acidosis each contribute to reduced overflow of noradrenaline after 10 min of myocardial

  19. Metformin-associated lactic acidosis precipitated by diarrhea.

    PubMed

    El-Hennawy, Adel S; Jacob, Sunitha; Mahmood, Aza K

    2007-01-01

    Metformin-associated lactic acidosis (MALA) is a serious metabolic complication that occurs because of metformin accumulation in patients who become dehydrated or developed acute renal failure. Bicarbonate hemodialysis treatment should take place early in the course of management, especially in patients with severe metabolic acidosis who fail to respond to intravenous bicarbonate therapy or in whom renal failure is present. We report a case of MALA in which acute renal failure resulting from dehydration secondary to diarrhea and poor oral intake likely caused MALA. Early recognition of this condition and initiation of effective treatment can improve outcome.

  20. Citric acid as the last therapeutic approach in an acute life-threatening metabolic decompensation of propionic acidaemia.

    PubMed

    Siekmeyer, Manuela; Petzold-Quinque, Stefanie; Terpe, Friederike; Beblo, Skadi; Gebhardt, Rolf; Schlensog-Schuster, Franziska; Kiess, Wieland; Siekmeyer, Werner

    2013-01-01

    The tricarboxylic acid (TCA) cycle represents the key enzymatic steps in cellular energy metabolism. Once the TCA cycle is impaired in case of inherited metabolic disorders, life-threatening episodes of metabolic decompensation and severe organ failure can arise. We present the case of a 6 ½-year-old girl with propionic acidaemia during an episode of acute life-threatening metabolic decompensation and severe lactic acidosis. Citric acid given as an oral formulation showed the potential to sustain the TCA cycle flux. This therapeutic approach may become a treatment option in a situation of acute metabolic crisis, possibly preventing severe disturbance of energy metabolism.

  1. The effect of sodium bicarbonate on cytokine secretion in CKD patients with metabolic acidosis.

    PubMed

    Ori, Yaacov; Zingerman, Boris; Bergman, Michael; Bessler, Hanna; Salman, Hertzel

    2015-04-01

    The incidence of acidosis increases with the progression of chronic kidney disease (CKD). Correction of acidosis by sodium bicarbonate may slow CKD deterioration. Inflammation, which is common in CKD, may be related to acidosis. Whether the slower rate of GFR decline following the correction of acidosis is related to changes in inflammatory markers is unknown. The current study examined whether correcting CKD-acidosis affected inflammatory cytokines secretion. Thirteen patients with CKD 4-5 and acidosis were tested for cytokines secretion from peripheral-blood mononuclear cells at baseline and after one month of oral sodium bicarbonate. Following treatment with sodium bicarbonate there was no change in weight, blood pressure, serum creatinine, albumin, sodium, calcium, phosphate, PTH, hemoglobin and CRP. Serum urea decreased (134±10-116±8 mg/dl, P=0.002), potassium decreased (5.1±0.4-4.8±0.1 mequiv./l, P=0.064), pH increased (7.29±0.01-7.33±0.01, P=0.008), and serum bicarbonate increased (18.6±0.4 mequiv./l to 21.3±0.3 mequiv./l, P=0.001). The secretion of the anti-inflammatory cytokine IL-10 decreased (2.75±0.25 ng/ml to 2.29±0.21 ng/ml, P=0.041). There was no significant change in the secretion of the other pro-inflammatory and anti-inflammatory cytokines, including IL-1β, IL-2, IL-6, TNFα, IFNγ, IL-1ra. Thus, correcting acidosis in CKD with bicarbonate decreases IL-10 secretion. Its significance needs to be further investigated.

  2. A guide for predicting arterial CO2 tension in metabolic acidosis.

    PubMed

    Fulop, M

    1997-01-01

    This presentation examines the relation of arterial CO2 tension to the severity of acidemia in three large groups of cases of diabetic ketoacidosis, totalling 405 episodes. In particular, it evaluates the previously reported anecdotal observation that PaCO2 (in torr) in such patients is usually numerically close to the two-digit number to the right of the pH decimal point, down to a pH of 7.10-7.15. The relations between measured arterial CO2 tension levels and calculated plasma bicarbonate concentration in the three groups were very similar to those previously reported by others and us, the regression equations approximating PaCO2 = 1.5 x [HCO3-] + 8. Further, in the 262 episodes with blood pH 7.10-7.37, down to a pH of 7.10-7.15, the average PaCO2 in torr often did approximate the two-digit number to the right of the decimal point in the pH value. This relation provides a quick and easily remembered alternative guide for predicting the approximate expected PaCO2 in patients with metabolic acidosis. The basis for this apparently fortuitous relation between PaCO2 and blood pH may be the closely similar correlation between PaCO2 and 1/cH+ (i.e., 10PH), which in turn derives from the physiologically significant relation of alveolar ventilation to blood pH, and the inverse relation between PaCO2 and alveolar ventilation.

  3. Adaptation of rabbit cortical collecting duct HCO3- transport to metabolic acidosis in vitro.

    PubMed Central

    Tsuruoka, S; Schwartz, G J

    1996-01-01

    Net HCO3- transport in the rabbit kidney cortical collecting duct (CCD) is mediated by simultaneous H+ secretion and HCO3- secretion, most likely occurring in a alpha- and beta-intercalated cells (ICs), respectively. The polarity of net HCO3- transport is shifted from secretion to absorption after metabolic acidosis or acid incubation of the CCD. We investigated this adaptation by measuring net HCO3- flux before and after incubating CCDs 1 h at pH 6.8 followed by 2 h at pH 7.4. Acid incubation always reversed HCO3- flux from net secretion to absorption, whereas incubation for 3 h at pH 7.4 did not. Inhibition of alpha-IC function (bath CL- removal or DIDS, luminal bafilomycin) stimulated net HCO3- secretion by approximately 2 pmol/min per mm before acid incubation, whereas after incubation these agents inhibited net HCO3- absorption by approximately 5 pmol/min per mm. Inhibition of beta-IC function (luminal Cl- removal) inhibited HCO3- secretion by approximately 9 pmol/min per mm before incubation, whereas after incubation HCO3- absorption by only 3 pmol/min per mm. After acid incubation, luminal SCH28080 inhibited HCO3- absorption by only 5-15% vs the circa 90% inhibitory effect of bafilomycin. In outer CCDs, which contain fewer alpha-ICs than midcortical segments, the reversal in polarity of HCO3- flux was blunted after acid incubation. We conclude that the CCD adapts to low pH in vitro by downregulation HCO3- secretion in beta-ICs via decreased apical CL-/base exchang activity and upregulating HCO3- absorption in alpha-ICs via increased apical H+ -ATPase and basolateral CL-/base exchange activities. Whether or not there is a reversal of IC polarity or recruitment of gamma-ICs in this adaptation remains to be established. PMID:8613531

  4. Contribution of individual superficial nephron segments to ammonium handling in chronic metabolic acidosis in the rat. Evidence for ammonia disequilibrium in the renal cortex.

    PubMed Central

    Simon, E; Martin, D; Buerkert, J

    1985-01-01

    Ammonia entry along surface nephron segments of rats was studied with micropuncture techniques under control and chronic metabolic acidosis conditions. Tubule fluid was collected successively from sites at the end and beginning of the distal tubule and at the end of the proximal tubule of the same nephron. During chronic metabolic acidosis, ammonium excretion doubled. As anticipated, the ammonium concentration (TFNH+4) was significantly higher in proximal tubule fluid during acidosis, and ammonium delivery to end proximal sites increased from 19.4 +/- 2.3 to 34.0 +/- 3.2 pmol/min (P less than 0.001). Although chronic acidosis did not affect TFNH+4 at the beginning of the distal tubule, ammonium delivery to the end of the distal tubule increased from 5.72 +/- 0.97 to 9.88 +/- 0.97 pmol/min. In both control and acidotic groups ammonium delivery was lower (P less than 0.001) to end distal sites than to end proximal sites, indicating net loss in the intervening segment. This loss was greater during chronic metabolic acidosis (23.9 +/- 3.3 vs. 13.6 +/- 2.0 pmol/min in controls, P less than 0.025). In both groups net entry of ammonia, in similar amounts, occurred along the distal tubule (P less than 0.05). In situ pH averaged 6.80 +/- 0.05 at end proximal tubule sites and fell to 6.54 +/- 0.08 at the beginning of the distal tubule (P less than 0.005). Chronic metabolic acidosis did not affect these measurements. The calculated free ammonia at the end of the proximal tubule rose from 9.3 +/- 2.2 to 21 +/- 9 microM (P less than 0.005) during chronic metabolic acidosis, and was also higher at beginning distal sites during acidosis (8.8 +/- 2.4 vs. 2.7 +/- 0.7 microM in controls, P less than 0.05). In both groups ammonia values for the beginning distal tubule fluid were lower than for end proximal tubule fluid. Thus, loss of ammonium in the loop segment is enhanced by chronic metabolic acidosis. Distal entry of ammonia is markedly less than along the proximal tubule and does

  5. Sympathetic activation in exercise is not dependent on muscle acidosis. Direct evidence from studies in metabolic myopathies

    NASA Technical Reports Server (NTRS)

    Vissing, J.; Vissing, S. F.; MacLean, D. A.; Saltin, B.; Quistorff, B.; Haller, R. G.; Blomqvist, C. G. (Principal Investigator)

    1998-01-01

    Muscle acidosis has been implicated as a major determinant of reflex sympathetic activation during exercise. To test this hypothesis we studied sympathetic exercise responses in metabolic myopathies in which muscle acidosis is impaired or augmented during exercise. As an index of reflex sympathetic activation to muscle, microneurographic measurements of muscle sympathetic nerve activity (MSNA) were obtained from the peroneal nerve. MSNA was measured during static handgrip exercise at 30% of maximal voluntary contraction force to exhaustion in patients in whom exercise-induced muscle acidosis is absent (seven myophosphorylase deficient patients; MD [McArdle's disease], and one patient with muscle phosphofructokinase deficiency [PFKD]), augmented (one patient with mitochondrial myopathy [MM]), or normal (five healthy controls). Muscle pH was monitored by 31P-magnetic resonance spectroscopy during handgrip exercise in the five control subjects, four MD patients, and the MM and PFKD patients. With handgrip to exhaustion, the increase in MSNA over baseline (bursts per minute [bpm] and total activity [%]) was not impaired in patients with MD (17+/-2 bpm, 124+/-42%) or PFKD (65 bpm, 307%), and was not enhanced in the MM patient (24 bpm, 131%) compared with controls (17+/-4 bpm, 115+/-17%). Post-handgrip ischemia studied in one McArdle patient, caused sustained elevation of MSNA above basal suggesting a chemoreflex activation of MSNA. Handgrip exercise elicited an enhanced drop in muscle pH of 0.51 U in the MM patient compared with the decrease in controls of 0.13+/-0.02 U. In contrast, muscle pH increased with exercise in MD by 0.12+/-0.05 U and in PFKD by 0.01 U. In conclusion, patients with glycogenolytic, glycolytic, and oxidative phosphorylation defects show normal muscle sympathetic nerve responses to static exercise. These findings indicate that muscle acidosis is not a prerequisite for sympathetic activation in exercise.

  6. [Topiramate in monotherapy or in combination as a cause of metabolic acidosis in adults with epilepsy].

    PubMed

    Ruiz-Granados, Velvet J; Márquez-Romero, Juan M

    2015-02-16

    Objetivo. Determinar la frecuencia de acidosis metabolica y sus factores relacionados en pacientes tratados con topiramato solo o como adyuvante para el tratamiento de epilepsia. Pacientes y metodos. Analisis transversal de la gasometria arterial de pacientes epilepticos que recibieron topiramato durante 2010 en la clinica de epilepsia del Centro Medico Nacional 20 de Noviembre en Mexico. Se registraron datos clinicos concernientes a la epilepsia y su tratamiento, asi como de los sintomas comunes de acidosis metabolica. Resultados. Se estudiaron 32 adultos con epilepsia, quienes recibieron topiramato en monoterapia o en combinacion por lo menos durante un mes. Se encontro acidosis metabolica en todos los pacientes (HCO3 < 22 Eq/L); nueve tomaron solo topiramato y 23 tomaron por lo menos dos farmacos antiepilepticos (FAE). Todos los pacientes fueron asintomaticos. No se encontro correlacion entre los niveles de bicarbonato y la dosis del medicamento o la duracion del tratamiento. La dosis fue significativamente mayor en el grupo de monoterapia y el nivel de bicarbonato fue mas bajo en los pacientes que tomaban mas de un FAE. Conclusiones. El uso concomitante de FAE incrementa los efectos conocidos del topiramato sobre los niveles sericos de bicarbonato y la presencia de acidosis metabolica; estos efectos parecen ser independientes del numero de FAE utilizados.

  7. TASK channels are not required to mount an aldosterone secretory response to metabolic acidosis in mice

    PubMed Central

    Guagliardo, Nick A.; Yao, Junlan; Bayliss, Douglas A.; Barrett, Paula Q.

    2010-01-01

    The stimulation of aldosterone production by acidosis enhances proton excretion and serves to limit disturbances in systemic acid-base equilibrium. Yet, the mechanisms by which protons stimulate aldosterone production from cells of the adrenal cortex remain largely unknown. TWIK-related acid sensitive K channels (TASK) are inhibited by extracellular protons within the physiological range and have emerged as important regulators of aldosterone production in the adrenal cortex. Here we show that congenic C57BL/6J mice with genetic deletion of TASK-1 (K2P3.1) and TASK-3 (K2P9.1) channel subunits overproduce aldosterone and display an enhanced sensitivity to steroidogenic stimuli, including a more pronounced steroidogenic response to chronic NH4Cl loading. Thus, we conclude that TASK channels are not required for the stimulation of aldosterone production by protons but their inhibition by physiological acidosis may contribute to full expression of the steroidogenic response. PMID:21111026

  8. Effect of collecting duct-specific deletion of both Rh B Glycoprotein (Rhbg) and Rh C Glycoprotein (Rhcg) on renal response to metabolic acidosis.

    PubMed

    Lee, Hyun-Wook; Verlander, Jill W; Handlogten, Mary E; Han, Ki-Hwan; Weiner, I David

    2014-02-15

    The Rhesus (Rh) glycoproteins, Rh B and Rh C Glycoprotein (Rhbg and Rhcg, respectively), are ammonia-specific transporters expressed in renal distal nephron and collecting duct sites that are necessary for normal rates of ammonia excretion. The purpose of the current studies was to determine the effect of their combined deletion from the renal collecting duct (CD-Rhbg/Rhcg-KO) on basal and acidosis-stimulated acid-base homeostasis. Under basal conditions, urine pH and ammonia excretion and serum HCO3(-) were similar in control (C) and CD-Rhbg/Rhcg-KO mice. After acid-loading for 7 days, CD-Rhbg/Rhcg-KO mice developed significantly more severe metabolic acidosis than did C mice. Acid loading increased ammonia excretion, but ammonia excretion increased more slowly in CD-Rhbg/Rhcg-KO and it was significantly less than in C mice on days 1-5. Urine pH was significantly more acidic in CD-Rhbg/Rhcg-KO mice on days 1, 3, and 5 of acid loading. Metabolic acidosis increased phosphenolpyruvate carboxykinase (PEPCK) and Na(+)/H(+) exchanger NHE-3 and decreased glutamine synthetase (GS) expression in both genotypes, and these changes were significantly greater in CD-Rhbg/Rhcg-KO than in C mice. We conclude that 1) Rhbg and Rhcg are critically important in the renal response to metabolic acidosis; 2) the significantly greater changes in PEPCK, NHE-3, and GS expression in acid-loaded CD-Rhbg/Rhcg-KO compared with acid-loaded C mice cause the role of Rhbg and Rhcg to be underestimated quantitatively; and 3) in mice with intact Rhbg and Rhcg expression, metabolic acidosis does not induce maximal changes in PEPCK, NHE-3, and GS expression despite the presence of persistent metabolic acidosis.

  9. Physiological and molecular responses of the goldfish (Carassius auratus) kidney to metabolic acidosis, and potential mechanisms of renal ammonia transport.

    PubMed

    Lawrence, Michael J; Wright, Patricia A; Wood, Chris M

    2015-07-01

    Relative to the gills, the mechanisms by which the kidney contributes to ammonia and acid-base homeostasis in fish are poorly understood. Goldfish were exposed to a low pH environment (pH 4.0, 48 h), which induced a characteristic metabolic acidosis and an increase in total plasma [ammonia] but reduced plasma ammonia partial pressure (PNH3). In the kidney tissue, total ammonia, lactate and intracellular pH remained unchanged. The urinary excretion rate of net base under control conditions changed to net acid excretion under low pH, with contributions from both the NH4 (+) (∼30%) and titratable acidity minus bicarbonate (∼70%; TA-HCO3 (-)) components. Inorganic phosphate (Pi), urea and Na(+) excretion rates were also elevated while Cl(-) excretion rates were unchanged. Renal alanine aminotransferase activity increased under acidosis. The increase in renal ammonia excretion was due to significant increases in both the glomerular filtration and the tubular secretion rates of ammonia, with the latter accounting for ∼75% of the increase. There was also a 3.5-fold increase in the mRNA expression of renal Rhcg-b (Rhcg1) mRNA. There was no relationship between ammonia secretion and Na(+) reabsorption. These data indicate that increased renal ammonia secretion during acidosis is probably mediated through Rhesus (Rh) glycoproteins and occurs independently of Na(+) transport, in contrast to branchial and epidermal models of Na(+)-dependent ammonia transport in freshwater fish. Rather, we propose a model of parallel H(+)/NH3 transport as the primary mechanism of renal tubular ammonia secretion that is dependent on renal amino acid catabolism.

  10. Localization of members of MCT monocarboxylate transporter family Slc16 in the kidney and regulation during metabolic acidosis.

    PubMed

    Becker, Helen M; Mohebbi, Nilufar; Perna, Angelica; Ganapathy, Vadivel; Capasso, Giovambattista; Wagner, Carsten A

    2010-07-01

    The monocarboxylate transporter family (MCT) comprises 14 members with distinct transport properties and tissue distribution. The kidney expresses several members of the MCT family, but only little is known about their exact distribution and function. Here, we investigated selected members of the MCT family in the mouse kidney. MCT1, MCT2, MCT7, and MCT8 localized to basolateral membranes of the epithelial cells lining the nephron. MCT1 and MCT8 were detected in proximal tubule cells whereas MCT7 and MCT2 were located in the thick ascending limb and the distal tubule. CD147, a beta-subunit of MCT1 and MCT4, showed partially overlapping expression with MCT1 and MCT2. However, CD147 was also found in intercalated cells. We also detected SMCT1 and SMCT2, two Na(+)-dependent monocarboxylate cotransporters, on the luminal membrane of type A intercalated cells. Moreover, mice were given an acid load for 2 and 7 days. Acidotic animals showed a marked but transient increase in urinary lactate excretion. During acidosis, a downregulation of MCT1, MCT8, and SMCT2 was observed at the mRNA level, whereas MCT7 and SMCT1 showed increased mRNA abundance. Only MCT7 showed lower protein abundance whereas all other transporters remained unchanged. In summary, we describe for the first time the localization of various MCT transporters in mammalian kidney and demonstrate that metabolic acidosis induces a transient increase in urinary lactate excretion paralleled by lower MCT7 protein expression.

  11. [Tubular renal acidosis].

    PubMed

    Seidowsky, A; Moulonguet-Doleris, L; Hanslik, T; Yattara, H; Ayari, H; Rouveix, E; Massy, Z A; Prinseau, J

    2014-01-01

    Renal tubular acidosis (RTAs) are a group of metabolic disorders characterized by metabolic acidosis with normal plasma anion gap. There are three main forms of RTA: a proximal RTA called type II and a distal RTA (type I and IV). The RTA type II is a consequence of the inability of the proximal tubule to reabsorb bicarbonate. The distal RTA is associated with the inability to excrete the daily acid load and may be associated with hyperkalaemia (type IV) or hypokalemia (type I). The most common etiology of RTA type IV is the hypoaldosteronism. The RTAs can be complicated by nephrocalcinosis and obstructive nephrolithiasis. Alkalinization is the cornerstone of treatment.

  12. Rh versus pH: the role of Rhesus glycoproteins in renal ammonia excretion during metabolic acidosis in a freshwater teleost fish.

    PubMed

    Wright, Patricia A; Wood, Chris M; Wilson, Jonathan M

    2014-08-15

    Increased renal ammonia excretion in response to metabolic acidosis is thought to be a conserved response in vertebrates. We tested the hypothesis that Rhesus (Rh) glycoproteins in the kidney of the freshwater common carp, Cyprinus carpio, play a crucial role in regulating renal ammonia excretion during chronic metabolic acidosis. Exposure to water pH 4.0 (72 h) resulted in a classic metabolic acidosis with reduced plasma arterial pH and [HCO3(-)], no change in PCO2 and large changes in renal function. Urine [NH4(+)] as well as [titratable acidity-HCO3(-)] rose significantly over the acid exposure, but the profound reduction (fivefold) in urine flow rates eliminated the expected elevations in renal ammonia excretion. Low urine flow rates may be a primary strategy to conserve ions, as urinary excretion rates of Na(+), Cl(-) and Ca(2+) were significantly lower during the acid exposure relative to the control period. Interestingly, renal Rhcg1 mRNA and protein levels were elevated in acid-exposed relative to control groups, along with mRNA levels of several ion transporters, including the Na(+)/H(+) exchanger, H(+)-ATPase and Na(+)/K(+)-ATPase. Immunofluorescence microscopy showed a strong apical Rhcg1 signal in distal tubules. Taken together, these data show that renal Rh glycoproteins and associated ion transporters are responsive to metabolic acidosis, but conservation of ions through reduced urine flow rates takes primacy over renal acid-base regulation in the freshwater C. carpio. We propose that an 'acid/base-ion balance' compromise explains the variable renal responses to metabolic acidosis in freshwater teleosts.

  13. Glucocorticoid activity and metabolism with NaCl-induced low-grade metabolic acidosis and oral alkalization: results of two randomized controlled trials.

    PubMed

    Buehlmeier, Judith; Remer, Thomas; Frings-Meuthen, Petra; Maser-Gluth, Christiane; Heer, Martina

    2016-04-01

    Low-grade metabolic acidosis (LGMA), as induced by high dietary acid load or sodium chloride (NaCl) intake, has been shown to increase bone and protein catabolism. Underlying mechanisms are not fully understood, but from clinical metabolic acidosis interactions of acid-base balance with glucocorticoid (GC) metabolism are known. We aimed to investigate GC activity/metabolism under alkaline supplementation and NaCl-induced LGMA. Eight young, healthy, normal-weight men participated in two crossover designed interventional studies. In Study A, two 10-day high NaCl diet (32 g/d) periods were conducted, one supplemented with 90 mmol KHCO3/day. In Study B, participants received a high and a low NaCl diet (31 vs. 3 g/day), each for 14 days. During low NaCl, the diet was moderately acidified by replacement of a bicarbonate-rich mineral water (consumed during high NaCl) with a non-alkalizing drinking water. In repeatedly collected 24-h urine samples, potentially bioactive-free GCs (urinary-free cortisol + free cortisone) were analyzed, as well as tetrahydrocortisol (THF), 5α-THF, and tetrahydrocortisone (THE). With supplementation of 90 mmol KHCO3, the marker of total adrenal GC secretion (THF + 5α-THF + THE) dropped (p = 0.047) and potentially bioactive-free GCs were reduced (p = 0.003). In Study B, however, GC secretion and potentially bioactive-free GCs did not exhibit the expected fall with NaCl-reduction as net acid excretion was raised by 30 mEq/d. Diet-induced acidification/alkalization affects GC activity and metabolism, which in case of long-term ingestion of habitually acidifying western diets may constitute an independent risk factor for bone degradation and cardiometabolic diseases.

  14. Hyperammonaemia with distal renal tubular acidosis.

    PubMed

    Miller, S G; Schwartz, G J

    1997-11-01

    The case is reported of an infant with hyperammonaemia secondary to severe distal renal tubular acidosis. A clinical association between increased concentrations of ammonia in serum and renal tubular acidosis has not previously been described. In response to acidosis the infant's kidneys presumably increased ammonia synthesis but did not excrete ammonia, resulting in hyperammonaemia. The patient showed poor feeding, frequent vomiting, and failure to thrive, but did not have an inborn error of metabolism. This case report should alert doctors to consider renal tubular acidosis in the differential diagnosis of severely ill infants with metabolic acidosis and hyperammonaemia.

  15. Proteomic profiling of the effect of metabolic acidosis on the apical membrane of the proximal convoluted tubule

    PubMed Central

    Walmsley, Scott J.; Freund, Dana M.

    2012-01-01

    The physiological response to the onset of metabolic acidosis requires pronounced changes in renal gene expression. Adaptations within the proximal convoluted tubule support the increased extraction of plasma glutamine and the increased synthesis and transport of glucose and of NH4+ and HCO3− ions. Many of these adaptations involve proteins associated with the apical membrane. To quantify the temporal changes in these proteins, proteomic profiling was performed using brush-border membrane vesicles isolated from proximal convoluted tubules (BBMVPCT) that were purified from normal and acidotic rats. This preparation is essentially free of contaminating apical membranes from other renal cortical cells. The analysis identified 298 proteins, 26% of which contained one or more transmembrane domains. Spectral counts were used to assess changes in protein abundance. The onset of acidosis produced a twofold, but transient, increase in the Na+-dependent glucose transporter and a more gradual, but sustained, increase (3-fold) in the Na+-dependent lactate transporter. These changes were associated with the loss of glycolytic and gluconeogenic enzymes that are contained in the BBMVPCT isolated from normal rats. In addition, the levels of γ-glutamyltranspeptidase increased twofold, while transporters that participate in the uptake of neutral amino acids, including glutamine, were decreased. These changes could facilitate the deamidation of glutamine within the tubular lumen. Finally, pronounced increases were also observed in the levels of DAB2 (3-fold) and myosin 9 (7-fold), proteins that may participate in endocytosis of apical membrane proteins. Western blot analysis and accurate mass and time analyses were used to validate the spectral counting. PMID:22357915

  16. Recent Advances in Targeting Tumor Energy Metabolism with Tumor Acidosis as a Biomarker of Drug Efficacy

    PubMed Central

    Akhenblit, Paul J; Pagel, Mark D

    2016-01-01

    Cancer cells employ a deregulated cellular metabolism to leverage survival and growth advantages. The unique tumor energy metabolism presents itself as a promising target for chemotherapy. A pool of tumor energy metabolism targeting agents has been developed after several decades of efforts. This review will cover glucose and fatty acid metabolism, PI3K/AKT/mTOR, HIF-1 and glutamine pathways in tumor energy metabolism, and how they are being exploited for treatments and therapies by promising pre-clinical or clinical drugs being developed or investigated. Additionally, acidification of the tumor extracellular microenvironment is hypothesized to be the result of active tumor metabolism. This implies that tumor extracellular pH (pHe) can be a biomarker for assessing the efficacy of therapies that target tumor metabolism. Several translational molecular imaging methods (PET, MRI) for interrogating tumor acidification and its suppression are discussed as well. PMID:26962408

  17. Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate.

    PubMed

    Goraya, Nimrit; Simoni, Jan; Jo, Chan-Hee; Wesson, Donald E

    2014-11-01

    Alkali therapy of metabolic acidosis in patients with chronic kidney disease (CKD) with plasma total CO2 (TCO2) below 22 mmol/l per KDOQI guidelines appears to preserve estimated glomerular filtration rate (eGFR). Since angiotensin II mediates GFR decline in partial nephrectomy models of CKD and even mild metabolic acidosis increases kidney angiotensin II in animals, alkali treatment of CKD-related metabolic acidosis in patients with plasma TCO2 over 22 mmol/l might preserve GFR through reduced kidney angiotensin II. To test this, we randomized 108 patients with stage 3 CKD and plasma TCO2 22-24 mmol/l to Usual Care or interventions designed to reduce dietary acid by 50% using sodium bicarbonate or base-producing fruits and vegetables. All were treated to achieve a systolic blood pressure below 130 mm Hg with regimens including angiotensin converting enzyme inhibition and followed for 3 years. Plasma TCO2 decreased in Usual Care but increased with bicarbonate or fruits and vegetables. By contrast, urine excretion of angiotensinogen, an index of kidney angiotensin II, increased in Usual Care but decreased with bicarbonate or fruits and vegetables. Creatinine-calculated and cystatin C-calculated eGFR decreased in all groups, but loss was less at 3 years with bicarbonate or fruits and vegetables than Usual Care. Thus, dietary alkali treatment of metabolic acidosis in CKD that is less severe than that for which KDOQI recommends therapy reduces kidney angiotensin II activity and preserves eGFR.

  18. Lactic acidosis in patients with cancer.

    PubMed

    Held-Warmkessel, Jeanne; Dell, Deena Damsky

    2014-10-01

    Lactic acidosis is the most common metabolic acidosis in hospitalized patients-the result from an underlying pathogenic process. To successfully manage lactic acid production, its cause needs to be eliminated. Patients with cancer have many risk factors for developing lactic acidosis, including the cancer diagnosis itself. Patients with lactic acidosis are critically ill, requiring an intense level of nursing care with accompanying frequent cardiopulmonary and renal assessments. The mortality rate from lactic acidosis is high. Therefore, appropriate nursing interventions may include end-of-life and palliative care.

  19. Chronic Metabolic Acidosis Activates Renal Tubular Sodium Chloride Cotransporter through Angiotension II-dependent WNK4-SPAK Phosphorylation Pathway.

    PubMed

    Fang, Yu-Wei; Yang, Sung-Sen; Cheng, Chih-Jen; Tseng, Min-Hua; Hsu, Hui-Min; Lin, Shih-Hua

    2016-01-05

    The mechanism by which chronic metabolic acidosis (CMA) regulates sodium (Na(+))-chloride (Cl(-)) cotransporter (NCC) in the renal distal convoluted tubules remains unexplored. We examined the role of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and with-no-lysine kinase 4 (WNK4) on expression of NCC in mouse models of CMA. CMA was induced by NH4Cl in wild type mice (WTA mice), SPAK, and WNK4 knockout mice. The quantities of Ncc mRNA, expression of total NCC, phosphorylated (p)-NCC, SPAK and WNK4 in the kidneys as well as NCC inhibition with hydrochlorothiazide and Na(+) balance were evaluated. Relative to WT mice, WTA mice had similar levels of Ncc mRNA, but increased expression of total and p-NCC, SPAK, and WNK4 and an exaggerated response to hydrochlorothiazide which could not be observed in SPAK or WNK4 knockout mice with CMA. In WTA mice, increased plasma renin activity, aldosterone and angiotensin II concentrations accompanied by a significantly negative Na(+) balance. High Na(+) diet abolished the enhanced NCC expression in WTA mice. Furthermore, an angiotensin II type 1 receptor blocker rather than a mineralocorticoid receptor antagonist exerted a marked inhibition on Na(+) reabsorption and NCC phosphorylation in WTA mice. CMA increases WNK4-SPAK-dependent NCC phosphorylation and appears to be secondary to previous natriuresis with volume-dependent angiotensin II activation.

  20. Chronic metabolic acidosis may be the cause of cachexia: body fluid pH correction may be an effective therapy.

    PubMed

    Drochioiu, Gabi

    2008-01-01

    Cachexia is a pathological state characterized by weight loss and protein mobilization during various diseases. Nutritional supplementation or appetite stimulants are unable to restore the loss of lean body mass. Agents interfering with TNF-alpha have not been very successful to date. Only eicosapentaenoic acid was able to interfere with the action of proteolysis-inducing factors. An acceleration of proteolysis and branched-chain amino acid oxidation was correlated with chronic metabolic acidosis. Therefore, we suggest here that the main cause of cachexia is the increased acidity of the body fluids, which results in a higher and non-specific proteolysis of muscle proteins. Moderate hypoxia might be close related to lactic acid production within the whole body, not only in the cancer cells. Anorexia seems to be a consequence, but a cause of cachexia: the cachectic patients are in fact well fed, unfortunately they use fatty acids from their fat and glucose via muscle proteins, amino acids, alanine, and lactic acid. Our hypothesis is consistent with the most findings reported in literature and opens new ways for cachexia prevention and therapy, such as pH correction or higher oxygenation.

  1. Dietary sodium chloride intake independently predicts the degree of hyperchloremic metabolic acidosis in healthy humans consuming a net acid-producing diet.

    PubMed

    Frassetto, Lynda A; Morris, R Curtis; Sebastian, Anthony

    2007-08-01

    We previously demonstrated that typical American net acid-producing diets predict a low-grade metabolic acidosis of severity proportional to the diet net acid load as indexed by the steady-state renal net acid excretion rate (NAE). We now investigate whether a sodium (Na) chloride (Cl) containing diet likewise associates with a low-grade metabolic acidosis of severity proportional to the sodium chloride content of the diet as indexed by the steady-state Na and Cl excretion rates. In the steady-state preintervention periods of our previously reported studies comprising 77 healthy subjects, we averaged in each subject three to six values of blood hydrogen ion concentration ([H]b), plasma bicarbonate concentration ([HCO(3)(-)]p), the partial pressure of carbon dioxide (Pco(2)), the urinary excretion rates of Na, Cl, NAE, and renal function as measured by creatinine clearance (CrCl), and performed multivariate analyses. Dietary Cl strongly correlated positively with dietary Na (P < 0.001) and was an independent negative predictor of [HCO(3)(-)]p after adjustment for diet net acid load, Pco(2) and CrCl, and positive and negative predictors, respectively, of [H]b and [HCO(3)(-)]p after adjustment for diet acid load and Pco(2). These data provide the first evidence that, in healthy humans, the diet loads of NaCl and net acid independently predict systemic acid-base status, with increasing degrees of low-grade hyperchloremic metabolic acidosis as the loads increase. Assuming a causal relationship, over their respective ranges of variation, NaCl has approximately 50-100% of the acidosis-producing effect of the diet net acid load.

  2. Respiratory acidosis

    MedlinePlus

    ... Names Ventilatory failure; Respiratory failure; Acidosis - respiratory Images Respiratory system References Effros RM, Swenson ER. Acid-base balance. In: Broaddus VC, Mason RJ, Ernst JD, et al, eds. Murray and Nadel's Textbook of Respiratory Medicine . 6th ed. Philadelphia, PA: Elsevier Saunders; 2016: ...

  3. Sodium bicarbonate use and the risk of hypernatremia in thoracic aortic surgical patients with metabolic acidosis following deep hypothermic circulatory arrest

    PubMed Central

    Ghadimi, Kamrouz; Gutsche, Jacob T.; Ramakrishna, Harish; Setegne, Samuel L.; Jackson, Kirk R.; Augoustides, John G.; Ochroch, E. Andrew; Weiss, Stuart J.; Bavaria, Joseph E.; Cheung, Albert T.

    2016-01-01

    Objective: Metabolic acidosis after deep hypothermic circulatory arrest (DHCA) for thoracic aortic operations is commonly managed with sodium bicarbonate (NaHCO3). The purpose of this study was to determine the relationships between total NaHCO3 dose and the severity of metabolic acidosis, duration of mechanical ventilation, duration of vasoactive infusions, and Intensive Care Unit (ICU) or hospital length of stay (LOS). Methods: In a single center, retrospective study, 87 consecutive elective thoracic aortic operations utilizing DHCA, were studied. Linear regression analysis was used to test for the relationships between the total NaHCO3 dose administered through postoperative day 2, clinical variables, arterial blood gas values, and short-term clinical outcomes. Results: Seventy-five patients (86%) received NaHCO3. Total NaHCO3 dose averaged 136 ± 112 mEq (range: 0.0–535 mEq) per patient. Total NaHCO3 dose correlated with minimum pH (r = 0.41, P < 0.0001), minimum serum bicarbonate (r = −0.40, P < 0.001), maximum serum lactate (r = 0.46, P = 0.007), duration of metabolic acidosis (r = 0.33, P = 0.002), and maximum serum sodium concentrations (r = 0.29, P = 0.007). Postoperative hypernatremia was present in 67% of patients and peaked at 12 h following DHCA. Eight percent of patients had a serum sodium ≥ 150 mEq/L. Total NaHCO3 dose did not correlate with anion gap, serum chloride, not the duration of mechanical ventilator support, vasoactive infusions, ICU or hospital LOS. Conclusion: Routine administration of NaHCO3 was common for the management of metabolic acidosis after DHCA. Total dose of NaHCO3 was a function of the severity and duration of metabolic acidosis. NaHCO3 administration contributed to postoperative hypernatremia that was often severe. The total NaHCO3 dose administered was unrelated to short-term clinical outcomes. PMID:27397449

  4. Use of Lactated Ringer’s solution does not eliminate the risk of strong ion difference-related metabolic acidosis following on-pump cardiac surgery.

    PubMed

    Jovaisa, T; Vicka, V; Linkaitė, G; Guseinovaitė, J; Ringaitienė, D; Norkienė, I

    2016-01-01

    There is a growing interest in the effects of plasma sodium levels on postoperative outcomes. A trend of using balanced crystalloid solutions is based on the extensive data on chloride and the strong ion difference-related acidosis. However, effects of sodium are often overlooked in this context. The aim of the study was to establish the effects of the routine use of Lactated Ringer’s Solution (RL) on postoperative changes in sodium concentrations and whether these changes result in metabolic acidosis. We performed database analysis of 358 consecutive elective on-pump cardiac surgery cases in a tertiary referral university hospital. Approval from the institutional ethics committee was obtained for this study. Intraoperative fluid balance was 2726±1073 ml and the total volume of intravenous infusions in the first 24 hours was 5865 (±1073) ml, 95% of which was RL; 58% of the patients had metabolic acidosis with a base excess below (–)2 mmol L–1 on arrival at the intensive care unit. There was a significant correlation between a strong ion difference and base excess (p less than 0.01). A significant improvement in metabolic acidosis was noted within the first 24 hours, from a base excess of (–)2.49±2.8 to 0.32±2.6 mmol L–1 (p less than 0.001). All of the improvement in the base excess is explained by a change in the strong ion difference from the mean value of 31±4.3 to 34.2±3.6 mmol L–1 (p less than 0.001). Changes in the strong ion difference were primarily driven by changes in the serum sodium concentration, which were three-fold higher compared to those of chloride [–2.36 (±2.6) mmol L–1 (p less than 0.001) and 0.84 (±3.2) mmol L–1, respectively (p = 0.01)]. In conclusion, our data confirm that there is a direct correlation between a strong ion difference and base excess following on-pump cardiac surgery. The use of RL prevented significant hyperchloraemia, but did not eliminate the risk of strong ion difference-related metabolic acidosis. The

  5. [D-Lactic acidosis secondary to short bowel syndrome].

    PubMed

    Tapia Guerrero, M J; Olveira, G; Bravo Utrera, M; Colomo Rodríguez, N; Fernández García, J C

    2010-01-01

    The short bowel syndrome appears for the reduction of intestinal absorptive surface due to functional or anatomical loss of part of the small bowel. We present the case of a 35-year-old woman with severe short bowel syndrome secondary to acute intestinal ischemia in adults, who presented at 5 years of evolution episodes of dizziness with gait instability and loss of strength in hands. The diagnosis was D-lactic acidosis. D-lactic acidosis is a rare complication, but important for their symptoms, of this syndrome. It is due to a change in intestinal flora secondary to an overgrowth of lactic acid bacteria that produce D-lactate. D-lactic acidosis should be looked for in cases of metabolic acidosis in which the identity of acidosis is not apparent, neurological manifestations without focality and the patient has short bowel syndrome or patients who have had jejunoileal bypass surgery. Appropriate treatment usually results in resolution of neurologic symptoms and prevents or reduces further recurrences.

  6. Old and new approaches to the interpretation of acid-base metabolism, starting from historical data applied to diabetic acidosis.

    PubMed

    Mioni, Roberto; Marega, Alessandra; Lo Cicero, Marco; Montanaro, Domenico

    2016-11-01

    The approach to acid-base chemistry in medicine includes several methods. Currently, the two most popular procedures are derived from Stewart's studies and from the bicarbonate/BE-based classical formulation. Another method, unfortunately little known, follows the Kildeberg theory applied to acid-base titration. By using the data produced by Dana Atchley in 1933, regarding electrolytes and blood gas analysis applied to diabetes, we compared the three aforementioned methods, in order to highlight their strengths and their weaknesses. The results obtained, by reprocessing the data of Atchley, have shown that Kildeberg's approach, unlike the other two methods, is consistent, rational and complete for describing the organ-physiological behavior of the hydrogen ion turnover in human organism. In contrast, the data obtained using the Stewart approach and the bicarbonate-based classical formulation are misleading and fail to specify which organs or systems are involved in causing or maintaining the diabetic acidosis. Stewart's approach, despite being considered 'quantitative', does not propose in any way the concept of 'an amount of acid' and becomes even more confusing, because it is not clear how to distinguish between 'strong' and 'weak' ions. As for Stewart's approach, the classical method makes no distinction between hydrogen ions managed by the intermediate metabolism and hydroxyl ions handled by the kidney, but, at least, it is based on the concept of titration (base-excess) and indirectly defines the concept of 'an amount of acid'. In conclusion, only Kildeberg's approach offers a complete understanding of the causes and remedies against any type of acid-base disturbance.

  7. Imaging acute ischemic tissue acidosis with pH-sensitive endogenous amide proton transfer (APT) MRI - Correction of tissue relaxation and concomitant RF irradiation effects toward mapping quantitative cerebral tissue pH

    PubMed Central

    Sun, Phillip Zhe; Wang, Enfeng; Cheung, Jerry S

    2011-01-01

    Amide proton transfer (APT) MRI is sensitive to ischemic tissue acidosis and has been increasingly used as a research tool to investigate disrupted tissue metabolism during acute stroke. However, magnetization transfer asymmetry (MTRasym) analysis is often used for calculating APT contrast, which only provides pH-weighted images. In addition to pH- dependent APT contrast, in vivo MTRasym is subject to a baseline shift (ΔMTR′asym) attributable to the slightly asymmetric magnetization transfer (MT) effect. Additionally, APT contrast approximately scales with T1 relaxation time. Tissue relaxation time may also affect the experimentally obtainable APT contrast via saturation efficiency and RF spillover effects. In this study, we acquired perfusion, diffusion, relaxation and pH-weighted APT MRI data, and spectroscopy (MRS) in an animal model of acute ischemic stroke. We modeled in vivo MTRasym as a superposition of pH-dependent APT contrast and a baseline shift ΔMTR′asym (i.e., MTRasym=APTR(pH) + ΔMTR′asym), and quantified tissue pH. We found pH of the contralateral normal tissue to be 7.03 ± 0.05 and the ipsilateral ischemic tissue pH was 6.44 ± 0.24, which correlated with tissue perfusion and diffusion rates. In summary, our study established an endogenous and quantitative pH imaging technique for improved characterization of ischemic tissue acidification and metabolism disruption. PMID:22178815

  8. Localization and hormonal control of serine dehydratase during metabolic acidosis differ markedly from those of phosphoenolpyruvate carboxykinase in rat kidney.

    PubMed

    Masuda, Tohru; Ogawa, Hirofumi; Matsushima, Takako; Kawamata, Seiichi; Sasahara, Masakiyo; Kuroda, Kazunari; Suzuki, Yasuhiro; Takata, Yoshimi; Yamazaki, Mitsuaki; Takusagawa, Fusao; Pitot, Henry C

    2003-08-01

    Serine dehydratase (SDH) is abundant in the rat liver but scarce in the kidney. When administrated with dexamethasone, the renal SDH activity was augmented 20-fold, whereas the hepatic SDH activity was affected little. In situ hybridization and immunohistochemistry revealed that SDH was localized to the proximal straight tubule of the nephron. To address the role of this hormone, rats were made acidotic by gavage of NH(4)Cl. Twenty-two hours later, the SDH activity was increased three-fold along with a six-fold increment in the phosphoenolpyruvate carboxykinase (PEPCK) activity, a rate-limiting enzyme of gluconeogenesis. PEPCK, which is localized to the proximal tubules under the normal condition, spreads throughout the entire cortex to the outer medullary rays by acidosis, whereas SDH does not change regardless of treatment with dexamethasone or NH(4)Cl. When NH(4)Cl was given to adrenalectomized rats, in contrast to the SDH activity no longer increasing, the PEPCK activity responded to acidosis to the same extent as in the intact rats. A simultaneous administration of dexamethasone and NH(4)Cl into the adrenalectomized rats fully restored the SDH activity, demonstrating that the rise in the SDH activity during acidosis is primarily controlled by glucocorticoids. The present findings clearly indicate that the localization of SDH and its hormonal regulation during acidosis are strikingly different from those of PEPCK.

  9. (Uncommon) Mechanisms of Branchial Ammonia Excretion in the Common Carp (Cyprinus carpio) in Response to Environmentally Induced Metabolic Acidosis.

    PubMed

    Wright, Patricia A; Wood, Chris M; Hiroi, Junya; Wilson, Jonathan M

    2016-01-01

    Freshwater fishes generally increase ammonia excretion in acidic waters. The new model of ammonia transport in freshwater fish involves an association between the Rhesus (Rh) protein Rhcg-b, the Na(+)/H(+) exchanger (NHE), and a suite of other membrane transporters. We tested the hypothesis that Rhcg-b and NHE3 together play a critical role in branchial ammonia excretion in common carp (Cyprinus carpio) chronically exposed to a low-pH environment. Carp were exposed to three sequential environmental treatments-control pH 7.6 water (24 h), pH 4.0 water (72 h), and recovery pH 7.6 water (24 h)-or in a separate series were simply exposed to either control (72 h) or pH 4.0 (72 h) water. Branchial ammonia excretion was increased by ∼2.5-fold in the acid compared with the control period, despite the absence of an increase in the plasma-to-water partial pressure NH3 gradient. Alanine aminotransferase activity was higher in the gills of fish exposed to pH 4 versus control water, suggesting that ammonia may be generated in gill tissue. Gill Rhcg-b and NHE3b messenger RNA levels were significantly elevated in acid-treated relative to control fish, but at the protein level Rhcg-b decreased (30%) and NHE3b increased (2-fold) in response to water of pH 4.0. Using immunofluorescence microscopy, NHE3b and Rhcg-b were found to be colocalized to ionocytes along the interlamellar space of the filament of control fish. After 72 h of acid exposure, Rhcg-b staining almost disappeared from this region, and NHE3b was more prominent along the lamellae. We propose that ammoniagenesis within the gill tissue itself is responsible for the higher rates of branchial ammonia excretion during chronic metabolic acidosis. Unexpectedly, gill Rhcg-b does not appear to be important in gill ammonia transport in low-pH water, but the strong induction of NHE3b suggests that some NH4(+) may be eliminated directly in exchange for Na(+). These findings contrast with previous studies in larval zebrafish

  10. [Inherited tubular renal acidosis].

    PubMed

    Bouzidi, Hassan; Hayek, Donia; Nasr, Dhekra; Daudon, Michel; Fadhel Najjar, Mohamed

    2011-01-01

    Renal tubular acidosis (RTA) is a tubulopathy characterized by metabolic acidosis with normal anion gap secondary to abnormalities of renal acidification. RTA can be classified into four main subtypes: distal RTA, proximal RTA, combined proximal and distal RTA, and hyperkalemic RTA. Distal RTA (type 1) is caused by the defect of H(+) secretion in the distal tubules and is characterized by the inability to acidify the urine below pH 5.5 during systemic acidemia. Proximal RTA (type 2) is caused by an impairment of bicarbonate reabsorption in the proximal tubules and characterized by a decreased renal bicarbonate threshold. Combined proximal and distal RTA (type 3) secondary to a reduction in tubular reclamation of bicarbonate and an inability to acidify the urine in the face of severe acidemia. Hyperkalemic RTA (type 4) may occur as a result of aldosterone deficiency or tubular insensitivity to aldosterone. Clinicians should be alert to the presence of RTA in patients with an unexplained normal anion gap acidosis, hypokalemia, recurrent nephrolithiasis and nephrocalcinosis. The mainstay of treatment of RTA remains alkali replacement.

  11. The duration of time that beef cattle are fed a high-grain diet affects feed sorting behavior both before and after acute ruminal acidosis1,2.

    PubMed

    DeVries, T J; Schwaiger, T; Beauchemin, K A; Penner, G B

    2014-04-01

    The objective of this study was to determine how duration of time that cattle are fed a high-grain diet affects feed sorting, both before and after an episode of acute ruminal acidosis. Sixteen Angus heifers (261 ± 6.1 kg; BW ± SEM) were assigned to 1 of 4 blocks and fed a backgrounding (BG) diet (60% forage, DM basis). Within block, heifers were randomly assigned to 1 of 2 treatments differing in days fed a high-grain (HG; 9% forage, DM basis, fed ad libitum) diet before a ruminal acidosis challenge: 34 d for long adapted (LA) and 8 d for short adapted (SA). Ruminal acidosis was induced by restricting feed to 50% of DMI as a proportion of BW (determined individually for each heifer) for 24 h followed by an intraruminal infusion of ground barley at 10% of DMI as a proportion of BW measured before feed restriction. Feed and orts were sampled during the BG period, the first 26 d on the HG diet (only for LA cattle), the 8-d baseline (BASE) period, on the day of the ruminal acidosis challenge (CH), and during 2 consecutive 8-d recovery periods (REC1 and REC2) for each heifer and subjected to particle size analysis: 19-mm (long), 8-mm (medium), and 1.18-mm (short) screens and a pan (fine). On the BG diet, sorting for medium particles tended to be greater (104.2 vs. 102.1%; P = 0.07) for LA heifers than SA heifers, while sorting against short particles was greater (98.2 vs. 100.0%; P = 0.05) for LA heifers. During the first 26 d on the HG diet, LA cattle sorted for (P < 0.001) long (118.8%), medium (117.8%), and short (104.1%) particles and sorted against (P < 0.001) fine particles (45.3%). This sorting pattern was consistent for LA heifers during BASE period, CH day, and recovery periods, across which SA heifers exhibited less sorting (P ≤ 0.1). Greater duration of pH < 5.5 during the BASE period was associated with greater sorting for long particles (R(2) = 0.75, P = 0.01) in LA heifers and for long (R(2) = 0.49, P = 0.05) and medium (R(2) = 0.88, P < 0

  12. [Gastric emptying and metabolic acidosis. II. Study, in an experimental model in rats, of gastric retention of a sodium bicarbonate solution].

    PubMed

    Belangero, V M; Collares, E F

    1992-01-01

    The gastric emptying of a 0.25 M sodium bicarbonate solution was studied in rats with metabolic acidosis induced by a previous (6 hours) orogastric infusion of a 0.5 M ammonium chloride solution. Two control groups were used: one previously infused with 0.5 M sodium chloride and the other with water, in the same volume that further solutions. Every animal was fed with 2 ml/100 g of its weight of these solutions. The test meal (bicarbonate solution) was utilized containing 6 mg% red fenol as a marker. The gastric retentions were determined 6 hours after those first meals at 5, 10, 20 and 30 minutes. The results demonstrated that the gastric retentions of the bicarbonate solution were significantly lower in the acidotic group than that one of water group (at 20 minutes) and that one of the sodium chloride (at 10, 20 and 30 minutes). The data here presented suggest that metabolic acidosis accelerates the gastric emptying of a sodium bicarbonate solution.

  13. Hyperammonaemia in a child with distal renal tubular acidosis.

    PubMed

    Seracini, D; Poggi, G M; Pela, I

    2005-11-01

    A 5-month-old girl with distal renal tubular acidosis (RTA) and hyperammonaemia that had lasted for 12 days, despite metabolic acidosis correction, is presented in this report. The patient showed failure to thrive, poor feeding, hypotonia and vomiting crisis in absence of inborn errors of metabolism. Probably, hyperammonaemia was the result of an imbalance between the increased ammonia synthesis, in response to metabolic acidosis, and the impaired ammonia excretion, typical of distal RTA. Our case confirms that hyperammonaemia may be observed in distal RTA, mimicking an inborn error of metabolism, and it underlines that hyperammonaemia may persist several days after metabolic acidosis correction.

  14. Interaction between bunk management and monensin concentration on finishing performance, feeding behavior, and ruminal metabolism during an acidosis challenge with feedlot cattle.

    PubMed

    Erickson, G E; Milton, C T; Fanning, K C; Cooper, R J; Swingle, R S; Parrott, J C; Vogel, G; Klopfenstein, T J

    2003-11-01

    Two commercial feedlot experiments and a metabolism study were conducted to evaluate the effects of monensin concentrations and bunk management strategies on performance, feed intake, and ruminal metabolism. In the feedlot experiments, 1,793 and 1,615 steers were used in Exp. 1 and 2, respectively, in 18 pens for each experiment (six pens/treatment). Three treatments were evaluated: 1) ad libitum bunk management with 28.6 mg/kg monensin and clean bunk management strategies with either 2) 28.6 or 3) 36.3 mg/kg monensin. In both experiments, 54 to 59% of the clean bunk pens were clean at targeted clean time, or 2200, compared with 24 to 28% of the ad libitum pens. However, only 13% of the pens were clean by 2000 in Exp. 1 (summer), whereas 44% of the pens in Exp. 2 (winter) were clean by 2000. In Exp. 1, bunk management and monensin concentration did not affect carcass-adjusted performance. In Exp. 2, steers fed ad libitum had greater DMI (P < 0.01) and carcass-adjusted ADG (P < 0.01) but feed efficiency (P > 0.13) similar to that of clean bunk-fed steers. Monensin concentration had no effect on carcass-adjusted performance (P > 0.20) in either experiment. A metabolism experiment was conducted with eight fistulated steers in a replicated 4 x 4 Latin square acidosis challenge experiment. An acidosis challenge was imposed by feeding 125% of the previous day's DMI, 4 h later than normal. Treatments consisted of monensin concentrations (mg/kg) of 0, 36.7, 48.9, or 36.7 until challenged and switched to 48.9 on the challenge day and 4 d following. Each replicate of the Latin square was managed with separate bunk management strategies (clean bunk or ad libitum). Feeding any concentration of monensin increased number of meals and decreased DMI rate (%/h) (P < 0.12) for the 4 d following the acidosis challenge. Meal size, pH change, and pH variance were lower (P < 0.10) for steers fed monensin with clean bunk management. However, no monensin effect was observed for steers fed

  15. Respiratory Adaptation to Acute Metabolic Acidosis in Goats with Ablated Carotid Bodies,

    DTIC Science & Technology

    1982-06-03

    values. DISCUSSION We have shown in a previous communication (26) that the goats used in the present study were deprived of peripheral chemoreception ...was manifest in the chemodenervated awake goats. This is in agreement with findings in anesthetized cats (14) and in anesthetized (12) and awake dogs...anesthetized cats by Katsaros (14). It appears that a respiratory adaptation to AMA, mani- fest in lowering the resting PaCO 2 and in shifting CO2

  16. Renal Tubular Acidosis

    MedlinePlus

    ... Old Feeding Your 1- to 2-Year-Old Renal Tubular Acidosis KidsHealth > For Parents > Renal Tubular Acidosis Print A A A What's in ... Causes Symptoms Diagnosis Treatment en español Acidosis tubular renal Each time our internal organs do something, such ...

  17. Pathogenesis of acidosis in hereditary fructose intolerance.

    PubMed

    Richardson, R M; Little, J A; Patten, R L; Goldstein, M B; Halperin, M L

    1979-11-01

    An 18-yr-old man with a classical history of hereditary fructose intolerance (HFI) developed typical biochemical changes following an oral fructose load: fructosemia, hypoglycemia, hypophosphatemia, hyperuricemia, and metabolic acidosis. Hypokalemia (3.1 meq/liter) was also noted. Three aspects of this case expand the published literature on this syndrome: (1) Metabolic acidosis was found to be due to both lactic acidosis and proximal renal tubular acidosis (RTA). We could quantitate the relative contribution of each, and found that urinary bicarbonate loss due to proximal RTA accounted for less than 10% of the fall in serum bicarbonate. The major cause of the metabolic acidosis was lactic acidosis. (2) Hypokalemia was found to be due to movement of potassium out of the extracellular space rather than to urinary loss. Potassium may have entered cells with phosphate or may have been sequestered in the gastrointestinal tract. (3) The coexistence of proximal RTA and acidemia made it possible to study the effect of acidemia on the urine-blood partial pressure of carbon dioxide (PCO2) gradient in alkaline urine (U-B PCO2). The U-B PCO2 measured during acidemia was much higher at the same urine bicarbonate concentration than in normal controls during alkalemia, providing evidence in humans that acidemia stimulates distal nephron hydrogen-ion secretion.

  18. Induction of Phosphoenolpyruvate Carboxykinase (PEPCK) during Acute Acidosis and Its Role in Acid Secretion by V-ATPase-Expressing Ionocytes

    PubMed Central

    Furukawa, Fumiya; Tseng, Yung-Che; Liu, Sian-Tai; Chou, Yi-Ling; Lin, Ching-Chun; Sung, Po-Hsuan; Uchida, Katsuhisa; Lin, Li-Yih; Hwang, Pung-Pung

    2015-01-01

    Vacuolar-Type H+-ATPase (V-ATPase) takes the central role in pumping H+ through cell membranes of diverse organisms, which is essential for surviving acid-base fluctuating lifestyles or environments. In mammals, although glucose is believed to be an important energy source to drive V-ATPase, and phosphoenolpyruvate carboxykinase (PEPCK), a key enzyme for gluconeogenesis, is known to be activated in response to acidosis, the link between acid secretion and PEPCK activation remains unclear. In the present study, we used zebrafish larva as an in vivo model to show the role of acid-inducible PEPCK activity in glucose production to support higher rate of H+ secretion via V-ATPase, by utilizing gene knockdown, glucose supplementation, and non-invasive scanning ion-selective electrode technique (SIET). Zebrafish larvae increased V-ATPase-mediated acid secretion and transiently expression of Pck1, a zebrafish homolog of PEPCK, in response to acid stress. When pck1 gene was knocked down by specific morpholino, the H+ secretion via V-ATPase decreased, but this effect was rescued by supplementation of glucose into the yolk. By assessing changes in amino acid content and gene expression of respective enzymes, glutamine and glutamate appeared to be the major source for replenishment of Krebs cycle intermediates, which are subtracted by Pck1 activity. Unexpectedly, pck1 knockdown did not affect glutamine/glutamate catalysis, which implies that Pck1 does not necessarily drive this process. The present study provides the first in vivo evidence that acid-induced PEPCK provides glucose for acid-base homeostasis at an individual level, which is supported by rapid pumping of H+ via V-ATPase at the cellular level. PMID:25999794

  19. Very Low-Protein Diet (VLPD) Reduces Metabolic Acidosis in Subjects with Chronic Kidney Disease: The “Nutritional Light Signal” of the Renal Acid Load

    PubMed Central

    Di Iorio, Biagio Raffaele; Di Micco, Lucia; Marzocco, Stefania; De Simone, Emanuele; De Blasio, Antonietta; Sirico, Maria Luisa; Nardone, Luca

    2017-01-01

    Background: Metabolic acidosis is a common complication of chronic kidney disease; current guidelines recommend treatment with alkali if bicarbonate levels are lower than 22 mMol/L. In fact, recent studies have shown that an early administration of alkali reduces progression of CKD. The aim of the study is to evaluate the effect of fruit and vegetables to reduce the acid load in CKD. Methods: We conducted a case-control study in 146 patients who received sodium bicarbonate. Of these, 54 patients assumed very low-protein diet (VLPD) and 92 were controls (ratio 1:2). We calculated every three months the potential renal acid load (PRAL) and the net endogenous acid production (NEAP), inversely correlated with serum bicarbonate levels and representing the non-volatile acid load derived from nutrition. Un-paired T-test and Chi-square test were used to assess differences between study groups at baseline and study completion. Two-tailed probability values ≤0.05 were considered statistically significant. Results: At baseline, there were no statistical differences between the two groups regarding systolic blood pressure (SBP), diastolic blood pressure (DBP), protein and phosphate intake, urinary sodium, potassium, phosphate and urea nitrogen, NEAP, and PRAL. VLPD patients showed at 6 and 12 months a significant reduction of SBP (p < 0.0001), DBP (p < 0.001), plasma urea (p < 0.0001) protein intake (p < 0.0001), calcemia (p < 0.0001), phosphatemia (p < 0.0001), phosphate intake (p < 0.0001), urinary sodium (p < 0.0001), urinary potassium (p < 0.002), and urinary phosphate (p < 0.0001). NEAP and PRAL were significantly reduced in VLPD during follow-up. Conclusion: VLPD reduces intake of acids; nutritional therapy of CKD, that has always taken into consideration a lower protein, salt, and phosphate intake, should be adopted to correct metabolic acidosis, an important target in the treatment of CKD patients. We provide useful indications regarding acid load of food and drinks

  20. [The value of alkalizing treatments in severe diabetic keto-acidosis].

    PubMed

    Verdon, F; Bringolf, M; Enrico, J F; Perret, C

    1976-12-11

    In 37 diabetic patients with severe acidosis (pH less than 7.0; [HCO3-] less than 5.0 mMol/l), administration of insulin was preceded by a rapid infusion of molar sodium bicarbonate in order to obtain partial correction of acidosis (pH approximately 7.20). 31 patients survived (83,8%); 6 patients died in cardio-circulatory failure associated in two cases with acute pulmonary edema. Initial administration of bicarbonate appears to be beneficial in preventing the deleterious effects of prolonged severe acidosis, such as cardiac arrhythmias, shock or acute pulmonary edema. Furthermore, partial correction of acidosis decreases the total dose of insulin necessary to compensate hyperglycemia and thereby reduces the danger of late hypoglycemia. This treatment calls for frequent checks on acid-base status and serum potassium. In most cases hypokalemia develops, but can be easily corrected by administration of potassium chloride. Normalization of arterial pH by bicarbonate infusion is not recommended in view of the development of late hypernatremia and metabolic alkalosis.

  1. Blood glucose threshold and the metabolic responses to incremental exercise tests with and without prior lactic acidosis induction.

    PubMed

    Simões, Herbert Gustavo; Campbell, Carmen S G; Kushnick, Michael R; Nakamura, Akiko; Katsanos, Christos S; Baldissera, Vilmar; Moffatt, Robert J

    2003-08-01

    This study compared the metabolic-ventilatory responses and the glycemic threshold identified during lactate minimum (LM) and individual anaerobic threshold (IAT) tests. In addition, the ability to determine the anaerobic power, aerobic-anaerobic transition (Trans) (e.g. ventilatory threshold; VT) and the maximal oxygen consumption (VO(2max)) all within a single incremental treadmill test (IT) was investigated. Fifteen physically fit men [25.9 (5.5) years; 77.4 (6.5) kg] performed the following: test 1, IT for IAT; and test 2, LM: 30-s Wingate test followed by 8 min rest and then an IT that was the same as test 1. Blood lactate concentration [lac], glucose concentration [gluc], pH, PO(2), PCO(2), base excess (BE) and ventilatory variables were measured. At the beginning of the IT for LM, the ventilation, PO(2) and VO(2) were higher and the pH, BE and PCO(2) were lower in relation to IAT ( P<0.05), while no differences were observed after reaching LM intensity during IT. Moreover, the Trans could be identified by [lac] (IAT, LM), minute ventilation [V(E;) VT identified during IAT protocol (VT-IAT) and VT identified during LM protocol (VT-LM)], and [gluc] (IGT, GM) during the IT for IAT and LM. The velocities (kilometers per hour) corresponding to IAT (12.6+/-1.6), VT-IAT (12.5+/-1.7), IGT (12.6+/-1.6), LM (12.5+/-1.5), VT-LM (12.3+/-1.5), and GM (12.6+/-1.9) were not different from each other and the LM and IAT protocols resulted in the similar VO(2max). We concluded that: (1) after reaching the LM the metabolic responses during IT are similar to IAT; (2) performing a Wingate test prior to an IT does not interfere with the Trans and VO(2max) attainment; (3) and the IGT and GM can predict the Trans.

  2. Acidosis-mediated regulation of the NHE1 isoform of the Na⁺/H⁺ exchanger in renal cells.

    PubMed

    Odunewu, Ayodeji; Fliegel, Larry

    2013-08-01

    The mammalian Na⁺/H⁺ exchanger isoform 1 (NHE1) is a ubiquitous plasma membrane protein that regulates intracellular pH by removing a proton in exchange for extracellular sodium. Renal tissues are subject to metabolic and respiratory acidosis, and acidosis has been shown to acutely activate NHE1 activity in other cell types. We examined if NHE1 is activated by acute acidosis in HEK293 and Madin-Darby canine kidney (MDCK) cells. Acute sustained intracellular acidosis (SIA) activated NHE1 in both cell types. We expressed wild-type and mutant NHE1 cDNAs in MDCK cells. All the cDNAs had a L163F/G174S mutation, which conferred a 100-fold resistance to EMD87580, an NHE1-specific inhibitor. We assayed exogenous NHE1 activity while inhibiting endogenous activity with EMD87580 and while inhibiting the NHE3 isoform of the Na⁺/H⁺ exchanger using the isoform-specific inhibitor S3226. We examined the activation and phosphorylation of the wild-type and mutant NHE1 proteins in response to SIA. In MDCK cells we demonstrated that the amino acids Ser⁷⁷¹, Ser⁷⁷⁶, Thr⁷⁷⁹, and Ser⁷⁸⁵ are important for NHE1 phosphorylation and activation after acute SIA. SIA activated ERK-dependent pathways in MDCK cells, and this was blocked by treatment with the MEK inhibitor U0126. Treatment with U0126 also blocked activation of NHE1 by SIA. These results suggest that acute acidosis activates NHE1 in mammalian kidney cells and that in MDCK cells this activation occurs through an ERK-dependent pathway affecting phosphorylation of a distinct set of amino acids in the cytosolic regulatory tail of NHE1.

  3. Distal renal tubular acidosis

    MedlinePlus

    ... get better with treatment. When to Contact a Medical Professional Call your health care provider if you have symptoms of distal renal tubular acidosis. Get medical help right away if you develop emergency symptoms ...

  4. Relation between blood pH and ionized calcium during acute metabolic alteration of the acid-base balance in vivo.

    PubMed

    Gaiter, A M; Bonfant, G; Manes, M; Belfanti, P; Alloatti, S

    1997-07-01

    We induced metabolic alkalosis and acidosis in 10 healthy volunteers in order to analyse in vivo relation between pH and ionized calcium (cCa2+). In the alkalinization test, 2.7 mol/kg NaHCO3 was injected. In the acidification test, volunteers took 4 mmol/kg NH4Cl. Blood pH and cCa2+ (mmol/l) mean values (SD) baseline, after alkalinization and acidification tests, were: 7.363 (0.018), 7.456 (0.031), 7.244 (0.031), 1.27 (0.03), 1.14 (0.03) and 1.38 (0.04). Mean slope of regression log cCa2+/pH was -0.39 (SD 0.11). Such a slope differs after in vivo or in vitro changes, due to the in vivo rapid restoration of equilibrium between the plasmatic and interstitial compartments following changes in water and electrolyte concentrations. The type of acid-base alteration-respiratory or metabolic-influences pH changes, and consequently the regression slope. The in vivo slope for log cCa2+/pH in normal subjects (-0.21) is much the same as in acute respiratory alterations (-0.17), whereas it differs in acute metabolic alterations (present study). Bicarbonates play different roles: the same changes in pH cause greater changes in cCa2+ after acute metabolic rather than respiratory alterations. Ca2+ homeostasis is maintained in acute respiratory acid-base imbalance, despite wide shifts in pH, whereas in acute metabolic alterations even small pH changes have striking repercussions on cCa2+. The experimental angular coefficient for in vivo acute metabolic acid-base alterations differs from the theoretical one calculated by Thode's differential equation (-0.25).

  5. Ruminal Acidosis in Feedlot: From Aetiology to Prevention

    PubMed Central

    Hernández, Joaquín; Benedito, José Luis; Abuelo, Angel; Castillo, Cristina

    2014-01-01

    Acute ruminal acidosis is a metabolic status defined by decreased blood pH and bicarbonate, caused by overproduction of ruminal D-lactate. It will appear when animals ingest excessive amount of nonstructural carbohydrates with low neutral detergent fiber. Animals will show ruminal hypotony/atony with hydrorumen and a typical parakeratosis-rumenitis liver abscess complex, associated with a plethora of systemic manifestations such as diarrhea and dehydration, liver abscesses, infections of the lung, the heart, and/or the kidney, and laminitis, as well as neurologic symptoms due to both cerebrocortical necrosis and the direct effect of D-lactate on neurons. In feedlots, warning signs include decrease in chewing activity, weight, and dry matter intake and increase in laminitis and diarrhea prevalence. The prognosis is quite variable. Treatment will be based on the control of systemic acidosis and dehydration. Prevention is the most important tool and will require normalization of ruminal pH and microbiota. Appropriate feeding strategies are essential and involve changing the dietary composition to increase neutral detergent fiber content and greater particle size and length. Appropriate grain processing can control the fermentation rate while additives such as prebiotics or probiotics can help to stabilize the ruminal environment. Immunization against producers of D-lactate is being explored. PMID:25489604

  6. Transient hyperkalemic distal renal tubular acidosis with bicarbonate wasting in a young child.

    PubMed

    Khositseth, Sookkasem

    2011-12-01

    Distal renal tubular acidosis is a clinical syndrome characterized by inability to acidify urine in the presence of metabolic acidosis. Classic dRTA patients exhibit failure to thrive, polyuria, metabolic acidosis and hypokalemia. Hyperkalemic dRTA without underlying disease is very rare. Transient bicarbonate wasting accompanied with hypokalemic dRTA was reported in infants. Herein, a transient hyperkalemic dRTA with bicarbonate wasting was reported in a young child.

  7. Acute nutritional ketosis: implications for exercise performance and metabolism.

    PubMed

    Cox, Pete J; Clarke, Kieran

    2014-01-01

    Ketone bodies acetoacetate (AcAc) and D-β-hydroxybutyrate (βHB) may provide an alternative carbon source to fuel exercise when delivered acutely in nutritional form. The metabolic actions of ketone bodies are based on sound evolutionary principles to prolong survival during caloric deprivation. By harnessing the potential of these metabolic actions during exercise, athletic performance could be influenced, providing a useful model for the application of ketosis in therapeutic conditions. This article examines the energetic implications of ketone body utilisation with particular reference to exercise metabolism and substrate energetics.

  8. Acute nutritional ketosis: implications for exercise performance and metabolism

    PubMed Central

    2014-01-01

    Ketone bodies acetoacetate (AcAc) and D-β-hydroxybutyrate (βHB) may provide an alternative carbon source to fuel exercise when delivered acutely in nutritional form. The metabolic actions of ketone bodies are based on sound evolutionary principles to prolong survival during caloric deprivation. By harnessing the potential of these metabolic actions during exercise, athletic performance could be influenced, providing a useful model for the application of ketosis in therapeutic conditions. This article examines the energetic implications of ketone body utilisation with particular reference to exercise metabolism and substrate energetics. PMID:25379174

  9. Severe lactic acidosis after an iatrogenic propylene glycol overdose.

    PubMed

    Zosel, Amy; Egelhoff, Elizabeth; Heard, Kennon

    2010-02-01

    Propylene glycol is a diluent found in many intravenous and oral drugs, including phenytoin, diazepam, and lorazepam. Propylene glycol is eliminated from the body by oxidation through alcohol dehydrogenase to form lactic acid. Under normal conditions, the body converts lactate to pyruvate and metabolizes pyruvate through the Krebs cycle. Lactic acidosis has occurred in patients, often those with renal dysfunction, who were receiving prolonged infusions of drugs that contain propylene glycol as a diluent. We describe a 50-year-old man who experienced severe lactic acidosis after receiving an accidental overdose of lorazepam, which contains propylene glycol. The patient was acutely intoxicated, with a serum ethanol concentration of 406 mg/dl. He had choked on a large piece of meat and subsequently experienced pulseless electrical activity with ventricular fibrillation cardiac arrest. He was brought to the emergency department; within 2 hours, he was admitted to the intensive care unit for initiation of the hypothermia protocol. The patient began to experience generalized tonic-clonic seizures 12 hours later, which resolved after several boluses of lorazepam. A lorazepam infusion was started; however, it was inadvertently administered at a rate of 2 mg/minute instead of the standard rate of 2 mg/hour. Ten hours later, the administration error was recognized and the infusion stopped. The patient's peak propylene glycol level was 659 mg/dl, pH 6.9, serum bicarbonate level 5 mEq/L, and lactate level 18.6 mmol/L. Fomepizole was started the next day and was continued until hospital day 3. Continuous renal replacement therapy was started and then replaced with continuous venovenous hemofiltration (CVVH) for the remainder of the hospital stay. The patient's acidosis resolved by day 3, when his propylene glycol level had decreased to 45 mg/dl. Fomepizole was discontinued, but the patient's prognosis was poor (anoxic brain injury); thus care was withdrawn and the patient died

  10. Klinefelter's syndrome with renal tubular acidosis: impact on height.

    PubMed

    Jebasingh, F; Paul, T V; Spurgeon, R; Abraham, S; Jacob, J J

    2010-02-01

    A 19-year-old Indian man presented with a history of proximal muscle weakness, knock knees and gynaecomastia. On examination he had features of rickets and bilateral small testes. Karyotyping revealed a chromosomal pattern of 47,XXX, confirming the diagnosis of Klinefelter's syndrome. He was also found to have hyperchloraemic metabolic acidosis with hypokalaemia, hypophosphataemia, phosphaturia and glycosuria, which favoured a diagnosis of proximal renal tubular acidosis. Patients with Klinefelter's syndrome typically have a tall stature due to androgen deficiency, resulting in unfused epiphyses and an additional X chromosome. However, this patient had a short stature due to associated proximal renal tubular acidosis. To the best of our knowledge, this is the second case of Klinefelter's syndrome with short stature due to associated renal tubular acidosis reported in the literature. This report highlights the need to consider other causes when patients with Klinefelter's syndrome present with a short stature.

  11. Understanding lactic acidosis in paracetamol (acetaminophen) poisoning.

    PubMed

    Shah, Anoop D; Wood, David M; Dargan, Paul I

    2011-01-01

    Paracetamol (acetaminophen) is one of the most commonly taken drugs in overdose in many areas of the world, and the most common cause of acute liver failure in both the UK and USA. Paracetamol poisoning can result in lactic acidosis in two different scenarios. First, early in the course of poisoning and before the onset of hepatotoxicity in patients with massive ingestion; a lactic acidosis is usually associated with coma. Experimental evidence from studies in whole animals, perfused liver slices and cell cultures has shown that the toxic metabolite of paracetamol, N-acetyl-p-benzo-quinone imine, inhibits electron transfer in the mitochondrial respiratory chain and thus inhibits aerobic respiration. This occurs only at very high concentrations of paracetamol, and precedes cellular injury by several hours. The second scenario in which lactic acidosis can occur is later in the course of paracetamol poisoning as a consequence of established liver failure. In these patients lactate is elevated primarily because of reduced hepatic clearance, but in shocked patients there may also be a contribution of peripheral anaerobic respiration because of tissue hypoperfusion. In patients admitted to a liver unit with paracetamol hepatotoxicity, the post-resuscitation arterial lactate concentration has been shown to be a strong predictor of mortality, and is included in the modified King's College criteria for consideration of liver transplantation. We would therefore recommend that post-resuscitation lactate is measured in all patients with a severe paracetamol overdose resulting in either reduced conscious level or hepatic failure.

  12. Type IV renal tubular acidosis and spironolactone therapy in the elderly.

    PubMed Central

    O'Connell, J. E.; Colledge, N. R.

    1993-01-01

    Spironolactone therapy is a well-known cause of hyperkalaemia, but in susceptible patient, it may also be associated with metabolic acidosis. We report a case of severe renal tubular acidosis (Type IV) with life-threatening hyperkalaemia caused by spironolactone, and discuss the mechanisms by which this may occur. PMID:8290440

  13. Acidosis-Induced Dysfunction of Cortical GABAergic Neurons through Astrocyte-Related Excitotoxicity

    PubMed Central

    Guan, Sudong; Zhu, Yan; Wang, Jin-Hui

    2015-01-01

    Background Acidosis impairs cognitions and behaviors presumably by acidification-induced changes in neuronal metabolism. Cortical GABAergic neurons are vulnerable to pathological factors and their injury leads to brain dysfunction. How acidosis induces GABAergic neuron injury remains elusive. As the glia cells and neurons interact each other, we intend to examine the role of the astrocytes in acidosis-induced GABAergic neuron injury. Results Experiments were done at GABAergic cells and astrocytes in mouse cortical slices. To identify astrocytic involvement in acidosis-induced impairment, we induced the acidification in single GABAergic neuron by infusing proton intracellularly or in both neurons and astrocytes by using proton extracellularly. Compared the effects of intracellular acidification and extracellular acidification on GABAergic neurons, we found that their active intrinsic properties and synaptic outputs appeared more severely impaired in extracellular acidosis than intracellular acidosis. Meanwhile, extracellular acidosis deteriorated glutamate transporter currents on the astrocytes and upregulated excitatory synaptic transmission on the GABAergic neurons. Moreover, the antagonists of glutamate NMDA-/AMPA-receptors partially reverse extracellular acidosis-induced injury in the GABAergic neurons. Conclusion Our studies suggest that acidosis leads to the dysfunction of cortical GABAergic neurons by astrocyte-mediated excitotoxicity, in addition to their metabolic changes as indicated previously. PMID:26474076

  14. Hyperkalemia in neonatal diarrheic calves depends on the degree of dehydration and the cause of the metabolic acidosis but does not require the presence of acidemia.

    PubMed

    Trefz, F M; Constable, P D; Sauter-Louis, C; Lorch, A; Knubben-Schweizer, G; Lorenz, I

    2013-01-01

    Hyperkalemia is a clinically important electrolyte imbalance in neonatal diarrheic calves that has previously been associated with skeletal muscle weakness and life-threatening cardiac arrhythmias. The aim of the present retrospective analysis was to identify risk factors for hyperkalemia in a convenience sample of 832 calves (≤ 21 d of age) with a clinical diagnosis of diarrhea admitted to a veterinary teaching hospital. Plasma potassium concentrations were most closely associated with parameters of dehydration and renal function such as serum creatinine [Spearman correlation (rs) = 0.61], urea (rs = 0.51), and inorganic phosphorus concentrations (rs = 0.64). Plasma potassium concentrations were weakly associated with venous blood pH (rs = -0.21). Although venous blood pH was not predictive in a multivariate linear regression analysis, the odds of having hyperkalemia (>5.8 mmol/L) in acidemic calves was found to be 8.6 times as high as in nonacidemic calves [95% confidence interval (CI): 4.8-15.4]. However, the presence of hyperkalemia depended on the nature of an existing acidosis, and the odds for the presence of hyperkalemia in acidemic calves with hyper-D-lactatemia (>3.96 mmol/L) were only 0.15 times as high as in acidemic calves with normal D-lactate concentrations (95% CI, 0.11-0.22). Acidemia in hyperkalemic diarrheic calves was associated with hyponatremia and increased concentrations of inorganic phosphorus, L-lactate, and unidentified strong anions that presumably included uremic anions such as sulfate. We conclude that hyper-D-lactatemia in neonatal diarrheic calves is not usually associated with elevated plasma potassium concentrations. Application of the simplified strong ion acid-base model indicated that dehydration is an important contributor to the pathogenesis of hyperkalemia and acidemia in neonatal calves with diarrhea.

  15. Type 4 renal tubular acidosis in a kidney transplant recipient.

    PubMed

    Kulkarni, Manjunath

    2016-02-01

    We report a case of a 66-year-old diabetic patient who presented with muscle weakness 2 weeks after kidney transplantation. Her immunosuppressive regimen included tacrolimus, mycophenolate mofetil, and steroids. She was found to have hyperkalemia and normal anion gap metabolic acidosis. Tacrolimus levels were in therapeutic range. All other drugs such as beta blockers and trimethoprim - sulfamethoxazole were stopped. She did not respond to routine antikalemic measures. Further evaluation revealed type 4 renal tubular acidosis. Serum potassium levels returned to normal after starting sodium bicarbonate and fludrocortisone therapy. Though hyperkalemia is common in kidney transplant recipients, determining exact cause can guide specific treatment.

  16. Acute metabolic effects of ammonia on the enzymes of glutamate metabolism in isolated astroglial cells.

    PubMed

    Subbalakshmi, G Y; Murthy, C R

    1983-01-01

    Enzymes of glutamate metabolism were studied in the astrocytes isolated from rats injected with a large dose of ammonium acetate and compared with those isolated from controls. The activities of glutamate dehydrogenase (GDH) and glutaminase decreased while those of glutamine synthetase (GS) and aspartate aminotransferase (AAT) increased both in convulsive and comatose states. The activity of alanine aminotransferase (A1AT) increased only in convulsive state. The results suggested that glutamate required for the formation of glutamine in astrocytes might have its origin in nerve endings and the depletion of citric acid cycle intermediates might occur in nerve endings at least in acute ammonia toxicity.

  17. Acute Ozone-Induced Pulmonary and Systemic Metabolic ...

    EPA Pesticide Factsheets

    Acute ozone exposure increases circulating stress hormones and induces metabolic alterations in animals and humans. We hypothesized that the increase of adrenal-derived stress hormones is necessary for both ozone-induced metabolic effects and lung injury. Male Wistar-Kyoto rats underwent adrenal demedullation (DEMED), total bilateral adrenalectomy (ADREX), or sham surgery (SHAM). After a 4 day recovery, rats were exposed to air or ozone (1ppm), 4h/day for 1 or 2 days. Circulating adrenaline levels dropped to nearly zero in DEMED and ADREX rats relative to air-exposed SHAM. Corticosterone levels tended to be low in DEMED rats and dropped to nearly zero in ADREX rats. Adrenalectomy in air-exposed rats caused modest changes in metabolites and lung toxicity parameters. Ozone-induced hyperglycemia and glucose intolerance were markedly attenuated in DEMED rats with nearly complete reversal in ADREX rats. Ozone increased circulating epinephrine and corticosterone in SHAM but not in DEMED or ADREX rats. Free fatty acids (p=0.15) and branched-chain amino acids increased after ozone exposure in SHAM but not in DEMED or ADREX rats. Lung minute volume was not affected by surgery or ozone but ozone-induced labored breathing was less pronounced in ADREX rats. Ozone-induced increases in lung protein leakage and neutrophilic inflammation were markedly reduced in DEMED and ADREX rats (ADREX>DMED). Ozone-mediated decreases in circulating white blood cells in SHAM were not obser

  18. Acute Ozone-Induced Pulmonary and Systemic Metabolic ...

    EPA Pesticide Factsheets

    Acute ozone exposure increases circulating stress hormones and induces peripheral metabolic alterations in animals and humans. We hypothesized that the increase of adrenal-derived stress hormones is necessary for ozone-induced systemic metabolic effects and lung injury. Male Wistar-Kyoto rats (12 week-old) underwent total bilateral adrenalectomy (ADREX), adrenal demedullation (DEMED) or sham surgery (SHEM). After 4 day recovery, rats were exposed to air or ozone (1ppm), 4h/day for 1 or 2 days. Circulating adrenaline levels dropped to nearly zero in DEMED and ADREX rats relative to air-exposed SHAM. Corticosterone levels tended to be low in DEMED rats and dropped to nearly zero in ADREX rats. Adrenalectomy in air-exposed rats caused modest changes in metabolites and lung toxicity parameters. Ozone-induced hyperglycemia and glucose intolerance were markedly attenuated in DEMED with nearly complete reversal in ADREX rats. Ozone increased circulating epinephrine and corticosterone in SHAM but not in DEMED or ADREX rats. Free fatty acids and branched-chain amino acids tended to increase after ozone exposure in SHAM but not in DEMED or ADREX rats. Lung minute volume was not affected by surgery or ozone but ozone-induced labored breathing was less pronounced in ADREX rats. Ozone-induced increases in lung protein leakage and neutrophilic inflammation were markedly reduced in DEMED and ADREX rats (ADREX>DMED). Ozone-mediated decrease in circulating WBC in SHAM was not

  19. Energetic metabolism during acute stretch-related atrial fibrillation Shortened title: atrial fibrillation and metabolism

    PubMed Central

    Kalifa, J; Maixent, JM; Chalvidan, T; Dalmasso, C; Colin, D; Cozma, D; Laurent, P; Deharo, JC; Djiane, P; Cozzone, P; Bernard, M

    2010-01-01

    Background and methods Perturbations in energetic metabolism and impaired atrial contractility may play an important role in the pathogenesis of atrial fibrillation (AF). Besides, atrial stretch is commonly associated with AF. However, the atrial energetics of stretch-related AF are poorly understood. Here, we measured indicators of energy metabolism during acute-stretch related AF. PCr, adenine nucleotides and derivatives concentrations as well as the activity of the F0F1-ATPase and Na,K-ATPase were obtained after one hour of stretch and/or AF in isolated rabbit hearts and compared to control hearts without stretch and AF. Results After one hour of stretch-related AF, the total adenine nucleotides pool was significantly lower (42.2±2.6 versus 63.7±8.3 µmol/g protein in control group, p<0.05) and the PCr/ATP ratio significantly higher (2.3±0.3 vs 1.1± 0.1 in control group p<0.05), because of ATP, ADP and AMP decrease and PCr increase. The sum of high energy phosphate compounds did not change. There were no significant differences in F0F1-ATPase nor Na,K-ATPase activity between the groups. Conclusions Results show that in this experimental model, acute-stretch related AF induces specific modifications of atrial myocytes energetics that may play a pivotal role in the perpetuation of the arrhythmia. PMID:18553177

  20. Water, acidosis, and experimental pyelonephritis

    PubMed Central

    Andriole, Vincent T.

    1970-01-01

    The effect of water restriction and ammonium chloride acidosis on the course of Escherichia coli pyelonephritis was determined in the nonobstructed kidney of the rat. To alter the chemical composition of the renal medulla, water intake was reduced in rats to one-half the normal daily intake. Water restriction increased the incidence of coliform pyelonephritis. Systemic acidosis, produced by giving a 300 mM solution of ammonium chloride, increased urinary osmolality to values comparable to water restriction and also predisposed to pyelonephritis. However, when rats were fed the same solution of ammonium chloride but were allowed access to tap water ad lib., urinary osmolality values were comparable to those observed in normal animals, and susceptibility to pyelonephritis was reduced or eliminated despite a degree of systemic acidosis similar to that observed in rats fed ammonium chloride solution without access to tap water. These results suggest that water diuresis may overcome the inactivation of complement produced by ammonium chloride acidosis and that renal medullary hypertonicity, produced by either water restriction or ammonium chloride acidosis, is a major determinant of this tissue's unique susceptibility to infection. PMID:4902827

  1. Life threatening hyperkalemia and acidosis secondary to trimethoprim-sulfamethoxazole treatment.

    PubMed

    Margassery, S; Bastani, B

    2001-01-01

    We present a 77-year-old male with moderate chronic renal insufficiency from diabetic nephropathy who developed severe metabolic acidosis and life threatening hyperkalemia on treatment with regular dose of trimethoprim-sulfamethoxazole (TMP-SMZ) for urinary tract infection. The metabolic acidosis and hyperkalemia resolved upon appropriate medical intervention and discontinuation of TMP-SMZ. While hyperkalemia has commonly been reported with high dose of TMP-SMZ, severe metabolic acidosis is quite uncommon with regular dose TMP-SMZ. We emphasize that patients with renal tubular acidosis (RTA), renal insufficiency, aldosterone deficiency, old age with reduced renal mass and function, and angiotensin converting enzyme (ACE)-inhibitor therapy are at high risk of developing these severe and potentially life threatening complications.

  2. Renal tubular acidosis type 4 in pregnancy.

    PubMed

    Jakes, Adam Daniel; Baynes, Kevin; Nelson-Piercy, Catherine

    2016-03-17

    We describe the clinical course of renal tubular acidosis (RTA) type 4 in pregnancy, which has not been previously published. Renal tubular acidosis type 4 is a condition associated with increased urinary ammonia secondary to hypoaldosteronism or pseudohypoaldosteronism. Pregnancy may worsen the hyperkalaemia and acidosis of renal tubular acidosis type 4, possibly through an antialdosterone effect. We advise regular monitoring of potassium and pH throughout pregnancy to ensure safe levels are maintained.

  3. Hyperkalemic distal renal tubular acidosis caused by immunosuppressant treatment with tacrolimus in a liver transplant patient: case report.

    PubMed

    Riveiro-Barciela, M; Campos-Varela, I; Tovar, J L; Vargas, V; Simón-Talero, M; Ventura-Cots, M; Crespo, M; Bilbao, I; Castells, L

    2011-12-01

    Nephrotoxicity is one of the most common side effects of long-term immunosuppressive therapy with calcineurin inhibitors. We describe a case of distal renal tubular acidosis secondary to tacrolimus administration. A 43-year-old man with end-stage liver disease due to hepatitis C and B virus infections and alcoholic cirrhosis received a liver transplantation under immunosuppressive treatment with tacrolimus and mycophenolate mofetil. In the postoperative period, the patient developed hyperkalemic hyperchloremic metabolic acidosis, with a normal serum anion gap and a positive urinary anion gap, suggesting distal renal tubular acidosis. We excluded other causes of hyperkalemia. Administration of intravenous bicarbonate, loop diuretics, and oral resin exchanger corrected the acidosis and potassium levels. Distal renal tubular acidosis is one of several types of nephrotoxicity induced by tacrolimus treatment, resulting from inhibition of potassium secretion in the collecting duct. Treatment to correct the acidosis and hyperkalemia should be promptly initiated, and the tacrolimus dose adjusted when possible.

  4. Acute Activation of Metabolic Syndrome Components in Pediatric Acute Lymphoblastic Leukemia Patients Treated with Dexamethasone

    PubMed Central

    Warris, Lidewij T.; van den Akker, Erica L. T.; Bierings, Marc B.; van den Bos, Cor; Zwaan, Christian M.; Sassen, Sebastiaan D. T.; Tissing, Wim J. E.; Veening, Margreet A.; Pieters, Rob; van den Heuvel-Eibrink, Marry M.

    2016-01-01

    Although dexamethasone is highly effective in the treatment of pediatric acute lymphoblastic leukemia (ALL), it can cause serious metabolic side effects. Because studies regarding the effects of dexamethasone are limited by their small scale, we prospectively studied the direct effects of treating pediatric ALL with dexamethasone administration with respect to activation of components of metabolic syndrome (MetS); in addition, we investigated whether these side effects were correlated with the level of dexamethasone. Fifty pediatric patients (3–16 years of age) with ALL were studied during a 5-day dexamethasone course during the maintenance phase of the Dutch Childhood Oncology Group ALL-10 and ALL-11 protocols. Fasting insulin, glucose, total cholesterol, HDL, LDL, and triglycerides levels were measured at baseline (before the start of dexamethasone; T1) and on the fifth day of treatment (T2). Dexamethasone trough levels were measured at T2. We found that dexamethasone treatment significantly increased the following fasting serum levels (P<0.05): HDL, LDL, total cholesterol, triglycerides, glucose, and insulin. In addition, dexamethasone increased insulin resistance (HOMA-IR>3.4) from 8% to 85% (P<0.01). Dexamethasone treatment also significantly increased the diastolic and systolic blood pressure. Lastly, dexamethasone trough levels (N = 24) were directly correlated with high glucose levels at T2, but not with other parameters. These results indicate that dexamethasone treatment acutely induces three components of the MetS. Together with the weight gain typically associated with dexamethasone treatment, these factors may contribute to the higher prevalence of MetS and cardiovascular risk among survivors of childhood leukemia who received dexamethasone treatment. PMID:27362350

  5. Anesthetic Management of a Surgical Patient with Chronic Renal Tubular Acidosis Complicated by Subclinical Hypothyroidism

    PubMed Central

    Yamazaki, Haruyuki; Yasumura, Rie; Wada, Kosuke

    2016-01-01

    A 53-year-old man with chronic renal tubular acidosis and subclinical hypothyroidism underwent lower leg amputation surgery under general anesthesia. Perioperative acid-base management in such patients poses many difficulties because both pathophysiologies have the potential to complicate the interpretation of capnometry and arterial blood gas analysis data; inappropriate correction of chronic metabolic acidosis may lead to postoperative respiratory deterioration. We discuss the management of perioperative acidosis in order to achieve successful weaning from mechanical ventilation and promise a complete recovery from anesthesia. PMID:27648310

  6. Effect of a metabolically created systemic acidosis on calcium homeostasis and the diurnal variation in urine pH in the non-lactating pregnant dairy cow.

    PubMed

    Roche, John R; Dalley, Dawn E; O'Mara, Frank P

    2007-02-01

    Reducing the dietary cation-anion difference (DCAD) has been shown to be an effective means of preventing parturient paresis in confinement systems where cows are offered a total mixed ration containing DCAD-reducing mineral compounds (anionic salts). Such a supplementation strategy is not possible in cows being group fed forages precalving, and little is known about the effect of supplementing these cows with large amounts of anionic salts twice daily. Eight non-lactating, pregnant Holstein-Friesian cows were allocated to two levels of DCAD (-20 and +18 meq/100 g DM) for 24 d, with an intensive Ca balance undertaken in metabolism stalls following a 2-week acclimatization to diet. The basal diet was 3 kg DM of crushed barley and 7 kg DM of pasture-hay. Urine and faeces were collected separately, weighed daily for 5 d and analysed for Ca content. Urinary Ca, creatinine and hydroxyproline concentration and plasma Ca concentration were determined during the period of the balance study. The diurnal pattern in urine and rumen pH was determined over 2 d. Decreasing DCAD reduced (P<0.001) the pH of urine, and increased (P<0.05) Ca absorption. Plasma Ca concentration was not affected by DCAD, and DCAD did not affect the output of urinary hydroxyproline, a marker of bone resorption. Twice-daily supplementation of anionic salts was sufficient to reduce the pH of blood and increase gastrointestinal Ca absorption. There was no diurnal variation in the pH of urine, suggesting that time of sampling to determine efficacy of DCAD in reducing systemic pH was not important.

  7. Deep Sequencing Reveals Novel Genetic Variants in Children with Acute Liver Failure and Tissue Evidence of Impaired Energy Metabolism

    PubMed Central

    Valencia, C. Alexander; Wang, Xinjian; Wang, Jin; Peters, Anna; Simmons, Julia R.; Moran, Molly C.; Mathur, Abhinav; Husami, Ammar; Qian, Yaping; Sheridan, Rachel; Bove, Kevin E.; Witte, David; Huang, Taosheng; Miethke, Alexander G.

    2016-01-01

    Background & Aims The etiology of acute liver failure (ALF) remains elusive in almost half of affected children. We hypothesized that inherited mitochondrial and fatty acid oxidation disorders were occult etiological factors in patients with idiopathic ALF and impaired energy metabolism. Methods Twelve patients with elevated blood molar lactate/pyruvate ratio and indeterminate etiology were selected from a retrospective cohort of 74 subjects with ALF because their fixed and frozen liver samples were available for histological, ultrastructural, molecular and biochemical analysis. Results A customized next-generation sequencing panel for 26 genes associated with mitochondrial and fatty acid oxidation defects revealed mutations and sequence variants in five subjects. Variants involved the genes ACAD9, POLG, POLG2, DGUOK, and RRM2B; the latter not previously reported in subjects with ALF. The explanted livers of the patients with heterozygous, truncating insertion mutations in RRM2B showed patchy micro- and macrovesicular steatosis, decreased mitochondrial DNA (mtDNA) content <30% of controls, and reduced respiratory chain complex activity; both patients had good post-transplant outcome. One infant with severe lactic acidosis was found to carry two heterozygous variants in ACAD9, which was associated with isolated complex I deficiency and diffuse hypergranular hepatocytes. The two subjects with heterozygous variants of unknown clinical significance in POLG and DGUOK developed ALF following drug exposure. Their hepatocytes displayed abnormal mitochondria by electron microscopy. Conclusion Targeted next generation sequencing and correlation with histological, ultrastructural and functional studies on liver tissue in children with elevated lactate/pyruvate ratio expand the spectrum of genes associated with pediatric ALF. PMID:27483465

  8. Ruminal acidosis in a 21-month-old Holstein heifer

    PubMed Central

    Golder, Helen M.; Celi, Pietro; Lean, Ian J.

    2014-01-01

    Rumen and blood biochemical profiles were monitored in 8 Holstein heifers exposed to a carbohydrate feeding challenge. One of the heifers had clinical signs consistent with acute ruminal acidosis on the day of, and subsequent to, the challenge. Within 24 h of challenge, 6 of 7 rumen volatile fatty acids measured were not detectable in this heifer and her rumen total lactate concentration was > 70 mM. PMID:24891639

  9. Metformin-associated lactic acidosis treated with continuous renal replacement therapy.

    PubMed

    Nakamura, Akihide; Suzuki, Kei; Imai, Hiroshi; Katayama, Naoyuki

    2017-02-10

    Metformin-associated lactic acidosis (MALA) is a rare but life-threatening complication. We report a case of MALA in a man aged 71 years who was treated with continuous renal replacement therapy (CRRT). The patient was brought to the hospital for prolonged and gradual worsening gastrointestinal symptoms. Although he received intravenous treatment, he developed catecholamine-resistant shock, and blood gas analysis revealed lactic acidosis. Bicarbonate and antibiotics for possible sepsis were initiated, but with no clear benefit. Owing to haemodynamic instability with metabolic acidosis, urgent CRRT was given: it was immediately effective in reducing lactate levels; pH values completely normalised within 18 hours, and he was stabilised. MALA sometimes presents with non-specific symptoms, and is important to consider when treating unexplainable metabolic acidosis. In severe cases, CRRT has potential merit, particularly in haemodynamically unstable patients. It is important to be familiar with MALA as a medical emergency, even for emergency physicians.

  10. Clinical approach to renal tubular acidosis in adult patients.

    PubMed

    Reddy, P

    2011-03-01

    Renal tubular acidosis (RTA) is a group of disorders observed in patients with normal anion gap metabolic acidosis. There are three major forms of RTA: A proximal (type II) RTA and two types of distal RTAs (type I and type IV). Proximal (type II) RTA originates from the inability to reabsorb bicarbonate normally in the proximal tubule. Type I RTA is associated with inability to excrete the daily acid load and may present with hyperkalaemia or hypokalaemia. The most prominent abnormality in type IV RTA is hyperkalaemia caused by hypoaldosteronism. This article extensively reviews the mechanism of hydrogen ion generation from metabolism of normal diet and various forms of RTA leading to disruptions of normal acid-base handling by the kidneys.

  11. Acidosis Activates Endoplasmic Reticulum Stress Pathways through GPR4 in Human Vascular Endothelial Cells

    PubMed Central

    Dong, Lixue; Krewson, Elizabeth A.; Yang, Li V.

    2017-01-01

    Acidosis commonly exists in the tissue microenvironment of various pathophysiological conditions such as tumors, inflammation, ischemia, metabolic disease, and respiratory disease. For instance, the tumor microenvironment is characterized by acidosis and hypoxia due to tumor heterogeneity, aerobic glycolysis (the “Warburg effect”), and the defective vasculature that cannot efficiently deliver oxygen and nutrients or remove metabolic acid byproduct. How the acidic microenvironment affects the function of blood vessels, however, is not well defined. GPR4 (G protein-coupled receptor 4) is a member of the proton-sensing G protein-coupled receptors and it has high expression in endothelial cells (ECs). We have previously reported that acidosis induces a broad inflammatory response in ECs. Acidosis also increases the expression of several endoplasmic reticulum (ER) stress response genes such as CHOP (C/EBP homologous protein) and ATF3 (activating transcription factor 3). In the current study, we have examined acidosis/GPR4-induced ER stress pathways in human umbilical vein endothelial cells (HUVEC) and other types of ECs. All three arms of the ER stress/unfolded protein response (UPR) pathways were activated by acidosis in ECs as an increased expression of phosphorylated eIF2α (eukaryotic initiation factor 2α), phosphorylated IRE1α (inositol-requiring enzyme 1α), and cleaved ATF6 upon acidic pH treatment was observed. The expression of other downstream mediators of the UPR, such as ATF4, ATF3, and spliced XBP-1 (X box-binding protein 1), was also induced by acidosis. Through genetic and pharmacological approaches to modulate the expression level or activity of GPR4 in HUVEC, we found that GPR4 plays an important role in mediating the ER stress response induced by acidosis. As ER stress/UPR can cause inflammation and cell apoptosis, acidosis/GPR4-induced ER stress pathways in ECs may regulate vascular growth and inflammatory response in the acidic microenvironment

  12. Acute metabolic response to fasted and postprandial exercise

    PubMed Central

    de Lima, Filipe Dinato; Correia, Ana Luiza Matias; Teixeira, Denilson da Silva; da Silva Neto, Domingos Vasco; Fernandes, Ítalo Sávio Gonçalves; Viana, Mário Boratto Xavier; Petitto, Mateus; da Silva Sampaio, Rodney Antônio; Chaves, Sandro Nobre; Alves, Simone Teixeira; Dantas, Renata Aparecida Elias; Mota, Márcio Rabelo

    2015-01-01

    The aim of this study was to analyze the acute metabolic response to exercise in fasting and postprandial. For this, ten individuals were submitted to an incremental treadmill test, with an initial speed of 5 and 1 km/h increments every minute, with no inclination, and a body composition assessment. After this 1st day, all volunteers were submitted to two experimental procedures (fasting and postprandial), with an aerobic exercise performed for 36 minutes at 65% of maximal oxygen consumption. At postprandial procedure, all subjects ingested a breakfast containing 59.3 g of carbohydrate (76.73%), 9.97 g of protein (12.90%), 8.01 g of lipids (10.37%), with a total energy intake of 349.17 kcal. An analysis of plasma concentration of triglycerides, lactate, and glucose was performed in two stages: before and after exercise. The Shapiro–Wilk test was used to verify the normality of the data. For analysis of glucose concentration, plasma lactate, and triglycerides, we used a repeated measures analysis of variance factorial 2×2, with Bonferroni multiple comparison test. The significance level of P<0.05 was adopted. The results indicated a maintenance level of glucose at fasting and a decrease in glucose concentration at postprandial exercise. Both conditions increase plasma lactate. Triglycerides also increased in the two experimental conditions; however, after exercise fasting, the increase was significantly higher than in the postprandial exercise. These data suggest that both exercises could increase plasma lactate and triglycerides. However, exercise performed in fasting condition decreases glucose concentration and increases triglycerides, even more than postprandial exercise. PMID:26316800

  13. Phenylbutyrate Therapy for Pyruvate Dehydrogenase Complex Deficiency and Lactic Acidosis

    PubMed Central

    Ferriero, Rosa; Manco, Giuseppe; Lamantea, Eleonora; Nusco, Edoardo; Ferrante, Mariella I.; Sordino, Paolo; Stacpoole, Peter W.; Lee, Brendan; Zeviani, Massimo; Brunetti-Pierri, Nicola

    2014-01-01

    Lactic acidosis is a build-up of lactic acid in the blood and tissues, which can be due to several inborn errors of metabolism as well as nongenetic conditions. Deficiency of pyruvate dehydrogenase complex (PDHC) is the most common genetic disorder leading to lactic acidosis. Phosphorylation of specific serine residues of the E1α subunit of PDHC by pyruvate dehydrogenase kinase (PDK) inactivates the enzyme, whereas dephosphorylation restores PDHC activity. We found that phenylbutyrate enhances PDHC enzymatic activity in vitro and in vivo by increasing the proportion of unphosphorylated enzyme through inhibition of PDK. Phenylbutyrate given to C57B6/L wild-type mice results in a significant increase in PDHC enzyme activity and a reduction of phosphorylated E1α in brain, muscle, and liver compared to saline-treated mice. By means of recombinant enzymes, we showed that phenylbutyrate prevents phosphorylation of E1α through binding and inhibition of PDK, providing a molecular explanation for the effect of phenylbutyrate on PDHC activity. Phenylbutyrate increases PDHC activity in fibroblasts from PDHC-deficient patients harboring various molecular defects and corrects the morphological, locomotor, and biochemical abnormalities in the noam631 zebrafish model of PDHC deficiency. In mice, phenylbutyrate prevents systemic lactic acidosis induced by partial hepatectomy. Because phenylbutyrate is already approved for human use in other diseases, the findings of this study have the potential to be rapidly translated for treatment of patients with PDHC deficiency and other forms of primary and secondary lactic acidosis. PMID:23467562

  14. Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects are Diminished in Adrenalectomized Rats#

    EPA Science Inventory

    Acute ozone exposure increases circulating stress hormones and induces metabolic alterations in animals and humans. We hypothesized that the increase of adrenal-derived stress hormones is necessary for both ozone-induced metabolic effects and lung injury. Male Wistar-Kyoto rats ...

  15. Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects are Diminished in Adrenalectomized Rats

    EPA Science Inventory

    Acute ozone exposure increases circulating stress hormones and induces peripheral metabolic alterations in animals and humans. We hypothesized that the increase of adrenal-derived stress hormones is necessary for ozone-induced systemic metabolic effects and lung injury. Male Wis...

  16. Distinct Metabolic Profile of Inhaled Budesonide and Salbutamol in Asthmatic Children during Acute Exacerbation.

    PubMed

    Quan-Jun, Yang; Jian-Ping, Zhang; Jian-Hua, Zhang; Yong-Long, Han; Bo, Xin; Jing-Xian, Zhang; Bona, Dai; Yuan, Zhang; Cheng, Guo

    2017-03-01

    Inhaled budesonide and salbutamol represent the most important and frequently used drugs in asthmatic children during acute exacerbation. However, there is still no consensus about their resulting metabolic derangements; thus, this study was conducted to determine the distinct metabolic profiles of these two drugs. A total of 69 children with asthma during acute exacerbation were included, and their serum and urine were investigated using high-resolution nuclear magnetic resonance (NMR). A metabolomics analysis was performed using a principal component analysis and orthogonal signal correction-partial least squares using SIMCA-P. The different metabolites were identified, and the distinct metabolic profiles were analysed using MetPA. A high-resolution NMR-based serum and urine metabolomics approach was established to study the overall metabolic changes after inhaled budesonide and salbutamol in asthmatic children during acute exacerbation. The perturbed metabolites included 22 different metabolites in the serum and 21 metabolites in the urine. Based on an integrated analysis, the changed metabolites included the following: increased 4-hydroxybutyrate, lactate, cis-aconitate, 5-hydroxyindoleacetate, taurine, trans-4-hydroxy-l-proline, tiglylglycine, 3-hydroxybutyrate, 3-methylhistidine, glucose, cis-aconitate, 2-deoxyinosine and 2-aminoadipate; and decreased alanine, glycerol, arginine, glycylproline, 2-hydroxy-3-methylvalerate, creatine, citrulline, glutamate, asparagine, 2-hydroxyvalerate, citrate, homoserine, histamine, sn-glycero-3-phosphocholine, sarcosine, ornithine, creatinine, glycine, isoleucine and trimethylamine N-oxide. The MetPA analysis revealed seven involved metabolic pathways: arginine and proline metabolism; taurine and hypotaurine metabolism; glycine, serine and threonine metabolism; glyoxylate and dicarboxylate metabolism; methane metabolism; citrate cycle; and pyruvate metabolism. The perturbed metabolic profiles suggest potential metabolic

  17. Acute metabolic and physiologic response of goats to narcosis

    NASA Technical Reports Server (NTRS)

    Schatte, C. L.; Bennett, P. B.

    1973-01-01

    Assessment of the metabolic consequences of exposure to elevated partial pressures of nitrogen and helium under normobaric and hyperbaric conditions in goats. The results include the finding that hyperbaric nitrogen causes and increase in metabolic rate and a general decrease in blood constituent levels which is interpreted as reflecting a shift toward fatty acid metabolism at the expense of carbohydrates. A similar but more pronounced pattern was observed with hyperbaric helium.

  18. Motor recovery after acute ischaemic stroke: a metabolic study.

    PubMed Central

    Di Piero, V; Chollet, F M; MacCarthy, P; Lenzi, G L; Frackowiak, R S

    1992-01-01

    The metabolic changes occurring after ischaemic stroke were measured to investigate the functional anatomy of clinical motor recovery. Positron emission tomography (PET) and the steady-state 15O technique was used to compare resting relative metabolic distributions at the onset of functional deficit with those following recovery. Ten patients were studied with repeat scans. Motor recovery was associated in some patients with an increase of relative oxygen metabolism in anatomical structures normally involved in motor function in the affected hemisphere, particularly in the cortical motor areas. In those patients without such metabolic changes in the cortex of the diseased hemisphere, relative increases in cortical metabolism in the contralateral hemisphere were associated with better motor recovery than in patients with no relative cortical metabolic increase in either hemisphere. There was no correlation between the degree of improvement in motor function and the severity of motor deficit at onset, the size and site of the lesion and the metabolic changes in the infarcted zone. No particular pattern of global metabolic changes was observed after recovery. Thus different relative patterns of metabolic recovery were seen in patients with different lesions and evidence was found for the participation of contralateral structures in the recovery process in some patients. Images PMID:1469418

  19. Metformin associated lactic acidosis in Auckland City Hospital 2005 to 2009

    PubMed Central

    Haloob, Imad; de Zoysa, Janak R

    2016-01-01

    AIM: To determine the incidence, clinical characteristics and outcomes of patients with metformin associated lactic acidosis (MALA). METHODS: Auckland City Hospital drains a population of just over 400000 people. All cases presenting with metabolic acidosis between July 2005 and July 2009 were identified using clinical coding. A retrospective case notes review identified patients with MALA. Prescribing data for metformin was obtained from the national pharmaceutical prescribing scheme. RESULTS: There were 42 cases of metabolic lactic acidosis over 1718000 patient years. There were 51000 patient years of metformin prescribed to patients over the study period. There were thirty two cases of lactic acidosis due to sepsis, seven in patients treated with metformin. Ten cases of MALA were identified. The incidence of MALA was estimated at 19.46 per 100000 patient year exposure to metformin. The relative risk of lactic acidosis in patients on metformin was 13.53 (95%CI: 7.88-21.66) compared to the general population. The mean age of patients with MALA was 63 years, range 40-83 years. A baseline estimated glomerular filtration rate was obtained in all patients and ranged from 23-130 mL/min per 1.73 m2. Only two patients had chronic kidney disease G4. Three patients required treatment with haemodialysis. Two patients died. CONCLUSION: Lactic acidosis is an uncommon but significant complication of use of metformin which carries a high risk of morbidity. PMID:27458565

  20. Acidosis-induced downregulation of hepatocyte mitochondrial aquaporin-8 and ureagenesis from ammonia.

    PubMed

    Molinas, Sara M; Soria, Leandro R; Marrone, Julieta; Danielli, Mauro; Trumper, Laura; Marinelli, Raúl A

    2015-08-01

    It has been proposed that, during metabolic acidosis, the liver downregulates mitochondrial ammonia detoxification via ureagenesis, a bicarbonate-consuming process. Since we previously demonstrated that hepatocyte mitochondrial aquaporin-8 channels (mtAQP8) facilitate the uptake of ammonia and its metabolism into urea, we studied whether mtAQP8 is involved in the liver adaptive response to acidosis. Primary cultured rat hepatocytes were adapted to acidosis by exposing them to culture medium at pH 7.0 for 40 h. Control cells were exposed to pH 7.4. Hepatocytes exposed to acid medium showed a decrease in mtAQP8 protein expression (-30%, p < 0.05). Ureagenesis from ammonia was assessed by incubating the cells with (15)N-labeled ammonia and measuring (15)N-labeled urea synthesis by nuclear magnetic resonance. Reduced ureagenesis was found in acidified hepatocytes (-31%, p < 0.05). In vivo studies in rats subjected to 7 days acidosis also showed decreased protein expression of hepatic mtAQP8 (-50%, p < 0.05) and reduced liver urea content (-35%; p < 0.05). In conclusion, our in vitro and in vivo data suggest that hepatic mtAQP8 expression is downregulated in acidosis, a mechanism that may contribute to decreased ureagenesis from ammonia in response to acidosis.

  1. Effect of acute heat stress on plant nutrient metabolism proteins

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Abrupt heating decreased the levels (per unit total root protein) of all but one of the nutrient metabolism proteins examined, and for most of the proteins, effects were greater for severe vs. moderate heat stress. For many of the nutrient metabolism proteins, initial effects of heat (1 d) were r...

  2. Computational modeling to predict nitrogen balance during acute metabolic decompensation in patients with urea cycle disorders.

    PubMed

    MacLeod, Erin L; Hall, Kevin D; McGuire, Peter J

    2016-01-01

    Nutritional management of acute metabolic decompensation in amino acid inborn errors of metabolism (AA IEM) aims to restore nitrogen balance. While nutritional recommendations have been published, they have never been rigorously evaluated. Furthermore, despite these recommendations, there is a wide variation in the nutritional strategies employed amongst providers, particularly regarding the inclusion of parenteral lipids for protein-free caloric support. Since randomized clinical trials during acute metabolic decompensation are difficult and potentially dangerous, mathematical modeling of metabolism can serve as a surrogate for the preclinical evaluation of nutritional interventions aimed at restoring nitrogen balance during acute decompensation in AA IEM. A validated computational model of human macronutrient metabolism was adapted to predict nitrogen balance in response to various nutritional interventions in a simulated patient with a urea cycle disorder (UCD) during acute metabolic decompensation due to dietary non-adherence or infection. The nutritional interventions were constructed from published recommendations as well as clinical anecdotes. Overall, dextrose alone (DEX) was predicted to be better at restoring nitrogen balance and limiting nitrogen excretion during dietary non-adherence and infection scenarios, suggesting that the published recommended nutritional strategy involving dextrose and parenteral lipids (ISO) may be suboptimal. The implications for patients with AA IEM are that the medical course during acute metabolic decompensation may be influenced by the choice of protein-free caloric support. These results are also applicable to intensive care patients undergoing catabolism (postoperative phase or sepsis), where parenteral nutritional support aimed at restoring nitrogen balance may be more tailored regarding metabolic fuel selection.

  3. Presence of acute phase changes in zinc, iron, and copper metabolism in turkey embryos

    SciTech Connect

    Klasing, K.C.; Richards, M.P.; Darcey, S.E.; Laurin, D.E.

    1987-01-01

    Acute phase changes in trace mineral metabolism were examined in turkey embryos. An endotoxin injection resulted in increased concentrations of serum copper and liver zinc and decreased concentrations of serum zinc in embryos incubated either in ovo or ex ovo. Changes in zinc and copper metabolism occurred when endotoxin either was injected intramuscularly, into the amnionic fluid, or administered onto the chorioallantoic membrane. Unlike poults, embryos did not respond to an inflammatory challenge with decreased serum iron concentrations. Acute phase changes in embryo serum zinc and copper as well as liver zinc concentrations were similar to those in poults. Increased liver zinc concentrations were associated with increased zinc in metallothionein (MT). An injection of a crude interleukin 1 preparation into embryos resulted in similar increases in hepatic zinc and MT concentrations as an endotoxin injection, suggesting a role for this cytokine in mediating the acute phase changes in embryonic zinc metabolism.

  4. McKittrick-Wheelock syndrome: a rare cause of acute renal failure and hypokalemia not to be overlooked.

    PubMed

    Podestà, Manuel Alfredo; Cucchiari, David; Merizzoli, Elisa; Elmore, Ugo; Angelini, Claudio; Badalamenti, Salvatore

    2014-06-01

    McKittrick-Wheelock syndrome is a rare disorder in which a colorectal tumor (usually a villous adenoma) determines secretory mucous diarrhea, which in turn leads to prerenal acute renal failure, hyponatremia, hypokalemia and metabolic acidosis. Even though the outcome is usually favorable with complete recovery after surgery, the diagnosis is often delayed, making the patient susceptible to life-threatening complications, mainly severe acidosis and hypokalemia. We present two paradigmatic cases with extreme electrolytes imbalance and complete recovery following the appropriate treatment. The pathogenesis of this degenerative condition is discussed in detail.

  5. Acute metabolic decompensation due to influenza in a mouse model of ornithine transcarbamylase deficiency.

    PubMed

    McGuire, Peter J; Tarasenko, Tatiana N; Wang, Tony; Levy, Ezra; Zerfas, Patricia M; Moran, Thomas; Lee, Hye Seung; Bequette, Brian J; Diaz, George A

    2014-02-01

    The urea cycle functions to incorporate ammonia, generated by normal metabolism, into urea. Urea cycle disorders (UCDs) are caused by loss of function in any of the enzymes responsible for ureagenesis, and are characterized by life-threatening episodes of acute metabolic decompensation with hyperammonemia (HA). A prospective analysis of interim HA events in a cohort of individuals with ornithine transcarbamylase (OTC) deficiency, the most common UCD, revealed that intercurrent infection was the most common precipitant of acute HA and was associated with markers of increased morbidity when compared with other precipitants. To further understand these clinical observations, we developed a model system of metabolic decompensation with HA triggered by viral infection (PR8 influenza) using spf-ash mice, a model of OTC deficiency. Both wild-type (WT) and spf-ash mice displayed similar cytokine profiles and lung viral titers in response to PR8 influenza infection. During infection, spf-ash mice displayed an increase in liver transaminases, suggesting a hepatic sensitivity to the inflammatory response and an altered hepatic immune response. Despite having no visible pathological changes by histology, WT and spf-ash mice had reduced CPS1 and OTC enzyme activities, and, unlike WT, spf-ash mice failed to increase ureagenesis. Depression of urea cycle function was seen in liver amino acid analysis, with reductions seen in aspartate, ornithine and arginine during infection. In conclusion, we developed a model system of acute metabolic decompensation due to infection in a mouse model of a UCD. In addition, we have identified metabolic perturbations during infection in the spf-ash mice, including a reduction of urea cycle intermediates. This model of acute metabolic decompensation with HA due to infection in UCD serves as a platform for exploring biochemical perturbations and the efficacy of treatments, and could be adapted to explore acute decompensation in other types of inborn

  6. The effect of treatment of acidosis on calcium balance in patients with chronic azotemic renal disease.

    PubMed

    Litzow, J R; Lemann, J; Lennon, E J

    1967-02-01

    Small but statistically significant negative calcium balances were found in each of eight studies in seven patients with chronic azotemic renal disease when stable metabolic acidosis was present. Only small quantities of calcium were excreted in the urine, but fecal calcium excretion equaled or exceeded dietary intake. Complete and continuous correction of acidosis by NaHCO(3) therapy reduced both urinary and fecal calcium excretion and produced a daily calcium balance indistinguishable from zero. Apparent acid retention was found throughout the studies during acidosis, despite no further reduction of the serum bicarbonate concentration. The negative calcium balances that accompanied acid retention support the suggestion that slow titration of alkaline bone salts provides an additional buffer reservoir in chronic metabolic acidosis. The treatment of metabolic acidosis prevented further calcium losses but did not induce net calcium retention. It is suggested that the normal homeostatic responses of the body to the alterations in ionized calcium and calcium distribution produced by raising the serum bicarbonate might paradoxically retard the repair of skeletal calcium deficits.

  7. Hemodynamic consequences of severe lactic acidosis in shock states: from bench to bedside.

    PubMed

    Kimmoun, Antoine; Novy, Emmanuel; Auchet, Thomas; Ducrocq, Nicolas; Levy, Bruno

    2015-04-09

    Lactic acidosis is a very common biological issue for shock patients. Experimental data clearly demonstrate that metabolic acidosis, including lactic acidosis, participates in the reduction of cardiac contractility and in the vascular hyporesponsiveness to vasopressors through various mechanisms. However, the contributions of each mechanism responsible for these deleterious effects have not been fully determined and their respective consequences on organ failure are still poorly defined, particularly in humans. Despite some convincing experimental data, no clinical trial has established the level at which pH becomes deleterious for hemodynamics. Consequently, the essential treatment for lactic acidosis in shock patients is to correct the cause. It is unknown, however, whether symptomatic pH correction is beneficial in shock patients. The latest Surviving Sepsis Campaign guidelines recommend against the use of buffer therapy with pH ≥7.15 and issue no recommendation for pH levels <7.15. Furthermore, based on strong experimental and clinical evidence, sodium bicarbonate infusion alone is not recommended for restoring pH. Indeed, bicarbonate induces carbon dioxide generation and hypocalcemia, both cardiovascular depressant factors. This review addresses the principal hemodynamic consequences of shock-associated lactic acidosis. Despite the lack of formal evidence, this review also highlights the various adapted supportive therapy options that could be putatively added to causal treatment in attempting to reverse the hemodynamic consequences of shock-associated lactic acidosis.

  8. Tumor Necrosis Factor, but Not Neutrophils, Alters the Metabolic Profile in Acute Experimental Arthritis

    PubMed Central

    Oliveira, Marina C.; Tavares, Luciana P.; Vago, Juliana P.; Batista, Nathália V.; Queiroz-Junior, Celso M.; Vieira, Angelica T.; Menezes, Gustavo B.; Sousa, Lirlândia P.; van de Loo, Fons A. J.; Teixeira, Mauro M.; Amaral, Flávio A.; Ferreira, Adaliene V. M.

    2016-01-01

    Metabolic alterations are associated with arthritis apart from obesity. However, it is still unclear which is the underlying process behind these metabolic changes. Here, we investigate the role of tumor necrosis factor (TNF) in this process in an acute model of antigen-induced arthritis (AIA). Immunized male BALB/c mice received an intra-articular injection of PBS (control) or methylated bovine serum albumin (mBSA) into their knees, and were also pre-treated with different drugs: Etanercept, an anti-TNF drug, DF2156A, a CXCR1/2 receptor antagonist, or a monoclonal antibody RB6-8C5 to deplete neutrophils. Local challenge with mBSA evoked an acute neutrophil influx into the knee joint, and enhanced the joint nociception, along with a transient systemic metabolic alteration (higher levels of glucose and lipids, and altered adipocytokines). Pre-treatment with the conventional biological Etanercept, an inhibitor of TNF action, ameliorated the nociception and the acute joint inflammation dominated by neutrophils, and markedly improved many of the altered systemic metabolites (glucose and lipids), adipocytokines and PTX3. However, the lessening of metabolic changes was not due to diminished accumulation of neutrophils in the joint by Etanercept. Reduction of neutrophil recruitment by pre-treating AIA mice with DF2156A, or even the depletion of these cells by using RB6-8C5 reduced all of the inflammatory parameters and hypernociception developed after AIA challenge, but could not prevent the metabolic changes. Therefore, the induction of joint inflammation provoked acute metabolic alterations which were involved with TNF. We suggest that the role of TNF in arthritis-associated metabolic changes is not due to local neutrophils, which are the major cells present in this model, but rather due to cytokines. PMID:26742100

  9. Tumor Necrosis Factor, but Not Neutrophils, Alters the Metabolic Profile in Acute Experimental Arthritis.

    PubMed

    Oliveira, Marina C; Tavares, Luciana P; Vago, Juliana P; Batista, Nathália V; Queiroz-Junior, Celso M; Vieira, Angelica T; Menezes, Gustavo B; Sousa, Lirlândia P; van de Loo, Fons A J; Teixeira, Mauro M; Amaral, Flávio A; Ferreira, Adaliene V M

    2016-01-01

    Metabolic alterations are associated with arthritis apart from obesity. However, it is still unclear which is the underlying process behind these metabolic changes. Here, we investigate the role of tumor necrosis factor (TNF) in this process in an acute model of antigen-induced arthritis (AIA). Immunized male BALB/c mice received an intra-articular injection of PBS (control) or methylated bovine serum albumin (mBSA) into their knees, and were also pre-treated with different drugs: Etanercept, an anti-TNF drug, DF2156A, a CXCR1/2 receptor antagonist, or a monoclonal antibody RB6-8C5 to deplete neutrophils. Local challenge with mBSA evoked an acute neutrophil influx into the knee joint, and enhanced the joint nociception, along with a transient systemic metabolic alteration (higher levels of glucose and lipids, and altered adipocytokines). Pre-treatment with the conventional biological Etanercept, an inhibitor of TNF action, ameliorated the nociception and the acute joint inflammation dominated by neutrophils, and markedly improved many of the altered systemic metabolites (glucose and lipids), adipocytokines and PTX3. However, the lessening of metabolic changes was not due to diminished accumulation of neutrophils in the joint by Etanercept. Reduction of neutrophil recruitment by pre-treating AIA mice with DF2156A, or even the depletion of these cells by using RB6-8C5 reduced all of the inflammatory parameters and hypernociception developed after AIA challenge, but could not prevent the metabolic changes. Therefore, the induction of joint inflammation provoked acute metabolic alterations which were involved with TNF. We suggest that the role of TNF in arthritis-associated metabolic changes is not due to local neutrophils, which are the major cells present in this model, but rather due to cytokines.

  10. AGE-DEPENDENT HEAPATIC AND PLASMA METABOLISM OF DELTAMETHRIN IN VITRO: ROLE IN ACUTE NEUROTOXICITY.

    EPA Science Inventory

    Deltamethrin (DLM) is a relatively potent and a widely used pyrethroid insecticide. Inefficient metabolism is proposed to be the reason for the greater sensitivity of immature rats to DLM acute neurotoxicity. The aim of this study was to test this hypothesis by characterizing the...

  11. Metabolic status, gonadotropin secretion, and ovarian function during acute nutrient restriction of beef heifers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effect of acute nutritional restriction on metabolic status, gonadotropin secretion, and ovarian function of heifers was determined in 2 experiments. In Exp. 1, 14-mo-old heifers were fed a diet supplying 1.2 × maintenance energy requirements (1.2M). After 10 d, heifers were fed 1.2M or were res...

  12. Long-term follow-up in distal renal tubular acidosis with sensorineural deafness.

    PubMed

    Peces, R

    2000-11-01

    A 20-year-old man presented with failure to thrive and bilateral genu valgum. On the basis of growth failure, skeletal deformity, hyperchloremic metabolic acidosis with alkaline urine and hypokalemia, nephrocalcinosis, and hearing loss, a diagnosis of distal renal tubular acidosis (DRTA) with sensorineural deafness was made. The genu valgum was treated by corrective osteotomy. Skeletal deformity was corrected and impaired growth improved after sustained therapy of metabolic acidosis with alkali supplementation. During an 8-year follow-up period the patient's glomerular filtration rate remained stable, the nephrocalcinosis did not progress, and his height increased 10 cm. Although nephrolithiasis led to atrophy of the right kidney, at last follow-up, when the patient was 44 years old, his creatinine clearance was 50 ml/min per 1.73 m2 body surface.

  13. Acidosis and correction of acidosis does not affect rFVIIa function in swine

    PubMed Central

    Darlington, Daniel N; Kheirabadi, Bijan S; Scherer, Michael R; Martini, Wenjun Z; Cap, Andrew P; Dubick, Michael A

    2012-01-01

    Background: Hemorrhagic shock and trauma are associated with acidosis and altered coagulation. A fall in pH has been reported to attenuate the activity of recombinant activated Factor VII (rFVIIa) in vitro. However, it is not known if acidosis induced by hemorrhagic shock or infusion of HCl attenuates FVIIa activity in vivo. The purpose of this study was to determine if acidosis, induced by two methods, affects recombinant FVIIa (rFVIIa) activity in swine, and if correction of the pH restores rFVIIa activity to normal. Methods: Acidosis was induce in anesthetized swine in two separate models: 1) HCl infusion (n=10) and 2) hemorrhage/hypoventilation (n=8). Three groups per model were used: Control (pH7.4), Acidosis (arterial pH7.1) and Acidosis-Corrected (bicarbonate infusion to return pH from 7.1 to 7.4). Pigs were then injected with rFVIIa (90 μg/kg) or vehicle (saline) at target pH and arterial blood samples were taken for measurement of coagulation function, including Thromboelastography -TEG, Thrombin Generation, Activated Clotting Time, Prothrombin Time, activated Partial Thromboplastin Time, Fibrinogen Concentration and Platelet count before and 5min after injection of rFVIIa. Results: Acidosis led to a hypocoagulation as measured by almost all coagulation parameters in both models. Furthermore, the change in coagulation function produced after infusion of rFVIIa was not different between control, acidosis and acidosis-corrected groups for all coagulation parameters measured. Conclusion: Acidosis associated with hemorrhagic shock or HCl infusion led to a hypocoagulation that was not corrected with bicarbonate infusion. Furthermore, acidosis did not affect rFVIIa function, and correction of the acidosis with bicarbonate had no effect on rFVIIa function in these models. This suggests that in vivo acidosis did not diminish rFVIIa function. PMID:23272296

  14. Hyperkalemia after acute metabolic decompensation in two children with vitamin B12-unresponsive methylmalonic acidemia and normal renal function.

    PubMed

    Pela, I; Gasperini, S; Pasquini, E; Donati, M A

    2006-07-01

    The patients affected by vitamin B12-unresponsive methylmalonic acidemia (MMA) on the long run develop chronic renal disease with interstitial nephropathy and progressive renal insufficiency. The mechanism of nephrotoxicity in vitamin B12-unresponsive MMA is not yet known. Chronic hyporeninemic hypoaldosteronism has been found in many cases of methylmalonic acidemia, hyperkalemia and renal tubular acidosis type 4. We report 2 patients affected by B12-unresponsive methylmalonic acidemia diagnosed at the age of 23 months and 5 years, respectively, with normal glomerular filtration and function. They showed hyporeninemic hypoaldosteronism and significant hyperkalemia requiring sodium potassium exchange resin (Kayexalate) therapy after an episode of metabolic decompensation leading to diagnosis of MMA. In both children, hyporeninemic hypoaldosteronism and hyperkalemia disappeared after 6 months of good metabolic control.

  15. A Rare Cause of Recurrent Acute Pancreatitis in a Child: Isovaleric Acidemia with Novel Mutation

    PubMed Central

    Sag, Elif; Cebi, Alper Han; Kaya, Gulay; Karaguzel, Gulay

    2017-01-01

    Recurrent acute pancreatic attacks is a rare clinical condition (2-5% of all acute pancreatis) in children and is mainly idiopathic in most cases. Sometimes it may be associated with congenital anomalies, metabolic diseases or hereditary conditions. Isovaleric acidemia (IVA) is a rare autosomal recessive amino acid metabolism disorder associated with isovaleryl coenzyme A dehydrogenase deficiency presenting the clinical findings such metabolic acidosis with increased anion gap, hyperammonemia, ketonemia, hypoglycemia, “the odor of sweaty feet,” abdominal pain, vomiting, feeding intolerance, shock and coma. Recurrent acute pancreatitis associated with IVA have been rarely reported. Herein; we report a child who admitted with recurrent acute pancreatic attacks and had the final diagnosis of IVA. Mutation analysis revealed a novel homozygous mutation of (p.E117K [c.349G>A]) in the IVA gene. Organic acidemias must kept in mind in the differential diagnosis of recurrent acute pancreatic attacks in children.

  16. Aliskiren-associated acute renal failure with hyperkalemia.

    PubMed

    Venzin, R M; Cohen, C D; Maggiorini, M; Wüthrich, R P

    2009-03-01

    We report the first case of acute renal failure with hyperkalemia associated with the recently marketed direct renin inhibitor aliskiren. To optimize blood pressure control, the antihypertensive medication of a 76-year-old hypertensive female patient was changed from the angiotensin II receptor antagonist irbesartan to aliskiren. Spironolactone was continued, as serum creatinine and potassium levels were initially normal. Two weeks later the patient presented with acute oliguric renal failure, symptomatic hyperkalemia and metabolic acidosis, necessitating emergency dialytic treatment. Unrecognized pre-existing renal insufficiency (CKD Stage 2 - 3) and the continuation of spironolactone were identified as predisposing risk factors.

  17. Effect of acute thioacetamide administration on rat brain phospholipid metabolism

    SciTech Connect

    Osada, J.; Aylagas, H.; Miro-Obradors, M.J.; Arce, C.; Palacios-Alaiz, E.; Cascales, M. )

    1990-09-01

    Brain phospholipid composition and the ({sup 32}P)orthophosphate incorporation into brain phospholipids of control and rats treated for 3 days with thioacetamide were studied. Brain phospholipid content, phosphatidylcholine, phosphatidylethanolamine, lysolecithin and phosphatidic acid did not show any significant change by the effect of thioacetamide. In contrast, thioacetamide induced a significant decrease in the levels of phosphatidylserine, sphingomyelin, phosphatidylinositol and diphosphatidylglycerol. After 75 minutes of intraperitoneal label injection, specific radioactivity of all the above phospholipids with the exception of phosphatidylethanolamine and phosphatidylcholine significantly increased. After 13 hours of isotope administration the specific radioactivity of almost all studied phospholipid classes was elevated, except for phosphatidic acid, the specific radioactivity of which did not change and for diphosphatidylglycerol which showed a decrease in specific radioactivity. These results suggest that under thioacetamide treatment brain phospholipids undergo metabolic transformations that may contribute to the hepatic encephalopathy induced by thioacetamide.

  18. Mechanisms in hyperkalemic renal tubular acidosis.

    PubMed

    Karet, Fiona E

    2009-02-01

    The form of renal tubular acidosis associated with hyperkalemia is usually attributable to real or apparent hypoaldosteronism. It is therefore a common feature in diabetes and a number of other conditions associated with underproduction of renin or aldosterone. In addition, the close relationship between potassium levels and ammonia production dictates that hyperkalemia per se can lead to acidosis. Here I describe the modern relationship between molecular function of the distal portion of the nephron, pathways of ammoniagenesis, and hyperkalemia.

  19. Burkholderia pseudomallei Colony Morphotypes Show a Synchronized Metabolic Pattern after Acute Infection

    PubMed Central

    Steinmetz, Ivo; Lalk, Michael

    2016-01-01

    Background Burkholderia pseudomallei is a water and soil bacterium and the causative agent of melioidosis. A characteristic feature of this bacterium is the formation of different colony morphologies which can be isolated from environmental samples as well as from clinical samples, but can also be induced in vitro. Previous studies indicate that morphotypes can differ in a number of characteristics such as resistance to oxidative stress, cellular adhesion and intracellular replication. Yet the metabolic features of B. pseudomallei and its different morphotypes have not been examined in detail so far. Therefore, this study aimed to characterize the exometabolome of B. pseudomallei morphotypes and the impact of acute infection on their metabolic characteristics. Methods and Principal Findings We applied nuclear magnetic resonance spectroscopy (1H-NMR) in a metabolic footprint approach to compare nutrition uptake and metabolite secretion of starvation induced morphotypes of the B. pseudomallei strains K96243 and E8. We observed gluconate production and uptake in all morphotype cultures. Our study also revealed that among all morphotypes amino acids could be classified with regard to their fast and slow consumption. In addition to these shared metabolic features, the morphotypes varied highly in amino acid uptake profiles, secretion of branched chain amino acid metabolites and carbon utilization. After intracellular passage in vitro or murine acute infection in vivo, we observed a switch of the various morphotypes towards a single morphotype and a synchronization of nutrient uptake and metabolite secretion. Conclusion To our knowledge, this study provides first insights into the basic metabolism of B. pseudomallei and its colony morphotypes. Furthermore, our data suggest, that acute infection leads to the synchronization of B. pseudomallei colony morphology and metabolism through yet unknown host signals and bacterial mechanisms. PMID:26943908

  20. Acute hypoxia increases the cerebral metabolic rate – a magnetic resonance imaging study

    PubMed Central

    Lindberg, Ulrich; Aachmann-Andersen, Niels Jacob; Lisbjerg, Kristian; Christensen, Søren Just; Law, Ian; Rasmussen, Peter; Olsen, Niels V; Larsson, Henrik BW

    2015-01-01

    The aim of the present study was to examine changes in cerebral metabolism by magnetic resonance imaging of healthy subjects during inhalation of 10% O2 hypoxic air. Hypoxic exposure elevates cerebral perfusion, but its effect on energy metabolism has been less investigated. Magnetic resonance imaging techniques were used to measure global cerebral blood flow and the venous oxygen saturation in the sagittal sinus. Global cerebral metabolic rate of oxygen was quantified from cerebral blood flow and arteriovenous oxygen saturation difference. Concentrations of lactate, glutamate, N-acetylaspartate, creatine and phosphocreatine were measured in the visual cortex by magnetic resonance spectroscopy. Twenty-three young healthy males were scanned for 60 min during normoxia, followed by 40 min of breathing hypoxic air. Inhalation of hypoxic air resulted in an increase in cerebral blood flow of 15.5% (p = 0.058), and an increase in cerebral metabolic rate of oxygen of 8.5% (p = 0.035). Cerebral lactate concentration increased by 180.3% (p<10-6), glutamate increased by 4.7% (p<10-4) and creatine and phosphocreatine decreased by 15.2% (p<10-3). The N-acetylaspartate concentration was unchanged (p = 0.36). In conclusion, acute hypoxia in healthy subjects increased perfusion and metabolic rate, which could represent an increase in neuronal activity. We conclude that marked changes in brain homeostasis occur in the healthy human brain during exposure to acute hypoxia. PMID:26661163

  1. ASAS Centennial Paper: contributions in the Journal of Animal Science to understanding cattle metabolic and digestive disorders.

    PubMed

    Vasconcelos, J T; Galyean, M L

    2008-07-01

    Acute and subacute ruminal acidosis, bloat, liver abscesses, and polioencephalomalacia (PEM) were reviewed with respect to contributions published in the Journal of Animal Science (JAS) regarding these metabolic and digestive disorders in beef cattle. Increased grain feeding and expansion of the feedlot industry in the 1960s led to considerable research on acidosis, and early publications defined ruminal changes with acute acidosis. The concept of subacute acidosis was developed in the 1970s. Significant research was published during the 1980s and 1990s on adaptation to high-grain diets, effects of ionophores, and the development of model systems to study ruminal and metabolic changes in acidosis. Since 2000, JAS publications on acidosis have largely focused on individual animal variability in response to acid loads and the role of management strategies in controlling acidosis. Increased grain feeding also was associated with an increase in the incidence of liver abscesses, which were quickly linked to insults to the ruminal epithelium associated with acidosis. The role of antibiotics, particularly tylosin, in decreasing the incidence and severity of liver abscesses was a significant contribution of JAS publications during the 1970s and 1980s. Papers on bloat were among the earliest published in JAS related to metabolic and digestive disorders in cattle. Noteworthy accomplishments in bloat research chronicled in JAS include the nature of ruminal contents in legume and feedlot bloat, the role of plant fractions and microbial populations in the development of bloat, and the efficacy of poloxalene, ionophores, and, more recently, condensed tannins in decreasing the incidence and severity of bloat. Although less research has been published on PEM in JAS, early publications highlighting the association between PEM and ruminal acidity and the role of thiaminase in certain forms of the disorder, as well as more recent publications related to the role of sulfur in the

  2. Primary sclerosing cholangitis: a new cause of distal renal tubular acidosis

    PubMed Central

    Goutaudier, Valentin; Szwarc, Ilan; Serre, Jean-Emmanuel; Pageaux, Georges-Philippe; Argilés, Àngel

    2016-01-01

    We describe the first case of distal renal tubular acidosis (dRTA) associated with primary sclerosing cholangitis. A 26-year-old Lao-Thai male patient presented with severe jaundice, metabolic acidosis and hypokalaemia. He was diagnosed of dRTA. Liver transplantation resulted in correction of electrolyte disturbances and hyperbilirubinaemia. A fludrocortisone-furosemide test revealed normal urinary acidification, demonstrating no residual dRTA. This observation suggests that dRTA may be an early manifestation of bilirubin-associated nephropathy or the consequence of an immune mechanism. PMID:27994859

  3. [Comparative characteristics of glucose metabolism in the liver of rats under acute alcohol and morphine intoxication].

    PubMed

    Lelevich, S V

    2011-01-01

    The comparative analysis effect of acute alcohol and morphine intoxications on rats on hepatic glycolysis and pentose phosphate pathway was done. The dose-dependent inhibitory effect of ethanol on activity of limiting enzymes of these metabolic ways, as well as anaerobic reorientation of glucose metabolism was recognised with the increase of the dose of the intake alcohol. Morfine (10 mg/kg) activated enymes of glycolysis and pentose phosphate pathway, but in contrast to ethanol it did not influence these parameters at the dose 20 or 40 mg/kg.

  4. [Case of distal renal tubular acidosis complicated with renal diabetes insipidus, showing aggravation of symptoms with occurrence of diabetes mellitus].

    PubMed

    Liu, Hexing; Tomoda, Fumihiro; Koike, Tsutomu; Ohara, Maiko; Nakagawa, Taizo; Kagitani, Satoshi; Inoue, Hiroshi

    2011-01-01

    We report herein a 27-year-old male case of inherited distal renal tubular acidosis complicated with renal diabetes insipidus, the symptoms of which were aggravated by the occurrence of diabetes mellitus. At 2 months after birth, he was diagnosed as having inherited distal renal tubular acidosis and thereafter supplementation of both potassium and alkali was started to treat his hypokalemia and metabolic acidosis. At the age of 4 years, calcification of the bilateral renal medulla was detected by computed tomography. Subsequently his urinary volume gradually increased and polyuria of approximately 4 L/day persisted. At the age of 27 years, he became fond of sugar-sweetened drinks and also often forgot to take the medicine. He was admitted to our hospital due to polyuria of more than 10 L day, muscle weakness and gait disturbance. Laboratory tests disclosed worsening of both hypokalemia and metabolic acidosis in addition to severe hyperglycemia. It seemed likely that occurrence of diabetes mellitus and cessation of medications can induce osmotic diuresis and aggravate hypokalemia and metabolic acidosis. Consequently, severe dehydration, hypokalemia-induced damage of his urinary concentration ability and enhancement of the renin angiotensin system occurred and thereby possibly worsened his hypokalemia and metabolic acidosis. As normalization of hyperglycemia and metabolic acidosis might have exacerbated hypokalemia further, dehydration and hypokalemia were treated first. Following intensive treatment, these abnormalities were improved, but polyuria persisted. Elevated plasma antidiuretic hormone (12.0 pg/mL) and deficit of renal responses to antidiuretic hormone suggested that the polyuria was attributable to the preexisting renal diabetes insipidus possibly caused by bilateral renal medulla calcification. Thiazide diuretic or nonsteroidal anti-inflammatory drugs were not effective for the treatment of diabetes insipidus in the present case.

  5. Metabolic changes in rat urine after acute paraquat poisoning and discriminated by support vector machine.

    PubMed

    Wen, Congcong; Wang, Zhiyi; Zhang, Meiling; Wang, Shuanghu; Geng, Peiwu; Sun, Fa; Chen, Mengchun; Lin, Guanyang; Hu, Lufeng; Ma, Jianshe; Wang, Xianqin

    2016-01-01

    Paraquat is quick-acting and non-selective, killing green plant tissue on contact; it is also toxic to human beings and animals. In this study, we developed a urine metabonomic method by gas chromatography-mass spectrometry to evaluate the effect of acute paraquat poisoning on rats. Pattern recognition analysis, including both partial least squares discriminate analysis and principal component analysis revealed that acute paraquat poisoning induced metabolic perturbations. Compared with the control group, the levels of benzeneacetic acid and hexadecanoic acid of the acute paraquat poisoning group (intragastric administration 36 mg/kg) increased, while the levels of butanedioic acid, pentanedioic acid, altronic acid decreased. Based on these urinary metabolomics data, support vector machine was applied to discriminate the metabolomic change of paraquat groups from the control group, which achieved 100% classification accuracy. In conclusion, metabonomic method combined with support vector machine can be used as a useful diagnostic tool in paraquat-poisoned rats.

  6. Effect of the acute crowding stress on the rat brown adipose tissue metabolic function.

    PubMed

    Djordjevic, Jelena; Cvijic, Gordana; Petrovic, Natasa; Davidovic, Vukosava

    2005-12-01

    Our previous results have shown that metabolic and thermal stressors influence interscapular brown adipose tissue (IBAT) metabolic activity by increasing oxygen consumption and, consequently, altering the toxic reactive oxygen species (ROS) production and the antioxidative system activity. Since there is not enough evidence about the effect of psychosocial stressors on these processes, we studied the effect of acute crowding stress on the IBAT and hypothalamic monoamine oxidase (MAO) activity as well as IBAT antioxidative enzymes, manganese (MnSOD), copper-zinc superoxide dismutase (CuZnSOD) and catalase (CAT), as the relevant indicators of IBAT metabolic alternations under the stress exposure and the returning of animals to control conditions. The results indicated that acute crowding stress did not change the hypothalamic and IBAT MAO activities, the generation of ROS and, consequently, the IBAT CuZnSOD and CAT activities. However, all three antioxidative enzymes were affected only after the recovery period. It seems that peripheral overheating of rats during acute crowding changes the stress nature, by becoming more thermal than psychosocial and by suppression the hypothalamic efferent pathways involved in the IBAT thermogenesis regulation. However, it seems that returning of the animals to the control conditions after the stress termination causes the reactivation of IBAT thermogenesis with tendency to normalise the body temperature.

  7. Iron metabolism and oxidative profile of dogs naturally infected by Ehrlichia canis: Acute and subclinical disease.

    PubMed

    Bottari, Nathieli B; Crivellenti, Leandro Z; Borin-Crivellenti, Sofia; Oliveira, Jéssica R; Coelho, Stefanie B; Contin, Catarina M; Tatsch, Etiane; Moresco, Rafael N; Santana, Aureo E; Tonin, Alexandre A; Tinucci-Costa, Mirela; Da Silva, Aleksandro S

    2016-03-01

    The aim of this study was to evaluate the oxidant profile and iron metabolism in serum of dogs infected by Ehrlichia canis. Banked sera samples of dogs were divided into two groups: negative control (n = 17) and infected by E. canis on acute (n = 24), and subclinical (n = 18) phases of the disease. The eritrogram, leucogram, and platelet counts were evaluate as well as iron, ferritin, and transferrin levels, latent iron binding capacity (LIBC), and transferrin saturation index (TSI) concentration. In addition, the advanced oxidation protein products (AOPP) and ferric reducing ability of plasma (FRAP) in sera were also analyzed. Blood samples were examined for the presence of E. canis by PCR techniques. History and clinical signals were recorded for each dog. During the acute phase of the disease, infected animals showed thrombocytopenia and anemia when compared to healthy animals (P < 0.05) as a consequence of lower iron levels. Ferritin and transferrin levels were higher in both phases (acute and subclinical) of the disease. The AOPP and FRAP levels increased in infected animals on the acute phase; however, the opposite occurred in the subclinical phase. We concluded that dogs naturally infected by E. canis showed changes in the iron metabolism and developed an oxidant status in consequence of disease pathophysiology.

  8. Dioscin relieves endotoxemia induced acute neuro-inflammation and protect neurogenesis via improving 5-HT metabolism

    PubMed Central

    Yang, Rui; Chen, Wei; Lu, Ye; Li, Yingke; Du, Hongli; Gao, Songyan; Dong, Xin; Yuan, Hongbin

    2017-01-01

    Sepsis, in addition to causing fatality, is an independent risk factor for cognitive impairment among sepsis survivors. The pathologic mechanism of endotoxemia induced acute neuro-inflammation still has not been fully understood. For the first time, we found the disruption of neurotransmitters 5-HT, impaired neurogenesis and activation of astrocytes coupled with concomitant neuro-inflammation were the potential pathogenesis of endotoxemia induced acute neuro-inflammation in sepsis survivors. In addition, dioscin a natural steroidal saponin isolated from Chinese medicinal herbs, enhanced the serotonergic system and produced anti-depressant effect by enhancing 5-HT levels in hippocampus. What is more, this finding was verified by metabolic analyses of hippocampus, indicating 5-HT related metabolic pathway was involved in the pathogenesis of endotoxemia induced acute neuro-inflammation. Moreover, neuro-inflammation and neurogenesis within hippocampus were indexed using quantitative immunofluorescence analysis of GFAP DCX and Ki67, as well as real-time RT-PCR analysis of some gene expression levels in hippocampus. Our in vivo and in vitro studies show dioscin protects hippocampus from endotoxemia induced cascade neuro-inflammation through neurotransmitter 5-HT and HMGB-1/TLR4 signaling pathway, which accounts for the dioscin therapeutic effect in behavioral tests. Therefore, the current findings suggest that dioscin could be a potential approach for the therapy of endotoxemia induced acute neuro-inflammation. PMID:28059131

  9. [A clinical case of development of lactic acid acidosis in a diabetic patient taking metformin].

    PubMed

    Cesur, Mustafa; Cekmen, Nedum; Cetinbas, Riza R; Badalov, Pavel; Erdemli, Ozcan

    2006-01-01

    Metformin is a biguanide. Due to its effects in suppressing the hepatic production of endogenous glucose and in increasing insulin sensitivity in adipose tissue and skeletal muscle, the agent is used particularly in type 2 diabetes mellitus and metabolic syndrome, in which insulin resistance is especially pronounced. Lactic acidosis is one of the most important side effects of metformin. A male patient, born in 1923, was admitted to the emergency unit of our hospital for sudden vertigo, weakness, dyspnea, cyanosis, and lethargy. His history data showed that the patient had been suffering from type 2 diabetes mellitus for 10 years and taking Glargin (insulin), 12 U/kg, once daily and Glucophage (metformin), 850 mg thrice daily. The patient's general condition was fair; stupor, time and spatial orientation were absent. Analysis of arterial blood gases showed the presence of metabolic acidosis, hypokalemia, hypoxemia, and hypercapnia. Thereafter the patient was transferred to the intensive care unit of the hospital; intubated and connected to a T-bird ventilation apparatus. On the following day, an analysis of arterial blood gases indicated the proximity of the results to their physiological parameters. Ventilation was stopped; and monitoring of the patient continued by following the T-shape type of ventilation discontinuation. There were no X-ray signs of pneumonia or pulmonary edema. On the same day, the patient was extubated and oxygen inhalation in a dose of L/min was continued through a mask. On day 4 since therapy was initiated, the patient's vital signs, serum sugar and lactate levels became normal. By determining a new treatment regimen, the patient was discharged from the intensive care unit. Dyspnea, acidosis, and hypoxia developed in the patient resulted from lactic acidosis caused by the use of metformin. It should be remembered that dyspnea, acidosis, and hypoxia, which suddenly developed in metformin-treated patients with type 2 diabetes mellitus, may be

  10. Pharmacokinetics and metabolism of digoxin- and beta-methyl-digoxin-12aplha-3 H in patients with acute hepatitis.

    PubMed

    Zilly, W; Richter, E; Rietbrock, N

    1975-03-01

    Pharmocokinetics and metabolism of digoxin and beta-methyldigoxin have been studied in patients with acute hepatits after intravenous administration of both H-labeled glycosides. In contrast to digoxin, the rate of decline of radioactivity after administration of beta-methyldigoxin was significantly retarded in patients with acute hepatitis. The increase in plasma concentration after beta-methyldigoxin to patients with acute hepatitis is probably related to decreased demethylation.

  11. Metabolic responses to the acute ingestion of two commercially available carbonated beverages: A pilot study

    PubMed Central

    Mendel, Ron W; Hofheins, Jennifer E

    2007-01-01

    Background The purpose of this placebo-controlled, double-blind cross-over study was to compare the effects of two commercially available soft drinks on metabolic rate. Methods After giving informed consent, twenty healthy men and women were randomly assigned to ingest 12 ounces of Celsius™ and, on a separate day, 12 ounces of Diet Coke®. All subjects completed both trials using a randomized, counterbalanced design. Metabolic rate (via indirect calorimetry) and substrate oxidation (via respiratory exchange ratio) were measured at baseline (pre-ingestion) and at the end of each hour for 3 hours post-ingestion. Results Two-way ANOVA revealed a significant interaction (p < 0.001) between trials in metabolic rate. Scheffe post-hoc testing indicated that metabolic rate increased by 13.8% (+ 0.6 L/min, p < 0.001) 1 hr post, 14.4% (+0.63 L/min, p < 0.001) 2 hr post, and 8.5% (+0.37 L/min, p < 0.004) 3 hr post Celsius™ ingestion. In contrast, small (~4–6%) but statistically insignificant increases in metabolic rate were noted following Diet Coke® ingestion. No differences in respiratory exchange ratio were noted between trials. Conclusion These preliminary findings indicate Celsius™ has thermogenic properties when ingested acutely. The effects of repeated, chronic ingestion of Celsius™ on body composition are unknown at this time. PMID:17908290

  12. Clinical review: Drug metabolism and nonrenal clearance in acute kidney injury

    PubMed Central

    Vilay, A Mary; Churchwell, Mariann D; Mueller, Bruce A

    2008-01-01

    Decreased renal drug clearance is an obvious consequence of acute kidney injury (AKI). However, there is growing evidence to suggest that nonrenal drug clearance is also affected. Data derived from human and animal studies suggest that hepatic drug metabolism and transporter function are components of nonrenal clearance affected by AKI. Acute kidney injury may also impair the clearance of formed metabolites. The fact that AKI does not solely influence kidney function may have important implications for drug dosing, not only of renally eliminated drugs but also of those that are hepatically cleared. A review of the literature addressing the topic of drug metabolism and clearance alterations in AKI reveals that changes in nonrenal clearance are highly complicated and poorly studied, but they may be quite common. At present, our understanding of how AKI affects drug metabolism and nonrenal clearance is limited. However, based on the available evidence, clinicians should be cognizant that even hepatically eliminated drugs and formed drug metabolites may accumulate during AKI, and renal replacement therapy may affect nonrenal clearance as well as drug metabolite clearance. PMID:19040780

  13. Acute effects of concentric and eccentric exercise on glucose metabolism and interleukin-6 concentration in healthy males

    PubMed Central

    Krüsmann, PJ; Mersa, L; Eder, EM; Gatterer, H; Melmer, A; Ebenbichler, C; Burtscher, M

    2016-01-01

    Acute muscle-damaging eccentric exercise (EE) negatively affects glucose metabolism. On the other hand, long-term eccentric endurance exercise seems to result in equal or superior positive effects on glucose metabolism compared to concentric endurance exercise. However, it is not known if acute non-muscle-damaging EE will have the same positive effects on glucose metabolism as acute concentric exercise (CE). Interleukin-6 (IL-6) released from the exercising muscles may be involved in the acute adaptations of glucose metabolism after CE and non-muscle-damaging EE. The aim of this study was to assess acute effects of uphill walking (CE) and non-muscle-damaging downhill walking (EE) on glucose metabolism and IL-6 secretion. Seven sedentary non-smoking, healthy males participated in a crossover trial consisting of a 1 h uphill (CE) and a 1 h downhill (EE) walking block on a treadmill. Venous blood samples were drawn before (pre), directly after (acute) and 24 h after (post) exercise. An oral glucose tolerance test (OGTT) was performed before and 24 h after exercise. Glucose tolerance after 1 and 2 hours significantly improved 24 hours after CE (-10.12±3.22%: P=0.039; -13.40±8.24%: P=0.028). After EE only the 1-hour value was improved (-5.03±5.48%: P=0.043). Acute IL-6 concentration rose significantly after CE but not after EE. We conclude that both a single bout of CE and a single bout of non-muscle-damaging EE elicit positive changes in glucose tolerance even in young, healthy subjects. Our experiment indicates that the overall metabolic cost is a major trigger for acute adaptations of glucose tolerance after exercise, but only the IL-6 production during EE was closely related to changes in glycaemic control. PMID:27274108

  14. The differential effects of acute right- vs. left-sided vestibular failure on brain metabolism.

    PubMed

    Becker-Bense, Sandra; Dieterich, Marianne; Buchholz, Hans-Georg; Bartenstein, Peter; Schreckenberger, Mathias; Brandt, Thomas

    2014-07-01

    The human vestibular system is represented in the brain bilaterally, but it has functional asymmetries, i.e., a dominance of ipsilateral pathways and of the right hemisphere in right-handers. To determine if acute right- or left-sided unilateral vestibular neuritis (VN) is associated with differential patterns of brain metabolism in areas representing the vestibular network and the visual-vestibular interaction, patients with acute VN (right n = 9; left n = 13) underwent resting state (18)F-FDG PET once in the acute phase and once 3 months later after central vestibular compensation. The contrast acute vs. chronic phase showed signal differences in contralateral vestibular areas and the inverse contrast in visual cortex areas, both more pronounced in VN right. In VN left additional regions were found in the cerebellar hemispheres and vermis bilaterally, accentuated in severe cases. In general, signal changes appeared more pronounced in patients with more severe vestibular deficits. Acute phase PET data of patients compared to that of age-matched healthy controls disclosed similarities to these patterns, thus permitting the interpretation that the signal changes in vestibular temporo-parietal areas reflect signal increases, and in visual areas, signal decreases. These data imply that brain activity in the acute phase of right- and left-sided VN exhibits different compensatory patterns, i.e., the dominant ascending input is shifted from the ipsilateral to the contralateral pathways, presumably due to the missing ipsilateral vestibular input. The visual-vestibular interaction patterns were preserved, but were of different prominence in each hemisphere and more pronounced in patients with right-sided failure and more severe vestibular deficits.

  15. Metabolic Changes in Masseter Muscle of Rats Submitted to Acute Stress Associated with Exodontia

    PubMed Central

    Iyomasa, Mamie Mizusaki; Fernandes, Fernanda Silva; Iyomasa, Daniela Mizusaki; Pereira, Yamba Carla Lara; Fernández, Rodrigo Alberto Restrepo; Calzzani, Ricardo Alexandre; Nascimento, Glauce Crivelaro; Leite-Panissi, Christie Ramos Andrade; Issa, João Paulo Mardegan

    2015-01-01

    Clinical evidence has shown that stress may be associated with alterations in masticatory muscle functions. Morphological changes in masticatory muscles induced by occlusal alterations and associated with emotional stress are still lacking in the literature. The objective of this study was to evaluate the influence of acute stress on metabolic activity and oxidative stress of masseter muscles of rats subjected to occlusal modification through morphological and histochemical analyses. In this study, adult Wistar rats were divided into 4 groups: a group with extraction and acute stress (E+A); group with extraction and without stress (E+C); group without extraction and with acute stress (NO+A); and control group without both extraction and stress (NO+C). Masseter muscles were analyzed by Succinate Dehydrogenase (SDH), Nicotinamide Adenine Dinucleotide Diaphorase (NADH) and Reactive Oxygen Species (ROS) techniques. Statistical analyses and two-way ANOVA were applied, followed by Tukey-Kramer tests. In the SDH test, the E+C, E+A and NO+A groups showed a decrease in high desidrogenase activities fibers (P < 0.05), compared to the NO+C group. In the NADH test, there was no difference among the different groups. In the ROS test, in contrast, E+A, E+C and NO+A groups showed a decrease in ROS expression, compared to NO+C groups (P < 0.05). Modified dental occlusion and acute stress - which are important and prevalent problems that affect the general population - are important etiologic factors in metabolic plasticity and ROS levels of masseter muscles. PMID:26053038

  16. Maternal and offspring xenobiotic metabolism haplotypes and the risk of childhood acute lymphoblastic leukemia

    PubMed Central

    Nousome, Darryl; Lupo, Philip J.; Okcu, M. Fatih; Scheurer, Michael E.

    2013-01-01

    Discovering genetic predictors of childhood acute lymphoblastic leukemia (ALL) necessitates the evaluation of novel factors including maternal genetic effects, which are a proxy for the intrauterine environment, and robust epidemiologic study designs. Therefore, we evaluated five maternal and offspring xenobiotic metabolism haplotypes and the risk of childhood ALL among 120 case-parent triads. Two of the five haplotypes were significantly associated with risk: GSTM3/GSTM4 (P=0.01) and GSTP1 (P=0.02). The EPHX1 haplotype was marginally associated with risk (P=0.05), whereas haplotypes in CYP1B1 and GSTA4 were not. Our results suggest genetic variation in xenobiotic metabolism is important in childhood ALL etiology. PMID:23433810

  17. Epinephrine-induced lactic acidosis in orthognathic surgery: a report of two cases

    PubMed Central

    2016-01-01

    Submucosal infiltration and the topical application of epinephrine as a vasoconstrictor produce excellent hemostasis during surgery. The hemodynamic effects of epinephrine have been documented in numerous studies. However, its metabolic effects (especially during surgery) have been seldom recognized clinically. We report two cases of significant metabolic effects (including lactic acidosis and hyperglycemia) as well as hemodynamic effects in healthy patients undergoing orthognathic surgery with general anesthesia. Epinephrine can induce glycolysis and pyruvate generation, which result in lactic acidosis, via β2-adrenergic receptors. Therefore, careful perioperative observation for changes in plasma lactate and glucose levels along with intensive monitoring of vital signs should be carried out when epinephrine is excessively used as a vasoconstrictor during surgery. PMID:27847739

  18. Acute Ethanol Causes Hepatic Mitochondrial Depolarization in Mice: Role of Ethanol Metabolism

    PubMed Central

    Zhong, Zhi; Ramshesh, Venkat K.; Rehman, Hasibur; Liu, Qinlong; Theruvath, Tom P.; Krishnasamy, Yasodha; Lemasters, John J.

    2014-01-01

    Background/Aims An increase of ethanol metabolism and hepatic mitochondrial respiration occurs in vivo after a single binge of alcohol. Here, our aim was to determine how ethanol intake affects hepatic mitochondrial polarization status in vivo in relation to ethanol metabolism and steatosis. Methods Hepatic mitochondrial polarization, permeability transition (MPT), and reduce pyridine nucleotides, and steatosis in mice were monitored by intravital confocal/multiphoton microscopy of the fluorescence of rhodamine 123 (Rh123), calcein, NAD(P)H, and BODIPY493/503, respectively, after gavage with ethanol (1–6 g/kg). Results Mitochondria depolarized in an all-or-nothing fashion in individual hepatocytes as early as 1 h after alcohol. Depolarization was dose- and time-dependent, peaked after 6 to 12 h and maximally affected 94% of hepatocytes. This mitochondrial depolarization was not due to onset of the MPT. After 24 h, mitochondria of most hepatocytes recovered normal polarization and were indistinguishable from untreated after 7 days. Cell death monitored by propidium iodide staining, histology and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was low throughout. After alcohol, mitochondrial NAD(P)H autofluorescence increased and decreased, respectively, in hepatocytes with polarized and depolarized mitochondria. Ethanol also caused steatosis mainly in hepatocytes with depolarized mitochondria. Depolarization was linked to ethanol metabolism, since deficiency of alcohol dehydrogenase and cytochrome-P450 2E1 (CYP2E1), the major ethanol-metabolizing enzymes, decreased mitochondrial depolarization by ∼70% and ∼20%, respectively. Activation of aldehyde dehydrogenase decreased depolarization, whereas inhibition of aldehyde dehydrogenase enhanced depolarization. Activation of aldehyde dehydrogenase also markedly decreased steatosis. Conclusions Acute ethanol causes reversible hepatic mitochondrial depolarization in vivo that may contribute to

  19. Plasmodium berghei infection: dichloroacetate improves survival in rats with lactic acidosis.

    PubMed

    Holloway, P A; Knox, K; Bajaj, N; Chapman, D; White, N J; O'Brien, R; Stacpoole, P W; Krishna, S

    1995-06-01

    The kinetics of Plasmodium berghei infection and the development of lactic acidosis, hypoglycemia, and anemia were defined in young Wistar rats. This model of metabolic dysfunction, which is similar to that of severe human malaria, was used to test the hypothesis that dichloroacetate, a treatment for lactic acidosis, prolonged survival in rats receiving a single antimalarial dose of quinine (20 mg/kg). Rats with hyperlactatemia (lactate > 5 mmol/liter, N = 183) were randomized to receive either dichloroacetate (100 mg/kg, N = 99) or saline (N = 84) and were monitored for outcome (survival or death) for 50 hr. Logistic regression modeling adjusting for baseline venous lactate concentration demonstrated that dichloroacetate increases survival rates in rats with venous lactate concentrations between 5 and 8.9 mmol/liter (odds ratio > 2.2, P < 0.021). This is the first demonstration that specific intervention to treat lactic acidosis can prolong survival and suggests that dichloroacetate may be useful as adjunctive therapy in the management of lactic acidosis complicating severe falciparum malaria.

  20. Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance

    PubMed Central

    Coen, Paul M.; DiStefano, Giovanna; Chacon, Alexander C.; Helbling, Nicole L.; Desimone, Marisa E.; Stafanovic-Racic, Maja; Hames, Kazanna C.; Despines, Alex A.; Toledo, Frederico G. S.; Goodpaster, Bret H.

    2014-01-01

    We hypothesized that acute lipid-induced insulin resistance would be attenuated in high-oxidative muscle of lean trained (LT) endurance athletes due to their enhanced metabolic flexibility and mitochondrial capacity. Lean sedentary (LS), obese sedentary (OS), and LT participants completed two hyperinsulinemic euglycemic clamp studies with and without (glycerol control) the coinfusion of Intralipid. Metabolic flexibility was measured by indirect calorimetry as the oxidation of fatty acids and glucose during fasted and insulin-stimulated conditions, the latter with and without lipid oversupply. Muscle biopsies were obtained for mitochondrial and insulin-signaling studies. During hyperinsulinemia without lipid, glucose infusion rate (GIR) was lowest in OS due to lower rates of nonoxidative glucose disposal (NOGD), whereas state 4 respiration was increased in all groups. Lipid infusion reduced GIR similarly in all subjects and reduced state 4 respiration. However, in LT subjects, fat oxidation was higher with lipid oversupply, and although glucose oxidation was reduced, NOGD was better preserved compared with LS and OS subjects. Mitochondrial performance was positively associated with better NOGD and insulin sensitivity in both conditions. We conclude that enhanced mitochondrial performance with exercise is related to better metabolic flexibility and insulin sensitivity in response to lipid overload. PMID:25352435

  1. Targeting Aberrant Glutathione Metabolism to Eradicate Human Acute Myelogenous Leukemia Cells*

    PubMed Central

    Pei, Shanshan; Minhajuddin, Mohammad; Callahan, Kevin P.; Balys, Marlene; Ashton, John M.; Neering, Sarah J.; Lagadinou, Eleni D.; Corbett, Cheryl; Ye, Haobin; Liesveld, Jane L.; O'Dwyer, Kristen M.; Li, Zheng; Shi, Lei; Greninger, Patricia; Settleman, Jeffrey; Benes, Cyril; Hagen, Fred K.; Munger, Joshua; Crooks, Peter A.; Becker, Michael W.; Jordan, Craig T.

    2013-01-01

    The development of strategies to eradicate primary human acute myelogenous leukemia (AML) cells is a major challenge to the leukemia research field. In particular, primitive leukemia cells, often termed leukemia stem cells, are typically refractory to many forms of therapy. To investigate improved strategies for targeting of human AML cells we compared the molecular mechanisms regulating oxidative state in primitive (CD34+) leukemic versus normal specimens. Our data indicate that CD34+ AML cells have elevated expression of multiple glutathione pathway regulatory proteins, presumably as a mechanism to compensate for increased oxidative stress in leukemic cells. Consistent with this observation, CD34+ AML cells have lower levels of reduced glutathione and increased levels of oxidized glutathione compared with normal CD34+ cells. These findings led us to hypothesize that AML cells will be hypersensitive to inhibition of glutathione metabolism. To test this premise, we identified compounds such as parthenolide (PTL) or piperlongumine that induce almost complete glutathione depletion and severe cell death in CD34+ AML cells. Importantly, these compounds only induce limited and transient glutathione depletion as well as significantly less toxicity in normal CD34+ cells. We further determined that PTL perturbs glutathione homeostasis by a multifactorial mechanism, which includes inhibiting key glutathione metabolic enzymes (GCLC and GPX1), as well as direct depletion of glutathione. These findings demonstrate that primitive leukemia cells are uniquely sensitive to agents that target aberrant glutathione metabolism, an intrinsic property of primary human AML cells. PMID:24089526

  2. Distal renal tubular acidosis with hereditary spherocytosis.

    PubMed

    Sinha, Rajiv; Agarwal, Indira; Bawazir, Waleed M; Bruce, Lesley J

    2013-07-01

    Hereditary spherocytosis (HS) and distal renal tubular acidosis (dRTA), although distinct entities, share the same protein i.e. the anion exchanger1 (AE1) protein. Despite this, their coexistence has been rarely reported. We hereby describe the largest family to date with co-existence of dRTA and HS and discuss the molecular basis for the co-inheritance of these conditions.

  3. Acute metabolic, hormonal, and psychological responses to different endurance training protocols.

    PubMed

    Wahl, P; Mathes, S; Köhler, K; Achtzehn, S; Bloch, W; Mester, J

    2013-10-01

    In the last years, mainly 2 high-intensity-training (HIT) protocols became common: first, a Wingate-based "all-out" protocol and second, a 4×4 min protocol. However, no direct comparison between these protocols exists, and also a comparison with high-volume-training (HVT) is missing. Therefore, the aim of the present study was to compare these 3 endurance training protocols on metabolic, hormonal, and psychological responses. Twelve subjects performed: 1) HVT [130 min at 55% peak power output (PPO)]; 2) 4×4 min at 95% PPO; 3) 4×30 s all-out. Human growth hormone (hGH), testosterone, and cortisol were determined before (pre) and 0', 30', 60', 180' after each intervention. Metabolic stimuli and perturbations were characterized by lactate, blood gas (pH, BE, HCO₃⁻, pO₂, PCO₂), and spirometric analysis. Furthermore, changes of the person's perceived physical state were determined. The 4×30 s training caused the highest increases in cortisol and hGH, followed by 4 × 4 min and HVT. Testosterone levels were significantly increased by all 3 exercise protocols. Metabolic stress was highest during and after 4×30 s, followed by 4×4 min and HVT. The 4×30 s training was also the most demanding intervention from an athlete's point of view. In conclusion, the results suggest that 4×30 s and 4×4 min promote anabolic processes more than HVT, due to higher increases of hGH, testosterone, and the T/C ratio. It can be speculated that the acute hormonal increase and the metabolic perturbations might play a positive role in optimizing training adaptation and in eliciting health benefits as it has been shown by previous long term training studies using similar exercise protocols.

  4. Redox state and energy metabolism during liver regeneration: alterations produced by acute ethanol administration.

    PubMed

    Gutiérrez-Salinas, J; Miranda-Garduño, L; Trejo-Izquierdo, E; Díaz-Muñoz, M; Vidrio, S; Morales-González, J A; Hernández-Muñoz, R

    1999-12-01

    Ethanol metabolism can induce modifications in liver metabolic pathways that are tightly regulated through the availability of cellular energy and through the redox state. Since partial hepatectomy (PH)-induced liver proliferation requires an oversupply of energy for enhanced syntheses of DNA and proteins, the present study was aimed at evaluating the effect of acute ethanol administration on the PH-induced changes in cellular redox and energy potentials. Ethanol (5 g/kg body weight) was administered to control rats and to two-thirds hepatectomized rats. Quantitation of the liver content of lactate, pyruvate, beta-hydroxybutyrate, acetoacetate, and adenine nucleotides led us to estimate the cytosolic and mitochondrial redox potentials and energy parameters. Specific activities in the liver of alcohol-metabolizing enzymes also were measured in these animals. Liver regeneration had no effect on cellular energy availability, but induced a more reduced cytosolic redox state accompanied by an oxidized mitochondrial redox state during the first 48 hr of treatment; the redox state normalized thereafter. Administration of ethanol did not modify energy parameters in PH rats, but this hepatotoxin readily blocked the PH-induced changes in the cellular redox state. In addition, proliferating liver promoted decreases in the activity of alcohol dehydrogenase (ADH) and of cytochrome P4502E1 (CYP2E1); ethanol treatment prevented the PH-induced diminution of ADH activity. In summary, our data suggest that ethanol could minimize the PH-promoted metabolic adjustments mediated by redox reactions, probably leading to an ineffective preparatory event that culminates in compensatory liver growth after PH in the rat.

  5. Chronic treatment with olanzapine increases adiposity by changing fuel substrate and causes desensitization of the acute metabolic side effects.

    PubMed

    Girault, Elodie M; Guigas, Bruno; Alkemade, Anneke; Foppen, Ewout; Ackermans, Mariëtte T; la Fleur, Susanne E; Fliers, Eric; Kalsbeek, Andries

    2014-02-01

    Atypical antipsychotic drugs such as olanzapine induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying these metabolic side-effects are unknown at the moment. In this study, we investigated the metabolic changes induced by a chronic treatment, as well as the influence of a preceding chronic treatment on the acute effects of olanzapine on glucose metabolism. The effect of chronic olanzapine treatment (±6.5 mg/kg/day, administered via drinking water) on body weight, locomotor activity, body temperature, fat distribution and energy expenditure was investigated in male rats. After 5 weeks, the animals received an acute olanzapine challenge (intragastric, IG) at 3 mg/kg/h during 160 min to investigate the acute effects of olanzapine on glucose metabolism. Chronic olanzapine-treated animals showed a slight decrease in nocturnal body temperature, and increased perirenal fat pad weights as well as plasma leptin. In addition, chronic olanzapine-treated animals showed hyperinsulinaemia with unchanged blood glucose concentrations. The acute challenge with IG olanzapine elevated blood glucose levels and endogenous glucose production in control animals, but not in chronic olanzapine-pre-treated rats. Chronic olanzapine-treated animals also showed reduced locomotor activity and a higher respiratory exchange ratio. Thus, chronic treatment with olanzapine in rats causes desensitization to its acute effects on glucose metabolism but promotes adiposity probably due to a shift from lipids to carbohydrates as an energy source. Chronic exposure to olanzapine changes body fat distribution and insulin sensitivity in an unfavourable direction, but it is still unclear what the primary mechanism is.

  6. Postoperative metabolic alkalosis and acute renal failure: rationale for the use of hydrochloric acid.

    PubMed

    Shavelle, H S; Parke, R

    1975-10-01

    Metabolic alkalosis secondary to chloride depletion, especially following gastrointestinal surgery and associated with acute renal failure, is a frequent clinical occurrence. Management of the resultant acid-base disturbance mandates chloride replacement. The presence of oliguria limits the choice of accompanying cation. The use of intravenous hydrochloric acid to correct and maintain proper chloride balance, secondary to external gastric fluid losses, is recommended as a straightforward approach. Two brief case synopses are presented. Both patients, florid examples of profound chloride depletion, required large amounts of intravenous hydrochloric acid. The options regarding the choice of chloride solution, hazards involved, and a simplified schema of replacement therapy are presented. Combined gastrointestinal and renal dysfunction create unusual biochemical and clinical alterations and may result in a complex management problem.

  7. Acute toxicity testing of some herbicides-, alkaloids-, and antibiotics-metabolizing soil bacteria in the rat.

    PubMed

    Kaiser, A; Classen, H G; Eberspächer, J; Lingens, F

    1981-01-01

    Seven strains of soil bacteria with the ability to metabolize herbicides, alkaloids or antibiotics were tested in rats for acute toxicity. 1. Upon oral administration of 9.0 x 10(8) to 6.6 x 10(10) cells daily during 7 d no adverse reactions were observed. 2. Exposure by air did not lead to specific pulmonary changes. 3. Intracutaneous injection of 7.5 x 10(6) to 1.4 x 10(8) cells did not lead to adverse skin reactions. 4. Intraperitoneal injections up to 10(8) cells per animal did not kill rats although bacteria entered blood. At higher concentrations some mortality occurred partly due to unspecific stress reactions. 5. Animal data and observations on 20 humans being exposed to these strains for 2 months up to 15 years support the view that the bacteria tested are essentially harmless for health.

  8. Acute phase response, inflammation and metabolic syndrome biomarkers of Libby asbestos exposure

    SciTech Connect

    Shannahan, Jonathan H.; Alzate, Oscar; Winnik, Witold M.; Andrews, Debora; Schladweiler, Mette C.; Ghio, Andrew J.; Gavett, Stephen H.; Kodavanti, Urmila P.

    2012-04-15

    Identification of biomarkers assists in the diagnosis of disease and the assessment of health risks from environmental exposures. We hypothesized that rats exposed to Libby amphibole (LA) would present with a unique serum proteomic profile which could help elucidate epidemiologically-relevant biomarkers. In four experiments spanning varied protocols and temporality, healthy (Wistar Kyoto, WKY; and F344) and cardiovascular compromised (CVD) rat models (spontaneously hypertensive, SH; and SH heart failure, SHHF) were intratracheally instilled with saline (control) or LA. Serum biomarkers of cancer, inflammation, metabolic syndrome (MetS), and the acute phase response (APR) were analyzed. All rat strains exhibited acute increases in α-2-macroglobulin, and α1-acid glycoprotein. Among markers of inflammation, lipocalin-2 was induced in WKY, SH and SHHF and osteopontin only in WKY after LA exposure. While rat strain- and age-related changes were apparent in MetS biomarkers, no LA effects were evident. The cancer marker mesothelin was increased only slightly at 1 month in WKY in one of the studies. Quantitative Intact Proteomic profiling of WKY serum at 1 day or 4 weeks after 4 weekly LA instillations indicated no oxidative protein modifications, however APR proteins were significantly increased. Those included serine protease inhibitor, apolipoprotein E, α-2-HS-glycoprotein, t-kininogen 1 and 2, ceruloplasmin, vitamin D binding protein, serum amyloid P, and more 1 day after last LA exposure. All changes were reversible after a short recovery regardless of the acute or long-term exposures. Thus, LA exposure induces an APR and systemic inflammatory biomarkers that could have implications in systemic and pulmonary disease in individuals exposed to LA. -- Highlights: ► Biomarkers of asbestos exposure are required for disease diagnosis. ► Libby amphibole exposure is associated with increased human mortality. ► Libby amphibole increases circulating proteins involved

  9. Medullary sponge kidney presenting in a neonate with distal renal tubular acidosis and failure to thrive: a case report

    PubMed Central

    2009-01-01

    Introduction Medullary sponge kidney is a congenital anomaly characterized by diffuse ectasy of the collecting tubules of one or both kidneys. It is usually diagnosed in the second or third decade of life. Case presentation Distal renal tubular acidosis is commonly observed in patients with medullary sponge kidney. We describe here a 50-day-old Egyptian Caucasian girl with medullary sponge kidney who had features of distal renal tubular acidosis, (persistent alkaline urine, hypercalciuria, hypocitraturia) and failure to thrive. Renal ultrasound revealed left renal increased medullary echogenicity and bilateral nephrocalcinosis. Conclusion Early gene(s) expression of medullary sponge kidney disease might be responsible for persistent metabolic acidosis during the neonatal period. PMID:19830120

  10. Modulation of the metabolic response to vaccination in naive beef steers using an acute versus chronic stress model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Available energy plays a critical role in the initiation and maintenance of an immune response to a pathogen a process that is further altered by activation of stress system. This study was designed to determine the effect of an acute versus chronic stress model on the metabolic response to vaccinat...

  11. Combined administration of hyperbaric oxygen and hydroxocobalamin improves cerebral metabolism after acute cyanide poisoning in rats.

    PubMed

    Hansen, M B; Olsen, N V; Hyldegaard, O

    2013-11-01

    Hyperbaric oxygen therapy (HBOT) or intravenous hydroxocobalamin (OHCob) both abolish cyanide (CN)-induced surges in interstitial brain lactate and glucose concentrations. HBOT has been shown to induce a delayed increase in whole blood CN concentrations, whereas OHCob may act as an intravascular CN scavenger. Additionally, HBOT may prevent respiratory distress and restore blood pressure during CN intoxication, an effect not seen with OHCob administration. In this report, we evaluated the combined effects of HBOT and OHCob on interstitial lactate, glucose, and glycerol concentrations as well as lactate-to-pyruvate ratio in rat brain by means of microdialysis during acute CN poisoning. Anesthetized rats were allocated to three groups: 1) vehicle (1.2 ml isotonic NaCl intra-arterially); 2) potassium CN (5.4 mg/kg intra-arterially); 3) potassium CN, OHCob (100 mg/kg intra-arterially) and subsequent HBOT (284 kPa in 90 min). OHCob and HBOT significantly attenuated the acute surges in interstitial cerebral lactate, glucose, and glycerol concentrations compared with the intoxicated rats given no treatment. Furthermore, the combined treatment resulted in consistent low lactate, glucose, and glycerol concentrations, as well as in low lactate-to-pyruvate ratios compared with CN intoxicated controls. In rats receiving OHCob and HBOT, respiration improved and cyanosis disappeared, with subsequent stabilization of mean arterial blood pressure. The present findings indicate that a combined administration of OHCob and HBOT has a beneficial and persistent effect on the cerebral metabolism during CN intoxication.

  12. The Role of Gut–brain Axis in Regulating Glucose Metabolism After Acute Pancreatitis

    PubMed Central

    Pendharkar, Sayali A; Asrani, Varsha M; Murphy, Rinki; Cutfield, Richard; Windsor, John A; Petrov, Maxim S

    2017-01-01

    Objectives: Diabetes has become an epidemic in developed and developing countries alike, with an increased demand for new efficacious treatments. A large body of pre-clinical evidence suggests that the gut–brain axis may be exploited as a potential therapeutic target for defective glucose homeostasis. This clinical study aimed to investigate a comprehensive panel of glucoregulatory peptides, released by both the gut and brain, in individuals after acute pancreatitis. Methods: Fasting levels of glucagon-like peptide-1 (GLP-1), glicentin, oxyntomodulin, peptide YY, ghrelin, cholecystokinin, vasoactive intestinal peptide (VIP), and secretin were studied. Modified Poisson and multivariable linear regression analyses were conducted. Pre-determined concentration ranges were used to categorize each peptide into quartiles. Results: A total of 83 individuals were included, of who 30 (36%) developed abnormal glucose metabolism (AGM) after acute pancreatitis. In individuals with AGM, the highest quartile of oxyntomodulin differed most significantly from the lowest quartile with a prevalence ratio (PR; 95% confidence interval) of 0.50 (0.21, 1.20; P=0.005); of glicentin with a PR of 0.26 (0.13, 0.54; P<0.001); and of VIP with a PR of 0.34 (0.13, 0.89; P=0.043). Peptide YY, GLP-1, cholecystokinin, ghrelin, and secretin were not significantly associated with AGM. Conclusions: Fasting circulating oxyntomodulin, glicentin, and VIP levels are significantly decreased in patients with defective glucose homeostasis after acute pancreatitis. Oxyntomodulin appears to be a promising therapeutic target for future clinical studies on diabetes associated with diseases of the exocrine pancreas. PMID:28055028

  13. Acute phase response, inflammation and metabolic syndrome biomarkers of Libby asbestos exposure.

    PubMed

    Shannahan, Jonathan H; Alzate, Oscar; Winnik, Witold M; Andrews, Debora; Schladweiler, Mette C; Ghio, Andrew J; Gavett, Stephen H; Kodavanti, Urmila P

    2012-04-15

    Identification of biomarkers assists in the diagnosis of disease and the assessment of health risks from environmental exposures. We hypothesized that rats exposed to Libby amphibole (LA) would present with a unique serum proteomic profile which could help elucidate epidemiologically-relevant biomarkers. In four experiments spanning varied protocols and temporality, healthy (Wistar Kyoto, WKY; and F344) and cardiovascular compromised (CVD) rat models (spontaneously hypertensive, SH; and SH heart failure, SHHF) were intratracheally instilled with saline (control) or LA. Serum biomarkers of cancer, inflammation, metabolic syndrome (MetS), and the acute phase response (APR) were analyzed. All rat strains exhibited acute increases in α-2-macroglobulin, and α1-acid glycoprotein. Among markers of inflammation, lipocalin-2 was induced in WKY, SH and SHHF and osteopontin only in WKY after LA exposure. While rat strain- and age-related changes were apparent in MetS biomarkers, no LA effects were evident. The cancer marker mesothelin was increased only slightly at 1 month in WKY in one of the studies. Quantitative Intact Proteomic profiling of WKY serum at 1 day or 4 weeks after 4 weekly LA instillations indicated no oxidative protein modifications, however APR proteins were significantly increased. Those included serine protease inhibitor, apolipoprotein E, α-2-HS-glycoprotein, t-kininogen 1 and 2, ceruloplasmin, vitamin D binding protein, serum amyloid P, and more 1 day after last LA exposure. All changes were reversible after a short recovery regardless of the acute or long-term exposures. Thus, LA exposure induces an APR and systemic inflammatory biomarkers that could have implications in systemic and pulmonary disease in individuals exposed to LA.

  14. A Comparative Metabolomics Approach Reveals Early Biomarkers for Metabolic Response to Acute Myocardial Infarction

    PubMed Central

    Ali, Sara E.; Farag, Mohamed A.; Holvoet, Paul; Hanafi, Rasha S.; Gad, Mohamed Z.

    2016-01-01

    Discovery of novel biomarkers is critical for early diagnosis of acute coronary syndrome (ACS). Serum metabolite profiling of ST-elevation myocardial infarction (STEMI), unstable angina (UA) and healthy controls was performed using gas chromatography mass spectrometry (GC/MS), solid-phase microextraction coupled to gas chromatography mass spectrometry (SPME-GC/MS) and nuclear magnetic resonance (1H-NMR). Multivariate data analysis revealed a metabolic signature that could robustly discriminate STEMI patients from both healthy controls and UA patients. This panel of biomarkers consisted of 19 metabolites identified in the serum of STEMI patients. One of the most intriguing biomarkers among these metabolites is hydrogen sulfide (H2S), an endogenous gasotransmitter with profound effect on the heart. Serum H2S absolute levels were further investigated using a quantitative double-antibody sandwich enzyme-linked immunosorbent assay (ELISA). This highly sensitive immunoassay confirmed the elevation of serum H2S in STEMI patients. H2S level discriminated between UA and STEMI groups, providing an initial insight into serum-free H2S bioavailability during ACS. In conclusion, the current study provides a detailed map illustrating the most predominant altered metabolic pathways and the biochemical linkages among the biomarker metabolites identified in STEMI patients. Metabolomics analysis may yield novel predictive biomarkers that will potentially allow for an earlier medical intervention. PMID:27821850

  15. Neuroleptic malignant syndrome and diabetic keto-acidosis.

    PubMed

    de Boer, C; Gaete, H P

    1992-12-01

    A patient suffering from schizophrenia developed diabetic keto-acidosis and NMS after treatment with neuroleptics. The combination of two uncommon complications of treatment with neuroleptics proved fatal.

  16. Effects of acute and chronic systemic methamphetamine on respiratory, cardiovascular and metabolic function, and cardiorespiratory reflexes

    PubMed Central

    Hassan, Sarah F.; Wearne, Travis A.; Cornish, Jennifer L.

    2016-01-01

    Key points Methamphetamine (METH) abuse is escalating worldwide, with the most common cause of death resulting from cardiovascular failure and hyperthermia; however, the underlying physiological mechanisms are poorly understood.Systemic administration of METH in anaesthetised rats reduced the effectiveness of some protective cardiorespiratory reflexes, increased central respiratory activity independently of metabolic function, and increased heart rate, metabolism and respiration in a pattern indicating that non‐shivering thermogenesis contributes to the well‐described hyperthermia.In animals that showed METH‐induced behavioural sensitisation following chronic METH treatment, no changes were evident in baseline cardiovascular, respiratory and metabolic measures and the METH‐evoked effects in these parameters were similar to those seen in saline‐treated or drug naïve animals.Physiological effects evoked by METH were retained but were neither facilitated nor depressed following chronic treatment with METH.These data highlight and identify potential mechanisms for targeted intervention in patients vulnerable to METH overdose. Abstract Methamphetamine (METH) is known to promote cardiovascular failure or life‐threatening hyperthermia; however, there is still limited understanding of the mechanisms responsible for evoking the physiological changes. In this study, we systematically determined the effects on both autonomic and respiratory outflows, as well as reflex function, following acute and repeated administration of METH, which enhances behavioural responses. Arterial pressure, heart rate, phrenic nerve discharge amplitude and frequency, lumbar and splanchnic sympathetic nerve discharge, interscapular brown adipose tissue and core temperatures, and expired CO2 were measured in urethane‐anaesthetised male Sprague‐Dawley rats. Novel findings include potent increases in central inspiratory drive and frequency that are not dependent on METH

  17. [A clinical case of lactic acidosis development in a diabetic patient taking metformin].

    PubMed

    Cezur, Mustafa; Celmen, Nedim; Cetinbas, Riza; Badalov, Pavel; Erdemli, Ozcan

    2009-01-01

    Metformin is a biguanide. Due to its effects in decreasing the hepatic production of glucose and in increasing insulin sensitivity in peripheral tissues, such as adipose tissue and skeletal muscle, the agent is used in metabolic syndrome and type 2 diabetes mellitus and, in which insulin resistance is especially pronounced. Eighty-one-year old male patient was admitted to the emergency unit with sudden vertigo, tiredness, dyspnea, cyanosis, and lethargy. He had had type 2 diabetes mellitus for 10 years and was taking glargin 12 U/kg once daily and metformin (glucophage) 850 mg thrice daily. The patient showed no cooperation and orientation. Metabolic acidosis, hypoxemia, and hypercapnea were detected in arterial blood gases (ABG). The patient was transferred to an intensive care unit of the hospital; endotracheal intubation was applied and mechanic ventilation was started. On the following day, his ABG got better; he was disconnected and weaning was applied. Lung X-ray study revealed no signs of pneumonia or pulmonary edema. On the same day, extubation was ended and O2 was given by mask at a rate of 4 L/min. After the patient's vital signs, blood sugar, and lactate levels were stabilized; his treatment regimen was arranged again and the patient was discharged on day 4 of his admission. Dyspnea, acidosis, and hypoxia seen in the patient were thought to be due to lactic acidosis which may rarely occur when metformin is used.

  18. Soymilk products affect ethanol absorption and metabolism in rats during acute and chronic ethanol intake.

    PubMed

    Kano, M; Ishikawa, F; Matsubara, S; Kikuchi-Hayakawa, H; Shimakawa, Y

    2002-02-01

    In this study we evaluated the effects of soy products on ethanol metabolism during periods of acute and chronic consumption in rats. Gastric ethanol content and blood ethanol and acetaldehyde concentrations were investigated after the oral administration of ethanol (34 mmol/kg) plus soy products such as soymilk (SM) or fermented soymilk (FSM). The gastric ethanol concentration of the FSM group was greater than that of the control group, whereas portal and aortal blood ethanol concentrations of the FSM group were lower than in controls. The aortal acetaldehyde concentration in the FSM group was lower than that of the control group. The direct effect of isoflavones on liver function was investigated by using hepatocytes isolated from untreated rats. Genistein (5 micromol/L) decreased ethanol (P = 0.045) and tended to decrease acetaldehyde (P = 0.10) concentrations in the culture filtrate. Some variables of ethanol metabolism in the liver were investigated after chronic ethanol exposure for 25 d. Rats consumed a 5% ethanol fluid plus the SM diet, the FSM diet or a control diet. Microsomal ethanol oxidizing activity was significantly lower in the FSM group than the control group. Furthermore, cytosolic glutathione S-transferase activity was higher in the SM and FSM groups than in the control group. Acetaldehyde dehydrogenase activity (low K(m)) in the FSM group (P = 0.15), but not in the SM group (P = 0.31), tended to be greater than in the control group. The amount of thiobarbituric acid reacting substances in the liver of the SM and FSM groups tended to be less than that of the control group (P = 0.18 and 0.10, respectively). These results demonstrate that soymilk products inhibit ethanol absorption and enhance ethanol metabolism in rats.

  19. Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects Are Diminished in Adrenalectomized Rats.

    PubMed

    Miller, Desinia B; Snow, Samantha J; Schladweiler, Mette C; Richards, Judy E; Ghio, Andrew J; Ledbetter, Allen D; Kodavanti, Urmila P

    2016-04-01

    Acute ozone exposure increases circulating stress hormones and induces metabolic alterations in animals. We hypothesized that the increase of adrenal-derived stress hormones is necessary for both ozone-induced metabolic effects and lung injury. Male Wistar-Kyoto rats underwent bilateral adrenal demedullation (DEMED), total bilateral adrenalectomy (ADREX), or sham surgery (SHAM). After a 4 day recovery, rats were exposed to air or ozone (1 ppm), 4 h/day for 1 or 2 days and responses assessed immediately postexposure. Circulating adrenaline levels dropped to nearly zero in DEMED and ADREX rats relative to SHAM. Corticosterone tended to be low in DEMED rats and dropped to nearly zero in ADREX rats. Adrenalectomy in air-exposed rats caused modest changes in metabolites and lung toxicity parameters. Ozone-induced hyperglycemia and glucose intolerance were markedly attenuated in DEMED rats with nearly complete reversal in ADREX rats. Ozone increased circulating epinephrine and corticosterone in SHAM but not in DEMED or ADREX rats. Free fatty acids (P = .15) and branched-chain amino acids increased after ozone exposure in SHAM but not in DEMED or ADREX rats. Lung minute volume was not affected by surgery or ozone but ozone-induced labored breathing was less pronounced in ADREX rats. Ozone-induced increases in lung protein leakage and neutrophilic inflammation were markedly reduced in DEMED and ADREX rats (ADREX > DEMED). Ozone-mediated decreases in circulating white blood cells in SHAM were not observed in DEMED and ADREX rats. We demonstrate that ozone-induced peripheral metabolic effects and lung injury/inflammation are mediated through adrenal-derived stress hormones likely via the activation of stress response pathway.

  20. Acute alcohol exposure during mouse gastrulation alters lipid metabolism in placental and heart development: Folate prevention

    PubMed Central

    Han, Mingda

    2016-01-01

    Background Embryonic acute exposure to ethanol (EtOH), lithium, and homocysteine (HCy) induces cardiac defects at the time of exposure; folic acid (FA) supplementation protects normal cardiogenesis (Han et al., 2009, 2012; Serrano et al., 2010). Our hypothesis is that EtOH exposure and FA protection relate to lipid and FA metabolism during mouse cardiogenesis and placentation. Methods On the morning of conception, pregnant C57BL/6J mice were placed on either of two FA‐containing diets: a 3.3 mg health maintenance diet or a high FA diet of 10.5 mg/kg. Mice were injected a binge level of EtOH, HCy, or saline on embryonic day (E) 6.75, targeting gastrulation. On E15.5, cardiac and umbilical blood flow were examined by ultrasound. Embryonic cardiac tissues were processed for gene expression of lipid and FA metabolism; the placenta and heart tissues for neutral lipid droplets, or for medium chain acyl‐dehydrogenase (MCAD) protein. Results EtOH exposure altered lipid‐related gene expression on E7.5 in comparison to control or FA‐supplemented groups and remained altered on E15.5 similarly to changes with HCy, signifying FA deficiency. In comparison to control tissues, the lipid‐related acyl CoA dehydrogenase medium length chain gene and its protein MCAD were altered with EtOH exposure, as were neutral lipid droplet localization in the heart and placenta. Conclusion EtOH altered gene expression associated with lipid and folate metabolism, as well as neutral lipids, in the E15.5 abnormally functioning heart and placenta. In comparison to controls, the high FA diet protected the embryo and placenta from these effects allowing normal development. Birth Defects Research (Part A) 106:749–760, 2016. © 2016 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc. PMID:27296863

  1. Effects of Acute Exposure to Moderate Altitude on Vascular Function, Metabolism and Systemic Inflammation

    PubMed Central

    Stöwhas, Anne-Christin; Latshang, Tsogyal D.; Lo Cascio, Christian M.; Lautwein, Sina; Stadelmann, Katrin; Tesler, Noemi; Ayers, Lisa; Berneis, Kaspar; Gerber, Philipp A.; Huber, Reto; Achermann, Peter; Bloch, Konrad E.; Kohler, Malcolm

    2013-01-01

    Background Travel to mountain areas is popular. However, the effects of acute exposure to moderate altitude on the cardiovascular system and metabolism are largely unknown. Objectives To investigate the effects of acute exposure to moderate altitude on vascular function, metabolism and systemic inflammation. Methods In 51 healthy male subjects with a mean (SD) age of 26.9 (9.3) years, oxygen saturation, blood pressure, heart rate, arterial stiffness, lipid profiles, low density lipoprotein (LDL) particle size, insulin resistance (HOMA-index), highly-sensitive C-reactive protein and pro-inflammatory cytokines were measured at 490 m (Zurich) and during two days at 2590 m, (Davos Jakobshorn, Switzerland) in randomized order. The largest differences in outcomes between the two altitudes are reported. Results Mean (SD) oxygen saturation was significantly lower at 2590 m, 91.0 (2.0)%, compared to 490 m, 96.0 (1.0)%, p<0.001. Mean blood pressure (mean difference +4.8 mmHg, p<0.001) and heart rate (mean difference +3.3 bpm, p<0.001) were significantly higher at 2590 m, compared to 490 m, but this was not associated with increased arterial stiffness. At 2590 m, lipid profiles improved (median difference triglycerides −0.14 mmol/l, p = 0.012, HDL +0.08 mmol/l, p<0.001, total cholesterol/HDL-ratio −0.25, p = 0.001), LDL particle size increased (median difference +0.45 nm, p = 0.048) and hsCRP decreased (median difference −0.18 mg/l, p = 0.024) compared to 490 m. No significant change in pro-inflammatory cytokines or insulin resistance was observed upon ascent to 2590 m. Conclusions Short-term stay at moderate altitude is associated with increased blood pressure and heart rate likely due to augmented sympathetic activity. Exposure to moderate altitude improves the lipid profile and systemic inflammation, but seems to have no significant effect on glucose metabolism. Trial Registration ClinicalTrials.gov NCT01130948 PMID:23936377

  2. Rare combination of bilateral putaminal necrosis, optic neuritis, and polyneuropathy in a case of acute methanol intoxication among patients met with hooch tragedy in Gujarat, India

    PubMed Central

    Jarwani, Bhavesh S; Motiani, Puja; Divetia, Ruchir; Thakkar, Gurudutta

    2012-01-01

    Methanol poisoning is a rare but extremely hazardous form of intoxication, generally occurring after suicidal or accidental events. Methanol is a cheap and potent adulterant of illicit liquors. In India, we have witnessed number of mass emergencies due to adulterated alcohol consumption. Although Gujarat State had banned alcohol consumption since 1961, worse hooch tragedies have often taken place. The most severe consequences of methanol intoxication are blindness, a profound metabolic acidosis and various forms of neurological impairment; which occur characteristically after a latent period of several hours or days after ingestion. We present a unique case of acute methanol intoxication presented with, apart from metabolic acidosis and optic neuritis, involvement of central nervous system and peripheral nervous system. He had bilateral optic neuritis, delayed onset polyneuropathy with axonopathy, and radiculopathy. Magnetic resonance imaging findings were consistent with bilateral putaminal necrosis. PMID:23248510

  3. Reversible lactic acidosis associated with repeated intravenous infusions of sorbitol and ethanol.

    PubMed Central

    Batstone, G. F.; Alberti, K. G.; Dewar, A. K.

    1977-01-01

    Infusions of fructose or sorbitol are used commonly in parenteral nutrition and may cause lactic acidosis. A case is reported in whom blood lactate concentration was monitored frequently over a 5-day period during intravenous feeding with a sorbitol-ethanol-amino acid mixture. During the first five infusions blood lactate rose only moderately, but with the final infusion lactate rose to 11-1 mmol/l and the patient had a severe metabolic acidosis. In retrospect the patient had shown deterioration in renal and hepatic function tests during the preceding 24 hr. On terminating the infusions the blood lactate concentration fell rapidly. It is suggested that great care should be exercised when using such infusions in ill patients and acid base status and renal and hepatic function should be monitored frequently. PMID:22069

  4. Renal tubular acidosis type IV as a complication of lupus nephritis.

    PubMed

    Sánchez-Marcos, C; Hoffman, V; Prieto-González, S; Hernández-Rodríguez, J; Espinosa, G

    2016-03-01

    Renal tubular acidosis (RTA) is a rare complication of renal involvement of systemic lupus erythematosus (SLE). We describe a 24-year-old male with type IV lupus nephropathy as a presenting manifestation of SLE. He presented with improvement of renal function following induction therapy with three pulses of methylprednisolone and 500 mg biweekly pulses of cyclophosphamide. However, a week after the first pulse of cyclophosphamide, the patient presented with a significant increase in legs edema and severe hyperkalemia. Type IV RTA associated with hyporeninemic hypoaldosteronism was suspected in the presence of metabolic acidosis with a normal anion gap, severe hyperkalemia without worsening renal function, and urinary pH of 5. RTA was confirmed with a transtubular potassium concentration gradient of 2 and low levels of plasma aldosterone, renin, angiotensin II, and cortisol. Intravenous bicarbonate, high-dose furosemide, and fludrocortisone were administered with normalization of potassium levels and renal function.

  5. Carbicarb: an effective substitute for NaHCO3 for the treatment of acidosis.

    PubMed

    Sun, J H; Filley, G F; Hord, K; Kindig, N B; Bartle, E J

    1987-11-01

    Carbicarb (Na2CO3 0.33 molar NaHCO3 0.33 molar), a mixture formulated to avoid the objections to sodium bicarbonate therapy, has been compared with 1 mol/L NaHCO3 and 1 mol/L NaCl in the treatment of mixed respiratory and metabolic acidosis (pH 7.17) produced by asphyxia in rats. In clinically appropriate doses, intravenous NaHCO3 raised arterial pH only 0.03 unit, elevated arterial carbon dioxide pressure, and doubled lactate concentration. With Carbicarb, the pH rise was three times as great and the blood lactate level was unchanged. The new drug should be effective in treating the acidosis of cardiopulmonary failure without raising blood carbon dioxide pressure or lactate levels and at lower sodium doses than required for NaHCO3.

  6. Acute doxorubicin cardiotoxicity alters cardiac cytochrome P450 expression and arachidonic acid metabolism in rats

    SciTech Connect

    Zordoky, Beshay N.M.; Anwar-Mohamed, Anwar; Aboutabl, Mona E.

    2010-01-01

    Doxorubicin (DOX) is a potent anti-neoplastic antibiotic used to treat a variety of malignancies; however, its use is limited by dose-dependent cardiotoxicity. Moreover, there is a strong correlation between cytochrome P450 (CYP)-mediated arachidonic acid metabolites and the pathogenesis of many cardiovascular diseases. Therefore, in the current study, we have investigated the effect of acute DOX toxicity on the expression of several CYP enzymes and their associated arachidonic acid metabolites in the heart of male Sprague-Dawley rats. Acute DOX toxicity was induced by a single intraperitoneal injection of 15 mg/kg of the drug. Our results showed that DOX treatment for 24 h caused a significant induction of CYP1A1, CYP1B1, CYP2C11, CYP2J3, CYP4A1, CYP4A3, CYP4F1, CYP4F4, and EPHX2 gene expression in the heart of DOX-treated rats as compared to the control. Similarly, there was a significant induction of CYP1A1, CYP1B1, CYP2C11, CYP2J3, CYP4A, and sEH proteins after 24 h of DOX administration. In the heart microsomes, acute DOX toxicity significantly increased the formation of 20-HETE which is consistent with the induction of the major CYP omega-hydroxylases: CYP4A1, CYP4A3, CYP4F1, and CYP4F4. On the other hand, the formation of 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) was significantly reduced, whereas the formation of their corresponding dihydroxyeicosatrienoic acids was significantly increased. The decrease in the cardioprotective EETs can be attributed to the increase of sEH activity parallel to the induction of the EPHX2 gene expression in the heart of DOX-treated rats. In conclusion, acute DOX toxicity alters the expression of several CYP and sEH enzymes with a consequent alteration in arachidonic acid metabolism. These results may represent a novel mechanism by which this drug causes progressive cardiotoxicity.

  7. The acute effects of time-of-day-dependent high fat feeding on whole body metabolic flexibility in mice

    PubMed Central

    Joo, J; Cox, C C; Kindred, E D; Lashinger, L M; Young, M E; Bray, M S

    2016-01-01

    Background: Both circadian disruption and timing of feeding have important roles in the development of metabolic disease. Despite growing acceptance that the timing of food consumption has long-term impact on metabolic homeostasis, little is known regarding the immediate influence on whole body metabolism, or the mechanisms involved. We aimed to examine the acute effects of time-of-day-dependent high fat feeding on whole body substrate metabolism and metabolic plasticity, and to determine the potential contribution of the adipocyte circadian clock. Methods: Mice were fed a regimen of 4-h meal at the beginning and end of the dark (waking) cycle, separated by 4 h of fasting. Daily experimental conditions consisted of either an early very high fat or high fat (EVHF or EHF, 60 or 45% kcals from fat, respectively) or late (LVHF or LHF) meal, paired with a low fat (LF, 10% kcals from fat) meal. Metabolic parameters, glucose tolerance, body fat composition and weight were assessed. To determine the role of the adipocyte circadian clock, an aP2-CLOCK mutant (ACM) mouse model was used. Results: Mice in the EVHF or EHF groups showed a 13.2 or 8.84 higher percentage of caloric intake from fat and had a 0.013 or 0.026 lower daily average respiratory exchange ratio, respectively, compared with mice eating the opposite feeding regime. Changes in glucose tolerance, body fat composition and weight were not significant at the end of the 9-day restricted feeding period. ACM mice did not exhibit different metabolic responses to the feeding regimes compared with wild-type littermates. Circadian clock disruption did not influence the short-term response to timed feeding. Conclusions: Both the total fat composition of diet and the timing of fat intake may differentially mediate the effect of timed feeding on substrate metabolism, but may not induce acute changes in metabolic flexibility. PMID:27133618

  8. Renal tubular acidosis in chronic liver disease

    PubMed Central

    Golding, Peter L.

    1975-01-01

    Renal tubular acidosis of the gradient or classic type, thought to be due to a disorder of the distal tubule, has been found to occur in 32% of 117 patients with chronic liver disease. Whilst the cause of this disorder is probably multifactorial, immunological mechanisms are considered to play a major role. The presence of this disorder might well be a cause, rather than the result of, the various electrolyte abnormalities seen in patients with chronic liver disease. ImagesFig. 1Fig. 6 PMID:1234340

  9. Distal Renal Tubular Acidosis and Calcium Nephrolithiasis

    NASA Astrophysics Data System (ADS)

    Moe, Orson W.; Fuster, Daniel G.; Xie, Xiao-Song

    2008-09-01

    Calcium stones are commonly encountered in patients with congenital distal renal tubular acidosis, a disease of renal acidification caused by mutations in either the vacuolar H+-ATPase (B1 or a4 subunit), anion exchanger-1, or carbonic anhydrase II. Based on the existing database, we present two hypotheses. First, heterozygotes with mutations in B1 subunit of H+-ATPase are not normal but may harbor biochemical abnormalities such as renal acidification defects, hypercalciuria, and hypocitraturia which can predispose them to kidney stone formation. Second, we propose at least two mechanisms by which mutant B1 subunit can impair H+-ATPase: defective pump assembly and defective pump activity.

  10. Quantum therapy in correction of the lipidic metabolism at acute pancreatitis

    NASA Astrophysics Data System (ADS)

    Anaskin, S. G.; Vlasov, A. P.; Spirina, M. A.; Vlasova, T. I.; Muratova, T. A.; Korniletsky, I. D.; Geraskin, V. S.

    2017-01-01

    Attempt to establish efficiency of laser therapy in correction of a lipid metabolism at patients with acute pancreatitis was the purpose of work. There were clinical laboratory researches of 48 patients with acute heavy pancreatitis. To the first clinical group (comparison) standard therapy was carried out. To patients of the second clinical group (main) in addition to basic therapy within 10 days daily sessions of laser therapy by the device "Matrix" were held later. Radiation with the wavelength of 635 nanometers, 2 MW was used. Percutaneous laser radiation of blood was carried out to projections of a cubital vein within 30 minutes daily. Inclusion of laser therapy in complex treatment of patients with pancreatitis led to more significant positive dynamics. Reduction of weight of endotoxemia in the main group is set that was verified by decrease in level of both hydrophilic, and hydrophobic toxins. The analysis of the data obtained as a result of research in the main group revealed decrease in concentration of products of free radical oxidation of lipids in comparison with group of comparison for 12,1 – 17,3% of % (p. <. 0,05). Laser radiation of blood as a part of complex treatment led to reliable inhibition of activity of enzymes of phospholipase system in blood plasma, in particular activity of a phospholipase of A2 fell for 13,2 – 34,4% (p <0,05). Thus, inclusion of laser therapy in structure of complex treatment of sharp pancreatitis allowed to reduce significantly expressiveness of endogenous intoxication, intensity of processes of free radical oxidation of membrane lipids and activity of phospholipase systems.

  11. Acute Exposure to Pacific Ciguatoxin Reduces Electroencephalogram Activity and Disrupts Neurotransmitter Metabolic Pathways in Motor Cortex.

    PubMed

    Kumar, Gajendra; Au, Ngan Pan Bennett; Lei, Elva Ngai Yu; Mak, Yim Ling; Chan, Leanne Lai Hang; Lam, Michael Hon Wah; Chan, Leo Lai; Lam, Paul Kwan Sing; Ma, Chi Him Eddie

    2016-09-10

    Ciguatera fish poisoning (CFP) is a common human food poisoning caused by consumption of ciguatoxin (CTX)-contaminated fish affecting over 50,000 people worldwide each year. CTXs are classified depending on their origin from the Pacific (P-CTXs), Indian Ocean (I-CTXs), and Caribbean (C-CTXs). P-CTX-1 is the most toxic CTX known and the major source of CFP causing an array of neurological symptoms. Neurological symptoms in some CFP patients last for several months or years; however, the underlying electrophysiological properties of acute exposure to CTXs remain unknown. Here, we used CTX purified from ciguatera fish sourced in the Pacific Ocean (P-CTX-1). Delta and theta electroencephalography (EEG) activity was reduced remarkably in 2 h and returned to normal in 6 h after a single exposure. However, second exposure to P-CTX-1 induced not only a further reduction in EEG activities but also a 2-week delay in returning to baseline EEG values. Ciguatoxicity was detected in the brain hours after the first and second exposure by mouse neuroblastoma assay. The spontaneous firing rate of single motor cortex neuron was reduced significantly measured by single-unit recording with high spatial resolution. Expression profile study of neurotransmitters using targeted profiling approach based on liquid chromatography-tandem mass spectrometry revealed an imbalance between excitatory and inhibitory neurotransmitters in the motor cortex. Our study provides a possible link between the brain oscillations and neurotransmitter release after acute exposure to P-CTX-1. Identification of EEG signatures and major metabolic pathways affected by P-CTX-1 provides new insight into potential biomarker development and therapeutic interventions.

  12. Role of hormonal factors in plasma K alterations in acute respiratory and metabolic alkalosis in dogs.

    PubMed

    Suzuki, H; Hishida, A; Ohishi, K; Kimura, M; Honda, N

    1990-02-01

    Studies were performed on previously nephrectomized dogs to examine roles of hormonal factors in plasma potassium alterations in acute alkalosis. Respiratory and metabolic alkalosis were induced by hyperventilation and intravenous NaHCO3 or tris(hydroxymethyl)aminomethane (Tris) infusion, respectively. Respiratory and NaHCO3-induced alkalosis provoked decreases in plasma potassium from the control value of 5.12 +/- 0.68 (SE) to 4.21 +/- 0.55 meq/l (P less than 0.01) and from 4.65 +/- 0.26 to 3.91 +/- 0.16 meq/l (P less than 0.01) within 180 min, respectively. In contrast, Tris-induced alkalosis elicited an increase in plasma potassium from the control value of 4.56 +/- 0.30 to 5.31 +/- 0.30 meq/l (P less than 0.01). Hypokalemia in respiratory alkalosis was associated with a decrease in the plasma norepinephrine concentration from the control level of 377 +/- 104 to 155 +/- 41 pg/ml (P less than 0.05) but not with changes in plasma levels of epinephrine, insulin, glucagon, cortisol, and aldosterone. However, this hypokalemia was not affected by phentolamine. Also, somatostatin did not modify the hypokalemic response. NaHCO3-induced hypokalemia was associated with a decline in the plasma aldosterone and norepinephrine concentrations. The decline in plasma norepinephrine in NaHCO3-induced alkalosis followed the decrease in plasma potassium. In Tris-induced alkalosis, plasma insulin increased but norepinephrine decreased. The findings do not suggest fundamental roles of the hormonal factors in the plasma potassium alterations in bilaterally nephrectomized dogs with acute alkalosis.

  13. Comparison of the acute metabolic responses to traditional resistance, body-weight, and battling rope exercises.

    PubMed

    Ratamess, Nicholas A; Rosenberg, Joseph G; Klei, Samantha; Dougherty, Brian M; Kang, Jie; Smith, Charles R; Ross, Ryan E; Faigenbaum, Avery D

    2015-01-01

    The purpose of this study was to quantify and compare the acute metabolic responses to resistance exercise protocols comprising free-weight, body-weight, and battling rope (BR) exercises. Ten resistance-trained men (age = 20.6 ± 1.3 years) performed 13 resistance exercise protocols on separate days in random order consisting of only one exercise per session. For free-weight exercise protocols, subjects performed 3 sets of up to 10 repetitions with 75% of their 1 repetition maximum. For the push-up (PU) and push-up on a BOSU ball protocols, subjects performed 3 sets of 20 repetitions. For the burpee and PU with lateral crawl protocols, subjects performed 3 sets of 10 repetitions. For the plank and BR circuit protocols, subjects performed 3 sets of 30-second bouts. A standard 2-minute rest interval (RI) was used in between all sets for each exercise. Data were averaged for the entire protocol including work and RIs. Mean oxygen consumption was significantly greatest during the BR (24.6 ± 2.6 ml·kg·min) and burpee (22.9 ± 2.1 ml·kg·min) protocols. For the free-weight exercises, highest mean values were seen in the squat (19.6 ± 1.8 ml·kg·min), deadlift (18.9 ± 3.0 ml·kg·min), and lunge (17.3 ± 2.6 ml·kg·min). No differences were observed between PUs performed on the floor vs. on a BOSU ball. However, adding a lateral crawl to the PU significantly increased mean oxygen consumption (19.5 ± 2.9 ml·kg·min). The lowest mean value was seen during the plank exercise (7.9 ± 0.7 ml·kg·min). These data indicate performance of exercises with BRs and a body-weight burpee exercise elicit relatively higher acute metabolic demands than traditional resistance exercises performed with moderately heavy loading.

  14. Persistent lactic acidosis after chronic topical application of silver sulfadiazine in a pediatric burn patient: a review of the literature.

    PubMed

    Willis, Monte S; Cairns, Bruce A; Purdy, Ashley; Bortsov, Andrey V; Jones, Samuel W; Ortiz-Pujols, Shiara M; Willis, Tina M Schade; Joyner, Benny L

    2013-01-01

    A 3-year old male who sustained 2(nd) and 3(rd) degree burns that covered approximately 60% TBSA presented to a large adult and pediatric verified burn center. On hospital day (HD) 26 of his stay, Candida fungemia was identified by blood culture, delaying operative management until HD 47. On HD 47, after his first operative intervention, the patient developed a persistent metabolic and lactic acidosis. On HD 66, a search for a cause of his osmol gap of 56 mOsm/kg revealed a potential source-propylene glycol. Previous studies have implicated the propylene glycol emulsifier in the silver sulfadiazine that was being applied to his skin as a rare cause of lactic acidosis in severely burned patients. Within 24 hours of stopping the silver sulfadiazine therapy, his lactic acidosis and osmol gap resolved; within 72 hours his metabolic acidosis resolved. Silver sulfadiazine is commonly used adjunct therapy in the treatment of 2(nd) and 3(rd) degree burns and generally has few adverse reactions. The absorption of propylene glycol systemically can rarely occur when applied to extensive burns, presumably due to the disruption of the skin barrier; the half-life of PG is 10 hours and can be prolonged with renal disease because ~50% of the sulfadiazine is excreted in the urine unchanged. When propylene glycol is present systemically, it is metabolized to lactic acid in the liver, which can cause a lactic acidosis. Several commonly used drugs also use propylene glycol as an emulsifier, including IV preparations of lorazepam, pentobarbital, phenobarbital, and phenytoin. In all of these clinical scenarios, including severe burn patients that are being treated with silver sulfadiazine, both lactic acid and propylene glycol levels should be measured to monitor for this rare, potentially serious co-morbidity.

  15. Resistance to chemotherapy is associated with altered glucose metabolism in acute myeloid leukemia

    PubMed Central

    SONG, KUI; LI, MIN; XU, XIAOJUN; XUAN, LI; HUANG, GUINIAN; LIU, QIFA

    2016-01-01

    Altered glucose metabolism has been described as a cause of chemoresistance in multiple tumor types. The present study aimed to identify the expression profile of glucose metabolism in drug-resistant acute myeloid leukemia (AML) cells and provide potential strategies for the treatment of drug-resistant AML. Bone marrow and serum samples were obtained from patients with AML that were newly diagnosed or had relapsed. The messenger RNA expression of hypoxia inducible factor (HIF)-1α, glucose transporter (GLUT)1, and hexokinase-II was measured by quantitative polymerase chain reaction. The levels of LDH and β subunit of human F1-F0 adenosine triphosphate synthase (β-F1-ATPase) were detected by enzyme-linked immunosorbent and western blot assays. The HL-60 and HL-60/ADR cell lines were used to evaluate glycolytic activity and effect of glycolysis inhibition on cellular proliferation and apoptosis. Drug-resistant HL-60/ADR cells exhibited a significantly increased level of glycolysis compared with the drug-sensitive HL-60 cell line. The expression of HIF-1α, hexokinase-II, GLUT1 and LDH were increased in AML patients with no remission (NR), compared to healthy control individuals and patients with complete remission (CR) and partial remission. The expression of β-F1-ATPase in patients with NR was decreased compared with the expression in the CR group. Treatment of HL-60/ADR cells with 2-deoxy-D-glucose or 3-bromopyruvate increased in vitro sensitivity to Adriamycin (ADR), while treatment of HL-60 cells did not affect drug cytotoxicity. Subsequent to treatment for 24 h, apoptosis in these two cell lines showed no significant difference. However, glycolytic inhibitors in combination with ADR increased cellular necrosis. These findings indicate that increased glycolysis and low efficiency of oxidative phosphorylation may contribute to drug resistance. Targeting glycolysis is a viable strategy for modulating chemoresistance in AML. PMID:27347147

  16. Hepatic alteration of tryptophan metabolism in an acute porphyria model Its relation with gluconeogenic blockage.

    PubMed

    Lelli, Sandra M; Mazzetti, Marta B; San Martín de Viale, Leonor C

    2008-02-01

    This study focuses on the alterations suffered by the serotoninergic and kinurenergic routes of tryptophan (TRP) metabolism in liver, and their relation with gluconeogenic phosphoenolpyruvate-carboxykinase (PEPCK) blockage in experimental acute porphyria. This porphyria was induced in rats by a combined treatment of 2-allyl-2-isopropylacetamide (100, 250, 500 mg/kg bw) and 3,5-dietoxicarbonil 1,4-dihydrocollidine (constant 50 mg/kg bw dose). Results showed a marked dose-dependent increase of all TRP pyrrolase (TRPp) forms, active (holo, total) and inactive (apo), and a decrease in the degree of enzyme saturation by heme. Increases for holo, total, and apo-TRPp were 90, 150, and 230%, respectively, at the highest dose assayed (H). The treatment also impaired the serotoninergic route of TRP metabolism in liver, causing a decrease in serotonin level (H, 38%), and a concomitant enhancement in TRP content (H, 23%). The porphyrinogenic treatment promoted a blockage in PEPCK activity (H, 30%). This occurred in correlation to the development of porphyria, to TRPp alterations and to the production of hepatic microsomal thiobarbituric acid reactive substances. Porphyria was estimated through increases in 5-aminolevulinic acid-synthase (ALA-S) activity, ALA and porphobilinogen contents, and a decrease in ferrochelatase activity. Thus, the TRP kynurenine route was augmented whereas the serotoninergic route was reduced. PEPCK blockage could be partly attributed to quinolinate generated from TRP by the increase of TRPp activity, which would be due to the effect of porphyrinogenic drugs on TRP. The contribution of ROS to PEPCK blockage is analyzed. Likewise, the implication of these results in the control of porphyrias by glucose is discussed.

  17. Acute Liver Injury Induces Nucleocytoplasmic Redistribution of Hepatic Methionine Metabolism Enzymes

    PubMed Central

    Delgado, Miguel; Garrido, Francisco; Pérez-Miguelsanz, Juliana; Pacheco, María; Partearroyo, Teresa; Pérez-Sala, Dolores

    2014-01-01

    Abstract Aims: The discovery of methionine metabolism enzymes in the cell nucleus, together with their association with key nuclear processes, suggested a putative relationship between alterations in their subcellular distribution and disease. Results: Using the rat model of d-galactosamine intoxication, severe changes in hepatic steady-state mRNA levels were found; the largest decreases corresponded to enzymes exhibiting the highest expression in normal tissue. Cytoplasmic protein levels, activities, and metabolite concentrations suffered more moderate changes following a similar trend. Interestingly, galactosamine treatment induced hepatic nuclear accumulation of methionine adenosyltransferase (MAT) α1 and S-adenosylhomocysteine hydrolase tetramers, their active assemblies. In fact, galactosamine-treated livers showed enhanced nuclear MAT activity. Acetaminophen (APAP) intoxication mimicked most galactosamine effects on hepatic MATα1, including accumulation of nuclear tetramers. H35 cells that overexpress tagged-MATα1 reproduced the subcellular distribution observed in liver, and the changes induced by galactosamine and APAP that were also observed upon glutathione depletion by buthionine sulfoximine. The H35 nuclear accumulation of tagged-MATα1 induced by these agents correlated with decreased glutathione reduced form/glutathione oxidized form ratios and was prevented by N-acetylcysteine (NAC) and glutathione ethyl ester. However, the changes in epigenetic modifications associated with tagged-MATα1 nuclear accumulation were only prevented by NAC in galactosamine-treated cells. Innovation: Cytoplasmic and nuclear changes in proteins that regulate the methylation index follow opposite trends in acute liver injury, their nuclear accumulation showing potential as disease marker. Conclusion: Altogether these results demonstrate galactosamine- and APAP-induced nuclear accumulation of methionine metabolism enzymes as active oligomers and unveil the implication of

  18. Mechanisms contributing to muscle-wasting in acute uremia: activation of amino acid catabolism.

    PubMed

    Price, S R; Reaich, D; Marinovic, A C; England, B K; Bailey, J L; Caban, R; Mitch, W E; Maroni, B J

    1998-03-01

    Acute uremia (ARF) causes metabolic defects in glucose and protein metabolism that contribute to muscle wasting. To examine whether there are also defects in the metabolism of essential amino acids in ARF, we measured the activity of the rate-limiting enzyme for branched-chain amino acid catabolism, branched-chain ketoacid dehydrogenase (BCKAD), in rat muscles. Because chronic acidosis activates muscle BCKAD, we also evaluated the influence of acidosis by studying ARF rats given either NaCl (ARF-NaCl) or NaHCO3 (ARF-HCO3) to prevent acidosis, and sham-operated, control rats given NaHCO3. ARF-NaCl rats became progressively acidemic (serum [HCO3] = 21.3 +/- 0.7 mM within 18 h and 14.7 +/- 0.8 mM after 44 h; mean +/- SEM), but this was corrected with NaHCO3. Plasma valine was low in ARF-NaCl and ARF-HCO3 rats. Plasma isoleucine, but not leucine, was low in ARF-NaCl rats, and isoleucine tended to be lower in ARF-HCO3 rats. Basal BCKAD activity (a measure of active BCKAD in muscle) was increased more than 17-fold (P < 0.01) in ARF-NaCl rat muscles, and this response was partially suppressed by NaHCO3. Maximal BCKAD activity (an estimate of BCKAD content), subunit mRNA levels, and BCKAD protein content were not different in ARF and control rat muscles. Thus, ARF increases branched-chain amino acid catabolism by activating BCKAD by a mechanism that includes acidosis. Moreover, in a muscle-wasting condition such as ARF, there is a coordinated increase in protein and essential amino acid catabolism.

  19. Effects of Rest Interval Length on Acute Battling Rope Exercise Metabolism.

    PubMed

    Ratamess, Nicholas A; Smith, Charles R; Beller, Noah A; Kang, Jie; Faigenbaum, Avery D; Bush, Jill A

    2015-09-01

    The purpose of this study was to quantify and compare the acute metabolic responses to battling rope (BR) exercise using 2 different rest intervals. Twelve men and 10 women (age = 20.8 ± 1.3 years) performed a control protocol and 2 BR exercise protocols on separate days (48-72 hours) in random order while connected to a metabolic system. The BR protocol consisted of 8 sets of 30-second intervals (15 seconds of single-arm waves and 15 seconds of double-arm waves) using either a 1-minute (1RI) or 2-minute (2RI) rest interval length. A metronome was used to standardize repetition number/frequency for each exercise, that is, 15 waves for each arm for single-arm waves and 15 repetitions of double-arm waves. The mean oxygen consumption (VO2) values for the entire protocol were significantly higher during the 1RI than 2RI protocol, and values in men were 11.1% (1RI) and 13.5% (2RI) higher than women, respectively, and equated to 52.8 ± 5.5% (men) and 50.0 ± 11.2% (women) of VO2max during 1RI and 40.5 ± 4.5% (men) and 37.7 ± 11.0% (women) of VO2max during 2RI. Energy expenditure values were significantly higher during the 1RI than the 2RI protocol in men (11.93 ± 1.4 vs. 8.78 ± 1.4 kcal·min) and women (7.69 ± 1.3 vs. 5.04 ± 1.7 kcal·min) with values in men statistically higher than women. Blood lactate, mean protocol minute ventilation, and heart rate were significantly higher during the 1RI protocol than the 2RI protocol, and these data were significantly higher in men compared with women. These data demonstrate that BR exercise poses a significant cardiovascular and metabolic stimulus with the mean effects augmented with the use of a short rest interval.

  20. Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes.

    PubMed

    Matre, Polina; Velez, Juliana; Jacamo, Rodrigo; Qi, Yuan; Su, Xiaoping; Cai, Tianyu; Chan, Steven M; Lodi, Alessia; Sweeney, Shannon R; Ma, Helen; Davis, Richard Eric; Baran, Natalia; Haferlach, Torsten; Su, Xiaohua; Flores, Elsa Renee; Gonzalez, Doriann; Konoplev, Sergej; Samudio, Ismael; DiNardo, Courtney; Majeti, Ravi; Schimmer, Aaron D; Li, Weiqun; Wang, Taotao; Tiziani, Stefano; Konopleva, Marina

    2016-11-29

    Metabolic reprogramming has been described as a hallmark of transformed cancer cells. In this study, we examined the role of the glutamine (Gln) utilization pathway in acute myeloid leukemia (AML) cell lines and primary AML samples. Our results indicate that a subset of AML cell lines is sensitive to Gln deprivation. Glutaminase (GLS) is a mitochondrial enzyme that catalyzes the conversion of Gln to glutamate. One of the two GLS isoenzymes, GLS1 is highly expressed in cancer and encodes two different isoforms: kidney (KGA) and glutaminase C (GAC). We analyzed mRNA expression of GLS1 splicing variants, GAC and KGA, in several large AML datasets and identified increased levels of expression in AML patients with complex cytogenetics and within specific molecular subsets. Inhibition of glutaminase by allosteric GLS inhibitor bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide or by novel, potent, orally bioavailable GLS inhibitor CB-839 reduced intracellular glutamate levels and inhibited growth of AML cells. In cell lines and patient samples harboring IDH1/IDH2 (Isocitrate dehydrogenase 1 and 2) mutations, CB-839 reduced production of oncometabolite 2-hydroxyglutarate, inducing differentiation. These findings indicate potential utility of glutaminase inhibitors in AML therapy, which can inhibit cell growth, induce apoptosis and/or differentiation in specific leukemia subtypes.

  1. Relation between acute and long-term cognitive decline after surgery: Influence of metabolic syndrome☆

    PubMed Central

    Gambús, P.L; Trocóniz, I.F.; Feng, X.; Gimenez-Milá, M.; Mellado, R.; Degos, V.; Vacas, S.; Maze, M.

    2015-01-01

    Introduction The relationship between persistent postoperative cognitive decline and the more common acute variety remains unknown; using data acquired in preclinical studies of postoperative cognitive decline we attempted to characterize this relationship. Methods Low capacity runner (LCR) rats, which have all the features of the metabolic syndrome, were compared postoperatively with high capacity runner (HCR) rats for memory, assessed by trace fear conditioning (TFC) on the 7th postoperative day, and learning and memory (probe trial [PT]) assessed by the Morris water-maze (MWM) at three months postoperatively. Rate of learning (AL) data from the MWM test, were estimated by non-linear mixed effects modeling. The individual rat's TFC result at postoperative day (POD) 7 was correlated with its AL and PT from the MWM data sets at postoperative day POD 90. Results A single exponential decay model best described AL in the MWM with LCR and surgery (LCR–SURG) being the only significant covariates; first order AL rate constant was 0.07 s−1 in LCR–SURG and 0.16 s−1 in the remaining groups (p<0.05). TFC was significantly correlated with both AL (R = 0.74; p < 0.0001) and PT (R = 0.49; p < 0.01). Conclusion Severity of memory decline at 1 week after surgery presaged long-lasting deteriorations in learning and memory. PMID:26164200

  2. Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia.

    PubMed

    den Hoed, M A H; Lopez-Lopez, E; te Winkel, M L; Tissing, W; de Rooij, J D E; Gutierrez-Camino, A; Garcia-Orad, A; den Boer, E; Pieters, R; Pluijm, S M F; de Jonge, R; van den Heuvel-Eibrink, M M

    2015-06-01

    Methotrexate (MTX) is an effective and toxic chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia(ALL). In this prospective study, we aimed to identify metabolic and genetic determinants of MTX toxicity. One hundred and thirty-four Dutch pediatric ALL patients were treated with four high infusions MTX (HD-MTX: 5 g m(-2)) every other week according to the DCOG-ALL-10 protocol. Mucositis (National Cancer Institute grade ⩾ 3) was the most frequent occurring toxicity during the HD-MTX phase (20%) and occurred especially after the first MTX course. Mucositis was not associated with plasma MTX, plasma folate or plasma homocysteine levels. Patients with mucositis had higher erythrocyte folate levels at the start of protocol M than patients without mucositis (median 1.4 vs 1.2 μmol l(-1), P<0.008), this could reflect an increased MTX uptake in mucosal cells of patients with mucositis. From 17 single-nucleotide polymorphisms in the MTX pathway, only patients with the wild-type variant of rs7317112 SNP in the ABCC4 gene had more mucositis (AA (39%) vs AG/GG (15%), P=0.016). We found no evidence that erythrocyte folate levels mediate in the association between the rs7317112 and mucositis.

  3. Acute nephropathy induced by gold sodium thiomalate: alterations in renal heme metabolism and morphology.

    PubMed

    Eiseman, J L; Ribas, J L; Knight, E; Alvares, A P

    1987-11-01

    Gold compounds are used clinically in rheumatoid arthritis therapy. Acute renal toxicity is observed in some patients receiving chrysotherapy. The present study addresses morphofunctional and biochemical changes in rat kidneys during the first 8 days following a single ip injection of gold sodium thiomalate (AuTM), one of the gold compounds presently in clinical use. Compared to controls, AuTM pretreatment resulted in increased urine output and elevated serum creatinine and urea nitrogen concentrations. Also, by Day 8, treated rats had decreased body weights and increased kidney weights. Postmortem examination on Day 1 showed pale and mottled kidneys and diffusely pale inner cortex. Microscopically, there was severe coagulative necrosis of the proximal tubular epithelium. Epithelial regeneration was prominent by Day 4 and was nearly complete by Day 8. The regenerating epithelium was hyperplastic with basophilic cytoplasm and pleomorphic nuclei. Alterations in renal heme biosynthesis and drug metabolism paralleled the morphologic changes. The activity of delta-aminolevulinic acid dehydratase and benzo[a]pyrene hydroxylase were inhibited on Days 1, 2, and 4 following AuTM administration. Decreases in monooxygenase activity were accompanied by decreases in renal cytochrome P-450 levels. In contrast, renal microsomal heme oxygenase activity was elevated 9.5-fold on Day 1 and 2.5-fold on Day 2. By Day 8, all renal enzymatic activities assayed for were similar to those obtained with untreated rats.

  4. Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes

    PubMed Central

    Jacamo, Rodrigo; Qi, Yuan; Su, Xiaoping; Cai, Tianyu; Chan, Steven M.; Lodi, Alessia; Sweeney, Shannon R.; Ma, Helen; Davis, Richard Eric; Baran, Natalia; Haferlach, Torsten; Su, Xiaohua; Flores, Elsa Renee; Gonzalez, Doriann; Konoplev, Sergej; Samudio, Ismael; DiNardo, Courtney; Majeti, Ravi; Schimmer, Aaron D.; Li, Weiqun; Wang, Taotao; Tiziani, Stefano; Konopleva, Marina

    2016-01-01

    Metabolic reprogramming has been described as a hallmark of transformed cancer cells. In this study, we examined the role of the glutamine (Gln) utilization pathway in acute myeloid leukemia (AML) cell lines and primary AML samples. Our results indicate that a subset of AML cell lines is sensitive to Gln deprivation. Glutaminase (GLS) is a mitochondrial enzyme that catalyzes the conversion of Gln to glutamate. One of the two GLS isoenzymes, GLS1 is highly expressed in cancer and encodes two different isoforms: kidney (KGA) and glutaminase C (GAC). We analyzed mRNA expression of GLS1 splicing variants, GAC and KGA, in several large AML datasets and identified increased levels of expression in AML patients with complex cytogenetics and within specific molecular subsets. Inhibition of glutaminase by allosteric GLS inhibitor bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide or by novel, potent, orally bioavailable GLS inhibitor CB-839 reduced intracellular glutamate levels and inhibited growth of AML cells. In cell lines and patient samples harboring IDH1/IDH2 (Isocitrate dehydrogenase 1 and 2) mutations, CB-839 reduced production of oncometabolite 2-hydroxyglutarate, inducing differentiation. These findings indicate potential utility of glutaminase inhibitors in AML therapy, which can inhibit cell growth, induce apoptosis and/or differentiation in specific leukemia subtypes. PMID:27806325

  5. Evidence for a Detrimental Effect of Bicarbonate Therapy in Hypoxic Lactic Acidosis

    NASA Astrophysics Data System (ADS)

    Graf, Helmut; Leach, William; Arieff, Allen I.

    1985-02-01

    Lactic acidosis, a clinical syndrome caused by the accumulation of lactic acid, is characterized by lactate concentration in blood greater than 5 mM. Therapy usually consists of intravenous sodium bicarbonate (NaHCO3), but resultant mortality is greater than 60 percent. The metabolic and systemic effects of NaHCO3 therapy of hypoxic lactic acidosis in dogs were studied and compared to the effects of sodium chloride or no therapy. Sodium bicarbonate elevated blood lactate concentrations to a greater extent than did either sodium chloride or no treatment. Despite the infusion of NaHCO3, both arterial pH and bicarbonate concentration decreased by a similar amount in all three groups of dogs. Additional detrimental effects of NaHCO3 were observed on the cardiovascular system, including decreases in cardiac output and blood pressure that were not observed with either sodium chloride or no treatment. Thus there is evidence for a harmful effect of NaHCO3 in the treatment of hypoxic lactic acidosis.

  6. Human immunodeficiency virus infection with human granulocytic ehrlichiosis complicated by symptomatic lactic acidosis.

    PubMed

    Springer, Sandra A; Altice, Frederick L

    2003-06-15

    Lactic acidosis has been reported as a complication associated with antiretroviral therapy; in particular, usually with use of nucleoside reverse-transcriptase inhibitors. We describe a human immunodeficiency virus (HIV)-infected patient with a history of lipodystrophy who presented with hepatic insult associated with documented human granulocytic ehrlichiosis (HGE). Despite a normal serum lactate level before the onset of acute coinfection, the patient developed symptomatic hyperlactatemia while receiving appropriate treatment for HGE. To date, this is the first presentation of symptomatic hyperlactatemia in a patient with HIV infection and HGE.

  7. Acute-phase protein concentration and metabolic status affect the outcome of treatment in cows with clinical and subclinical endometritis.

    PubMed

    Heidarpour, M; Mohri, M; Fallah-Rad, A H; Dehghan Shahreza, F; Mohammadi, M

    2012-09-01

    The aim of this study was to investigate the role of acute-phase protein concentration and metabolic status in the establishment and resistance of clinical endometritis (CE) and subclinical endometritis (SE) in dairy cows. We also characterised the treatment-related changes in the concentration of acute-phase proteins and metabolic variables in dairy cows affected by CE and SE. Cows of the SE and CE groups presented a significantly higher β-hydroxybutyrate (BHB), haptoglobin and total sialic acid (TSA) concentrations compared with a healthy group of animals. A significantly lower serum calcium concentration, and a significantly higher serum aspartate aminotransferase activity in the CE group, were observed when compared with SE and healthy groups. The comparison of parameters before treatment indicated that cows suffering from CE or SE with lower concentrations of hepatic and inflammatory markers showed a better response to further treatment, and endometritis was not detected in the second examination. Moreover, decreased concentrations of BHB, acute-phase proteins and hepatic markers were observed after successful treatment for endometritis in CE and SE cows. The results obtained in this study suggest that improved liver function and a decrease in the acute-phase protein concentration might favour the resolution of endometritis after treatment.

  8. Celiac Crisis in a 64-Year-Old Woman: An Unusual Cause of Severe Diarrhea, Acidosis, and Malabsorption

    PubMed Central

    Mrad, Rachel Abou; Ghaddara, Hussein Abou; Green, Peter H.; El-Majzoub, Nadim

    2015-01-01

    Celiac disease (CD) rarely presents with life-threatening complications in older individuals. We report a 64-year-old woman who presented with profuse diarrhea, weight loss, hemodynamic instability, hypokalemia, hypoproteinemia, acidosis, and vitamin and iron deficiency. Pathologic and serologic studies confirmed CD presenting with celiac crisis with extensive and severe intestinal disease. Although celiac crisis occurs mostly in childhood and early adulthood, it should be considered in adults presenting with acute severe diarrheal illness, electrolyte abnormalities, and malabsorption. PMID:26157925

  9. [Chronic kidney diseases, metformin and lactic acidosis].

    PubMed

    Borbély, Zoltán

    2016-04-01

    Chronic kidney disease and diabetes mellitus represent a worldwide public health problem. The incidence of these diseases is gradually growing into epidemic proportions. In many cases they occur simultaneously, what leads to increased morbidity and mortality among the affected patients. The majority of the patients treated for diabetes mellitus are unaware of the presence of renal insufficiency. Vascular hypertrophy and diabetic kidney disease in patients with type 2 diabetes are the most common causes of kidney failure in countries with advanced healthcare systems. Metformin is a basic drug used for the treatment of type 2 diabetes mellitus. It is excreted in an unchanged form by the kidneys. When administered to patients with renal insufficiency, sepsis, dehydration or after the parenteral administration of iodinated contrast agents, metformin can cause lactic acidosis, which is also associated with an increased mortality rate.

  10. Subacute ruminal acidosis in Dutch dairy herds.

    PubMed

    Kleen, J L; Hooijer, G A; Rehage, J; Noordhuizen, J P T M

    2009-05-30

    The prevalence of subacute ruminal acidosis (SARA) was determined in 197 dairy cows in 18 herds in the Dutch province of Friesland. Samples of rumen fluid were taken by rumenocentesis from between five and 19 animals on each farm and the pH of each sample was determined. The body condition of 139 of the cows was scored approximately three weeks before they calved and three weeks after they calved. The overall prevalence of SARA was 13.8 per cent, and the prevalence on individual farms ranged between 0 per cent (on seven of the farms) and 38 per cent (on one farm). The stage of lactation did not influence the prevalence of SARA but the cows with the condition lost more body condition over the calving period.

  11. Lactic acidosis and the relationship with metformin usage

    PubMed Central

    Huang, Weiyi; Castelino, Ronald L.; Peterson, Gregory M.

    2016-01-01

    Abstract Aims: The principal objective of this study was to retrospectively review a series of cases of lactic acidosis (LA) in patients with type 2 diabetes mellitus (T2DM) and examine the relationship with the use of metformin. More generally, the study enabled an investigation of the profiles of patients diagnosed with LA and clinical variables associated with in-hospital mortality. Methods: All patients admitted to the Royal Hobart Hospital in Tasmania with LA (lactate >5.0 mmol/L and pH <7.35) over a 4-year period were included. Data extracted included patient demographics, medical history, medications, acute and chronic conditions associated with LA, and relevant pathology results. Multivariate logistic regression analysis was used to identify predictors for in-hospital mortality in patients with LA. Results: A total of 139 patients with LA were included in this study. Of these, 23 patients had T2DM and 11 patients were taking metformin. All metformin-treated patients had at least 1 additional medical condition (either chronic or acute) associated with an increased risk for LA. More than half (n = 72, 51.8%) of the patients with LA died during hospitalization. Multivariate logistic regression revealed older age and lower pH as the significant independent predictors (P < 0.05) for in-hospital mortality. Conclusion: LA was associated with high in-hospital mortality, with older age and lower pH as the significant risk factors for mortality. In patients with LA, approximately half of the patients with T2DM were receiving metformin. All the patients treated with metformin had other medical conditions that were risk factors for developing LA. The role of LA in patients treated with metformin is seemingly overemphasized. PMID:27861334

  12. Short-term time course of liver metabolic response to acute handling stress in rainbow trout, Oncorhynchus mykiss.

    PubMed

    López-Patiño, Marcos A; Hernández-Pérez, Juan; Gesto, Manuel; Librán-Pérez, Marta; Míguez, Jesús M; Soengas, José L

    2014-02-01

    To elucidate the short-term time-course of liver metabolic response in rainbow trout to acute handling stress we subjected rainbow trout to 5min chasing and obtained samples 0 to 480min post-stress. Levels of cortisol, glucose and lactate were measured in plasma, whereas metabolite levels, enzyme activities, mRNA abundance of parameters related to energy metabolism, and glucocorticoid receptors were assessed in liver. Acute stress affected many parameters related to energy metabolism, with most of them turning back to normal levels after 480min. In general, the present results support the existence of two stages in the short-term time-course of metabolic response to handling stress. A first stage occurring few minutes post-stress (15-45min), was characterized by increased mobilization of liver glycogen resulting in increased production of endogenous glucose, reduced use of exogenous glucose and reduced lipogenic potential. A second stage, occurring 60-120min post-stress onwards was characterized by the recovery of liver glycogen levels, the increased capacity of liver for releasing glucose, and the recovery of lipogenic capacity whereas no changes were noted in gluconeogenic potential, which probably needs longer time periods to become enhanced.

  13. Cellular metabolic, stress, and histological response on exposure to acute toxicity of endosulfan in tilapia (Oreochromis mossambicus).

    PubMed

    Kumar, Neeraj; Sharma, Rupam; Tripathi, Gayatri; Kumar, Kundan; Dalvi, Rishikesh S; Krishna, Gopal

    2016-01-01

    Endosulfan is one of the most hazardous organochlorines pesticides responsible for environmental pollution, as it is very persistent and shows bio-magnification. This study evaluated the impact of acute endosulfan toxicity on metabolic enzymes, lysozyme activities, heat shock protein (Hsp) 70 expression, and histopathology in Tilapia (Oreochromis mossambicus). Among the indicators that were induced in dose dependent manner were the enzymes of amino acid metabolism (serum alanine aminotransferase and aspartate aminotransferase), carbohydrate metabolism (serum lactate dehydrogenase), pentose phosphate pathway (Glucose-6-phosphate dehydrogenase) as well as lysozyme and Hsp70 in liver and gill, while liver and gill Isocitrate dehydrogenase (TCA cycle enzyme) and marker of general energetics (Total adenosine triphosphatase) were inhibited. Histopathological alterations in gill were clubbing of secondary gill lamellae, marked hyperplasia, complete loss of secondary lamellae and atrophy of primary gill filaments. Whereas in liver, swollen hepatocyte, and degeneration with loss of cellular boundaries were distinctly noticed. Overall results clearly demonstrated the unbalanced metabolism and damage of the vital organs like liver and gill in Tilapia due to acute endosulfan exposure.

  14. Compound danshen dripping pills modulate the perturbed energy metabolism in a rat model of acute myocardial ischemia.

    PubMed

    Guo, Jiahua; Yong, Yonghong; Aa, Jiye; Cao, Bei; Sun, Runbin; Yu, Xiaoyi; Huang, Jingqiu; Yang, Na; Yan, Lulu; Li, Xinxin; Cao, Jing; Aa, Nan; Yang, Zhijian; Kong, Xiangqing; Wang, Liansheng; Zhu, Xuanxuan; Ma, Xiaohui; Guo, Zhixin; Zhou, Shuiping; Sun, He; Wang, Guangji

    2016-12-01

    The continuous administration of compound danshen dripping pills (CDDP) showed good efficacy in relieving myocardial ischemia clinically. To probe the underlying mechanism, metabolic features were evaluated in a rat model of acute myocardial ischemia induced by isoproterenol (ISO) and administrated with CDDP using a metabolomics platform. Our data revealed that the ISO-induced animal model showed obvious myocardial injury, decreased energy production, and a marked change in metabolomic patterns in plasma and heart tissue. CDDP pretreatment increased energy production, ameliorated biochemical indices, modulated the changes and metabolomic pattern induced by ISO, especially in heart tissue. For the first time, we found that ISO induced myocardial ischemia was accomplished with a reduced fatty acids metabolism and an elevated glycolysis for energy supply upon the ischemic stress; while CDDP pretreatment prevented the tendency induced by ISO and enhanced a metabolic shift towards fatty acids metabolism that conventionally dominates energy supply to cardiac muscle cells. These data suggested that the underlying mechanism of CDDP involved regulating the dominant energy production mode and enhancing a metabolic shift toward fatty acids metabolism in ischemic heart. It was further indicated that CDDP had the potential to prevent myocardial ischemia in clinic.

  15. Compound danshen dripping pills modulate the perturbed energy metabolism in a rat model of acute myocardial ischemia

    PubMed Central

    Guo, Jiahua; Yong, Yonghong; Aa, Jiye; Cao, Bei; Sun, Runbin; Yu, Xiaoyi; Huang, Jingqiu; Yang, Na; Yan, Lulu; Li, Xinxin; Cao, Jing; Aa, Nan; Yang, Zhijian; Kong, Xiangqing; Wang, Liansheng; Zhu, Xuanxuan; Ma, Xiaohui; Guo, Zhixin; Zhou, Shuiping; Sun, He; Wang, Guangji

    2016-01-01

    The continuous administration of compound danshen dripping pills (CDDP) showed good efficacy in relieving myocardial ischemia clinically. To probe the underlying mechanism, metabolic features were evaluated in a rat model of acute myocardial ischemia induced by isoproterenol (ISO) and administrated with CDDP using a metabolomics platform. Our data revealed that the ISO-induced animal model showed obvious myocardial injury, decreased energy production, and a marked change in metabolomic patterns in plasma and heart tissue. CDDP pretreatment increased energy production, ameliorated biochemical indices, modulated the changes and metabolomic pattern induced by ISO, especially in heart tissue. For the first time, we found that ISO induced myocardial ischemia was accomplished with a reduced fatty acids metabolism and an elevated glycolysis for energy supply upon the ischemic stress; while CDDP pretreatment prevented the tendency induced by ISO and enhanced a metabolic shift towards fatty acids metabolism that conventionally dominates energy supply to cardiac muscle cells. These data suggested that the underlying mechanism of CDDP involved regulating the dominant energy production mode and enhancing a metabolic shift toward fatty acids metabolism in ischemic heart. It was further indicated that CDDP had the potential to prevent myocardial ischemia in clinic. PMID:27905409

  16. Acute and long-term renal and metabolic effects of piretanide in congestive cardiac failure.

    PubMed Central

    McNabb, W R; Noormohamed, F H; Lant, A F

    1988-01-01

    1. The renal and metabolic effects of the sulphamoylbenzoic acid diuretic, piretanide, have been studied, under controlled dietary conditions, in 39 patients with congestive cardiac failure. 2. In acute studies, peak saluresis occurred within 4 h of oral piretanide administration; saluresis was complete within 6 h, after which a significant antidiuretic effect was observed. Addition of triamterene, 50 mg, blunted the 0-6 h kaliuretic effect of piretanide. Over 24 h, piretanide, alone, caused insignificant urinary losses of potassium when compared with control. 3. In comparative studies, the piretanide dose-response curve was found to be parallel to that of frusemide over the dose range studied. The 0-6 h saluretic responses of piretanide, 6, 12 and 18 mg, were found to be equivalent to frusemide, 40, 80 and 120 mg respectively. The collective mean ratios of all the saluretic responses to each dose of piretanide with the corresponding dose of frusemide was observed to be 0.99 +/- 0.12, over 0-6 h period, and 0.86 +/- 0.09 over the 24 h period. The relative potency of piretanide, when compared with frusemide was found to be 6.18 (95% confidence limits 4.87-8.33), over the 0-6 h period, and 4.73 (95% confidence limits 3.65-6.14), over 24 h period. 4. In 15 patients in severe cardiac failure, urinary recovery of piretanide, over first 6 h, at the start of treatment was 21.2 +/- 2.1% while efficiency of the diuretic (mmol Na/mg drug) was 47.3 +/- 4.1. Long-term piretanide therapy was continued in the same group for up to and in some cases over 3 years. No other diuretics or potassium supplements were given. Piretanide dosage ranged from 6 to 24 mg day-1 according to clinical need. Plasma potassium fell significantly at 12 and 24 months, though remaining within the normal range. At these same times, significant elevations in both plasma urate and total fasting cholesterol were observed. Two patients developed overt gout on high dose piretanide therapy (24 mg day-1

  17. Metformin-induced lactic acidosis: no one left behind

    PubMed Central

    2011-01-01

    Metformin is a safe drug when correctly used in properly selected patients. In real life, however, associated lactic acidosis has been repeatedly, although rarely, reported. The term metformin-induced lactic acidosis refers to cases that cannot be explained by any major risk factor other than drug accumulation, usually due to renal failure. Treatment consists of vital function support and drug removal, mainly achieved by renal replacement therapy. Despite dramatic clinical presentation, the prognosis of metformin-induced lactic acidosis is usually surprisingly good. PMID:21349142

  18. Osteomalacia complicating renal tubular acidosis in association with Sjogren's syndrome.

    PubMed

    El Ati, Zohra; Fatma, Lilia Ben; Boulahya, Ghada; Rais, Lamia; Krid, Madiha; Smaoui, Wided; Maiz, Hedi Ben; Beji, Soumaya; Zouaghi, Karim; Moussa, Fatma Ben

    2014-09-01

    Renal involvement in Sjogren's syndrome (SS) is not uncommon and may precede other complaints. Tubulointerstitial nephritis is the most common renal disease in SS and may lead to renal tubular acidosis (RTA), which in turn may cause osteomalacia. Nevertheless, osteomalacia rarely occurs as the first manifestation of a renal tubule disorder due to SS. We herewith describe a 43-year-old woman who was admitted to our hospital for weakness, lumbago and inability to walk. X-ray of the long bones showed extensive demineralization of the bones. Laboratory investigations revealed chronic kidney disease with serum creatinine of 2.3 mg/dL and creatinine clearance of 40 mL/min, hypokalemia (3.2 mmol/L), hypophosphatemia (0.4 mmol/L), hypocalcemia (2.14 mmol/L) and hyperchloremic metabolic acidosis (chlorine: 114 mmol/L; alkaline reserve: 14 mmol/L). The serum alkaline phosphatase levels were elevated. The serum levels of 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D were low and borderline low, respectively, and the parathyroid hormone level was 70 pg/L. Urinalysis showed inappropriate alkaline urine (urinary PH: 7), glycosuria with normal blood glucose, phosphaturia and uricosuria. These values indicated the presence of both distal and proximal RTA. Our patient reported dryness of the mouth and eyes and Schirmer's test showed xerophthalmia. An accessory salivary gland biopsy showed changes corresponding to stage IV of Chisholm and Masson score. Kidney biopsy showed diffuse and severe tubulo-interstitial nephritis with dense lymphoplasmocyte infiltrates. Sicca syndrome and renal interstitial infiltrates indicated SS as the underlying cause of the RTA and osteomalacia. The patient received alkalinization, vitamin D (Sterogyl ®), calcium supplements and steroids in an initial dose of 1 mg/kg/day, tapered to 10 mg daily. The prognosis was favorable and the serum creatinine level was 1.7 mg/dL, calcium was 2.2 mmol/L and serum phosphate was 0.9 mmol/L.

  19. Acute methanol toxicity in minipigs

    SciTech Connect

    Dorman, D.C.; Dye, J.A.; Nassise, M.P.; Ekuta, J.; Bolon, B.

    1993-01-01

    The pig has been proposed as a potential animal model for methanol-induced neuro-ocular toxicosis in humans because of its low liver tetrahydrofolate levels and slower rate of formate metabolism compared to those of humans. To examine the validity of this animal model, 12 4-month-old female minipigs (minipig YU) were given a single oral dose of water or methanol at 1.0, 2.5, or 5.0 g/kg body wt by gavage (n = 3 pigs/dose). Dose-dependent signs of acute methanol intoxication, which included mild CNS depression, tremors, ataxia, and recumbency, developed within 0.5 to 2.0 hr, and resolved by 52 hr. Methanol- and formate-dosed pigs did not develop optic nerve lesions, toxicologically significant formate accumulation, or metabolic acidosis. Based on results following a single dose, female minipigs do not appear to be overtly sensitive to methanol and thus may not be a suitable animal model for acute methanol-induced neuroocular toxicosis.

  20. Cysteine Metabolism and Oxidative Processes in the Rat Liver and Kidney after Acute and Repeated Cocaine Treatment

    PubMed Central

    Kowalczyk-Pachel, Danuta; Iciek, Małgorzata; Wydra, Karolina; Nowak, Ewa; Górny, Magdalena; Filip, Małgorzata; Włodek, Lidia; Lorenc-Koci, Elżbieta

    2016-01-01

    The role of cocaine in modulating the metabolism of sulfur-containing compounds in the peripheral tissues is poorly understood. In the present study we addressed the question about the effects of acute and repeated (5 days) cocaine (10 mg/kg i.p.) administration on the total cysteine (Cys) metabolism and on the oxidative processes in the rat liver and kidney. The whole pool of sulfane sulfur, its bound fraction and hydrogen sulfide (H2S) were considered as markers of anaerobic Cys metabolism while the sulfate as a measure of its aerobic metabolism. The total-, non-protein- and protein- SH group levels were assayed as indicators of the redox status of thiols. Additionally, the activities of enzymes involved in H2S formation (cystathionine γ-lyase, CSE; 3-mercaptopyruvate sulfurtransferase, 3-MST) and GSH metabolism (γ-glutamyl transpeptidase, γ-GT; glutathione S-transferase, GST) were determined. Finally, we assayed the concentrations of reactive oxygen species (ROS) and malondialdehyde (MDA) as markers of oxidative stress and lipid peroxidation, respectively. In the liver, acute cocaine treatment, did not change concentrations of the whole pool of sulfane sulfur, its bound fraction, H2S or sulfate but markedly decreased levels of non-protein SH groups (NPSH), ROS and GST activity while γ-GT was unaffected. In the kidney, acute cocaine significantly increased concentration of the whole pool of sulfane sulfur, reduced the content of its bound fraction but H2S, sulfate and NPSH levels were unchanged while ROS and activities of GST and γ-GT were reduced. Acute cocaine enhanced activity of the CSE and 3-MST in the liver and kidney, respectively. Repeatedly administered cocaine enhanced the whole pool of sulfane sulfur and reduced H2S level simultaneously increasing sulfate content both in the liver and kidney. After repeated cocaine, a significant decrease in ROS was still observed in the liver while in the kidney, despite unchanged ROS content, a marked increase

  1. Cysteine Metabolism and Oxidative Processes in the Rat Liver and Kidney after Acute and Repeated Cocaine Treatment.

    PubMed

    Kowalczyk-Pachel, Danuta; Iciek, Małgorzata; Wydra, Karolina; Nowak, Ewa; Górny, Magdalena; Filip, Małgorzata; Włodek, Lidia; Lorenc-Koci, Elżbieta

    2016-01-01

    The role of cocaine in modulating the metabolism of sulfur-containing compounds in the peripheral tissues is poorly understood. In the present study we addressed the question about the effects of acute and repeated (5 days) cocaine (10 mg/kg i.p.) administration on the total cysteine (Cys) metabolism and on the oxidative processes in the rat liver and kidney. The whole pool of sulfane sulfur, its bound fraction and hydrogen sulfide (H2S) were considered as markers of anaerobic Cys metabolism while the sulfate as a measure of its aerobic metabolism. The total-, non-protein- and protein- SH group levels were assayed as indicators of the redox status of thiols. Additionally, the activities of enzymes involved in H2S formation (cystathionine γ-lyase, CSE; 3-mercaptopyruvate sulfurtransferase, 3-MST) and GSH metabolism (γ-glutamyl transpeptidase, γ-GT; glutathione S-transferase, GST) were determined. Finally, we assayed the concentrations of reactive oxygen species (ROS) and malondialdehyde (MDA) as markers of oxidative stress and lipid peroxidation, respectively. In the liver, acute cocaine treatment, did not change concentrations of the whole pool of sulfane sulfur, its bound fraction, H2S or sulfate but markedly decreased levels of non-protein SH groups (NPSH), ROS and GST activity while γ-GT was unaffected. In the kidney, acute cocaine significantly increased concentration of the whole pool of sulfane sulfur, reduced the content of its bound fraction but H2S, sulfate and NPSH levels were unchanged while ROS and activities of GST and γ-GT were reduced. Acute cocaine enhanced activity of the CSE and 3-MST in the liver and kidney, respectively. Repeatedly administered cocaine enhanced the whole pool of sulfane sulfur and reduced H2S level simultaneously increasing sulfate content both in the liver and kidney. After repeated cocaine, a significant decrease in ROS was still observed in the liver while in the kidney, despite unchanged ROS content, a marked increase

  2. Exercise-mediated vasodilation in human obesity and metabolic syndrome: effect of acute ascorbic acid infusion.

    PubMed

    Limberg, Jacqueline K; Kellawan, J Mikhail; Harrell, John W; Johansson, Rebecca E; Eldridge, Marlowe W; Proctor, Lester T; Sebranek, Joshua J; Schrage, William G

    2014-09-15

    We tested the hypothesis that infusion of ascorbic acid (AA), a potent antioxidant, would alter vasodilator responses to exercise in human obesity and metabolic syndrome (MetSyn). Forearm blood flow (FBF, Doppler ultrasound) was measured in lean, obese, and MetSyn adults (n = 39, 32 ± 2 yr). A brachial artery catheter was inserted for blood pressure monitoring and local infusion of AA. FBF was measured during dynamic handgrip exercise (15% maximal effort) with and without AA infusion. To account for group differences in blood pressure and forearm size, and to assess vasodilation, forearm vascular conductance (FVC = FBF/mean arterial blood pressure/lean forearm mass) was calculated. We examined the time to achieve steady-state FVC (mean response time, MRT) and the rise in FVC from rest to steady-state exercise (Δ, exercise - rest) before and during acute AA infusion. The MRT (P = 0.26) and steady-state vasodilator responses to exercise (ΔFVC, P = 0.31) were not different between groups. Intra-arterial infusion of AA resulted in a significant increase in plasma total antioxidant capacity (174 ± 37%). AA infusion did not alter MRT or steady-state FVC in any group (P = 0.90 and P = 0.85, respectively). Interestingly, higher levels of C-reactive protein predicted longer MRT (r = 0.52, P < 0.01) and a greater reduction in MRT with AA infusion (r = -0.43, P = 0.02). We concluded that AA infusion during moderate-intensity, rhythmic forearm exercise does not alter the time course or magnitude of exercise-mediated vasodilation in groups of young lean, obese, or MetSyn adults. However, systemic inflammation may limit the MRT to exercise, which can be improved with AA.

  3. Metabolic and behavior changes in surubim acutely exposed to a glyphosate-based herbicide.

    PubMed

    Sinhorin, Valéria D G; Sinhorin, Adilson P; Teixeira, Jhonnes Marcos S; Miléski, Kelly Márcia L; Hansen, Paula Carine; Moeller, Paulo Rafael; Moreira, Paula Sueli A; Baviera, Amanda M; Loro, Vânia L

    2014-11-01

    This study examined the effect of glyphosate-based herbicide (Roundup Original), the major herbicide used in soybean crops in Mato Grosso state, at concentrations of 0, 2.25, 4.5, 7.5, and 15 mg L(-1) on metabolic and behavior parameters of the hybrid fish surubim in an acute exposure lasting 96 h. Glycogen content, glucose, lactate, and protein levels were measured in different tissues. Plasma levels of cholesterol, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were also determined. Ventilatory frequency (VF) and swimming activity (SA) were considered behavior parameters. Results showed that herbicide exposure decreased plasma glucose levels and increased it in surubim liver. Lactate increased in both plasma and liver but decreased in muscle. Protein levels decreased in plasma and muscle but increased in liver. After herbicide exposure, liver and muscle glycogen was decreased. Cholesterol levels decreased in plasma at all concentrations tested. Plasma ALT increased, and no alterations were recorded for AST levels. VF increased after glyphosate exposure (5 min) and decreased after 96 h. SA showed differences among all groups (5 min). At the end of 96 h, SA was altered by the 7.5 mg L(-1) concentration. Fish used anaerobic glycolysis as indicated by generally decreased glycogen levels and decreased lactate levels in muscle but increased ones in plasma and liver. We suggest that the studied parameters could be used as indicators of herbicide toxicity in surubim and may provide extremely important information for understanding the biology of the animal and its responsiveness to external stimuli (stressors).

  4. Addisonian crisis and severe acidosis in a cat: a case of feline hypoadrenocorticism.

    PubMed

    Sicken, Julia; Neiger, Reto

    2013-10-01

    A 4-year-old female neutered British Shorthair cat was presented as an emergency owing to progressive apathy, anorexia, adipsia, weight loss and weakness. Clinical findings showed severe weakness, collapse, weak pulse, bradycardia, hypovolaemia and hypothermia. Blood examinations revealed marked metabolic acidosis, hyponatraemia, hyperkalaemia, hyperphosphataemia, hypercalcaemia, hypochloraemia and azotaemia. The diagnosis of feline hypoadrenocorticism was based on low cortisol and aldosterone plasma levels before and after synthetic adrenocorticotropic hormone administration. Initial treatment consisted of intravenous fluid therapy. After stabilisation a combination of fludrocortisone and prednisolone was given orally. One year after diagnosis the cat is free of clinical signs and in good condition.

  5. Investigation into the acute effects of total and partial energy restriction on postprandial metabolism among overweight/obese participants.

    PubMed

    Antoni, Rona; Johnston, Kelly L; Collins, Adam L; Robertson, M Denise

    2016-03-28

    The intermittent energy restriction (IER) approach to weight loss involves short periods of substantial (75-100 %) energy restriction (ER) interspersed with normal eating. This study aimed to characterise the early metabolic response to these varying degrees of ER, which occurs acutely and prior to weight loss. Ten (three female) healthy, overweight/obese participants (36 (SEM 5) years; 29·0 (sem 1·1) kg/m2) took part in this acute three-way cross-over study. Participants completed three 1-d dietary interventions in a randomised order with a 1-week washout period: isoenergetic intake, partial 75 % ER and total 100 % ER. Fasting and postprandial (6-h) metabolic responses to a liquid test meal were assessed the following morning via serial blood sampling and indirect calorimetry. Food intake was also recorded for two subsequent days of ad libitum intake. Relative to the isoenergetic control, postprandial glucose responses were increased following total ER (+142 %; P=0·015) and to a lesser extent after partial ER (+76 %; P=0·051). There was also a delay in the glucose time to peak after total ER only (P=0·024). Both total and partial ER interventions produced comparable reductions in postprandial TAG responses (-75 and -59 %, respectively; both P<0·05) and 3-d energy intake deficits of approximately 30 % (both P=0·015). Resting and meal-induced thermogenesis were not significantly affected by either ER intervention. In conclusion, our data demonstrate the ability of substantial ER to acutely alter postprandial glucose-lipid metabolism (with partial ER producing the more favourable overall response), as well as incomplete energy-intake compensation amongst overweight/obese participants. Further investigations are required to establish how metabolism adapts over time to the repeated perturbations experienced during IER, as well as the implications for long-term health.

  6. Complex III deficiency due to an in-frame MT-CYB deletion presenting as ketotic hypoglycemia and lactic acidosis.

    PubMed

    Mori, Mari; Goldstein, Jennifer; Young, Sarah P; Bossen, Edward H; Shoffner, John; Koeberl, Dwight D

    2015-09-01

    Complex III deficiency due to a MT-CYB mutation has been reported in patients with myopathy. Here, we describe a 15-year-old boy who presented with metabolic acidosis, ketotic hypoglycemia and carnitine deficiency. Electron transport chain analysis and mitochondrial DNA sequencing on muscle tissue lead to the eventual diagnosis of complex III deficiency. This case demonstrates the critical role of muscle biopsies in a myopathy work-up, and the clinical efficacy of supplement therapy.

  7. Devastating metabolic brain disorders of newborns and young infants.

    PubMed

    Yoon, Hyun Jung; Kim, Ji Hye; Jeon, Tae Yeon; Yoo, So-Young; Eo, Hong

    2014-01-01

    Metabolic disorders of the brain that manifest in the neonatal or early infantile period are usually associated with acute and severe illness and are thus referred to as devastating metabolic disorders. Most of these disorders may be classified as organic acid disorders, amino acid metabolism disorders, primary lactic acidosis, or fatty acid oxidation disorders. Each disorder has distinctive clinical, biochemical, and radiologic features. Early diagnosis is important both for prompt treatment to prevent death or serious sequelae and for genetic counseling. However, diagnosis is often challenging because many findings overlap and may mimic those of more common neonatal conditions, such as hypoxic-ischemic encephalopathy and infection. Ultrasonography (US) may be an initial screening method for the neonatal brain, and magnetic resonance (MR) imaging is the modality of choice for evaluating metabolic brain disorders. Although nonspecific imaging findings are common in early-onset metabolic disorders, characteristic patterns of brain involvement have been described for several disorders. In addition, diffusion-weighted images may be used to characterize edema during an acute episode of encephalopathy, and MR spectroscopy depicts changes in metabolites that may help diagnose metabolic disorders and assess response to treatment. Imaging findings, including those of advanced MR imaging techniques, must be closely reviewed. If one of these rare disorders is suspected, the appropriate biochemical test or analysis of the specific gene should be performed to confirm the diagnosis.

  8. Distal Renal Tubular Acidosis in Infancy: A Bicarbonate Wasting State

    ERIC Educational Resources Information Center

    Rodriguez-Soriano, J.; And Others

    1975-01-01

    Studied were three unrelated infants with distal renal tubular acidosis (a condition characterized by an inability to acidify the urine to minimal pH levels resulting in the loss of bicarbonates). (DB)

  9. Hepatic cytochrome P450 3A drug metabolism is reduced in cancer patients who have an acute-phase response

    PubMed Central

    Rivory, L P; Slaviero, K A; Clarke, S J

    2002-01-01

    Inflammatory disease states (infection, arthritis) are associated with reduced drug oxidation by the cytochrome P450 3A system. Many chemotherapy agents are metabolised through this pathway, and disease may therefore influence inter-individual differences in drug pharmacokinetics. The purpose of this study was to assess cytochrome P450 3A function in patients with advanced cancer, and its relation to the acute-phase response. We evaluated hepatic cytochrome P450 3A function in 40 patients with advanced cancer using the erythromycin breath test. Both the traditional C20min measure and the recently proposed 1/TMAX values were estimated. The marker of acute-phase response, C-reactive protein and the pro-inflammatory cytokines IL-6, IL-1β, TNFα and IL-8 were measured in serum or plasma at baseline. Cancer patients with an acute phase response (C-reactive protein >10 mg l−1, n=26) had reduced metabolism as measured with the erythromycin breath test 1/TMAX (Kruskal–Wallis Anova, P=0.0062) as compared to controls (C-reactive protein ⩽10 mg l−1, n=14). Indeed, metabolism was significantly associated with C-reactive protein over the whole concentration range of this acute-phase marker (r=−0.64, Spearman Rank Correlation, P<0.00001). C-reactive protein serum levels were significantly correlated with those of IL-6 (Spearman coefficient=0.58, P<0.0003). The reduction in cytochrome P450 3A function with acute-phase reaction was independent of the tumour type and C-reactive protein elevation was associated with poor performance status. This indicates that the sub-group of cancer patients with significant acute-phase response have compromised drug metabolism, which may have implications for the safety of chemotherapy in this population. British Journal of Cancer (2002) 87, 277–280. doi:10.1038/sj.bjc.6600448 www.bjcancer.com © 2002 Cancer Research UK PMID:12177794

  10. Does amifostine reduce metabolic rate? Effect of the drug on gas exchange and acute ventilatory hypoxic response in humans.

    PubMed

    Pandit, Jaideep J; Allen, Caroline; Little, Evelyn; Formenti, Federico; Harris, Adrian L; Robbins, Peter A

    2015-04-16

    Amifostine is added to chemoradiation regimens in the treatment of many cancers on the basis that, by reducing the metabolic rate, it protects normal cells from toxic effects of therapy. We tested this hypothesis by measuring the metabolic rate (by gas exchange) over 255 min in 6 healthy subjects, at two doses (500 mg and 1000 mg) of amifostine infused over 15 min at the start of the protocol. We also assessed the ventilatory response to six 1 min exposures to isocapnic hypoxia mid-protocol. There was no change in metabolic rate with amifostine as measured by oxygen uptake (p = 0.113). However in carbon dioxide output and respiratory quotient, we detected a small decline over time in control and drug protocols, consistent with a gradual change from carbohydrate to fat metabolism over the course of the relatively long study protocol. A novel result was that amifostine (1000 mg) increased the mean ± SD acute hypoxic ventilatory response from 12.4 ± 5.1 L/min to 20.3 ± 11.9 L/min (p = 0.045). In conclusion, any cellular protective effects of amifostine are unlikely due to metabolic effects. The stimulatory effect on hypoxic ventilatory responses may be due to increased levels of hypoxia inducible factor, either peripherally in the carotid body, or centrally in the brain.

  11. Renal tubular acidosis: an immunopathological study on four patients

    PubMed Central

    Pasternack, A.; Linder, E.

    1970-01-01

    Renal biopsies and sera of four patients with distal renal tubular acidosis were examined. The findings consisted of immunoglobulin containing mononuclear cellular infiltrates around the distal tubules, bound immunoglobulin and complement in tubules. The sera of the patients contained antibodies reacting with various tissue antigens, among them renal tubular antigens. The results suggest that autoimmunity was involved in the pathogenesis of the renal tubular acidosis in these patients. ImagesFig. 1Fig. 2 PMID:5202740

  12. Transient Distal Renal Tubular Acidosis in Organophosphate Poisoning

    PubMed Central

    Narayan, Ram; Abdulla, Mansoor C.; Alungal, Jemshad

    2017-01-01

    Renal complications due to organophosphate poisoning are very rare. We are presenting a unique case of transient distal renal tubular acidosis due to organophosphate poisoning, which to the best of our knowledge is the first of its kind. An elderly female after deliberate self-harm with ingestion of chlorpyrifos had multiple ventricular arrhythmias due to hypokalemia secondary to distal renal tubular acidosis which improved completely after treatment.

  13. Metabolism

    MedlinePlus

    Metabolism refers to all the physical and chemical processes in the body that convert or use energy, ... Tortora GJ, Derrickson BH. Metabolism. In: Tortora GJ, Derrickson ... Physiology . 14th ed. Hoboken, NJ: John Wiley & Sons; 2014:chap ...

  14. Metabolism

    MedlinePlus

    ... El metabolismo Metabolism Basics Our bodies get the energy they need from food through metabolism, the chemical ... that convert the fuel from food into the energy needed to do everything from moving to thinking ...

  15. The acute impact of polyphenols from Hibiscus sabdariffa in metabolic homeostasis: an approach combining metabolomics and gene-expression analyses.

    PubMed

    Beltrán-Debón, Raúl; Rodríguez-Gallego, Esther; Fernández-Arroyo, Salvador; Senan-Campos, Oriol; Massucci, Francesco A; Hernández-Aguilera, Anna; Sales-Pardo, Marta; Guimerà, Roger; Camps, Jordi; Menendez, Javier A; Joven, Jorge

    2015-09-01

    We explored the acute multifunctional effects of polyphenols from Hibiscus sabdariffa in humans to assess possible consequences on the host's health. The expected dynamic response was studied using a combination of transcriptomics and metabolomics to integrate specific functional pathways through network-based methods and to generate hypotheses established by acute metabolic effects and/or modifications in the expression of relevant genes. Data were obtained from healthy male volunteers after 3 hours of ingestion of an aqueous Hibiscus sabdariffa extract. The data were compared with data obtained prior to the ingestion, and the overall findings suggest that these particular polyphenols had a simultaneous role in mitochondrial function, energy homeostasis and protection of the cardiovascular system. These findings suggest beneficial actions in inflammation, endothelial dysfunction, and oxidation, which are interrelated mechanisms. Among other effects, the activation of the heme oxygenase-biliverdin reductase axis, the systemic inhibition of the renin-angiotensin system, the inhibition of the angiotensin-converting enzyme, and several actions mirroring those of the peroxisome proliferator-activated receptor agonists further support this notion. We also found concordant findings in the serum of the participants, which include a decrease in cortisol levels and a significant increase in the active vasodilator metabolite of bradykinin (des-Arg(9)-bradykinin). Therefore, our data support the view that polyphenols from Hibiscus sabdariffa play a regulatory role in metabolic health and in the maintenance of blood pressure, thus implying a multi-faceted impact in metabolic and cardiovascular diseases.

  16. Acute porcine renal metabolic effect of endogastric soft drink administration assessed with hyperpolarized [1‐13c]pyruvate

    PubMed Central

    Hansen, Esben Søvsø Szocska; Kjærgaard, Uffe; Bertelsen, Lotte Bonde; Ringgaard, Steffen; Stødkilde‐Jørgensen, Hans

    2015-01-01

    Purpose Our aim was to determine the quantitative reproducibility of metabolic breakdown products in the kidney following intravenous injection of hyperpolarized [1‐13C]pyruvate and secondly to investigate the metabolic effect on the pyruvate metabolism of oral sucrose load using dissolution dynamic nuclear polarization. By this technique, metabolic alterations in several different metabolic related diseases and their metabolic treatment responses can be accessed. Methods In four healthy pigs the lactate‐to‐pyruvate, alanine‐to‐pyruvate and bicarbonate‐to‐pyruvate ratio was measured following administration of regular cola and consecutive injections of hyperpolarized [1‐13C]pyruvate four times within an hour. Results The overall lactate‐to‐pyruvate metabolic profile changed significantly over one hour following an acute sucrose load leading to a significant rise in blood glucose. Conclusion The reproducibility of hyperpolarized magnetic resonance spectroscopy in the healthy pig kidney demonstrated a repeatability of more than 94% for all metabolites and, furthermore, that the pyruvate to lactate conversion and the blood glucose level is elevated following endogastric sucrose administration. Magn Reson Med 74:558–563, 2015. © 2015 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. PMID:26014387

  17. Metabolic decompensation in methylmalonic aciduria: which biochemical parameters are discriminative?

    PubMed

    Zwickler, Tamaris; Haege, Gisela; Riderer, Alina; Hörster, Friederike; Hoffmann, Georg F; Burgard, Peter; Kölker, Stefan

    2012-09-01

    Recurrent, life-threatening metabolic decompensations often occur in patients with methylmalonic aciduria (MMAuria). Our study evaluated (impending) metabolic decompensations in these patients aiming to identify the most frequent and reliable clinical and biochemical abnormalities that could be helpful for decision-making on when to start an emergency treatment. Seventy-six unscheduled and 179 regular visits of 10 patients with confirmed MMAuria continuously followed by our metabolic centre between 1975 and 2009 were analysed. The most frequent symptom of an impending acute metabolic decompensation was vomiting (90% of episodes), whereas symptoms of intercurrent infectious disease (29%) or other symptoms (such as food refusal and impaired consciousness) were found less often. Thirty-five biochemical parameters were included in the analysis. Among them, pathological changes of acid-base balance reflecting metabolic acidosis with partial respiratory compensation (decreased pH, pCO(2), standard bicarbonate, and base excess) and elevated ammonia were the most reliable biochemical parameters for the identification of a metabolic decompensation and the estimation of its severity. In contrast, analyses of organic acids, acylcarnitines and carnitine status were less discriminative. In conclusion, careful history taking and identification of suspicious symptoms in combination with a small number of rapidly available biochemical parameters are helpful to differentiate compensated metabolic condition and (impending) metabolic crisis and to decide when to start an emergency treatment.

  18. [Effect of a new derivative of glutamic and apovincaminic acids on brain metabolism in post-ischemic period].

    PubMed

    Makarova, L M; Prikhod'ko, M A; Pogorelyĭ, V E; Skachilova, S Ia; Mirzoian, R S

    2014-01-01

    Neuroprotective properties of the new derivative of glutamic and apovincaminic acids, ethyl -(3-alpha,16-alpha)-eburnamenin-14-carbopxylate of 2-aminopentadionic acid (LHT 1-02) were studied on a model of acute brain ischemia in cats. LHT 1-02 has proved to be more effective than the reference drugs vinpocetin and glycine in preventing the reperfusive damage, which was manifested by decreased postischemic hyperglycemia, activated utilization of oxygen in the brain, and suppressed postischemic metabolic lactate acidosis. Thus, the results of this comparative study show expediency of further investigations of LHT 1 - 02 as a potential neuroprotective drug.

  19. Non-Specific Inhibition of Ischemia- and Acidosis-Induced Intracellular Calcium Elevations and Membrane Currents by α-Phenyl-N-tert-butylnitrone, Butylated Hydroxytoluene and Trolox

    PubMed Central

    Katnik, Christopher; Cuevas, Javier

    2014-01-01

    Ischemia, and subsequent acidosis, induces neuronal death following brain injury. Oxidative stress is believed to be a key component of this neuronal degeneration. Acute chemical ischemia (azide in the absence of external glucose) and acidosis (external media buffered to pH 6.0) produce increases in intracellular calcium concentration ([Ca2+]i) and inward membrane currents in cultured rat cortical neurons. Two α-tocopherol analogues, trolox and butylated hydroxytoluene (BHT), and the spin trapping molecule α-Phenyl-N-tert-butylnitrone (PBN) were used to determine the role of free radicals in these responses. PBN and BHT inhibited the initial transient increases in [Ca2+]i, produced by ischemia, acidosis and acidic ischemia and increased steady state levels in response to acidosis and the acidic ischemia. BHT and PBN also potentiated the rate at which [Ca2+]i increased after the initial transients during acidic ischemia. Trolox inhibited peak and sustained increases in [Ca2+]i during ischemia. BHT inhibited ischemia induced initial inward currents and trolox inhibited initial inward currents activated by acidosis and acidic ischemia. Given the inconsistent results obtained using these antioxidants, it is unlikely their effects were due to elimination of free radicals. Instead, it appears these compounds have non-specific effects on the ion channels and exchangers responsible for these responses. PMID:24583849

  20. Genetic and metabolic signals during acute enteric bacterial infection alter the microbiota and drive progression to chronic inflammatory disease

    SciTech Connect

    Kamdar, Karishma; Khakpour, Samira; Chen, Jingyu; Leone, Vanessa; Brulc, Jennifer; Mangatu, Thomas; Antonopoulos, Dionysios A.; Chang, Eugene B; Kahn, Stacy A.; Kirschner, Barbara S; Young, Glenn; DePaolo, R. William

    2016-01-13

    Chronic inflammatory disorders are thought to arise due to an interplay between predisposing host genetics and environmental factors. For example, the onset of inflammatory bowel disease is associated with enteric proteobacterial infection, yet the mechanistic basis for this association is unclear. We have shown previously that genetic defiency in TLR1 promotes acute enteric infection by the proteobacteria Yersinia enterocolitica. Examining that model further, we uncovered an altered cellular immune response that promotes the recruitment of neutrophils which in turn increases metabolism of the respiratory electron acceptor tetrathionate by Yersinia. These events drive permanent alterations in anti-commensal immunity, microbiota composition, and chronic inflammation, which persist long after Yersinia clearence. Deletion of the bacterial genes involved in tetrathionate respiration or treatment using targeted probiotics could prevent microbiota alterations and inflammation. Thus, acute infection can drive long term immune and microbiota alterations leading to chronic inflammatory disease in genetically predisposed individuals.

  1. Elevated plasma cholecystokinin at high altitude: metabolic implications for the anorexia of acute mountain sickness.

    PubMed

    Bailey, D M; Davies, B; Milledge, J S; Richards, M; Williams, S R; Jordinson, M; Calam, J

    2000-01-01

    The aims of the present study were to measure the satiety neuropeptide cholecystokinin (CCK) in humans at terrestrial high altitude to investigate its possible role in the pathophysiology of anorexia, cachexia, and acute mountain sickness (AMS). Nineteen male mountaineers aged 38 +/- 12 years participated in a 20 +/- 5 day trek to Mt. Kanchenjunga basecamp (BC) located at 5,100 m, where they remained for 7 +/- 5 days. Subjects were examined at rest and during a maximal exercise test at sea-level before/after the expedition (SL1/SL2) and during the BC sojourn. There was a mild increase in Lake Louise AMS score from 1.1 +/- 1.2 points at SL1 to 2.3 +/- 2.3 points by the end of the first day at BC (P < 0.05). A marked increase in resting plasma CCK was observed on the morning of the second day at BC relative to sea-level control values (62.9 +/- 42.2 pmol/L(-1) vs. SL1: 4.3 +/- 8.3 pmol/L(-1), P < 0.05 vs. SL2: 26.5 +/- 25.2 pmol/L(-1), P < 0.05). Maximal exercise increased CCK by 78.5 +/- 24.8 pmol/L(-1), (P < 0.05 vs. resting value) during the SL1 test and increased the plasma concentration of non-esterified fatty acids and glycerol at BC (P < 0.05 vs. SL1/SL2). The CCK response was not different in five subjects who presented with anorexia on Day 2 compared with those with a normal appetite. While there was no relationship between the increase in CCK and AMS score at BC, a more pronounced increase in resting CCK was observed in subjects with AMS (> or =3 points at the end of Day 1 at BC) compared with those without (+98.9 +/- 1.4 pmol/L(-1) vs. +67.6 +/- 37.2 pmol/L(-1), P < 0.05). Caloric intake remained remarkably low during the stay at BC (8.9 +/- 1.4 MJ.d(-1)) despite a progressive decrease in total body mass (-4.5 +/- 2.1 kg after 31 +/- 13 h at BC, P < 0.05 vs. SL1/SL2), which appeared to be due to a selective loss of torso adipose tissue. These findings suggest that the satiogenic effects of CCK may have contributed to the observed caloric deficit and

  2. Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

    PubMed Central

    Ongaro, Alessia; De Mattei, Monica; Della Porta, Matteo Giovanni; Rigolin, GianMatteo; Ambrosio, Cristina; Di Raimondo, Francesco; Pellati, Agnese; Masieri, Federica Francesca; Caruso, Angelo; Catozzi, Linda; Gemmati, Donato

    2009-01-01

    Background The antifolate agent methotrexate is an important component of maintenance therapy in acute lymphoblastic leukemia, although methotrexate-related toxicity is often a reason for interruption of chemotherapy. Prediction of toxicity is difficult because of inter-individual variability susceptibility to antileukemic agents. Methotrexate interferes with folate metabolism leading to depletion of reduced folates. Design and Methods The aim of this study was to investigate the influence of polymorphisms for folate metabolizing enzymes with respect to toxicity and survival in adult patients with acute lymphoblastic leukemia treated with methotrexate maintenance therapy. To this purpose, we evaluated possible associations between genotype and hematologic and non-hematologic toxicity and effects on survival at 2 years of follow-up in patients with acute lymphoblastic leukemia. Results Polymorphisms in the genes encoding for methylenetetrahydrofolate reductase (MTHFR 677C>T) and in dihydrofolate reductase (DHFR 19 bp deletion) significantly increased the risk of hepatotoxicity in single (odds ratio 5.23, 95% confidence interval 1.13–21.95 and odds ratio 4.57, 95% confidence interval 1.01–20.77, respectively) and in combined analysis (odds ratio 6.82, 95% confidence interval 1.38–33.59). MTHFR 677C>T also increased the risk of leukopenia and gastrointestinal toxicity, whilst thymidylate synthase 28 bp repeat polymorphism increased the risk of anemia (odds ratio 8.48, 95% confidence interval 2.00–36.09). Finally, patients with MTHFR 677TT had a decreased overall survival rate (hazard ratio 2.37, 95% confidence interval 1.46–8.45). Conclusions Genotyping of folate polymorphisms might be useful in adult acute lymphoblastic leukemia to optimize methotrexate therapy, reducing the associated toxicity with possible effects on survival. PMID:19648163

  3. Acute cyanide poisoning among jewelry and textile industry workers.

    PubMed

    Coentrão, Luís; Moura, Daniel

    2011-01-01

    Limited work has focused on occupational exposures that may increase the risk of cyanide poisoning by ingestion. A retrospective chart review of all admissions for acute cyanide poisoning by ingestion for the years 1988 to 2008 was conducted in a tertiary university hospital serving the largest population in the country working in jewelry and textile facilities. Of the 9 patients admitted to the hospital during the study period, 8 (7 males, 1 female; age 36 ± 11 years, mean ± SD) attempted suicide by ingestion of potassium cyanide used in their profession as goldsmiths or textile industry workers. Five patients had severe neurologic impairment and severe metabolic acidosis (pH 7.02 ± 0.08, mean ± SD) with high anion gap (23 ± 4 mmol/L, mean ± SD). Of the 5 severely intoxicated patients, 3 received antidote therapy (sodium thiosulfate or hydroxocobalamin) and resumed full consciousness in less than 8 hours. All patients survived without major sequelae. Cyanide intoxication by ingestion in our patients was mainly suicidal and occurred in specific jobs where potassium cyanide is used. Metabolic acidosis with high anion is a good surrogated marker of severe cyanide poisoning. Sodium thiosulfate and hydroxocobalamin are both safe and effective antidotes.

  4. Acute pancreatitis and severe hypertriglyceridaemia masking unsuspected underlying diabetic ketoacidosis

    PubMed Central

    Aboulhosn, Kewan; Arnason, Terra

    2013-01-01

    A healthy 18-year-old girl presented to a local emergency room with 48 h of abdominal pain and vomiting. A radiological and biochemical diagnosis of moderate acute pancreatitis was made. Bloodwork demonstrated prominent hypertriglyceridaemia (HTG) of 19.5 mmol/L (severe HTG: 11.2–22.4), detectable urine ketones and a random blood glucose of 13 mmol/L dropping to 10.5 mmol/L on repeat (normal random <11). Ketone levels were deemed consistent with fasting ketosis after 48 h of vomiting. There was no known history of diabetes in the patient. Management included aggressive rehydration and pain control, yet the patient rapidly decompensated into shock requiring intensive care unit support. Blood gases revealed severe metabolic acidosis (pH 6.99) and unsuspected underlying diabetic ketoacidosis was diagnosed. The HTG gradually resolved following intravenous fluids and insulin infusion with slower correction of the metabolic acidosis. Importantly, her glycated haemoglobin was 12%, indicating the silent presence of chronic glucose elevations. PMID:24005972

  5. Acute pancreatitis and severe hypertriglyceridaemia masking unsuspected underlying diabetic ketoacidosis.

    PubMed

    Aboulhosn, Kewan; Arnason, Terra

    2013-09-04

    A healthy 18-year-old girl presented to a local emergency room with 48 h of abdominal pain and vomiting. A radiological and biochemical diagnosis of moderate acute pancreatitis was made. Bloodwork demonstrated prominent hypertriglyceridaemia (HTG) of 19.5 mmol/L (severe HTG: 11.2-22.4), detectable urine ketones and a random blood glucose of 13 mmol/L dropping to 10.5 mmol/L on repeat (normal random <11). Ketone levels were deemed consistent with fasting ketosis after 48 h of vomiting. There was no known history of diabetes in the patient. Management included aggressive rehydration and pain control, yet the patient rapidly decompensated into shock requiring intensive care unit support. Blood gases revealed severe metabolic acidosis (pH 6.99) and unsuspected underlying diabetic ketoacidosis was diagnosed. The HTG gradually resolved following intravenous fluids and insulin infusion with slower correction of the metabolic acidosis. Importantly, her glycated haemoglobin was 12%, indicating the silent presence of chronic glucose elevations.

  6. Women with metabolic syndrome present different autonomic modulation and blood pressure response to an acute resistance exercise session compared with women without metabolic syndrome.

    PubMed

    Tibana, Ramires A; Boullosa, Daniel A; Leicht, Anthony S; Prestes, Jonato

    2013-09-01

    Metabolic syndrome (MetS) is a cluster of risk factors in individuals with high risk of diabetes and heart disease. Resistance training (RT) has been proposed to be a safe, effective and worthwhile method for the prevention and treatment of metabolic and cardiovascular diseases. However, no study has analysed the acute response of blood pressure (BP) and autonomic control of heart rate (HR) after a RT session in female patients with MetS. The aim of the present study was to analyse the response of laboratory assessed and ambulatory BP and cardiac autonomic modulation after a RT session in women with MetS. Nine women without MetS (35.0 ± 6.7 years) and 10 women with MetS (34.1 ± 9.4 years) completed one experimental exercise session and a control session. Laboratory BP, heart rate variability (HRV) and ambulatory BP of each subject were measured at rest, over 60 min, and for 24 h after the end of the sessions, respectively. There was a significant reduction in systolic blood pressure (SBP), night time diastolic blood pressure (DBP) and mean blood pressure (MBP) only for women with MetS, for all periods after the RT session when compared with the control session (P<0.05). Significantly lower laboratory values of SBP and DBP (10, 30 and 40 min postexercise) and MBP (10, 40 and 50 min postexercise) were observed in women with MetS (P<0.05). Patients with MetS exhibited significant lower basal HRV and a lower autonomic responsiveness during the 60 min of acute recovery. These results confirmed that an acute session of resistance exercise induced a lower BP during day time and sleeping hours in women with MetS that may offer a cardio-protective effect. Women with MetS exhibited an impaired autonomic modulation at rest and a lower acute autonomic responsiveness to a RT session. The dissociation between BP and HRV responses suggests that other factors than autonomic control could be involved in the hypotensive effect of a RT session in MetS patients.

  7. Acidosis and Correction of Acidosis Does Not Affect rFVIIa Function in Swine

    DTIC Science & Technology

    2012-12-15

    normaliza- tion of respiration returned arterial pH to 7.4 and restored PaCO2, PaO2 and BE to baseline (Table 3). Ionized calcium was maintained near...model Control Acidosis Acidosis corrected n=10 pH 7.38±0.01 7.14±0.01 7.43±0.01 PaCO2 (mmHg) 47.3±1.8 43.0±1.8 55.0±3.1 PaO2 (mmHg) 433.6±26.4 400.9±33.1...mmHg) 49.5±1.3 48.2±1.8 94.0±5.2 *# PaO2 (mmHg) 142.8±3.3 133.5±8.6 99.6±9.6 *# HCO3 - (mM) 31.2±0.7 24.3±1.1* 29.5±1.2# BE (mM) 5.8±0.6 -1.5±1.0* -2.1

  8. Regulation of oxidative phosphorylation complex activity: effects of tissue-specific metabolic stress within an allometric series and acute changes in workload.

    PubMed

    Phillips, Darci; Covian, Raul; Aponte, Angel M; Glancy, Brian; Taylor, Joni F; Chess, David; Balaban, Robert S

    2012-05-01

    The concentration of mitochondrial oxidative phosphorylation complexes (MOPCs) is tuned to the maximum energy conversion requirements of a given tissue; however, whether the activity of MOPCs is altered in response to acute changes in energy conversion demand is unclear. We hypothesized that MOPCs activity is modulated by tissue metabolic stress to maintain the energy-metabolism homeostasis. Metabolic stress was defined as the observed energy conversion rate/maximum energy conversion rate. The maximum energy conversion rate was assumed to be proportional to the concentration of MOPCs, as determined with optical spectroscopy, gel electrophoresis, and mass spectrometry. The resting metabolic stress of the heart and liver across the range of resting metabolic rates within an allometric series (mouse, rabbit, and pig) was determined from MPOCs content and literature respiratory values. The metabolic stress of the liver was high and nearly constant across the allometric series due to the proportional increase in MOPCs content with resting metabolic rate. In contrast, the MOPCs content of the heart was essentially constant in the allometric series, resulting in an increasing metabolic stress with decreasing animal size. The MOPCs activity was determined in native gels, with an emphasis on Complex V. Extracted MOPCs enzyme activity was proportional to resting metabolic stress across tissues and species. Complex V activity was also shown to be acutely modulated by changes in metabolic stress in the heart, in vivo and in vitro. The modulation of extracted MOPCs activity suggests that persistent posttranslational modifications (PTMs) alter MOPCs activity both chronically and acutely, specifically in the heart. Protein phosphorylation of Complex V was correlated with activity inhibition under several conditions, suggesting that protein phosphorylation may contribute to activity modulation with energy metabolic stress. These data are consistent with the notion that metabolic

  9. Cerebrospinal fluid lactic acidosis in bacterial meningitis.

    PubMed Central

    Eross, J; Silink, M; Dorman, D

    1981-01-01

    A rapid, microenzymatic method was used to measure cerebrospinal fluid lactate levels in 205 children with suspected bacterial meningitis. Fifty children with normal CSF containing fewer than 0.005 X 10(9)/l WBC, no segmented neutrophils, glucose 3.4 +/- 0.8 mmol/l (61.2 +/- 14.4 mg/100 ml), and a protein of less than 0.30 g/l had CSF lactate levels below 2.0 mmol/l (18 mg/100 ml) (mean and standard deviation 1.3 +/- 0.3 mmol/l (11.8 +/- 2.7 mg/100 ml)). In 31 cases of proved viral meningitis as with 58 cases of clinically diagnosed viral meningitis, levels were below 3.8 mmol/l (34.5 mg/100 ml), being 2.3 +/- 0.6 mmol/l (20.9 +/- 5.4 mg/100 ml), and 2.1 +/- 0.7 mmol/l (19.1 +/- 6.4 mg/100 ml) respectively. Sixty-six cases of bacterial meningitis had CSF lactate levels ranging from 3.9 mmol/l (35.4 mg/100 ml) to greater than 10.0 mmol/l (90.0 mg/100 ml). Longitudinal studies in 7 children with bacterial meningitis showed that cerebrospinal fluid lactate levels differentiated bacterial from viral meningitis up to 4 days after starting treatment with antibiotics. Use of CSF lactate measurement for monitoring the efficacy of treatment is illustrated in a case of bacterial meningitis due to Pseudomonas aeruginosa. The origin of the cerebrospinal fluid lactate acidosis and the role of lactate in the pathophysiological cycle leading to intensification of brain tissue hypoxia and cellular damage is discussed with respect to the short-term prognosis and the long-term neurological sequelae. PMID:7294872

  10. Subacute ruminal acidosis (SARA): a review.

    PubMed

    Kleen, J L; Hooijer, G A; Rehage, J; Noordhuizen, J P T M

    2003-10-01

    Subacute ruminal acidosis (SARA) is likely to arise when an easily palatable, high-energy diet meets a ruminal environment not adapted to this type of substrate. Increase of short-chained fatty acids (SCFA) will occur. Eventually, this may result in a transient nadir of ruminal pH below 5.5. Two situations are likely to represent the risk of SARA. First, fresh lactating cows are confronted with a diet considerably differing from that in the dry-period. A diet change carried out too rapidly or without proper transition management will put the animals at risk. Secondly, further in lactation, inaccurate calculation of dry-matter-intake (DMI) leading to wrong roughage/concentrate ratio, an inadequate content of structure within the diet or mistakes in preparing of total mixed rations may produce SARA. The consequences of SARA are diverse and complex. Laminitis is regularly connected to SARA and the negative impact of organic acids on the ruminal wall may lead to parakeratosis enabling translocation of pathogens into the bloodstream provoking inflammation and abscessation throughout the ruminant body. Moreover, milk-fat depression (MFD) can be related to SARA. In order to achieve a proper diagnosis, SARA has to be understood as a herd-management problem. A screening of the herd for SARA by means of a rumenocentesis, performed on a sample-group, preferably 12 individuals, may reveal the presence of SARA. The herd screening should include the risk group suspected, preferably. The prevention of SARA applies to the principles of ruminant feeding. Careful transition management from the dry to the lactation period and control of fibre-content and ration quality should be more yielding than the use of buffers or antibiotic drugs.

  11. Palmitate acutely raises glycogen synthesis in rat soleus muscle by a mechanism that requires its metabolization (Randle cycle).

    PubMed

    Massao Hirabara, Sandro; de Oliveira Carvalho, Carla Roberta; Mendonça, José Roberto; Piltcher Haber, Esther; Fernandes, Luiz Claudio; Curi, Rui

    2003-04-24

    The acute effect of palmitate on glucose metabolism in rat skeletal muscle was examined. Soleus muscles from Wistar male rats were incubated in Krebs-Ringer bicarbonate buffer, for 1 h, in the absence or presence of 10 mU/ml insulin and 0, 50 or 100 microM palmitate. Palmitate increased the insulin-stimulated [(14)C]glycogen synthesis, decreased lactate production, and did not alter D-[U-(14)C]glucose decarboxylation and 2-deoxy-D-[2,6-(3)H]glucose uptake. This fatty acid decreased the conversion of pyruvate to lactate and [1-(14)C]pyruvate decarboxylation and increased (14)CO(2) produced from [2-(14)C]pyruvate. Palmitate reduced insulin-stimulated phosphorylation of insulin receptor substrate-1/2, Akt, and p44/42 mitogen-activated protein kinases. Bromopalmitate, a non-metabolizable analogue of palmitate, reduced [(14)C]glycogen synthesis. A strong correlation was found between [U-(14)C]palmitate decarboxylation and [(14)C]glycogen synthesis (r=0.99). Also, palmitate increased intracellular content of glucose 6-phosphate in the presence of insulin. These results led us to postulate that palmitate acutely potentiates insulin-stimulated glycogen synthesis by a mechanism that requires its metabolization (Randle cycle). The inhibitory effect of palmitate on insulin-stimulated protein phosphorylation might play an important role for the development of insulin resistance in conditions of chronic exposure to high levels of fatty acids.

  12. High incidence of abnormal glucose metabolism in acute coronary syndrome patients at a moderate altitude: A sub-Himalayan study

    PubMed Central

    Mokta, Jitender; Kumar, Subash; Ganju, Neeraj; Mokta, Kiran; Panda, Prashant Kumar; Gupta, Swatantra

    2017-01-01

    Background: Abnormal glucose metabolic status at admission is an important marker of future cardiovascular events and long-term mortality after acute coronary syndrome (ACS), whether or not they are known diabetics. Objective: The aims were to study the prevalence of abnormal glucose metabolism in ACS patients and to compare the different methods of diagnosing diabetes in ACS patients. Methods: We did a prospective study. About 250 consecutive nondiabetic patients (200 men and 50 women) with ACS admitted to a tertiary care institute of Himachal Pradesh in 1 year were enrolled. Admission plasma glucose, next morning fasting plasma glucose (FPG), A1C, and a standardized 75-g oral glucose tolerance test (OGTT) 72 h after admission were done. Glucose metabolism was categorized as normal glucose metabolism, impaired glucose metabolism (impaired fasting glucose or impaired glucose tolerance [IGT]), and diabetes. Diabetes was arbitrarily classified further as undiagnosed (HBA1c ≥6.5%) or possibly stress diabetes (HBA1c <6.5%). A repeat OGTT after 3 months in objects with IGT and stress hyperglycemia at a time of admission was done. Results: The mean age was 54 ± 12.46 years. The mean plasma glucose at admission was 124 ± 53.96 mg/dL, and the mean FPG was 102 ± 27.07 mg/dL. The mean 2-h postglucose load concentration was 159.5 ± 56.58 mg/dL. At baseline, 95 (38%) had normal glucose metabolism, 95 (38%) had impaired glucose metabolism (IGT and or IGT) and 60 (24%) had diabetes; 48 (19.2%) were undiagnosed diabetes and 12 (4.8%) had stress hyperglycemia. At follow up 58.66% and 55.55% of patients with impaired glucose tolerance and stress hyperglycemia continued to have impaired glucose tolerance respectively. About 75 gm OGTT has highest sensitivity and specificity to diagnose diabetes, whereas A1C most specific to rule out stress hyperglycemia. Conclusions: In this small hilly state of India, abnormal glucose metabolism (previously undiagnosed diabetes and IGT) is

  13. Impact of the Metabolic Syndrome on the Clinical Outcome of Patients with Acute ST-Elevation Myocardial Infarction

    PubMed Central

    Lee, Min Goo; Ahn, Youngkeun; Chae, Shung Chull; Hur, Seung Ho; Hong, Taek Jong; Kim, Young Jo; Seong, In Whan; Chae, Jei Keon; Rhew, Jay Young; Chae, In Ho; Cho, Myeong Chan; Bae, Jang Ho; Rha, Seung Woon; Kim, Chong Jin; Choi, Donghoon; Jang, Yang Soo; Yoon, Junghan; Chung, Wook Sung; Cho, Jeong Gwan; Seung, Ki Bae; Park, Seung Jung

    2010-01-01

    We sought to determine the prevalence of metabolic syndrome (MS) in patients with acute myocardial infarction and its effect on clinical outcomes. Employing data from the Korea Acute Myocardial Infarction Registry, a total of 1,990 patients suffered from acute ST-elevation myocardial infarction (STEMI) between November 2005 and December 2006 were categorized according to the National Cholesterol Education Program-Adult Treatment Panel III criteria of MS. Primary study outcomes included major adverse cardiac events (MACE) during one-year follow-up. Patients were grouped based on existence of MS: group I: MS (n=1,182, 777 men, 62.8±12.3 yr); group II: Non-MS (n=808, 675 men, 64.2±13.1 yr). Group I showed lower left ventricular ejection fraction (LVEF) (P=0.005). There were no differences between two groups in the coronary angiographic findings except for multivessel involvement (P=0.01). The incidence of in-hospital death was higher in group I than in group II (P=0.047), but the rates of composite MACE during one-year clinical follow-up showed no significant differences. Multivariate analysis showed that low LVEF, old age, MS, low high density lipoprotein cholesterol and multivessel involvement were associated with high in-hospital death rate. In conclusion, MS is an important predictor for in-hospital death in patients with STEMI. PMID:20890426

  14. Pioglitazone acutely reduces insulin secretion and causes metabolic deceleration of the pancreatic beta-cell at submaximal glucose concentrations.

    PubMed

    Lamontagne, Julien; Pepin, Emilie; Peyot, Marie-Line; Joly, Erik; Ruderman, Neil B; Poitout, Vincent; Madiraju, S R Murthy; Nolan, Christopher J; Prentki, Marc

    2009-08-01

    Thiazolidinediones (TZDs) have beneficial effects on glucose homeostasis via enhancement of insulin sensitivity and preservation of beta-cell function. How TZDs preserve beta-cells is uncertain, but it might involve direct effects via both peroxisome proliferator-activated receptor-gamma-dependent and -independent pathways. To gain insight into the independent pathway(s), we assessed the effects of short-term (metabolism in INS 832/13 beta-cells and rat islets. Pio caused a right shift in the dose-dependence of GIIS, such that insulin release was reduced at intermediate glucose but unaffected at either basal or maximal glucose concentrations. This was associated in INS 832/13 cells with alterations in energy metabolism, characterized by reduced glucose oxidation, mitochondrial membrane polarization, and ATP levels. Pio caused AMPK phosphorylation and its action on GIIS was reversed by the AMPK inhibitor compound C. Pio also reduced palmitate esterification into complex lipids and inhibited lipolysis. As for insulin secretion, the alterations in beta-cell metabolic processes were mostly alleviated at elevated glucose. Similarly, the antidiabetic agents and AMPK activators metformin and berberine caused a right shift in the dose dependence of GIIS. In conclusion, Pio acutely reduces glucose oxidation, energy metabolism, and glycerolipid/fatty acid cycling of the beta-cell at intermediate glucose concentrations. We suggest that AMPK activation and the metabolic deceleration of the beta-cell caused by Pio contribute to its known effects to reduce hyperinsulinemia and preserve beta-cell function and act as an antidiabetic agent.

  15. Acute Cardiorespiratory and Metabolic Responses During Exoskeleton-Assisted Walking Overground Among Persons with Chronic Spinal Cord Injury

    PubMed Central

    Hartigan, Clare; Kandilakis, Casey; Pharo, Elizabeth; Clesson, Ismari

    2015-01-01

    Background: Lower extremity robotic exoskeleton technology is being developed with the promise of affording people with spinal cord injury (SCI) the opportunity to stand and walk. The mobility benefits of exoskeleton-assisted walking can be realized immediately, however the cardiorespiratory and metabolic benefits of this technology have not been thoroughly investigated. Objective: The purpose of this pilot study was to evaluate the acute cardiorespiratory and metabolic responses associated with exoskeleton-assisted walking overground and to determine the degree to which these responses change at differing walking speeds. Methods: Five subjects (4 male, 1 female) with chronic SCI (AIS A) volunteered for the study. Expired gases were collected during maximal graded exercise testing and two, 6-minute bouts of exoskeleton-assisted walking overground. Outcome measures included peak oxygen consumption (V̇O2peak), average oxygen consumption (V̇O2avg), peak heart rate (HRpeak), walking economy, metabolic equivalent of tasks for SCI (METssci), walk speed, and walk distance. Results: Significant differences were observed between walk-1 and walk-2 for walk speed, total walk distance, V̇O2avg, and METssci. Exoskeleton-assisted walking resulted in %V̇O2peak range of 51.5% to 63.2%. The metabolic cost of exoskeleton-assisted walking ranged from 3.5 to 4.3 METssci. Conclusion: Persons with motor-complete SCI may be limited in their capacity to perform physical exercise to the extent needed to improve health and fitness. Based on preliminary data, cardiorespiratory and metabolic demands of exoskeleton-assisted walking are consistent with activities performed at a moderate intensity. PMID:26364281

  16. Endocrine, metabolic, and behavioral effects of and recovery from acute stress in a free-ranging bird.

    PubMed

    Deviche, Pierre; Bittner, Stephanie; Davies, Scott; Valle, Shelley; Gao, Sisi; Carpentier, Elodie

    2016-08-01

    Acute stress in vertebrates generally stimulates the hypothalamo-pituitary-adrenal axis and is often associated with multiple metabolic changes, such as increased gluconeogenesis, and with behavioral alterations. Little information is available, especially in free-ranging organisms, on the duration of these reversible effects once animals are no longer exposed to the stressor. To investigate this question, we exposed free-ranging adult male Rufous-winged Sparrows, Peucaea carpalis, in breeding condition to a standard protocol consisting of a social challenge (conspecific song playback) followed with capture and restraint for 30min, after which birds were released on site. Capture and restraint increased plasma corticosterone (CORT) and decreased plasma testosterone (T), glucose (GLU), and uric acid (UA). In birds that we recaptured the next day after exposure to conspecific song playback, plasma CORT and UA levels no longer differed from levels immediately after capture the preceding day. However, plasma T was similar to that measured after stress exposure the preceding day, and plasma GLU was markedly elevated. Thus, exposure to social challenge and acute stress resulted in persistent (⩾24h) parameter-specific effects. In recaptured sparrows, the territorial aggressive response to conspecific song playback, as measured by song rate and the number of flights over the song-broadcasting speakers, did not, however, differ between the first capture and the recapture, suggesting no proximate functional association between plasma T and conspecific territorial aggression. The study is the first in free-ranging birds to report the endocrine, metabolic, and behavioral recovery from the effects of combined social challenge and acute stress.

  17. Proton magnetic resonance spectroscopy of brain metabolic shifts induced by acute administration of 2-deoxy-d-glucose and lipopolysaccharides.

    PubMed

    Moshkin, Mikhail P; Akulov, Andrey E; Petrovski, Dmitriy V; Saik, Olga V; Petrovskiy, Evgeny D; Savelov, Andrey A; Koptyug, Igor V

    2014-04-01

    In vivo proton magnetic resonance spectroscopy ((1) H MRS) of outbred stock ICR male mice (originating from the Institute of Cancer Research) was used to study the brain (hippocampus) metabolic response to the pro-inflammatory stimulus and to the acute deficiency of the available energy, which was confirmed by measuring the maximum oxygen consumption. Inhibition of glycolysis by means of an injection with 2-deoxy-d-glucose (2DG) reduced the levels of gamma-aminobutyric acid (GABA, p < 0.05, in comparison with control, least significant difference (LSD) test), N-acetylaspartate (NAA, p < 0.05, LSD test) and choline compounds, and at the same time increased the levels of glutamate and glutamine. An opposite effect was found after injection with bacterial lipopolysaccharide (LPS) - a very common pro-inflammatory inducer. An increase in the amounts of GABA, NAA and choline compounds in the brain occurred in mice treated with LPS. Different metabolic responses to the energy deficiency and the pro-inflammatory stimuli can explain the contradictory results of the brain (1) H MRS studies under neurodegenerative pathology, which is accompanied by both mitochondrial dysfunction and inflammation. The prevalence of the excitatory metabolites such as glutamate and glutamine in 2DG treated mice is in good agreement with excitation observed during temporary reduction of the available energy under acute hypoxia or starvation. In turn, LPS, as an inducer of the sickness behavior, which was manifested as depression, sleepiness, loss of appetite etc., shifts the brain metabolic pattern toward the prevalence of the inhibitory neurotransmitter GABA.

  18. The metabolic syndrome in survivors of childhood acute lymphoblastic leukemia in Isfahan, Iran

    PubMed Central

    Reisi, Nahid; Azhir, Afshin; Hashemipour, Mahin; Raeissi, Pouran; Amini, Abasgholi; Moafi, Alireza

    2009-01-01

    BACKGROUND: To determine the prevalence of metabolic syndrome in survivors of childhood leukemia in Isfahan, Iran. METHODS: During a 4-year period (2003 to 2007), 55 children (33 male and 22 female) diagnosed with ALL at Unit of Hematology/ Oncology, Department of Pediatrics, Isfahan University of Medical Science, were enrolled in this cross-sectional study. Metabolic syndrome was defined using the modified version of Adult Treatment Panel (ATP III) crite-ria. Insulin resistance was defined based on the homeostasis model assessment index (HOMA-IR). RESULTS: The mean age of participates was 10.4 years (range 6-19 years) and the mean interval since completion of chemotherapy was 35 months. Twenty percent (11/55) of survivors (10 male, 1 female) met criteria for diagnosis of metabolic syndrome. Obesity was observed in one forth of patients and nearly 3/4 of obese patients had metabolic syndrome. High serum insulin levels were found in 16% of participants and in 63% of obese survivors. The mean insulin levels in survivors with metabolic syndrome was three-times more than those without (28.3 mu/l vs. 9.57 mu/l, p = 0.004). Insulin resistance was detected in 72.7% of survivors with metabolic syndrome and it was positively correlated with serum triglycerides (0.543, p ≤ 0.001), systolic and diastolic BP (0.348, p = 0.01 and 0.368, p = 006 respectively), insulin levels (0.914, p < 0.001) and blood sugar (0.398, p = 003). CONCLUSIONS: The prevalence of metabolic syndrome in survivors of childhood leukemia in Iran is higher than developed countries. Nearly all of the obese patients had metabolic syndrome. Weight control and regular physical exercise are recommended to the survivors. PMID:21772869

  19. Mechanistic Modeling of the Effects of Acidosis on Thrombin Generation

    PubMed Central

    Mitrophanov, Alexander Y.; Rosendaal, Frits R.

    2015-01-01

    BACKGROUND: Acidosis, a frequent complication of trauma and complex surgery, results from tissue hypoperfusion and IV resuscitation with acidic fluids. While acidosis is known to inhibit the function of distinct enzymatic reactions, its cumulative effect on the blood coagulation system is not fully understood. Here, we use computational modeling to test the hypothesis that acidosis delays and reduces the amount of thrombin generation in human blood plasma. Moreover, we investigate the sensitivity of different thrombin generation parameters to acidosis, both at the individual and population level. METHODS: We used a kinetic model to simulate and analyze the generation of thrombin and thrombin–antithrombin complexes (TAT), which were the end points of this study. Large groups of temporal thrombin and TAT trajectories were simulated and used to calculate quantitative parameters, such as clotting time (CT), thrombin peak time, maximum slope of the thrombin curve, thrombin peak height, area under the thrombin trajectory (AUC), and prothrombin time. The resulting samples of parameter values at different pH levels were compared to assess the acidosis-induced effects. To investigate intersubject variability, we parameterized the computational model using the data on clotting factor composition for 472 subjects from the Leiden Thrombophilia Study. To compare acidosis-induced relative parameter changes in individual (“virtual”) subjects, we estimated the probabilities of relative change patterns by counting the pattern occurrences in our virtual subjects. Distribution overlaps for thrombin generation parameters at distinct pH levels were quantified using the Bhattacharyya coefficient. RESULTS: Acidosis in the range of pH 6.9 to 7.3 progressively increased CT, thrombin peak time, AUC, and prothrombin time, while decreasing maximum slope of the thrombin curve and thrombin peak height (P < 10–5). Acidosis delayed the onset and decreased the amount of TAT generation (P

  20. Changes in autophagy, proteasome activity and metabolism to determine a specific signature for acute and chronic senescent mesenchymal stromal cells.

    PubMed

    Capasso, Stefania; Alessio, Nicola; Squillaro, Tiziana; Di Bernardo, Giovanni; Melone, Mariarosa A; Cipollaro, Marilena; Peluso, Gianfranco; Galderisi, Umberto

    2015-11-24

    A sharp definition of what a senescent cell is still lacking since we do not have in depth understanding of mechanisms that induce cellular senescence. In addition, senescent cells are heterogeneous, in that not all of them express the same genes and present the same phenotype. To further clarify the classification of senescent cells, hints may be derived by the study of cellular metabolism, autophagy and proteasome activity. In this scenario, we decided to study these biological features in senescence of Mesenchymal Stromal Cells (MSC). These cells contain a subpopulation of stem cells that are able to differentiate in mesodermal derivatives (adipocytes, chondrocytes, osteocytes). In addition, they can also contribute to the homeostatic maintenance of many organs, hence, their senescence could be very deleterious for human body functions. We induced MSC senescence by oxidative stress, doxorubicin treatment, X-ray irradiation and replicative exhaustion. The first three are considered inducers of acute senescence while extensive proliferation triggers replicative senescence also named as chronic senescence. In all conditions, but replicative and high IR dose senescence, we detected a reduction of the autophagic flux, while proteasome activity was impaired in peroxide-treated and irradiated cells. Differences were observed also in metabolic status. In general, all senescent cells evidenced metabolic inflexibility and prefer to use glucose as energy fuel. Irradiated cells with low dose of X-ray and replicative senescent cells show a residual capacity to use fatty acids and glutamine as alternative fuels, respectively. Our study may be useful to discriminate among different senescent phenotypes.

  1. Integrating a prospective pilot trial and patient-derived xenografts to trace metabolic changes associated with acute myeloid leukemia.

    PubMed

    Carrabba, Matteo G; Tavel, Laurette; Oliveira, Giacomo; Forcina, Alessandra; Quilici, Giacomo; Nardelli, Francesca; Tresoldi, Cristina; Ambrosi, Alessandro; Ciceri, Fabio; Bernardi, Massimo; Vago, Luca; Musco, Giovanna

    2016-10-28

    Despite the considerable progress in understanding the molecular bases of acute myeloid leukemia (AML), new tools to link disease biology to the unpredictable patient clinical course are still needed. Herein, high-throughput metabolomics, combined with the other "-omics" disciplines, holds promise in identifying disease-specific and clinically relevant features.In this study, we took advantage of nuclear magnetic resonance (NMR) to trace AML-associated metabolic trajectory employing two complementary strategies. On the one hand, we performed a prospective observational clinical trial to identify metabolic changes associated with blast clearance during the first two cycles of intensive chemotherapy in nine adult patients. On the other hand, to reduce the intrinsic variability associated with human samples and AML genetic heterogeneity, we analyzed the metabolic changes in the plasma of immunocompromised mice upon engraftment of primary human AML blasts.Combining the two longitudinal approaches, we narrowed our screen to seven common metabolites, for which we observed a mirror-like trajectory in mice and humans, tracing AML progression and remission, respectively. We interpreted this set of metabolites as a dynamic fingerprint of AML evolution.Overall, these NMR-based metabolomic data, to be consolidated in larger cohorts and integrated in more comprehensive system biology approaches, hold promise for providing valuable and non-redundant information on the systemic effects of leukemia.

  2. Coagulopathy induced by acidosis, hypothermia and hypocalcaemia in severe bleeding.

    PubMed

    De Robertis, E; Kozek-Langenecker, S A; Tufano, R; Romano, G M; Piazza, O; Zito Marinosci, G

    2015-01-01

    Acidosis, hypothermia and hypocalcaemia are determinants for morbidity and mortality during massive hemorrhages. However, precise pathological mechanisms of these environmental factors and their potential additive or synergistic anticoagulant and/or antiplatelet effects are not fully elucidated and are at least in part controversial. Best available evidences from experimental trials indicate that acidosis and hypothermia progressively impair platelet aggregability and clot formation. Considering the cell-based model of coagulation physiology, hypothermia predominantly prolongs the initiation phase, while acidosis prolongs the propagation phase of thrombin generation. Acidosis increases fibrinogen breakdown while hypothermia impairs its synthesis. Acidosis and hypothermia have additive effects. The effect of hypocalcaemia on coagulopathy is less investigated but it appears that below the cut-off of 0.9 mmol/L, several enzymatic steps in the plasmatic coagulation system are blocked while above that cut-off effects remain without clinical sequalae. The impact of environmental factor on hemostasis is underestimated in clinical practice due to our current practice of using routine coagulation laboratory tests such as partial thromboplastin time or prothrombin time, which are performed at standardized test temperature, after pH correction, and upon recalcification. Temperature-adjustments are feasible in viscoelastic point-of-care tests such as thrombelastography and thromboelastometry which may permit quantification of hypothermia-induced coagulopathy. Rewarming hypothermic bleeding patients is highly recommended because it improves patient outcome. Despite the absence of high-quality evidence, calcium supplementation is clinical routine in bleeding management. Buffer administration may not reverse acidosis-induced coagulopathy but may be essential for the efficacy of coagulation factor concentrates such as recombinant activated factor VII.

  3. Metabolism

    MedlinePlus

    ... and intestines. Several of the hormones of the endocrine system are involved in controlling the rate and direction ... For Kids For Parents MORE ON THIS TOPIC Endocrine System What Can I Do About My High Metabolism? ...

  4. Metabolism

    MedlinePlus

    ... symptoms. Metabolic diseases and conditions include: Hyperthyroidism (pronounced: hi-per-THIGH-roy-dih-zum). Hyperthyroidism is caused ... or through surgery or radiation treatments. Hypothyroidism (pronounced: hi-po-THIGH-roy-dih-zum). Hypothyroidism is caused ...

  5. Intracellular acidosis enhances the excitability of working muscle.

    PubMed

    Pedersen, Thomas H; Nielsen, Ole B; Lamb, Graham D; Stephenson, D George

    2004-08-20

    Intracellular acidification of skeletal muscles is commonly thought to contribute to muscle fatigue. However, intracellular acidosis also acts to preserve muscle excitability when muscles become depolarized, which occurs with working muscles. Here, we show that this process may be mediated by decreased chloride permeability, which enables action potentials to still be propagated along the internal network of tubules in a muscle fiber (the T system) despite muscle depolarization. These results implicate chloride ion channels in muscle function and emphasize that intracellular acidosis of muscle has protective effects during muscle fatigue.

  6. [Pathophysiology of hormonal, immune, metabolic changes in acute and chronic pancreatitis. Experimental and clinical studies].

    PubMed

    Trubitsyna, I E; Chikunova, B Z; Tkachenko, E V; Tsaregorodtseva, T M; Vinokurova, L V; Varvanina, G G

    2008-01-01

    There is literature review of the acute and chronic pancreatitis experimental models. Patogenetic necrosis mechanisms with fibrosis progress in pancreas were revealed. The stimulation of the proteolytic enzymes synthesis and secretion, that was examined in experiments were compared with clinical examinations. The patients with chronic pancreatitis were investigated in the Central Research Institute of Gastroenterology.

  7. Systemic Metabolic Responses of Broiler Chickens and Piglets to Acute T-2 Toxin Intravenous Exposure.

    PubMed

    Wan, Qianfen; He, Qinghua; Deng, Xianbai; Hao, Fuhua; Tang, Huiru; Wang, Yulan

    2016-01-27

    The aim of this study is to thoroughly investigate the toxicity mechanism of mycotoxin T-2 toxin and to further understand the endogenous metabolic alterations induced by T-2 toxin. To achieve this, a nuclear magnetic resonance (NMR)-based metabonomics approach was used to analyze the metabolic alterations induced by a single intravenous injection of T-2 toxin (0.5 mg/kg of body weight) in piglets and broiler chickens. A range of metabolites in the plasma, liver, kidney, and spleen of broiler chickens and plasma of piglets was changed following T-2 toxin injection. For example, a rapid increase of amino acids together with a significant reduction of glucose and lipid occurred in the plasma of broiler chickens and piglets following T-2 toxin treatment. A significant accumulation of amino acids and modulated nucleotides were detected in the liver, kidney, and spleen of T-2 toxin-treated broiler chickens. These data indicated that T-2 toxin caused endogenous metabolic changes in multiple organs and perturbed various metabolic pathways, including energy, amino acid, and nucleotide metabolism, as well as oxidative stress. We also observed elevated levels of tryptophan in the T-2 toxin-treated broiler chickens, which may explain the reported neurotoxic effects of T-2 toxin. These findings provide important information on the toxicity of T-2 toxin and demonstrate the power of the NMR-based metabonomics approach in exploring the toxicity mechanism of xenobiotics.

  8. Response of AMP-activated protein kinase and energy metabolism to acute nitrite exposure in the Nile tilapia Oreochromis niloticus.

    PubMed

    Xu, Zhixin; Li, Erchao; Xu, Chang; Gan, Lei; Qin, Jian G; Chen, Liqiao

    2016-08-01

    Adenosine monophosphate-activated protein kinase (AMPK) is a prevalent mammalian energy metabolism sensor, but little is known about its role as an energy sensor in fish experiencing stress. We aimed to study AMPK in Oreochromis niloticus on both the molecular and the physical level. We found that the cDNAs encoding the AMPKα1 and AMPKα2 variants of the O. niloticus catalytic α subunit were 1753bp and 2563 bp long and encoded 571 and 557 amino acids, respectively. Both the AMPKα1 and the AMPKα2 isoform possess structural features similar to mammalian AMPKα, including a phosphorylation site at Thr172 in the N-terminus, and exhibit high homology with other fish and vertebrate AMPKα sequences (81.3%-98.1%). mRNA encoding the AMPKα isoforms was widely expressed in various tissues with distinctive patterns. AMPKα1 and AMPKα2 were primarily expressed in the intestines and brain, respectively. Under acute nitrite challenge, the mRNA encoding the AMPKα isoforms, as well as AMPK activity, changed over time. Its recovery period in freshwater, combined with the fact that it is highly conserved, suggests that fish AMPK, like its mammalian orthologues, acts as an energy metabolism sensor. Furthermore, subsequent decreases in AMPK mRNA levels and activity suggested that its action was transient but efficient. Physically, glucose, lactic acid and TGs in plasma, as well as energy materials in the hepatopancreas and muscle, were significantly altered over time, indicating changes in energy metabolism during the experimental period. These data have enabled us to characterize energy utilization in O. niloticus and further illustrate the role of fish AMPK as an energy sensor. This study provides new insight into energy metabolism and sensing by AMPK in teleost and necessitates further study of the multiple physiologic roles of AMPK in fish.

  9. Lipoyltransferase 1 Gene Defect Resulting in Fatal Lactic Acidosis in Two Siblings

    PubMed Central

    Taché, Véronique; Bivina, Liga; White, Sophie; Gregg, Jeffrey; Deignan, Joshua; Boyadjievd, Simeon A.; Poulain, Francis R.

    2016-01-01

    A term male neonate developed severe intractable lactic acidosis on day of life 1 and died the same day at our institution. The family previously lost another term, female newborn on day of life 1 from suspected sepsis at an outside hospital. After performing an autopsy on the neonate who died at our institution, extensive and lengthy neonatal and parental genetic testing, as well as biochemical analyses, and whole exome sequencing analysis identified compound heterozygous mutations in the lipoyltransferase 1 (LIPT1) gene responsible for the lipoylation of the 2-keto dehydrogenase complexes in the proband. These mutations were also identified in the deceased sibling. The clinical manifestations of these two siblings are consistent with those recently described in two unrelated families with lactic acidosis due to LIPT1 mutations, an underrecognized and underreported cause of neonatal death. Conclusions. Our observations contribute to the delineation of a new autosomal recessive metabolic disorder, leading to neonatal death. Our case report also highlights the importance of an interdisciplinary team in solving challenging cases. PMID:27247813

  10. Treatment of acute cyanide intoxication with hemodialysis.

    PubMed

    Wesson, D E; Foley, R; Sabatini, S; Wharton, J; Kapusnik, J; Kurtzman, N A

    1985-01-01

    A dramatic response was noted in a patient at our hospital who received hemodialysis therapy for severe acidosis secondary to an unknown toxin, subsequently identified as cyanide. We were unable to find any information concerning the hemodialysis clearance and extraction ratio of cyanide; thus, we studied the effect of hemodialysis in dogs receiving a constant infusion of cyanide with and without a simultaneous infusion of thiosulfate. The hemodialysis clearance of cyanide in the presence of thiosulfate was 38.3 +/- 5.4 ml/min with an extraction ratio of 0.43 +/- 0.06 (n = 4). Hemodialysis was found to increase the lethal dose of cyanide without thiosulfate infusion, and a further increase was noted with the thiosulfate infusion. Thiosulfate promotes mitochondrial metabolism of cyanide to thiocyanate. The end product, thiocyanate, is quickly removed by hemodialysis. We believe that the demonstrated effectiveness of hemodialysis in the treatment of acute cyanide intoxication is related not only to the hemodialysis clearance of cyanide, but also to the removal of its metabolic end product, thiocyanate. Based on our observations, we feel that hemodialysis is an effective adjunct in the treatment of acute cyanide intoxication.

  11. Acute Alcohol Intoxication Decreases Glucose Metabolism but Increases Acetate Uptake in the Human Brain

    PubMed Central

    Volkow, Nora D.; Kim, Sung Won; Wang, Gene-Jack; Alexoff, David; Logan, Jean; Muench, Lisa; Shea, Colleen; Telang, Frank; Fowler, Joanna S.; Wong, Christopher; Benveniste, Helene; Tomasi, Dardo

    2012-01-01

    Alcohol intoxication results in marked reductions in brain glucose metabolism, which we hypothesized reflect not just its GABAergic enhancing effects but also metabolism of acetate as an alternative brain energy source. To test this hypothesis we separately assessed the effects of alcohol intoxication on brain glucose and acetate metabolism using Positron Emission Tomography (PET). We found that alcohol intoxication significantly decreased whole brain glucose metabolism (measured with FDG) with the largest decrements in cerebellum and occipital cortex and the smallest in thalamus. In contrast, alcohol intoxication caused a significant increase in [1-11C]acetate brain uptake (measured as standard uptake value, SUV), with the largest increases occurring in cerebellum and the smallest in thalamus. In heavy alcohol drinkers [1-11C]acetate brain uptake during alcohol challenge trended to be higher than in occasional drinkers (p <0.06) and the increases in [1-11C]acetate uptake in cerebellum with alcohol were positively associated with the reported amount of alcohol consumed (r=0.66, p<0.01). Our findings corroborate a reduction of brain glucose metabolism during intoxication and document an increase in brain acetate uptake. The opposite changes observed between regional brain metabolic decrements and regional increases in [1-11C]acetate uptake support the hypothesis that during alcohol intoxication the brain may rely on acetate as an alternative brain energy source and provides preliminary evidence that heavy alcohol exposures may facilitate the use of acetate as an energy substrate. These findings raise the question of the potential therapeutic benefits that increasing plasma acetate concentration (ie ketogenic diets) may have in alcoholics undergoing alcohol detoxification. PMID:22947541

  12. Metabolic aspects of acute tissue hypoxia during extracorporeal circulation and their modification induced by L-carnitine treatment.

    PubMed

    Corbucci, G G; Menichetti, A; Cogliatti, A; Nicoli, P; Ruvolo, C

    1992-01-01

    In this study the authors examine the effects of acute hypoxia due to extracorporeal circulation (ECC) and the role played by L-carnitine treatment on some plasmatic metabolites linked to glycolytic cellular metabolism. To obtain biochemical data, 120 patients in extracorporeal circulation during aortopulmonary bypass surgery were evaluated. The patients received either sodium bicarbonate (40 patients), or L-carnitine during ECC (40 patients) or before and during ECC (40 patients), and plasma samples were collected before ECC, during ECC and after ECC. The levels of lactate and pyruvate showed significant alterations in sodium bicarbonate-treated patients, and there was also a considerable imbalance in the succinate/fumarate ratio. This means that tissue hypoxia due to ECC leads to cellular oxidative damage and to a considerable decrease in the intracellular energy pools. The use of L-carnitine antagonizes the oxidative stress, as is well documented by the levels of plasmatic metabolites which remain confined to normal amounts.

  13. METABOLISM AS A DETERMINING FACTOR IN ACUTE AND CHRONIC TOXICITY OF INORGANIC ARSENIC

    EPA Science Inventory

    The metabolism of inorganic arsenic (iAs) in humans involves reduction of As(V)-species to trivalency and oxidative methylation of As(III)-species. In this pathway, iAs is converted to methylarsenic (MAs) and dimethyl arsenic (DMAs) metabolites that contain As(III) or As(V). Rec...

  14. Cerebral acetylcholine and energy metabolism changes in acute ammonia intoxication in the lower primate Tupaia glis.

    PubMed

    McCandless, D W; Looney, G A; Modak, A T; Stavinoha, W B

    1985-08-01

    Ammonia levels are elevated in many patients with hepatic encephalopathy. This observation, coupled with animal studies showing an encephalogenic role for ammonia, has led to the concept that ammonia is an important toxin in the production of neurologic symptoms. Studies in rodents have shown that ammonia alters cerebral energy metabolism in the reticular formation, an area important in the modulation of consciousness. Our study was undertaken to extend these observations to the lower primate Tupaia glis, the tree shrew. The energy metabolites glucose, glycogen, lactate, adenosine triphosphate, and phosphocreatine were measured in the reticular formation by microanalytic techniques and enzymatic cycling. Acetylcholine was measured in brain regions by gas chromatography. Acetylcholine levels were increased significantly only in the medulla-pons and diencephalon in the coma stage. The energy metabolites glucose, glycogen, and phosphocreatine were decreased in reticular formation cells during the coma, whereas lactate was increased. During the precoma, glycogen and phosphocreatine were decreased. It appears, therefore, that the tree shrew has a metabolic response to ammonia similar to that of mice. A lowering of energy metabolism in the area of brain-regulating consciousness may act to place the animal in a coma. This coma in turn acts to decrease overall metabolic demand, which allows the animal an opportunity to conserve its threatened energy reserves.

  15. An experimental renal acidification defect in patients with hereditary fructose intolerance. I. Its resemblance to renal tubular acidosis.

    PubMed

    Morris, R C

    1968-06-01

    In three unrelated patients with hereditary fructose intolerance (HFI), but in none of five normal subjects, the experimental administration of fructose invariably induced a reversible dysfunction of the renal tubule with biochemical and physiological characteristics of renal tubular acidosis. During a state of ammonium chloride-induced acidosis, (a) urinary pH was greater than six and the rate of excretion of net acid (titratable acid plus ammonium minus bicarbonate) was inappropriately low, (b) the glomerular filtration rate remained unchanged or decreased modestly, and (c) urinary excretion of titratable acid increased briskly with diuresis of infused phosphate, although urinary pH changed little. The tubular dysfunction, which also includes impaired tubular reabsorption of alpha amino nitrogen and phosphate, persisted throughout administration of fructose and disappeared afterward. The tubular dysfunction was not causally dependent on hypoglucosemia, ammonium chloride-induced acidosis or osmotic diuresis. Rather, it appeared causally related to the fructose-induced metabolic abnormality of patients with HFI. The causal enzymatic defect, the virtual absence of fructose-1-phosphate aldolase, occurs in the kidney as well as in the liver of patients with HFI.

  16. Relation between the kinetics of thallium-201 in myocardial scintigraphy and myocardial metabolism in patients with acute myocardial infarction

    PubMed Central

    Yamagishi, H; Akioka, K; Takagi, M; Tanaka, A; Takeuchi, K; Yoshikawa, J; Ochi, H

    1998-01-01

    Objective—To investigate the relations between myocardial metabolism and the kinetics of thallium-201 in myocardial scintigraphy.
Methods—46 patients within six weeks after the onset of acute myocardial infarction underwent resting myocardial dual isotope, single acquisition, single photon emission computed tomography (SPECT) using radioiodinated 15-iodophenyl 3-methyl pentadecaenoic acid (BMIPP) and thallium-201, exercise thallium-201 SPECT, and positron emission tomography (PET) using nitrogen-13 ammonia (NH3) and [F18]fluorodeoxyglucose (FDG) under fasting conditions. The left ventricle was divided into nine segments, and the severity of defects was assessed visually.
Results—In the resting SPECT, less BMIPP uptake than thallium-201 uptake was observed in all of 40 segments with reverse redistribution of thallium-201, and in 21 of 88 segments with a fixed defect of thallium-201 (p < 0.0001); and more FDG uptake than NH3 uptake (NH3-FDG mismatch) was observed in 35 of 40 segments with reverse redistribution and in 38 of 88 segments with fixed defect (p < 0.0001). Less BMIPP uptake in the resting SPECT was observed in 49 of 54 segments with slow stress redistribution in exercise SPECT, and in nine of 17 segments with rapid stress redistribution (p < 0.0005); NH3-FDG mismatch was observed in 42 of 54 segments with slow stress redistribution and in five of 17 segments with rapid stress redistribution (p < 0.0005).
Conclusions—Thallium-201 myocardial scintigraphy provides information about not only myocardial perfusion and viability but also about myocardial metabolism in patients with acute myocardial infarction.

 Keywords: thallium-201 SPECT;  BMIPP SPECT;  FDG PET;  myocardial infarction;  redistribution PMID:9764055

  17. Calcium flux and metabolism in the pigeon heart following doxorubicin treatment: an acute study

    SciTech Connect

    Revis, N.

    1981-01-01

    The present studies were performed to determine in vivo the initial and secondary acute effects of doxorubicin on the influx of calcium into myocardial cells. Studies are also described showing the effect of doxorubicin on a calcium-activated neutral protease from cardiac tissue. These latter studies were performed in an attempt to explain the loss of myofibrilular structures in myocardial cells following doxorubicin treatment.

  18. Metabolic causes and prevention of ventricular fibrillation during acute coronary syndromes.

    PubMed

    Oliver, Michael F

    2002-03-01

    The mechanisms leading to ventricular fibrillation that occur during acute myocardial ischemia are ill understood. Whether primary ventricular fibrillation is due to a transient imbalance of electrolytes, an alteration of membrane permeability, electrical re-entry phenomena, or other factors, one overriding influence is the development of regional myocardial energy crises. Acute alteration in the balance of substrate supply may lead, during greatly reduced blood flow, to instability of myocardial electrical conduction with the development of re-entry circuits. An immediate response to the angor animi and initial symptoms of an acute coronary syndrome is a rapid and marked increase in catecholamine release, which leads to adipose tissue lipolysis with an acute increase in plasma free fatty acid concentrations, suppression of insulin activity, and a reduction in glucose uptake by the myocardium. The utilization of free fatty acids instead of glucose by the ischemic myocardium could precipitate regional oxygen or energy crises. Prevention therefore should focus on minimizing the catecholamine response and providing the myocardium with an optimum supply of energy substrates. Since catecholamines are inotropic, the aim should be to redress the imbalance of substrate availability by controlling adipose lipolysis with reduction of plasma free fatty acid concentrations, increasing the availability of glucose, or both. Other approaches include inhibition of acylcarnitine transport and manipulation of fatty acid intermediaries. To combat primary ventricular fibrillation, preventive treatment must be established within 6 to 10 hours of the onset of ischemia. There is already experimental and clinical evidence that antilipolytic drugs decrease the incidence of ventricular fibrillation, but their potential has not been explored extensively.

  19. [Metabolism of hexobarbital in patients with acute hepatitis and cirrhosis (author's transl)].

    PubMed

    Richter, E; Gallenkamp, H; Keller, B; Brachtel, D; Zilly, W; Breimer, D D

    1977-06-01

    16 patients with acute hepatitis, 18 patients with cirrhosis and a total of 21 volunteers and patients with normal liver function received 7.32 mg/kg hexobarbital by linear intravenous infusion within 60 min. Hexobarbital was determined gaschromatographically in serial blood samples and the hexobarbital-clearance was calculated from the plasma concentration curve versus time. Additional experiments were performed in rats suffering from so called "galactosamine hepatitis". In half of the patients with acute hepatitis a normal hexobarbital clearance could be found. In the other patients this was distinctly reduced but not correlation was found to other liver function tests. Patients with cirrhosis were subdivided into two groups. The patients in group 1 were well compensated. The patients in group 2 had a decompensated state with ascites and oesophageal varices. In nearly all patients with cirrhosis the hexobarbital-clearance was diminished. This was more pronounced in group 2. Ketohexobarbital excretion in healthy subjects was in the range of 40-60% of dose. Patients with acute hepatitis excreted only 10-20% of dose and patients with liver cirrhosis only about 5% of dose. In rats with "galactosamine hepatitis" hexobarbital clearance in vivo was distinctly reduced and this could be explained by diminished microsomal cytochrome p 45- and hexobarbital oxidation rate.

  20. Heart diseases in mitochondrial encephalomyopathy, lactic acidosis, and stroke syndrome.

    PubMed

    Fayssoil, Abdallah

    2009-01-01

    Mitochondrial encephalomyopathy, lactic acidosis, and stroke (MELAS) syndrome is a mitochondrial genetic disorder caused by a point mutation, resulting in the substitution of guanine for adenine at nucleotide 3243 (A3243G) of mitochondrial DNA. This disease is characterized by a multisystem disorder with variable manifestations. The authors review heart involvement in this disease.

  1. Acidosis, magnesium and acetylsalicylic acid: Effects on thrombin

    NASA Astrophysics Data System (ADS)

    Borisevich, Nikolaj; Loznikova, Svetlana; Sukhodola, Aleksandr; Halets, Inessa; Bryszewska, Maria; Shcharbin, Dzmitry

    2013-03-01

    Thrombin, an enzyme from the hydrolase family, is the main component of the blood coagulation system. In ischemic stroke it acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin forming blood clots in the brain. It has been found to phosphoresce at room temperature in the millisecond and microsecond ranges. The phosphorescence of thrombin was studied under physiological conditions, in acidosis (decrease of pH from 8.0 to 5.0) and on the addition of salts (magnesium sulfate and sodium chloride) and of acetylsalicylic acid, and its connection with thrombin function is discussed. Acidosis significantly increased the internal dynamics of thrombin. We propose that lactate-acidosis plays a protective role in stroke, preventing the formation of clots. The addition of NaCl and MgSO4 in different concentrations increased the internal dynamics of thrombin. Also, the addition of MgSO4 decreased thrombin-induced platelet aggregation. However, magnesium sulfate and acetylsalicylic acid in the therapeutic concentrations used for treatment of ischemic stroke had no effect on thrombin internal dynamics. The data obtained will help to elucidate the conformational stability of thrombin under conditions modulating lactate-acidosis and in the presence of magnesium sulfate.

  2. [Oliguria and acute renal dysfunction in a six-month-old infant].

    PubMed

    Cui, Ya-Jie; Song, Chun-Lan; Cheng, Yi-Bing

    2017-02-01

    The infant (a girl aged 6 months) was admitted to the hospital because of oliguria and acute renal dysfunction. The laboratory examination results showed serious metabolic acidosis and increased blood urea nitrogen and serum creatinine levels. The patient continued to be anuric after 10 days of treatment with continuous renal replacement therapy (CRRT). she died a day later. The family history showed that the patient's sister died of acute renal failure 6 months after birth. The genomic sequencing results showed AGXT mutation in the patient and confirmed the diagnosis of primary hyperoxaluria type 1 (PH1). Her parents were heterozygous carriers. PH1 should be considered when the children have abnormal renal function or recurrent renal calculi or have a family history of these symptoms. AGXT gene analysis is an important method for PH1 diagnosis.

  3. pH-sensitive MRI demarcates graded tissue acidification during acute stroke - pH specificity enhancement with magnetization transfer and relaxation-normalized amide proton transfer (APT) MRI.

    PubMed

    Guo, Yingkun; Zhou, Iris Yuwen; Chan, Suk-Tak; Wang, Yu; Mandeville, Emiri T; Igarashi, Takahiro; Lo, Eng H; Ji, Xunming; Sun, Phillip Zhe

    2016-11-01

    pH-sensitive amide proton transfer (APT) MRI provides a surrogate metabolic biomarker that complements the widely-used perfusion and diffusion imaging. However, the endogenous APT MRI is often calculated using the asymmetry analysis (MTRasym), which is susceptible to an inhomogeneous shift due to concomitant semisolid magnetization transfer (MT) and nuclear overhauser (NOE) effects. Although the intact brain tissue has little pH variation, white and gray matter appears distinct in the MTRasym image. Herein we showed that the heterogeneous MTRasym shift not related to pH highly correlates with MT ratio (MTR) and longitudinal relaxation rate (R1w), which can be reasonably corrected using the multiple regression analysis. Because there are relatively small MT and R1w changes during acute stroke, we postulate that magnetization transfer and relaxation-normalized APT (MRAPT) analysis increases MRI specificity to acidosis over the routine MTRasym image, hence facilitates ischemic lesion segmentation. We found significant differences in perfusion, pH and diffusion lesion volumes (P<0.001, ANOVA). Furthermore, MRAPT MRI depicted graded ischemic acidosis, with the most severe acidosis in the diffusion lesion (-1.05±0.29%/s), moderate acidification within the pH/diffusion mismatch (i.e., metabolic penumbra, -0.67±0.27%/s) and little pH change in the perfusion/pH mismatch (i.e., benign oligemia, -0.04±0.14%/s), providing refined stratification of ischemic tissue injury.

  4. Sex differences in Δ(9)-tetrahydrocannabinol metabolism and in vivo pharmacology following acute and repeated dosing in adolescent rats.

    PubMed

    Wiley, Jenny L; Burston, James J

    2014-07-25

    Mechanisms that may underlie age and sex differences in the pharmacological effects of cannabinoids are relatively unexplored. The purpose of the present study was to determine whether sex differences in metabolism of Δ(9)-tetrahydrocannabinol (THC), similar to those observed previously in adult rats, also occurred in adolescent rats and might contribute to age and sex differences in its in vivo pharmacology. Male and female adolescent rats were exposed to THC acutely or repeatedly for 10 days. Subsequently, some of the rats were sacrificed and blood and brain levels of THC and one of its metabolites, 11-hydroxy-Δ(9)-THC (11-OH-THC), were measured. Other rats were evaluated in a battery of in vivo tests that are sensitive to cannabinoids. Concentrations of 11-OH-THC in the brains of female adult and adolescent rats exceeded those observed in male conspecifics, particularly after repeated THC administration. In contrast, brain levels of THC did not differ between the sexes. In vivo, acute THC produced dose-related hypothermia, catalepsy and suppression of locomotion in adolescent rats of both sexes, with tolerance developing after repeated administration. With a minor exception, sex differences in THC's effects in the in vivo assays were not apparent. Together with previous findings, the present results suggest that sex differences in pharmacokinetics cannot fully explain the patterns of sex differences (and lack of sex differences) in cannabinoid effects across behaviors. Hormonal and/or pharmacodynamic factors are also likely to play a role.

  5. High Prevalence of Obesity in Acute Promyelocytic Leukemia (APL): Implications for Differentiating Agents in APL and Metabolic Syndrome

    PubMed Central

    Tedesco, Jason; Qualtieri, Julianne; Head, David; Savani, Bipin N.; Reddy, Nishitha

    2011-01-01

    Background: Between January 1999 and December 2008, 469 patients treated for acute myeloid leukemia (AML) were included in this single-institution study. Methods: We performed a case-control analysis to study the rate of obesity among patients with acute promyelocytic leukemia (APL) and non-APL AML. Results: A total of 81% of APL patients analyzed were obese compared with 41.7% in the non-APL group (p < 0.001). Body mass index (BMI) >30 was seen in 57% of APL patients compared with 31% for the non-APL group (p = 0.01). Neither obesity nor the chemotherapy dosing based on ideal body weight affected survival. Conclusions: Our findings generate the hypothesis that APL and metabolic syndromes may share a common pathogenic pathway via retinoic acid receptors (RARs), the ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth and survival. If this link is confirmed in larger studies, our data will instigate further studies using RXR and RAR modulators as a preventive strategy among obese individuals. PMID:23556085

  6. [Lymphocyte metabolism in patients with acute pancreatitis with different genotypes of GSTM1 and GSTT1 genes].

    PubMed

    Markova, E V; Zotova, N V; Savchenko, A A; Titova, N M; Slepov, E V; Cherdantsev, D V; Konovalenko, A N

    2006-01-01

    In this study, we have investigated correlation between enzymatic activity of NAD(P)-dependent dehydrogenases of lymphocytes and polymorphic variants of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genes in the group of unrelated patients with acute pancreatitis in comparison with healthy Russians from Krasnoyarsk. Thus, genotype GSTM1 0/0 is the marker of predisposition to the acute pancreatitis, wheras polymorphism of the GSTT1 gene is not involved in the development of the pancreatitis, at least in our group. The bioluminescence analysis showed statistically significant decrease of the levels of G3PD, NAD(+)MDH and the increase of NADH(+)LDH, NAD(+)GDH, NADH(+)GDH in lymphocytes of pancreatic group. Development of pancreatitis in patients with different genotypes GSTM1 and GSTT1 genes showed the rearrangement of the basic intracellular processes: dominance of a plastic metabolism in the patients with GSTM1--deletions and predominance of energetic processes at GSTT1 0 - pancreatitis.

  7. Acute and chronic effects of sprint interval exercise on postprandial lipemia in women at-risk for the metabolic syndrome.

    PubMed

    Freese, Eric C; Gist, Nicholas H; Acitelli, Rachelle M; McConnell, Whitni J; Beck, Catherine D; Hausman, Dorothy B; Murrow, Jonathan R; Cureton, Kirk J; Evans, Ellen M

    2015-04-01

    Individuals diagnosed with the metabolic syndrome (MetS) exhibit elevated postprandial lipemia (PPL). The aims of this investigation were to determine 1) if an acute bout of sprint interval training (SIT) attenuates PPL; and 2) if the attenuation of PPL following 6 wk of SIT is magnified compared with a single session of SIT prior to training in women at-risk for MetS (n = 45; 30-65 yr). Women were randomized to SIT (n = 22) or a nonexercise control (n = 23; CON) for 6 wk. Postprandial responses to a high-fat meal challenge (HFMC) were assessed in the CON group before (B-HFMC) and after (Post-HFMC) without prior exercise and in the SIT group at baseline (B-HFMC) without prior exercise, after an acute bout of SIT (four 30-s all-out sprints with 4-min recovery) prior to (Pre-HFMC), and after the 6-wk intervention (Post-HFMC). Responses to the HFMC were assessed by collecting venous blood samples in the fasted state and at 0, 30, 60, 120, and 180 min postprandial. Compared with baseline, an acute bout of SIT before (Pre-HFMC) and after the 6-wk intervention (Post-HFMC) significantly attenuated fasted TG (P < 0.05; 16.6% and 12.3%, respectively) and postprandial area under the curve (13.1% and 9.7%, respectively; tAUC) TG responses. There was no difference in fasted or tAUC TG responses between Pre-HFMC and Post-HFMC. SIT is an effective mode of exercise to reduce fasted and postprandial TG concentrations in women at-risk for MetS. Six weeks of SIT does not magnify the attenuation of PPL in response to a single session of SIT.

  8. Low-flow CO2 removal integrated into a renal-replacement circuit can reduce acidosis and decrease vasopressor requirements

    PubMed Central

    2013-01-01

    Introduction Lung-protective ventilation in patients with ARDS and multiorgan failure, including renal failure, is often paralleled with a combined respiratory and metabolic acidosis. We assessed the effectiveness of a hollow-fiber gas exchanger integrated into a conventional renal-replacement circuit on CO2 removal, acidosis, and hemodynamics. Methods In ten ventilated critically ill patients with ARDS and AKI undergoing renal- and respiratory-replacement therapy, effects of low-flow CO2 removal on respiratory acidosis compensation were tested by using a hollow-fiber gas exchanger added to the renal-replacement circuit. This was an observational study on safety, CO2-removal capacity, effects on pH, ventilator settings, and hemodynamics. Results CO2 elimination in the low-flow circuit was safe and was well tolerated by all patients. After 4 hours of treatment, a mean reduction of 17.3 mm Hg (−28.1%) pCO2 was observed, in line with an increase in pH. In hemodynamically instable patients, low-flow CO2 elimination was paralleled by hemodynamic improvement, with an average reduction of vasopressors of 65% in five of six catecholamine-dependent patients during the first 24 hours. Conclusions Because no further catheters are needed, besides those for renal replacement, the implementation of a hollow-fiber gas exchanger in a renal circuit could be an attractive therapeutic tool with only a little additional trauma for patients with mild to moderate ARDS undergoing invasive ventilation with concomitant respiratory acidosis, as long as no severe oxygenation defects indicate ECMO therapy. PMID:23883472

  9. Acute peripheral polyneuropathy with multiorgan failure: a diagnostic dilemma

    PubMed Central

    Hussain, Kosar; Abubaker, Jawed; Ahmad Dar, Javeed; Ahmed, Raees

    2014-01-01

    We describe the case of a young man who presented with abdominal pain, vomiting and acute symmetric peripheral polyneuropathy. He was noted to have high anion gap metabolic acidosis with high lactate levels and persistently high arterial and venous pO2 values. The cerebrospinal fluid was acellular with a high protein and the nerve conduction study was consistent with axonal sensorimotor neuropathy. His clinical condition deteriorated rapidly despite full supportive care and he subsequently died of multiorgan failure. An extensive workup for various infectious, autoimmune and other possible aetiologies was carried out to identify the underlying cause for his fulminant illness. All diagnostic workup was non-conclusive except for a significantly elevated serum aluminium level. We have discussed the possibility of aluminium phosphide poisoning in view of the clinical presentation. PMID:24899008

  10. The Acute Effects of Simple Sugar Ingestion on Appetite, Gut-Derived Hormone Response, and Metabolic Markers in Men

    PubMed Central

    Yau, Adora M. W.; McLaughlin, John; Gilmore, William; Maughan, Ronald J.; Evans, Gethin H.

    2017-01-01

    This pilot study aimed to investigate the effect of simple sugar ingestion, in amounts typical of common ingestion, on appetite and the gut-derived hormone response. Seven healthy men ingested water (W) and equicaloric solutions containing 39.6 g glucose monohydrate (G), 36 g fructose (F), 36 g sucrose (S), and 19.8 g glucose monohydrate + 18 g fructose (C), in a randomised order. Serum concentrations of ghrelin, glucose dependent insulinotropic polypeptide (GIP), glucagon like peptide-1 (GLP-1), insulin, lactate, triglycerides, non-esterified fatty acids (NEFA), and d-3 hydroxybutyrate, were measured for 60 min. Appetite was measured using visual analogue scales (VAS). The ingestion of F and S resulted in a lower GIP incremental area under the curve (iAUC) compared to the ingestion of G (p < 0.05). No differences in the iAUC for GLP-1 or ghrelin were present between the trials, nor for insulin between the sugars. No differences in appetite ratings or hepatic metabolism measures were found, except for lactate, which was greater following the ingestion of F, S, and C, when compared to W and G (p < 0.05). The acute ingestion of typical amounts of fructose, in a variety of forms, results in marked differences in circulating GIP and lactate concentration, but no differences in appetite ratings, triglyceride concentration, indicative lipolysis, or NEFA metabolism, when compared to glucose. PMID:28216550

  11. Endocrine and metabolic aspects of the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

    SciTech Connect

    Gorski, J.R.

    1988-01-01

    Toxic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were characterized in male Sprague-Dawley rats in order to elucidate the mechanism of acute toxicity of this potent halogenated hydrocarbon. Studies in TCDD-treated, pair-fed control and ad libitum-fed control rates, as well as in thyroidectomized, adrenalectomized and hypophysectomized, revealed differential hormonal, toxicologic and histophathologic responses suggesting that these manifestations of TCDD exposure are the results of an insult to intermediary metabolism. Tissue specific alterations in de novo fatty acid synthesis were directly related to differential changes observed in thyroid hormone homeostasis. The increased hepatic de novo fatty acid synthesis provided a likely mechanism for the documented fact that TCDD-treated rats lose more body weight than corresponding pair-fed controls because de novo fatty acid synthesis represents an energy inefficient metabolic process. Experiments in adrenalectomized and hypophysectomized rats led to the hypothesis that severe hypoglycemia due to inhibition of gluconeogenesis is the cause of TCDD-induced death. A subsequent characterization of gluconeogenesis in TCDD-treated rats confirmed this hypothesis.

  12. Metabolic aspects of acute cerebral hypoxia during extracorporeal circulation and their modification induced by acetyl-carnitine treatment.

    PubMed

    Corbucci, G G; Menichetti, A; Cogliatti, A; Nicoli, P; Arduini, A; Damonti, W; Marchionni, A; Calvani, M

    1992-01-01

    Following their previous research experiences in human tissue hypoxia, in the present study the authors. investigated the metabolic effects of acute brain hypoxia in a group of patients in course of extracorporeal circulation for aorto-pulmonary bypass. One hundred subjects were treated, half with a placebo and half with acetyl-carnitine to evaluate the effects of oxidative stress in some brain plasmatic metabolites and to verify the effect of acetyl-carnitine on the tissue energy capacity. The levels of lactate, pyruvate, succinate and fumarate showed a significant imbalance due to hypoxia, while the acetyl-carnitine treatment confined the metabolic gradients within physiological limits. This means that during the course of extracorporeal circulation brain hypoxia plays a pathological role assuming the typical picture of cellular oxidative damage and the acetyl-carnitine antagonizes these deleterious effects of hypoxia by a protective mechanism on the energy processes and then on the cellular enzymic activities. In this regard, the d-tyrosine levels, considered as a proteolytic index, confirm the action of acetyl-carnitine on the cell morpho-functional integrity.

  13. Integrating metabolic performance, thermal tolerance, and plasticity enables for more accurate predictions on species vulnerability to acute and chronic effects of global warming.

    PubMed

    Magozzi, Sarah; Calosi, Piero

    2015-01-01

    Predicting species vulnerability to global warming requires a comprehensive, mechanistic understanding of sublethal and lethal thermal tolerances. To date, however, most studies investigating species physiological responses to increasing temperature have focused on the underlying physiological traits of either acute or chronic tolerance in isolation. Here we propose an integrative, synthetic approach including the investigation of multiple physiological traits (metabolic performance and thermal tolerance), and their plasticity, to provide more accurate and balanced predictions on species and assemblage vulnerability to both acute and chronic effects of global warming. We applied this approach to more accurately elucidate relative species vulnerability to warming within an assemblage of six caridean prawns occurring in the same geographic, hence macroclimatic, region, but living in different thermal habitats. Prawns were exposed to four incubation temperatures (10, 15, 20 and 25 °C) for 7 days, their metabolic rates and upper thermal limits were measured, and plasticity was calculated according to the concept of Reaction Norms, as well as Q10 for metabolism. Compared to species occupying narrower/more stable thermal niches, species inhabiting broader/more variable thermal environments (including the invasive Palaemon macrodactylus) are likely to be less vulnerable to extreme acute thermal events as a result of their higher upper thermal limits. Nevertheless, they may be at greater risk from chronic exposure to warming due to the greater metabolic costs they incur. Indeed, a trade-off between acute and chronic tolerance was apparent in the assemblage investigated. However, the invasive species P. macrodactylus represents an exception to this pattern, showing elevated thermal limits and plasticity of these limits, as well as a high metabolic control. In general, integrating multiple proxies for species physiological acute and chronic responses to increasing

  14. Changes in metabolic profiles during acute kidney injury and recovery following ischemia/reperfusion.

    PubMed

    Wei, Qingqing; Xiao, Xiao; Fogle, Paul; Dong, Zheng

    2014-01-01

    Changes of metabolism have been implicated in renal ischemia/reperfusion injury (IRI). However, a global analysis of the metabolic changes in renal IRI is lacking and the association of the changes with ischemic kidney injury and subsequent recovery are unclear. In this study, mice were subjected to 25 minutes of bilateral renal IRI followed by 2 hours to 7 days of reperfusion. Kidney injury and subsequent recovery was verified by serum creatinine and blood urea nitrogen measurements. The metabolome of plasma, kidney cortex, and medulla were profiled by the newly developed global metabolomics analysis. Renal IRI induced overall changes of the metabolome in plasma and kidney tissues. The changes started in renal cortex, followed by medulla and plasma. In addition, we identified specific metabolites that may contribute to early renal injury response, perturbed energy metabolism, impaired purine metabolism, impacted osmotic regulation and the induction of inflammation. Some metabolites, such as 3-indoxyl sulfate, were induced at the earliest time point of renal IRI, suggesting the potential of being used as diagnostic biomarkers. There was a notable switch of energy source from glucose to lipids, implicating the importance of appropriate nutrition supply during treatment. In addition, we detected the depressed polyols for osmotic regulation which may contribute to the loss of kidney function. Several pathways involved in inflammation regulation were also induced. Finally, there was a late induction of prostaglandins, suggesting their possible involvement in kidney recovery. In conclusion, this study demonstrates significant changes of metabolome kidney tissues and plasma in renal IRI. The changes in specific metabolites are associated with and may contribute to early injury, shift of energy source, inflammation, and late phase kidney recovery.

  15. Oxygen-inducible glutamate oxaloacetate transaminase as protective switch transforming neurotoxic glutamate to metabolic fuel during acute ischemic stroke.

    PubMed

    Rink, Cameron; Gnyawali, Surya; Peterson, Laura; Khanna, Savita

    2011-05-15

    This work rests on our previous report (J Cereb Blood Flow Metab 30: 1275-1287, 2010) recognizing that glutamate (Glu) oxaloacetate transaminase (GOT) is induced when brain tissue hypoxia is corrected during acute ischemic stroke (AIS). GOT can metabolize Glu into tricarboxylic acid cycle intermediates and may therefore be useful to harness excess neurotoxic extracellular Glu during AIS as a metabolic substrate. We report that in cultured neural cells challenged with hypoglycemia, extracellular Glu can support cell survival as long as there is sufficient oxygenation. This effect is abrogated by GOT knockdown. In a rodent model of AIS, supplemental oxygen (100% O(2) inhaled) during ischemia significantly increased GOT expression and activity in the stroke-affected brain tissue and prevented loss of ATP. Biochemical analyses and in vivo magnetic resonance spectroscopy during stroke demonstrated that such elevated GOT decreased Glu levels at the stroke-affected site. In vivo lentiviral gene delivery of GOT minimized lesion volume, whereas GOT knockdown worsened stroke outcomes. Thus, brain tissue GOT emerges as a novel target in managing stroke outcomes. This work demonstrates that correction of hypoxia during AIS can help clear extracellular neurotoxic Glu by enabling utilization of this amino acid as a metabolic fuel to support survival of the hypoglycemic brain tissue. Strategies to mitigate extracellular Glu-mediated neurodegeneration via blocking receptor-mediated excitotoxicity have failed in clinical trials. We introduce the concept that under hypoglycemic conditions extracellular Glu can be transformed from a neurotoxin to a survival factor by GOT, provided there is sufficient oxygen to sustain cellular respiration.

  16. [Metabolic emergencies in critically ill cancer patients].

    PubMed

    Namendys-Silva, Silvio A; Hernández-Garay, Marisol; García-Guillén, Francisco J; Correa-García, Paulina; Herrera Gómez, Angel; Meneses-García, Abelardo

    2013-11-01

    Severe metabolic alterations frequently occur in critically ill cancer patients; hypercalcemia, hypocalcemia, hyponatremia, tumor lysis syndrome, metabolic complications of renal failure and lactic acidosis. Cancer patients with metabolic emergencies should be treated in a medical oncology department or an intensive care unit. Most metabolic emergencies can be treated properly when they are identified early. The clinician should consider that the prognosis of critically ill cancer patients depends on their primary disease, comorbidities and organ failure.

  17. Paradoxical Effect of Hyperoncotic Albumin in Acutely Burned Children

    DTIC Science & Technology

    1981-01-01

    lob (gnil respiratory acidosis : but within a few hours, she suffered a I 12 2.880 1,8) 1(0.0 cardiac arrest and (tied. Acute tubular necrosis and...only minimally, and the acidosis er- stitial pulmonary edema were found at autopsy. sisted. Thirty-six hours postburn, the patient suffered the first...urea fluids and protein as fluid infusion proceeds (1). .4 nitrogen 48 mg/di. The hyperkalemia was treated with glucose, Certainly, the most

  18. Secondary hypoxia exacerbates acute disruptions of energy metabolism in rats resulting from fluid percussion injury.

    PubMed

    Bauman, Richard A; Widholm, John; Long, Joseph B

    2005-05-07

    The purpose of these experiments was to determine whether secondary hypoxia exacerbates the metabolic consequences of fluid percussion injury (FPI). In Experiment I, rats were trained to press a lever for their entire daily ration of food at any time during a 12-h light/dark cycle and run in an activity wheel. After food intake and body weight stabilized, rats were surgically prepared, assigned to one of four groups [FPI+Hypoxia (IH), FPI+Normoxia (IN), Sham Injury+Hypoxia (SH), Sham Injury+Normoxia (SN)] and, after recovery from surgery, anesthetized with halothane delivered by a 21% O2 source. Immediately after injury or sham injury, the O2 source was switched to 13% for rats in Groups IH and SH for 30 min. Post-traumatic hypoxemia exacerbated the ensuing FPI-induced reductions of food intake and body weight, but did not change FPI-induced reduction in wheel running. In Experiment II, rats were assigned to one of three groups (SH, IN, or IH) and subjected to sham injury and 13% O2 or FPI and either 13 or 21% O2. Immediately after 30 min of hypoxia or normoxia, rats were confined to metabolism cages that were used to quantify rates of oxygen consumption (VO2), carbon dioxide production (VCO2), and heat production (H). Post-traumatic hypoxia exacerbated the FPI-induced increases in VO2, VCO2, and H. The results of Experiments I and II provide convergent confirmation that secondary hypoxemia exacerbates the FPI-induced hypermetabolic state in rats and therefore might significantly exacerbate the brain injury-induced disruptions of energy metabolism in humans.

  19. Plasmodium berghei: lactic acidosis and hypoglycaemia in a rodent model of severe malaria; effects of glucose, quinine, and dichloroacetate.

    PubMed

    Holloway, P A; Krishna, S; White, N J

    1991-02-01

    Fulminant malaria infections are characterised by hypoglycaemia and potentially lethal lactic acidosis. In young adult Wistar rats (n = 26) infected with Plasmodium berghei (ANKA strain), hyperparasitaemia (greater than 50%), anaemia (PCV 19.6 +/- 5.3%; mean +/- SD) hypoglycaemia (1.04 +/- 0.74 mmol/litre), hyperlactataemia (13.2 +/- 2.20 mmol/litre), hyperpyruvicaemia (0.51 +/- 0.12 mmol/litre) and metabolic acidosis (arterial pH 6.96 +/- 0.11) developed after approximately 14 days of infection. Hypoglycaemia was associated with appropriate suppression of plasma insulin concentrations. In a second series of experiments the metabolic effects of treatment with glucose (500 mg/kg/hr), quinine (5 mg/kg bolus followed by 10 mg/kg over 1 hr) and a potent activator of pyruvate dehydrogenase, dichloroacetate (300 mg/kg) were studied over a 1-hr period. In control animals quinine had no measurable effects, but dichloroacetate significantly reduced arterial blood lactate (74%) and pyruvate (80%). In infected animals, glucose infusion attenuated the rise in lactate (38% compared with 82%; P less than 0.01) but quinine had no additional metabolic effects. Dichloroacetate further attenuated the rise in lactate (14%; P less than 0.01).

  20. Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity

    PubMed Central

    Sun, Jinchun; Slavov, Svetoslav; Schnackenberg, Laura K.; Ando, Yosuke; Greenhaw, James; Yang, Xi; Salminen, William; Mendrick, Donna L.; Beger, Richard

    2014-01-01

    It has been estimated that 10% of acute liver failure is due to “idiosyncratic hepatotoxicity”. The inability to identify such compounds with classical preclinical markers of hepatotoxicity has driven the need to discover a mechanism-based biomarker panel for hepatotoxicity. Seven compounds were included in this study: two overt hepatotoxicants (acetaminophen and carbon tetrachloride), two idiosyncratic hepatotoxicants (felbamate and dantrolene), and three non-hepatotoxicants (meloxicam, penicillin and metformin). Male Sprague–Dawley rats were orally gavaged with a single dose of vehicle, low dose or high dose of the compounds. At 6 h and 24 h post-dosing, blood was collected for metabolomics and clinical chemistry analyses, while organs were collected for histopathology analysis. Forty-one metabolites from previous hepatotoxicity studies were semi-quantified and were used to build models to predict hepatotoxicity. The selected metabolites were involved in various pathways, which have been noted to be linked to the underlying mechanisms of hepatotoxicity. PLS models based on all 41 metabolite or smaller subsets of 6 (6 h), 7 (24 h) and 20 (6 h and 24 h) metabolites resulted in models with an accuracy of at least 97.4% for the hold-out test set and 100% for training sets. When applied to the external test sets, the PLS models predicted that 1 of 9 rats at both 6 h and 24 h treated with idiosyncratic liver toxicants was exposed to a hepatotoxic chemical. In conclusion, the biomarker panel might provide information that along with other endpoint data (e.g., transcriptomics and proteomics) may diagnose acute and idiosyncratic hepatotoxicity in a clinical setting. PMID:25379137

  1. Disrupted Nitric Oxide Metabolism from Type II Diabetes and Acute Exposure to Particulate Air Pollution.

    PubMed

    Pettit, Ashley P; Kipen, Howard; Laumbach, Robert; Ohman-Strickland, Pamela; Kelly-McNeill, Kathleen; Cepeda, Clarimel; Fan, Zhi-Hua; Amorosa, Louis; Lubitz, Sara; Schneider, Stephen; Gow, Andrew

    2015-01-01

    Type II diabetes is an established cause of vascular impairment. Particulate air pollution is known to exacerbate cardiovascular and respiratory conditions, particularly in susceptible populations. This study set out to determine the impact of exposure to traffic pollution, with and without particle filtration, on vascular endothelial function in Type II diabetes. Endothelial production of nitric oxide (NO) has previously been linked to vascular health. Reactive hyperemia induces a significant increase in plasma nitrite, the proximal metabolite of NO, in healthy subjects, while diabetics have a lower and more variable level of response. Twenty type II diabetics and 20 controls (ages 46-70 years) were taken on a 1.5 hr roadway traffic air pollution exposure as passengers. We analyzed plasma nitrite, as a measure of vascular function, using forearm ischemia to elicit a reactive hyperemic response before and after exposure to one ride with and one without filtration of the particle components of pollution. Control subjects displayed a significant increase in plasma nitrite levels during reactive hyperemia. This response was no longer present following exposure to traffic air pollution, but did not vary with whether or not the particle phase was filtered out. Diabetics did not display an increase in nitrite levels following reactive hyperemia. This response was not altered following pollution exposure. These data suggest that components of acute traffic pollution exposure diminish vascular reactivity in non-diabetic individuals. It also confirms that type II diabetics have a preexisting diminished ability to appropriately respond to a vascular challenge, and that traffic pollution exposure does not cause a further measureable acute change in plasma nitrite levels in Type II diabetics.

  2. Metabolic and endocrine consequences of acute suppression of FFAs by acipimox in polycystic ovary syndrome.

    PubMed

    Ciampelli, M; Muzj, G; Leoni, F; Romualdi, D; Belosi, C; Cento, R M; Lanzone, A

    2001-11-01

    To evaluate the effects of acute lowering of FFAs on glucose-induced insulin secretion and GH response to GHRH in polycystic ovary syndrome (PCOS), 27 PCOS subjects (11 lean and 16 obese) and 17 body mass index-matched controls (8 lean and 9 obese) were investigated. Patients underwent an oral glucose tolerance test and a GHRH test before and after administration of the antilipolytic drug acipimox (250 mg orally 3 h and 1 h before the starting of the tests). Blood samples were collected for 2 h after GHRH bolus and for 4 h after the oral glucose tolerance test. Serum concentrations of GH, insulin, glucose, and c-peptide were assayed in each sample, and the results were expressed as area under the curve (AUC). No significant differences were found as to glucose, insulin, and c-peptide AUC before and after acute FFA plasma reduction in any of the investigated groups. Basally, lower GH-AUC was found in lean PCOS compared with body mass index-matched controls and in obese vs. lean controls; no significant differences were found as to the same variable between the two obese groups. The acipimox induced FFA suppression elicited in the four groups a sustained increase in the GH response to its trophic hormone; indeed, the GH-AUC nearly doubled with respect to basal evaluation in all the studied groups. However, the antilipolytic drug was not able to abolish the differences found between lean groups in basal conditions. In conclusion, the presented data confirm that FFAs have a main role in regulating GH secretion at the pituitary level; however, it does not seem that they could explain the GH as well as insulin dysfunction of PCOS.

  3. Disrupted Nitric Oxide Metabolism from Type II Diabetes and Acute Exposure to Particulate Air Pollution

    PubMed Central

    Pettit, Ashley P.; Kipen, Howard; Laumbach, Robert; Ohman-Strickland, Pamela; Kelly-McNeill, Kathleen; Cepeda, Clarimel; Fan, Zhi-Hua; Amorosa, Louis; Lubitz, Sara; Schneider, Stephen; Gow, Andrew

    2015-01-01

    Type II diabetes is an established cause of vascular impairment. Particulate air pollution is known to exacerbate cardiovascular and respiratory conditions, particularly in susceptible populations. This study set out to determine the impact of exposure to traffic pollution, with and without particle filtration, on vascular endothelial function in Type II diabetes. Endothelial production of nitric oxide (NO) has previously been linked to vascular health. Reactive hyperemia induces a significant increase in plasma nitrite, the proximal metabolite of NO, in healthy subjects, while diabetics have a lower and more variable level of response. Twenty type II diabetics and 20 controls (ages 46–70 years) were taken on a 1.5hr roadway traffic air pollution exposure as passengers. We analyzed plasma nitrite, as a measure of vascular function, using forearm ischemia to elicit a reactive hyperemic response before and after exposure to one ride with and one without filtration of the particle components of pollution. Control subjects displayed a significant increase in plasma nitrite levels during reactive hyperemia. This response was no longer present following exposure to traffic air pollution, but did not vary with whether or not the particle phase was filtered out. Diabetics did not display an increase in nitrite levels following reactive hyperemia. This response was not altered following pollution exposure. These data suggest that components of acute traffic pollution exposure diminish vascular reactivity in non-diabetic individuals. It also confirms that type II diabetics have a preexisting diminished ability to appropriately respond to a vascular challenge, and that traffic pollution exposure does not cause a further measureable acute change in plasma nitrite levels in Type II diabetics. PMID:26656561

  4. Exaggerated Acute Lung Injury and Impaired Antibacterial Defenses During Staphylococcus aureus Infection in Rats with the Metabolic Syndrome

    PubMed Central

    Feng, Xiaomei; Maze, Mervyn; Koch, Lauren G.; Britton, Steven L.; Hellman, Judith

    2015-01-01

    Rats with Metabolic Syndrome (MetaS) have a dysregulated immune response to the aseptic trauma of surgery. We hypothesized that rats with MetaS would have dysregulated inflammation, increased lung injury, and less effective antibacterial defenses during Staphylococcus (S.) aureus sepsis as compared to rats without MetaS. Low capacity runner (LCR; a model of MetaS) and high capacity runner (HCR) rats were challenged intravenously with S. aureus bacteria. After 48 h, inflammatory mediators and bacteria were quantified in the blood, bronchoalveolar lavage fluid (BALF), and lung homogenates. Lungs were analyzed histologically. BALF protein and lung wet-dry ratios were quantified to assess for vascular leak. Endpoints were compared in infected LCR vs HCR rats. LCR rats had higher blood and lung S. aureus counts, as well as higher levels of IL-6 in plasma, lungs and BALF, MIP-2 in plasma and lung, and IL-17A in lungs. Conversely, LCR rats had lower levels of IL-10 in plasma and lungs. Although lactate levels, and liver and renal function tests were similar between groups, LCR rats had higher BALF protein and lung wet-dry ratios, and more pronounced acute lung injury histologically. During S. aureus bacteremia, as compared with HCR rats, LCR (MetaS) rats have heightened pro-inflammatory responses, accompanied by increased acute lung injury and vascular leak. Notably, despite an augmented pro-inflammatory phenotype, LCR rats have higher bacterial levels in their blood and lungs. The MetaS state may exacerbate lung injury and vascular leak by attenuating the inflammation-resolving response, and by weakening antimicrobial defenses. PMID:25978669

  5. Exogenous Sphingosine-1-Phosphate Boosts Acclimatization in Rats Exposed to Acute Hypobaric Hypoxia: Assessment of Haematological and Metabolic Effects

    PubMed Central

    Chawla, Sonam; Rahar, Babita; Singh, Mrinalini; Bansal, Anju; Saraswat, Deepika; Saxena, Shweta

    2014-01-01

    Background The physiological challenges posed by hypobaric hypoxia warrant exploration of pharmacological entities to improve acclimatization to hypoxia. The present study investigates the preclinical efficacy of sphingosine-1-phosphate (S1P) to improve acclimatization to simulated hypobaric hypoxia. Experimental Approach Efficacy of intravenously administered S1P in improving haematological and metabolic acclimatization was evaluated in rats exposed to simulated acute hypobaric hypoxia (7620m for 6 hours) following S1P pre-treatment for three days. Major Findings Altitude exposure of the control rats caused systemic hypoxia, hypocapnia (plausible sign of hyperventilation) and respiratory alkalosis due to suboptimal renal compensation indicated by an overt alkaline pH of the mixed venous blood. This was associated with pronounced energy deficit in the hepatic tissue along with systemic oxidative stress and inflammation. S1P pre-treatment improved blood oxygen-carrying-capacity by increasing haemoglobin, haematocrit, and RBC count, probably as an outcome of hypoxia inducible factor-1α mediated erythropoiesis and renal S1P receptor 1 mediated haemoconcentation. The improved partial pressure of oxygen in the blood could further restore aerobic respiration and increase ATP content in the hepatic tissue of S1P treated animals. S1P could also protect the animals from hypoxia mediated oxidative stress and inflammation. Conclusion The study findings highlight S1P’s merits as a preconditioning agent for improving acclimatization to acute hypobaric hypoxia exposure. The results may have long term clinical application for improving physiological acclimatization of subjects venturing into high altitude for occupational or recreational purposes. PMID:24887065

  6. Association between Metabolic Syndrome and Cognitive Impairment after Acute Ischemic Stroke: A Cross-Sectional Study in a Chinese Population

    PubMed Central

    Li, Pan; Quan, Wei; Lu, Da; Wang, Yan; Zhang, Hui-Hong; Liu, Shuai; Jiang, Rong-Cai; Zhou, Yu-Ying

    2016-01-01

    Background and Objectives Metabolic syndrome (MetS), a risk factor for many vascular conditions, is associated with vascular cognitive disorders. The objective of the present study was to explore the associations of MetS and its individual components with the risks of cognitive impairment and neurological dysfunction in patients after acute stroke. Methods This cross-sectional study enrolled 840 patients ranging in age from 53 to 89 years from the Tianjin area of North China. Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination. Neuropsychiatric behavior was assessed using the Neuropsychiatric Inventory Questionnaire. Emotional state was examined according to the Hamilton Depression Rating Scale, and neuromotor function was evaluated using the National Institutes of Health Stroke Scale, Barthel index, and the Activity of Daily Living test. After overnight fasting, blood samples were obtained to measure biochemistry indicators. Results MetS and its individual components were closely correlated with MoCA score. MetS patients had high levels of inflammation and a 3.542-fold increased odds ratio (OR) for cognitive impairment [95% confidence interval (CI): 1.972–6.361]. Of the individual MetS components, central obesity (OR 3.039; 95% CI: 1.839–5.023), high fasting plasma glucose (OR 1.915; 95% CI: 1.016–3.607), and type 2 diabetes (OR 2.241; 95% CI: 1.630–3.081) were associated with an increased incidence of cognitive impairment. Consistent and significant worsening in different neurological domains was observed with greater numbers of MetS components. Conclusions MetS was associated with worse cognitive function, neuromotor dysfunction, and neuropsychological symptoms among Chinese acute stroke patients. PMID:27936074

  7. Exaggerated Acute Lung Injury and Impaired Antibacterial Defenses During Staphylococcus aureus Infection in Rats with the Metabolic Syndrome.

    PubMed

    Feng, Xiaomei; Maze, Mervyn; Koch, Lauren G; Britton, Steven L; Hellman, Judith

    2015-01-01

    Rats with Metabolic Syndrome (MetaS) have a dysregulated immune response to the aseptic trauma of surgery. We hypothesized that rats with MetaS would have dysregulated inflammation, increased lung injury, and less effective antibacterial defenses during Staphylococcus (S.) aureus sepsis as compared to rats without MetaS. Low capacity runner (LCR; a model of MetaS) and high capacity runner (HCR) rats were challenged intravenously with S. aureus bacteria. After 48 h, inflammatory mediators and bacteria were quantified in the blood, bronchoalveolar lavage fluid (BALF), and lung homogenates. Lungs were analyzed histologically. BALF protein and lung wet-dry ratios were quantified to assess for vascular leak. Endpoints were compared in infected LCR vs HCR rats. LCR rats had higher blood and lung S. aureus counts, as well as higher levels of IL-6 in plasma, lungs and BALF, MIP-2 in plasma and lung, and IL-17A in lungs. Conversely, LCR rats had lower levels of IL-10 in plasma and lungs. Although lactate levels, and liver and renal function tests were similar between groups, LCR rats had higher BALF protein and lung wet-dry ratios, and more pronounced acute lung injury histologically. During S. aureus bacteremia, as compared with HCR rats, LCR (MetaS) rats have heightened pro-inflammatory responses, accompanied by increased acute lung injury and vascular leak. Notably, despite an augmented pro-inflammatory phenotype, LCR rats have higher bacterial levels in their blood and lungs. The MetaS state may exacerbate lung injury and vascular leak by attenuating the inflammation-resolving response, and by weakening antimicrobial defenses.

  8. Pioglitazone Attenuates Acute Cocaine Toxicity in Rat Isolated Heart: Potential Protection by Metabolic Modulation

    PubMed Central

    Weinberg, Guy L.; Ripper, Richard; Bern, Sarah; Lin, Bocheng; Edelman, Lucas; DiGregorio, Guido; Piano, Mariann; Feinstein, Douglas L.

    2013-01-01

    Background The authors test whether cocaine depresses mitochondrial acylcarnitine exchange and if a drug that enhances glucose metabolism could protect against cocaine-induced cardiac dysfunction. Methods Oxygen consumption with and without cocaine was compared in rat cardiac mitochondria using either octanoylcarnitine (lipid) or pyruvate (non-lipid) substrates. Isolated hearts from rats with or without pioglitazone-supplemented diet were exposed to cocaine. Results Cocaine 0.5mM inhibited respiration supported by octanoylcarnitine (82 +/− 10.4 and 45.7 +/− 4.24 ngatomO min −1 mg −1 protein +/− SEM, for control and cocaine treatment, respectively; p < 0.02) but not pyruvate-supported respiration (281 +/− 12.5 and 267 +/− 12.7 ngatomO min −1 mg −1 protein +/− SEM; p = 0.45). Cocaine altered contractility, lusitropy, coronary resistance and lactate production in isolated heart. These effects were each blunted in pioglitazone-treated hearts. Pioglitazone diet attenuated the drop in rate-pressure product (p = 0.002), cocaine-induced diastolic dysfunction (p = 0.04) and myocardial vascular resistance (p = 0.05) compared to controls. Lactate production was higher in pretreated hearts (p = 0.008) and in ventricular myocytes cultured with pioglitazone (p = 0.0001). Conclusions Cocaine inhibited octanoylcarnitine-supported mitochondrial respiration. Pioglitazone diet significantly attenuated the effects of cocaine on isolated heart. The authors postulate that inhibition of acylcarnitine exchange could contribute to cocaine-induced cardiac dysfunction and that metabolic modulation warrants further study a potential treatment for such toxicity. PMID:21487283

  9. Can phenformin-induced lactic acidosis be prevented?

    PubMed Central

    Gale, E A; Tattersall, R B

    1976-01-01

    Although patients taking phenformin are more likely to develop lactic acidosis in the presence of renal, cardiovascular, or hepatic disease, criteria for safe use of the drug are not well established. Eight diabetics died of lactic acidosis in Nottingham in 1972-5 and all were taking phenformin in therapeutic doses. Six had attended the diabetic clinic within a month of their terminal illness. Two patients had appreciable renal impairment and should not have been given phenformin. Four had hypertension and minimal evidence of renal disease, while in two no predisposing factor was identified. There are so many contraindications to the use of phenformin that it is doubtful whether patients on the drug can be monitored adequately. We suggest that phenformin should be withdrawn from general use. PMID:974710

  10. Ethylene Glycol Poisoning: An Unusual Cause of Altered Mental Status and the Lessons Learned from Management of the Disease in the Acute Setting

    PubMed Central

    Arain, E.; Buth, A.; Kado, J.; Soubani, A.

    2016-01-01

    Ethylene glycol is found in many household products and is a common toxic ingestion. Acute ingestions present with altered sensorium and an osmolal gap. The true toxicity of ethylene glycol is mediated by its metabolites, which are responsible for the increased anion gap metabolic acidosis, renal tubular damage, and crystalluria seen later in ingestions. Early intervention is key; however, diagnosis is often delayed, especially in elderly patients presenting with altered mental status. There are several laboratory tests which can be exploited for the diagnosis, quantification of ingestion, and monitoring of treatment, including the lactate and osmolal gaps. As methods of direct measurement of ethylene glycol are often not readily available, it is important to have a high degree of suspicion based on these indirect laboratory findings. Mainstay of treatment is bicarbonate, fomepizole or ethanol, and, often, hemodialysis. A validated equation can be used to estimate necessary duration of hemodialysis, and even if direct measurements of ethylene glycol are not available, monitoring for the closure of the anion, lactate, and osmolal gaps can guide treatment. We present the case of an elderly male with altered mental status, acute kidney injury, elevated anion gap metabolic acidosis, and profound lactate and osmolal gaps. PMID:27847651

  11. Search of a solution correction of a lipidic metabolism at acute pancreatitis

    NASA Astrophysics Data System (ADS)

    Anaskin, S. G.; Vlasov, A. P.; Korniletsky, I. D.

    2017-01-01

    Following the results of a pilot study on studying of influence of an emoksipin, verapamil and a reamberin at acute pancreatitis it is possible to say that under the influence of these drugs in fabric structures of the inflamed pancreas there is a decrease in intensity of free radical processes of a lipopereokisleniye, activity of phospholipases, hypoxia phenomena. Level of antioxidant protection of fabric of body increases. In the first three days of supervision the accurate tendency to normalization of the transformed lipidic structure of fabric structures of a pancreas is revealed. At the same time these positive effects are noted in all experienced groups. It demonstrates that though pharmacological drugs are used multidirectional action (antioxidant emoksipin, an antigipoksant reamberin, inhibitor of calcium channels verapamil), they in a varying degree influence on studied pathological (membranodestruktivny, hypoxemic) processes, leading finally to reduction of their expressiveness. So, emoksipin found big ability to increase stability of membranes of pankreatotsit to pathological influence of molecular products the FLOOR, verapamil – to stopping of the activated phospholipases, reamberin – to a hypoxia. The question solution on the key (prevailing) mechanism in trigger processes of sharp pancreatitis of a definite answer has no. Undoubtedly only the fact that efficiency of antioxidant and inhibitor of calcic channels was rather higher. It suggests that free radical processes of a lipopereokisleniye and activity of fosfolipazny systems predetermine the level and nature of defeat of a cellular biomembrane of pankreatotsit already on the earliest terms of inflammatory process.

  12. Complement and contact activation in term neonates after fetal acidosis

    PubMed Central

    Sonntag, J.; Wagner, M.; Strauss, E.; Obladen, M.

    1998-01-01

    AIMS—To evaluate complement and contact activation after fetal acidosis.
METHODS—Fifteen term neonates with hypoxic-ischaemic encephalopathy after umbilical arterial pH < 7.10 were compared with 15 healthy neonates with umbilical arterial pH > 7.20. Determinations of the complement function and C1-inhibitor activity were performed as kinetic tests 22-28 hours after birth. C1q, C1-inhibitor, and factor B concentrations were determined by radial immunodiffusion and those of C3a, C5a, and factor XIIa by enzyme immunoabsorbent assay.
RESULTS—Median complement function (46 vs 73 %), C1q (4.3 vs 9.1 mg/dl), and factor B (5.2 vs 7.7 mg/dl) decreased after fetal acidosis. The activated split products C3a (260 vs 185 µg/l), C5a (5.0 vs 0.6 µg/l), and factor XIIa (3.2 vs 1.3 µg/l) increased in the neonates after fetal acidosis. No differences were found in the concentration and activity of C1-inhibitor.
CONCLUSIONS—Complement and contact activation occurred in the newborns with hypoxic-ischaemic encephalopathy. Activation of these systems generates mediators which can trigger inflammation and tissue injury.

 PMID:9577283

  13. Regulation of intracellular pH in cnidarians: response to acidosis in Anemonia viridis.

    PubMed

    Laurent, Julien; Venn, Alexander; Tambutté, Éric; Ganot, Philippe; Allemand, Denis; Tambutté, Sylvie

    2014-02-01

    The regulation of intracellular pH (pHi) is a fundamental aspect of cell physiology that has received little attention in studies of the phylum Cnidaria, which includes ecologically important sea anemones and reef-building corals. Like all organisms, cnidarians must maintain pH homeostasis to counterbalance reductions in pHi, which can arise because of changes in either intrinsic or extrinsic parameters. Corals and sea anemones face natural daily changes in internal fluids, where the extracellular pH can range from 8.9 during the day to 7.4 at night. Furthermore, cnidarians are likely to experience future CO₂-driven declines in seawater pH, a process known as ocean acidification. Here, we carried out the first mechanistic investigation to determine how cnidarian pHi regulation responds to decreases in extracellular and intracellular pH. Using the anemone Anemonia viridis, we employed confocal live cell imaging and a pH-sensitive dye to track the dynamics of pHi after intracellular acidosis induced by acute exposure to decreases in seawater pH and NH₄Cl prepulses. The investigation was conducted on cells that contained intracellular symbiotic algae (Symbiodinium sp.) and on symbiont-free endoderm cells. Experiments using inhibitors and Na⁺-free seawater indicate a potential role of Na⁺/H⁺ plasma membrane exchangers (NHEs) in mediating pHi recovery following intracellular acidosis in both cell types. We also measured the buffering capacity of cells, and obtained values between 20.8 and 43.8 mM per pH unit, which are comparable to those in other invertebrates. Our findings provide the first steps towards a better understanding of acid-base regulation in these basal metazoans, for which information on cell physiology is extremely limited.

  14. Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress

    PubMed Central

    Picard, Martin; McManus, Meagan J.; Gray, Jason D.; Nasca, Carla; Moffat, Cynthia; Kopinski, Piotr K.; Seifert, Erin L.; McEwen, Bruce S.; Wallace, Douglas C.

    2015-01-01

    The experience of psychological stress triggers neuroendocrine, inflammatory, metabolic, and transcriptional perturbations that ultimately predispose to disease. However, the subcellular determinants of this integrated, multisystemic stress response have not been defined. Central to stress adaptation is cellular energetics, involving mitochondrial energy production and oxidative stress. We therefore hypothesized that abnormal mitochondrial functions would differentially modulate the organism’s multisystemic response to psychological stress. By mutating or deleting mitochondrial genes encoded in the mtDNA [NADH dehydrogenase 6 (ND6) and cytochrome c oxidase subunit I (COI)] or nuclear DNA [adenine nucleotide translocator 1 (ANT1) and nicotinamide nucleotide transhydrogenase (NNT)], we selectively impaired mitochondrial respiratory chain function, energy exchange, and mitochondrial redox balance in mice. The resulting impact on physiological reactivity and recovery from restraint stress were then characterized. We show that mitochondrial dysfunctions altered the hypothalamic–pituitary–adrenal axis, sympathetic adrenal–medullary activation and catecholamine levels, the inflammatory cytokine IL-6, circulating metabolites, and hippocampal gene expression responses to stress. Each mitochondrial defect generated a distinct whole-body stress-response signature. These results demonstrate the role of mitochondrial energetics and redox balance as modulators of key pathophysiological perturbations previously linked to disease. This work establishes mitochondria as stress-response modulators, with implications for understanding the mechanisms of stress pathophysiology and mitochondrial diseases. PMID:26627253

  15. Acute effects of walking in forest environments on cardiovascular and metabolic parameters.

    PubMed

    Li, Qing; Otsuka, Toshiaki; Kobayashi, Maiko; Wakayama, Yoko; Inagaki, Hirofumi; Katsumata, Masao; Hirata, Yukiyo; Li, YingJi; Hirata, Kimiko; Shimizu, Takako; Suzuki, Hiroko; Kawada, Tomoyuki; Kagawa, Takahide

    2011-11-01

    We previously found that forest environments reduced stress hormones such as adrenaline and noradrenaline and showed the relaxing effect both in male and female subjects. In the present study, we investigated the effects of walking under forest environments on cardiovascular and metabolic parameters. Sixteen healthy male subjects (mean age 57.4 ± 11.6 years) were selected after obtaining informed consent. The subjects took day trips to a forest park in the suburbs of Tokyo and to an urban area of Tokyo as a control in September 2010. On both trips, they walked for 2 h in the morning and afternoon on a Sunday. Blood and urine were sampled on the morning before each trip and after each trip. Blood pressure was measured on the morning (0800) before each trip, at noon (1300), in the afternoon (1600) during each trip, and on the morning (0800) after each trip. The day trip to the forest park significantly reduced blood pressure and urinary noradrenaline and dopamine levels and significantly increased serum adiponectin and dehydroepiandrosterone sulfate (DHEA-S) levels. Walking exercise also reduced the levels of serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and urinary dopamine. Taken together, habitual walking in forest environments may lower blood pressure by reducing sympathetic nerve activity and have beneficial effects on blood adiponectin and DHEA-S levels, and habitual walking exercise may have beneficial effects on blood NT-proBNP levels.

  16. Differential gene expression and lipid metabolism in fatty liver induced by acute ethanol treatment in mice

    SciTech Connect

    Yin Huquan; Kim, Mingoo; Kim, Ju-Han; Kong, Gu; Kang, Kyung-Sun; Kim, Hyung-Lae; Yoon, Byung-IL; Lee, Mi-Ock; Lee, Byung-Hoon

    2007-09-15

    Ethanol induces cumulative liver damage including steatosis, steatohepatitis and cirrhosis. The aim of this study is to investigate the global intrahepatic gene expression profile in the mouse liver treated with ethanol. A single oral dose of 0.5 or 5 g/kg ethanol was administered to male ICR mice, and liver samples were obtained after 6, 24 and 72 h. Histopathological evaluation showed typical fatty livers in the high-dose group at 24 h. Microarray analysis identified 28 genes as being ethanol responsive (two-way ANOVA; p < 0.05), after adjustment by the Benjamini-Hochberg multiple testing correction; these genes displayed {>=} 2-fold induction or repression. The expression of genes that are known to be involved in fatty acid synthesis was examined. The transcript for lipogenic transcription factor, sterol regulatory element (SRE)-binding factor 1 (Srebf1), was upregulated by acute ethanol exposure. Of the genes known to contain SRE or SRE-like sequences and to be regulated by SRE-binding protein 1 (SREBP1), those encoding malic enzyme (Mod1), ATP-citrate lyase (Acly), fatty acid synthase (Fasn) and stearyl-CoA desaturase (Scd1) were induced by ethanol. Quantitative real-time PCR confirmed the changes in the expression levels of the selected genes. The change in the Srebf1 mRNA level correlates well with that of the SREBP1 protein expression as well as its binding to the promoters of the target genes. The present study identifies differentially expressed genes that can be applied to the biomarkers for alcohol-binge-induced fatty liver. These results support the hypothesis by which ethanol-induced steatosis in mice is mediated by the fatty acid synthetic pathway regulated by SREBP1.

  17. Nitrite Reduces Cytoplasmic Acidosis under Anoxia1

    PubMed Central

    Libourel, I.G.L.; van Bodegom, P.M.; Fricker, M.D.; Ratcliffe, R.G.

    2006-01-01

    The ameliorating effect of nitrate on the acidification of the cytoplasm during short-term anoxia was investigated in maize (Zea mays) root segments. Seedlings were grown in the presence or absence of nitrate, and changes in the cytoplasmic and vacuolar pH in response to the imposition of anoxia were measured by in vivo 31P nuclear magnetic resonance spectroscopy. Soluble ions and metabolites released to the suspending medium by the anoxic root segments were measured by high-performance liquid chromatography and 1H nuclear magnetic resonance spectroscopy, and volatile metabolites were measured by gas chromatography and gas chromatography-mass spectrometry. The beneficial effect of nitrate on cytoplasmic pH regulation under anoxia occurred despite limited metabolism of nitrate under anoxia, and modest effects on the ions and metabolites, including fermentation end products, released from the anoxic root segments. Interestingly, exposing roots grown and treated in the absence of nitrate to micromolar levels of nitrite during anoxia had a beneficial effect on the cytoplasmic pH that was comparable to the effect observed for roots grown and treated in the presence of nitrate. It is argued that nitrate itself is not directly responsible for improved pH regulation under anoxia, contrary to the usual assumption, and that nitrite rather than nitrate should be the focus for further work on the beneficial effect of nitrate on flooding tolerance. PMID:17071644

  18. Acute neuromuscular and metabolic responses to combined strength and endurance loadings: the "order effect" in recreationally endurance trained runners.

    PubMed

    Taipale, Ritva S; Schumann, Moritz; Mikkola, Jussi; Nyman, Kai; Kyröläinen, Heikki; Nummela, Ari; Häkkinen, Keijo

    2014-01-01

    The study examined the acute neuromuscular and metabolic responses and recovery (24 and 48 h) to combined strength and endurance sessions (SEs). Recreationally endurance trained men (n = 12) and women (n = 10) performed: endurance running followed immediately by a strength loading (combined endurance and strength session (ES)) and the reverse order (SE). Maximal strength (MVC), countermovement jump height (CMJ), and creatine kinase activity were measured pre-, mid-, post-loading and at 24 and 48 h of recovery. MVC and CMJ were decreased (P < 0.05) at post-ES and SE sessions in men. Only MVC decreased in ES and SE women (P < 0.05). During recovery, no order differences in MVC were observed between sessions in men, but MVC and CMJ remained decreased. During recovery in women, a delayed decrease in CMJ was observed in ES but not in SE (P < 0.01), while MVC returned to baseline at 24 h. Creatine kinase increased (P < 0.05) during both ES and SE and peaked in all groups at 24 h. The present combined ES and SE sessions induced greater neuromuscular fatigue at post in men than in women. The delayed fatigue response in ES women may be an order effect related to muscle damage.

  19. Antibiotics Increase Gut Metabolism and Antioxidant Proteins and Decrease Acute Phase Response and Necrotizing Enterocolitis in Preterm Neonates

    PubMed Central

    Jiang, Pingping; Jensen, Michael Ladegaard; Cilieborg, Malene Skovsted; Thymann, Thomas; Wan, Jennifer Man-Fan; Sit, Wai-Hung; Tipoe, George L.; Sangild, Per Torp

    2012-01-01

    Background The appropriate use of antibiotics for preterm infants, which are highly susceptible to develop necrotizing enterocolitis (NEC), is not clear. While antibiotic therapy is commonly used in neonates with NEC symptoms and sepsis, it remains unknown how antibiotics may affect the intestine and NEC sensitivity. We hypothesized that broad-spectrum antibiotics, given immediately after preterm birth, would reduce NEC sensitivity and support intestinal protective mechanisms. Methodology/Principal Findings Preterm pigs were treated with antibiotics for 5 d (oral and systemic doses of gentamycin, ampicillin and metrodinazole; AB group) and compared with untreated pigs. Only the untreated pigs showed evidence of NEC lesions and reduced digestive function, as indicated by lowered villus height and activity of brush border enzymes. In addition, 53 intestinal and 22 plasma proteins differed in expression between AB and untreated pigs. AB treatment increased the abundance of intestinal proteins related to carbohydrate and protein metabolism, actin filaments, iron homeostasis and antioxidants. Further, heat shock proteins and the complement system were affected suggesting that all these proteins were involved in the colonization-dependent early onset of NEC. In plasma, acute phase proteins (haptoglobin, complement proteins) decreased, while albumin, cleaved C3, ficolin and transferrin increased. Conclusions/Significance Depressed bacterial colonization following AB treatment increases mucosal integrity and reduces bacteria-associated inflammatory responses in preterm neonates. The plasma proteins C3, ficolin, and transferrin are potential biomarkers of the colonization-dependent NEC progression in preterm neonates. PMID:23028687

  20. Selective alterations in cerebral metabolism within the mesocorticolimbic dopaminergic system produced by acute cocaine administration in rats

    SciTech Connect

    Porrino, L.J.; Domer, F.R.; Crane, A.M.; Sokoloff, L.

    1988-05-01

    The 2-(/sup 14/C)deoxyglucose method was used to examine the effects of acute intravenous administration of cocaine on local cerebral glucose utilization in rats. These effects were correlated with the effects of cocaine on locomotor activity assessed simultaneously in the same animals. At the lowest dose of cocaine, 0.5 mg/kg (1.47 mumol/kg), alterations in glucose utilization were restricted to the medial prefrontal cortex and nucleus accumbens. Metabolic activity at 1.0 mg/kg (2.9 mumol/kg) was altered in these structures, but in the substantia nigra reticulata and lateral habenula as well. The selectivity of cocaine's effects at low doses demonstrates the particular sensitivity of these structures to cocaine's actions in the brain. In contrast, 5.0 mg/kg (14.7 mumol/kg) produced widespread changes in glucose utilization, particularly in the extrapyramidal system. Only this dose significantly increased locomotor activity above levels in vehicle-treated controls. Rates of glucose utilization were positively correlated with locomotor activity in the globus pallidus, substantia nigra reticulata, and subthalamic nucleus, and negatively correlated in the lateral habenula.

  1. Gene-gene interactions in the folate metabolic pathway influence the risk for acute lymphoblastic leukemia in children.

    PubMed

    Petra, Bohanec Grabar; Janez, Jazbec; Vita, Dolzan

    2007-04-01

    Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Genetic polymorphisms in the folate metabolic pathway may contribute to the susceptibility to childhood ALL because they affect the DNA synthesis, methylation and repair. We analysed common genetic polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), methionine synthase (MS) and methionine synthase reductase (MTRR) in 68 children with ALL and 258 healthy controls to investigate their influence on the risk for ALL. No significant differences in frequencies of separate polymorphisms were observed between both groups. Combined MTHFR 677CT/TT and MS 2756AG/GG genotypes showed a nonsignificant tendency to reduce the risk for ALL 2.24-fold (CI: 0.191 - 1.037, P: 0.061). The risk was significantly reduced in carriers of combined MTHFR 677CT/TT, MS 2756AG/GG and MTRR 66AG/GG genotypes (OR: 0.312; CI: 0.107 - 0.907; P: 0.032). Our results suggest that gene - gene interactions that may decrease the methylation capacity might have a protective effect on the risk for childhood ALL.

  2. Breeding status affects the hormonal and metabolic response to acute stress in a long-lived seabird, the king penguin.

    PubMed

    Viblanc, Vincent A; Gineste, Benoit; Robin, Jean-Patrice; Groscolas, René

    2016-09-15

    Stress responses are suggested to physiologically underlie parental decisions promoting the redirection of behaviour away from offspring care when survival is jeopardized (e.g., when facing a predator). Besides this classical view, the "brood-value hypothesis" suggests that parents' stress responses may be adaptively attenuated to increase fitness, ensuring continued breeding when the relative value of the brood is high. Here, we test the brood-value hypothesis in breeding king penguins (Aptenodytes patagonicus), long-lived seabirds for which the energy commitment to reproduction is high. We subjected birds at different breeding stages (courtship, incubation and chick brooding) to an acute 30-min capture stress and measured their hormonal (corticosterone, CORT) and metabolic (non-esterified fatty acid, NEFA) responses to stress. We found that CORT responses were markedly attenuated in chick-brooding birds when compared to earlier stages of breeding (courtship and incubation). In addition, NEFA responses appeared to be rapidly attenuated in incubating and brooding birds, but a progressive increase in NEFA plasma levels in courting birds suggested energy mobilization to deal with the threat. Our results support the idea that stress responses may constitute an important life-history mechanism mediating parental reproductive decisions in relation to their expected fitness outcome.

  3. Effect of acupuncture on rats with acute gouty arthritis inflammation: a metabonomic method for profiling of both urine and plasma metabolic perturbation.

    PubMed

    Wen, Si-Lan; Liu, Yu-Jie; Yin, Hai-Lin; Zhang, Liu; Xiao, Jin; Zhu, Hong-Yuan; Xue, Jin-Tao; Ye, Li-Ming

    2011-01-01

    Acute gouty arthritis is a common inflammation model with multiple pathogenic mechanisms seen in clinical practice, for which acupuncture may potentially be an alternative therapy. To investigate the effect of acupuncture on acute gouty arthritis and search for its mechanism, a metabonomic method was developed in this investigation. Acute gouty arthritis model rats were induced by monosodium urate (MSU) crystals. The urine and plasma samples were collected at several time points and the endogenous metabolites were analyzed by an ultra-performance liquid chromatography coupled with a mass spectrometry (UPLC-MS). Data were analyzed using principal components analysis (PCA) and partial least squares (PLS) analysis to compare metabolic profiles of MSU crystal-induced acute gouty arthritis rats with MSU crystal-induced acute gouty arthritis, treated with acupuncture rats. The results showed that acupuncture could restore the metabolite network that disturbed by MSU administration. Our study indicates that UPLC-MS-based metabonomics can be used as a potential tool for the investigation of biological effect of acupuncture on acute gouty arthritis.

  4. Glyphosate Poisoning with Acute Pulmonary Edema

    PubMed Central

    Thakur, Darshana Sudip; Khot, Rajashree; Joshi, P. P.; Pandharipande, Madhuri; Nagpure, Keshav

    2014-01-01

    GlySH-surfactant herbicide (GlySH), one of the most commonly used herbicides worldwide, has been considered as minimally toxic to humans. However, clinical toxicologists occasionally encounter cases of severe systemic toxicity. The US Environmental Protection Agency (EPA) states that ‘GlySH’ is of relatively low oral and acute dermal toxicity. It does not have anticholinesterase effect and no organophosphate-like central nervous system (CNS) effects. The clinical features range from skin and throat irritation to hypotension and death. Severe GlySH-surfactant poisoning is manifested by gastroenteritis, respiratory disturbances, altered mental status, hypotension refractory to the treatment, renal failure, and shock.[1] GlySH intoxication has a case fatality rate 3.2–29.3%. Pulmonary toxicity and renal toxicity seem to be responsible for mortality. Metabolic acidosis, abnormal chest X-ray, arrhythmias, and elevated serum creatinine levels are useful prognostic factors for predicting GlySH mortality.[2] There is no antidote and the mainstay of treatment for systemic toxicity is decontamination and aggressive supportive therapy. We report a case of acute pulmonary edema, which is a rare but severe manifestation of oral GlySH poisoning, where patient survived with aggressive supportive therapy. PMID:25948977

  5. The clinical experience of acute cyanide poisoning.

    PubMed

    Yen, D; Tsai, J; Wang, L M; Kao, W F; Hu, S C; Lee, C H; Deng, J F

    1995-09-01

    The authors reviewed the clinical manifestations, complications, and the prognosis affected by Lilly Cyanide Antidote in 21 victims of acute cyanide poisoning over a 10-year period. The clinical signs and symptoms in cyanide poisoning are variable. Among 21 cases, loss of consciousness (15), metabolic acidosis (14), and cardiopulmonary failure (9) were the three leading manifestations of cyanide intoxication. Anoxic encephalopathy (6) was not uncommon in the severely intoxicated victims. Diabetes insipidus (1) or clinical signs and symptoms mimicking diabetes insipidus (3) may be an ominous sign to encephalopathy victims. The major cause of fatal cyanide poisoning is the intentional ingestion of cyanide compounds as part of a suicide attempt. Decrease of arteriovenous difference of O2 partial pressure may be a clue for the suspicion of cyanide intoxication. Although the authors cannot show a statistically significant difference (P = .47) for the Lilly cyanide antidote kit in terms of improving the survival rate for victims of cyanide poisoning, the antidote kit was always mandatory in our study in the cases of severely intoxicated victims who survived. Early diagnosis, prompt, intensive therapy with antidote, and supportive care are still the golden rules for the treatment of acute cyanide poisoning, whether in the ED or on the scene.

  6. Influences of methamphetamine-induced acute intoxication on urinary and plasma metabolic profiles in the rat.

    PubMed

    Shima, Noriaki; Miyawaki, Izuru; Bando, Kiyoko; Horie, Hiroshi; Zaitsu, Kei; Katagi, Munehiro; Bamba, Takeshi; Tsuchihashi, Hitoshi; Fukusaki, Eiichiro

    2011-09-05

    Methamphetamine (MA) is an illicit psychostimulant, and its abuse has become an international public health problem. MA intoxication can cause life-threatening hyperthermia, renal and liver failure, cardiac arrhythmias, and neurological damage. To investigate the relationship between the underlying mechanism of such intoxication and metabolic networks, mass spectrometry-based metabolomics experiments were performed on Sprague-Dawley rats treated with MA at 10mgkg(-1)h(-1) for 4h. Using a combination of gas chromatography-time-of-flight mass spectrometry and capillary electrophoresis-tandem mass spectrometry, global and targeted analyses were performed on biological samples collected during 0-24 and 72-96h (for urine), and at 24 and 96h (for plasma) after the last drug administration. Body temperature and plasma biochemical parameters were also measured to detect abnormal reactions in neuronal and other several tissues. 5-Oxoproline, saccharic acid, uracil, 3-hydroxybutyrate (3-HB), adipic acid, glucose, glucose 6-phosphate, fructose 1,6-bisphosphate, and tricarboxylic acid (TCA) cycle intermediates, such as fumarate, were proposed as potential biomarkers related to MA-induced intoxications. In particular, the observation of decreased TCA cycle intermediates and 3-HB and increased glucose suggested that high doses of MA inhibit biogenic energy production by glycolysis, oxidative phosphorylation via the TCA cycle, and the beta-oxidation of fatty acids. These results may provide not only a clue to clarify the underlying mechanism of diverse intoxication effects, but also biological fluid-based diagnostic and forensic methods with which to objectively demonstrate intoxication without directly determining the drug.

  7. Acute metabolic responses to a 24-h ultra-marathon race in male amateur runners.

    PubMed

    Waśkiewicz, Zbigniew; Kłapcińska, Barbara; Sadowska-Krępa, Ewa; Czuba, Milosz; Kempa, Katarzyna; Kimsa, Elżbieta; Gerasimuk, Dagmara

    2012-05-01

    The study was conducted to evaluate the metabolic responses to a 24 h ultra-endurance race in male runners. Paired venous and capillary blood samples from 14 athletes (mean age 43.0 ± 10.8 years, body weight 64.3 ± 7.2 kg, VO(2max) 57.8 ± 6.1 ml kg(-1) min(-1)), taken 3 h before the run, after completing the marathon distance (42.195 km), after 12 h, and at the finish of the race, were analyzed for blood morphology, acid-base balance and electrolytes, lipid profile, interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and serum enzyme activities. Mean distance covered during the race was 168.5 ± 23.1 km (range 125.2-218.5 km). Prolonged ultra-endurance exercise triggered immune and inflammatory responses, as evidenced by a twofold increase in total leukocyte count with neutrophils and monocytes as main contributors, nearly 30-fold increase in serum IL-6 and over 20-fold rise in hsCRP. A progressive exponential increase in mean creatine kinase activity up to the level 70-fold higher than the respective pre-race value, a several fold rise in serum activities of aspartate aminotransferase and alanine aminotransferase, and a fairly stable serum γ-glutamyl transferase level, were indicative of muscle, but not of liver damage. With duration of exercise, there was a progressive development of hyperventilation-induced hypocapnic alkalosis, and a marked alteration in substrate utilization towards fat oxidation to maintain blood glucose homeostasis. The results of this study may imply that progressive decline in partial CO(2) pressure (hypocapnia) that develops during prolonged exercise may contribute to increased interleukin-6 production.

  8. Urinary metabolic signatures and early triage of acute radiation exposure in rat model.

    PubMed

    Zhao, Mingxiao; Lau, Kim Kt; Zhou, Xian; Wu, Jianfang; Yang, Jun; Wang, Chang

    2017-03-28

    After a large-scale radiological accident, early-response biomarkers to assess radiation exposure over a broad dose range are not only the basis of rapid radiation triage, but are also the key to the rational use of limited medical resources and to the improvement of treatment efficiency. Because of its high throughput, rapid assays and minimally invasive sample collection, metabolomics has been applied to research into radiation exposure biomarkers in recent years. Due to the complexity of radiobiological effects, most of the potential biomarkers are both dose-dependent and time-dependent. In reality, it is very difficult to find a single biomarker that is both sensitive and specific in a given radiation exposure scenario. Therefore, a multi-parameters approach for radiation exposure assessment is more realistic in real nuclear accidents. In this study, untargeted metabolomic profiling based on gas chromatography-mass spectrometry (GC-MS) and targeted amino acid profiling based on LC-MS/MS were combined to investigate early urinary metabolite responses within 48 h post-exposure in a rat model. A few of the key early-response metabolites for radiation exposure were identified, which revealed the most relevant metabolic pathways. Furthermore, a panel of potential urinary biomarkers was selected through a multi-criteria approach and applied to early triage following irradiation. Our study suggests that it is feasible to use a multi-parameters approach to triage radiation damage, and the urinary excretion levels of the relevant metabolites provide insights into radiation damage and repair.

  9. Could hydroxyethyl starch be a therapeutic option in management of acute aluminum phosphide toxicity?

    PubMed

    Marashi, Sayed Mahdi; Arefi, Mohammad; Behnoush, Behnam; Nasrabad, Mahdi Ghazanfari; Nasrabadi, Zeynab Nasri

    2011-04-01

    Acute aluminum phosphide poisoning is a serious toxicity and results in high mortality rate despite the progress of critical care. After ingestion, phosphine gas is released and absorbed quickly, causing systemic poisoning and cell hypoxia. Excessive thirst, severe hypotension, arrhythmias, tachypnea, and severe metabolic acidosis are the common clinical manifestations. We think acute metabolic response which characteristically occurs in severe injury also happens in aluminum phosphide poisoning. Necropsy examinations indicate congestion in almost all vital organs because of leakage of fluids from intravascular to extravascular space. The most favorable type of fluid for intravascular volume resuscitation persists and is disputed. Colloids remain in the intravascular space rather than crystalloids, and provide more rapid hemodynamic stabilization. Furthermore, hydroxyethyl starch solution may have other benefits e.g. it can reduce the extra vascular leak of albumin and fluids from an endothelial injury site. As refractory hypotension and cardiovascular collapse, because leakage of fluids from intravascular to extravascular space are common cause of death in this toxicity, we propose that hydroxyethyl starch can dominate this refractory hypotension and consequently acute metabolic response.

  10. Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis.

    PubMed

    Liu, T; Kishton, R J; Macintyre, A N; Gerriets, V A; Xiang, H; Liu, X; Abel, E D; Rizzieri, D; Locasale, J W; Rathmell, J C

    2014-10-16

    The metabolic profiles of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. In particular, a wide range of both solid and liquid tumors use aerobic glycolysis to supply energy and support cell growth. This metabolic program leads to high rates of glucose consumption through glycolysis with secretion of lactate even in the presence of oxygen. Identifying the limiting events in aerobic glycolysis and the response of cancer cells to metabolic inhibition is now essential to exploit this potential metabolic dependency. Here, we examine the role of glucose uptake and the glucose transporter Glut1 in the metabolism and metabolic stress response of BCR-Abl+ B-cell acute lymphoblastic leukemia cells (B-ALL). B-ALL cells were highly glycolytic and primary human B-ALL samples were dependent on glycolysis. We show B-ALL cells express multiple glucose transporters and conditional genetic deletion of Glut1 led to a partial loss of glucose uptake. This reduced glucose transport capacity, however, was sufficient to metabolically reprogram B-ALL cells to decrease anabolic and increase catabolic flux. Cell proliferation decreased and a limited degree of apoptosis was also observed. Importantly, Glut1-deficient B-ALL cells failed to accumulate in vivo and leukemic progression was suppressed by Glut1 deletion. Similarly, pharmacologic inhibition of aerobic glycolysis with moderate doses of 2-deoxyglucose (2-DG) slowed B-ALL cell proliferation, but extensive apoptosis only occurred at high doses. Nevertheless, 2-DG induced the pro-apoptotic protein Bim and sensitized B-ALL cells to the tyrosine kinase inhibitor Dasatinib in vivo. Together, these data show that despite expression of multiple glucose transporters, B-ALL cells are reliant on Glut1 to maintain aerobic glycolysis and anabolic metabolism. Further, partial inhibition of glucose metabolism is sufficient to sensitize cancer cells to specifically targeted therapies, suggesting

  11. Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis

    PubMed Central

    Liu, T; Kishton, R J; Macintyre, A N; Gerriets, V A; Xiang, H; Liu, X; Abel, E D; Rizzieri, D; Locasale, J W; Rathmell, J C

    2014-01-01

    The metabolic profiles of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. In particular, a wide range of both solid and liquid tumors use aerobic glycolysis to supply energy and support cell growth. This metabolic program leads to high rates of glucose consumption through glycolysis with secretion of lactate even in the presence of oxygen. Identifying the limiting events in aerobic glycolysis and the response of cancer cells to metabolic inhibition is now essential to exploit this potential metabolic dependency. Here, we examine the role of glucose uptake and the glucose transporter Glut1 in the metabolism and metabolic stress response of BCR-Abl+ B-cell acute lymphoblastic leukemia cells (B-ALL). B-ALL cells were highly glycolytic and primary human B-ALL samples were dependent on glycolysis. We show B-ALL cells express multiple glucose transporters and conditional genetic deletion of Glut1 led to a partial loss of glucose uptake. This reduced glucose transport capacity, however, was sufficient to metabolically reprogram B-ALL cells to decrease anabolic and increase catabolic flux. Cell proliferation decreased and a limited degree of apoptosis was also observed. Importantly, Glut1-deficient B-ALL cells failed to accumulate in vivo and leukemic progression was suppressed by Glut1 deletion. Similarly, pharmacologic inhibition of aerobic glycolysis with moderate doses of 2-deoxyglucose (2-DG) slowed B-ALL cell proliferation, but extensive apoptosis only occurred at high doses. Nevertheless, 2-DG induced the pro-apoptotic protein Bim and sensitized B-ALL cells to the tyrosine kinase inhibitor Dasatinib in vivo. Together, these data show that despite expression of multiple glucose transporters, B-ALL cells are reliant on Glut1 to maintain aerobic glycolysis and anabolic metabolism. Further, partial inhibition of glucose metabolism is sufficient to sensitize cancer cells to specifically targeted therapies, suggesting

  12. Tumor cell metabolism

    PubMed Central

    Romero-Garcia, Susana; Lopez-Gonzalez, Jose Sullivan; B´ez-Viveros, José Luis; Aguilar-Cazares, Dolores

    2011-01-01

    Cancer is a genetic disease that is caused by mutations in oncogenes, tumor suppressor genes and stability genes. The fact that the metabolism of tumor cells is altered has been known for many years. However, the mechanisms and consequences of metabolic reprogramming have just begun to be understood. In this review, an integral view of tumor cell metabolism is presented, showing how metabolic pathways are reprogrammed to satisfy tumor cell proliferation and survival requirements. In tumor cells, glycolysis is strongly enhanced to fulfill the high ATP demands of these cells; glucose carbons are the main building blocks in fatty acid and nucleotide biosynthesis. Glutaminolysis is also increased to satisfy NADPH regeneration, whereas glutamine carbons replenish the Krebs cycle, which produces metabolites that are constantly used for macromolecular biosynthesis. A characteristic feature of the tumor microenvironment is acidosis, which results from the local increase in lactic acid production by tumor cells. This phenomenon is attributed to the carbons from glutamine and glucose, which are also used for lactic acid production. Lactic acidosis also directs the metabolic reprogramming of tumor cells and serves as an additional selective pressure. Finally, we also discuss the role of mitochondria in supporting tumor cell metabolism. PMID:22057267

  13. Ethylene glycol poisoning: a rare but life-threatening cause of metabolic acidosis—a single-centre experience

    PubMed Central

    Kimmel, Martin; Alscher, Mark Dominik; Braun, Niko

    2012-01-01

    Background. Intoxication with ethylene glycol happen all around the world and without rapid recognition and early treatment, mortality from this is high. Methods. In our study, we retrospectively analysed six cases of ethylene glycol intoxication in our department. We measured ethylene glycol or glycolate levels, lactate levels and calculated the osmolal and anion gap. Results. Data from six patients admitted to the nephrology department between 1999 and 2011 with ethylene glycol poisoning are reported. All patients were men. The mean pH on admission was 7.15 ± 0.20 and the anion and osmolal gap were elevated in five of six patients. Four patients had an acute kidney injury and one patient had an acute-on-chronic kidney injury. All patients survived and after being discharged, two patients required chronic intermittent haemodialysis. Interestingly, at the time of admission, all patients had elevated lactate levels but there was no linear regression between toxic levels and lactate levels and no linear correlation was found between initial lactate levels and anion gap and osmolal gap. Conclusions. The initial diagnosis of ethylene glycol poisoning is difficult and poisoning with ethylene glycol is rare but life threatening and needs rapid recognition and early treatment. Therefore, intoxication with ethylene glycol should not be misdiagnosed as lactic acidosis in patients with metabolic acidosis and elevated lactate levels. PMID:25503773

  14. Impacts of acute imipramine treatment on plasma and brain amino acid metabolism in mice given graded levels of dietary chicken protein.

    PubMed

    Nagasawa, Mao; Murakami, Tatsuro; Tomonaga, Shozo; Sato, Mikako; Takahata, Yoshihisa; Morimatsu, Fumiki; Furuse, Mitsuhiro

    2012-12-01

    Several studies have shown a relationship between depression and animal protein intake. To evaluate whether the difference of dietary chicken protein levels induces an antidepressant-like effect and potentiates acute antidepressant effects, three levels of dietary chicken protein were used as the representative animal protein with imipramine used as the antidepressant. In addition, the effects of dietary chicken protein on brain metabolism were evaluated. Open field test (OFT) and forced swimming test (FST) were conducted on the 27th and 28th days, respectively. OFT and FST were not influenced by both imipramine and dietary protein levels. However, characteristic effects of imipramine treatment on brain monoamine metabolism were observed in the cerebral cortex and hypothalamus. In addition, dietary protein significantly increased taurine and L-ornithine levels even though these amino acids were not contained in the diets. In conclusion, the metabolism of several amino acids in the plasma and brain were altered by dietary chicken protein.

  15. Metabolic studies of transient tyrosinemia in premature infants

    NASA Technical Reports Server (NTRS)

    Fernbach, S. A.; Summons, R. E.; Pereira, W. E.; Duffield, A. M.

    1975-01-01

    The recently developed technique of gas chromatography-mass spectrometry supported by computer has considerably improved the analysis of physiologic fluids. This study attempted to demonstrate the value of this system in the investigation of metabolite patterns in urine in two metabolic problems of prematurity, transient tyrosinemia and late metabolic acidosis. Serial 24-hr urine specimens were analyzed in 9 infants. Transient tyrosinemia, characterized by 5- 10-fold increases over basal excretion of tyrosine, p-hydroxyphenyllactate, and p-hydroxyphenylpyruvate in urine, was noted in five of the infants. Late metabolic acidosis was seen in four infants, but bore no relation to transient tyrosinemia.

  16. Neuromuscular Functions on Experimental Acute Methanol Intoxication

    PubMed Central

    Moral, Ali Reşat; Çankayalı, İlkin; Sergin, Demet; Boyacılar, Özden

    2015-01-01

    Objective The incidence of accidental or suicidal ingestion of methyl alcohol is high and methyl alcohol intoxication has high mortality. Methyl alcohol intoxication causes severe neurological sequelae and appears to be a significant problem. Methyl alcohol causes acute metabolic acidosis, optic neuropathy leading to permanent blindness, respiratory failure, circulatory failure and death. It is metabolised in the liver, and its metabolite formic acid has direct toxic effects, causing oxidative stress, mitochondrial damage and increased lipid peroxidation associated with the mechanism of neurotoxicity. Methanol is known to cause acute toxicity of the central nervous system; however, the effects on peripheral neuromuscular transmission are unknown. In our study, we aimed to investigate the electrophysiological effects of experimentally induced acute methanol intoxication on neuromuscular transmission in the early period (first 24 h). Methods After approval by the Animal Experiment Ethics Committee of Ege University, the study was carried out on 10 Wistar rats, each weighing about 200 g. During electrophysiological recordings and orogastric tube insertion, the rats were anaesthetised using intra-peritoneal (IP) injection of ketamine 100 mg kg−1 and IP injection of xylazine 10 mg kg−1. The rats were given 3 g kg−1 methyl alcohol by the orogastric tube. Electrophysiological measurements from the gastrocnemius muscle were compared with baseline. Results Latency measurements before and 24 h after methanol injection were 0.81±0.11 ms and 0.76±0.12 ms, respectively. CMAP amplitude measurements before and 24 h after methanol injection were 9.85±0.98 mV and 9.99±0.40 mV, respectively. CMAP duration measurements before and 24 h after methanol injection were 9.86±0.03 ms and 9.86±0.045 ms, respectively. Conclusion It was concluded that experimental methanol intoxication in the acute phase (first 24 h) did not affect neuromuscular function. PMID:27366524

  17. Examination of the influence of leptin and acute metabolic challenge on RFRP-3 neurons of mice in development and adulthood

    PubMed Central

    Poling, Matthew C.; Shieh, Morris P.; Munaganuru, Nagambika; Luo, Elena; Kauffman, Alexander S.

    2014-01-01

    Background The neuropeptide RFamide-related peptide-3 (RFRP-3; mammalian ortholog to GnIH) can inhibit LH release and increases feeding, but the regulation and development of RFRP-3 neurons remains poorly characterized, especially in mice. Methods and Results We first confirmed that peripheral injections of murine RFRP-3 peptide could markedly suppress luteinizing hormone secretion in adult mice, as in other species. Second, given RFRP-3′s reported orexigenic properties, we performed double-label in situ hybridization for metabolic genes in Rfrp neurons of mice. While Rfrp neurons did not readily co-express NPY, TRH, or MC4R, a small subset of Rfrp neurons did express leptin receptor in both sexes. Surprisingly, we identified no changes in Rfrp expression or neuronal activation in adult mice after acute fasting. However, we determined that Rfrp mRNA levels in the DMN were significantly reduced in adult Obese (Ob) mice of both sexes. Given the lower Rfrp levels observed in adult Ob mice, we asked whether leptin might also regulate RFRP-3 neuron development. Rfrp gene expression changed markedly over juvenile development, correlating with the timing of the juvenile “leptin surge” known to govern hypothalamic feeding circuit development. However, the dramatic developmental changes in juvenile Rfrp expression did not appear to be leptin-driven, as the pattern and timing of Rfrp neuron development were unaltered in Ob juveniles. Conclusion Leptin status modulates RFRP-3 expression in adulthood, but is not required for normal development of the RFRP-3 system. Leptin's regulation of adult RFRP-3 neurons likely occurs via primarily indirect signaling, and may be secondary to obesity, as only a small subset of RFRP-3 neurons express LepRb. PMID:25378037

  18. Acidosis slows electrical conduction through the atrio-ventricular node

    PubMed Central

    Nisbet, Ashley M.; Burton, Francis L.; Walker, Nicola L.; Craig, Margaret A.; Cheng, Hongwei; Hancox, Jules C.; Orchard, Clive H.; Smith, Godfrey L.

    2014-01-01

    Acidosis affects the mechanical and electrical activity of mammalian hearts but comparatively little is known about its effects on the function of the atrio-ventricular node (AVN). In this study, the electrical activity of the epicardial surface of the left ventricle of isolated Langendorff-perfused rabbit hearts was examined using optical methods. Perfusion with hypercapnic Tyrode's solution (20% CO2, pH 6.7) increased the time of earliest activation (Tact) from 100.5 ± 7.9 to 166.1 ± 7.2 ms (n = 8) at a pacing cycle length (PCL) of 300 ms (37°C). Tact increased at shorter PCL, and the hypercapnic solution prolonged Tact further: at 150 ms PCL, Tact was prolonged from 131.0 ± 5.2 to 174.9 ± 16.3 ms. 2:1 AVN block was common at shorter cycle lengths. Atrial and ventricular conduction times were not significantly affected by the hypercapnic solution suggesting that the increased delay originated in the AVN. Isolated right atrial preparations were superfused with Tyrode's solutions at pH 7.4 (control), 6.8 and 6.3. Low pH prolonged the atrial-Hisian (AH) interval, the AVN effective and functional refractory periods and Wenckebach cycle length significantly. Complete AVN block occurred in 6 out of 9 preparations. Optical imaging of conduction at the AV junction revealed increased conduction delay in the region of the AVN, with less marked effects in atrial and ventricular tissue. Thus acidosis can dramatically prolong the AVN delay, and in combination with short cycle lengths, this can cause partial or complete AVN block and is therefore implicated in the development of brady-arrhythmias in conditions of local or systemic acidosis. PMID:25009505

  19. Acidosis slows electrical conduction through the atrio-ventricular node.

    PubMed

    Nisbet, Ashley M; Burton, Francis L; Walker, Nicola L; Craig, Margaret A; Cheng, Hongwei; Hancox, Jules C; Orchard, Clive H; Smith, Godfrey L

    2014-01-01

    Acidosis affects the mechanical and electrical activity of mammalian hearts but comparatively little is known about its effects on the function of the atrio-ventricular node (AVN). In this study, the electrical activity of the epicardial surface of the left ventricle of isolated Langendorff-perfused rabbit hearts was examined using optical methods. Perfusion with hypercapnic Tyrode's solution (20% CO2, pH 6.7) increased the time of earliest activation (Tact) from 100.5 ± 7.9 to 166.1 ± 7.2 ms (n = 8) at a pacing cycle length (PCL) of 300 ms (37°C). Tact increased at shorter PCL, and the hypercapnic solution prolonged Tact further: at 150 ms PCL, Tact was prolonged from 131.0 ± 5.2 to 174.9 ± 16.3 ms. 2:1 AVN block was common at shorter cycle lengths. Atrial and ventricular conduction times were not significantly affected by the hypercapnic solution suggesting that the increased delay originated in the AVN. Isolated right atrial preparations were superfused with Tyrode's solutions at pH 7.4 (control), 6.8 and 6.3. Low pH prolonged the atrial-Hisian (AH) interval, the AVN effective and functional refractory periods and Wenckebach cycle length significantly. Complete AVN block occurred in 6 out of 9 preparations. Optical imaging of conduction at the AV junction revealed increased conduction delay in the region of the AVN, with less marked effects in atrial and ventricular tissue. Thus acidosis can dramatically prolong the AVN delay, and in combination with short cycle lengths, this can cause partial or complete AVN block and is therefore implicated in the development of brady-arrhythmias in conditions of local or systemic acidosis.

  20. Does Bicarbonate Correct Coagulation Function Impaired by Acidosis in Swine?

    DTIC Science & Technology

    2006-07-01

    L bicarbonate to a pH of 7.4 (A-Bi, n 6). Blood samples were taken at base - line, 15 minutes after acidosis induction, and 15 minutes after...Behring, Deerfield, IL). Plasma fibrinogen concentra- tion was determined by BCS Coagulation System based on fibrinogen functional activities in the...0.05). Hct decreased from 31 1% to 28 1% in A-LR and from 29 1% to 25 1% in A-Bi (p 0.05). Arterial base excess (BE) dropped from 7.1 0.7

  1. Case report of acute thiamine deficiency occurring as a complication of vitamin-free parenteral nutrition.

    PubMed

    Ferrie, Suzie

    2012-02-01

    Parenteral nutrition (PN) is a relatively recent life-saving development in medicine but brings with it a range of new potential complications. Much of our knowledge about the signs and symptoms of individual micronutrient deficiencies comes from observations of patients receiving PN, and an example of this is the pivotal paper by Velez and colleagues published in Journal of Parenteral and Enteral Nutrition in 1985. This case report was the first published study to identify acute thiamine deficiency with cardiopathy and metabolic acidosis occurring in adult patients receiving vitamin-free PN. Although the importance of thiamine has been recognized since the late 19th century, it is still unclear exactly what dose is required for full repletion of a deficient patient, and further research would be useful to elucidate this question.

  2. Metformin-associated lactic acidosis in a patient with normal kidney function.

    PubMed

    van Sloten, T T; Pijpers, E; Stehouwer, C D A; Brouwers, M C G J

    2012-06-01

    The existence of metformin-induced lactic acidosis has been questioned, in particular in the absence of specific risk factors such as impaired renal function. This report describes the presence of lactic acidosis in a patient with normal kidney function and normal doses of metformin. Subsequent positive rechallenge with metformin confirms causality.

  3. Anoxia and Acidosis Tolerance of the Heart in an Air-Breathing Fish (Pangasianodon hypophthalmus).

    PubMed

    Joyce, William; Gesser, Hans; Bayley, Mark; Wang, Tobias

    2015-01-01

    Air breathing has evolved repeatedly in fishes and may protect the heart during stress. We investigated myocardial performance in the air-breathing catfish Pangasianodon hypophthalmus, a species that can withstand prolonged exposure to severe hypoxia and acidosis. Isometric ventricular preparations were exposed to anoxia, lactic acidosis, hypercapnic acidosis, and combinations of these treatments. Ventricular preparations were remarkably tolerant to anoxia, exhibiting an inotropic reduction of only 40%, which fully recovered during reoxygenation. Myocardial anoxia tolerance was unaffected by physiologically relevant elevations of bicarbonate concentration, in contrast to previous results in other fishes. Both lactic acidosis (5 mM; pH 7.10) and hypercapnic acidosis (10% CO2; pH 6.70) elicited a biphasic response, with an initial and transient decrease in force followed by overcompensation above control values. Spongy myocardial preparations were significantly more tolerant to hypercapnic acidosis than compact myocardial preparations. While ventricular preparations were tolerant to the isolated effects of anoxia and acidosis, their combination severely impaired myocardial performance and contraction kinetics. This suggests that air breathing may be a particularly important myocardial oxygen source during combined anoxia and acidosis, which may occur during exercise or environmental stress.

  4. 1H NMR spectroscopic analysis detects metabolic disturbances in rat urine on acute exposure to heavy metal tungsten alloy based metals salt.

    PubMed

    Tyagi, Ritu; Rana, Poonam; Gupta, Mamta; Bhatnagar, Deepak; Srivastava, Shatakshi; Roy, Raja; Khushu, Subash

    2014-03-25

    Heavy metal tungsten alloys (HMTAs) have been found to be safer alternatives for making military munitions. Recently, some studies demonstrating the toxic potential of HMTAs have raised concern over the safety issues, and further propose that HMTAs exposure may lead to physiological disturbances as well. To look for the systemic effect of acute toxicity of HMTA based metals salt, (1)H nuclear magnetic resonance ((1)H NMR) spectroscopic profiling of rat urine was carried out. Male Sprague Dawley rats were administered (intraperitoneal) low and high dose of mixture of HMTA based metals salt and NMR spectroscopy was carried out in urine samples collected at 8, 24, 72 and 120 h post dosing (p.d.). Serum biochemical parameters and liver histopathology were also conducted. The (1)H NMR spectra were analysed using multivariate analysis techniques to show the time- and dose-dependent biochemical variations in post HMTA based metals salt exposure. Urine metabolomic analysis showed changes associated with energy metabolism, amino acids, N-methyl nicotinamide, membrane and gut flora metabolites. Multivariate analysis showed maximum variation with best classification of control and treated groups at 24h p.d. At the end of the study, for the low dose group most of the changes at metabolite level reverted to control except for the energy metabolites; whereas, in the high dose group some of the changes still persisted. The observations were well correlated with histopathological and serum biochemical parameters. Further, metabolic pathway analysis clarified that amongst all the metabolic pathways analysed, tricarboxylic acid cycle was most affected at all the time points indicating a switchover in energy metabolism from aerobic to anaerobic. These results suggest that exposure of rats to acute doses of HMTA based metals salt disrupts physiological metabolism with moderate injury to the liver, which might indirectly result from heavy metals induced oxidative stress.

  5. Acute bovine laminitis: a new induction model using alimentary oligofructose overload.

    PubMed

    Thoefner, M B; Pollitt, C C; Van Eps, A W; Milinovich, G J; Trott, D J; Wattle, O; Andersen, P H

    2004-09-01

    Twelve dairy heifers were used to examine the clinical response of an alimentary oligofructose overload. Six animals were divided into 3 subgroups, and each was given a bolus dose of 13, 17, or 21 g/kg of oligofructose orally. The control group (n = 6) was sham-treated with tap water. Signs of lameness, cardiovascular function, and gastrointestinal function were monitored every 6 h during development of rumen acidosis. The heifers were euthanized 48 and 72 h after administration of oligofructose. All animals given oligofructose developed depression, anorexia, and diarrhea 9 to 39 h after receiving oligofructose. By 33 to 45 h after treatment, the feces returned to normal consistency and the heifers began eating again. Animals given oligofructose developed transient fever, severe metabolic acidosis, and moderate dehydration, which were alleviated by supportive therapy. Four of 6 animals given oligofructose displayed clinical signs of laminitis starting 39 to 45 h after receiving oligofructose and lasting until euthanasia. The lameness was obvious, but could easily be overlooked by the untrained eye, because the heifers continued to stand and walk, and did not interrupt their eating behavior. No positive pain reactions or lameness were seen in control animals. Based on these results, we conclude that an alimentary oligofructose overload is able to induce signs of acute laminitis in cattle. This model offers a new method, which can be used in further investigation of the pathogenesis and pathophysiology of bovine laminitis.

  6. Effects of high-fructose corn syrup and sucrose on the pharmacokinetics of fructose and acute metabolic and hemodynamic responses in healthy subjects.

    PubMed

    Le, Myphuong T; Frye, Reginald F; Rivard, Christopher J; Cheng, Jing; McFann, Kim K; Segal, Mark S; Johnson, Richard J; Johnson, Julie A

    2012-05-01

    It is unclear whether high-fructose corn syrup (HFCS), which contains a higher amount of fructose and provides an immediate source of free fructose, induces greater systemic concentrations of fructose as compared with sucrose. It is also unclear whether exposure to higher levels of fructose leads to increased fructose-induced adverse effects. The objective was to prospectively compare the effects of HFCS- vs sucrose-sweetened soft drinks on acute metabolic and hemodynamic effects. Forty men and women consumed 24 oz of HFCS- or sucrose-sweetened beverages in a randomized crossover design study. Blood and urine samples were collected over 6 hours. Blood pressure, heart rate, fructose, and a variety of other metabolic biomarkers were measured. Fructose area under the curve and maximum concentration, dose-normalized glucose area under the curve and maximum concentration, relative bioavailability of glucose, changes in postprandial concentrations of serum uric acid, and systolic blood pressure maximum levels were higher when HFCS-sweetened beverages were consumed as compared with sucrose-sweetened beverages. Compared with sucrose, HFCS leads to greater fructose systemic exposure and significantly different acute metabolic effects.

  7. Diet-induced ketosis does not cause cerebral acidosis.

    PubMed

    Al-Mudallal, A S; LaManna, J C; Lust, W D; Harik, S I

    1996-03-01

    Ketosis is beneficial for seizure control, possibly through induction of cerebral acidosis. However, cerebral intracellular pH has not previously been measured in ketotic humans and the animal data are sparse. We describe a high-fat diet, avidly consumed by rats, that induced consistent and moderate ketosis. Adult male rats were fed either the high-fat ketogenic diet, a high-carbohydrate diet with the same protein content as the ketogenic diet, or regular laboratory chow. Five to 6 weeks later, the rats were anesthetized, paralyzed, and injected with neutral red; their brains were frozen in situ. Intracellular pH of the cerebral cortex and cerebral glucose, lactate, ATP, phosphocreatine, and gama-aminobutyric acid (GABA) levels were measured. Rats fed the ketogenic diet had > 10-fold increase in their plasma ketones, but we noted no significant differences in cerebral pH or in cerebral metabolites and GABA levels among the three groups. Therefore, the antiepileptic effect of the ketogenic diet probably is not mediated by cerebral acidosis or changes in total cerebral GABA levels.

  8. Plasma reactive oxygen metabolites and non-enzymatic antioxidant capacity are not affected by an acute increase of metabolic rate in zebra finches.

    PubMed

    Beamonte-Barrientos, Rene; Verhulst, Simon

    2013-07-01

    Understanding the sources of variation in oxidative stress level is a challenging issue due to the implications of oxidative stress for late age diseases, longevity and life-history trade-offs. Reactive oxygen species that cause oxidative stress are mostly a by-product of energy metabolism and it is therefore often assumed that oxidative stress is proportional to energy consumption. In mammals, an increased metabolic rate induced by cold exposure generally increases oxidative stress. However, compared to mammals, birds generate fewer free radicals per ATP produced and hence it is not obvious that, in birds, a cold-induced increase of metabolic rate increase oxidative stress. We tested whether cold-induced increase in metabolic rate increased oxidative stress in zebra finches by exposing individuals to cold and warm overnight temperatures. We registered metabolic rate and plasma levels of non-enzymatic antioxidants and reactive oxygen metabolites (ROMs), a measure of oxidative damage. Metabolic rate was on average 88 % higher in cold compared to warm temperature, with females being stronger affected than males. However, temperature had no effect on plasma antioxidants or our measure of oxidative damage. Middle-age birds had higher levels of plasma antioxidants than younger and older birds, but age was unrelated to ROMs. Birds showed repeatability of plasma ROMs across temperatures but not of non-enzymatic antioxidants. In contrast to similar studies in mammals, our results do not show evidence of increased oxidative stress in plasma after an acute cold-induced increase of metabolic rate but research in more bird species is needed to assess the generality of this pattern.

  9. Emerging therapeutic targets for the treatment of human acute myeloid leukemia (part 1) - gene transcription, cell cycle regulation, metabolism and intercellular communication.

    PubMed

    Reikvam, Håkon; Hauge, Michelle; Brenner, Annette K; Hatfield, Kimberley Joanne; Bruserud, Øystein

    2015-06-01

    Human acute myeloid leukemia is a heterogeneous disease and the effect of therapeutic targeting of specific molecular mechanisms will probably vary between patient subsets. Cell cycle regulators are among the emerging targets (e.g., aurora and polo-like kinases, cyclin-dependent kinases). Inhibition of communication between acute myeloid leukemia and stromal cells is also considered; among the most promising of these strategies are inhibition of hedgehog-initiated, CXCR4-CXCL12 and Axl-Gas6 signaling. Finally, targeting of energy and protein metabolism is considered, the most promising strategy being inhibition of isocitrate dehydrogenase in patients with IDH mutations. Thus, several strategies are now considered, and a major common challenge for all of them is to clarify how they should be combined with each other or with conventional chemotherapy, and whether their use should be limited to certain subsets of patients.

  10. Founder p.Arg 446* mutation in the PDHX gene explains over half of cases with congenital lactic acidosis in Roma children.

    PubMed

    Ivanov, Ivan S; Azmanov, Dimitar N; Ivanova, Mariya B; Chamova, Teodora; Pacheva, Ilyana H; Panova, Margarita V; Song, Sharon; Morar, Bharti; Yordanova, Ralitsa V; Galabova, Fani K; Sotkova, Iglika G; Linev, Alexandar J; Bitchev, Stoyan; Shearwood, Anne-Marie J; Kancheva, Dalia; Gabrikova, Dana; Karcagi, Veronika; Guergueltcheva, Velina; Geneva, Ina E; Bozhinova, Veneta; Stoyanova, Vili K; Kremensky, Ivo; Jordanova, Albena; Savov, Aleksey; Horvath, Rita; Brown, Matthew A; Tournev, Ivailo; Filipovska, Aleksandra; Kalaydjieva, Luba

    2014-01-01

    Investigation of 31 of Roma patients with congenital lactic acidosis (CLA) from Bulgaria identified homozygosity for the R446* mutation in the PDHX gene as the most common cause of the disorder in this ethnic group. It accounted for around 60% of patients in the study and over 25% of all CLA cases referred to the National Genetic Laboratory in Bulgaria. The detection of a homozygous patient from Hungary and carriers among population controls from Romania and Slovakia suggests a wide spread of the mutation in the European Roma population. The clinical phenotype of the twenty R446* homozygotes was relatively homogeneous, with lactic acidosis crisis in the first days or months of life as the most common initial presentation (15/20 patients) and delayed psychomotor development and/or seizures in infancy as the leading manifestations in a smaller group (5/20 patients). The subsequent clinical picture was dominated by impaired physical growth and a very consistent pattern of static cerebral palsy-like encephalopathy with spasticity and severe to profound mental retardation seen in over 80% of cases. Most patients had a positive family history. We propose testing for the R446* mutation in PDHX as a rapid first screening in Roma infants with metabolic acidosis. It will facilitate and accelerate diagnosis in a large proportion of cases, allow early rehabilitation to alleviate the chronic clinical course, and prevent further affected births in high-risk families.

  11. The acetaminophen metabolite N-acetyl-p-benzoquinone imine (NAPQI) inhibits glutathione synthetase in vitro; a clue to the mechanism of 5-oxoprolinuric acidosis?

    PubMed

    Walker, Valerie; Mills, Graham A; Anderson, Mary E; Ingle, Brandall L; Jackson, John M; Moss, Charlotte L; Sharrod-Cole, Hayley; Skipp, Paul J

    2017-02-01

    1. Metabolic acidosis due to accumulation of l-5-oxoproline is a rare, poorly understood, disorder associated with acetaminophen treatment in malnourished patients with chronic morbidity. l-5-Oxoprolinuria signals abnormal functioning of the γ-glutamyl cycle, which recycles and synthesises glutathione. Inhibition of glutathione synthetase (GS) by N-acetyl-p-benzoquinone imine (NAPQI) could contribute to 5-oxoprolinuric acidosis in such patients. We investigated the interaction of NAPQI with GS in vitro. 2. Peptide mapping of co-incubated NAPQI and GS using mass spectrometry demonstrated binding of NAPQI with cysteine-422 of GS, which is known to be essential for GS activity. Computational docking shows that NAPQI is properly positioned for covalent bonding with cysteine-422 via Michael addition and hence supports adduct formation. 3. Co-incubation of 0.77 μM of GS with NAPQI (25-400 μM) decreased enzyme activity by 16-89%. Inhibition correlated strongly with the concentration of NAPQI and was irreversible. 4. NAPQI binds covalently to GS causing irreversible enzyme inhibition in vitro. This is an important novel biochemical observation. It is the first indication that NAPQI may inhibit glutathione synthesis, which is pivotal in NAPQI detoxification. Further studies are required to investigate its biological significance and its role in 5-oxoprolinuric acidosis.

  12. Disorders of pyruvate metabolism.

    PubMed

    De Meirleir, Linda

    2013-01-01

    Pyruvate dehydrogenase and pyruvate carboxylase deficiency are the most common disorders in pyruvate metabolism. Diagnosis is made by enzymatic and DNA analysis after basic biochemical tests in plasma, urine, and CSF. Pyruvate dehydrogenase has three main subunits, an additional E3-binding protein and two complex regulatory enzymes. Most frequent are deficiencies in PDH-E1α. There is a spectrum of clinical presentations in E1α deficiency, ranging in boys from severe neonatal lactic acidosis, Leigh encephalopathy, to later onset of neurological disease such as intermittent ataxia or dystonia. Females tend to have a more uniform presentation resembling nonprogressive cerebral palsy. Neuroradiological abnormalities such as corpus callosum agenesis are seen more frequently in girls, basal ganglia and midbrain disturbances in boys. Deficiencies in the other subunits have also been described, but in a smaller number of patients. Pyruvate carboxylase deficiency has three clinical phenotypes. The infantile type is characterized mainly by severe developmental delay, failure to thrive, and seizures. The second type is characterized by neonatal onset of severe lactic acidosis with rigidity and hypokinesia. A third form is rarer with intermittent episodes of lactic acidosis and ketoacidosis. Neuroradiological findings such as cystic periventricular leukomalacia have been described.

  13. Sprague-Dawley rats display metabolism-mediated sex differences in the acute toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)

    SciTech Connect

    Fonsart, Julien ||; Menet, Marie-Claude |; Decleves, Xavier ||; Galons, Herve |; Crete, Dominique; Debray, Marcel; Scherrmann, Jean-Michel ||; Noble, Florence ||

    2008-07-01

    The use of the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has been associated with unexplained deaths. Male humans and rodents are more sensitive to acute toxicity than are females, including a potentially lethal hyperthermia. MDMA is highly metabolized to five main metabolites, by the enzymes CYP1A2 and CYP2D. The major metabolite in rats, 3,4-methylenedioxyamphetamine (MDA), also causes hyperthermia. We postulated that the reported sex difference in rats is due to a sexual dimorphism(s). We therefore determined (1) the LD50 of MDMA and MDA, (2) their hyperthermic effects, (3) the activities of liver CYP1A2 and CYP2D, (4) the liver microsomal metabolism of MDMA and MDA, (5) and the plasma concentrations of MDMA and its metabolites 3 h after giving male and female Sprague-Dawley (SD) rats MDMA (5 mg.kg{sup -1} sc). The LD50 of MDMA was 2.4-times lower in males than in females. MDMA induced greater hyperthermia (0.9 deg. C) in males. The plasma MDA concentration was 1.3-fold higher in males, as were CYP1A2 activity (twice) and N-demethylation to MDA (3.3-fold), but the plasma MDMA concentration (1.4-fold) and CYP2D activity (1.3-fold) were higher in females. These results suggest that male SD rats are more sensitive to MDMA acute toxicity than are females, probably because their CYP1A2 is more active, leading to higher N-demethylation and plasma MDA concentration. This metabolic pathway could be responsible for the lethality of MDMA, as the LD50 of MDA is the same in both sexes. These data strongly suggest that the toxicity of amphetamine-related drugs largely depends on metabolic differences.

  14. Midostaurin, a Novel Protein Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia: Insights from Human Absorption, Metabolism and Excretion Studies of a BDDCS II Drug.

    PubMed

    He, Handan; Tran, Phi; Gu, Helen; Tedesco, Vivienne; Zhang, Jin; Lin, Wen; Gatlik, Ewa; Klein, Kai; Heimbach, Tycho

    2017-03-07

    The absorption, metabolism and excretion of midostaurin, a potent class III tyrosine protein kinase inhibitor for acute myelogenous leukemia, were evaluated in healthy subjects. A microemulsion formulation was chosen to optimize absorption. After a 50 mg [14C]midostaurin dose, oral absorption was high (> 90%) and relatively rapid. In plasma, the major circulating components were midostaurin (22%), CGP52421 (32.7%), and CGP62221 (27.7%). Long plasma half-lives were observed for midostaurin (20.3 h), CGP52421 (495 h), and CGP62221 (33.4 h). Through careful mass-balance study design, the recovery achieved was good (81.6%), despite the long radioactivity half-lives. Most of the radioactive dose was recovered in feces (77.6%) mainly as metabolites; as only 3.43% was unchanged, suggesting mainly hepatic metabolism. Renal elimination was minor (4%). Midostaurin metabolism pathways involved hydroxylation, O demethylation, amide hydrolysis and N demethylation. High plasma CGP52421 and CGP62221 exposures in humans, along with relatively potent cell-based IC50 for FLT3-ITD inhibition, suggested that the antileukemic activity in AML patients may also be maintained by the metabolites. Very high plasma protein binding (>99%) required equilibrium gel filtration to identify differences between humans and animals. As midostaurin, CGP52421 and CGP62221 are metabolized mainly by CYP3A4 and are inhibitors/inducers for CYP3A, potential drug-drug interactions with mainly CYP3A4 modulators/CYP3A substrates could be expected. Given its low aqueous solubility, high oral absorption and extensive metabolism (> 90%), midostaurin is a BCS/BDDCS class II drug in human, consistent with rat BDDCS in vivo data showing high absorption (>90%) and extensive metabolism (>90%).

  15. [Review of the knowledge on acute kidney failure in the critical patient].

    PubMed

    Romero García, M; Delgado Hito, P; de la Cueva Ariza, L

    2013-01-01

    Acute renal failure affects from 1% to 25% of patients admitted to intensive care units. These figures vary depending on the population studied and criteria. The complications of acute renal failure (fluid overload, metabolic acidosis, hyperkalemia, bleeding) are treated. However, mortality remains high despite the technological advances of recent years because acute renal failure is usually associated with sepsis, respiratory failure, serious injury, surgical complications or consumption coagulopathy. Mortality ranges from 30% to 90%. Although there is no universally accepted definition, the RIFLE classification gives us an operational tool to define the degree of acute renal failure and to standardize the initiation of renal replacement techniques as well as to evaluate the results. Therefore, nurses working within the intensive care unit must be familiar with this disease, with its treatment (drug or alternative) and with the prevention of possible complications. Equally, they must be capable of detecting the manifestations of dependency each one of the basic needs and to be able to identify the collaboration problems in order to achieve an individualized care plan.

  16. The Anion Gap is a Predictive Clinical Marker for Death in Patients with Acute Pesticide Intoxication.

    PubMed

    Lee, Sun-Hyo; Park, Samel; Lee, Jung-Won; Hwang, Il-Woong; Moon, Hyung-Jun; Kim, Ki-Hwan; Park, Su-Yeon; Gil, Hyo-Wook; Hong, Sae-Yong

    2016-07-01

    Pesticide formulation includes solvents (methanol and xylene) and antifreeze (ethylene glycol) whose metabolites are anions such as formic acid, hippuric acid, and oxalate. However, the effect of the anion gap on clinical outcome in acute pesticide intoxication requires clarification. In this prospective study, we compared the anion gap and other parameters between surviving versus deceased patients with acute pesticide intoxication. The following parameters were assessed in 1,058 patients with acute pesticide intoxication: blood chemistry (blood urea nitrogen, creatinine, glucose, lactic acid, liver enzymes, albumin, globulin, and urate), urinalysis (ketone bodies), arterial blood gas analysis, electrolytes (Na(+), K(+), Cl(-) HCO3 (-), Ca(++)), pesticide field of use, class, and ingestion amount, clinical outcome (death rate, length of hospital stay, length of intensive care unit stay, and seriousness of toxic symptoms), and the calculated anion gap. Among the 481 patients with a high anion gap, 52.2% had a blood pH in the physiologic range, 35.8% had metabolic acidosis, and 12.1% had acidemia. Age, anion gap, pesticide field of use, pesticide class, seriousness of symptoms (all P < 0.001), and time lag after ingestion (P = 0.048) were significant risk factors for death in univariate analyses. Among these, age, anion gap, and pesticide class were significant risk factors for death in a multiple logistic regression analysis (P < 0.001). In conclusions, high anion gap is a significant risk factor for death, regardless of the accompanying acid-base balance status in patients with acute pesticide intoxication.

  17. Beyond Warburg effect – dual metabolic nature of cancer cells

    PubMed Central

    Xie, Jiansheng; Wu, Hao; Dai, Chunyan; Pan, Qiangrong; Ding, Zonghui; Hu, Danqing; Ji, Bingyan; Luo, Yan; Hu, Xun

    2014-01-01

    Warburg effect is a dominant phenotype of most cancer cells. Here we show that this phenotype depends on its environment. When cancer cells are under regular culture condition, they show Warburg effect; whereas under lactic acidosis, they show a nonglycolytic phenotype, characterized by a high ratio of oxygen consumption rate over glycolytic rate, negligible lactate production and efficient incorporation of glucose carbon(s) into cellular mass. These two metabolic modes are intimately interrelated, for Warburg effect generates lactic acidosis that promotes a transition to a nonglycolytic mode. This dual metabolic nature confers growth advantage to cancer cells adapting to ever changing microenvironment. PMID:24820099

  18. Successful Management of Refractory Type 1 Renal Tubular Acidosis with Amiloride

    PubMed Central

    Chow, Robert; Yim, Kenneth; Jaar, Bernard G.

    2017-01-01

    A 28-year-old female with history of hypothyroidism, Sjögren's Syndrome, and Systemic Lupus Erythematosus (SLE) presented with complaints of severe generalized weakness, muscle pain, nausea, vomiting, and anorexia. Physical examination was unremarkable. Laboratory test showed hypokalemia at 1.6 mmol/l, nonanion metabolic acidosis with HCO3 of 11 mmol/l, random urine pH of 7.0, and urine anion gap of 8 mmol/l. CT scan of the abdomen revealed bilateral nephrocalcinosis. A diagnosis of type 1 RTA likely secondary to Sjögren's Syndrome was made. She was started on citric acid potassium citrate with escalating dosages to a maximum dose of 60 mEq daily and potassium chloride over 5 years without significant improvement in serum K+ and HCO3 levels. She had multiple emergency room visits for persistent muscle pain, generalized weakness, and cardiac arrhythmias. Citric acid potassium citrate was then replaced with sodium bicarbonate at 15.5 mEq every 6 hours which was continued for 2 years without significant improvement in her symptoms and electrolytes. Amiloride 5 mg daily was added to her regimen as a potassium sparing treatment with dramatic improvement in her symptoms and electrolyte levels (as shown in the figures). Amiloride was increased to 10 mg daily and potassium supplementation was discontinued without affecting her electrolytes. Her sodium bicarbonate was weaned to 7.7 mEq daily. PMID:28127482

  19. Acute dim light at night increases body mass, alters metabolism, and shifts core body temperature circadian rhythms.

    PubMed

    Borniger, Jeremy C; Maurya, Santosh K; Periasamy, Muthu; Nelson, Randy J

    2014-10-01

    The circadian system is primarily entrained by the ambient light environment and is fundamentally linked to metabolism. Mounting evidence suggests a causal relationship among aberrant light exposure, shift work, and metabolic disease. Previous research has demonstrated deleterious metabolic phenotypes elicited by chronic (>4 weeks) exposure to dim light at night (DLAN) (∼ 5 lux). However, the metabolic effects of short-term (<2 weeks) exposure to DLAN are unspecified. We hypothesized that metabolic alterations would arise in response to just 2 weeks of DLAN. Specifically, we predicted that mice exposed to dim light would gain more body mass, alter whole body metabolism, and display altered body temperature (Tb) and activity rhythms compared to mice maintained in dark nights. Our data largely support these predictions; DLAN mice gained significantly more mass, reduced whole body energy expenditure, increased carbohydrate over fat oxidation, and altered temperature circadian rhythms. Importantly, these alterations occurred despite similar activity locomotor levels (and rhythms) and total food intake between groups. Peripheral clocks are potently entrained by body temperature rhythms, and the deregulation of body temperature we observed may contribute to metabolic problems due to "internal desynchrony" between the central circadian oscillator and temperature sensitive peripheral clocks. We conclude that even relatively short-term exposure to low levels of nighttime light can influence metabolism to increase mass gain.

  20. Acidosis inhibits spontaneous activity and membrane currents in myocytes isolated from the rabbit atrioventricular node.

    PubMed

    Cheng, Hongwei; Smith, Godfrey L; Orchard, Clive H; Hancox, Jules C

    2009-01-01

    Recent evidence from intact hearts suggests that the function of cardiac nodal tissue may be particularly susceptible to acidosis. Little is currently known, however, about the effects of acidosis on the cellular electrophysiology of the atrioventricular node (AVN). This study was conducted, therefore, to determine the effect of acidosis on the spontaneous activity and membrane currents of myocytes isolated from the rabbit AVN, recorded at 35-37 degrees C using whole-cell patch-clamp. Reduction of extracellular pH (pH(e); from 7.4 to 6.8 or 6.3) produced pH-dependent slowing of spontaneous action potential rate and upstroke velocity, and reductions in maximum diastolic potential and action potential amplitude. Ionic current recordings under voltage-clamp indicated that acidosis (pH(e) 6.3) decreased L-type Ca current (I(Ca,L)), without significant changes in voltage-dependent activation or inactivation. Acidosis reduced the E-4031-sensitive, rapid delayed rectifier current (I(Kr)) tail amplitude at -40 mV following command pulses to between -30 and +50 mV, and accelerated tail-current deactivation. In contrast, the time-dependent hyperpolarisation-activated current, I(f), was unaffected by acidosis. Background current insensitive to E-4031 and nifedipine was reduced by acidosis. Measurement of intracellular pH (pH(i)) from undialysed cells using BCECF showed a reduction in mean pH(i) from 7.24 to 6.45 (n=17) when pH(e) was lowered from 7.4 to 6.3. We conclude that I(f) is unlikely to be involved in the response of the AVN to acidosis, whilst inhibition of I(Ca,L) and I(Kr) by acidosis are likely to play a significant role in effects on AVN cellular electrophysiology.

  1. Inhibition of metabolism of diethylene glycol prevents target organ toxicity in rats.

    PubMed

    Besenhofer, Lauren M; Adegboyega, Patrick A; Bartels, Michael; Filary, Mark J; Perala, Adam W; McLaren, Marie C; McMartin, Kenneth E

    2010-09-01

    Diethylene glycol (DEG) is an industrial chemical, the misuse of which has led to numerous epidemic poisonings worldwide. The mechanism of its toxicity has not been defined as to the precise relationship between the metabolism of DEG and target organ toxicity. The purpose of this study was to investigate the mechanism for the acute toxicity of DEG, and the effect of the alcohol dehydrogenase inhibitor 4-methylpyrazole (fomepizole), by determining the relationship between accumulation of DEG or its metabolites and the resulting kidney and liver toxicity. Rats were treated by oral gavage with water, 2 g/kg DEG (low dose), 10 g/kg DEG (high dose), or 10 g/kg DEG + fomepizole, and blood and urine were collected over 48 h. Rats treated with high-dose DEG had metabolic acidosis, increased BUN and creatinine, and marked kidney necrosis, noted by histopathology. A minor degree of liver damage was noted at the high dose. After low and high doses of DEG, 2-hydroxyethoxyacetic acid (HEAA) was the primary metabolite in the urine, with only minor amounts of urinary diglycolic acid (DGA). Small amounts of ethylene glycol (EG), but not oxalate or glycolate, were observed in the urine. Treatment with fomepizole blocked the formation of HEAA and DGA and the development of metabolic acidosis and the kidney and liver toxicity. These results indicate that the mechanism for the target organ toxicity results from metabolites of DEG, and not DEG itself nor formation of EG from DEG, and that fomepizole may be a useful antidote for treating DEG poisoning.

  2. The Effect of Osmotherapy and Tight Control of Acidosis on Early Graft Function among Deceased-Donor Kidney Transplant Recipients: A Randomized Controlled Trial

    PubMed Central

    Etezadi, F.; Najafi Abrandabadi, A. H.; Motaharinia, J.; Mojtahedzadeh, M.; Pourfakhr, P.; Khajavi, M. R.; Gooran, S.; Shariat Moharari, R.; Dehghani, S.

    2017-01-01

    Background: Reperfusion injury and the acid-base status of the transplant are important factors affecting post-transplantation graft function. Objective: We hypothesized that infusing hypertonic saline (HS) or tight control of acid-base status of the blood rushing through renal graft using sodium bicarbonate may have beneficial effects on early graft function. Methods: Candidates for deceased-donor kidney transplant were randomized into three groups. HS group (n=33) received 50 mL/kg normal saline (NS) titrated during operation plus 4 mL/kg of 5% HS just within graft reperfusion phase; bicarbonate group (n=37) was administered 60 mL/kg NS while their metabolic acidosis (base excess ≤5 mEq/L) was tightly corrected every 30 min with sodium bicarbonate; and a control group (n=36) that received 60 mL/kg normal saline while they were administered sodium bicarbonate only, if they encountered severe metabolic acidosis (base excess ≤15 mEq/L). The primary outcome was defined as early post-operative renal function evaluated based on serial serum creatinine levels. The study was registered in Iranian Registry of Clinical Trials (IRCT2013122815841N19). Results: Post-operative early graft function improved significantly during the first 3 days in the intervention groups (p<0.05). However, that beneficial effect no longer remained at the same level after the day four. Conclusion: Timely administration of HS or tight control of metabolic acidosis with sodium bicarbonate infusion improve early renal function during renal transplant surgery. PMID:28299023

  3. The Dramatic Recovery of a Patient with Biguanide-associated Severe Lactic Acidosis Following Thiamine Supplementation

    PubMed Central

    Godo, Shigeo; Yoshida, Yoshitaro; Fujita, Motoo; Kudo, Daisuke; Nomura, Ryosuke; Shimokawa, Hiroaki; Kushimoto, Shigeki

    2017-01-01

    Biguanides are a drug of choice for the treatment of type 2 diabetes mellitus. Although they can cause lactic acidosis in susceptible patients with predisposing risk factors, the incidence of lactic acidosis is reported to be very low when they are used properly. We herein present a case of biguanide-associated severe lactic acidosis complicated with thiamine deficiency that was provoked without predisposing factors for thiamine deficiency. Diabetic patients taking biguanide may be predisposed to thiamine deficiency, even when there is no evidence of risk factors, and the high-dose administration of thiamine may be essential in the treatment of this otherwise under-recognized disorder. PMID:28202871

  4. Three cases of intravenous sodium benzoate and sodium phenylacetate toxicity occurring in the treatment of acute hyperammonaemia.

    PubMed

    Praphanphoj, V; Boyadjiev, S A; Waber, L J; Brusilow, S W; Geraghty, M T

    2000-03-01

    Intravenous sodium benzoate and sodium phenylacetate have been used successfully in the treatment of acute hyperammonaemia in patients with urea cycle disorders. They provide alternative pathways for waste nitrogen disposal and help maintain nitrogen homeostasis. However, we report three patients with hyperammonaemia who received inappropriate doses of intravenous sodium benzoate and sodium phenylacetate that resulted in severe complications. Ambiguous medical prescriptions and inadequate cross-checking of drug dosage by physicians, nurses and pharmacists were the main causes of these incidents. All the patients presented with alteration in mental status, Kussmaul respiration and a partially compensated metabolic acidosis with an increased anion gap. Two patients developed cerebral oedema and hypotension and died. The third survived after haemodialysis. Plasma levels of benzoate and phenylacetate were excessively high. The possible mechanisms of toxicity, management and safety measures are discussed.

  5. Symmorphosis through Dietary Regulation: A Combinatorial Role for Proteolysis, Autophagy and Protein Synthesis in Normalising Muscle Metabolism and Function of Hypertrophic Mice after Acute Starvation

    PubMed Central

    Giallourou, Natasa; Matsakas, Antonios; Mitchell, Robert; Mararenkova, Helen; Flasskamp, Hannah; Macharia, Raymond; Ray, Steve; Swann, Jonathan R.; Sandri, Marco; Patel, Ketan

    2015-01-01

    Animals are imbued with adaptive mechanisms spanning from the tissue/organ to the cellular scale which insure that processes of homeostasis are preserved in the landscape of size change. However we and others have postulated that the degree of adaptation is limited and that once outside the normal levels of size fluctuations, cells and tissues function in an aberant manner. In this study we examine the function of muscle in the myostatin null mouse which is an excellent model for hypertrophy beyond levels of normal growth and consequeces of acute starvation to restore mass. We show that muscle growth is sustained through protein synthesis driven by Serum/Glucocorticoid Kinase 1 (SGK1) rather than Akt1. Furthermore our metabonomic profiling of hypertrophic muscle shows that carbon from nutrient sources is being channelled for the production of biomass rather than ATP production. However the muscle displays elevated levels of autophagy and decreased levels of muscle tension. We demonstrate the myostatin null muscle is acutely sensitive to changes in diet and activates both the proteolytic and autophagy programmes and shutting down protein synthesis more extensively than is the case for wild-types. Poignantly we show that acute starvation which is detrimental to wild-type animals is beneficial in terms of metabolism and muscle function in the myostatin null mice by normalising tension production. PMID:25807490

  6. Effect of Resveratrol Administration on the Element Metabolism in the Blood and Brain Tissues of Rats Subjected to Acute Swimming Exercise.

    PubMed

    Baltaci, Abdulkerim Kasim; Arslangil, Dilek; Mogulkoc, Rasim; Patlar, Suleyman

    2017-02-01

    The aim of the present study is to examine how resveratrol administration affects the element metabolism in the blood and brain cortex tissues of rats subjected to an acute swimming exercise. The study was carried out on Wistar-Albino-type adult male rats supplied by the Center. Group 1 is the control group. Group 2 is the swimming control group. Group 3 is the resveratrol (10 mg/kg/day) + swimming group. Group 4 is the resveratrol (10 mg/kg/day) group. Blood and brain cortex tissues were analyzed for some elements. The acute swimming exercise led to increases in the rats' serum iron, selenium, lead, cobalt, and boron levels, while the resveratrol-swimming group has increases in copper, phosphorus, and calcium values. The brain cortex tissue of the resveratrol-swimming group had significantly higher molybdenum levels than others. The results obtained in the study indicate that acute swimming exercise altered the distribution of elements in the serum to a considerable extent; however, resveratrol's affect is limited. Especially, resveratrol supplementation may have a regulatory affect on serum iron and magnesium levels.

  7. Dietary polyunsaturated fats of the W-6 and W-3 series reduce postprandial lipoprotein levels. Chronic and acute effects of fat saturation on postprandial lipoprotein metabolism.

    PubMed Central

    Weintraub, M S; Zechner, R; Brown, A; Eisenberg, S; Breslow, J L

    1988-01-01

    The chronic and acute effects of different types of dietary fat on postprandial lipoprotein metabolism were studied in eight normolipidemic subjects. Each person was placed for 25 d on each of three isocaloric diets: a saturated fat (SFA), a w-6 polyunsaturated fat (w-6 PUFA) and a w-3 polyunsaturated fat (w-3 PUFA) diet. Two vitamin A-fat loading tests were done on each diet. The concentrations in total plasma and chylomicron (Sf greater than 1,000) and nonchylomicron (Sf less than 1,000) fractions of retinyl palmitate (RP) were measured for 12 h postprandially. Compared with the SFA diet, the w-6 PUFA diet reduced chylomicron and nonchylomicron RP levels 56 and 38%, respectively, and the w-3 PUFA diet reduced these levels 67 and 53%, respectively. On further analysis, the main determinant of postprandial lipoprotein levels was the type of fat that was chronically fed, which appeared to mediate its effect by changing the concentration of the endogenous competitor for the system that catabolizes triglyeride-rich lipoproteins. However, there was a significant effect of the acute dietary fat load, which appeared to be due to a differential susceptibility to lipolysis of chylomicrons produced by SFA as opposed to PUFA fat loads. The levels of postprandial lipoproteins are determined by the interaction of these chronic and acute effects. PMID:3058748

  8. Acute and chronic systemic CB1 cannabinoid receptor blockade improves blood pressure regulation and metabolic profile in hypertensive (mRen2)27 rats.

    PubMed

    Schaich, Chris L; Shaltout, Hossam A; Brosnihan, K Bridget; Howlett, Allyn C; Diz, Debra I

    2014-08-01

    We investigated acute and chronic effects of CB1 cannabinoid receptor blockade in renin-angiotensin system-dependent hypertension using rimonabant (SR141716A), an orally active antagonist with central and peripheral actions. In transgenic (mRen2)27 rats, a model of angiotensin II-dependent hypertension with increased body mass and insulin resistance, acute systemic blockade of CB1 receptors significantly reduced blood pressure within 90 min but had no effect in Sprague-Dawley rats. No changes in metabolic hormones occurred with the acute treatment. During chronic CB1 receptor blockade, (mRen2)27 rats received daily oral administration of SR141716A (10 mg/kg/day) for 28 days. Systolic blood pressure was significantly reduced within 24 h, and at Day 21 of treatment values were 173 mmHg in vehicle versus 149 mmHg in drug-treated rats (P < 0.01). This accompanied lower cumulative weight gain (22 vs. 42 g vehicle; P < 0.001), fat mass (2.0 vs. 2.9% of body weight; P < 0.05), and serum leptin (2.8 vs. 6.0 ng/mL; P < 0.05) and insulin (1.0 vs. 1.9 ng/mL; P < 0.01), following an initial transient decrease in food consumption. Conscious hemodynamic recordings indicate twofold increases occurred in spontaneous baroreflex sensitivity (P < 0.05) and heart rate variability (P < 0.01), measures of cardiac vagal tone. The beneficial actions of CB1 receptor blockade in (mRen2)27 rats support the interpretation that an upregulated endocannabinoid system contributes to hypertension and impaired autonomic function in this angiotensin II-dependent model. We conclude that systemic CB1 receptor blockade may be an effective therapy for angiotensin II-dependent hypertension and associated metabolic syndrome.

  9. Identification of HIF-1 signaling pathway in Pelteobagrus vachelli using RNA-Seq: effects of acute hypoxia and reoxygenation on oxygen sensors, respiratory metabolism, and hematology indices.

    PubMed

    Zhang, Guosong; Zhao, Cheng; Wang, Qintao; Gu, Yichun; Li, Zecheng; Tao, Panfeng; Chen, Jiawei; Yin, Shaowu

    2017-03-28

    Oxygen is a vital element in aquatic environments. The concentration of oxygen to which aquatic organisms are exposed is influenced by salinity, water temperature, weather, and surface water runoff. Hypoxia has a serious effect on fish populations, and can lead to the loss of habitat and die-offs. Therefore, in the present study we used next-generation sequencing technology to characterize the transcriptomes of Pelteobagrus vachelli and identified 70 candidate genes in the HIF-1 signaling pathway that are important for the hypoxic response in all metazoan species. For the first time, the present study reported the effects of acute hypoxia and reoxygenation on oxygen sensors, respiratory metabolism, and hematology indices in P. vachelli. The predicted physiological adjustments show that P. vachelli's blood oxygen-carrying capacity was increased through increased RBC, HB, and SI after hypoxia exposure. Glycolysis-related enzyme activities (PFK, HK, and PK) and LDH in the brain and liver also increased, indicating a rise in anaerobic metabolism. The observed reduction in oxidative enzyme level (CS) in the liver during hypoxia suggests a concomitant depression in aerobic metabolism. There were significant increases in oxygen sensor mRNA expression and HIF-1α protein expression during hypoxia and reoxygenation exposure, suggesting that the HIF-1 signaling pathway was activated in the liver and brain of P. vachelli in response to acute hypoxia and reoxygenation. Our findings suggest that oxygen sensors (e.g., HIF-1α) of P. vachelli are potentially useful biomarkers of environmental hypoxic exposure. These data contribute to a better understanding of the molecular mechanisms of the hypoxia signaling pathway in fish under hypoxia and reoxygenation.

  10. Liquid chromatographic-mass spectrometric method for simultaneous determination of small organic acids potentially contributing to acidosis in severe malaria.

    PubMed

    Sriboonvorakul, Natthida; Leepipatpiboon, Natchanun; Dondorp, Arjen M; Pouplin, Thomas; White, Nicholas J; Tarning, Joel; Lindegardh, Niklas

    2013-12-15

    Acidosis is an important cause of mortality in severe falciparum malaria. Lactic acid is a major contributor to metabolic acidosis, but accounts for only one-quarter of the strong anion gap. Other unidentified organic acids have an independent strong prognostic significance for a fatal outcome. In this study, a simultaneous bio-analytical method for qualitative and quantitative assessment in plasma and urine of eight small organic acids potentially contributing to acidosis in severe malaria was developed and validated. High-throughput strong anion exchange solid-phase extraction in a 96-well plate format was used for sample preparation. Hydrophilic interaction liquid chromatography (HILIC) coupled to negative mass spectroscopy was utilized for separation and detection. Eight possible small organic acids; l-lactic acid (LA), α-hydroxybutyric acid (aHBA), β-hydroxybutyric acid (bHBA), p-hydroxyphenyllactic acid (pHPLA), malonic acid (MA), methylmalonic acid (MMA), ethylmalonic acid (EMA) and α-ketoglutaric acid (aKGA) were analyzed simultaneously using a ZIC-HILIC column with an isocratic elution containing acetonitrile and ammonium acetate buffer. This method was validated according to U.S. Food and Drug Administration guidelines with additional validation procedures for endogenous substances. Accuracy for all eight acids ranged from 93.1% to 104.0%, and the within-day and between-day precisions (i.e. relative standard deviations) were lower than 5.5% at all tested concentrations. The calibration ranges were: 2.5-2500μg/mL for LA, 0.125-125μg/mL for aHBA, 7.5-375μg/mL for bHBA, 0.1-100μg/mL for pHPLA, 1-1000μg/mL for MA, 0.25-250μg/mL for MMA, 0.25-100μg/mL for EMA, and 30-1500μg/mL for aKGA. Clinical applicability was demonstrated by analyzing plasma and urine samples from five patients with severe falciparum malaria; five acids had increased concentrations in plasma (range LA=177-1169μg/mL, aHBA=4.70-38.4μg/mL, bHBA=7.70-38.0μg/mL, pHPLA=0.900-4.30

  11. Evaluation of in vitro models for predicting acidosis risk of barley grain in finishing beef cattle.

    PubMed

    Anele, U Y; Swift, M-L; McAllister, T A; Galyean, M L; Yang, W Z

    2015-10-01

    Our objective was to develop a model to predict the acidosis potential of barley based on the in vitro batch culture incubation of 50 samples varying in bulk density, starch content, processing method, growing location, and agronomic practices. The model was an adaptation of the acidosis index (calculated from a combination of in situ and in vitro analyses and from several components of grain chemical composition) developed in Australia for use in the feed industry to estimate the potential for grains to increase the risk of ruminal acidosis. Of the independent variables considered, DM disappearance at 6 h of incubation (DMD6) using reduced-strength (20%) buffer in the batch culture accounted for 90.5% of the variation in the acidosis index with a root mean square error (RMSE) of 4.46%. To evaluate our model using independent datasets (derived from previous batch culture studies using full-strength [100%] buffer), we performed another batch culture study using full-strength buffer. The full-strength buffer model using in vitro DMD6 (DMD6-FS) accounted for 66.5% of the variation in the acidosis index with an RMSE of 8.30%. When the new full-strength buffer model was applied to 3 independent datasets to predict acidosis, it accounted for 20.1, 28.5, and 30.2% of the variation in the calculated acidosis index. Significant ( < 0.001) mean bias was evident in 2 of the datasets, for which the DMD6 model underpredicted the acidosis index by 46.9 and 5.73%. Ranking of samples from the most diverse independent dataset using the DMD6-FS model and the Black (2008) model (calculated using in situ starch degradation) indicated the relationship between the rankings using Spearman's rank correlation was negative (ρ = -0.30; = 0.059). When the reduced-strength buffer model was used, however, there were similarities in the acidosis index ranking of barley samples by the models as shown by the result of a correlation analysis between calculated (using the Australian model) and

  12. Acute upregulation of neuronal mitochondrial type-1 cannabinoid receptor and it's role in metabolic defects and neuronal apoptosis after TBI.

    PubMed

    Xu, Zhen; Lv, Xiao-Ai; Dai, Qun; Ge, Yu-Qing; Xu, Jie

    2016-08-02

    Metabolic defects and neuronal apoptosis initiated by traumatic brain injury (TBI) contribute to subsequent neurodegeneration. They are all regulated by mechanisms centered around mitochondrion. Type-1 cannabinoid receptor (CB1) is a G-protein coupled receptor (GPCR) enriched on neuronal plasma membrane. Recent evidences point to the substantial presence of CB1 receptors on neuronal mitochondrial outer membranes (mtCB1) and the activation of mtCB1 influences aerobic respiration via inhibiting mitochondrial cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/complex I pathway. The expression and role of neuronal mtCB1 under TBI are unknown. Using TBI models of cultured neurons, wild type and CB1 knockout mice, we found mtCB1 quickly upregulated after TBI. Activation of mtCB1 promoted metabolic defects accompanied with ATP shortage but protected neurons from apoptosis. Selective activation of plasma membrane CB1 showed no effects on neuronal metabolism and apoptosis. Activation of mtCB1 receptors inhibited mitochondrial cAMP/PKA/complex I and resulted in exacerbated metabolic defects accompanied with a higher ratio of ATP reduction to oxygen consumption decrease as well as neuronal apoptosis. Further research found the remarkable accumulation of protein kinase B (AKT) on neuronal mitochondria following TBI and the activation of mtCB1 upregulated mitochondrial AKT/complex V activity. Upregulation of mitochondrial AKT/complex V activity showed anti-apoptosis effects and alleviated ATP shortage in metabolic defects. Taken together, we have identified mtCB1 quickly upregulate after TBI and a dual role the mtCB1 might play in metabolic defects and neuronal apoptosis initiated by TBI: the inhibition of mitochondrial cAMP/PKA/complex I aggravates metabolic defects, energy insufficiency as well as neuronal apoptosis, but the coactivation of mitochondrial AKT/complex V mitigates energy insufficiency and neuronal apoptosis.

  13. Inborn errors of metabolism in infancy: a guide to diagnosis.

    PubMed

    Burton, B K

    1998-12-01

    Recent advances in the diagnosis and treatment of inborn errors of metabolism have improved substantially the prognosis for many of these conditions. This makes it essential that the practicing pediatrician be familiar with the clinical presentation of these disorders. A practical clinical approach to the recognition of inborn errors of metabolism in the young infant is presented in this review. Indications for specific laboratory studies are discussed. Guidelines are provided for the stabilization and emergency treatment of critically ill infants. This approach will identify those infants who will benefit from additional evaluation and specific treatment. Many of the inborn errors of metabolism, including urea cycle defects, organic acidemias, and certain disorders of amino acid metabolism, present in the young infant with symptoms of an acute or chronic metabolic encephalopathy. Typical symptoms include lethargy, poor feeding, apnea or tachypnea, and recurrent vomiting. Metabolic acidosis and/or hyperammonemia are observed in many of these conditions, but there are notable exceptions, including nonketotic hyperglycinemia and molybdenum co-factor deficiency. Therefore, appropriate laboratory testing for metabolic disorders should be performed in any infant who exhibits these findings. Although sepsis may be the initial consideration in a neonate with these symptoms, inborn errors of metabolism should always be in the differential diagnosis, particularly in a full-term infant with no specific risk factors. Hypoglycemia may be the predominant finding in a number of inborn errors of metabolism, including glycogen storage disorders, defects in gluconeogenesis, and fatty acid oxidation defects. The latter disorders, among the most common encountered, exhibit marked clinical variability and also may present as a sudden death, a Reye's-like episode, or a cardiomyopathy. Jaundice or other evidence of hepatic dysfunction is the mode of presentation of another important

  14. Mechanisms of adaptation to chronic respiratory acidosis in the rabbit proximal tubule.

    PubMed Central

    Krapf, R

    1989-01-01

    The hyperbicarbonatemia of chronic respiratory acidosis is maintained by enhanced bicarbonate reabsorption in the proximal tubule. To investigate the cellular mechanisms involved in this adaptation, cell and luminal pH were measured microfluorometrically using (2",7')-bis(carboxyethyl)-(5,6)-carboxyfluorescein in isolated, microperfused S2 proximal convoluted tubules from control and acidotic rabbits. Chronic respiratory acidosis was induced by exposure to 10% CO2 for 52-56 h. Tubules from acidotic rabbits had a significantly lower luminal pH after 1-mm perfused length (7.03 +/- 0.09 vs. 7.26 +/- 0.06 in controls, perfusion rate = 10 nl/min). Chronic respiratory acidosis increased the initial rate of cell acidification (dpHi/dt) in response to luminal sodium removal by 63% and in response to lowering luminal pH (7.4-6.8) by 69%. Chronic respiratory acidosis also increased dpHi/dt in response to peritubular sodium removal by 63% and in response to lowering peritubular pH by 73%. In conclusion, chronic respiratory acidosis induces a parallel increase in the rates of the luminal Na/H antiporter and the basolateral Na/(HCO3)3 cotransporter. Therefore, the enhanced proximal tubule reabsorption of bicarbonate in chronic respiratory acidosis may be, at least in part, mediated by a parallel adaptation of these transporters. PMID:2537851

  15. PREDICTING THE ACUTE BEHAVIORAL EFFECTS OF TOLUENE INHALED FOR 24 HRS IN RATS: DOSE METRICS, METABOLISM AND BEHAVIORAL TOLERANCE

    EPA Science Inventory

    Purpose: Recent research on the acute effects of volatile organic compounds (VOCs) suggests that extrapolation from short (~ 1 h) to long durations (up to 4 h) is improved by using estimates of brain toluene concentration ( Br[ToI)] instead of cumulative inhaled dose (C x t) as a...

  16. High phosphorus intakes acutely and negatively affect Ca and bone metabolism in a dose-dependent manner in healthy young females.

    PubMed

    Kemi, Virpi E; Kärkkäinen, Merja U M; Lamberg-Allardt, Christel J E

    2006-09-01

    Ca and P are both essential nutrients for bone and are known to affect one of the most important regulators of bone metabolism, parathyroid hormone (PTH). Too ample a P intake, typical of Western diets, could be deleterious to bone through the increased PTH secretion. Few controlled dose-response studies are available on the effects of high P intake in man. We studied the short-term effects of four P doses on Ca and bone metabolism in fourteen healthy women, 20-28 years of age, who were randomized to four controlled study days; thus each study subject served as her own control. P supplement doses of 0 (placebo), 250, 750 or 1500 mg were taken, divided into three doses during the study day. The meals served were exactly the same during each study day and provided 495 mg P and 250 mg Ca. The P doses affected the serum PTH (S-PTH) in a dose-dependent manner (P=0.0005). There was a decrease in serum ionized Ca concentration only in the highest P dose (P=0.004). The marker of bone formation, bone-specific alkaline phosphatase, decreased (P=0.05) and the bone resorption marker, N-terminal telopeptide of collagen type I, increased in response to the P doses (P=0.05). This controlled dose-response study showed that P has a dose-dependent effect on S-PTH and increases PTH secretion significantly when Ca intake is low. Acutely high P intake adversely affects bone metabolism by decreasing bone formation and increasing bone resorption, as indicated by the bone metabolism markers.

  17. Bone turnover response is linked to both acute and established metabolic changes in ultra-marathon runners.

    PubMed

    Sansoni, Veronica; Vernillo, Gianluca; Perego, Silvia; Barbuti, Andrea; Merati, Giampiero; Schena, Federico; La Torre, Antonio; Banfi, Giuseppe; Lombardi, Giovanni

    2017-04-01

    Bone and energy metabolisms regulation depends on a two-way street aimed at regulating energy utilization. Mountain ultra-marathons are highly demanding aerobic performances that deeply affect the whole body homeostasis. In this study we aimed to investigate and characterize the metabolic profile (in terms of hormones involved in energy metabolism), the inflammatory adipokines, and the bone turnover; in particular the osteocalcin-mediated response has been compared in experienced mountain ultra-marathons runners versus control subjects. Serum concentrations of specific markers of bone turnover (pro-collagen type I N-terminal propeptide, carboxylated/undercarboxylated osteocalcin), measured by enzyme-linked immunosorbent assay, and metabolic hormones (C-peptide, insulin, glucagon, glucagon-like peptide, gastric-inhibitory peptide, ghrelin, leptin, resistin, and visfatin), measured by fluorescent-based multiplex assay, were compared before and after a 65 km mountain ultra-marathons in 17 trained runners and 12 age-matched controls characterized by a low physical activity profile. After the mountain ultra-marathons, runners experienced a reduction in pro-collagen type I N-terminal propeptide, though it remained higher than in controls; while carboxylated osteocalcin remained unchanged. Among the metabolic hormones, only glucagon and leptin were different between runners and controls at rest. C-peptide and leptin decreased after the mountain ultra-marathons in runners; while glucagon, glucagon-like peptide 1, resistin, and visfatin were all increased. Uncarboxylated osteocalcin (and uncarboxylated/carboxylated osteocalcin ratio) was decreased and this highly correlated with insulin and C-peptide levels. In conditions of high energy expenditure, homeostasis is maintained at expenses of bone metabolism. Changes in the uncarboxylated osteocalcin clearly mark the global energy needs of the body.

  18. Thiamine Deficiency in Tropical Pediatrics: New Insights into a Neglected but Vital Metabolic Challenge.

    PubMed

    Hiffler, Laurent; Rakotoambinina, Benjamin; Lafferty, Nadia; Martinez Garcia, Daniel

    2016-01-01

    In humans, thiamine is a micronutrient prone to depletion that may result in severe clinical abnormalities. This narrative review summarizes current knowledge on thiamine deficiency (TD) and bridges the gap between pathophysiology and clinical presentation by integrating thiamine metabolism at subcellular level with its function to vital organs. The broad clinical spectrum of TD is outlined, with emphasis on conditions encountered in tropical pediatric practice. In particular, TD is associated with type B lactic acidosis and classic forms of beriberi in children, but it is often unrecognized. Other severe acute conditions are associated with hypermetabolism, inducing a functional TD. The crucial role of thiamine in infant cognitive development is also highlighted in this review, along with analysis of the potential impact of TD in refeeding syndrome during severe acute malnutrition (SAM). This review aims to increase clinical awareness of TD in tropical settings where access to diagnostic tests is poor, and advocates for an early therapeutic thiamine challenge in resource-limited settings. Moreover, it provides evidence for thiamine as treatment in critical conditions requiring metabolic resuscitation, and gives rationale to the consideration of increased thiamine supplementation in therapeutic foods for malnourished children.

  19. Thiamine Deficiency in Tropical Pediatrics: New Insights into a Neglected but Vital Metabolic Challenge

    PubMed Central

    Hiffler, Laurent; Rakotoambinina, Benjamin; Lafferty, Nadia; Martinez Garcia, Daniel

    2016-01-01

    In humans, thiamine is a micronutrient prone to depletion that may result in severe clinical abnormalities. This narrative review summarizes current knowledge on thiamine deficiency (TD) and bridges the gap between pathophysiology and clinical presentation by integrating thiamine metabolism at subcellular level with its function to vital organs. The broad clinical spectrum of TD is outlined, with emphasis on conditions encountered in tropical pediatric practice. In particular, TD is associated with type B lactic acidosis and classic forms of beriberi in children, but it is often unrecognized. Other severe acute conditions are associated with hypermetabolism, inducing a functional TD. The crucial role of thiamine in infant cognitive development is also highlighted in this review, along with analysis of the potential impact of TD in refeeding syndrome during severe acute malnutrition (SAM). This review aims to increase clinical awareness of TD in tropical settings where access to diagnostic tests is poor, and advocates for an early therapeutic thiamine challenge in resource-limited settings. Moreover, it provides evidence for thiamine as treatment in critical conditions requiring metabolic resuscitation, and gives rationale to the consideration of increased thiamine supplementation in therapeutic foods for malnourished children. PMID:27379239

  20. G418-mediated ribosomal read-through of a nonsense mutation causing autosomal recessive proximal renal tubular acidosis

    PubMed Central

    Azimov, Rustam; Abuladze, Natalia; Sassani, Pakan; Newman, Debra; Kao, Liyo; Liu, Weixin; Orozco, Nicholas; Ruchala, Piotr; Pushkin, Alexander; Kurtz, Ira

    2008-01-01

    Autosomal recessive proximal renal tubular acidosis is caused by mutations in the SLC4A4 gene encoding the electrogenic sodium bicarbonate cotransporter NBCe1-A. The mutations that have been characterized thus far result in premature truncation, mistargeting, or decreased function of the cotransporter. Despite bicarbonate treatment to correct the metabolic acidosis, extrarenal manifestations persist, including glaucoma, cataracts, corneal opacification, and mental retardation. Currently, there are no known therapeutic approaches that can specifically target mutant NBCe1-A proteins. In the present study, we tested the hypothesis that the NBCe1-A-Q29X mutation can be rescued in vitro by treatment with aminoglycoside antibiotics, which are known for their ability to suppress premature stop codons. As a model system, we cloned the NBCe1-A-Q29X mutant into a vector lacking an aminoglycoside resistance gene and transfected the mutant cotransporter in HEK293-H cells. Cells transfected with the NBCe1-A-Q29X mutant failed to express the cotransporter because of the premature stop codon. Treatment of the cells with G418 significantly increased the expression of the full-length cotransporter, as assessed by immunoblot analysis. Furthermore, immunocytochemical studies demonstrated that G418 treatment induced cotransporter expression on the plasma membrane whereas in the absence of G418, NBCe1-A-Q29X was not expressed. In HEK293-H cells transfected with the NBCe1-A-Q29X mutant not treated with G418, NBCe1-A-mediated flux was not detectable. In contrast, in cells transfected with the NBCe1-A-Q29X mutant, G418 treatment induced Na+- and HCO3−-dependent transport that did not differ from wild-type NBCe1-A function. G418 treatment in mock-transfected cells was without effect. In conclusion, G418 induces ribosomal read-through of the NBCe1-A-Q29X mutation in HEK293-H cells. These findings represent the first evidence that in the presence of the NBCe1-A-Q29X mutation that causes

  1. G418-mediated ribosomal read-through of a nonsense mutation causing autosomal recessive proximal renal tubular acidosis.

    PubMed

    Azimov, Rustam; Abuladze, Natalia; Sassani, Pakan; Newman, Debra; Kao, Liyo; Liu, Weixin; Orozco, Nicholas; Ruchala, Piotr; Pushkin, Alexander; Kurtz, Ira

    2008-09-01

    Autosomal recessive proximal renal tubular acidosis is caused by mutations in the SLC4A4 gene encoding the electrogenic sodium bicarbonate cotransporter NBCe1-A. The mutations that have been characterized thus far result in premature truncation, mistargeting, or decreased function of the cotransporter. Despite bicarbonate treatment to correct the metabolic acidosis, extrarenal manifestations persist, including glaucoma, cataracts, corneal opacification, and mental retardation. Currently, there are no known therapeutic approaches that can specifically target mutant NBCe1-A proteins. In the present study, we tested the hypothesis that the NBCe1-A-Q29X mutation can be rescued in vitro by treatment with aminoglycoside antibiotics, which are known for their ability to suppress premature stop codons. As a model system, we cloned the NBCe1-A-Q29X mutant into a vector lacking an aminoglycoside resistance gene and transfected the mutant cotransporter in HEK293-H cells. Cells transfected with the NBCe1-A-Q29X mutant failed to express the cotransporter because of the premature stop codon. Treatment of the cells with G418 significantly increased the expression of the full-length cotransporter, as assessed by immunoblot analysis. Furthermore, immunocytochemical studies demonstrated that G418 treatment induced cotransporter expression on the plasma membrane whereas in the absence of G418, NBCe1-A-Q29X was not expressed. In HEK293-H cells transfected with the NBCe1-A-Q29X mutant not treated with G418, NBCe1-A-mediated flux was not detectable. In contrast, in cells transfected with the NBCe1-A-Q29X mutant, G418 treatment induced Na(+)- and HCO(3)(-)-dependent transport that did not differ from wild-type NBCe1-A function. G418 treatment in mock-transfected cells was without effect. In conclusion, G418 induces ribosomal read-through of the NBCe1-A-Q29X mutation in HEK293-H cells. These findings represent the first evidence that in the presence of the NBCe1-A-Q29X mutation that

  2. The StarD4 subfamily of steroidogenic acute regulatory-related lipid transfer (START) domain proteins: new players in cholesterol metabolism.

    PubMed

    Calderon-Dominguez, Maria; Gil, Gregorio; Medina, Miguel Angel; Pandak, William M; Rodríguez-Agudo, Daniel

    2014-04-01

    Cholesterol levels in the body are maintained through the coordinated regulation of its uptake, synthesis, distribution, storage and efflux. However, the way cholesterol is sorted within cells remains poorly defined. The discovery of the newly described StarD4 subfamily, part of the steroidogenic acute regulatory lipid transfer (START) domain family of proteins, affords an opportunity for the study of intracellular cholesterol movement, metabolism and its disorders. The three members of this intracellular subfamily of proteins (StarD4, StarD5 and StarD6) have a similar lipid binding pocket specific for sterols (cholesterol in particular), but differing regulation and localization. The ability to bind and transport cholesterol through a non-vesicular mean suggests that they play a previously unappreciated role in cholesterol homeostasis.

  3. Acute Self-Induced Poisoning With Sodium Ferrocyanide and Methanol Treated With Plasmapheresis and Continuous Renal Replacement Therapy Successfully

    PubMed Central

    Liu, Zhenning; Sun, Mingli; Zhao, Hongyu; Zhao, Min

    2015-01-01

    Abstract Self-induced poisoning with chemicals is one of the most commonly used suicide methods. Suicide attempts using massive pure sodium ferrocyanide and methanol are rare. This article discusses the management of acute intentional self-poisoning using sodium ferrocyanide and methanol. We present a case of acute self-induced poisoning using sodium ferrocyanide and methanol admitted to our hospital 2 hours after ingestion. He was deeply unconscious and unresponsive to painful stimuli. The laboratory findings showed acute kidney injury and severe metabolic acidosis. We took effective measures including endotracheal intubation and mechanical ventilation to ensure the vital signs were stable. Subsequently, we treated the patient using gastric lavage, bicarbonate, ethanol, plasmapheresis (plasma exchange), and continuous renal replacement therapy (CRRT) successfully. He gradually recovered from poisoning and was discharged without abnormalities on the 6th day. Follow-up for 3 months revealed no sequelae. Blood purification including plasmapheresis and CRRT is an effective method to scavenge toxicants from the body for acute self-poisoning with sodium ferrocyanide and methanol. Treatment strategies in the management of poisoning, multiple factors including the removal efficiency of toxin, the protection of vital organs, and the maintenance of homeostasis must be considered. PMID:26020397

  4. Baking soda induced severe metabolic alkalosis in a haemodialysis patient.

    PubMed

    Solak, Yalcin; Turkmen, Kultigin; Atalay, Huseyin; Turk, Suleyman

    2009-08-01

    Metabolic alkalosis is a rare occurence in hemodialysis population compared to metabolic acidosis unless some precipitating factors such as nasogastric suction, vomiting and alkali ingestion or infusion are present. When metabolic alkalosis develops, it may cause serious clinical consequences among them are sleep apnea, resistent hypertension, dysrhythmia and seizures. Here, we present a 54-year-old female hemodialysis patient who developed a severe metabolic alkalosis due to baking soda ingestion to relieve dyspepsia. She had sleep apnea, volume overload and uncontrolled hypertension due to metabolic alkalosis. Metabolic alkalosis was corrected and the patient's clinical condition was relieved with negative-bicarbonate hemodialysis.

  5. Englerin A induces an acute inflammatory response and reveals lipid metabolism and ER stress as targetable vulnerabilities in renal cell carcinoma

    PubMed Central

    Batova, Ayse; Altomare, Diego; Creek, Kim E.; Naviaux, Robert K.; Wang, Lin; Li, Kefeng; Green, Erica; Williams, Richard; Naviaux, Jane C.; Diccianni, Mitchell; Yu, Alice L.

    2017-01-01

    Renal cell carcinoma (RCC) is among the top ten most common forms of cancer and is the most common malignancy of the kidney. Clear cell renal carcinoma (cc-RCC), the most common type of RCC, is one of the most refractory cancers with an incidence that is on the rise. Screening of plant extracts in search of new anti-cancer agents resulted in the discovery of englerin A, a guaiane sesquiterpene with potent cytotoxicity against renal cancer cells and a small subset of other cancer cells. Though a few cellular targets have been identified for englerin A, it is still not clear what mechanisms account for the cytotoxicity of englerin A in RCC, which occurs at concentrations well below those used to engage the targets previously identified. Unlike any prior study, the current study used a systems biology approach to explore the mechanism(s) of action of englerin A. Metabolomics analyses indicated that englerin A profoundly altered lipid metabolism by 24 h in cc-RCC cell lines and generated significant levels of ceramides that were highly toxic to these cells. Microarray analyses determined that englerin A induced ER stress signaling and an acute inflammatory response, which was confirmed by quantitative PCR and Western Blot analyses. Additionally, fluorescence confocal microscopy revealed that englerin A at 25 nM disrupted the morphology of the ER confirming the deleterious effect of englerin A on the ER. Collectively, our findings suggest that cc-RCC is highly sensitive to disruptions in lipid metabolism and ER stress and that these vulnerabilities can be targeted for the treatment of cc-RCC and possibly other lipid storing cancers. Furthermore, our results suggest that ceramides may be a mediator of some of the actions of englerin A. Lastly, the acute inflammatory response induced by englerin A may mediate anti-tumor immunity. PMID:28296891

  6. Englerin A induces an acute inflammatory response and reveals lipid metabolism and ER stress as targetable vulnerabilities in renal cell carcinoma.

    PubMed

    Batova, Ayse; Altomare, Diego; Creek, Kim E; Naviaux, Robert K; Wang, Lin; Li, Kefeng; Green, Erica; Williams, Richard; Naviaux, Jane C; Diccianni, Mitchell; Yu, Alice L

    2017-01-01

    Renal cell carcinoma (RCC) is among the top ten most common forms of cancer and is the most common malignancy of the kidney. Clear cell renal carcinoma (cc-RCC), the most common type of RCC, is one of the most refractory cancers with an incidence that is on the rise. Screening of plant extracts in search of new anti-cancer agents resulted in the discovery of englerin A, a guaiane sesquiterpene with potent cytotoxicity against renal cancer cells and a small subset of other cancer cells. Though a few cellular targets have been identified for englerin A, it is still not clear what mechanisms account for the cytotoxicity of englerin A in RCC, which occurs at concentrations well below those used to engage the targets previously identified. Unlike any prior study, the current study used a systems biology approach to explore the mechanism(s) of action of englerin A. Metabolomics analyses indicated that englerin A profoundly altered lipid metabolism by 24 h in cc-RCC cell lines and generated significant levels of ceramides that were highly toxic to these cells. Microarray analyses determined that englerin A induced ER stress signaling and an acute inflammatory response, which was confirmed by quantitative PCR and Western Blot analyses. Additionally, fluorescence confocal microscopy revealed that englerin A at 25 nM disrupted the morphology of the ER confirming the deleterious effect of englerin A on the ER. Collectively, our findings suggest that cc-RCC is highly sensitive to disruptions in lipid metabolism and ER stress and that these vulnerabilities can be targeted for the treatment of cc-RCC and possibly other lipid storing cancers. Furthermore, our results suggest that ceramides may be a mediator of some of the actions of englerin A. Lastly, the acute inflammatory response induced by englerin A may mediate anti-tumor immunity.

  7. Acute and Fatal Isoniazid-Induced Hepatotoxicity: A Case Report and Review of the Literature

    PubMed Central

    Sarkis, Aline T.; Saroufim, Paola G.

    2016-01-01

    This paper describes a case of an acute and fatal isoniazid-induced hepatotoxicity and provides a review of the literature. A 65-year-old female diagnosed with latent Mycobacterium tuberculosis infection was receiving oral isoniazid 300 mg daily. She was admitted to the hospital for epigastric and right sided flank pain of one-week duration. Laboratory results and imaging confirmed hepatitis. After ruling out all other possible causes, she was diagnosed with isoniazid-induced acute hepatitis (probable association by the Naranjo scale). After discharge, the patient was readmitted and suffered from severe coagulopathy, metabolic acidosis, acute kidney injury, hepatic encephalopathy, and cardiorespiratory arrest necessitating two rounds of cardiopulmonary resuscitation. Despite maximal hemodynamic support, the patient did not survive. A review of the literature, from several European countries and the United States of America, revealed a low incidence of mortality due to isoniazid-induced hepatotoxicity when used as a single agent for latent Mycobacterium tuberculosis infection. As for the management, the first step consists of withdrawing isoniazid and rechallenge is usually discouraged. Few treatment modalities have been proposed; however there is no robust evidence to support any of them. Routine monitoring for hepatotoxicity in patients receiving isoniazid is warranted to prevent morbidity and mortality. PMID:27648319

  8. Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification.

    PubMed

    Sly, W S; Whyte, M P; Sundaram, V; Tashian, R E; Hewett-Emmett, D; Guibaud, P; Vainsel, M; Baluarte, H J; Gruskin, A; Al-Mosawi, M

    1985-07-18

    Osteopetrosis with renal tubular acidosis and cerebral calcification was identified as a recessively inherited syndrome in 1972. In 1983, we reported a deficiency of carbonic anhydrase II, one of the isozymes of carbonic anhydrase, in three sisters with this disorder. We now describe our study of 18 similarly affected patients with this syndrome in 11 unrelated families of different geographic and ethnic origins. Virtual absence of the carbonic anhydrase II peak on high-performance liquid chromatography, of the esterase and carbon dioxide hydratase activities of carbonic anhydrase II, and of immunoprecipitable isozyme II was demonstrated on extracts of erythrocyte hemolysates from all patients studied. Reduced levels of isozyme II were found in obligate heterozygotes. These observations demonstrate the generality of the findings that we reported earlier in one family and provide further evidence that a deficiency of carbonic anhydrase II is the enzymatic basis for the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. We also summarize the clinical findings in these families, propose mechanisms by which a deficiency of carbonic anhydrase II could produce this metabolic disorder of bone, kidney, and brain, and discuss the clinical evidence for genetic heterogeneity in patients from different kindreds with this inborn error of metabolism.

  9. Pathology of acute ischemic myocardium. Special references to (I) evaluation of morphological methods for detection of early myocardial infarcts, and (II) lipid metabolism in infarcted myocardium.

    PubMed

    Sakurai, I

    1977-09-01

    Morphological changes of early myocardial infarction within 24 hours after the onset of the acute attack were described together with a review of the literatures. For the practical purpose in detecting very early infarcts, enzymatic histochemistry is the most reliable method. Other methods previously reported such as wavy pattern of the muscle fibers and fuchsinophilia are still controvertial. Lipid metabolism in the infarcted myocardium of dogs was studied both morphologically and biochemically. Up to 3 hours, after the coronary ligation, the tissue lipids accumulated in the necrotic areas with a rise of triglyceride, but later than 6 hours the lipids decreased and were lost from the necrotic tissue, while the surrounding living cells were accumulated with neutral lipids. Serum free fatty acids were elevated in the coronary sinus blood in 6 hours after the ligation. Linolic acids were contained in high proportion in both coronary venous blood after 6 hours, and normal myocardial phospholipid. These results may lead to another possible factor in addition to catecholamine activity to elevate serum FFA in acute myocardial infarction that fatty acids may be released partly from tissue phospholipid and once ever accumulated triglyceride.

  10. Similarities in acute phase protein response during hibernation in black bears and major depression in humans: A response to underlying metabolic depression?

    USGS Publications Warehouse

    Tsiouris, J.A.; Chauhan, V.P.S.; Sheikh, A.M.; Chauhan, A.; Malik, M.; Vaughan, M.R.

    2004-01-01

    This study investigated the effects of hibernation with mild hypothermia and the stress of captivity on levels of six acute-phase proteins (APPs) in serial samples of serum from 11 wild and 6 captive black bears (Ursus americanus Pallas, 1780) during active and hibernating states. We hypothesize that during hibernation with mild hypothermia, bears would show an APP response similar to that observed in major depression. Enzyme-linked immunoabsorbent assay was used to measure alpha2-macroglobulin and C-reactive protein, and a nephelometer to measure alpha1-antitrypsin, haptoglobin, ceruloplasmin, and transferrin. Levels of all other proteins except ceruloplasmin were significantly elevated during hibernation in both wild and captive bears at the p < 0.05 to p < 0.001 level. Alpha 2-macroglobulin and C-reactive-protein levels were increased in captive versus wild bears in both active and hibernating states at the p < 0.01 to p < 0.0001 level. During hibernation with mild hypothermia, black bears do not show immunosuppression, but show an increased APP response similar to that in patients with major depression. This APP response is explained as an adaptive response to the underlying metabolic depression in both conditions. Metabolic depression in hibernating bears is suggested as a natural model for research to explain the neurobiology of depression.

  11. In vivo imaging of hemodynamics and oxygen metabolism in acute focal cerebral ischemic rats with laser speckle imaging and functional photoacoustic microscopy

    NASA Astrophysics Data System (ADS)

    Deng, Zilin; Wang, Zhen; Yang, Xiaoquan; Luo, Qingming; Gong, Hui

    2012-08-01

    Stroke is a devastating disease. The changes in cerebral hemodynamics and oxygen metabolism associated with stroke play an important role in pathophysiology study. But the changes were difficult to describe with a single imaging modality. Here the changes in cerebral blood flow (CBF), cerebral blood volume (CBV), and oxygen saturation (SO2) were yielded with laser speckle imaging (LSI) and photoacoustic microscopy (PAM) during and after 3-h acute focal ischemic rats. These hemodynamic measures were further synthesized to deduce the changes in oxygen extraction fraction (OEF). The results indicate that all the hemodynamics except CBV had rapid declines within 40-min occlusion of middle cerebral artery (MCAO). CBV in arteries and veins first increased to the maximum value of 112.42±36.69% and 130.58±31.01% by 15 min MCAO; then all the hemodynamics had a persistent reduction with small fluctuations during the ischemic. When ischemia lasted for 3 h, CBF in arteries, veins decreased to 17±14.65%, 24.52±20.66%, respectively, CBV dropped to 62±18.56% and 59±18.48%. And the absolute SO2 decreased by 40.52±22.42% and 54.24±11.77%. After 180-min MCAO, the changes in hemodynamics and oxygen metabolism were also quantified. The study suggested that combining LSI and PAM provides an attractive approach for stroke detection in small animal studies.

  12. Salecan protected against concanavalin A-induced acute liver injury by modulating T cell immune responses and NMR-based metabolic profiles.

    PubMed

    Sun, Qi; Xu, Xi; Yang, Xiao; Weng, Dan; Wang, Junsong; Zhang, Jianfa

    2017-02-15

    Salecan, a water-soluble extracellular β-glucan produced by Agrobacterium sp. ZX09, has been reported to exhibit a wide range of biological effects. The aims of the present study were to investigate the protective effect of salecan against Concanavalin A (ConA)-induced hepatitis, a well-established animal model of immune-mediated liver injury, and to search for possible mechanisms. C57BL/6 mice were pretreated with salecan followed by ConA injection. Salecan treatment significantly reduced ConA-induced acute liver injury, and suppressed the expression and secretion of inflammatory cytokines including interferon (IFN)-γ, interleukin (IL)-6 and IL-1β in ConA-induced liver injury model. The high expression levels of chemokines and adhesion molecules such as MIP-1α, MIP-1β, ICAM-1, MCP-1 and RANTES in the liver induced by ConA were also down-regulated after salecan treatment. Salecan inhibited the infiltration and activation of inflammatory cells, especially T cells, in the liver induced by ConA. Moreover, salecan reversed the metabolic profiles of ConA-treated mice towards the control group by partly recovering the metabolic perturbations induced by ConA. Our results suggest the preventive and therapeutic potential of salecan in immune-mediated hepatitis.

  13. In vivo imaging of hemodynamics and oxygen metabolism in acute focal cerebral ischemic rats with laser speckle imaging and functional photoacoustic microscopy.

    PubMed

    Deng, Zilin; Wang, Zhen; Yang, Xiaoquan; Luo, Qingming; Gong, Hui

    2012-08-01

    Stroke is a devastating disease. The changes in cerebral hemodynamics and oxygen metabolism associated with stroke play an important role in pathophysiology study. But the changes were difficult to describe with a single imaging modality. Here the changes in cerebral blood flow (CBF), cerebral blood volume (CBV), and oxygen saturation (SO2) were yielded with laser speckle imaging (LSI) and photoacoustic microscopy (PAM) during and after 3-h acute focal ischemic rats. These hemodynamic measures were further synthesized to deduce the changes in oxygen extraction fraction (OEF). The results indicate that all the hemodynamics except CBV had rapid declines within 40-min occlusion of middle cerebral artery (MCAO). CBV in arteries and veins first increased to the maximum value of 112.42 ± 36.69% and 130.58 ± 31.01% by 15 min MCAO; then all the hemodynamics had a persistent reduction with small fluctuations during the ischemic. When ischemia lasted for 3 h, CBF in arteries, veins decreased to 17 ± 14.65%, 24.52 ± 20.66%, respectively, CBV dropped to 62 ± 18.56% and 59 ± 18.48%. And the absolute SO2 decreased by 40.52 ± 22.42% and 54.24 ± 11.77%. After 180-min MCAO, the changes in hemodynamics and oxygen metabolism were also quantified. The study suggested that combining LSI and PAM provides an attractive approach for stroke detection in small animal studies.

  14. Rapidly fatal community-acquired pneumonia due to Klebsiella pneumoniae complicated with acute myocarditis and accelerated idioventricular rhythm.

    PubMed

    Chuang, Tzu-Yi; Lin, Chou-Jui; Lee, Shih-Wei; Chuang, Chun-Pin; Jong, Yuh-Shiun; Chen, Wen-Jone; Hsueh, Po-Ren

    2012-08-01

    We describe a previously healthy 52-year-old man with rapidly fatal community-acquired pneumonia caused by Klebsiella pneumoniae. The patient developed acute renal dysfunction, accelerated idioventricular rhythm (acute myocarditis), lactic acidosis and septic shock. He died within 15 hours after admission despite intravenous levofloxacin (750 mg daily) and aggressive medical treatment.

  15. Pyruvate dehydrogenase-E1α deficiency presenting as recurrent acute proximal muscle weakness of upper and lower extremities in an 8-year-old boy.

    PubMed

    Kara, Bülent; Genç, Hülya Maraş; Uyur-Yalçın, Emek; Sakarya-Güneş, Ayfer; Topçu, Uğur; Mülayim, Serap; Ceylaner, Serdar

    2017-01-01

    The mitochondrial pyruvate dehydrogenase enzyme complex (PDHC) plays an important role in aerobic energy metabolism and acid-base equilibrium. PDHC contains of 5 enzymes, 3 catalytic (E1, E2, E3) and 2 regulatory, as well as 3 cofactors and an additional protein (E3-binding protein) encoded by nuclear genes. The clinical presentation of PDHC deficiency ranges from fatal neonatal lactic acidosis to chronic neurologic dysfunction without lactic acidosis. Paroxysmal neurologic problems such as intermittent ataxia, episodic weakness, exercise-induced dystonia and recurrent demyelination may also be seen although they are rare. Here, we present an 8-year-old boy complaining of acute proximal muscle weakness of upper and lower extremities with normal mental status. He had a history of Guillain-Barré-like syndrome at the age of 2 years. Electrophysiologic studies showed sensorial polyneuropathy findings in the first attack and sensorimotor axonal polyneuropathy findings in the last attack. The genetic analysis revealed a previously reported hemizygote novel mutation of the PDHA1 gene (p.A353T/c.1057G > A), which encodes the E1α subunit of PDHC. Thiamine was ordered (15 mg/kg/day), dietary carbohydrates were restricted and clinical findings improved in a few weeks. This rare phenotype of PDHC deficiency is discussed.

  16. How porphyrinogenic drugs modeling acute porphyria impair the hormonal status that regulates glucose metabolism. Their relevance in the onset of this disease.

    PubMed

    Matkovic, Laura B; D'Andrea, Florencia; Fornes, Daiana; San Martín de Viale, Leonor C; Mazzetti, Marta B

    2011-11-28

    This work deals with the study of how porphyrinogenic drugs modeling acute porphyrias interfere with the status of carbohydrate-regulating hormones in relation to key glucose enzymes and to porphyria, considering that glucose modulates the development of the disease. Female Wistar rats were treated with 2-allyl-2-isopropylacetamide (AIA) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) using different doses of AIA (100, 250 and 500mg/kg body weight) and a single dose of DDC (50mg DDC/kg body weight). Rats were sacrificed 16h after AIA/DDC administration. In the group treated with the highest dose of AIA (group H), hepatic 5-aminolevulinic acid synthase (ALA-S) increased more than 300%, phosphoenolpyruvate carboxykinase (PEPCK) and glycogen phosphorylase (GP) activities were 43% and 46% lower than the controls, respectively, plasmatic insulin levels exceeded normal values by 617%, and plasmatic glucocorticoids (GC) decreased 20%. GC results are related to a decrease in corticosterone (CORT) adrenal production (33%) and a significant reduction in its metabolization by UDP-glucuronosyltransferase (UGT) (62%). Adrenocorticotropic hormone (ACTH) stimulated adrenal production 3-fold and drugs did not alter this process. Thus, porphyria-inducing drugs AIA and DDC dramatically altered the status of hormones that regulate carbohydrate metabolism increasing insulin levels and reducing GC production, metabolization and plasmatic levels. In this acute porphyria model, gluconeogenic and glycogenolytic blockages caused by PEPCK and GP depressed activities, respectively, would be mainly a consequence of the negative regulatory action of insulin on these enzymes. GC could also contribute to PEPCK blockage both because they were depressed by the treatment and because they are positive effectors on PEPCK. These disturbances in carbohydrates and their regulation, through ALA-S de-repression, would enhance the porphyria state promoted by the drugs on heme synthesis and destruction

  17. A novel heterozygous mutation in the ATP6V0A4 gene encoding the V-ATPase a4 subunit in an adult patient with incomplete distal renal tubular acidosis

    PubMed Central

    Imai, Eri; Kaneko, Shuzo; Mori, Takayasu; Okado, Tomokazu; Uchida, Shinichi; Tsukamoto, Yusuke

    2016-01-01

    A 40-year-old Japanese man who had a medical history of hypokalemic periodic paralysis 4 months prior was hospitalized to undergo a cholecystectomy. Hypokalemia, nephrocalcinosis and alkaluria suggesting distal renal tubular acidosis (dRTA) were detected, but metabolic acidosis was not evident. An ammonium chloride/furosemide–fludrocortisone/bicarbonate loading test demonstrated a remarkable disability in urinary H+ excretion. A novel heterozygous mutation in the ATP6V0A4 gene encoding the vacuolar H+-ATPase (V-ATPase) a4 subunit p.S544L was detected. Among cases of V-ATPase a4 mutations, this is the first case in which a heterozygous mutation developed to an incomplete or latent form of dRTA. PMID:27274828

  18. Antiretroviral drugs and acute pancreatitis in HIV/AIDS patients: is there any association? A literature review

    PubMed Central

    Oliveira, Natalia Mejias; Ferreira, Felipe Augusto Yamauti; Yonamine, Raquel Yumi; Chehter, Ethel Zimberg

    2014-01-01

    ABSTRACT In HIV-seropositive individuals, the incidence of acute pancreatitis may achieve 40% per year, higher than the 2% found in the general population. Since 1996, when combined antiretroviral therapy, known as HAART (highly active antiretroviral therapy), was introduced, a broad spectrum of harmful factors to the pancreas, such as opportunistic infections and drugs used for chemoprophylaxis, dropped considerably. Nucleotide analogues and metabolic abnormalities, hepatic steatosis and lactic acidosis have emerged as new conditions that can affect the pancreas. To evaluate the role of antiretroviral drugs to treat HIV/AIDS in a scenario of high incidence of acute pancreatitis in this population, a systematic review was performed, including original articles, case reports and case series studies, whose targets were HIV-seropositive patients that developed acute pancreatitis after exposure to any antiretroviral drugs. This association was confirmed after exclusion of other possible etiologies and/or a recurrent episode of acute pancreatitis after re-exposure to the suspected drug. Zidovudine, efavirenz, and protease inhibitors are thought to lead to acute pancreatitis secondary to hyperlipidemia. Nucleotide reverse transcriptase inhibitors, despite being powerful inhibitors of viral replication, induce a wide spectrum of side effects, including myelotoxicity and acute pancreatitis. Didanosine, zalcitabine and stavudine have been reported as causes of acute and chronic pancreatitis. They pose a high risk with cumulative doses. Didanosine with hydroxyurea, alcohol or pentamidine are additional risk factors, leading to lethal pancreatitis, which is not a frequent event. In addition, other drugs used for prophylaxis of AIDS-related opportunistic diseases, such as sulfamethoxazole-trimethoprim and pentamidine, can produce necrotizing pancreatitis. Despite comorbidities that can lead to pancreatic involvement in the HIV/AIDS population, antiretroviral drug

  19. Antiretroviral drugs and acute pancreatitis in HIV/AIDS patients: is there any association? A literature review.

    PubMed

    Oliveira, Natalia Mejias; Ferreira, Felipe Augusto Yamauti; Yonamine, Raquel Yumi; Chehter, Ethel Zimberg

    2014-01-01

    In HIV-seropositive individuals, the incidence of acute pancreatitis may achieve 40% per year, higher than the 2% found in the general population. Since 1996, when combined antiretroviral therapy, known as HAART (highly active antiretroviral therapy), was introduced, a broad spectrum of harmful factors to the pancreas, such as opportunistic infections and drugs used for chemoprophylaxis, dropped considerably. Nucleotide analogues and metabolic abnormalities, hepatic steatosis and lactic acidosis have emerged as new conditions that can affect the pancreas. To evaluate the role of antiretroviral drugs to treat HIV/AIDS in a scenario of high incidence of acute pancreatitis in this population, a systematic review was performed, including original articles, case reports and case series studies, whose targets were HIV-seropositive patients that developed acute pancreatitis after exposure to any antiretroviral drugs. This association was confirmed after exclusion of other possible etiologies and/or a recurrent episode of acute pancreatitis after re-exposure to the suspected drug. Zidovudine, efavirenz, and protease inhibitors are thought to lead to acute pancreatitis secondary to hyperlipidemia. Nucleotide reverse transcriptase inhibitors, despite being powerful inhibitors of viral replication, induce a wide spectrum of side effects, including myelotoxicity and acute pancreatitis. Didanosine, zalcitabine and stavudine have been reported as causes of acute and chronic pancreatitis. They pose a high risk with cumulative doses. Didanosine with hydroxyurea, alcohol or pentamidine are additional risk factors, leading to lethal pancreatitis, which is not a frequent event. In addition, other drugs used for prophylaxis of AIDS-related opportunistic diseases, such as sulfamethoxazole-trimethoprim and pentamidine, can produce necrotizing pancreatitis. Despite comorbidities that can lead to pancreatic involvement in the HIV/AIDS population, antiretroviral drug-induced pancreatitis

  20. Intensity-dependent and sex-specific alterations in hepatic triglyceride metabolism in mice following acute exercise.

    PubMed

    Tuazon, Marc A; McConnell, Taylor R; Wilson, Gabriel J; Anthony, Tracy G; Henderson, Gregory C

    2015-01-01

    Precise regulation of hepatic triglyceride (TG) metabolism and secretion is critical for health, and exercise could play a significant role. We compared one session of high-intensity interval exercise (HIIE) vs. continuous exercise (CE) on hepatic TG metabolism. Female and male mice were assigned to CE, HIIE, or sedentary control (CON). HIIE was a 30-min session of 30-s running intervals (30 m/min) interspersed with 60-s walking periods (5 m/min). CE was a distance- and duration-matched run at 13.8 m/min. Hepatic content of TG and TG secretion rates, as well as expression of relevant genes/proteins, were measured at 3 h (day 1) and 28 h (day 2) postexercise. On day 1, hepatic [TG] in CE and HIIE were both elevated vs. CON in both sexes with an approximately twofold greater elevation in HIIE vs. CE in females. In both sexes, hepatic perilipin 2 (PLIN2) protein on day 1 was increased significantly by both exercise types with a significantly greater increase with HIIE than CE, whereas the increase in mRNA reached significance only after HIIE. On day 2 in both sexes the increases in hepatic TG and PLIN2 with exercise declined toward CON levels. Only HIIE on day 2 resulted in reduced hepatic TG secretion by ∼20% in females with no effect in males. Neither exercise modality altered AMPK signaling or microsomal triglyceride transfer protein expression. Females exhibited higher hepatic TG secretion than males in association with different expression levels of related metabolic enzymes. These intensity-dependent and sex-specific alterations following exercise may have implications for sex-based exercise prescription.

  1. Lack of effect of acute enteral arginine infusion on whole-body and intestinal protein metabolism in humans.

    PubMed

    Claeyssens, Sophie; Lecleire, Stéphane; Leblond, Jonathan; Marion, Rachel; Hecketsweiler, Bernadette; Lavoinne, Alain; Ducrotté, Philippe; Déchelotte, Pierre; Coëffier, Moïse

    2007-08-01

    Arginine is a conditionally essential amino acid and exerts anabolic effects. We studied the effects of enteral arginine on whole-body and duodenal protein metabolism. Eight healthy fasted volunteers received randomly a 5-hr enteral infusion of either arginine (Arg; 20 g) or an isonitrogenous amino acid mixture (AA) and an IV infusion of [13C]leucine. Duodenal biopsies were performed. Whole-body protein turnover and duodenal protein synthesis (FSR) were calculated from GC/MS-assessed enrichment. The mRNA levels for major components of proteolytic pathways, ubiquitin, cathepsin D, and m-calpain, were evaluated by RT-PCR. Results were compared using paired Wilcoxon test. Endogenous, oxidative, and nonoxidative leucine fluxes were not different after Arg and AA infusions, respectively. Duodenal mucosal protein FSR (71% +/- 26% vs 81% +/- 30%/day) and mRNA levels of ubiquitin, cathepsin D, and m-calpain were also similar after Arg and AA infusions. We conclude that in healthy subjects, arginine infusion exerts no effect on whole-body and duodenal protein metabolism. Whether arginine might specifically affect these parameters in catabolic or inflammatory situations remains to be determined.

  2. Metabolic Consequences after Urinary Diversion

    PubMed Central

    Stein, Raimund; Rubenwolf, Peter

    2014-01-01

    Metabolic disturbances are well-known, but sometimes neglected immediate consequences or late sequelae following urinary diversion (UD) using bowel segments. Whereas subclinical disturbances appear to be quite common, clinically relevant metabolic complications, however, are rare. Exclusion of bowel segments for UD results in loss of absorptive surface for its physiological function. Previous studies demonstrated that at least some of the absorptive and secreting properties of the bowel are preserved when exposed to urine. For each bowel segment typical consequences and complications have been reported. The use of ileal and/or colonic segments may result in hyperchloremic metabolic acidosis, which can be prevented if prophylactic treatment with alkali supplementation is started early. The resection of ileal segments may be responsible for malabsorption of vitamin B12 and bile acids with subsequent neurological and hematological late sequelae as well as potential worsening of the patient’s bowel habits. Hence, careful patient and procedure selection, meticulous long-term follow-up, and prophylactic treatment of subclinical acidosis is of paramount importance in the prevention of true metabolic complications. PMID:24653981

  3. Acute effects of an arginine-based supplement on neuromuscular, ventilatory, and metabolic fatigue thresholds during cycle ergometry.

    PubMed

    Zak, Roksana B; Camic, Clayton L; Hill, Ethan C; Monaghan, Molly M; Kovacs, Attila J; Wright, Glenn A

    2015-04-01

    The purpose of the present study was to examine the effects of an acute dose of an arginine-based supplement on the physical working capacity at the fatigue threshold (PWCFT), lactate threshold (LT), ventilatory threshold (VT), and peak oxygen uptake during incremental cycle ergometry. This study used a double-blinded, placebo-controlled, within-subjects crossover design. Nineteen untrained men (mean age ± SD = 22.0 ± 1.7 years) were randomly assigned to ingest either the supplement (3.0 g of arginine, 300 mg of grape seed extract, and 300 mg of polyethylene glycol) or placebo (microcrystalline cellulose) and performed an incremental test on a cycle ergometer for determination of PWCFT, LT, VT, and peak oxygen uptake. Following a 1-week period, the subjects returned to the laboratory and ingested the opposite substance (either supplement or placebo) prior to completing another incremental test to be reassessed for PWCFT, LT, VT, and peak oxygen uptake. The paired-samples t tests indicated there were significant (P < 0.05) mean differences between the arginine and placebo conditions for the PWCFT (192 ± 42 vs. 168 ± 53 W, respectively) and VT (2546 ± 313 vs. 2452 ± 342 mL·min(-1)), but not the LT (135 ± 26 vs. 138 ± 22 W), absolute peak oxygen uptake (3663 ± 445 vs. 3645 ± 438 mL·min(-1)), or relative peak oxygen uptake (46.5 ± 6.0 vs. 46.2 ± 5.0 mL·kg(-1)·min(-1)). These findings suggested that the arginine-based supplement may be used on an acute basis for delaying the onset of neuromuscular fatigue (i.e., PWCFT) and improving the VT in untrained individuals.

  4. Acute and sustained effects of methylphenidate on cognition and presynaptic dopamine metabolism: an [18F]FDOPA PET study.

    PubMed

    Schabram, Ina; Henkel, Karsten; Mohammadkhani Shali, Siamak; Dietrich, Claudia; Schmaljohann, Jörn; Winz, Oliver; Prinz, Susanne; Rademacher, Lena; Neumaier, Bernd; Felzen, Marc; Kumakura, Yoshitaka; Cumming, Paul; Mottaghy, Felix M; Gründer, Gerhard; Vernaleken, Ingo

    2014-10-29

    Methylphenidate (MPH) inhibits the reuptake of dopamine and noradrenaline. PET studies with MPH challenge show increased competition at postsynaptic D2/3-receptors, thus indirectly revealing presynaptic dopamine release. We used [(18)F]fluorodopamine ([(18)F]FDOPA)-PET in conjunction with the inlet-outlet model (IOM) of Kumakura et al. (2007) to investigate acute and long-term changes in dopamine synthesis capacity and turnover in nigrostriatal fibers of healthy subjects with MPH challenge. Twenty healthy human females underwent two dynamic [(18)F]FDOPA PET scans (124 min; slow bolus-injection; arterial blood sampling), with one scan in untreated baseline condition and the other after MPH administration (0.5 mg/kg, p.o.), in randomized order. Subjects underwent cognitive testing at each PET session. Time activity curves were obtained for ventral putamen and caudate and were analyzed according to the IOM to obtain the regional net-uptake of [(18)F]FDOPA (K; dopamine synthesis capacity) as well as the [(18)F]fluorodopamine washout rate (kloss, index of dopamine turnover). MPH substantially decreased kloss in putamen (-22%; p = 0.003). In the reversed treatment order group (MPH/no drug), K was increased by 18% at no drug follow-up. The magnitude of K at the no drug baseline correlated with cognitive parameters. Furthermore, individual kloss changes correlated with altered cognitive performance under MPH. [(18)F]FDOPA PET in combination with the IOM detects an MPH-evoked decrease in striatal dopamine turnover, in accordance with the known acute pharmacodynamics of MPH. Furthermore, the scan-ordering effect on K suggested that a single MPH challenge persistently increased striatal dopamine synthesis capacity. Attenuation of dopamine turnover by MPH is linked to enhanced cognitive performance in healthy females.

  5. S1P prophylaxis mitigates acute hypobaric hypoxia-induced molecular, biochemical, and metabolic disturbances: A preclinical report.

    PubMed

    Chawla, Sonam; Rahar, Babita; Saxena, Shweta

    2016-05-01

    Sphingosine-1-phosphate (S1P) is emerging to have hypoxic preconditioning potential in various preclinical studies. The study aims to evaluate the preclinical preconditioning efficacy of exogenously administered S1P against acute hypobaric hypoxia (HH)-induced pathological disturbances. Male Sprague Dawley rats (200 ± 20 g) were preconditioned with 1, 10, and 100 μg/kg body weight (b.w.) S1P (i.v.) for three consecutive days. On the third day, S1P preconditioned animals, along with hypoxia control animals, were exposed to HH equivalent to 7,620 m (280 mm Hg) for 6 h. Postexposure status of cardiac energy production, circulatory vasoactive mediators, pulmonary and cerebral oxidative damage, and inflammation were assessed. HH exposure led to cardiac energy deficit indicated by low ATP levels and pronounced AMPK activation levels, raised circulatory levels of brain natriuretic peptide and endothelin-1 with respect to total nitrate (NOx), redox imbalance, inflammation, and alterations in NOx levels in the pulmonary and cerebral tissues. These pathological precursors have been routinely reported to be coincident with high-altitude diseases. Preconditioning with S1P, especially 1 µg/kg b.w. dose, was seen to reverse the manifestation of these pathological disturbances. The protective efficacy could be attributed, at least in part, to enhanced activity of cardioprotective protein kinase C and activation of small GTPase Rac1, which led to further induction of hypoxia-adaptive molecular mediators: hypoxia-inducible factor (HIF)-1α and Hsp70. This is a first such report, to the best of our knowledge, elucidating the mechanism of exogenous S1P-mediated HIF-1α/Hsp70 induction. Conclusively, systemic preconditioning with 1 μg/kg b.w. S1P in rats protects against acute HH-induced pathological disturbances. © 2016 IUBMB Life 68(5):365-375, 2016.

  6. Metformin-Associated Lactic Acidosis in a Patient with Normal Renal Function.

    PubMed

    Omar, Ahmed; Ellen, Ruth; Sorisky, Alexander

    2016-08-01

    We report a case of metformin-associated lactic acidosis (MALA) in the setting of normal renal function and review the relevant medical literature. A 77-year-old female diagnosed with type 2 diabetes mellitus previously treated with insulin and gliclazide MR was started on metformin. A few weeks later, she was found to have lactic acidosis. Renal function was normal, and no severe underlying illness was identified. Metformin was discontinued, and lactate levels normalized within 4 days, suggesting metformin was a reversible precipitant of the lactic acidosis. MALA can occur in the absence of renal impairment, systemic hypoperfusion or severe liver disease. A possible mechanism is a genetically determined alteration in metformin pharmacokinetics. Metformin is beneficial and safe in patients with normal renal function, but the development of MALA, although rare, should be kept in mind to prevent potentially life-threatening toxicity.

  7. Influence of acidosis and hypoxia on liver ischemia and reperfusion injury in an in vivo rat model.

    PubMed

    Heijnen, Bob H M; Elkhaloufi, Yasser; Straatsburg, Irene H; Van Gulik, Thomas M

    2002-07-01

    The contribution of acidosis to the development of reperfusion injury is controversial. In this study, we examined the effects of respiratory acidosis and hypoxia in a frequently used in vivo liver ischemia and reperfusion (I/R) injury rat model. Rats were anesthetized with intraperitoneal anesthetics and subjected to partial liver ischemia (70%) for 60 min and subsequent reperfusion for 90 min under the following conditions: 1) no acidosis and normoxia, maintained by controlled ventilation; 2) acidosis and normoxia, maintained by passive supply with oxygen; 3) no acidosis and hypoxia, maintained by bicarbonate administration without respiratory support; and 4) acidosis and hypoxia, i.e., without respiratory support or pH correction. Changes in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured as parameters of hepatocellular injury, and bile secretion was monitored. AST and ALT levels were lowest in the ventilated rats and highest in the bicarbonate-treated rats. No differences in bile secretion were found between groups. Our results suggest that respiratory acidosis significantly enhanced liver I/R injury under normoxic conditions, whereas respiratory acidosis significantly reduced liver I/R injury under hypoxic conditions.

  8. Acute Effects of Muscarinic M1 Receptor Modulation on AβPP Metabolism and Amyloid-β Levels in vivo: A Microdialysis Study.

    PubMed

    Welt, Tobias; Kulic, Luka; Hoey, Sarah E; McAfoose, Jordan; Späni, Claudia; Chadha, Antonella Santuccione; Fisher, Abraham; Nitsch, Roger M

    2015-01-01

    Indirect modulation of cholinergic activity by cholinesterase inhibition is currently a widely established symptomatic treatment for Alzheimer's disease (AD). Selective activation of certain muscarinic receptor subtypes has emerged as an alternative cholinergic-based amyloid-lowering strategy for AD, as selective muscarinic M1 receptor agonists can reduce amyloid-β (Aβ) production by shifting endoproteolytic amyloid-β protein precursor (AβPP) processing toward non-amyloidogenic pathways. In this study, we addressed the hypothesis that acute stimulation of muscarinic M1 receptors can inhibit Aβ production in awake and freely moving AβPP transgenic mice. By combining intracerebral microdialysis with retrodialysis, we determined hippocampal Aβ concentrations during simultaneous pharmacological modulation of brain M1 receptor function. Infusion with a M1 receptor agonist AF102B resulted in a rapid reduction of interstitial fluid (ISF) Aβ levels while treatment with the M1 antagonist dicyclomine increased ISF Aβ levels reaching significance within 120 minutes of treatment. The reduction in Aβ levels was associated with PKCα and ERK activation resulting in increased levels of the α-secretase ADAM17 and a shift in AβPP processing toward the non-amyloidogenic processing pathway. In contrast, treatment with the M1 receptor antagonist dicyclomine caused a decrease in levels of phosphorylated ERK that was independent of PKCα, and led to an elevation of β-secretase levels associated with increased amyloidogenic AβPP processing. The results of this study demonstrate rapid effects of in vivo M1 receptor modulation on the ISF pool of Aβ and suggest that intracerebral microdialysis with retrodialysis is a useful technical approach for monitoring acute treatment effects of muscarinic receptor modulators on AβPP/Aβ metabolism.

  9. Acute effects of calcium carbonate, calcium citrate and potassium citrate on markers of calcium and bone metabolism in young women.

    PubMed

    Karp, Heini J; Ketola, Maarit E; Lamberg-Allardt, Christel J E

    2009-11-01

    Both K and Ca supplementation may have beneficial effects on bone through separate mechanisms. K in the form of citrate or bicarbonate affects bone by neutralising the acid load caused by a high protein intake or a low intake of alkalising foods, i.e. fruits and vegetables. Ca is known to decrease serum parathyroid hormone (S-PTH) concentration and bone resorption. We compared the effects of calcium carbonate, calcium citrate and potassium citrate on markers of Ca and bone metabolism in young women. Twelve healthy women aged 22-30 years were randomised into four controlled 24 h study sessions, each subject serving as her own control. At the beginning of each session, subjects received a single dose of calcium carbonate, calcium citrate, potassium citrate or a placebo in randomised order. The diet during each session was identical, containing 300 mg Ca. Both the calcium carbonate and calcium citrate supplement contained 1000 mg Ca; the potassium citrate supplement contained 2250 mg K. Markers of Ca and bone metabolism were followed. Potassium citrate decreased the bone resorption marker (N-terminal telopeptide of type I collagen) and increased Ca retention relative to the control session. Both Ca supplements decreased S-PTH concentration. Ca supplements also decreased bone resorption relative to the control session, but this was significant only for calcium carbonate. No differences in bone formation marker (bone-specific alkaline phosphatase) were seen among the study sessions. The results suggest that potassium citrate has a positive effect on the resorption marker despite low Ca intake. Both Ca supplements were absorbed well and decreased S-PTH efficiently.

  10. Rare mutation in the SLC26A3 transporter causes life-long diarrhoea with metabolic alkalosis.

    PubMed

    Abou Ziki, Maen D; Verjee, Mohamud A

    2015-01-07

    SLC26A3, a chloride/bicarbonate transporter mainly expressed in the intestines, plays a pivotal role in chloride absorption. We present a 23-year-old woman with a history of congenital chloride diarrhoea (CCD) and renal transplant who was admitted for rehydration and treatment of acute kidney injury after she presented with an acute diarrhoeal episode. Laboratory investigations confirmed metabolic alkalosis and severe hypochloraemia, consistent with her underlying CCD. This contrasts with most other forms of diarrhoea, which are normally associated with metabolic acidosis. Genetic testing was offered and revealed a homozygous non-sense mutation in SLC26A3 (Gly-187-Stop). This loss-of-function mutation results in bicarbonate retention in the blood and chloride loss into the intestinal lumen. Symptomatic management with daily NaCl and KCl oral syrups was supplemented with omeprazole therapy. The loss of her own kidneys is most likely due to crystal-induced nephropathy secondary to chronic volume contraction and chloride depletion. This case summarises the pathophysiology and management of CCD.

  11. Reduced Cortisol and Metabolic Responses of Thin Ewes to an Acute Cold Challenge in Mid-Pregnancy: Implications for Animal Physiology and Welfare

    PubMed Central

    Verbeek, Else; Oliver, Mark Hope; Waas, Joseph Rupert; McLeay, Lance Maxwell; Blache, Dominique; Matthews, Lindsay Ross

    2012-01-01

    Background Low food availability leading to reductions in Body Condition Score (BCS; 0 indicates emaciation and 5 obesity) in sheep often coincides with low temperatures associated with the onset of winter in New Zealand. The ability to adapt to reductions in environmental temperature may be impaired in animals with low BCS, in particular during pregnancy when metabolic demand is higher. Here we assess whether BCS affects a pregnant animal's ability to cope with cold challenges. Methods Eighteen pregnant ewes with a BCS of 2.7±0.1 were fed to attain low (LBC: BCS2.3±0.1), medium (MBC: BCS3.2±0.2) or high BCS (HBC: BCS3.6±0.2). Shorn ewes were exposed to a 6-h acute cold challenge in a climate-controlled room (wet and windy conditions, 4.4±0.1°C) in mid-pregnancy. Blood samples were collected during the BCS change phase, acute cold challenge and recovery phase. Results During the BCS change phase, plasma glucose and leptin concentrations declined while free fatty acids (FFA) increased in LBC compared to MBC (P<0.01, P<0.01 and P<0.05, respectively) and HBC ewes (P<0.05, P<0.01 and P<0.01, respectively). During the cold challenge, plasma cortisol concentrations were lower in LBC than MBC (P<0.05) and HBC ewes (P<0.05), and FFA and insulin concentrations were lower in LBC than HBC ewes (P<0.05 and P<0.001, respectively). Leptin concentrations declined in MBC and HBC ewes while remaining unchanged in LBC ewes (P<0.01). Glucose concentrations and internal body temperature (Tcore) increased in all treatments, although peak Tcore tended to be higher in HBC ewes (P<0.1). During the recovery phase, T4 concentrations were lower in LBC ewes (P<0.05). Conclusion Even though all ewes were able to increase Tcore and mobilize glucose, low BCS animals had considerably reduced cortisol and metabolic responses to a cold challenge in mid-pregnancy, suggesting that their ability to adapt to cold challenges through some of the expected pathways was reduced. PMID:22662144

  12. A Rare Case of Persistent Lactic Acidosis in the ICU: Glycogenic Hepatopathy and Mauriac Syndrome

    PubMed Central

    Alvarez, George F.

    2016-01-01

    Mauriac syndrome is a rare disorder that can present with the single feature of glycogenic hepatopathy in children and adults with poorly controlled diabetes mellitus. An often underrecognized finding of glycogenic hepatopathy is lactic acidosis and hyperlactatemia. Primary treatment of glycogenic hepatopathy is improved long-term blood glucose control. Resolution of symptoms and hepatomegaly will occur with improvement in hemoglobin A1C. We present here a case of a young adult female presenting to the intensive care unit with Mauriac syndrome. This case demonstrates exacerbation of lactic acidosis in a patient with glycogenic hepatopathy treated for diabetic ketoacidosis with high dose insulin and dextrose. PMID:27699071

  13. The duration of time that beef cattle are fed a high-grain diet affects the recovery from a bout of ruminal acidosis: dry matter intake and ruminal fermentation.

    PubMed

    Schwaiger, T; Beauchemin, K A; Penner, G B

    2013-12-01

    confirmed that the LA heifers experienced a quicker linear (P = 0.019) recovery from induced acidosis over time. These results indicate adaptation of the ruminal epithelium continues with advancing time as evidenced by more stable ruminal pH both before and after an induced bout of acute ruminal acidosis but does not affect susceptibility of cattle to ruminal acidosis.

  14. No effect of acute beetroot juice ingestion on oxygen consumption, glucose kinetics, or skeletal muscle metabolism during submaximal exercise in males.

    PubMed

    Betteridge, Scott; Bescós, Raúl; Martorell, Miquel; Pons, Antoni; Garnham, Andrew P; Stathis, Christos C; McConell, Glenn K

    2016-02-15

    Beetroot juice, which is rich in nitrate (NO3 (-)), has been shown in some studies to decrease oxygen consumption (V̇o2) for a given exercise workload, i.e., increasing efficiency and exercise tolerance. Few studies have examined the effect of beetroot juice or nitrate supplementation on exercise metabolism. Eight healthy recreationally active males participated in three trials involving ingestion of either beetroot juice (Beet; ∼8 mmol NO3 (-)), Placebo (nitrate-depleted Beet), or Beet + mouthwash (Beet+MW), all of which were performed in a randomized single-blind crossover design. Two-and-a-half hours later, participants cycled for 60 min on an ergometer at 65% of V̇o2 peak. [6,6-(2)H]glucose was infused to determine glucose kinetics, blood samples obtained throughout exercise, and skeletal muscle biopsies that were obtained pre- and postexercise. Plasma nitrite [NO2 (-)] increased significantly (∼130%) with Beet, and this was attenuated in MW+Beet. Beet and Beet+MW had no significant effect on oxygen consumption, blood glucose, blood lactate, plasma nonesterified fatty acids, or plasma insulin during exercise. Beet and Beet+MW also had no significant effect on the increase in glucose disposal during exercise. In addition, Beet and Beet+MW had no significant effect on the decrease in muscle glycogen and phosphocreatine and the increase in muscle creatine, lactate, and phosphorylated acetyl CoA carboxylase during exercise. In conclusion, at the dose used, acute ingestion of beetroot juice had little effect on skeletal muscle metabolism during exercise.

  15. miR-125b regulates differentiation and metabolic reprogramming of T cell acute lymphoblastic leukemia by directly targeting A20

    PubMed Central

    Liu, Zixing; Smith, Kelly R.; Khong, Hung T.; Huang, Jingshan; Ahn, Eun-Young Erin; Zhou, Ming; Tan, Ming

    2016-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy. Although it has been reported that overexpression of miR-125b leads to T-ALL development, the underlying mechanisms of miR-125b action are still unclear. The goal of this study is to delineate the role of miR-125b in T-ALL development. We found that miR-125b is highly expressed in undifferentiated leukemic T cells (CD4-negative) while its expression is low in differentiated T cells (CD4-positive). Overexpression of miR-125b increased the CD4-negative population in T cells, whereas depletion of miR-125b by miR-125b-sponge decreased the CD4-negative cell population. We identified that A20